Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[NH:6][C:5](=[O:7])[NH:4][C:3]1=[O:8].CC(C)([O-])C.[K+].Cl[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>CN(C)C=O>[CH2:18]([O:17][CH2:16][N:4]1[C:3](=[O:8])[CH:2]([CH3:1])[NH:6][C:5]1=[O:7])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: ClCOCc1ccccc1
Reactant: CC1NC(=O)NC1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1NC(=O)N(COCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
5-Methylimidazolidine-2,4-dione (1.00 g) was dissolved in N,N-dimethylformamide (20 mL), potassium tert-butoxide (1.08 g) and benzyl chloromethyl ether (1.32 mL) were added under ice-cooling, and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the title compound (0.98 g).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[O:12][CH2:13][O:14][C:9]2=[CH:8][C:3]=1[C:4]([O:6]C)=O.Cl[C:16]1[N:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([OH:20])=[O:19].CO>CN(C=O)C>[CH2:13]1[O:12][C:10]2[CH:11]=[C:2]3[C:3]([C:4](=[O:6])[N:24]4[CH:23]=[CH:22][CH:21]=[C:17]([C:18]([OH:20])=[O:19])[C:16]4=[N:1]3)=[CH:8][C:9]=2[O:14]1
Reactant: COC(=O)c1cc2c(cc1N)OCO2
Reactant: O=C(O)c1cccnc1Cl
Solvent: CO
Solvent: CN(C)C=O
Product: O=C(O)c1cccn2c(=O)c3cc4c(cc3nc12)OCO4

Procedure:
A mixture of 2.00g (10.4 mmol) of methyl 2-amino-4,5-methylenedioxybenzoate, 1.67g (10.4 mmol) of 2-chloronicotinic acid and 50mg of KI was heated at 170° for 1 hour. The fusion or melt gradually solidified to an orange cake. The solid material was heated in boiling methanol (250 ml) and then filtered to yield 1.60g of crude product, mp. 273°-280° dec. The analytical sample was obtained by recrystallization from DMF, mp. 300°-304° dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[CH:6][CH:7]=1.N1(C(N2C=CN=C2)=S)C=CN=[CH:10]1.[Cl:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=1[C:29]1[NH:30][C:31]2[CH:37]=[C:36]([C:38]([NH:40][NH2:41])=[O:39])[CH:35]=[CH:34][C:32]=2[N:33]=1.CCN=C=NCCCN(C)C>CN(C=O)C.CCOC(C)=O>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([NH:1][C:10]2[O:39][C:38]([C:36]3[CH:35]=[CH:34][C:32]4[N:33]=[C:29]([C:23]5[C:24]([Cl:28])=[CH:25][CH:26]=[CH:27][C:22]=5[Cl:21])[NH:30][C:31]=4[CH:37]=3)=[N:40][N:41]=2)=[CH:7][CH:6]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NNC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reactant: Nc1ccc(Cl)nc1
Agent: CCN=C=NCCCN(C)C
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1ccc(Nc2nnc(-c3ccc4nc(-c5c(Cl)cccc5Cl)[nH]c4c3)o2)cn1
Reaction time: 72 h

Procedure:
Combine 3-amino-6-chloro-pyridine (78 mg, 0.606 mmol) and di-imidazol -1-yl-methanethione (108 mg, 0.606 mmol) in DMF (1.5 mL) and stir for 4 hr. Add 2-(2,6-dichloro-phenyl)-3H-benzoimidazole-5-carboxylic acid hydrazide (150 mg, 0.466 mmol) and DMF (1 mL). Stir for 3 days. Add EDCI (179 mg, 0.932 mmol) and heat to 80° C. for 45 min. Upon cooling, dilute the reaction with EtOAc (50 mL) and extract with water (10 mL) and 1 N NaOH (10 mL). Combine the aqueous layers and allow to stand overnight. Evaporate the organic phase. Filter the combined aqueous layers and wash the collected solid with Et2O. Combine the solid with the residue from the organic phase and purify the material by reverse phase HPLC (20-65% ACN/H2O+5 mM NH4OH) to afford the title compound: 1H NMR (400 MHz, DMSO-d6) ppm 7.56 (d, J=8.72 Hz, 1H) 7.63-7.68 (m, 1 H) 7.70 (s, 1 H) 7.72 (d, J=2.02 Hz, 1 H) 7.86 (br. s., 2 H) 8.13 (br. s., 1 H) 8.16 (dd, J=8.78, 2.97 Hz, 1 H) 8.64 (d, J=2.91 Hz, 1 H) 11.16 (s, 1 H) 13.31 (br. s., 1 H); MS m/z=458.9 (M+1).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)=[O:4].[OH-].[K+].O.CO>C(OCC)C>[C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:12][CH2:13][C@H:14]([CH:16]([CH3:18])[CH3:17])[N:15]=2)=[CH:7][CH:6]=1)([OH:4])=[O:2]
Reactant: COC(=O)c1ccc(C2=N[C@@H](C(C)C)CO2)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: CC(C)[C@H]1COC(c2ccc(C(=O)O)cc2)=N1
Temperature: 75 °C

Procedure:
A mixture of 3 g of (S)-2-(4-[methoxycarbonyl]phenyl)-4-isopropyl-2-oxazoline, 3 g of potassium hydroxide, 5 ml of water and 50 ml of methanol is heated at 75° C. on an oil bath for 4 hours. The cooled mixture is treated with 10 ml of ice-cold 3N hydrochloric acid and the liberated acid is taken up in 150 ml of diethyl ether. The separated aqueous phase is back-extracted twice with 100 ml of diethyl ether each time. The combined organic phases are washed with 50 ml of 2N sodium carbonate solution and several times with water, dried over magnesium sulphate and concentrated. Recrystallization of the resulting crude product from ethanol yields (S)-2-(4-carboxyphenyl)-4-isopropyl-2-oxazoline.
Reaction SMILES: S(=O)(=O)(O)O.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]2[C:14]([CH2:16][CH:17]([CH2:18][C:19]([OH:21])=[O:20])[C:10]=2[CH:9]=1)=[O:15].[CH3:22]O>>[CH3:22][O:20][C:19](=[O:21])[CH2:18][CH:17]1[C:10]2[C:11](=[CH:12][CH:13]=[C:8]([O:7][CH3:6])[CH:9]=2)[C:14](=[O:15])[CH2:16]1
Reactant: CO
Reactant: COc1ccc2c(c1)C(CC(=O)O)CC2=O
Agent: O=S(=O)(O)O
Product: COC(=O)CC1CC(=O)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
Concentrated sulfuric acid (3.0 mL) is added to 5-methoxy-1-indanone-3-acetic acid (13.0 g) dissolved in methanol (100 mL). The solution is stirred at reflux temperature for 4 h and then cooled to room temperature. About two third of the methanol is removed under reduced pressure and water (100 mL) and ethyl acetate (200 mL) are added to the remainder. The organic phase is separated and washed with water, 1 M NaOH solution, and brine. The organic phase is dried (MgSO4) and the solvent is evaporated to give the product as a yellow oil.
Reaction SMILES: CN(C=O)C.[C:6](Cl)([C:8]([Cl:10])=O)=[O:7].[N:12]1[C:17]2[C:18]3[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=3OC=2C(=O)[NH:14][CH:13]=1.O>ClCCCl>[Cl:10][C:8]1[C:6]2[O:7][C:19]3[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=3[C:17]=2[N:12]=[CH:13][N:14]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=c1[nH]cnc2c1oc1ccccc12
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: O
Product: Clc1ncnc2c1oc1ccccc12
Temperature: 25 °C
Yield: 92.9 %

Procedure:
DMF (0.23 mL, 3.1 mmol) is added dropwise to a solution of (COCl)2 (0.28 mL, 3.1 mmol) in 1,2-dichloroethane (15 mL) at 25° C. After gas evolution ceases, 3H-benzofurano[3,2-d]pyrimid-4-one (113 mg, 0.61 mmol) is added. The resulting mixture is heated at reflux for 1 h. After the reaction has cooled to 25° C., water is added and the resulting mixture is extracted with CHCl3. The combined extracts are washed with water, saturated brine and dried (MgSO4). The solvent is removed under reduced pressure to give 4-chlorobenzofurano[3,2-d]pyrimidine (116 mg, 93%) as a yellow solid. 1H NMR (DMSO) δ9.08 (1H, s), 8.30 (1H, d. J=8.1 Hz), 8.02 (1H, d, J=8.5 Hz), 7.90, (1H, dt, Jd=1.3 Hz, Jt=7.1 Hz), 7.64 (1H, dt, Jd=1.0 Hz, Jt=7.8 Hz).
Reaction SMILES: [OH:1][CH2:2][CH:3]([NH:7][C:8]([N:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)=[O:9])[C:4]([OH:6])=O.[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C>ClCCl>[CH:16]1[C:26]2[CH:25]=[CH:24][C:23]3[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=3[C:21](=[C:31]3[CH2:32][CH2:33][N:34]([C:4](=[O:6])[CH:3]([NH:7][C:8]([N:10]4[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]4)=[O:9])[CH2:2][OH:1])[CH2:35][CH2:36]3)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: O=C(O)C(CO)NC(=O)N1CCCCC1
Reactant: C1=Cc2ccccc2C(=C2CCNCC2)c2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC(CO)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)N1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
64.0 mg (0.296 mmol) of 3-hydroxy-2-[(1-piperidinylcarbonyl)amino]propionic acid, 80.9 mg (0.296 mmol) of 4-(5H-dibenzo[a,d][7]annulen-5-ylidene)piperidine and 85.1 mg (0.444 mmol) of 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride were dissolved in 10 ml of dichloromethane. 0.091 ml (0.651 mmol) of triethylamine was added to the obtained solution, and they were stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue. After washing with saturated aqueous sodium chloride solution, the reaction product was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resultant product was purified by the silica gel chromatography (dichloromethane:methanol=9:1) to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]2[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:3]=12.[Br:22]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[Br:22][CH2:15][C:14]1[C:3]2[C:4](=[N:5][C:6]3[C:11]([C:2]=2[Cl:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:12]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=2)[N:13]=1
Reactant: Cc1nn(-c2ccccn2)c2nc3ccccc3c(Cl)c12
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c2ccccc2nc2c1c(CBr)nn2-c1ccccn1
Temperature: 25 °C
Yield: 53.5 %

Procedure:
A solution of 4-chloro-3-methyl-1-(2-pyridinyl)-1H-pyrazolo[3,4-b]quinoline (1.22 g, 4.1 mmol), N-bromosuccinimide (0.87 g, 4.9 mmol) and 2,2′-azobis(isobutyronitrile) (66 mg, 0.4 mmol) in carbon tetrachloride (40 mL) was heated under reflux under an argon atmosphere for 3 hours. The solution was allowed to cool to room temperature, the insoluble solid was removed and the solution was concentrated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (hexane:chloroform:ethyl acetate=2:1:1) to give the title compound (0.82 g, 53% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[N:22]([CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([CH:20]=O)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][N:39]([CH2:20][C:17]2[CH:16]=[N:15][C:14]([NH:13][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:1])[CH3:28])[N:22]([CH:23]5[CH2:27][CH2:26][CH2:25][CH2:24]5)[C:8]=4[N:9]=3)=[CH:19][CH:18]=2)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C=O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(CN4CCN(C(=O)OC(C)(C)C)CC4)cn3)nc2n1C1CCCC1
Yield: 65.5 %

Procedure:
Following General Procedure B, 7-cyclopentyl-2-(5-formyl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (0.35 g, 0.926 mmol) and piperazine-1-carboxylic acid tert-butyl ester (0.19 g, 1.02 mmol) gave 4-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-ylmethyl]-piperazine-1-carboxylic acid tert-butyl ester as a white solid (0.333 g, 60%). The material is used directly in the next step. MS (ESI) m/z 549.3 (M+H)−
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=S.Cl.[NH:24]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[NH2:25].ClCCl>C(O)C>[CH2:30]([O:29][C:27]([CH2:26][NH:24][N:25]=[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Cl:1])[C:10]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:11]=1[NH:17][CH2:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:28])[CH3:31]
Reactant: CC(C)(C)CNc1ccc(Cl)cc1C(=S)c1ccccc1Cl
Reactant: CCOC(=O)CNN
Agent: Cl
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)CNN=C(c1ccccc1Cl)c1cc(Cl)ccc1NCC(C)(C)C
Temperature: 70 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
To a solution of 5-chloro-2-neopentylaminophenyl 2-chlorophenyl thioketone (0.54 g) in ethanol (7 ml) was added ethyl hydrazinoacetate hydrochloride (0.11 g). The mixture was stirred for one day at 70° C. To the reaction mixture was added dichloromethane (50 ml), which was washed with water and, then, dried over anhydrous sodium sulfate. The solvent was distilled off. The residue was purified by means of a silica-gel column chromatography (hexane:acetic acid ethyl ester=15:1 v/v as an eluent) to give 0.16 g of an oily product.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([Cl:18])=[CH:4][C:3]=1[C:19]([OH:21])=[O:20])[O:12][CH2:11][CH2:10][O:9]3.C(Cl)(=O)C(Cl)=O.[C:28]1(=O)[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH2:29]1.C(N(CC)CC)C>CN(C)C=O.C(Cl)Cl>[Cl:1][C:2]1[C:7]2[C:8]3([CH2:13][CH2:14][S:15](=[O:17])(=[O:16])[C:6]=2[C:5]([Cl:18])=[CH:4][C:3]=1[C:19]([O:21][C:28]1[CH2:33][CH2:32][CH2:31][C:30](=[O:34])[CH:29]=1)=[O:20])[O:9][CH2:10][CH2:11][O:12]3
Reactant: O=C1CCCC(=O)C1
Reactant: O=C(O)c1cc(Cl)c2c(c1Cl)C1(CCS2(=O)=O)OCCO1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1C=C(OC(=O)c2cc(Cl)c3c(c2Cl)C2(CCS3(=O)=O)OCCO2)CCC1
Temperature: 0 °C
Reaction time: 48 h
Yield: 27.9 %

Procedure:
1.75 g (4.97 mmol) of the title compound of Step F, 1.30 mL (0.015 mol) of oxalyl chloride (purchased from Janssen), and 2 drops of N,N-dimethylformamide were added to 50 mL of methylene chloride. The mixture was refluxed under nitrogen for 2 h and was then evaporated to dryness. 50 mL of methylene chloride was added to the residue and the resulting mixture was evaporated to dryness. Another 50 mL of methylene chloride was added to the residue, and the solution was cooled to about 0° C. 0.61 g (5.5 mmol) of 1,3-cyclohexanedione (purchased from Aldrich Chemical Company) was added followed by 2.15 mL (0.0154 mol) of triethylamine, and the mixture was stirred over 2 days while warming to room temperature. The mixture was evaporated to dryness and the crude product was chromatographed over silica gel eluting with a mixture of ethyl acetate:hexane (6:4) to yield 0.62 g of the title compound of Step G as a solid melting at 168° C. (dec). 1H NMR (CDCl3): δ2.1 (m,2H), 2.5 (t,2H), 2.7 (t,4H), 3.6 (m,2H), 4.2 (m,2H), 4.4 (m,2H), 6.1 (s,1H), 7.8 (s,1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[C:12]([Si:16]([CH3:26])([CH3:25])[O:17][CH:18]1[CH2:23][CH2:22][CH:21](O)[CH2:20][CH2:19]1)([CH3:15])([CH3:14])[CH3:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1.C(OCC)(=O)C.CCCCCC>[C:12]([Si:16]([O:17][CH:18]1[CH2:19][CH2:20][CH:21]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[N+:9]([O-:11])=[O:10])[CH2:22][CH2:23]1)([CH3:26])[CH3:25])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OC1CCC(Oc2ccc(Cl)cc2[N+](=O)[O-])CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 76.8 %

Procedure:
A solution of diisopropylazadicarboxylate (1.65 g, 8.16 mmol) in anhydrous tetrahydrofuran (5 mL) was added, dropwise, at 0° C., to a solution of 4-chloro-2-nitrophenol (0.75 g, 4.32 mmol), 4-(tert-butyl-dimethyl-silanyloxy)-cyclohexanol (1.2 g, 5.21 mmol) and triphenylphosphine (2.27 g, 8.65 mmol) in anhydrous tetrahydrofuran (10 mL). The resulting mixture was stirred at 0° C. for 1 hour and at room temperature overnight. The reaction mixture was then sonicated for 20 minutes at room temperature and for 30 minutes at 40° C. and then was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure and the residue was partitioned between ethyl acetate and an aqueous solution of sodium bicarbonate (5%), the organic layer was separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure. The yellow oily residue was purified on a silica gel plug (hexane/EtOAc, from 99/1 to 90/10) to give a yellow oil. This material was dissolved in a mixture of ethyl acetate and hexane (1/1) and the resulting solution was washed twice with an aqueous solution of sodium hydroxide (3 M) and once with brine, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 1.28 g (79% yield) of tert-butyl-[4-(4-chloro-2-nitro-phenoxy)-cyclohexyloxy]-dimethyl-silane as a light yellow oil.
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[H][H].Cl[CH2:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][N:19]1[C:31]2[C:30]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[N:24]=[C:23]([NH2:32])[C:22]=2[N:21]=[C:20]1[CH2:33][CH2:34][CH3:35]>CN(C=O)C>[C:1]1([S:7][CH2:13][CH2:14][CH2:15][O: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]=[C:23]([NH2:32])[C:22]=3[N:21]=[C:20]2[CH2:33][CH2:34][CH3:35])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Sc1ccccc1
Reactant: [H][H]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(N)nc3ccccc3c2n1CCOCCCSc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under a nitrogen atmosphere thiophenol (0.9 mL, 8.6 mmol) was added to a suspension of sodium hydride (0.19 g, 7.9 mmol) in DMF (25 mL). After hydrogen evolution had ceased, 1-[2-(3-chloropropoxy)ethyl]-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine (2.50 g, 7.2 mmol, prepared by the methods of Parts A-I) was added. The reaction mixture was stirred at ambient temperature for 1.5 hours at which time analysis by HPLC indicated that all of the starting material had been consumed. The reaction mixture was poured into water (250 mL) with rapid stirring. Sodium carbonated (˜0.5 g) was added to neutralize any excess thiolate and the pH was adjusted to ˜14 with 50% sodium hydroxide. The resulting tan precipitate was isolated by filtration and then recrystallized from acetonitrile to provide 1.95 g of 1-{2-[3-(phenylthio)propoxy]ethyl}-2-propyl-1H-imidazo[4,5-c]quinolin-4-amine as a tan crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=2)=O)[CH:5]=[C:4]([NH:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[N:3]=1.COC(OC)[N:28]([CH3:30])C.O.[NH2:34]N>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:11]3[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([O:18][CH3:19])[CH:12]=3)=[N:34][NH:28][CH:30]=2)[CH:5]=[C:4]([NH:20][CH2:21][C@@H:22]([OH:24])[CH3:23])[N:3]=1
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: COc1cc(C)cc(C(=O)Cc2cc(NC[C@H](C)O)nc(Cl)n2)c1
Solvent: O
Product: COc1cc(C)cc(-c2n[nH]cc2-c2cc(NC[C@H](C)O)nc(Cl)n2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 43.8 %

Procedure:
2-[2-chloro-6-(2(S)-hydroxypropylamino)pyrimidin-4-yl]-1-(3-methoxy-5-methylphenyl)ethanone (2.16 g, 6.17 mmol) was heated at 90° C. for 20 hours together with N,N-dimethylformamide dimethylacetal (8.23 mL, 61.7 mmol). Excess N,N-dimethylformamide dimethylacetal was removed by vacuum distillation, and the reaction mixture was dissolved in anhydrous ethanol (50 mL). To this solution was dropwise added hydrazine hydrate (617 μL, 12.35 mmol), and stirred at room temperature for 12 hours. After completion of the cyclization, the solvent was removed by vacuum distillation. The concentrate was treated in water and ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate, filtered and distilled under vacuum. Recrystallization in dichloromethane gave the title compound (1.01 g, 44%).
Reaction SMILES: [CH:1]1([CH2:6][C@@H:7]([C:13]([NH:15][NH:16][C:17]2[C:22]([F:23])=[C:21]([N:24]3[CH2:28][CH2:27][C@@H:26]([CH2:29][OH:30])[CH2:25]3)[N:20]=[C:19]([CH3:31])[N:18]=2)=[O:14])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1C([F:39])=C(Cl)N=C(CF)N=1.[CH3:43][CH2:44][N:45](C(C)C)C(C)C>>[CH:1]1([CH2:6][C@@H:7]([C:13]([NH:15][NH:16][C:17]2[C:22]([F:23])=[C:21]([N:24]3[CH2:28][CH2:27][N:45]4[C@H:26]([CH2:29][O:30][CH2:43][CH2:44]4)[CH2:25]3)[N:20]=[C:19]([CH2:31][F:39])[N:18]=2)=[O:14])[CH2:8][N:9]([OH:12])[CH:10]=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(O)C=O)c(F)c(N2CC[C@@H](CO)C2)n1
Reactant: FCc1nc(Cl)c(F)c(Cl)n1
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(CF)nc(N2CCN3CCOC[C@@H]3C2)c1F

Procedure:
[(2R)-2-(Cyclopentylmethyl)-3-(2-{5-fluoro-2-(fluoromethyl)-6-[(9aS)-hexahydropyrazino[2,1-c][1,4]oxazin-8(1H)-yl]-4-pyrimidinyl}hydrazino)-3-oxopropyl]hydroxyformamide was prepared according to General Procedure A, utilizing (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (Example 22) in place of pyrrolidine, using 4,6-dichloro-5-fluoro-2-(fluoromethyl)pyrimidine in place of 4,6-dichloro-5-fluoro-2-methylpyrimidine, and using 3 equivalents of DIPEA in Part A. LCMS: (M+H)+: 498.3.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=O)[NH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.P(Cl)(Cl)([Cl:22])=O.O>C1(C)C=CC=CC=1>[Cl:22][C:6]1[C:5]2[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: Cc1ccc2c(=O)[nH]cnc2c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc2c(Cl)ncnc2c1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
To a solution of 7-methyl-3H-quinazolin-4-one (10.6 g, 69 mmol) in toluene (350 mL) is added triethylamine (17.5 g, 173 mmol) followed by phosphorous oxychloride (12.3 g, 80 mmol). The resulting solution is heated to 80° C. After 4 hours, the solution is cooled to ambient temperature. The reaction mixture is poured into 500 mL of water. The layers are separated and the organic layer is washed with H2O, saturated NaHCO3, and saturated NaCl, dried over MgSO4, filtered and concentrated. The resulting crude product is purified by recrystallization from EtOAc. The title compound is obtained as a white solid (10 g, 56 mmol). 1H NMR (CDCl3, 300 MHz) δ9.02 (s, 1H), 8.16 (d, 1H), 7.87 (s, 1H), 7.55 (d, 1H), 2.62 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH:25]=O)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23]([CH2:25][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:22]=[C:21]([C:27]#[N:28])[CH:20]=2)[C:12]=1[F:29])=[O:8]
Reactant: C1COCCN1
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(C#N)cc(C=O)c2)c1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Solvent: ClCCCl
Product: N#Cc1cc(CN2CCOCC2)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
4-chloro-N-({4-chloro-3-[(3-cyano-5-formylphenyl)oxy]-2-fluorophenyl}methyl)-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (40 mg, 0.071 mmol) and morpholine (6.18 mg, 0.071 mmol) were mixed in 1,2-dichloroethane (2 mL) and treated with sodium triacetoxyborohydride (21 mg, 0.099 mmol) and acetic acid (4.06 μl, 0.071 mmol). The mixture was stirred at RT for 1 h then TFA (2 ml, 26.0 mmol) was added to the solution and stirred for 30 min. The solvent was removed under vacuum and the crude product was purified by Reverse Phase HPLC (MeCN/water 0.1% formic acid) to give 30 mg (84%) of the title compound as a white solid. 1H NMR (400 MHz, methanol-d4) δ ppm 8.08 (s, 1H), 7.61-7.81 (m, 1H), 7.46 (s, 1H), 7.29-7.41 (m, 2H), 7.24 (s, 1H), 7.08-7.19 (m, 1H), 4.63 (s, 2H), 3.52-3.84 (m, 4H), 2.53 (m., 4H). LC-MS (ES+) m/z 502.9 [M+1].