Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:33]=[CH:32][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:11])[CH3:10].[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2[O:16][N:15]=[C:14]([C:17]3[CH:33]=[CH:32][C:20]4[CH2:21][CH2:22][N:23]([CH2:26][C:27]([OH:29])=[O:28])[CH2:24][CH2:25][C:19]=4[CH:18]=3)[N:13]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH:9]([CH3:10])[CH3:11]
Reactant: CCOC(=O)CN1CCc2ccc(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)cc2CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)Oc1ccc(-c2nc(-c3ccc4c(c3)CCN(CC(=O)O)CC4)no2)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 28.7 %

Procedure:
A solution of ethyl [7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-1,2,4,5-tetrahydro-3H-3-benzazepin-3-yl]acetate (Preparation 46) (77 mg, 0.164 mmol) in methanol (30 ml) was stirred at room temp and sodium hydroxide (3 ml, 6.00 mmol) added. The reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo, the solid was triturated with methanol (˜5 ml) and the resultant solid filtered off and dried. The solid was suspended in methanol (˜30 ml) and acetic acid added to take the pH of the solution to 5-6, the solvent was removed in vacuo. The resultant residue was dissolved in DCM (˜30 ml) and water (˜30 ml) and the layers partitioned. The aqueous was re-extracted with DCM (˜20 ml) and the combined organics were passed through a phase separation cartridge and the solvent reduced in vacuo. The resultant residue was dried in a drying pistol at 60° C. to yield the title compound (22 mg, 0.047 mmol, 29% yield) as an off white solid. δH (d6DMSO, 400 MHz): 8.19 (1H, s), 8.11 (1H, d), 7.82-7.90 (2H, m), 7.44 (1H, d), 7.36 (1H, d), 4.89 (1H, sept), 3.34 (2H, s), 3.07-2.98 (4H, m), 2.91-2.86 (4H, m), 1.37 (6H, d. MS (ES+): C23H2435ClN3O4 requires 441; found 442 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:15]=[C:14]([C:16](=[O:22])[N:17]([CH3:21])[CH2:18][CH2:19][CH3:20])[CH:13]=[C:7]([C:8]([O:10]CC)=[O:9])[CH:6]=1)[CH3:2].[OH-].[Na+].Cl>C(O)C>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:15]=[C:14]([C:16](=[O:22])[N:17]([CH3:21])[CH2:18][CH2:19][CH3:20])[CH:13]=[C:7]([C:8]([OH:10])=[O:9])[CH:6]=1)[CH3:2]
Reactant: CCCN(C)C(=O)c1cc(C(=O)OCC)cc(C(=O)OCC)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCN(C)C(=O)c1cc(C(=O)O)cc(C(=O)OCC)c1
Yield: 75.8 %

Procedure:
Stir a solution of 5-(methyl-propylcarbamoyl)-isophthalic acid diethyl ester (2.02 g, 6.3 mmol), NaOH (0.25 g, 6.3 mmol) and ethanol (32 mL) at room temperature overnight. Add 0.2 N HCl (60 mL) and extract with ethyl acetate (2×50 mL). Dry (magnesium sulfate), concentrate and purify (silica gel chromatography, eluting with 50:50 ethyl acetate:hexanes with 1% acetic acid then 100% ethyl acetate with 1% acetic acid) to give the title compound as an oil (1.4 g, 75%).
Reaction SMILES: CN(C1C=[CH:18][C:19]([C:22](N[C@H](C(O)=O)CCC(O)=O)=[O:23])=CC=1)CC1C=NC2N=C(N)N=C(N)C=2N=1.Cl.[NH2:35][C:36]1[N:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[C:37]=1[NH2:44].OC(O)C(=O)C>O>[NH2:42][C:40]1[N:41]=[C:36]([NH2:35])[C:37]2[C:38](=[N:43][C:19]([CH3:18])=[C:22]([OH:23])[N:44]=2)[N:39]=1
Reactant: Nc1nc(N)c(N)c(N)n1
Reactant: CN(Cc1cnc2nc(N)nc(N)c2n1)c1ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc1
Agent: CC(=O)C(O)O
Agent: Cl
Solvent: O
Product: Cc1nc2nc(N)nc(N)c2nc1O

Procedure:
The well-known Ellard process is exemplified by U.S. Pat. No. 4,080,325 Ellard and claim 1 of the patent sets out the steps for preparing methotrexate as follows: (a) reacting tetraaminopyrimidinehydrochloride with dihydroxyacetone in the presence of air and water and at a pH in the range of 5.5±0.2 to give 2,4-diamino-6-hydroxy-methylpteridine; (b) converting the 2,4-diamino-6-hydroxy-methylpteridine to the hydrobromide salt, namely, 2,4-diamino-6-hydroxymethylpteridine hydrobromide salt; (c) reacting the 2,4-diamino-6-hydroxymethylpteridine hydrobromide salt with triphenyldibromophosphorane to give 2,4-bis(triphenylphosphazine)-6-bromomethylpteridine hydrobromide; (d) reacting the 2,4-bis(triphenylphosphazino)-6-bromomethylpteridine hydrobromide with ethyl N-(p-methylamino)benzylglutamate to give the phosphazino derivative of methotrexate ester; (e) hydrolyzing the phosphazino derivative of methotrexate ester to give triphenylphosphine oxide and methotrexate ester; and (f) hydrolyzing the methotrexate ester to give methotrexate.
Reaction SMILES: [CH:1]1([C:7]2[S:11][C:10]([N:12]3[CH:17]([OH:18])[CH2:16][CH2:15][N:14]([CH3:19])[C:13]3=[O:20])=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1C=CC=CC=1>[CH:1]1([C:7]2[S:11][C:10]([N:12]3[CH:17]([O:18][C:28](=[O:35])[C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:16][CH2:15][N:14]([CH3:19])[C:13]3=[O:20])=[N:9][N:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCC(O)N(c2nnc(C3CCCCC3)s2)C1=O
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CN1CCC(OC(=O)c2ccccc2)N(c2nnc(C3CCCCC3)s2)C1=O

Procedure:
Tetrahydro-1-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole), triethylamine (0.06 mole) and benzene (50 ml) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Benzoyl chloride (0.05 mole) is then added dropwise with stirring. After the addition is completed, the reaction mixture is heated at reflux with continued stirring for a period of about 30 minutes. After this time the reaction is filtered and the filtrate is stripped of solvent under reduced pressure to yield a solid residue. The residue is recrystallized to yield the desired product tetrahydro-1-(5-cyclohexyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-benzoyloxy-2(1H)-pyrimidinone.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[NH:27]1)[CH3:25]>>[CH2:24]([C@@H:26]1[CH2:30][O:29][C:28](=[O:31])[N:27]1[C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:6][N:7]=1)[CH3:25]
Reactant: Cc1ccc(OC2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1
Reactant: CC[C@@H]1COC(=O)N1
Product: CC[C@@H]1COC(=O)N1c1ccc(C(=O)N2CCC(Oc3ccc(C)cc3)CC2)cn1
Yield: 20 %

Procedure:
By reaction and treatment in the same manner as in Example 40 and using (6-bromopyridin-3-yl)(4-p-tolyloxypiperidin-1-yl)methanone (1.2 g) described in Preparation Example 28 and (R)-4-ethyloxazolidin-2-one (525 mg) described in Preparation Example 26, the title compound (262 mg) was obtained.
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([N:18]3[C@H:22]([C:23]([OH:25])=[O:24])[CH2:21][C@@H:20]4[CH2:26][CH2:27][CH2:28][C@H:19]34)=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Cl:29][CH2:30][CH2:31][CH2:32][CH2:33]O.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl>[N:18]1([C:16]([O:15][CH2:14][CH:12]2[C:13]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[C:6]3[C:11]2=[CH:10][CH:9]=[CH:8][CH:7]=3)=[O:17])[C@H:22]([C:23]([O:25][CH2:33][CH2:32][CH2:31][CH2:30][Cl:29])=[O:24])[CH2:21][C@@H:20]2[CH2:26][CH2:27][CH2:28][C@H:19]12
Reactant: O=C(O)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: OCCCCCl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(OCCCCCl)[C@@H]1C[C@@H]2CCC[C@@H]2N1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 4 h
Yield: 45.3 %

Procedure:
(2S,3aS,6aS)-1-(((9H-fluoren-9-yl)methoxy)carbonyl)octahydrocyclopenta[b]pyrrole-2-carboxylic acid (0.250 g, 0.66 mmol) and 4-chloro-1-butanol (0.1 ml, 0.99 mmol) were dissolved under nitrogen in CH2Cl2 (5 ml) and the mixture was cooled to 0° C. N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC) (0.190 g, 0.99 mmol) and N,N-dimethylaminopyridine (DMAP) (0.016 g, 0.13 mmol) were added and the reaction was slowly warmed to room temperature and stirred for 4 h. Then the mixture was diluted with CH2Cl2 (10 ml) and washed with 5% aqueous NaHCO3, 5% aqueous Na2HPO4 and brine. The organic layer was dried over sodium sulphate, concentrated under reduced pressure and purified by flash chromatography (n-hexane/EtOAc 80:20 as eluent) affording the title compound as an oil (0.14 g, 45%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:16]=[CH:17][C:18]=1[O:19][CH3:20])[CH2:13][C:14]#[N:15]>>[CH3:8][O:9][C:10]1[CH:11]=[C:12](/[C:13](=[CH:13]/[C:12]2[CH:16]=[CH:17][C:18]([O:19][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[CH:10][CH:11]=2)/[C:14]#[N:15])[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(CC#N)cc1OC
Reactant: COCCOCCl
Product: COCCOCOc1ccc(/C=C(\C#N)c2ccc(OC)c(OC)c2)cc1
Yield: 146.7 %

Procedure:
The hydroxyl group of 4-hydroxybenzaldehyde (24.9 g) was protected by use of 2-methoxyethoxymethyl chloride (24.4 g) in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzaldehyde (33.5 g, yield: 80%). The thus-produced 4-methoxyethoxymethoxybenzaldehyde (21.0 g) and 3,4-dimethoxybenzyl cyanide (17.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxyphenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (29.1 g, yield: 86%). Separately, 2-methoxyethoxymethyl chloride (4.1 g), which had been prepared in a manner similar to that described above, and 3,4-dimethoxybenzyl cyanide (3.4 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (5.2 g, yield: 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylonitrile (10.2 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (6.22 g, yield: 74%).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]([CH2:23][CH2:24][CH2:25]O)=[CH:15]1)(=[O:13])[CH3:12].CCN(CC)CC.[C:34]([CH:39]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:36][CH2:37][CH3:38])=[O:35]>C(Cl)Cl.CCOCC>[CH2:37]([O:36][C:34](=[O:35])[CH:39]=[CH:25][CH2:24][CH2:23][C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:14]([C:11](=[O:13])[CH3:12])[CH:15]=1)[CH3:38]
Reactant: CC(=O)n1cc(CCCO)c2ccccc21
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: CS(C)=O
Product: CCOC(=O)C=CCCc1cn(C(C)=O)c2ccccc12
Reaction time: 0.08 h
Yield: 56.4 %

Procedure:
To a stirring solution of oxalyl chloride (11.4 mL, 0.13 mol) in CH2Cl2 (440 mL) at -78° C. was added dry DMSO (12.4 mL, 0.17 mol) dropwise. After 5 minutes, gas evolution ceased and the alcohol 4 (19 g, 87 mmol) in CH2Cl2 (40 mL) was added. After 30 minutes, NEt3 (73 mL, 0.52 mol) was added to effect a thick slurry. The cooling bath was removed and the reaction stirred for an additional 15 minutes before adding (carbethoxymethylene)triphenyl phosphorane (33.5 g, 96 mmol). After 2.0 hours, the reaction mixture was diluted with ether and then washed with H2O (2 times), 5% KHSO4 and brine, dried (MgSO4), and concentrated. Flash chromatography (20% ethyl acetate/hexanes) gave the olefin 5 (14 g) as a white solid. TLC Rf=0.54 (60% ethyl acetate/hexanes); 1H NMR (CDCl3) 8.42 (bd, 1H), 7.50 (d, J=7 Hz, 1H), 7.34 (t, J=7 Hz, 1H), 7.28 (t, J=7 Hz, 1H), 7.19 (bs, 1H), 7.03 (dt, J=18 and 7 Hz, 1H), 5.88 (d, J=18 Hz, 1H), 4.19 (q, J=7 Hz, 2H), 2.87 (t, J=7 HZ, 2H), 2.63 (m, 2H), 2.61 (s, 3H), 1.28 (t, J=7 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[OH:13])=[O:2].C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[CH:21]=[CH2:22]>CC(C)=O>[CH2:22]([O:13][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:3]=1[CH:1]=[O:2])[C:7]([O:9][CH3:10])=[O:8])[CH:21]=[CH2:20]
Reactant: C=CCBr
Reactant: COC(=O)c1ccc(C=O)c(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCOc1cc(C(=O)OC)ccc1C=O
Temperature: 48 °C
Yield: 94.1 %

Procedure:
To a stirred solution of methyl 4-formyl-3-hydroxybenzoate [see: Harayama, Chem. Pharm. Bull. 1994, 2170] (0.8 g, 4.1 mmol) and anhydrous K2CO3 (1.1 g, 8.0 mmol) in acetone (12 mL) is added allyl bromide (0.70 mL, 8.1 mmol). The mixture is heated in a 48° C. oil bath for 2 h. The reaction mixture is cooled to rt and filtered. The mother liquor is concentrated in vacuo to a brown oil. The crude product is purified by flash chromatography on SiO2. Elution with hexanes-EtOAc (85:15) gives 0.85 g (49%) of methyl 3-(allyloxy)-4-formylbenzoate as a clear solid: 1H NMR (400 MHz, CDCl3) δ 10.6, 7.9, 7.7, 6.1, 5.5, 5.4, 4.8, 4.0.
Reaction SMILES: Br[C:2]1[N:6]2[N:7]=[C:8]([NH:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH3:16][NH:17][C:18]([C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1)=[O:19].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>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(COC)OC.O>[CH2:12]([NH:11][C:8]1[CH:9]=[CH:10][C:5]2[N:6]([C:2]([C:23]3[CH:24]=[CH:25][C:20]([C:18]([NH:17][CH3:16])=[O:19])=[CH:21][CH:22]=3)=[CH:3][N:4]=2)[N:7]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CNC(=O)c1ccc(B(O)O)cc1
Reactant: CCCCNc1ccc2ncc(Br)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: CCCCNc1ccc2ncc(-c3ccc(C(=O)NC)cc3)n2n1
Temperature: 160 °C
Yield: 26.8 %

Procedure:
To a mixture of 3-bromo-N-butylimidazo[1,2-b]pyridazin-6-amine (100 mg, 0.37 mmol), (4-(methylcarbamoyl)phenyl)boronic acid (166 mg, 0.93 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (15 mg, 0.02 mmol) and potassium phosphate (236 mg, 1.11 mmol) was added 1:1 Dimethoxyethane/water (5 mL). The resulting mixture was heated at 160° C. (microwave) for 6 min. The reaction was then filtered and diluted with a mixture of 1:1:1 methanol/water/acetonitrile, and then filtered again. The filtration was finally purified by preparative HPLC (acidic) to afford 4-(6-(butylamino)imidazo[1,2-b]pyridazin-3-yl)-N-methylbenzamide (32.1 mg, 27% yield) as a white solid: 1H NMR (METHANOL-d4) δ: 8.21-8.41 (m, 2H), 7.86-7.94 (m, 3H), 7.64 (d, J=9.6 Hz, 1H), 6.74 (d, J=9.6 Hz, 1H), 3.35-3.44 (m, 5H), 2.97 (s, 3H), 1.68-1.77 (m, 2H), 1.46-1.56 (m, 2H), 1.03 (t, J=7.3 Hz, 3H); LRMS (ESI) m/e 324.4 [(M+H)+, calcd for C18H22N5O 324.2].
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:14]=[CH:13][CH:12]=[C:11]3[C:7]=2[C:8]2([C:20]4=[CH:21][C:22]5[O:26][CH2:25][O:24][C:23]=5[CH:27]=[C:19]4[O:18][CH2:17]2)[C:9](=[O:16])[N:10]3[CH3:15])=[CH:2]1.[H][H]>C(OCC)(=O)C.[Pd]>[CH3:15][N:10]1[C:11]2[C:7](=[C:6]([CH:3]3[CH2:4][CH2:5][O:1][CH2:2]3)[CH:14]=[CH:13][CH:12]=2)[C:8]2([C:20]3=[CH:21][C:22]4[O:26][CH2:25][O:24][C:23]=4[CH:27]=[C:19]3[O:18][CH2:17]2)[C:9]1=[O:16]
Reactant: [H][H]
Reactant: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(-c3ccoc3)cccc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1C(=O)C2(COc3cc4c(cc32)OCO4)c2c(C3CCOC3)cccc21
Yield: 72.5 %

Procedure:
To a solution of 4′-furan-3-yl-1′-methylspiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.60 g, 1.66 mmol) in ethyl acetate (30 mL) was added palladium on carbon (10% w/w, 0.40 g). The reaction mixture was shaken under a pressure of hydrogen gas (60 psi) in a Parr hydrogenation apparatus at ambient temperature for 16 h and filtered through a pad of diatomaceous earth. The filtrate was concentrated in vacuo and the residue recrystallized from dichloromethane/diethyl ether to afford methyl-4′-(tetrahydrofuran-3-yl)spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.44 g, 73%) as a colorless solid: mp 182-184° C. (dichloromethane/ether); 1H NMR (300 MHz, CDCl3) δ 7.31-7.35 (m, 1H), 7.08-7.01 (m, 1H), 6.77 (d, J=7.7 Hz, 1H), 6.52-6.48 (m, 1H), 6.15 (d, J=13.3 Hz, 1H), 5.90-5.84 (m, 2H), 4.96 (dd, J=9.26, 1.0 Hz, 1H), 4.78-4.67 (m, 1H), 4.11-3.59 (m, 3H), 3.39-3.18 (m, 2H), 2.40-1.94 (m, 1H), 1.63-1.36 (m, 1H); MS (ES+) m/z 365.9 (M+1).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C@H:13]1[CH2:16][O:15][C:14]1=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C>[N:18]([CH2:16][C@@H:13]([C:14]([OH:15])=[O:17])[NH2:12])=[N+:19]=[N-:20]
Reactant: N[C@H]1COC1=O
Reactant: [N-]=[N+]=[N-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@H](N)C(=O)O
Reaction time: 3.5 h
Yield: 96.5 %

Procedure:
A solution of (S)-3-amino-2-oxetanone p-toluenesulfonic acid salt (53.0 mg, 0.204 mmol) in DMF (1 mL) was added to NaN3 (14.6 mg, 0.225 mmol) in DMF (5 mL) and the mixture was stirred 3.5 h. The solvent was removed in vacuo at 25° C. The residue was dissolved in H2O (0.3 mL) and applied to a column of Bio-Rad Ion Retardation Resin Ag11 A8 (trademark) (15 g, 1×20 cm) and eluted with H2O (0.3 mL/min). Fractions containing amino acid were pooled and lyophilized to yield 25.6 mg (96%) of pure β-azido-L-alanine. For the optimum melting point this material was recrystallized by dissolving in a minimal volume of H2O at 40° C., adding MeOH (3 vol.) and acetone (until cloudy) and cooling to -20° C.: mp 174°-175° C. (dec); [α]D 25 +37.2 (± 0.5) (c 0.5, H2O); IR (K8r disk) 3420 (m, br), 3070 (s, br), 2113 (s), 1600 (vs, br), 1440 (s) cm-1 ; 1H NMR (300 MHz, d4 -MeOD)δ 3.63 (dd, 1H, 4.5, 12 Hz, CHHN3), 3.53 (dd, 1H, 7.2, 12 Hz, CHN3), 3.37 (dd, 1H, 4.5, 7.2 Hz, CH); 1H NMR (300 MHz, D2O)δ 3.93 (dd, 1H, 5.0, 17.5 Hz, CHHN3), 3.92 (m, 1H, CH), 3.84 (dd, 1H, 7.0, 17.5 Hz, CHHN3); EI-MS: 131.0570 (MH+, Calc. 131.0570 for C3H7N4O2), 88.0400 (MH+ -HN3), 85.0515 (M-CO2H), 74.0245 (Base peak, M-CH2N3); POSFAB-MS (glycerol) 131 (MH+); Rf 0.80 (System A; UV active; brown-purple with ninhydrin).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>C(O)CCC>[N:26]1([CH2:25][CH2:24][N:18]2[CH2:19][CH2:20][N:21]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:22][CH2:23]2)[CH2:27][CH2:28][O:29][CH2:30][CH2:31]1
Reactant: Nc1cc(Cl)ncn1
Reactant: C1CN(CCN2CCOCC2)CCN1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: Nc1cc(N2CCN(CCN3CCOCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-chloropyrimidin-4-amine 7-2 (3.09 g, 23.9 mmol) and diisopropylethylamine (3.08 g, 23.9 mmol) were suspended in n-butanol and then 4-(2-piperazin-1-ylethyl)morpholine 7-3 (4.75 g, 23.9 mmol) was added. The reaction was stirred at 125° C. for 18 hours and then the product was filtered off, washed with n-butanol and ethyl ether and then air dried. Hi-Res MS: calc: 293.2084 found: 293.2078. 1H-NMR (DMSO): 7.94 ppm (s, 1H); 6.18 ppm (s, 2H); 5.57 ppm (s, 1H); 3.56 ppm (m, 6H); 3.39 ppm (m, 8H); 2.47 ppm (m, 6H).
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][CH2:7][CH2:8][NH:9][C@@H:10]([CH3:20])[C@@H:11]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)[OH:12])=[C:4]([CH3:24])[CH:3]=1.[CH3:25][C:26]1[CH:27]=[C:28]([CH:34]=[CH:35][C:36]=1B1OC(C)(C)C(C)(C)O1)[O:29][CH2:30][C:31]([OH:33])=[O:32].[F-].[Cs+].O1CCOCC1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O.C(O)C>[OH:12][C@H:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[C@@H:10]([NH:9][CH2:8][CH2:7][O:6][C:5]1[C:21]([CH3:23])=[CH:22][C:2]([C:36]2[CH:35]=[CH:34][C:28]([O:29][CH2:30][C:31]([OH:33])=[O:32])=[CH:27][C:26]=2[CH3:25])=[CH:3][C:4]=1[CH3:24])[CH3:20]
Reactant: Cc1cc(OCC(=O)O)ccc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Br)cc(C)c1OCCN[C@@H](C)[C@H](O)c1ccc(O)cc1
Agent: [Pd]
Agent: [Cs+]
Agent: [F-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1cc(OCC(=O)O)ccc1-c1cc(C)c(OCCN[C@@H](C)[C@H](O)c2ccc(O)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.3 %

Procedure:
A mixture of 4-{(1R,2S)-2-[2-(4-bromo-2,6-dimethyl-phenoxy)ethylamino]-1-hydroxypropyl}phenol (0.03 g), [3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetic acid (0.045 g), tetrakis(triphenylphosphine)-palladium (0.0046 g), cesium fluoride (0.069 g), 1,4-dioxane (0.75 mL), ethanol (0.25 mL) and water (0.15 mL) was stirred at 100° C. overnight. After being cooled to room temperature, the reaction mixture was diluted with tetra hydrofuran (2.5 mL). The crude product was purified firstly by SCX ion exchange column chromatography (Argonaut 1 g, preconditioning: tetra hydrofuran, washing solvent: tetra hydrofuran, eluent:2 mol/L ammonia in methanol), and then by reverse phase column chromatography (Shiseido Capcell Pak C18 ODS, 5 μm, 120 Å, 20×50 mm, linear gradient 0.1% aqueous formic acid/acetonitrile=90/10-60/40) to afford the title compound (0.0085 g) as a white amorphous. The structure and physical data were shown in table 2.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][OH:6])[CH3:2].[H-].[Na+].Br[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]>>[C:17]([OH:19])(=[O:18])[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][O:6][CH2:5][CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCCO
Reactant: O=C(O)CCCCCCCBr
Agent: [H-]
Agent: [Na+]
Product: CCOCCOCCCCCCCC(=O)O

Procedure:
Illustratively, 2-butoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 6-bromohexanoic acid to give 7,10-dioxatetradecanoic acid. So also, 2-ethoxyethanol can be reacted with sodium hydride and the resulting alcoholate reacted with 8-bromooctanoic acid to provide 9,12-dioxatetradecanoic acid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:7])[CH2:4][NH:5][CH3:6].COC(=O)[C@H](CC1N=CNC=1)NCC1C=CC=CC=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C=O)C.[C:66]1([CH3:81])[CH:71]=[CH:70][C:69]([S:72](N(CC(O)=O)C)(=[O:74])=[O:73])=[CH:68][CH:67]=1>>[CH3:1][O:2][C:3](=[O:7])[CH2:4][N:5]([S:72]([C:69]1[CH:70]=[CH:71][C:66]([CH3:81])=[CH:67][CH:68]=1)(=[O:74])=[O:73])[CH3:6]
Reactant: Cc1ccc(S(=O)(=O)N(C)CC(=O)O)cc1
Reactant: CNCC(=O)OC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: COC(=O)[C@H](Cc1c[nH]cn1)NCc1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(=O)CN(C)S(=O)(=O)c1ccc(C)cc1

Procedure:
N-(Toluene-4-sulfonyl)sarcosine methyl ester was prepared from sarcosine methyl ester using the procedure described in Method 1. The title compound was prepared by coupling in DMF N-(toluene-4-sulfonyl)sarcosine with (N-benzyl)histidine methyl ester in the presence of BOP and NMM, to give after aqueous workup and flash chromatography, the title compound.
Reaction SMILES: S(O[CH2:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]2)=[CH:17][CH:16]=1)(C1C=CC(C)=CC=1)(=O)=O.[NH:35]1[CH:39]=[N:38][CH:37]=[N:36]1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C.CN(C=O)C>[N:35]1([CH2:12][CH2:13][CH2:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[CH:39]=[N:38][CH:37]=[N:36]1
Reactant: Cc1ccc(S(=O)(=O)OCCCc2ccc(N3CCC(NC(=O)OC(C)(C)C)CC3)cc2)cc1
Reactant: c1nc[nH]n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(CCCn3cncn3)cc2)CC1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The N-(4-(3-tosyloxypropyl)phenyl)-4-tert-butoxycarbonylaminopiperidine (330 mg, 0.68 mmol) obtained in Example 8(4) was dissolved in a mixed solvent of acetonitrile (5 ml) and DMF (5 ml), and 1,2,4-triazole (54 mg, 0.81 mmol) and potassium carbonate (187 mg, 1.35 mmol) were added thereto, followed by stirring at 60° C. for 1 hour. After the reaction mixture was cooled to room temperature, water was added thereto, and the precipitate was collected by filtration, thereby obtaining N-(4-(3-(1,2,4-triazol-1-yl)-propyl)-phenyl)-4-tert-butoxycarbonylaminopiperidine (192 mg, 74%).