Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([OH:18])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([O:18][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH2:15][CH2:16][CH2:17][C:12]=3[N:11]=[C:10]2[CH:19]([CH3:21])[CH3:20])=[CH:6][CH:7]=1
Reactant: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(O)CCC2
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2c(n1Cc1ccc(Cl)cc1)C(OCC(=O)OC(C)(C)C)CCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of Intermediate 58 (352 mg) in anhydrous N,N-dimethylformamide (15 mL) at 0° C. under an atmosphere of nitrogen was added sodium hydride (55 mg) as a 60% by weight suspension on mineral oil in one charge. The reaction was stirred at 0° C. for 30 min. To the reaction was added neat tert-butyl bromoacetate (0.18 mL) in one charge the reaction was stirred at 0° C. for a further 30 min before allowing to warm to ambient temperature over 1 hr. The reaction was stirred at ambient temperature for 3 hr. Sodium hydride (55 mg) as a 60% wt suspension on oil was added and the reaction stirred for 30 min. To the reaction was added tert-butyl bromoacetate (0.18 mL) in one charge. The reaction was quenched with water (75 mL) and extracted with ethyl acetate (75 mL). The extract was dried (hydrophobic frit) and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-25% methanol-dichloromethane gradient. Separation poor all product containing fractions were combined and concentrated in vacuo. The sample was loaded in dichloromethane and purified on silica using a 0-100% ethyl acetate-cyclohexane gradient. The appropriate fractions were combined and concentrated in vacuo to give the title compound (130 mg). LC/MS MH+ 419, 421, Rt 1.00 min (2 min run). Chiral separation of this material using a chiralpak AD column eluting with 5% ethanol in heptane to provide the two enantiomers in order of elution:
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[OH:17])[NH:13][N:12]=[C:11]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)(O)=[O:6].C1(C)C=CC=CC=1>C1COCC1>[Cl:3][C:5]([C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][C:16]=1[OH:17])[NH:13][N:12]=[C:11]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=1)=[O:6]
Reactant: Cc1cccc(Cc2n[nH]c3cc(O)c(C(=O)O)cc23)c1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cc1cccc(Cc2n[nH]c3cc(O)c(C(=O)Cl)cc23)c1

Procedure:
4.6 0.1 ml of thionyl chloride is added to a suspension of 200 mg of “4e” in 4 ml of THF, and the mixture is stirred for a further hour. 3 ml of toluene are added, and the solvents are removed at 300, giving 5-chlorocarbonyl-6-hydroxy-3-(3-methylbenzyl)-1H-indazole (“4f”)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH:12]=2)[CH:8]=[N:7]1.[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:45]=[CH:46][CH:47]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([N:26]5[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]5)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4cccc(N5CCN(C(C)C)CC5)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)N1CCN(c2cccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)c2)CC1
Yield: 13.4 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-5-(3-(4-isopropylpiperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (79 mg, 0.121 mmol) was hydrolyzed by lithium hydroxide (55 mg, 1.21 mmol), THF/Methanol/water (15/5/5 ml) to yield 8 mg (13.3% yield) of the titled compound. 1H NMR (CDCl3, 300 MHz): δ 9.0 (b, 1H), 8.55 (s, 1H), 8.15 (s, 1H), 7.88 (s, 1H), 7.7 (s, 1H), 7.46-7.3 (m, 3H), 7.2-6.9 (m, 3H), 5.389 (s, 2H), 3.4 (m, 4H), 2.7 (m, 4H), 1.4-1.0 (m, 7H). MS: m/z=495.4 (M+1); HPLC: 89.22% in method B.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]([CH2:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:5])C.[OH-].[Na+].Cl>O1CCOCC1.O>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][CH2:15][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[CH:14]=[C:6]2[C:4]([OH:5])=[O:3])=[CH:22][CH:21]=1
Reactant: CCOC(=O)c1cc2ccccc2n1CCc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2ccccc2n1CCc1ccc(Cl)cc1
Temperature: 60 °C

Procedure:
480 mg (1.5 mmol) of 1-[2-(4-Chloro-phenyl)-ethyl]-1H-indole-2-carboxylic acid ethyl ester was dissolved in 5 ml of dioxan and 5 ml of 2N aqueous sodium hydroxide was added. The reaction was heated to 60° C. for 2 h, then was cooled to 0° C. The solution was diluted with 10 ml of water and the pH of the solution was adjusted to between 2 and 3 by the addition of concentrated aqueous HCl, whereupon the product precipitates. The product was filtered off and dried under reduced pressure. Yield: 390 mg MS (Cl+): m/e=300, chloro pattern.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13].[H-].[Na+].Br[CH2:17][CH2:18][CH:19]([CH3:21])[CH3:20]>C1COCC1>[CH2:17]([O:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]=1[CH:12]=[O:13])[CH2:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)CCBr
Reactant: O=Cc1c(O)ccc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)CCOc1ccc2ccccc2c1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Hydroxy-1-naphthaldehyde (1.72 g, 10.0 mmol) and THF (50 ml) were combined in a flask. NaH (312 mg, 13 mmol) was added, followed by 1-bromo-3-methylbutane (1.20 mL, 10.0 mmol). The solution was stirred at room temperature overnight, the solvent was removed in vacuo, and the residue was purified by chromatography (5–10% ethyl acetate/hexane): 1H NMR (400 MHz, CDCl3) δ 10.9 (s, 1H), 9.28 (dd, 1H, J=0.7 Hz, 8.6 Hz), 8.02 (d, 1H, J=9.1 Hz), 7.75 (d, 1H, J=8.1 Hz), 7.63–7.59 (m, 1H), 7.43–7.39 (m, 1H), 7.27 (d, 1H, J=9.2 Hz), 4.25 (t, 2H, J=6.5 Hz), 1.98–1.84 (m, 1H), 1.80–1.75 (m, 2H), 0.99 (d, 6H, J=6.6 Hz); ESMS m/e: 242.8 (M+H)+.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][N:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([N+:21]([O-])=O)[CH:17]=3)[NH:12][C:11]2=[O:24])[CH:5]=[CH:4][N:3]=[CH:2]1.[H][H]>[Pd].C(O)C>[NH2:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[NH:12][C:11](=[O:24])[N:10]([CH2:9][CH2:8][CH2:7][CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[C:19]2=[O:20]
Reactant: O=c1[nH]c2ccc([N+](=O)[O-])cc2c(=O)n1CCCCn1ccnc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc2[nH]c(=O)n(CCCCn3ccnc3)c(=O)c2c1

Procedure:
A mixture of 2.0 g of 3-[4-(1H-imidazol-1-yl)butyl]-6-nitro-2,4(1H,3H)-quinazolinedione, 1.0 g of 10% palladium-on-carbon catalyst and 200 ml of ethanol is shaken in a Parr hydrogenater under 45 pounds of hydrogen pressure until the hydrogen uptake is complete. The reaction mixture is heated to the boil and the catalyst is filtered off. The ethanolic solution is concentrated to a low volume and the desired product is recovered by filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[CH:12]=[N:13][C:14]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[N:15][CH:16]=2)=[O:10])=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH:22]1([O:20][C:19](=[O:21])[CH2:18][O:17][C:14]2[N:13]=[CH:12][C:11]([C:9](=[O:10])[NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[CH:16][N:15]=2)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: O=C(O)COc1ncc(C(=O)Nc2ccc(F)cc2)cn1
Reactant: OC1CCCCCC1
Product: O=C(COc1ncc(C(=O)Nc2ccc(F)cc2)cn1)OC1CCCCCC1
Yield: 80 %

Procedure:
The titled compound was prepared from [5-(4-fluorophenylcarbamoyl)pyrimidin-2-yloxy]acetic acid using cycloheptanol (39 mg, 0.34 mmol) as the coupling partner. Concentration (no chromatography) yielded 53 mg (80%) of the titled compound. ESI-MS m/z 388 (MH+), 386 (M−H−).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=2)(=[O:28])=[O:27])[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Fc1cccc(C2CCCN2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)N2CCCC2c2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.1 %

Procedure:
To a stirred solution of (RS)-2-(3-fluoro-phenyl)-pyrrolidine (0.24 g, 1.45 mmol) and triethylamine (0.40 ml, 2.87 mmol) in dichloromethane (40 ml) was added at 0° C. toluene-4-sulfonyl chloride (0.42 g, 2.20 mmol). The mixture was stirred at RT for 16 h, evaporated, dissolved in water (40 ml) and extracted with ethyl acetate (2×40 ml). The combined organic layers were washed with water (40 ml), brine (40 ml), dried (MgSO4) and evaporated. The crude product was purified by crystallization from ethyl acetate/hexane to give the product (0.38 g, 83%) as a white solid, m.p. 116° C. and MS: m/e=319 (M+).
Reaction SMILES: [CH2:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH2:4][CH2:3][CH:2]1[NH2:14].[C:15]1([CH3:24])[C:16]([C:21](Cl)=[O:22])=[CH:17][CH:18]=[CH:19][CH:20]=1.C(N(CC)CC)C>O1CCCC1>[CH3:24][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH:14][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]3[CH2:13][CH2:12][CH2:11][CH2:10][C:8]=3[C:9]=2[CH:1]=1)=[O:22]
Reactant: NC1CCc2oc3ccccc3c2C1
Reactant: Cc1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccccc1C(=O)Nc1ccc2oc3c(c2c1)CCCC3
Yield: 65.5 %

Procedure:
Following the procedure of Example 1, tetrahydro-dibenzofuran-2-ylamine (0.94 g, 5.0 mmol), o-toluoyl chloride (0.69 mL, 5.2 mmol), and triethylamine (2.1 mL, 15 mmol) in tetrahydrofuran (30 mL) provided 2-methyl-N-(6,7,8,9-tetrahydro-dibenzofuran-2-yl)-benzamide (1.0 g). Mp 209-210° C.;Anal. Calcd. for C20H19NO2: C, 78.66; H, 6.27; N, 4.59; Found: C, 78.52; H, 6.28; N, 4.67.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][CH:10]=[C:9]2[C:13]#[N:14])=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)([CH3:22])([CH3:21])[CH3:20]>ClCCl>[C:19]([C:11]1[CH:10]=[C:9]([C:13]#[N:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:12]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: Cc1ccc(-n2cccc2C#N)cc1
Reactant: CC(C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1ccc(-n2cc(C(C)(C)C)cc2C#N)cc1
Reaction time: 0.33 h
Yield: 92.4 %

Procedure:
To a mixture of 1-(4-methylphenyl)pyrrole-2-carbonitrile (546 mg) and aluminum chloride (532 mg) in dichloromethane (10 ml) was added t-butyl chloride (368 mg) in dichloromethane (10 ml) in one portion at 5° C. The mixture was stirred at the same temperature for 20 minutes. The reaction mixture was quenched with 10% hydrochloric acid. The separated organic layer was washed with 10% hydrochloric acid and water, successively, dried, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluted by a mixture of ethyl acetate and n-hexane (1:6) to yield 4-t-butyl-1-(4-methylphenyl)pyrrole-2-carbonitrile (660 mg).
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[CH2:8][O:9][C:10](=[O:11])[C:5]2=[CH:4][CH:3]=1.[Se](=O)=[O:13]>O1CCOCC1>[O:11]=[C:10]1[C:5]2[C:6](=[N:7][C:2]([CH:1]=[O:13])=[CH:3][CH:4]=2)[CH2:8][O:9]1
Reactant: Cc1ccc2c(n1)COC2=O
Reactant: O=[Se]=O
Solvent: C1COCCO1
Product: O=Cc1ccc2c(n1)COC2=O
Temperature: 100 °C
Yield: 79.7 %

Procedure:
A solution of 2-methyl-7H-furo[3,4-b]pyridin-5-one (1.41 g, 9.46 mmol) in dioxane (50 mL) is treated with selenium dioxide (1.2 g, 10.8 mmol) and the reaction mixture is heated at 100° C. for 3 h. Additional selenium dioxide (1.2 g, 10.8 mmol) is added at 3 and 6 hours and the reaction mixture is heated at 100° C. The reaction is heated at 100° C. for an additional 42 h. The reaction mixture is filtered through celite and washed with dioxane. The filtrate is concentrated under reduced pressure and subject to chromatography (silica gel, EtOAc/hexane). The high Rf product containing fractions are concentrated to give 5-Oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carbaldehyde (1.23 g, 80%). The low Rf containing fractions are concentrated to give 5-oxo-5,7-dihydro-furo[3,4-b]pyridine-2-carboxylic acid (159 mg, 9%).
Reaction SMILES: Cl.CN(C)CCCCl.[CH3:9][N:10]([CH3:42])[CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[N:25](COCC[Si](C)(C)C)[C:24]2[C:23]3[CH:34]=[CH:35][CH:36]=[CH:37][C:22]=3[S:21][C:20]3[CH:38]=[CH:39][CH:40]=[CH:41][C:19]=3[C:18]=2[N:17]=1>>[CH3:42][N:10]([CH3:9])[CH2:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[NH:17][C:18]2[C:19]3[CH:41]=[CH:40][CH:39]=[CH:38][C:20]=3[S:21][C:22]3[CH:37]=[CH:36][CH:35]=[CH:34][C:23]=3[C:24]=2[N:25]=1
Reactant: CN(C)CCCOCc1nc2c(n1COCC[Si](C)(C)C)-c1ccccc1Sc1ccccc1-2
Agent: CN(C)CCCCl
Agent: Cl
Product: CN(C)CCCOCc1nc2c([nH]1)-c1ccccc1Sc1ccccc1-2

Procedure:
By a reaction of alcohol 31 (0.58 mmole) and 3-dimethylaminopropylchloride-hydrochloride (8.1 mmole), dimethyl-{3-[1-(2-trimethylsilyl-ethoxymethyl)-1H-8-thia-1,3-diaza-dibenzo[e,h]azulene-2-ylmethoxy]-propyl}-amine in the form of an oily product was obtained;
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:8][C:7](Cl)=[N:6][C:5]=2[NH:4][CH:3]=1.[NH2:17][C:18]1[CH:26]=[C:25]2[C:21]([CH:22]=[N:23][NH:24]2)=[CH:20][CH:19]=1.C[Si](Cl)(C)C>C(O)CCC>[Br:1][C:2]1[C:10]2[C:9]([NH:11][CH:12]3[CH2:15][CH2:14][CH2:13]3)=[N:8][C:7]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([CH:22]=[N:23][NH:24]4)=[CH:20][CH:19]=3)=[N:6][C:5]=2[NH:4][CH:3]=1
Reactant: Nc1ccc2cn[nH]c2c1
Reactant: Clc1nc(NC2CCC2)c2c(Br)c[nH]c2n1
Agent: C[Si](C)(C)Cl
Solvent: CCCCO
Product: Brc1c[nH]c2nc(Nc3ccc4cn[nH]c4c3)nc(NC3CCC3)c12
Temperature: 116 °C
Reaction time: 4 h
Yield: 1.2 %

Procedure:
A mixture of 5-bromo-2-chloro-N-cyclobutyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (64 mg, 0.21 mmol), 6-aminoindazole (56 mg, 0.42 mmol) and TMSCl (0.050 mL, 0.40 mmol) in nBuOH (2 mL) was stirred at 116° C. for 4 h. It was then concentrated in vacuo. The residue was purified by HPLC to give a sample, which was further purified by preparative TLC using CH2Cl2/MeOH (95/5) as developing solvents to give the titled compound (1 mg). MS 398.3, 400.3 (M+H, Br pattern); UV 203.8, 247.4, 309.1 nm.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.C(O)(=O)C.[CH:18](N)=[NH:19]>C(O)C>[N+:11]([C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:6])=[N:19][CH:18]=[N:1]2)=[CH:7][CH:8]=1)([O-:13])=[O:12]
Reactant: Nc1cc([N+](=O)[O-])ccc1C(=O)O
Reactant: N=CN
Solvent: CCO
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc2c(O)ncnc2c1
Temperature: 25 °C
Yield: 88.9 %

Procedure:
To a solution of 2-amino-4-nitrobenzoic acid (6.00 g, 32.94 mmol) in ethanol (40 mL) was added formamidin acetate (6.80 g, 65.32 mmol). The reaction mixture was refluxed for 5 h. The reaction mixture was cooled to room temperature and refrigerated. The precipitate was filtered out, washed with several portions of cooled ethanol, and then dried in vacuo to give 5.60 g (89%) of 7-nitroquinazolin-4-ol as a yellow solid.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]([CH:11]1[CH:17]([OH:18])[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[N+:9]=[N-:10]>C(Cl)Cl>[N:8]([CH:11]1[CH2:12][CH2:13][NH:14][CH2:15][CH2:16][CH:17]1[OH:18])=[N+:9]=[N-:10]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C(N=[N+]=[N-])CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: [N-]=[N+]=NC1CCNCCC1O
Temperature: 35 °C
Yield: 96.6 %

Procedure:
Trifluoroacetic acid (20 mL) was added to a solution of tert-butyl 4-azido-5-hydroxyazepane-1-carboxylate (7.43 g, 29.0 mmol) in DCM (70 mL) and the mixture heated behind a blast shield at 35° C. for 4 hr. The solvents were removed under reduced pressure and the residue re-dissolved in MeOH and passed through an SCX column, washing with DCM and MeOH and eluting with 3-10% 7 N ammonia in MeOH/DCM to give 5-azidoazepan-4-ol as a yellow oil (4.38 g, 28.0 mmol) which was dissolved in dry DMSO (100 mL). 5-Chloro-1-methyl-4-nitro-1H-pyrazole from Example 1 (5.20 g, 32.2 mmol) and potassium fluoride (6.51 g, 112 mmol) were added. The mixture was heated at 70° C. for 16 hr, allowed to cool to room temperature, poured into water (1000 mL) and extracted into EtOAc (4×250 mL). The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. Purification via silica gel column chromatography (0-100% EtOAc/isohexane) gave 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol as a yellow gum (7.27 g, 77% over two steps). 1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 3.94-3.66 (m, 4H), 3.65 (td, J=9.7, 3.8 Hz, 1H), 3.44-3.18 (m, 4H), 2.50 (d, J=2.8 Hz, 1H), 2.24-2.12 (m, 2H), 2.02-1.89 (m, 2H).
Reaction SMILES: ClC1C=C(CN2C(=O)C3=CC=CC=C3C2=O)N=C(OC)N=1.COC1N=C(OC)C=C(CN2C(=O)C3=CC=CC=C3C2=O)N=1.Cl[C:45]1[CH:50]=[C:49]([CH2:51][N:52]2[C:56](=[O:57])[C:55]3=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]3[C:53]2=[O:62])[N:48]=[C:47]([S:63][CH3:64])[N:46]=1.[CH3:65][S-:66].[Na+]>>[CH3:64][S:63][C:47]1[N:46]=[C:45]([S:66][CH3:65])[CH:50]=[C:49]([CH2:51][N:52]2[C:56](=[O:57])[C:55]3=[CH:58][CH:59]=[CH:60][CH:61]=[C:54]3[C:53]2=[O:62])[N:48]=1
Reactant: C[S-]
Reactant: CSc1nc(Cl)cc(CN2C(=O)c3ccccc3C2=O)n1
Agent: COc1cc(CN2C(=O)c3ccccc3C2=O)nc(OC)n1
Agent: COc1nc(Cl)cc(CN2C(=O)c3ccccc3C2=O)n1
Agent: [Na+]
Product: CSc1cc(CN2C(=O)c3ccccc3C2=O)nc(SC)n1

Procedure:
Using the above method, 4-chloro-2-methoxy-6-phthalimidomethylpyrimidine could be converted to 2,4-dimethoxy-6-phthalimidomethylpyrimidine. Similarly, 4-chloro-2-methylthio-6-phthalimidomethylpyrimidine was reacted with sodium methanethiolate to provide 2,4-bis(methylthio)-6-phthalimidomethylpyrimidine, identical in all respects with the compound prepared in Example 1, part D.
Reaction SMILES: [F:1][CH:2]([F:29])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[O:24][CH2:25][CH3:26])[N:14]=2)=[CH:6][C:5]=1[OH:28].Br[CH2:31][CH:32]1[CH2:35][CH2:34][CH2:33]1>>[CH:32]1([CH2:31][O:28][C:5]2[CH:6]=[C:7]([C:10]3[O:11][CH:12]=[C:13]([CH2:15][NH:16][C:17](=[O:27])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=4[O:24][CH2:25][CH3:26])[N:14]=3)[CH:8]=[CH:9][C:4]=2[O:3][CH:2]([F:1])[F:29])[CH2:35][CH2:34][CH2:33]1
Reactant: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(O)c2)n1
Reactant: BrCC1CCC1
Product: CCOc1ccccc1C(=O)NCc1coc(-c2ccc(OC(F)F)c(OCC3CCC3)c2)n1

Procedure:
Using the compound obtained in Example 347 and (bromomethyl)cyclobutane, white powdery N-[2-(3-Cyclobutylmethoxy-4-difluoromethoxyphenyl)oxazol-4-ylmethyl]-2-ethoxybenzamide was obtained following the procedure of Example 348.
Reaction SMILES: Cl.[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([C:12]([OH:14])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1.Cl.[CH3:16]O>>[CH3:2][C:3]1[NH:4][C:5]2[CH:11]=[C:10]([C:12]([O:14][CH3:16])=[O:13])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cc1nc2ccc(C(=O)O)cc2[nH]1
Reactant: CO
Agent: Cl
Product: COC(=O)c1ccc2nc(C)[nH]c2c1
Yield: 93.2 %

Procedure:
Mass spectrum (FAB, Pos): m/z 177 (M+ +1, as a free base). ##STR15## 2-Methylbenzimidazole-5-carboxylic acid hydrochloride, 6.6 g (32.5 mmols), was added to 200 ml of methanol and 5 ml of conc. hydrochloric acid was added to the mixture followed by heating to reflux for 8 hours. The solvent was distilled off under reduced pressure and 200 ml of water was added to the residue. After 1 N sodium hydroxide solution was added to the mixture to adjust pH to 9 to 10, the mixture was extracted with ethyl acetate. The ethyl acetate layer was dried over anhydrous magnesium sulfate and filtered. The solvent was distilled off to give 5.5 g (93.2%) of methyl 2-methyl-benzimidazole-5-carboxylate.
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:30][C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:19]2[C:31](=[O:41])[N:32](C(OC(C)(C)C)=O)[CH2:33][C:18]=2[C:17]=1[F:42])=O)(C)(C)C.[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44]>C(Cl)Cl>[C:43]([OH:49])([C:45]([F:48])([F:47])[F:46])=[O:44].[NH2:8][C@H:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C@H:10]1[NH:15][C:16]1[N:21]=[C:20]([C:22]2[S:30][C:25]3=[CH:26][N:27]=[CH:28][CH:29]=[C:24]3[CH:23]=2)[C:19]2[C:31](=[O:41])[NH:32][CH2:33][C:18]=2[C:17]=1[F:42]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CN(C(=O)OC(C)(C)C)C2=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cc3ccncc3s2)c2c(c1F)CNC2=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
To a solution of tert-butyl 6-(((1R,2S)-2-((tert-butoxycarbonyl)amino)cyclohexyl)amino)-7-fluoro-3-oxo-4-(thieno[2,3-c]pyridin-2-yl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxylate (135 mg, 226 mmol) in DCM (3 mL) was added TFA in DCM (1:1, 10 mL). The reaction mixture was stirred at room temperature for 1 hour. After removal of the solvent, the resulting crude material was reconstituted in MeOH/DMF/DCM (10.0 mL) and was purified via preparative mass trigger LCMS, eluting with a gradient of 10-25% ACN (0.035% TFA) and H2O (0.05% TFA). The collected fractions were combined and the solvent was stripped to dryness via rotary evaporation to give a TFA salt of the title compound (76 mg, 48% two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.48-2.06 (m, 8H), 3.83 (br s, 1H), 4.34 (d, J=3.28 Hz, 1H), 4.57 (s, 2H), 7.35 (d, J=6.06 Hz, 1H), 7.88 (br s, 2H), 8.20 (d, J=5.81 Hz, 1H), 8.58 (d, J=5.81 Hz, 1H), 8.81 (s, 1H), 9.47 (s, 1H), 9.61 (s, 1H). ESI-MS m/z [M+H]+ calc'd for C20H20FN5OS, 398. found, 398.
Reaction SMILES: CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:41]1[O:50][C:44]2([CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[O:43][CH2:42]1.[CH3:51][O:52][C:53](=[O:61])[C:54]1[CH:59]=[CH:58][C:57](Br)=[CH:56][CH:55]=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(O)(C)C>[CH3:51][O:52][C:53](=[O:61])[C:54]1[CH:59]=[CH:58][C:57]([N:47]2[CH2:48][CH2:49][C:44]3([O:50][CH2:41][CH2:42][O:43]3)[CH2:45][CH2:46]2)=[CH:56][CH:55]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: COC(=O)c1ccc(Br)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Solvent: CC(C)(C)O
Product: COC(=O)c1ccc(N2CCC3(CC2)OCCO3)cc1
Temperature: 120 °C
Reaction time: 0.03 h

Procedure:
Procedure adopted from Tetrahedron Lett., 2007, 48, 2519. A thick-walled glass reaction vessel was charged with palladium(II)acetate (157 mg, 0.698 mmol), X-Phos (332 mg, 0.698 mmol, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl), cesium carbonate (4.55 g, 13.96 mmol) and 5:1 (v/v) toluene:t-BuOH (20 mL). The stirred contents were purged with nitrogen and a solution of 4-piperidone ethylene ketal (1.80 mL, 13.96 mmol) and methyl-4-bromobenzoate (3.30 g, 15.36 mmol) in 5:1 (v/v) toluene:t-BuOH (100 mL) was added. After stirring for 2 minutes, the vessel was sealed and the reaction mixture was heated at 120° C. for 18 hours. Upon cooling to room temperature, the reaction mixture was filtered through celite and the filtrate was concentrated. Elution through a flash column (silica gel 60, 230-400 mesh, 3:2 hexanes:EtOAc) gave the title compound as an off-white, crystalline solid (3.20 g, 83%).