Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH:12]=O)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[F:22][C:23]([F:37])([F:36])[C:24]1[CH:25]=[C:26]([CH:29]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:31]=1)[CH2:27][NH2:28].C(O)C.[BH4-].[Na+]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1([C:10]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][C:11]=2[CH2:12][NH:28][CH2:27][C:26]2[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=[C:24]([C:23]([F:22])([F:36])[F:37])[CH:25]=2)[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: COC1(c2ccc(C(F)(F)F)cc2C=O)CCCCCC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC1(c2ccc(C(F)(F)F)cc2CNCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)CCCCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 2-(1-methoxycycloheptyl)-5-(trifluoromethyl)benzaldehyde (167 mg; 0.556 mmol) and 3,5-bistrifluoromethyl benzylamine (150 mg; 0.616 mmol) in toluene (4 mL) was heated at reflux for 16 hours, after which solvent was removed. Ethanol (4 mL) and sodium borohydride (31 mg; 0.819 mmol) were added to the residue. The resulting mixture was stirred at room temperature for 16 hours. Solvent was evaporated under reduced pressure. The residue was taken up in ethyl acetate and washed twice with water and dried over sodium sulfate and concentrated under reduced pressure. The residue was purified over a 12 g RediSep column (Teledyne Isco Inc., Lincoln Nebr.) (eluted with 5-25% ethyl acetate in heptane) to yield 194 mg (66.1% for 2 steps) of the title compound as a gum. MS (ES+): Calc: 527.4 Found: 528.4 (M+H).
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:4]([CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([CH2:17][C@H:18]([NH:31][C:32](=[O:44])[C:33]4[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[C:35]([Cl:43])[CH:34]=4)[CH2:19][N:20]4C(=O)C5C(=CC=CC=5)C4=O)=[CH:13][CH:12]=3)[N:10]=2)[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[NH2:20][CH2:19][C@@H:18]([NH:31][C:32](=[O:44])[C:33]1[CH:38]=[CH:37][C:36]([O:39][CH:40]([CH3:42])[CH3:41])=[C:35]([Cl:43])[CH:34]=1)[CH2:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:3]3[C:2]([Br:1])=[CH:7][CH:6]=[CH:5][N:4]3[CH:8]=2)=[CH:12][CH:13]=1
Reactant: CC(C)Oc1ccc(C(=O)N[C@@H](Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)CN2C(=O)c3ccccc3C2=O)cc1Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1ccc(C(=O)N[C@H](CN)Cc2ccc(-c3cn4cccc(Br)c4n3)cc2)cc1Cl
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of N-{(1S)-2-[4-(8-bromoimidazo[1,2-a]pyridin-2-yl)phenyl]-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]ethyl}-3-chloro-4-[(1-methylethyl)oxy]benzamide (1.5 mmol) in ethanol (10 mL) was added hydrazine monohydrate (7.6 mmol). The reaction stirred for 18 h at 50° C. upon which a white precipitate formed and was filtered. The filtrate was concentrated in vacuo. The resultant light yellow solid was used directly in the next reaction without further purification. ESMS [M+H]+: 533.2
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:12][CH2:11][CH2:10][C:9]2[C:8]([C:13]3[N:17]=[C:16]([C:18]4[CH:19]=[CH:20][C:21]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH:25]=4)[C:23]#[N:24])[O:15][N:14]=3)=[CH:7][CH:6]=[CH:5][C:4]1=2.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>C(Cl)Cl>[C:23]([C:22]1[CH:25]=[C:18]([C:16]2[O:15][N:14]=[C:13]([C:8]3[CH:7]=[CH:6][CH:5]=[C:4]4[C:9]=3[CH2:10][CH2:11][CH2:12][C@H:3]4[NH:2][S:31]([CH3:30])(=[O:33])=[O:32])[N:17]=2)[CH:19]=[CH:20][C:21]=1[O:26][CH:27]([CH3:29])[CH3:28])#[N:24]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4N)no2)cc1C#N
Agent: Cl
Solvent: ClCCl
Product: CC(C)Oc1ccc(-c2nc(-c3cccc4c3CCC[C@H]4NS(C)(=O)=O)no2)cc1C#N
Temperature: 25 °C
Yield: 56.6 %

Procedure:
Prepared using General Procedure 6: To a stirring solution of (R)-5-(3-(5-amino-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile hydrochloride 3 (20 mg, 0.05 mmol) in DCM (1 mL) at 0° C. was added TEA (20 μL, 0.15 mmol) and methanesulfonyl chloride (4.5 μL, 0.06 mmol). The mixture was allowed to warm to room temperature over 2 h. The solvent was evaporated and crude mixture was purified by preparative HPLC to afford 12.8 mg (58%) of (R)-N-(5-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-1,2,3,4-tetrahydronaphthalen-1-yl)methanesulfonamide 28. LCMS-ESI (m/z) calculated for C23H24N4O4S: 452.5; found 453.1 [M+H]+, tR=3.68 min. 1H NMR (400 MHz, CDCl3) δ 8.40 (t, J=3.5 Hz, 1H), 8.32 (dd, J=8.9, 2.2 Hz, 1H), 7.96 (dd, J=7.7, 1.1 Hz, 1H), 7.67 (d, J=7.7 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.16-7.07 (m, 1H), 4.88-4.70 (m, 1H), 4.54 (d, J=8.4 Hz, 1H), 3.19 (dt, J=18.0, 5.9 Hz, 1H), 3.10 (d, J=5.0 Hz, 3H), 3.09-2.95 (m, 1H), 2.14 (qt, J=14.5, 7.3 Hz, 1H), 2.06-1.83 (m, 3H), 1.47 (t, J=5.5 Hz, 6H).
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:21]=[CH:20][C:11]([CH:12]=[C:13]2[S:17][C:16](=[O:18])[NH:15][C:14]2=[O:19])=[CH:10][CH:9]=1.[NH2:22][CH2:23][C@H:24]([OH:33])[CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[OH:33][C@H:24]([CH2:25][O:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:23][NH:22][CH:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:21]=[CH:20][C:11]([CH:12]=[C:13]3[S:17][C:16](=[O:18])[NH:15][C:14]3=[O:19])=[CH:10][CH:9]=2)[CH2:2][CH2:7]1
Reactant: NC[C@H](O)COc1ccccc1
Reactant: O=C1NC(=O)C(=Cc2ccc(N3CCCCC3=O)cc2)S1
Product: O=C1NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 5-[4-(4-oxo-piperidine-1-yl)-benzylidene]-thiazolidine-2,4-dione (which was obtained in Example 36) and (2S)-1-amino-3-phenoxy-propan-2-ol (which was obtained in Example 3) according to the procedure of Example 73 as a pale yellowish solid; mp 208-210° C.; MS (ES) m/z: 454.0 (MH+); HRMS Calcd. for C24H27N3O4S (M+): 453.1723. Found: 453.1710.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([OH:21])[CH2:14][CH:15]2[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:38]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:32][C:31]2[C:26]1=[CH:27][CH:28]=[CH:29][CH:30]=2)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.N1C=CC=CC=1.Cl.[N:62]1([CH2:67][C:68](O)=[O:69])[CH:66]=[CH:65][N:64]=[CH:63]1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH:13]([O:21][C:68](=[O:69])[CH2:67][N:62]2[CH:66]=[CH:65][N:64]=[CH:63]2)[CH2:14][CH:15]2[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]2)=[CH:7][C:6]=1[NH:22][C:23](=[O:39])[CH2:24][CH:25]1[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:31]=2[O:32][C:33]2[C:38]1=[CH:37][CH:36]=[CH:35][CH:34]=2)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(O)Cn1ccnc1
Reactant: CC(C)(C)c1ccc(CCC(O)CC2CCCCC2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(CCC(CC2CCCCC2)OC(=O)Cn2ccnc2)cc1NC(=O)CC1c2ccccc2Oc2ccccc21
Reaction time: 72 h

Procedure:
A suspension comprising 422 mg (0.80 mmol) of N-[2-t-butyl-5-(4-cyclohexyl-3-hydroxybutyl)phenyl]-2-(9H-xanthen-9-yl)acetamide (prepared as described in Example 12), 311 mg (1.51 mmol) of dicyclohexyl-carbodiimide, 142 μl (1.76 mmol) of pyridine, 20 mg (0.16 mmol) of 4-(N,N-dimethylamino)pyridine and 156 mg (0.96 mmol) of 2-(1-imidazolyl)acetic acid hydrochloride in 10 ml of methylene chloride was stirred for 3 days. At the end of this time, insoluble materials were filtered off, and the filtrate was washed with water and with a saturated aqueous solution of sodium chloride, in that order, after which it was dried over anhydrous sodium sulfate. The solvent was then removed by distillation under reduced pressure. The resulting residue was purified by column chromatography through 75 g of silica gel, using a 1: 4 by volume mixture of ethyl acetate and hexane as the eluent, to give 507 mg (a quantitative yield) of the title compound as a colorless foam-like material.
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]2[C@H:13]([OH:16])[CH2:14][CH2:15][C@@H:10]2[CH2:9]1)C1C=CC=CC=1.[H][H]>C(O)C>[CH2:9]1[C@H:10]2[CH2:15][CH2:14][C@@H:13]([OH:16])[C@H:11]2[CH2:12][NH:8]1
Reactant: O[C@@H]1CC[C@@H]2CN(Cc3ccccc3)C[C@@H]21
Reactant: [H][H]
Solvent: CCO
Product: O[C@@H]1CC[C@@H]2CNC[C@@H]21

Procedure:
(3aR,4R,6aS)-2-Benzyloctahydrocyclopenta[c]pyrrol-4-ol (2.88 g, 13.25 mmol) from Step 1 and ethanol (40 mL) were added to 20% Pd(OH)2—C, wet (0.576 g, 4.10 mmol) in a 250 mL stainless steel pressure bottle and stirred for 2 hours under 30 psi hydrogen gas at 50° C. The mixture was filtered through a nylon membrane and the solvent was removed in vacuo to give (3aR,4R,6aS)-octahydrocyclopenta[c]pyrrol-4-ol: 1H NMR (500 MHz, pyridine-d5) δ ppm 4.82 (s, 4H), 4.37 (dd, J=10.5, 4.8, 1H), 3.52 (dd, J=10.8, 1.7, 1H), 2.96-2.86 (m, 1H), 2.76 (dd, J=10.8, 6.9, 1H), 2.71 (dd, J=10.8, 1.8, 1H), 2.56-2.45 (m, 2H), 1.89 (td, J=11.7, 5.3, 1H), 1.80 (ddd, J=12.5, 10.3, 6.8, 1H), 1.66-1.58 (m, 1H), 1.50-1.42 (m, 1H); MS (ESI+) m/z 128 (M+H)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]([CH3:26])([CH3:25])[CH3:24])=[CH:19][CH:18]=3)[N:14]=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][C:28]=3[OH:34])[N:12]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Cl[CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46]>CC(C)=O>[C:23]([C:20]1[CH:21]=[CH:22][C:17]([C:15]2[N:16]=[C:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=3)[N:12]=[C:13]([C:27]3[CH:32]=[CH:31][C:30]([O:33][CH2:44][C:45]([O:47][CH2:48][CH3:49])=[O:46])=[CH:29][C:28]=3[OH:34])[N:14]=2)=[CH:18][CH:19]=1)([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)c1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(O)cc3O)n2)cc1
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(-c2nc(-c3ccc(C(C)(C)C)cc3)nc(-c3ccc(C(C)(C)C)cc3)n2)c(O)c1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a stirred mixture of 14 g of 2,4-bis(4-tert-butylphenyl)-6-(2,4-dihydroxyphenyl)-1,3,5-triazine, 10.8 g of anhydrous potassium carbonate, 0.47 g of potassium iodide, and 90 mL of acetone was added 3.7 mL (4,2 g) of ethyl chloroacetate. The mixture was stirred at reflux for 3 hr, and then cooled to room temperature. The solids were removed by filtration and washed with methylene chloride. The product was crystallized from the combined filtrate, washed with cold acetone, and dried in vacuo to give 12.5 g of 2,4-bis(4-tert-butylphenyl)-6-(2-hydroxy-4-ethoxycarbonylmethoxyphenyl)-1,3,5-triazine as a near white powder. The structure was verified by 1H-NMR spectroscopy.
Reaction SMILES: [Cl:1][C:2]1[CH:34]=[CH:33][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH:12]=O)[C:9]([CH2:14][N:15]3[CH2:20][CH2:19][C:18]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)=[N:8]2)=[CH:4][CH:3]=1.[OH:35][CH2:36][CH2:37][N:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C)C=O.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH:11]=[C:10]([CH2:12][N:41]3[CH2:42][CH2:43][N:38]([CH2:37][CH2:36][OH:35])[CH2:39][CH2:40]3)[C:9]([CH2:14][N:15]3[CH2:16][CH2:17][C:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:19][CH2:20]3)=[N:8]2)=[CH:33][CH:34]=1
Reactant: O=Cc1cn(Cc2ccc(Cl)cc2)nc1CN1CCC(c2ccccc2)(c2ccccc2)CC1
Reactant: OCCN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: OCCN1CCN(Cc2cn(Cc3ccc(Cl)cc3)nc2CN2CCC(c3ccccc3)(c3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 15 (0.001 g) was dissolved in N,N-dimethylformamide (0.2 ml), N-(2-hydroxyethyl)piperazine (0.0008 g) and 1 drop of acetic acid were added. After 1 hour a solution of sodium triacetoxyborohydride (0.0013 g) in N,N-dimethylformamide (0.1 ml) was added and the solution shaken at room temperature for 24 hours. The solvent was removed to give the product as an oil.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@H:6]([S:7][C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:5][C:4]1=[O:27].C(N1[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]2[C:34]1=[O:43])(OCC)=O>C1C=CC=CC=1>[C:34]1(=[O:43])[N:1]([CH2:2][C@H:3]2[C@H:6]([S:7][C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[NH:5][C:4]2=[O:27])[C:37](=[O:38])[C:36]2=[CH:39][CH:40]=[CH:41][CH:42]=[C:35]12
Reactant: NC[C@@H]1C(=O)N[C@H]1SC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Solvent: c1ccccc1
Product: O=C1N[C@@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)[C@@H]1CN1C(=O)c2ccccc2C1=O
Yield: 92.7 %

Procedure:
A solution of trans 3-aminomethyl-4-tritylthio-2-azetidinone (13.9 g, 37.2 mmol) and N-carbethoxyphthalimide (8.3 g, 37.9 mmol) in benzene (200 ml) was heated under reflux for 15 h. The solvent was evaporated in vacuo and the residue crystallized from ether to give 17.4 g (93%) of the title compound; mp 172°-3° C.; Anal. calcd for C31H24N2O3S: C 73.78, H 4.79, N 5.55, found: C 73.92, H 4.87, N 5.49; ir (CHCl3) νmax : 1770 and 1715 cm-1 ; 1Hmr (CDCl3) δ: 7.8 (4H, m), 7.3 (15H, m), 4.45 (1H, d, J=2 Hz), 3.3-4.1 (3H, m) and 3.3-4.6 ppm (1H, m).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[NH:6][CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:11])[CH3:10])[O:3]1.[C:13]1([CH3:25])[CH:18]=[CH:17][C:16]([S:19]([N:22]=[C:23]=[O:24])(=[O:21])=[O:20])=[CH:15][CH:14]=1>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[N:6]([C:23](=[O:24])[NH:22][S:19]([C:16]2[CH:17]=[CH:18][C:13]([CH3:25])=[CH:14][CH:15]=2)(=[O:20])=[O:21])[CH2:5][CH:4]([CH2:7][O:8][CH:9]([CH3:10])[CH3:11])[O:3]1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC(C)OCC1CNC(C)(C)O1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)N2CC(COC(C)C)OC2(C)C)cc1

Procedure:
To 20.8 milliliters of 25 percent w/v, 2,2-dimethyl-5-isopropoxymethyl oxazolidine solution in 50 milliliters of benzene was added 5.9 grams of p-toluene sulfonyl isocyanate. Upon completion of the reaction the solvent, benzene, was removed in vacuo. There was obtained 12.8 grams of the title compound, as a glass. Analytical data supports the structure.
Reaction SMILES: [CH3:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][C:9]([CH3:11])=[CH:10][C:4]=2[N:3]=1.[H][H]>>[CH3:1][C:2]1[NH:6][C:5]2[CH2:7][CH2:8][CH:9]([CH3:11])[CH2:10][C:4]=2[N:3]=1
Reactant: [H][H]
Reactant: Cc1ccc2[nH]c(C)nc2c1
Product: Cc1nc2c([nH]1)CCC(C)C2

Procedure:
20.0 g (0.137 mol) of 2,5-dimethyl-1H-benzimidazole are dissolved in 150 ml glacial acid and 2.50 g Pt-Mohr catalyst are added under argon. The solution is treated with hydrogen at 80° C. and at 3 bar pressure for 72 h. The solution is filtrated over celite and washed with glacial acid. The solvent is evaporated under vacuum and a few milliliters of water are added to the residue. Sodium hydrogen solution is added to a pH of 12-14. The mixture is extracted with ethyl acetate, the organic phase is extracted with water and dried over sodium sulfate. The ethyl acetate is evaporated under pressure and the residue is dissolved in a little bit of dichlormethane. Diethylether is added and the precipitate is filtrated and washed with diethylether to yield 1.0 g (4.87% of th.).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10](Cl)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1.[O:16]1[C:20]([C:21]2[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=2)[NH2:24])=[CH:19][N:18]=[CH:17]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([NH:24][C:23]3[CH:25]=[CH:26][CH:27]=[C:21]([C:20]4[O:16][CH:17]=[N:18][CH:19]=4)[CH:22]=3)(=[O:12])=[O:11])=[C:7]([CH3:14])[C:6]=2[CH:15]=1
Reactant: Nc1cccc(-c2cnco2)c1
Reactant: Cc1c(S(=O)(=O)Cl)sc2ccc(Cl)cc12
Product: Cc1c(S(=O)(=O)Nc2cccc(-c3cnco3)c2)sc2ccc(Cl)cc12
Yield: 28.2 %

Procedure:
The product was prepared according to General Procedure 1, described in Example 1, starting with 5-chloro-3-methyl-benzothiophene-2-sulfonyl chloride (15.5 mg, 0.055 mmol) and 3-(1,3-oxazol-5-yl)-aniline (8 mg, 0.05 mmol) yielding 5.7 mg (26%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ ppm 7.06 (d, 1 H) 7.29 (t, 1 H) 7.39 (d, 1 H) 7.45 (br. s., 1 H) 7.49 (d, 1 H) 7.54 (s, 1 H) 7.93 (s, 1 H) 8.00 (d, 1 H) 8.36 (s, 1 H) 10.87 (br. s., 1 H) (Note; CH3 in DMSO-peak).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH2:9].Br[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[CH3:18].C(P(C(C)(C)C)=O)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][C:12]=1[CH3:18]
Reactant: Cc1ccc(N)c(C)c1
Reactant: Cc1ccc(Br)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)[PH](=O)C(C)(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(Nc2ccc(C)cc2C)c(C)c1
Temperature: 25 °C

Procedure:
Into a 1 liter three-necked reaction vessel fitted with a cooling tube and a mechanical stirrer, 133 g (1.1 mols) of 2,4-dimethylphenylamine, 185 g (1.0 mol) of 1-bromo-2,4-dimethylbenzene, 11.2 g (0.05 mol) of palladium acetate, 32.4 g (0.2 mol) of 2-tert-butylphosphinoyl-2-methylpropane, 212 g (1.0 mol) of tripotassium phosphate and 500 mL of dimethylformamide were introduced to effect reflux for 12 hours in a nitrogen gas atmosphere and with heating in an oil bath. After the reaction was completed, the reaction mixture was left to cool to room temperature, followed by extraction with toluene/water, then washing with hydrochloric acid water, and thereafter distillation of the organic layer under reduced pressure to give the desired bis(2,4-dimethylphenyl)amine. The compound obtained was in a yield of 189 g corresponding to 84%. The compound obtained was measured with an elementary analyzer (CHN CORDER MT-5, manufactured by Yanako K.K.). In the following elementary analyses, the units of the found values and calculated values are % by weight.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:18][NH2:19])[CH2:3][CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1.OC1C=CC(CCC[C@@H](NC(=O)[O-])CNC(=O)OC(C)(C)C)=CC=1.OC1C=CC(CCC[C@H](NC(=O)[O-])CNC(=O)OC(C)(C)C)=CC=1>>[NH2:1][C@H:2]([CH2:18][NH2:19])[CH2:3][CH2:4][CH2:5][C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C@H:12]([OH:15])[CH2:13][OH:14])=[CH:8][CH:7]=1
Reactant: NC[C@H](N)CCCc1ccc(OC[C@H](O)CO)cc1
Agent: CC(C)(C)OC(=O)NC[C@@H](CCCc1ccc(O)cc1)NC(=O)[O-]
Agent: CC(C)(C)OC(=O)NC[C@H](CCCc1ccc(O)cc1)NC(=O)[O-]
Product: NC[C@@H](N)CCCc1ccc(OC[C@H](O)CO)cc1

Procedure:
This compound is prepared analogously to Intermediate O replacing (R)-tert-butyl 5-(4-hydroxyphenyl)pentane-1,2-diyldicarbamate (Intermediate M with (S)-tert-butyl 5-(4-hydroxyphenyl)pentane-1,2-diyldicarbamate (Intermediate N); [M+H}+ 269
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][C:35]#[CH:36])[C:28]=2[CH:37]=1.C(O)C>C(Cl)Cl>[Cl:23][C:24]1[CH:25]=[CH:26][C:27]2[O:32][CH2:31][C:30](=[O:33])[N:29]([CH2:34][C:35]#[C:36][C:16]3[S:17][C:13]4[N:12]5[C:19]([CH3:22])=[N:20][N:21]=[C:11]5[CH2:10][N:9]=[C:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[Cl:1])[C:14]=4[CH:15]=3)[C:28]=2[CH:37]=1
Reactant: C#CCN1C(=O)COc2ccc(Cl)cc21
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Solvent: CCO
Solvent: ClCCl
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)COc4ccc(Cl)cc43)cc1C(c1ccccc1Cl)=NC2
Reaction time: 72 h

Procedure:
The titIe compound was prepared by coupling 4-(2-chlorophenyl)-2-iodo-9-methyl-6H-thieno [3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine with 6-chloro4-(2-propynyl)-2H-1,4-benzoxazin 3(4H)-one [ref. p. Rao et al. Indian J. Chem. 24 B, 1120 (1985)]as described in Example 37 but the reaction time was extended to 72 hours. The product was isolated by chromatography over the 100 -fold amount of silica gel (Merck 230-400 mesh) using 10% (v/v) of ethanol in methylene chloride. Crystallization of the residue obtained after evaporation of the combined clean fractions from ethyl acetate gave colorless crystals of 6-chloro-4-{3-[4-(2-chlorophenyl)-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3 a][1,4]diazepin-2-yl]-2-propynyl}-2H-1,4-benzoxazin-3(4H)-one with m.p. 202°-205°.
Reaction SMILES: [CH3:1][C:2](=[CH:5][C:6]#[C:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11])[CH:3]=[O:4].[H][H].N1C2C(=CC=CC=2)C=CC=1>C(=O)([O-])[O-].[Ca+2].[Pd+2].C(=O)([O-])[O-].C1(C)C=CC=CC=1>[CH3:1][C:2](=[CH:5][CH:6]=[CH:7][C:8]([CH3:12])=[CH:9][CH2:10][OH:11])[CH:3]=[O:4]
Reactant: [H][H]
Reactant: CC(C#CC=C(C)C=O)=CCO
Agent: [Pd+2]
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: c1ccc2ncccc2c1
Solvent: Cc1ccccc1
Product: CC(C=O)=CC=CC(C)=CCO

Procedure:
The residue obtained (240 g.) is dissolved in 1800 ml. of acetone, treated with 300 ml. of N-sulfuric acid and allowed to stand at room temperature in a nitrogen atmosphere for 1 hour. Then the reaction mixture, after dilution with 4000 ml. of water, is taken up in ether. The ether extract is washed with sodium bicarbonate solution and water, dried over sodium sulfate, filtered, and evaporated. 170 g. of crude 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al is obtained which can be purified through adsorption on aluminum oxide (activity II deactivated by the addition of 7 per cent water). A small portion is removed by washing with petroleum ether/ether mixture (4:1). By elution with a petroleum ether/ether mixture (3:2) there is obtained pure 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al (Abs. Max. 312 mμ; E11 = 1200) (in 96 per cent ethyl alcohol). 125 g. of 2,6-dimethyl-8-hydroxy-2,6-octadien-4-in-1-al are dissolved in 600 ml. of toluene and hydrogenated until the cessation of hydrogen takeup after the addition of 15 g. of a lead/palladium-calcium carbonate catalyst and 2 ml. of quinoline in the usual manner. After filtration and evaporation of the solution, there is obtained 2,6-dimethyl-8-hydroxy-2,4,6-octatrien-1-al.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][NH:11][C:10](=[O:16])[CH:9]=2)[CH:7]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][CH:18]([F:20])[F:19])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[C:10](=[O:16])[CH:9]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COc1c[nH]c(=O)cc1-c1cc(Cl)ccc1OC(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COc1cn(CC(=O)OC(C)(C)C)c(=O)cc1-c1cc(Cl)ccc1OC(F)F

Procedure:
5.43 g (purity 80%, 14.4 mmol) of 4-[5-chloro-2-(difluoromethoxy)phenyl]-5-methoxypyridin-2(1H)-one and 1.2 eq. of tert-butyl bromoacetate in the presence of 1.5 eq. of potassium carbonate were reacted according to General Method 4B at 100° C. Yield: 3.64 g (61% of theory)