Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)=[C:6]([F:19])[C:5]([CH3:20])=[CH:4][CH:3]=1.[Br:21]N1C(=O)CCC1=O.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:21][CH2:20][C:5]1[C:6]([F:19])=[C:7]([O:8][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11][CH:10]=2)[C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(Cl)c(Oc2cccc3ccccc23)c1F
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1c(CBr)ccc(Cl)c1Oc1cccc2ccccc12
Yield: 45.5 %

Procedure:
To a solution of 1-[(6-chloro-2-fluoro-3-methylphenyl)oxy]naphthalene (1.69 g, 5.89 mmol) in carbon tetrachloride (20 mL) was added N-bromosuccinimide (1.154 g, 6.48 mmol) and AIBN (0.048 g, 0.295 mmol). The mixture was heated at reflux overnight. The reaction mixture was filtered through Celite and the solvent was evaporated. The residue was purified by flash chromatography (hexane:ethyl acetate) to give the desired product (0.98 g, 45.5%) as a light yellow oil. 1H NMR (400 MHz, chloroform-d) δ ppm 8.43-8.51 (m, 1H), 7.84-7.92 (m, 1H), 7.53-7.64 (m, 3H), 7.23-7.34 (m, 3H), 6.50 (d, 1H), 4.50 (d, 2H).
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)=[CH:9][S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[NH2:18][CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=1.C(N(C(C)C)CC)(C)C>CN(C)C=O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:10]2[C:3]3[C:2]([NH:18][CH2:19][CH2:20][CH2:21][O:22][C:23]4[CH:24]=[C:25]([NH:29][C:30](=[O:32])[CH3:31])[CH:26]=[CH:27][CH:28]=4)=[N:7][CH:6]=[N:5][C:4]=3[S:8][CH:9]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2csc3ncnc(Cl)c23)cc1
Reactant: CC(=O)Nc1cccc(OCCCN)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1cccc(OCCCNc2ncnc3scc(-c4ccc(F)cc4)c23)c1
Temperature: 120 °C
Yield: 75.8 %

Procedure:
A mixture of 4-chloro-5-(4-fluorophenyl)thieno[2,3-d]pyrimidine (100 mg, 0.378 mmol), N-[3-(3-amino-propoxy)-phenyl]-acetamide (94 mg, 0.45 mmol), diisopropylethylamine (147 mg, 1.14 mmol) and N,N-dimethylformamide (3.0 mL) was warmed to 120° C. for 20 minutes by microwave irradiation. The solvent was then concentrated in vacuo and the residue was dissolved in ethyl acetate (50 mL) and washed with of aqueous sodium bicarbonate (2×30 mL). The organic layer was concentrated in vacuo and purified by column chromatography over silica gel using 1% methanol in dichloromethane as eluant to give 125 mg (73%) of N-[3-(3-{[5-(4-fluorophenyl)thieno[2,3-d]pyrimidin-4-yl]amino}propoxy)phenyl]acetamide as a white solid. MS [M+H] 437.1, 1H NMR (CDCl3) 6 (ppm) 8.50 (s, 1H), 7.41-7.36 (m, 2H), 7.25 (s, 1H), 7.21 (t, J=8.1 Hz, 1H), 7.07-6.95 (m, 3H), 6.94 (d, J=8.1 Hz, 1H), 6.55 (d, J=8.4 Hz, 1H), 5.01 (b, 1H), 3.89 (t, J=6.0 Hz, 2H), 3.64 (m, 2H), 2.19 (s, 3H), 1.98 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=[N:10][C:9]=2[C:25]([O:27]CC)=O)=[CH:4][CH:3]=1.[CH3:30][NH2:31]>CO>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])=[N:10][C:9]=2[C:25](=[O:27])[NH:31][CH3:30])=[CH:4][CH:3]=1
Reactant: CN
Reactant: CCOC(=O)c1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(Br)cc1
Solvent: CO
Product: CNC(=O)c1nc([C@@H]2CCCN2C(=O)OC(C)(C)C)[nH]c1-c1ccc(Br)cc1
Temperature: 70 °C

Procedure:
(S)-ethyl 5-(4-bromophenyl)-2-(1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-1H-imidazole-4-carboxylate (1 g, 2.1 mmol) was dissolved in 2M methylamine in MeOH (35 mL) and heated in a pressure vessel at 70° C. for 48 h. The reaction mixture was concentrated and the residue applied to a Biotage 25 m silica gel cartridge and eluted by 10-100% gradient, ethyl acetate/Hex to give 556 mg (57%). 1H NMR (300 MHz, DMSO-d6) δ 12.5 (br.s, 1H), 7.86-7.82 (m, 1H), 7.77 (d, J=8.4 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 4.83-4.70 (m, 1H), 3.69-3.52 (br.s, 1H), 3.42-3.32 (m, 1H), 2.71 (d, 4.8 Hz, 3H), 2.30-1.78 (m, 4H), 1.19-1.14 (m, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]([CH3:18])([CH3:17])[CH2:15][OH:16])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:18][C:14]([N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)([CH3:17])[CH2:15][OH:16]
Reactant: CC(C)(C)OC(=O)N1CCN(C(C)(C)CO)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(CO)N1CCNCC1
Reaction time: 3 h

Procedure:
To a solution of 4-(2-hydroxy-1,1-dimethylethyl)piperazine-1-carboxylic acid tert-butyl ester (110 mg, 0.43 mmol) in DCM (3 mL) was added TFA (1 mL) and the resulting mixture stirred for 3 h. The reaction mixture was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording the title compound as an off-white solid (62 mg, 91%). 1H NMR (CDCl3, 400 MHz): δ 3.32 (2 H, s), 2.90 (5 H, t, J=4.78 Hz), 2.38-2.13 (4 H, m), 1.03 (6 H, s)
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C>CCCCO>[CH2:1]([S:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11]([NH:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Clc1nc(SCc2ccccc2)nc2nc[nH]c12
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: c1ccc(CSc2nc(Nc3ccccc3)c3[nH]cnc3n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-Benzylthio-6-chloropurine (3.9 g) and aniline (3.42 g) in n-BuOH (100 ml) in the presence of triethylamine (7.5 ml) were refluxed for 2 h. Reaction mixture was cooled to room temperature, dried at a rotary vacuum evaporator, cooled with ice and 400 ml water was added with vigorous shaking. At standing overnight at −16° C. crude dark-brown solid was formed, which was dried into constant weight and chromatographically purified over 100 g silica packed in chloroform. The column was eluted with 500 ml 100% chloroform followed by 500 ml 1.25% MeOH/chloroform and then 1.5 L 2.5% MeOH/chloroform; 100 ml fractions collected and fractions 12 to 15 were dried to yield light-brown solid which were recrystallized from MeOH in the presence of active carbon. Yield 1.18 g of white, amorphous solid. TLC (2.5% MeOH/chloroform) shows only a single spot with no contaminants. HPLC purity: 98+%.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=O.O.[NH2:21][NH2:22]>C(O)COCCO>[F:1][C:2]([F:19])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([NH2:17])=[C:7]([CH:16]=1)[C:8](=[N:21][NH2:22])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NN
Reactant: Nc1ccc(C(F)(F)F)cc1C(=O)c1ccccc1
Solvent: O
Solvent: OCCOCCO
Product: NN=C(c1ccccc1)c1cc(C(F)(F)F)ccc1N

Procedure:
In the manner given in Preparation 1, 5-(trifluoromethyl)-2-aminobenzophenone is refluxed with hydrazine hydrate in diethylene glycol to give 5-(trifluoromethyl)-2-aminobenzophenone hydrazone.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[CH:7]=1.[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH:33]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[O:21]=[C:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24](=[O:31])[N:23]1[CH2:32][CH2:33][NH:1][C:2]1[C:3]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:4][CH:5]=[C:6]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([F:15])=[CH:13][CH:14]=2)[CH:7]=1
Reactant: O=CCN1C(=O)c2ccccc2C1=O
Reactant: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ncc(Cc2ccc(F)cc2)cc1NCCN1C(=O)c2ccccc2C1=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
A solution of ethyl 3-amino-5-(4-fluorobenzyl)-2-pyridinecarboxylate (1.50 g, 5.47 mmol) and (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde (2.27 g, 12 mmol) under nitrogen in glacial acetic acid (50 mL) was treated with sodium triacetoxyborohydride (2.56 g, 12.1 mmol) at ambient temperature. After stirring for 30 min., 40 mL of glacial acetic acid (40 mL) was added, to dilute the reaction, followed by 0.17 g of (1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetaldehyde and 0.45 g sodium triacetoxyborohydride. After stirring another 2½ h, the reaction was heated to 45° C. for another hour. The reaction was evaporated in vacuo and the residue was triturated with water (500 mL), filtered, and washed with water. The resulting solid was dissolved in CH2Cl2 dried over MgSO4, filtered and evaporated in vacuo. The residue was dissolved in CH2Cl2 and chromatographed on silica gel eluting with 0-50% EtOAc in hexanes to provide the product as an solid. 1H NMR (400 MHz, DMSO-D6) δ ppm 1.2 (t, J=7.1 Hz, 3 H), 3.5 (q, J=6.2 Hz, 2 H), 3.8 (t, J=6.0 Hz, 2 H), 3.9 (s, 2 H), 4.2 (q, J=7.0 Hz, 2 H), 7.1 (ddd, J=9.1, 6.9, 1.8 Hz, 2 H), 7.3 (m, 3 H), 7.6 (t, J=6.2 Hz, 1 H), 7.7 (d, J=1.6 Hz, 1 H), 7.8 (m, 4 H); ES+MS: 447 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36](Br)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1.[CH3:40][O:41][C:42]1[CH:43]=[N:44][CH:45]=[C:46](B2OC(C)(C)C(C)(C)O2)[CH:47]=1.C(#N)C.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][C@H:15]([NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C:16]([OH:18])=[O:17])=[CH:10][CH:9]=2)[CH:5]=[C:4]([O:27][C@@H:28]([C:33]2[CH:38]=[CH:37][C:36]([C:46]3[CH:45]=[N:44][CH:43]=[C:42]([O:41][CH3:40])[CH:47]=3)=[CH:35][CH:34]=2)[C:29]([F:32])([F:31])[F:30])[N:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cc(O[C@@H](c3ccc(Br)cc3)C(F)(F)F)nc(N)n2)cc1)C(=O)O
Reactant: COc1cncc(B2OC(C)(C)C(C)(C)O2)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: COc1cncc(-c2ccc([C@H](Oc3cc(-c4ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc4)nc(N)n3)C(F)(F)F)cc2)c1
Temperature: 150 °C
Yield: 40.8 %

Procedure:
A microwave vial (2 ml) was charged with (S)-3-(4-{2-amino-6-[(S)-1-(4-bromo-phenyl)-2,2,2-trifluoro-ethoxy]-pyrimidin-4-yl}-phenyl)-2-tert-butoxycarbonylamino-propionic acid (139 mg, 0.23 mmol), 3-methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)-pyridine (69 mg, 0.27 mmol), 1 ml of acetonitrile, and 0.7 ml of water. To this mixture was added 0.4 ml of aqueous sodium carbonate (1M), followed by 14 mg of dichlorobis-(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave irradiation. After cooling, the reaction mixture was evaporated to dryness, the residue was dissolved in 2.5 ml of methanol and purified by preparative HPLC to give 60 mg of (S)-3-[4-(2-amino-6-{(S)-2,2,2-trifluoro-1-[4-(5-methoxy-pyridin-3-yl)-phenyl]-ethoxy}-pyrimidin-4-yl)-phenyl]-2-tert butoxycarbonylamino-propionic acid.
Reaction SMILES: O.[NH2:2][NH2:3].[Cl:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([CH:13]([C:19](=O)[CH3:20])[CH2:14][C:15]([O:17][CH3:18])=[O:16])=O)=[CH:7][CH:6]=1.O>C(O)C>[CH3:18][O:17][C:15](=[O:16])[CH2:14][C:13]1[C:19]([CH3:20])=[N:2][NH:3][C:11]=1[C:8]1[CH:9]=[CH:10][C:5]([Cl:4])=[CH:6][CH:7]=1
Reactant: NN
Reactant: COC(=O)CC(C(C)=O)C(=O)c1ccc(Cl)cc1
Solvent: O
Solvent: CCO
Product: COC(=O)Cc1c(C)n[nH]c1-c1ccc(Cl)cc1

Procedure:
2.236 g (45 mmol) of hydrazine hydrate were added to a solution of 10 g (37 mmol) of methyl 3-[(4-chlorophenyl)carbonyl]-4-oxopentanoate in ethanol (100 ml). The mixture was heated under reflux for 6 hours and then added to water and extracted with dichloromethane. The combined organic phases were dried with magnesium sulfate, filtered and concentrated. This gave 6.9 g of product (63% of theory); NMR (CDCl3, 400 MHz): 2.28 (s, 3H); 3.5 (s, 2H); 3.7 (s, 3H); 7.39 (d, 2H); 7.5 (d, 2H).
Reaction SMILES: [SH-:1].[Na+].Cl[C:4]1[N:9]2[N:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=[C:8]2[N:7]=[C:6]([CH3:16])[CH:5]=1>O>[SH:1][C:4]1[N:9]2[N:10]=[C:11]([CH2:13][O:14][CH3:15])[N:12]=[C:8]2[N:7]=[C:6]([CH3:16])[CH:5]=1
Reactant: [SH-]
Reactant: COCc1nc2nc(C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: COCc1nc2nc(C)cc(S)n2n1
Temperature: 55 °C
Reaction time: 1 h
Yield: 88.5 %

Procedure:
In 350 ml of water was dissolved 24 g of sodium hydrosulfide and 34.5 g of 7-chloro-2-methoxymethyl-5-methyl-s-triazolo[1,5-a]pyrimidine was added thereto, and the mixture was stirred at 55° C. for one hour. After the reaction mixture was filtered, it was ice-cooled and adjusted to pH 1 with addition of a 2N-hydrochloric acid. The precipitates were collected by filtration, washed with water and with isopropanol, and dried to obtain 30.18 g of the title compound.
Reaction SMILES: Cl.[N:2]1([C:8](=[O:21])[CH2:9][C:10]2[CH:15]=[CH:14][C:13]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)=[CH:12][CH:11]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.N1([C:27]2C=CC(CC(O)=O)=C[CH:28]=2)C=NN=N1.C12N(C(OC(C)(C)C)=O)C(CC1)CNC2>>[CH:4]12[NH:5][CH:6]([CH2:27][CH2:28]1)[CH2:7][N:2]([C:8](=[O:21])[CH2:9][C:10]1[CH:11]=[CH:12][C:13]([N:16]3[CH:20]=[N:19][N:18]=[N:17]3)=[CH:14][CH:15]=1)[CH2:3]2
Reactant: O=C(Cc1ccc(-n2cnnn2)cc1)N1CCNCC1
Reactant: O=C(O)Cc1ccc(-n2cnnn2)cc1
Agent: CC(C)(C)OC(=O)N1C2CCC1CNC2
Agent: Cl
Product: O=C(Cc1ccc(-n2cnnn2)cc1)N1CC2CCC(C1)N2

Procedure:
1-(3,8-Diazabicyclo[3.2.1]oct-3-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone was prepared in an analogous fashion as described above in the synthesis of 1-(piperazin-1-yl)-2-[4-(1H-tetrazol-1-yl)phenyl]ethanone hydrochloride starting from [4-(1H-tetrazol-1-yl)phenyl]acetic acid and tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate. LC/MS: [(M+1)]+=299.
Reaction SMILES: C([N:8]([CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](=[O:60])[N:41]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:47]([O:49][CH3:50])=[O:48])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:34])[N:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])(OC(C)(C)C)=O.[F:61][C:62]([F:67])([F:66])[C:63]([OH:65])=[O:64]>C(Cl)Cl>[OH:65][C:63]([C:62]([F:67])([F:66])[F:61])=[O:64].[CH3:50][O:49][C:47]([CH2:46][CH2:45][CH2:44][CH2:43][CH2:42][N:41]([CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][C:56]([O:58][CH3:59])=[O:57])[C:40]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=[O:34])[N:15]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23][CH3:24])=[O:22])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH3:33])=[O:31])=[O:60])=[O:48]
Reactant: COC(=O)CCCCCN(CCCCCC(=O)OC)C(=O)CCCCCN(CCCCCC(=O)N(CCCCCC(=O)OC)CCCCCC(=O)OC)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCCCCN(CCCCCC(=O)OC)C(=O)CCCCCNCCCCCC(=O)N(CCCCCC(=O)OC)CCCCCC(=O)OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a 250 mL round bottom flask, charged with 1.50 g (1.75 mmol) of N-BOC-N,N-bis-(N′,N′-bis(5-methoxycarbonylpentyl)-5-carbamyl pentyl)-amine (17) in 15 mL of methylene chloride, was added 15 mL of trifluoroacetic acid. The mixture was stirred at room temperature for 15 minutes and then concentrated. The residue was diluted with 50 mL of methylene chloride and then concentrated via rotary evaporation. The residue was then diluted with 50 mL of methanol and re-concentrated via rotary evaporation. The residue was again re-diluted with 50 mL of methylene chloride and re-concentrated, first via rotary evaporation and then under full vacuum pump pressure (<0.5 mm Hg).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]2[CH2:13][N:14]([C:16]3[CH:17]=[N:18][CH:19]=[C:20]([CH:24]=3)[C:21]([OH:23])=O)[CH2:15][C@H:10]2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:25][C:26]1[CH:27]=[C:28]([CH:30]=[C:31]([F:33])[CH:32]=1)[NH2:29]>>[F:25][C:26]1[CH:27]=[C:28]([NH:29][C:21]([C:20]2[CH:24]=[C:16]([N:14]3[CH2:13][C@@H:11]4[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][C@@H:10]4[CH2:15]3)[CH:17]=[N:18][CH:19]=2)=[O:23])[CH:30]=[C:31]([F:33])[CH:32]=1
Reactant: Nc1cc(F)cc(F)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)O)c3)C[C@@H]2C1
Product: CC(C)(C)OC(=O)N1C[C@@H]2CN(c3cncc(C(=O)Nc4cc(F)cc(F)c4)c3)C[C@@H]2C1

Procedure:
The product from Example 33B and 3,5-difluoroaniline were processed as described in Example 33C to provide the title compound. MS (APCI) m/z 445 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14](=O)[CH2:15][C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C(O)=O.[CH2:32]([NH:34][NH2:35])[CH3:33]>CO>[CH2:17]([C:16]1[N:34]([CH2:32][CH3:33])[N:35]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]2)[CH:15]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCNN
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)CC(=O)Cc2ccccc2)CC1
Agent: O=C(O)C(=O)O
Solvent: CO
Product: CCn1nc(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Cc1ccccc1
Reaction time: 15 h

Procedure:
1-(1-(t-Butoxycarbonyl)piperidin-4-yl)-4-phenylbutane-1,3-dione from Step A, from Method A or Method B, Step B3, (0.851 g, 2.46 mmol) in methanol (25 mL) was added over 10 min to a suspension of ethylhydrazine oxalate (0.444 g, 2.96 mmol) in methanol (5 mL) in a 60° C. oil bath. After 15 h, the reaction was concentrated in vacuo and the residue was purified by repeated FC using a gradient of 50-100% ethyl acetate in hexanes to give first 4-(5-benzyl-1-ethyl-(1H)-pyrazol-3-yl)-1-(t-butoxycarbonyl)piperidine (0.148 g total) as the higher Rf product isomer and then the title compound (0.373 g total) as the lower Rf.
Reaction SMILES: [OH:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][C:3]=1[O:17][CH3:18].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:27][C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[N:32][CH:33]=1>C(#N)C.O>[CH3:18][O:17][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:2]=1[O:1][CH2:27][C:28]1[CH:33]=[N:32][C:31]([CH3:34])=[CH:30][CH:29]=1)[CH2:6][NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11]
Reactant: Cc1ccc(CCl)cn1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 63 h
Yield: 106.2 %

Procedure:
To a stirred solution of tert-butyl 4-hydroxy-3-methoxybenzylcarbamate (21.02 g, 82.99 mmol) in acetonitrile (250 mL) was added potassium carbonate (30.61 g, 221.5 mmol) and 5-(chloromethyl)-2-methylpyridine hydrochloride (16.25 g, 91.29 mmol). The resulting mixture was heated to reflux. After 63 h, the brown suspension was allowed to cool to room temperature and was diluted with water (1000 mL). The mixture was extracted with dichloromethane (3×250 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 31.59 g (>100%) of tert-butyl 3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate as a brown oil.
Reaction SMILES: Cl.Cl.Cl.[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1.C(N(CC)C(C)C)(C)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([N:45]=[C:46]=[O:47])=[CH:41][CH:40]=1>CN(C=O)C>[S:4]1[C:8]2[CH:9]=[C:10]([NH:13][C:14]3[C:15]4[CH:22]=[C:21]([C:23]5[CH2:24][CH2:25][N:26]([C:46]([NH:45][C:42]6[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=6)=[O:47])[CH2:27][CH:28]=5)[NH:20][C:16]=4[N:17]=[CH:18][N:19]=3)[CH:11]=[CH:12][C:7]=2[N:6]=[CH:5]1
Reactant: O=C=Nc1ccc(F)cc1
Reactant: C1=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CCNC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(F)cc1)N1CC=C(c2cc3c(Nc4ccc5ncsc5c4)ncnc3[nH]2)CC1
Temperature: -20 °C
Reaction time: 0.08 h

Procedure:
To a suspension of benzothiazol-6-yl-[6-(1,2,3,6-tetrahydropyridin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amine trihydrochloride (50.0 mg, 0.11 mmol) in DMF (1.5 mL) was added N,N-diisopropylethylamine (0.04 mL, 0.20 mmol). The reaction mixture stirred at −20° C. for 5 min prior to the addition of 4-fluorophenyl isocyanate (9.5 mg, 0.07 mmol) in DMF (0.5 mL). The mixture was left to stir at rt for 1 h. The mixture was concentrated in vacuo and purified via MDP, which afforded the title compound as a white solid. MS (ES+): m/z: 485.88 (100) [MH+]. HPLC: tr=2.73 min (ZQ2000: polar—5 min). 1H NMR (400 MHz, CDCl3): δ=2.52-2.56 (m, 2H), 3.31 (s, 1H), 3.70 (t, 2H), 4.20 (s, 2H), 6.94 (m, 1H), 6.86 (d, J=0.8 Hz, 1H), 7.06-7.11 (m, 2H), 7.48-7.51 (m, 2H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 8.04 (d, J=8.8 Hz, 1H), 8.35 (s, 1H), 8.59 (s, 1H), 8.92 (d, J=2.0 Hz, 1H), 9.24 (s, 1H), 9.62 (s, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH2:10][CH:9]1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16](OC(N1CC(C)(C)NCC1C)=O)(C)(C)C>>[CH2:1]([N:8]1[CH2:13][CH:12]([CH3:14])[NH:11][CH2:10][C:9]1([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(Cc2ccccc2)C(C)CN1
Reactant: CC1CNC(C)(C)CN1C(=O)OC(C)(C)C
Product: CC1CN(Cc2ccccc2)C(C)(C)CN1

Procedure:
1-Benzyl-2,2,5-trimethyl-piperazine was prepared in analogy to the preparation of benzyl-2,5-dimethyl-piperazine (see above) starting form 2,5,5-trimethyl-piperazine-1-carbox ylic acid tert-butyl ester.
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][NH2:4].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH3:28])[C:16]([NH:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](OC)=[O:25])=[O:17])=[O:13])([CH3:10])([CH3:9])[CH3:8].C[Al](C)C.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.O>[O:17]=[C:16]([NH:18][N:19]1[CH:23]=[CH:22][CH:21]=[C:20]1[C:24](=[O:25])[NH:4][CH2:3][C:2]([F:6])([F:5])[F:1])[C@@H:15]([NH:14][C:12](=[O:13])[O:11][C:7]([CH3:10])([CH3:9])[CH3:8])[CH3:28]
Reactant: COC(=O)c1cccn1NC(=O)[C@H](C)NC(=O)OC(C)(C)C
Reactant: NCC(F)(F)F
Agent: C[Al](C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)Nn1cccc1C(=O)NCC(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
2,2,2-Trifluoroethanamine (680 microl, 8.66 mmols) was added to a solution of (S)-methyl 1-(2-(tert-butoxycarbonylamino)propanamido)-1H-pyrrole-2-carboxylate (900 mg, 2.89 mmols) in toluene (36 ml). A 2M solution of trimethyl aluminium in toluene (7 ml, 14.00 mmols) was added and it was stirred at 80° C. overnight. Water (50 ml) and a 0.5M solution of sodium tartrate (25 ml) were added. It was extracted with ethylacetate. The combined organic layers were washed with water and brine. It was dried, filtered and concentrated in vacuum. The title compound was obtained (1.021 g, 93%).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:11]=1[C:12](=[O:15])[CH2:13]Br)[CH3:8].[CH3:21][C:22]1[C:23]([CH3:31])=[N:24][C:25]([SH:30])=[C:26]([CH:29]=1)[C:27]#[N:28]>CN(C=O)C.C(OCC)(=O)C>[CH3:21][C:22]1[CH:29]=[C:26]2[C:27]([NH2:28])=[C:13]([C:12](=[O:15])[C:11]3[CH:16]=[C:17]([F:20])[CH:18]=[CH:19][C:10]=3[O:9][CH2:7][CH3:8])[S:30][C:25]2=[N:24][C:23]=1[CH3:31]
Reactant: CCOc1ccc(F)cc1C(=O)CBr
Reactant: Cc1cc(C#N)c(S)nc1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1ccc(F)cc1C(=O)c1sc2nc(C)c(C)cc2c1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A suspension of potassium carbonate (0.189 g, 1.37 mmol), 2-ethoxy-5-fluorophenacyl bromide (1.02 g, 3.95 mmol) and 5,6-dimethyl-2-mercaptonicotine nitrile (0.50 g, 3.04 mmol) in dry DMF (10 ml) is stirred at room temperature for 16 h. The resulting mixture is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 170° C.