Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[F:13][C:14]([F:23])([F:22])[C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=1.[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[NH:27][N:26]=1>>[CH3:24][C:25]1[CH:29]=[C:28]([CH3:30])[N:27]([C:2]2[N:11]=[C:10]([NH:19][C:18]3[CH:20]=[CH:21][C:15]([C:14]([F:22])([F:23])[F:13])=[CH:16][CH:17]=3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=2)[N:26]=1
Reactant: Cc1cc(C)[nH]n1
Reactant: Clc1nc(Cl)c2ccccc2n1
Reactant: Nc1ccc(C(F)(F)F)cc1
Product: Cc1cc(C)n(-c2nc(Nc3ccc(C(F)(F)F)cc3)c3ccccc3n2)n1

Procedure:
Was prepared according to Method B from 2,4-dichloroquinazoline, 4-trifluoromethylaniline and 3,5-dimethylpyrazole. Mp. 218.8-220.1° C.
Reaction SMILES: [C:1]([C:6]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[N:8]([CH2:17][C:18]([OH:20])=O)[N:7]=1)(=[O:5])[CH:2]([CH3:4])[CH3:3].C1C=C2N=NN(O)C2=CC=1.O.Cl.[CH2:33]([NH:35][CH2:36][CH2:37][C:38]([CH3:41])([CH3:40])[CH3:39])[CH3:34].CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH3:39][C:38]([CH3:41])([CH3:40])[CH2:37][CH2:36][N:35]([CH2:33][CH3:34])[C:18](=[O:20])[CH2:17][N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([O:15][CH3:16])[CH:10]=2)[C:6]([C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])=[N:7]1
Reactant: COc1ccc2c(C(=O)C(C)C)nn(CC(=O)O)c2c1
Reactant: CCNCCC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCN(CCC(C)(C)C)C(=O)Cn1nc(C(=O)C(C)C)c2ccc(OC)cc21
Reaction time: 8 h

Procedure:
Charge a 13×100 mm screw-capped tube with 27.6 mg (3-isobutyryl-6-methoxy-1H-indazol-1-yl)acetic acid, 23.0 mg HOBt hydrate, 18.6 mg N-ethyl-3,3-dimethylbutan-1-amine hydrochloride, and 89 μL DIEA. Dissolve the mixture in 1 mL anhydrous DMF. Add 38.3 mg EDC HCl salt and let the mixture sit at room temperature overnight. The title compound was isolated from the reaction mixture using RP-HPLC with 65-100% MeCN gradient with 0.1% TFA. LC-MS: 3.89 min. (m/Z=388.2, 410.1)
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[CH3:5][C:6]([CH3:11])=[CH:7][C:8](Cl)=[O:9]>ClCCl.COCCOCCOCCOCCOCCOCCO>[CH3:5][C:6]([CH3:11])=[CH:7][C:8]([N:3]=[C:2]=[S:1])=[O:9]
Reactant: CC(C)=CC(=O)Cl
Reactant: N#C[S-]
Agent: COCCOCCOCCOCCOCCOCCO
Agent: [K+]
Solvent: ClCCl
Product: CC(C)=CC(=O)N=C=S
Temperature: 25 °C
Reaction time: 3 h
Yield: 70 %

Procedure:
To a solution of potassium thiocyanate (10 g, 101 mmol, Eq: 1.00) and hexaethylene glycol monomethyl ether (896 mg, 830 μl, 3.02 mmol, Eq: 0.03) in dry dichloromethane (120 ml) was added dropwise at 0° C. a solution of 3-methylbut-2-enoyl chloride (12.0 g, 11.2 ml, 101 mmol, Eq: 1.00) in dry dichloromethane (20.0 ml) over 1 hour under argon atmosphere. After the addition was completed, the mixture (now light brown & turbid) was allowed to warm to 25° C. and was stirred for additional 3 hours. The mixture was filtrated, the filtrate was evaporated the residue was distilled under reduced pressure affording 3-methyl-but-2-enoyl isothiocyanate (9.989 g/70.2%) as a yellow liquid. GC-MS: m/ei=141 (M)/bp: 86° C./2 mbar
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH2:14][CH2:15][CH:9]1[CH2:10][N:11]([C:16]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=1[C:18](=[O:37])[N:19]([CH2:26][C:27]1[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=1)[C:20]3=[O:25])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH:39](C1C=CC=CC=1)C.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.[Pd]>[CH3:36][O:35][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[O:33][CH3:34])[CH2:26][N:19]1[C:18](=[O:37])[C:17]2[C:21](=[CH:22][CH:23]=[CH:24][C:16]=2[N:11]2[CH2:10][CH:9]3[N:8]([CH:1]([C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[CH3:39])[CH:13]([CH2:14][CH2:15]3)[CH2:12]2)[C:20]1=[O:25]
Reactant: COc1ccc(CN2C(=O)c3cccc(N4CC5CCC(C4)N5Cc4ccccc4)c3C2=O)cc1OC
Reactant: CC(Br)c1ccccc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COc1ccc(CN2C(=O)c3cccc(N4CC5CCC(C4)N5C(C)c4ccccc4)c3C2=O)cc1OC
Temperature: 50 °C
Yield: 38.5 %

Procedure:
Compound 7 (50 mg, 0.10 mmol) was hydrogenated (50 psi H2) with 10% Pd/C (5 mg) in EtOAc (1.0 mL) for 5 h. The mixture was filtered through Celite®, and concentrated in vacuo. The crude oil was dissolved in THF (0.4 mL). A portion of 1-bromoethylbenzene (0.03 mL, 0.22 mmol) and K2CO3 (36 mg, 0.26 mmol) were added. The mixture was heated to 50° C. for 4 h. The mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. The crude oil was purified on a Gilson HPLC with a reversed phase Kromasil column (10μ, 100 Å C18, column length 250×50 mm, gradient 90:10-0:100 H2O:MeCN) to give the 19.7 mg (38%) of the title Compound 32 as a yellow solid. 1H NMR (300 MHz, CDCl3) δ 7.71 (ovdd, J=7.6 Hz, 1 H), 7.49-7.60 (m, 6 H), 7.30 (d, J=8.2 Hz, 1 H), 6.94-7.00 (m, 1 H), 6.86-6.91 (m, 2 H), 4.73 (s, 2 H), 4.00-4.11 (m, 1 H), 3.81 (s, 3 H), 3.80 (s, 3 H), 3.43-3.60 (m, 4 H), 2.67-2.75 (m, 2 H), 2.43-2.51 (m, 2 H), 2.17-2.25 (m, 2 H), and 1.82 (d, J=6.7 Hz, 3 H); MS (ES+) 512.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[NH:10][C:11](=S)[S-:12].C([NH+](CC)CC)C.C(N(CC)CC)C.C(Cl)(=O)OCC>C(Cl)(Cl)Cl>[F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1[N:10]=[C:11]=[S:12]
Reactant: Fc1ccc(NC(=S)[S-])c(F)c1F
Agent: CCOC(=O)Cl
Agent: CC[NH+](CC)CC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Fc1ccc(N=C=S)c(F)c1F
Reaction time: 1 h
Yield: 78.3 %

Procedure:
Triethylammonium N-(2,3,4-trifluorophenyl)dithiocarbamate (92.0 g) and triethylamine (31.5 g) were added to chloroform (360 ml) and thereto ethyl chlorocarbonate (33.8 g) was added dropwise at 2°-6° C. with stirring over a period of 1 hour. The mixture was stirred for 10 minutes and washed with 3N hydrochloric acid and then with water. The organic layer was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica-gel column chromatography (Silica gel 60, 230-400 mesh, made by Merck Co., 220 g, eluent: hexane) under medium pressure, followed by distillation under reduced pressure to give the title compound (42.0 g) as colorless liquid, b.p.: 96°-97° C./17 mmHg.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[CH3:17])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:6].[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[S:28])[CH:22]=[C:23]([Cl:25])[CH:24]=1>C(OCC)(=O)C>[Cl:18][C:19]1[CH:20]=[C:21]([NH:26][C:27](=[S:28])[NH:1][C:2]2[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=2[CH3:17])[C:5]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:6])[CH:22]=[C:23]([Cl:25])[CH:24]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: Cc1ccc(C(=O)Nc2ccccc2)cc1N
Solvent: CCOC(C)=O
Product: Cc1ccc(C(=O)Nc2ccccc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Yield: 84.7 %

Procedure:
Prepared according to the procedure described for Example 60 using of 3-amino-4-methyl-N-phenyl-benzamide (0.5 g, 2.2 mmol) and 3,5-dichlorophenyl isothiocyanate (0.458 g, 2.2 mmol). Trituration in ethyl acetate afforded the product (0.802 g) in two crops; m.p. 182-184° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH3:12])=[N:9]2)=[CH:4][CH:3]=1.[CH:13]([C:15]1[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=1)[O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=O>C(OC(=O)C)(=O)C>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH:12]=[CH:13][C:15]3[CH:16]=[C:17]([CH:27]=[CH:28][CH:29]=3)[O:18][CH2:19][CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[N:9]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc2ccc(Br)cc2n1
Reactant: CCOC(=O)CCCOc1cccc(C=O)c1
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)CCCOc1cccc(C=Cc2ccc3ccc(Br)cc3n2)c1

Procedure:
A solution of 7-bromoquinaldine (22 g, 0.1M) and ethyl 4-(3-formylphenoxy)butanoate (20 g) in acetic anhydride (100 ml) was heated at 135° for 34 hours cooled and evaporated. Flash chromatography of the residue using 1:1 ether in hexane as eluant afforded crude adduct. Recrystallization from hexane ethyl acetate afforded the title compound: m.p. 92-93°.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[F:15][C:16]1[N:21]=[C:20]([CH:22]=O)[CH:19]=[CH:18][CH:17]=1.OS([O-])=O.[Na+].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C>[F:15][C:16]1[N:21]=[C:20]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:19]=[CH:18][CH:17]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1cccc(F)n1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cccc(F)n3)nc2c1
Temperature: 120 °C
Yield: 48.6 %

Procedure:
To a solution of 2-amino-4,6-dimethoxybenzamide (0.737 g, 3.76 mmol) and 6-fluoropicolinaldehyde (0.470 g, 3.76 mmol) in N,N-dimethylacetamide (20 mL), NaHSO3 (58.5% SO2 content, 1.0 g, 5.63 mmol) and p-toluenesulfonic acid monohydrate (0.143 g, 0.75 mmol) were added. The reaction was heated at 120° C. for 20 h. After that time the reaction was cooled to rt, concentrated under reduced pressure, diluted with water (50 mL) and saturated NaHCO3 solution was added to adjust the pH to 8. The precipitated solids were collected by filtration, washed with water and dried. The product was purified by flash column chromatography (silica gel, 99:1 dichloromethane/methanol to 97:3 dichloromethane/methanol) to give 2-(6-fluoropyridin-2-yl)-5,7-dimethoxyquinazolin-4(3H)-one (0.550 g, 49%) as a yellow solid: 1H NMR (400 MHz, DMSO-d6) δ 11.34 (s, 1H), 8.28-8.33 (m, 1H), 8.19-8.27 (m, 1H), 7.47 (dd, J=8.01, 1.76 Hz, 1H), 6.82 (d, J=2.34 Hz, 1H), 6.62 (d, J=2.34 Hz, 1H), 3.91 (s, 3H), 3.86 (s, 3H); 19F NMR (376 MHz, DMSO-d6) δ −68.08 (d, J=8.03 Hz); ESI MS m/z 302 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][N:29](C(OC(C)(C)C)=O)[CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1.C(O)(C(F)(F)F)=O.CCOCC>C(Cl)Cl>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:10]=[C:11]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[S:12][C:13]=1[C:14]1[CH:15]=[CH:16][C:17]2[N:18]([C:20]([CH:23]([CH3:25])[CH3:24])=[N:21][N:22]=2)[N:19]=1
Reactant: CC(C)c1nnc2ccc(-c3sc(C4CCN(C(=O)OC(C)(C)C)CC4)nc3-c3ccc(F)cc3F)nn12
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1nnc2ccc(-c3sc(C4CCNCC4)nc3-c3ccc(F)cc3F)nn12
Temperature: 25 °C
Reaction time: 19 h
Yield: 76.1 %

Procedure:
A 100 mL flask was charged with tert-butyl 4-(4-(2,4-difluorophenyl)-5-(3-isopropyl-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)thiazol-2-yl)piperidine-1-carboxylate (1.05 g, 1.94 mmol, prepared using General Procedure O from Preparation #A.2 and tert-butyl 4-(aminocarbothioyl) tetrahydropyridine-1-(2H)-carboxylate) in DCM (10 mL) to give a yellow solution. To the solution was added TFA (1.50 mL, 19.4 mmol) and the mixture was stirred at ambient temperature. After about 19 h, the reaction was concentrated under reduced pressure to give a yellow oil which was redissolved in DCM and washed sequentially with 10% aqueous NaOH, water, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to dryness under reduced pressure to give a yellow oil. Upon addition of Et2O, a cloudy solution was formed. Concentration of this solution yielded the title compound as a yellow powder (0.65 g, 76%): LC/MS (Table 1, Method a) Rt=1.54 min; MS m/z: 441.2 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)[NH2:6].[C:14](Cl)(=[O:25])[O:15][C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.C(N(CC)C(C)C)(C)C.[Cl-].[NH4+]>C1COCC1>[CH3:2][C:3]1[CH:4]=[C:5]([NH:6][C:14](=[O:25])[O:15][C:16]2[CH:17]=[CH:18][C:19]([N+:22]([O-:24])=[O:23])=[CH:20][CH:21]=2)[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cc(N)cc(C(F)(F)F)c1
Agent: Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)Oc2ccc([N+](=O)[O-])cc2)cc(C(F)(F)F)c1
Temperature: 5 °C
Reaction time: 1 h
Yield: 98.9 %

Procedure:
3-Methyl-5-(trifluoromethyl)aniline monohydrochloride (2.93 g) synthesized in reference to a known method (U.S. Pat. No. 4,532,353) was dissolved in THF (25 mL), and 4-nitrophenyl chlorocarbonate (3.07 g) and N,N-diisopropylethylamine (1.97 mL) were added dropwise at 5° C. The reaction mixture was stirred at 5° C. for 1 hr, poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, dried and concentrated under reduced pressure to give the title compound (4.66 g) as a white powder.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]([C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)(O)[CH3:7])C.O.[NH2:24][NH2:25]>>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:6]3([CH3:7])[CH2:5][C:4](=[O:3])[NH:25][NH:24]3)=[CH:10][CH:11]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)CC(C)(O)c1ccc(-c2ccc(F)cc2)cc1
Reactant: NN
Solvent: O
Product: CC1(c2ccc(-c3ccc(F)cc3)cc2)CC(=O)NN1

Procedure:
A mixture of 30.2 g of 3-(4'-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester and 25 g of 100% strength hydrazine hydrate is heated at 100° for 4 hours. The mixture is worked up in the usual manner to give 3-(4'-fluoro-4-biphenylyl)-3-methyl-pyrazolidin-5-one, m.p. 194°-196 °.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[CH:8][C:3]=1[NH:4][CH:5]([CH3:7])[CH3:6].N[C:14](N)=[O:15]>O>[Cl:12][C:10]1[CH:9]=[CH:8][C:3]2[N:4]([CH:5]([CH3:7])[CH3:6])[C:14](=[O:15])[NH:1][C:2]=2[CH:11]=1
Reactant: CC(C)Nc1ccc(Cl)cc1N
Reactant: NC(N)=O
Solvent: O
Product: CC(C)n1c(=O)[nH]c2cc(Cl)ccc21
Temperature: 160 °C
Reaction time: 3.5 h
Yield: 43.8 %

Procedure:
A mixture of 2-amino-4-chloro-N-isopropylaniline (14 g) and urea (15 g) was stirred at 160° C. for 3.5 hours. After cooling, water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with diluted hydrochloric acid, an aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over anhydrous magnesium sulfate and then the solvent was distilled off under reduced pressure. To the residue was added isopropyl alcohol and the obtained crystal was separated by filtration and recrystallized from acetonitrile to give 5-chloro-1-isopropylbenzimidazol-2-one (7 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[P:6]([O:11][CH2:12][CH3:13])(=[O:10])[O:7][CH2:8][CH3:9].[Li+].CC([N-]C(C)C)C.[CH:22](OC)=[O:23]>O1CCCC1>[CH2:12]([O:11][P:6]([C:2]1[S:1][C:5]([CH:22]=[O:23])=[CH:4][CH:3]=1)([O:7][CH2:8][CH3:9])=[O:10])[CH3:13]
Reactant: COC=O
Reactant: CCOP(=O)(OCC)c1cccs1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOP(=O)(OCC)c1ccc(C=O)s1
Reaction time: 1 h

Procedure:
A solution 1.0 mmol of diethyl 2-thiophenephosphonate in tetrahydrofuran was treated with 1.12 mmol LDA at -78° C. for 20 min. 1.5 mmol methyl formate was added and the reaction was stirred for 1 hr. Extraction and chromotagraphy gave 5-diethylphosphono-2-thiophenecarboxaldehyde as a clear yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[OH:8].C([O-])([O-])=O.[K+].[K+].[F:25][C:26]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:27]=1[CH2:28]Br>CC(N(C)C)=O>[Cl:1][C:2]1[C:3](=[O:18])[N:4]([CH2:10][C:11]2[CH:16]=[N:15][C:14]([CH3:17])=[CH:13][N:12]=2)[C:5]([CH3:9])=[CH:6][C:7]=1[O:8][CH2:28][C:27]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:26]=1[F:25]
Reactant: Cc1cnc(Cn2c(C)cc(O)c(Cl)c2=O)cn1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Cc1cnc(Cn2c(C)cc(OCc3ccc(F)cc3F)c(Cl)c2=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of 3-chloro-4-hydroxy-6-methyl-1-[(5 methylpyrazin-2-yl)methyl]pyridin-2(1H)-one (2.48 g, 9.3 mmol) in DMA (7 mL)was added K2CO3 (1.54 g, 11.0 mmol) followed by 2,4-difluorobenzyl bromide (1.2 mL, 9.3 mmol). The reaction mixture stirred at room temperature under nitrogen for 1.5 hours. The solvent was distilled in vacuo. The resulting residue was diluted in dichloromethane and washed with water. The organic extracts were concentrated and the resulting residue was purified by flash column chromatography (ethyl acetate). The appropriate fractions were combined, and concentrated. 1H NMR (CD3OD, 400 MHz) δ 8.49 (d, 1H, J=1.2 Hz), 8.40 (s, 1H), 7.59 (m, 1H), 7.04 (m, 2H), 6.54 (s, 1H), 5.41 (s, 2H), 5.28 (s, 2H), 2.54 (s, 3H), 2.40 (s, 3H); ES-HRMS m/z 392.1014 (M+H calculated for C19H17N3O2ClF2 requires 392.0972).
Reaction SMILES: N[CH:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].[BrH:18].C(N(CC)CC)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.N(OCCC(C)C)=O>C(Cl)Cl>[Br:18][CH:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17]
Reactant: Br
Reactant: C=CC[C@@H]1C(N)C(=O)N1C(C(=O)OC)=C(C)C
Agent: CC(C)CCON=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CC[C@@H]1C(Br)C(=O)N1C(C(=O)OC)=C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 81.3 %

Procedure:
A mixture of methyl 2-[(4R)-3-amino-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (815 mg), triethylamine hydrobromide (2.50 g) and p-toluenesulfonic acid hydrate (1.17 g) in methylene chloride (30 ml) was cooled to 0° C. and isopentyl nitrite (0.54 ml) was added. After stirring for 20 minutes at the same temperature, the mixture was concentrated and the residue was dissolved in ethyl acetate (50 ml). The solution was washed successively with 10% aqueous sodium bisulfite, water and brine, dried over magnesium sulfate and evaporated to give methyl 2-[(4R)-3-bromo-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (840 mg) as a crude oil.
Reaction SMILES: C1C2SC3C(=CC=CC=3)SC=2C=CC=1S(Cl)(=O)=O.[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33](Cl)(=[O:35])=[O:34].C([O:41][C:42](=[O:48])[C@H:43]([CH:45](C)C)[NH2:44])(C)(C)C.C(OC(=O)[C@H](C)N)(C)(C)C>>[CH:19]1[C:32]2[S:31][C:30]3[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=3)[O:24][C:23]=2[CH:22]=[CH:21][C:20]=1[S:33]([NH:44][C@@H:43]([CH3:45])[C:42]([OH:48])=[O:41])(=[O:35])=[O:34]
Reactant: CC(C)[C@H](N)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1O2
Agent: C[C@H](N)C(=O)OC(C)(C)C
Agent: O=S(=O)(Cl)c1ccc2c(c1)Sc1ccccc1S2
Product: C[C@H](NS(=O)(=O)c1ccc2c(c1)Sc1ccccc1O2)C(=O)O

Procedure:
When in the procedure of Example 1, Step (b), thianthrene-2-sulfonyl chloride is replaced by phenoxathiine-2-sulfonyl chloride and (L)-valine-t-butyl ester is replaced with (L)-alanine-t-butyl ester, (S)-2-(phenoxathiine-2-sulfonylamino)-propionic acid is obtained as a white solid; mp 75-85° C.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22](O)=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].C[N:31]1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH4+].[OH-]>O.O1CCCC1>[Cl:1][C:2]1[C:3](=[O:29])[N:4]([C:19]2[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=2[F:28])[C:22]([NH2:31])=[O:23])[C:5]([CH3:18])=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: CN1CCOCC1
Reactant: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(=O)O)ccc1F
Agent: COc1nc(Cl)nc(OC)n1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(OCc2ccc(F)cc2F)c(Cl)c(=O)n1-c1cc(C(N)=O)ccc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.9 %

Procedure:
A 250 mL round bottomed flask equipped with stirbar and nitrogen inlet was charged with 3-[3-chloro-4-[(2,4-difluorobenzyl)oxy]-6-methyl-2-oxopyridin-1(2H)-yl]-4-fluorobenzoic acid (2.58 g, 6.1 mmol), 4-methylmorpholine (2.0 L, 18.3 mmol), 2-chloro-4,6-dimethoxy-1,3,5-triazine (1.28 g, 7.3 mmol) and tetrahydrofuran (30 mL). After stirring the mixture for 30 min at 25° C., NH4OH (15.0 mL) was added. The mixture was stirred for 30 min and diluted with water. The product precipitated from solution. The precipitated was filtered and washed with water and diethyl ether to give the title compound (2.55 g, 78%) as a white solid. 1H NMR (400 MHz, (CD3)2SO) δ 8.10 (m, 1H), 7.9 (dd, J=2.1 and 5.2 Hz, 1H), 7.65 (q, 6.7 and 8.5 Hz, 1H), 7.56 (t, J=9.1 Hz, 1H), 7.35 (td, J=2.4 and 8.2 Hz, 1H) 7.17 (td, J=2 and 6.6 Hz, 1H) 6.78 (s, 1H), 5.36 (s, 2H), 2 (s, 3H) ppm. ES-HRMS m/z 423. 0719 (M+H calcd for C20H15ClF3N2O3 requires 423.0718).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[N+:18]([O-])=O)[C:5]([NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH3:14])[CH2:10][CH2:9]1)=[O:6].CCO>[Pt].C(Cl)Cl>[NH2:18][C:17]1[CH:16]=[CH:15][C:4]([C:5]([NH:7][CH:8]2[CH2:9][CH2:10][N:11]([CH3:14])[CH2:12][CH2:13]2)=[O:6])=[CH:3][C:2]=1[Cl:1]
Reactant: CN1CCC(NC(=O)c2ccc([N+](=O)[O-])c(Cl)c2)CC1
Agent: [Pt]
Solvent: ClCCl
Solvent: CCO
Product: CN1CCC(NC(=O)c2ccc(N)c(Cl)c2)CC1
Yield: 100.8 %

Procedure:
3-chloro-N-(1-methyl-4-piperidyl)-4-nitro-benzamide (Intermediate 56; 1.8 g, 6 mmol) hydrogenated over 2 hours with agitation at 298K and pressure of 5 bar using a 5% Pt/C catalyst and EtOH (50 mL) solvent. The catalyst was filtered and the filtrate concentrated to give a yellow crystalline solid which was dissolved in DCM and purified by column chromatography (5% MeOH/DCM) to give the title compound as a pale yellow crystalline solid (1.62 g, 100%)
Reaction SMILES: C[O:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:4]=1[C:5]#[N:6].Cl.N1C=CC=CC=1.O>C(Cl)Cl>[OH:2][C:3]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-:13])=[O:12])[C:4]=1[C:5]#[N:6]
Reactant: COc1cccc([N+](=O)[O-])c1C#N
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Solvent: O
Product: N#Cc1c(O)cccc1[N+](=O)[O-]
Temperature: 200 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
2-Methoxy-6-nitrobenzonitrile (Example 129f) (10.73 g, 60.2 mmol) and pyridine hydrochloride (16.0 g, 138 mmol) were mixed together as solids under nitrogen, and then heated in a preheated oil bath at 200° C. for 40 min. After cooling to room temperature, water (200 mL) and CH2Cl2 (200 mL) were added and stirred vigorously for 1 hour. Then, the precipitated product was collected by filtration and recrystallized from water, to give 8.2 g, (83%) of 2-hydroxy-6-nitrobenzonitrile as a brown solid. 1H-NMR (400 MHz, DMSO-d6) δ 12.13 (broad s, 1H), 7.68-7.79 (m, 2H), 7.39-7.44 (m, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C@H:9]([CH3:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20](=[O:22])[NH2:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=O)[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:46].[C-]#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][C:42]([F:43])([F:45])[F:44])[C@H:9]([CH3:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20](=[O:22])[NH2:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([NH2:46])=[O:28])[CH2:15][CH2:14]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: N
Reactant: COC(=O)CCCN1CCc2cc(C[C@@H](C)N(CCOc3ccccc3OCC(F)(F)F)C(=O)OC(C)(C)C)cc(C(N)=O)c21
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCC(N)=O)CC2)N(CCOc1ccccc1OCC(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 71 h

Procedure:
To a solution of methyl (R)-(-)-4-[5-[2-[N-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-carbamoylindolin-1-yl]butyrate (187 mg) in a saturated ammonia in methanol (2 ml) was added sodium cyanide (2 mg), and the mixture was stirred in a sealed tube at 50° C. for 71 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of methylene chloride, diethyl ether and methanol (5/5/1) as eluent to give 145 mg of (R)-(-)-4-[5-[2-[N-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-carbamoylindolin-1-yl]butyramide as an oil.