Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:10]2[C:9]3[CH:11]=[C:12]([C:15]#[N:16])[N:13]=[CH:14][C:8]=3[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:5]=[CH:4][CH:3]=1.[NH:25]1[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:26]1>CN(C)C(=O)C.C(OCC)(=O)C>[C:15]([C:12]1[N:13]=[CH:14][C:8]2[N:7]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]3[N:5]=[CH:4][CH:3]=[C:2]([N:25]4[CH2:29][CH2:28][C@H:27]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:26]4)[C:10]=3[C:9]=2[CH:11]=1)#[N:16]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Reactant: C[Si](C)(C)CCOCn1c2cnc(C#N)cc2c2c(Cl)ccnc21
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Temperature: 100 °C

Procedure:
A mixture of 4-chloro-9-(2-trimethylsilanyl-ethoxymethyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrole-6-carbonitrile (590 mg, 1.6 mmol) and (S)-tert-butyl pyrrolidin-3-ylcarbamate (918 mg, 4.9 mmol) in N,N-dimethylacetamide (7.6 mL) was heated at 100° C. for 2 hours. The cooled reaction mixture was diluted with ethyl acetate (100 mL) and washed with water (40 mL). The organic layer was separated, dried over sodium sulfate, filtered, concentrated in vacuo, and purified by flash chromatography (silica, 12 g, ISCO, 0-90% ethyl acetate in heptane) to afford the title compound as a white solid, which was used in the next step without any further purification (530 mg, 63%).
Reaction SMILES: [CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=O)[CH3:5])([CH3:3])[CH3:2].[NH2:15][CH2:16][C:17]([NH2:20])([CH3:19])[CH3:18]>>[CH:1]([N:4]([C:6]1[CH:7]=[C:8]([OH:14])[C:9](=[CH:12][CH:13]=1)[CH:10]=[N:15][CH2:16][C:17]([CH3:19])([N:20]=[CH:10][C:9]1[C:8](=[CH:7][C:6]([N:4]([CH3:5])[CH:1]([CH3:2])[CH3:3])=[CH:13][CH:12]=1)[OH:14])[CH3:18])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(N)CN
Reactant: CC(C)N(C)c1ccc(C=O)c(O)c1
Product: CC(C)N(C)c1ccc(C=NCC(C)(C)N=Cc2ccc(N(C)C(C)C)cc2O)c(O)c1

Procedure:
Synthesis and working up are carried out as in Example 9, starting from 500 mg (2.59 mmol) of 4-(N-isopropyl-N-methylamino)salicylaldehyde and 109 mg (1.23 mmol) of 1,2-diamino-2-methylpropane.
Reaction SMILES: C([O:5][P:6]([O:13][CH2:14][C:15]([NH:18][C:19]([C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:33]=[CH:32][C:31]([NH:34]C(=O)OC(C)(C)C)=[CH:30][CH:29]=2)=[C:23]([NH:42][C:43]2[C:44]3[CH:52]=[CH:51][C:50]([CH:53]([CH3:55])[CH3:54])=[N:49][C:45]=3[N:46]=[CH:47][N:48]=2)[CH:22]=1)=[O:20])([CH3:17])[CH3:16])([O:8]C(C)(C)C)=[O:7])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+:67]>ClCCl>[P:6]([O-:7])([O-:8])([O:13][CH2:14][C:15]([NH:18][C:19](=[O:20])[C:21]1[CH:26]=[CH:25][C:24]([S:27][C:28]2[CH:29]=[CH:30][C:31]([NH2:34])=[CH:32][CH:33]=2)=[C:23]([NH:42][C:43]2[C:44]3[CH:52]=[CH:51][C:50]([CH:53]([CH3:54])[CH3:55])=[N:49][C:45]=3[N:46]=[CH:47][N:48]=2)[CH:22]=1)([CH3:17])[CH3:16])=[O:5].[Na+:67].[Na+:67]
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)COP(=O)(OC(C)(C)C)OC(C)(C)C)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NC(C)(C)COP(=O)([O-])[O-])ccc3Sc3ccc(N)cc3)ncnc2n1
Reaction time: 1 h
Yield: 90.7 %

Procedure:
The product of Example 438D (90 mg, 0.11 mmol) in dichloromethane (0.5 mL) was reacted with trifluoroacetic acid [TFA] (0.5 mL) dropwise at room temperature then stirred for 1 hour. The reaction was concentrated and re-dissolved in a mixture of methanol and water to which was added sodium hydrogencarbonate (0.10 g, 1.19 mmol). Purification of the residue on a reverse phase C18 column eluting with a gradient of methanol in water (0-100%) gave the title compound as a yellow solid (62.5 mg, 88%). 1H NMR (300 MHz, DMSO-D6) δ ppm 1.29 (d, J=6.99 Hz, 6 H) 1.32 (s, 6 H) 3.03-3.20 (m, 1 H) 3.54 (d, J=11.40 Hz, 2 H) 5.45 (s, 2 H) 6.50-6.53 (m, 1 H) 6.62 (d, J=8.46 Hz, 2 H) 7.11 (d, J=8.46 Hz, 2 H) 7.34 (s, 1 H) 7.60 (s, 1 H) 7.87 (s, 1 H) 8.29 (s, 1 H) 8.74 (s, 1 H) 9.82 (s, 1 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2I)[CH2:14][C:13]2[C:8](=[C:9]([F:16])[CH:10]=[CH:11][C:12]=2[F:15])[CH2:7]1)=[O:5])[CH3:2].[CH3:28][C:29]([CH3:40])=[CH:30]B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].N#N>O1CCOCC1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH2:1]([O:3][C:4]([C:6]1([NH:17][C:18](=[O:27])[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=2[CH:28]=[C:29]([CH3:40])[CH3:30])[CH2:14][C:13]2[C:8](=[C:9]([F:16])[CH:10]=[CH:11][C:12]=2[F:15])[CH2:7]1)=[O:5])[CH3:2]
Reactant: CC(C)=CB1OC(C)(C)C(C)(C)O1
Reactant: CCOC(=O)C1(NC(=O)c2cccc(C)c2I)Cc2c(F)ccc(F)c2C1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2C=C(C)C)Cc2c(F)ccc(F)c2C1
Temperature: 100 °C
Reaction time: 4 h

Procedure:
To a solution of 4,7-difluoro-2-(2-iodo-3-methyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (390) (451 mg, 1 mmol) and 2-methyl-1-propenyl boronic acid pinacol ester (364 mg, 2 mmol) in dioxane (20 mL) was added dichloro[1,1′-bis(diphenylphosphino)-ferrocene]palladium (II) dichloromethane adduct (65 mg, 8.2% mmol) and 2M aqueous solution of K2CO3 (1.5 mL, 3 mmol). The resulting reaction mixture is filled in with N2, heated to 100° C. and stirred continuously for 4 h. The reaction mixture is filtered and concentrated in vacuo, and the resulting residue is purified by flash column chromatography (12 g silica gel, gradient elution: 0%-50% EtOAc in heptane) to give a pure product (391) as light brown oil (150 mg, 36%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6].[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30]OS(C)(=O)=O)=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]>O1CCCC1.C(OCC)(=O)C>[Cl:7][C:8]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH2:30][NH:1][CH2:2][CH2:3][CH2:4][CH2:5][OH:6])=[CH:24][C:9]=1[C:10]([NH:12][CH2:13][C:14]12[CH2:23][CH:18]3[CH2:19][CH:20]([CH2:22][CH:16]([CH2:17]3)[CH2:15]1)[CH2:21]2)=[O:11]
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Reactant: NCCCCO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCCCO)ccc1Cl
Temperature: 60 °C

Procedure:
4-Amino-1-butanol (0.11 ml) was added to a solution of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl)-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (0.25 g, Example 6e) in tetrahydrofuran (4 ml) and heated at 60° C. in a sealed tube for 12 h. On cooling to ambient temperature, the mixture was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25-95%) gave the title compound as the acetate salt. Treatment with aqueous 2M sodium hydroxide and extraction into ethyl acetate gave the title compound (0.065 g).
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[C:5]([Si:9]([CH3:30])([CH3:29])[O:10][CH:11]1[CH2:16][CH2:15][C:14]([CH:21]=[N:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([C:17]([F:20])([F:19])[F:18])[CH2:13][CH2:12]1)([CH3:8])([CH3:7])[CH3:6].[O-]S([O-])(=O)=O.[Na+].[Na+]>C(OCC)C>[C:5]([Si:9]([CH3:30])([CH3:29])[O:10][CH:11]1[CH2:12][CH2:13][C:14]([CH:21]([NH:22][S:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])[CH2:1][CH3:2])([C:17]([F:19])([F:20])[F:18])[CH2:15][CH2:16]1)([CH3:8])([CH3:7])[CH3:6]
Reactant: CC(C)(C)S(=O)N=CC1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Reactant: CC[Mg]Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOCC
Product: CCC(NS(=O)C(C)(C)C)C1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
13.4 ml (26.8 mmol) of a 2M solution of ethylmagnesium chloride in diethyl ether were diluted using 8 ml of anhydrous diethyl ether and cooled to −78° C. At that temperature, a solution of 3.7 g (8.95 mmol) of 2-methyl-propane-2-sulfinic acid 1-[4-(tert-butyl-dimethyl-silanyloxy)-1-trifluoromethyl-cyclohexyl]methylideneamide (72) in anhydrous diethyl ether was added dropwise. Afterwards, the mixture was allowed to warm to ambient temperature and was stirred for 2 h at ambient temperature. 100 ml of a saturated aqueous Na2SO4-solution was added, the organic layer separated, dried using MgSO4 and evaporated to give 3.22 g of 73 as an oil, used without further purification. Rt=1.09 min (Method Q).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1.[CH2:21]([O-:24])[CH:22]=[CH2:23].[Na+]>CN(C=O)C>[CH2:21]([O:24][C:2]1[N:7]=[C:6]([N:8]([CH2:11][C:12]2[S:16][C:15]([Cl:17])=[N:14][CH:13]=2)[CH2:9][CH3:10])[C:5]([N+:18]([O-:20])=[O:19])=[CH:4][CH:3]=1)[CH:22]=[CH2:23]
Reactant: C=CC[O-]
Reactant: CCN(Cc1cnc(Cl)s1)c1nc(Cl)ccc1[N+](=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc([N+](=O)[O-])c(N(CC)Cc2cnc(Cl)s2)n1
Temperature: 7.5 °C
Yield: 21.3 %

Procedure:
1.10 g of 6-chloro-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-3-nitropyridine-2-amine, prepared according to the example 1, in 30 mL of DMF was added into a 100 mL three-necked flask equipped with a magnetic stirrer, a condenser and a drying tube, under stirring at 5-10° C., 1.02 g of sodium prop-2-en-1-olate (the content of 30.7%) in 20 mL of DMF was added dropwise, and the reaction was complete after further stirred for 4 to 6 hours. The reaction mixture was treated by the method according to the example 1 to obtain 0.25 g of 6-allyloxy-N-((2-chlorothiazole-5-yl)methyl)-N-ethyl-nitropyridine-2-amine, having the content of 91%, as a brown sticky solid in a yield of 19.4%. GC-MS (M+) (EI, 70 eV, m/z) calc: 354. found: 354. 1H NMR (CDCl3/TMS, 300 MHz) δ (ppm) 1.221 (t, J=7.2 Hz, 3H, CH3), 3.291 (q, J=7.2 Hz, 2H, CH2), 4.817 (s, 2H, CH2), 4.869 (d J=2.7 Hz, 2H, CH2), 5.464-5.267 (m, 2H, CH2), 6.086-5.957 (m, 1H, CH), 6.231 (d, J=8.7 Hz, 1H, Py H), 7.473 (s, 1H, Thiazole-H), 8.171 (d, J=8.7 Hz, 1H, Py H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:15]([O:17][CH2:18][CH2:19][N:20]1[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[N:22]=[C:21]1[NH:29][CH:30]1[CH2:35][CH2:34][N:33]([CH2:36][CH2:37][C:38]2([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:42][CH2:41][NH:40][CH2:39]2)[CH2:32][CH2:31]1)[CH3:16]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([C:12]#[N:13])=[CH:8][C:4]=1[C:5]([N:40]1[CH2:41][CH2:42][C:38]([CH2:37][CH2:36][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:21]3[N:20]([CH2:19][CH2:18][O:17][CH2:15][CH3:16])[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=4[N:22]=3)[CH2:31][CH2:32]2)([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[CH2:39]1)=[O:7]
Reactant: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(C#N)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(NC2CCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(C#N)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 59.1 using 2-methoxy-5-cyanobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-(2-hydroxyethyl)-3-phenylpyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1N=C(N)C(C2C=CC([N+:32]([O-:34])=[O:33])=CC=2C2C=CC=C(Cl)C=2Cl)=CN=1.NC1N=C(N)C(C2C=C([N+]([O-])=O)C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: Nc1ncc(-c2ccc([N+](=O)[O-])cc2-c2cccc(Cl)c2Cl)c(N)n1
Agent: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: [C:1]1([C:11]2[CH:15]=[C:14]([NH2:16])[NH:13][N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:17](OC)(=O)[CH2:18][C:19](OC)=O.C(O)C.C[O-].[Na+].CO>>[C:1]1([C:11]2[CH:15]=[C:14]3[N:16]=[CH:17][CH:18]=[CH:19][N:13]3[N:12]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: COC(=O)CC(=O)OC
Reactant: Nc1cc(-c2cccc3ccccc23)n[nH]1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: CCO
Product: c1ccc2c(-c3cc4ncccn4n3)cccc2c1
Temperature: 120 °C

Procedure:
To a solution of 3-(1-naphthyl)-1H-pyrazol-5-amine (654 mg, 3.12 mmol) and dimethyl malonate (0.394 mL, 3.44 mmol) in anhydrous ethanol (9.44 mL, 162 mmol) is added 0.5 M sodium methoxide in methanol (12.5 mL, 6.25 mmol). The mixture is heated at 120° C. under a nitrogen atmosphere overnight. The reaction mixture is cooled to room temperature and the solvent is removed in vacuo. The residue is suspended in water and the precipitate is collected in a Buchner funnel to provide 2-(1-naphthyl)pyrazolo[1,5-a]pyrimidine, 7-diol (534 mg, yield 62%). LCMS: (AA) M+1 278; 1H NMR (400 MHz, DMSO) δ 10.17 (s, 1H), 8.73 (dd, J=8.2, 4.8 Hz, 1H), 7.99-7.88 (m, 2H), 7.72 (dd, J=7.1, 1.1 Hz, 1H), 7.58-7.49 (m, 4H), 5.83 (s, 1H), 4.14 (s, 1H).
Reaction SMILES: [C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([CH:7](Br)[CH:8](Br)[C:9]#[N:10])=[CH:3][CH:2]=1.[CH3:19][O-:20].[Na+]>CO>[C:1]1([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][C:4]([C:7]([O:20][CH3:19])=[CH:8][C:9]#[N:10])=[CH:3][CH:2]=1
Reactant: C[O-]
Reactant: N#CC(Br)C(Br)c1ccc(-c2ccccc2)cc1
Agent: [Na+]
Solvent: CO
Product: COC(=CC#N)c1ccc(-c2ccccc2)cc1
Reaction time: 2 h

Procedure:
3-(4-Biphenylyl)-2,3-dibromopropionitrile (16 grams) and sodium methoxide (4.7 grams) in 500 ml. of methanol were reacted in an ice bath. A solid precipitated at once and then the reaction mixture was stirred for 2 hours. The final product was determined by NMR to be a mixture of 3-(4-biphenylyl)-3-methoxyacrylonitrile plus 3-(4-biphenylyl)-3,3-dimethoxypropionitrile.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][C:15]2[CH:16]=[C:17]3[C:21](=[C:22]([Cl:24])[CH:23]=2)[C:20](=[O:25])[N:19]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([O:33][C:34]([F:37])([F:36])[F:35])=[CH:29][CH:28]=2)[CH2:18]3)[CH2:10][CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[Cl:24][C:22]1[CH:23]=[C:15]([CH2:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)[CH:16]=[C:17]2[C:21]=1[C:20](=[O:25])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][C:34]([F:36])([F:37])[F:35])=[CH:29][CH:28]=1)[CH2:18]2
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1c2c(Cl)cc(CC3CCNCC3)cc2CN1Cc1ccc(OC(F)(F)F)cc1
Yield: 109.2 %

Procedure:
4-[7-Chloro-1-oxo-2-(4-trifluoromethoxybenzyl)-2,3-dihydro-1H-isoindol-5-ylmethyl]-piperidine-1-carboxylic acid tert-butyl ester (54.90 mg, 0.102 mmol) was stirred in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) overnight. The reaction mixture was quenched with sodium carbonate to pH=8-9 and the free base was extracted with dichloromethane. The organic layer was washed with water, brine, dried over sodium sulfate, filtered and concentrated to provide the title compound (48.9 mg, 100%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[OH:13])[C:7]([OH:9])=O)(=[O:3])[CH3:2].CC[N:16]([CH:20]([CH3:22])C)[CH:17]([CH3:19])C.N1CCCC1>CN(C=O)C>[OH:13][C:12]1[CH:11]=[CH:10][C:6]([C:7]([N:16]2[CH2:17][CH2:19][CH2:22][CH2:20]2)=[O:9])=[CH:5][C:4]=1[C:1](=[O:3])[CH3:2]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(=O)c1cc(C(=O)O)ccc1O
Solvent: C1CCNC1
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(=O)N2CCCC2)ccc1O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.8 %

Procedure:
To a solution of 500 mg (2.8 mmol) of 3-acetyl-4-hydroxy-benzoic acid in 5 mL of DMF, 721.6 μL (4.2 mmol) of TFA-OPfp and 731.5 μL (4.2 mmol) of DIEA were added. The clear solution was stirred at room temperature for 15 minutes, then 467.5 μL (5.6 mmol) of pyrrolidine was added. The mixture was stirred for another hour and was then evaporated to dryness. The oily residue was taken up in 50 mL water-50 mL ethyl acetate mixture, the EtOAc phase was separated, washed twice with 1 M HCl, water, saturated NaHCO3, brine and was dried with Na2SO4. The EtOAc was evaporated; the oil was purified on an open silica gel column using a toluene/ethyl acetate gradient containing 5% acetic acid to yield 410 mg (51%) Compound 18.
Reaction SMILES: [N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36](=O)[CH2:37]Br)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:17])([F:16])[F:15])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:42]([NH2:45])(=[O:44])[CH3:43]>CN(C=O)C.C(OCC)(=O)C>[N+:1]([C:4]1[CH:41]=[CH:40][C:7]([C:8]([O:10][C@@:11]([C:18]2[N:19]=[N:20][N:21]([CH2:23][C:24]3[CH:33]=[C:32]4[C:27]([C:28]([C:36]5[N:45]=[C:42]([CH3:43])[O:44][CH:37]=5)=[CH:29][C:30]([C:34]#[N:35])=[N:31]4)=[CH:26][CH:25]=3)[CH:22]=2)([C:14]([F:15])([F:16])[F:17])[CH2:12][CH3:13])=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(C(=O)CBr)cc(C#N)nc3c2)nn1)C(F)(F)F
Reactant: CC(N)=O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC[C@](OC(=O)c1ccc([N+](=O)[O-])cc1)(c1cn(Cc2ccc3c(-c4coc(C)n4)cc(C#N)nc3c2)nn1)C(F)(F)F

Procedure:
A solution of (S)-1-(1-{[4-(bromoacetyl)-2-cyanoquinolin-7-yl]methyl}-1H-1,2,3-triazol-4-yl)-1-(trifluoromethyl)propyl 4-nitrobenzoate (0.16 g, 0.25 mmol) and acetamide (16 mg, 0.28 mmol) in DMF (0.25 mL) was stirred at room temperature for 4 h then at 100° C. overnight. The reaction mixture was diluted in ethyl acetate, washed with water, brine and dried over MgSO4. The crude compound was purified on silica gel (eluting solvent: 2% to 5% acetone in dichloromethane) to give the desired titled product. 1H NMR (acetone-d6): δ 8.9 (d, 1H), 8.72 (s, 1H), 8.53 (s, 1H), 8.42 (d, 2H), 8.30 (d, 2H), 8.25 (s, 1H), 8.05 (s, 1H), 7.77 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (m, 1H), 2.6 (s, 3H), 1.15 (t, 3H); and also the reduced compound 1-{1-[(4-acetyl-2-cyanoquinolin-7-yl)methyl]-1H-1,2,3-triazol-4-yl}-1-(trifluoromethyl)propyl 4-nitrobenzoate. 1H NMR (acetone-d6): δ 8.55 (m, 2H), 8.45 (m, 3H), 8.3 (d, 2H), 8.07 (s, 1H), 7.82 (d, 1H), 6.05 (s, 2H), 3.05 (m, 1H), 2.85 (s, 3H), 2.82 (m, 1H), 1.12 (t, 3H).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10](Br)[CH:9]=1)(=O)C.[CH3:27][C:28]1[C:32](B(O)O)=[C:31]([CH3:36])[O:30][N:29]=1>>[O:7]([C:8]1[CH:13]=[CH:12][N:11]=[C:10]([C:32]2[C:28]([CH3:27])=[N:29][O:30][C:31]=2[CH3:36])[CH:9]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccnc(Br)c1
Reactant: Cc1noc(C)c1B(O)O
Product: Cc1noc(C)c1-c1cc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)ccn1

Procedure:
By carrying out the operation analogously to example 239, starting from 2-bromo-4-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation VII, and 3,5-dimethyl-4-isoxazoleboronic acid, the desired product is obtained in the form of white crystals (yield=25%).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]2[C:7]([I:15])=[N:6]1.[NH:16]1[CH:20]=[CH:19][N:18]=[CH:17]1.C(N(CC)CC)C>CN(C)C=O>[N:16]1([CH2:2][CH2:3][CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[N:12][C:13]([NH2:14])=[C:8]3[C:7]([I:15])=[N:6]2)[CH:20]=[CH:19][N:18]=[CH:17]1
Reactant: Nc1ncnc2c1c(I)nn2CCCBr
Reactant: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Nc1ncnc2c1c(I)nn2CCCn1ccnc1
Temperature: 70 °C
Reaction time: 25.5 h
Yield: 17.8 %

Procedure:
A suspension of 1-(3-bromopropyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.500 g, 1.31 mmol) in dimethylformamide (10 mL) was treated with imidazole (0.107 g, 1.572 mmol) and triethylamine (0.133 g, 1.31 mmol). The reaction mixture was stirred at 70° C. for 25.5 h. Solvent was removed under reduced pressure. Dichloromethane (15 mL) and 1 N hydrochloric acid (20 mL) were added. The layers were partitioned and the aqueous layer was washed with dichloromethane (100 mL). The aqueous layer was neutralized to pH 14 and then extracted with dichloromethane (250 mL). The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure. The crude material was purified by flash chromatography on silica gel using 10% methanol in dichloromethane as the eluent. The column afforded 0.086 g (18%) of pure 1-[3-(1H-1-imidazolyl)propyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine. 1H NMR (DMSO-d6, 400 MHz) δ 8.211 (s, 1H), 7.896 (s, 1H), 7.264 (s, 1H), 6.96 (s, 1H), 4.32-4.227 (m, 2H), 4.011-3.977 (m, 2H), 2.329-2.215 (m, 2H); LCMS (Thermoquest AQA single-quad MS, Genesis C18 column, 3 μm particle size, 33×4.6 mm; 70% 50 mM ammonium acetate in water to 95% acetonitrile over 6 min, 0.8 to 0.5 mL/min) Rt 0.46 min (100%), MH+ 370.0.
Reaction SMILES: [OH:1][C:2]1[CH:13]=[CH:12][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.Br[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[CH2:15]([O:1][C:2]1[CH:3]=[CH:4][C:5](/[CH:6]=[CH:7]/[C:8]([O:10][CH3:11])=[O:9])=[CH:12][CH:13]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCBr
Reactant: COC(=O)/C=C/c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCOc1ccc(/C=C/C(=O)OC)cc1

Procedure:
Trans methyl 4-hydroxycinnamate (20.0 g, 11.2 mmol), 1-bromohexane (18.5 g, 112 mmol) and potassium carbonate (16.6 g, 120 mmol) were stirred under reflux in butanone. The mixture was allowed to cool after 16 hours, evaporated to dryness and the residue was partitioned between DCM and water. The DCM layer was removed and dried (Na2SO4) and evaporated to leave a yellow solid methyl (E)-3-(4-hexyloxyphenyl)-2-propenoate which was recrystallized from petroleum. Yield=20.0 g, 71%.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([NH2:11])[CH3:10].C(N(CC)C(C)C)(C)C.[F:21][C:22]1[CH:30]=[C:29]2[C:25]([C:26]([C:32]3[N:33]=[C:34]4[C:40]([C:41](O)=[O:42])=[CH:39][N:38]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[C:35]4=[N:36][CH:37]=3)=[N:27][N:28]2[CH3:31])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C@H:9]([NH:11][C:41]([C:40]1[C:34]2[C:35](=[N:36][CH:37]=[C:32]([C:26]3[C:25]4[C:29](=[CH:30][C:22]([F:21])=[CH:23][CH:24]=4)[N:28]([CH3:31])[N:27]=3)[N:33]=2)[N:38]([CH2:44][O:45][CH2:46][CH2:47][Si:48]([CH3:51])([CH3:50])[CH3:49])[CH:39]=1)=[O:42])[CH3:10]
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(F)cc21
Reactant: C[C@@H](N)c1ccccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(F)ccc34)nc12)c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
To a solution of (R)-1-pyridin-2-yl-ethylamine dihydrochloride (66 mg, 0.34 mmol) in DMF (2 mL) was added N,N-diisopropylethylamine (0.20 mL, 1.13 mmol), 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (100 mg, 0.23 mmol), and HATU (95 mg, 0.25 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (3×). The combined organics were washed with water (3×) and brine then dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography with 50% to 100% EtOAc/hexanes to give 117 mg (95%) of 2-(6-fluoro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-1-pyridin-2-yl-ethyl)-amide as a white solid.