Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1[CH:5]=[N:4][N:3]=[C:2]1[C:6]1[CH:14]=[CH:13][C:9]2[N:10]=[CH:11][NH:12][C:8]=2[CH:7]=1.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH2:21])=[CH:18][CH:17]=1>>[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][N:21]2[CH:5]=[N:4][N:3]=[C:2]2[C:6]2[CH:14]=[CH:13][C:9]3[NH:10][CH:11]=[N:12][C:8]=3[CH:7]=2)=[CH:18][CH:17]=1
Reactant: c1nc2ccc(-c3nnco3)cc2[nH]1
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2cnnc2-c2ccc3[nH]cnc3c2)cc1

Procedure:
The compound was synthesized starting from 5-(1,3,4-oxadiazol-2-yl)benzimidazole (186 mg, 1 mmol) and 4-methylbenzylamine (0.5 ml) as described above; yield: 0.071 g (24.6%);
Reaction SMILES: [CH2:1]([O:8][C:9]([C@@:11]([OH:19])([CH2:16][CH:17]=[CH2:18])[CH2:12][C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.ClC1C=C(Cl)C=C(Cl)C=1C(Cl)=O>C(Cl)Cl>[CH2:16]([C@:11]1([C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:12][C:13](=[O:15])[O:19]1)[CH:17]=[CH2:18]
Reactant: C=CC[C@@](O)(CC(=O)O)C(=O)OCc1ccccc1
Agent: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@]1(C(=O)OCc2ccccc2)CC(=O)O1
Reaction time: 0.5 h
Yield: 67.2 %

Procedure:
A solution of hydroxyacid 81 (1.02 g, 3.86 mmol, 1.00 equiv) and triethylamine (519 μL, 17.37 mmol, 4.50 equiv) in CH2Cl2 (77 mL) was added via syringe pump over 4 h to a solution of 2,4,6-trichlorobenzoyl chloride (904 μL, 5.79 mmol, 1.50 equiv) and N,N-dimethylaminopyridine (DMAP) (519 mg, 4.25 mmol, 1.10 equiv) in CH2Cl2 (39 mL). The solution was then allowed to stir for 30 minutes after complete addition after which it was quenched with H2O (100 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (2×100 mL). The organic phases were combined, dried over MgSO4, and the solvent was removed via rotary evaporation to yield a black oil which was purified by silica gel column chromatography (CH2Cl2) to yield 82 (639 mg, 67%) as a yellow oil. Rf=0.52 (CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.38 (m, 5H, aryl H), 5.76 (m, 1H, vinyl H), 5.26 (s, 2H, PhCH2), 5.22 (m, 2H, vinyl H), 3.65 (d, 1H, J=16.5 Hz, C(O)CH2), 3.42 (d, 1H, J=16.5 Hz, C(O)CH2), 2.89 (dd, 1H, J=14.6, 6.8 Hz, CHCH2), 2.80 (dd, 1H, J=14.6, 6.8 Hz, CHCH2); 13C NMR (125 MHz, CDCl3) δ 169.03, 165.61, 134.75, 129.10, 128.95, 128.89, 128.59, 121.82, 75.65, 68.17, 45.86, 39.06; IR (neat film) 3034 (w), 1843 (s), 1741 (s), 1644 (w), 1456 (m) cm−1; LRMS (ESI) calcd. for C14H14O4Na (M+Na+) 269.1, observed 269.1.
Reaction SMILES: [ClH:1].[OH:2][C@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([OH:11])=[O:10])[CH2:4]1.[CH3:12]O>>[ClH:1].[OH:2][C@H:3]1[CH2:7][N:6]([CH3:8])[C@H:5]([C:9]([O:11][CH3:12])=[O:10])[CH2:4]1
Reactant: CO
Reactant: CN1C[C@H](O)C[C@H]1C(=O)O
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](O)CN1C
Yield: 100 %

Procedure:
Concentrated hydrochloric acid (3 mL) was added to a suspension of (2S,4R)-4-hydroxy-1-methyl-2-pyrrolidinecarboxylic acid (3 g) in methanol (15 mL), and the mixture was refluxed for 4 hours. The solvent of the reaction mixture was removed by distillation under reduced pressure to give the title compound (4.0 g, yield 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:46])[NH:5][C@@H:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[C:16]([C:18]#[N:19])[CH:15]=[C:14]([NH:20][C:21]3[N:26]=[C:25]([N:27](CC)[CH2:28][C:29]4C=CC(OC)=CC=4)[C:24]4=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:23]4[N:22]=3)[C:13]=2[Cl:44])[CH2:8][C@H:7]1[OH:45])[CH3:2].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:44][C:13]1[C:14]([NH:20][C:21]2[N:26]=[C:25]([NH:27][CH2:28][CH3:29])[C:24]3=[N:39][CH:40]=[C:41]([C:42]#[N:43])[N:23]3[N:22]=2)=[CH:15][C:16]([C:18]#[N:19])=[CH:17][C:12]=1[N:9]1[CH2:10][CH2:11][C@@H:6]([NH:5][C:4](=[O:46])[O:3][CH2:1][CH3:2])[C@H:7]([OH:45])[CH2:8]1
Reactant: CCOC(=O)N[C@@H]1CCN(c2cc(C#N)cc(Nc3nc(N(CC)Cc4ccc(OC)cc4)c4ncc(C#N)n4n3)c2Cl)C[C@H]1O
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: ClCCCl
Product: CCNc1nc(Nc2cc(C#N)cc(N3CC[C@@H](NC(=O)OCC)[C@H](O)C3)c2Cl)nn2c(C#N)cnc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 28 %

Procedure:
To ethyl((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (50 mg, 0.068 mmol), in DCE (0.8 mL) was added anisole (0.1 mL, 0.915 mmol) and TFA (0.5 mL, 6.49 mmol); the mixture stirred 2 h at 25° C. and solvent was removed. 2N NH3/MeOH (5 ml) was added and the mixture stirred for 30 min at 25° C. The solution was stored at −20° C. and a white precipitate formed. The material was collected by filtration, washed with 20 ml cold MeOH, 5 ml ether and dried under air-suction for 0.5 h to afford ethyl ((3R,4R)-1-(2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-3-hydroxypiperidin-4-yl)carbamate (10 mg).
Reaction SMILES: [C:1](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:2].[CH3:17][O:18][C:19]1[N:24]=[CH:23][N:22]=[C:21]([NH2:25])[CH:20]=1>ClCCl>[N:25]([C:21]1[CH:20]=[C:19]([O:18][CH3:17])[N:24]=[CH:23][N:22]=1)=[C:1]=[S:2]
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Reactant: COc1cc(N)ncn1
Solvent: ClCCl
Product: COc1cc(N=C=S)ncn1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a bright orange solution of 1,1′-thiocarbonyldipyridin-2(1H)-one (1.86 g, 7.99 mmol) in dichloromethane at room temperature was added 6-methoxypyrimidin-4-amine (1 g, 8 mmol). The orange solution was stirred at room temperature for 18 hours. The LC/MS showed the desired product as one of the major peaks. The deep orange solution was concentrated and the remaining residue was filtered. The filtrate was purified by silica gel chromatography (10-50% ethyl acetate/hexanes) to afford 4-isothiocyanato-6-methoxypyrimidine (0.72 g, 4.3 mmol, 54% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 8.49 (1H, d, J=5.79 Hz), 6.95 (1H, d, J=5.79 Hz), 3.92 (3H, s). MS (LC/MS) R.T.=3.15; [M+H]+=168.1.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)=[O:4].[CH3:16][C:17]([CH3:29])([NH2:28])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27].C(=O)([O-])[O-].[K+].[K+].[BH4-].[Na+]>CN(C)C=O.CO>[OH:4][CH:3]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10](=[O:15])[CH2:9][CH2:8]2)[CH2:2][NH:28][C:17]([CH3:29])([CH3:16])[CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[O:26][CH3:27]
Reactant: O=C1CCc2cc(C(=O)CBr)ccc2N1
Reactant: COc1ccccc1CCC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Product: COc1ccccc1CCC(C)(C)NCC(O)c1ccc2c(c1)CCC(=O)N2

Procedure:
6.0 g (0.023 mole) of 3,4-dihydro-6-bromoacetylquinolin-2(1H)-one, 4.8 g (0.025 mole) of 1,1-dimethyl-3-(2-methoxy-phenyl)-propanamine and 3.2 g (0.03 mole) of potassium carbonate are stirred in 100 ml of dimethylformamide at room temperature for 24 hours. After dilution with methanol, the product is reduced with an excess of sodium borohydride. The solvents are removed in vacuo, the residue is taken up in methylene chloride and the mixture is extracted with water. Column chromatography on silica gel (CHCl3 /MeOH 90/10) gives 3,4-dihydro-6-[1-hydroxy-2-[[1,1-dimethyl-3-(2-methoxy-phenyl)-propyl]-amino]-ethyl]-quinolin-2(1H)-one as a base, which is converted into the hydrochloride in the customary manner. Melting point 180° C. (decomposition).
Reaction SMILES: C([O:3][C:4](=[O:47])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]([C:15]2[CH:20]=[CH:19][C:18]([S:21]([N:24]3[CH2:29][CH2:28][CH:27]([CH2:30][NH:31][CH2:32][C@H:33]([OH:46])[C:34]4[CH:39]=[CH:38][C:37]([OH:40])=[C:36](S(C)(=O)=O)[C:35]=4N)[CH2:26][CH2:25]3)(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:7]=1)C.[OH-:48].[Na+].Cl>CO>[OH:46][C@H:33]([C:34]1[CH:39]=[CH:38][C:37]([OH:40])=[C:36]([NH:24][S:21]([CH3:18])(=[O:22])=[O:48])[CH:35]=1)[CH2:32][NH:31][CH2:30][CH:27]1[CH2:28][CH2:29][N:24]([S:21]([C:18]2[CH:17]=[CH:16][C:15]([N:8]3[C:9]4[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=4)[C:6]([CH2:5][C:4]([OH:3])=[O:47])=[CH:7]3)=[CH:20][CH:19]=2)(=[O:22])=[O:23])[CH2:25][CH2:26]1
Reactant: [OH-]
Reactant: CCOC(=O)Cc1cn(-c2ccc(S(=O)(=O)N3CCC(CNC[C@H](O)c4ccc(O)c(S(C)(=O)=O)c4N)CC3)cc2)c2ccccc12
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CS(=O)(=O)Nc1cc([C@@H](O)CNCC2CCN(S(=O)(=O)c3ccc(-n4cc(CC(=O)O)c5ccccc54)cc3)CC2)ccc1O

Procedure:
A solution of {1-[4-(4-{[(2R)-2-hydroxy-2-(4-hydroxy-3-methane-sulfonyl-amino-phenyl)-ethylamino]-methyl}-piperidine-1-sulfonyl)-phenyl]-1H-indol-3-yl}-acetic acid ethyl ester (0.154 g, 0.225 mmol) and 0.67 mL of 1N NaOH in 10 mL methanol was heated at reflux overnight. On cooling the reaction was neutralized with 0.67 mL of 1N HCl. The reaction mixture was concentrated in vacuo and triturated with H2O. The solids were filtered and dried (high vacuum) to give 0.070 g of the title compound as an off white solid.
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]2[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=2[CH:3]=1.CC1(C)C(C)(C)OB([C:26]2[CH:27]=[CH:28][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[N:30][CH:31]=2)O1.C([O-])([O-])=O.[Na+].[Na+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.CO.O>[OH:35][C:32]([C:29]1[N:30]=[CH:31][C:26]([C:2]2[N:11]=[C:10]([NH:12][CH:13]([CH3:15])[CH3:14])[C:9]3[C:8](=[O:16])[N:7]([CH3:17])[CH:6]=[N:5][C:4]=3[CH:3]=2)=[CH:27][CH:28]=1)([CH3:34])[CH3:33]
Reactant: CC(C)(O)c1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: CC(C)Nc1nc(Cl)cc2ncn(C)c(=O)c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC(C)Nc1nc(-c2ccc(C(C)(C)O)nc2)cc2ncn(C)c(=O)c12
Temperature: 90 °C

Procedure:
A mixture of crude 7-chloro-5-(isopropylamino)-3-methylpyrido[4,3-d]pyrimidin-4(3H)-one (455 mg, ˜1.80 mmol), crude 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)propan-2-ol (570 mg, ˜2.10 mmol), Pd(PPh3)4 (208 mg, 0.18 mmol) and Na2CO3 (1.90 g, 18.0 mol) in a mixed solvent of dioxane (30 mL) and H2O (10 mL) was purged with N2, heated at 90° C. for 16 hours, poured into water (400 mL) and extracted with EtOAc (5×70 mL). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and evaporated to result in a residue that was subjected to chromatography with gradient mixed solvents from DCM/MeOH/28% aqueous NH4OH (24:10:1) to (15:10:1) to afford the title compound. 1H NMR (DMSO-d6) 1.29 (d, J=6.4 Hz, 6H, 2CH3), 1.47 (s, 6H, 2CH3), 3.44 (s, 3H, NCH3), 4.42 (m, 1H), 5.30 (s, 1H, OH), 7.23 (s, 1H), 7.76 (d, J=8.4 Hz, 1H), 8.44 (d, J=8.4 Hz, 1H), 8.45 (s, 1H), 8.75 (d, J=6.8 Hz, 1H, NH), 9.22 (s, 1H); ESI-MS m/z 354.2 (MH+); Anal. Calcd for C19H23N5O2: C, 64.57; H, 6.56; N, 19.82. Found: C, 64.39; H, 6.47; N, 19.75.
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([CH3:8])[CH:7]=1.CN1CCCC1=O.[NH2:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23].C(N(CC)CC)C>O>[N+:9]([C:5]1[CH:4]=[CH:3][C:2]([NH:19][CH2:20][CH2:21][CH:22]([OH:24])[CH3:23])=[CH:7][C:6]=1[CH3:8])([O-:11])=[O:10]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: CC(O)CCN
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN1CCCC1=O
Product: Cc1cc(NCCC(C)O)ccc1[N+](=O)[O-]
Temperature: 60 °C
Yield: 99.6 %

Procedure:
2 g of 5-fluoro-2-nitrotoluene were added to a solution of 20 ml of N-methylpyrrolidinone, 1.38 g of 4-amino-2-butanol and 1.57 g of triethylamine. The reaction medium was heated at 60° C. for 10 hours and, after cooling to room temperature, was then poured into a water and ice mixture. The resulting medium was extracted with ethyl acetate and the organic phase was then concentrated under vacuum. 2.88 g of 4-(4-nitro-3-methylphenylamino)butan-2-ol (31) were obtained.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[N:8][C:9]([NH2:10])=[C:4]2[CH:3]=[N:2]1.[I:11]NC(=O)CCC(N)=O>>[I:11][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[N:8][C:9]=2[NH2:10])[NH:1][N:2]=1
Reactant: Nc1ncnc2[nH]ncc12
Reactant: NC(=O)CCC(=O)NI
Product: Nc1ncnc2[nH]nc(I)c12

Procedure:
Halogenation of commercially available 1H-pyrazolo[3,4-d]pyrimidin-4-amine provides an entry into the synthesis of compounds of Formula (A), (B), (C) and/or (D). In one embodiment, 1H-pyrazolo[3,4-d]pyrimidin-4-amine is treated with N-iodosuccinamide to give 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. Metal catalyzed cross coupling reactions are then carried out on 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. In one embodiment, palladium mediated cross-coupling of a suitably substituted phenyl boronic acid under basic conditions constructs intermediate 2. Intermediate 2 is coupled with N-Boc-3-hydroxypiperidine (as non-limiting example) via Mitsunobu reaction to give the Boc (tert-butyloxycarbonyl) protected intermediate 3. After deprotection with acid, coupling with, but not limited to, an acid chloride, such as, but not limited to, acryloyl chloride, completes the synthesis to give compound 4.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][C:3]=1[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7].[Br:16]N1C(=O)CCC1=O>N(C1(C#N)CCCCC1)=NC1(C#N)CCCCC1.FC1C=CC=CC=1>[Br:16][CH2:15][C:12]1[CH:13]=[CH:14][C:2]([Cl:1])=[C:3]([CH:11]=1)[O:4][CH:5]([CH3:10])[C:6]([O:8][CH3:9])=[O:7]
Reactant: COC(=O)C(C)Oc1cc(C)ccc1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: N#CC1(N=NC2(C#N)CCCCC2)CCCCC1
Solvent: Fc1ccccc1
Product: COC(=O)C(C)Oc1cc(CBr)ccc1Cl
Yield: 87.3 %

Procedure:
Into 150 ml of fluorobenzene was dissolved 5.61 g of methyl 2-(2-chloro-5-methylphenoxy)propionate obtained above; 4.37 g of N-bromosuccinimide and then 0.2 g of 1,1′-azobis(cyclohexanecarbonitrile) were added, and the mixture was stirred under reflux for 2 hours. After the reaction was completed, the solution was allowed to left for cooling; the reaction solution was filtered; the filtrate was concentrated under reduced pressure; and the residue was subjected to silica gel chromatography to give 6.59 g of methyl 2-[5-(bromomethyl)-2-chlorophenoxy]propionate.
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[O:9])=[C:6]([Cl:10])[N:5]=[C:4]([S:11][CH3:12])[N:3]=1.[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16]>>[Cl:10][C:6]1[C:7]([CH:8]=[O:9])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[CH:20][C:14]=2[F:13])[N:3]=[C:4]([S:11][CH3:12])[N:5]=1
Reactant: CSc1nc(Cl)c(C=O)c(Cl)n1
Reactant: Nc1ccccc1F
Product: CSc1nc(Cl)c(C=O)c(Nc2ccccc2F)n1

Procedure:
Prepared as described above in Example 2 starting from 4,6-dichloro-2-methylsulfanyl-pyrimidine-5-carbaldehyde and 2-fluoroaniline to give the title compound 4-chloro-6-(2-fluoro-phenylamino)-2-methylsulfanyl-pyrimidine-5-carbaldehyde. 1H-NMR: δ 2.53 (s, 3H), 7.15 (m, 3H), 8.25 (m, 1H), 7.44 (m, 1H), 10.31 (s, 1H), 11.35 (br s, 1H). LC MS (m/e)=298 (MH+).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH2:6].C(N(CC)CC)C.[C:25](Cl)(=[O:35])[C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1>C(Cl)Cl>[CH3:2][O:3][C:4](=[O:17])[C@@H:5]([CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1)[NH:6][C:25]([C:26]1[CH:34]=[CH:33][C:32]2[O:31][CH2:30][O:29][C:28]=2[CH:27]=1)=[O:35]
Reactant: COC(=O)[C@H](N)Cc1c[nH]c2ccccc12
Reactant: O=C(Cl)c1ccc2c(c1)OCO2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 2 h
Yield: 100.2 %

Procedure:
To a suspension of D-tryptophan methyl ester hydrochloride (10.2 g) in anhydrous CH2Cl2 (150 ml) cooled at 0° C. was added dropwise triethylamine (12.3 ml). To the resulting solution solid piperonyloyl chloride (8.16 g) was added portionwise at the same temperature, and the mixture was stirred at room temperature for 2 h. The mixture was washed successively with water, 0.5N hydrochloric acid, water, a saturated aqueous solution of NaHCO3 and again with water. After drying over Na2SO4 and evaporation of the solvent under reduced presure, the resulting oil on trituration from hot cyclohexane afforded the title compound as a white solid (14.7 g).
Reaction SMILES: [CH:1]1([C:7]#[CH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]=[O:10]>CCOCC>[CH:1]1([C:7]#[C:8][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=O
Reactant: C#CC1CCCCC1
Solvent: CCOCC
Product: OCC#CC1CCCCC1
Temperature: 25 °C

Procedure:
To a solution of ethyl magesium bromide (prepared from 2.5 g of magnesium turning and 11.3 g of bromoethane) in ether was added dropwise a solution of 10.2 g of cyclohexylacetylene in ether and the reaction mixture was refluxed for 2 hours. The reaction mixture was cooled to ambient temperature and anhydrous formaldehyde (prepared from the thermal decomposition of 50 g of paraformaldehyde for 20 minutes) was bubbled into the mixture. After cooling, the reaction was quenched with saturated ammonium chloride and extracted with ether (2×100 ml). The combined ether extracts were washed with brine, dried over magnesium sulfate and evaporated to yield the product which was distilled under high vacuum at 68°-74° C. to yield 6.4 g as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14](Cl)=[O:15].O.[NH3:18].O>O1CCCC1>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([Cl:13])=[CH:8][CH:9]=[N:10]2)=[CH:5][C:4]=1[C:14]([NH2:18])=[O:15]
Reactant: COc1cc2nccc(Cl)c2cc1C(=O)Cl
Reactant: N
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2nccc(Cl)c2cc1C(N)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
7-Methoxy-4-chloroquinoline-6-carbonyl chloride (2.7 g) was dissolved in tetrahydrofuran (150 ml), and the solution was cooled to 0° C. After adding 30% ammonia water (5 ml), the mixture was stirred at room temperature for 30 minutes. Water was added, extraction was performed 3 times with ethyl acetate, and then the organic layers were combined, washed with water and saturated brine, dried over sodium sulfate and dried under reduced pressure to obtain the title compound (1.35 g).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH:18]=[CH:19][C:20]=1[F:21])[CH2:9][NH:10]C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:22][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([CH2:9][NH2:10])[CH:18]=[CH:19][C:20]=1[F:21]
Reactant: CN(C)CCCc1cc(CNC(=O)OC(C)(C)C)ccc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)CCCc1cc(CN)ccc1F
Reaction time: 1 h

Procedure:
To [3-(3-Dimethylamino-propyl)-4-fluoro-benzyl]-Boc-amine (3.0 g, 10 mmol) in 100 mL of CH2Cl2 was slowly added TFA (10 mL). The resulting solution was stirred for 1 h, then concentrated. The residue was diluted with CH2Cl2 and aq. NaHCO3 solution. The organic layer was dried over Na2SO4 and concentrated to give the title compound. MS (ES+): 211 (M+H)+; (ES−): 209 (M−H). Calc'd C12H19FN2-210.29.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:8][C@H:7]([N:9]([C:14]([C:16]2[N:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])[C:19]3[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=3[N:17]=2)=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][N:5]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:4]1)#[N:2].[N:38]([Si](C)(C)C)=[N+:39]=[N-:40].C([Sn](CCCC)=O)CCC>O1CCCC1>[CH3:26][O:25][CH2:24][CH2:23][CH2:22][CH2:21][N:20]1[C:19]2[CH:27]=[CH:28][CH:29]=[CH:30][C:18]=2[N:17]=[C:16]1[C:14]([N:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[C@H:7]1[CH2:8][C@@H:3]([C:1]2[NH:40][N:39]=[N:38][N:2]=2)[CH2:4][N:5]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[CH2:6]1)=[O:15]
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C#N)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](c3nnn[nH]3)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reaction time: 43 h

Procedure:
tert-Butyl (3R,5S)-3-cyano-5-{{{1-(4-methoxybutyl)-1H-benzimidazol-2-yl}carbonyl}(2-methylpropyl)amino}piperidine-1-carboxylate (320 mg) was dissolved in tetrahydrofuran (20 ml), azido(trimethyl)silane (1.5 ml) and dibutyl(oxo)stannane (100 mg) were added, and the mixture was heated under reflux with stirring for 43 hr. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography, and a fraction eluted with ethyl acetate-ethyl acetate-methanol (8:2) was concentrated under reduced pressure to give the object product (304 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]2[O:13][CH:12](C)[CH2:11][C:10]=12)=[O:4].N1C(C)=CC=CC=1C.B(Br)(Br)Br.COC(C1C=C(OC)C=C2OC=CC=12)=O>>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([OH:15])[CH:8]=[C:9]2[O:13][CH:12]=[CH:11][C:10]=12)=[O:4]
Reactant: COC(=O)c1cc(O)cc2c1CC(C)O2
Agent: BrB(Br)Br
Agent: COC(=O)c1cc(OC)cc2occc12
Solvent: Cc1cccc(C)n1
Product: COC(=O)c1cc(O)cc2occc12

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1e, from 2,6-lutidine (1.42 mL, 12.2 mmol), BBr3 (12.2 mL, 12.2 mmol, 1.0 M in CH2Cl2) and 6-methoxy-benzofuran-4-carboxylic acid methyl ester (6c) (840 mg, 4.07 mmol). Purification by flash column chromatography (10-15% EtOAc in hexanes) gave a pale yellow solid (350 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J=2.27 Hz, 1 H) 7.61 (d, J=2.02 Hz, 1 H) 7.24 (dd, J=3.28, 2.27 Hz, 2 H) 5.66 (s, 1 H) 4.00 (s, 3 H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11](Cl)=[O:12])=[C:4]2[CH:3]=1.[CH:14]1([NH2:20])[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>ClCCl>[Cl:1][C:2]1[N:7]=[CH:6][N:5]2[N:8]=[CH:9][C:10]([C:11]([NH:20][CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[O:12])=[C:4]2[CH:3]=1
Reactant: NC1CCCCC1
Reactant: O=C(Cl)c1cnn2cnc(Cl)cc12
Solvent: ClCCl
Product: O=C(NC1CCCCC1)c1cnn2cnc(Cl)cc12
Reaction time: 0.25 h
Yield: 100 %

Procedure:
To a stirred solution of crude 5-chloropyrazolo[1,5-c]pyrimidine-3-carbonyl chloride (200 mg, 0.9 mM, 1.0 equiv) in 15 mL of dichloromethane was added cyclohexylamine (400 ul, 4.0 mM, 4 equiv). The reaction mixture was stirred for 15 minutes then quenched with 0.4 mL of acetic acid. The reaction mixture was concentrated under reduced pressure and the residue partitioned between water and dichloromethane. The dichloromethane phase was concentrated, and the crude product purified by flash chromatography on silica gel (97:3 dichloromethane:methanol) to yield 310 mg (100%) of 5-chloro-N-cyclohexylpyrazolo[1,5-c]pyrimidine-3-carboxamide. LCMS (ESI) m+H=279.1; 1H NMR (400 MHz, CDCl3) δ: 8.66 (s, 1H), 8.65 (d, 1H), 7.47 (d (broad exchangeable) 1H), 6.93 (d, 1H), 4.08 (m, 1H), 2.02 (m, 2H), 1.80 (m, 2H), 1.62 (m, 1H), 1.40 (m, 5H).
Reaction SMILES: [Br:1][C:2]1[C:18]([OH:19])=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.C1C(=O)N([I:27])C(=O)C1>C(O)(C(F)(F)F)=O>[Br:1][C:2]1[C:18]([OH:19])=[C:17]([I:27])[C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1
Reactant: O=C(N1CCc2cc(O)c(Br)cc2CC1)C(F)(F)F
Reactant: O=C1CCC(=O)N1I
Solvent: O=C(O)C(F)(F)F
Product: O=C(N1CCc2cc(Br)c(O)c(I)c2CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 11.7 %

Procedure:
Into a 100 ml flask, the product of step (e) (1.03 g, 3.05 mmol) dissolved in TFA (10 ml) was added. To this stirred solution, NIS (828 mg, 3.68 mmol) was added. The reaction mixture was stirred at room temperature for 45 minutes, then carefully poured over ice-cold saturated aqueous NaHCO3 (200 ml). The aqueous mixture was extracted with EtOAc (3×). The combined EtOAc extracts were washed with brine, dried over Na2SO4, and solvent evaporated in vacuo to give the crude product. Purification by silica-gel chromatography (gradient elution: 0 to 30% EtOAc in hexanes) gave the sub-title compound as a yellow solid (166 mg). 1H NMR (300 MHz, CDCl3) δ 7.29 (s, 1H); 5.99 (s, 1H); 3.76-3.67 (m, 4H); 3.33-3.30 (m, 2H); 3.00-2.96 (m, 2H); MS: ESI (positive): 464, 466 (M+H).