Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16][CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5].I([O-])(=O)(=O)=[O:30].[Na+]>CO.O>[CH3:1][C:2]1[CH:28]=[CH:27][CH:26]=[CH:25][C:3]=1[C:4]([NH:6][C:7]1[CH:24]=[CH:23][C:10]([C:11]([N:13]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[S:16](=[O:30])[CH2:15][CH2:14]2)=[O:12])=[CH:9][CH:8]=1)=[O:5]
Reactant: [O-][I+3]([O-])([O-])[O-]
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCSc3ccccc32)cc1
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCS(=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 65.3 %

Procedure:
To a suspension of 4-[4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-1,4-benzothiazine (0.5 g) in methanol (15 ml) is added an aqueous solution of sodium metaperiodate (0.28 g) in water (2.5 ml) and the mixture is stirred at room temperature for 72 hours. Water is added to the reaction solution and extracted with dichloromethane. The extract is dried over magnesium sulfate and the solvent is distilled off under reduced pressure. The resulting residue is purified by silica gel column chromatography (eluent; dichloromethane:methanol=100:1), and recrystallized from dichloromethane/diethyl ether to give 4-[4-(2-methylbenzoylamino)benzoyl]-3,4-dihydro-2H-1,4-benzothiazin-1-oxide (0.34 g) as white powder, m.p. 240°-241° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[NH:14][C:13]=2[CH3:22])[CH:6]=1)[CH3:2].Br[C:25]1[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([S:11][C:12]2[C:20]3[C:15](=[CH:16][C:17]([Cl:21])=[CH:18][CH:19]=3)[N:14]([C:25]3[CH:26]=[N:27][N:28]([CH:30]([CH3:32])[CH3:31])[CH:29]=3)[C:13]=2[CH3:22])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: CC(C)n1cc(Br)cn1
Product: CCOC(=O)c1cccc(Sc2c(C)n(-c3cnn(C(C)C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 42, Step 4, using the following starting materials: 3-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-benzoic acid ethyl ester and 4-bromo-1-isopropylpyrazole.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:12][CH2:11][C@:10]([CH:15]([CH3:17])[CH3:16])([C:13]#[N:14])[C:9]2=[O:18])[CH:5]=[CH:4][N:3]=1.[NH2:19][C:20]1[CH:21]=[N:22][N:23]([CH:25]2[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]2)[CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)(C)(C)C.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([C@@:10]1([CH:15]([CH3:17])[CH3:16])[CH2:11][CH2:12][N:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:19][C:20]3[CH:21]=[N:22][N:23]([CH:25]4[CH2:28][N:27]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:26]4)[CH:24]=3)[N:7]=2)[C:9]1=[O:18])#[N:14]
Reactant: CC(C)(C)OC(=O)N1CC(n2cc(N)cn2)C1
Reactant: CC(C)[C@]1(C#N)CCN(c2ccnc(Cl)n2)C1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: CC(C)(C)O
Product: CC(C)[C@]1(C#N)CCN(c2ccnc(Nc3cnn(C4CN(C(=O)OC(C)(C)C)C4)c3)n2)C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 11.6 %

Procedure:
To a mixture of (3S)-1-(2-chloropyrimidin-4-yl)-3-isopropyl-2-oxopyrrolidine-3-carbonitrile (200 mg) obtained in Step A of Example 9, tert-butyl 3-(4-amino-1H-pyrazol-1-yl)azetidine-1-carboxylate (97 mg) obtained in Step B of Example 131, cesium carbonate (370 mg) and dicyclohexyl(2′,4′,6′-triisopopropyl-3,6-dimethoxybiphenyl-2-yl)phosphine (57 mg) in tert-butanol (2.0 mL) was added tris(dibenzylideneacetone)dipalladium(0) (48 mg), and the mixture was stirred at 100° C. for 5 hr. The insoluble substance was removed by filtration through Celite, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (22 mg).
Reaction SMILES: Cl.[CH2:2]([C:8]([NH2:10])=[NH:9])[CH2:3][CH2:4][CH2:5][CH2:6]C.CC[O:13][CH:14]=[C:15]([C:21](OCC)=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[O-]CC.[Na+].[Na]>C(O)C>[CH2:2]([C:8]1[N:9]=[C:14]([OH:13])[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:21][N:10]=1)[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: CCCCCCC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCCCCc1ncc(C(=O)OCC)c(O)n1
Yield: 57.8 %

Procedure:
Hexanecarboxamidine hydrochloride (22.36 g, 0.148 mol) and diethyl ethoxymethylene malonate (31.08 g, 0.143 mol) were dissolved in ethanol (70 mL) in an ice bath. A solution of sodium ethoxide, prepared from dissolving sodium (6.65 g, 0.289 mol) in ethanol (120 mL), was added slowly. The resulting solution was heated at reflux for 2 hours and then concentrated in vacuo. Ether and water (50 mL) were added and the resulting sodium salt was removed by filtration and washed with ether. It was suspended in water and acidified with acetic acid to give the title compound (19.69 g). m.p. 127°-129° C. after crystallization from chloroform/ether.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[CH3:31]>>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:8][N:9]([CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[CH3:31])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1ccccc1CCBr
Reactant: c1ccc(NN=C(c2ccccc2)c2ccccc2)cc1
Product: Cc1ccccc1CCN(N=C(c1ccccc1)c1ccccc1)c1ccccc1

Procedure:
General procedure B was used to convert 1-(diphenylmethylene)-2-phenylhydrazine (200 mg, 0.943 mmol; Example 79A) and 1-(2-bromoethyl)-2-methylbenzene (1.46 g, 7.37 mmol; Aldrich) into the title compound: MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH3:10].[Li]CCCC.[B:16](OC(C)C)([O:21]C(C)C)[O:17]C(C)C>C1COCC1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([S:9][CH3:10])=[C:2]([B:16]([OH:21])[OH:17])[CH:7]=1
Reactant: CSc1ccc(F)cc1Br
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.03 h

Procedure:
The (2-bromo-4-fluorophenyl)(methyl)sulfane (700 mg, 3.17 mmol) was dissolved in THF (5 mL) and cooled to −78° C. To the cooled solution was added n-BuLi (2.18 mL, 3.48 mmol) dropwise. The reaction was stirred for 2 min at −78° C. then the triisopropyl borate (0.804 mL, 3.48 mmol) was added dropwise and the reaction mixture was allowed to warm to 0° C. over a period of approximately 90 min. The reaction was quenched by addition of 1N HCl solution and was stirred for 5 min. The mixture was then extracted with EtOAc (2×50 mL). The combined organic layers were washed with water (1×30 mL), brine (1×30 mL) and dried over magnesium sulfate. The crude product was then triturated with hexanes. The resulting solid was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 5-fluoro-2-(methylthio)phenylboronic acid. Mass Spectrum (ESI) m/e=187.0 (M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:40])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[CH:39]=[N:38][CH:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2cncn2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3cncn3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (290 mg, 1.0 mmol) and 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert-butyl ester (Example K15) (287 mg, 1.0 mmol) according to the general procedure M. Obtained as a white foam (420 mg, 83%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15](Cl)=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1.Cl.[C:23]([O:27][C:28](=[O:32])[CH2:29][NH:30][CH3:31])([CH3:26])([CH3:25])[CH3:24]>>[CH3:1][O:2][C:3]1[C:12]([O:13][CH3:14])=[N:11][C:10]2[C:9]([C:15]([N:30]([CH2:29][C:28]([O:27][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:32])[CH3:31])=[O:16])=[C:8]([CH3:18])[C:7]([N+:19]([O-:21])=[O:20])=[CH:6][C:5]=2[N:4]=1
Reactant: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)Cl)c2nc1OC
Reactant: CNCC(=O)OC(C)(C)C
Agent: Cl
Product: COc1nc2cc([N+](=O)[O-])c(C)c(C(=O)N(C)CC(=O)OC(C)(C)C)c2nc1OC
Reaction time: 24 h

Procedure:
Prepared from 2,3-dimethoxy-6-methyl-7-nitro-quinoxaline-5-carbonyl chloride (13) 200 mg (0.64 mmol) and sarcosine tert-butyl ester hydrochloride 122 mg (0.67 mmol). Reaction was continued for 24 hours, and the crude product was eluted through a flash column (4:1 hexanes:ethyl acetate), 200 mg (74%), mp 102-105° C.; 1H NMR (CDCl3): δ 8.29 (s, 1H), 4.27 (br s, 2H), 4.02 (s, 3H), 3.96 (s, 3H), 3.35 (br s, 3H), 2.54 (s, 3H), 1.41 (s, 9H); MS (APCI): m/z 421 (M+H). Anal. Calcd. for C19H24N4O7: C, 54.28; H, 5.75; N, 13.33. Found: C, 54.51; H, 5.76; N, 13.35.
Reaction SMILES: [CH3:1][C:2]([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]2[C:23]([CH3:26])=[N:24][N:25]=[C:18]2[CH2:17][CH2:16]3)[CH:12]=1)([CH3:6])[C:3]([OH:5])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:38]2[N:39]=[CH:40]C=CC=2N=N1.CNC.O1CCCC1.C(N(C(C)C)CC)(C)C.[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71]>CN(C)C=O>[F:68][C:69]([F:74])([F:73])[C:70]([OH:72])=[O:71].[CH3:38][N:39]([CH3:40])[C:3](=[O:5])[C:2]([CH3:6])([C:7]1[CH:8]=[N:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[N:19]2[C:23]([CH3:26])=[N:24][N:25]=[C:18]2[CH2:17][CH2:16]3)[CH:12]=1)[CH3:1]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Cc1nnc2n1-c1ccc(-c3cncc(C(C)(C)C(=O)O)c3)cc1CC2
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nnc2n1-c1ccc(-c3cncc(C(C)(C)C(=O)N(C)C)c3)cc1CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a flask containing the title compound from Example 54 Step A (10 mg, 0.03 mmol) and O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (13 mg, 0.034 mmol) in N,N-dimethylformamide (290 μL) was added a solution of dimethylamine in tetrahydrofuran (2 M, 17 μL, 0.034 mmol) followed by diisopropylethylamine (25 μL, 0.14 mmol). The reaction was stirred at room temperature overnight. The reaction was then acidified with trifluoroacetic acid, passed through a syringe filter and purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid) to afford the title compound: LCMS m/z 376.06 [M+H]+; 1H NMR (500 MHz, CDCl3) 8.76 (s, 1H), 8.57 (s, 1H), 7.69 (s, 1H), 7.61-7.57 (m, 3H), 3.20-3.17 (m, 2H), 3.12-3.09 (m, 2H), 2.97 (br s, 3H), 2.81 (s, 3H), 2.59 (br s, 3H), 1.65 (s, 6H).
Reaction SMILES: [H-].[Na+].[O:3]1[C:7]2([CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1>C1COCC1>[O:3]1[C:7]2([CH2:12][CH2:11][C:10](=[CH:8][C:7]([O:3][CH2:4][CH3:5])=[O:6])[CH2:9][CH2:8]2)[O:6][CH2:5][CH2:4]1
Reactant: O=C1CCC2(CC1)OCCO2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 216.7 %

Procedure:
To a suspension of NaH (60% mineral oil suspension, 33.3 g, 832.38 mmol) in anhydrous THF (1 L) was added a solution of 1,4-dioxaspiro[4.5]decan-8-one (100 g, 640.29 mmol) in anhydrous THF (500 mL) dropwise at 0° C. for 1 h and continued to stir for 1 h. Then triethyl phosphonoacetate (203.23 g, 832.38 mmol) was added to the above suspension dropwise at −20° C. in 1 h. The resulting mixture was allowed to warm to rt, stirred for 2 h, quenched with H2O (1 L) and extracted with EtOAC (1 L×3). The combined organic phases were washed with brine (1 L), dried over anhydrous Na2SO4, then filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/PE (v/v)=1/10) to give the title compound as pale yellow oil (157 g, 100%).
Reaction SMILES: [CH3:1][C:2]([CH3:10])([CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[CH2:11](Br)[CH:12]=[CH2:13]>O1CCCC1>[CH3:1][C:2]([CH:3]([CH2:13][CH:12]=[CH2:11])[C:4]([O:6][CH2:7][CH3:8])=[O:5])([CH3:10])[CH3:9]
Reactant: C=CCBr
Reactant: CCOC(=O)CC(C)(C)C
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCC)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
The reaction mixture was then allowed to warm to 0° C. before being cooled to -70° C. A solution of ethyl 3,3-dimethylbutanoate (14.4 g) in dry tetrahydrofuran (20 cm3) was then added dropwise to the reaction mixture which was maintained at -70° C. After the addition was complete, the reaction temperature was allowed to rise to -60° C. for 15 minutes, before being cooled again to -70° C. A solution of allyl bromide (13.4 g) in dry tetrahydrofuran (5 cm3) was then added in portions to the reaction mixture, which was allowed to warm to the ambient temperature, and stirred for a further 16 hours.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[C:3]1=[O:24].Cl[C:26]1[CH:31]=[CH:30][N:29]=[C:28]([N:32]2[C:44](=[O:45])[C:43]3[S:42][C:41]4[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=4[C:35]=3[CH:34]=[N:33]2)[C:27]=1[CH:46]=[O:47].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[CH3:1][N:2]1[C:3](=[O:24])[C:4]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:5][C:6]([C:26]2[CH:31]=[CH:30][N:29]=[C:28]([N:32]3[C:44](=[O:45])[C:43]4[S:42][C:41]5[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=5[C:35]=4[CH:34]=[N:33]3)[C:27]=2[CH:46]=[O:47])=[CH:7]1
Reactant: O=Cc1c(Cl)ccnc1-n1ncc2c3c(sc2c1=O)CCCC3
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccccn2)c1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CC#N
Solvent: O
Product: Cn1cc(-c2ccnc(-n3ncc4c5c(sc4c3=O)CCCC5)c2C=O)cc(Nc2ccccn2)c1=O
Temperature: 25 °C
Yield: 88.1 %

Procedure:
A 50-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with 178b (131 mg, 0.40 mmol), 4-chloro-2-{6-oxo-8-thia-4,5-diazatricyclo[7.4.0.02,7]trideca-1(9),2(7),3-trien-5-yl}pyridine-3-carbaldehyde 124a (138 mg, 0.40 mmol), Pd(dppf)Cl2 (33 mg, 0.040 mmol), K3PO4 (170 mg, 0.80 mmol), sodium acetate (66 mg, 0.80 mmol), water (6 drops), and acetonitrile (10 mL). After three cycles of vacuum/argon flush, the mixture was heated at reflux for 2 h. It was then cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica-gel column chromatography eluting with 30:1 dichloromethane/methanol to afford 178c as a yellow solid (180 mg, 88%). MS-ESI: [M+H]+ 511.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:21]=[C:20]([CH3:22])[C:14]2[N:15]=[C:16]([NH2:19])[N:17]=[N:18][C:13]=2[CH:12]=1.Br[C:24]1[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][CH2:35][N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)(=[O:32])=[O:31])=[CH:26][CH:25]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[K+]>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[C:11]1[CH:21]=[C:20]([CH3:22])[C:14]2[N:15]=[C:16]([NH:19][C:24]3[CH:29]=[CH:28][C:27]([S:30]([NH:33][CH2:34][CH2:35][N:36]4[CH2:37][CH2:38][CH2:39][CH2:40]4)(=[O:32])=[O:31])=[CH:26][CH:25]=3)[N:17]=[N:18][C:13]=2[CH:12]=1
Reactant: O=S(=O)(NCCN1CCCC1)c1ccc(Br)cc1
Reactant: Cc1cc(-c2cc([N+](=O)[O-])ccc2Cl)cc2nnc(N)nc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[O-]
Solvent: C1COCCO1
Product: Cc1cc(-c2cc([N+](=O)[O-])ccc2Cl)cc2nnc(Nc3ccc(S(=O)(=O)NCCN4CCCC4)cc3)nc12
Temperature: 100 °C

Procedure:
7-(2-chloro-5-nitro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamine (0.65 mmol, 1.0 equiv), 4-bromo-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide (0.95 mmol, 1.5 equiv), Xantphos (0.065 mmol, 0.10 equiv), Pd(OAc)2 (0.033 mmol, 0.05 equiv), and potassium-t-butoxide (1.3 mmol, 2.0 equiv) were dissolved in 45 mL of dioxane and placed under an argon atmosphere. The reaction mixture was refluxed at 100° C. for 18 h and then cooled to room temperature. Inorganic salts were filtered out of solution and the organics were concentrated under reduced pressure. The residue was precipitated using EtOAC/hexanes (1:5 v/v) to afford 4-[7-(2-chloro-5-nitro-phenyl)-5-methyl-benzo[1,2,4]triazin-3-ylamino]-N-(2-pyrrolidin-1-yl-ethyl)-benzenesulfonamide, as a red solid (232 mg, 63% yield). Rf=0.42 MS (ES+) m/z=570. LC retention time 2.56 min.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)[NH2:6])[CH3:2].C([O-])(O)=O.[Na+].[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>O1CCCC1>[CH2:1]([O:3][C:4](=[O:15])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([OH:14])=[CH:12][CH:13]=1)[NH:6][C:24](=[O:25])[C:23]1[CH:27]=[CH:28][CH:29]=[CH:30][C:22]=1[Cl:21])[CH3:2]
Reactant: CCOC(=O)[C@@H](N)Cc1ccc(O)cc1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)c1ccccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Into a 2L round bottom flask was added 21 g (100 mmol) of (L)-tyrosine ethyl ester (1) (Bachem) and 500 mL of tetrahydrofuran (THF). The mixture was magnetically stirred at room temperature until dissolved, and 500 mL of aqueous NaHCO3 (0.5 M) was added. The mixture was cooled in an ice bath and 19.3 g (110 mmol) of 2-chlorobenzoyl chloride (Aldrich) was added slowly via a glass syringe. The ice bath was removed and the reaction was allowed to warm to room temperature with stirring. After 30 min., the reaction mixture was rotory evaporated under reduced pressure to remove the THF and the remaining aqueous bicarbonate solution was extracted twice with 400 mL ethyl acetate. The combined extracts were washed with 400 mL of satd. aqueous NaHCO3, 400 mL of 0.1 N HCl, 400 mL of water, and 400 mL of satd. aqueous NaCl. The remaining organic layer was dried over Na2SO4 and evaporated to dryness to afford ˜40 g of crude (2) as a pale yellow oil. The crude product (2) was recrystallized from ˜800 mL of boiling ethyl acetate/hexane (˜1:3) and cooled to 4° C. overnight. The resulting crystalline product was filtered and dried under a stream of nitrogen to afford 32 g (92% isolated yield) of purified (2). The N-(2-chlorobenzoyl)-(L)-tyrosine ethyl ester product (2) was confirmed by NMR and electrospray mass spectrometry (see attached) and judged >95% pure by HPLC and TLC (Rf=0.6, 1:1 ethyl acetate/hexane). The remaining 5% impurity (Rf=0.7) was identified as 2-chlorobenzoic acid by HPLC and TLC versus authentic material. Synthesis of Thiochloroformate Intermediate (3)
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:20](=[CH:21][CH:22]=2)[NH:19][C:18](=[O:23])[CH2:17][CH2:16]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:26]I>CN(C)C=O.O>[CH3:26][N:19]1[C:20]2[C:15](=[CH:14][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[CH:22][CH:21]=2)[CH2:16][CH2:17][C:18]1=[O:23]
Reactant: CI
Reactant: O=C1CCc2cc(OCCCCSc3ccccc3)ccc2N1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CN1C(=O)CCc2cc(OCCCCSc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h

Procedure:
16.2 gm of 6-(4-phenylmercapto-butoxy)-3,4-dihydro-carbostyril were dissolved in 100 ml of dimethylformamide, and 4.8 gm of a 50% sodium hydride suspension in paraffin oil were added to this solution. After addition of 12.5 ml of methyl iodide, the mixture was stirred for 3 hours at room temperature, diluted with water and extracted with chloroform. The evaporation residue of the chloroform extract was recrystallized with methanol in the presence of activated charcoal.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH2:19][CH2:18][C:13]3([O:17][CH2:16][CH2:15][O:14]3)[CH2:12][CH:11]=2)=[C:6]([F:20])[C:5]=1[F:21])[CH3:2].C([OH:24])C.[OH-].[Na+].OO>C1COCC1.O>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:19][CH2:18][C:13]3([O:14][CH2:15][CH2:16][O:17]3)[CH2:12][CH:11]2[OH:24])=[C:6]([F:20])[C:5]=1[F:21])[CH3:2]
Reactant: CCOc1ccc(C2=CCC3(CC2)OCCO3)c(F)c1F
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1ccc(C2CCC3(CC2O)OCCO3)c(F)c1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
1400 ml (1.40 mol) of borane/THF complex (1 M solution) are added at −7° C. to a solution of 320.0 g (1.08 mol) of 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]dec-7-ene in 3000 ml of THF, and the reaction mixture is stirred at room temperature for 3 h. 262 ml (4.50 mol) of ethanol, 650 ml (2.6 mol) of aqueous sodium hydroxide solution (4 M) and 360 ml (4.11 mol) of aqueous hydrogen peroxide soln. (35%) are added successively to the batch, during which the internal temperature does not exceed 47° C. (ice bath). When the addition is complete, the mixture is refluxed for 2 h, and the solution is cooled, added to water and stirred vigorously. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with sat. sodium chloride solution and dried using sodium sulfate. The solution is concentrated to dryness, and the crude product (336 g of yellow oil) is purified by column chromatography (SiO2, dichloromethane: MTBE=8:2), giving 8-(4-ethoxy-2,3-difluorophenyl)-1,4-dioxaspiro[4.5]decan-7-ol as pale-yellow oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10]([C:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([C:21]4[CH:26]=[C:25]([O:27][CH3:28])[CH:24]=[CH:23][C:22]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)=[C:15]3[NH:14][C:13]=2[CH3:34])=[O:11])[CH2:5][CH2:4]1.[C:35](Cl)(=[O:38])[CH2:36][CH3:37]>>[CH:31]1([CH2:30][O:29][C:22]2[CH:23]=[CH:24][C:25]([O:27][CH3:28])=[CH:26][C:21]=2[C:20]2[CH:19]=[CH:18][N:17]=[C:16]3[C:12]([C:10]([NH:9][C@H:6]4[CH2:7][CH2:8][C@H:3]([NH:2][C:35](=[O:38])[CH2:36][CH3:37])[CH2:4][CH2:5]4)=[O:11])=[C:13]([CH3:34])[NH:14][C:15]=23)[CH2:32][CH2:33]1
Reactant: COc1ccc(OCC2CC2)c(-c2ccnc3c(C(=O)N[C@H]4CC[C@H](N)CC4)c(C)[nH]c23)c1
Reactant: CCC(=O)Cl
Agent: Cl
Product: CCC(=O)N[C@H]1CC[C@H](NC(=O)c2c(C)[nH]c3c(-c4cc(OC)ccc4OCC4CC4)ccnc23)CC1

Procedure:
Starting from N-(trans-4-aminocyclohexyl)-7-[2-(cyclopropylmethoxy)-5-methoxyphenyl]-2-methyl-1H-pyrrolo[3,2-b]pyridine-3-carboxamide hydrochloride (example D.f15) and commercially available propionyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[F:15][C:16]([F:37])([F:36])[O:17][C:18]1[CH:23]=[CH:22][C:21]([CH:24]([NH2:35])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:34])([F:33])[F:32])[CH:26]=2)=[CH:20][CH:19]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:35][CH:24]([C:21]2[CH:22]=[CH:23][C:18]([O:17][C:16]([F:15])([F:36])[F:37])=[CH:19][CH:20]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([F:33])([F:34])[F:32])[CH:26]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Reactant: NC(c1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1
Product: O=C(CNC(=O)c1ccc(F)cc1)NC(c1ccc(OC(F)(F)F)cc1)c1cccc(C(F)(F)F)c1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-trifluoromethoxy-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.8).