Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]2[N:8]=[C:9]([CH3:11])[S:10][C:6]=2[C:5](I)=[CH:4][N:3]=1.[CH3:13][S:14]([C:17]1[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15].[NH2:26][C:27]1[S:28][CH:29]=[C:30]([CH3:32])[N:31]=1>>[CH3:13][S:14]([C:17]1[CH:18]=[C:19]([C:5]2[C:6]3[S:10][C:9]([CH3:11])=[N:8][C:7]=3[C:2]([NH:26][C:27]3[S:28][CH:29]=[C:30]([CH3:32])[N:31]=3)=[N:3][CH:4]=2)[CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15]
Reactant: Cc1nc2c(Cl)ncc(I)c2s1
Reactant: Cc1csc(N)n1
Reactant: CS(=O)(=O)c1cccc(B(O)O)c1
Product: Cc1csc(Nc2ncc(-c3cccc(S(C)(=O)=O)c3)c3sc(C)nc23)n1

Procedure:
The title compound, MS: m/e=417.2 (M+H+), was prepared in accordance with the general method of example 2, step 1 and step 2 from 4-chloro-7-iodo-2-methyl-thiazolo[4,5-c]pyridine (Example B), (3-methylsulfonylphenyl)boronic acid and 2-amino-4-methylthiazole.
Reaction SMILES: [OH:1][C:2]1[C:19]([NH:20][S:21]([CH3:24])(=[O:23])=[O:22])=[CH:18][C:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Br[CH2:26][CH2:27]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.O>[CH3:24][S:21]([N:20]1[C:19]2=[CH:18][C:5]3[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10][C:4]=3[CH:3]=[C:2]2[O:1][CH2:27][CH2:26]1)(=[O:23])=[O:22]
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)c(NS(C)(=O)=O)cc2CC1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(S(C)(=O)=O)CCO3

Procedure:
1,1-dimethylethyl 7-hydroxy-8-[(methylsulfonyl)amino]-1,2,4,5-tetrahydro-3H-3-benzazepine-3-carboxylate (0.55 g) and 1,2-dibromoethane (0.23 ml) in the presence of potassium carbonate (0.4 g) were heated in acetone/water (1/1, 8 ml) for 6 h at reflux. Volatiles were evaporated under reduced pressure, the residue was partitioned between aqueous NaHCO3 and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined organic layers were concentrated and submitted to column chromatography to provide the title compound (0.75 mmol) as a white slightly hygroscopic solid. MS (m/z): 383 [MH]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]=[C:5]([O:20][CH2:21][CH2:22][CH3:23])[C:6]2[N:11]=[C:10]([C:12]3[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=3[Cl:19])[O:9][C:7]=2[N:8]=1.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.ClCCl>[Cl:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[C:10]1[O:9][C:7]2[N:8]=[C:3]([CH2:2][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[N:4]=[C:5]([O:20][CH2:21][CH2:22][CH3:23])[C:6]=2[N:11]=1
Reactant: CCCOc1nc(CBr)nc2oc(-c3cc(F)ccc3Cl)nc12
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1nc(CN2CCOCC2)nc2oc(-c3cc(F)ccc3Cl)nc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 54.5 %

Procedure:
A mixture of 130 mg of 5-bromomethyl-2-(2-chloro-5-fluoro-phenyl)-7-propoxy-oxazolo[5,4-d]pyrimidine, 33.9 mg of morpholine and 135 mg of potassium carbonate in 3 ml of dimethylformamide was stirred at room temperature for 4 h. Then 50 ml water and 50 ml of dichloromethane were added. The phases were separated and the aqueous layer was extracted with 50 ml of dichloromethane. The combined organic layers were dried with sodium sulfate, filtered, and evaporated in vacuo. The residue was purified by preparative HPLC (Method HPLC1) to give 72 mg of the title compound in the form of 2-(2-chloro-5-fluoro-phenyl)-5-morpholin-4-ylmethyl-7-propoxy-oxazolo[5,4-d]pyrimidine trifluoroacetic acid salt.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[C:34]1([S:40]([NH:43][C:44]2[N:48]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[N:47]=[C:46]([C:55]3[CH:63]=[CH:62][C:58]([C:59]([OH:61])=O)=[CH:57][CH:56]=3)[CH:45]=2)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(CC)C(C)C)(C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.CN(C1C=CN=CC=1)C.O>[C:12]1([NH:8][C:59](=[O:61])[C:58]2[CH:62]=[CH:63][C:55]([C:46]3[CH:45]=[C:44]([NH:43][S:40]([C:34]4[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=4)(=[O:42])=[O:41])[N:48]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=4)[N:47]=3)=[CH:56][CH:57]=2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:11]=1
Reactant: O=C(O)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Reactant: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Nc1ccccc1)c1ccc(-c2cc(NS(=O)(=O)c3ccccc3)n(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Benzotriazol-1-yloxytripyrrolid inophosphonium hexafluorophosphate (0.136 g, 0.26 mmol) was added to a solution of 4-(5-benzenesulfonylamino-1-phenyl-1H-pyrazole-3-yl)-benzoic acid (0.10 g, 0.24 mmol) and N,N-diisopropylethylamine (0.062 ml, 0.36 mmol) in N,N-dimethylformamide (2 ml). 1-Hydroxybenzotriazole hydrate (30 mg, 0.24 mmol) and 4-(N,N-dimethylamino)pyridine (catalytic) were added and the resulting solution was stirred at room temperature for 3 hours. Water (7 ml) was added, and a precipitate was collected by filtration and washed with water. The solid was purified by preparative thin layer silica gel chromatography, using 2% methanol in dichloromethane as the eluant, to yield N-Phenyl-4-[1-phenyl-5-[(phenylsulfonyl)amino]-1H-pyrazol-3-yl]benzamide as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N:8]([CH3:17])[C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:6]([Cl:18])[N:5]=[CH:4][N:3]=1.P(Cl)(Cl)(Cl)=O>>[Cl:18][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[C:7]=1[N:8]([CH3:17])[C:9]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:1]2
Reactant: CN(C(=O)c1ccccc1)c1c(N)ncnc1Cl
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1c(-c2ccccc2)nc2ncnc(Cl)c21
Temperature: 115 °C
Yield: 84.8 %

Procedure:
A suspension of N-(4-amino-6-chloropyrimidin-5-yl)-N-methylbenzamide (0.285 g, 0.00108 mol) in phosphoryl chloride (8 mL, 0.08 mol) was heated at 115° C. overnight. The mixture was cooled, concentrated and triturated in diethyl ether to obtain 224 mg (84.4%) yellow solid. LC/MS: Rt=1.30 min, ES+ 245.08 (AA standard).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:2]1.[CH3:12]C(C)([O-])C.[K+].IC>C1COCC1.CCOCC.C1OCCOCCOCCOCCOCCOC1>[CH3:12][N:1]1[CH:5]=[CH:4][C:3]([C:6](=[O:11])[C:7]([O:9][CH3:10])=[O:8])=[CH:2]1
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)C(=O)c1cc[nH]c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(=O)C(=O)c1ccn(C)c1
Reaction time: 0.5 h
Yield: 70.8 %

Procedure:
A solution of methyl pyrrol-3-yloxoacetate (3.3 g, 22 mol) in THF (70 ml) was added at room temperature to a stirred suspension of potassium tert-butoxide (2.7 g, 24 mmol) and 18-crown-6 (0.1 g, 0.39 mmol) in ether (250 ml). The reaction mixture was stirred for 30 minutes then iodomethane (1.6 ml, 26 mmol) in ether (50 ml) was added dropwise. The reaction mixture was stirred for 16 hours then filtered through hyflo supercell and washed with brine, dried and concentrated to give methyl N-methylpyrrol-3-yloxoacetate (2.84 g, 79% yield) as a clear oil, IR (thin film) 1725, 1645 cm-1, 1H nmr: delta 3.64 (3H, s), 3.85 (3H, s), 6.5 (1H, m) 6.7 (1H, m), 7.6 (1H, m) ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([OH:15])=[O:14].[C:19]1([C:25]([CH:27](Br)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:16]=[CH:17][CH:18]=1)[CH2:6][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:8]1[C:13]([O:15][CH:27]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:25](=[O:26])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:14]
Reactant: COc1cccc(CN2CCCCC2C(=O)O)c1
Reactant: O=C(c1ccccc1)C(Br)c1ccccc1
Product: COc1cccc(CN2CCCCC2C(=O)OC(C(=O)c2ccccc2)c2ccccc2)c1

Procedure:
2-Oxo-1,2-diphenylethyl 1-(3-methoxybenzyl)-2-piperidinecarboxylate was prepared from 1-(3-methoxybenzyl)-2-piperidinecarboxylic acid and desyl bromide in a similar manner to that of Preparation 65. (+) APCI-MS (m/z): 444 (M+ +1) IR (Film): 1730, 1690, 1260 cm-1
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([CH:13]=1)[C:9]([O:11]C)=O)(=[O:3])[CH3:2].[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][NH2:25]>>[C:1]([NH2:22])(=[O:3])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:13]=1.[C:1]([C:4]1[CH:5]=[CH:6][C:7]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[C:8]([CH:13]=1)[C:9]([NH:25][CH2:24][CH2:23][N:22]([CH3:26])[CH3:21])=[O:11])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(C(C)=O)ccc1OCCCC(=O)O
Reactant: CN(C)CCN
Product: CC(=O)c1ccc(OCCCC(=O)O)c(C(=O)NCCN(C)C)c1
Product: NC(=O)c1ccccc1
Yield: 21.9 %

Procedure:
A sample of 0.140 g (0.50 mmol) of 5-acetyl-2-(3-carboxypropoxy)-benzoic acid, methyl ester (Example 19) is heated on a steam bath, under dry conditions with 5.49 mL (50.0 mmol) of N,N-dimethylethylenediamine for 5 hours. The mixture is allowed to cool for 20 hours to ambient temperature and evaporated under vacuum at 55° C. The brown gum produced is triturated with ether, and the remaining residue taken up in water and acidified with hydrochloric acid. This is then extracted with ethyl acetate, and the aqueous solution is evaporated under vacuum, leaving a gum. It is next triturated with hot chloroform and this solution is evaporated to give a brown glass. This is chromatographed on a preparatory silica gel plate which is eluted with a 9/1 mixture of chloroform to methanol. The product band is cut from the plate, triturated with the above solvent mixture, filtered, and evaporated leaving 0.025 g (15%) of 5-acetyl-2-(3-carboxypropoxy)-N-(2-dimethylaminoethyl)benzamide benzamide as a light brown gum: MS (FAB) m/e 337.1753 Δ=+0.9 mmμ (M+ +H), 359 (M+ +Na). 1HNMR (CDCl3) is consistent with the desired product.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH:11]12[CH2:16][CH:15]1[CH2:14][NH:13][CH2:12]2.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH:11]12[CH2:16][CH:15]1[CH2:14][N:13]([C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1)[CH2:12]2
Reactant: C1NCC2CC12
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CC3CC3C2)nc1
Yield: 85.1 %

Procedure:
A suspension of 0.2 g (1.26 mmol) of 2-chloro-5-nitropyridine, of 0.166 g (1.39 mmol) of 3-azabicyclo[3.1.0]hexane (Bioorg. & Med. Chem. Lett. 2005, 15(8) 2093) and of 0.52 g (3.78 mmol) of potassium carbonate in 5 ml of dimethylformamide is stirred at ambient temperature for 36 hours. The mixture is subsequently poured into 5 ml of water and then extracted 3 times with 20 ml of ethyl acetate. The organic phases are subsequently combined, dried over magnesium sulfate, and then concentrated under reduced pressure. 0.22 g of the expected product is thus obtained, which product is used as it is in the rest of the synthesis.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[Cl:17])[N:5]=[C:4]([C:18]([O:20][CH3:21])=[O:19])[C:3]=1[Cl:22]>C(O)C1C=CC=CC=1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([O:15][CH3:16])[C:9]=2[Cl:17])[N:5]=[C:4]([C:18]([O:20][CH2:21][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:19])[C:3]=1[Cl:22]
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(OC)c2Cl)cc(N)c1Cl
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: OCc1ccccc1
Product: COc1c(Cl)ccc(-c2cc(N)c(Cl)c(C(=O)OCc3ccccc3)n2)c1Cl
Temperature: 87.5 °C
Reaction time: 2 h
Yield: 61 %

Procedure:
Methyl 4-amino-3-chloro-6-(2,4-dichloro-3-methoxyphenyl)picolinate (Compound C, prepared by the methods described in U.S. Pat. No. 7,314,849 B2; 500 mg, 1.4 mmol) was dissolved in benzyl alcohol (10 mL), treated with titanium(IV) isopropoxide (ca 100 μL) and heated at 85-90° C. After 2 h, another portion of titanium(IV) isopropoxide (100 μL) was added and heating was continued for another 18 h. The volatiles were removed under high vacuum, and the residue was purified by silica gel chromatography (eluting with 5% Et2O-30% dichloromethane (CH2Cl2)-65% hexane). The material was further purified by reverse phase high performance liquid chromatography (RP-HPLC; eluting with 70% acetonitrile) to give the title compound (375 mg, 61%): mp 107-108° C.; 1H NMR (400 MHz, CDCl3) δ 7.50-7.26 (m, 8H), 6.97 (s, 1H), 5.42 (s, 2H), 4.85 (s, 2H), 3.91 (s, 3H); ESIMS m/z 437 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19](N)=O)[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.ClC1C=C(C#CC2CC3(CCNC3)ON=2)C=CC=1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:47]=[CH:48][CH:49]=1)[C:44](Cl)=[O:45].CN=C=O>>[Cl:40][C:41]1[CH:42]=[C:43]([C:44]([N:16]2[CH2:19][CH2:15][C:13]3([CH2:14][C:10]([C:9]#[C:8][C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)=[N:11][O:12]3)[CH2:18][CH2:17]2)=[O:45])[CH:47]=[CH:48][CH:49]=1
Reactant: NC(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Reactant: O=C(Cl)c1cccc(Cl)c1
Agent: CN=C=O
Agent: Clc1cccc(C#CC2=NOC3(CCNC3)C2)c1
Product: O=C(c1cccc(Cl)c1)N1CCC2(CC1)CC(C#Cc1cccc(Cl)c1)=NO2

Procedure:
The title compound was synthesized following the method herein described for the compound of Example 96 but replacing Compound 22c for Compound 27d and 3-chlorobenzoyl chloride for methyl isocyanate. After the usual work-up procedure the crude was purified by means of automated flash chromatography (Isolera®TM-Biotage; gradient Petroleum Ether-EtOAc from 8:2 to 6:4) giving 122 mg of the title compound a s a pale yellow oil. Yield: 67.5%.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].N[C@H:7]([C:9]([OH:11])=[O:10])[CH3:8]>>[NH2:1][C@H:2]([C:3]([OH:5])=[O:4])[CH2:8][CH2:7][C:9](=[O:10])[OH:11]
Reactant: NCC(=O)O
Reactant: C[C@H](N)C(=O)O
Product: N[C@@H](CCC(=O)O)C(=O)O

Procedure:
Gly 523.3; Ala 456.8;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH:41]([NH2:43])=[S:42].C(N(C(C)C)CC)(C)C>ClCCl>[CH:41]([NH:43][C:14]([CH:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]1)=[O:16])=[S:42]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: NC=S
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)NC=S)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (747 mg, 3.26 mmol), HATU (1549 mg, 4.07 mmol) and the product from step A (166 mg, 2.72 mmol) were mixed in anhydrous dichloromethane (5 mL). The reaction mixture was stirred at room temperature for 30 min. N,N-diisopropyl-N-ethylamine (1.423 mL, 8.15 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The solution was concentrated and the crude was purified on SiO2 (10 to 60% ethyl acetate/hexanes) to afford the title compound. HPLC/MS: 170.1 (M−102), Rt=2.91 (LC4).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C@@H:5]([OH:9])[C:6](O)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C@H:5]1[O:9][CH2:6]1
Reactant: O=C(O)[C@H](O)c1cccc(Cl)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Clc1cccc([C@@H]2CO2)c1
Temperature: 70 °C
Reaction time: 2 h
Yield: 79.7 %

Procedure:
Into toluene (1,000 ml) were added (R)-3-chloromandelic acid (10 g) and p-toluenesulfonic acid (0.2 g), and the resulting mixture was stirred at 70° C. for 2 hours. The solvent was distilled off under reduced pressure. To the residue were added toluene (100 ml) and then, under ice-cooling and dropwise, 3,4-dihydro-2H-pyran (5.0 g), and the resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, then the organic layer was further washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off and then a 70% sodium dihydrobis(2-methoxyethoxy)aluminate toluene solution (16.7 g) was dropwise added to the filtrate with ice-cooling. The resulting mixture was stirred at the same temperature for 1 hour. The reaction mixture was added into a 30% aqueous (+)−potassium sodium tartrate solution (60.0 g), stirred for 1 hour and then the organic layer was separated. The organic layer obtained was washed with water and further with a saturated aqueous sodium chloride solution and then dried with anhydrous magnesium sulfate. The desiccant was filtered off. Then, to the filtrate were added triethylamine (10.8 g) and, under ice-cooling and dropwise, methanesulfonyl chloride (6.42 g). The resulting mixture was stirred at the same temperature for 1 hour, the reaction mixture was washed with water, then methanol (20 ml) and p-toluenesulfonic acid (10.4 g) were added thereto, and the resulting mixture was stirred at 50° C. for 1 hour. The reaction mixture was washed with water, then a 20% aqueous NaOH solution (40 g) was added thereto under ice-cooling, and the resulting mixture was stirred at the same temperature for 2 hours. The reaction mixture was washed with water, further the organic layer was washed with a saturated aqueous sodium chloride solution and dried with anhydrous magnesium sulfate. The desiccant was filtered off, then the solvent was distilled off under reduced pressure, and the resulting oily substance was distilled under reduced pressure to obtain a colorless oily compound mentioned above (6.6 g, yield 79.7%). The optical purity of the product obtained was 99.9% e.e. as determined by HPLC.
Reaction SMILES: Cl.[CH:2]1([NH2:15])[C:14]2[NH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH2:5][CH2:4][CH2:3]1.[C:16]1([N:22]=[C:23]=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:16]1([NH:22][C:23]([NH:15][CH:2]2[C:14]3[NH:13][C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[C:6]=3[CH2:5][CH2:4][CH2:3]2)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC1CCCc2c1[nH]c1ccccc21
Reactant: O=C=Nc1ccccc1
Agent: Cl
Product: O=C(Nc1ccccc1)NC1CCCc2c1[nH]c1ccccc21

Procedure:
N-Phenyl-N′-(2,3,4,9-tetrahydro-1H-carbazol-1-yl)urea was prepared from 2,3,4,9-tetrahydro-1H-carbazol-1-amine hydrochloride and phenyl isocyanate in a similar manner as described above to give a white solid (60% yield). 1H-NMR (DMSO-d6): δ 10.72 (s, 1H), 8.28 (s, 1H), 7.43-7.33 (m, 3H), 7.29-7.17 (m, 3H), 7.00 (m, 1H), 6.94-6.83 (m, 2H), 6.52 (d, 1H), 4.95 (m, 1H), 2.62 (m, 2H), 1.99 (m, 1H), 1.88-1.70 (m, 3H); MS m/z 304 (M−1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8](=[O:13])[CH2:9][CH2:10][CH2:11][F:12])[CH:5]=[CH:6][CH:7]=1.[BH4-].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:13])[CH2:9][CH2:10][CH2:11][F:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCCF)c1cccc(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: OC(CCCF)c1cccc(Br)c1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of 0.3 gm (1.22 mmol) of 1-(3-bromo-phenyl)-4-fluorobutan-1-one in THF at 0° C. was treated with 0.055 gm (1.47 mmol) of solid NaBH4, stirred at 0° C. for 0.5 h, allowed to warm to room temperature, stirred for 18 h, quenched with aqueous NH4Cl and poured into EtOAC. The phases were separated. The organic phase was washed sequentially with water and brine, dried over Na2SO4 and concentrated under reduced pressure to give 1-(3-bromophenyl)-4-fluorobutan-1-ol as an oil, 0.29 gm (96% yield) of an oil. This oil was dissolved in CH2Cl2, cooled to 0° C., treated with 0.23 mL (1.75 mmol) of DAST, stirred at 0° C. for 0.5 h, allowed to warm to room temperature, and stirred at room temperature for 18 h, quenched with water and poured into EtOAc. The phases were separated. The organic phase was washed sequentially with water and brine, dried over Na2SO4 and carefully concentrated at reduced pressure. The concentrate was used without further purification in Step e.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[B-](F)(F)F.C[N+](C)=C(N(C)C)O.C(N(CC)CC)C.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][CH3:48])=[C:43]([NH2:49])[CH:42]=1>CN(C)C=O>[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[N:39]([CH2:51][CH2:52][C:53]([O:55][CH2:56][CH3:57])=[O:54])[C:40](=[O:50])[C:41]1[CH:46]=[CH:45][C:44]([NH:47][CH3:48])=[C:43]([NH:49][C:10](=[O:12])[CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:42]=1
Reactant: CCOC(=O)CCN(C(=O)c1ccc(NC)c(N)c1)c1ccccn1
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: CN(C)C(O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN(C(=O)c1ccc(NC)c(NC(=O)CNC(=O)OC(C)(C)C)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
19.2 g (0.11 mol) of N-tert-butyloxycarbonylglycine were dissolved in 175 mL of dimethylformamide, mixed with 35.2 g (0.11 mol) of O-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, 11.0 g of triethylamine, and 34.2 g (0.10 mol) of 3-amino-4-methylaminobenzoic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide and stirred for 2.5 hours at ambient temperature. Then the reaction solution was mixed with 5 l of ice water and stirred for 2 hours. The grey precipitate formed was filtered off, washed with water, dried, and recrystallized from ethyl acetate with the addition of activated charcoal. Yield: 39.85 g (80% of theory), C25H33N5O6 (499.6); Rf value: 0.55 (silica gel; methylene chloride/ethanol=19:1).
Reaction SMILES: [CH2:1]([C@@:8]([C:38]([OH:40])=[O:39])([CH2:17][CH2:18][C:19]([NH:21][CH:22]([C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:29][CH:28]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[NH:9]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O.O>ClCCl>[CH2:1]([C@@:8]([C:38]([OH:40])=[O:39])([CH2:17][CH2:18][C:19]([NH:21][CH:22]([C:27]1[CH:28]=[CH:29][C:30]([CH2:33][C:34]([O:36][CH3:37])=[O:35])=[CH:31][CH:32]=1)[C:23]([O:25][CH3:26])=[O:24])=[O:20])[NH2:9])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)Cc1ccc(C(NC(=O)CC[C@](Cc2ccccc2)(NC(=O)OC(C)(C)C)C(=O)O)C(=O)OC)cc1
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1ccc(C(NC(=O)CC[C@@](N)(Cc2ccccc2)C(=O)O)C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 127.8 %

Procedure:
To a solution of methyl (2RS)-2-{N-[α-benzyl-N-(tert-butoxycarbonyl)-L-γ-glutamyl]amino}-2-[p-(methoxycarbonylmethyl)phenyl]acetate (1.35 g, 2.4 mmol) in 5 ml of dichloromethane was added 5 ml of TFA and 0.5 ml of water. After stirring for 1 hour at room temperature the solution was evaporated to dryness and the resulting solid was azeotroped with toluene to give methyl (2RS)-2-[N-(α-benzyl-L-γ-glutamyl)-amino]-2-[p-(methoxycarbonylmethyl)phenyl]acetate (1.4 g) as a gummy solid;
Reaction SMILES: Br.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[N:7]=1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:11][O:10][C:8]([C:6]1[N:7]=[C:3]([NH:2][S:13]([CH3:12])(=[O:15])=[O:14])[S:4][CH:5]=1)=[O:9]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1csc(N)n1
Agent: Br
Solvent: ClCCl
Product: COC(=O)c1csc(NS(C)(=O)=O)n1
Reaction time: 1 h
Yield: 45.6 %

Procedure:
To a well stirred solution of methyl 2-amino-thiazole-4-carboxylate hydrobromide (Justus Liebigs Ann. Chem. 1951, 571, 44, Heterocycles 1997, 45, 1299) (13 g, 51 mmol) and TEA (40 mL, 290 mmol) in DCM (130 mL) at rt was added methanesulfonyl chloride (11 mL, 140 mmol) dropwise. After stirring for 1 h, the reaction mixture was filtered and the filtrate concentrated. The residue was re-suspended in ethyl acetate, filtered and chromatographed on silica gel (ethyl acetate/ethanol, 97:3) to provide 2-methanesulfonylamino-thiazole-4-carboxylic acid methyl ester (5.5 g). MS (ESI−) for C6H8N2O4S2 m/z 234.9 (M−H)−.