Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C(C2C=CC=CC=2)[N:8]2[CH2:11][CH:10]([N:12]3[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C@@H:13]3[CH3:19])[CH2:9]2)C=CC=CC=1>[OH-].[Pd+2].[OH-].[C].CO>[NH:8]1[CH2:11][CH:10]([N:12]2[CH2:17][CH2:16][N:15]([CH3:18])[CH2:14][C@@H:13]2[CH3:19])[CH2:9]1
Reactant: C[C@H]1CN(C)CCN1C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: C[C@H]1CN(C)CCN1C1CNC1
Yield: 162.4 %

Procedure:
To a mixed solution of (2S)-1-(1-(diphenylmethyl)azetidin-3-yl)-2,4-dimethylpiperazine (321 mg, 0.957 mmol) described in Production Example 6-2 and methanol (7.0 mL) was added palladium hydroxide-carbon (150 mg) at room temperature. The resultant mixture was stirred under a hydrogen atmosphere at room temperature and at 0.35 MPa to 0.40 MPa for 5 hours. The reaction mixture was purged with a nitrogen atmosphere and then filtrated using Celite. A filtrate was concentrated under a reduced pressure to give a mixture (263 mg) of the title compound and benzylbenzene. The product was used in the subsequent reaction without further purification.
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=2)[C:11]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=2[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:9]1)=[O:7])(C)(C)C.[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38]>ClCCl>[F:35][C:36]([F:41])([F:40])[C:37]([OH:39])=[O:38].[Br:19][C:15]1[CH:14]=[C:13]([CH:12]2[C:11]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:10]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:9][CH:8]2[C:6]([OH:7])=[O:5])[CH:18]=[CH:17][CH:16]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Br)c2)C1(C#N)c1ccc(Cl)cc1F
Yield: 83 %

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 66b (1.2 g, 2.2 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3R,4R,5S)-3-(3-bromo-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a white solid (1.1 g, 83%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=2[CH:16]=1.[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:29]=[CH:28][C:27]([Sn](C)(C)C)=[CH:26][CH:25]=1)=[O:20].[Cl-].[Li+]>CN1CCCC1=O.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:17][CH:18]([F:37])[C:19]([NH:21][C@H:22]([CH2:35][F:36])[C@H:23]([OH:34])[C:24]1[CH:25]=[CH:26][C:27]([C:2]2[CH:3]=[CH:4][C:5]3[S:9][C:8]([CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13])=[N:7][C:6]=3[CH:16]=2)=[CH:28][CH:29]=1)=[O:20]
Reactant: CS(=O)(=O)NCc1nc2cc(Br)ccc2s1
Reactant: C[Sn](C)(C)c1ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)NCc1nc2cc(-c3ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc3)ccc2s1
Temperature: 90 °C
Yield: 1.6 %

Procedure:
To a stirred solution of N-(5-Bromo-benzothiazol-2-ylmethyl) methane sulfonamide (0.21 g, 0.656 mmol) and 2,2-Difluoro-N-[(1S,2R)-1-fluoromethyl-2-hydroxy-2-(4-trimethylstannanyl-phenyl)-ethyl]-acetamide (0.404 g, 0.984 mmol) in N-Methyl-2-pyrrolidone (9 mL) is added lithium chloride (0.084 g, 1.968 mmol) at room temperature. Resulting reaction mixture is degassed with nitrogen for 15 minutes then Pd(PPh3)2Cl2 (0.046 g, 0.065 mmol) is added. The reaction mixture heated to 90° C. for 16 hours. Reaction mixture is cooled to room temperature, diluted with water and extracted with ethyl acetate. Organic layer is dried over sodium sulfate, solvent is evaporated in vacuo to give the crude material purified by flash column chromatography using 2.4% methanol in CH2Cl2 as an eluent to give impure compound. The impure compound is again purified by prep-HPLC to give the title compound (5 mg). 1HNMR (400 MHz, DMSO) δ: 3.04 (s, 3H), 4.26-4.33 (m, 1H), 4.41-4.43 (m, 0.5H), 4.44-4.50 (m, 0.5H), 4.62 (s, 2H), 4.65-4.68 (m, 0.5H), 4.75-4.79 (m, 0.5H), 4.87-4.88 (m, 1H), 5.9 (d, J=4.56 Hz, 1H), 6.20 (d, J=56.36 Hz, 1H), 7.45 (d, J=8.24 Hz, 2H), 7.63, (d, J=8.16 Hz, 1H), 7.73 (d, J=8.28 Hz, 2H). 7.81 (d, J1=1.8 Hz, J2=8.52 Hz, 1H), 8.42 (d, J=1.6 Hz, 1H), 8.82-8.83 (m, 2H). LC-Ms (m/z): [M−H]=485.8.
Reaction SMILES: [CH:1]1([C:5]2[C:14]([C:15]3[CH:19]=[C:18]([CH2:20][CH3:21])[NH:17][N:16]=3)=[CH:13][C:8]([C:9]([O:11]C)=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>CO>[CH:1]1([C:5]2[C:14]([C:15]3[CH:19]=[C:18]([CH2:20][CH3:21])[NH:17][N:16]=3)=[CH:13][C:8]([C:9]([OH:11])=[O:10])=[C:7]([CH3:22])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: CCc1cc(-c2cc(C(=O)OC)c(C)cc2C2CCC2)n[nH]1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCc1cc(-c2cc(C(=O)O)c(C)cc2C2CCC2)n[nH]1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
To a solution of methyl 4-cyclobutyl-5-(5-ethyl-1H-pyrazol-3-yl)-2-methylbenzoate (compound 445.2, 188 mg, 0.630 mmol, 1.00 equiv) in methanol (6 mL) was added aqueous sodium hydroxide (76.0 mg, 1.90 mmol, 3.00 equiv in 3 mL water). The resulting solution was stirred for 2 h at 70° C. in an oil bath. After cooling to ambient temperature, the mixtue was concentrated under reduced pressure. The residue was diluted with 20 mL of H2O. The pH of the mixture was adjusted to −4 with aqueous HCl (2 M). The mixture was then extracted with 3×20 mL of ethyl acetate. The combined organic layers were washed with 3×20 mL of brine, dried (Na2SO4), and concentrated under reduced pressure. This resulted in 0.180 g (crude) of the title compound as a yellow oil.
Reaction SMILES: C[N:2]([CH3:17])[CH:3]=[CH:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1)=O.NC1[N:20]=[CH:21][NH:22][C:23]=1[Br:24]>C(O)(=O)C>[F:16][C:13]([F:14])([F:15])[C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:5]2[N:20]3[CH:21]=[N:22][C:23]([Br:24])=[C:17]3[N:2]=[CH:3][CH:4]=2)[CH:8]=1
Reactant: CN(C)C=CC(=O)c1cccc(C(F)(F)F)c1
Reactant: Nc1nc[nH]c1Br
Solvent: CC(=O)O
Product: FC(F)(F)c1cccc(-c2ccnc3c(Br)ncn23)c1

Procedure:
A mixture of 0.01 mole of 3-dimethylamino-3'-(trifluoromethyl)acrylophenone, 0.01 mole of 4-amino-5-bromoimidazole and 50 ml. of glacial acetic acid is refluxed for 6 hours. The solvent is removed and the residue worked up as for Example 29 to give the product of the example.
Reaction SMILES: [F:1][C:2]1([F:7])[CH2:5][CH:4]([NH2:6])[CH2:3]1.Cl.CCN(C(C)C)C(C)C.[F:18][C:19]([F:42])([F:41])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:40])[C:28]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([NH:37][CH3:38])=[CH:30][C:29]=2F)[CH2:22][CH2:21]1>CC#N>[F:18][C:19]([F:41])([F:42])[C@H:20]1[CH2:25][CH2:24][C@H:23]([NH:26][C:27](=[O:40])[C:28]2[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[C:31]([NH:37][CH3:38])=[CH:30][C:29]=2[NH:6][CH:4]2[CH2:5][C:2]([F:7])([F:1])[CH2:3]2)[CH2:22][CH2:21]1
Reactant: NC1CC(F)(F)C1
Reactant: CNc1cc(F)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CNc1cc(NC2CC(F)(F)C2)c(C(=O)N[C@H]2CC[C@H](C(F)(F)F)CC2)cc1[N+](=O)[O-]
Reaction time: 16 h

Procedure:
A mixture of 3,3-difluoro-cyclobutylamine×HCl (49 mg, 0.34 mmol), DIPEA (0.26 ml, 1.5 mmol), N-(trans-4-trifluoromethyl-cyclohexyl)-2-fluoro-4-methylamino-5-nitro-benzoic acid amide (125 mg, 0.34 mmol, prepared according to WO2010/100249) and MeCN (5 mL) is stirred for 16 h at reflux. Then the mixture is concentrated, diluted with EtOAc, washed with water, concentrated, dried and directly used in the next step.
Reaction SMILES: N(S([O-])(=O)=O)(S([O-])(=O)=[O:4])[O].[K+].[K+].[OH:13][C:14]1[C:19]([O:20][CH3:21])=[C:18]([O:22][CH3:23])[CH:17]=[C:16]([CH3:24])[C:15]=1[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35].Cl>O.[OH-].[Na+].CC(C)=O>[CH3:21][O:20][C:19]1[C:14](=[O:13])[C:15]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[C:16]([CH3:24])[C:17](=[O:4])[C:18]=1[O:22][CH3:23]
Reactant: COc1cc(C)c(CCCCCCCCCC(=O)O)c(O)c1OC
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Agent: Cl
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: COC1=C(OC)C(=O)C(CCCCCCCCCC(=O)O)=C(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of potassium nitrosodisulfonate (0.8 part) in water (10 volume parts) was added to a solution of 10-(2'-hydroxy-3', 4'-dimethoxy-6'-methylphenyl)decanoic acid (formula II-2 wherein R=H3CO, X=H, Y=OH, n=8, in the free form) (0.097 part) in a mixture of 1% sodium hydroxide (0.67 volume part) and acetone (2 volume parts) and the mixture was stirred at room temperature for 2 hours. The reaction mixture was rendered acidic with dilute hydrochloric acid and extracted with diethyl ether. The extract was washed with water and dried, followed by evaporation to dryness. The procedure provided 2,3-dimethoxy-5-methyl-6-(9'-carboxynonyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=8, in the free form) (0.099 part) as orange-colored needles melting at 59°-60.5° C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:39])[CH2:23][NH:24][C:25]([CH:27]4[CH2:31][CH2:30][CH2:29][N:28]4C(OC(C)(C)C)=O)=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:40].O1CCOCC1>O1CCOCC1>[ClH:40].[CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:39])[CH2:23][NH:24][C:25]([C@H:27]4[CH2:31][CH2:30][CH2:29][NH:28]4)=[O:26])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(NCC(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1)[C@H]1CCCN1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
854 mg (1.62 mmol) of the compound obtained in step 1 described above was dissolved in 20 ml of 1,4-dioxane. 2 ml of 4 N hydrochloric acid/1,4-dioxane was added to the obtained solution under cooling with ice, and they were stirred at room temperature for 2.5 hours. The reaction mixture was cooled with ice, 5 ml of 4 N hydrochloric acid/1,4-dioxane was added thereto, and they were stirred at room temperature for 2 hours. 2.5 ml of 4 N hydrochloric acid/1,4-dioxane was added to the reaction mixture under cooling with ice. After stirring at room temperature for 1 hour, 7.5 ml of 4 N hydrochloric acid/1,4-dioxane was added to the reaction mixture, and they were stirred at room temperature for 2 hours. The solvent was concentrated under reduced pressure. Diethyl ether was added to the residue, and crystals thus formed were taken by the filtration to obtain the title compound.
Reaction SMILES: CC1C=CC(S(O[CH:12]2[CH2:40][CH2:39][C:15]3([O:19][N:18]=[C:17]([C:20]4[C:21]([NH:32][CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[C:22]5[C:28]([CH3:29])=[N:27][N:26]([CH2:30][CH3:31])[C:23]5=[N:24][CH:25]=4)[CH2:16]3)[CH2:14][CH2:13]2)(=O)=O)=CC=1.[C-:41]#[N:42].[Na+].O>CN(C)C=O>[CH:33]1([NH:32][C:21]2[C:20]([C:17]3[CH2:16][C:15]4([CH2:14][CH2:13][CH:12]([C:41]#[N:42])[CH2:40][CH2:39]4)[O:19][N:18]=3)=[CH:25][N:24]=[C:23]3[N:26]([CH2:30][CH3:31])[N:27]=[C:28]([CH3:29])[C:22]=23)[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(OS(=O)(=O)c5ccc(C)cc5)CC4)C3)cnc21
Reactant: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1nc(C)c2c(NC3CCCCC3)c(C3=NOC4(CCC(C#N)CC4)C3)cnc21
Temperature: 62.5 °C
Reaction time: 8 h

Procedure:
3-[4-(Cyclohexylamino)-1-ethyl-3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl]-1-oxa-2-azaspiro[4.5]dec-2-en-8-yl 4-methylbenzenesulfonate (0.0018 mole) (example 39) is taken in dimethylformamide. Sodium cyanide (0.0036 mole) is added and the reaction mixture is stirred at 60-65° C. overnight. Water is added and extraction is done with ethyl acetate. The organic layer is washed with brine, dried and concentrated under reduced pressure to give crude compound, which is purified by column chromatography.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(CC)CC)C.[N:21]1([CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C1COCC1>[N+:11]([C:8]1[CH:9]=[CH:10][C:5]([O:4][C:2]([N:30]2[CH2:31][CH2:32][CH:27]([N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[CH2:28][CH2:29]2)=[O:3])=[CH:6][CH:7]=1)([O-:13])=[O:12]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCC(N2CCCCC2)CC1
Reaction time: 2 h

Procedure:
To a solution of 4-nitrophenyl chloroformate (31) (5.15 g, 25.6 mmol) in 150 mL of dry THF at −78° C. was added triethylamine (10.7 mL, 76.2 mmol), followed by a solution of 4-piperidinopiperidine (30) (4.51 g, 25.6 mmol) in 40 mL of THF. This solution was stirred for two hours, after which the solvent was removed, and the residue was taken up in AcOEt, filtered and evaporated. The crude yellow solid was passed through a pad of neutral alumina using AcOEt as an eluent to yield, after evaporation, 6.73 g (79%) of a white solid: IR (CHCl3, cm−1) 3046, 2937, 2859, 1704, 1620, 1513, 1466, 1242, 1197; 1H NMR (300 MHz, CDCl3) δ 1.20-1.80 (m, 8H), 1.90 (d, J=12.7 Hz, 2H), 2.20-2.70 (m, 5H), 2.87 (t, J=12 Hz, 1H), 3.01 (t, J=12 Hz, 1H), 4.30 (br s, 2H), 7.29 (d, J=9 Hz, 2H), 8.26 (d, J=9 Hz, 2H);
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:13][CH2:12][C:6]2([O:10][C:9](=[O:11])[NH:8][CH2:7]2)[CH2:5][CH2:4]1.[H-].[Na+].[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[N:21][C:22]=1Cl>O1CCCC1.CN(C)C=O>[Cl:16][C:17]1[CH:18]=[C:19]([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[N:21][C:22]=1[O:1][CH2:2][CH:3]1[CH2:13][CH2:12][C:6]2([O:10][C:9](=[O:11])[NH:8][CH2:7]2)[CH2:5][CH2:4]1
Reactant: NS(=O)(=O)c1cnc(Cl)c(Cl)c1
Reactant: O=C1NCC2(CCC(CO)CC2)O1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cnc(OCC2CCC3(CC2)CNC(=O)O3)c(Cl)c1
Reaction time: 0.5 h

Procedure:
To a solution of EXAMPLE 385C (325 mg, 1.755 mmol) in a mixture of tetrahydrofuran (16 mL) and N,N-dimethylformamide (8 mL) was added sodium hydride (281 mg, 7.02 mmol) and the mixture was stirred for 30 minutes. 5,6-Dichloropyridine-3-sulfonamide (389 mg) was added and the reaction was stirred for 42 hours. The reaction was quenched with water (5 mL) and concentrated. The residue was diluted with 75% brine (200 mL) and extracted with methylene chloride (3×200 mL). The organics were dried over sodium sulfate, filtered, and concentrated. The residue was purified on silica gel and eluted with a 1, 5, and 10% methanol in methylene chloride step gradient to provide the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([O:15][CH3:16])=[C:6]([NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11])[CH:7]=1.[CH3:17][Si:18]([C:21]#[CH:22])([CH3:20])[CH3:19]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[F:11][C:10]([F:13])([F:12])[C:9]([NH:8][C:6]1[CH:7]=[C:2]([C:22]#[C:21][Si:18]([CH3:20])([CH3:19])[CH3:17])[CH:3]=[CH:4][C:5]=1[O:15][CH3:16])=[O:14]
Reactant: COc1ccc(Br)cc1NC(=O)C(F)(F)F
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: COc1ccc(C#C[Si](C)(C)C)cc1NC(=O)C(F)(F)F
Temperature: 60 °C
Yield: 43.1 %

Procedure:
To an oven-dried flask under N2 was added N-[5-bromo-2-(methyloxy)phenyl]-2,2,2-trifluoroacetamide (1.53 g, 0.005 mol), anhydrous degassed THF (100 mL), dichlorobis(triphenylphosphine)palladium(II) (0.45 mg, 0.6 mmol), copper(I) iodide (73 mg, 0.38 mmol), and trimethylsilylacetylene (1.26 g, 0.013 mol). Next, TEA (5.19 g, 0.05 mol) was added dropwise and the resulting mixture was heated at 60° C. overnight. The crude reaction mixture was adsorbed to silica gel and purified by column chromatography (0-10% EtOAc in hexanes) to afford the desired product (0.68 g, 42%) as an off white solid. ES-LC/MS m/z=314 [M−H]+.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=2[N:7]=1.[CH2:20]([N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[CH3:21]>C(Cl)(Cl)Cl>[CH2:20]([N:22]1[CH2:27][CH2:26][N:25]([C:2]2[N:3]=[CH:4][C:5]3[C:11](=[O:12])[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:9][N:8]([CH2:18][CH3:19])[C:6]=3[N:7]=2)[CH2:24][CH2:23]1)[CH3:21]
Reactant: CCOC(=O)c1cn(CC)c2nc(Cl)ncc2c1=O
Reactant: CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(CC)CC3)ncc2c1=O
Yield: 90.7 %

Procedure:
3.8 g of 2-chloro-5-oxo-6-carbethoxy-8-ethyl-5,8-dihydro-pyrido(2,3-d)pyrimidine and 2.9 g of 1-ethylpiperazine, dissolved in 50 cm3 of chloroform, are heated under reflux for 2 hours. After cooling, the organic solution is washed with water and dried over MgSO4 ; the solvent is evaporated and the residue is recrystallised from a mixture of isopropyl ether (15 cm3) and benzene (25 cm3) and gives 4.4 g (yield: 93%) of 2-(4'-ethylpiperazino)-5-oxo-8-ethyl-6-carbethoxy-5,8-dihydro-pyrido(2,3-d)pyrimidine; melting point 161° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](=[S:8])[NH2:7])=[CH:4][CH:3]=1.Cl[CH:12]([C:18](=O)[CH3:19])[C:13]([O:15][CH2:16][CH3:17])=[O:14]>C(O)C>[CH3:19][C:18]1[N:7]=[C:6]([C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][CH:4]=2)[S:8][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Cc1ccc(C(N)=S)cc1
Reactant: CCOC(=O)C(Cl)C(C)=O
Solvent: CCO
Product: CCOC(=O)c1sc(-c2ccc(C)cc2)nc1C
Yield: 68.7 %

Procedure:
4-Methylbenzothioamide (0.312 g; 2.00 mmol) and ethyl 2-chloro-3-oxobutanoate (0.323 mL; 2.10 mmol) were dissolved in ethanol (3 mL). The mixture was irradiated in a microwave oven at 170° C. for 10 min. After evaporation, the residue was purified by flash chromatography on silica gel (eluent: 20 to 100% dichloromethane in heptane) to afford 0.359 g (69%) of ethyl 4-methyl-2-p-tolylthiazole-5-carboxylate as a solid.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21](F)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1>>[C:1]([N:11]1[CH2:16][CH2:15][CH:14]([C:17](=[O:25])[C:18]2[CH:23]=[CH:22][C:21]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:20][CH:19]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2]
Reactant: O=C(c1ccc(F)cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Reactant: C1CCNC1
Product: O=C(c1ccc(N2CCCC2)cc1)C1CCN(C(=O)OCc2ccccc2)CC1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 4.1 g of 1-carbobenzoxy-4-(4-fluorobenzoyl)piperidine and 8 ml of pyrrolidine was stirred at 100° C. for 24 hours and the reaction mixtures was then worked up in the same manner as Example 2 to give 3.2 g of the title compound as oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]([C:24](=[O:34])[N:25]([CH2:31][CH:32]=[CH2:33])[CH:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:18]=1)[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].B1C2CCCC1CCC2.[OH:45]O.[OH-].[Na+]>>[C:1]([O:5][C:6](=[O:35])[N:7]([CH2:14][CH2:15][O:16][C:17]1[CH:18]=[C:19]([C:24](=[O:34])[N:25]([CH:26]2[CH2:27][CH2:28][CH2:29][CH2:30]2)[CH2:31][CH2:32][CH2:33][OH:45])[CH:20]=[C:21]([Cl:23])[CH:22]=1)[C:8]1[CH:9]=[CH:10][N:11]=[CH:12][CH:13]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C=CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C1CCCC1
Reactant: OO
Agent: B1C2CCCC1CCC2
Agent: [Na+]
Agent: [OH-]
Product: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)N(CCCO)C2CCCC2)c1)c1ccncc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To {2-[3-(allyl-cyclopentyl-carbamoyl)-5-chloro-phenoxy]-ethyl}-pyridin-4-yl-carbamic acid tert-butyl ester (0.11 g) was added 9-BBN (0.5M in THF, 2.2 ml) and the resulting solution stirred at room temperature under nitrogen for 20 h. A mixture of 28% aqueous hydrogen peroxide solution (1.8 ml) and 2M aqueous sodium hydroxide (0.9 ml) was added and the reaction mixture stirred at reflux for 2 h. The solvent was removed in vacuo and the residue purified by preparative hplc and the title compound (0.064 g) was obtained as a colourless gum by concentration of the required fraction under reduced pressure and drying by repetitive addition of acetonitrile and concentration under reduced pressure.
Reaction SMILES: C(N1CCN([NH:14][C:15](=[O:23])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)CC1)(OC(C)(C)C)=O.[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42]N(C(OC(C)(C)C)=O)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]>>[CH2:24]([C:26]1[S:34][C:33]2[N:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[N:30]=[C:29]([N:38]3[CH2:43][CH2:42][N:14]([C:15](=[O:23])[CH2:16][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH2:40][CH2:39]3)[C:28]=2[CH:27]=1)[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)Cc2ccccc2)CC1
Reactant: CCc1cc2c(N3CCN(C(=O)OC(C)(C)C)CC3)nc(C(C)C)nc2s1
Product: CCc1cc2c(N3CCN(C(=O)Cc4ccccc4)CC3)nc(C(C)C)nc2s1
Yield: 21 %

Procedure:
Phenylacetamidopiperazine hydrochloride (Example 141) was reacted 2-isopropyl-4-chloro-6-ethylthienopyrimidine (Example 162) according to Example 87. Yield=21%, ES-MS: (M+H)+ 409.
Reaction SMILES: [CH:1]12[O:7][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6]2.[NH:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1.O>C(OCC)C>[OH:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: C1CCC2OC2C1
Reactant: C1CCNC1
Solvent: O
Solvent: CCOCC
Product: OC1CCCCC1N1CCCC1
Yield: 88.6 %

Procedure:
Cyclohexene oxide (982 mg, 10 mmol), pyrolidine (2.134 g, 30 mmol), and 1.8 mL of water were heated at 90° C. for 18 hours. The reaction was then cooled and diluted with 75 mL of diethyl ether. The mixture was then washed with aqueous sodium bicarbonate (15 mL), brine (2×15 mL), dried over magnesium sulfate, filtered, and evaporated to give 1.499 g (89%) of the title compound.