Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[N:3]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH:4]=1.[Cl:12][C:13]1[N:18]=[C:17]([Cl:19])[C:16]([Br:20])=[CH:15][N:14]=1>CN(C=O)C.CCOC(C)=O>[Cl:12][C:13]1[N:18]=[C:17]([N:3]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[N:5]=[CH:4]2)[C:16]([Br:20])=[CH:15][N:14]=1.[N:3]1([C:13]2[N:18]=[C:17]([Cl:19])[C:16]([Br:20])=[CH:15][N:14]=2)[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[N:5]=[CH:4]1
Reactant: c1ccc2[nH]cnc2c1
Reactant: Clc1ncc(Br)c(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Clc1nc(-n2cnc3ccccc32)ncc1Br
Product: Clc1ncc(Br)c(-n2cnc3ccccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of NaH (23 mg) in 1.5 mL of DMF was added benzimidazole (111 mg). After gas evolution ceased, the mixture was stirred at room temperature for 10 min, then added to a solution of 2,4-dichloro-5-bromopyrimidine (178 mg) in 1 mL of DMF. The mixture was stirred for 3 h at room temperature, then diluted with 10 mL of EtOAc and quenched with 5 mL of water. The phases were separated and the organic phase was washed with 5 mL of water and 5 mL of brine, then dried over Na2SO4 and concentrated. The residue was purified by flash chromatography, eluting with 4:1 hexanes-acetone to provide 151 mg of the title compound (polar isomer) and 15 mg of the regioisomer 2-(benzimidazol-1-yl)-4-chloro-5-bromopyrimidine (nonpolar isomer). Mass spectrum (ESI) 310.9 (M+1).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10](=[NH:14])[O:11][CH2:12][CH3:13].[N:15]#[C:16]N>C(O)C.CCOCC>[C:16]([N:14]=[C:10]([O:11][CH2:12][CH3:13])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH3:2])#[N:15]
Reactant: CCOC(=N)Cc1ccccc1C
Reactant: N#CN
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(Cc1ccccc1C)=NC#N
Temperature: 25 °C
Reaction time: 72 h
Yield: 71.8 %

Procedure:
A solution of Example 26A (15 g, 70.2 mmol) in absolute ethanol (200 mL) was treated with a solution of cyanamide (2.95 g, 70.2 mmol) in dry ether (40 mL) and stirred at room temperature for 72 h. The resulting precipitate was filtered and the solution was concentrated to dryness under reduced pressure to give 10.2 g of the title compound.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH2:11])[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=1[OH:16])([CH3:4])([CH3:3])[CH3:2].[C:17]([O-:20])(=[O:19])[CH3:18].[Na+].[C:22](OCCBr)(=O)[CH3:23].O>C(O)C>[C:17]([O:20][N:11]([CH2:22][CH3:23])[C:9]1[CH:8]=[C:7]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]([OH:16])=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:10]=1)(=[O:19])[CH3:18]
Reactant: CC(C)(C)c1cc(N)cc(C(C)(C)C)c1O
Reactant: CC(=O)[O-]
Reactant: CC(=O)OCCBr
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCN(OC(C)=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 65 °C

Procedure:
1 g (4.5 mmol) of 2,6-di-t-butyl-4-aminophenol (intermediate 10.2) and 0.65 g of sodium acetate (7.9 mmol) are put into suspension in 1 ml of ethanol. Then bromoethyl acetate (0.94 g, 5.65 mmol) is added to the medium and the reaction medium is heated at 65° C. for 2 hours. The reaction mixture is poured into 20 ml of ice-cooled water and the reaction product is extracted with dichloromethane (3 times 15 ml). The organic phases are dried and the solvent is evaporated off under reduced pressure. The residue is passed over silica gel in dichloromethane. A colourless oil is obtained constituted by a mixture of 2 compounds: the product of mono- and di-substitution. The mixture of these 2 compounds is used without further purification in the following stage.
Reaction SMILES: C(NC(C)C)(C)C.[Li]CCCC.[CH:13]1[CH:14]=[C:15]([N:21]2[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]3[CH:33]=[CH:34][C:35]4[CH2:42][CH2:41][C:39](=[O:40])[NH:38][C:36]=4[CH:37]=3)[CH2:23][CH2:22]2)[C:16]([Cl:20])=[C:17]([Cl:19])[CH:18]=1.[CH2:43]([O:49][C:50](Cl)=[O:51])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CC1CCCO1>[Cl:20][C:16]1[C:17]([Cl:19])=[CH:18][CH:13]=[CH:14][C:15]=1[N:21]1[CH2:26][CH2:25][N:24]([CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]2[CH:37]=[C:36]3[C:35]([CH2:42][CH2:41][C:39](=[O:40])[N:38]3[C:50]([O:49][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH3:48])=[O:51])=[CH:34][CH:33]=2)[CH2:23][CH2:22]1
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Reactant: CCCCCCOC(=O)Cl
Agent: [Li]CCCC
Solvent: CC1CCCO1
Solvent: CC(C)NC(C)C
Product: CCCCCCOC(=O)N1C(=O)CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc21
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
To a solution of diisopropylamine (1.11 mL, 7.87 mmol) in 2-methyltetrahydrofuran (37 mL) at −5° C. was added n-BuLi (3.0 mL, 2.5 M in hexanes, 7.49 mmol) slowly. After 20 minutes, the reaction was cooled to −78° C. and Aripiprazole (1.68 g, 3.74 mmol) was added. After a further 10 minutes, hexylchloroformate (1.53 mL, 9.37 mmol) was added. The reaction was held at −78° C. for 2 hours before allowing to warm to room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution (30 mL) and extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium hydrogen carbonate solution (30 mL), brine (30 mL), dried over MgSO4 and concentrated. The crude product was purified by column chromatography on silica eluting with 0 to 3% tetrahydrofuran in ethyl acetate. The product was triturated in heptane to remove aliphatic impurities and then filtered and dried to afford Compound-59 (0.487 g) as a colorless solid.
Reaction SMILES: Cl.[N:2]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][N:4]=[N:3]1.[F:11][C:12]1[CH:41]=[CH:40][C:15]([O:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24]([C@@H:26]3[CH2:30][C@@H:29]([CH2:31][C:32]4[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=4)[CH2:28][NH:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:14][CH:13]=1>>[N:2]1([CH2:7][C:8]([N:27]2[CH2:28][C@H:29]([CH2:31][C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=3)[CH2:30][C@H:26]2[C:24]([NH:23][C:20]2[CH:21]=[CH:22][C:17]([O:16][C:15]3[CH:14]=[CH:13][C:12]([F:11])=[CH:41][CH:40]=3)=[CH:18][CH:19]=2)=[O:25])=[O:10])[CH:6]=[CH:5][N:4]=[N:3]1
Reactant: COc1cccc(C[C@H]2CN[C@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)C2)c1
Reactant: O=C(O)Cn1ccnn1
Agent: Cl
Product: COc1cccc(C[C@@H]2C[C@@H](C(=O)Nc3ccc(Oc4ccc(F)cc4)cc3)N(C(=O)Cn3ccnn3)C2)c1
Yield: 91 %

Procedure:
Proceeding as in Example 1, but substituting 2-(1H-1,2,3-triazol-1-yl)acetic acid hydrochloride and (2S,4R)—N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide, gave Compound 68, (2S,4R)-1-(2-(1H-1,2,3-triazol-1-yl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)-4-(3-methoxybenzyl)pyrrolidine-2-carboxamide (176 mg, 91%). 1H-NMR (400 MHz, CDCl3): σ 8.95 (s, 1H), 7.78 (s, 1H), 7.75 (s, 1H), 7.43 (d, 2H), 7.00 (t, 2H), 6.93-6.89 (m, 4H), 6.79-6.88 (m, 4H), 5.27 (d, 1H), 5.15 (d, 1H), 4.78 (d, 1H), 4.80 (d, 1H), 3.81 (s, 3H), 3.67 (dd, 1H), 3.27 (t, 1H), 3.07-2.88 (m, 2H), 2.66-2.61 (m, 2H), 1.77-1.69 (m, 1H). MS (EI) for C29H28FN5O4. found 530.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[C:4]([O:9][CH3:10])[CH:3]=1.[C:11](=O)([O-])[O-].[K+].[K+].IC.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH3:11])=[C:4]([O:9][CH3:10])[CH:3]=1
Reactant: COc1cc(Br)ccc1S
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc(Br)ccc1SC
Reaction time: 0.17 h
Yield: 71.5 %

Procedure:
To a solution of 4-bromo-2-methoxybenzenethiol (1.21 g, 5.52 mmol) in DMF (5 mL) was added potassium carbonate (2.29 g, 16.5 mmol) under argon. The resulting mixture was stirred for 10 min, and then iodomethane (3.44 mL, 55.2 mmol) was slowly added over 2 min. The resulting mixture was stirred at r.t. overnight. Then the reaction mixture was poured into water (75 ml), and extracted with ethyl acetate. The organic layer was dried and the solvent was evaporated, the residue was purified by flash chromatography on silica gel with n-heptane/ethyl acetate (7:3) to give 920 mg (72%) of the subtitle compound.
Reaction SMILES: [NH2:1][C:2]1[C:3](Br)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[CH:10]=[CH2:11].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:3](/[CH:11]=[CH:10]/[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC(=O)OC(C)(C)C
Reactant: Nc1cccnc1Br
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)/C=C/c1ncccc1N

Procedure:
950 mg (4.94 mmol) of the bromide from Example 5A, 1900 mg (14.83 mmol) of tert-butyl acrylate, 330 mg (1.50 mmol) of palladium(II) acetate, 450 mg (1.50 mmol) of tri-ortho-tolylphospine are dissolved in 15 ml of acetonitrile, and 1000 mg (9.88 mmol) of triethylamine are added. The mixture is stirred under reflux for 16 h. The reaction mixture is concentrated, mixed with ethyl acetate and washed with saturated aqueous sodium chloride solution. The organic phase is dried over sodium sulphate, filtered, concentrated and purified by column chromatography on silica gel with cyclohexane/ethyl acetate (7:3). 95 mg (6% of theory) of product are obtained.
Reaction SMILES: Cl.[C:2]1([C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH2:20])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1.C1N=CN([C:26]([N:28]2[CH:32]=N[CH:30]=[CH:29]2)=[O:27])C=1.N1CCC[CH2:34]1>N1C=CC=CC=1>[C:2]1([C@@H:14]2[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20][C:26]([N:28]3[CH2:29][CH2:30][CH2:34][CH2:32]3)=[O:27])[CH2:15]2)[N:6]2[C:7]3[CH:13]=[CH:12][NH:11][C:8]=3[N:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: C1CCNC1
Reactant: N[C@H]1CCC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(N[C@H]1CCC[C@@H](c2nnc3cnc4[nH]ccc4n23)C1)N1CCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 16.5 %

Procedure:
To a flask containing cis-3-(6H-pyrrolo[2,3-e][1,2,4]triazolo[4,3-a]pyrazin-1-yl)cyclohexanamine hydrochloride (0.050 g, 0.171 mmol, Example #F.1.3) was added CDI (0.030 g, 0.188 mmol) and pyridine (2 mL). The reaction mixture was stirred at ambient temperature for about 16 h. Pyrrolidine (0.016 mL, 0.188 mmol) was added to the reaction mixture and stirred for about 16 h. The solvent was removed under reduced pressure and the crude material was purified by RP-HPLC (Table 2, Method j). The appropriate fractions were combined, the solvent was mostly removed under reduced pressure, and the solid was filtered and dried under lyophilization to give N-(cis-3-(6H-pyrrolo[2,3-e][1, 2, 4]triazolo[4,3-a]pyrazin-1-yl)cyclohexyl)pyrrolidine-1-carboxamide (0.010 g, 16%): LC/MS (Table 2, Method a) Rt=1.45 min; MS m/z 354 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[C:7](=O)[CH:6]=[CH:5][CH2:4][O:3]1.[C:9]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])(=[O:12])[NH:10][NH2:11].C(O)(=O)C>[Pd].CO>[C:14]([O:13][C:9]([NH:10][N:11]=[C:7]1[CH2:6][CH2:5][CH2:4][O:3][CH:2]1[CH3:1])=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: CC1OCC=CC1=O
Reactant: CC(C)(C)OC(=O)NN
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC1OCCCC1=NNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A methanol (9 mL) solution of (±)-2-methyl-2H-pyran-3(6H)-one (370 mg, 3.30 mmol) was treated with a suspension of 10% palladium on carbon (185 mg) in methanol (3 mL). The mixture was sparged under hydrogen and stirred for 45 minutes at ambient temperature. The mixture was sparged under nitrogen, treated with tert-butyl carbazate (436 mg, 3.30 mmol, 1 equiv) and acetic acid (0.756 mL, 13.2 mmol, 4 equiv) and sparged under hydrogen. After stirring for 1 hour, the mixture was sparged under nitrogen and filtered through a pad of celite. The filtrate was concentrated in vacuo and the residue was dissolved in ethyl acetate, washed with sodium bicarbonate (30 mL, saturated aqueous) and the organic extract was dried with sodium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel gradient chromatography (100:0 to 20:80; hexanes:ethyl acetate) to provide the titled compound.
Reaction SMILES: Cl.C[N:3]([C:10]1[CH:15]=[N:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][N:11]=1)[C@H:4]1[CH2:8][CH2:7][CH2:6][C@@H:5]1[NH2:9].[N:20]1[N:21]([C:25]2[C:26]([C:31]([OH:33])=O)=[N:27][CH:28]=[CH:29][CH:30]=2)[N:22]=[CH:23][CH:24]=1.[CH2:34](Cl)CCl.N1C2C(=NC=CC=2)N(O)N=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:34][C:15]1[C:10]([NH:3][C@H:4]2[CH2:8][CH2:7][CH2:6][C@@H:5]2[NH:9][C:31]([C:26]2[C:25]([N:21]3[N:22]=[CH:23][CH:24]=[N:20]3)=[CH:30][CH:29]=[CH:28][N:27]=2)=[O:33])=[N:11][CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[N:14]=1
Reactant: CN(c1cnc(C(F)(F)F)cn1)[C@H]1CCC[C@@H]1N
Reactant: ClCCCl
Reactant: O=C(O)c1ncccc1-n1nccn1
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(C(F)(F)F)cnc1N[C@H]1CCC[C@@H]1NC(=O)c1ncccc1-n1nccn1

Procedure:
A solution of (1S,2S)-1-N-methyl-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 23; 60 mg, 0.20 mmol), 3-(2H-1,2,3-triazol-2-yl)pyridine-2-carboxylic acid (CAS number 1252907-86-0; 40 mg, 0.21 mmol), EDC (58 mg, 0.30 mmol), 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (41 mg, 0.30 mmol) and triethylamine (0.085 ml, 0.61 mmol) in DCM (1 ml) was stirred at room temperature over the weekend. The reaction was concentrated in vacuo and was then purified by column chromatography (basic silica, 20 to 100% ethyl acetate/petrol) followed by column chromatography (silica, 0 to 100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [C:1]([O:4][C:5]([CH3:8])([CH3:7])[CH3:6])(=[O:3])[CH3:2].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C(OP([C:27]([C:35]#[N:36])=[CH:28][CH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)(=O)OCC)C.[CH2:37]([O:39][C:40]1[C:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[F:52])=[CH:44][C:43]([CH:53]=O)=[C:42]([N+:55]([O-:57])=[O:56])[CH:41]=1)[CH3:38]>C1COCC1.[Cu]I.C(OCC)(=O)C>[C:5]([O:4][C:1](=[O:3])[CH2:2][CH:28]([CH:29]1[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1)[C:27]([C:35]#[N:36])=[CH:53][C:43]1[CH:44]=[C:45]([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=2[F:52])[C:40]([O:39][CH2:37][CH3:38])=[CH:41][C:42]=1[N+:55]([O-:57])=[O:56])([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(=O)OC(C)(C)C
Reactant: CCOP(=O)(OCC)C(C#N)=CC1CCOCC1
Reactant: CCOc1cc([N+](=O)[O-])c(C=O)cc1-c1ccccc1F
Agent: [Cu]I
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CC(=O)OC(C)(C)C)C2CCOCC2)cc1-c1ccccc1F
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of tert-butyl acetate (217 μL, 1.6 mmol) in THF (0.92 mL) at −78° C., LHMDS (1.0 M in THF, 1.4 mL) was added slowly. After 30 min of stirring at −78° C., [1-cyano-2-(tetrahydro-pyran-4-yl)-vinyl]-phosphonic acid diethyl ester (302 mg, 1.1 mmol) dissolved in THF (0.92 mL) was added, followed by CuI (6.3 mg, 0.03 mmol). The resulting solution was warmed to room temperature, stirred for 2 h, and then 6-ethoxy-2′-fluoro-4-nitro-biphenyl-3-carbaldehyde (266.0 mg, 0.9195 mmol), prepared as in Step C above, was added. The resulting solution was stirred at room temperature for another 20 h. Ethyl acetate was then added, and the resulting solution was washed with hydrochloric acid solution (1.0 M) two times and with brine one time, and then dried over magnesium sulfate. The resulting solution was filtered and concentrated. The residue was purified on a silica gel column eluted with a solvent mixture of ethyl acetate and heptanes from 0:100 to 25:75 to yield a residue.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[N:6][C:7]([C@H:17]([NH2:19])[CH3:18])=[C:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH:9]=2)[CH:4]=[CH:3]1.[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23](Cl)[N:22]=1.CCN(CC)CC.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:20][C:21]1[N:26]=[C:25]([NH2:27])[C:24]([C:28]#[N:29])=[C:23]([NH:19][C@@H:17]([C:7]2[N:6]=[C:5]3[CH:4]=[CH:3][N:2]([CH3:1])[C:10]3=[CH:9][C:8]=2[N:11]2[CH2:12][CH2:13][O:14][CH2:15][CH2:16]2)[CH3:18])[N:22]=1
Reactant: N#Cc1c(N)nc(N)nc1Cl
Reactant: C[C@@H](N)c1nc2ccn(C)c2cc1N1CCOCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@@H](Nc1nc(N)nc(N)c1C#N)c1nc2ccn(C)c2cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 45 %

Procedure:
To a 50 mL pear flask were added (R)-1-(1-methyl-6-morpholino-1H-pyrrolo[3,2-b]pyridin-5-yl)ethan-1-amine (0.5 g, 1.921 mmol) and 2,4-diamino-6-chloropyrimidine-5-carbonitrile (0.326 g, 1.92 mmol) in DMF (9.60 mL) to give a white suspension. To the suspension was added Et3N (0.535 mL, 3.84 mmol) and the mixture was stirred at 100° C. for 6 hours. The mixture was allowed to stand at RT overnight. Saturated aqueous sodium bicarbonate solution (100 mL) was added, and the mixture was extracted with EtOAc (3×). The organic layers were combined, dried over MgSO4, filtered, and concentrated. The damp residue was slurried in Et2O. The solids were collected on a fritted glass funnel and washed with Et2O. UPLC indicated the presence of a small impurity having a slightly shorter retention time than the desired product. The solids were dissolved in hot EtOH and recrystallized overnight to give the title compound as an off-white solid (340 mg, 45.0%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.39 (d, J=6.32 Hz, 3 H), 2.70-2.83 (m, 2 H), 3.05 (br s, 2 H), 3.72-3.91 (m, 7 H), 5.90 (quin, J=6.76 Hz, 1 H), 6.41 (s, 2 H), 6.45-6.53 (m, 2 H), 6.58 (s, 2 H), 7.51-7.61 (m, 1 H), 7.84 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H23N9O, 394; found 394.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([OH:10])=O)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:46][C:47]1[S:48][CH:49]=[CH:50][N:51]=1.C(N(CC)CC)C>C(Cl)Cl.O>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([Cl:18])[CH:12]=2)[C:8]([NH:46][C:47]2[S:48][CH:49]=[CH:50][N:51]=2)=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Nc1nccs1
Reactant: O=C(O)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(Nc1nccs1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Reaction time: 14 h
Yield: 96.5 %

Procedure:
A solution of 3-cyclopentyl-2-(3,4-dichlorophenyl)-propionic acid (prepared in Example 38, 2.0 g, 6.96 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (4.62 g, 10.44 mmol), and 2-aminothiazole (1.05 g, 10.44 mmol) in methylene chloride (50 mL) at 25° C. was treated with triethylamine (2.9 mL, 20.88 mmol). The reaction mixture was stirred for 14 h. The reaction mixture was then diluted with water (10 mL) and extracted with methylene chloride (3×10 mL). The combined organic layers were sequentially washed with water (1×10 mL), a 1 N aqueous sodium hydroxide solution (1×10 mL), a 1 N aqueous hydrochloric acid solution (1×10 mL), and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 80/20 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-thiazol-2-yl-propionamide (2.48 g, 96%) as a white solid: mp 143.5-145.5° C.; EI-HRMS m/e calcd for C17H18Cl2N2OS (M+) 368.0516, found 368.0516.
Reaction SMILES: [F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]=O)=[CH:10][C:4]=2[O:3]1.[CH3:14][C:15]1([CH3:23])[O:22][C:20](=[O:21])[CH2:19][C:17](=[O:18])[O:16]1.N1CCCC1C(O)=O.[CH3:32][S:33][CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[C:39]2[C:43]=1[NH:42][CH:41]=[CH:40]2>C(#N)C>[F:1][C:2]1([F:13])[O:6][C:5]2[CH:7]=[CH:8][C:9]([CH:11]([C:40]3[C:39]4[C:43](=[C:35]([CH2:34][S:33][CH3:32])[CH:36]=[CH:37][CH:38]=4)[NH:42][CH:41]=3)[CH:19]3[C:20](=[O:21])[O:22][C:15]([CH3:23])([CH3:14])[O:16][C:17]3=[O:18])=[CH:10][C:4]=2[O:3]1
Reactant: CSCc1cccc2cc[nH]c12
Reactant: O=Cc1ccc2c(c1)OC(F)(F)O2
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: O=C(O)C1CCCN1
Solvent: CC#N
Product: CSCc1cccc2c(C(c3ccc4c(c3)OC(F)(F)O4)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.57 g (8.46 mmol) of 2,2-difluoro-1,3-benzodioxole-5-carbaldehyde, 1.22 g (8.46 mmol) of Meldrum's acid and 0.05 g (0.42 mmol) of D,L-proline were added to a solution of 1.50 g (8.46 mmol) of the compound from Example 8A in 12 ml of acetonitrile. The reaction mixture was stirred at RT overnight. The precipitated solid was filtered off with suction, washed with acetonitrile and dried under high vacuum. 2.67 g (91% of theory) of the title compound were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]#[N:12])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1>CC#N.CCOC(C)=O>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]#[N:12])[CH2:9][CH2:10]2)=[CH:6][C:7]=1[Br:20]
Reactant: O=C1CCC(=O)N1Br
Reactant: N#CC1(c2ccc(N)cc2)CC1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: N#CC1(c2ccc(N)c(Br)c2)CC1
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 1-(4-amino-phenyl)-cyclopropanecarbonitrile (96 mg, 0.60 mmol) in MeCN (3 mL) at 0° C. was added NBS (108 mg, 0.60 mmol) and the reaction was allowed to stir overnight. The reaction was diluted with EtOAc (25 mL) and was then washed with saturated aqueous NaHCO3 (1×25 mL). The organic layer was dried (Na2SO4) and concentrated in vacuo to give 114 mg (80%) of 1-(4-amino-3-bromo-phenyl)-cyclopropanecarbonitrile. The crude product was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([N:8]=[CH:9][N:10]=2)[N:7]=1.[NH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18]>C(O)C>[N:10]1[CH:9]=[N:8][N:6]2[C:5]=1[CH:4]=[CH:3][C:2]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][OH:18])=[N:7]2
Reactant: Clc1ccc2ncnn2n1
Reactant: NCCCCCCO
Solvent: CCO
Product: OCCCCCCNc1ccc2ncnn2n1
Yield: 117.8 %

Procedure:
2.03 g of 6-chloro[1,2,4]triazolo[1,5-b]pyridazine was dissolved in 20 ml of ethanol; 3.85 g of 6-amino-1-hexanol was added, followed by heating and refluxing for 19 hours. After cooling, the crystal obtained was collected by filtration, washed with ethanol and dried to yield 3.64 g of the title compound.