Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][CH:8]([CH2:10][N:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)[CH2:7][C:6]=2[CH:17]=1.C(N(CC)CC)C.[Cl:25][CH2:26][C:27](Cl)=[O:28]>ClCCl>[Cl:25][CH2:26][C:27]([N:14]1[CH2:13][CH2:12][N:11]([CH2:10][CH:8]2[CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:9]2)[CH2:16][CH2:15]1)=[O:28]
Reactant: Clc1ccc2c(c1)CC(CN1CCNCC1)O2
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)N1CCN(CC2Cc3cc(Cl)ccc3O2)CC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
To a solution of 1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (1.3 g, 5.1 mmol) in dichloromethane (50 ml) was added triethylamine (782 mg, 7.73 mmol, 1.5 eq) and 2-chloroacetyl chloride (758 mg, 6.71 mmol, 1.3 eq) dropwise with stirring at 0° C. for 1 hour at room temperature. The reaction mixture was quenched by the addition of water (80 ml) and extracted with dichloromethane (3×50 ml). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under vacuum. The crude material was purified by silica gel chromatography using 3% ethyl acetate in petroleum ether to elute. The product-containing fractions were combined and concentrated under vacuum to afford 2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one as yellow oil (1.0 g, 59%); (ES, m/z): [M+H]+ 329; 1H NMR (300 MHz, CDCl3): δ 7.04-7.12 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 4.95-5.08 (m, 1H), 4.11 (s, 2H), 3.56-3.73 (m, 5H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H), 2.91-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (dd, J=7.8 Hz, 13.5 Hz, 1H), 2.48-2.75 (m, 4H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:20]([CH3:22])[CH3:21])[CH:5]=[C:6]2[C:10]=1[NH:9][C:8]1[C:11]([CH2:17][CH2:18][OH:19])([CH2:15][CH3:16])[O:12][CH2:13][CH2:14][C:7]2=1.[F:23][C:24]1[CH:29]=[C:28](B(O)O)[CH:27]=[CH:26][C:25]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:15]([C:11]1([CH2:17][CH2:18][OH:19])[C:8]2[NH:9][C:10]3[C:6]([C:7]=2[CH2:14][CH2:13][O:12]1)=[CH:5][C:4]([CH:20]([CH3:22])[CH3:21])=[CH:3][C:2]=3[C:28]1[CH:27]=[CH:26][C:25]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)=[C:24]([F:23])[CH:29]=1)[CH3:16]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(Br)cc(C(C)C)cc21
Reactant: OB(O)c1ccc(-c2ccccc2)c(F)c1
Product: CCC1(CCO)OCCc2c1[nH]c1c(-c3ccc(-c4ccccc4)c(F)c3)cc(C(C)C)cc21

Procedure:
The title compound is prepared in a manner analogous to Example 1, except using 2-(8-bromo-1-ethyl-6-isopropyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indol-1-yl)-ethanol and 2-fluorobiphenyl-4-boronic acid in step 1.F.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([C@H:21]3[O:25]C(C)(C)[N:23]([C:28](=[O:32])[CH:29]([F:31])[F:30])[C@@H:22]3[CH2:33][F:34])=[CH:17][CH:16]=2)=[CH:13][CH:14]=1)(C)(C)C.[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>C(Cl)Cl>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[NH2:7][CH2:8][C:9]1[N:10]=[N:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]([C@@H:21]([OH:25])[C@H:22]([NH:23][C:28](=[O:32])[CH:29]([F:30])[F:31])[CH2:33][F:34])=[CH:19][CH:20]=2)=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)nn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)nn1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a stirred solution of (6-{4-[(4S,5R)-3-(2,2-Difluoro-acetyl)-4-fluoromethyl-2,2-dimethyl-oxazolidin-5-yl]-phenyl}-pyridazin-3-ylmethyl)-carbamic acid tert-butyl ester (0.25 g, 0.506 mmol) in CH2Cl2 (10 mL) is added trifluoroacetic acid (1.5 mL) at room temperature. Resulting reaction mixture is allowed to stir at room temperature for 5 h. The solvent evaporated in vacuo and the crude material is striped out with CH2Cl2 followed by washing with n-pentane and diethyl ether and dried to afford title compound (0.181 g): 1H NMR (400 MHz, DMSO-d6) 4.32-4.39 (m, 1.5H), 4.46 (m, 2.5H), 4.55-4.58 (m, 0.5H), 4.68-4.71 (m, 0.5H), 4.94 (bs, 1H), 5.99 (bs, 1H), 6.19 (t, J=53.76 Hz, 1H), 7.54 (d, J=8.28 Hz, 2H), 7.85 (d, J=8.92 Hz, 1H), 8.13 (d, J=8.32 Hz, 2H), 8.36 (d, J=10 HZ, 1H), 8.51 (bs, 2H), 8.87 (d, J=8.72 Hz, 1H). LC-MS (m/z): [M+H]=355.
Reaction SMILES: [NH2:1][C:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Cl:15])=[CH:3][C:4]([O:6]CC)=O.[H-].[Na+].[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29](=O)[O:30]CC)=[CH:24][CH:23]=1>CN(C)C=O>[CH3:18][O:19][CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[C:4](=[O:6])[CH:3]=[C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[NH:1][C:29]2=[O:30])=[CH:24][CH:23]=1
Reactant: CCOC(=O)Nc1ccc(OCOC)cc1
Reactant: CCOC(=O)C=C(N)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCOc1ccc(-n2c(=O)cc(-c3ccccc3Cl)[nH]c2=O)cc1
Temperature: 0 °C
Yield: 87.2 %

Procedure:
8.7 g of ethyl 3-amino-3-(2-chlorophenyl)-2-propenoate was added dropwise to a 40 ml dimethylformamide of 1.8 g of sodium hydride (purity: 55%) with stirring at 0° C. The solution was stirred at room temperature for 15 minutes, cooled to 0° C. and added dropwise with a 20 ml dimethylformamide solution of 7.2 g of ethyl 4-methoxymethoxyphenylcarbamate. After stirring the solution at 120° C. for 2 hours, the solvent was distilled away under reduced pressure. The residue was dissolved with 200 ml of water and washed with diethyl ether. The obtained aqueous layer was added into a mixed solution of 50 ml of concentrated hydrochloric acid and 150 g of ice. The precipitated crystals were filtered out and dried under reduced pressure to obtain 10.0 g of 3-(4-methoxymethoxyphenyl)-6-(2-chlorophenyl)-2,4(1H,3H)-pyrimidinedione.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5](C(OC(C)(C)C)=O)[CH2:4][CH2:3]1.ClCCCl.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(=O)([O-])O.[Na+]>CCOC(C)=O>[C:19]([O:1][CH:2]1[CH2:3][CH2:4][NH:5][CH2:6][CH2:7]1)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: O=C(OC1CCNCC1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.3 %

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (3.0 g) was mixed with DCE (30 ml), and TEA (3.0 ml) and benzoyl chloride (2.4 g) was added thereto, followed by stirring at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and EtOAc were added to the reaction mixture, and the organic layer was dried over Na2SO4 and concentrated under reduced pressure. The obtained residue was mixed with DCE (30 ml), and TFA (10 ml) was added thereto, followed by stirring at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, and then the residue was purified by basic silica gel column chromatography (CHCl3/MeOH) to obtain piperidin-4-yl benzoate (3.1 g).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]([NH:17][CH:18]([C:20]2[CH:25]=[C:24]([F:26])[CH:23]=[C:22]([F:27])[CH:21]=2)[CH3:19])[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1)([O-])=O.[BH4-].[Na+]>CO.O.O.O.O.O.O.[Ni](Cl)Cl>[C:11]1([CH:10]([NH:17][CH:18]([C:20]2[CH:21]=[C:22]([F:27])[CH:23]=[C:24]([F:26])[CH:25]=2)[CH3:19])[C:6]2[CH:5]=[C:4]([NH2:1])[CH:9]=[CH:8][CH:7]=2)[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CC(NC(c1ccccc1)c1cccc([N+](=O)[O-])c1)c1cc(F)cc(F)c1
Agent: Cl[Ni]Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(NC(c1ccccc1)c1cccc(N)c1)c1cc(F)cc(F)c1
Yield: 89.4 %

Procedure:
In a similar manner to that described in Example (1b), a solution of isomer A of [(3-nitrophenyl)phenylmethyl]-[1-(3,5-difluorophenyl)ethyl]amine (900 mg) [prepared as described in step (a) above] in methanol (20 ml), nickel chloride hexahydrate (1.14 g) and sodium borohydride (363 mg) were reacted, to afford isomer A of the title compound (739 mg) as a pale yellow oil.
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]([NH:15][CH3:16])[C:13]#[N:14]>C1(C)C=CC=CC=1.O.[OH-].[Na+]>[CH3:7][O:8][C:9]1[CH:10]=[C:11]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[CH:12]([N:15]([CH3:16])[C:3](=[O:4])[CH:2]([Cl:6])[Cl:1])[C:13]#[N:14]
Reactant: CNC(C#N)c1ccc(OC)c(OC)c1
Reactant: O=C(Cl)C(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(C#N)N(C)C(=O)C(Cl)Cl)cc1OC

Procedure:
A solution of 14.7 g of dichloroacetylchloride in 10 ml of toluene are added dropwise, while stirring at a temperature of -10° to 15° C. to another solution of 20.6 g of N-(3,4-dimethoxy-α-cyanobenzyl-N-methylamine (prepared according to J. Prakt. Chem. 285 (1961) p. 258) in 80 ml of toluene and 20 ml of water, in which was dissolved 4 g of solid NaOH. A solid reaction product precipitates, which is filtered and washed with water until the aqueous filtrate is neutral. The solid acid amide is dried under vacuum to yield 27.7 g of raw product melting at 102°. After treating it with charcoal and recrystallisation from ethanol one obtains 125 g of crystalline title product, melting at 111°-112°.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[N+:21]([CH3:24])([O-:23])=[O:22]>C(O)(=O)C>[F:1][C:2]1[C:7](/[CH:8]=[CH:24]/[N+:21]([O-:23])=[O:22])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:10][C:11](=[O:20])[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=Cc1cccc(NC(=O)OCc2ccccc2)c1F
Reactant: C[N+](=O)[O-]
Solvent: CC(=O)O
Product: O=C(Nc1cccc(/C=C/[N+](=O)[O-])c1F)OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.4 %

Procedure:
A solution of benzyl 2-fluoro-3-formylphenylcarbamate (4.0253 g, 14.73 mmol), nitromethane (1.98 mL, 36.8 mmol) and nitromethane (1.979 mL, 36.8 mmol) in acetic acid (49.1 mL) under nitrogen was heated at 90° C. After 2 hr, the reaction was cooled to room temperature and concentrated in vacuo. The residue was dissolved in CH2Cl2 (75 mL) and water (75 mL), and Na2CO3 (s) was added until pH basic by litmus paper. After separation of layers, the aqueous layer was extracted with CH2Cl2 (3×75 mL). The organic layers were combined and washed with brine (50 mL), dried over MgSO4, and concentrated in vacuo to give the desired product (4.251 g, 10.08 mmol, 68.4% yield) as a burgundy oil.
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:17])([F:16])[F:15])[CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.OC1C2N=NNC=2C=CC=1.[N:43]1([C:49]2[CH:54]=[CH:53][C:52]([OH:55])=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1>>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][C:14]([F:15])([F:16])[F:17])[CH:8]=2)[C:3]=1[C:18]([N:46]1[CH2:45][CH2:44][N:43]([C:49]2[CH:50]=[CH:51][C:52]([OH:55])=[CH:53][CH:54]=2)[CH2:48][CH2:47]1)=[O:20]
Reactant: Oc1ccc(N2CCNCC2)cc1
Reactant: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Product: Nc1onc(-c2cccc(OC(F)(F)F)c2)c1C(=O)N1CCN(c2ccc(O)cc2)CC1
Yield: 72.8 %

Procedure:
In a similar manner as described in Example 1, by using dimethylformimide (15 mL), 5-amino-3-(3-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol), hydroxybenzotriazole (299 mg, 2.21 mmol) and 4-(piperazine-1-yl)phenol (328 mg, 1.84 mmol), a white solid required compound (601 mg, 1.34 mmol, 72%) was obtained.
Reaction SMILES: [CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:27])[CH2:18][NH:19][CH2:20][CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:29][CH2:30][OH:31].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[CH:1]1([CH:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:10][CH2:9][N:8]2[C:17](=[O:27])[CH2:18][N:19]([CH2:20][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:29][CH2:30][OH:31])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: OCCBr
Reactant: O=C(CNCC1CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: O=C(CN(CCO)CC1CCCCC1)N1CCc2ccccc2C1C1CCCCC1
Yield: 46.8 %

Procedure:
2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-N-(cyclohexylmethyl)-2-oxoethanamine (296 mg) was dissolved in acetonitrile (10 mL). To the reaction liquid were added 2-bromoethanol (400 mg), potassium carbonate (555 mg), and potassium iodide (133 mg), followed by stirring under heating at reflux for 16 hours. Thereafter, the solvent was evaporated and water was added to the reaction liquid, followed by extraction with chloroform. The extract was washed with saturated brine, and then dried over magnesium sulfate. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (chloroform-MeOH) to obtain 2-{[2-(1-cyclohexyl-3,4-dihydroisoquinolin-2(1H)-yl)-2-oxoethyl](cyclohexylmethyl)amino}ethanol (155 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:12]1C(=O)C2=CC=CC=C2C1=O.O.NN.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([O:24][CH2:25][CH:26]=[C:27]([Cl:29])[Cl:28])[CH:5]=[C:6]([Cl:23])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: Cl
Agent: NN
Solvent: O
Solvent: CCO
Product: NCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Yield: 71 %

Procedure:
A reaction vessel was charged with 4.67 g of crude 3,5-dichloro-4-(3-phthalimidopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 0.55 g of hydrazine monohydrate and 200 ml of ethanol. After heating under reflux for 2 hours, the reaction mixture was made weak acidic by the addition of concentrated hydrochloric acid, and then further heated under reflux for 1 hours. The deposited solid was collected by filtration, and the filtrate was concentrated. Water was poured into the concentrated, and the mixture was extracted twice with 150 ml of chloroform. The chloroform layers were combined, washed with water, dried over anhydrous magnesium sulfate, and then concentrated to give a crude product. The crude product was subjected to silica gel chromatography which afforded 2.4 of 3,5-dichloro-4-(3-aminopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (71% yield), nD23.5 1.5672.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1.[C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[CH2:41][C:42]([O:44][CH3:45])=[O:43])#[CH:34].C(N(CC)CC)C>CN(C=O)C.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>[CH3:45][O:44][C:42](=[O:43])[CH2:41][C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:33]#[C:34][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:32]=[CH:31][C:16]([CH2:17][N:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)=[CH:15][CH:14]=2)[N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2ccc(Nc3ncc(C(F)(F)F)c(Cl)n3)cc2)CC1
Reactant: C#Cc1ccccc1CC(=O)OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)Cc1ccccc1C#Cc1nc(Nc2ccc(CN3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Temperature: 100 °C
Yield: 30 %

Procedure:
tert-Butyl 4-(4-((4-chloro-5-(trifluoromethyl)pyrimidin-2-yl)amino)benzyl)piperazine-1-carboxylate (I94) (0.500 g, 1.06 mmol) and methyl 2-(2-ethynylphenyl)acetate (I4) (0.203 g, 1.17 mmol) were dissolved in DMF (10 mL) and bis(triphenylphosphine)palladium(II) chloride (37 mg, 5 mol %) was added. The mixture was degassed with nitrogen for ten minutes, then copper(I) iodide (10 mg, 5 mol %) and triethylamine (0.738 mL, 5.30 mmol) were added. The mixture was heated under microwave irradiation (100° C./20 minutes) then concentrated. Chromatography of the residue (12 g silica cartridge, 0-100% ethyl acetate/petroleum benzine 40-60° C.) gave the title compound (I95) (192 mg, 30% yield) as a brown oil;
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-])=O)[CH:5]=1)=[C:2]=[O:3].[NH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1>C(Cl)Cl>[NH2:10][C:6]1[CH:5]=[C:4]([NH:1][C:2]([N:13]2[CH2:17][CH:16]=[CH:15][CH2:14]2)=[O:3])[CH:9]=[CH:8][CH:7]=1
Reactant: O=C=Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCNC1
Solvent: ClCCl
Product: Nc1cccc(NC(=O)N2CC=CC2)c1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
A mixture of 1-isocyanato-3-nitrobenzene (1.125 g, 6.18 mmoles) and pyrrolidine (485 mg, 6.8 mmoles) in DCM (20 mL) was stirred at r.t. for 14 hrs. After concentrated, the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous citric acid solution and dried over MgSO4, followed by hydrogenation with Pd/C (wet, 10%, 0.15 g) under a hydrogen balloon overnight. After filtration and concentration, the reasonable pure N-(3-aminophenyl)-2,5-dihydro-1H-pyrrole-1-carboxamide (3, 1.44 g) was used for the next reactions. MS+: 224.2, UV: λ=271.6 nm. 1H NMR: (DMSO) δ7.44 (s, 1H), δ6.78 (m, 1H), δ6.20 (m, 1H), δ3.32 (m, 4H), δ1.83 (m, 4H).
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:18])=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=O)[S:5][C:6]=1[Br:7].C([SiH](CC)CC)C.B(F)(F)F>C(Cl)Cl.CC#N>[Br:7][C:6]1[S:5][C:4]([CH2:8][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)=[C:3]([CH3:18])[C:2]=1[Br:1]
Reactant: CCc1ccc(C(=O)c2sc(Br)c(Br)c2C)cc1
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: CCc1ccc(Cc2sc(Br)c(Br)c2C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.1 %

Procedure:
To a solution of (4,5-dibromo-3-methylthiophen-2-yl)(4-ethylphenyl)methanone (54) (4.28 g, 10.6 mmole) in DCM/CH3CN (30 mL/30 mL) were added triethylsilane (5.1 mL, 31.9 mmole) and borontrifluoride diethyletherate (3.1 mL, 25.4 mmole) at 0° C. The resulting solution was stirred at ambient temperature overnight. The reaction mixture was quenched by adding MeOH (10 mL) and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the compound 55 2,3-dibromo-5-(4-ethylbenzyl)-4-methylthiophene (3.65 g, 9.76 mmole, 92%) as yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12](=[O:26])[NH:13][NH:14][C:15](=[N:18]C(OC(C)(C)C)=O)[S:16][CH3:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>>[CH2:1]([O:8][C:9]([NH:11][C:12](=[O:26])[NH:13][NH:14][C:15](=[NH:18])[S:16][CH3:17])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CSC(=NC(=O)OC(C)(C)C)NNC(=O)NC(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CSC(=N)NNC(=O)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 141.7 %

Procedure:
Compound 35 (401 mg, 1.0 mmol) was treated with TFA (1.0 mL) and was stirred for 30 min at room temperature, evaporated to dryness and dried under reduced pressure for 2 h, triturated with anhydrous Et2O to give 400 mg of 13 as a solid. This crude product was carried on without further purification. 1H NMR (300 MHz, CD3OD): δ2.64 (3H, m); 5.21 (2H, m); 7.31 (5H, m) ppm. IR (NaCl, CH2Cl2): 3252, 2959, 1790, 1682, 1203, 1137, 1025, 778, 722 cm-1.
Reaction SMILES: CO[C:3](=[O:26])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][C:21]([F:24])=[C:20]([F:25])[CH:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:6][CH:5]=1.[NH2:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30]>>[F:25][C:20]1[CH:19]=[C:18]([C:13]2[C:12]([CH2:11][O:10][C:7]3[CH:8]=[CH:9][C:4]([C:3]([NH:27][C:28]([CH3:32])([CH3:31])[CH2:29][OH:30])=[O:26])=[CH:5][N:6]=3)=[C:16]([CH3:17])[O:15][N:14]=2)[CH:23]=[CH:22][C:21]=1[F:24]
Reactant: CC(C)(N)CO
Reactant: COC(=O)c1ccc(OCc2c(-c3ccc(F)c(F)c3)noc2C)nc1
Product: Cc1onc(-c2ccc(F)c(F)c2)c1COc1ccc(C(=O)NC(C)(C)CO)cn1
Yield: 50 %

Procedure:
As described for example 125f, 6-[3-(3,4-difluoro-phenyl)-5-methyl-isoxazol-4-ylmethoxy]-nicotinic acid methyl ester (200 mg, 0.56 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of 2,2,2-trifluoroethylamine, to the title compound (120 mg, 50%) which was obtained as a colourless oil. MS: m/e=418.3 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[C:6]([O:8][C:9]([C:11]3[CH:15]=[CH:14][S:13][C:12]=3[C:2]1=2)=[O:10])=O.C1(C)C=CC=CC=1.[CH2:23]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:32][NH2:33])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C1C=CN=CC=1.C(OCC)C>[CH2:23]([CH:31]([CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43])[CH2:32][N:33]1[C:6](=[O:8])[C:3]2[CH:4]=[CH:5][S:1][C:2]=2[C:12]2[S:13][CH:14]=[CH:15][C:11]=2[C:9]1=[O:10])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCC(CN)CCCCCCCC
Reactant: O=c1oc(=O)c2ccsc2c2sccc12
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: CCCCCCCCCCC(CCCCCCCC)Cn1c(=O)c2ccsc2c2sccc2c1=O
Reaction time: 0.25 h
Yield: 187.4 %

Procedure:
A dry 8 mL microwave reaction tube was charged with a micro-stirbar, anhydride (4) (354 mg, 1.50 mmol), 4-(dimethylamino)pyridine (61 mg, 0.50 mmol), and 5 mL of toluene. Next, 2-octyldodecylamine (446 mg, 1.5 mmol) was added dropwise to the suspension over 15 minutes and the reaction was allowed to stir for an additional 15 minutes until no solid remained. The reaction tube was then irradiated with microwaves (PMAX=300 W) for 2 hours at a constant temperature of 220° C. This procedure was repeated four more times and the five reaction mixtures were combined in 250 mL of diethyl ether, washed six times with 150 mL of water, one time with 100 mL of brine, and the organics dried over Mg2SO4. After filtration, the solvent was removed by evaporation to afford a yellow oil (90% pure by 1H NMR) that was purified by column chromatography on silica gel with a mixture of diethyl ether (10%) and hexane (90%) as the eluent. A light yellow oil (1.45 g, 37% yield) was obtained upon concentration of the main fractions.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[CH:14]=[C:13]([N+:15]([O-])=O)[C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:11][C:10]=2[O:26][CH3:27])=[N:6][CH:7]=1.[NH4+].[Cl-].O>C(O)C.[Fe]>[Cl:1][C:2]1[C:3]([C:28]2[CH:29]=[N:30][N:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=23)=[N:4][C:5]([NH:8][C:9]2[C:10]([O:26][CH3:27])=[CH:11][C:12]([N:18]3[CH2:22][CH2:21][C@@H:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[C:13]([NH2:15])[CH:14]=2)=[N:6][CH:7]=1
Reactant: COc1cc(N2CC[C@@H](N(C)C)C2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(N2CC[C@@H](N(C)C)C2)c(N)cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Yield: 83.5 %

Procedure:
A mixture of 5-chloro-N-{4-[(3R)-3-dimethylaminopyrrolidin-1-yl]-2-methoxy-5-nitrophenyl}-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 19, 145 mg, 0.28 mmol), iron (95 mg, 1.71 mmol) and NH4Cl (11.4 mg, 0.21 mmol) was heated at reflux in ethanol (6 mL) and water (2 mL) for 1.5 h. The mixture was then cooled and concentrated in vacuo. The resulting residue was triturated using 10% CH3OH in CH2Cl2 (15 mL) for 15 minutes and the mixture was then filtered. The residues were triturated again using 10% CH3OH in CH2Cl2 (15 mL) and the mixture was filtered. The combined filtrates were washed with brine, dried (Na2SO4) and concentrated in vacuo. Purification by FCC, eluting with 2% 7N methanolic ammonia in CH2Cl2 gave the title compound (112 mg, 82%) as a yellow gum; 1H NMR: (CDCl3) 1.83-1.96 (1H, m), 2.08-2.23 (1H, m), 2.30 (6H, s), 2.82-2.92 (1H, m), 2.99-3.13 (2H, m), 3.17-3.28 (2H, m), 3.65 (2H, s), 3.84 (3H, s), 6.72 (1H, s), 6.96 (1H, td), 7.38 (1H, ddd), 7.52 (1H, s), 7.90 (1H, s), 8.36 (1H, s), 8.55-8.60 (1H, m), 8.65 (1H, dd), 8.94 (1H, s); m/z: ES+ MH+ 479.5.