Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[CH:15]=[C:14]([CH2:19][CH2:20]OS(C)(=O)=O)[CH:13]=[CH:12]3)[CH:6]=[N:7][CH:8]=1)#[N:2].[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][NH:28]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C>[CH3:26][C@@H:27]1[CH2:31][CH2:30][CH2:29][N:28]1[CH2:20][CH2:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[CH:10]=[C:9]([C:5]1[CH:6]=[N:7][CH:8]=[C:3]([CH:4]=1)[C:1]#[N:2])[CH:18]=[CH:17]2
Reactant: C[C@@H]1CCCN1
Reactant: CS(=O)(=O)OCCc1ccc2cc(-c3cncc(C#N)c3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3cncc(C#N)c3)ccc2c1
Yield: 57.4 %

Procedure:
Methanesulfonic acid 2-[6-(5-cyano-pyridin-3-yl)-naphthalen-2-yl]-ethyl ester (Example 81B, 190 mg, 0.54 mmol), (2R)-2-methylpyrrolidine (138 mg, 1.62 mmol, 3.0 equiv.), and cesium carbonate (176 mg, 0.54 mmol) in anhydrous acetonitrile (6 mL) were stirred in a sealed tube at 50° C. for 18 hours. The reaction mixture was concentrated under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous Na2CO3. The organic layer was washed with brine, then dried (MgSO4), and filtered. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (98:2:trace dichloromethane/methanol/NH4OH). Fractions containing product were combined and concentrated under reduced pressure to provide the free base of the title compound as a white solid (105.9 mg, 57% yield). This free base was dissolved in methanol and treated with excess dioxane-HCl. Ether was added to induce crystallization of the dihydrochloride salt of the title compound. 1H NMR (CD3OD, 300 MHz) δ 9.26 (br s, 1H), 8.97 (br s, 1H), 8.68 (s, 1H), 8.29 (s, 1H), 8.05 (s, 1H), 8.02 (s, 1H), 7.90 (br s, 1H), 7.88 (dd, J=2, 9 Hz, 1H), 7.56 (d, J=8 Hz, 1H), 3.84-3.49 (m, 7H), 2.45-2.30 (m, 1H), 2.27-1.99 (m, 2H), 1.84-1.69 (m, 1H), 1.50 (d, J=6 Hz, 3H). MS (DCI-NH3) [M+H]+ at 342.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]([NH2:25])=[O:24])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1.N1C=CN=C1.[C:31]([Si:35](Cl)([CH3:37])[CH3:36])([CH3:34])([CH3:33])[CH3:32]>C(Cl)Cl>[Si:35]([O:1][CH2:2][C:3]1[C:8]([O:9][C:10]2[C:11]([C:23]([NH2:25])=[O:24])=[N:12][CH:13]=[C:14]([S:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=3)[CH:15]=2)=[CH:7][CH:6]=[CH:5][N:4]=1)([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:37])[CH3:36]
Reactant: NC(=O)c1ncc(Sc2ccccn2)cc1Oc1cccnc1CO
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1ncccc1Oc1cc(Sc2ccccn2)cnc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 51.5 %

Procedure:
3-(2-(Hydroxymethyl)pyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (575 mg, 1.62 mmol) was dissolved in CH2Cl2 (20 mL) and 1H-imidazole (166 mg, 2.43 mmol) and tert-butylchlorodimethylsilane (293 mg, 1.95 mmol) were added. The reaction was stirred at ambient temperature for 2 hours. The solids were filtered and the filtrate was concentrated. The residue was purified on silica gel (5% methanol in EtOAc) to afford 3-(2-((tert-butyldimethylsilyloxy)methyl)pyridin-3-yloxy)-5-(pyridin-2-ylthio)picolinamide (391 mg, 0.834 mmol, 51.4% yield).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([O:9][C:10]1[CH:15]=[CH:14][C:13]([S:16][C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)=[CH:12][CH:11]=1)[CH2:2]2.[CH:24](O)([CH3:26])[CH3:25]>>[CH:24]([O:23][C:20]1[CH:21]=[CH:22][C:17]([S:16][C:13]2[CH:12]=[CH:11][C:10]([O:9][CH:3]3[CH:4]4[CH2:7][CH2:8][N:1]([CH2:6][CH2:5]4)[CH2:2]3)=[CH:15][CH:14]=2)=[CH:18][CH:19]=1)([CH3:26])[CH3:25]
Reactant: Oc1ccc(Sc2ccc(OC3CN4CCC3CC4)cc2)cc1
Reactant: CC(C)O
Product: CC(C)Oc1ccc(Sc2ccc(OC3CN4CCC3CC4)cc2)cc1

Procedure:
The product of Example 10A (80 mg, 0.24 mmol) was treated with isopropyl alcohol (60 mg, 1 mmol) according to the procedure of Example 1A. The title compound was purified by chromatography (SiO2, CH2Cl2:MeOH:NH3.H2O, 90:10:1, Rf. 0.5) as oil (80 mg, yield, 90%). 1H NMR (MeOH-d4, 300 MHz) δ 1.30 (d, J=6.1 Hz, 6H), 1.60–2.10 (m, 3H), 2.15–2.25 (m, 1H), 2.30–2.40 (m, 2H), 2,98–3.20 (m, 6H), 3.50–3.60 (m, 1H), 4.50–4.58(m, 1H), 7.70–4.78 (m, 1H), 6.87 (t, J =9.2 Hz), 4H), 7.23 (d, J=8.8 Hz, 2H), 7.24 (d, J=9.2 Hz, 2H) ppm. MS (DCl/NH3) m/z 370 (M+H)+.
Reaction SMILES: S(Cl)([Cl:3])=O.[ClH:5].[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([OH:30])=O)[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1>C(Cl)Cl>[ClH:3].[N:6]1([CH2:11][CH:12]([N:14]2[C:27]3[CH:26]=[C:25]([C:28]([Cl:5])=[O:30])[CH:24]=[CH:23][C:22]=3[S:21][C:20]3[C:15]2=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH3:13])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: O=S(Cl)Cl
Reactant: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)O)cc21
Agent: Cl
Solvent: ClCCl
Product: CC(CN1CCCC1)N1c2ccccc2Sc2ccc(C(=O)Cl)cc21
Reaction time: 1.5 h

Procedure:
Thionyl chloride (12.7 cc) is added in the course of 5 minutes, with stirring at a temperature of 4° C., to a suspension of 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxylic acid hydrochloride (9.77 g) in methylene chloride (250 cc), and stirring is continued for 90 minutes at a temperature of 20° C. The clear yellow solution obtained is concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. and dried to constant weight under reduced pressure (5 mm Hg; 0.67 kPa) at 50° C. to give 10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarbonyl chloride hydrochloride (10.2 g) in the form of a yellow paste.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:12]=[CH:11][N:10]=[C:9]2[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[CH:29])[CH:23]=1.[Na].[N:31]1[CH:36]=[CH:35][C:34](=[O:37])[CH2:33][CH:32]=1>CO.C(Cl)(Cl)Cl>[ClH:2].[C:28]([C:24]1[CH:23]=[C:22]([NH:21][C:9]2[C:8]3[C:13](=[CH:14][C:15]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:6]([O:5][CH2:4][CH2:3][N:31]4[CH:36]=[CH:35][C:34](=[O:37])[CH:33]=[CH:32]4)[CH:7]=3)[N:12]=[CH:11][N:10]=2)[CH:27]=[CH:26][CH:25]=1)#[CH:29]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Reactant: O=C1C=CN=CC1
Agent: Cl
Agent: [Na]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCn4ccc(=O)cc4)cc23)c1

Procedure:
The free base of this product was prepared from the title product of Example 30 and the sodium salt of pyrid-4-one as described for Example 50. The free base was isolated by flash chromatography with 15% methanol/CHCl3 and converted to the title product according to the procedure described for Example 28 (32%; M.P. 155°-168° C. (dec); LC-MS: 457 (MH+); anal. RP-HPLC RT: 3.45 min).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[C:28](=[O:35])[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6].[BH4-].[Na+]>CO.C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([N:24]2[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[CH:28]([OH:35])[CH2:27][CH2:26][CH2:25]2)=[O:23])[CH:19]=[CH:18][C:4]=1[C:5]([NH:7][C:8]1[C:16]2[N:15]=[C:14]([CH3:17])[NH:13][C:12]=2[CH:11]=[CH:10][CH:9]=1)=[O:6]
Reactant: COc1cc(C(=O)N2CCCC(=O)c3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc(C(=O)N2CCCC(O)c3ccccc32)ccc1C(=O)Nc1cccc2[nH]c(C)nc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 99.6 %

Procedure:
To an ice-bath-cooled solution of 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl) -4-(2,3,4,5-tetrahydro-5-oxo-1H-1-benzazepin-1-yl)carbonylbenzamide (123 mg) in methanol (5 ml) was added sodium borohydride (10 mg), and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was diluted with chloroform and the solution was washed with water and brine. The solution was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was triturated with ether to give 2-methoxy-N-(2-methyl-1H-benzimidazol-4-yl)-4-(2,3,4,5-tetrahydro-5-hydroxy-1H-1-benzazepin-1-yl)carbonylbenzamide (123 mg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([C:16]2[NH:17][C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CS(O[CH:40]([CH3:42])[CH3:41])(=O)=O>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]([C:16]2[N:17]([CH:40]([CH3:42])[CH3:41])[C:18]3[C:23]([CH:24]=2)=[CH:22][C:21]([O:25][CH:26]2[CH2:31][CH2:30][N:29]([CH:32]([CH3:34])[CH3:33])[CH2:28][CH2:27]2)=[CH:20][CH:19]=3)=[O:15])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)OS(C)(=O)=O
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCN(C(=O)OC(C)(C)C)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)n3C(C)C)CC1

Procedure:
The title compound was prepared in analogy to example 40a), from 4-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carbonyl]-piperazine-1-carboxylic acid tert-butyl ester and isopropyl methanesulfonate. Light-yellow foam. MS (m/z): 513.4 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1.[CH3:18][C:19]([CH3:24])([CH3:23])[C:20](Cl)=[O:21]>>[CH3:18][C:19]([CH3:24])([CH3:23])[C:20]([NH:1][C:2]1[N:7]=[C:6]2[C:8]([CH:11]3[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)=[CH:9][NH:10][C:5]2=[CH:4][CH:3]=1)=[O:21]
Reactant: CC(C)(C)C(=O)Cl
Reactant: CN1CCC(c2c[nH]c3ccc(N)nc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=O)C(C)(C)C)nc23)CC1
Yield: 484.3 %

Procedure:
Beginning with 0.010 gm (0.044 mMol) 5-amino-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.067 mL (0.048 mMol) 2,2-dimethylpropanoyl chloride, 0.067 gm (48%) of the title compound were prepared essentially by the procedure described in Example 7.
Reaction SMILES: C([O:5][C:6](=[O:22])[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[C:9]([O:17][CH2:18][CH2:19][CH:20]=[CH2:21])[CH:8]=1)CC=C.[OH-].[Na+].Cl>CO>[CH2:18]([O:17][C:9]1[CH:8]=[C:7]([CH:12]=[C:11]([C:13]([F:14])([F:15])[F:16])[CH:10]=1)[C:6]([OH:22])=[O:5])[CH2:19][CH:20]=[CH2:21]
Reactant: C=CCCOC(=O)c1cc(OCCC=C)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: C=CCCOc1cc(C(=O)O)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.6 %

Procedure:
3-But-3-enyloxy-5-trifluoromethyl-benzoic acid but-3-enyl ester (2.64 g, 8.39 mmol) was dissolved in methanol. A 5 N aqueous sodium hydroxide solution (5.1 ml, 25.2 mmol) was added and the mixture was stirred at room temperature for two hours. The reaction solution was cooled, quenched with 2 N hydrochloric acid (20 ml, 40 mmol) and then extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 3-but-3-enyloxy-5-trifluoromethyl-benzoic acid (2.13 g, 98%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.C1C(=O)N([Br:21])C(=O)C1>CC#N>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][C:7]=1[Br:21]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)CCc1cnc(N)cn1
Solvent: CC#N
Product: COC(=O)CCc1cnc(N)c(Br)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(5-aminopyrazin-2-yl)propanoate (25 mg, 0.138 mmol) in CH3CN (690 μL) was added NBS (24.56 mg, 0.138 mmol). The reaction mixture was stirred for 1 h at room temperature. After quenched with Na2S2O3 solution, the reaction mixture was stirred with NaHCO3 solution for 20 min and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude methyl 3-(5-amino-6-bromopyrazin-2-yl)propanoate was obtained (28%). LCMS (m/z): 260.2/262.2 (MH+), 0.54 min.
Reaction SMILES: C[O:2][C:3](=[O:36])[C@H:4]([CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[NH:29][CH:28]=1)[NH:5][C:6](=[O:25])[CH2:7][N:8]1[C:12](=[O:13])[CH2:11][CH:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH:21]=[N:22][NH2:23])=[CH:17][CH:16]=2)[C:9]1=[O:24]>Cl>[NH2:23][N:22]=[CH:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][CH:10]2[CH2:11][C:12](=[O:13])[N:8]([CH2:7][C:6]([NH:5][C@H:4]([C:3]([OH:36])=[O:2])[CH2:26][C:27]3[C:35]4[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=4)[NH:29][CH:28]=3)=[O:25])[C:9]2=[O:24])=[CH:16][CH:17]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)CN1C(=O)CC(Cc2ccc(C=NN)cc2)C1=O
Agent: Cl
Product: NN=Cc1ccc(CC2CC(=O)N(CC(=O)N[C@@H](Cc3c[nH]c4ccccc34)C(=O)O)C2=O)cc1
Yield: 34.3 %

Procedure:
204 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophan methyl ester are heated with 10 ml of 6N HCl for 3 min, then the mixture is evaporated to dryness and the residue is redistilled twice with water. The residue is taken up in a little water and freeze-dried. 68 mg of {3-[4-(aminoiminomethyl)benzyl]-2,5-dioxopyrrolidin-1-yl}acetyl-L-tryptophan are obtained.
Reaction SMILES: C1(COC(=O)[NH:10][C:11]2[CH:16]=[C:15]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:14]=[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:12]=2)C=CC=CC=1>[Pd].C(OCC)(=O)C>[CH2:18]([O:17][C:15]1[CH:16]=[C:11]([NH2:10])[CH:12]=[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH:14]=1)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCOc1cc(NC(=O)OCc2ccccc2)cc(OCCCCCCCCCC)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCCCOc1cc(N)cc(OCCCCCCCCCC)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 97.8 %

Procedure:
A mixture of 34 g (0.063 mol) of 3,5-bis(decyloxy)phenylcarbamic acid phenylmethyl ester and 4.0 g of 10% palladium on charcoal in 650 ml of ethyl acetate was shaken under a hydrogen atmosphere at room temperature for 4 hours. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to yield 25 g (98% yield, mp 48°-50°) of 3,5-bis(decyloxy)benzeneamine.
Reaction SMILES: [CH2:1]([NH:11][O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH3:20][N:21]=[C:22]=[O:23]>C(Cl)Cl>[CH2:13]([O:12][N:11]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[C:22]([NH:21][CH3:20])=[O:23])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CN=C=O
Reactant: CCCCCCCCCCNOCc1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCN(OCc1ccccc1)C(=O)NC
Reaction time: 2 h
Yield: 83 %

Procedure:
Purification by chromatography on silica gave t-butyl N-benzyloxy-N-decylcarbamate as a colorless oil (8.39 g, 79% yield). To a solution of this urethane (7.0 g) in methylene chloride (15 ml) at room temperature under nitrogen was added trifluoroacetic acid (15 ml). After 30 minutes, the solution was evaporated at 40° C. lN NaHCO3 was added and solid Na2CO3 was added to bring the pH to 9. The mixture was extracted twice with methylene chloride, and the combined extracts were dried (MgSO4), filtered, and evaporated to give decyl-N-benzyloxyamine as a colorless oil (5.0g g, 100% yield). To a stirred solution of this amine (4.92 g, 18.8 mmol) in methylene chloride (30 ml) at room temperature under nitrogen was added methyl isocyanate (1.2 ml). After two hours, the reaction mixture was evaporated and triturated with cold pentane to give N-benzyloxy-N-decyl-N'-methylurea as a white solid (4.98 g, 83% yield). This urea (745 mg) was dissolved in ethanol (10 ml) under nitrogen at room temperature, and ammonium formate (0.8 g) was added. After 20 minutes, 10% palladium on carbon (0.25 g) was added. After stirring for two hours, the reaction mixture was filtered through celite and evaporated. Water was added, and the resulting solid was collected by filtration. Recrystallization from isopropanol gave the title compound as a white solid (420 mg, mp 96°-97° C.).
Reaction SMILES: N[C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12.N(OCCC(C)C)=O.C(=O)(O)[O-].[Na+].[I:39]CI>ClCCl>[I:39][C:2]1[N:7]=[C:6]2[N:8]([CH2:20][CH3:21])[C:9]([C:11]([N:13]([CH:17]3[CH2:19][CH2:18]3)[CH:14]3[CH2:16][CH2:15]3)=[O:12])=[CH:10][C:5]2=[C:4]2[N:22]([CH3:25])[CH:23]=[N:24][C:3]=12
Reactant: ICI
Reactant: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(N)nc21
Agent: CC(C)CCON=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCn1c(C(=O)N(C2CC2)C2CC2)cc2c3c(ncn3C)c(I)nc21
Temperature: 60 °C
Reaction time: 16 h

Procedure:
To a stirred suspension of 4-amino-N,N-dicyclopropyl-6-ethyl-1-methyl-1,6-dihydroimidazo[4,5-d]pyrrolo[2,3-b]pyridine-7-carboxamide (34.4 mg, 0.102 mmol) in diiodomethane (102 μL) at 60° C. was slowly added isoamyl nitrite (27.4 μL, 0.203 mmol). The reaction mixture was stirred at 60° C. 5 h. After cooling to rt, the reaction mixture was diluted with dichloromethane. Saturated aqueous sodium bicarbonate was added and the aqueous layer was extracted with dichloromethane (3×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude residue was placed on the pump for 16 h to remove any additional diiodomethane. LCMS was deemed pure enough to be carried forward crude. The product was used immediately in the next reaction.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9].[CH2:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[O:23][CH3:24])[CH3:16]>C(Cl)Cl>[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([C:21]1[CH:20]=[CH:19][C:18]([O:23][CH3:24])=[C:17]([CH2:15][CH3:16])[CH:22]=1)=[O:9]
Reactant: CCc1ccccc1OC
Reactant: O=C(Cl)c1ccccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1cc(C(=O)c2ccccc2Cl)ccc1OC
Reaction time: 4 h
Yield: 94.2 %

Procedure:
At ambient temperature, to a stirred solution containing aluminum chloride (20 g, 0.150 mol), 2-chlorobenzoylchloride (19 mL, 0.150 mol) in CH2Cl2 (100 mL) was added dropwise 2-ethylanisole (20.4 g, 0.150 mol). After 4 h, the reaction was diluted with CH2Cl2 (400 mL) washed with aq. KH2PO4 (2×200 mL), brine (1×200 mL), filtered though Celite and concentrated to give 38.82 g (94%) of the title compound. 1H NMR: consistent.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[CH:15][CH:14]=3)[C:9](=[O:25])[C:8]=2[C:7]([O:26][CH2:27][CH3:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2].C(=O)([O-])[O-].[K+].[K+].C(O)C>O>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:14]=[CH:15][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[CH:17][CH:18]=3)[C:9](=[O:25])[C:8]=2[C:7]([O:26][CH2:27][CH3:28])=[C:6]2[CH:29]=[CH:30][CH:31]=[CH:32][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)cc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.2 %

Procedure:
Ethyl [4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetate (5.86 g, 13.5 mmol) and potassium carbonate (12 g) were added to a mixture of ethanol (146 ml) and water (70 ml) and heated to reflux for 2 h. The solution was cooled to room temperature and the solvent evaporated under vacuum to leave an off-white solid. The solid was slurried in water and the water was evaporated under vacuum. The residue was stirred in hydrochloric acid (2N) for 2 h, filtered and washed with water. Drying of the solid at 40° C. in a vacuum oven gave [4-(4,9-diethoxy-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl)phenyl]acetic acid as a white solid (4.5 g, 82%)
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[C:10]([O:11][CH3:12])=[C:9]([F:13])[C:8]([F:14])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: COc1c(F)c(F)cc(C(=O)O)c1F
Reactant: O=S(Cl)Cl
Product: COc1c(F)c(F)cc(C(=O)Cl)c1F

Procedure:
A mixture of 2,4,5-trifluoro-3-methoxybenzoic acid (154 mg, 0.75 mmol) and thionyl chloride (8 mL) is refluxed for 4 h. Excess thionyl chloride is removed in vacuo, and the remaining residue is used directly in the next synthetic step.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[CH2:7][N:6](C(OC(C)(C)C)=O)[C@@H:5]([C:15]([O-:17])=[O:16])[CH2:4]1.[ClH:18]>O1CCCC1.C(#N)C>[ClH:18].[CH3:1][O:2][C@H:3]1[CH2:7][NH:6][C@@H:5]([C:15]([OH:17])=[O:16])[CH2:4]1
Reactant: CO[C@@H]1C[C@H](C(=O)[O-])N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CO[C@H]1CN[C@@H](C(=O)O)C1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
8.72 g 1-tert-butyl (2R,4R)-4-methoxy-pyrrolidine-1,2-dicarboxylate are dissolved in 60 ml of tetrahydrofuran, combined dropwise with 60 ml of a 6 M aqueous hydrochloric acid solution and stirred for 4 hours at ambient temperature. Then the solvents are eliminated in vacuo and the residue is taken up twice in 100 ml acetonitrile and the latter is in each case eliminated again in vacuo.
Reaction SMILES: C(O)(=O)C.[CH:5]([NH2:7])=[NH:6].[Na].[CH3:9][O:10][C:11]1[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH3:30])[C:12]=1[CH2:13][CH:14]([C:20](OCC)=[O:21])[C:15](OCC)=[O:16]>C(O)C>[CH3:30][O:29][C:25]1[CH:26]=[CH:27][CH:28]=[C:11]([O:10][CH3:9])[C:12]=1[CH2:13][C:14]1[C:15]([OH:16])=[N:6][CH:5]=[N:7][C:20]=1[OH:21]
Reactant: CCOC(=O)C(Cc1c(OC)cccc1OC)C(=O)OCC
Reactant: N=CN
Agent: [Na]
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cccc(OC)c1Cc1c(O)ncnc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 33.4 %

Procedure:
0.23 g of formamidine acetate in 15 ml of ethanol was added to 0.14 g of sodium in 15 ml of ethanol. The reaction mixture was stirred 25° C. for 30 minutes and treated dropwise with 0.62 g of diethyl (2,6-dimethoxybenzyl)malonate in 10 ml of ethanol. Starting material was no longer present after 2 days. The residue was removed by filtration under suction, dissolved in a small amount of water and acidified with 1N HCl. The precipitated crystals were removed by filtration under suction and dried at 90° C. in a high vacuum. There was obtained 0.175 g of 5-(2,6-dimethoxy-benzyl)-4,6-pyrimidinediol of melting point >245° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[CH:18])[CH:8]=[CH:9][C:10]=1[N:11]([CH2:14][CH3:15])[CH2:12][CH3:13])([CH3:4])([CH3:3])[CH3:2].I[C:21]1[CH:22]=[C:23]([OH:31])[C:24](=[CH:29][CH:30]=1)[C:25]([O:27][CH3:28])=[O:26]>[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([C:5]1[CH:6]=[C:7]([CH:16]([OH:19])[C:17]#[C:18][C:21]2[CH:30]=[CH:29][C:24]([C:25]([O:27][CH3:28])=[O:26])=[C:23]([OH:31])[CH:22]=2)[CH:8]=[CH:9][C:10]=1[N:11]([CH2:12][CH3:13])[CH2:14][CH3:15])([CH3:3])([CH3:2])[CH3:4]
Reactant: C#CC(O)c1ccc(N(CC)CC)c(C(C)(C)C)c1
Reactant: COC(=O)c1ccc(I)cc1O
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Product: CCN(CC)c1ccc(C(O)C#Cc2ccc(C(=O)OC)c(O)c2)cc1C(C)(C)C
Yield: 81.4 %

Procedure:
In a manner analogous to example 1 e, the process is carried out by a reaction of 3.7 g (15 mmol) of 1-(3-tert-butyl-4-diethylaminophenyl)prop-2-yn-1-ol with 3.3 g (12 mmol) of methyl 4-iodosalicylate, 114 mg (0.6 mmol) of copper iodide and 210 mg (0.3 mmol) of bis(triphenylphosphine)palladium chloride. 4 g of methyl 4-[3-(3-tert-butyl-4-diethylaminophenyl)-3-hydroxyprop-1-ynyl]-2-hydroxybenzoate are obtained in the form of yellow oil (yield=66%).