Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([OH:17])=[O:16])=[CH:10][CH:9]=2)=[O:5].Cl.[CH3:19][CH2:20]O>>[CH2:2]([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([O:17][CH2:19][CH3:20])=[O:16])=[CH:10][CH:9]=2)=[O:5])[CH3:1]
Reactant: CCOC(=O)c1cc2cc(C(=O)O)ccc2[nH]1
Reactant: CCO
Agent: Cl
Product: CCOC(=O)c1ccc2[nH]c(C(=O)OCC)cc2c1
Temperature: 55 °C
Reaction time: 24 h
Yield: 99 %

Procedure:
A suspension of 1H-Indole-2,5-dicarboxylic acid 2-ethyl ester (20.0 g, 85.75 mmole) in a saturated HCl/EtOH (200 ml) was stirred at 55° C. for 24 h and evaporated in vacuo to dryness. The residue was freeze-dried from dioxane to give 22.18 g (99%) of 1H-indole-2,5-dicarboxylic acid diethyl ester, 16 as white powder. MS: 262.12 (M+H). 1H-NMR (DMSO-d6): δ 12.23 (s, 1H, H-1, indole); 8.34 (m, 1H, H-4, indole); 7.83 (m, 1H, H-6, indole); 7.49 (m, 1H, H-7, indole); 7.30 (s, 1H, H-3, indole); 4.31 (m, 4H, —OCH2CH3); 1.32 (m, 4H, —OCH2CH3).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([C:11]1[CH:12]=[CH:13][C:14]([O:20][CH3:21])=[C:15](B(O)O)[CH:16]=1)=[O:10]>>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][C:14]=2[O:20][CH3:21])[CH:9]=[O:10])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: COc1ccc(C=O)cc1B(O)O
Product: COc1ccc(C=O)cc1-c1ccnc(Cl)n1
Yield: 70 %

Procedure:
2,4 dichloropyrimidine and 5-formyl-2-methoxyphenylboronic acid was coupled following procedure A. The yield was 70%. LC-MS showed the product was >95% pure and had the expected M+H+ of 249. 1H NMR (Varian 300 MHz, MeOD-d6, shifts relative to the solvent peak at 3.33 ppm) δ 9.9 (s, 1H) 8.7 (d, 1H) 8.4 (s, 1H) 8.0 (d, 2H) 7.4 (d, 1H) 3.9 (s, 3H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[O:19].[C:20]1([C:30](Cl)=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:30]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[O:19])=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)c1cccc2ccccc12

Procedure:
The procedure of Example 134 was carried out using 3(RS)-amino-1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one (39.2 mg, 0.156 mmole) in place of 1,3-dihydro-3(RS)-amino-5-(2-fluorophenyl)-2H-1,4-benzodiazepin-2-one and 1-naphthoyl chloride (29.7 mg, 0.156 mmole) in place of p-trifluoromethylbenzoyl chloride. The product was chromatographed on silica gel (15% (v/v) Et2O in CH2Cl2 elution). The combined product fractions were evaporated to dryness in vacuo and crystallized from Et2O to give the title compound which was dried in vacuo at 65° C.: (m.p. 162°-167° C.).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.[CH3:29][O:30][C:31](=[O:49])[C@H:32]([CH2:41][C:42]1[CH:47]=[CH:46][C:45]([OH:48])=[CH:44][CH:43]=1)[NH:33][C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35]>O>[CH3:29][O:30][C:31](=[O:49])[C@@H:32]([NH:33][C:34]([O:36][C:37]([CH3:39])([CH3:38])[CH3:40])=[O:35])[CH2:41][C:42]1[CH:47]=[CH:46][C:45]([O:48][CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([O:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:7][CH:6]=2)=[CH:44][CH:43]=1
Reactant: COC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)OC(C)(C)C
Reactant: BrCCOc1ccc(Oc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)[C@H](Cc1ccc(OCCOc2ccc(Oc3ccccc3)cc2)cc1)NC(=O)OC(C)(C)C
Yield: 64.6 %

Procedure:
To a solution of 1-(2-Bromo-ethoxy)-4-phenoxy-benzene (2.5 g, 8.53 mmol), potassium carbonate (3.21 g, 23.3 mmol), and N,N-Dimethylformamide (150 mL) was added Boc-L-Tyrosine methyl ester (2.3 g, 7.75 mmol). The mixture was poured into 200 mL water solution and extracted with ethyl acetate (EtOAc) (3×100 mL). The combined organic layers were washed with brine (40 mL) and dried over anhydrous Na2SO4. The organic layer was concentrated in vacuo to obtain the crude mixture, which was purified by of silica gel flash chromatography, using EtOAc/hexane (gradient system), to obtain the product (2.54 g, 59%): 1H NMR (400 MHz, CDCL3).
Reaction SMILES: [C:1]([C:3]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([OH:20])[CH:18]=2)[N:13](C(OC(C)(C)C)=O)[CH:12]=1)=[CH:4][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)#[N:2].[CH:28](I)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+].C[O-].[Na+]>CS(C)=O.CCCCCCC.C(OCC)C>[CH:28]([O:20][C:17]1[CH:18]=[C:19]2[C:14](=[CH:15][CH:16]=1)[NH:13][CH:12]=[C:11]2/[C:3](=[CH:4]/[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)/[C:1]#[N:2])([CH3:30])[CH3:29]
Reactant: CC(C)(C)OC(=O)n1cc(C(C#N)=Cc2cccnc2)c2cc(O)ccc21
Reactant: CC(C)I
Agent: C[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCCC
Solvent: CS(C)=O
Solvent: CCOCC
Product: CC(C)Oc1ccc2[nH]cc(/C(C#N)=C/c3cccnc3)c2c1
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 3-(1-cyano-2-(pyridin-3-yl)vinyl)-5-hydroxy-1H-indole-1-carboxylate (see example 22) (110 mg, 0.30 mmol, 1.0 eq.) and isopropyl iodide (40 μL, 0.40 mmol, 1.3 eq.) in DMSO (8 mL) was added potassium carbonate (100 mg, 0.73 mmol, 2.4 eq.). The reaction apparatus was protected from light and the mixture was stirred at room temperature for 24 hours before sodium methanolate (41 mg, 0.75 mmol, 2.5 eq.) was added. The reaction was pursued at room temperature for 1 hour, and then quenched with a saturated aqueous ammonium chloride solution. The mixture was extracted with ethyl acetate and the organic layer was washed with brine, and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel flash-column chromatography (eluent: heptane/EtOAc, 60:40 to 40:60) to afford, after trituration with diethyl ether, the compound (23) as a yellow powder (50 mg, 55%). TLC: Rf=0.25 (heptane 40/EtOAc 60); mp: 211° C.; IR νmax (cm-1): 2218 (νCN); 1H NMR (DMSO, 300 MHz): δ (ppm): 1.29 (6H, d, J9′-8′=J9′-8′=6.1 Hz, 3H9′ and 3H10′), 4.65 (1H, h, J8′-9′=J8′-9′=6.1 Hz, H8′), 6.90 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.39 (1H, d, J7′-6′=8.9 Hz, H7′), 7.51 (1H, d, J4′-6′=2.1 Hz, H4′), 7.54 (1H, dd, J5″-4″=7.9 Hz, J5″-6″=4.9 Hz, H5″), 7.73 (1H, s, H3), 7.79 (1H, s, H2′), 8.32 (1H, d, J4″-5″=7.9 Hz, H4″), 8.59 (1H, dd, J6″-5″=4.9 Hz, J6″-4″=1.2 Hz, H6″), 8.98 (1H, d, J2″-4″=1.6 Hz, H2″), 11.64 (1H, s, indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 22.5 (C9′ and C10′), 70.7 (C8′), 105.9 (C4′), 108.7 (C2), 110.6 (C3′), 113.6 (C6′), 114.6 (C7′), 118.6 (C1), 124.1 (C5″), 124.6 (C3a′), 128.1 (C2′), 131.4 (C3″), 132.7 (C3), 132.9 (C7a′), 135.1 (C4″), 150.0 (C6″), 150.4 (C2″), 152.9 (C5′); ESI-MS: m/z 304.1 ([M+H]+), 326.1 ([M+Na]+); HRESI-MS: m/z 304.1448 (calcd for C19H18N3O, 304.1450).
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([NH:14]C(=O)OCC3C=CC=CC=3)=[C:10]([O:25][CH:26]([CH3:28])[CH3:27])[CH:9]=2)[CH2:6][CH2:5][N:4]([CH3:29])[CH2:3]1>CO>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([CH3:29])[CH2:3][CH:2]2[OH:1])=[CH:9][C:10]=1[O:25][CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)Oc1cc(C2CCN(C)CC2O)ccc1NC(=O)OCc1ccccc1
Solvent: CO
Product: CC(C)Oc1cc(C2CCN(C)CC2O)ccc1N
Yield: 106.9 %

Procedure:
179 mg of benzyl [4-(3-hydroxy-1-methylpiperidin-4-yl)-2-(propan-2-yloxy)phenyl]carbamate (mixture of the trans diastereoisomers) are dissolved in 45 ml of methanol. The solution is filtered on 0.45 μm Acrodisc and then hydrogenated in an H-cube (Pd/C 10% cartridge and P H2=1 atm). The reaction medium is evaporated to dryness under reduced pressure, so as to give 127 mg of 4-[4-amino-3-(propan-2-yloxy)phenyl]-1-methylpiperidin-3-ol in the form of a brown gum (mixture of the trans diastereoisomers).
Reaction SMILES: C(N(C(C)C)CC)(C)C.Cl[N:11]1[CH2:20][CH:19]=[CH:18][C:17]2[N:16]=[CH:15][C:14]([N+:21]([O-:23])=[O:22])=[CH:13][C:12]1=2.[NH2:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31]>ClCCl.NCCNC(=O)OC(C)(C)C>[N+:21]([C:14]1[CH:15]=[N:16][C:17]2[C:12]([C:13]=1[NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:34])[O:29][C:30]([CH3:32])([CH3:31])[CH3:33])=[N:11][CH:20]=[CH:19][CH:18]=2)([O-:23])=[O:22]
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O=[N+]([O-])c1cnc2c(c1)N(Cl)CC=C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCNc1c([N+](=O)[O-])cnc2cccnc12
Temperature: 25 °C
Yield: 86.5 %

Procedure:
A solution of diisopropylethylamine (13.47 g, 0.10 mole) in dichloromethane (25 mL) was added to a solution of 5-chloro-3-nitro[1,5]naphthyridine (18.2 g, 0.086 mol) in dichloromethane (250 mL). A solution of tert-butyl N-(2-aminoethyl)carbamate (16.7 g, 0.10 mol) in dichloromethane (75 mL) was slowly added to the reaction mixture. The reaction mixture was heated at reflux overnight. Additional tert-butyl N-(2-aminoethyl)carbamate (1 g) was added and the reaction mixture was heated at reflux for an additional 3 hours. The reaction mixture was allowed to cool to ambient temperature and then it was diluted with additional dichloromethane, washed with water and with brine, dried, and then concentrated under vacuum to provide a dark solid. This solid was purified by flash chromatography (silica gel eluting with dichloromethane) to provide 24.8 g of 1,1-dimethylethyl N-{2-[(3-nitro[1,5]naphthyridin-4-yl)amino]ethyl}carbamate as a canary yellow solid. A portion (0.3 g) was recrystallized from toluene (10 mL) and heptane (10 mL) to provide 0.2 g of canary yellow needles, m.p. 149-151° C. Analysis: Calculated for C15H19N5O4: %C, 54.05; %H, 5.75; %N, 21.01; Found: %C, 54.17; %H, 5.73; %N, 20.90.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:3]1.C1C(=O)N([Br:18])C(=O)C1>O1CCCC1>[Br:18][C:6]1[N:2]([CH3:1])[CH:3]=[C:4]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=1
Reactant: COC(=O)c1ccn(C)c1
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COC(=O)c1cc(Br)n(C)c1
Yield: 79 %

Procedure:
A solution of methyl 1-methyl-1H-pyrrole-3-carboxylate (690 mg, 4.96 mmol) and NBS (883 mg, 4.96 mmol) in tetrahydrofuran (24.800 ml) was stirred at 25° C. for 1 h. The solution was then partitioned between H2O-DCM and the aqueous phase was washed several times with DCM. The combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (10-50% EtOAc in hexanes) affording methyl 5-bromo-1-methyl-1H-pyrrole-3-carboxylate (950 mg, 3.92 mmol, 79% yield) as an orange solid: LCMS (ES) m/e 218, 220 (M, M+2)+.
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])=[CH:13][CH:12]=1)(C)(C)C.[ClH:27].C(OCC)(=O)C>>[ClH:27].[NH2:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Product: N[C@@H]1C[C@H]1c1ccc(NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
tert-Butyl(trans-2-{4-[(phenylcarbonyl)amino]phenyl}cyclopropyl)carbamate (212 mg) was dissolved in 4N hydrochloric acid/ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 2 hr and the solvent was evaporated under reduced pressure to give the title compound (148 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[C:9]2[C:10]([CH3:27])=[N:11][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=1>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:29][C:30]2[CH:31]=[C:32]([CH3:38])[C:33](=[O:37])[N:34]([CH3:36])[CH:35]=2)[C:9]2[C:10]([CH3:27])=[N:11][N:12]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([O:25][CH3:26])[N:20]=3)[C:13]=2[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:4][CH:3]=1
Reactant: Cc1cc(N)cn(C)c1=O
Reactant: CCOC(=O)c1c(C(O)c2ccc(Cl)cc2)c(C)nn1-c1ccnc(OC)n1
Solvent: CO
Solvent: ClCCl
Product: CCOC(=O)c1c(C(Nc2cc(C)c(=O)n(C)c2)c2ccc(Cl)cc2)c(C)nn1-c1ccnc(OC)n1

Procedure:
The title compound was prepared in analogy to the procedure described in Step 10.3 using ethyl 4-((4-chlorophenyl)(hydroxy)methyl)-1-(2-methoxypyrimidin-4-yl)-3-methyl-1H-pyrazole-5-carboxylate (Step 59.4) and 5-amino-1,3-dimethylpyridin-2(1H)-one (Step 20.2). tR: 4.90 min (HPLC 1); tR: 1.15 min (LC-MS 2); ESI-MS: 523 [M+H]+ (LC-MS 2); Rf=0.47 (CH2Cl2/MeOH 9:1).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]2.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([SH:30])=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:25]=[CH:26][C:27]([S:30][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]3[CH:8]=[C:9]4[C:14](=[CH:15][CH:16]=3)[NH:13][C:12](=[O:17])[CH:11]=[CH:10]4)=[CH:28][CH:29]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=c1ccc2cc(OCCCCBr)ccc2[nH]1
Reactant: Sc1ccc(C2CCCCC2)cc1
Product: O=c1ccc2cc(OCCCCSc3ccc(C4CCCCC4)cc3)ccc2[nH]1

Procedure:
Prepared analogous to Example 122 from 6-(4-bromobutoxy)-carbostyril (m.p. 188°-189° C.) and 4-cyclohexylthiophenol.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[N:7]=[C:8]([NH2:11])[S:9][CH:10]=1)C.[NH4+:13].[OH-]>>[NH2:11][C:8]1[S:9][CH:10]=[C:6]([CH2:5][C:4]([NH2:13])=[O:3])[N:7]=1
Reactant: [NH4+]
Reactant: CCOC(=O)Cc1csc(N)n1
Agent: [OH-]
Product: NC(=O)Cc1csc(N)n1
Temperature: 50 °C
Yield: 47.4 %

Procedure:
A 18 ml vial was loaded with (2-Amino-thiazol-4-yl)-acetic acid ethyl ester (500 mg, 2.68 mmole) and 5 ml of 30% NH4OH. The vial was sealed and the mixture was heated at 50° C. for 3 days. The mixture was cooled down and concentrated to half. The suspension was filtered off, solid was washed with water and dried to give 200 mg product, 47.4% yield
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[C:12]([NH:15][C:16]4[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][N:17]=4)[N:13]=[CH:14][C:9]=3[CH:8]=[C:7]2[C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:30]([O:34][C:35]([N:37]1[CH:43]2[CH2:44][CH2:45][CH:38]1[CH2:39][NH:40][CH2:41][CH2:42]2)=[O:36])([CH3:33])([CH3:32])[CH3:31]>>[C:30]([O:34][C:35]([N:37]1[CH:43]2[CH2:44][CH2:45][CH:38]1[CH2:39][N:40]([C:20]([C:19]1[CH:18]=[N:17][C:16]([NH:15][C:12]3[N:13]=[CH:14][C:9]4[CH:8]=[C:7]([C:25](=[O:29])[N:26]([CH3:28])[CH3:27])[N:6]([CH:1]5[CH2:5][CH2:4][CH2:3][CH2:2]5)[C:10]=4[N:11]=3)=[CH:24][CH:23]=1)=[O:21])[CH2:41][CH2:42]2)=[O:36])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)N1C2CCNCC1CC2
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)O)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(C(=O)N4CCC5CCC(C4)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 85.4 %

Procedure:
Following general amide formation method 3, 6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)nicotinic acid (0.2 g, 0.507 mmol) was combined with 3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.136 g, 0.6 mmol) which gave 3-[6-(7-Cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridine-3-carbonyl]-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.269 g, 0.433 mmol) in 85% yield. MS m/z 602.7 (M+H)+.
Reaction SMILES: C([O:8][CH2:9][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:31][CH3:32])[CH:16]=2)[N:11]=1)C1C=CC=CC=1.[H][H]>[Pd].C(OCC)(=O)C.C(O)C>[OH:8][CH2:9][C:10]1[N:19]=[C:18]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([O:31][CH3:32])[CH:16]=2)[N:11]=1
Reactant: [H][H]
Reactant: COc1ccc2nc(COCc3ccccc3)nc(NCc3ccc4c(c3)OCO4)c2c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccc2nc(CO)nc(NCc3ccc4c(c3)OCO4)c2c1
Yield: 89.5 %

Procedure:
1.5 g of 10% palladium/carbon powder was added to a solution of 1.26 g (2.93 mmol) of 2-benzyloxymethyl-4-(3,4-methylenedioxybenzyl)amino-6-methoxyquinazoline in an ethyl acetate/ethanol (20 ml-20 ml) mixture. The obtained mixture was stirred at room temperature in a stream of hydrogen for 24 hours and filtered through Celite. The filter cake was washed with hot ethyl acetate/ethanol. The filtrate and the washings were distilled under a reduced pressure to remove the solvent. Thus 0.89 g of the title compound was obtained as a pale-yellow crystal.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)=[CH:4][CH:3]=[N:2]1.Br[CH2:19][C@H:20]([N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])[CH3:21].CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>[Cu]I.CNCCNC.O>[O:32]=[C:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:30](=[O:31])[N:22]1[C@H:20]([CH3:21])[CH2:19][N:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=2)=[N:1]1
Reactant: C[C@H](CBr)N1C(=O)c2ccccc2C1=O
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1C(F)(F)F
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@H](Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1)N1C(=O)c2ccccc2C1=O
Temperature: 160 °C
Yield: 11.1 %

Procedure:
4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)benzonitrile (1.0 g, 4.22 mmol) and (R)-2-(1-bromopropan-2-yl)isoindoline-1,3-dione (1.35 g, 5.06 mmol) were weighed into a microreaction vial and DMF (10 ml) was added. Then, potassium carbonate (1.165 g, 8.43 mmol), copper(I) iodide (0.040 g, 0.21 mmol) and N,N′-dimethyl-ethylenediamine (0.004 ml, 0.042 mmol) were added and the reaction vial was capped under nitrogen and was heated in the microwave oven (Biotage) at 160° C. for 30 min. The mixture was then poured into water and extracted with DCM and 2% MeOH/DCM. Organic layers were combined, dried with Na2SO4, filtered and evaporated to dryness. CombiFlash purifications using normal and reversed phase columns afforded 0.199 g of the title compound. 1H-NMR (400 MHz; d6-DMSO): δ 1.54 (m, 3H), 4.55-4.65 (m, 3H), 6.95 (d, 1H), 7.77 (m, 4H), 7.82 (m, 1H), 7.86-7.89 (m, 2H), 8.01 (d, 1H).
Reaction SMILES: C1(C2NC=CN=2)CC1.II.[OH-].[Na+].[I:13][C:14]1[N:15]=[C:16]([CH:20]2[CH2:22][CH2:21]2)[NH:17][C:18]=1I.S([O-])([O-])=O.[Na+].[Na+]>>[CH:20]1([C:16]2[NH:15][C:14]([I:13])=[CH:18][N:17]=2)[CH2:22][CH2:21]1
Reactant: Ic1nc(C2CC2)[nH]c1I
Agent: II
Agent: O=S([O-])[O-]
Agent: [Na+]
Product: Ic1cnc(C2CC2)[nH]1

Procedure:
The title compound was prepared in accordance with the literature reference of Cliff & Pyne, Synthesis-Stuttgart (7), 681–682(1994) by reacting 2-cyclopropyl-1H-imidazole with iodine in the presence of NaOH. The obtained 4,5-diiodo-2-cyclopropyl-1H-imidazole was then reacted with sodium sulfite to obtain the title compound.
Reaction SMILES: [NH2-].[Li+].N.[Li].Br[CH2:6][CH2:7][CH2:8][CH2:9][OH:10].[CH2:11]([C:19]1[CH:27]=[CH:26][C:22]([CH2:23][C:24]#[CH:25])=[CH:21][CH:20]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>>[CH2:11]([C:19]1[CH:20]=[CH:21][C:22]([CH2:23][C:24]#[C:25][CH2:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:26][CH:27]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: C#CCc1ccc(CCCCCCCC)cc1
Reactant: OCCCCBr
Agent: N
Agent: [Li+]
Agent: [Li]
Product: CCCCCCCCc1ccc(CC#CCCCCO)cc1

Procedure:
A solution of lithium amide in liquid ammonia is prepared by the addition of lithium metal (2 mmoles) to liquid ammonia containing a trace amount of ferrous sulfate. To this solution is added 4-bromo-n-butanol (1 mmole) and p-(n-octyl)benzylacetylene (1 mmole, prepared as described in paragraph B of Example 6 or in paragraph A of this example). After a suitable time at refluxing liquid ammonia temperatures, the ammonia is removed by evaporation and the residue dissolved in water. After extraction with chloroform, the chloroform layer is separated and the solvent removed by evaporation to give a residue. This residue is purified by distillation under vacuum to give 7-[p-(n-octyl)phenyl]-5-heptyn-1-ol.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[N:12]([CH2:13][C:14]#[CH:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[C:10]([C:20](OCC)=[O:21])[O:9]1.[Na].[K]>C(OCC)C>[OH:21][CH2:20][C:10]1[O:9][C:8](=[O:7])[N:12]([CH2:13][C:14]#[CH:15])[C:11]=1[C:16]([F:18])([F:19])[F:17]
Reactant: C#CCn1c(C(F)(F)F)c(C(=O)OCC)oc1=O
Agent: [Al+3]
Agent: [H-]
Agent: [K]
Solvent: CCOCC
Product: C#CCn1c(C(F)(F)F)c(CO)oc1=O
Reaction time: 16 h
Yield: 31.7 %

Procedure:
520 mg of lithium aluminium hydride were introduced at -30° C. to a solution of 3.6 g of the product of Step A in 7.5 ml of ethyl ether and the mixture was poured into a solution of sodium and potassium double tartrate. The mixture was stirred for 16 hours and after decanting and extracting with ethyl acetate, the extracts were dried, filtered and concentrated. The residue was chromatographed on silica and eluted with a hexane-ethyl acetate mixture (7-3) to obtain 0.96 g of the expected product melting at 64° C.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1>CN(C=O)C>[Cl:1][C:2]1[N:6]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: IC1CCCC1
Reactant: Clc1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Clc1nc2ccccc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 58.9 %

Procedure:
To a solution of 2-chloro-1H-benzo[d]imidazole (152 mg, 1.0 mmol.) in DMF was added K2CO3 (277 mg, 2.0 mmol.) and iodocyclopentane (295 mg, 1.5 mmol.). The reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was poured into ice-water. The mixture was extracted with ethyl acetate (30 mL×3), washed with brine, dried over Na2SO4, concentrated to give a residue, which was purified by column chromatography to afford 2-chloro-1-cyclopentyl-1H-benzo[d]imidazole (130 mg, 59%). 1H NMR (400 MHz, CDCl3) δ 7.68˜7.60 (m, 1 H), 7.39˜7.30 (m, 1 H), 7.20˜7.15 (m, 2 H), 5.04˜4.90 (m, 1 H), 2.25˜1.92 (m, 6 H), 1.85˜1.70 (m, 2 H).
Reaction SMILES: [BH4-].[Na+].Cl.[CH3:4][N:5]([CH3:15])[CH2:6][CH2:7][C:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)=[O:9].Cl>[OH-].[Na+]>[CH3:15][N:5]([CH3:4])[CH2:6][CH2:7][CH:8]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[OH:9]
Reactant: CN(C)CCC(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Product: CN(C)CCC(O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71.4 %

Procedure:
To a suspension of NaBH4 (310 mg, 0.30 equivalents) in aqueous NaOH (30% w/w) was added 3-dimethylamino-1-thiophen-2-yl-propan-1-one hydrochloride (5.95 gm, 27.2 mmol) in portions, over 30 minutes. The cloudy mixture was stirred at room temperature. After 1 h a second portion of NaBH4 (310 mg, 0.30 equivalents) was added. The reaction mixture was stirred at room temperature under nitrogen. After approximately 20 h, HPLC showed complete conversion, and the cloudy mixture was cooled to 0° C. The reaction mixture was carefully acidified with 37% HCl (aq.) to pH 1, while maintaining the temperature less than 10° C. The cloudy mixture gradually turned homogenous. The reaction mixture was washed with toluene (2×20 mL). The aqueous layer was cooled to 0° C., and carefully added 30% NaOH (aq.) to pH 12, while maintaining the temperature less than 20° C. There was formation of a white precipitate. The aqueous solution was extracted with warm toluene (45° C.; 3×80 mL). The toluene was removed under reduced pressure (bath temperature 45° C.). The white solid was taken up in ethylcyclohexane (20 mL) and heated to 70° C. until a clear homogenous mixture was obtained. The solution was stirred at 70° C. for 2 h. The solution was cooled to 0° C. After approximately 45 minutes at 0° C., the white solid was filtered and washed with ice-cold ethylcyclohexane (2×15 mL). The white solid was dried under vacuum at 40° C. for 18 h to give 3.6 gm (72%) of 2 as a racemic mixture.