Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([O:12][Si](C(C)(C)C)(C)C)[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])=[O:6])[CH:2]=[CH2:3].Cl.C(OCC)(=O)C.O>O1CCCC1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][C@H:10]([OH:12])[CH2:9][C@H:8]1[CH2:20][CH2:21][N:22]=[N+:23]=[N-:24])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1C[C@H](O[Si](C)(C)C(C)(C)C)C[C@H]1CCN=[N+]=[N-]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: C=CCOC(=O)N1C[C@H](O)C[C@H]1CCN=[N+]=[N-]
Reaction time: 6 h
Yield: 99.4 %

Procedure:
To a solution of (2R,4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-(t-butyldimethylsilyloxy) pyrrolidine (29.7 g) in tetrahydrofuran was added dropwise 12N hydrochloric acid (15 ml) at ambient temperature. After stirring for 6 hours, the mixture was poured into a mixture of ethyl acetate and water. The organic layer was separated and the aqueous layer was extracted twice with ethyl acetate. The combined organic layer was washed with sat. sodium bicarbonate and brine, dried over magnesium sulfate and evaporated under reduced pressure to give (2R, 4R)-1-allyloxycarbonyl-2-(2-azidoethyl)-4-hydroxypyrrolidine (20.0 g).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[CH:5][CH:4]=1)#[CH:2].Br[C:18]1[CH:19]=[N:20][CH:21]=[C:22]([CH:35]=1)[C:23]([N:25]=[S@@:26]([CH3:34])(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:24].CCN(CC)CC>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.CCOC(C)=O>[CH3:34][S@:26](=[O:33])([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:25][C:23](=[O:24])[C:22]1[CH:35]=[C:18]([C:2]#[C:1][C:3]2[CH:4]=[CH:5][C:6]([NH:9][C:10]([C:12]3[S:13][CH:14]=[CH:15][CH:16]=3)=[O:11])=[CH:7][CH:8]=2)[CH:19]=[N:20][CH:21]=1
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1ccc(NC(=O)c2cccs2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C[S@@](=O)(=NC(=O)c1cncc(C#Cc2ccc(NC(=O)c3cccs3)cc2)c1)c1ccccc1
Temperature: 50 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
In a 4 mL vial, thiophene-2-carboxylic acid (4-ethynyl-phenyl)-amide (0.100 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were added and dissolved into EtOAc (2 mL). The mixture was then degassed for ˜20 min after which NEt3 (0.141 mL, 1.035 mmol) was added followed by Pd(PPh3)2Cl2 (20.7 mg, 0.0295 mmol) and CuI (2.8 mg, 0.148 mmol). The reaction mixture was allowed to stir at 50° C. for 3 hours after which the reaction mixture was extracted twice with EtOAc (˜5 mL) and of water (˜5 mL). The organic extracts were combined and dried over anhydrous Na2SO4(s) and then concentrated in vacuo. The crude residue was then purified by chromatography (silica gel, gradient elution, 25% EtOAc/hexanes to 100% EtOAc/hexanes). The product containing fractions were concentrated to give the title compound as a tan solid (87 mg, 0.18 mmol, 61%).
Reaction SMILES: C(O)(=O)C.C(OC(=O)C)(=O)C.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:19]([O:21][CH3:22])=[O:20].[N+:28]([O-])([OH:30])=[O:29]>O>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[C:25]([O:26][CH3:27])=[CH:24][C:23]([N+:28]([O-:30])=[O:29])=[C:18]([CH:17]=1)[C:19]([O:21][CH3:22])=[O:20]
Reactant: COC(=O)c1ccc(OC)c(OCCCl)c1
Reactant: O=[N+]([O-])O
Solvent: CC(=O)OC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc(OCCCl)c(OC)cc1[N+](=O)[O-]
Temperature: 50 °C
Yield: 86 %

Procedure:
To acetic acid (42 mL) and acetic anhydride (8.5 mL) was added methyl 3-(2-chloroethoxy)-4-methoxybenzoate (4.0 g, 16.3 mmol) followed by 70% nitric acid (2.8 mL) and the mixture heated at 50° C. for 1 hour. The mixture was poured into H2O, filtered, and washed with H2O to give methyl 5-(2-chloroethoxy)-4-methoxy-2-nitrobenzoate (4.08 g, 14.1 mmol, 86%). 1H NMR (300 MHz, DMSO-d6) δ 7.67 (s, 1H), 7.38 (s, 1H), 4.43 (t, 2H), 3.99 (t, 2H), 3.94 (s, 3H), 3.85 (s, 3H).
Reaction SMILES: [C:1]([N:4]1[CH:7]([S:8][CH3:9])[CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)Cl>[C:1]([N:4]1[CH:7]([S:8]([CH3:9])=[O:19])[CH2:6][C:5]1=[O:10])(=[O:3])[CH3:2]
Reactant: CSC1CC(=O)N1C(C)=O
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(=O)N1C(=O)CC1S(C)=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 39.8 %

Procedure:
A mixture of 130 mg (0.82 mM) N-acetyl-4-methylthioazetidinone and 200 mg (0.93 mM) 80% m-chloroperbenzoic acid in 5 ml methylene chloride was stirred at room temperature 5 minutes. After removing the solvent in vacuo. The residue was chromatographed on 2-2000μ silica gel plates in hexane/ethyl acetate to yield 57 mg (40%) of 1-acetyl-4-methylsulfinylazetidine-2-one.
Reaction SMILES: [I:1][C:2]1[N:3]=[CH:4][N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1.[Li+].CC([N-]C(C)C)C.CN([CH:26]=[O:27])C>C1COCC1>[I:1][C:2]1[N:3]=[C:4]([CH:26]=[O:27])[N:5]([CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]=1
Reactant: Ic1cn(CCc2ccccc2)cn1
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=Cc1nc(I)cn1CCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of 4-iodo-1-phenethyl-imidazole (example 2C) (563 mg, 1.89 mmoles) in THF (13 mL) under argon is cooled to −78° C. A 2.0M LDA solution (1.04 mL, 2.08 mmoles) is added dropwise. After 30 minutes at −78° C., DMF (161 μL, 2.08 mmoles) is added dropwise. The reaction mixture is allowed to reach 0° C., then it is quenched by adding a half-saturated NaHCO3 solution. The aqueous phase is extracted three times with AcOEt. The organic phase is washed with water, brine, dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (heptane:AcOEt) as eluent with a gradient from (95:5) to (70:30) to give 4-iodo-1-phenethyl-imidazole-2-carbaldehyde.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@:8]12[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]1[CH2:12][S:11][C:10]([NH2:18])=[N:9]2.FC(F)(F)C(O)=O.S(=O)(=O)(O)O.[Br:31]N1C(=O)CCC1=O>O.[OH-].[Na+]>[Br:31][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[C:3]([C@:8]23[CH2:16][O:15][C@H:14]([CH3:17])[C@H:13]2[CH2:12][S:11][C:10]([NH2:18])=[N:9]3)[CH:4]=1
Reactant: C[C@H]1OC[C@]2(c3ccccc3F)N=C(N)SC[C@H]12
Reactant: O=C1CCC(=O)N1Br
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1OC[C@]2(c3cc(Br)ccc3F)N=C(N)SC[C@H]12
Temperature: 57.5 °C
Reaction time: 0.5 h

Procedure:
(4aS,5R,7aS)-7a-(2-Fluorophenyl)-5-methyl-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine* (1.0 g, 3.75 mmol) was dissolved in trifluoroacetic acid (3.5 mL, 45.4 mmol). Sulfuric acid (1.2 mL, 22 mmol) was carefully added dropwise, keeping temperature below 30° C. N-Bromosuccinimide (0.74 g, 4.13 mmol) was added portionwise and the reaction was warmed to 55-60° C. After 30 minutes, the reaction was cooled to room temperature and added dropwise to a cooled solution of sodium hydroxide (3.00 g, 75.1 mmol) in water (25 mL). The solution of reaction mixture in sodium hydroxide solution was extracted with EtOAc (×2), checking the pH to ensure the TFA/H2SO4 had all been neutralised. The organic layer was washed with brine and concentrated to leave a brown solid. The solid was recrystalised from IPA (10 mL): heating to 50° C. for 15 minutes on the rotavap under slight vacuum. The suspension was cooled to room temperature, filtered and washed with IPA (2 mL) and heptane (10 mL). The solid was dried overnight to give the title compound (1.30 g). 1H NMR (400 MHz, CDCl3) δ ppm: 7.55 (dd, J=7.2, 2.7 Hz, 1H), 7.36 (ddd, J=8.7, 4.2, 2.5 Hz, 1H), 6.94 (dd, J=11.6, 8.6 Hz, 1H), 4.55 (dd, J=8.8, 1.3 Hz, 1H), 4.35 (q, J=1.0 Hz, 1H), 3.77 (dd, J=8.8, 2.3 Hz, 1H), 3.07 (dd, J=13.4, 3.5 Hz, 1H), 2.71 (dd, J=13.3, 3.9 Hz, 1H), 2.44-2.53 (m, 1H), 1.37 (d, J=6.1 Hz, 3H)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=1[NH2:8].[CH:17]12[CH2:24][CH2:23][CH2:22][CH:21]1[CH2:20][CH2:19][CH:18]2[C:25](O)=O>>[C@@H:17]12[CH2:24][CH2:23][CH2:22][C@@H:21]1[CH2:20][CH2:19][C@H:18]2[C:25]1[NH:1][C:2]2[C:3](=[O:16])[N:4]([CH2:13][CH2:14][CH3:15])[C:5](=[S:12])[N:6]([CH2:9][CH2:10][CH3:11])[C:7]=2[N:8]=1
Reactant: O=C(O)C1CCC2CCCC21
Reactant: CCCn1c(N)c(N)c(=O)n(CCC)c1=S
Product: CCCn1c(=O)c2[nH]c([C@@H]3CC[C@H]4CCC[C@H]43)nc2n(CCC)c1=S
Yield: 57 %

Procedure:
The substantially same operations as in Example 1 were repeated except for using 2.00 g (8.26 mmol) of 5,6-diamino-1,3-dipropyl-2-thiouracil [J. Med. Chem., 32, 1873 (1989)] and 1.42 ml (9.92 mmol) of bicyclo[3.3.01octan-2-carboxylic acid to afford 1.70 g (overall yield: 57%) of the captioned Compound 24 as a white crystal.
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH2:8][C:7](=O)[C:6]=2[CH:11]=1.Cl.[NH:13]([C:15]1[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])N>C(O)C.O>[I:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[C:23]4[C:15](=[C:16]([C:17]([OH:19])=[O:18])[CH:20]=[CH:21][CH:22]=4)[NH:13][C:7]=3[C:6]=2[CH:11]=1
Reactant: O=C1COc2ccc(I)cc21
Reactant: NNc1ccccc1C(=O)O
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(O)c1cccc2c1[nH]c1c3cc(I)ccc3oc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of 5-iodo-3(2H)-benzofuranone (0.551 g, 2.12 mmol) [Cagniant, P. et al. Hebd. Seances Acad. Sci., Ser. C, 1976, 282 (21), 993-6] in ethanol (100 mL) was added a solution of 2-hydrazinobenzoic acid hydrochloride (0.800 g, 4.24 mmol) in deionized water (50 mL). The mixture was stirred for one hour at room temperature and then allowed to sit while cooled (0° C.). Vacuum filtration and drying in vacuo afforded 0.480 g (58%) of the title compound as a tan solid: mp 169° C.(dec) which was used without further purification.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:14]=[CH:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]#[N:16])[CH:11]=2)[CH:6]=1)=[O:4].[Li+].[OH-]>C1COCC1.ClCCl.O>[C:15]([C:10]1[CH:11]=[C:12]2[C:7](=[CH:8][CH:9]=1)[CH:6]=[C:5]([C:3]([OH:4])=[O:2])[CH:14]=[CH:13]2)#[N:16]
Reactant: COC(=O)c1ccc2cc(C#N)ccc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc2cc(C(=O)O)ccc2c1
Yield: 86.2 %

Procedure:
A solution of 6-cyano-naphthalene-2-carboxylic acid methyl ester from Example 96 (2.00 g, 9.47 mmol) in THF (19 mL) and 1M aqueous LiOH (18.94 mL, 18,94 mmol) was vigorously stirred at room temperature for 3 hours. The reaction mixture was then diluted with 150 mL of 1:1 dichloromethane/water, and the organics were discarded. The aqueous material was acidified to pH 2 with 1N HC1, extracted with EtOAc (2×150 mL), extracts dried over MgSO4, and concentrated to provide the desired compound as a white solid (1.61 g, 86%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][NH:6]2.[C:11](Cl)([C:13](Cl)=[O:14])=[O:12].[CH3:17][CH2:18][OH:19]>C1COCC1>[CH2:18]([O:19][C:13](=[O:14])[C:11]([C:4]1[C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[NH:6][CH:5]=1)=[O:12])[CH3:17]
Reactant: CCO
Reactant: Clc1cccc2[nH]ccc12
Reactant: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C(=O)c1c[nH]c2cccc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloroindole (5.00 g, 33.0 mmol) in dry THF (0.2 L), at 0° C. under argon was added (COCl)2 (3.6 mL, 40.4 mmol). The reaction mixture was stirred overnight while warming to rt, cooled to 0° C., and EtOH (4 mL, 69 mmol) was added. The reaction mixture was stirred at rt overnight, then partitioned between cold 0.2 M aq HCl and EtOAc. The aqueous layer was separated and re-extracted with EtOAc. The EtOAc extracts were washed with saturated aqueous NaHCO3 and brine. The extracts were dried, filtered, and concentrated to give a solid. The solid was purified by silica chromatography to give the title compound: TLC Rf=0.40 (19:1 CH2Cl2/Me2CO); MS (ESI+) m/z 274.0; 1H NMR (300 MHz, CDCl3) δ 9.22 (1H), 8.26 (1H), 7.36 (1H), 7.31 (1H), 7.22 (1H), 4.71 (2H), 1.41 (3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([O-:13])=O)[S:10][C:3]=12.[Li+].S(Cl)(Cl)=O.[CH3:19][N:20]([CH3:26])[C@@H:21]1[CH2:25][CH2:24][NH:23][CH2:22]1.CCN(CC)CC>>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:23]3[CH2:24][CH2:25][C@@H:21]([N:20]([CH3:26])[CH3:19])[CH2:22]3)=[O:13])[S:10][C:3]=12
Reactant: O=C([O-])c1cc2nccc(Cl)c2s1
Reactant: CN(C)[C@@H]1CCNC1
Agent: [Li+]
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Product: CN(C)[C@@H]1CCN(C(=O)c2cc3nccc(Cl)c3s2)C1
Yield: 43.3 %

Procedure:
This material was prepared from lithium 7-chlorothieno[3,2-b]pyridine-2-carboxylate (0.214 g, 1.0 mmole) by treatment with thionyl chloride followed by reaction of the resultant acyl chloride with (3R)-N,N-dimethylpyrrolidin-3-amine (0.114 g, 1.0 mmole) and Et3N (0.139 ml, 1.0 mmole), in a manner as previously described for example 9d to give a brown solid (0.134 g, 43%). 1H NMR (300 MHz, CD3OD) δ σ7.24 (1H, d, J=5.1 Hz), 6.57 (1H, d, J=8.48 Hz), 6.15 (1H, d, J=5.1 Hz), 2.70 (1H, m), 2.51 (2H, m), 2.24 (1H, m), 2.04 (1H, m), 1.49 (1H, m), 0.93 (3H, s), 0.90 (3H, s), 0.52 (1H, m); ESIMS (MH+): 310.10.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=O)=[CH:2]1.Cl.Cl.[CH3:11][NH:12][O:13][CH3:14].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>>[CH3:14][O:13][N:12]([CH3:11])[C:6]([C:3]1[CH:4]=[CH:5][O:1][CH:2]=1)=[O:8]
Reactant: O=C(O)c1ccoc1
Reactant: CNOC
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Product: CON(C)C(=O)c1ccoc1

Procedure:
The title compound was prepared from furan-3-carboxylic acid (3.4 g, 0.030 mol), N,O-dimethylhydroxylamine hydrochloride hydrochloride (2.9 g, 0.030 mol) triethylamine (8.3 mL, 0.060 mol) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorphosphate (13.3 g, 0.030 mol) according to the general procedure described in Example 1 for N-(3-pyridylmethyl)-5-chloro-3-phenylthio-2-carboxamide. NMR (DMSO-d6) δ8.25 (1H, s), 7.75 (1H, s), 3.70 (3H, s), 3.22 (3H, s).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]([NH:8][C:9]2[N:14]=[CH:13][N:12]=[C:11]3[NH:15][N:16]=[CH:17][C:10]=23)[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:39][C:40]1[CH:41]=[C:42]([NH:47][CH2:48][C:49](O)=[O:50])[CH:43]=[C:44]([Cl:46])[CH:45]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:15]1[C:11]2=[N:12][CH:13]=[N:14][C:9]([NH:8][CH:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:1]([C:49](=[O:50])[CH2:48][NH:47][C:42]4[CH:41]=[C:40]([Cl:39])[CH:45]=[C:44]([Cl:46])[CH:43]=4)[CH2:2]3)=[C:10]2[CH:17]=[N:16]1
Reactant: c1nc(NC2CCCCNC2)c2cn[nH]c2n1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ncc23)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.1 %

Procedure:
To a solution of N-(azepan-3-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (200 mg, 0.862 mmol) in DMF (4 mL) was added EDCI (196 mg, 1.03 mmol), HOBt (139 mg, 1.03 mmol), 2-(3,5-dichlorophenylamino)acetic acid (189 mg, 0.862 mmol) and DIEA (0.22 mL, 1.29 mmol) at 0° C. The reaction mixture was stirred overnight at rt, diluted with EtOAc (100 mL) and washed with water (50 mL). The organic layer was dried over Na2SO4 and evaporated in vacuo to give the crude compound that purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (150 mg, 40%). 1H NMR (DMSO-d6, 400 MHz): δ 13.49-13.36 (m, 1H), 8.27-7.96 (m, 2H), 6.74 (s, 1H), 6.67 (s, 1H), 6.62 (s, 1H), 6.34 (s, 1H), 4.50-4.30 (m, 1H), 4.08-3.8 (m, 5H), 3.36 (m, 2H), 1.8-2.2 (m, 2H), 1.8-1.35 (m, 2H), 1.3-1.1 (m, 2H), LCMS: m/z [M+1]=434 & [M+23]=456.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].[CH2:5]([O:7][C:8]([N:10]=[C:11]=[S:12])=[O:9])[CH3:6]>C(OCC)C>[CH2:5]([O:7][C:8]([NH:10][C:11]([NH:4][CH:1]([CH3:3])[CH3:2])=[S:12])=[O:9])[CH3:6]
Reactant: CC(C)N
Reactant: CCOC(=O)N=C=S
Solvent: CCOCC
Product: CCOC(=O)NC(=S)NC(C)C

Procedure:
A solution of 7.1 grams of isopropylamine in 40 ml of anhydrous ethyl ether was added dropwise in 30 minutes with stirring to a solution of 15.5 grams of ethoxycarbonyl isothiocyanate (Preparation 1) in 10 ml of anhydrous ethyl ether. The reaction vessel was cooled with an ice-water bath. The reaction mixture was let stand at an ambient room temperature. After the reaction was complete, the solution was concentrated by stripping off most of the solvent under reduced pressure. The crystals were collected by filtering and washing with hexanes. The first crop weighed 8.1 grams, m.p. 52.5°-54° C. The second crop weighed 7 grams, m.p. 52°-54° C.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:12])([CH3:11])[CH2:7][NH:8]2)=[CH:4][CH:3]=1.Cl[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:24])[CH:22]=2)[N:17]=[C:16]([CH3:25])[C:15]=1[CH3:26]>>[Cl:24][C:21]1[CH:22]=[C:23]2[C:18](=[CH:19][CH:20]=1)[N:17]=[C:16]([CH3:25])[C:15]([CH3:26])=[C:14]2[N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([I:1])[CH:10]=2)[C:6]([CH3:12])([CH3:11])[CH2:7]1
Reactant: CC1(C)CNc2cc(I)ccc21
Reactant: Cc1nc2ccc(Cl)cc2c(Cl)c1C
Product: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(I)cc32)c1C

Procedure:
Prepared according to procedure M using 6-iodo-3,3-dimethylindoline (0.604 g, 2.21 mmol) and 4,6-dichloro-2,3-dimethylquinoline (0.5 g, 2.21 mmol) to give 6-chloro-4-(6-iodo-3,3-dimethylindolin-1-yl)-2,3-dimethylquinoline as a brown solid: Mass Spectrum (ESI) m/e=463.0 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]([NH2:16])[CH2:8][CH2:7]1)=[O:5])[CH3:2].C([O-])(O)=O.[Na+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]([N:6]1[C:10]2([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:9]([NH:16][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)Cl
Reactant: CCOC(=O)N1CCC(N)C12CCCCC2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCOC(=O)NC1CCN(C(=O)OCC)C12CCCCC2
Temperature: 25 °C
Yield: 79.8 %

Procedure:
To a stirring suspension of 5.7 g of 1-ethoxycarbonyl-4-amino-1-azaspiro[4.5]decane of Example 1e and 7. g of NaHCO3 in 100 ml of CHCl3 was added in a dropwise fashion 3.8 g of ethyl chloroformate. The mixture was refluxed for 4 hours, cooled to room temperature, filtered, washed with water, 3 N-HCl, saturated sodium bicarbonate solution and saturated NaCl solution, dried over Na2SO4 and then evaporated to give 6 g of 1-ethoxycarbonyl-4-(ethoxycarbonylamino)-1-azaspiro[4.5]decane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([NH:24][C:25]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: S=C=Nc1ccccc1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Product: CN1CCC(c2c[nH]c3ccc(NC(=S)Nc4ccccc4)cc23)CC1
Yield: 70.4 %

Procedure:
Beginning with 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 13.26 mg (0.098 mMol) phenyl isothiocyanate, 16.8 mg (71%) of the title compound were recovered.
Reaction SMILES: [CH2:1]([N:8]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:11][C:10]([C:19]([CH3:23])([CH3:22])[C:20]#[N:21])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([N:8]1[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)=[CH:11][C:10]([C:19]([CH3:23])([CH3:22])[CH2:20][NH2:21])=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Agent: B
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(CN)c1cc(-c2ccccc2)n(Cc2ccccc2)n1
Temperature: 60 °C
Yield: 102.3 %

Procedure:
2-(1-Benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropanenitrile (50 mg, 0.16 mmol) was dissolved in THF (1.6 mL). Borane-tetrahydrofuran (0.8 mL, 1 M solution) was added and the reaction was heated to 60° C. for 3 h. Minimal water was added to quench the reaction. Ethyl acetate was added followed by sodium sulfate and the solids were removed by filtration. The filtrate was concentrated under reduced pressure to yield 2-(1-benzyl-5-phenyl-1H-pyrazol-3-yl)-2-methylpropan-1-amine (50 mg, crude), which was carried through without further purification. MS (ESI) m/z: Calculated for C20H23N3: 305.19. found: 306.2 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([OH:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6].[OH-].[NH4+]>>[NH4+:1].[NH2:1][C@@H:2]([C:22](=[O:24])[NH2:23])[CH2:3][CH2:4][C:5]([NH:7][C@@H:8]([C:19]([O-:21])=[O:20])[CH2:9][C:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[NH:12][CH:11]=1)=[O:6]
Reactant: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Product: NC(=O)[C@H](N)CCC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)[O-]
Reaction time: 2 h

Procedure:
H-D-iGlu-D-Trp-OH (1 g from Example 3) was mixed with ammonium hydroxide (0.55M, 6 mL). The mixture was stirred and the pH was measured to be around 4.5. Ammonium hydroxide (0.55 M) was added dropwise until the pH of the solution reached between 7.0 to 7.5. Volatile materials were removed in vacuo, and the residual oil was mixed with isopropanol. A white precipitate appeared. After 2 h, the solid ammonium salt was collected by suction filtration. The solid was dried to constant weight (1 g) under high vacuum for 12 h to give the D-isoglutamyl-D-tryptophan, ammonium salt (1:1). The water content as determined by the Karl-Fisher test was 4.6%.
Reaction SMILES: F[C:2]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[O-]P([O-])([O-])=O.[K+].[K+].[K+].[OH:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][CH:27]=[CH:26]2.CCOCC>COCCOCCOC>[NH:28]1[C:29]2[C:25](=[CH:24][C:23]([O:22][C:2]3[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:3]=3[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:31][CH:30]=2)[CH:26]=[CH:27]1
Reactant: CCOC(=O)c1ccc(F)cc1F
Reactant: Oc1ccc2[nH]ccc2c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: CCOC(=O)c1ccc(F)cc1Oc1ccc2[nH]ccc2c1

Procedure:
Ethyl 2,4-difluorobenzoate (12.75 g), K3PO4 (14.54 g) and 5-hydroxyindole (9.12 g) were stirred at 110° C. in diglyme (125 mL) for 24 hours. The reaction was cooled and poured into ether. The solution was washed three times with 1M NaOH solution, and brine, and dried. The solution was then concentrated, and the crude product was poured into hexanes, stirred, and filtered to give the product.