Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[CH:2]1[CH2:6][CH2:5][CH2:4][C:3]1([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=1)[C:7]([OH:9])=[O:8].S(=O)(=O)(O)O.[C:22](=O)([O-])[O-].[Na+].[Na+]>CO>[F:16][C:12]1[CH:11]=[C:10]([C:3]2([C:7]([O:9][CH3:22])=[O:8])[CH2:4][CH2:5][CH2:6][CH2:2]2)[CH:15]=[CH:14][CH:13]=1
Reactant: O=C([O-])[O-]
Reactant: CC1CCCC1(C(=O)O)c1cccc(F)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C1(c2cccc(F)c2)CCCC1

Procedure:
To a solution of methyl 1-(3-fluorophenyl)cyclopentanecarboxylic acid (5.0 g, 24.01 mmol) in anhydrous methanol was added 1 mL of concentrated sulfuric acid. The mixture was refluxed overnight. The mixture was neutralized to pH 4-5 with sodium carbonate. The solvent was evaporated. The residue was dissolved in ethyl acetate (50 mL), washed with brine (3×10 mL, dried over MgSO4. The crude product was used for the next reaction without further purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH2:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:11]([O-:14])([O-])=[O:12].[K+].[K+]>C1COCC1>[C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][C:11](=[O:12])[O:14][C:1]([CH3:7])([CH3:6])[CH3:2])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1C[C@H]1c1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 189.3 %

Procedure:
Over a solution of (trans)-2-phenylcyclopropanamine (intermediate A, 1.14 g, 1 eq) in 50 mL of THF, 1.25 g (1.05 eq) of K2CO3 was added and stirred 3 hours at room temperature. After removal of the solvent, CH2Cl2 was added, then washed with a saturated solution of NaHCO3 and brine. The organic layer was extracted, dried with MgSO4 and filtered. The crude was purified by silica gel chromatography (Hexane-MTBE 90:10) affording 1.89 g of tert-butyl (trans)-2-phenylcyclopropylcarbamate. Yield: 95%
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)=[O:29])[CH3:26]>>[CH2:25]([O:27][C:28]([C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[C:14](=[O:24])[CH2:15][CH2:16][CH2:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:31][CH2:32]1)=[O:29])[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)CCCc1ccccc1
Reactant: CCOC(=O)C1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4C(=O)CCCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using 1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-butan-1-one and 1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropanecarboxylic acid ethyl ester.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.[Cl:18][C:19]1[CH:30]=[C:29]([Cl:31])[C:28]([OH:32])=[CH:27][C:20]=1[O:21][CH2:22][C:23]([O:25][CH3:26])=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[CH3:26][O:25][C:23](=[O:24])[CH2:22][O:21][C:20]1[CH:27]=[C:28]([O:32][CH2:4][CH:2]2[CH2:3][O:1]2)[C:29]([Cl:31])=[CH:30][C:19]=1[Cl:18]
Reactant: COC(=O)COc1cc(O)c(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1cc(OCC2CO2)c(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.4 %

Procedure:
A mixture of (2S)-oxiran-2-ylmethyl-3-nitrobenzenesulfonate (0.4 g), methyl (2,4-dichloro-5-hydroxyphenoxy)acetate (0.39 g) and Cs2CO3 (0.58 g) in DMF (2 ml) was stirred at r.t. overnight. Water was added and (2,4-dichloro-5-oxiranylmethoxy-phenoxy)-acetic acid methyl ester (0.22 g) was isolated by filtration and dried in vacuo. 5-Chloro-3H-spiro[1-benzofuran-2,4′-piperidine] (0.16 g) in ethanol (5 ml) was added and heated at 70° C. for 2 h. The mixture was allowed to cool and water (1 ml) followed by LiOH (2 eq) was added. Stirred for 3 h. RPHPLC (Xterra, gradient 95-5%, ammonia (0.2% aq.): acetonitrile) gave the title compound (0.1 g) as a white solid.
Reaction SMILES: [CH3:1][C:2]([Si:5]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][C:9]=1[CH2:14][OH:15])([CH3:4])[CH3:3].Cl[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2=[N:39][N:40]=[C:41]([C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[N:31]2[N:30]=1>>[CH3:4][C:2]([Si:5]([O:6][CH2:7][C:8]1[N:12]([CH3:13])[N:11]=[N:10][C:9]=1[CH2:14][O:15][C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]2=[N:39][N:40]=[C:41]([C:42]3[CH:46]=[C:45]([CH3:47])[O:44][N:43]=3)[N:31]2[N:30]=1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:1])[CH3:3]
Reactant: Cn1nnc(CO)c1CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C
Reactant: Cc1cc(-c2nnc3c4ccccc4c(Cl)nn23)no1
Product: Cc1cc(-c2nnc3c4ccccc4c(OCc4nnn(C)c4CO[Si](c4ccccc4)(c4ccccc4)C(C)(C)C)nn23)no1
Yield: 95.9 %

Procedure:
The reaction was carried out according to Example 1 step 4 using [5-({[(1,1-dimethylethyl)(diphenyl)silyl]oxy}methyl)-1-methyl-1H-[1,2,3]triazol-4-yl]methanol (1.20 g, 3.14 mmol) and 6-chloro-3-(5-methylisoxazol-3-yl)-[1,2,4]triazolo[3,4-α]phthalazine (0.90 mg, 3.14 mmol). The crude residue was purified by column chromatography on silica using 1-2% MeOH/CH2Cl2 containing 1% NH3 to yield the desired phthalazine (1.90 g, 96%). 1H NMR (360 MHz, CDCl3) δ 8.68 (1H, d, J=7.9 Hz), 7.99 (1H, d, J=7.9 Hz), 7.91 (1H, t, J=7.9 Hz), 7.69 (1H, t, J=7.9 Hz), 7.55 (4H, d, J=7.9 Hz), 7.34-7.18 (6H, m), 6.90 (1H, s), 5.43 (2H, s), 4.90 (2H, s), 4.10 (3H, s), 2.58 (3H, s), 0.99 (9H, s). m/z (ES+) 632 (M+2H+).
Reaction SMILES: [CH2:1]1[O:36][C:35]2[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[C@H:9]([NH:18][S:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=3[CH3:31])(=[O:21])=[O:20])[CH2:10][O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:4][C:3]=2[O:2]1.[CH2:37]1[O:45][C:44]2[CH:43]=[CH:42][C:41]([CH2:46]O)=[CH:40][C:39]=2[O:38]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]1[O:36][C:35]2[CH:34]=[CH:33][C:5]([CH2:6][O:7][C:8](=[O:32])[C@H:9]([N:18]([CH2:46][C:41]3[CH:42]=[CH:43][C:44]4[O:45][CH2:37][O:38][C:39]=4[CH:40]=3)[S:19]([C:22]3[C:27]([CH3:28])=[CH:26][C:25]([O:29][CH3:30])=[CH:24][C:23]=3[CH3:31])(=[O:21])=[O:20])[CH2:10][O:11][CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][O:13]3)=[CH:4][C:3]=2[O:2]1
Reactant: COc1cc(C)c(S(=O)(=O)N[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Reactant: OCc1ccc2c(c1)OCO2
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@H](COC2CCCCO2)C(=O)OCc2ccc3c(c2)OCO3)c(C)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.8 %

Procedure:
To a solution of 2(R)-(4-methoxy-2,6-dimethylbenzenesulfonyl-amino)-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (9.0 g, 16.8 mmol) in benzene (150 mL) at 0° C. was added 3,4-methylenedioxyphenyl methanol (3.8 g, 25.2 mmol), tri-n-butylphosphine (5.1 g, 25.2 mmol), followed by 1,1′-[azodicarbonyl]dipiperidine (6.35 g, 25.2 mmol). The reaction mixture was allowed to warm to room temperature over 4 h. After 16 h, the reaction mixture was diluted with an equal volume of hexanes, cooled to 0° C. for 2 h and filtered. The residue was chromatographed (300 g SiO2, 15% ethyl acetate-hexanes) to afford 2(R)-[(3,4-methylenedioxybenzyl)-(4-methoxy-2,6-dimethylbenzenesulfonyl)amino]-3-(tetrahydropyran-2-yloxy)propionic acid 3,4-methylenedioxybenzyl ester (10.0 g) as a pale orange oil.
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH2:30])[CH:25]=4)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:31](OC(=O)C)(=[O:33])[CH3:32].Cl>ClCCl.N1C=CC=CC=1>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:22]#[C:23][C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][C:31](=[O:33])[CH3:32])[CH:25]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COc1ccc(C2(C#Cc3cccc(N)c3)CCC(=O)CC2)cc1OC1CCCC1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(C2(C#Cc3cccc(NC(C)=O)c3)CCC(=O)CC2)cc1OC1CCCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-aminophenylethynyl)cyclohexan-1-one (0.07 g, 0.18 mmol) in dichloromethane (2 mL) under an argon atmosphere. were added pyridine (three drops) and acetic anhydride (0.05 mL, 0.53 mmol) and the reaction was stirred at room temperature for 2 h. Hydrochloric acid (1N) was added, the mixture was extracted three times with dichloromethane, the extract was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 45:55 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(3-acetamidophenylethynyl)cyclohexanone as a white solid. mp 63°-64° C.; Anal. (C28H31NO4.1.75 H2O) calcd: C, 70.49; H, 7.29; N, 2.94; found: C, 70.09; H, 6.94; N, 2.83.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][N:20]=[C:15]2[CH:14]=1.C([Li])CCC.C1(C)C=CC(S([Cl:36])(=O)=O)=CC=1>COC(OC)(O)C>[Cl:36][C:7]1[N:8]([CH3:12])[C:9]2[C:5]([C:6]=1[C:13]1[NH:21][C:16]3=[N:17][CH:18]=[CH:19][N:20]=[C:15]3[CH:14]=1)=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=2
Reactant: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)cn2C
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: COC(C)(O)OC
Agent: [Li]CCCC
Product: COc1ccc2c(c1)c(-c1cc3nccnc3[nH]1)c(Cl)n2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
A solution of 6-(5-methoxy-1-methyl-1H-indol-3-yl)-5H-pyrrolo[2,3-b]pyrazine [100 mg, Example 1(a)] in dimethoxy ethanol (25 mL), cooled to −78° C., was treated with a solution of n-butyllithium in hexanes (172 μl, 2.5M). After stirring for 30 minutes the mixture was treated with 4-toluenesulfonyl chloride (82 mg) then allowed to warm slowly to ambient temperature and then evaporated. The residue was subjected to flash chromatography on silica eluting with a mixture of dichloromethane and methanol (19:1, v/v) to give the title compound (45 mg) as a black solid. MS: 313 (MH+). 1H NMR [(CD3)2SO]: δ 12.20 (1H, s); 8.39 (1H, d, J=3 Hz); 8.21 (1H, d, J=3 Hz); 7.54 (1H, d, J=9 Hz); 7.30 (1H, d, J=2 Hz); 6.96 (1H, dd, J=9 and 2 Hz); 6.84 (1H, d, J=2 Hz); 3.82 (3H, s); 3.81 (3H, s).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[OH:10][C:11]1[C:18]([CH3:19])=[CH:17][C:14]([CH:15]=[O:16])=[CH:13][C:12]=1[CH3:20].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[F:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[CH2:2][O:10][C:11]1[C:12]([CH3:20])=[CH:13][C:14]([CH:15]=[O:16])=[CH:17][C:18]=1[CH3:19]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C=O)cc(C)c1OCc1ccccc1F

Procedure:
0.5 M Solution of 1-bromomethyl-2-fluoro-benzene (1.51 g, 8.0 mmol) in DMF was added dropwise to a suspension containing 1.1 g of 4-hydroxy-3,5-dimethyl-benzaldehyde (7.3 mmol), 1.51 g of K2CO3 (11 mmol) and 120 mg of KI (0.73 mmol) in 100 ml DMF. The reaction followed the same procedure described in Example 3. The residue was purified on silica gel, obtaining a quantitative recovery of the title compound. (1.88 g).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[NH2:17][C:18]1[N:23]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[CH:21]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH2:41])[CH2:34]2)[N:19]=1>C1COCC1>[NH2:17][C:18]1[N:19]=[C:20]([N:33]2[C@H:38]([CH3:39])[CH2:37][O:36][C@H:35]([CH2:40][NH:41][C:8](=[O:15])[C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:34]2)[CH:21]=[C:22]([C:24]2[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([F:32])[CH:25]=2)[N:23]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@@H]1CO[C@H](CN)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@@H]1CO[C@H](CNC(=O)c2ccccc2)CN1c1cc(-c2ccc(C#N)c(F)c2)nc(N)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 112 %

Procedure:
Triethylamine (48 μL, 0.34 mmol) and benzoyl chloride (31 μL, 0.27 mmol) were added to a solution of 4-{2-amino-6-[(2R,5R)-2-(aminomethyl)-5-methyl-4-morpholinyl]-4-pyrimidinyl}-2-fluorobenzonitrile (77 mg, 0.23 mmol) in THF (5 mL), and the mixture was stirred at room temperature under nitrogen for 30 minutes. The mixture was quenched with saturated aqueous NaHCO3 (15 mL) and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo to give the title compound (115 mg) as a yellow glass. LC-MS (ES) m/z=447 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([SH:10])[CH2:8][CH3:9].CN(C=O)C.[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[N:33]=[C:32](Cl)[C:31]([S:35][C:36]2[CH:41]=[CH:40][C:39]([S:42]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[CH:38][CH:37]=2)=[CH:30][N:29]=1)(=[O:26])=[O:25]>CC(C)=O>[Cl:16][C:17]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=1[S:24]([NH:27][C:28]1[N:33]=[C:32]([S:10][CH2:7][CH2:8][CH3:9])[C:31]([S:35][C:36]2[CH:37]=[CH:38][C:39]([S:42]([N:45]3[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]3)(=[O:44])=[O:43])=[CH:40][CH:41]=2)=[CH:30][N:29]=1)(=[O:26])=[O:25]
Reactant: CCCS
Reactant: O=S(=O)(Nc1ncc(Sc2ccc(S(=O)(=O)N3CCCCC3)cc2)c(Cl)n1)c1ccc(Cl)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCSc1nc(NS(=O)(=O)c2ccc(Cl)cc2Cl)ncc1Sc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 50 °C
Yield: 39.5 %

Procedure:
Cesium carbonate (65 mg, 0.2 mmol) was added to a solution of propanethiol (8 μl, 0.09 mmol) in acetone (0.5 mL). The reaction mixture was heated to 50° C. for 45 minutes then cooled to r.t. DMF (2 mL) and 2,4-Dichloro-N-{4-chloro-5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-pyrimidin-2-yl}-benzenesulfonamide 11 (50 mg, 0.08 mmol) were added and the resultant mixture heated to 50° C. for 2 hours. The reaction was allowed to cool, filtered through celite and the solvent evaporated in vacuo. The crude product was purified by flash column chromatography (2% MeOH in DCM) to afford 2,4-Dichloro-N-{5-[4-(piperidine-1-sulfonyl)-phenylsulfanyl]-4-propylsulfanyl-pyrimidin-2-yl}-benzenesulfonamide 32 (20 mg). 1H NMR (CDCl3): δ 1.00 (m, 3H), 1.27 (m, 2H), 1.66 (m, 6H), 2.88 (m, 2H), 2.99 (m, 4H), 7.26 (m, 2H), 7.45 (d, 1H), 7.55 (s, 1H), 7.66 (d, 2H), 8.27 (d, 1H), 8.5149 (s, 1H), 12.61 (br s, 1H) ppm. Mass Spectrum m/e=632.8 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7]C(=O)OC(C)(C)C)=[C:4]([C:17](=[O:20])[NH:18][CH3:19])[CH:3]=1.[C:21]([C:25]([OH:27])=[O:26])([F:24])([F:23])[F:22]>C(Cl)Cl>[F:22][C:21]([F:24])([F:23])[C:25]([OH:27])=[O:26].[NH2:7][CH2:6][C:5]1[CH:15]=[CH:16][C:2]([F:1])=[CH:3][C:4]=1[C:17]([NH:18][CH3:19])=[O:20]
Reactant: CNC(=O)c1cc(F)ccc1CNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1cc(F)ccc1CN
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99 %

Procedure:
To a solution of tert-butyl 4-fluoro-2-(methylcarbamoyl)benzylcarbamate (7.70 g, 27.3 mmol; prepared from 2-bromo-5-fluorobenzoic acid using literature methods) in CH2Cl2 (100 mL) was added CF3CO2H (25 mL) and the mixture stirred at room temperature for 15 min. This was concentrated in vacuo and the residue triturated with diethyl ether to provide 8.0 g (Yield 99%) of the title compound as a white powder. 1H NMR (300 MHz, D2O) δ ppm: 2.93 (3H, s) 4.20 (2H, s) 7.35 (1H, dt, J=8.5, 3 Hz) 7.42 (1H, dd, J=9.0, 2.7 Hz) 7.57 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 183 (M+H).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=1.CC1C=CC(S(O[CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35])(=O)=O)=CC=1>CN(C=O)C>[CH3:7][O:8][C:9]1[CH:15]=[CH:14][C:12]([NH:13][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH2:33][C:34]#[CH:35])=[CH:11][CH:10]=1
Reactant: C#CCOCCOCCOS(=O)(=O)c1ccc(C)cc1
Reactant: COc1ccc(N)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C#CCOCCOCCNc1ccc(OC)cc1
Temperature: 100 °C
Reaction time: 12 h

Procedure:
K2CO3 (380 mg, 2.76 mmol, 2.5 equiv.) was added to a solution of 4-methoxyaniline (136 mg, 1.1 mmol, 1 equiv.) in 1 mL of DMF, and the resulting slurry was heated to 100° C. 2-(2-(prop-2-ynyloxy)ethoxy)ethyl 4-methylbenzenesulfonate (s-8) (100 mg, 0.276 mmol, 0.25 equiv.), dissolved in DMF (1 mL), was then added to the reaction via syringe-pump over 5 hours. The reaction was stirred for an additional 12 hours, after which time it was concentrated under reduced pressure and partially purified (Silica Gel, 12 g RediSep pre-packed column, 0% EtOAc:Hexanes→20% EtOAc:Hexanes→50% EtOAc:Hexanes, followed by EtOAc flush). The material obtained after chromatography was carried directly on to the next step without further purification.
Reaction SMILES: N1C=CC=CC=1.[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1)([O-:9])=[O:8].[CH3:20][C:21]1([CH3:28])[O:25][CH:24]([CH2:26][OH:27])[CH2:23][O:22]1.[N+]([O-])([O-])=O>ClCCl>[N+:7]([C:10]1[CH:11]=[CH:12][C:13]([S:16]([O:27][CH2:26][CH:24]2[CH2:23][O:22][C:21]([CH3:28])([CH3:20])[O:25]2)(=[O:18])=[O:17])=[CH:14][CH:15]=1)([O-:9])=[O:8]
Reactant: CC1(C)OCC(CO)O1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Agent: O=[N+]([O-])[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)OCC(COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Pyridine (29.96 g, 0.37 mol) was added to a solution of 4-nitrobenzenesulfonyl chloride (58.7 g, 0.26 mol) in dichloromethane (300 mL) at 0° C. followed by the dropwise addition of 2,2-dimethyl-1,3-dioxolane-4-methanol (50 g, 0.37 mol). After stirring the mixture at temperature for 1 h, the reaction mixture was allowed to warm to room temperature and stirring continued for 4 h. The reaction nitrate was washed with 1N HCl (2×200 mL), dried (MgSO4), and evaporated to a solid which was recrystallized (ethyl acetate/hexane) to give 60 g (50%) of the desired product: mp 92°-94° C.
Reaction SMILES: [CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].Cl[CH2:21][CH2:22][NH:23][C:24]([NH:26][C:27]1[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=1)=[O:25]>C1COCC1>[CH2:1]([C:8]1([OH:14])[CH2:13][CH2:12][N:11]([CH2:21][CH2:22][NH:23][C:24]([NH:26][C:27]2[CH:32]=[C:31]([CH3:33])[N:30]=[C:29]([CH3:34])[CH:28]=2)=[O:25])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OC1(Cc2ccccc2)CCNCC1
Reactant: Cc1cc(NC(=O)NCCCl)cc(C)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(NC(=O)NCCN2CCC(O)(Cc3ccccc3)CC2)cc(C)n1

Procedure:
A suspension of commercially available 4-benzyl-piperidin-4-ol (383 mg, 2.0 mmol). NaHCO3 (672 mg, 8.0 mmol) and 1-(2-chloro-ethyl)-3-(2,6-dimethyl-pyridin-4-yl)-urea (Example D1., 227.7 mg 1.0 mmol) in THF (4 mL) is stirred at 50° C. for 4 days. The mixture is quenched with Na2CO3 (10 mL) and extracted with CH2Cl2 (3×10 mL). The organic extracts are washed with sat. aq. Na2CO3 (10 mL), dried (Na2SO4), filtered and evaporated. The residue is purified by HPLC to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:17][CH:18]1[CH2:20][O:19]1>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][CH2:17][CH:18]2[CH2:20][O:19]2)=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: BrCC1CO1
Product: c1ccc(COc2ccc(OCC3CO3)cc2)cc1
Yield: 79 %

Procedure:
Alkylation of 4-(benzyloxy)phenol with 2-(bromomethyl)oxirane (76) as in Example 2A, followed by chromatography of the product on silica gel, eluting with 0-25% CH2Cl2/petroleum ether (foreruns) and then with 25% CH2Cl2/petroleum ether, gave 2-{[4-(benzyloxy)phenoxy]methyl}oxirane (78) (reported by Kopka et al., 2003 using epichlorohydrin) (79%) as a white solid: mp (CH2Cl2/pentane) 61-62° C.; 1H NMR (CDCl3) δ 7.44-7.28 (m, 5H), 6.90 (dt, J=9.3, 2.8 Hz, 2H), 6.85 (dt, J=9.3, 2.8 Hz, 2H), 4.16 (dd, J=11.1, 3.3 Hz, 1H), 3.92 (dd, J=11.1, 5.6 Hz, 1H), 3.32 (m, 1H), 2.89 (dd, J=4.8, 4.3 Hz, 1H), 2.73 (dd, J=5.0, 2.7 Hz, 1H).
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.S(Cl)([Cl:14])=O.C(N(CC)C=O)C>CN(C)C=O>[Cl:14][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2ccccc12
Reactant: O=S(Cl)Cl
Agent: CCN(C=O)CC
Solvent: CN(C)C=O
Product: Clc1ccnc2ccccc12

Procedure:
reacting the 4-hydroxyquinoline of formula (11) with thionyl chloride in the presence N,N-dimethylformamide or N,N-diethylformamide to obtain a 4-chloroquinoline of formula (12), ##STR11##
Reaction SMILES: [CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8](O)=[O:9])[CH2:3][CH2:2]1.CN(C=O)C.C(Cl)(=O)C([Cl:20])=O>C(Cl)Cl>[CH:1]1([N:4]([CH3:11])[CH2:5]/[CH:6]=[CH:7]/[C:8]([Cl:20])=[O:9])[CH2:3][CH2:2]1
Reactant: CN(C/C=C/C(=O)O)C1CC1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN(C/C=C/C(=O)Cl)C1CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of (E)-4-(cyclopropyl(methyl)amino)but-2-enoic acid (2.00 g, 12.9 mmol) in DCM (60 mL) was added DMF (0.2 mL) and oxalyl chloride (4.42 mL, 51.6 mmol). The mixture was stirred at RT for 4 h and concentrated in vacuo to dryness to afford (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. In a similar manner as described in Example 70, (R,E)-3-(1-(4-(cyclopropyl(methyl)amino)but-2-enoyl)pyrrolidin-3-ylamino)-5-(4-(morpholine-4-carbonyl)phenylamino)-1,2,4-triazine-6-carboxamide (85) was prepared using (E)-4-(cyclopropyl(methyl)amino)but-2-enoyl chloride. MS found for C27H35N9O4 as (M+H)+ 550.2, (M−H)− 548.3. UV: λ=248 nm.
Reaction SMILES: [F:1][C:2]1([C:5](=O)[CH3:6])[CH2:4][CH2:3]1.ClC1(C2C=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]([CH3:22])[N:13]=2)CC1>>[F:1][C:2]1([C:5]2[CH:6]=[C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[N:14]([CH3:22])[N:13]=2)[CH2:4][CH2:3]1
Reactant: CC(=O)C1(F)CC1
Reactant: CCOC(=O)c1cc(C2(Cl)CC2)nn1C
Product: CCOC(=O)c1cc(C2(F)CC2)nn1C

Procedure:
Ethyl 3-(1-fluorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate is prepared from 1-(1-fluorocyclopropyl)ethanone analogously to the process described in the synthesis of ethyl 3-(1-chlorocyclopropyl)-1-methyl-1H-pyrazole-5-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][C:3]=1[OH:14].[Cl:15][CH2:16][C:17](OC)(OC)OC>>[Cl:15][CH2:16][C:17]1[O:14][C:3]2[CH:4]=[CH:5][C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:7][C:2]=2[N:1]=1
Reactant: Nc1cc(-c2ccccc2)ccc1O
Reactant: COC(CCl)(OC)OC
Product: ClCc1nc2cc(-c3ccccc3)ccc2o1
Temperature: 160 °C
Reaction time: 0 h

Procedure:
2-amino-4-phenylphenol (0.180 g, 0.97 mmol) was placed in a Smith Process Vial™ (Personal Chemistry, Inc., Uppsala) (3 mL glass vessel) followed by the addition of 1-chloro-2,2,2-trimethoxyethane (1 mL). The vial was sealed and the mixture was heated in the Emrys Optimizer™ (Personal Chemistry, Inc., Uppsala) microwave at 160° C. for 300 s, fixed hold time on, absorption level normal, pre-stirring 10 s. It was then cooled to room temperature, diluted with 2 mL of methanol and purified by semi-prep HPLC. The HPLC fractions were evaporated under reduced pressure to furnish 2-(chloromethyl)-5-phenyl-benzoxazole as an off-white solid.