Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH:2]1[CH:7]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3]1.Br[CH2:23][CH2:24][CH2:25][O:26][C:27]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=1[F:34]>>[F:34][C:28]1[CH:29]=[CH:30][C:31]([F:33])=[CH:32][C:27]=1[O:26][CH2:25][CH2:24][CH2:23][O:14][C:11]1[CH:10]=[CH:9][C:8]([CH:7]2[CH2:6][CH2:5][N:4]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:3][CH:2]2[OH:1])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(O)cc2)C(O)C1
Reactant: Fc1ccc(F)c(OCCCBr)c1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOc3cc(F)ccc3F)cc2)C(O)C1

Procedure:
Analogously to Method I, 0.750 g of tert-butyl 3-hydroxy-4(4-hydroxyphenyl)piperidine-1-carboxylate and 0.812 g of 2-(3-bromopropoxy)-1,4-difluorobenzene are reacted. The title compound is obtained as a slightly yellowish oil. Rf=0.35 (1:1 EtOAc-heptane); Rt=5.14.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24](=[O:26])[NH:25][C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:40][N:41]1[CH2:46][CH2:45][CH:44](Br)[CH2:43][CH2:42]1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:31]([CH3:32])=[CH:30][C:15]2[N:16]=[C:17]([C:19]3[CH:29]=[CH:28][C:22]4[N:23]([CH3:27])[C:24](=[O:26])[N:25]([CH:44]5[CH2:45][CH2:46][N:41]([CH3:40])[CH2:42][CH2:43]5)[C:21]=4[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CN1CCC(Br)CC1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)[nH]c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)n(C3CCN(C)CC3)c(=O)n4C)sc2c1-c1ccc(Cl)cc1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzo[d]thiazol-6-yl)acetate (47 mg, 0.083 mmol) in DMF (1 mL), pyridine (0.5 mL), was added N-methyl-4-bromopiperidine (26 mg, 0.146 mmol). The reaction was stirred at 85° C. overnight. Then Cs2CO3 (54 mg) was added, raised temp to 100° C. and stirred overnight. More N-methyl-4-bromopiperidine (50 mg 0.28 mmol), the mixture was heated at 100° C. for 2 days. The reaction was quenched by adding water, extracted by EtOAc, dried by MgSO4, filtered, concentrated down and purified by silica gel column, first 0-100% EtOAc in hexanes to elute (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(1-methyl-2-oxo-2,3-dihydro-1H-benzo[d]imidazol-5-yl)benzo[d]thiazol-6-yl)acetate , then switched to 0-20% MeOH in DCM to elute the product. LCMS-ESI+: calc'd for C36H41ClN4O4S: 661.2 (M+H+); found: 661.3.
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:16](B2OC(C)(C)C(C)(C)O2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)S(O[C:34]1[CH:43]=[CH:42][C:41]2[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=2[CH:35]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][CH:6]([C:12]1[C:16]([C:34]2[CH:43]=[CH:42][C:41]3[CH2:40][CH2:39][CH2:38][CH2:37][C:36]=3[CH:35]=2)=[C:15]([CH3:26])[S:14][C:13]=1[CH3:27])[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1B1OC(C)(C)C(C)(C)O1
Reactant: O=S(=O)(Oc1ccc2c(c1)CCCC2)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(OC(C)(C)C)c1c(C)sc(C)c1-c1ccc2c(c1)CCCC2
Temperature: 100 °C
Reaction time: 4 h
Yield: 83.3 %

Procedure:
Under argon atmosphere, ethyl 2-(tert-butoxy)-2-[2,5-dimethyl-4-(tetramethyl-1,3,2-dioxaborolan-2-yl)thiophen-3-yl]acetate (28f) (50 mg, 0.12 mmol), 5,6,7,8-tetrahydronaphthalen-2-yl trifluoromethanesulfonate (39a) (41.4 mg, 0.15 mmol) and sodium carbonate (13.7 mg, 0.13 mmol) were dissolved in dimethylformamide (2.5 mL) and water (0.85 mL). The solution was degassed under argon for 10 minutes and Tetrakis(triphenylphosphine)palladium (28.5 mg, 0.02 mmol) was added. The reaction was heated and shaken at 100° C. for 4 hours. After cooling at room temperature, water was added and the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by preparative TLC (cyclohexane/ethyl acetate: 9/1) to provide the desired product (39b) (40 mg, 0.1 mmol, 77%).
Reaction SMILES: C(O[C@H:9]1[C@H:14](OCC2C=CC=CC=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]3[CH:46]=[CH:45][C:44]([O:47][CH2:48][CH:49]([F:51])[F:50])=[CH:43][CH:42]=3)[CH:34]=2)([O:31][CH3:32])[O:11][C:10]1([CH2:54][OH:55])CO)C1C=CC=CC=1.F[C:57](F)(F)[C:58]([OH:60])=O>ClCCl>[CH2:12]([O:11][C@H:9]1[C@H:14]([O:60][CH2:58][C:57]2[CH:13]=[CH:14][CH:9]=[CH:10][CH:54]=2)[C@@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@:12]2([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([CH2:40][C:41]4[CH:42]=[CH:43][C:44]([O:47][CH2:48][CH:49]([F:50])[F:51])=[CH:45][CH:46]=4)[CH:34]=3)[O:11][C@@:10]1([CH2:54][OH:55])[CH2:32][O:31]2)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: CO[C@@]1(c2ccc(Cl)c(Cc3ccc(OCC(F)F)cc3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC[C@@]12CO[C@@](c3ccc(Cl)c(Cc4ccc(OCC(F)F)cc4)c3)(O1)[C@H](OCc1ccccc1)[C@@H](OCc1ccccc1)[C@@H]2OCc1ccccc1
Reaction time: 1 h

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 12k (293 mg, 0.38 mmol) was dissolved in 10 mL dichloromethane, followed by dropwise addition of trifluoroacetic acid (0.1 mL). The reaction mixture was stirred for 1 hour. Thereafter, the reaction mixture was concentrated under reduced pressure and the resulting residue was purified by column chromatography to obtain the title compound [(1S,2S,3S,4R,5S)-2,3,4-tribenzyloxy-5-[4-chloro-3-[[4-(2,2-difluoroethoxy)phenyl]methyl]phenyl]-6,8-dioxabicyclo[3.2.1]octan-1-yl]methanol 12m (76 mg, white solid), yield: 27.6%.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)=[O:13].N1C=CC=CC=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][C:33]=1[S:39](Cl)(=[O:41])=[O:40]>C(Cl)Cl>[Cl:1][C:2]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[NH:11][C:12]([CH:14]1[CH2:19][CH2:18][N:17]([S:39]([C:33]2[CH:34]=[C:35]([Cl:38])[CH:36]=[CH:37][C:32]=2[Cl:31])(=[O:41])=[O:40])[CH2:16][CH2:15]1)=[O:13]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCN(S(=O)(=O)c2cc(Cl)ccc2Cl)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44 %

Procedure:
To an ice cooled solution of piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)-phenyl]amide (AMR01038, 80 mg, 0.219 mmol) in dry DCM (6 mL) were added pyridine (0.035 mL, 0.438 mmol) and 2,5-dichlorobenzenesulphonyl chloride (59.2 mg, 0.241 mmol). The reaction mixture was stirred at room temperature for 24 h, and then at reflux for 3 h. After quenching with saturated NaHCO3, the resulting solution was extracted with DCM (3×20 mL), and the combined organic layers were washed with water, 1M HCl (3×20 mL) and brine, dried (MgSO4), filtered and evaporated. Flash column chromatography on silica gel using hexane/EtOAc 8:2 as eluent gave 1-(2,5-dichlorobenzenesulfonyl)piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)-phenyl]amide (56 mg, 44%) as a white solid, mp 194-196° C. Rf: 0.81 (DCM/MeOH 9:1). 1H NMR (300 MHz, CDCl3) δ 1.74-1.96 (4H, m, 2CH2), 2.34 (1H, m, CH), 3.80 (2H, td, J=13.1, 3.4 Hz, CH2), 6.65 (1H, dd, J=8.1, 1.4 Hz, ArH), 6.87 (1H, d, J=8.8 Hz, ArH), 6.94 (1H, td, J=7.7, 1.7 Hz, ArH), 7.05 (1H, td, J=8.0, 1.4 Hz, ArH), 7.15 (1H, dd, J=8.8, 2.5 Hz, ArH), 7.37 (2H, d, J=1.4 Hz, ArH), 7.41 (1H, d, J=2.5 Hz, ArH), 7.68 (1H, br s, NH), 7.97 (1H, t, J=1.4 Hz, ArH) and 8.29 (1H, dd, J=8.0, 1.0 Hz, ArH). LC/MS (APCI) tr=5.62 min, m/z 577.21 (59), 575.26 (100), 573.24 (M++H, 90) HPLC tr=3.363 min (97.70%)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[CH:12]=[C:13]([OH:15])[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7].[F:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:37]=1>>[CH3:1][O:2][C:3](=[O:30])[CH:4]([C:9]1[CH:10]=[C:11]([C:16]2[CH:21]=[C:20]([C:22]([F:23])([F:25])[F:24])[CH:19]=[C:18]([C:26]([F:27])([F:28])[F:29])[CH:17]=2)[CH:12]=[C:13]([O:15][C:34]2[CH:35]=[C:36]([C:38]([F:40])([F:39])[F:41])[CH:37]=[C:32]([F:31])[CH:33]=2)[CH:14]=1)[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Reactant: OB(O)c1cc(F)cc(C(F)(F)F)c1
Product: COC(=O)C(CC(C)C)c1cc(Oc2cc(F)cc(C(F)(F)F)c2)cc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c1
Yield: 35 %

Procedure:
The title compound was prepared in 35% yield from 2-(5-hydroxy-3′,5′-bis-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example C) and 3-fluoro-5-trifluoromethylphenyl-boronic acid under the conditions described in Example 15, step (g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:6]=[CH:7][C:8]([C:10]1[N:17]2[C:13]([S:14][C:15]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:16]=32)=[N:12][CH:11]=1)=[O:9].[H-].[H-].[H-].[H-].[Li+].[Al+3]>>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][CH:8]([C:10]1[N:17]2[C:13]([S:14][C:15]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][C:16]=32)=[N:12][CH:11]=1)[OH:9]
Reactant: O=C(C=Cc1ccco1)c1cnc2sc3c(n12)CCCCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: OC(CCc1ccco1)c1cnc2sc3c(n12)CCCCC3

Procedure:
3-(2-Furanyl)-1-(6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-yl)-propene-1-one (Formula P-2, X=0), 0.94 g, was reduced with LiAlH4 by non-critical variations of EXAMPLE 23 to provide α-[2-(2-Furanyl)ethyl]-6,7,8,9-tetrahydro-5H-cyclohept[d]imidazo[2,1-b]thiazol-3-methanol (Formula P-5, X=0), after two crystallizations from ethanol.
Reaction SMILES: F[C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)=[O:7])=[CH:4][C:3]=1[N+:18]([O-:20])=[O:19].[OH-].[K+].[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=1)([CH3:26])([CH3:25])[CH3:24]>CS(C)=O.O>[C:23]([O:27][C:28](=[O:37])[NH:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][C:2]2[CH:17]=[CH:16][C:5]([C:6](=[O:7])[NH:8][C:9]3[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=3)=[CH:4][C:3]=2[N+:18]([O-:20])=[O:19])=[CH:34][CH:35]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: Cc1ccc(NC(=O)c2ccc(F)c([N+](=O)[O-])c2)cc1
Reactant: CC(C)(C)OC(=O)Nc1ccc(O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccc(NC(=O)c2ccc(Oc3ccc(NC(=O)OC(C)(C)C)cc3)c([N+](=O)[O-])c2)cc1
Temperature: 80 °C

Procedure:
To the product from Example 86B (1.77 g, 5.45 mmol), KOH (736 mg, 12.9 mmol), and (4-Hydroxy-phenyl)-carbamic acid tert-butyl ester (1.35 g, 6.45 mmol) were dissolved in DMSO and heated to 80° C. for 2 hrs. At this time the reaction mixture was cooled to room temperature and diluted with water. The title compound was then collected by filtration (380 mg, 12.7%).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([CH:15]([O:19][CH3:20])[C:16]([OH:18])=O)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:21][CH2:22][C:23]1[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=1>>[C:22]([C:23]1[CH:30]=[CH:29][C:26]([CH2:27][NH:28][C:16](=[O:18])[CH:15]([C:9]2[CH:10]=[CH:11][C:12]([O:13][CH3:14])=[C:7]([O:6][CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)[CH:8]=2)[O:19][CH3:20])=[CH:25][CH:24]=1)#[N:21]
Reactant: COc1ccc(C(OC)C(=O)O)cc1OC1CCCC1
Reactant: N#Cc1ccc(CN)cc1
Product: COc1ccc(C(OC)C(=O)NCc2ccc(C#N)cc2)cc1OC1CCCC1

Procedure:
(RS)-(3-Cyclopentyloxy-4-methoxy-phenyl)-methoxy-acetic acid was coupled with 4-aminomethyl benzonitrile according to general procedure B to give (RS)-N-(4-cyano-benzyl)-2-(3-cyclopentyloxy-4-methoxy-phenyl)-2-methoxy-acetamide. Colorless solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][F:9])[N:3]=1.[CH2:10]([N:14]1[CH:18]=[C:17]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)[CH:16]=[N:15]1)[CH2:11][C:12]#[CH:13]>>[F:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]#[C:12][CH2:11][CH2:10][N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)[CH:16]=[N:15]2)[N:3]=1
Reactant: FCc1cccc(Br)n1
Reactant: C#CCCn1cc(-c2ccc(F)cc2)cn1
Product: FCc1cccc(C#CCCn2cc(-c3ccc(F)cc3)cn2)n1
Yield: 38260.9 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-bromo-6-(fluoromethyl)-pyridine (49 mg, 0.26 mmol) and 1-but-3-ynyl-4-(4-fluoro-phenyl)-1H-pyrazole (50 mg, 0.23 mmol, Example 140(A)). Reaction time: 13 hours. The crude residue was purified by flash chromatography (DCM/MeOH 98:2) to yield 29 mg (88 mmol, 38%) of 2-(fluoromethyl)-6-(4-(4-(4-fluorophenyl)-1H-pyrazol-1-yl)but-1-ynyl)pyridine as a yellow solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:14][CH2:13][CH2:12][C:11]3[S:10][C:9]([C:15]4[N:16]([CH:20]([CH3:22])[CH3:21])[N:17]=[CH:18][N:19]=4)=[N:8][C:7]=3[C:6]=2[CH:23]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26](B(O)O)[CH:25]=1>>[CH:20]([N:16]1[C:15]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:5]4[CH:4]=[CH:3][C:2]([C:26]5[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=5)=[CH:23][C:6]=4[C:7]=3[N:8]=2)=[N:19][CH:18]=[N:17]1)([CH3:22])[CH3:21]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(Br)cc1-2
Reactant: OB(O)c1cccnc1
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1ccc(-c3cccnc3)cc1-2
Yield: 22 %

Procedure:
Following the procedure for 128, 9-Bromo-2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene from Example 6 and pyridin-3-ylboronic acid were reacted to give 342 (0.120 g, 22%). 1H NMR (400 MHz, DMSO) δ 8.91 (d, J=1.7, 1H), 8.72 (d, J=2.3, 1H), 8.57 (dd, J=7.2, 3.7, 1H), 8.11 (s, 1H), 8.07 (d, J=8.0, 1H), 7.69 (dd, J=8.4, 2.3, 1H), 7.53 (dd, J=7.9, 4.8, 1H), 7.22 (d, J=8.4, 1H), 5.79 (dt, J=13.2, 6.6, 1H), 4.44 (t, J=4.9, 2H), 3.49 (t, J=4.9, 2H), 1.57 (d, J=6.6, 6H). MS (ESI(+)): m/z 390.1 (M+H)
Reaction SMILES: [C:1]12([CH2:11][OH:12])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[H-].[Na+].F[C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=1[Br:24]>O1CCCC1>[C:1]12([CH2:11][O:12][C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][C:17]=3[Br:24])[CH2:8][CH:7]3[CH2:6][CH:5]([CH2:4][CH:3]([CH2:9]3)[CH2:2]1)[CH2:10]2
Reactant: OCC12CC3CC(CC(C3)C1)C2
Reactant: N#Cc1ccc(F)c(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1ccc(OCC23CC4CC(CC(C4)C2)C3)c(Br)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.9 %

Procedure:
To a mixture of adamantan-1-ylmethanol (12.47 g, 75.00 mmol) in anhydrous tetrahydrofuran (100 mL) was added sodium hydride (60% w/w in mineral oil, 3.30 g, 82.50 mmol) at 0° C. The resulting mixture was stirred at ambient temperature for 2 h, followed by the addition of 4-fluoro-3-bromobenzonitrile (15.00 g, 75.00 mmol). Stirring was continued at ambient temperature for 17 h, cooled to 0° C. and quenched with saturated ammonium chloride solution (20 mL). The volatiles were removed by evaporation in vacuo. The residue was washed with water and diethyl ether to give the title compound as a pale yellow solid (21.00 g, 80%): 1H NMR (300 MHz, CDCl3) δ 7.80-7.78 (m, 1H), 7.56-7.51 (m, 1H), 6.88-6.84 (m, 1H), 3.57 (s, 3H), 2.02 (br s, 3H), 1.73-1.55 (m, 12H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[C:25]([Cl:30])[CH:24]=2)[C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@@H:13]2[C:18]([NH2:20])=[O:19])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Fc1ccc(CBr)cc1Cl
Reactant: NC(=O)[C@H]1CCCC[C@H]1NS(=O)(=O)c1ccc(Cl)cc1
Product: NC(=O)[C@H]1CCCC[C@H]1N(Cc1ccc(F)c(Cl)c1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 43 %

Procedure:
The titled compound was prepared in 43% yield from (1S,2R)-2-(4-chlorobenzenesulfonylamino)-cyclohexanecarboxylic acid amide (75 mg, 0.237 mmol) and 4-bromomethyl-2-chloro-1-fluoro-benzene (56 mg, 0.249 mmol) according to the procedure described for Example 3: 1H NMR (500 Mz, DMSO) δ 7.80 (d, 2 H, J=8.5), 7.63 (d, 2 H, J=8.8), 7.38–7.27 (m, 4 H), 6.67 (br s, 1 H), 4.52 (ABq, 2 H, Δv=92.1, Jab=17.1), 3.87, 2.79 (m, 1 H), 2.44 (m, 1 H), 1.78 (m, 1 H), 1.64 (m, 2 H), 1.42–1.20 (m, 3 H), 0.90 (m, 1 H); MS m/e 481.2 (M+Na)+.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=O)=[CH:4][CH:3]=1.[CH:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:13][CH:12]=1.N>C(O)C>[C:14]1([N:17]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:23]=3[N:24]=[C:6]2[C:5]2[CH:9]=[CH:10][C:2]([I:1])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(I)cc1
Reactant: Nc1ccccc1Nc1ccccc1
Agent: N
Solvent: CCO
Product: Ic1ccc(-c2nc3ccccc3n2-c2ccccc2)cc1
Temperature: 75 °C
Reaction time: 3 h

Procedure:
37.47 g (136 mmol) of 97% 4-iodobenzoyl chloride and 12.82 g (68.2 mmol) of 98% o-aminodiphenylamine were heated to 100° C., in the course of which a stirrable melt formed from 85-90° C. Once the gas evolution had ended (5 min), the melt solidified. The reaction mixture was kept at 100° C. for another 3 hours. After cooling, it was admixed with 100 ml of ethanol with stirring. The precipitate was filtered off with suction, washed with ethanol and stirred up again in 400 ml of ethanol. The suspension was heated to 75° C., which formed a solution which was adjusted to pH 8 with 29 ml of 25% ammonia. After cooling to 5-10° C., the precipitate was filtered off with suction, washed with cold ethanol and dried at 75° C. in a vacuum drying cabinet. 18.37 g (68% of theory) of light gray microcrystals having an m.p. of 178-181° C. were obtained.
Reaction SMILES: [CH3:1][C:2]([CH:4]([CH3:6])[CH3:5])=[CH2:3].[CH3:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([NH:17]Cl)(=[O:16])=[O:15])=[CH:12][CH:13]=1.[Br-].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>C(#N)C>[CH:2]([C:4]1([CH3:6])[CH2:5][N:17]1[S:14]([C:11]1[CH:12]=[CH:13][C:8]([CH3:7])=[CH:9][CH:10]=1)(=[O:15])=[O:16])([CH3:1])[CH3:3]
Reactant: C=C(C)C(C)C
Reactant: Cc1ccc(S(=O)(=O)NCl)cc1
Agent: C[N+](C)(C)c1ccccc1
Agent: [Br-]
Solvent: CC#N
Product: Cc1ccc(S(=O)(=O)N2CC2(C)C(C)C)cc1
Temperature: 20 °C
Reaction time: 48 h
Yield: 51.7 %

Procedure:
To a solution of 2,3-dimethyl butene (300 ml, 2.42 mol) in 7.8 L of dry acetonitrile was added Chloramine-T (749.9 g, 1.1 eq) portionwise over 90 min. The temperature was maintained at approximately 20° C. To this reaction mixture was added phenyltrimethylammonium tribromide (91.4 g, 0.1 eq) in 10 g portions over 90 min. The temperature increased to 26° C. during the addition. The reaction mixture was stirred at room temperature for 2 days. The reaction mixture was concentrated down to approximately 15% of the initial volume and was them filtered, washing the solid with 1 L of acetonitrile. The organic liquid phase was concentrated and the residue dissolved in 2.5 L of EtOAc. The resulting solution was washed twice with water, dried over MgSO4, and concentrated to give a solid. The crude was purified on a large plug of celite using gradient elution 5% to 25% EtOAc/heptanes to afford 317 g of 2-isopropyl-2-methyl-1-[(4-methylphenyl)sulfonyl]aziridine as a solid.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]1[CH:51]=[CH:50][C:14]([CH2:15][C:16]2[C:17]([CH3:49])=[CH:18][C:19]([O:45][C:46](=[O:48])[CH3:47])=[C:20]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:21]=2)=[CH:13][CH:12]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[NH2:8][CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:15][C:16]2[C:17]([CH3:49])=[CH:18][C:19]([O:45][C:46](=[O:48])[CH3:47])=[C:20]([C@@H:22]3[O:39][C@H:38]([CH2:40][O:41][C:42](=[O:44])[CH3:43])[C@@H:33]([O:34][C:35](=[O:37])[CH3:36])[C@H:28]([O:29][C:30](=[O:32])[CH3:31])[C@H:23]3[O:24][C:25](=[O:27])[CH3:26])[CH:21]=2)=[CH:50][CH:51]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(CCNC(=O)OC(C)(C)C)cc3)c(C)cc2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OC[C@H]1O[C@@H](c2cc(Cc3ccc(CCN)cc3)c(C)cc2OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a chloroform solution (80 mL) of (1S)-1-[5-[4-(2-tert-butoxycarbonylaminoethyl)benzyl]-2-acetoxy-4-methylphenyl]-1,5-anhydro-2,3,4,6-tetra-O-acetyl-D-glucitol was added trifluoroacetic acid (23 mL), and the mixture was stirred for 1.5 hours at room temperature. The solvent was evaporated under reduced pressure to obtain a residue. Thus obtained residue was diluted with chloroform, and washed with a saturated sodium bicarbonate aqueous solution and brine. This solution was dried with anhydrous magnesium sulfate. The drying agent was filtered off, and the solvent was evaporated under reduced pressure to obtain the title compound (4.67 g, quant.) as a colorless powder.
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)N)=[CH:5][CH:4]=1.CO[CH:24](OC)[CH2:25][CH2:26][CH2:27][NH:28][CH3:29]>>[F:1][C:2]([F:21])([F:20])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[C:13]3[C:18](=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[C:25]([CH2:26][CH2:27][NH:28][CH3:29])=[CH:24]2)=[CH:5][CH:4]=1
Reactant: Cc1ccc(N(N)CCc2ccc(C(F)(F)F)nc2)cc1
Reactant: CNCCCC(OC)OC
Product: CNCCc1cn(CCc2ccc(C(F)(F)F)nc2)c2ccc(C)cc12

Procedure:
The title compound is prepared by General Method 10 using 1-(2-(6-(trifluoromethyl)pyridin-3-yl)ethyl)-1-p-tolylhydrazine (Example 2) and 4,4-dimethoxy-N-methylbutan-1-amine.
Reaction SMILES: [CH2:1]([NH2:9])[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=[C:15]([C:17]2[CH:22]=[N:21][CH:20]=[CH:19][N:18]=2)[N:16]=1>>[N:18]1[CH:19]=[CH:20][N:21]=[CH:22][C:17]=1[C:15]1[N:16]=[C:11]([NH:9][CH2:1][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:12]2[C:25]([CH3:26])=[CH:24][S:23][C:13]=2[N:14]=1
Reactant: Cc1csc2nc(-c3cnccn3)nc(Cl)c12
Reactant: NCCc1ccccc1
Product: Cc1csc2nc(-c3cnccn3)nc(NCCc3ccccc3)c12

Procedure:
With the procedure of Example 1, the reaction of phenethylamine with 4-chloro-2-(pyrazin-2-yl)-5-methyl-thieno-[2,3-d]-pyrimidine yields 2-(pyrazin-2-yl)-4-phenethylamino-5-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=O)[CH2:3][CH2:2]1.[NH3:11]>C(O)C>[CH:1]1([NH:4][C:5](=[O:10])/[CH:6]=[C:7](\[NH2:11])/[CH3:9])[CH2:3][CH2:2]1
Reactant: CC(=O)CC(=O)NC1CC1
Reactant: N
Solvent: CCO
Product: C/C(N)=C/C(=O)NC1CC1
Reaction time: 8 h

Procedure:
Acetoacetic cyclopropylamide (209.4 g, 1.48 mole) is dissolved in ethanol (160 ml) and thereto is passed ammonia gas, while the temperature is controlled below 30° C. by cooling with a water bath. After passing ammonia gas for about 3 hours, yellow crystals precipitate. The reaction mixture is allowed to stand at 0° C. overnight. The precipitates are separated by filtration and washed with diethyl