Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[NH2:16][C:17](N)=[O:18]>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:17]([NH2:16])=[O:18])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NC(N)=O
Reactant: c1ccc2c(c1)CNCc1ccccc1-2
Product: NC(=O)N1Cc2ccccc2-c2ccccc2C1
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A mixture of 1.95 g of 6,7-dihydro-5H-dibenz[c,e]azepine and 3 g of urea is stirred at 120° C. for 15 minutes and then poured onto ice/water. After extracting the resulting aqueous mixture with methylene chloride the combined extracts are washed with water, dried over anhydrous sodium sulphate and evaporated. The solid residue is recrystallized from n-hexane/ethyl acetate, and in this manner there is obtained pure 5,7-dihydro-6H-dibenz[c,e]azepine-6-carboxamide, m.p. 212°-214° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][CH:3]=1.Cl[CH2:10][C:11]#[N:12].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:10][C:11]#[N:12])=[CH:4][CH:3]=1
Reactant: N#CCCl
Reactant: Cc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1ccc(SCC#N)cc1

Procedure:
The compound 4-methylthiophenoxyacetonitrile was prepared by heating 4-methylthiophenol, chloroacetonitrile and anhydrous K2CO3 in DMSO, employing substantially the same procedure described in previous examples.
Reaction SMILES: S=[C:2]1[CH2:6][S:5][C:4](=[O:7])[NH:3]1.[CH2:8]([NH2:11])[CH2:9][CH3:10]>C(O)C>[CH2:8]([NH:11][C:2]1[CH2:6][S:5][C:4](=[O:7])[N:3]=1)[CH2:9][CH3:10]
Reactant: O=C1NC(=S)CS1
Reactant: CCCN
Solvent: CCO
Product: CCCNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-thioxo-1,3-thiazolidin-2-one (640 mg) in ethanol (6 mL) was added propan-1-amine (0.397 mL), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (450 mg).
Reaction SMILES: [C@@H:1]1([C:8](Cl)=[O:9])[CH2:4][CH2:3][C@H:2]1[C:5](Cl)=[O:6].[BH4-].[Na+].O.[Cl-].[Na+].O1CCC[CH2:17]1>C(O)C.C(OCC)C>[OH:9][CH2:8][C@@H:1]1[CH2:4][CH2:3][CH2:17][C@H:2]1[CH2:5][OH:6]
Reactant: C1CCOC1
Reactant: O=C(Cl)[C@@H]1CC[C@H]1C(=O)Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: OC[C@@H]1CCC[C@H]1CO
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
A solution of 20 g of trans-1,2-cyclobutanedicarboxylic acid dichloride in 40 ml of tetrahydrofuran is carefully instilled at -15° C. in a solution of 8.4 g of sodium borohydride in 280 ml of ethyl alcohol. After completion of the gas generation it is stirred for 30 minutes at -15° C. and then 150 ml of water is slowly instilled. It is stirred for 30 minutes at 22° C. and then diluted with 1.5 liter of diethyl ether. It is shaken twice with water, twice with semiconcentrated sodium chloride solution, dried on anhydrous sodium sulfate and concentrated by evaporation in a vacuum. The residue is purified by chromatography on silica gel. With ethyl acetate, 9.5 g of trans-1,2-dihydroxymethylcyclopentane is obtained as colorless liquid.
Reaction SMILES: [ClH:1].Cl.[C@H]1(C[N:14]2[CH2:19][CH2:18][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:16][CH2:15]2)[C@@H]2N(CCCC2)CCC1.Cl.Cl.Cl.NC1CCN([CH2:54][CH2:55][N:56]2[CH2:61][CH2:60][C@H:59]([OH:62])[C@@H:58]([CH3:63])[CH2:57]2)CC1>>[ClH:1].[ClH:1].[OH:62][C@H:59]1[CH2:60][CH2:61][N:56]([CH2:55][CH2:54][N:14]2[CH2:15][CH2:16][CH:17]([NH:20][C:21]([C:23]3[NH:24][C:25]4[C:30]([CH:31]=3)=[C:29]([O:32][CH2:33][C:34]3[C:38]5[CH:39]=[CH:40][C:41]([F:43])=[CH:42][C:37]=5[O:36][CH:35]=3)[CH:28]=[CH:27][CH:26]=4)=[O:22])[CH2:18][CH2:19]2)[CH2:57][C@@H:58]1[CH3:63]
Reactant: O=C(NC1CCN(C[C@@H]2CCCN3CCCC[C@H]23)CC1)c1cc2c(OCc3coc4cc(F)ccc34)cccc2[nH]1
Reactant: C[C@H]1CN(CCN2CCC(N)CC2)CC[C@@H]1O
Agent: Cl
Product: C[C@H]1CN(CCN2CCC(NC(=O)c3cc4c(OCc5coc6cc(F)ccc56)cccc4[nH]3)CC2)CC[C@@H]1O

Procedure:
This compound is synthesized from 4-(6-fluoro-benzofuran-3-ylmethoxy)-1H-indole-2-carboxylic acid (106, see example 55) and amine 14 analogously to the method described in example 1.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]([O:29]C(C)(C)C)=[O:28]>>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([N:14]([CH2:26][C:27]([OH:29])=[O:28])[C:15]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:16]=2[CH:17]=[CH:18][N:19]=[CH:20]3)(=[O:12])=[O:13])=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Nc2cccc3cnccc23)cc1
Product: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2cccc3cnccc23)cc1

Procedure:
prepared by reaction of 4-tert-butyl-N-isoquinolin-5-yl-benzenesulfonamide with tert-butyl bromoacetate
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[N:5](C(=O)C(F)(F)F)[CH2:4]1.C([O-])([O-])=O.[Cs+].[Cs+].O>CO.C(Cl)Cl>[Cl:1][CH2:2][CH:3]1[C:11]2[C:10]3[CH:12]=[C:13]([C:16]([O:18][CH3:19])=[O:17])[CH:14]=[CH:15][C:9]=3[C:8]([N+:20]([O-:22])=[O:21])=[CH:7][C:6]=2[NH:5][CH2:4]1
Reactant: COC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: O
Solvent: ClCCl
Product: COC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3
Yield: 98.7 %

Procedure:
A solution of 184 (100 mg, 0.24 mmol) and Cs2CO3 (312 mg, 0.96 mmol) in MeOH (10 mL) and CH2Cl2 (15 mL) was stirred for 1.5 h. Water was added and the mixture was extracted with CH2Cl2 (×3). The combined organic extracts were washed with water, brine and dried. The solvent was evaporated and the residue was dissolved in CH2Cl2MeOH and, solvents were evaporated under reduced pressure until precipitation began. The precipitate was filtered off and washed with MeOH to give methyl 1-(chloromethyl)-5-nitro-1,2-dihydro-3H-benzo[e]indole-8-carboxylate (186) (76 mg, 100%): mp 161-163° C.; 1H NMR [(CD3)2SO] δ 8.40 (dd, J=1.6, 0.6 Hz, 1H), 8.22 (dd, J=9.1, 0.4 Hz, 1H), 7.82 (dd, J=9.1, 1.7 Hz, 1H), 7.78 (s, 1H), 6.49 (d, J=1.6 Hz, 1H), 4.35-4.28 (m, 1H), 3.93 (s, 3H), 3.89-3.82 (m, 2H), 3.79-3.69 (m, 2H). HRMS (CI) calcd. for C15H1335ClN2O4 (M+) m/z 320.0534, found 320.0563.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10].[C:11]1(=[O:21])[NH:15][C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]12.[K].O>CS(C)=O>[CH2:2]([N:15]1[C:14](=[O:16])[C:13]2=[CH:17][CH:18]=[CH:19][CH:20]=[C:12]2[C:11]1=[O:21])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH:9]=[CH2:10]
Reactant: C=CCCCCCCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCCCCN1C(=O)c2ccccc2C1=O
Reaction time: 8 h
Yield: 70 %

Procedure:
This example illustrates a synthesis of N-(9,8-Oxidononyl)phthalimide (inventive compound no. 1105). 1-bromo-8-nonene (8.2 g, 40 mmol) was added to a suspension of potassium phthalimide (7.4 g, 40 mmol) in 50 mL of dimethyl sulfoxide and stirred overnight. After 12 hours of stirring at room temperature, the reaction product was poured into a separatory funnel containing 300 mL of water and extracted with dichloromethane (5×200 mL). Organic extracts were combined, washed with water (100 mL) and brine (100 mL), dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The crude product obtained was further purified by flash chromatography over silica gel (using an eluant of 10% acetone/hexane) to yield 7.6 g (70.4% yield) of N-(8-Nonenyl)phthalimide (inventive compound no 1101).
Reaction SMILES: [C:1]1([CH:7]([CH3:11])[CH2:8][C:9]#[N:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH2:13]([OH:15])[CH3:14]>>[ClH:12].[C:1]1([CH:7]([CH3:11])[CH2:8][C:9](=[NH:10])[O:15][CH2:13][CH3:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CC#N)c1ccccc1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)CC(C)c1ccccc1
Reaction time: 8 h

Procedure:
Through a stirred solution of Example 52A (3.9 g, 26.8 mmol) in absolute ethanol (30 mL) was bubbled with hydrogen chloride gas for 20 min. The mixture was allowed to stand for overnight in the refrigerator. The product was precipitated with anhydrous ether and filtered to obtain 4.8 g of the title compound. MS (ESI/NH3) m/Z 192 (M+H)+.
Reaction SMILES: [C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH:19]C(OC(C)(C)C)=O)[CH2:13]2)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:27].O1CCOCC1>C(O)(=O)C>[ClH:27].[C:1]([O:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[CH2:15][CH:14]([NH2:19])[CH2:13]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: NC1Cc2ccc(OC(=O)c3ccccc3)cc2C1

Procedure:
Using 5-benzoyloxy-2-(tert-butoxycarbonylamino)indan (130 mg, 0.37 mmol), 4N hydrochloric acid-dioxane (2 ml) and acetic acid (6 ml), a similar procedure to Production Example 213 was carried out to obtain 5-benzoyloxy-2-aminoindan hydrochloride (67 mg, 0.35 mmol) having the following physical properties:
Reaction SMILES: [CH:1]1([NH:8][CH2:9][CH:10]([N:12]([CH2:23][CH2:24][C:25]2[C:33]3[S:32][C:31](=[O:34])[NH:30][C:29]=3[C:28]([OH:35])=[CH:27][CH:26]=2)[C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:48](Cl)(=[O:51])[CH:49]=[CH2:50]>C(Cl)Cl>[C:48]([N:8]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1)[CH2:9][CH:10]([N:12]([CH2:23][CH2:24][C:25]1[C:33]2[S:32][C:31](=[O:34])[NH:30][C:29]=2[C:28]([OH:35])=[CH:27][CH:26]=1)[C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:11])(=[O:51])[CH:49]=[CH2:50]
Reactant: CC(CNC1CCCCCC1)N(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1
Reactant: C=CC(=O)Cl
Agent: C[Si](C)(C)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N(CC(C)N(CCc1ccc(O)c2[nH]c(=O)sc12)C(=O)OCc1ccccc1)C1CCCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Benzyl [2-(cycloheptylamino)-1-methylethyl][2-(4-hydroxy-2-oxo-2,3-dihydro-1,3-benzothiazol-7-yl)ethyl]carbamate (0.46 g) in CH2Cl2 (10 mL) was added triethylamine (0.773 mL) and trimethylsilyl chloride (0.586 mL) and the mixture was stirred for 1 h at room temperature. The reaction mixture was cooled in ice and acryloyl chloride (0.0976 mL) was added. The mixture was allowed to warm slowly to RT, diluted with CH2Cl2 and washed with 2M HCl and brine. Drying and evaporation afforded an orange foam (470 mg), which was used directly in the next step.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]1[CH2:20][CH2:19][CH:18]([C:21](=[O:38])[NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][C:31]=2[Cl:37])[CH2:17][CH2:16]1)=O)(C)(C)C.C([O-])([O-])=O.[K+].[K+].O>C(Cl)Cl>[Cl:37][C:31]1[CH:32]=[C:33]([Cl:36])[CH:34]=[CH:35][C:30]=1[O:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[NH:22][C:21]([CH:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH2:17]1)=[O:38]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2ccccc2Oc2ccc(Cl)cc2Cl)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1ccccc1Oc1ccc(Cl)cc1Cl)C1CCNCC1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.7 %

Procedure:
AMR01036 Trifluoroacetic acid (TFA, 1 mL) was added to a solution of 4-[2-(2,4-dichlorophenoxy)-phenylcarbamoyl]piperidine-1-carboxylic acid tert-butyl ester (AMR01.032, 100 mg, 0.215 mmol) in dry DCM (2 mL) at 0° C. After stirring at 0° C. for 30 min, the mixture was poured into solid K2CO3 (2.8 g) and water (11 mL) was added. The solution was extracted with DCM (3×20 mL) and the organic layer was dried (MgSO4), filtered and evaporated to give piperidine-4-carboxylic acid [2-(2,4-dichlorophenoxy)phenyl]amide (61 mg, 90%) as an oil which was used in the next step without further purification. Rf: 0.175 (DCM/methanol 4:1 plus 3 drops of triethylamine) 1H NMR (270 MHz, CDCl3) δ 1.66 (2H, m, CH2), 1.87 (2H, m, CH2), 2.24 (1H, br s, NH), 2.40 (1H, tt, CH), 2.66 (2H, td, CH2), 3.15 (2H, br d, J=12.6 Hz, CH2), 6.72 (1H, dd, J=8.2, 1.5 Hz, ArH), 6.93 (1H, d, J=8.6 Hz, ArH), 6.99 (1H, td, J=7.9, 1.5 Hz, ArH), 7.12 (1H, td, J=7.9, 1.2 Hz, ArH), 7.20 (1H, dd, J=8.9, 2.5 Hz, ArH), 7.47 (1H, d, J=2.5 Hz, ArH) and 8.41 (1H, dd, J=7.9, 1.2 Hz, ArH).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([NH:16][CH2:17][CH:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)=[N:6][C:7]=1[C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([F:15])[CH:9]=1.[C:24]([O-])([O-])=O.[Na+].[Na+].CB(O)O.C(Cl)Cl>COCCOC.CCOC(C)=O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:13]1[C:8]([C:7]2[N:6]=[C:5]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[CH:4]=[N:3][C:2]=2[CH3:24])=[CH:9][C:10]([F:15])=[N:11][CH:12]=1
Reactant: O=C([O-])[O-]
Reactant: Fc1cc(-c2nc(NCC3CCOCC3)cnc2Cl)c(Cl)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CB(O)O
Solvent: ClCCl
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: Cc1ncc(NCC2CCOCC2)nc1-c1cc(F)ncc1Cl
Temperature: 105 °C
Yield: 75 %

Procedure:
To a degassed suspension of 5-chloro-6-(5-chloro-2-fluoropyridin-4-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (10 mg, 0.028 mmol), Na2CO3 (0.036 ml, 2 M, 0.072 mmol) and methylboronic acid (5 mg, 0.084 mmol) in DME (1 ml) was added PdCl2(dppf).CH2Cl2 adduct (6 mg, 7.35 μmol). The reaction was capped and heated to 105° C. for 4 hr an oil bath. The reaction was diluted with EtOAc and washed with H2O, sat NaCl. The organic layer was dried Na2SO4, filtered and concentrated. The crude was purified by column chromatography on silica gel (50% EtOAc/Hexane) to yield 6-(5-chloro-2-fluoropyridin-4-yl)-5-methyl-N-((tetrahydro-2H-pyran-4-yl)methyl)pyrazin-2-amine (7 mg, 0.021 mmol, 74.2% yield). LCMS (m/z): 337.2 (MH+), retention time=0.81 min.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][N:7]1[C:11]([CH3:12])=[CH:10][CH:9]=[C:8]1[CH3:13])(=[O:3])[CH3:2].[C:14](OC(=O)C)(=[O:16])[CH3:15].COCCOC>CCOCC.[Cl-].[Zn+2].[Cl-]>[C:14]([C:10]1[CH:9]=[C:8]([CH3:13])[N:7]([CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[C:11]=1[CH3:12])(=[O:16])[CH3:15]
Reactant: CC(=O)NCCn1c(C)ccc1C
Reactant: CC(=O)OC(C)=O
Agent: [Cl-]
Agent: [Zn+2]
Solvent: COCCOC
Solvent: CCOCC
Product: CC(=O)NCCn1c(C)cc(C(C)=O)c1C
Reaction time: 1 h

Procedure:
13.7 g (0.1 mol) of anhydrous zinc chloride are dissolved in 100 ml of ether and the solution is added to 18.0 g (0.1 mol) of 1-(2-acetylaminoethyl)-2,5-dimethylpyrrole and 9.5 ml (0.1 mol) of acetic anhydride in 50 ml of ether. After 1 hour at room temperature, 50 ml of ethylene glycol dimethyl ether are added and stirring is continued for 20 hours. After the hydrolysis, the organic phase is concentrated, the residue is chromatographed and the product is recrystallized from ethyl acetate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]2([CH3:26])[CH2:12]OS(=O)(=O)[N:9]2[CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])[CH:7]=1.[C:28]([O:32][CH2:33][CH3:34])(=[O:31])[CH2:29][SH:30].CN(C)C(N(C)C)=N>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:27])=[C:6]([C@:8]([NH:9][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:17]=2[O:24][CH3:25])([CH3:26])[CH2:12][S:30][CH2:29][C:28]([O:32][CH2:33][CH3:34])=[O:31])[CH:7]=1
Reactant: COc1ccc(CN2[C@](C)(c3cc(Br)ccc3F)COS2(=O)=O)c(OC)c1
Reactant: CCOC(=O)CS
Agent: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)CSC[C@](C)(NCc1ccc(OC)cc1OC)c1cc(Br)ccc1F
Temperature: 23 °C
Reaction time: 16 h
Yield: 100.5 %

Procedure:
To a solution of (R)-4-(5-bromo-2-fluoro-phenyl)-3-(2,4-dimethoxy-benzyl)-4-methyl-[1,2,3]oxathiazolidine 2,2-dioxide (10 g, 21.7 mmol, Eq: 1.00) and ethyl thioglycolate (3.92 g, 3.57 ml, 32.6 mmol, Eq: 1.5) in DMF (134 ml) was added at 23° C. 1,1,3,3-tetramethylguanidine (3.75 g, 4.09 ml, 32.6 mmol, Eq: 1.5). The reaction mixture was stirred at 23° C. for 16 hours. The solution was evaporated at HV. The resulting residue was stirred vigorously overnight between 100 ml of dichloromethane and 20% (v/v) sulfuric acid solution (100 ml). Sat. NaHCO3-solution was slowly added (pH=8), then extracted with dichloromethane twice. The combined organic layers were dried over Na2SO4, filtered and evaporated to give the crude product (14.4 g, 132%). The residue was chromatographed on 70 g silica gel with 0-50% ethyl acetate in heptane to give the (R)-ethyl 2-(2-(5-bromo-2-fluorophenyl)-2-(2,4-dimethoxybenzylamino)propylthio)acetate (10.9 g, 21.8 mmol, 100% yield) as a light yellow oil. MS (ISP): m/z=500.2 [M+H]+ and 502.2 [M+2+H]+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][C:14](C(O)=O)=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1.C(=O)=O.CCCCCC>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH:12]=[N:13][CH:14]=[C:10]3[CH2:9][N:8]([CH3:18])[C:7](=[O:19])[C:6]=2[CH:20]=1
Reactant: CN1Cc2c(C(=O)O)ncn2-c2ccc(F)cc2C1=O
Agent: O=C=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CN1Cc2cncn2-c2ccc(F)cc2C1=O

Procedure:
9.2 g of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid are heated to 290°. After completion of the carbon dioxide evolution, the product is dissolved in chloroform and treated with hexane. The precipitated crystals are filtered off under suction and dried. There is obtained 8-fluoro-4,5-dihydro-5-methyl-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 236°.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][OH:28])[CH:12]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>ClCCl>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:16]=[C:15]3[N:17]([CH:21]4[CH2:26][CH2:25][CH2:24][CH2:23][O:22]4)[N:18]=[C:19]([CH3:20])[C:14]3=[C:13]([CH2:27][O:28][S:37]([CH3:36])(=[O:39])=[O:38])[CH:12]=2)=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COCOc1ccc(-c2cc(CO)c3c(C)nn(C4CCCCO4)c3n2)cc1
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(-c2cc(COS(C)(=O)=O)c3c(C)nn(C4CCCCO4)c3n2)cc1

Procedure:
A solution of 120 mg [6-(4-methoxymethoxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridin-4-yl]-methanol and 44 mg of triethylamine in 4 ml of dry dichloromethane was cooled to 0° C. and 47 mg of methanesulfonyl chloride were added. The reaction was brought to room temperature, dichloromethane and water were added and the phasese were separated. The aqueous phase was extracted with dichloromethane. The combined organic phases were dried over sodium sulphate, filtrated and concentrated. 170 mg (quant.) of the crude product were obtained as a yellow solid, which was used without further purification.
Reaction SMILES: [C:1]1([C:7]2[S:11][C:10]([NH2:12])=[N:9][C:8]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:19](Cl)(=[O:21])[CH3:20].O>CN(C)C(=O)C>[C:1]1([C:7]2[S:11][C:10]([NH:12][C:19](=[O:21])[CH3:20])=[N:9][C:8]=2[C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(=O)Cl
Reactant: Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1nc(-c2cccnc2)c(-c2ccccc2)s1
Temperature: 80 °C
Reaction time: 3 h
Yield: 58.5 %

Procedure:
To a solution of [5-phenyl-4-(3-pyridyl)-1,3-thiazol-2-yl]amine (1.10 g, 4.34 mmol) in N,N-dimethylacetamide (20 mL) was added acetyl chloride (680 mg, 8.68 mmol) and stirred at 80° C. for 3 h. Water was added to the reaction mixture and extracted with ethyl acetate twice. The combined organic phases were washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was recrystallized from chloroform-ethyl ether to give the title compound (750 mg, yield 59%).
Reaction SMILES: [C:1]1([O:7][C:8]2[C:12]([F:14])([F:13])[C:11]([F:16])([F:15])[C:10]([F:18])([F:17])[C:9]=2Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B([O-])([O-])[O-].Cl.[H][H]>[C].[Pd]>[CH:1]1([O:7][CH:8]2[CH2:9][C:10]([F:17])([F:18])[C:11]([F:15])([F:16])[C:12]2([F:13])[F:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: FC1(F)C(Cl)=C(Oc2ccccc2)C(F)(F)C1(F)F
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Agent: [O-]B([O-])[O-]
Product: FC1(F)CC(OC2CCCCC2)C(F)(F)C1(F)F

Procedure:
605 g (2 mol) of 2-chloro-3,3,4,4,5,5-hexafluorocyclopentenyl phenyl ether are suspended in 500 ml of pH 9 buffer (borate/HCl) in a 1.3 1 autoclave and hydrogenated over 50 g of palladium-carbon at 7020 -80° C. using 80 bar of hydrogen. The mixture is worked up analogously to Example 7 and 2,2,3,3,4,4-hexafluorocyclopentyl cyclohexyl ether is obtained.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]2[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]2[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[Cl:25][C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33].O1CCOCC1>CO.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:25][C:26]1[CH:27]=[C:28]([C:2]2[N:7]3[N:8]=[C:9]([CH3:11])[CH:10]=[C:6]3[N:5]=[C:4]([NH:12][C:13](=[O:24])[C:14]3[CH:19]=[CH:18][C:17]([C:20]([OH:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)[CH:3]=2)[CH:29]=[CH:30][C:31]=1[O:32][CH3:33]
Reactant: COc1ccc(B(O)O)cc1Cl
Reactant: Cc1cc2nc(NC(=O)c3ccc(C(C)(C)O)cc3)cc(Cl)n2n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CO
Solvent: C1COCCO1
Product: COc1ccc(-c2cc(NC(=O)c3ccc(C(C)(C)O)cc3)nc3cc(C)nn23)cc1Cl
Temperature: 120 °C
Yield: 20.4 %

Procedure:
A suspension of N-(7-chloro-2-methylpyrazolo[1,5-a]pyrimidin-5-yl)-4-(2-hydroxypropan-2-yl)benzamide (2F, 90 mg, 0.261 mmol), 3-Chloro-4-methoxyphenylboronic acid (97 mg, 0.522 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (17 mg, 21 μmol) in 2:1 1,4-dioxane/saturated aqueous NaHCO3 (0.5 mL of 1,4-dioxane and 1 mL of saturated aqueous NaHCO3) was prepared in a 2 mL microwave reaction vessel and the sealed reaction vessel warmed to 120° C. for 20 minutes. The reaction mixture was cooled to rt, diluted with methanol, filtered, and purified via preparative HPLC (60-70% MeCN/H2O gradient+0.01% TFA). Lyophilization of the combined fractions gave the titled compound as a yellow solid (24 mg, 20%). 1H NMR (DMSO-d6) δ: 11.19 (s, 1H), 8.25 (d, J=2.3 Hz, 1H), 7.90-8.17 (m, 4H), 7.54-7.73 (m, 2H), 7.41 (d, J=8.8 Hz, 1H), 6.39 (s, 1H), 5.19 (s, 1H), 3.99 (s, 3H), 2.42 (s, 3H), 1.46 (s, 6H). ESI-MS: m/z 451.0 (M+H)+.
Reaction SMILES: [ClH:1].[C:2]([NH:5][C:6]1[S:7][CH:8]=[C:9]([CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[NH:23])OCC)=[CH:15][CH:14]=2)[N:10]=1)(=[O:4])[CH3:3].[Cl-].[NH4+:25].N>C(O)C.CO>[ClH:1].[NH2:25][C:19](=[NH:23])[C:16]1[CH:15]=[CH:14][C:13]([CH2:12][CH2:11][C:9]2[N:10]=[C:6]([NH:5][C:2](=[O:4])[CH3:3])[S:7][CH:8]=2)=[CH:18][CH:17]=1
Reactant: CCOC(=N)c1ccc(CCc2csc(NC(C)=O)n2)cc1
Reactant: [NH4+]
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: CCO
Solvent: CO
Product: CC(=O)Nc1nc(CCc2ccc(C(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 85 %

Procedure:
Ethyl 4-{2-[2-(acetylamino)-1,3-thiazol-4-yl]ethyl}benzenecarboximidoate hydrochloride (300 mg) was dissolved in ethanol (6 ml). Then ammonium chloride (68 mg) and ammonia in methanol (1 ml) were added to the solution. The reaction mixture was refluxed for 5 hours under nitrogen atmosphere. After cooled to room temperature, the suspension was filtered in vacuo. The filtrate was concentrated in vacuo, and the residue was solidified with ethanol/diethyl ether to give N-[4-(2-{4-[amino(imino)methyl]phenyl}ethyl)-1,3-thiazol-2-yl]acetamide hydrochloride (234 mg) as a colorless solid.