Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](N)[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-:30].[Cs+].II.N(OCCC(C)C)=O>C(COC)OC.[Cu](I)I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:24][C:25]([F:28])([F:27])[F:26])[C:15]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([I:30])[N:18]=3)=[CH:16][C:10]=2[C:9]1=[O:29])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2c(cc(-c3ccnc(N)n3)n2CC(F)(F)F)C1=O
Reactant: [I-]
Agent: I[Cu]I
Agent: CC(C)CCON=O
Agent: II
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCc2c(cc(-c3ccnc(I)n3)n2CC(F)(F)F)C1=O
Yield: 35 %

Procedure:
To a well stirred suspension of 2-(2-amino-pyrimidin-4-yl)-4-oxo-1-(2,2,2-trifluoro-ethyl)-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester prepared as reported in Example 9 (180 mg, 0.43 mmol) in dimethoxyethane (10 mL) under N2, cesium iodide (170 mg, 0.65 mmol), bisublimated iodine (83 mg, 0.33 mmol), copper iodide (37 mg, 0.20 mmol) and isopentyl nitrite (0.13 mL, 0.98 mmol) were added in sequence. The reaction mixture was stirred vigorously at 80° C. for 4 hours. After cooling in a ice-water bath, the solid was filtered off. The filtrate was diluted with dichloromethane (100 mL), washed with 30% ammonium hydroxide (50 mL), sodium thiosulphate (50 mL), brine (50 mL), dried over anhydrous Na2SO4 and concentrated. Purification by flash chromatography on silica gel (eluant: dichloromethane/hexane 1/1) afforded 80 mg (35%) of the title compound as solid.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:6]1[CH:7]=[C:8]([CH:12]=[CH:13][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[C:9]([OH:11])=[O:10])([O-:16])=[O:15]
Reactant: CC(=O)Nc1ccc(C(=O)O)cc1
Reactant: O=[N+]([O-])O
Product: CC(=O)Nc1ccc(C(=O)O)cc1[N+](=O)[O-]

Procedure:
In this reaction sequence, partially described by Kumar et al., J. Med. Chem., 27, pp. 1083-1089 (1984), 4-acetamidobenzoic acid is utilized as a starting material and is nitrated using, for instance, fuming nitric acid at about -10° to about 10° C. for 1-4 hours to afford 3-nitro-4-acetamidobenzoic acid. This compound is then reacted with thionyl chloride in a non-polar, aprotic solvent to afford the corresponding 3-nitro-4-acetamidobenzoyl chloride, which is then further reacted with the R'1 --H amine wherein R'1 is an amino group or a --NR4R5 group, to afford the 3-nitro-4-acetamino compound of formula V.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[N:6][CH:7]=1.[C:13](Cl)(Cl)=[S:14].C(=O)([O-])[O-].[K+].[K+]>O.C(Cl)(Cl)Cl>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:4]=[CH:3][C:2]([N:1]=[C:13]=[S:14])=[CH:7][N:6]=1)[CH3:10]
Reactant: CCN(CC)c1ccc(N)cn1
Reactant: S=C(Cl)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCN(CC)c1ccc(N=C=S)cn1
Yield: 19.1 %

Procedure:
Using procedures similar to those employed in Step A of Example 8, the reaction of i5.9 g (0.096 mole of 5-amino-2-diethylaminopyridine with 22.2 g (0.193 mole) of thiophosgene and 5.0 g (0.036 mole) of potassium carbonate in 50 ml of water and 150 ml of chloroform yielded 3.8 g of (2-diethylaminopyridin-5-yl) isothiocyanate as a solid. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30]O)[CH:21]=1)=[N:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:10][CH:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(C)(O)[C:56]#[N:57].N(C(OC(C)C)=O)=NC(OC(C)C)=O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:34])[N:4]=[C:5]([S:32][CH3:33])[C:6]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[C:23]([O:28][CH3:29])=[C:22]([CH2:30][C:56]#[N:57])[CH:21]=1)=[N:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[CH:12][CH:13]=1
Reactant: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CO)c(OC)c(OC)c1
Reactant: CC(C)(O)C#N
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)N=C(SC)C(=Nc1ccc(-c2noc(C)n2)cc1)c1cc(CC#N)c(OC)c(OC)c1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
After dissolving 194 mg of [2-(3-hydroxymethyl-4,5-dimethoxyphenyl)-2-[4-(5-methyl-[1,2,4]oxadiazol-3-yl)phenylimino]-1-methylsulfanylethylidene]carbamic acid methyl ester (Example (22b)), 315 mg of triphenylphosphine and 0.11 ml of acetone cyanohydrin in 4 ml of THF under a nitrogen atmosphere, the solution was cooled to −78° C. Next, 0.23 ml of diisopropyl azodicarboxylate (hereinafter, “DIAD”) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate-heptane) to give the title compound (197 mg, isomeric mixture) as a light yellow solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][C:6]([OH:8])=O)(=[O:3])[CH3:2].CN1CCOCC1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:38]([O:40][C:41](=[O:65])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[C:55](=[O:56])[CH:54]=[CH:53][C:52]([C:57]3[CH:62]=[CH:61][C:60]([CH2:63][NH2:64])=[CH:59][CH:58]=3)=[N:51]2)[CH:44]=1)[CH3:39]>CN(C=O)C>[CH2:38]([O:40][C:41](=[O:65])[NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49][N:50]2[C:55](=[O:56])[CH:54]=[CH:53][C:52]([C:57]3[CH:58]=[CH:59][C:60]([CH2:63][NH:64][C:6](=[O:8])[CH2:5][NH:4][C:1](=[O:3])[CH3:2])=[CH:61][CH:62]=3)=[N:51]2)[CH:44]=1)[CH3:39]
Reactant: CC(=O)NCC(=O)O
Reactant: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CN)cc3)ccc2=O)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCOC(=O)Nc1cccc(Cn2nc(-c3ccc(CNC(=O)CNC(C)=O)cc3)ccc2=O)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
61 mg (0.52 mmol) of N-acetylglycine are suspended in 2 ml of DMF, 106 μl (0.95 mmol) of 4-methylmorpholine, 66 mg (0.47 mmol) of 1-hydroxybenzotriazole and 184 mg (0.95 mmol) of N-(3-dimethylamino-propyl)-N′-ethylcarbodiimide hydrochloride are added. The reaction mixture is stirred at room temperature for 10 min, 180 mg (0.48 mmol) of ethyl{3-[3-(4-aminomethylphenyl)-6-oxo-6H-pyridazin-1-ylmethyl]-phenyl}carbamate are subsequently added, and the mixture is stirred at room temperature for 24 h.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14]O)=[CH:9][CH:8]=1)([CH3:6])[CH3:5].S(Cl)([Cl:19])=O.ClCCl>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]([C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][Cl:19])=[CH:9][CH:8]=1)([CH3:6])[CH3:5]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)C(C)(C)c1ccc(CCO)cc1
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)c1ccc(CCCl)cc1
Yield: 92.3 %

Procedure:
In a reaction vessel, 2-[4-(2-hydroxy-ethyl)-phenyl]-2-methyl-propionic acid methylester (1 g) prepared in the Examples 1-3, thionyl chloride (2.7 g) and dichloromethane (15 mL) were introduced, and the mixture was reacted at room temperature for 2 hours. Toluene (30 mL) was added, the mixture was condensed under reduced pressure, and the solvent was removed. Dichloromethane (50 mL) and sodium hydrogen carbonate solution (30 mL) were added thereto, and the mixture was stirred to separate layers. The separated organic layer was dehydrated with Na2SO4, and then condensed by filtration to obtain 2-[4-(2-chloro-ethyl)-phenyl]-2-methyl-propionic acid methylester (1.0 g, yield 92%).
Reaction SMILES: [CH2:1]([C@:8]1([C:21](=[O:23])[NH2:22])[C:14]([CH3:16])([CH3:15])[S@@:13](=[O:17])[C@H:12]2[N:9]1[C:10](=[O:20])[C:11]2(Br)[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl>O>[CH2:1]([C@:8]1([C:21](=[O:23])[NH2:22])[C:14]([CH3:16])([CH3:15])[S@:13](=[O:17])[C@H:12]2[N:9]1[C:10](=[O:20])[C@@H:11]2[Br:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1(C)[S@@](=O)[C@H]2N(C(=O)C2(Br)Br)[C@@]1(Cc1ccccc1)C(N)=O
Solvent: ClCCl
Solvent: O
Product: CC1(C)[S@](=O)[C@@H]2[C@@H](Br)C(=O)N2[C@@]1(Cc1ccccc1)C(N)=O
Reaction time: 0.25 h
Yield: 81 %

Procedure:
To a cold (0° C.) solution of (2S,4R,5R)-2-benzyl-carbamoyl-6,6-dibromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-4-oxide (1160 mg, 2.5 mmole) in dry methylene chloride (30 ml) triphenyl phosphine (837 mg, 5 mmole) was added and it was stirred for 15 minutes. The reaction mixture was treated with water and the layers were separated. The organic layer was washed with water, then with a saturated sodium hydrogen carbonate solution and again with water. The evaporation of dry (Na2SO4) organic layer under reduced pressure gave a foamy residue, which after chromatography on silica gel gave (2S,4S,5R,6S)-2-benzyl-carbamoyl-6-bromo-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-4-oxide (780 mg, 81.0%). Crystallization from diethyl ether gave the product as a white crystalline powder.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[Cl:5][C:6]1[CH:7]=[CH:8][C:9]2[N:18]([C:19]([C:21]3[CH:26]=[CH:25][C:24]([CH2:27][CH2:28][C:29]([N:31]4[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]4)=[O:30])=[C:23]([CH3:37])[CH:22]=3)=[O:20])[CH2:17][C:16]3[CH:15]=[N:14][N:13]([CH3:38])[C:12]=3[NH:11][C:10]=2[CH:39]=1>ClCCl.C(N(CC)CC)C>[C:1]([N:34]1[CH2:33][CH2:32][N:31]([C:29](=[O:30])[CH2:28][CH2:27][C:24]2[CH:25]=[CH:26][C:21]([C:19]([N:18]3[CH2:17][C:16]4[CH:15]=[N:14][N:13]([CH3:38])[C:12]=4[NH:11][C:10]4[CH:39]=[C:6]([Cl:5])[CH:7]=[CH:8][C:9]3=4)=[O:20])=[CH:22][C:23]=2[CH3:37])[CH2:36][CH2:35]1)(=[O:3])[CH3:2]
Reactant: Cc1cc(C(=O)N2Cc3cnn(C)c3Nc3cc(Cl)ccc32)ccc1CCC(=O)N1CCNCC1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCN(C(=O)CCc2ccc(C(=O)N3Cc4cnn(C)c4Nc4cc(Cl)ccc43)cc2C)CC1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of acetyl chloride (0.39 mg, 0.005 mmol) in dichloromethane (0.05 ml) was added to a solution of 3-[4-(6-chloro-3-methyl-4,10-dihydro-3H-2,3,4,9-tetraaza-benzo[f]azulene-9-carbonyl)-2-methyl-phenyl]-1-piperazin-1-yl-propan-1-one (2.47 mg, 0.005 mmol) in di-chloromethane (0.05 ml) and triethylamine (0.0035 ml). The mixture was stirred at room temperature for 20 h then solvents were removed in vacuo to yield the title compound. (ESI)+: [M+H]+=535.5
Reaction SMILES: [B-](F)(F)(F)F.[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+]([F:21])(CC2)C1.[CH3:22][O:23][C:24]1[CH:48]=[CH:47][C:27]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[N:35]=[C:36]([NH:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=4)[S:37][CH:38]=3)[CH:31]=[N:30]2)=[CH:26][CH:25]=1.CC1C=CC=C(C)N=1>CN(C=O)C>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][C:27]([CH2:28][N:29]2[CH:33]=[C:32]([C:34]3[N:35]=[C:36]([NH:39][C:40]4[CH:45]=[CH:44][C:43]([F:46])=[CH:42][N:41]=4)[S:37][C:38]=3[F:21])[CH:31]=[N:30]2)=[CH:47][CH:48]=1
Reactant: COc1ccc(Cn2cc(-c3csc(Nc4ccc(F)cn4)n3)cn2)cc1
Reactant: F[N+]12CC[N+](CCl)(CC1)CC2
Agent: F[B-](F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: CN(C)C=O
Product: COc1ccc(Cn2cc(-c3nc(Nc4ccc(F)cn4)sc3F)cn2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
According to Scheme 7 Step 1: Selectfluor (3.28 mmol, 1.16 g) was added portionwise to a solution of N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)thiazol-2-yl)-5-fluoropyridin-2-amine (2.18 mmol, 833 mg) and of 2,6-dimethylpyridine (2.18 mmol, 0.25 mL) in DMF (25 mL) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The reaction was quenched with water (70 mL). A precipitate was formed, was filtered and was dried to yield N-(4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-5-fluorothiazol-2-yl)-5-fluoropyridin-2-amine (1.85 mmol, 739 mg, 85%).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[CH:4][C:5]2[CH2:6][C:7](=[O:24])[NH:8][C:9]3[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][CH2:19][CH2:20][N:21]([CH3:23])[CH3:22])=[CH:13][C:10]=3[C:11]=2[N:12]=1.Br[C:26]1[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=1.C(O)(C)(C)C.CC(C)([O-])C.[K+]>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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.O>[Cl:17][C:15]1[C:14]([CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[CH3:23])=[CH:13][C:10]2[C:11]3[N:12]=[C:2]([NH:1][C:26]4[C:27]([CH3:32])=[N:28][CH:29]=[CH:30][CH:31]=4)[N:3]=[CH:4][C:5]=3[CH2:6][C:7](=[O:24])[NH:8][C:9]=2[CH:16]=1
Reactant: Cc1ncccc1Br
Reactant: CN(C)CCCc1cc2c(cc1Cl)NC(=O)Cc1cnc(N)nc1-2
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: O
Solvent: CC(C)(C)O
Product: Cc1ncccc1Nc1ncc2c(n1)-c1cc(CCCN(C)C)c(Cl)cc1NC(=O)C2
Temperature: 150 °C
Yield: 72.4 %

Procedure:
To a mixture of 2-amino-9-chloro-10-[3-(dimethylamino)propyl]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (0.10 g, 0.29 mmol), Xphos (8.6 mg, 0.018 mmol), tris(dibenzylideneacetone)dipalladium (4.7 mg, 0.0052 mmol) and 3-bromo-2-methylpyridine (50 mg, 0.29 mmol) in a dry, sealed microwave tube under an atmosphere of argon was added tert-butyl alcohol (1.0 mL) followed by a 1.0 M solution of potassium tert-butoxide in tert-butyl alcohol (0.58 mL, 0.58 mmol). The mixture was heated under microwave irradiation at 150° C. for 30 min. The reaction mixture was allowed to cool to rt and then added to water (50 mL). The precipitated solid was collected via suction filtration, washed with water, and dried to produce 9-chloro-10-[3-(dimethylamino)propyl]-2-[(2-methylpyridin-3-yl)amino]-5,7-dihydro-6H-pyrimido[5,4-d][1]benzazepin-6-one (95 mg, 0.21 mmol, 75%) as a brown solid. LCMS (FA): m/z=453.5 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH3:14][NH:15][CH2:16][CH3:17].C(Cl)(Cl)Cl.C(N(CC)CC)C>O>[CH2:16]([N:15]([CH3:14])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])[CH3:17]
Reactant: CCNC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCN(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 5 h
Yield: 116.2 %

Procedure:
To a mixture of 2-nitrobenzenesulfonyl chloride (5.09 g), N-methylethylamine (1.35 g) and chloroform (100 mL), triethylamine (4.11 mL) was added under ice cooling and stirred at room temperature for 5 hours. The reaction mixture was diluted with water and extracted with chloroform. The organic layer was washed sequentially with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give N-ethyl-N-methyl-2-nitrobenzenesulfonamide (6.48 g) as a brown oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[CH2:18][CH:14]2[CH:13]=[CH:12]3)[CH:9]1[C:19](C)(C)[O:20][SiH2]C(C)(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O)(=O)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C:16](=[O:17])[CH:15]2[CH:10]([CH:11]3[CH2:18][CH:14]2[CH:13]=[CH:12]3)[CH:9]1[CH2:19][OH:20])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1C(C)(C)O[SiH2]C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C(=O)C2C3C=CC(C3)C2C1CO
Reaction time: 16 h
Yield: 80 %

Procedure:
A solution of 28 (3.2 g; 8.1 mmol) in 60 mL of THF and acetic acid (1.16 mL; 20.3 mmol) was treated with TBAF 1M in THF. The reaction mixture was stirred for 16 h then was diluted with CH2Cl2 (120 mL) and washed with water (75 mL). The organic layer was dried with sodium sulfate and concentrated in vacuo to a yellow oil. Flash chromatography (60% EtOAc/40% hexanes) afforded 1.81 g (81%) of the desired product 29. 1H NMR (CDCl3) δ 6.2 (bs, 1H), 6.1 (bs, 1H), 3.8 (d, 1H), 3.6 (m, 2H), 3.3 (s, 1H), 3.15 (dd, 1H), 3.1 (s, 1H), 2.5 (dd, 1H), 1.5 (app.t, 3H), 1.35 (s, 9H) ppm.
Reaction SMILES: C[CH2:2][CH:3]([S:14]([O-:18])=[N:15]C#N)[C:4]1[CH:5]=[N:6][C:7]([C:10]([F:13])([F:12])[F:11])=[CH:8][CH:9]=1.F[C:20](F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl>[CH3:20][S:14]([CH:3]([C:4]1[CH:9]=[CH:8][C:7]([C:10]([F:13])([F:12])[F:11])=[N:6][CH:5]=1)[CH3:2])(=[NH:15])=[O:18]
Reactant: CCC(c1ccc(C(F)(F)F)nc1)S([O-])=NC#N
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CC(c1ccc(C(F)(F)F)nc1)S(C)(=N)=O
Temperature: 25 °C
Yield: 77.1 %

Procedure:
To a stirred solution of methyl(oxido){1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}-λ4-sulfanylidenecyanamide (5 g, 18 mmol) in CH2Cl2 (300 mL) at 0° C. was added trifluoroacetic anhydride (7.5 mL, 54 mmol). The mixture was allowed to react at 25° C. until the starting material was fully consumed. The reaction mixture was concentrated in vacuo, dissolved in methanol (125 mL) and treated with potassium carbonate (12.5 g, 90 mmol). The mixture was allowed to stir at 25° C. until the starting material was consumed. The crude reaction mixture was filtered, concentrated and purified by chromatography (acetone-hexanes) to furnish 5-[1-(methylsulfonimidoyl)ethyl]-2-(trifluoromethyl)pyridine as a white solid (3.5 g, 77%): ESIMS m/z 253 ([M+H]+).
Reaction SMILES: Cl[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:19]#[N:20])[C:8]([CH3:18])=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:10]=2[F:11])[N:6]=1.C(N(C(C)C)CC)(C)C.[CH3:30][NH:31][CH2:32][CH2:33][OH:34]>ClCCl>[F:11][C:10]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:8]([CH3:18])[C:7]([C:19]#[N:20])=[C:5]2[C:4]=1[O:3][C:2]([N:31]([CH2:32][CH2:33][OH:34])[CH3:30])=[N:6]2
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(Cl)nc2c1C#N
Reactant: CNCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(-c2ccccc2)c(F)c2oc(N(C)CCO)nc2c1C#N
Yield: 92.2 %

Procedure:
2-Chloro-7-fluoro-5-methyl-6-phenyl-1,3-benzoxazole-4-cabonitrile (I-130) (0.20 g, 0.70 mmol) was dissolved in dichloromethane (10 ml), and diisopropylethylamine (0.13 ml, 0.76 mmol) and N-methylethanolamine (62.0 μl, 0.78 mmol) were added. After heating under reflux for 3 hours, N-methylethanolamine (62.0 μl, 0.78 mmol) was added. After heated under reflux for 3 hours, this was diluted with dichloromethane. After washing with water and drying over anhydrous sodium sulfate, the solvent was evaporated away under reduced pressure, and the resulting residue was purified by silica gel column chromatography (dichloromethane:methanol=40:1) to obtain a pale yellow oil (0.21 g, 93%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[F:9].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].C(=O)([O-])[O-].[K+].[K+]>CC(=O)CC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH3:11])=[CH:4][C:3]=1[F:9]
Reactant: Oc1ccc(Br)c(F)c1
Reactant: CCCCCCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCCCCCCCCCCCCOc1ccc(Br)c(F)c1

Procedure:
This was prepared using a similar method to that described for compound 3. Quantities: compound 1 (4.02 g, 21.1 mmol), 1-bromotridecane (6.11 g, 23.2 mmol), potassium carbonate (5.22 g, 37.8 mmol) and butanone (115 ml).
Reaction SMILES: [O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[N:10]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([O:22]CC)=[O:21].[ClH:25]>>[ClH:25].[O:1]=[C:2]1[CH:6]([CH2:7][CH2:8][C:9]2[CH:18]=[CH:17][C:16]3[CH2:15][CH2:14][CH2:13][NH:12][C:11]=3[N:10]=2)[CH2:5][CH2:4][N:3]1[CH2:19][C:20]([OH:22])=[O:21]
Reactant: CCOC(=O)CN1CCC(CCc2ccc3c(n2)NCCC3)C1=O
Agent: Cl
Product: O=C(O)CN1CCC(CCc2ccc3c(n2)NCCC3)C1=O
Temperature: 50 °C

Procedure:
A stirred mixture of 2-7 (0.45 g, 1.4 mmol) and 6N HCl (10 mL) was heated at 50° C. for 1 h, followed by concentration to give 2-8 as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[C:8]1[S:9][CH:10]=[C:11]([C:13]2[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=2)[C:16]([OH:18])=O)[N:12]=1.S(Cl)(Cl)=O.[CH2:26]([NH2:28])[CH3:27]>>[CH2:26]([NH:28][C:16](=[O:18])[C:15]1[CH:19]=[CH:20][CH:21]=[C:13]([C:11]2[N:12]=[C:8]([C:3]3[CH:4]=[N:5][CH:6]=[CH:7][C:2]=3[CH3:1])[S:9][CH:10]=2)[CH:14]=1)[CH3:27]
Reactant: CCN
Reactant: Cc1ccncc1-c1nc(-c2cccc(C(=O)O)c2)cs1
Solvent: O=S(Cl)Cl
Product: CCNC(=O)c1cccc(-c2csc(-c3cnccc3C)n2)c1

Procedure:
By the reaction in the same manner as in Example 60 using 3-[2-(4-methylpyridin-3-yl)-1,3-thiazol-4-yl]benzoic acid (259 mg), thionyl chloride (0.09 ml) and aqueous ethylamine solution (70%, 5 ml), the title compound (215 mg) was obtained as pale-brown powder crystals.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH2:33])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:35]([S:37](Cl)(=[O:39])=[O:38])[CH3:36]>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[C:20]([O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[O:28][CH3:29])=[C:19]([O:30][CH2:31][CH2:32][NH:33][S:37]([CH2:35][CH3:36])(=[O:39])=[O:38])[N:18]=[C:17]([CH3:34])[N:16]=2)(=[O:12])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)nc(C)nc1OCCN
Product: CCS(=O)(=O)NCCOc1nc(C)nc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1Oc1ccccc1OC

Procedure:
According to the procedure described in Example 4a) 103 mg 4-tert.-butyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide was reacted with ethanesulfonylchloride to give 92 mg 4-tert.-butyl-N-[6-(2-(ethanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-methyl-4-pyrimidinyl]-benzene sulfonamide. LC-MS: tR=5.12 min, [M+1]+=579.60, [M−1]−=577.72.
Reaction SMILES: [C:1]([NH:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])(=[S:3])[CH3:2].[C:15]([O-])([O-])=O.[K+].[K+].IC>C(#N)C>[CH3:15][S:3][C:1](=[N:4][C:5](=[O:14])[C:6]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:7]=1[Cl:13])[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CC(=S)NC(=O)c1ccc(Cl)cc1Cl
Agent: [K+]
Solvent: CI
Solvent: CC#N
Product: CSC(C)=NC(=O)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.8 %

Procedure:
A mixture of N-(thioacetyl)-2,4-dichlorobenzamide (400 mg, 1.6 mmol) and K2CO3 (445 mg, 3.22 mmol) in anhydrous acetonitrile (20 mL) was stirred at ambient temperature. Iodomethane (458 mg, 0.2 mL, 3.22 mmol) was added and the reaction mixture was then stirred for 2.5 h. Solvent was removed in vacuo and the residue was partitioned between ether and water. The combined organic layers were dried over MgSO4, filtered and concentrated in vacuo to give an oil (406 mg): NMR (CDCl3, 300 MHz): δ 7.86 (d, 1H, J=8), 7.47 (d, 1H, J=2), 7.32 (dd, 1H, J=8, 2), 2.40 (s, 3H), 2.29 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([C@@H:15]([N:17]3[CH2:22][CH2:21][C@:20]([CH2:29][C:30]([OH:33])([CH3:32])[CH3:31])([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:19][C:18]3=[O:34])[CH3:16])=[CH:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[NH2:8].[C:35](O)(=O)[CH3:36]>>[OH:33][C:30]([CH3:31])([CH3:32])[CH2:29][C@@:20]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:19][C:18](=[O:34])[N:17]([C@H:15]([C:12]2[CH:11]=[CH:10][C:9]([C:4]3[CH:5]=[CH:6][C:7]4[N:8]=[C:35]([CH3:36])[NH:1][C:2]=4[CH:3]=3)=[CH:14][CH:13]=2)[CH3:16])[CH2:22][CH2:21]1
Reactant: CC(=O)O
Reactant: C[C@@H](c1ccc(-c2ccc(N)c(N)c2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nc2ccc(-c3ccc([C@H](C)N4CC[C@](CC(C)(C)O)(c5ccccc5)OC4=O)cc3)cc2[nH]1
Temperature: 150 °C
Reaction time: 0.5 h

Procedure:
3-[(S)-1-(3′,4′-Diamino-biphenyl-4-yl)-ethyl]-(S)-6-(2-hydroxy-2-methyl-propyl)-6-phenyl-[1,3]oxazinan-2-one (120 mg) taken up in acetic acid (2 mL) was stirred under microwave irradiation at 150° C. for 30 min. After cooling to ambient temperature, the mixture was concentrated under reduced pressure and the residue was purified by HPLC on reversed phase (MeCN/H2O) to afford the title compound.