Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[C:3]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][C:4]=1[CH2:5][OH:6].C([Li])CCC.[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH:24]=[O:25].[Cl-].[NH4+]>CCOCC.CCCCCC>[OH:6][CH2:5][C:4]1[CH:3]=[CH:10][CH:9]=[C:8]([O:11][CH3:12])[C:7]=1[CH:24]([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=1)[OH:25]
Reactant: COc1ccc(OC)c(CO)c1
Reactant: O=Cc1ccccn1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: CCOCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 11.7 %

Procedure:
To a mixture of 10 g (0.059 mol) of 2,5-dimethoxybenzyl alcohol in 250 ml of ether cooled to -20° C. was added in portions 12.75 ml (0.127 mol) of n-butyllithium (10M) in hexane over a 10 min period, and the reaction mixture was allowed to warm to room temperature and stirred 1 hr. The above reaction mixture was cooled to -20° C., 7.58 g (0.07 mol) of pyridine-2-carboxaldehyde was added to the mixture, and the resulting reaction mixture was allowed to warm to room temperature (a brown precipitate formed) and stirred for 1 hr. Ammonium chloride solution (60 ml) was added, the mixture was extracted with ethyl acetate, the combined organic layer was washed with brine, dried over sodium sulfate, and concentrated. The diol was purified by chromatography on silica eluting with ethyl acetate/hexane (9:1) to afford 1.7 g (10.5%) of 2-[(2',5'-dimethoxy-6'-hydroxymethyl)benzyl]pyridine (Formula XIII: R1 =R7 =H; R2 =2',5'(OCH3)2), as a white solid, m.p. 102°-104° C.
Reaction SMILES: [OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([OH:10])=[O:9])[C:4]([CH3:12])([CH3:11])[CH2:3]1.S(=O)(=O)(O)O.[CH3:41]O>O>[OH:1][C@@:2]1([C:13]2[S:14][C:15]([C:18]3[CH:23]=[C:22]([NH:24][C:25]4[N:30]=[C:29]([C:31]([F:33])([F:34])[F:32])[CH:28]=[CH:27][N:26]=4)[CH:21]=[C:20]([CH3:35])[CH:19]=3)=[CH:16][N:17]=2)[CH2:7][CH2:6][C@@H:5]([C:8]([O:10][CH3:41])=[O:9])[C:4]([CH3:11])([CH3:12])[CH2:3]1
Reactant: CO
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc([C@]3(O)CC[C@@H](C(=O)O)C(C)(C)C3)s2)c1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(=O)[C@@H]1CC[C@@](O)(c2ncc(-c3cc(C)cc(Nc4nccc(C(F)(F)F)n4)c3)s2)CC1(C)C
Reaction time: 16 h
Yield: 83 %

Procedure:
(1R,4S)-4-hydroxy-2,2-dimethyl-4-[5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]cyclohexanecarboxylic acid (100 mg, 0.197 mmol) was dissolved in methanol (3 ml) and concentrated sulfuric acid (10.52 μl, 0.197 mmol) added. The reaction mixture was stirred for 16 hours. The reaction mixture was diluted with water, extracted with ethyl acetate (3×) and washed with saturated aqueous sodium bicarbonate. Solvent evaporation gave the title compound (85 mg, 0.163 mmol, 83% yield). MS ESI: [M+H]+ m/z 521.1. 1H NMR (500 MHz, DMSO-d6) 1H NMR δ 10.25 (s, 1H), 8.83 (d, J=4.9, 1H), 7.93 (s, 2H), 7.46 (s, 1H), 7.28 (d, J=4.9, 1H), 7.14 (s, 1H), 5.92 (s, 1H), 3.59 (s, 3H), 2.31 (s, 4H), 1.84 (s, 3H), 1.65 (m, 3H), 1.08 (s, 3H), 0.96 (s, 3H). rhSYK activity=+++
Reaction SMILES: CN(C1C=CC=CN=1)C.[OH:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1.[C:25](Cl)(=[O:29])[CH:26]([CH3:28])[CH3:27]>N1C=CC=CC=1>[C:25]([O:10][CH2:11][C@H:12]1[CH2:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)(=[O:29])[CH:26]([CH3:28])[CH3:27]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](CO)C1
Reactant: CC(C)C(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: CC(C)C(=O)OC[C@H]1CCCN(C(=O)OC(C)(C)C)C1

Procedure:
170 mg of dimethylaminopyridine and 3.4 mg of pyridine are added to 3.0 g of t-butyl (S)-3-hydroxymethyl-1-piperidinecarboxylate. 1.66 ml of isobutyryl chloride are added dropwise thereto. The reaction mixture is then concentrated. The residue is taken up in ether and the ether phase is washed in succession with 20 ml of citric acid, water, sodium bicarbonate solution and water. After drying and evaporation of the ether phase there are obtained 3.9 g of t-butyl (S)-3-isobutyroxymethyl-1-piperidinecarboxylate, Rf=0.87 (ether). 3.09 g of this ester are dissolved in 80 ml of methylene chloride and treated with 20 ml of trifluoroacetic acid. After stirring for 30 minutes the solution is concentrated. 30 ml of methanol are added to the residue and saturated sodium bicarbonate solution is then added dropwise. The aqueous phase is extracted with methylene chloride and the methylene chloride extracts are dried and concentrated. There are obtained 2.82 g of (S)-3-iso- butyroxymethyl-1-piperidinecarboxylic acid trifluoroacetic acid salt, Rf=0.4 (Takeda solution).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=1)(C)(C)[CH3:2].C(Cl)(=[O:27])C.[Sn](Cl)(Cl)(Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1.ClCCl>[C:1]([C:5]1[N:9]([CH2:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[C:8]([CH3:19])=[C:7]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH:6]=1)(=[O:27])[CH3:2]
Reactant: CCOC(=O)c1cc(C(C)(C)C)n(CCc2ccc(F)cc2)c1C
Reactant: CC(=O)Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCOC(=O)c1cc(C(C)=O)n(CCc2ccc(F)cc2)c1C
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Bioorganic & Medicinal Chem. Lett., 14 (2004), 1295-1298, was used as a reference. A 1.00 g portion of ethyl 5-tert-butyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate was dissolved in 15 ml of toluene, 0.26 ml of acetyl chloride was added thereto, and 3.6 ml of tin(IV) chloride (a 1 M dichloromethane solution) was added dropwise thereto at 0° C., followed by stirring at room temperature for 6 hours. After adjusting to pH 12 by adding 25 ml of a 1 M sodium hydroxide aqueous solution at 0° C., extraction was carried out with ethyl acetate, followed by washing with saturated brine. After drying with anhydrous sodium sulfate, the solvent was evaporated under a reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:10-1:7-1:5) to obtain 668 mg of ethyl 5-acetyl-1-[2-(4-fluorophenyl)ethyl]-2-methyl-1H-pyrrole-3-carboxylate as a beige solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](B(O)O)[C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=1.Br[C:17]1[CH:24]=[C:23]([Cl:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]>>[Cl:25][C:23]1[CH:24]=[CH:17][C:18]([C:19]#[N:20])=[C:21]([C:7]2[C:6]([C:12]([F:15])([F:14])[F:13])=[CH:5][N:4]=[C:3]([O:2][CH3:1])[CH:8]=2)[CH:22]=1
Reactant: COc1cc(B(O)O)c(C(F)(F)F)cn1
Reactant: N#Cc1ccc(Cl)cc1Br
Product: COc1cc(-c2cc(Cl)ccc2C#N)c(C(F)(F)F)cn1

Procedure:
1.0 g (4.4 mmol) of 2-methoxy-5-trifluoromethylpyridin-4-ylboronic acid and 0.95 g (4.4 mmol) of 2-bromo-4-chlorobenzonitrile in the presence of [1,1-bis(diphenylphosphino)ferrocene]palladium(II) chloride/dichloromethane monoadduct were reacted according to General Method 2A. Yield: 351 mg (purity 71%, 18% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[C:33]([O:37][C:38]([N:40]1[CH2:43][CH:42]([C:44](O)=[O:45])[CH2:41]1)=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:15][C:14]1[CH:13]=[C:12]([NH:16][C:17]([C:19]2([C:22](=[O:23])[NH:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:21][CH2:20]2)=[O:18])[C:11]([F:32])=[CH:10][C:9]=1[O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:1][C:44]([CH:42]2[CH2:43][N:40]([C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[CH2:41]2)=[O:45])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(C(=O)Nc2cc(Oc3cc(F)c(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)C1
Temperature: 50 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a solution of N-(4-((2-aminopyridin-4-yl)oxy)-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (440 mg, 1 mmol) (as prepared in Example 9) and 1-(tert-butoxycarbonyl) azetidine-3-carboxylic acid (402 mg, 2 mmol) in DMF (5 mL) was added HATU (1.1 g, 3 mmol), followed by DIEA (516 mg, 4 mmol). The mixture was sparged with nitrogen and then stirred 50° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column on a silica gel chromatography to give tert-butyl 3-(4-(2,5-difluoro-4-(1-(4-fluorophenylcarbamoyl)cyclopropanecarboxamido)phenoxy)pyridin-2-ylcarbamoyl)azetidine-1-carboxylate (250 mg, 40% yield). 1H-NMR (400 MHz, DMSO-d6): δ 11.01 (s, 1H), 10.72 (s, 1H), 9.79 (s, 1H), 8.19 (d, J=5.6 Hz, 1H), 8.10-8.05 (m, 1H), 7.66 (s, 1H), 7.58-7.53 (m, 3H), 7.14 (t, J=8.8 Hz, 2H), 6.77-6.75 (m, 1H), 3.90-3.84 (m, 4H), 3.55-5.53 (m, 1H), 1.63-1.53 (m, 4H), 1.33 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)(=O)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[CH2:1]([NH:4][C:5]1[N:10]=[C:9]2[C:11]([CH:14]3[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]3)=[CH:12][NH:13][C:8]2=[CH:7][CH:6]=1)[CH3:2]
Reactant: CC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: CCNc1ccc2[nH]cc(C3CCN(C)CC3)c2n1
Temperature: 75 °C
Yield: 52.3 %

Procedure:
A mixture of 0.200 gm (0.74 mMol) 5-(N-[acetyl]amino)-3-(1-methylpiperidin-4-yl)pyrrolo[3,2-b]pyridine and 0.125 gm (3.31 mMol) lithium aluminum hydride in 40 mL tetrahydrofuran was heated at 75° C. for 18 hours. The reaction mixture was cooled to 0° C. and was then treated with sodium sulfate decahydrate. After vigorous stirring the reaction mixture was filtered through a pad of celite and the filtrate concentrated under reduced pressure. The residue was subjected to flash silica gel chromatography, eluting with dichloromethane containing from 0-20% methanol. Fractions containing product were combined and concentrated under reduced pressure to provide 0.10 gm (54%) of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[C:3]2[C:7]([O:9][C:10](=[O:11])[C:2]=12)=[O:8].[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15]>C(O)C>[NH2:15][CH2:14][CH2:13][CH2:12][NH:16][C:7]([C:3]1[C:2]([C:10]([OH:9])=[O:11])=[N:1][CH:6]=[CH:5][N:4]=1)=[O:8]
Reactant: O=C1OC(=O)c2nccnc21
Reactant: NCCCN
Solvent: CCO
Product: NCCCNC(=O)c1nccnc1C(=O)O
Temperature: 25 °C
Yield: 94.2 %

Procedure:
To a solution of 2,3-pyrazinedicarboxylic anhydride (6.50 g, 43.3 mmol) in ethanol (25 mL) was added 1,3-propanediamine (3.42 g, 46.0 mmol) dropwise over 5 min. The reaction was stirred over night at RT and the precipitated product was collected by filtration to yield 9.15 g of 3-(3-Amino-propylcarbamoyl)-pyrazine-2-carboxylic acid as a white solid (94%). This intermediate (200 mg) was dissolved in DMF (3 mL) and heated in a microwave reactor for 3 min at 175° C. to produce 7,8-Dihydro-6H-1,4,5,8a-tetraaza-fluoren-9-one, which was used without further purification.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:32]([O:35][CH3:36])[O:33][CH3:34])=[N:9][C:10]2[N:11]([C:17](=[O:31])[NH:18][C:19]3[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.C(N(CC)CC)C.[C:44]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)(=[O:46])[CH3:45]>C(Cl)Cl.O>[C:44]([N:47]1[CH2:52][CH2:51][N:50]([CH2:6][C:7]2[CH:16]=[C:15]3[C:10](=[N:9][C:8]=2[CH:32]([O:33][CH3:34])[O:35][CH3:36])[N:11]([C:17]([NH:18][C:19]2[CH:24]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[C:22]([C:29]#[N:30])=[CH:21][N:20]=2)=[O:31])[CH2:12][CH2:13][CH2:14]3)[CH2:49][CH2:48]1)(=[O:46])[CH3:45]
Reactant: COC(OC)c1nc2c(cc1COS(C)(=O)=O)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Reactant: CC(=O)N1CCNCC1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(OC)c1nc2c(cc1CN1CCN(C(C)=O)CC1)CCCN2C(=O)Nc1cc(OC(C)C)c(C#N)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (8-((5-cyano-4-isopropoxypyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 167, 188 mg, 0.362 mmol) in DCM (1 ml) was added triethylamine (0.176 mL, 1.267 mmol) followed by 1-acetylpiperazine (71.0 mg, 0.543 mmol) and the reaction mixture was stirred at room temperature for approximately 2 h. The reaction mixture was diluted with DCM and water and extracted. The water phase was extracted with DCM (2×), the combined organic layers were dried using Na2SO4, filtered and concentrated. The crude product was purified via silica gel column chromatography, eluting with a gradient of MeOH (1-5%) in DCM. Product fractions were combined and concentrated to yield the title compound as a white solid. (UPLC-MS 3) tR 0.97 min, ESI-MS 552.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 14.01 (s, 1H), 8.38 (s, 1H), 7.96 (s, 1H), 7.62 (s, 1H), 5.68 (s, 1H), 4.88-4.80 (m, 1H), 4.07-4.02 (m, 2H), 3.66-3.58 (m, 4H), 3.47-3.42 (m, 8H), 2.86 (t, 2H), 2.45 (t, 2H), 2.41 (t, 2H), 2.09 (s, 3H), 2.04-1.96 (m, 2H), 1.44 (d, 6H).
Reaction SMILES: [CH3:1][C:2]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([OH:17])[C:13]([NH:15][CH3:16])=[O:14].[C:23](OC(=O)C)(=[O:25])[CH3:24]>N1C=CC=CC=1>[C:23]([O:17][CH:12]([C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:5][O:4][C:3]1[CH:18]=[C:19]([CH3:22])[CH:20]=[CH:21][C:2]=1[CH3:1])[C:13]([NH:15][CH3:16])=[O:14])(=[O:25])[CH3:24]
Reactant: CNC(=O)C(O)c1ccccc1COc1cc(C)ccc1C
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CNC(=O)C(OC(C)=O)c1ccccc1COc1cc(C)ccc1C
Yield: 81.7 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-hydroxy-N-methylacetamide (0.57 g, 1.9 mmol) and acetic anhydride (0.43 g, 4.2 mmol) in pyridine (3 ml) was stirred at room temperature for 8 hours, and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=1/1) to give the desired compound 2-acetoxy-2-[2-(2,5-dimethylphenoxymethyl)phenyl]-N-methylacetamide (0.53 g, 82%) as colorless crystals.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]2[CH:43]=[CH:42][C:11]([CH:12]=[CH:13][C:14]3[C:22]4[C:17](=[CH:18][C:19](/[CH:23]=[C:24]5/[C:25](=[O:33])[NH:26][C:27]6[C:32]/5=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:20][CH:21]=4)[N:16](COCC[Si](C)(C)C)[N:15]=3)=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.B(F)(F)F.CCOCC.Cl>>[O:1]1[CH2:2][CH2:3][N:4]([CH2:7][C:8]2[CH:43]=[CH:42][C:11]([CH:12]=[CH:13][C:14]3[C:22]4[C:17](=[CH:18][C:19](/[CH:23]=[C:24]5/[C:25](=[O:33])[NH:26][C:27]6[C:32]/5=[CH:31][CH:30]=[CH:29][CH:28]=6)=[CH:20][CH:21]=4)[NH:16][N:15]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: C[Si](C)(C)CCOCn1nc(C=Cc2ccc(CN3CCOCC3)cc2)c2ccc(/C=C3/C(=O)Nc4ccccc43)cc21
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(C=Cc3ccc(CN4CCOCC4)cc3)n[nH]c2c1
Yield: 44.6 %

Procedure:
According to the method of A57C, (E)-3-((3-(4-(morpholinomethyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-yl)methylene)indolin-2-one (95 mg, 0.16 mmol) was treated with boron trifluoride etherate, followed by 2 N HCl to give the title compound as an orange solid (33 mg, 42%). 1H NMR (400 MHz, CD3OD) δ 8.21 (d, J=8.4 Hz, 1H), 7.85 (d, J=6.0 Hz), 7.78 (d, J=8.2 Hz, 2H), 7.66 (d, J=7.6 Hz, 1H), 7.53-7.58 (m, 5H), 7.24 (t, J=7.7 Hz, 1H), 6.93 (d, J=7.6 Hz, 1H), 6.87 (td, J=6.7 Hz, 0.9 Hz, 1H), 4.39 (s, 2H), 4.05-4.09 (m, 2H), 3.72-3.78 (m, 2H), 3.40-3.43 (m, 2H), 3.21-3.26 (m, 2H); MS ESI 463.3 [M+H]+, calcd for [C29H26N4O2+H]+ 463.2.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14](Br)[N:13]=2)=[O:9])[CH:5]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1.[NH4+:24].[OH-].C(O)CO.O>Cl.[Cu-]=O>[NH2:1][C:2]1[N:7]=[C:6]([C:8]([NH:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([NH2:24])[N:13]=2)=[O:9])[CH:5]=[C:4]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[N:3]=1
Reactant: Nc1nc(C(=O)NCc2cccc(Br)n2)cc(-c2ccco2)n1
Reactant: [NH4+]
Agent: O=[Cu-]
Agent: Cl
Agent: [OH-]
Solvent: O
Solvent: OCCO
Product: Nc1cccc(CNC(=O)c2cc(-c3ccco3)nc(N)n2)n1
Temperature: 90 °C
Yield: 22 %

Procedure:
A mixture of 2-amino-N-(6-bromo-2-pyridylmethyl)-6-(2-furyl)pyrimidine-4-carboxamide (350 mg, 0.93 mmol) and copper(I)oxide (6.7 mg, 0.046 mmol) in 4-M NH4OH in ethylene glycol (20.23 ml, 80.92 mmol) was heated in a sealed tube at 90° C. for 20 h, cooled, poured into water (100 mL) and extracted with EtOAc (2×25 mL). The combined organic phase was washed with brine (10 mL), dried (MgSO4), concentrated in vacuo and purified by chromatography [SiO2; Hexane:EtOAc (1:4)-(0:1)] to give the title compound (65 mg, 22%) as a cream solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16](=[O:31])[NH:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](OCC)=[O:26])=[C:20]([Cl:30])[CH:19]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[Li+].[Cl-]>C1COCC1.CCO>[Cl:30][C:20]1[CH:19]=[C:18]([NH:17][C:16](=[O:31])[NH:15][CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH:9]2[NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH:23]=[CH:22][C:21]=1[CH2:24][CH2:25][OH:26]
Reactant: CCOC(=O)Cc1ccc(NC(=O)NC2CCCCC2NC(=O)OC(C)(C)C)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)(C)OC(=O)NC1CCCCC1NC(=O)Nc1ccc(CCO)c(Cl)c1

Procedure:
To a solution of ethyl 2-(4-(3-(2-(tert-butoxycarbonylamino)cyclohexyl)ureido)-2-chlorophenyl)acetate (452 mg, 0.996 mmol) in a mixture of THF:EtOH (1:2, 12 mL) at room temperature, was added NaBH4 (124 mg, 3.29 mmol) and LiCl (139 mg, 3.29 mmol). The reaction mixture was stirred overnite. The solvents were distilled off and the crude was diluted with saturated aqueous NH4Cl (20 mL), the product was extracted with ethyl acetate (2×20 mL). The combined organic extracts were dried over Na2SO4 and the solvent distilled off under reduced pressure. The crude product was purified by flash column chromatography to separate cis 964 mg, 0.155 mmol) and trans (83 mg, 0.201 mmol) diastereomers. These alcohols were converted into tosylates using general procedure for the preparation of tosylates. 1H NMR (cis): 1.23-1.26 (m, 3H), 1.36 (s, 9H), 1.70-1.74 (m, 2H), 1.99-2.06 (m, 2H), 2.41-2.43 (m, 1H), 2.92 (t, 2H, J=6.4 Hz), 3.25-3.29 (m, 1H), 3.51-3.54 (m, 1H), 3.83-3.86 (m, 2H), 5.03 (d, 1H, J=8.8 Hz), 5.62 (d, 1H, J=8.4 Hz), 7.04 (d, 1H, J=8.4 Hz), 7.09 (d, 1H, J=8 Hz), 7.32 (s, 2H). 1H NMR (trans): 1.26-1.29 (m, 1H), 1.37-1.42 (m, 12H), 1.69-1.72 (m, 2H), 1.97 (s, 1H), 2.53-2.55 (m, 1H), 2.85 (t, 2H, J=6.4 Hz), 3.75-3.77 (m, 3H), 3.97-3.99 (m, 1H), 5.15 (br s, 1H), 5.86 (br s, 1H), 6.98-7.05 (m, 2H), 7.30 (s, 1H), 7.41 (s, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=[O:6].S(=O)(=O)(O)O.[OH-].[Na+].[CH3:19]O>CCOCC>[Cl:1][C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([O:7][CH3:19])=[O:6]
Reactant: CO
Reactant: Cc1c(Cl)cccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: COC(=O)c1cccc(Cl)c1C
Temperature: 25 °C
Yield: 99 %

Procedure:
A solution of 3-chloro-2-methylbenzoic acid (1 g, 5.86 mmol) and sulfuric acid (0.312 mL, 5.86 mmol) in Methanol (5 mL) was charged into a round bottom flask. The reaction was stirred at reflux overnight and cooled to RT. 1N NaOH was added to adjust pH to 7. The mixture was diluted with ether, which was washed with brine. The organic layer was dried over MgSO4 and the solvent was removed to afford 1.07 g of crude product (99%). 1H NMR (400 MHz, CDCl3) δppm 7.71 (m, 1H), 7.52 (m, 1H), 7.20 (m, 1H), 3.92 (s, 3H). 2.62 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:17]=[CH:16][C:7]2[N:8]=[C:9]([S:11][CH2:12][C:13]([OH:15])=O)[S:10][C:6]=2[CH:5]=1)[CH3:2].C(N(CC)CC)C.N1(OC(=[N+](C)C)N(C)C)C2C=CC=CC=2N=N1.[B-](F)(F)(F)F.CCCC[P+](C1SC(C(OC)=O)=C(C(OC)=O)S1)(CCCC)CCCC.[Cl:73][C:74]1[CH:75]=[C:76]([CH:84]=[CH:85][C:86]=1[Cl:87])[CH2:77][N:78]1[CH2:81][CH:80]([CH2:82][NH2:83])[CH2:79]1>ClCCl>[Cl:73][C:74]1[CH:75]=[C:76]([CH:84]=[CH:85][C:86]=1[Cl:87])[CH2:77][N:78]1[CH2:81][CH:80]([CH2:82][NH:83][C:13](=[O:15])[CH2:12][S:11][C:9]2[S:10][C:6]3[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:17]=[CH:16][C:7]=3[N:8]=2)[CH2:79]1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)C1
Reactant: CCOc1ccc2nc(SCC(=O)O)sc2c1
Agent: CCCC[P+](CCCC)(CCCC)C1SC(C(=O)OC)=C(C(=O)OC)S1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOc1ccc2nc(SCC(=O)NCC3CN(Cc4ccc(Cl)c(Cl)c4)C3)sc2c1
Reaction time: 3 h

Procedure:
A solution of (6-Ethoxy-benzothiazol-2-ylsulfanyl)-acetic acid (0.087 g, 0.326 mmol) in dichloromethane (3 ml) is treated with triethylamine (0.041 ml, 0.326 mmol) and [(Benzotriazol-1-yloxy)-dimethylamino-methylene]-dimethyl-ammonium; tetrafluoro borate (0.104 g, 0.326 mmol) and stirred at ambient temperature for 3 minutes. To the reaction mixture is added a solution of C-[1-(3,4-Dichloro-benzyl)-azetidin-3-yl]-methylamine (0.08 g, 3.26 mmol) in dichloromethane (1 ml), with stirred for a further 3 hours. The reaction mixture is partitioned between ethyl acetate and sodium bicarbonate solution. The organic phase is dried over magnesium sulphate and evaporated. The crude product is purified by flash silica chromatography using 95:5 dichloromethane:methanol as eluent to afford N-[1-(3,4-Dichloro-benzyl)-azetidin-3-ylmethyl]-2-(6-ethoxy-benzothiazol-2-ylsulfanyl)-acetamide. [MH]+ 495.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]([CH:16]=1)[CH2:7][NH:8][C:9](=[O:15])[CH:10](OC)OC.OS(O)(=O)=O.OS(O)(=O)=O.O=S(=O)=O.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:17])=[C:6]2[C:16]=1[CH:10]=[C:9]([OH:15])[N:8]=[CH:7]2
Reactant: COC(OC)C(=O)NCc1cc(Cl)ccc1F
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: O=S(=O)=O
Product: Oc1cc2c(Cl)ccc(F)c2cn1
Temperature: 85 °C

Procedure:
To N-(5-chloro-2-fluorobenzyl)-2,2-dimethoxyacetamide (9.00 g, 34.3 mmol) were added conc. H2SO4 (25.0 mL, 465 mmol) and oleum (30%, 25.0 mL, 394 mmol). The mixture was heated at 85° C. for 2 h. Then, the reaction mixture was cooled to RT and poured slowly into a cold aqueous satd. solution of NaHCO3 (2.0 L) in a beaker with efficient stirring (Note: frothing occurs). The solid formed was filtered off, washed with water (50 mL), and dried in vacuo to give the title compound as yellow solid. 1H NMR (CDCl3, 300 MHz): δ=6.72 (t, J=8.4 Hz, 1H), 7.15 (s, 1H), 7.43 (dd, J=8.1, 4.2 Hz), 8.80 (s, 1H), —OH not visible. MS (ES+): m/z 197.72/199.77 [MH+]. HPLC: tR=2.58 min (ZQ2, polar—5 min).