Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][CH2:13][N:14]([CH3:16])[CH3:15])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[CH:19]=1>C(O)C.Cl>[CH3:15][N:14]([CH3:16])[CH2:13][CH2:12][NH:11][S:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([NH:1][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)[CH:3]=1)(=[O:10])=[O:9]
Reactant: CN(C)CCNS(=O)(=O)c1cccc(N)c1
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: Cl
Solvent: CCO
Product: Cc1cc(Nc2cccc(S(=O)(=O)NCCN(C)C)c2)c2ccccc2n1
Yield: 3.2 %

Procedure:
To a solution of 4 (0.3 g, 1.23 mmol) and 4-chloroquinaldine (5, 0.26 mL, 1.29 mmol) in ethanol (10 mL) were added 2 drops of conc. HCl. The resulting mixture was heated under reflux overnight before ethanol was removed under reduced pressure. The residue was basified with saturated NaHCO3 (aq. 20 mL) and the basic solution was extracted with EtOAc (2×20 mL). The combined organic layers were dried over MgSO4, the solids were filtered and the filtrate was concentrated on a rotavap. The residue was purified on Florisil® to give the title compound as an orange solid (15 mg).
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([N:11]2[C:15](=[O:16])[C:14]([C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][NH:12]2)[CH:6]=1.C(N(CC)CC)C.[C:30]([Cl:33])(=[O:32])[CH3:31]>CN(C=O)C>[ClH:33].[O:16]=[C:15]1[N:11]([C:7]2[CH:6]=[C:5]([CH2:4][NH:3][C:30](=[O:32])[CH3:31])[CH:10]=[CH:9][N:8]=2)[NH:12][CH:13]=[C:14]1[C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1
Reactant: NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
80.0 mg (235 μmol) of the compound from Example 35 are dissolved in 5 ml DMF, 71.4 mg (705 μmol) triethylamine and 20.3 mg (259 μmol) acetyl chloride are added, while cooling with ice, and the mixture is stirred overnight at RT. The reaction mixture is purified directly by means of preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% conc. hydrochloric acid).
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]2[C:17]([CH:18](O)[CH2:19][N:20]([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][CH:15]=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].C([SiH](CC)CC)C.FC(F)(F)C(O)=O.C(=O)([O-])[O-].[K+].[K+]>C(OCC)C>[CH2:1]([C:3]1[O:4][C:5]2[C:17]([CH2:18][CH2:19][N:20]([CH2:21][CH3:22])[CH2:23][CH3:24])=[CH:16][CH:15]=[CH:14][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCc1oc2c(C(O)CN(CC)CC)cccc2c1-c1ccccc1
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CCOCC
Product: CCc1oc2c(CCN(CC)CC)cccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
180 mg (0.53 mmol) of 2-ethyl-3-phenyl-7-(2-diethylamino-1-hydroxyethyl)benzofuran, 1 ml of triethylsilane and 1 ml of trifluoroacetic acid are introduced into a 25 ml three-necked flask equipped with a reflux condenser. The mixture is stirred for 2 hours at room temperature and then 2 ml of triethylsilane and 1 ml of trifluoroacetic acid are added. The mixture is heated at 70° C. for 48 hours. Potassium carbonate and ethyl ether (30 ml) are added and the mixture is filtered. The filtrate is concentrated under vacuum and the residue is purified by silica column chromatography (elution solvent: 5% methanol in dichloromethane). 80 mg of 2-ethyl-3-phenyl-7-(2-(diethylamino)ethyl)benzofuran are obtained in the form of a wax.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[N:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:7]=O)[CH:2]=[CH2:3].C1COCC1.[Br-].[N+:23]([C:26]1[CH:51]=[CH:50][C:29]([CH2:30][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:28][CH:27]=1)([O-:25])=[O:24].C(=O)([O-])[O-].[Na+].[Na+]>O>[CH2:14]([N:12]([CH3:13])[C:11]1[CH:10]=[CH:9][C:6]([CH:7]=[CH:30][C:29]2[CH:50]=[CH:51][C:26]([N+:23]([O-:25])=[O:24])=[CH:27][CH:28]=2)=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3])[CH:15]=[CH2:16]
Reactant: O=[N+]([O-])c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: C=CCc1cc(C=O)ccc1N(C)CC=C
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C=CCc1cc(C=Cc2ccc([N+](=O)[O-])cc2)ccc1N(C)CC=C
Reaction time: 2 h

Procedure:
A mixture of 3-allyl-4-(N-allyl-N-methylamino)benzaldehyde (10.25 g, 0.05 mol), THF (100'ml), p-nitrobenzyl triphenylphosphonium bromide (27.4 g, 0.55 mol) and water (50 ml) is mixed at room temperature while 2M sodium carbonate solution (50 ml) is added over 5 minutes. The mixture is stirred mechanically for 2 hours. The mixture is diluted With water (300 ml) and extracted two times with ether (250 ml portions). The extracts are washed with water and brine, dried over magnesium sulfate and concentrated. The mixture is diluted with toluene (100 ml) and hexane (200 ml) and the triphenyl phosphine oxide filtered off. The filtrate is concentrated and chromatographed on silica with hexane-ethyl acetate to give pure N,2-diallyl-N-methyl-4-[2-(4-nitrophenyl)ethenyl]aniline.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([F:13])[F:12])=[N:9][N:10]=2)[N:7]=1.[F:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)[CH3:22])=[CH:17][CH:16]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[F:12][CH:11]([F:13])[C:8]1[N:6]2[N:7]=[C:2]([N:26]3[CH2:25][CH2:24][N:23]([C@@H:21]([C:18]4[CH:19]=[CH:20][C:15]([F:14])=[CH:16][CH:17]=4)[CH3:22])[CH2:28][CH2:27]3)[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: FC(F)c1nnc2ccc(Cl)nn12
Reactant: C[C@H](c1ccc(F)cc1)N1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](c1ccc(F)cc1)N1CCN(c2ccc3nnc(C(F)F)n3n2)CC1
Yield: 84 %

Procedure:
A stirred solution of 6-chloro-3-(difluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine (103 mg, 0.5 mmol), (R)-1-[1-(4-fluorophenyl)ethyl]piperazine (125 mg, 0.6 mmol) (prepared as described in J. Med. Chem. 2007, 50, 3528) and DIPEA (97 mg, 0.75 mmol, 129 μl) in DMF (2 mL) was heated at 100° C. for 2 hours. The crude product was purified by preparative HPLC (Waters XBridge Prep C18 OBD column, 5μ silica, 19 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-(difluoromethyl)-6-[4-[(1R)-1-(4-fluorophenyl)ethyl]piperazin-1-yl][1,2,4]triazolo[4,3-b]pyridazine (158 mg, 84%) as a crisp foam.
Reaction SMILES: [CH2:1]([N:3]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[C:6](=[O:13])[NH:5][C:4]1=[O:14])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1[N:33]([CH2:34][C:35]([CH3:38])([CH3:37])[CH3:36])[C:26]2[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=2[CH:24]=1>CS(C)=O>[CH3:36][C:35]([CH3:38])([CH3:37])[CH2:34][N:33]1[C:26]2[N:27]=[C:28]([C:31]#[N:32])[N:29]=[CH:30][C:25]=2[CH:24]=[C:23]1[CH2:22][N:10]1[CH2:11][CH2:12][C:7]2([N:3]([CH2:1][CH3:2])[C:4](=[O:14])[NH:5][C:6]2=[O:13])[CH2:8][CH2:9]1
Reactant: CCN1C(=O)NC(=O)C12CCNCC2
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCN1C(=O)NC(=O)C12CCN(Cc1cc3cnc(C#N)nc3n1CC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 3 h
Yield: 49.2 %

Procedure:
To a solution of 2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-3,8-dicarboxylic acid di-tert-butyl ester (0.4 g, 1.1 mmol) in DMF (8 ml), NaH (80 mg, 2.2 mmol) and ethyl bromide (166 □1, 2.16 mmol) are added at room temperature. The reaction mixture is stirred at ambient temperature for 15 h, quenched with saturated ammonium clroride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and filtrated. To a solution of 1-ethyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-3,8-dicarboxylic acid di-tert-butyl ester (1.1 mmol) in CH2Cl2 (10 ml), TFA (10 ml) are added at 0° C. The reaction mixture is stirred at room temperature for 1 h. After removal of the solvent, ethyl ether is added to the residue to give 34 mg of desired product in 10% yield. To a solution of 1-ethyl-1,3,8-triaza-spiro[4.5]decane-2,4-dione (30 mg, 0.096 mmol) in DMSO (1 ml), potassium carbonate (13.8 mg, 0.1 mmol) and 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (30.7 mg, 0.1 mmol) are added to the mixture at ambient temperature. The reaction mixture is stirred at ambient temperature for 3 h, quenched with saturated ammonium clroride and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The combined extracts are concentrated and the residue is purified by reverse phase preparative HPLC to give 20 mg of desired product in 3.6% yield.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[S:9][C:8]([C:10]2([CH3:15])[O:14][CH2:13][CH2:12][O:11]2)=[CH:7][CH:6]=1.[C-:16]#[N:17].[Na+].O>CS(C)=O>[CH3:15][C:10]1([C:8]2[S:9][C:5]([CH2:4][C:16]#[N:17])=[CH:6][CH:7]=2)[O:14][CH2:13][CH2:12][O:11]1
Reactant: [C-]#N
Reactant: CC1(c2ccc(CCl)s2)OCCO1
Agent: N#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC1(c2ccc(CC#N)s2)OCCO1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of [5-(2-methyl-[1,3]dioxolan-2-yl)-thiophen-2-yl]-methanol (10.00 g, 49.94 mmol) in dry CH2Cl2 (100 mL) was treated at 0° C. with Et3N (9.04 mL, 64.92 mmol) followed by DMAP (610 mg, 4.99 mmol) and Ms-Cl (4.65 mL, 59.92 mmol). After stirring at rt for 2 h, the reaction was quenched with water (200 mL). The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane as a yellow oil. In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of this crude 2-(5-chloromethyl-thiophen-2-yl)-2-methyl-[1,3]dioxolane in DMSO (400 mL) was treated with sodium cyanide (9.07 g, 185.09 mmol) and the reaction mixture was stirred at 80° C. for 1 h. Water (400 mL) was added to the cooled reaction mixture and the product was extracted with EA (2×500 mL). The combined org. extracts were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (60:40 hept-EA) gave the title compound: TLC: rf (60:40 hept-EA)=0.34. LC-MS-conditions 02: tR=0.89 min.
Reaction SMILES: [ClH:1].COC1C=CC(C[N:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][C:13]([CH3:25])=[C:14]([O:19][C@@H:20]4[CH2:24][CH2:23][NH:22][CH2:21]4)[CH:15]=3)[C:10]2=[O:26])=CC=1.F[C:30](F)(F)C(O)=O>>[ClH:1].[CH3:25][C:13]1[CH:12]=[C:11]2[C:16]([CH:17]=[CH:18][NH:9][C:10]2=[O:26])=[CH:15][C:14]=1[O:19][CH2:20][C@@H:24]1[CH2:30][CH2:21][NH:22][CH2:23]1
Reactant: COc1ccc(Cn2ccc3cc(O[C@@H]4CCNC4)c(C)cc3c2=O)cc1
Reactant: O=C(O)C(F)(F)F
Agent: Cl
Product: Cc1cc2c(=O)[nH]ccc2cc1OC[C@@H]1CCNC1
Temperature: 150 °C
Yield: 74.4 %

Procedure:
245 mg of 2-(4-Methoxy-benzyl)-7-methyl-6-((R)-pyrrolidin-3-yloxy)-2H-isoquinolin-1-one hydrochloride were dissolved in 1.4 g trifluoroacetic acid and the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 10 ml 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride twice and then it was freeze dried to give 134 mg 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one hydrochloride. Rt=0.92 min (Method B). Detected mass: 245.1 (M+H+).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH2:23]([NH:25][CH2:26][CH2:27][OH:28])[CH3:24]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH2:23][CH3:24])[CH2:26][CH2:27][OH:28])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: CCNCCO
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: CCN(CCO)CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1

Procedure:
According to the method in example 4, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and 2-(ethylamino)ethanol were converted to yield 2-[[4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-ethyl-amino]-ethanol, MS: 450 (MH+, 1Br).
Reaction SMILES: [CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C:2]1=O.[NH2:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17].Cl>CN(C=O)C.CO>[CH2:1]1[C@:7]([OH:10])([CH2:8][OH:9])[C@@H:6]([OH:11])[C@H:5]([OH:12])[C@@H:4]([OH:13])[C@H:2]1[NH:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17]
Reactant: NC(CO)CO
Reactant: O=C1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: Cl
Solvent: CO
Solvent: CN(C)C=O
Product: OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5 mmol of valiolone and 5 mmol of 2-amino-1,3-propanediol in 25 mL DMF or methanol is added a catalytic amount of HCl. After 1 hour at room temperature, 2.5 mmol of solid Na(CN)BH3 is added and the reaction mixture is stirred over night at room temperature. The reaction mixture is then concentrated under reduced pressure and the residue is dissolved in water and applied to a Dowex 50 (H+) column. The column is washed with water and the product is eluted with 0.5 N NH4OH. After concentrating the eluate, the residue is dissolved in water and applied successively first to a Amberlite CG-50 (NH4+) or Diaion WK-100 (NH4+) and then a Dowex 1 (OH-) column and each time the product is eluted with water to give voglibose.
Reaction SMILES: C[Si](C)(C)[C:3]#[C:4][C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[C:4]([C:5]1[CH:6]=[CH:7][C:8]2[S:13][CH2:12][CH2:11][C:10](=[O:14])[C:9]=2[CH:15]=1)#[CH:3]
Reactant: C[Si](C)(C)C#Cc1ccc2c(c1)C(=O)CCS2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: C#Cc1ccc2c(c1)C(=O)CCS2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution containing 600.0 mg (2.25 mmol) of 2,3-dihydro-6-(2-trimethylsilylethynyl)-(4H)-1-benzothiopyran-4-one and 100.0 mg (0.72 mmol) K2CO3 in 15 ml MeOH was stirred at room temperature for 20 hours. The solution was diluted with H2O and extracted with Et2O. The combined organic layers were washed with H2O and saturated aqueous NaCl before being dried over MgSO4. Removal of the solvents under reduced pressure afforded the title compound as an orange solid. 1H NMR (CDCl3): δ 8.17 (1H, d, J=1.8 Hz), 7.40 (1H, dd, J=1.8, 8.2 Hz), 7.19 (1H, d, J=8.2 Hz), 3.22 (2H, t, J=6.3 Hz), 3.08 (1H, s) 2.94 (2H, t, J=6.3 Hz).
Reaction SMILES: [CH3:1][C:2](=[O:5])[C:3]#[CH:4].[CH2:6]([O:8][C:9](=[O:13])[CH:10]=[N+:11]=[N-:12])[CH3:7]>O>[CH2:6]([O:8][C:9]([C:10]1[CH:4]=[C:3]([C:2](=[O:5])[CH3:1])[NH:12][N:11]=1)=[O:13])[CH3:7]
Reactant: C#CC(C)=O
Reactant: CCOC(=O)C=[N+]=[N-]
Solvent: O
Product: CCOC(=O)c1cc(C(C)=O)[nH]n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
But-3-yn-2-one (Int 5, 1 eq) and diazo-acetic acid ethyl ester (Int 6, 1.1 eq) are added to a solution of InCl3 (0.2 eq) in water and stirred for 30 min at room temperature. After overnight stirring at room temperature, the mixture is diluted with water and extracted with EtOAc. The resulting organic phase is dried and evaporated to give the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:35]=[CH:34][C:9]3[N:10]([C:13]4[CH:14]=[C:15]([NH:27][S:28]([CH:31]5[CH2:33][CH2:32]5)(=[O:30])=[O:29])[CH:16]=[C:17]([C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=5[F:26])[CH:18]=4)[CH:11]=[N:12][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.N1C=CC=CC=1.[CH3:42][S:43](Cl)(=[O:45])=[O:44]>C(Cl)Cl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[C:17]1[CH:18]=[C:13]([N:10]2[C:9]3[CH:34]=[CH:35][C:6]([C:4]4[CH:5]=[N:1][N:2]([S:43]([CH3:42])(=[O:45])=[O:44])[CH:3]=4)=[CH:7][C:8]=3[N:12]=[CH:11]2)[CH:14]=[C:15]([NH:27][S:28]([CH:31]2[CH2:32][CH2:33]2)(=[O:29])=[O:30])[CH:16]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=S(=O)(Nc1cc(-c2ccc(F)cc2F)cc(-n2cnc3cc(-c4cn[nH]c4)ccc32)c1)C1CC1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)n1cc(-c2ccc3c(c2)ncn3-c2cc(NS(=O)(=O)C3CC3)cc(-c3ccc(F)cc3F)c2)cn1
Reaction time: 1 h
Yield: 60 %

Procedure:
To a solution of the compound of Example 203 (50 mg, 0.101 mmol) in DCM was added pyridine (16 mg, 0.202 mmol, 2.0 eq.) followed by methanesulfonyl chloride (14 mg, 0.122 mmol, 1.2 eq.). The mixture was stirred for 1 h and quenched and extracted as in Example 2(b). The solvent was distilled off to afford the crude residue which was purified by preparative HPLC to give the product in 60% yield (40 mg). H-NMR (400 MHz, DMSO-D6) δ=10.32 (s, 1H), 8.95 (s, 1H), 8.90 (s, 1H), 8.62 (s, 1H), 8.29 (s, 1H), 7.88 (d, 1H), 7.76 (dd, 2H), 7.63 (d, 2H), 7.52 (s, 1H), 7.50-7.47 (m, 1H), 7.30-7.29 (dt, 1H), 3.61 (s, 3H), 2.90-2.86 (m, 1H), 1.04-1.02 (d, 4H); LC-MS (ESI): Calculated mass: 569.6; Observed mass: 569.9 [M+H]+ (rt: 0.64 min).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([O:24][C:25]([F:28])([F:27])[F:26])=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([OH:23])=O)=[CH:17][CH:16]=2)[CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:29]([S:32]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=2)[CH2:37][CH2:36]1)(=[O:34])=[O:33])[CH2:30][CH3:31].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21](=[O:23])[NH:48][C:45]3[CH:46]=[CH:47][C:42]([CH2:41][N:38]4[CH2:37][CH2:36][N:35]([S:32]([CH2:29][CH2:30][CH3:31])(=[O:34])=[O:33])[CH2:40][CH2:39]4)=[CH:43][CH:44]=3)=[CH:17][CH:16]=2)[C:12]([O:24][C:25]([F:26])([F:27])[F:28])=[CH:11][CH:10]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCCS(=O)(=O)N1CCN(Cc2ccc(N)cc2)CC1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCS(=O)(=O)N1CCN(Cc2ccc(NC(=O)c3ccc(-c4cc(NC(=O)OC(C)(C)C)ccc4OC(F)(F)F)cc3)cc2)CC1
Reaction time: 16 h

Procedure:
A mixture of 5′-tert-butoxycarbonylamino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (300 mg), 4-[4-(propane-1-sulfonyl)-piperazin-1-ylmethyl]-phenylamine (224 mg), EDAC (144 mg), HOBT (102 mg) and N-Methylmorpholine (166 ul) in dry DMF (3 ml) was stirred for 16 hrs.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:4]([N:9]2[CH2:15][CH2:14][C:13]3[C:16](O)=[N:17][CH:18]=[N:19][C:12]=3[CH2:11][CH2:10]2)=[N:5][CH:6]=[CH:7][CH:8]=1.O=P(Cl)(Cl)[Cl:25]>CC#N.CCOC(C)=O>[Cl:25][C:16]1[C:13]2[CH2:14][CH2:15][N:9]([C:4]3[C:3]([C:2]([F:22])([F:21])[F:1])=[CH:8][CH:7]=[CH:6][N:5]=3)[CH2:10][CH2:11][C:12]=2[N:19]=[CH:18][N:17]=1
Reactant: Oc1ncnc2c1CCN(c1ncccc1C(F)(F)F)CC2
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: FC(F)(F)c1cccnc1N1CCc2ncnc(Cl)c2CC1
Temperature: 90 °C
Yield: 33 %

Procedure:
To a solution of 7-(3-trifluoromethyl-pyridin-2-yl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-d]azepin-4-ol (185 mg, 0.60 mmol) in CH3CN (2 mL) was added POCl3 (0.11 mL, 1.19 mmol). The reaction mixture was heated at 90° C. for 2 h. The mixture was cooled to rt, diluted with EtOAc, and quenched slowly with saturated (satd.) aq. NaHCO3. The combined organic layers were dried (Na2SO4) and concentrated. The crude residue was purified (FCC) to give the title compound (65 mg, 33%).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=O.[NH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.O>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[CH2:20][CH2:19][NH:18][CH2:13][C:12]1[CH:15]=[CH:16][CH:17]=[C:10]([CH2:9][CH2:8][O:7][CH:2]2[CH2:3][CH2:4][CH2:5][CH2:6][O:1]2)[CH:11]=1
Reactant: NCCc1ccccn1
Reactant: O=Cc1cccc(CCOC2CCCCO2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(CCNCc2cccc(CCOC3CCCCO3)c2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
To a solution of 3-[2-(tetrahydro-pyran-2-yloxy)-ethyl]-benzaldehyde (Example 50, step A, 6.1 g) and 2-(2-aminoethyl)pyridine (3.18 g, 3.1 ml) in toluene (150 mL) was added p-toluene sulfonic acid (100 mg). The reaction was heated at reflux in a Dean-Stark apparatus for couple of hours. Around 2 mL water were displaced. The mixture was cooled and washed with aqueous bicarbonate and concentrated in vacuo. The residue was taken up in ethanol (100 ml) and cooled. Sodium borohydride (1.0 g) was added slowly and the reaction left 1 hour to warm to room temperature. Water was added (100 mL) and ethanol removed by distillation. The reaction was partitioned between aqueous bicarbonate and ethyl acetate. The organic layers were dried over sodium sulfate and concentrated in vacuo to give yellow oil (6.5 g). The material was used in the next step without further purification.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][N:5]([CH2:8][CH2:9][C@@:10]([CH3:25])([S:21]([CH3:24])(=[O:23])=[O:22])[C:11]([NH:13][O:14][C@@H]2CCCCO2)=[O:12])[C:4](=[O:26])[CH:3]=1.CC1(C)C(C)(C)OB([C:35]2[CH:55]=[CH:54][C:38]([O:39][CH2:40][C@H:41]3[CH2:46][CH2:45][C@H:44]([O:47]C4CCCCO4)[CH2:43][CH2:42]3)=[CH:37][CH:36]=2)O1.C(N)(=O)CCC>>[OH:14][NH:13][C:11](=[O:12])[C@:10]([CH3:25])([S:21]([CH3:24])(=[O:22])=[O:23])[CH2:9][CH2:8][N:5]1[CH:6]=[CH:7][C:2]([C:35]2[CH:36]=[CH:37][C:38]([O:39][CH2:40][C@H:41]3[CH2:46][CH2:45][C@H:44]([OH:47])[CH2:43][CH2:42]3)=[CH:54][CH:55]=2)=[CH:3][C:4]1=[O:26]
Reactant: C[C@@](CCn1ccc(I)cc1=O)(C(=O)NO[C@@H]1CCCCO1)S(C)(=O)=O
Reactant: CC1(C)OB(c2ccc(OC[C@H]3CC[C@H](OC4CCCCO4)CC3)cc2)OC1(C)C
Agent: CCCC(N)=O
Product: C[C@@](CCn1ccc(-c2ccc(OC[C@H]3CC[C@H](O)CC3)cc2)cc1=O)(C(=O)NO)S(C)(=O)=O

Procedure:
The title compound (489 mg, 49.7%) was prepared from (2R)-4-(4-iodo-2-oxopyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)-N-[(2R)-tetrahydro-2H-pyran-2-yloxy]butanamide (742 mg, 1.49 mmol) and 2-[(trans-4-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}cyclohexyl)oxy]tetrahydro-2H-pyran (620 mg, 1.49 mmol) by a procedure analogous to that described for (2R)-2-methyl-2-(methylsulfonyl)-4-[2-oxo-4-(4-{[cis-4-(tetrahydro-2H-pyran-2-yloxy)cyclohexyl]methoxy}phenyl)pyridin-1(2H)-yl]-Netrahydro-2H-pyran-2-yloxy)butanamide, Example 8, Step E. LCMS m/z 659.8 (M−1).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.CS([CH2:14][C:15]#[C:16][CH:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[CH:21]=[CH:20][C:19]2[CH:28]=[CH:29][CH:30]=[CH:31][C:18]1=2)(=O)=O>ClCCl>[OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:14][C:15]#[C:16][CH:17]2[C:18]3[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=3[CH:20]=[CH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]2=3)[CH2:6][CH2:5]1
Reactant: CS(=O)(=O)CC#CC1c2ccccc2C=Cc2ccccc21
Reactant: OCCN1CCNCC1
Solvent: ClCCl
Product: OCCN1CCN(CC#CC2c3ccccc3C=Cc3ccccc32)CC1

Procedure:
This preparation illustrates methods of preparing cyclic amine derivatives of formula A. In this preparation 1 gram of N-β-hydroxyethyl-piperazine is added to a solution containing 0.31 g. of 5-(3-methanesulfonylprop-1-ynyl)-5H-dibenzo[a,d]cycloheptene, according to Example 3, in 20 ml. of dichloromethane at 0°C. The resulting mixture is monitored by thin-layer chromatographic analysis and allowed to stand at room temperature until conversion of the sulfonate ester is essentially complete. The mixture is then worked up and purified according to the procedure described in Example 4, yielding 5-[3-(N'-β-hydroxyethyl-1-piperazinyl)prop-1-ynyl]-5H-dibenzo[a,d]cycloheptene.