Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16](Br)=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1.[CH3:35][Sn](C)(C)C>CN(C)C=O.C1(P([Pd-4](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)C=CC=CC=1>[F:1][C:2]([F:34])([F:33])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:12][C:13]([C:15]2[C:16]([CH3:35])=[C:17]([C:24]([N:26]3[CH2:30][CH2:29][CH2:28][C@@H:27]3[CH3:31])=[O:25])[N:18]3[CH2:23][CH2:22][O:21][CH2:20][C:19]=23)=[O:14])[CH2:10][CH3:11])=[CH:5][CH:4]=1
Reactant: CC[C@@H](NC(=O)c1c(Br)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Reactant: C[Sn](C)(C)C
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC[C@@H](NC(=O)c1c(C)c(C(=O)N2CCC[C@@H]2C)n2c1COCC2)c1ccc(C(F)(F)F)nc1
Yield: 92 %

Procedure:
A solution of 7-bromo-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide (Comp. No. 16ru) (55 mg, 0.101 mmol), tetramethylstannane (101 mg, 0.57 mmol) and tetrakis(triphenylphosphino)palladium(0) (6 mg, 5 pmol) in dimethylformamide (2 ml) was heated at 110° C. under microwave irradiation for 1 h. The crude product was purified by reverse phase HPLC to give 45 mg (92%) of 7-methyl-6-((S)-2-methyl-pyrrolidine-1-carbonyl)-3,4-dihydro-1H-pyrrolo[2,1-c][1,4]oxazine-8-carboxylic acid [(R)-1-(6-trifluoromethyl-pyridin-3-yl)-propyl]-amide. LC/MS (method 3): Rt=1.85 min; m/z=479.32 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([NH:15][C@H:16]1[CH2:21][CH2:20][C@H:19](O)[CH2:18][CH2:17]1)[CH:7]=[N:6]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[N+](C1C=CC(C(O)=O)=CC=1)([O-])=O>C1COCC1>[CH:16]1([NH:15][C:8]2[CH:7]=[N:6][C:5]3[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=3)[N:9]=2)[CH2:21][CH2:20][CH:19]=[CH:18][CH2:17]1
Reactant: COc1cc2ncc(N[C@H]3CC[C@H](O)CC3)nc2cc1OC
Agent: CCOC(=O)N=NC(=O)OCC
Agent: O=C(O)c1ccc([N+](=O)[O-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COc1cc2ncc(NC3CC=CCC3)nc2cc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 87.6 %

Procedure:
To a solution of trans-4-(6,7-dimethoxy-quinoxalin-2-ylamino)-cyclohexanol (303 mg, 1 mmol) in 10 mL of THF at −78° C. are added triphenylphosphine (524 mg, 2 mmol) and diethyl azodicarboxylate (1 mL). The mixture is stirred at −78° C. for one hour before addition of 4-nitrobenzoic acid (334 mg, 2 mmol). After being stirred at −78° C. for one hour, the mixture is continued to stir at ROOM TEMPERATURE for additional hour and then concentrated. The residue is chromatographed on silica gel (ether) to give 250 mg (87.7%) of cyclohex-3-enyl-(6,7-dimethoxyquinoxalin-2-yl)-amine.
Reaction SMILES: [N:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([OH:11])[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[CH2:13]=[O:14]>>[OH:14][CH2:13][C:9]1[C:10]2[N:1]=[CH:2][CH:3]=[CH:4][C:5]=2[C:6]([OH:11])=[CH:7][CH:8]=1
Reactant: Oc1cccc2ncccc12
Reactant: C=O
Agent: Cl
Product: OCc1ccc(O)c2cccnc12
Reaction time: 8 h

Procedure:
3.40 g of quinolin-5-ol is combined with 8 ml of conc. hydrochloric acid and 8 ml of 37% formalin solution while cooling with an ice bath. Then hydrogen chloride gas is piped through the reaction mixture for about two hours, while the temperature slowly rises. The reaction mixture is stirred first overnight while cooling with an ice bath, then at ambient temperature and then evaporated down in vacuo. The flask residue is taken up in water, covered with a layer of diethyl ether and adjusted to pH 10 while cooling with an ice bath and vigorously stirring with dilute ammonia solution. After another two hours' vigorous stirring at ambient temperature the organic phase is separated off and the aqueous phase is extracted with diethyl ether. The combined organic phases are washed with water and saturated sodium chloride solution, dried over magnesium sulphate and evaporated down. The flask residue is chromatographed through a silica gel column with methylene chloride/methanol (20:1) as eluant.
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>P(=O)(O)(O)O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]2=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: N#Cc1ccc(C=O)cc1
Reactant: O=C1CCCCCC1
Agent: O=P(O)(O)O
Product: N#Cc1ccc(C=C2CCCCCC2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 20.0 g of 4-cyanobenzaldehyde, 30.5 g of cycloheptanone, and 200 mL of 85% phosphoric acid is heated for 1.5 h at 100° C. The mixture is cooled to room temperature, and filtered. The filtrate is poured into water (800 mL), and the precipitate is filtered, washed with water, and dried. The solid is purified by flash chromatography eluting with a mixture of ether:hexane, 1:2 to afford (4-cyanophenylmethylene)cycloheptanone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]3[C:14]4[C:15]([NH2:19])=[N:16][CH:17]=[CH:18][C:13]=4[S:12][CH:11]=3)=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]([C:46]1[CH:47]=[C:48]([CH2:52][C:53](O)=[O:54])[CH:49]=[CH:50][CH:51]=1)#[N:45].CCN(C(C)C)C(C)C>O.CN(C)C=O>[NH2:19][C:15]1[C:14]2[C:10]([C:6]3[CH:5]=[C:4]4[C:9](=[CH:8][CH:7]=3)[N:1]([C:53](=[O:54])[CH2:52][C:48]3[CH:47]=[C:46]([CH:51]=[CH:50][CH:49]=3)[C:44]#[N:45])[CH2:2][CH2:3]4)=[CH:11][S:12][C:13]=2[CH:18]=[CH:17][N:16]=1
Reactant: Nc1nccc2scc(-c3ccc4c(c3)CCN4)c12
Reactant: N#Cc1cccc(CC(=O)O)c1
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: O
Product: N#Cc1cccc(CC(=O)N2CCc3cc(-c4csc5ccnc(N)c45)ccc32)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.6 %

Procedure:
To a 4 mL screw cap vial was added 3-(2,3-dihydro-1H-indol-5-yl)thieno[3,2-c]pyridin-4-amine (100 mg, 0.329 mmol) followed by HATU (125 mg, 0.329 mmol), 3-cyanophenylacetic acid (53.0 mg, 0.329 mmol) and DIEA (0.230 mL, 1.317 mmol). N,N-Dimethylformamide (DMF) (2 mL) was added and the reaction was sealed and left to stir at room temperature overnight. The reaction mixture was poured into water (4 mL) and extracted with EtOAc (5 mL). The organics were dried over Na2SO4 and concentrated. The residue was taken up in DCM and purified via normal phase chromatography (0-10% MeOH/DCM). Fractions were collected and concentrated to afford 3-{2-[5-(4-aminothieno[3,2-c]pyridin-3-yl)-2,3-dihydro-1H-indol-1-yl]-2-oxoethyl}benzonitrile (100.8 mg). 1H NMR (400 MHz, DMSO-d6) d ppm 8.13 (d, J=8.1 Hz, 1H) 7.83 (d, J=5.8 Hz, 1H) 7.73-7.79 (m, 2H) 7.66 (d, J=7.8 Hz, 1H) 7.52-7.61 (m, 1H) 7.44 (s, 1H) 7.35 (s, 1H) 7.28 (d, J=5.6 Hz, 1H) 7.20-7.26 (m, 1H) 5.48 (br. s., 2H) 4.29 (t, J=8.5 Hz, 2H) 4.00 (s, 2H) 3.27 (t, 2H).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH:2]1[O:4][CH2:3]1.[CH3:12][C:13]1[CH:22]=[C:21]([NH:23][CH2:24][CH2:25][NH2:26])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=1.CN(C)C=O>C(Cl)Cl>[O:5]([CH2:1][CH:2]([OH:4])[CH2:3][NH:26][CH2:25][CH2:24][NH:23][C:21]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]=[C:13]([CH3:12])[CH:22]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: Cc1cc(NCCN)c2ccccc2n1
Reactant: c1ccc(OCC2CO2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1cc(NCCNCC(O)COc2ccccc2)c2ccccc2n1
Reaction time: 48 h

Procedure:
A solution of 4.4 g. phenyl glycidyl ether and 12 g. 2-methyl-4-(2-aminoethylamino)-quinoline in 60 ml. dimethylformamide is left to stand for 48 hours at ambient temperature. The reaction mixture is then taken up in methylene chloride, washed with water, dried and purified chromatographically on a silica gel column using, as elution agent, methylene chloride-methanoltriethylamine (26:3:0.6 v/v/v), and then recrystallized from isopropyl alcohol. There are obtained 3.5 g. (34% of theory) of the desired product in the form of colorless crystals; m.p. 151°-152° C.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[S:5]1(=[O:17])(=[O:16])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7][CH:6]1[C:13]([OH:15])=[O:14]>CN(C=O)C>[CH3:3][C:6]1([C:13]([OH:15])=[O:14])[S:5](=[O:17])(=[O:16])[C:9]2[S:10][CH:11]=[CH:12][C:8]=2[CH2:7]1
Reactant: CI
Reactant: O=C(O)C1Cc2ccsc2S1(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C(=O)O)Cc2ccsc2S1(=O)=O
Temperature: 0 °C

Procedure:
A suspension of sodium hydride (12.3 g, 60% dispersion in oil) in DMF (200 mL, distilled from calcium hydride) was cooled with stirring to 0° C. under a nitrogen atmosphere. Methyl iodide (18.5 mL, 0.29 mol) was added followed by the dropwise addition of 2,3-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-1,1-dioxide (21.33 g. 0.0978 mol) in DMF (200 mL) over a period 1.25 hours. The reaction was stirred at 0° C. for an additional 2.25 hours, then quenched with water (100 mL) and 40% sodium hydroxide (2 mL). The basic solution was stirred for an additional 1 hour at 0° C., until hydrolysis of the ester was complete by tlc. 10% HCl was added to adjust the pH to 6, and the DMF removed in vacuo. The residue was partitioned between ethyl acetate and water. The pH of the aqueous phase was adjusted to 0 with 10% HCl, and the cloudy solution extracted with ethyl acetate (3×500 mL). The volume of ethyl acetate was reduced to 500 mL and extracted with 10% sodium hydroxide (3×300 mL). The aqueous phase was made acidic with concentrated HCl and extracted with two 400 mL portions of ethyl acetate. The combined organic extracts were washed with saturated brine, dried over magnesium sulfate, and filtered. The solvent was removed in vacuo to give an oil which solidified. The solid was triturated with cold methylene chloride (50 mL), filtered and dried in vacuo (0.5 mm, 40° C.) to give the title compound as a light tan powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)[CH3:27])=[CH:25][C:18]=2[N:17]=1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH2:36][C:37]1[CH:42]=[CH:41][C:40]([CH2:43][S:44]([NH2:47])(=[O:46])=[O:45])=[CH:39][CH:38]=1>>[C:1]([O:5][C:6](=[O:35])[N:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:16]1[N:20]([CH3:21])[C:19]2[CH:22]=[CH:23][C:24]([N:26]([CH3:27])[C:28]3[CH:33]=[CH:32][N:31]=[C:30]([NH:36][C:37]4[CH:42]=[CH:41][C:40]([CH2:43][S:44](=[O:46])(=[O:45])[NH2:47])=[CH:39][CH:38]=4)[N:29]=3)=[CH:25][C:18]=2[N:17]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(CS(N)(=O)=O)cc1
Reactant: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Cl)n4)ccc3n2C)cc1
Product: COc1ccc(N(C(=O)OC(C)(C)C)c2nc3cc(N(C)c4ccnc(Nc5ccc(CS(N)(=O)=O)cc5)n4)ccc3n2C)cc1

Procedure:
The title compound was prepared following the procedure of example 78 using {5-[(2-Chloro-pyrimidin-4-yl)-methyl-amino]-1-methyl-1H-benzoimidazol-2-yl}-(4-methoxy-phenyl)-carbamic acid tert-butyl ester (100 mg, 0.20 mmol) and (4-amino-phenyl)-methanesulfonamide (37 mg, 0.20 mmol) to give the desired product as a white solid. 1H NMR (300 MHz, d6-DMSO) δ 9.20 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.65-7.73 (m, 3H), 7.54 (d, J=1.8 Hz, 1H), 7.34 (d, J=8.7 Hz, 2H), 7.24 (dd, J=8.4 and 1.8 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 6.97 (d, J=9.0 Hz, 2H), 6.75 (s, 2H), 5.69 (d, J=6.0 Hz, 1H), 4.14 (s, 2H), 3.78 (s, 3H), 3.74 (s, 3H), 3.46 (s, 3H), 1.41 (s, 9H). MS (ESI) m/z=645 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:3]=1[C:4](=[S:7])[NH:5][NH2:6].[N:13]([CH2:16][CH2:17][CH2:18][C:19]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=O)=[N+:14]=[N-:15]>CCO.ClCCl.C(O)(=O)C>[N:13]([CH2:16][CH2:17][CH2:18][C:19]1([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[NH:6][N:5]=[C:4]([C:3]2[CH:8]=[C:9]([F:12])[CH:10]=[CH:11][C:2]=2[F:1])[S:7]1)=[N+:14]=[N-:15]
Reactant: NNC(=S)c1cc(F)ccc1F
Reactant: [N-]=[N+]=NCCCC(=O)c1ccccc1
Solvent: ClCCl
Solvent: CCO
Solvent: CC(=O)O
Product: [N-]=[N+]=NCCCC1(c2ccccc2)NN=C(c2cc(F)ccc2F)S1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.7 %

Procedure:
To a solution of 2,5-difluorobenzothiohydrazide (1.5 g, 7.97 mmol) in EtOH/dichloromethane (3:1, 16 mL) was added 4-azido-1-phenylbutan-1-one (1.36 g, 7.17 mmol). After stirring at room temperature for 16 hours, acetic acid (2 drops) was added and the mixture was stirred for another 16 hours. The reaction mixture was then concentrated under reduced pressure and chromatographed (9:1 hexanes/ethyl acetate) to provide the product (1.41 g, 41%) as a bright yellow syrup.
Reaction SMILES: Br[C:2]1[C:15]2[S:14](=[O:17])(=[O:16])[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[CH:12]=3)[NH:7][C:6]=2[CH:5]=[C:4]([O:20][CH3:21])[C:3]=1[OH:22].O.ClC1C(=O)C(C#N)=C(C#N)C(=[O:32])C=1Cl.CCCCCC>C1COCC1>[OH:32][C:2]1[C:3](=[O:22])[C:4]([O:20][CH3:21])=[CH:5][C:6]2[C:15]=1[S:14](=[O:17])(=[O:16])[C:13]1[C:8](=[CH:9][CH:10]=[C:11]([O:18][CH3:19])[CH:12]=1)[N:7]=2
Reactant: COc1ccc2c(c1)S(=O)(=O)c1c(cc(OC)c(O)c1Br)N2
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1=CC2=Nc3ccc(OC)cc3S(=O)(=O)C2=C(O)C1=O
Reaction time: 0.33 h

Procedure:
To a stirred suspension of 4-bromo-3-hydroxy-2,7-dimethoxy-10H-phenothiazine-5,5-dioxide (100 mg) in THF (10 ml) was added water (0.1 ml) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (0.12 g). After 20 minutes, hexane was added and the solid was filtered, washed with ether and air dried to afford the title compound, m.p. 333°-335° C. (dec.)
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:10]=[CH:11][C:12]2[N:13]([C:15]([C:18]([F:21])([F:20])[F:19])=[N:16][N:17]=2)[N:14]=1.[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=1>>[F:22][C:23]1[CH:30]=[CH:29][C:26]([CH2:27][N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]4[CH:10]=[CH:11][C:12]5[N:13]([C:15]([C:18]([F:20])([F:21])[F:19])=[N:16][N:17]=5)[N:14]=4)[CH2:3]3)[CH2:6]2)=[CH:25][CH:24]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CC4CNCC4C3)nn12
Reactant: O=Cc1ccc(F)cc1
Product: Fc1ccc(CN2CC3CN(c4ccc5nnc(C(F)(F)F)n5n4)CC3C2)cc1

Procedure:
Reductive amination of 6-(hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-fluorobenzaldehyde was carried out according to General Synthetic Method 10. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[2-[(4-fluorophenyl)methyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrol-5-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=2[CH:19]=1.[Cl:20][C:21]1[CH:22]=[C:23]([SH:28])[CH:24]=[CH:25][C:26]=1[Cl:27]>>[Cl:20][C:21]1[CH:22]=[C:23]([S:28][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]2[CH:8]=[CH:9][C:10]3[NH:15][C:14](=[O:16])[O:13][C:12]([CH3:18])([CH3:17])[C:11]=3[CH:19]=2)[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: CC1(C)OC(=O)Nc2ccc(OCCCCCl)cc21
Reactant: Sc1ccc(Cl)c(Cl)c1
Product: CC1(C)OC(=O)Nc2ccc(OCCCCSc3ccc(Cl)c(Cl)c3)cc21

Procedure:
Prepared analogously to Example 1 from 6-(4-chlorobutoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 3,4-dichloro-thiophenol.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[C:26](F)[CH:25]=2)[N:3]=1.O.[NH2:34][NH2:35]>C(O)C>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][CH2:11][C@H:10]([NH:15][C:16](=[O:23])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:9]2)[CH:5]=[C:4]([C:24]2[CH:25]=[C:26]3[C:27]([C:30]([NH2:31])=[N:34][NH:35]3)=[CH:28][CH:29]=2)[N:3]=1
Reactant: C[C@@H]1CC[C@H](NC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Reactant: NN
Solvent: O
Solvent: CCO
Product: C[C@@H]1CC[C@H](NC(=O)c2ccccc2)CN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 100 °C
Yield: 19.3 %

Procedure:
To N-{(3S,6R)-1-[2-amino-6-(4-cyano-3-fluorophenyl)-4-pyrimidinyl]-6-methyl-3-piperidinyl}benzamide (101 mg, 0.234 mmol) in ethanol (2 mL) into a 5 mL sealable vial was added hydrazine monohydrate (0.22 mL, 7.02 mmol), and the reaction was capped and heat overnight at 100° C. The reaction was concentrated, re dissolved in 1 mL of DMSO, and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (30 ml/min, 15% CH3CN/H2O, 0.1% TFA to 40% CH3CN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were combined and the volume was reduced to remove most of the CH3CN. To the resulting aqueous mixture was added sat. aqueous NaHCO3, and then it was extracted with EtOAc (3×15 mL). The organic was washed with brine, dried over MgSO4, filtered and concentrated to afford the title compound (20 mg) as a light yellow solid. LC-MS (ES) m/z=443 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 1.19 (d, J=6.8 Hz, 3H), 1.24 (s, 1H), 1.66-1.93 (m, 5H), 2.54 (s, 1H), 3.89 (d, J=4.0 Hz, 1H), 5.39 (s, 2H), 6.13 (bs, 1H), 6.62 (s, 1H), 7.47-7.59 (m, 5H), 7.71 (d, J=8.6 Hz, 1H), 7.90 (d, J=7.1 Hz, 2H), 7.94 (s, 1H), 8.43 (d, J=8.1 Hz, 1H), 11.51 (bs, 1H).
Reaction SMILES: FC(F)(F)C1C=CC(C2C=C(CO)C=CC=2)=NC=1.C[O:20][C:21](=[O:51])[CH2:22][O:23][C:24]1[CH:32]=[CH:31][C:30]([S:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][N:42]=3)[CH:36]=2)=[C:29]2[C:25]=1[CH2:26][CH2:27][CH2:28]2>>[F:50][C:47]([F:48])([F:49])[C:44]1[CH:45]=[CH:46][C:41]([C:37]2[CH:36]=[C:35]([CH:40]=[CH:39][CH:38]=2)[CH2:34][S:33][C:30]2[CH:31]=[CH:32][C:24]([O:23][CH2:22][C:21]([OH:51])=[O:20])=[C:25]3[C:29]=2[CH2:28][CH2:27][CH2:26]3)=[N:42][CH:43]=1
Reactant: COC(=O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cn3)c2)c2c1CCC2
Agent: OCc1cccc(-c2ccc(C(F)(F)F)cn2)c1
Product: O=C(O)COc1ccc(SCc2cccc(-c3ccc(C(F)(F)F)cn3)c2)c2c1CCC2

Procedure:
Preparation of [3-(5-Trifluoromethyl-pyridin-2-yl)-phenyl]-methanol (compound 53A) The title compound was prepared in the manner analogous to Example 3A using 3-(hydroxymethyl)phenyl boronic acid and 2-chloro-5-trifluoromethyl-pyridine. MS m/z 253 (M+1). Step 2. Preparation of 2-(3-Chloromethyl-phenyl)-5-trifluoromethyl-pyridine (compound 53B) The title compound was prepared in the manner analogous to Example 3B using 53A. MS m/z 237 (M+1-Cl). Step 3. Preparation of {7-[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-acetic acid methyl ester (compound 53C) The title compound was prepared in the manner analogous to Example 1F using 12C and 53B. MS m/z 474 (M+1). Step 4. Preparation of {7 -[3-(5-Trifluoromethyl-pyridin-2-yl)-benzylsulfanyl]-indan-4-yloxy}-acetic acid (compound 53) The title compound was prepared in the manner analogous to Example 1 using 53C. 400 MHz 1H NMR (DMSO-d6) δ 8.98 (m, 1H), 8.23 (dd, 1H, J=1.7 Hz, J′=8.5 Hz), 7.99 (m, 2H), 7.87 (s, 1H), 7.39 (t, 1H, J=7.6 Hz), 7.33 (m, 1H), 7.11 (d, 1H, J=8.5 Hz), 6.58 (d, 1H, J=8.5 Hz), 4.61 (s, 2H), 4.08 (s, 2H), 2.70 (t, 2H, J=7.3 Hz), 2.63 (t, 2H, J=7.6 Hz), 1.84 (m, 2H). MS m/z 460 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@H:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]([OH:19])([C@H:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CS(=O)(=O)Cl
Reactant: C[C@@H](O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: C[C@@H](OS(C)(=O)=O)[C@@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
In ethyl acetate (40 ml) was dissolved (2S,3R)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (2.5 g). To the solution were added, under ice-cooling, triethylamine (1.82 ml) and methanesulfonyl chloride (1.51 g). The mixture was stirred for 30 minutes at room temperature. To the reaction mixture was added ethyl acetate (40 ml), which was washed with water and dried (anhydrous magnesium sulfate), followed by concentration to give (2S,3R)-2-(2,4-difluorophenyl)-3-methanesulfonyloxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol as an oily product. This product was dissolved in methanol (40 ml), to which was added, under ice-cooling, a 28% methanol solution of sodium methylate (2.04 g). The mixture was stirred for 30 minutes at room temperature, then the reaction mixture was concentrated under reduced pressure. To the concentrate was added ethyl acetate (100 ml), which was washed with water, followed by drying (anhydrous magnesium sulfate). The solvent was distilled off under reduced pressure, and the residue was purified by means of a silica gel chromatography (eluent: ethyl acetate-dichloromethane=4:1) to give (2S,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane (1.62 g) as a colorless oily product. This product became a colorless solid in a freezer. m.p. 41°-43° C. [α]D23 =+5.8° (c=1.0 in methanol)
Reaction SMILES: [NH2:1][C@H:2]1[C@H:6]([F:7])[CH2:5][N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]([CH3:19])[CH3:18])=[C:10]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:9]=2)[CH2:3]1.C([O-])(O)=O.[Na+].[C:32](Cl)(=[O:35])[CH:33]=[CH2:34]>C(Cl)Cl>[F:7][C@@H:6]1[CH2:5][N:4]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[CH:13][N:14]3[CH:17]([CH3:19])[CH3:18])=[C:10]([NH:20][C:21]3[CH:22]=[N:23][N:24]([CH3:26])[CH:25]=3)[N:9]=2)[CH2:3][C@H:2]1[NH:1][C:32](=[O:35])[CH:33]=[CH2:34]
Reactant: C=CC(=O)Cl
Reactant: CC(C)n1cnc2c(Nc3cnn(C)c3)nc(N3C[C@@H](N)[C@H](F)C3)nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: C=CC(=O)N[C@@H]1CN(c2nc(Nc3cnn(C)c3)c3ncn(C(C)C)c3n2)C[C@H]1F

Procedure:
Crude 2-((trans)-3-amino-4-fluoropyrrolidin-1-yl)-9-isopropyl-N-(1-methyl-1H-pyrazol-4-yl)-9H-purin-6-amine (assumed 1 mmol ca.) was partitioned between DCM (30 mL) and sat. aq. NaHCO3 (10 mL) and stirred vigorously. Acryloyl chloride (121 μL, 1.5 mmol) was added in one portion and the mixture stirred for 30 min. The mixture was then diluted with DCM (50 mL) and the organic layer was separated, dried over Na2SO4 and evaporated to give a dark residue that was subjected to chiral SFC purification to separate the two trans enantiomers (Chiralpak AD-H 21.2×250 mm 5μ column. Eluted with 30% EtOH (200 proof) in CO2 held 38° C. at 100 bar, ˜60.0 mL/min, UV detection at λ=260 nm. Peak 1(−) elutes 3.99-4.68 min. Peak 2(+) elutes 5.80-6.38 min). Yielded:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][C:3]=1[CH:4]=[O:5].Cl.Cl[CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][O:18][CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][CH2:13][CH2:14][N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: ClCCN1CCOCC1
Reactant: O=Cc1cc(O)ccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cc(OCCN2CCOCC2)ccc1Br
Yield: 70 %

Procedure:
To a mixture of 2-bromo-5-hydroxybenzaldehyde (62; 3 g, 15 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (120; 5.6 g, 30 mmol) in DMF (75 mL) was added K2CO3 (10.3 g, 74.6 mmol). After reaction 2 h at 120° C. for 3 h, the reaction mixture was quenched by addition of water and extracted with EtOAc. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. Column chromatography afforded 2-bromo-5-(2-morpholinoethoxy)benzaldehyde 121 (3.3 g, 72%) as a brown solid.