Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.C[N:32](C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH4+].[Cl-]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:32])=[O:30])=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccc(F)cc3)sc2c1
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 85.2 %

Procedure:
(E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylic acid (48 mg, 0.115 mmol) was dissolved in DMF (3.00 mL). The vial was charged with HATU (65.6 mg, 0.173 mmol), DIEA (0.060 mL, 0.345 mmol), and NH4Cl (6.16 mg, 0.115 mmol). The reaction mixture was stirred for 10 min at room temperature. The reaction was quenched with sat. NH4Cl and diluted with DCM. The organic phase was collected (phase separator) and concentrated by vacuum to afford to crude product. The crude material was purified by reverse phase HPLC (neutral condition, 3% 1-propanol in 1-100% CH3CN/H2O) to afford (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol, 85% yield) as a pale orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.77 (s, 3H) 6.40 (d, J=15.66 Hz, 1H) 6.78-6.90 (m, 3H) 6.95-7.06 (m, 2H) 7.16 (d, J=8.59 Hz, 1H) 7.29-7.49 (m, 4H) 7.55-7.69 (m, 2H).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([OH:21])[C:14]=2[O:13]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:11][C:12]1([CH3:22])[CH2:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:20]([O:21][C:2]3[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)[C:14]=2[O:13]1
Reactant: CC1(C)Cc2cccc(O)c2O1
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)Cc2cccc(Oc3ncccc3[N+](=O)[O-])c2O1
Temperature: 80 °C
Yield: 73.5 %

Procedure:
A solution of 2-chloro-3-nitropyridine (4.9 g, 30.9 mmol) in DMF (50 mL) was treated with 2,2-dimethyl-2,3-dihydrobenzofuran-7-ol (5.3 mL, 46.4 mmol) and cesium carbonate (30.2 g, 92.7 mmol). The mixture was heated at 80° C. for 10 h. The reaction was cooled to rt, and the mixture was poured in water (200 mL) with stirring. The yellow precipitate formed was filtered and washed with water, and recrystallized from ethanol (50 mL) to afford 134a as brown crystals (6.5 g, 73% yield). [M+H]+=287.16. 1H NMR (500 MHz, deuterochloroform) δ ppm 8.38 (dd, 1H, J=1.7 Hz, J=5.0 Hz), 8.31 (dd, 1H, J=5.0 Hz, J=1.7 Hz), 7.12 (dd, 1H, J=10.0 Hz, J=5.0 Hz), 7.05 (d, 1H, J=5.0 Hz), 7.00 (d, 1H, J=10.0 Hz), 6.86 (t, 1H, J=10.0 Hz), 3.05 (s, 2H), 1.39 (s, 6H); 13C (125 MHz, deuterochloroform) δ (ppm), 155.42, 151.76, 150.16, 136.03, 135.40, 134.04, 129.76, 122.60, 121.06, 120.37, 118.07, 88.40, 43.07, 27.98.
Reaction SMILES: [C:1]1(=[O:11])[C:10]2[CH:5]([CH2:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][NH:2]1.[Br:12]Br.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[Br:12][C:4]1[C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[C:1](=[O:11])[NH:2][CH:3]=1
Reactant: BrBr
Reactant: O=C1NCCC2CC=CC=C12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: O=c1[nH]cc(Br)c2c1CCCC2
Yield: 96.4 %

Procedure:
32.4 g (217 mmol) of tetrahydroisoquinolinone (compound 5) is dissolved in 300 ml of chloroform at 5° C. and then 11.2 ml (34.7 g, 217 mmol) of bromine, dissolved in 150 ml of chloroform, are added dropwise over the course of 1 h. The mixture is stirred while cooling in ice for a further hour and then neutralized with 150 ml of saturated NaHCO3 solution and filtered with suction. The organic phase of the filtrate is extracted with dichloromethane and concentrated. The residue is mixed with ethyl acetate, filtered off with suction and dried together with the first residue in a vacuum drying oven at 45° C. 47.7 g (96%) of colorless bromide are obtained.
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[CH2:17][NH2:18].CCCCCC.CC(=O)OCC>S(Cl)(Cl)=O>[F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH:18][CH2:17][C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:6]
Reactant: NCc1cccs1
Reactant: O=C(O)c1ccc(F)nc1F
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O=S(Cl)Cl
Product: O=C(NCc1cccs1)c1ccc(F)nc1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 48 %

Procedure:
795 mg (5.0 mmol) of 2,6-difluoro-nicotinic acid were dissolved in thionyl chloride (15 ml) and the solution was heated for 2 h at 80° C. Concentration in vacuo was then carried out and the residue was taken up in dioxane (15 ml). 566 mg (5.0 mmol) of thiophen-2-yl-methanamine were then added and the mixture was stirred for 1 h at RT. Concentration in vacuo was then carried out and the residue was taken up in EA, washed with water, a sat. aq. Na2CO3 sol., water again and brine, dried over Na2SO4, filtered and concentrated in vacuo. CC (hexane/EA 7:3) of the residue yielded 605 mg (2.4 mmol, 48%) of 2,6-difluoro-N-(thiophen-2-ylmethyl)nicotinamide.
Reaction SMILES: [CH:1]1[CH:2]=[C:3]([N:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][C:23]4[CH2:30][CH2:29][C:27](=[O:28])[NH:26][C:24]=4[CH:25]=3)[CH2:11][CH2:10]2)[C:4]([Cl:8])=[C:5]([Cl:7])[CH:6]=1.[H-].[Na+].Cl[C:34]([O:36][CH2:37][Cl:38])=[O:35]>CC1CCCO1.C(OCC)(=O)C>[Cl:8][C:4]1[C:5]([Cl:7])=[CH:6][CH:1]=[CH:2][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][CH2:18][O:19][C:20]2[CH:25]=[C:24]3[C:23]([CH2:30][CH2:29][C:27](=[O:28])[N:26]3[C:34]([O:36][CH2:37][Cl:38])=[O:35])=[CH:22][CH:21]=2)[CH2:11][CH2:10]1
Reactant: O=C(Cl)OCCl
Reactant: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1
Agent: [H-]
Agent: [Na+]
Solvent: CC1CCCO1
Solvent: CCOC(C)=O
Product: O=C1CCc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2N1C(=O)OCCl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of aripiprazole (1 g, 2.23 mmol) in 2-methyltetrahydrofuran (20 mL) was added NaH (178 mg, 4.46 mmol). After 1 hour, a further of NaH (178 mg) was added. The reaction was stirred at ambient temperature overnight then heated to reflux for 3 hours. The reaction was cooled to room temperature and chloromethyl chloroformate (0.60 mL, 6.69 mmol) was then added and the reaction stirred for 2 hours. The reaction was cooled to 0° C., diluted with ethyl acetate (20 mL) and quenched with aqueous saturated NaHCO3 solution (20 mL). The reaction was extracted with ethyl acetate (3×20 mL) and the combined organics washed with brine (50 mL), then dried (MgSO4) and concentrated to give chloromethyl 7-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butoxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (crude yield 1.54 g) as a 2:1 mixture of product/aripiprazole. The product was taken onto the next step crude.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10]2)[CH:3]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C@@H:9]2[CH2:14][CH2:13][CH2:12][NH:11][CH2:10]2)[CH:3]=1
Reactant: Cc1ccnc(N[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1
Agent: Cl
Solvent: CO
Product: Cc1ccnc(N[C@@H]2CCCNC2)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
tert-Butyl (3R)-3-[(4-methyl-2-pyridyl)amino]piperidine-1-carboxylate (271 mg, 0.93 mmol) was dissolved in methanol (1 ml). Hydrochloric acid (4N in dioxane, 4.65 ml, 18.6 mmol) was added and the mixture was stirred at room temperature for three hours. The mixture was concentrated under reduced pressure, the residue was treated twice with diethylether and separated by decantation, dissolved in methanol and evaporated to dryness to yield 246 mg (quantitative) MS (ESI) m/z=192.2 [M+1]+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH2:27][CH:28]4[O:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37].C(N(CC)C(C)C)(C)C>CO>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH2:27][CH:28]3[O:33][CH2:32][CH2:31][N:30]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: CN(C)C(=O)CCl
Reactant: Nc1ncnn2c(CC3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)C(=O)CN1CCOC(Cc2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 60 °C
Reaction time: 17 h
Yield: 51.9 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(morpholin-2-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (80 mg, 0.18 mmol) in MeOH (1.5 mL) was added 2-chloro-N,N-dimethylacetamide (24 mg, 0.20 mmol) and N,N-diisopropylethylamine (95 μL, 0.55 mmol). The reaction was stirred at 60° C. for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 15% to 45% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 49 mg (52%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.51-8.57 (m, 1H), 7.86-7.93 (m, 1 H), 7.76-7.84 (m, 1 H), 7.55-7.62 (m, 1 H), 7.26-7.41 (m, 5 H), 7.09-7.18 (m, 1 H), 6.58-6.66 (m, 1 H), 5.71-5.77 (m, 1 H), 5.62-5.68 (m, 2 H), 3.79-3.91 (m, 1 H), 3.68-3.79 (m, 1 H), 3.39-3.53 (m, 1 H), 2.90-3.20 (m, 7H), 2.69-2.82 (m, 4 H), 2.62 (d, 1 H), 2.11-2.24 (m, 1 H), 1.96-2.09 (m, 1 H); ES-MS m/z 525.38 [M+H]+, HPLC RT (min) 2.03.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH:12]=[C:11]([C:23](O)=[O:24])[C@H:10]([OH:26])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH3:29].C1COCC1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Si:16]([O:15][CH2:14][C@@H:13]1[CH:12]=[C:11]([C:23](=[O:24])[N:28]([CH3:29])[CH3:27])[C@H:10]([OH:26])[CH2:9][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](O)C(C(=O)O)=C[C@H]1CO[Si](C)(C)C(C)(C)C
Reactant: CNC
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: CN(C)C=O
Solvent: C1CCOC1
Product: CN(C)C(=O)C1=C[C@@H](CO[Si](C)(C)C(C)(C)C)N(C(=O)OC(C)(C)C)C[C@H]1O
Temperature: 25 °C
Yield: 70 %

Procedure:
To a solution of (3S,6S)-1-(tert-butoxycarbonyl)-6-((tert-butyldimethylsilyloxy)methyl)-3-hydroxy-1,2,3,6-tetrahydropyridine-4-carboxylic acid (Intermediate 136, 4.07 g, 10.50 mmol) in DMF (20 mL) at room temperature was added 2M dimethylamine in THF (5.25 mL, 10.50 mmol), HATU (5.99 g, 15.75 mmol) and then DIEA (5.50 mL, 31.51 mmol). The reaction mixture was stirred at room temperature. The reaction ran until the starting material was consumed, then it was quenched with water and extracted with EtOAc. The organic solutions was then washed with brine, and purified via flash chromatography (35-100% EA/Hex) to isolate the desired product (3.05 g, 70.0%) as a pink glassy solid.
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[N:7]([C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]4)=[CH:14][CH:13]=3)[CH:6]=[N:5][C:4]=2[CH:3]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.O>C(OCC)(=O)C>[CH3:24][N:23]([CH3:25])[C@@H:20]1[CH2:21][CH2:22][N:18]([C:15]2[CH:16]=[CH:17][C:12]([N:7]3[C:8](=[O:11])[C:9]4[S:10][C:2]([N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:3][C:4]=4[N:5]=[CH:6]3)=[CH:13][CH:14]=2)[CH2:19]1
Reactant: C1CCNCC1
Reactant: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(Br)sc4c3=O)cc2)C1
Solvent: O
Solvent: CCOC(C)=O
Product: CN(C)[C@@H]1CCN(c2ccc(-n3cnc4cc(N5CCCCC5)sc4c3=O)cc2)C1
Temperature: 100 °C

Procedure:
A mixture of 6-bromo-3-[4-((R)-3-dimethylaminopyrrolidin-1-yl)phenyl]-3H-thieno[3,2-d]pyrimidin-4-one (40 mg) and piperidine (492 mg) was heated at 100° C. for 2 days. Water and ethyl acetate were then added, and the organic phase was washed twice with water. The ethyl acetate phase was dried over sodium sulfate and the solvent was removed in vacuo. The residue was purified by preparative HPLC. The product with the molecular weight of 423.58 (C23H29N50S) was obtained in this way; MS (ESI): 424 (M+H+).
Reaction SMILES: C([O:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]([C:16]2([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][C:23]3[C:22]([CH3:26])([CH3:25])[CH2:21][CH2:20][C:19]([CH3:28])([CH3:27])[C:18]=3[CH2:17]2)=[O:15])=[CH:9][CH:8]=1)=[O:6])C=C>C1COCC1>[C:5]([C:7]1[CH:8]=[CH:9][C:10]([O:13][C:14]([C:16]2([CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])[CH2:24][C:23]3[C:22]([CH3:25])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:27])([CH3:28])[C:18]=3[CH2:17]2)=[O:15])=[CH:11][CH:12]=1)([OH:6])=[O:4]
Reactant: C=CCOC(=O)c1ccc(OC(=O)C2(CCCCC)CC3=C(C2)C(C)(C)CCC3(C)C)cc1
Solvent: C1CCOC1
Product: CCCCCC1(C(=O)Oc2ccc(C(=O)O)cc2)CC2=C(C1)C(C)(C)CCC2(C)C
Temperature: 25 °C
Reaction time: 4 h
Yield: 73.7 %

Procedure:
19.2 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid 4-allyloxycarbonyl-phenyl ester were dissolved in 460 ml of THF. The reaction flask was evacuated and ventilated with argon twice. 4.6 g of tetrakis (triphenylphosphine) palladium were added, followed by 37 g of morpholine. The reaction mixture was stirred for 4 hours at room temperature, poured on 1500 ml of ice/water, acidified with 6N HCl and extracted with ethyl acetate. The organic phase was washed with water, dried over Na2SO4 and evaporated to yield a yellow solid. Purification by column chromatography (SiO2, hexane/ethyl acetate=1:3) and crystallization from ethyl acetate/hexane afforded 12.9 g of 4,4,7,7-tetramethyl-2-pentyl-2,3,4,5,6,7-hexahydro-1H-indene-2-carboxylic acid 4-carboxy-phenyl ester, m.p. 156-158° C.
Reaction SMILES: [CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([OH:16])=O)[CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:18][C:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[N:22]=[CH:21][CH:20]=1>>[CH:1]1([N:7]([CH3:17])[C:8]2[N:13]=[CH:12][N:11]=[C:10]([C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=[CH:21][CH:20]=3)=[O:16])[CH:9]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN(c1cc(C(=O)O)ncn1)C1CCCCC1
Reactant: Nc1ccnc2ccccc12
Product: CN(c1cc(C(=O)Nc2ccnc3ccccc23)ncn1)C1CCCCC1

Procedure:
Following the general method as outlined in Example 1, starting from 6-[cyclohexyl(methyl)amino]pyrimidine-4-carboxylic acid (Intermediate 10) and 4-aminoquinoline (Tyger), the title compound was obtained as an off-white solid after purification by column chromatography (silica) eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]([F:22])([F:21])[S:10]([O:13]S(C(F)(F)F)(=O)=O)(=[O:12])=[O:11].O[C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2.C(=O)([O-])O.[Na+]>ClCCl>[F:8][C:9]([F:22])([F:21])[S:10]([O:13][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH2:30][N:29]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:28][CH2:27]2)(=[O:12])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCc2cc(O)ccc2C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCc2cc(OS(=O)(=O)C(F)(F)F)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 113.9 %

Procedure:
Firstly 0.22 ml (0.00160 mol) of triethylamine and then 0.26 ml (0.00155 mol) of trifluoromethanesulphonic anhydride were added dropwise under argon to an ice-cold solution of 0.38 g (0.00152 mol) of tert.-butyl 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylate in 7.5 ml of dichloromethane. The mixture was stirred at room temperature for 1 hour, poured into saturated sodium hydrogen carbonate solution, extracted with ethyl acetate and completely freed from the solvents. 0.66 g of oily crude tert.-butyl 6-(trifluoromethanesulphonyloxy)-3,4-dihydro-1H-isoquinoline-2-carboxylate was obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1.Cl.[CH3:27][N:28]([CH2:30][C:31](Cl)=[O:32])[CH3:29].C(N(CC)CC)C>C1COCC1>[CH3:27][N:28]([CH3:29])[CH2:30][C:31]([NH:2][C@H:3]1[CH2:8][CH2:7][CH2:6][N:5]([C:9]([C:11]2[S:12][C:13]([C:16]3[C:20]([CH3:21])=[C:19]([C:22]([F:25])([F:24])[F:23])[O:18][N:17]=3)=[CH:14][CH:15]=2)=[O:10])[CH2:4]1)=[O:32]
Reactant: CN(C)CC(=O)Cl
Reactant: Cc1c(-c2ccc(C(=O)N3CCC[C@H](N)C3)s2)noc1C(F)(F)F
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1c(-c2ccc(C(=O)N3CCC[C@H](NC(=O)CN(C)C)C3)s2)noc1C(F)(F)F
Reaction time: 16 h
Yield: 77.6 %

Procedure:
A solution of ((S)-3-Amino-piperidin-1-yl)-[5-(4-methyl-5-trifluoromethyl-isoxazol-3-yl)-thiophen-2-yl]-methanone, hydrochloride (Example 26, 79 mg, 0.20 mmol) in THF (3 mL) was treated with dimethylaminoacetyl chloride hydrochloride (40 mg, 0.24 mmol) followed by triethylamine (62 μL, 0.44 mmol). The resulting mixture was stirred for 16 hr, evaporated to an oil, and dissolved in water (3 mL). The solution was then basified with a saturated aqueous K2CO3 solution and the precipitated product filtered, washed with water, and air dried to afford product as a colorless solid (69 mg, 78%). 1H NMR (CDCl3) 1.62-1.72 (m, 2 H), 1.78-1.84 (m, 1 H), 1.94-2.04 (m, 1 H), 2.25 (s, 6 H), 2.32 (d, J=1.3, 3 H), 2.49 (s, 2 H), 3.24-3.40 (m, 2 H), 3.94-4.04 (m, 2 H), 4.12 (br d, J=13.2, 1 H), 7.23 (br d, J=7.5, 1 H), 7.44 (d, J=4.0, 1 H), 7.47 (br s, 1 H). 13C NMR 7.9, 23.5, 30.4, 45.6, 46.2, ˜51 (br), 63.2, 114.8, 118.8 (q, J=271), 128.3, 129.5, 131.6, 140.2, 155.1 (q, J=40), 157.9, 163.1, 170.7. 19F NMR −63.1. LC/MS 4.59 min, [M+1]+ 445.
Reaction SMILES: [C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][C:9](=[O:18])[N:8]2[CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25](C=O)[CH2:24][CH2:23]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.Cl>[C:1]1([N:7]2[CH:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH2:10][C:9](=[O:18])[N:8]2[CH2:19][CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=CN1CCN(CCCN2C(=O)CC(c3ccccc3)N2c2ccccc2)CC1
Agent: Cl
Solvent: CCO
Product: O=C1CC(c2ccccc2)N(c2ccccc2)N1CCCN1CCNCC1
Reaction time: 12 h

Procedure:
19.2 g of 1,5-diphenyl-2-[3-(4-formylpiperazin-1-yl)-propyl]-pyrazolin-3-one are dissolved in 200 ml of a mixture of ethanol and 20% strength hydrochloric acid (1:1). The solution is left to stand at room temperature for 12 hours and is then heated under reflux for another 2 hours, and the ethanol is then distilled off in vacuo. Toluene and dilute sodium hydroxide solution are added to the residue. The toluene phase is separated off, washed with water, dried over sodium sulphate and evaporated in vacuo. 1,5-Diphenyl-2-[3-(piperazin-1-yl)-propyl]-pyrazolin-3-one is obtained as the residue.
Reaction SMILES: [CH3:1][C:2]([S:23]([CH3:26])(=[O:25])=[O:24])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:18][C:17]([CH3:20])([CH3:19])[C:16]([CH3:22])([CH3:21])[O:15]2)=[CH:10][CH:9]=1)[C:3]([OH:5])=O.[O:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH:28]1[O:33][NH2:34].BrC1C=CC(CCC(C)(S(C)(=O)=O)C(NOC2CCCCO2)=O)=CC=1>>[CH3:1][C:2]([S:23]([CH3:26])(=[O:24])=[O:25])([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([B:14]2[O:15][C:16]([CH3:21])([CH3:22])[C:17]([CH3:20])([CH3:19])[O:18]2)=[CH:10][CH:9]=1)[C:3]([NH:34][O:33][CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][O:27]1)=[O:5]
Reactant: CC1(C)OB(c2ccc(CCC(C)(C(=O)O)S(C)(=O)=O)cc2)OC1(C)C
Reactant: NOC1CCCCO1
Agent: CC(CCc1ccc(Br)cc1)(C(=O)NOC1CCCCO1)S(C)(=O)=O
Product: CC1(C)OB(c2ccc(CCC(C)(C(=O)NOC3CCCCO3)S(C)(=O)=O)cc2)OC1(C)C
Yield: 60.4 %

Procedure:
The title compound (3.69 g, 60.4%) was prepared from (+/−)-2-methyl-2-(methylsulfonyl)-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]butanoic acid (4.86 g, 12.7 mmol) and O-tetrahydro-2H-pyran-2-yl-hydroxylamine (2.1 g, 18.0 mmol) by a procedure analogous to that described for (+/−)-4-(4-bromophenyl)-2-methyl-2-(methylsulfonyl)-N-(tetrahydro-2H-pyran-2-yloxy)butanamide (III/Step 4—Preparation Number 2). LCMS m/z 480.3 (M−1).
Reaction SMILES: [Si]([O:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]2[CH:19]=[C:18]([C:20]3[CH:25]=[N:24][C:23]([NH2:26])=[C:22]4[O:27][C:28](Cl)=[CH:29][C:21]=34)[CH:17]=[N:16]2)[CH2:11][CH2:10]1)(C(C)(C)C)(C)C.[F:31][C:32]1[CH:40]=[CH:39][C:35]2[N:36]=[CH:37][S:38][C:34]=2[C:33]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].Cl>O1CCOCC1.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>[NH2:26][C:23]1[N:24]=[CH:25][C:20]([C:18]2[CH:17]=[N:16][N:15]([C@H:12]3[CH2:11][CH2:10][C@H:9]([OH:8])[CH2:14][CH2:13]3)[CH:19]=2)=[C:21]2[CH:29]=[C:28]([C:33]3[C:34]4[S:38][CH:37]=[N:36][C:35]=4[CH:39]=[CH:40][C:32]=3[F:31])[O:27][C:22]=12
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](n2cc(-c3cnc(N)c4oc(Cl)cc34)cn2)CC1
Reactant: OB(O)c1c(F)ccc2ncsc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn([C@H]3CC[C@H](O)CC3)c2)c2cc(-c3c(F)ccc4ncsc34)oc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 4-[1-(trans-4-{[tert-butyl(dimethyl)silyl]oxy}cyclohexyl)-1H-pyrazol-4-yl]-2-chlorofuro[2,3-c]pyridin-7-amine (70.5 mg, 0.158 mmol), (6-fluoro-1,3-benzothiazol-7-yl)boronic acid (44.0 mg, 0.22 mmol), and Pd(PPh3)4 (18.2 mg, 0.0158 mmol) in 1,4-dioxane (1.23 mL) and aqueous 1.0 N sodium carbonate solution (0.615 mL, 0.615 mmol) was heated to 120° C. in a microwave for 60 min. Into the reaction mixture was added hydrochloric acid in 1,4-dioxane (4 N in 1,4-dioxane, 0.59 mL, 2.36 mmol), and the reaction mixture was stirred at rt for 30 min, then purified by MDPS to afford 4.4 mg (6%) of the title compound as a brown solid. 1H NMR (400 MHz, DMSO-d6): δ 9.63 (s, 1H), 8.23 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.16 (s, 1H), 7.91 (s, 1H), 7.81 (s, 1H), 6.52 (brs, 2H), 4.67 (brd, J=3.2 Hz, 1H), 4.21 (tt, J=11.4, 4.0 Hz, 1H), 3.55-3.45 (m, 1H), 2.08-2.02 (m, 2H), 1.97-1.78 (m, 4H), 1.44-1.30 (m, 2H); MS (ESI): 450.03 [M+H]+; HPLC: tR=2.85 min (ZQ3: polar—5 min).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]([OH:10])=O)[CH2:4][CH2:3]1.S(Cl)(Cl)=O.[CH3:15][Si](C=[N+]=[N-])(C)C.[BrH:22]>ClCCl.C(O)(=O)C>[BrH:22].[Br:22][CH2:15][C:8]([CH:5]1[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]1)=[O:10]
Reactant: CN1CCC(C(=O)O)CC1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Agent: Br
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CC(=O)O
Product: CN1CCC(C(=O)CBr)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33 %

Procedure:
A mixture of 1-methyl-piperidine-4-carboxylic acid (0.40 g, 2.79 mmol) and thionyl chloride (0.32 mL, 4.44 mmol) in dichloromethane (10 mL) was heated to reflux for 6 h. The reaction mixture was distilled under reduced pressure and the residue dissolved in dry acetonitrile (4 mL). Trimethylsilyl diazomethane (4 mL, 8.08 mmol) was added and the mixture stirred for 2 h at ambient temperature. The reaction was cooled to 0° C. and 30% HBr in acetic acid (2 mL) added dropwise. The reaction mixture was warmed to room temperature and stirred for 1 h. The precipitate was filtered and washed with ether to afford 2-bromo-1-(1-methyl-piperidin-4-yl)-ethanone hydrobromide (200 mg, 33%).