Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1C(=O)N([Br:8])C(=O)C1.[CH3:9][C:10]1[S:14][C:13]([C:15]([O:17]C)=[O:16])=[CH:12][C:11]=1[C:19]1[N:23]([CH3:24])[N:22]=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1>[Br:8][C:20]1[CH:21]=[N:22][N:23]([CH3:24])[C:19]=1[C:11]1[CH:12]=[C:13]([C:15]([OH:17])=[O:16])[S:14][C:10]=1[CH3:9]
Reactant: COC(=O)c1cc(-c2ccnn2C)c(C)s1
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1sc(C(=O)O)cc1-c1c(Br)cnn1C
Temperature: 70 °C
Reaction time: 2 h
Yield: 105.2 %

Procedure:
NBS (1.84 g, 10.33 mmol) was added in portions to a 150 mL sealed tube reactor containing methyl 5-methyl-4-(1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylate (2 g, 8.46 mmol) [prepared according to the procedure of Preparation 10] in Tetrahydrofuran (THF) (40 ml) at room temperature. The mixture was heated to 70° C. for 1 h. 6N NaOH (28 ml, 168 mmol) was then added and the mixture stirred at 70° C. for 2 h. The mixture was partitioned between CHCl3 and H2O and the aqueous layer was made acidic with 6N HCl. The aqueous phase was washed several times with CHCl3 and the organic fractions were combined, dried over Na2SO4 and concentrated affording the title compound (2.68 g, 8.9 mmol, quant.): LC-MS (ES) m/z=302 (M+H)+.
Reaction SMILES: [CH2:1]([N:12]([CH2:17][C:18]([O-:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15])[CH2:2][N:3]([CH2:8][C:9]([O-:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6].[Na+].[Na+].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O:28]=[CH:29][C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31]>O>[CH2:2]([N:3]([CH2:8][C:9]([OH:11])=[O:10])[CH2:4][C:5]([OH:7])=[O:6])[CH2:1][N:12]([CH2:17][C:18]([OH:20])=[O:19])[CH2:13][C:14]([OH:16])=[O:15].[NH2:23][CH2:24][C:25]([OH:27])=[O:26].[O:28]=[CH:29][C@@H:30]([C@H:32]([C@@H:34]([C@@H:36]([CH2:38][OH:39])[OH:37])[OH:35])[OH:33])[OH:31]
Reactant: O=C([O-])CN(CCN(CC(=O)[O-])CC(=O)O)CC(=O)O
Agent: NCC(=O)O
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [Na+]
Solvent: O
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Yield: 1 %

Procedure:
A 10% (volume/volume) Tween 80 solution was prepared by adding 10 ml Tween 80 to 90 ml H2O. A 1% (weight/volume) EDTA solution was prepared by adding 1 g Na2EDTA to 100 ml H2O. A 0.1 M glycine solution was prepared by adding 1.5 g glycine (M. W. 75) to 200 ml H2O. A 0.5% w/v) hydroxypropyl-methyl-cellulose (HPMC, 100 centipoise) solution was prepare by adding 1 g EPMC to 200 ml H2O and gently mixing until fully dissolved. A 250 unit/ml GOX (Type VII from Aspergillus niger, Sigma Chemicals) was prepared in H2O. A 0.1 M glucose solution was prepared by adding 1.8 g D-glucose (M. W. 180) to 100 ml H2O.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([OH:14])=[O:13])=[CH:6][CH:5]=1.[CH:26](O)([CH3:28])[CH3:27]>>[NH2:3][C:4]1[N:9]=[CH:8][C:7]([CH2:10][CH:11]([C:15]2[N:16]=[CH:17][N:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:19]=2)[C:12]([O:14][CH:26]([CH3:28])[CH3:27])=[O:13])=[CH:6][CH:5]=1
Reactant: CC(C)O
Reactant: Nc1ccc(CC(C(=O)O)c2cn(C3CCCCC3)cn2)cn1
Agent: Cl
Product: CC(C)OC(=O)C(Cc1ccc(N)nc1)c1cn(C2CCCCC2)cn1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2 ml of an HCl-saturated ether solution were added to a solution of 38.0 mg (0.12 mmol) of the compound from example 1i in 5 ml of isopropanol and stirred at RT for 4 h. The solution was then concentrated to dryness, and the resulting residue was dried under high vacuum. 25 mg of the title compound resulted as bishydrochloride in the form of an amorphous solid.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[CH:2]1.C([Li])CCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18].[F-].[K+]>O1CCCC1.CCCCCC>[O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH:3]=[C:2]1[Sn:17]([CH3:19])([CH3:18])[CH3:16]
Reactant: C1=COc2ccccc2O1
Reactant: C[Sn](C)(C)Cl
Agent: [F-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Sn](C)(C)C1=COc2ccccc2O1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
14.91 mmol of 1,4-benzodioxine are dissolved in 18 ml of anhydrous tetrahydrofuran under an anhydrous atmosphere, and the temperature of the solution is lowered to −78° C. 23.86 mmol of a 1.5M solution of n-butyllithium in hexane are added dropwise to the reaction mixture, which is stirred at −78° C. for 2 hours 15 minutes. 37.28 mmol of trimethyltin chloride dissolved in 10 ml of anhydrous tetrahydrofuran are added dropwise and the reaction mixture is stirred at −78° C. for 45 minutes and then returned to ambient temperature for 15 hours. The reaction mixture is hydrolysed with 15% aqueous potassium fluoride solution and is stirred for 45 minutes. The precipitated tin salts are removed by filtration, and the aqueous phase is extracted 3 times with ethyl acetate. The organic phases are combined and concentrated. Purification by flash chromatography over silica gel (petroleum ether/ethyl acetate: 95/5) allows the expected product to be obtained.
Reaction SMILES: [CH2:1]([C:3]1[C:24]([N:25]2[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]2)=[CH:23][C:6]2[C:7]([CH3:22])([CH3:21])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2].[O:32]=[C:33]1[CH2:38][NH:37][CH2:36][CH2:35][NH:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[CH2:1]([C:3]1[C:24]([N:25]2[CH2:26][CH2:27][CH:28]([N:37]3[CH2:36][CH2:35][NH:34][C:33](=[O:32])[CH2:38]3)[CH2:29][CH2:30]2)=[CH:23][C:6]2[C:7]([CH3:21])([CH3:22])[C:8]3[NH:9][C:10]4[C:15]([C:16]=3[C:17](=[O:18])[C:5]=2[CH:4]=1)=[CH:14][CH:13]=[C:12]([C:19]#[N:20])[CH:11]=4)[CH3:2]
Reactant: CCc1cc2c(cc1N1CCC(=O)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Reactant: O=C1CNCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCc1cc2c(cc1N1CCC(N3CCNC(=O)C3)CC1)C(C)(C)c1[nH]c3cc(C#N)ccc3c1C2=O
Temperature: 30 °C
Reaction time: 6 h
Yield: 31.8 %

Procedure:
9-Ethyl-6,6-dimethyl-11-oxo-8-(4-oxopiperidin-1-yl)-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (30 mg) and 2-ketopiperazine (10 mg) were dissolved in THF (2 ml), added with sodium triacetoxy borohydride (30 mg), and the mixture was stirred at 30° C. for 6 hrs. The reaction mixture was diluted with ethyl acetate (20 ml). The organic layer was washed with 10% brine, and then concentrated under reduced pressure. The resulting residues were purified by silica gel column (dichloromethane/methanol=99/1 to 90/10) to obtain the title compound (11.5 mg, yield 32%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6](N)[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2].[C:20](Cl)(=[O:27])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C[N:30]1CCCC1=O>CN(C)C1C=CN=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([C:26]2[C:21]([C:20]([NH2:30])=[O:27])=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:7]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1CCCC1=O
Reactant: Nc1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Product: NC(=O)c1ccccc1-c1cc([N+](=O)[O-])ccc1-c1ccc([N+](=O)[O-])cc1
Temperature: 160 °C
Yield: 99 %

Procedure:
A solution of 4,4'-dinitro-2-biphenylamine (12.00 g, 46.29 mmol), 4-dimethylaminopyridine (5.77 g, 47.22 mmol) and N-methyl-2-pyrrolidinone (130ml) was stirred under a nitrogen atmosphere. Benzoyl chloride (9.69 g, 68.92 mmol) was added by dropping funnel at ambient temperature and the mixture heated to 160° C. and maintained at that temperature for 18 h. The resulting solution was poured into 1200 ml ice water with stirring and continued stirring overnight to give a light brown precipitate. The precipitate was filtered out and washed with water (2×100 ml), 5% sodium bicarbonate solution (2×100 ml) and water (4×200 ml) until the filtrate was clear. The crude product was dried under reduced pressure at 138° C. for 24 h to give 4,4'-dinitrobiphenyl-2-benzamide as a light brown powder (16.65 g, 99%), m.p. 242°-244° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1.Cl>[Cl-].[Cl-].[Zn+2]>[Cl:11][C:12]1[CH:18]=[CH:17][C:15]([NH:16][C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)=[C:14]([C:6](=[O:7])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=2)[CH:13]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Product: O=C(Nc1ccc(Cl)cc1C(=O)c1ccc(F)cc1)c1ccc(F)cc1
Temperature: 180 °C
Yield: 29 %

Procedure:
To p-fluorobenzoyl chloride (49.7 g, 314 mmol), heated to 120° C., was added p-chloroaniline (17.8 g, 139 mmol) over 10 min. The mixture was then heated to 180° C. and ZnCl2 (23.8 g, 174 mmol) was added over 10 min. The resulting mixture was heated at 205° C. for 2 h. After cooling to 120° C., 3N HCl (125 mL) was added cautiously and the mixture was maintained at 120° C. for 1 h. The hot aqueous portion was then decanted and the remaining residue was washed with hot 3N HCl (2×125 mL). The residue was poured onto ice and extracted with CH2Cl2 (3×100 mL). The combined organic portions were washed with 3N HCl (2×50 mL), 5N NaOH (2×50 mL) and H2O (3×50 mL) and were then dried over MgSO4, filtered and concentrated in vacuo to provide 15 g (29%) of the N-[4-chloro-2-(4-fluoro-benzoyl)-phenyl]-4-fluoro-benzamide as a dark yellow powder. To a flask containing the acylated amino-benzophenone (6.7 g, 18 mmol) was added 1:1 conc. HCl:AcOH (700 mL) and the resulting mixture was heated to 105° C. and stirred for 16 h. The mixture was cooled to room temperature and concentrated in vacuo. The residue was poured onto ice and extracted with CH2Cl2 (3×100 mL). The combined organic portions were washed with 5N NaOH (2×50 mL) and H2O (3×50 mL) and then dried over MgSO4, filtered and evaporated in vacuo. The resulting residue was purified by column chromatography (silica gel, 5 to 25% EtOAc/hexanes) and recrystallized from hexanes to provide 1t (3.4 g, 76%) MS m/z=250 (M+H).
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH:8]=[CH2:9])(=[O:6])[O:4][CH3:5].[OH:10]O>CC(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[V]>[CH3:1][O:2][P:3]([CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:6])[O:4][CH3:5]
Reactant: OO
Reactant: C=CCP(=O)(OC)OC
Agent: [V]
Agent: CC(=O)/C=C(/C)O
Solvent: CC(C)=O
Product: COP(=O)(CC1CO1)OC

Procedure:
In a flask having a capacity of 500 ml, equipped with a stirrer, thermostatic temperature control, reflux condenser, dropping funnel and internal thermometer, 0.5 g of vanadium (III) acetylacetonate is dissolved in 120 ml of acetone (previously purified with KMnO4). Then 75 g (0.5 mole) of allylphosphonic acid dimethyl ester is mixed in. With intense stirring, 65 ml of 30% hydrogen peroxide is added by drop over a period of about 20 minutes at 30° C. Then the mixture is refluxed for 2 hours, after which the acetone is largely removed by distillation, whereupon the product separates as the heavy phase. The aqueous phase is extracted with methylene chloride. 77 grams of glycidylphosphonic acid dimethyl ester are obtained by vacuum distillation.
Reaction SMILES: [F:1][C:2]([F:48])([F:47])[C:3]1[CH:4]=[C:5]([CH:40]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:42]=1)[CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:37])[CH3:36])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15]([CH3:17])=[O:16])[N:12]=1.ClC1C=CC=C(C(OO)=[O:57])C=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[F:44][C:43]([F:46])([F:45])[C:41]1[CH:40]=[C:5]([CH:4]=[C:3]([C:2]([F:47])([F:1])[F:48])[CH:42]=1)[CH2:6][N:7]([CH2:18][C:19]1[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[CH:21][C:20]=1[C:29]1[CH:34]=[C:33]([CH:35]([CH3:36])[CH3:37])[CH:32]=[CH:31][C:30]=1[O:38][CH3:39])[C:8]1[N:9]=[N:10][N:11]([CH2:13][CH2:14][S:15]([CH3:17])(=[O:57])=[O:16])[N:12]=1
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCS(C)=O)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(CCS(C)(=O)=O)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
(3,5-Bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfinyl-ethyl)-2H-tetrazol-5-yl]-amine (129 mg) is dissolved in chloroform (2 ml), and thereto is added m-chloroperbenzoic acid (50 mg) and the mixture is stirred at room temperature overnight. To the reaction solution is added a saturated aqueous sodium bicarbonate solution, and the mixture is extracted with ethyl acetate, and the organic layer is washed with a brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=2:1) to give (3,5-bis-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-[2-(2-methanesulfonyl-ethyl)-2H-tetrazol-5-yl]-amine (81 mg). MS (m/z): 724 [M+H]+
Reaction SMILES: ClC1C=C(Cl)C=CC=1C(Cl)=O.[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][C:36]=1[O:37][CH3:38])[N:33]=[CH:32][CH:31]=[C:30]2[O:39][C:40]1[CH:46]=[CH:45][C:43]([NH2:44])=[CH:42][C:41]=1[F:47].C1(C)C=CC=CC=1>C(O)C>[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([N:22]=[C:23]=[S:24])=[O:21].[Cl:12][C:13]1[CH:18]=[C:17]([Cl:19])[CH:16]=[CH:15][C:14]=1[C:20]([NH:22][C:23]([NH:44][C:43]1[CH:45]=[CH:46][C:40]([O:39][C:30]2[C:29]3[C:34](=[CH:35][C:36]([O:37][CH3:38])=[C:27]([O:26][CH3:25])[CH:28]=3)[N:33]=[CH:32][CH:31]=2)=[C:41]([F:47])[CH:42]=1)=[S:24])=[O:21]
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Agent: O=C(Cl)c1ccc(Cl)cc1Cl
Agent: O=C(N=C=S)c1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CCO
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(Cl)cc4Cl)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
2,4-Dichloro-1-benzenecarbonyl isothiocyanate was prepared using commercially available 2,4-dichloro-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 2,4-Dichloro-1-benzenecarbonyl isothiocyanate was dissolved in ethanol (1 ml) to prepare a solution. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]-3-fluoroaniline (50 mg), toluene (5 ml), and ethanol (1 ml) were added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (64 mg, yield 74%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:30])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:29])[NH:27][OH:28])=[CH:22][CH:21]=3)=[N:14]2)[CH:7]=1)[CH3:2].N1C=CC=CC=1.Cl[C:38](OCC)=[O:39].Cl>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:30])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]2[C:18](=[O:19])[CH:17]=[CH:16][C:15]([C:20]3[CH:21]=[CH:22][C:23]([C:26]4[NH:29][C:38](=[O:39])[O:28][N:27]=4)=[CH:24][CH:25]=3)=[N:14]2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(C(=N)NO)cc3)ccc2=O)c1
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(-c4noc(=O)[nH]4)cc3)ccc2=O)c1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
500 mg (123 mmol) of ethyl(3-{3-[4-(N-hydroxycarbamimidoyl)phenyl]-6-oxo-6H-pyridazin-1-ylmethyl}phenyl)carbamate are dissolved in 20 ml of DMF, and 300 μl of pyridine are added. 128 μl (1.35 mmol) of ethyl chloroformate are subsequently added, and the solution is stirred at 100° C. for 24 h. 10 ml of 1 N HCl and water are added to the reaction mixture. The batch is evaporated to dryness, ethyl acetate is added, and the mixture is extracted with water. The organic phase is dried over sodium sulfate, evaporated to dryness and purified by means of preparative HPLC.
Reaction SMILES: [CH:1]([N:3]1[CH2:8][CH2:7][S:6][CH2:5][CH:4]1[CH2:9][CH:10]([CH3:12])[CH3:11])=O.[P:13]([OH:16])([OH:15])[OH:14].P(Cl)(Cl)Cl>O>[CH2:9]([CH:4]1[CH2:5][S:6][CH2:7][CH2:8][N:3]1[CH:1]([P:13](=[O:14])([OH:16])[OH:15])[P:13](=[O:16])([OH:15])[OH:14])[CH:10]([CH3:12])[CH3:11]
Reactant: OP(O)O
Reactant: CC(C)CC1CSCCN1C=O
Solvent: ClP(Cl)Cl
Solvent: O
Product: CC(C)CC1CSCCN1C(P(=O)(O)O)P(=O)(O)O
Temperature: 100 °C

Procedure:
A mixture of N-formyl-3-isobutyl-thiomorpholine (18.7 g) and phosphorous acid (16.4 g) was heated at 100° C. for 2 hours. Phosphorus trichloride (30 ml) was added dropwise with stirring, and after reflux for 3 hours water (180 ml) was added slowly. The mixture was refluxed for 1 hour and filtered. Evaporation of the filtrate gave a residue which was triturated with ethanol to yield a crystalline compound which was isolated by filtration. M.p.: 237°-238° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH2:20])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[N:21]1[CH:26]=[CH:25][N:24]=[CH:23][C:22]=1[C:27](Cl)=[O:28].C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:9]2[N:10]=[C:11]([NH:20][C:27]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][N:21]=3)=[O:28])[S:12][C:13]=2[C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(C)cc(-c2nc(N)sc2-c2ccncc2)c1
Reactant: O=C(Cl)c1cnccn1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(C)cc(-c2nc(NC(=O)c3cnccn3)sc2-c2ccncc2)c1
Temperature: 70 °C
Reaction time: 14 h
Yield: 58.8 %

Procedure:
To a solution of [4-(3,5-dimethylphenyl)-5-(4-pyridyl)-1,3-thiazol-2-yl]amine (0.50 g, 1.8 mmol) and 4-dimethylaminopyridine (0.06 g, 0.53 mmol) in N,N-dimethylacetamide (5 mL) was added pyrazinecarbonyl chloride (0.44 g, 2.7 mmol) and the mixture was stirred at 70° C. for 14 h. To the reaction mixture was poured aqueous sodium hydrogencarbonate solution and the precipitated solid was collected by filtration. The obtained solid was washed with water and dried. The crude crystals were recrystallized from ethanol to give the title compound (0.41 g, yield 59%).
Reaction SMILES: [Cl:1][C:2]1[C:7](CC=C)=[C:6](I)[CH:5]=[C:4]([CH:12]([OH:14])[CH3:13])[N:3]=1.[PH2](O)=O.C(N(CC)CC)C.[CH2:25]1C[O:28][CH2:27][CH2:26]1>>[Cl:1][C:2]1[N:3]=[C:4]([CH:12]([OH:14])[CH3:13])[CH:5]=[C:6]2[CH:26]([CH3:25])[CH2:27][O:28][C:7]=12
Reactant: C1CCOC1
Reactant: C=CCc1c(I)cc(C(C)O)nc1Cl
Agent: O=[PH2]O
Solvent: CCN(CC)CC
Product: CC(O)c1cc2c(c(Cl)n1)OCC2C
Yield: 97 %

Procedure:
A solution of 2-chloro-3-(1-propen-3-yl)-4-iodo-6-(1-hydroxyethyl)-pyridine (1.06 g, 3.14 mmol) in THF (5 mL) is treated with 50% hypophosphorous acid (2.13 g, 15.73 mmol), triethylamine (1.75 g, 17.33 mmol), and 2,2'-azobis(2-methylpropino-nitrile) (AIBN; 192 mg, 1.23 mmol). The solution is stirred at reflux for 2 hours. The solution is allowed to cool and concentrated in vacuo. Sat'd NaHCO3 is added, and the mixture is extracted 3× EtOAc. The organics are dried over MgSO4, and concentrated in vacuo. The crude light yellow oil is chromatographed (SiO2, hexane/ethyl acetate, 2:1) to yield 650 mg (97%) of 7-chloro-2,3-dihydro-5-(1-hydroxyethyl)-3-methyl-furo[2,3-c]pyridine, mp 67-68° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([O:25]C)=[O:24])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>C1COCC1.O>[CH2:1]([O:8][C:9]1[C:10]([NH:15][C:16]2[S:17][CH:18]=[C:19]([CH2:21][CH2:22][C:23]([OH:25])=[O:24])[N:20]=2)=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)CCc1csc(Nc2ncccc2OCc2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.2 %

Procedure:
Methyl 3-(2-(3-(benzyloxy)pyridin-2-ylamino)thiazol-4-yl)propanoate (2.00 g, 5.41 mmol) was dissolved in THF (5 mL), and a solution of lithium hydroxide monohydrate (469 mg, 11.18 mmol) in water (1 mL) was added at room temperature. The resulting mixture was stirred at room temperature for 18 hours. The mixture was concentrated in vacuo to remove most of the THF, and the resulting aqueous phase was acidified to pH 3 with 2 M aqueous HCl. The resulting cloudy mixture was extracted with CH2Cl2 (3×10 mL), and the combined organic phases were washed with brine (10 mL), dried (Na2SO4), filtered and concentrated in vacuo to a white solid. The solid was further dried under high vacuum overnight to provide the title compound as an off-white powder (1.79 g, 5.04 mmol, 93% yield). 1H NMR (DMSO-d6) δ 2.60 (t, J=7.0 Hz, 2H), 2.82 (t, J=7.2 Hz, 2H), 5.26 (s, 2H), 6.62 (s, 1H), 6.89 (dd, J=7.8, 5.1 Hz, 1H), 7.35 (m, 4H), 7.57 (s, 1H), 7.58 (m, 1H), 7.86 (dd, J=1.5, 5 Hz, 1H), 9.96 (br s, 1H), 12.14 (br s, 1H); Mass spectrum (apci) m/z 354.0 (M−H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:11]([OH:13])=O)[NH:10][C:4]=2[CH:3]=1.Cl.[NH2:15][C@@H:16]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:17]([N:19]1[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]1)=[O:18]>>[F:32][C:29]1[CH:30]=[CH:31][C:26]([CH2:25][C@H:16]([NH:15][C:11]([C:9]2[NH:10][C:4]3[CH:3]=[C:2]([Cl:1])[N:7]=[CH:6][C:5]=3[CH:8]=2)=[O:13])[C:17]([N:19]2[CH2:23][CH2:22][C@H:21]([OH:24])[CH2:20]2)=[O:18])=[CH:27][CH:28]=1
Reactant: O=C(O)c1cc2cnc(Cl)cc2[nH]1
Reactant: N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1
Agent: Cl
Product: O=C(N[C@@H](Cc1ccc(F)cc1)C(=O)N1CC[C@H](O)C1)c1cc2cnc(Cl)cc2[nH]1

Procedure:
The title compound was prepared as outlined in EXAMPLE 295 from 6-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (Preparation 116) and 2-(S)-amino-3-(4-fluorophenyl)-1-(3-(S)-hydroxypyrrolidin-1-yl)propan-1-one hydrochloride (Preparation 103). The crude product was recrystallised from ethyl acetate to give the title compound. δH (CD3OD): 1.77–1.98 (2H, m), 3.08–3.88 (6H, 6 m), 4.30, 4.42 (1H, 2 m), 5.07, 5.09 (1H, 2m), 7.00 (2H, m), 7.30 (3H, m), 7.43 (1H, m), 8.67 (1H, s); m/z (ES+)=430.90 [M+H]+; RT=3.29 min.