Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11]Cl)[N:10]=2)[CH:7]=1.[CH3:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1)=[O:15]>C1COCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[C:9]([CH2:11][N:25]3[CH2:24][CH2:23][N:22]([C:19]4[CH:18]=[CH:17][C:16]([C:14](=[O:15])[CH3:13])=[CH:21][CH:20]=4)[CH2:27][CH2:26]3)[N:10]=2)[CH:7]=1
Reactant: ClCc1cn2cc(Cl)ccc2n1
Reactant: CC(=O)c1ccc(N2CCNCC2)cc1
Solvent: C1CCOC1
Product: CC(=O)c1ccc(N2CCN(Cc3cn4cc(Cl)ccc4n3)CC2)cc1
Yield: 50.1 %

Procedure:
Following the general procedure of Example 39, Step 2, 6-chloro-2-(chloromethyl) imidazo[1,2-α]pyridine (Example 4. Step 1; 0.294 g), 4-piperazinoacetophenone (Aldrich; 0.366 g), and THF (3 mL) are converted to product, which is chromatographed on silica gel using methanol/dichlormethane (2/98), followed by crystallization from ethyl acetate/dichloromethane, to give 0.270 g of the title compound in two crops; mp 185.5-187° C.; MS m/z 368; IR (mineral oil) 1600, 1661, 1252, 1327, 1197 cm-1 ; 1H NMR (CDCl3) δ2.52, 2.72, 3.40, 3.76, 6.86, 7.13, 7.52, 7.54, 7.86, 8.15.
Reaction SMILES: [S:1]1(=[O:11])(=[O:10])[CH:5]=[CH:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[H][H]>[Pd].C(O)C>[S:1]1(=[O:10])(=[O:11])[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2
Reactant: [H][H]
Reactant: O=S1(=O)C=Cc2ccccc21
Agent: [Pd]
Solvent: CCO
Product: O=S1(=O)CCc2ccccc21
Yield: 100 %

Procedure:
In a Parr shaker bottle was placed benzo[b]thiophene 1,1-dioxide (5.0 g, 30.08 mmol), palladium on activated carbon (500 mg) and ethanol (100 mL). The bottle was placed on a Parr shaker and charged with 50 psi of hydrogen for 1 h. The reaction mixture was removed from the Parr shaker and filtered through a plug of celite and concentrated in vacuo to afford 2,3-dihydro-benzo[b]thiophene 1,1-dioxide (5.06 g, 100%) as a white solid.
Reaction SMILES: [C:1]12([C:7]3[CH:12]=[CH:11][C:10]([N:13]4[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15][C:14]4=[O:23])=[CH:9][CH:8]=3)[CH2:6][CH:5]1[CH2:4][NH:3][CH2:2]2.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([CH:30]=O)[CH:25]=1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[O:23]=[C:14]1[N:13]([C:10]2[CH:9]=[CH:8][C:7]([C:1]34[CH2:6][CH:5]3[CH2:4][N:3]([CH2:30][C:26]3[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=3)[CH2:2]4)=[CH:12][CH:11]=2)[CH2:17][C@H:16]([CH2:18][NH:19][C:20](=[O:22])[CH3:21])[O:15]1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C34CNCC3C4)cc2)C(=O)O1
Reactant: O=Cc1cccnc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: CC(=O)NC[C@H]1CN(c2ccc(C34CC3CN(Cc3cccnc3)C4)cc2)C(=O)O1
Temperature: 25 °C
Yield: 40.2 %

Procedure:
To a stirred solution of hydrochloride salt of N-{3-[4-(3-aza-bicyclo[3.1.0]hex-1-yl)-phenyl]-2-oxo-oxazolidin-5(S)-yl-methyl}-acetamide (Intermediate IV) (210 mg, 0.6 mmol), in dichloroethane (25 mL), were added 3-pyridinecarboxaldehyde (0.06 mL, 0.6 mmol), triethyl amine (0.17 mL, 1.2 mmol) and sodium triacetoxyborohydride (254 mg, 1.2 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at r.t. and progress of the reaction was monitored by TLC. On completion, the reaction mixture was quenched by adding saturated aq. NaHCO3 solution (20 mL) and product was extracted with DCM (3×25 mL). The organic layer was washed with water (25 mL), brine (25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo. The residue was purified by column chromatography (silica gel, 0.5:9.5 MeOH:CHCl3) to provide the title compound (98 mg, 40%) as off white solid.
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:13])=[O:11])[C:4]=2[CH:3]=[CH:2]1.Cl[CH2:15][C:16]([N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:13][O:12][C:10]([C:5]1[C:4]2[CH:3]=[CH:2][N:1]([CH2:15][C:16](=[O:17])[N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:11]
Reactant: COC(=O)c1cccc2[nH]ccc12
Reactant: CCN(CC)C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)Cn1ccc2c(C(=O)OC)cccc21

Procedure:
Methyl indole-4-carboxylate (50 mg, 2.85 mmol) and 2-chloro-N,N-diethylacetamide (854 mg, 5.71 mmol) are dissolved in DMF (10 ml) and to the solution is added potassium carbonate (986 mg, 7.14 mmol). The reaction is heated using microwave radiation at 100° C. for 2 hours, then diluted with DCM (60 ml) and washed with water (5×10 ml). Drying over MgSO4, concentration in vacuo, and trituration with Et2O affords 1-Diethylcarbamoylmethyl-1H-indole-4-carboxylic acid methyl ester; [M+H]+ 289.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[CH2:11]([NH:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCCc1ccc(O)cc1
Reactant: O=Cc1ccccc1
Solvent: CCO
Product: Oc1ccc(CCNCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 519.9 %

Procedure:
Combine tyramine (3.0 g, 3.3 mmol), benzaldehyde (3.0, 2.2 mmol), 3 Å molecular sieves (5 g), and ethanol (3 mL) and stir overnight at room temperature. Filter off the sieves then add sodium borohydride (2.5 g) to the reaction at 0° C. then stirred at room temperature overnight. Concentrate on a rotary evaporator, take up residue in water, and then extract with dichloromethane (3×100 mL). Dry the dichloromethane extracts over sodium chloride/magnesium sulfate, filter, then concentrate on a rotary evaporator to yield 4.3 g of the crude product. The crude product is purified by flash column chromatography on silica gel eluting with 10% conc. ammonium hydroxide in ethanol and chloroform to yield 4-(2-benzylamino-ethyl)-phenol (2.6 g): 1H NMR (DMSO-D6, 300.00 MHz): 9.17 (s, 1H), 7.31 (m, 5H), 6.99 (d, 2H, J=8.4 Hz), 6.67 (d, 2H, J=8.8 Hz), 3.70 (s, 2H), 2.64 (m, 4H), 2.11 (s, 1H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH2:17][CH2:16][CH2:15][C:4]=2[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[N:7]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:21][CH:20]=1>>[Cl:14][C:10]1[CH:9]=[C:8]([C:6]2[N:7]=[C:2]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([CH2:25][C@@H:26]([OH:28])[CH3:27])=[CH:23][CH:24]=3)[C:3]3[CH2:17][CH2:16][CH2:15][C:4]=3[N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cccc(-c2nc(Cl)c3c(n2)CCC3)c1
Reactant: C[C@H](O)Cc1ccc(N)cc1
Product: C[C@H](O)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Yield: 80.9 %

Procedure:
Following general procedure B1, 4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.107 g, 0.40 mmol) was reacted with (S)-1-(4-aminophenyl)propan-2-ol (0.066 g, 0.44 mmol) to afford the title compound (0.123 g, 80%) as a light yellow solid. MW=379.88. 1H NMR (DMSO-d6, 500 MHz) δ 8.77 (s, 1H), 8.29-8.16 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 4.54 (d, J=5.0 Hz, 1H), 3.87-3.80 (m, 1H), 2.93-2.84 (m, 4H), 2.72-2.66 (m, 1H), 2.58-2.53 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H), 1.06 (d, J=6.0 Hz, 3H); APCI MS m/z 380 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10](Cl)=[O:11].[C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:16])[NH:14][NH2:15].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][C:10]([NH:15][NH:14][C:13]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[O:11]
Reactant: O=C(Cl)Cc1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)NN
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NNC(=O)Cc1ccc(F)cc1Cl
Reaction time: 2 h
Yield: 64.1 %

Procedure:
A solution of 2-chloro-4-fluorophenylacetyl chloride (10 mmol) in dry DCM (15 ml) was added over 20 min to a mixture of t-butyl carbazate (1.32 g, 10 mmol) and DIPEA (1.77 ml, 10.2 mmol) in dry DCM (20 ml). After stirring for a further 2 h, the mixture was washed with 1M HCl then with aqueous NaHCO3. A white solid precipitated at this point, which was filtered off, washed with water and DCM then dried to yield 1,1-dimethylethyl 2-[(2-chloro-4-fluorophenyl)acetyl]hydrazinecarboxylate (1.94 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[CH2:10][CH:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7].Cl[CH:37]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:38]([O:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[C:43]([CH3:48])[CH:42]=1)=[O:39].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[F:35][C:2]([F:34])([F:1])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:31])[F:32])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([N:14]2[CH2:15][CH2:16][N:17]([CH:37]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:38]([O:40][C:41]3[CH:42]=[C:43]([CH3:48])[CH:44]=[C:45]([CH3:47])[CH:46]=3)=[O:39])[CH2:18][CH2:19]2)[CH2:10][C@@H:9]1[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:7]
Reactant: O=C(c1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCC(N2CCNCC2)CC1Cc1ccccc1
Reactant: Cc1cc(C)cc(OC(=O)C(Cl)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: Cc1cc(C)cc(OC(=O)C(c2ccccc2)N2CCN([C@H]3CCN(C(=O)c4cc(C(F)(F)F)cc(C(F)(F)F)c4)[C@@H](Cc4ccccc4)C3)CC2)c1
Yield: 43.1 %

Procedure:
A mixture of compound 15 (2.5 g), intermediate 5 (1.65 g) and sodium carbonate (0.64 g) in methylisobutylketon (50 ml) was stirred and refluxed for 3 hours. The reaction mixture was washed and the separated organic layer was dried, filtered and the solvent was evaporated. The residue was purified over silica gel on a glass filter (eluent: CH2Cl2/CH3OH 100/0 and 99.5/0.5). The pure fractions were collected and the solvent was evaporated, yielding 1.59 g (43%) of (±)-3,5-dimethylphenyl cis-4-[1-[3,5-bis(trifluoromethyl)benzoyl]-2-(phenylmethyl)-4-piperidinyl]-α-phenyl-1-piperazineacetate compound 43; mp. 88.1° C.).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([OH:8])[N:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[N:3]=1.[CH2:19]([NH2:21])[CH3:20].C(OCC)C>C(O)C>[CH2:19]([NH:21][C:2]1[N:3]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:15][CH2:16][CH2:17][CH3:18])[NH:5][C:6](=[O:8])[CH:7]=1)[CH3:20]
Reactant: CCN
Reactant: CCCOc1ccccc1-c1nc(O)cc(Cl)n1
Solvent: CCO
Solvent: CCOCC
Product: CCCOc1ccccc1-c1nc(NCC)cc(=O)[nH]1

Procedure:
4-Chloro-6-hydroxy-2-(2-propoxyphenyl)-pyrimidine (0.66 g) and ethylamine in ethanol (33%, 20 ml) was heated at 90° C. in a pressure vessel for 16 hours. The cooled reaction mixture was evaporated under reduced pressure to yield an oil which solidified on trituration with diethyl ether. The residue was recrystallized from isopropanol:diethyl ether, washed with water and recrystallized from isopropanol:water to yield the title compound, 0.47 g, m.p. 187-8° C.
Reaction SMILES: [Li+].[CH3:2][CH:3]([N-:5]C(C)C)C.C[O:10][C:11]([C:13]1([CH2:16][OH:17])[CH2:15][CH2:14]1)=O.CC#N>C1COCC1>[OH:17][CH2:16][C:13]1([C:11](=[O:10])[CH2:2][C:3]#[N:5])[CH2:15][CH2:14]1
Reactant: CC(C)[N-]C(C)C
Reactant: COC(=O)C1(CO)CC1
Agent: [Li+]
Solvent: CC#N
Solvent: C1CCOC1
Product: N#CCC(=O)C1(CO)CC1

Procedure:
To a solution of LDA (115 mmol) in THF (300 mL), at −78° C., a solution of 1-hydroxymethyl-cyclopropanecarboxylic acid methyl ester (5 g, 28.4 mmol) in CH3CN (5.91 mL, 115 mmol) is added. The reaction is allowed to reach rt. At this point it is quenched with 1N HCl (200 mL) and extracted with EtOAc (200 mL, ×3). It is then dried and evaporated to give 3-(1-hydroxymethyl-cyclopropyl)-3-oxo-propionitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 4.26 (s, 2 H) 4.03 (s, 1 H) 3.58 (br. s., 2 H) 1.15-1.16 (m, 2 H) 0.92-0.95 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([OH:11])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1.I[CH3:62].[H-].[Na+]>CN(C=O)C.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:10]2[O:9][CH2:8][CH:7]([O:11][CH3:62])[C:6]=2[C:5]([CH:12]2[C@H:17]([O:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[C@@H:16]([O:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:15]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C@@H:14]([CH2:42][O:43][CH2:44][C:45]3[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=3)[O:13]2)=[CH:4][C:3]=1[CH2:51][C:52]1[CH:57]=[CH:56][C:55]([O:58][CH2:59][CH3:60])=[CH:54][CH:53]=1
Reactant: CI
Reactant: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3O)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c3c(c2Cl)OCC3OC)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.1 %

Procedure:
To a mixture solution of 7-chloro-6-(4-ethoxybenzyl)-4-((3S,4R,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)-tetrahydro-2H-pyran-2-yl)-2,3-dihydrobenzofuran-3-ol (260 mg, 0.314 mmole) and iodomethane (40 μL, 0.628 mmole) in DMF (10 mL) was added NaH (25.1 mg, 0.628 mmole) at 0° C. The resulting solution was stirred at rt overnight, diluted with sat. NaHCO3 and extracted with ethyl acetate. The organic layer was washed with water then brine, dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified on Biotage® purification apparatus to yield the title compound (238 mg, 90%) as a yellow gum.
Reaction SMILES: [CH3:1][CH:2]([S-:4])[CH3:3].[Na+].[NH2:6][C:7]1[CH:14]=[C:13](F)[C:10]([C:11]#[N:12])=[CH:9][N:8]=1>C1COCC1>[NH2:6][C:7]1[CH:14]=[C:13]([S:4][CH:2]([CH3:3])[CH3:1])[C:10]([C:11]#[N:12])=[CH:9][N:8]=1
Reactant: CC(C)[S-]
Reactant: N#Cc1cnc(N)cc1F
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)Sc1cc(N)ncc1C#N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Sodium propane-2-thiolate (1.59 g, 15.68 mmol) was added to 6-amino-4-fluoronicotinonitrile (intermediate 21, 2.15 g, 15.68 mmol), in THF (75 ml) and the mixture stirred for 16 h at room temperature. Additional sodium propane-2-thiolate (1.59 g, 15.68 mmol) was added and the reaction stirred at room temperature for a further 4 days, then partitioned between saturated aqueous NaHCO3 solution and EtOAc, the combined organic layers washed with brine, dried over MgSO4 and evaporated. The residue was purified by normal phase chromatography: 80 g RediSep® column, eluting with a gradient from heptane to EtOAc. Product containing fractions were combined, evaporated and recrystallised from EtOAc to give the title compound as a white solid. (UPLC-MS 3) tR 0.78; ESI-MS 194.0 [M+H]+.
Reaction SMILES: C([SiH](CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH:28]=[N:29][O:30][CH3:31]>ClCCl.FC(F)(F)C(O)=O>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[N:17]([CH3:26])[C:16]2=[O:27])=[CH:11][C:10]=1[CH2:28][NH:29][O:30][CH3:31]
Reactant: CON=Cc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CONCc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)ccc1Cl
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Triethylsilane (1.9 ml) was added dropwise to a solution of 3-(4-chloro-3-methoxyiminomethylphenyl)-1-methyl-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4-dione (3.6 g) in a mixture of 30 ml of dichloromethane and 50 ml of trifluoroacetic acid. After the mixture had been stirred for 20 hours at room temperature, the solvent was distilled off. The residue was taken up in 200 ml of dichloromethane, whereupon the organic phase was washed four times using 50 ml of water in each case, dried over sodium sulfate and finally concentrated. Crystallization using diisopropyl ether and petroleum ether gave the title compound (m.p. 83-85° C.).
Reaction SMILES: [F:1][C:2]([F:12])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[C:3]([NH2:5])=[S:4].Br.Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=O>C(O)C>[F:12][C:2]([C:3]1[S:4][CH:15]=[C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[N:5]=1)([F:1])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: NC(=S)C(F)(F)c1ccccc1
Reactant: O=C(CBr)c1ccncc1
Agent: Br
Solvent: CCO
Product: FC(F)(c1ccccc1)c1nc(-c2ccncc2)cs1
Yield: 47.9 %

Procedure:
To a solution of 2,2-difluoro-2-phenylthioacetamide (1.57 g, 0.0092 mol) in 95% ethanol (20 mL) was added α-bromo-4-acetylpyridine hydrobromide (3.20 g, 0.012 mol) and the mixture warmed on a steam bath for thirty minutes. The product was isolated in the usual way and recrystallized from ethyl acetate/hexane to afford 1,1-difluoro-1-phenyl-[4-(4-pyridyl)-2-thiazolyl]methane (1.27 g, 48%). mp. 54.5°-55.5° C.
Reaction SMILES: [C:1]([C@@H:3]1[C@@H:10]2[C@@H:6]([O:7][C:8]([CH3:12])([CH3:11])[O:9]2)[C@H:5]([O:13][CH3:14])[O:4]1)#[CH:2].C[Si]([N:19]=[N+:20]=[N-:21])(C)C>>[CH3:14][O:13][C@H:5]1[C@@H:6]2[O:7][C:8]([CH3:11])([CH3:12])[O:9][C@@H:10]2[C@@H:3]([C:1]2[CH:2]=[N:21][NH:20][N:19]=2)[O:4]1
Reactant: C#C[C@H]1O[C@@H](OC)[C@@H]2OC(C)(C)O[C@@H]21
Reactant: C[Si](C)(C)N=[N+]=[N-]
Product: CO[C@@H]1O[C@H](c2cn[nH]n2)[C@H]2OC(C)(C)O[C@@H]12
Temperature: 25 °C

Procedure:
A solution of (3aR,4R,6R,6aR)-4-ethynyl-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole (Helv. Chim. Acta, 1980, 63(5), 1181) (0.55 g, 2.8 mmol), in trimethylsilylazide (5 ml) was heated at 120 □C. in a teflon lined bomb for 12 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane gradually changing to dichloromethane:methanol (98:2 by volume) to give the title compound as a pale brown oil which solidified on standing (0.36 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([OH:7])=O.CN1CCOCC1.[CH:18]([NH2:21])([CH3:20])[CH3:19].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C(Cl)Cl>[CH:18]([NH:21][C:5](=[O:7])[C:4]1[CH:8]=[CH:9][CH:10]=[C:2]([OH:1])[CH:3]=1)([CH3:20])[CH3:19]
Reactant: O=C(O)c1cccc(O)c1
Reactant: CC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)NC(=O)c1cccc(O)c1
Reaction time: 16 h

Procedure:
3-Hydroxybenzoic acid (0.966 g, 7.0 mmol), N-methylmorpholine (2.3 mL, 21 mmol), iso-propylamine (1.78 mL, 21 mmol) and CH2Cl2 (30 mL) were dissolved together and hydroxybenzotriazole (1.03 g, 7.7 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1.47 g, 7.7 mmol) was added; stirred 16 h, diluted with CH2Cl2 (70 mL) and the organic phase was washed with satd aq NaHCO3, H2O, 0.3 N HCl, H2O, and satd aq NaCl, dried (Na2SO4) and concentrated to afford 443 mg as a white foam. 1H NMR (CDCl3): d 7.23 (m, 3), 6.90 (m, 1), 4.22 (m, 1), 1.25 (d, 6).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([OH:8])[CH:4]=1.S(Cl)([Cl:12])(=O)=O>C1C=CC=CC=1>[Cl:12][C:4]1[C:5]([OH:8])=[N:6][O:7][C:3]=1[CH2:2][Cl:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: Oc1cc(CCl)on1
Solvent: c1ccccc1
Product: Oc1noc(CCl)c1Cl

Procedure:
To a solution of 8.01 g of 5-chloromethyl-3-hydroxyisoxazole in 50 ml of benzene were added 10 g of sulphuryl chloride, and then the mixture was refluxed for 10 hours. At the end of this time, the solvent and the excess sulphuryl chloride were distilled off from the reaction mixture, and the residue was dissolved in 50 ml of diethyl ether and washed five times, each time with 20 ml of water. The washed diethyl ether solution was dried over anhydrous sodium sulphate, the solvent was removed by distillation, and the residue was extracted three times, each time with 30 ml of hot hexane. The hexane was distilled off from the extract and the residue was recrystallized from carbon tetrachloride, to give 4-chloro-5-chloromethyl-3-hydroxyisoxazole in the form of colourless crystals melting at 116°-118° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:26][CH2:25][CH2:24]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH:30]([CH3:32])[CH3:31]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH:30]([CH3:32])[CH3:31])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:22][CH2:21][CH2:20][N:19]([CH:23]2[CH2:24][CH2:25][CH2:26]2)[CH2:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCCN(C2CCC2)CC1
Reactant: CC(C)Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)O[C@@H]1C[C@@H](C(=O)N2CCCN(C3CCC3)CC2)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 8.1 %

Procedure:
To a solution of (2S,4R)-2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-hydroxy-pyrrolidine-1-carboxylic acid tert-butyl ester (287 mg, 0.78 mmol) in DMF (7.8 mL) was added NaH (90%; 31 mg). After 30 min, 2-bromopropane (109 μL, 1.17 mmol) was added and the mixture was allowed to warm to rt and was stirred for 18 h. The mixture was diluted with satd. aq. NaHCO3 and extracted with CH2Cl2. The combined organic layers were dried and concentrated. The crude product was purified by FCC to provide the desired product (26 mg, 8%). MS (ESI): mass calcd. for C22H39N3O4, 409.29; m/z found, 410.4 [M+H]+. 1H NMR (CDCl3): 4.74-4.58 (m, 1H), 4.33-4.16 (m, 1H), 3.74-3.33 (m, 7H), 2.90-2.78 (m, 1H), 2.59-2.30 (m, 4H), 2.19-2.11 (m, 1H), 2.10-1.96 (m, 4H), 1.87-1.72 (m, 3H), 1.69-1.53 (m, 2H), 1.40 (d, J=17.6 Hz, 9H), 1.12 (dd, J=6.0, 2.2 Hz, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[C:14]1([S:20](Cl)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CC=CC=1>CC(C)=O>[C:14]1([S:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:6][CH:7]=2)(=[O:22])=[O:21])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Nc1ccc(CCCC(=O)O)cc1
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: O=C(O)CCCc1ccc(NS(=O)(=O)c2ccccc2)cc1

Procedure:
To a solution of 4-(4-aminophenyl)butyric acid (1 g, 5.6 mmol) in dry acetone (30 ml) was added dropwise a solution of benzenesulphonyl chloride (0.99 g) and pyridine (1.1 g) in dry acetone (10 ml). The mixture was heated at reflux for 3 hours, then concentrated in vacuo. The resulting oil was dissolved in dichloromethane (100 ml) and the solution was washed with 2N aqueous HCl (2×100 ml), followed by water (2×100 ml). The dichloromethane solution was extracted with 10% aqueous NaOH (2×50 ml), followed by water (2×50 ml), and these extracts were combined and stirred with dichloromethane (100 ml) while conc. HCl was added to adjust the pH of the mixture to 5. The layers were separated and the organic solution was dried (MgSO04) and concentrated in vacuo. The resulting solid was recrystallised from isopropanol to give 4-[4-(phenyl-sulphonamido)phenyl]butyric acid. (1.03 g, 58%) mp. 128°-130 ° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][C:3]=1[Cl:13].[C:14]1([N:20]=[C:21]=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.CCN(CC)CC>C1COCC1>[Cl:13][C:3]1[CH:4]=[C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:21]([NH:20][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:22]
Reactant: COC(=O)Cc1ccc(N)c(Cl)c1
Reactant: O=C=Nc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)Cc1ccc(NC(=O)Nc2ccccc2)c(Cl)c1
Reaction time: 15 h
Yield: 85.6 %

Procedure:
To a mixture of methyl 4-amino-3-chlorophenylacetate (1.31 g, 6.56 mmol) and phenyl isocyanate (0.71 ml, 6.56 mmol) in THF (20 ml) was added Et3N (0.19 ml, 1.33 mmol) at room temperature. After 15 h stirring, the reaction mixture was concentrated in vacuo. The residue was triturated by the addition of n-hexane to give methyl 3-chloro-4-(N′-phenylureido)phenylacetate (1.79 g, 86%) as a pale brown solid. 1H-NMR (CDCl3) δ3.56 (s, 2H), 3.70 (s, 3H), 6.70 (m, 1H), 7.06 (s, 1H), 7.14-7.18 (m, 2H), 7.26 (dd, J=7.8, 1.9 Hz, 1H), 7.33-7.38 (m, 4H), 8.14 (dd, J=8.3, 3.0 Hz, 1H); MS (ESI) m/z 319 (M++1), 321 (M++3).