Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7]=[CH:8][CH2:9][O:10][C:11]([C:13]2([C:44]([O:46][CH2:47][CH:48]=[CH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:45])[O:17][C:16]3[CH:18]=[CH:19][C:20]([CH2:22][C@H:23]([N:25]([CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=4)[OH:36])C(OCC(Cl)(Cl)Cl)=O)[CH3:24])=[CH:21][C:15]=3[O:14]2)=[O:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(Cl)(Cl)Cl.CO>[C:1]1([CH:7]=[CH:8][CH2:9][O:10][C:11]([C:13]2([C:44]([O:46][CH2:47][CH:48]=[CH:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:45])[O:17][C:16]3[CH:18]=[CH:19][C:20]([CH2:22][C@H:23]([NH:25][CH2:34][C@@H:35]([C:37]4[CH:42]=[CH:41][CH:40]=[C:39]([Cl:43])[CH:38]=4)[OH:36])[CH3:24])=[CH:21][C:15]=3[O:14]2)=[O:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC=Cc1ccccc1)(C(=O)OCC=Cc1ccccc1)O2)N(C[C@H](O)c1cccc(Cl)c1)C(=O)OCC(Cl)(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC=Cc1ccccc1)(C(=O)OCC=Cc1ccccc1)O2)NC[C@H](O)c1cccc(Cl)c1
Yield: 59 %

Procedure:
The fide compound was prepared as a colorless oil according to the procedure of Example 4, Step 6 except that 5-{(2R)-2-[[(2R)2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid bis-(3-phenyl-allyl) ester was used in place of 5-{(2R)-2-[[(2R)-2-(3-chloro-phenyl)-2-hydroxy-ethyl]-(2,2,2-trichloro-ethoxycarbonyl)-amino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid diallyl ester; yield 59%; Rf =0.35 (10/1 CHCl3 /MeOH); 1H NMR (300 MHz, CDCl3): δ 1.15 (d, J=6.3 Hz, 3H), 2.50-3.70 (brs, 2H), 2.60-2.71 (m, 1H), 2.80-2.92 (m, 2H), 2.95-3.15 (m, 2H), 4.83-4.95 (m, 5H), 5.25-5.40 (m, 4H), 6.08-6.30 (complex m, 2H), 6.66-6.91 (m, 5H), 7.15-7.40 (m, 14H); MS (ES) m/z (relative intensity): 654 (M+, 100).
Reaction SMILES: [O:1]1[CH2:28][CH:2]1[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27].[NH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:1][CH:2]([CH2:28][N:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([C:9]([O:15][C:16]3[CH:17]=[C:18]4[C:22](=[CH:23][CH:24]=3)[NH:21][C:20]([CH3:25])=[CH:19]4)=[N:10][CH:11]=[N:12]2)=[CH:7][C:6]=1[O:26][CH3:27]
Reactant: C1CCNCC1
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCC(O)CN1CCCCC1
Temperature: 70 °C
Yield: 64.1 %

Procedure:
A mixture of 7-(2,3-epoxypropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (100 mg, 0.27 mmol) and piperidine (79 μl, 0.8 mmol) in DMF (4 ml) was heated at 70° C. for 24 hours. The solvent was removed by evaporation and the residue was recrystallised from acetonitrile. The solid was filtered, washed with diethyl ether and dried to give 7-(2-hydroxy-3-piperidinopropoxy)-6-methoxy-4-(2-methylindol-5-yloxy)quinazoline (80 mg, 65%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C:9]1([CH3:22])[CH3:21])=O)(C)(C)C.Cl>CO>[CH2:14]([N:11]1[CH2:12][CH2:13][NH:8][C:9]([CH3:22])([CH3:21])[CH2:10]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccccc2)CC1(C)C
Agent: Cl
Solvent: CO
Product: CC1(C)CN(Cc2ccccc2)CCN1
Yield: 108.4 %

Procedure:
3.30 g of 4-benzyl-2,2-dimethyl-piperazine-1-carboxylic acid tert-butyl ester were dissolved in 50 ml methanol, and 25 ml of 1N aqueous hydrochloric acid were added. After stirring overnight 5 ml of concentrated aqueous hydrochloric acid were added. After 2 h the volatiles were removed in vacuo and 2.40 g (97%) of the title compound were obtained as hydrochloride salt, which could be use without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]2)=[N:4][N:3]=1.FC(F)(F)C(O)=O.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([N:12]2[CH2:17][CH2:16][NH:15][CH:14]([C:25]([O:27][CH3:28])=[O:26])[CH2:13]2)=[N:4][N:3]=1
Reactant: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1CN(c2nnc(Cl)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
1-tert-butyl 2-methyl 4-(4-chlorophthalazin-1-yl)piperazine-1,2-dicarboxylate (754 mg, 1.85 mmol) was partially dissolved in dichloromethane (20 mL). Trifluoroacetic acid (3.50 mL) was added and the reaction stirred at rt for 4 hours. Saturated sodium bicarbonate (50 mL) was added and stirred for 15 minutes. The layers were separated and the aqueous phase was extracted two more times with dichloromethane. The combined extracts were dried (MgSO4) and evaporated to give a foamy yellow solid. MS (M+H)+=307.1.
Reaction SMILES: N[C:2]1[CH:11]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:9]=[C:8]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:3]=1[C:4](OC)=[O:5].C(O)(=O)C.[CH:32]([NH2:34])=[NH:33]>COCCO>[CH2:21]([O:20][C:8]1[CH:9]=[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=[C:2]2[C:3]=1[C:4](=[O:5])[NH:33][CH:32]=[N:34]2)[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: N=CN
Reactant: COC(=O)c1c(N)cc(OCc2ccccc2)cc1OCc1ccccc1
Solvent: COCCO
Solvent: CC(=O)O
Product: O=c1[nH]cnc2cc(OCc3ccccc3)cc(OCc3ccccc3)c12
Yield: 89.5 %

Procedure:
A mixture of methyl 2-amino-4,6-dibenzyloxybenzoate (7.7 g), formamidine acetate (7.2 g) and 2-methoxyethanol (100 ml) was stirred and heated to reflux until all of the starting material had reacted. The mixture was evaporated and the residue was triturated under water (60 ml). The resultant solid was isolated, washed with water and dried under vacuum to give 5,7-dibenzyloxy-3,4-dihydroquinazolin-4-one (6.8 g); NMR Spectrum: (DMSOd6) 5.24 (s, 4H), 6.75 (s, 1H), 6.8 (s, 1H), 7.3–7.7 (m, 10H), 7.95 (s, 1H), 11.75 (br s, 1H).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].[Cl:6][C:7]1[CH:20]=[CH:19][C:10]([C:11]([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O.[OH-].[NH4+]>>[N+:1]([C:8]1[CH:9]=[C:10]([CH:19]=[CH:20][C:7]=1[Cl:6])[C:11]([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)=[O:12])([O-:4])=[O:2]
Reactant: O=C(c1ccc(Cl)cc1)c1cccnc1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=C(c1cccnc1)c1ccc(Cl)c([N+](=O)[O-])c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
15.5 g. (0.153 mol) of potassium nitrate was added portion-wise to a stirred solution of 33 g. (0.152 mol) of 3-(4-chlorobenzoyl)pyridine in 200 ml. of sulfuric acid while maintaining the temperature below 40° . After 1 hr. the mixture was cautiously poured into 2 liters of ice-water, neutralized with ammonium hydroxide and the product collected to yield 3-(3-nitro-4-chlorobenzoyl)pyridine as yellow prisms, mp. 112° -113° C. (carbon tetrachloride-Norite).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:37]=[CH:36][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C@@H:19]2[CH2:28][CH2:27][C:26]3[CH:25]=[C:24]([O:29]C(=O)C(C)(C)C)[CH:23]=[CH:22][C:21]=3[CH2:20]2)=[CH:7][CH:6]=1)(O)=O.Cl.[CH:39]12[NH:45][CH:42]([CH2:43][CH2:44]1)[CH2:41][CH2:40]2>>[CH:42]12[N:45]([CH2:1][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C@@H:19]4[CH2:28][CH2:27][C:26]5[CH:25]=[C:24]([OH:29])[CH:23]=[CH:22][C:21]=5[CH2:20]4)=[CH:36][CH:37]=3)[CH:39]([CH2:44][CH2:43]1)[CH2:40][CH2:41]2
Reactant: CC(C)(C)C(=O)Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CC(=O)O)cc1)C2
Reactant: C1CC2CCC1N2
Agent: Cl
Product: Oc1ccc2c(c1)CC[C@@H](c1ccccc1NCCCc1ccc(CCN3C4CCC3CC4)cc1)C2
Yield: 23 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]phenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (28 mg) and 7-azabicyclo[2.2.1]heptane hydrochloride (38 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (6.2 mg) was obtained.
Reaction SMILES: [ClH:1].CCOCC.C(OC([N:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:23]=[N:24][CH:25]=1)=O)(C)(C)C>CO>[ClH:1].[NH:14]1[CH2:17][CH2:16][C@H:15]1[CH2:18][O:19][C:20]1[CH:21]=[C:22]([C@H:26]2[CH2:28][C@@H:27]2[CH2:29][CH2:30][CH2:31][CH2:32][OH:33])[CH:23]=[N:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1COc1cncc([C@H]2C[C@@H]2CCCCO)c1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: OCCCC[C@H]1C[C@@H]1c1cncc(OC[C@@H]2CCN2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
2M anhydrous HCl/ether (2.0 mL) was added to a stirred solution of 4-[(1S,2S)-2-[5-[[1-(tert-butoxycarbonyl)-2(S)-azetidinyl]methoxy]-3-pyridyl]cyclopropyl]-1-butanol (200 mg, 0.53 mmol) in dry MeOH (2.0 mL) at 0° C. The mixture was stirred at room temperature for 12 h. The above solution was concentrated in vacuo and purified by HPLC to obtain 4-[(1S,2S)-2-[5-[(2(S)-azetidinyl)methoxy]-3-pyridyl]cyclopropyl]-1-butanol hydrochloride (128 mg). 1H NMR (CD3OD, 300 MHz) δ 8.25 (br s, 2H), 7.51 (s, 1H), 5.02-4.93 (m, 2H), 4.55-4.38 (m, 2H), 4.21-4.00 (m, 2H), 3.56 (t, 2H, J=6.2 Hz), 2.82-2.55 (m, 2H), 1.93-1.75 (m, 1H), 1.70-1.36 (m, 6H), 1.33-1.17 (m, 1H), 1.16-1.06 (m, 1H), 1.05-0.93 (m, 1H). MS (ESI) m/z 277 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][C:5]#[N:6].[Br:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:11]([N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])[CH3:14])=[O:12]>CN(C=O)C>[Br:7][C:8]1[CH:9]=[C:10]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:11]([N:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH2:2][CH2:3][CH2:4][C:5]#[N:6])[CH3:14])=[O:12]
Reactant: N#CCCCBr
Reactant: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1O
Solvent: CN(C)C=O
Product: CN(C(=O)c1ccc(Cl)c(Br)c1)c1ccccc1OCCCC#N
Temperature: 25 °C
Reaction time: 16 h
Yield: 92.7 %

Procedure:
CsCO3 (5.17 g, 15.87 mmol) was added to a solution of 4-bromo-butyronitrile (0.63 mL, 6.35 mmol) and 3-bromo-4-chloro-N-(2-hydroxy-phenyl)-N-methyl-benzamide (1.80 g, 5.29 mmol, Step 3B) in DMF (20 mL). The mixture was stirred at room temperature for approximately 16 hrs and was partitioned between ethyl acetate and water. The ethyl acetate layer was separated, washed with water and brine, and was dried over MgSO4. The organic filtrate was evaporated to yield 3-bromo-4-chloro-N-[2-(3-cyano-propoxy)-phenyl]-N-methyl-benzamide as a light yellow solid (2.0 g). MS [M+H]+: 408.9; tR=2.39 min. (method 1)
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:31][CH2:32][CH3:33])[C:24]=1[C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1)[C:19](O)=[O:20])[CH3:14].Cl.Cl.[O:36]=[C:37]1[C:51]2[C:46](=[CH:47][CH:48]=[C:49]([C:52]3[CH:53]=[C:54]([C:58]([OH:60])=[O:59])[CH:55]=[N:56][CH:57]=3)[CH:50]=2)[O:45][C:39]2([CH2:44][CH2:43][NH:42][CH2:41][CH2:40]2)[CH2:38]1.Cl>O.C(N(CC)CC)C.CN(C=O)C>[CH2:13]([O:15][C:16]1[CH:17]=[C:18]([C:19]([N:42]2[CH2:41][CH2:40][C:39]3([CH2:38][C:37](=[O:36])[C:51]4[C:46](=[CH:47][CH:48]=[C:49]([C:52]5[CH:53]=[C:54]([C:58]([OH:60])=[O:59])[CH:55]=[N:56][CH:57]=5)[CH:50]=4)[O:45]3)[CH2:44][CH2:43]2)=[O:20])[CH:22]=[C:23]([O:31][CH2:32][CH3:33])[C:24]=1[C:25]1[CH:26]=[N:27][N:28]([CH3:30])[CH:29]=1)[CH3:14]
Reactant: CCOc1cc(C(=O)O)cc(OCC)c1-c1cnn(C)c1
Reactant: O=C(O)c1cncc(-c2ccc3c(c2)C(=O)CC2(CCNCC2)O3)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: CCOc1cc(C(=O)N2CCC3(CC2)CC(=O)c2cc(-c4cncc(C(=O)O)c4)ccc2O3)cc(OCC)c1-c1cnn(C)c1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
Carbonyldiimidazole (130 mg) and triethylamine (0.446 mL) were added to a DMF solution (4 mL) of 3,5-diethoxy-4-(1-methyl-1H-pyrazol-4-yl)benzoic acid (232 mg), and stirred at 70° C. for 2 hours. To the reaction liquid, added was a DMF suspension (2 ml) of 5-(4-oxospiro[chroman-2,4′-piperidin]-6-yl)pyridine-3-carboxylic acid dihydrochloride (370 mg) and triethylamine (0.335 ml) that had been prepared separately, and further stirred at that temperature for 1 hour. 1 N hydrochloric acid and water were added to the reaction liquid, the resulting solid was taken out through filtration, and recrystallized from methanol to obtain the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].C([O:17][C:18](=O)[CH:19]=[C:20]([NH2:24])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:24][C:20]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=2)[C:18](=[O:17])[CH:19]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(CNN)cc1C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1C(F)(F)F
Reaction time: 8 h

Procedure:
34 g of 4-methyl-3-trifluoromethylbenzylhydrazine were added dropwise, under nitrogen, to a solution of 26.5 g of β-amino-β-ethoxyacrylic acid ethyl ester and a pinch of p-toluenesulphonic acid in 100 ml of ethanol. After stirring overnight, the compound identified above, which had precipitated, was filtered off and recrystallised from ethanol. Melting point: 103°, 20 g (44%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[C:10]([C:12]1[CH:13]=[C:14]([CH:16]=[CH:17][C:18]=1[OH:19])[NH2:15])#[N:11]>CO.O>[OH:19][C:18]1[CH:17]=[CH:16][C:14]([NH:15][C:2]2[N:7]=[C:6]([NH:15][C:14]3[CH:16]=[CH:17][C:18]([OH:19])=[C:12]([C:10]#[N:11])[CH:13]=3)[C:5]([F:9])=[CH:4][N:3]=2)=[CH:13][C:12]=1[C:10]#[N:11]
Reactant: N#Cc1cc(N)ccc1O
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CO
Solvent: O
Product: N#Cc1cc(Nc2ncc(F)c(Nc3ccc(O)c(C#N)c3)n2)ccc1O
Temperature: 70 °C

Procedure:
2,4-Dichloro-5-fluoropyrimidine (50 mg, 0.30 mmol) was dissolved in a mixture of MeOH (1 ml) and H2O (0.1 ml). 3-cyano-4-hydroxyaniline (241 mg, 1.8 mmol) was added and the mixture was refluxed for 2 days (70° C. oil-bath temperature). The mixture was cooled to 22° C., concentrated to dryness under reduced pressure and subjected to column chromatography on silica gel (CHCl3—Acetone, 9:1) to give N2,N4-bis(4-hydroxy-3-cyanophenyl)-5-fluoro-2,4-pyrimidinediamine. 1H NMR (CDCl3): δ 7.96 (d, 1H, J=3.5 Hz), 7.82 (d, 1H, J=3.0 Hz), 7.79 (d, 1H, J=3.0 Hz), 7.71 (dd, 1H, J=3.0, 8.8 Hz), 7.54 (dd, J=3.0, 8.8 Hz), 6.94 (d, 1H, J=8.8 Hz), 6.84 (d, 1H, J=8.8 Hz); LCMS: purity: 97.2%; MS (m/e): 362.98 (M+, 100).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH2:14])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1([O:37][C:38](=O)[NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)C=CC=CC=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@@H:11]([NH:14][C:38]([NH:39][C:40]2[CH:45]=[CH:44][CH:43]=[C:42]([C:46]3[N:50]([CH3:51])[N:49]=[N:48][N:47]=3)[CH:41]=2)=[O:37])[C@H:10]([C:15]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([CH2:23][C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:18]2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1nnnc1-c1cccc(NC(=O)Oc2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)[C@H](C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)C1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1nnnc1-c1cccc(NC(=O)N[C@@H]2CCN(C(=O)OC(C)(C)C)C[C@H]2C(=O)N2CCC[C@@H](Cc3ccc(F)cc3)C2)c1
Reaction time: 19 h
Yield: 74.8 %

Procedure:
In a dry flask (3R,4R)-4-amino-3-[(S)-3-(4-fluoro-benzyl)-piperidine-1-carbonyl]-piperidine-1-carboxylic acid t-butyl ester (350 mg, 0.834 mmol) was dissolved in dimethylformamide (5 mL) and [3-(1-methyl-1H-tetrazol-5-yl)-phenyl]-carbamic acid phenyl ester (285 mg, 0.965 mmol) was added. The reaction mixture was stirred for 19 hours. The reaction mixture was diluted with ethyl acetate and extracted three times with water. The combined aqueous extracts were extracted with ethyl acetate. The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The resulting oil was purified by flash column chromatography with 70-100% ethyl acetate/hexanes to give a solid (387 mg, 75%). A small amount was further purified by preparative reverse-phase HPLC (10-80% acetonitrile in water with 0.05% trifluoroacetic acid) to give a white amorphous solid (33 mg, 62%). 1H NMR (300 MHz, CDCl3), δ: 7.88 (m, 1H), 7.49 (m, 2H), 7.40 (m, 1H), 7.19 (m, 1H), 7.01 (m, 1H), 6.95 (m, 1H), 6.86 (m, 1H), 4.31 (m, 1H), 4.17 (s, 3H), 4.03 (m, 4H), 3.16 (m, 1H), 3.05 (m, 1H), 2.88 (m, 3H), 2.67 (m, 1H), 2.50 (m, 2H), 2.37 (m, 1H), 1.95 (m, 1H), 1.65 (m, 5H), 1.47 (s, 9H), 1.23 (m, 1H). HRMS (ESI), C32H42FN8O4 m+/z: calc.=621.3313, found=621.3337.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][C:7]1[N:8]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][CH:25]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([O:21]C)=[CH:11][CH:10]=2)[CH3:2].CC(S)(C)C.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[CH2:1]([O:3][C:4](=[O:33])[C:5]([CH3:32])([CH3:31])[CH2:6][C:7]1[N:8]([CH2:23][C:24]2[CH:25]=[CH:26][C:27]([Br:30])=[CH:28][CH:29]=2)[C:9]2[C:14]([C:15]=1[S:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:13][C:12]([OH:21])=[CH:11][CH:10]=2)[CH3:2]
Reactant: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OC)ccc2n1Cc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: CC(C)(C)S
Product: CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(O)ccc2n1Cc1ccc(Br)cc1
Temperature: -2.5 °C
Reaction time: 2 h

Procedure:
To a reaction vessel containing dichloromethane (3.3-fold, V/W of starting material) was added 3-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester (1.0 eq) under nitrogen. 2-Methyl-2-propanethiol (7.80 eq) was added to the mixture, and the reaction was cooled to a temperature of −5-0° C. While maintaining the reaction mixture at less than 0° C., aluminum chloride (3.30 eq) was added portion-wise, and the reaction was stirred at 0-5° C. for 2 hours. Once no starting material was seen by tlc analysis (5% ethyl acetate/hexanes), the reaction was warmed to room temperature and quenched with ice-water (6.5-fold, V/W of starting material). The mixture was acidified to pH 2 with aqueous 2.0M hydrochloric acid, and the organic layer was separated. The aqueous layer was extracted with dichlormethane to recover remaining product, and the combined organic layers were washed successively with aqueous 1.0M hydrochloric acid, water, and brine, and concentrated in vacuo. Ethyl acetate (1.0-fold, V/W of starting material) was added to the crude material, and the mixture was heated until all the product was in solution. The flask was gradually cooled to 0-2° C., and hexane (11.0-fold, V/W of starting material) was slowly added. The mixture was agitated for 2 hours, and the precipitate was isolated by filtration and dried under vacuum to give the desired product.
Reaction SMILES: [Zn](C)C.[CH3:4][O:5][C:6](=[O:15])[C:7]1[C:12](Br)=[CH:11][CH:10]=[N:9][C:8]=1[Cl:14].[CH3:16]O>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:4][O:5][C:6](=[O:15])[C:7]1[C:12]([CH3:16])=[CH:11][CH:10]=[N:9][C:8]=1[Cl:14]
Reactant: CO
Reactant: COC(=O)c1c(Br)ccnc1Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: C1COCCO1
Product: COC(=O)c1c(C)ccnc1Cl
Temperature: 70 °C
Reaction time: 8 h

Procedure:
ZnMe2 (2.0 M in toluene, 15.5 mL, 25 mmol) was added to a stirred mixture of 4-bromo-2-chloro-nicotinic acid methyl ester (9.6 g, 38 mmol) and Pd(dppf)Cl2 (0.50 g, 0.61 mmol) in anhydrous dioxane (180 mL). After stirring for 8 h at 70° C., the reaction mixture was cooled to room temperature, MeOH (15 mL) was added and the solvent was removed in vacuo. The residue was partitioned between EA (300 mL) and water (50 mL). Concentrated aqueous HCl was then added until the emulsion became homogeneous. The organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (elution with hexane/EA 2:1) to give the title compound. MS (m/z): 186.0 [M+H+].
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:9])[NH:4][C:5](=[O:8])[NH:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH2:20][Cl:21].O>CS(C)=O>[Cl:21][CH2:20][CH2:19][CH2:18][CH2:17][N:6]1[CH:7]=[C:2]([CH3:1])[C:3](=[O:9])[NH:4][C:5]1=[O:8]
Reactant: ClCCCCBr
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn(CCCCCl)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 5-methyl-2,4(1H,3H)-pyrimidinedione (thimine, 500 mg, commercially available from Aldrich) and K2CO3 (546 mg) in dry DMSO (15 mL) was stirred for 1 hour at room temperature. 1-bromo-4-chlorobutane (0.46 mL) was then added and the mixture was stirred at room temperature for 20 hours. Water was then added and the resulting mixture was extracted with EtAcO. The aqueous phase was acidified to pH 7 with aqueous 2% HCl solution and extracted with DCM. The organic phases were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was purified by a silica SPE cartridge (25 g) eluting with toluene/acetone from 95/5 to 75/25 to give the title compound as a colourless oil (250 mg).
Reaction SMILES: [C:1]([N:3]1[C:11]2[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=2[C:5]2[CH2:13][N:14]([CH3:17])[CH2:15][CH2:16][C:4]1=2)#[CH:2].Br[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][N:20]=1>C(N(CC)CC)C.[Cu](I)I>[CH3:17][N:14]1[CH2:15][CH2:16][C:4]2[N:3]([C:1]#[C:2][C:19]3[CH:24]=[CH:23][N:22]=[CH:21][N:20]=3)[C:11]3[CH:10]=[CH:9][C:8]([CH3:12])=[CH:7][C:6]=3[C:5]=2[CH2:13]1
Reactant: C#Cn1c2c(c3cc(C)ccc31)CN(C)CC2
Reactant: Brc1ccncn1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1ccc2c(c1)c1c(n2C#Cc2ccncn2)CCN(C)C1
Temperature: 40 °C
Yield: 17.7 %

Procedure:
5-Ethynyl-2,8-dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (100 mg, 0.466 mmol) and 4-bromopyrimidine (126 mg, 0.797 mmol) were dissolved in triethylamine (1.5 mL), and the solution was purged with nitrogen. Dichlorobis (triphenylphosphine) palladium (12.5 mg, 0.017 mmol) and copper iodide (6.7 mg, 0.035 mmol) were added and the reaction mixture was purged again with nitrogen. The reaction mixture was heated by microwave at 40° C. for 90 min. The reaction mixture was quenched with 30 mL water and extracted with EtOAc (3×15 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain crude product. The crude product was purified with column chromatography (silica gel: 100-200 mesh, eluent 0-10% MeOH in DCM) to obtain 25 mg product. 1H NMR (CDCl3, freebase) δ (ppm): 9.17 (s, 1H), 8.76 (d, 1H), 7.57 (d, 1H), 7.40 (d, 1H), 7.18 (m, 2H), 3.64 (s, 2H), 3.06 (d, 2H), 2.98 (d, 2H), 2.61 (s, 3H), 2.43 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18](=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.[I-].[K+]>[O:20]=[C:18]([CH3:19])[CH2:17][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([C:14]#[N:15])=[CH:10][CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccccc1-c1ccc(O)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)COc1ccc(-c2ccccc2C#N)cc1
Temperature: 60 °C
Yield: 116.5 %

Procedure:
The title B compound of Example 1, 4'-hydroxy-[1,1'-biphenyl]-2-carbonitrile (3.00 g, 15.4 mmol) was dissolved in acetone (8 mL) and chloroacetone (1.59 mL, 20.0 mmol), freshly ground potassium carbonate (2.12 g, 15.4 mmol) and potassium iodide (128 mg, 0.77 mmol) were added. The mixture was heated to 60° C. for 15 hours then partitioned between hydrochloric acid (1.0 M) and ethyl acetate. The aqueous phase was extracted with ethyl acetate and the combined organic extracts dried over magnesium sulfate, filtered and the solvent removed to yield a tan solid (4.51 g). This solid was recrystalized from a mixture of toluene and hexane to yield a tan solid (3.34 g, 87%); m.p. 102-105° C.