Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25].C(OCC)(=O)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.OP(O)=O.O[Mo](O)(=O)=O.O.C1CCCCC1>[CH2:25]([N:7]1[CH2:11][CH2:10][CH2:9][C:8]1=[O:12])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH3:14]
Reactant: CCCCCCCCCCCCBr
Reactant: O=C1CCCN1
Agent: O=[Mo](=O)(O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCN1CCCC1=O
Temperature: 50 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
Step A is conducted by adding tetrabutylammonium bromide (950 mg-3 mmol-0.05 eq.) and powder potash (23.1 g-411 mmol-7 eq.) under agitation to a solution of 2-pyrrolidinone (5.00 g-58.8 mmol) and bromododecane (18.5 mL, 76.4 mmol, 1.3 eq.) in toluene (60 mL). The mixture is heated to 50° C. overnight. After disappearance of the 2-pyrrolidinone (verified by TLC using a 4:1 v/v mixture of ethyl acetate and cyclohexane, and phosphomolybdic acid for detection) and cooling, 60 mL of water is added and the mixture left under agitation for a further 15 minutes. The aqueous and organic phases are separated and the aqueous phase is extracted once with diethylether (60 mL). The organic phases are combined, dried over Na2SO4, filtered and concentrated. After vacuum distillation (146° C.-0.5 mbars), N-dodecylpyrrolidin-2-one is obtained (Yield: 80%) for which the 1H and 13C NMR characterisations are as follows:
Reaction SMILES: [Br:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Br:1][C:2]1[C:3]([F:21])=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(F)c(Br)cnc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Fc1c(Br)cnc2[nH]ccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
5-Bromo-4-fluoro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyri dine (12.60 g, 33.9 mmol) was placed in THF (200 mL) at 0° C. TBAF (33.9 mL, 1M THF solution) was then added, and the reaction was then stirred for 1 hour at 0° C. The reaction was quenched with NaHCO3 (aq.) and extracted into DCM. The organic fractions were combined, dried, filtered and concentrated to give a crude residue that was purified by column chromatography (500:5 DCM:MeOH) to give 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridine (6.8 g, 93.2% yield).
Reaction SMILES: C1(C2CC(O)C3C(=CC=C(O)C=3)O2)C=CC=CC=1.[OH:19][C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[O:26][CH:25]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][CH3:37])[CH:31]=1)[CH2:24][C:23]2=[O:38]>>[CH3:37][O:36][C:32]1[CH:31]=[C:30]([CH:25]2[CH2:24][CH:23]([OH:38])[C:22]3[C:27](=[CH:28][CH:29]=[C:20]([OH:19])[CH:21]=3)[O:26]2)[CH:35]=[CH:34][CH:33]=1
Reactant: COc1cccc(C2CC(=O)c3cc(O)ccc3O2)c1
Agent: Oc1ccc2c(c1)C(O)CC(c1ccccc1)O2
Product: COc1cccc(C2CC(O)c3cc(O)ccc3O2)c1

Procedure:
2-(3-Methoxyphenyl)chroman-4,6-diol was prepared as described for 2-phenylchroman-4,6-diol in Example 8(a) starting from 6-hydroxy-2-(3-methoxyphenyl)-chroman-4-one. 1H NMR (400 MHz, d6-DMSO) δ: 8.82 (s, 1H), 7.31 (t, 1H, J 15.7, 7.9 Hz), 6.99-7.02 (m, 2H), 6.88-6.90 (m, 2H), 6.59 (d, 1H, J 8.7 Hz), 6.54 (dd, 1H, J 8.7, 2.8 Hz), 5.40 (d, 1H, J 7.0 Hz), 5.08 (d, 1H, J 11.5 Hz), 4.83-4.89 (m, 1H), 3.77 (s, 3H), 2.23-2.28 (m, 1H), 1.83-1.92 (m, 1H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:14]=[CH:15][CH:16]=1)[NH2:13]>>[Cl:9][C:10]1[CH:11]=[C:12]([NH:13][C:2]2[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: Nc1cccc(Cl)c1
Reactant: Nc1cc(Cl)ncn1
Product: Nc1cc(Nc2cccc(Cl)c2)ncn1

Procedure:
The title compound is prepared analogously as described in Example 105A from 6-chloro-pyrimidin-4-ylamine and 3-chloroaniline.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([CH:20]=[CH:21][CH:22]=1)[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[S:15][CH:16]=[C:17]([CH3:19])[N:18]=2)[CH:8]=1.BrB(Br)Br.CC(=CC)C.C([O-])(O)=O.[Na+]>O.ClCCl>[CH3:19][C:17]1[N:18]=[C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:4]=[C:3]([OH:2])[CH:22]=[CH:21][CH:20]=3)[CH:12]=[CH:11][N:10]=2)[S:15][CH:16]=1
Reactant: COc1cccc(Oc2ccnc(Nc3nc(C)cs3)c2)c1
Agent: BrB(Br)Br
Agent: CC=C(C)C
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: Cc1csc(Nc2cc(Oc3cccc(O)c3)ccn2)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.9 %

Procedure:
A 50 mL round bottom flask was charged with 4-(3-methoxyphenoxy)-N-(4-methylthiazol-2-yl)pyridin-2-amine (0.2 g, 0.638 mmol) and dichloromethane (6 mL). The solution was cooled to 0° C., and tribromoborane (0.181 mL, 1.91 mmol) and 1 mL of 2-methyl-2-butene were added. The reaction mixture was stirred at 0° C. for 1 hour. Water and saturated solution of NaHCO3 were added, and the reaction mixture was extracted with EtOAc. The organic layer was dried over magnesium sulfate, filtered and concentrated. The residue was purified on a prepacked silica gel column eluting with 20-35% ethyl acetate in hexanes to give 3-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenol (0.124 g, 64.3% yield) as light orange solid. 1H NMR (DMSO) δ 10.98 (bs, 1H), 9.78 (bs, 1H), 8.15 (d, 1H), 7.26 (t, 1H), 6.69 (ddd, 1H), 6.56 (m, 2H), 6.51 (m, 3H), 2.20 (d, 3H); Mass spectrum (esi) m/z 300 (100) (M+H).
Reaction SMILES: [CH2:1]([N:3](S(F)(F)F)[CH2:4][CH3:5])[CH3:2].[C:10]([C:12]1[NH:16][C:15]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[Cl:28])=[N:14][C:13]=1[C:29]([OH:31])=O)#[N:11].[F-].[K+].C(NCC)C>COCCOCCOC.ClCCl>[CH2:1]([N:3]([CH2:4][CH3:5])[C:29]([C:13]1[N:14]=[C:15]([C:17]2[C:22]([Cl:23])=[CH:21][C:20]([C:24]([F:25])([F:27])[F:26])=[CH:19][C:18]=2[Cl:28])[NH:16][C:12]=1[C:10]#[N:11])=[O:31])[CH3:2]
Reactant: N#Cc1[nH]c(-c2c(Cl)cc(C(F)(F)F)cc2Cl)nc1C(=O)O
Reactant: CCN(CC)S(F)(F)F
Agent: [F-]
Agent: [K+]
Solvent: CCNCC
Solvent: ClCCl
Solvent: COCCOCCOC
Product: CCN(CC)C(=O)c1nc(-c2c(Cl)cc(C(F)(F)F)cc2Cl)[nH]c1C#N
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Diethylaminosulphur trifluoride (1.5 ml) was added dropwise to a stirred suspension of 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxylic acid (1.4 g, 0.004 mol) in 2-methoxyethyl ether (11 ml) whilst maintaining the temperature at about 0° C. Potassium fluoride (0.67 g, 0.0115 mol) was added and the mixture was stirred at 0° C. for 0.5 hours, and added slowly to a solution of diethylamine (8.8 g, 12.5 ml, 0.12 mol) in dichloromethane (75 ml) whilst maintaining the temperature in the range 0°-5° C. The mixture was stirred at 0°-5° C. for 1 hour and at room temperature for 0.5 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml), dried over anhydrous sodium sulphate and evaporated to dryness. The residue was purified by mplc on silica eluting with a mixture of ethyl acetate and dichloromethane (1:2) to give N,N-diethyl 5-cyano-2-(2,6-dichloro-4-trifluoromethylphenyl)imidazole-4-carboxamide (0.26 g) m.p. 195°-197° C. as an off-white solid.
Reaction SMILES: [CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([OH:23])=O)=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.CCCP(=O)=O.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:1]([N:3]([CH3:25])[C:4]1[N:24]=[C:7]2[CH:8]=[C:9]([NH:12][C:13]([C:15]3[N:19]([CH3:20])[N:18]=[CH:17][C:16]=3[C:21]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)=[O:23])=[O:14])[CH:10]=[CH:11][N:6]2[N:5]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCOCC4)cnn3C)ccn2n1
Yield: 81.6 %

Procedure:
A mixture of 5-(2-(ethyl(methyl)amino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (144 mg, 419 μmol), morpholine (365 mg, 4.19 mmol), propylphosphonic anhydride (50% in ethyl acetate, 618 μl, 1.05 mmol) and N,N-diisopropylethylamine (214 μL, 1.26 mmol) in tetrahydrofuran (7.00 ml) was refluxed for 2.5 days (weekend). The solvent was evaporated, the residue was triturated with sodium hydrogencarbonate solution. The precipitated solid was filtered off, washed with water and dried affording 2-methyl-4-(morpholine-4-carbonyl)-2H-pyrazole-3-carboxylic acid [2-(ethyl-methyl-amino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl]-amide (141 mg, 81.5%) as a white solid. mp: 167-169° C., MS: m/z=413.4 (M+H+)
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:23])=[C:4]([F:22])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([S:12]COC)[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]2[OH:21].O>O1CCOCC1.Cl>[Cl:1][C:2]1[C:3]([F:23])=[C:4]([F:22])[CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([SH:12])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:7]2[OH:21]
Reactant: CCOC(=O)c1c(SCOC)nc2c(Cl)c(F)c(F)cc2c1O
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1c(S)nc2c(Cl)c(F)c(F)cc2c1O
Yield: 81.2 %

Procedure:
To a solution of 15.7 g of ethyl 8-chloro-6,7-difluoro-4-hydroxy-2-(methoxymethylthio)quinoline-3-carboxylate in 125 ml of 1,4-dioxane, 95 ml of 35% hydrochloric acid was added dropwise at 40° C. with stirring. The mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into 500 ml of water. The precipitate was collected by filtration and recrystallized from acetonitrile to give 11.2 g of the desired compound as pale yellow needles, m.p. 125°-130° C. (decomp.).
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][N:6]1[CH:10]=[C:9](/[CH:11]=[C:12]2\[CH2:13][N:14]([C:19]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:16][CH:17]\2O)[N:8]=[N:7]1)=[O:4].[C:38]([OH:41])(=[S:40])[CH3:39].C(OC(OCC(C)(C)C)N(C)C)C(C)(C)C>>[C:38]([S:40][CH:17]1[CH2:16][CH2:15][N:14]([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:13]/[C:12]/1=[CH:11]\[C:9]1[N:8]=[N:7][N:6]([CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:10]=1)(=[O:41])[CH3:39]
Reactant: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2O)nn1
Reactant: CC(O)=S
Agent: CN(C)C(OCC(C)(C)C)OCC(C)(C)C
Product: COC(=O)Cn1cc(/C=C2\CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCC2SC(C)=O)nn1

Procedure:
Following a procedure similar to that described in Example 160-(e), (E)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidin-4-ol (4.7 g) was treated with thioacetic acid and N,N-dimethylformamide dineopentyl acetal. After extraction, the obtained substance was purified by silica gel chromatography to afford (E)-4-(acetylsulfanyl)-3-{[1-(methoxycarbonylmethyl)-1H-1,2,3-triazol-4-yl]methylidene}-1-(triphenylmethyl)piperidine (2.6 g). This compound was similarly treated with trifluoroacetic acid in dichloromethane and the residue obtained by concentration of the reaction mixture was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.026 N aqueous trifluoroacetic acid solution, 18/82, v/v) to afford the title compound (550 mg, yield: 14%) as a yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([O:12]C)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]>I>[NH2:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:8]([OH:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1cc(C(=O)O)c(N)cc1C
Agent: I
Product: Cc1cc(N)c(C(=O)O)cc1O
Yield: 100 %

Procedure:
2-Amino-5-methoxy-4-methylbenzoic acid (2.7 g, 14.9 mmol, 61%) and aqueous hydriodic acid (40%, 80 mL) were heated at reflux for 36 h. The aqueous was evaporated under vacuum and the residue washed with ether to yield 2-amino-5-hydroxy-4-methylbenzoic acid (INTERMEDIATE V.1) (2.5 g, 14.9 mmol 100%)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=O)[C@@H:10]([CH3:13])[O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][NH:18][CH3:19].C(N(C(C)C)C(C)C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C=O)C.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([N:18]([CH3:19])[CH3:17])=[O:16])[C@@H:10]([CH3:13])[O:11][CH3:12])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CO[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 77.7 %

Procedure:
To a solution of N-(tert-butoxycarbonyl)-O-methyl-L-threonine (2.33 g), 50% aqueous dimethylamine solution (1.08 g) and N-ethyl-N-(1-methylethyl)propan-2-amine (2.58 g) in DMF (30 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (4.18 g) under ice-cooling. The reaction mixture was stirred at room temperature overnight, the reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.02 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].F[C:8]1[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=1.[NH2:18][C:19]1[C:24]([C:25]2[CH:30]=[CH:29][C:28]([OH:31])=[CH:27][CH:26]=2)=[CH:23][C:22]([Cl:32])=[CH:21][N:20]=1.O>CS(C)=O>[Cl:32][C:22]1[CH:23]=[C:24]([C:25]2[CH:26]=[CH:27][C:28]([O:31][C:8]3[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:29][CH:30]=2)[C:19]([NH2:18])=[N:20][CH:21]=1
Reactant: Nc1ncc(Cl)cc1-c1ccc(O)cc1
Reactant: Fc1ncccc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1ncc(Cl)cc1-c1ccc(Oc2ncccc2C(F)(F)F)cc1
Temperature: 120 °C
Reaction time: 3 h
Yield: 94.5 %

Procedure:
A mixture of potassium carbonate (376 mg), 2-fluoro-3-(trifluoromethyl)pyridine (269 mg) and 4-(2-amino-5-chloropyridin-3-yl)phenol (300 mg) in DMSO (10 mL) was stirred at 120° C. for 3 hr. The mixture was poured into water and extracted with EtOAc. The organic layer was separated, washed with 1N NaOH aq. and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with EtOAc in hexane) to give the title compound (470 mg) as a pale yellow solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]([N:17]([CH3:19])[CH3:18])[CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:5][CH:4]=1.O.[CH2:21]([Mg]Cl)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>O1CCCC1>[ClH:2].[CH2:21]([C:11]1([OH:16])[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[CH:9]([C:6]1[CH:5]=[CH:4][C:3]([Cl:2])=[CH:8][CH:7]=1)[N:17]([CH3:19])[CH3:18])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: Cl[Mg]Cc1ccccc1
Reactant: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1=O
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(c1ccc(Cl)cc1)C1CCCCC1(O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 46.7 %

Procedure:
The base was freed from 2.5 g (8.27 mmole) of the hydrochloride of 2-[(4-chlorophenyl)dimethylaminomethyl]cyclohexanone obtained according to stage 1 with 30 ml of water and 5 ml of amnonia solution (25 vol. %), was extracted three times with 30 ml of ether each time, and the combined organic extracts were dried over sodium sulfate, filtered, and concentrated by evaporation on a rotary evaporator without heating (500 to 10 mbar). 1.80 g (6.75 mmole) of this base were dissolved in 10 ml of tetrahydrofuran, added dropwise while cooling in an ice bath to 4.05 ml (8.13 mmole) of benzylmagnesium chloride (2 M solution in tetrahydro-furan), and stirred for 15 hours at RT. 2.30 g of crude base (94.9% of theory) were obtained, from which 1.24 g of 1-benzyl-2-[(4-chlorophenyl)dimethylaminomethyl]cyclohexanol, hydrochloride (46.7% of theory) were obtained according to the procedure described in Example 1 (3rd Stage) with chlorotrimethylsilane/water in 2-butanone. The hydrochloride decomposes on heating above 130° C.
Reaction SMILES: CC(C)([O-])C.[K+].[N+:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)([O-:9])=[O:8].[CH:15](Cl)([Cl:17])[Cl:16].CO>CN(C)C=O.[Cl-].[Na+].O.C(O)(=O)C>[Cl:16][CH:15]([Cl:17])[C:14]1[CH:13]=[CH:12][S:11][C:10]=1[N+:7]([O-:9])=[O:8]
Reactant: O=[N+]([O-])c1cccs1
Reactant: ClC(Cl)Cl
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1sccc1C(Cl)Cl
Reaction time: 0.08 h
Yield: 93.8 %

Procedure:
To a solution of potassium tert-butoxide (23.0 mL, 1.0M tetrahydrofuran solution, 23.2 mmol) in N,N-dimethyl formamide (20 mL) were added a mixture solution of 2-nitro-thiophene (1.00 g, 7.74 mmol) in chloroform (682 μl, 8.51 mmol) and N,N-dimethylformamide (2 mL) dropwise at −78° C., the solution was stirred for 5 minutes, and then, methanol and acetic acid were added at 0° C. Brine was added to the reaction solution, which was then extracted with ethyl acetate. The solvent was evaporated in vacuo, the residue was purified by silica gel column chromatography (hexane:ethyl acetate=20:1), and the title compound (1.54 g, 7.26 mmol, 94%) was obtained as a light brown solid.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1.[CH3:25][C@H]1N[C@H](C)CC1>>[CH3:1][C@@H:2]1[CH2:6][CH2:5][C@@H:4]([CH3:25])[N:3]1[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[C:22]2[C:14]([N:15]3[C:20](=[CH:21]2)[C:19](=[O:24])[NH:18][CH2:17][CH2:16]3)=[N:13][CH:12]=1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: C[C@H]1CCCN1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Product: C[C@@H]1CC[C@@H](C)N1CCCOc1cnc2c(c1)cc1n2CCNC1=O
Yield: 19 %

Procedure:
The title compound was synthesized in analogy to example 2, from 7-(3-chloro-propoxy)-3,4-dihydro-2H-2,4a,5-triaza-fluoren-1-one (example 85, intermediate) and (2R,5R)-(−)-trans-2,5-dimethylpyrrolidine (commercially available), to give the desired product as a colorless solid (19%).
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][CH:16]([CH3:20])[C:17]([OH:19])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].ClC(OCC(C)C)=O.S(C1C=CC(C)=CC=1)(O)(=O)=O.[NH2:40][CH:41]([C:47](=[O:49])[CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1COCC1>[C:8]([O:12][C:13]([NH:15][CH:16]([CH3:20])[C:17]([NH:40][CH:41]([C:47](=[O:49])[CH3:48])[C:42]([O:44][CH2:45][CH3:46])=[O:43])=[O:19])=[O:14])([CH3:9])([CH3:10])[CH3:11]
Reactant: CC(NC(=O)OC(C)(C)C)C(=O)O
Reactant: CCOC(=O)C(N)C(C)=O
Agent: CC(C)COC(=O)Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)C(NC(=O)C(C)NC(=O)OC(C)(C)C)C(C)=O
Temperature: -25 °C
Reaction time: 0.5 h
Yield: 68.7 %

Procedure:
A solution of 4-methylmorpholine (900 g) in THF (15 L) was added to 2-(tert-butoxycarbonylamino)propanoic acid (1690 g, 8933.17 mmol). The mixture was cooled to −25° C. and isobutyl chloroformate (1.164 L, 8933.17 mmol) was added. After 20 minutes the second equivalent of 4-methylmorpholine (900 g) was added followed by ethyl 2-amino-3-oxobutanoate Tosylate salt (see J-P. Genet et al, Eur. J. Org. Chem., 2004, 3017-3026) (2700 g, 8507.78 mmol) suspended in THF (2.5 L). The mixture was stirred at −25° C. for 30 minutes and then left to warm to ambient temperature overnight. The reaction was quenched with water (15 L), extracted with EtOAc (3×5 L) and the combined extracts washed with 50% saturated brine (5 L). The organic layer was dried over MgSO4, filtered and evaporated to afford crude product. The crude product was purified by flash silica chromatography, elution gradient 50 to 80% EtOAc in isohexane. Pure fractions were evaporated to dryness to afford ethyl 2-(2-(tert-butoxycarbonylamino)propanamido)-3-oxobutanoate (1850 g, 68.7%).
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:21]C1C=CC(B(O)O)=CC=1>>[F:21][C:4]1[CH:3]=[CH:2][C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)=[CH:6][CH:5]=1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1NCCc2c(-c3ccc(F)cc3)[nH]c3cccc1c23

Procedure:
In a manner similar to that described for Compound 12, the tricyclic bromide (100 mg, 0.54 mmol) and 4-fluorobenzeneboronic acid (79 mg, 0.57 mmol) were coupled to yield 2-(4-fluorophenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one, 107 mg (99%), as a pale-yellow solid. 1H NMR (300 MHz, d6-DMSO) δ 3.04 (m, 2H), 3.38 (m, 2H), 7.22 (app t, 1H, J=7.7 Hz), 7.39 (m, 2H), 7.56 (dd, 1H, J=8.0, 0.9 Hz), 7.64 (m, 3H), 8.05 (br t, 1H), 11.57 (br s, 1H); HRMS (FAB, MH+) Calcd for C17H14FN2O: 281.1090, Found: 281.1093; Anal. (C17H13FN2O.0.6 H2O) C, H, N.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:23]=[C:11]3[N:12]=[C:13]([Cl:22])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.CC(C)([O-])C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH:43]1[CH2:48][CH2:47][S:46][CH2:45][CH2:44]1>C1(C)C=CC=CC=1.[Pd].[Pd].C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.C(=CC(C=CC1C=CC=CC=1)=O)C1C=CC=CC=1.O>[Cl:22][C:13]1[CH:14]=[C:15]([N:16]2[CH2:21][CH2:20][O:19][CH2:18][CH2:17]2)[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:43]4[CH2:48][CH2:47][S:46][CH2:45][CH2:44]4)=[CH:3][CH:4]=3)[CH:23]=[C:11]2[N:12]=1
Reactant: Clc1cc(N2CCOCC2)n2nc(-c3ccc(Br)cc3)cc2n1
Reactant: C1CSCCN1
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: O
Solvent: Cc1ccccc1
Product: Clc1cc(N2CCOCC2)n2nc(-c3ccc(N4CCSCC4)cc3)cc2n1
Temperature: 90 °C
Reaction time: 4 h
Yield: 57 %

Procedure:
To a solution of 2-(4-bromophenyl)-5-chloro-7-morpholin-4-yl-pyrazolo[1,5-a]-pyrimidine (100 mg, 0.25 mM) in toluene (7.0 mL), there were, in order, added sodium tert-butoxide (49 mg, 0.51 mM), tris(dibenzylidene-acetone) dipalladium (12 mg, 0.013 mM), tri-tert-butyl-phosphine (25 μL, 0.10 mM) and thio-morpholine (38 μL, 0.38 mM) and the mixture was stirred at 90° C. for 4 hours. After cooling the mixture to room temperature, water was added thereto and the mixture was extracted with ethyl acetate. The organic phase thus obtained was washed with a saturated aqueous common salt solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was washed with methanol to thus give the title compound (60 mg, yield: 57%).
Reaction SMILES: [F:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=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.CN1C(=O)CCC1>CCOC(C)=O>[F:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[S:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Reactant: N[C@@H]1CCCC[C@H]1O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(F)ccc43)cc2s1
Temperature: 130 °C
Yield: 33.2 %

Procedure:
A stirred mixture of 6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)-2-(methylsulfinyl)benzo[d]thiazole (0.20 g, 0.57 mmol) from the previous step, (1R,2R)-2-aminocyclohexanol (0.20 g, 1.7 mmol), DIEA (0.73 g, 5.7 mmol) and NMP (2 mL), was heated at 130° C. for 12 h. The reaction mixture was cooled to rt, diluted with EtOAc (30 mL), and washed with water (10 mL×2). The organic layer was separated, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 3% MeOH in DCM to afford (1R,2R)-2-((6-((5-fluoro-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]thiazol-2-yl)amino)cyclohexanol (75 mg, 33%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.45 (s, 1H), 7.93 (d, J=7.2 Hz, 1H), 7.65 (d, J=1.5 Hz, 1H), 7.56 (m, 1H), 7.43 (dd, J=9.6, 2.4 Hz, 1H), 7.28 (m, 1H), 7.19 (dd, J=8.4, 1.8 Hz, 1H), 7.08 (dt, J=9.6, 3.0 Hz, 1H), 5.46 (s, 2H), 4.69 (d, J=5.4 Hz, 1H), 3.51 (m, 1H), 3.37 (m, 1H), 2.01 (m, 1H), 1.87 (m, 1H), 1.59-1.63 (m, 2H), 1.15-1.23 (m, 4H); LCMS (ESI) m/z 397 (M+H)+.