Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(S(F)(F)[F:7])CC)C.[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([C:27]3[C:28]([O:42][CH:43]4[CH2:46][CH2:45][CH2:44]4)=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:37]([O:39][CH3:40])=[O:38])[C@@H:32]([CH3:41])[CH2:31][CH2:30]4)[N:26]=2)(O)[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>ClCCl>[C:10]([O:14][C:15]([N:17]1[CH2:20][C:19]([C:22]2[S:23][CH:24]=[C:25]([C:27]3[C:28]([O:42][CH:43]4[CH2:46][CH2:45][CH2:44]4)=[C:29]4[C:34](=[CH:35][CH:36]=3)[N:33]([C:37]([O:39][CH3:40])=[O:38])[C@@H:32]([CH3:41])[CH2:31][CH2:30]4)[N:26]=2)([F:7])[CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]
Reactant: CCN(CC)S(F)(F)F
Reactant: COC(=O)N1c2ccc(-c3csc(C4(O)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)N1c2ccc(-c3csc(C4(F)CN(C(=O)OC(C)(C)C)C4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: -78 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
(Diethylamino)sulfur trifluoride (DAST) (0.152 g, 0.94 mmol) was added to a −78° C. solution of (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-hydroxyazetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.100 g, 0.19 mmol) in dichloromethane (4 mL), and the resulting solution stirred for 2 h at −78° C. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (20 mL) and extracted with dichloromethane (3×20 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via preparative thin layer chromatography (eluting with 30% ethyl acetate/petroleum ether) to afford (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-3-fluoro azetidin-3-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.059 g, 59%) as a yellow solid. MS (ESI, pos. ion) m/z 532 [M+H]+.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[CH:7][C:6]=2[C:5]([F:16])=[C:4]([F:17])[CH:3]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[CH:7][C:6]=3[C:5]([F:16])=[C:4]([F:17])[CH:3]=2)=[CH:21][CH:20]=1
Reactant: O=C1NCCn2c1cc1c(F)c(F)cc(Br)c12
Reactant: OB(O)c1ccc(Cl)cc1
Product: O=C1NCCn2c1cc1c(F)c(F)cc(-c3ccc(Cl)cc3)c12

Procedure:
The title compound, grey solid (42 mg, 51%), MS (ISP) m/z=333.1 [(M+H)+], mp 327° C., was prepared in accordance with the general method of example 1 from 6-bromo-8,9-difluoro-3,4-dihydro-2H-pyrazino[1,2-a]indol-1-one (intermediate 4) (75.3 mg, 0.25 mmol) and commercially available 4-chloro-phenylboronic acid (50.8 mg, 0.325 mmol).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[S:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11].[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@@H:21](O)[CH3:22]>>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C@H:21]([O:1][C:2]1[CH:6]=[C:5]([N+:7]([O-:9])=[O:8])[S:4][C:3]=1[C:10]([O:12][CH3:13])=[O:11])[CH3:22]
Reactant: COC(=O)c1sc([N+](=O)[O-])cc1O
Reactant: C[C@H](O)c1ccccc1Cl
Product: COC(=O)c1sc([N+](=O)[O-])cc1O[C@H](C)c1ccccc1Cl

Procedure:
Methyl 3-{[(1R)-1-(2-chlorophenyl)ethyl]oxy}-5-nitro-2-thiophenecarboxylate was prepared from methyl 3-hydroxy-5-nitro-2-thiophenecarboxylate and (1S)-1-(2-chlorophenyl)ethanol by a procedure analogous to Intermediate Example 1, Step A. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (s, 1H), 7.65 (dd, 1H, J=1.7, 7.8 Hz), 7.47 (dd, 1H, J=1.5, 7.7 Hz), 7.40 (dt, 1H, J=1.3, 7.5 Hz), 7.34 (dt, 1H, J=1.9, 7.5 Hz), 5.98 (q, 1H, J=6.0 Hz), 3.85 (s, 3H), 1.59 (d, 3H, J=6.2 Hz).
Reaction SMILES: [C:1]([N:4]1[C@H:8]([C@H:9]([OH:12])CO)[C@@H:7]([OH:13])[CH2:6][NH:5]1)(=[O:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+].[BH4-].[Na+]>C(O)C.O>[C:1]([N:4]1[C@H:8]([CH2:9][OH:12])[C@@H:7]([OH:13])[CH2:6][NH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1NC[C@H](O)[C@H]1[C@H](O)CO
Agent: [BH4-]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CCO
Solvent: O
Product: CC(=O)N1NC[C@H](O)[C@H]1CO
Temperature: 5 °C
Yield: 75.8 %

Procedure:
A solution of 19 (80 mg, 0.42 mmol) in ethanol (5 mL) was added dropwise to a stirred solution of sodium periodate (150 mg, 0.7 mmol) in water (5 mL) at such a rate so as to maintain the reaction temperature at 5° C. On completion, sodium borohydride (135 mg, xs) was added portionwise to the resulting suspension at such a rate so as to maintain the reaction temperature at 0° C. and on complete addition the reaction was allowed to warm to r.t. Flash chromatography grade silica was added to the reaction and the resulting suspension was concentrated in vacuo to afford a white solid. The solid was purified by chromatography to afford 20 (51 mg, 76%) as a colourless oil. 1H NMR δ 4.43 (dd, J=5.7, 3.3 Hz, 1H), 3.91 (q, J=4.7 Hz, 1H), 3.75 (d, J=4.7 Hz, 1H), 3.31 (m, 1H), 3.28 (dd, J=11.8, 5.7 Hz, 1H), 2.75 (dd, J=11.8, 5.5 Hz, 1H), 2.17 (s, 3H). 13C NMR δ 173.9, 76.5, 68.2, 62.5, 55.8, 21.7. HRMS (MH+) calc. for C6H13N2O3: 161.0926. Found 161.0920.
Reaction SMILES: [F:1][CH2:2][C:3](=[O:34])[CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:33]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[S:27][C:26]2[C:21]1=[CH:22][CH:23]=[CH:24][CH:25]=2)=[O:19])=[O:11])[CH2:5][C:6]([OH:8])=O.N=C=N.[CH2:38]([NH:40][CH2:41][CH3:42])[CH3:39]>C(Cl)Cl>[CH2:38]([N:40]([CH2:41][CH3:42])[C:6](=[O:8])[CH2:5][CH:4]([NH:9][C:10]([CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][N:13]1[C:18]([N:20]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=2[S:27][C:28]2[C:33]1=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:19])=[O:11])[C:3](=[O:34])[CH2:2][F:1])[CH3:39]
Reactant: O=C(O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Reactant: CCNCC
Agent: N=C=N
Solvent: ClCCl
Product: CCN(CC)C(=O)CC(NC(=O)C1CCCCN1C(=O)N1c2ccccc2Sc2ccccc21)C(=O)CF
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.7 %

Procedure:
To a stirred mixture of [3S/R, (2S)]-5-fluoro-4-oxo-3-{[1-(phenothiazine-10-carbonyl)piperidine-2-carbonyl]amino}-pentanoic acid (200 mg, 0.4 mmol), prepared as in Example 1, in anhydrous DCM (4 ml), was added carbodiimide (74 mg, 0.44 mmol) and a diethylamine (0.62 ml, 6 mmol). The mixture was stirred at room temperature for 16 h then concentrated under reduced pressure. The residue was purified by flash chromatography (2.5% Methanol in dichloromethane) to afford the title compound as a white solid (25.3 mg, 11%): 1H NMR (400 MHz, CDCl3) δ 1.00-1.23 (6H, m), 1.45-1.67 (6H, m), 2.18 (1H, m), 2.74 (1H, m), 2.92 (1H, m), 3.21-3.33 (4H,m), 3.65 (1H, m), 4.68 (1H, m), 4.85 (1H, m), 4.98-5.36 (2H, m) and 7.12-7.95 (8H, m). 19F NMR (376 MHz, CDCl3) δ −232.37 and −232.72.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:11][CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH:13]2[F:25])=[C:4]2[S:10][CH:9]=[CH:8][C:5]2=[N:6][CH:7]=1.[OH:26][C@H:27]([CH3:31])[C:28](O)=[O:29].C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[F:25][CH:13]1[CH:12]([NH:11][C:3]2[C:2]([NH:1][C:28](=[O:29])[C@H:27]([OH:26])[CH3:31])=[CH:7][N:6]=[C:5]3[CH:8]=[CH:9][S:10][C:4]=23)[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])[CH2:14]1
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c(N)cnc3ccsc23)C(F)C1
Reactant: C[C@@H](O)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@@H](O)C(=O)Nc1cnc2ccsc2c1NC1CCN(C(=O)OC(C)(C)C)CC1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a mixture of tert-butyl 4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]-3-fluoropiperidine-1-carboxylate (0.21 g, 0.57 mmol) and (R)-2-hydroxypropanoic acid (0.059 g, 0.65 mmol) in methylene chloride (5 mL) was added N,N-diisopropylethylamine (0.23 mL, 1.3 mmol) and N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (0.23 g, 0.60 mmol). The resulting mixture was stirred at room temperature overnight. The reaction mixture was washed with water, concentrated and purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-[(6-{[(2R)-2-hydroxypropanoyl]amino}thieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (0.155 g, 62%). LCMS calculated for C20H28FN4O4S (M+H)+: m/z=439.2. Found: 439.1. A solution of the amide intermediate in acetic acid (1 mL) was heated at reflux for 2 h. The resulting mixture was purified on silica gel (eluting with 0-10% MeOH in dichloromethane) to give tert-butyl 3-fluoro-4-{2-[(1R)-1-hydroxyethyl]-1H-imidazo[4,5-d]thieno[3,2-b]pyridin-1-yl}piperidine-1-carboxylate (16 mg, 10%). LCMS calculated for C20H26FN4O3S (M+H)+: m/z=421.2. Found: 421.1. The Boc protected intermediate was treated with trifluoroacetic acid (0.1 mL, 1 mmol) in methylene chloride (0.2 mL) at room temperature for 1 h. The mixture was concentrated and purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give two desired products. First peak retention time 0.253 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1. Second peak retention time 0.514 min. LCMS calculated for C15H18FN4OS (M+H)+: m/z=321.1. Found: 321.1.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:10]=N1.C1(C[C@H](N2CC3C(=CC=CC=3)C2=O)C(O)=O)CCCCC1.NC1NC2C=CC=CC=2N=1.[CH:59]1([CH2:65][C@H:66]([N:75]2[CH2:83][C:82]3[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=3)[C:76]2=[O:84])[C:67]([NH:69][C:70]2SC=CN=2)=[O:68])[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1>>[NH:10]1[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:8]=[C:70]1[NH:69][C:67](=[O:68])[CH:66]([N:75]1[CH2:83][C:82]2[C:77](=[CH:78][CH:79]=[CH:80][CH:81]=2)[C:76]1=[O:84])[CH2:65][CH:59]1[CH2:64][CH2:63][CH2:62][CH2:61][CH2:60]1
Reactant: O=C(Nc1nccs1)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: Nc1nc2ccccc2[nH]1
Agent: O=C(O)[C@H](CC1CCCCC1)N1Cc2ccccc2C1=O
Product: O=C(Nc1nc2ccccc2[nH]1)C(CC1CCCCC1)N1Cc2ccccc2C1=O
Yield: 60 %

Procedure:
This compound was prepared via BOP coupling of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid (prepared in Example 1, Step A, 287 mg; 1.0 mmol and 2-amino-benzimidazole (119 mg; 1.0 mmol) in a manner similar to that used for the preparation of (S)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-N-thiazol-2-yl-propionamide (outlined in Example 9, Step B) to provide crude N-(5-Bromo-thiazol-2-yl)-3-cyclohexyl-2-(5,6-dichloro-1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide. The crude product was purified by reverse-phase HPLC (Rainin Dynamax SD-1 instrument) using a gradient of 10% acetonitrile/water/0.1% trifluoroacetic acid to 100% acetonitrile on a C18 column. The combined fractions containing product were concentrated to remove most of the acetonitrile and then extracted with ethyl acetate. The extracts were dried (sodium sulfate) and concentrated in vacuo to give 240 mg (60%) of N-(1H-Benzoimidazol-2-yl)-3-cyclohexyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionamide as a white solid: EI-HRMS m/e calcd for C24H26N4O2 (M+) 402.2056, found 402.2056.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][OH:20])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1.C(N(CC)CC)C>[F:1][C:2]1[CH:3]=[C:4]([N:14]2[CH2:18][C@H:17]([CH2:19][O:20][S:23]([CH3:22])(=[O:25])=[O:24])[O:16][C:15]2=[O:21])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1
Reactant: Cc1cn(-c2ccc(N3C[C@H](CO)OC3=O)cc2F)cn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: Cc1cn(-c2ccc(N3C[C@H](COS(C)(=O)=O)OC3=O)cc2F)cn1
Reaction time: 2 h
Yield: 78.2 %

Procedure:
3-(3-Fluoro-4-(4-methylimidazol-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one (11.8 g, 40.5 mM) was stirred in a mixture of pyridine (200 ml) and triethylamine (4.86 g, 48.2 mM) under nitrogen in an ice-bath. Methanesulfonyl chloride (5.16 g, 45 mM) was added dropwise, and the mixture stirrd for 2 hours, allowing the temperature to rise to ambient. Solvent was evaporated, and the residue stirred vigorously with a mixture of aqueous sodium bicarbonate (5%, 200 ml) and isohexane (200 ml). The precipitate was filtered, washed with water then isohexane, and dried. The residue was recrystallised from hot acetone (200 ml) by dilution with isohexane (300 ml) to give the title product (11.7 g), mp 151–153°.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[N:67]1([C:73]2[CH:80]=[CH:79][C:76]([CH:77]=O)=[CH:75][CH:74]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[N:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:77]([C:76]3[CH:75]=[CH:74][C:73]([N:67]4[CH2:72][CH2:71][O:70][CH2:69][CH2:68]4)=[CH:80][CH:79]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cncnc3)CC2)c1[N+](=O)[O-]
Reactant: O=Cc1ccc(N2CCOCC2)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(N4CCOCC4)cc3)nc2c1N1CCN(Cc2cncnc2)CC1
Reaction time: 6 h
Yield: 29.3 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyrimidin-5-ylmethyl)piperazin-1-yl)pyridin-2-amine (20 mg, 0.051 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.15 mmol, 0.15 mL) and 4-morpholin-4-yl-benzaldehyde (1.1 eq, 0.052 mmol, 11 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (8 mg, 30%) as a pale yellow solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.24 (t, J=4.7 Hz, 4H, morpholine N(CH2)2), 3.62-3.65 (m, 6H, piperazine N(CH2)2 & CH2), 3.76 (t, J=4.8 Hz, 4H, morpholine O(CH2)2), 7.06 (d, J=9.0 Hz, 2H, phenyl H-3 & H-5), 8.04 (d, J=8.9 Hz, 2H, phenyl H-2 & H-6), 8.18 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.80 (s, 2H, pyrimidine H-4 & H-6), 9.12 (s, 1H, pyrimidine H-2), 13.23 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18]Cl)[CH2:13][CH3:14].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6](=[O:12])[C:5]2([CH2:15][CH2:16][CH2:17][CH2:18][N:30]1[CH2:29][CH2:28][N:27]([C:24]2[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=2)[CH2:32][CH2:31]1)[CH2:13][CH3:14]
Reactant: Clc1ccc(N2CCNCC2)cc1
Reactant: CCC1(CCCCCl)C(=O)Nc2cc(F)c(Cl)cc21
Product: CCC1(CCCCN2CCN(c3ccc(Cl)cc3)CC2)C(=O)Nc2cc(F)c(Cl)cc21

Procedure:
The title compound is prepared according to process H by applying processing method 2 from 5-chloro-3-(4-chlorobutyl)-3-ethyl-6-fluoro-1,3-dihydro-2H-indol-2-one and 1-(4-chlorophenyl)-piperazine.
Reaction SMILES: [CH3:1][C:2]1[CH:14]=[C:13]([CH3:15])[N:5]2[S:6](=[O:12])(=[O:11])[NH:7][C:8](=[O:10])[N:9]=[C:4]2[N:3]=1.[CH3:16][O:17][NH:18][CH3:19]>C(Cl)Cl>[CH3:16][O:17][N:18]([S:6]([NH:7][C:8]([NH:9][C:4]1[N:3]=[C:2]([CH3:1])[CH:14]=[C:13]([CH3:15])[N:5]=1)=[O:10])(=[O:12])=[O:11])[CH3:19]
Reactant: CC1=CC(C)=NC2=NC(=O)NS(=O)(=O)N12
Reactant: CNOC
Solvent: ClCCl
Product: CON(C)S(=O)(=O)NC(=O)Nc1nc(C)cc(C)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
5.7 g (0.025 mol) of 2,3-dihydro-6,8-dimethyl-3-oxopyrimidino-[1,2-b][1,2,4,6]-thiatriazine 1,1-dioxide (cf. Example 1) are suspended in 100 ml of methylene dichloride, and 3.05 g (0.05 mol) of O,N-dimethylhydroxylamine--dissolved in 50 ml of methylene dichloride--are added at -40° C. in the course of one hour. The mixture is stirred for a further 18 hours at room temperature and evaporated to dryness, and the residue is taken up in water and acidified to pH 4-5 with 0.5 N HCl. After extraction with methylene dichloride, the mixture is worked up as under Example 17. 4.9 g (67.8% of theory) of 1-[(N-methoxy-N-methylamino)-sulfonyl]-3-(4,6-dimethyl-2-pyrimidinyl)-urea of melting point 152° C. are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:14]1[N:19]=[CH:18][N:17]=[C:16]([NH:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[CH:15]=1.Cl[C:33]([C:35]1[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=1)[CH2:38][S:39][CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[O:34]>ClCCl>[N:8]1([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:33]([C:35]3[CH:36]=[C:37]([CH:49]=[CH:50][CH:51]=3)[CH2:38][S:39][CH2:40][CH2:41][C:42]([O:44][C:45]([CH3:48])([CH3:46])[CH3:47])=[O:43])=[O:34])=[C:3]([C:14]3[CH:15]=[C:16]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:29])[F:31])[CH:23]=4)[N:17]=[CH:18][N:19]=3)[CH:4]=2)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Cl)c1
Reactant: Nc1ccc(N2CCCCC2)cc1-c1cc(NCc2cccc(C(F)(F)F)c2)ncn1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CCSCc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(NCc3cccc(C(F)(F)F)c3)ncn2)c1
Reaction time: 8 h
Yield: 99.1 %

Procedure:
A solution of 6-(2-amino-5-(piperidin-1-yl)phenyl)-N-(3-(trifluoromethyl)benzyl)pyrimidin-4-amine (122 mg) in 1.0 mL of dichloromethane was treated with 54 mg of tert-butyl 3-((3-(chlorocarbonyl)benzyl)thio)propanoate. The mixture was stirred overnight. The solvent was evaporated and the residue was purified by silica gel chromatography to give 120 mg of product as a yellow oil.
Reaction SMILES: [CH3:1][CH2:2]/[C:3](=[C:11](/[CH2:19][CH3:20])\[C:12]1[CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)/[C:4]1[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=1.O.[N+:22]([O-])([OH:24])=[O:23]>C(O)(=O)C>[OH:16][C:15]1[CH:14]=[CH:13][C:12]([C:11](=[C:3]([C:4]2[CH:10]=[CH:9][C:7]([OH:8])=[CH:6][CH:5]=2)[CH2:2][CH3:1])[CH2:19][CH3:20])=[CH:18][C:17]=1[N+:22]([O-:24])=[O:23]
Reactant: O=[N+]([O-])O
Reactant: CC/C(=C(/CC)c1ccc(O)cc1)c1ccc(O)cc1
Solvent: CC(=O)O
Solvent: O
Product: CCC(=C(CC)c1ccc(O)c([N+](=O)[O-])c1)c1ccc(O)cc1
Temperature: 5 °C
Reaction time: 5 h
Yield: 18.8 %

Procedure:
Under a nitrogen atmosphere, a suspension of diethylstilbestrol (1.0 g) in acetic acid (160 ml)-water (16 ml) was cooled to 5° C., and 70% nitric acid (0.34 g) was added dropwise thereto. Then, the resulting mixture was heated to 20° C. and stirred for 5 hours. The solvent was distilled off under reduced pressure and an aqueous sodium hydrogencarbonate solution was added to the residue, followed by two runs of extraction with ethyl acetate (150 ml). The combined organic layer was washed with water (200 ml), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (n-hexane:ethyl acetate=9:1) to obtain 3-(4-hydroxy-3-nitrophenyl)-4-(4-hydroxyphenyl)-3-hexene (0.22 g, yield 19%).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[C:19]([N+:25]([O-])=O)=[CH:18][CH:17]=1>C1COCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[C:21]2[CH:22]=[CH:23][S:24][C:20]=2[C:19]([NH2:25])=[CH:18][CH:17]=1
Reactant: Cc1oc(-c2ccccc2)nc1CCOc1ccc([N+](=O)[O-])c2sccc12
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1CCOc1ccc(N)c2sccc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
50 g (1.052 mol) of 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole were solved in 1 l of THF at 20 to 25° C. 75 ml Lewatit M 600 (OH−-form) (Bayer AG) were washed with about 100 ml THF, added to the 5-methyl-4-[2-(7- nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole solution and stirred at room temperature for 1 hour. Then the Lewatit M 600 material was filtered with suction and washed with 100 ml THF. 12.5 g of Raney nickel were added to the combined THF solutions followed by hydrogenation of the 5-methyl-4-[2-(7-nitro-benzothiophene-4-yloxy)-ethyl]-2-phenyl-oxazole at standard pressure. The temperature of the reaction mixture should not exceed 35 to 40° C. Hydrogen pressure was increased to 6 bar within 6 hours. After hydrogenation the reaction mixture was stirred for 1 hour. Then the catalyst was filtered with suction, the THF was distilled off, 180 ml ethanol was added and the residue was boiled out for 30 minutes. The reaction mixture was stirred at 0° C. for 1 hour. The precipitate was filtered with suction and the residue was washed with 25 ml ethanol and dried for 24 hours at 50° C. (vacuum).
Reaction SMILES: [C:1]([C:9]([C:24]([OH:26])=[O:25])([OH:23])[C:10]([C:15](=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([OH:14])[C:11]([OH:13])=[O:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]1([C@:33]23[NH:40][C@H:37]([CH2:38][CH2:39]2)[CH2:36][CH2:35][C@H:34]3[OH:41])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C(O)(C)C>C(OCC)(=O)C>[C:15]([C:10]([C:11]([OH:13])=[O:12])([OH:14])[C:9]([C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([OH:23])[C:24]([OH:26])=[O:25])(=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[C:27]1([C@@:33]23[NH:40][C@@H:37]([CH2:38][CH2:39]2)[CH2:36][CH2:35][C@@H:34]3[OH:41])[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1
Reactant: O[C@@H]1CC[C@H]2CC[C@]1(c1ccccc1)N2
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: O[C@H]1CC[C@@H]2CC[C@@]1(c1ccccc1)N2
Temperature: 25 °C

Procedure:
A solution of (−)-dibenzoyl tartaric acid (4.85 g, 13.5 mmol) in ethyl acetate (100 ml) was added dropwise to a solution of (1R*,2R*,5R*)-1-phenyl-8-azabicyclo[3.2.1]octan-2-ol (Description 47; 11 g, 54.2 mmol) in hot ethyl acetate (250 ml). Iso-propyl alcohol (500 ml) was added and the mixture heated at reflux for 1 hour. The mixture was allowed to cool slowly to room temperature then filtered to yield the title compound (4.8 g, 46%, e.e. >99%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([S:14]([C:17]3[CH:18]=[C:19]([C:24]#[N:25])[S:20][C:21]=3[S:22][CH3:23])(=[O:16])=[O:15])[CH:11]=[CH:12][CH:13]=2)[CH2:4][CH2:3]1.[CH3:26][O-:27].[Na+]>O.CO>[CH3:26][O:27][C:24]([C:19]1[S:20][C:21]([S:22][CH3:23])=[C:17]([S:14]([C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([N:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:9]=2)(=[O:16])=[O:15])[CH:18]=1)=[NH:25]
Reactant: C[O-]
Reactant: CSc1sc(C#N)cc1S(=O)(=O)c1cccc(N2CCN(C)CC2)c1
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=N)c1cc(S(=O)(=O)c2cccc(N3CCN(C)CC3)c2)c(SC)s1
Temperature: 50 °C
Yield: 74 %

Procedure:
To a flask containing 15 mg (0.03 mmol) of 4-[3-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-carbonitrile (Example 292: step a) was added 1 mL of MeOH and the resultant solution was treated with 1 mL 2M NaOMe in MeOH (2 mmol) at room temperature. The reaction was heated to 50° C. for 2 h. At this time it was cooled to room temperature and 2 drops of H2O was added. Concentration of the mixture in vacuo 5 followed by purification by preparative TLC (5% MeOH-CHCl3) yielded 12 mg (74%) of 4-[3-(4-methyl-piperazin-1-yl)-benzenesulfonyl]-5-methylsulfanyl-thiophene-2-carboximidic acid methyl ester as a yellow solid.