Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]3=[N:10][C:9]=2[C:17]2[CH:18]=[C:19]([CH:31]=[CH:32][CH:33]=2)[C:20]([NH:22][C:23]2[C:28]([F:29])=[CH:27][CH:26]=[CH:25][C:24]=2[F:30])=[O:21])[CH:5]=[CH:4][N:3]=1.[CH2:34]([O:36][C:37]1[CH:43]=[C:42]([CH2:44][CH2:45][N:46]2[CH2:51][CH2:50][N:49]([CH3:52])[CH2:48][CH2:47]2)[CH:41]=[CH:40][C:38]=1[NH2:39])[CH3:35].C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O-].[Na+]>C(Cl)Cl.CC(O)C>[F:30][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]([F:29])[C:23]=1[NH:22][C:20](=[O:21])[C:19]1[CH:31]=[CH:32][CH:33]=[C:17]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]3[C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:39][C:38]3[CH:40]=[CH:41][C:42]([CH2:44][CH2:45][N:46]4[CH2:47][CH2:48][N:49]([CH3:52])[CH2:50][CH2:51]4)=[CH:43][C:37]=3[O:36][CH2:34][CH3:35])[N:7]=2)[CH:18]=1
Reactant: O=C(Nc1c(F)cccc1F)c1cccc(-c2nc3ccccn3c2-c2ccnc(Cl)n2)c1
Reactant: CCOc1cc(CCN2CCN(C)CC2)ccc1N
Agent: C[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(C)O
Product: CCOc1cc(CCN2CCN(C)CC2)ccc1Nc1nccc(-c2c(-c3cccc(C(=O)Nc4c(F)cccc4F)c3)nc3ccccn23)n1
Temperature: 130 °C
Yield: 52.9 %

Procedure:
3-[3-(2-Chloro-4-pyrimidinyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1) (100 mg, 0.22 mmol), 2-(ethyloxy)-4-[2-(4-methyl-1-piperazinyl)ethyl]aniline (Example 146, step D) (46 mg, 0.17 mmol), and p-toluenesulfonic acid (99 mg, 0.52 mmol) were weighed into a 20 mL vial. 7 mL of iPrOH was added and the mixture was heated to 130° C. for 72 h. The mixture was transferred to a 50 mL round bottom and neutralized with 2 mL of 0.5 N sodium methoxide. The solvent was rotovaped down. The residue was taken up in 10 mL of DCM. 1 g of silica gel was added. The solvent was rotovaped down and the pre-adsorbed solids were purified by flash chromatography to give the title compound (67 mg, 0.09 mmol, 56%); 1H NMR (400 MHz, DMSO-d6) δ ppm 10.21 (s, 1H), 9.34 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 8.27 (s, 1H), 8.02 (s, 1H), 7.80 (s, 1H), 7.73 (s, 1H), 7.65 (s, 1H), 7.59 (s, 1H), 7.46 (s, 1H), 7.38 (s, 1H), 7.18 (s, 2H), 6.96 (s, 2H), 6.72 (s, 1H), 6.46 (s, 1H), 4.02-4.11 (m, 2H), 2.60-2.71 (m, 2H), 2.25-2.32 (m, 10H), 2.12 (s, 3H), 1.26 (s, 3H). MS (ESI): 689 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH:9]([B-](F)(F)F)=[CH2:10].[K+].C(N(CC)CC)C>C(O)CC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[Cl:1][C:2]1[N:7]=[C:6]([CH:9]=[CH2:10])[CH:5]=[CH:4][N:3]=1
Reactant: C=C[B-](F)(F)F
Reactant: Clc1ccnc(Cl)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [K+]
Solvent: ClCCl
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1ccnc(Cl)n1
Temperature: 100 °C

Procedure:
To a mixture of 2,4-dichloropyrimidine (4.4 g, 29.5 mmol), potassium vinyltrifluoroborate (4.58 g, 32.5 mmol), PdCl2(dppf)-CH2Cl2 (1.21 g, 1.48 mmol) and triethylamine (4.12 mL, 29.5 mmol) in nPrOH (148 mL) was purged with nitrogen for 15 min, heated to 100° C. for 5 h, and then cooled to room temperature. The mixture was treated with water and extracted with EtOAc (×3). The combined organics were washed with brine, dried (sodium sulfate), filtered and concentrated, and purified by flash chromotography to afford 2-chloro-4-ethenylpyrimidine as a colorless oil. 1H NMR (500 MHz, CDCl3) δ 8.56 (d, J=5.1, 1H), 7.21 (d, J=5.1, 1H), 6.70 (dd, J=10.6, 17.4, 1H), 6.57-6.51 (m, 1H), 5.79 (dd, J=0.8, 10.6, 1H).
Reaction SMILES: Cl/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5].[I-:14].[Na+]>CC(C)=O>[I:14]/[CH:2]=[CH:3]/[C:4]([C:6]1([CH3:13])[CH2:9][C:8]2([CH2:12][CH2:11][CH2:10]2)[CH2:7]1)=[O:5]
Reactant: CC1(C(=O)/C=C/Cl)CC2(CCC2)C1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC1(C(=O)/C=C/I)CC2(CCC2)C1
Yield: 87 %

Procedure:
In a procedure as described in Example 9H, 1-chloro-3-(2-methylspiro[3.3]hept-2-yl)-1E-propen-3-one was reacted with sodium iodide in acetone to yield 1-iodo-3-(2-methyspiro[3.3]hept-2-yl)-1E-propen-3-one (87%).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]([O:18][CH2:19][CH3:20])(=[O:17])[CH:15]=[CH2:16].C(OCC)C>C(O)C>[C:14]([CH2:15][CH2:16][N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: C=CC(=O)OCC
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)CCN1CCN(C(=O)OC(C)(C)C)CC1

Procedure:
Combine t-butyl 1-piperazinecarboxylate (10.47 g, 56.2 mmol), ethyl acrylate (8 mL) in ethanol (30 mL). Heat at reflux. After 5.5. hours, cool the reaction mixture and evaporate in vacuo to give a residue. Combine the residue and diethyl ether (200 mL) and extract with a 1 M aqueous solution of hydrochloric acid. Adjust the pH of the aqueous layer to basic using sodium bicarbonate and then extract with ethyl acetate. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give t-butyl 4-carboethoxyethyl-1-piperazinecaboxylate.
Reaction SMILES: C([O:8][C:9]([CH2:11][CH2:12][N:13]1[C:17]([SH:18])=[N:16][N:15]=[N:14]1)=[O:10])C1C=CC=CC=1.[OH-].[Na+]>O1CCCC1>[C:9]([CH2:11][CH2:12][N:13]1[C:17]([SH:18])=[N:16][N:15]=[N:14]1)([OH:10])=[O:8]
Reactant: O=C(CCn1nnnc1S)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)CCn1nnnc1S
Reaction time: 2 h
Yield: 75.1 %

Procedure:
A mixture of 3.84 g of 1-(2-benzyloxycarbonylethyl)-1H-tetrazole-5-thiol, 30 ml of tetrahydrofuran and 29 ml of 1 N-sodium hydroxide was allowed to stand at room temperature for 2 hours. The reaction mixture was washed with ethyl acetate and the water layer was adjusted to pH 1 with 10% hydrochloric acid and extracted with ethyl acetate. The extract was washed with an aqueous solution of sodium chloride, dried and concentrated to dryness. By the above procedure there were obtained 1.9 g of powder of the captioned compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:14][C:15]1[C:16]([CH:21]=O)=[N:17][CH:18]=[CH:19][CH:20]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([CH2:12][NH:13][CH2:21][C:16]2[C:15]([CH3:14])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(CN)C1
Reactant: Cc1cccnc1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cccnc1CNCC1CN(C(=O)OC(C)(C)C)C1

Procedure:
Using General Procedure B: Reaction of 3-aminomethyl-azetidine-1-carboxylic acid tert-butyl ester (Falgueyret, J.-P. et al. J. Med. Chem. 2001, 44, 94-104) in CH2Cl2 with 3-methyl-pyridine-2-carbaldehyde and NaBH(OAc)3 gave 3-{[(3-methyl-pyridin-2-ylmethyl)-amino]-methyl}-azetidine-1-carboxylic acid tert-butyl ester as a yellow oil. 1H NMR (CDCl3) δ 1.44 (s, 9H), 2.30 (s, 3H), 2.66-2.75 (m, 1H), 2.92 (d, 2H, J=6.0 Hz), 3.61-3.66 (m, 2H), 3.88 (s, 2H), 4.02 (t, 2H, J=9.0 Hz).
Reaction SMILES: N1CCCC1.[H-].COCCO[Al+]OCCOC.[Na+].[H-].CC(C)([O-])C.[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1)[C:30](OC)=[O:31].[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[CH3:25][O:26][C:27]1[CH:28]=[C:29]([CH:34]=[CH:35][C:36]=1[N:37]1[CH:41]=[C:40]([CH3:42])[N:39]=[CH:38]1)[CH:30]=[O:31]
Reactant: COC(=O)c1ccc(-n2cnc(C)c2)c(OC)c1
Agent: CC(C)(C)[O-]
Agent: COCCO[Al+]OCCOC
Agent: [H-]
Solvent: C1CCNC1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc(C=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.4 %

Procedure:
A solution of pyrrolidine (18 mL) in THF (45 mL) was added dropwise to a solution of sodium bis(2-methoxyethoxy)aluminum hydride (65% solution in toluene, 56 mL) in THF (60 mL) at −5° C. or less over 15 minutes. The reaction solution was stirred at room temperature for one hour. Then, a suspension of tert-butoxide (2.10 g) in THF (15 mL) was added dropwise to the reaction solution at room temperature, and the reaction solution was stirred for 15 minutes. The above reaction solution was added dropwise to a solution of methyl 3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzoate (20 g) in THF (50 mL) under ice-cooling over 30 minutes. The reaction solution was stirred at room temperature for two hours, and then a 5 N sodium hydroxide solution (150 mL) was added dropwise to the reaction solution. Ethyl acetate was added to the reaction solution, and the organic layer was separated. The organic layer was washed with a saturated ammonium chloride solution and brine in this order. The organic layer was dried over anhydrous magnesium sulfate and filtered on a silica gel pad, and then the filtrate was concentrated under reduced pressure. The residue was diluted with ethyl acetate, and the precipitated solid was collected by filtration. The resulting solid was air-dried overnight to obtain 7.10 g of the title compound. Further, the crystallization mother liquor was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent: heptane-ethyl acetate-2-propanol system) to obtain 2.65 g of the title compound.
Reaction SMILES: [N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([O:17]CC)=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1>C([O-])([O-])=O.[Na+].[Na+]>[N:1]1([C:6]2[N:11]=[CH:10][C:9]([C:12](=[O:20])[CH2:13][CH2:14][C:15]([OH:17])=[O:16])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: CCOC(=O)CCC(=O)c1ccc(-n2ccnc2)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: O=C(O)CCC(=O)c1ccc(-n2ccnc2)nc1

Procedure:
A solution of ethyl, 4-cyano-4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-N-morpholino butyrate (2.34 g, 6.34 mmol) in 14 ml of acetic acid containing 0.9 ml of water is heated to reflux for 1 day. The solvent is removed and the residue is dissolved in CHCl3 and extracted with saturated aqueous NaHCO3 solution. The organic layer is then separated, dried (Na2SO4) and evaporated to give crude ethyl 4-[6-(1H-imidazol-1-yl)pyrid-3-yl]-4-oxo-butanoate. Saponification of the ester in aqueous Na2CO3 at 23° C. generates the desired product used in the next step without further purification.
Reaction SMILES: S[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6].[N+]([O-])([O-])=O.[K+].[S:20]([Cl:24])(Cl)(=[O:22])=[O:21].C([O-])(O)=O.[Na+]>>[Cl:24][S:20]([CH2:2][CH2:3][CH2:4][C:5]([O:7][CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:6])(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(CCCS)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=[N+]([O-])[O-]
Agent: [K+]
Product: O=C(CCCS(=O)(=O)Cl)OCc1ccccc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 75.1 %

Procedure:
To a mixture of benzyl 4-mercaptobutyrate (9.96 g, 47.4 mmol) and potassium nitrate (12 g, 118 mmol) was added dropwise sulfuryl chloride (16 g, 118 mmol) at 0° C., and the mixture was stirred for 10 hours at room temperature. The resulting suspension was adjusted to pH 7 with saturated NaHCO3 solution. The organic layer was separated, washed with saturated NaHCO3 solution and brine, and dried over MgSO4. The solvent was removed under reduced pressure. The residue was dissolved in CHCl3 and the solution was passed through short SiO2 column to give 9.85 g of benzyl 4-chlorosulfonylbutyrate as a slightly brown oil.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[N:16]=[C:15]([CH:25]([CH3:27])[CH3:26])[C:14]=2[CH:28]=O)=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:28][C:14]1[C:15]([CH:25]([CH3:27])[CH3:26])=[N:16][C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:18][C:13]=1[C:10]1[CH:9]=[CH:8][C:7]([F:6])=[CH:12][CH:11]=1
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)c1nc(-c2ccccc2)cc(-c2ccc(F)cc2)c1C=C(Br)Br
Reaction time: 0.33 h
Yield: 102.2 %

Procedure:
A solution of carbon tetrabromide (2.204 gm, 6.65 mmol) in CH2Cl2 (8 ml) was added over a 12 minute period to a cold (-12° C.) solution of 4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenyl-3-pyridinecarboxaldehyde (1.415 gm, 4.43 mmol) (the preparation of which is described in Example 1) and triphenylphosphine (3.488 gm, 13.3 mmol) in CH2Cl2 (25 ml). After the addition was complete, the cooling bath was removed and the mixture was stirred for 20 minutes. The solution was quenched with saturated NaHCO3 and extracted 3× with CH2Cl2. The combined organic layers were washed with saturated NaHCO3, dried (Na2SO4), filtered and stripped to give a yellow oil. The oil was chromatographed (flash, Merck SiO2, 40% CH2Cl2 in hexane) to give 3-(2,2-dibromoethenyl)-4-(4-fluorophenyl)-2-(1-methylethyl)-6-phenylpyridine as a colorless foam (2.152 gm, 100%).
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[CH:3]([CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[O:4][Si:5]([CH2:10][CH3:11])([CH2:8][CH3:9])[CH2:6][CH3:7].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29].O>ClCCl>[CH3:27][S:28]([N:15]1[CH2:16][CH2:17][CH:12]([CH:3]([O:4][Si:5]([CH2:8][CH3:9])([CH2:6][CH3:7])[CH2:10][CH3:11])[C:2]([F:18])([F:1])[F:19])[CH2:13][CH2:14]1)(=[O:30])=[O:29]
Reactant: CC[Si](CC)(CC)OC(C1CCNCC1)C(F)(F)F
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC[Si](CC)(CC)OC(C1CCN(S(C)(=O)=O)CC1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
4-[2,2,2-Trifluoro-1-(triethylsiloxy)ethyl]piperidine (303 mg, 1.02 mmol) was dissolved in dichloromethane (6 mL). To this, triethylamine (0.213 mL, 1.53 mmol) and methanesulfonyl chloride (0.118 mL, 1.53 mmol) were added at 0° C. and the mixture was stirred at room temperature for 30 minutes. The reaction was stopped by addition of water to the reaction mixture, and extraction with dichloromethane was performed, followed by drying over anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/1) to give 1-methanesulfonyl-4-[2,2,2-trifluoro-1-(triethylsiloxy)-ethyl]piperidine (302 mg, yield: 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[C:20]([OH:22])[CH:21]=1)[C:5]([N:7]([CH:16]([CH3:18])[CH3:17])[CH2:8][CH2:9][C:10]1[N:14]([CH3:15])[N:13]=[N:12][N:11]=1)=[O:6].[H-].[Na+].[C:25]([O:29][C:30]([N:32]([C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)[CH2:33][CH2:34]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CN(C=O)C>[C:25]([O:29][C:30](=[O:31])[N:32]([CH2:33][CH2:34][O:22][C:20]1[CH:19]=[C:4]([C:5](=[O:6])[N:7]([CH:16]([CH3:17])[CH3:18])[CH2:8][CH2:9][C:10]2[N:14]([CH3:15])[N:13]=[N:12][N:11]=2)[CH:3]=[C:2]([Cl:1])[CH:21]=1)[C:46]1[CH:51]=[CH:50][N:49]=[CH:48][CH:47]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1ccc(S(=O)(=O)OCCN(C(=O)OC(C)(C)C)c2ccncc2)cc1
Reactant: CC(C)N(CCc1nnnn1C)C(=O)c1cc(O)cc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)N(CCc1nnnn1C)C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1
Reaction time: 88 h
Yield: 23.8 %

Procedure:
To a solution of 3-chloro-5-hydroxy-N-isopropyl-N-[2-(1-methyl-1H-tetrazol-5-yl)-ethyl]-benzamide (0.070 g) in DMF (2.0 ml) stirred at room temperature under nitrogen was added sodium hydride (60% dispersion in oil, 0.010 g) and after 10 min was added toluene-4-sulfonic acid 2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethyl ester (0.120 g). The reaction was stirred for 88 h and the sovent removed in vacuo. The residue was partitioned between ethyl acetate and water. The organic phase was washed with further water and 1M aqueous sodium hydroxide, water and dried with brine and over sodium sulphate and concentrated under reduced pressure to give the crude product which was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (4:1 v/v) and 24:1 dichloromethane:methanol (24:1 v/v), to give the title compound as a colourless gum (0.028 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:17]1[N:22]=[C:21]([NH:23][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]([CH:30]=[O:31])=[CH:19][CH:18]=1>CN(C=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][O:13][C:17]1[N:22]=[C:21]([NH:23][C:24](=[O:29])[C:25]([CH3:26])([CH3:27])[CH3:28])[C:20]([CH:30]=[O:31])=[CH:19][CH:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)C(=O)Nc1nc(Cl)ccc1C=O
Reactant: OCCCCOCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1nc(OCCCCOCc2ccccc2)ccc1C=O
Reaction time: 0.33 h
Yield: 30.7 %

Procedure:
To a solution of 4-(benzyloxy)butan-1-ol (15.42 g, 85.6 mmol) in DMF (120 mL) was added sodium hydride (4.11 g, 171 mmol) at 0° C. The mixture was stirred for 20 min, then intermediate 6 (10.28 g, 42.7 mmol) was added portion-wise and the resulting mixture was stirred overnight. The mixture was quenched with saturated aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with water, brine, dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel column (elution with PE/EtOAc=8:1-4:1) to give N-(6-(4-(benzyloxy)butoxy)-3-formylpyridin-2-yl)pivalamide (intermediate 7) (5.04 g, 31%).
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:21]=[C:22]([CH2:26][CH:27]3[CH2:32][CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]3)[CH:23]=[CH:24][CH:25]=2)=[O:19])=[CH:4][CH:3]=1.C[C@H:41]1[CH2:46][NH:45][CH2:44][CH2:43][N:42]1C(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[F:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:42]3[CH2:43][CH2:44][NH:45][CH2:46][CH2:41]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18](=[O:19])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH:27]3[CH2:28][CH2:29][NH:30][CH2:31][CH2:32]3)[CH:21]=2)=[CH:4][CH:3]=1
Reactant: C[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(C(=O)NCc3ccc(F)c(-c4cccc(C=O)c4)c3)c2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: O=C(NCc1ccc(F)c(-c2cccc(CN3CCNCC3)c2)c1)c1cccc(CC2CCNCC2)c1
Reaction time: 16 h
Yield: 27.1 %

Procedure:
A solution of 1,1-dimethylethyl 4-{[3-({[(6-fluoro-3′-formyl-3-biphenylyl)methyl]amino}carbonyl)phenyl]methyl}-1-piperidinecarboxylate (74 mg, 0.14 mmol) in CH2Cl2 (5 mL) was mixed with 1,1-dimethylethyl (2S)-2-methyl-1-piperazinecarboxylate (26 mg, 0.14 mmol) and NaB(OAc)3H (45 mg, 0.21 mmol). The resulting mixture was stirred for 16 hours, diluted with dichloromethane (30 mL) and washed with brine (10 mL). The organic layer was collected, dried over Na2SO4 and concentrated under vacuum. The residue was purified by loading onto a 2 g amminopropyl SPE cartridge, eluting sequentially with DCM (3×5 mL), EtOAc (3×5 mL), and MeOH (3×5 mL). The DCM fractions were combined, and mixed with 2 mL of TFA. After stirring for 1 h, the mixture was concentrated under vacuum, and the residue thus obtained was purified by Gilson reverse phase HPLC, eluting with acetonitrile/water/0.1% TFA (10/90 to 70/30, v/v, over 12 min), to give the title compound (19 mg, 27%). LC/MS: m/z, 501 (M+H), 1.35 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(CC)C(C)C)(C)C>CN(C)C=O.C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[N:10]([CH3:11])[CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: Cn1ccc2nc(Cl)nc(Cl)c21
Reactant: C1COCCN1
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ccc2nc(Cl)nc(N3CCOCC3)c21
Temperature: 25 °C
Reaction time: 15 h
Yield: 94 %

Procedure:
A mixture of 2,4-dichloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidine (1.25 g, 6.19 mmol), morpholine (1.08 mL, 12.37 mmol), and N,N-diisopropylethylamine (2.37 mL, 13.61 mmol) in N,N-dimethylformamide (36 mL) was stirred at RT under N2 for 15 h. The reaction mixture was diluted with 1:1 diethyl ether/ethyl acetate, and the organic layer was washed with 1:1 water/brine (3×) and brine (1×), dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 1.47 g (94.0%) of 4-(2-chloro-5-methyl-5H-pyrrolo[3,2-d]pyrimidin-4-yl)morpholine as a white solid. MS(ESI) m/z: 253.1/255.1 [M+1]−.
Reaction SMILES: C(ON=O)(C)(C)C.[CH3:8][CH:9]([C:11]1[N:15]=[C:14](N)[S:13][N:12]=1)[CH3:10].[BrH:17].O>CC(C)=O.C(Cl)Cl>[Br:17][C:14]1[S:13][N:12]=[C:11]([CH:9]([CH3:10])[CH3:8])[N:15]=1
Reactant: CC(C)c1nsc(N)n1
Reactant: Br
Agent: CC(C)(C)ON=O
Solvent: CC(C)=O
Solvent: O
Solvent: ClCCl
Product: CC(C)c1nsc(Br)n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 111.1 %

Procedure:
t-Butylnitrite (50%, 2.3 mL, 17.22 mmol) was added dropwise to a degassed solution of CuBr2 (1.64 g, 7.35 mmol) in acetone (30 mL) at 0° C. under N2. The mixture was stirred at ambient temperature for 90 min, then charged with a solution of 3-(1-methylethyl)-1,2,4-thiadiazol-5-amine (1 g, 7 mmol) in acetone (7 mL), and stirred at ambient temperature for 1 h. The mixture was cooled to 0° C., and was charged dropwise with 48% HBr (1.8 mL, 4.65 mmol). The mixture was stirred at 0° C. for 30 min, and then brought to ambient temperature. The mixture was charged with water (100 mL) and CH2Cl2 (75 mL), then stirred at ambient temperature for 10 min. The organics were separated, dried over MgSO4, filtered, and the filtrate was concentrated. The crude product was purified by chromatography on a silica gel column using 0 to 15% EtOAc/hexane to give 1.07 g (74%) of 5-bromo-3-(1-methylethyl)-1,2,4-thiadiazole as a golden oil. 1H NMR (400 MHz, CDCl3): δ 3.29 (septet, 1H, J=6.9 Hz), 1.37 (d, 6H, J=6.9 Hz); LRMS (ESI), m/z 207/209 (M+H).
Reaction SMILES: Cl[CH2:2][C:3]([CH:5]([NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:6][CH:7]([CH3:9])[CH3:8])=O.[NH2:18][C:19]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][N:20]=1>CO>[C:11]([NH:10][C@H:5]([C:3]1[N:18]=[C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][N:20]2[CH:2]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:17]
Reactant: Nc1cc(Cl)ccn1
Reactant: CC(C)CC(NC(=O)OC(C)(C)C)C(=O)CCl
Solvent: CO
Product: CC(C)C[C@H](NC(=O)OC(C)(C)C)c1cn2ccc(Cl)cc2n1

Procedure:
1.68 g (6.37 mmol) tert.-butyl [1-(2-chloro-acetyl)-3-methyl-butyl]-carbamate in 15 ml of methanol are combined with 819 mg (6.37 mmol) 2-amino-4-chloro-pyridine at ambient temperature with stirring and the mixture is refluxed for 3 days. After evaporation i. vac. the residue is combined with 5% sodium hydrogen carbonate solution and stirred for 20 h at ambient temperature. Then it is extracted with dichloromethane, the combined organic phases are dried over sodium sulphate and evaporated down completely i. vac. The residue is purified by chromatography on silica gel (eluting gradient: dichloromethane/ethanol=100:0->94:6).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[O:11])=[CH:6][CH:5]=1.[CH:13]([Mg]Cl)([CH3:15])[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:11])[CH:13]([CH3:15])[CH3:14])=[CH:6][CH:5]=1
Reactant: CC(C)[Mg]Cl
Reactant: COC(=O)c1ccc(C=O)cc1
Product: COC(=O)c1ccc(C(O)C(C)C)cc1

Procedure:
This compound is made from 4-formyl-benzoic acid methyl ester and isopropylmagnesium chloride following the general method exemplified in Preparation 1.