Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:6][CH2:5][NH:4][CH:3]([C:7]([O:9][CH3:10])=[O:8])[CH2:2]1.[Cl:18][C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[C:21](Cl)[N:20]=1.CCN(C(C)C)C(C)C>C(#N)C>[Cl:18][C:19]1[N:20]=[C:21]([N:4]2[CH2:5][CH2:6][N:1]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:2][CH:3]2[C:7]([O:9][CH3:10])=[O:8])[CH:22]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[N:24]=1
Reactant: COC(=O)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: COC(=O)c1cc(Cl)nc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: COC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2C(=O)OC)nc(Cl)n1
Temperature: 50 °C

Procedure:
A mixture of 1-tert-butyl 3-methyl piperazine-1,3-dicarboxylate (5.133 g, 21.01 mmol), methyl 2,6-dichloropyrimidine-4-carboxylate (4.354 g, 21.03 mmol), and iPr2NEt (4.0 mL, 23.0 mmol) in acetonitrile (50 mL) was heated at 50° C. for 4 h. After cooling, the reaction mixture was evaporated in vacuo and the residue chromatographed over silica gel with 20-70% EtOAc in hexanes. The product fractions were evaporated in vacuo to give 1-tert-butyl 3-methyl 4-(2-chloro-6-(methoxycarbonyl)pyrimidin-4-yl)piperazine-1,3-dicarboxylate as a very pale yellow powder (6.626 g, 15.97 mmol, 76% yield). LC/MS: m/z=415.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10]([CH:15]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])=[N:6][CH:7]=1.Br[C:28]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][CH:31]=[CH:30][C:29]=1[F:38].C(=O)([O-])[O-].[Cs+].[Cs+].O.CN(C)C=O>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:38][C:29]1[CH:30]=[CH:31][CH:32]=[C:33]([C:34]([F:35])([F:36])[F:37])[C:28]=1[C:16]1[CH:17]=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:9]=[C:10]([C:11]([O:13][CH3:14])=[O:12])[CH:15]=1
Reactant: COC(=O)c1cc(B2OC(C)(C)C(C)(C)O2)cc(-c2ccc(C)cn2)c1
Reactant: Fc1cccc(C(F)(F)F)c1Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2ccc(C)cn2)cc(-c2c(F)cccc2C(F)(F)F)c1

Procedure:
In a 5 mL microwave vial, methyl 3-(5-methylpyridin-2-yl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate (300.0 mg, 0.8493 mmol), 2-bromo-1-fluoro-3-(trifluoromethyl)benzene (412.8 mg, 1.699 mmol), cesium carbonate (1384 mg, 4.247 mmol), tetra-n-butylammonium iodide (313.7 mg, 0.8493 mmol), and POPd (42.61 mg, 0.08493 mmol) were dissolved in Water (0.6 mL, 40 mmol) and N,N-dimethylformamide (3 mL, 40 mmol). The reaction mixture was microwaved for 10 mins at 150 degrees. The reaction mixture was extracted with ethylacetate and washed repeatedly with brine. The solvent removed under reduced pressure (yellow oil) and used in the next reaction without further purification.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:34])[C@H:7]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][CH2:9][O:10][Si](C(C)(C)C)(C)C)([CH3:4])[CH3:3]>C(O)(=O)C.O>[CH3:1][C:2]([O:5][C:6](=[O:34])[C@H:7]([NH:18][C@H:19]([C:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)=[O:25])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH2:8][CH2:9][OH:10])([CH3:4])[CH3:3]
Reactant: CC(C)C[C@H](N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)C[C@H](N[C@H](CCO)C(=O)OC(C)(C)C)C(=O)NCc1cccnc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
1.18 g of 2-(R)-[[3-methyl-1-(S)-[((pyridin-3-yl-methyl)amino)carbonyl]butyl]amino]-4-[((1,1-dimethylethyl)dimethylsilyl)oxy]-butanoic acid-1,1-dimethylethyl ester, prepared as in Example O, was added to 48 mL of acetic acid:water (9:1) and the mixture was heated to 45° C. and stirred 16 h. The solvents were removed by evaporation and the residue was dissolved in ethyl acetate, washed with saturated sodium bicarbonate, dried (MgSO4). The solvent was removed by evaporation and the residue was purified by silica chromatography using acetone:methylene chloride (1:1) as eluents to give the title compound; 0.513 g.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=1.[NH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][N:18]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:17]1.C(N(CC)CC)C.O>CC#N.CCOC(C)=O>[CH2:25]([O:24][C:22]([N:18]1[CH2:19][CH2:20][CH2:21][CH:16]([CH2:15][NH:14][C:6]2[C:5]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:17]1)=[O:23])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: NCC1CCCN(C(=O)OCc2ccccc2)C1
Reactant: CCOC(=O)c1cnc(Cl)nc1Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cnc(Cl)nc1NCC1CCCN(C(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88.2 %

Procedure:
A mixture of ethyl 2,4-dichloropyrimidine-5-carboxylate (0.221 g, 1.00 mmol), 3-aminomethyl-1-N-CBz-piperidine (0.248 g, 1.00 mmol) and triethylamine (0.300 mL, 2.15 mmol) in CH3CN (10 mL) was stirred at room temperature for 20 h. Water and EtOAc were added. The organic phase was separated, washed with 1N HCl, then with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give ethyl 4-((1-(benzyloxycarbonyl)piperidin-3-yl)methylamino)-2-chloropyrimidine-5-carboxylate (0.382 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[CH:14]2[CH:9]([C:10](O)([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(CC)CC)C.P(Cl)(Cl)(Cl)=O.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>>[CH2:1]([O:3][C:4]([N:6]1[CH:14]2[C:9](=[C:10]([C:15]#[C:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][CH2:12][CH2:13]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)N1CCC2C1CCCC2(O)C#Cc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)N1CCC2=C(C#Cc3ccccc3)CCCC21
Temperature: 0 °C
Yield: 1.1 %

Procedure:
A solution of 4-hydroxy-4-phenylethynyl-octahydro-indole-1-carboxylic acid ethyl ester (1.0 g, 3.19 mmol), triethylamine (2.2 ml, 16 mmol) and phosphorous oxychloride 0.877 ml, 10 mmol) is heated to 40° C. for 4 hours. The dark mixture is cooled to 0° C. and treated with 1M sodium hydroxide (5 ml) and then acidified with a 10% aqueous citric acid solution. The mixture is extracted with dichloromethane, the organic extracts are washed with brine, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue is chromatographed on silica with hexane and diethyl ether (4:1 v/v). The first product containing fractions afforded (±)-(RS)-4-phenylethynyl-2,3,5,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (10 mg, 1%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.44 (m, 2H), 7.32 (m, 3H), 4.24-3.97 (m, 3H), 3.8 (m, 1H), 3.25 (m, 1 H), 2.93 (m, 1H), 2.56 (m, 1H), 2.28 (m, 2H), 1.90 (m, 1H), 1.60 (m, 2H), 1.28 (t, J=7 Hz, 3H), 1.14 (m,1H). ES-MS (+): 296.1. After collecting a mixture of the two products (475 mg, 50%), the third product containing fractions yielded (±)-(3RS,7aRS)-4-phenylethynyl-2,3,3a,6,7,7a-hexahydro-indole-1-carboxylic acid ethyl ester (64 mg, 7%) as a yellowish oil. 1H-NMR (400 MHz; CDCl3): 7.43 (m, 2H), 7.31 (m, 3H), 6.27 (m, 1H), 4.15 (m, 2H), 4.01-3.83 (m, 1H), 3.46(m, 2H), 2.82 (m, 1H), 2.37-1.82 (m, 5H), 1.57 (m, 1H), 1.27 (t, J=7 Hz, 3H). ES-MS (±): 296.2.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:13]2[C:17](=[O:18])[C:16]([CH3:20])([CH3:19])[N:15]([CH2:21][C:22]3[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=3)[C:14]2=[O:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[C:29](Cl)(=[O:32])[CH:30]=[CH2:31]>ClCCCl>[CH3:19][C:16]1([CH3:20])[C:17](=[O:18])[N:13]([C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]([F:10])([F:11])[F:12])=[C:2]([NH:1][C:29](=[O:32])[CH:30]=[CH2:31])[CH:3]=2)[C:14](=[O:28])[N:15]1[CH2:21][C:22]1[CH:27]=[CH:26][N:25]=[CH:24][CH:23]=1
Reactant: C=CC(=O)Cl
Reactant: CC1(C)C(=O)N(c2ccc(OC(F)(F)F)c(N)c2)C(=O)N1Cc1ccncc1
Solvent: ClCCCl
Product: C=CC(=O)Nc1cc(N2C(=O)N(Cc3ccncc3)C(C)(C)C2=O)ccc1OC(F)(F)F
Temperature: -20 °C

Procedure:
1000 mg (2.54 mmol) 3-(3-amino-4-trifluormethoxy-phenyl)-5,5-dimethyl-1-pyridin-4-ylmethyl-imidazolidine-2,4-dione were dissolved in 25 ml 1,2-dichloroethane. The mixture was cooled to −20° C. and treated with a solution of 272 mg (3.00 mmol) acrylic acid chloride in 5 ml 1,2-dichloroethane. The mixture was allowed to reach RT, and then evapoarted to dryness. The raw material was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:16])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13].O.[C:28](OC(=O)C)(=[O:30])[CH3:29]>>[CH3:1][O:2][C:3]1[C:4]([CH3:26])=[C:5]([C:17]([O:24][CH3:25])=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:16][C:28](=[O:30])[CH3:29])=[C:11]([CH:15]=1)[C:12]([OH:14])=[O:13]
Reactant: CC(=O)OC(C)=O
Reactant: COc1c(C)c(Cc2ccc(O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Solvent: O
Product: COc1c(C)c(Cc2ccc(OC(C)=O)c(C(=O)O)c2)c(OC)c(OC)c1OC
Temperature: 65 °C
Yield: 68 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-hydroxybenzoic acid (1.30 g, 3.59 mmol) was dissolved in acetic anhydride (5 ml) and the resulting solution was stirred under heating at 65° C. for 3 hours. The reaction solution was cooled and after adding thereto water (20 ml) and stirring at room temperature for 1 hour, extracted with ethyl acetate. The extract was washed with saturated brine and then dried, and the solvent was removed by distillation. The residue was purified by silica gel column chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.99 g, 2.45 mmol, 68%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].O>C1COCC1>[OH:5][CH2:4][C:3]1[CH:7]=[CH:8][C:9]([C:11]([F:13])([F:14])[F:12])=[CH:10][C:2]=1[OH:1]
Reactant: O=C(O)c1ccc(C(F)(F)F)cc1O
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccc(C(F)(F)F)cc1O
Temperature: 25 °C
Reaction time: 18 h
Yield: 116.1 %

Procedure:
To a solution of 600 mg (2.91 mmol) of 2-hydroxy-4-trifluoromethyl-benzoic acid in THF (3 ml) were added dropwise 5.82 ml of a 1 molar solution of BH3-THF complex in THF at 0° C. After the reaction mixture was stirred for 18 h at RT, water was added to destroy excess reducing agent. Then 15 ml of 2N NaOH-solution were added and the mixture was stirred for 30 min. Then ether (10 ml) was added and the aqueous phase was separated. The volatile solvents of the organic phase were removed and the remaining residue was combined with the aqueous phase. The pH of the aqueous phase was then carefully adjusted to 6-7 by addition of dilute acetic acid at 0° C. and the mixture was extracted with ether. The combined extracts were then dried (MgSO4) and concentrated to yield 649 mg (93%) of crude 2-hydroxymethyl-5-trifluoromethyl-phenol (purity ˜80%) as a light yellow oil. MS (ISP) 191.2 (M−H)−.
Reaction SMILES: C[O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.O>C1COCC1>[CH2:12]([O:6][CH2:5][C:4]([CH3:8])([CH3:7])[C:3]([OH:2])=[O:9])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)C(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(COCc1ccccc1)C(=O)O
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.8 %

Procedure:
3-Hydroxy-2,2-dimethyl-propionic acid methyl ester (3.00 g, 22.7 mmol) in 40 mL of THF at 0° C. was treated with 1.0 g (25 mmol) of 60% NaH in mineral oil for 20 min. Benzyl bromide (2.97 mL, 25.0 mmol) was added dropwise over 10 minutes. The mixture was stirred overnight, 30 mL of water was added, and the mixture was extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was dissolved in 40 mL of EtOH, 28 mL of 2M NaOH was added, and the mixture was heated to 80° C. for 12 h. The mixture was cooled, neutralized with 2M HCl, and extracted with EtOAc (3×100 mL). The combined extracts were washed with brine, dried with MgSO4, filtered, concentrated, and chromatographed (10-100% EtOAc in hexanes) to provide 2.4 g of 3-benzyloxy-2,2-dimethyl-propionic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7](N)[C:6]=2[CH:15]=1.[C:16]1(=O)[CH2:20][CH2:19][CH2:18][CH2:17]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)CC.C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:12][CH2:11][N:10]([CH3:13])[CH2:9][CH2:8][N:7]3[C:6]=2[C:15]=1[C:16]1[CH2:20][CH2:19][CH2:18][C:17]=13
Reactant: O=C1CCCC1
Reactant: CN1CCc2ccc(Cl)cc2N(N)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Solvent: CCCO
Product: CN1CCc2ccc(Cl)c3c4c(n(c23)CC1)CCC4
Temperature: 25 °C
Yield: 30.5 %

Procedure:
To a solution of 9-chloro-4-methyl-3,4,5,6-tetrahydro-2H-benzo[e][1,4]diazocin-1-ylamine (3.5 g, 15.5 mmole) in 1-propanol (200 mL) was added cyclopentanone (20.0 ml, 226.1 mmole), followed by p-toluenesulfonic acid monohydrate (11.0 g, 57.8 mmole), and the resulting reaction mixture was refluxed for 30 hours. The reaction mixture was cooled to room temperature and solvent removed in vacuo to produce a brown residue. The residue was diluted with methylene chloride (300 mL) and washed with saturated aqueous sodium bicarbonate (200 mL), saturated aqueous sodium chloride (200 mL), dried (sodium sulfate) and concentrated in vacuo. Purification by flash column chromatography (silica gel, ethyl acetate:hexanes 1:1) provided 1.3 g of the title compound. 0.11 g of the free amine was treated with one equivalent of fumaric acid in ethanol to form a fumarate salt (0.12 g, mp 209-211° C.). MS (ES) m/z 275.1 ([M+H]+).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1.[CH3:9][NH2:10].C(O)C>>[CH3:9][NH:10][CH2:2][CH2:3][N:4]1[CH:8]=[CH:7][CH:6]=[CH:5]1
Reactant: ClCCn1cccc1
Reactant: CN
Solvent: CCO
Product: CNCCn1cccc1
Temperature: 90 °C
Yield: 88 %

Procedure:
1-(2-Chloroethyl)pyrrole (2.0 g, 15.43 mmol) was combined with a solution of 33% methylamine in ethanol (7.3 mL of 33% w/v, 77.15 mmol). The mixture was heated at 90° C. for 16 h before it was concentrated under reduced pressure to provide N-methyl-2-pyrrol-1-yl-ethanamine (2.19 g, 88%) which was used directly in next reaction. ESI-MS m/z calc. 124.1, found 125.3 (M+1)+; Retention time: 0.22 minutes (3 min run). 1H NMR (400 MHz, CDCl3) δ 6.73-6.68 (m, 2H), 6.22-6.14 (m, 2H), 4.05 (t, J=5.9 Hz, 2H), 2.94 (t, J=5.9 Hz, 2H), 2.45 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[O:9][C:10]([F:13])([F:12])[F:11].Cl[C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.O.C(OCC)(=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][N:16]=2)=[CH:4][C:3]=1[O:9][C:10]([F:11])([F:12])[F:13]
Reactant: Cc1ccc(O)cc1OC(F)(F)F
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(Oc2ccc([N+](=O)[O-])cn2)cc1OC(F)(F)F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a suspension of 4-methyl-3-(trifluoromethoxy)phenol (Intermediate 29, 364 mg, 1.89 mmol) and 2 chloro-5-nitropyridine (300 mg, 1.89 mmol) in acetonitrile (4 mL) was added K2CO3 (653 mg, 4.72 mmol) at room temperature. The mixture was heated at reflux for 18 hrs until completion. The resulting mixture was cooled down to room temperature, diluted with water (10 mL) and ethyl acetate (10 mL). Phases were separated, the organic layer was washed with an aqueous 10% solution of ammonium chloride (10 mL) and aqueous 13% solution of NaCl (10 mL). The organic layer was dried over Na2SO4 and evaporated to dryness to give the title compound (594 mg) as pale brown oil.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[CH3:13][C:14]1[CH:15]=[C:16]([CH:18]=[CH:19][CH:20]=1)[NH2:17]>C(O)(C)C.Cl>[ClH:1].[F:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][CH:8]=1)[N:5]=[CH:4][N:3]=[C:2]2[NH:17][C:16]1[CH:18]=[CH:19][CH:20]=[C:14]([CH3:13])[CH:15]=1
Reactant: Cc1cccc(N)c1
Reactant: Fc1ccc2ncnc(Cl)c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1cccc(Nc2ncnc3ccc(F)cc23)c1
Yield: 43 %

Procedure:
4-Chloro-6-fluoroquinazoline (1.1 g) was suspended in isopropanol (20 ml) and 3-methylaniline (0.65 ml) was added. The mixture was heated to reflux for 2 hours. The reaction mixture was allowed to cool and the precipitate was filtered off. The solid so obtained was suspended in 2N aqueous hydrochloric acid and stirred for several minutes. The mixture was filtered to give 6-fluoro-4-(3-methylanilino)quinazoline hydrochloride salt in 43% yield, m.p. 255-260° C.;
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([CH:15]=1)[CH:13]=[O:14].[Cl-].[NH4+]>C1COCC1>[Br:7][C:8]1[CH:9]=[CH:10][C:11]([O:16][CH2:17][CH2:18][N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[C:12]([CH2:13][OH:14])[CH:15]=1
Reactant: O=Cc1cc(Br)ccc1OCCN1CCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cc(Br)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3.4 mL (3.40 mmol) of a lithium aluminum hydride solution (1M in THF) was added under argon at 0° C. to a solution of 1.00 g (3.35 mmol) of 5-bromo-2-(2-pyrrolidin-1-ylethoxy)benzaldehyde (Example 24.1a) in 20 mL of THF and the mixture was stirred for 2 hours at RT. A further 6.8 mL of lithium aluminum hydride solution (1M in THF) was added and the mixture was stirred for 2 hours at RT. The reaction mixture was slowly combined with sat. aqueous ammonium chloride solution and the aqueous phase was exhaustively extracted with EtOAc. The combined organic extracts were dried over magnesium sulfate and evaporated down in vacuo. As some starting material could still be detected, the reaction was repeated with 1.7 mL of lithium aluminum hydride solution (1M in THF) and the working up was repeated. Yield: 0.82 g (81% of theoretical); C13H18BrNO2 (M=300.192); calc.: molpeak (M+H)+: 300/302 (Br); found: molpeak (M+H)+: 300/302 (Br); HPLC-MS: 4.62 minutes (method A).
Reaction SMILES: [CH3:1][N:2]([CH3:15])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][C:21]([S:24](Cl)(=[O:26])=[O:25])=[CH:20][CH:19]=1>N1C=CC=CC=1>[CH3:15][N:2]([CH3:1])[CH2:3][CH2:4][CH2:5][C:6]#[C:7][C:8]1[CH:9]=[N:10][C:11]([NH:14][S:24]([C:21]2[CH:20]=[CH:19][C:18]([C:17]([F:16])([F:28])[F:29])=[CH:23][CH:22]=2)(=[O:26])=[O:25])=[N:12][CH:13]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CN(C)CCCC#Cc1cnc(N)nc1
Solvent: c1ccncc1
Product: CN(C)CCCC#Cc1cnc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)nc1
Temperature: 70 °C
Yield: 33.9 %

Procedure:
A solution of 102 mg (0.5 mmol) of 5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-ylamine in 3.9 ml pyridine was treated with 257 mg (1.05 mmol) 4-(trifluoromethyl)benzenesulfonyl chloride. The reaction was stirred over night at 70° C., evaporated and extracted with aqueous saturated NaHCO3(2×)/CH2Cl2 (3×). The organic phases were washed with aqueous 10% NaCl solution, dried (Na2SO4) and evaporated. Flash column chromatography on silica gel with CH2Cl2/MeOH (95:5 to 9:1) yielded 70 mg (34%) of N-[5-(5-Dimethylamino-pent-1-ynyl)-pyrimidin-2-yl]-4-trifluoromethyl-benzenesulfonamide, mp: 194-202° C.,slowly dec.; MS: 413 (MH+).
Reaction SMILES: C(OC([NH:8][C:9]1[C:10]([CH3:21])=[N:11][C:12]([O:16][CH2:17][C:18]([OH:20])=O)=[N:13][C:14]=1[CH3:15])=O)(C)(C)C.[CH:22]1([N:27]2[CH2:32][CH2:31][CH:30]([NH:33][CH3:34])[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:8][C:9]1[C:14]([CH3:15])=[N:13][C:12]([O:16][CH2:17][C:18]([N:33]([CH:30]2[CH2:31][CH2:32][N:27]([CH:22]3[CH2:23][CH2:24][CH2:25][CH2:26]3)[CH2:28][CH2:29]2)[CH3:34])=[O:20])=[N:11][C:10]=1[CH3:21]
Reactant: CNC1CCN(C2CCCC2)CC1
Reactant: Cc1nc(OCC(=O)O)nc(C)c1NC(=O)OC(C)(C)C
Product: Cc1nc(OCC(=O)N(C)C2CCN(C3CCCC3)CC2)nc(C)c1N

Procedure:
The title compound was synthesized from Compound 9 and 1-cyclopentyl-N-methylpiperidine-4-amine in the same manner as in Example 64.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)(=[O:11])[CH3:10].[Br:18][C:19]1[C:20]([OH:28])=[C:21]([C:24](OC)=[O:25])[S:22][CH:23]=1>O1CCCC1>[Br:18][C:19]1[C:20]([OH:28])=[C:21]([C:24](=[O:25])[CH2:10][C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[O:11])[S:22][CH:23]=1
Reactant: COC(=O)c1scc(Br)c1O
Reactant: CC(=O)N1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)N1CCOCC1)c1scc(Br)c1O
Temperature: 0 °C
Yield: 138.2 %

Procedure:
An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar, tetrahydrofuran (5 mL) and lithium diisopropylamide (2.0M in hexanes, 6.7 mL, 13.5 mmol). The reaction mixture was magnetically stirred and cooled to 0° C. under argon gas. A solution of N-acetylmorpholine (6.75 mmol) in tetrahydrofuran (1 mL) was added, and the reaction was stirred at 0° C. for 1 hour. A solution of methyl 4-bromo-3-hydroxythiophene-2-carboxylate (4.22 mmol) in tetrahydrofuran (2 mL) was added dropwise over 5 minutes and the reaction was allowed to warm to room temperature overnight. The reaction was quenched by the addition of aqueous 10% hydrochloric acid solution (20 mL). The resulting solution was transferred to a separatory funnel, diluted with water (80 mL), and extracted three times with dichloromethane (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give 1-(4-bromo-3-hydroxythiophen-2-yl)-3-morpholinopropane-1,3-dione (1.95 g, 5.83 mmol, 138% yield) as a brown solid.
Reaction SMILES: C([O:5][C:6](=[O:42])[C@@H:7]([NH:28][S:29]([C:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]2[NH:22][CH2:23][CH2:24][CH2:25][N:26]=2)=[CH:11][CH:10]=1)(C)(C)C>FC(F)(F)C(O)=O.O>[C:32]1([S:29]([NH:28][C@@H:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][C:19](=[O:27])[NH:20][C:21]3[NH:26][CH2:25][CH2:24][CH2:23][N:22]=3)=[CH:11][CH:10]=2)[C:6]([OH:42])=[O:5])(=[O:31])=[O:30])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)NS(=O)(=O)c1cccc2ccccc12
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C(CCCOc1ccc(C[C@H](NS(=O)(=O)c2cccc3ccccc23)C(=O)O)cc1)NC1=NCCCN1
Reaction time: 2 h

Procedure:
31 mg of (2S)-2-(naphthalene-1-sulfonylamino)-3-{4-[3-(1,4,5,6-tetrahydropyrimidin-2-ylcarbamoyl)-propoxy]-phenyl}-propionic acid tert-butyl ester were dissolved in trifluoroacetic acid/water (95/5) and stirred for 2 hours. The solvent was removed in vacuo, and the residue was dissolved in acetic acid/water and lyophilized. Yield 19.7 mg. MS (ES+): m/e=539.3 (M+H)+.
Reaction SMILES: CN(C)/[CH:3]=[CH:4]/[C:5]([C:7]1[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[CH:16][CH:15]=2)[N:8]=1)=O.[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([NH:37][NH2:38])=[CH:29][CH:28]=1>>[N:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([N:37]2[C:5]([C:7]3[C:12](=[O:13])[CH:11]=[CH:10][N:9]([C:14]4[CH:19]=[CH:18][C:17]([O:20][CH2:21][C:22]([F:25])([F:23])[F:24])=[CH:16][CH:15]=4)[N:8]=3)=[CH:4][CH:3]=[N:38]2)=[CH:29][CH:28]=1
Reactant: CN(C)/C=C/C(=O)c1nn(-c2ccc(OCC(F)(F)F)cc2)ccc1=O
Reactant: NNc1ccnc2ccccc12
Product: O=c1ccn(-c2ccc(OCC(F)(F)F)cc2)nc1-c1ccnn1-c1ccnc2ccccc12

Procedure:
The product was obtained starting from 3-((E)-3-Dimethylamino-acryloyl)-1-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-1H-pyridazin-4-one (A-32) and quinolin-4-yl-hydrazine according to the method described for example 43. MS: M=464.2 (M+H)+