Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15])=O)(C)(C)C.C1(OC)C=CC=CC=1.[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55]>C(Cl)Cl>[F:52][C:53]([F:58])([F:57])[C:54]([OH:56])=[O:55].[NH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:37]=[C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)[CH:35]=[CH:34][C:13]=1[C:14]([NH:16][C:17]1[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:18]=1[C:19]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][N:23]=1)=[O:20])=[O:15]
Reactant: CC(C)(C)OC(=O)NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: NCCOc1cc(N2CCOCC2)ccc1C(=O)Nc1cc(F)ccc1C(=O)Nc1ccc(Cl)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
The 2-[2-(2-tert-butoxycarbonylaminoethoxy)-4-(morpholin-4-yl)benzoylamino]-N-(5-chloropyridin-2-yl)-4-fluorobenzamide (570 mg, 0.93 mmol) was mixed with CH2Cl2 (5 mL), anisole (1 mL), and trifluoroacetic acid (2 mL). The mixture was stirred at ambient temperature for 2 hours, concentrated to dryness, mixed with diethyl ether, and sonicated for 5 minutes to give a white fluffy solid which was filtered to give 490 mg (62%) of the desired product as the trifluoroacetate salt.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:16])([F:15])[F:14])[C:10](=[O:11])[C:5]=2[C:4]([C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)=[CH:3]1.[Br:23]Br.C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=S.[Na+].[Na+]>CN(C=O)C.O>[Br:23][C:3]1[N:2]([CH3:1])[C:6]2[N:7]=[CH:8][N:9]([CH2:12][C:13]([F:15])([F:16])[F:14])[C:10](=[O:11])[C:5]=2[C:4]=1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cn1cc(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Reactant: BrBr
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Br)c(-c2cccnc2)c2c(=O)n(CC(F)(F)F)cnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 37 %

Procedure:
7-methyl-5-(pyridin-3-yl)-3-(2,2,2-trifluoroethyl)-3H-pyrrolo[2,3-d]pyrimidin-4(7H)-one (0.28 g, 0.908 mmol) was dissolved in DMF (8 ml). The solution was cooled down to 0° C. Bromine (0.056 ml, 1.09 mmol) was added in dropwise. After 30 min, the reaction mixture was diluted with a aqueous mixture (3:1:4 water, saturated sodium bicarbonate solution and 20% w/w sodium thiosulfate solution, 80 ml) and extracted with ethyl acetate (3×50 ml). The combined organic phase was washed with water (4×60 ml), brine and concentrated to give title compound (0.13 g, 37%). LCMS RT=0.81 min, [M+H+(79Br)]=387.0, [M+H+(81Br)]=389.0.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].CS(O[CH2:18][C:19]([F:22])([F:21])[F:20])(=O)=O>CN(P(N(C)C)(N(C)C)=O)C>[F:20][C:19]([F:22])([F:21])[CH2:18][O:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1
Reactant: CS(=O)(=O)OCC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C

Procedure:
To prewashed sodium hydride (0.61 g, 25.5 mmol) in 10 ml of hexamethylphosphorotriamide (HMPT) is added 4-nitrophenol (3.55 g, 25.5 mmol) in 10 ml of HMPT at 25°-30°. Five ml more of HMPT is added and the mixture is warmed gently to 45°-50° for 30 min. 2,2,2-Trifluoroethyl methansulfonate (5.0 g, 28.0 mmol) and HMPT (1 ml) are then added and the mixture is heated to 146°-151° for 20 hours. The reaction mixture is cooled to RT and is then poured into ice water and extracted with ether (3X). The combined ether layers are washed with water and brine, dried, filtered and rotoevaporated to give 4-(2,2,2-trifluoroethoxy)nitrobenzene.
Reaction SMILES: [N:1]1([C:7]2[N:11]3[CH:12]=[C:13]([O:16][C@@H:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=5)[C@@H:20]([NH2:27])[CH2:19][CH2:18]4)[CH:14]=[CH:15][C:10]3=[N:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.ClC(Cl)(Cl)C[O:31][C:32](=O)[NH:33][C:34]1[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=[C:37]([C:39]([CH3:42])([CH3:41])[CH3:40])[CH:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:39]([C:37]1[CH:38]=[C:34]([NH:33][C:32]([NH:27][C@@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@@H:17]([O:16][C:13]3[CH:14]=[CH:15][C:10]4[N:11]([C:7]([N:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)=[N:8][N:9]=4)[CH:12]=3)[CH2:18][CH2:19]2)=[O:31])[N:35]([C:43]2[CH:48]=[CH:47][C:46]([CH3:49])=[CH:45][CH:44]=2)[N:36]=1)([CH3:42])([CH3:40])[CH3:41]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: N[C@H]1CC[C@H](Oc2ccc3nnc(N4CCCCC4)n3c2)c2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@H](Oc3ccc4nnc(N5CCCCC5)n4c3)c3ccccc32)cc1
Yield: 20 %

Procedure:
A mixture of Intermediate 55a (120 mg, 0.33 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 147 mg, 0.36 mmol), DIPEA (86.0 μL, 110.50 mmol) and 1,4-dioxane (2.5 mL) were heated to 60° C. for 18 h. After cooling the solvent was evaporated in vacuo. The residue was purified by FCC, using 0-10% MeOH in DCM, to give a pale yellow foam. This was lyophilised to provide the title compound as an off-white solid (28 mg, 20%). LCMS (Method 5) Rt 4.76 min, m/z 619 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.26 (9H, s), 1.61 (2H, m), 1.72 (5H, m), 2.02-2.17 (3H, m), 2.35 (3H, s), 3.13 (4H, m), 4.90 (1H, m), 5.58 (1H, m), 6.31 (1H, s), 6.99 (1H, d, J 7.8), 7.19 (1H, dd, J 9.7, 2.2), 7.26-7.43 (8H, m), 7.58-7.64 (2H, m), 7.98 (1H, s).
Reaction SMILES: [C:1](=[O:19])(OC1C=CC([N+]([O-])=O)=CC=1)[O:2][CH2:3][C:4]1[N:5]=[CH:6][S:7][CH:8]=1.[NH:20]1[CH2:24][CH2:23][CH:22]([CH2:25][OH:26])[CH2:21]1.O>ClCCl.CO>[OH:26][CH2:25][CH:22]1[CH2:23][CH2:24][N:20]([C:1]([O:2][CH2:3][C:4]2[N:5]=[CH:6][S:7][CH:8]=2)=[O:19])[CH2:21]1
Reactant: OCC1CCNC1
Reactant: O=C(OCc1cscn1)Oc1ccc([N+](=O)[O-])cc1
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: O=C(OCc1cscn1)N1CCC(CO)C1
Reaction time: 15 h
Yield: 21.6 %

Procedure:
A solution of 3.00 g (10.70 mmol) of thiazol-4-ylmethyl 4-nitrophenyl carbonate in 20 ml of dichloromethane is added at ambient temperature, via a dropping funnel, to a solution of 1.13 g (11.24 mmol) of pyrrolidin-3-ylmethanol (commercial) in 20 ml of methanol. The solution is stirred for 15 hours. Water is subsequently added to the reaction medium. After extraction of the aqueous phase with dichloromethane, the organic phases are successively washed with a 1M aqueous sodium hydroxide solution and then with a saturated aqueous sodium chloride solution. After having dried the organic phases over sodium sulphate, the mixture is filtered and the filtrate is evaporated to dryness. 0.56 g of the desired product is thus obtained in the form of an oil after purification on a column of silica gel, elution being carried out with a dichloromethane/methanol (97/3 to 95/5) mixture.
Reaction SMILES: [C:1]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=[CH:5][C:4]([CH:7]([NH:14][CH3:15])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1.[CH2:22]([O:24][C:25]([C:27]1[CH:28]=[CH:29][C:30]2[O:35][CH2:34][C:33](=[O:36])[N:32]([CH2:37][C:38]([OH:40])=O)[C:31]=2[CH:41]=1)=[O:26])[CH3:23].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.FC(F)(F)C(O)=O>C(Cl)Cl.CC#N.O>[C:1]1([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:6]=[CH:5][C:4]([CH:7]([N:14]([CH3:15])[C:38](=[O:40])[CH2:37][N:32]2[C:31]3[CH:41]=[C:27]([C:25]([O:24][CH2:22][CH3:23])=[O:26])[CH:28]=[CH:29][C:30]=3[O:35][CH2:34][C:33]2=[O:36])[CH2:8][N:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:3][CH:2]=1
Reactant: CNC(CN1CCCC1)c1ccc(-c2ccccc2)cc1
Reactant: CCOC(=O)c1ccc2c(c1)N(CC(=O)O)C(=O)CO2
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOC(=O)c1ccc2c(c1)N(CC(=O)N(C)C(CN1CCCC1)c1ccc(-c3ccccc3)cc1)C(=O)CO2
Reaction time: 0.25 h
Yield: 77.8 %

Procedure:
[1-(4-biphenylyl)-2-(1-pyrrolidinyl)ethyl]methylamine (0.5 g, 1.8 mmol) and {6-[(ethyloxy)carbonyl]-3-oxo-2,3-dihydro-4H-1,4-benzoxazin-4-yl}acetic acid (0.63 g, 2.0 mmol) were dissolved in 10 mL of methylene chloride. Triethylamine (1.0 mL, 7.1 mmol) was delivered to the room temperature mixture, and the solution was allowed to stir for several minutes before a separate solution of 1H-1,2,3-benzotriazol-1-yloxy-tris(dimethylamino)-phosphonium hexafluorophosphate (BOP reagent, 0.89 g, 2.0 mmol) dissolved in 4 mL of methylene chloride was added at room temperature to the mixture. The reaction was maintained at that temperature for 72 hours, before it was determined to be complete by LCMS (two Aquasil C18, 20×1 mm columns were run in sequence, 4 minutes at 0.1 mL/min, 1-99% CH3CN/H2O with 0.018% trifluoroacetic acid, ES) Rt=2.7 min and m/e 542 [M+1]+. Solvent was removed by rotary evaporation and the crude residue was purified by prep HPLC (Waters, 50×100 mm, 84 mL/min, A: acetonitrile B: water (pH=10, NH4OH), A: 10 to 99% over 15 min, UV detection at 214 nm) to give the title compound (0.75 g. 1.4 mmol, 77%) as a pale yellow amorphous solid. MS (ES) m/e 542 [M+H]+.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:19]=[CH:18][C:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][NH:26]C(OC(C)(C)C)=O)=[O:22])=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:39])[CH3:38])[CH2:6][C@@H:5]1[CH3:41])(=[O:3])[CH3:2].[ClH:42]>O1CCOCC1>[ClH:42].[C:1]([N:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[CH:16][C:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][NH2:26])=[O:22])=[CH:18][CH:19]=3)=[CH:11][CH:12]=2)[C@H:7]([NH:34][C:35](=[O:40])[O:36][CH:37]([CH3:38])[CH3:39])[CH2:6][C@@H:5]1[CH3:41])(=[O:3])[CH3:2]
Reactant: CC(=O)N1c2ccc(-c3ccc(CC(=O)NCCNC(=O)OC(C)(C)C)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: Cl
Solvent: C1COCCO1
Product: CC(=O)N1c2ccc(-c3ccc(CC(=O)NCCN)cc3)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 52.6 %

Procedure:
A solution of 1-methylethyl {(2S,4R)-1-acetyl-6-[4-(2-{[2-({[(1,1-dimethylethyl)oxy]carbonyl}amino)ethyl]amino}-2-oxoethyl)phenyl]-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl}carbamate (for a preparation see Intermediate 38) (60 mg, 0.106 mmol) in 1,4-dioxane (2 ml) was treated with hydrogen chloride in 1,4-dioxane (4N, 2 mL, 8.00 mmol) and the resulting mixture stirred at room temperature for 5 h then concentrated in vacuo. The residue was triturated with Et2O and the solid isolated by filtration to give 1-methylethyl [(2S,4R)-1-acetyl-6-(4-{2-[(2-aminoethyl)amino]-2-oxoethyl}phenyl)-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate hydrochloride (28 mg, 0.056 mmol, 52.6% yield) as a pale yellow solid. LCMS (HpH, 2 min), Rt=0.79 min, MH+=467.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[C:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(C(OC)=O)[CH2:6][CH2:5]2.[Cl-].[Li+].O>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH:7]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:6][CH2:5]2
Reactant: COC(=O)C1(c2ccccc2)CCc2cc(F)ccc2C1=O
Agent: [Cl-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccc(F)cc2CCC1c1ccccc1
Temperature: 150 °C
Yield: 87 %

Procedure:
The tetralone from Step B (2.8 g, 9.4 mmole) was dissolved in 45 ml of dimethylformamide. To this solution was added lithium chloride (2.0 g, 47 mmole) and water (0.42 ml, 23 mmole). The reaction mixture was heated to 150° C. for 2.5 hrs and then cooled and partitioned between ether and water. The aqueous Phase was separated and extracted three times with ether. The combined organic phases were washed once with water, dried (MgSO4), and concentrated (1.96 g, 87% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.Cl[C:34]([O:36][CH2:37][CH3:38])=[O:35]>ClCCl>[CH2:37]([O:36][C:34](=[O:35])[NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23](=[O:25])[CH3:24])[CH2:18][CH2:17]3)[CH2:10][CH2:9]2)[CH:3]=1)[CH3:38]
Reactant: CCOC(=O)Cl
Reactant: CC(=O)CN1CCC(CCN2CCN(c3cccc(N)c3)CC2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)Nc1cccc(N2CCN(CCC3CCN(CC(C)=O)CC3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a cooled solution of 0.1 g (0.3 mmol) of 1-(4-{2-[4-(3-aminophenyl)piperazin-1-yl]ethyl}piperidin-1-yl)propan-2-one in 5 mL of dichloromethane and 0.03 g (0.3 mmol) of triethylamine, is slowly added 0.032 g (0.3 mmol) of ethyl chloroformate. The mixture is stirred overnight at room temperature then concentrated under reduced pressure. The product is dissolved in ethyl acetate, washed twice with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The oily residue is purified over 10 g of silica gel (eluant dichloromethane/methanol 95/5) to give 0.025 g (20%) of [3-(4-{2-[1-(2-oxopropyl)piperidin-4-yl]ethyl}piperazin-1-yl)phenyl]carbamic acid ethyl ester as a solid.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.C[O-].[Na+].O.[C:19](OCC)(=[O:21])C>CO>[CH3:19][O:21][C:2]1[N:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2
Reactant: FC(F)(F)c1nc(Cl)c2[nH]cnc2n1
Reactant: CCOC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COc1nc(C(F)(F)F)nc2nc[nH]c12
Temperature: 20 °C
Yield: 49 %

Procedure:
6-Chloro-2-trifluoromethylpurine (1.10 g, 5.0 mmol) in 25 ml of methanol was treated with 1.35 g (25 mmol) of sodium methoxide at 80° C. for 60 hours. Water (50 ml) and ethyl acetate (50 ml) were added after the reaction mixture was cooled to 20° C. The organic layer was separated and concentrated. Chromatography gave 535 mg (49%) of the title compound.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH2:2][SH:3].[Br:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11](F)[CH:10]=1.C(N(CC)CC)C>CS(C)=O>[Br:8][C:9]1[CH:10]=[CH:11][C:12]2[CH:13]=[C:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[S:3][C:15]=2[CH:16]=1
Reactant: O=Cc1ccc(Br)cc1F
Reactant: CCOC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCOC(=O)c1cc2ccc(Br)cc2s1
Yield: 91.8 %

Procedure:
A solution of ethyl thioglycolate (0.65 g, 5.42 mmol), 4-bromo-2-fluorobenzaldehyde (1.0 g, 4.93 mmol) and triethylamine (1.25 mL, 12.3 mmol) in DMSO (5 mL) was heated at 75° C. for 2 h. The mixture was partitioned between H2O (50 mL) and CH2Cl2 (2×50 mL), and the combined organic layers were dried over Na2SO4. The drying agent was filtered off, and the solvent was removed in vacuo to give the title compound as an oil (1.29 g, 92%).
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.[F:18][C:19]1[CH:27]=[C:26]2[C:22]([C:23]([CH:28]3[CH2:33][CH2:32][C:31](=O)[CH2:30][CH2:29]3)=[CH:24][NH:25]2)=[CH:21][CH:20]=1>>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([N:9]2[CH2:15][CH2:14][CH2:13][N:12]([CH:31]3[CH2:30][CH2:29][CH:28]([C:23]4[C:22]5[C:26](=[CH:27][C:19]([F:18])=[CH:20][CH:21]=5)[NH:25][CH:24]=4)[CH2:33][CH2:32]3)[CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cccc(N2CCCNCC2)c1
Reactant: O=C1CCC(c2c[nH]c3cc(F)ccc23)CC1
Product: Fc1ccc2c(C3CCC(N4CCCN(c5cccc(C(F)(F)F)c5)CC4)CC3)c[nH]c2c1
Yield: 64 %

Procedure:
The title compound was prepared according to Example 3, Step 4 except 1-(3-trifluoromethyl-phenyl)-[1,4]diazepane was used instead of 1-(2-methoxy-phenyl)-[1,4]diazepane and 4-(6-fluoro-1H-indol-3-yl)-cyclohexanone was used in place of 4-(5-fluoro-1H-3-indolyl)-cyclohexanone. Yield: 64%; MS (ES) m/z (relative intensity): 460 (M++H, 100).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]4[O:22][CH2:21][O:20][C:18]4=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][CH2:30][CH2:31]Cl>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([CH:33]=[CH:34][CH:35]=1)[O:28][CH2:29][CH2:30][CH2:31][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][N:8]2[C:14](=[O:15])[CH2:13][C:12]3[CH:16]=[C:17]4[O:22][CH2:21][O:20][C:18]4=[CH:19][C:11]=3[CH2:10][CH2:9]2)[CH2:2]1
Reactant: O=C1Cc2cc3c(cc2CCN1CC1CCCNC1)OCO3
Reactant: COc1cccc(OCCCCl)c1
Product: COc1cccc(OCCCN2CCCC(CN3CCc4cc5c(cc4CC3=O)OCO5)C2)c1

Procedure:
Prepared from 3-[(piperidin-3-yl)-methyl]-7,8-methylenedioxy-1,3,4,5-tetrahydro-2H-3-benzazepin-2-one and 3-(3-methoxyphenoxy)-propyl chloride analogously to Example 1.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[S:27][C:28]2[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:29]=2[N:30]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[S:27][C:28]5[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:29]=5[N:30]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Clc1nc2cc(Cl)c(Cl)cc2s1
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4nc5cc(Cl)c(Cl)cc5s4)cc3CC[C@@H]12
Yield: 30.7 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2,5,6-trichloro benzothiazole (110 mg, 0.46 mmol) and 1 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (80% ethyl acetate/hexanes eluent) to give 54 mg (31%) of the title compound as an amorphous foam. FDMS: m/e=463.
Reaction SMILES: [CH3:1][CH:2]([OH:8])[CH:3]=[CH:4][CH:5]([OH:7])[CH3:6].[CH:9](=O)[CH2:10][CH2:11][CH3:12].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH2:10]([CH:9]1[O:8][CH:2]([CH3:1])[CH:3]=[CH:4][CH:5]([CH3:6])[O:7]1)[CH2:11][CH3:12]
Reactant: CC(O)C=CC(C)O
Reactant: CCCC=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCC1OC(C)C=CC(C)O1
Temperature: 25 °C
Yield: 80 %

Procedure:
A mixture of 580 g (5 moles) of hex-3-ene-2,5-diol, 3 g of p-toluenesulfonic acid, 360 g (5 moles) of n-butanal and 1 l of toluene was refluxed, and the resulting water of reaction (108 ml) was removed in the course of 3 h. Thereafter, the mixture was left to cool to room temperature, 10 ml of a 25% strength aqueous sodium hydroxide solution were added, the mixture was washed neutral with a little water and the toluene was removed under reduced pressure at from 50° to 60° C. The residue obtained was distilled under 0.1 mbar to give 681 g (4 moles) of 2-propyl-4,7-dimethyl-4,7-dihydro-1,3-dioxepin of boiling point 70° C./0.1 mbar.
Reaction SMILES: FC(F)(F)C(O)=O.[NH:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1.[N+](C1C=CC([O:32][C:33](=O)[NH:34][C:35]2[CH:40]=[CH:39][C:38]([N:41]3[CH:46]=[CH:45][CH:44]=[CH:43][C:42]3=[O:47])=[CH:37][C:36]=2[F:48])=CC=1)([O-])=O>>[F:48][C:36]1[CH:37]=[C:38]([N:41]2[CH:46]=[CH:45][CH:44]=[CH:43][C:42]2=[O:47])[CH:39]=[CH:40][C:35]=1[NH:34][C:33]([N:8]1[CH2:12][CH2:11][C@H:10]([CH2:13][NH:14][C:15]([C:17]2[S:18][C:19]([Br:22])=[CH:20][CH:21]=2)=[O:16])[CH2:9]1)=[O:32]
Reactant: O=C(Nc1ccc(-n2ccccc2=O)cc1F)Oc1ccc([N+](=O)[O-])cc1
Reactant: O=C(NC[C@H]1CCNC1)c1ccc(Br)s1
Solvent: O=C(O)C(F)(F)F
Product: O=C(NC[C@H]1CCN(C(=O)Nc2ccc(-n3ccccc3=O)cc2F)C1)c1ccc(Br)s1

Procedure:
56.3 Using general method H. 5-bromo-thiophene-2-carboxylic acid ((S)-1-pyrrolidin-3-ylmethyl)-amide trifluoro acetate was reacted with [2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-carbamic acid 4-nitro-phenyl ester (prepared according to example 54.3) to give (R)-3-{[(5-bromo-thiophene-2-carbonyl)-amino]-methyl}-pyrrolidine-1-carboxylic acid[2-fluoro-4-(2-oxo-2H-pyridin-1-yl)-phenyl]-amide. White solid. MS 521.3 ([M+H]+)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17](S(C)=O)[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:1][C:2]1[CH:3]=[C:4]2[N:10]=[CH:9][N:8]([CH2:11][C:12]3[CH:23]=[CH:22][C:15]4[N:16]=[C:17]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:18][C:14]=4[CH:13]=3)[C:5]2=[N:6][CH:7]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)cnc43)cc2s1
Temperature: 125 °C
Yield: 39.7 %

Procedure:
A stirred mixture of 6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (90 mg, 0.260 mmol) from Step 4 of this Example, (1R,2R)-(−)-2-aminocyclohexanol (120 mg, 1.03 mmol), and DIEA (133 mg, 1.03 mmol) in anhydrous DMA (3 mL) was heated at 125° C. for 15 h. After the reaction mixture had cooled to rt, the mixture was purified directly by reverse-phase HPLC using a mixture of water (5% CH3CN, 0.05% HCOOH) and CH3CN (0.05% HCOOH) as the mobile phase and Varian Pursuit XRs C-18 column as the stationary phase to afford (1R,2R)-2-((6-((6-fluoro-3H-imidazo[4,5-b]pyridin-3-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (41 mg) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.68 (s, 1H), 8.42 (s, 1H), 8.08 (dd, J=2.4, 9.4 Hz, 1H), 7.98 (d, J=7.5 Hz, 1H), 7.66 (s, 1H), 7.17-7.33 (m, 2H), 5.48 (s, 2H), 4.76 (br s, 1H), 3.45-3.55 (m, 2H), 2.03 (m, 1H), 1.87 (m, 1H), 1.55-1.67 (m, 2H), 1.10-1.33 (m, 4H). LCMS (ESI) m/z 398 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])=[CH:4][CH:3]=1.[NH2:17][C:18]1[C:22]([C:23]2[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=2)=[CH:21][NH:20][N:19]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[N:19]3[N:20]=[CH:21][C:22]([C:23]4[CH:28]=[C:27]([CH3:29])[N:26]=[C:25]([CH3:30])[CH:24]=4)=[C:18]3[N:17]=2)=[CH:4][CH:3]=1
Reactant: Cc1cc(-c2c[nH]nc2N)cc(C)n1
Reactant: O=C(CC(=O)C(F)(F)F)c1ccc(Cl)cc1
Product: Cc1cc(-c2cnn3c(C(F)(F)F)cc(-c4ccc(Cl)cc4)nc23)cc(C)n1
Yield: 47.2 %

Procedure:
Reaction of 1-(4-chloro-phenyl)-4,4,4-trifluoro-butane-1,3-dione (125 mg, 0.5 mmol), prepared from commercially available 4-chloro-acetophenone according to general procedure A, and 3-amino-4-(2,6-dimethyl-4-pyridinyl)-pyrazole [prepared from 4-cyanomethyl-2,6-dimethyl-pyridine, CAS No. 130138-46-4, see part synthesis of amino-pyrazole derivatives] (94 mg, 0.5 mmol) according to general procedure B yielded the title compound as a yellow solid (95 mg, 47%). MS (ISP) 403.2 [(M+H)+]; mp 256° C.