Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20].[I:26]I.[O-]S([O-])(=S)=O.[Na+].[Na+]>C1COCC1>[F:16][C:17]1[C:24]([I:26])=[C:23]([CH3:25])[CH:22]=[CH:21][C:18]=1[C:19]#[N:20]
Reactant: II
Reactant: Cc1ccc(C#N)c(F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: O=S([O-])([O-])=S
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C#N)c(F)c1I
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A solution of 2,2,6,6,-tetramethylpiperidine (45 mL, 267 mmol) in THF (400 mL) was cooled below −80° C. under N2-atmosphere. n-Butyl lithium (2.5M in hexane, 110 mL, 275 mmol) was added slowly maintaining the temperature of the mixture below −70° C. After complete addition, the reaction mixture was warmed to −50° C. and stirred at this temperature for 30 minutes. The clear solution became turbid indicating the salt formation. It was cooled to −80° C. again and a solution of 2-fluoro-4-methylbenzonitrile (32.4 g, 240 mmol) in THF (150 mL) was slowly added taking care that the temperature of the reaction mixture remained below −70° C. It was then warmed up to −50° C. and stirred for 30 minutes. The mixture was then cooled to −70° C. and a saturated solution of I2 (67 g, 264 mmol) in THF was added slowly maintaining the temperature at −70° C. After complete addition, the mixture was warmed to ambient temperature. It was added to a solution of Na2S2O3 (160 g in 1.5 L of water) and stirred for an hour. The organic part was separated and the aqueous layer was extracted with EtOAc. The organic layers were combined and washed with brine. The organic layer was then dried over Na2SO4 and filtered. The volatiles were evaporated under reduced pressure. The crude product was subjected to vacuum distillation; at about 60° C., excess TMP was removed, at about 100° C., the starting compound 2-fluoro-4-methylbenzonitrile and a small amount of product was removed and, finally at 115° C., pure 2-fluoro-3-iodo-4-methylbenzonitrile was obtained (30 g, 48% yield). MS (M+H)+ 262.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[C:3]([SH:6])([CH3:5])[CH3:4].[CH3:10][C:11]1[CH:18]=[CH:17][C:14]([CH:15]=O)=[CH:13][CH:12]=1>CO>[CH3:4][C:3]1([CH3:5])[S:6][CH:10]([C:11]2[CH:18]=[CH:17][C:14]([CH3:15])=[CH:13][CH:12]=2)[NH:1][C@H:2]1[C:7]([OH:9])=[O:8]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: Cc1ccc(C=O)cc1
Solvent: CO
Product: Cc1ccc(C2N[C@@H](C(=O)O)C(C)(C)S2)cc1
Reaction time: 1 h

Procedure:
A solution containing 1.50 g (10 mmoles) of D-penicillamine and 1.18 ml (10 mmoles) of 4-methylbenzaldehyde in 30 ml of 30% methanol is stirred for 1 hour. The precipitated crystals are filtered out and washed with 30% methanol to give the crude title acid in a yield of 2.25 g (89.5%) which can be recrystallized from methanol by adding water, m.p.: 89°-90° C., [α]D =+53.5 (c=0.784, dimethylsulphoxide).
Reaction SMILES: [C:1]1([C:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([CH:11]2[CH2:16][CH2:15]C[N:13]([CH2:17][CH3:18])[CH2:12]2)C(N)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(C(C2C=CC=CC=2)(C2C=CN(CC)C=CC=2)C(N)=O)C=CC=CC=1>>[CH2:17]([N:13]1[CH2:15][CH2:16][C:11](=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH2:12]1)[CH3:18]
Reactant: CCN1CCCC(C(C(N)=O)(c2ccccc2)c2ccccc2)C1
Agent: CCN1C=CC=C(C(C(N)=O)(c2ccccc2)c2ccccc2)C=C1
Product: CCN1CCC(=C(c2ccccc2)c2ccccc2)C1

Procedure:
Following the same procedure, employing α,α-diphenyl-α-(1-ethyl-3-piperidinyl)acetamide or α,α-diphenyl-α-(1-ethyl-4-azepinyl)acetamide as the starting material yields 1-ethyl-3-diphenylmethylenepyrrolidine or 1-ethyl-4-diphenylmethyleneazepine, respectively.
Reaction SMILES: C([O:3][CH:4](OCC)[CH2:5][CH2:6][CH2:7][N:8]([CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH3:9])C.Cl>C1COCC1>[CH3:9][N:8]([CH2:10][C:11]1[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=1)[CH2:7][CH2:6][CH2:5][CH:4]=[O:3]
Reactant: CCOC(CCCN(C)Cc1ccc(C#N)cc1)OCC
Agent: Cl
Solvent: C1CCOC1
Product: CN(CCCC=O)Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 86.9 %

Procedure:
The compound (1.22 g) obtained in Example 44-2 was dissolved in THF (12.2 ml) and added with 1 mol/l hydrochloric acid (12.2 ml). The whole was stirred at room temperature for 19 hours. The reaction solution was concentrated under reduced pressure. The residue was added with a 1 mol/l sodium hydroxide aqueous solution and the whole was subjected to extraction with chloroform. The organic layer was washed with a saturated saline solution and dried with anhydrous sodium sulfate, followed by concentration under reduced pressure. The residue was purified through silica gel column chromatography (chloroform/methanol), thereby obtaining the subject compound (0.790 g) as a yellow oily substance.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10](Cl)=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[Cl:36][C:37]1[CH:42]=[C:41](B2OC(C)(C)C(C)(C)O2)[CH:40]=[C:39]([F:52])[C:38]=1[OH:53]>>[C:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]3[CH2:25][CH2:24][CH:23]([N:26]([CH3:34])[C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:31])[CH3:32])[CH2:22]3)=[N:19][CH:20]=1)=[N:11][C:10]([C:41]1[CH:40]=[C:39]([F:52])[C:38]([OH:53])=[C:37]([Cl:36])[CH:42]=1)=[CH:9][CH:8]=2)(=[O:3])[CH3:2]
Reactant: CC1(C)OB(c2cc(F)c(O)c(Cl)c2)OC1(C)C
Reactant: CC(=O)c1cnc2ccc(Cl)nc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCC(N(C)C(=O)OC(C)(C)C)C2)nc1
Yield: 68.5 %

Procedure:
Following general procedure II, tert-butyl 1-[5-(3-acetyl-6-chloro-1,5-naphthyridin-4-ylamino)-pyridin-2-yl]pyrrolidin-3-yl(methyl)carbamate (94 mg, 0.19 mmol) was reacted with 2-chloro-6-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (77 mg, 0.28 mmol) to afford crude product (79 mg) as an orange solid which was carried forward without any purification: ESI MS m/z 607 [M+H]+
Reaction SMILES: C([O:3][C:4](=[O:36])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[CH:17]=[C:16]([C:30]#[C:31][CH2:32][O:33][CH3:34])[CH:15]=2)=[CH:9][C:8]=1[Cl:35])C.[OH-].[Na+].Cl>C(O)C>[Cl:35][C:8]1[CH:9]=[C:10]([S:13][C:14]2[CH:19]=[C:18]([O:20][CH2:21][CH2:22][CH2:23][N:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[CH:17]=[C:16]([C:30]#[C:31][CH2:32][O:33][CH3:34])[CH:15]=2)[CH:11]=[CH:12][C:7]=1[O:6][CH2:5][C:4]([OH:36])=[O:3]
Reactant: CCOC(=O)COc1ccc(Sc2cc(C#CCOC)cc(OCCCN3CCOCC3)c2)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COCC#Cc1cc(OCCCN2CCOCC2)cc(Sc2ccc(OCC(=O)O)c(Cl)c2)c1
Reaction time: 1 h

Procedure:
{2-Chloro-4-[3-(3-methoxy-prop-1-ynyl)-5-(3-morpholin-4-yl-propoxy)-phenyl-sulfanyl]-phenoxy}-acetic acid ethyl ester (150 mg; 0.30 mmol) was dissolved in ethanol (10 mL), and aqueous 1 N sodium hydroxide (3 mL) was added. The reaction mixture was stirred for 1 h, acidified with 1 N aqueous hydrochloric acid, and extracted with ethyl acetate. The organic phase was dried, and evaporated to dryness and purified by preparative HPLC (method B). Yield: 50 mg. HPLC-MS: m/z: 506.0 (M+); Rt: 1.56 min. δH (400 MHz; CDCl3) 2.06-2.15 (m, 2H), 2.82-2.92 (m, 2H), 3.15-3.23 (m, 2H), 3.45 (s, 3H), 3.56 (d, 2H), 3.78 (t, 2H), 3.95-4.03 (m, 4H), 4.30 (s, 2H), 4.89 (s, 2H), 5.91-5.94 (m, 1H), 6.63-6.66 (m, 1H), 6.93 (d, 1H), 7.01-7.03 (m, 1H), 7.40 (dd, 1H), 7.58 (d, 1H).
Reaction SMILES: [CH2:1]([N:5]1[C:10]([CH3:11])=[CH:9][C:8]([CH3:13])([CH3:12])[N:7]([CH3:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4].[Na]>C(O)C>[CH2:1]([N:5]1[CH:10]([CH3:11])[CH2:9][C:8]([CH3:12])([CH3:13])[N:7]([CH3:14])[CH2:6]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN1CN(C)C(C)(C)C=C1C
Agent: [Na]
Solvent: CCO
Product: CCCCN1CN(C)C(C)(C)CC1C
Reaction time: 18 h
Yield: 95.3 %

Procedure:
To a mixture of 40 grams of 1-butyl 3,4,4,6-tetramethyl 1,2,3,4-tetrahydropyrimidine prepared as described in example 7, and 177 grams of absolute ethanol was added over a 1/2 hour period 4.7 grams of sodium hydribodorate. The reaction mixture was stirred for 18 hours and the ethanol evaporated under diminished pressure. To the resulting product was added water and stirring was continued for 24 hours. The organic layer was separated, dissolved in ether, and the ethereal solution washed with diminished pressure to yield 38.5 grams of 1-butyl 3,4,4,6-tetramethyl hexahydropyrimidine. C13 n.m.r., solvent CDCl3 ; ref. T.M.S.; ##STR13## As described above the following substituted 1,2,3,4-tetrahydropyrimidines of the general structure: ##STR14## were prepared, and are listed in Table I.
Reaction SMILES: [CH:1]1([CH:7]=[CH:8][C:9]([OH:11])=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:14])=O>ClCCl.CN(C=O)C>[CH:1]1([CH:7]=[CH:8][C:9]([Cl:14])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)C=CC1CCCCC1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)C=CC1CCCCC1
Yield: 100.1 %

Procedure:
4.22 g (27.3 mmol) of 3-cylcohexyl-2-propenoic acid are suspended in dichloromethane (30 ml), 5 drops of DMF are added and at RT 1.9 ml (164 mmol) of thionyl chloride are slowly added dropwise. The reaction mixture is heated to reflux for 2 h, cooled and concentrated to dryness on a rotary evaporator. The oily residue is taken up twice using toluene, concentrated to dryness and dried in vacuo. 4.72 g of product are obtained, which is directly reacted further.
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:14]=[C:13]([OH:15])[CH:12]=[C:11]([NH:16][C@H:17]([CH3:20])[CH2:18][OH:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:21]NC(=O)CCC(N)=O>CC(O)=O>[CH2:1]([S:8][C:9]1[N:14]=[C:13]([OH:15])[C:12]([Cl:21])=[C:11]([NH:16][C@H:17]([CH3:20])[CH2:18][OH:19])[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)CCC(=O)NCl
Reactant: C[C@H](CO)Nc1cc(O)nc(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc(O)c1Cl
Reaction time: 3 h

Procedure:
The product of Example 1 (0.5 g) was dissolved in AcOH (10 ml), N-chlorosuccinamide (0.23 g) added and stirred for 3 h. The mixture was evaporated and purified by silica gel chromatography (5% methanol/DCM) to yield the title product as a white solid. Yield 0.42 g.
Reaction SMILES: [H-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](/[CH:19]=[CH:20]/[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]1.O>CS(C)=O>[CH3:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([C@@H:19]2[CH2:4][C@H:20]2[C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:11]1
Reactant: CCOC(=O)/C=C/c1cn(C)c2ccccc12
Reactant: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)[C@@H]1C[C@H]1c1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 21.5 %

Procedure:
To a suspension of sodium hydride (ca 60%, 21 mg, 0.52 mmol) in DMSO (1 mL) was added trimethylsulfoxonium iodide (115 mg, 0.52 mmol), and the mixture was stirred at room temperature for 20 minutes. Then, ethyl (E)-3-(1-methyl-1H-indol-3-yl)acrylate (Synlett, (9), 1319-1322 (2006)) (100 mg, 0.44 mmol) was added to the mixture, and the mixture was stirred at room temperature for 1 hour and at 60° C. for 20 hours. After cooling to room temperature, the mixture was poured into water (30 mL), and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over Magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (7:1) to give 23 mg (21% yield) of the title compound as a pale yellow oil:
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.[Cl:11][CH2:12][C:13](O)=O>Cl>[Cl:11][CH2:12][C:13]1[NH:10][C:4]2[CH:3]=[C:2]([Cl:1])[C:7]([Cl:8])=[CH:6][C:5]=2[N:9]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: O=C(O)CCl
Agent: Cl
Product: ClCc1nc2cc(Cl)c(Cl)cc2[nH]1
Temperature: 25 °C
Yield: 80.7 %

Procedure:
A solution of 1.77 g (10 m mol) of 4,5-dichloro-1,2-phenylenediamine in 15 ml of 4N aqueous hydrochloric acid was stored at room temperature overnight. To the solution was added 1.42 g (15 m mol) of monochloroacetic acid, and refluxed for 3 hours and filtered. The filterate was cooled to room temperature, stirred and rendered alkaline by addition of ammonium hydroxide. The separated precipitate was washed with water and dried to give 1.9 g (68%) of the title compound.
Reaction SMILES: C1(O)C=CC=CC=1.C1(O)C=CC=CC=1.CC(C)=O.[C:19]1([CH:25]([CH3:27])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O-]O.C1(C(C)C)C=CC=CC=1.CC(C)(C1C=CC=CC=1)O>>[CH3:27][C:25]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[CH2:26]
Reactant: CC(C)c1ccccc1
Agent: CC(C)(O)c1ccccc1
Agent: [O-]O
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: C=C(C)c1ccccc1

Procedure:
Phenol is manufactured via air oxidation of cumene to cumene hydroperoxide (CHP), followed by acid-catalyzed cleavage of the latter to phenol and acetone, and known as CHP decomposition. CHP decomposition is a very exothermic reaction which is normally carried out on a commercial scale in continuous stirred or back-mixed reactors. In such reactors only a small fraction of CHP is unreacted at any given time and the reaction medium consists essentially of the products of decomposition of CHP, i.e., phenol and acetone, plus any solvent (e.g., cumene) and other materials added with CHP to the reactor. During cumene oxidation small amounts of dimethyl phenyl carbinol (DMPC) and acetophenone are also formed. In the presence of acid catalyst, DMPC dehydrates to alphamethylstyrene (AMS), a useful by-product. Very high yields of AMS can be obtained from pure DMPC, e.g., 98% yield upon dehydration over acidic silica at 300° C. In the presence of phenol, however, and more specifically in a phenol/acetone/cumene mixture which is a solvent in the decomposition of CHP/DMPC mixtures, the ultimate AMS yield is normally about 50–60 mol % of the DMPC. Main by-products are AMS dimers and cumylphenol which have no commercial value. Formation of cumylphenol also reduces the phenol yield.
Reaction SMILES: [C:1]([N:9]1[CH2:12][CH:11]([NH:13][C:14]2[CH:23]=[CH:22][N:21]=[C:20]3[C:15]=2[C:16]2[CH:28]=[CH:27][CH:26]=[CH:25][C:17]=2[C:18](=[O:24])[NH:19]3)[CH2:10]1)(=O)C1C=CC=CC=1.C([O-])([O-])=O.[K+].[K+].ClC[C:37]([NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:38]>CO>[O:24]=[C:18]1[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[C:15]2[C:20](=[N:21][CH:22]=[CH:23][C:14]=2[NH:13][CH:11]2[CH2:10][N:9]([CH2:1][C:37]([NH:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:38])[CH2:12]2)[NH:19]1
Reactant: O=C(c1ccccc1)N1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1
Reactant: O=C(CCl)Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=C(CN1CC(Nc2ccnc3[nH]c(=O)c4ccccc4c23)C1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 40 h
Yield: 7.8 %

Procedure:
The amine intermediate from Example 366 (60 mg, 0.16 mmol), K2CO3 (33 mg, 0.24 mmol), and 2-chloro-N-phenylacetamide (26 mg, 0.16 mmol) were suspended in MeOH (2 mL), and stirred for 40 h at room temperature. The crude reaction mixture was purified directly via HP-LC to provide 370 (5 mg, 6% yield) as a solid. LC-MS (M+H=400, obsd.=400).
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:29][C:30]1[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][C:31]=1[CH:32]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:32][C:31]3[CH:34]=[C:35]([OH:38])[CH:36]=[CH:37][C:30]=3[OH:29])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=Cc1cc(O)ccc1O
Product: Oc1ccc(O)c(CNc2cccc(-c3c(Cc4ccccc4)cnc4c(C(F)(F)F)cccc34)c2)c1

Procedure:
This compound was prepared according to the procedure of example 66, substituting 3-(3-benzyl-8-trifluoromethyl-quinolin-4-yl)-phenylamine and 2,5 dihydroxybenzaldehyde. MS (ESI) m/z 501.
Reaction SMILES: [N:1]([C@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)[CH3:5])=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[N+:12]([C:8]1[CH:7]=[C:6]([C@@H:4]([NH2:1])[CH3:5])[CH:11]=[CH:10][CH:9]=1)([O-:14])=[O:13]
Reactant: C[C@H](N=[N+]=[N-])c1cccc([N+](=O)[O-])c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: C[C@H](N)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 91.7 %

Procedure:
To a solution of 1-[(1S)-1-azidoethyl]-3-nitrobenzene (16.5 g, 86 mmol) in a mixture of toluene (325 mL) and water (40 mL) was added triphenylphosphine (44.5 g, 170 mmol) in one portion. The mixture was immediately heated to 80° C. where it was stirred for 3 hours. After this time the mixture was allowed to cool to room temperature, was diluted with ethyl acetate (100 mL), the two phases separated and the organic phase extracted with dilute aqueous hydrochloric acid (2M, 3×100 mL). The acidic extracts were basified to pH>10 with solid potassium hydroxide and were then extracted with dichloromethane (3×100 mL). The organic extracts were washed with brine (100 mL), dried (MgSO4) and concentrated under reduced pressure to give (1S)-1-(3-nitrophenyl)ethanamine (13.1 g, 92%) as a yellow liquid.
Reaction SMILES: [C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.FC(N(C)C)=[N+](C)C.C(N(CC)CC)C.O.[NH2:46][NH2:47]>CN(C)C=O.O>[C:1]1([C:7]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([NH:46][NH2:47])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: O=C(O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CN(C)C(F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: NNC(=O)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65 %

Procedure:
Triphenylacetic acid (499.6 mg, 1.73 mmol) was dissolved in N,N-dimethylformamide (DMF, 3.46 mL). Fluoro-N,N,N′,N′-tetramethylformamidinium hexafluorophosphate (TFFH, 460.1 mg, 1.742 mmol) and anhydrous triethylamine (480 μl, 3.44 mmol) were added and the solution was cooled to 0° C. After 10 minutes hydrazine monohydrate (168 μl, 3.46 mmol) was added. The reaction was allowed to warm, and after stirring at room temperature for 30 minutes, it was worked up by adding water and filtering the resulting precipitate. The precipitate was dried under vacuum to give 2,2,2-triphenylacetohydrazide (340.1 mg).
Reaction SMILES: [C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([OH:23])=O)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[NH2:39][CH2:40][CH2:41][C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43]>>[C:1]([O:18][CH:19]([CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38])[CH2:20][C:21]([NH:39][CH2:40][CH2:41][C:42]([NH:44][C@H:45]([C:49]([OH:51])=[O:50])[C@@H:46]([CH3:48])[OH:47])=[O:43])=[O:23])(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: C[C@@H](O)[C@H](NC(=O)CCN)C(=O)O
Reactant: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)O
Product: CCCCCCCCCCCCCCCC(=O)OC(CCCCCCCCCCCCCCC)CC(=O)NCCC(=O)N[C@H](C(=O)O)[C@@H](C)O
Yield: 48 %

Procedure:
Starting from 3-hexadecanoyloxyoctadecanoic acid (150 mg) prepared by the method described in Preparation A-2 (5) and N-β-alanyl-L-threonine (110 mg), N-[N-(3-hexadecanoyloxyoctadecanoyl)-β-alanyl]-L-threonine (95 mg) was obtained as powder according to similar manner to that of Preparation B-1.
Reaction SMILES: [C:1](=[O:3])=O.Cl.[CH2:5]([O:7][C:8](=[O:12])[CH2:9][CH2:10][NH2:11])[CH3:6].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O>ClCCl.C(OCC)C>[N-:11]=[C:1]=[O:3].[CH2:5]([O:7][C:8](=[O:12])[CH2:9][CH2:10][NH2:11])[CH3:6]
Reactant: O=C=O
Agent: CCOC(=O)CCN
Agent: Cl
Solvent: O=P(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCOCC
Product: [N-]=C=O

Procedure:
Carbon dioxide was added subsurface to a dichloromethane (40 mL) solution containing β-alanine ethyl ester hydrochloride salt (0.03 mol, 4.6 g), N-cyclohexyl-N',N',N",N"-tetraethylguanidine (0.03 mol, 7.6 g) and triethylamine (0.12 mol, 12.0 g) at -10° C. (ice and salt bath) for 40 min at a pressure of 0 psig. The reaction mixture was transferred rapidly via cannula under carbon dioxide to the precooled solution of phosphorus oxychloride (0.03 mol, 4.8 g) in 40 mL dichloromethane. After stirring for 20 min at -10° C. diethylether (50 mL) was added to the reaction mixture. A white ppt formed and was filtered off. The filtrate was concentrated in vacuo and the residue was extracted with 3×25 mL diethylether. The ether layers were concentrated and the residue was distilled under vacuum collecting product, β-alanine ethyl ester isocyanate, at 37°-39° C. (2.74 g, 64%) of 97.3% purity as judged by GC. IR (neat) 2272, 1732 cm-1. 1H NMR (CDCl3) δ 4.16 (q, 2H, J=4.3), 3.56 (t, 2H, J=6.4), 2.57 (t, 2H, J=6.4), 1.25 (t, 3H, J=7.2) ppm.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:18][NH:19][NH2:20].Cl.C([O-])(=O)C.[Na+]>O.N1C=CC=CC=1>[CH3:18][N:19]1[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:9][C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[N:20]1
Reactant: CNN
Reactant: O=C(CC(=O)c1ccccc1)c1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: Cn1nc(-c2ccccc2)cc1-c1ccccc1
Temperature: 80 °C
Yield: 94 %

Procedure:
545.0 Grams (2.43 moles) of dibenzoylmethane and 533 ml. of pyridine are stirred together and heated to 80° C. 112 Grams (2.43 moles) of methylhydrazine are then slowly added to the mixture and a strong exothermic reaction ensues necessitating cooling of the mixture with a water bath. When addition is complete, the mixture is heated to reflux and maintained in this condition for 40 minutes. The mixture is then cooled to 30° C., poured into 19 liters of 3 N HCl, filtered, and the solid collected. This is reslurried in 198 grams (2.43 moles) of sodium acetate dissolved in 19 liters of water. The mixture is filtered, water washed and air dried to give 535 grams of product, 94.5% yield, having melting point 58° C. to 59° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([CH2:12][OH:13])[C:3]=1[N:14]1[CH2:19][C@H:18]([CH3:20])[O:17][C@H:16]([CH3:21])[CH2:15]1.C[N+]1([O-])CCOCC1>C(Cl)Cl.CCC[N+](CCC)(CCC)CCC.[O-][Ru](=O)(=O)=O>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([CH3:11])[C:6]=2[CH:5]=[C:4]([CH:12]=[O:13])[C:3]=1[N:14]1[CH2:15][C@H:16]([CH3:21])[O:17][C@H:18]([CH3:20])[CH2:19]1
Reactant: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO)cc12
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(C=O)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To the solution of {7-chloro-6-[(2R,6S)-2,6-dimethylmorpholin-4-yl]-3-methyl-1,2-benzoxazol-5-yl}methanol (Intermediate 372, 130 mg, 4.4 mmol) in anhydrous DCM (5 mL), was added NMO (103 mg, 8.8 mmol) and TPAP (31 mg, 0.88 mmol) at 0° C. and allowed to stir for 1 h at room temperature. The reaction mixture was filtered and the solvents were removed under vacuum and the residue was purified over silica gel chromatography column using ethylacetate-pet. ether gradient to give solid. Yield: 35 mg, (27%).