Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])(=O)=[O:17])[CH:11]=2)[C:5]([C:20]([F:23])([F:22])[F:21])=[CH:4][N:3]=1.ClC1N=C(Cl)C(C(F)(F)F)=CN=1.Cl.CS(C1C=C(CN)C=CC=1)=O.C(N(C(C)C)CC)(C)C>C1COCC1>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([CH3:19])=[O:17])[CH:11]=2)[C:5]([C:20]([F:22])([F:21])[F:23])=[CH:4][N:3]=1
Reactant: CS(=O)(=O)c1cccc(CNc2nc(Cl)ncc2C(F)(F)F)c1
Agent: CS(=O)c1cccc(CN)c1
Agent: Cl
Agent: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)c1cccc(CNc2nc(Cl)ncc2C(F)(F)F)c1

Procedure:
Prepared according to the procedure described above for 2-chloro-N-[3-(methylsulfonyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine (XLIVa) using 2,4-dichloro-5-trifluoromethylpyrimidine (XL, 324 mg, 1.5 mmol), 1-[3-(methylsulfinyl)phenyl]methanamine hydrochloride (249 mg, 1.2 mmol) and diisopropylethylamine (0.65 mL, 3.75 mmol) in THF (10 mL). Pure desired 2-chloro-N-[3-(methylsulfinyl)benzyl]-5-(trifluoromethyl)pyrimidin-4-amine (XLVa, 162 mg) was isolated as the non-polar component by chromatography eluting with hexane:ethyl acetate 25:75. 1H NMR (DMSO-d6) δ: 8.61 (t, J=5.7 Hz, 1H), 8.44 (s, 1H), 7.67 (s, 1H), 7.49-7.58 (m, 2H), 7.45 (dt, J=6.6, 2.0 Hz, 1H), 4.70 (d, J=5.9 Hz, 2H), 2.72 (s, 3H). 13C NMR (DMSO-d6) δ: 162.59, 158.35, 155.74 (q, J=5 Hz), 146.49, 139.73, 129.47, 129.24, 123.43 (q, J=272 Hz), 122.40, 122.36, 105.16 (q, J=32 Hz), 43.84, 43.23. A HMBC 3-bond correlation is observed between the C4—N-proton at 8.61 ppm and the C5-carbon at ˜105 ppm.
Reaction SMILES: C([O:3][C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:12]1)=[O:5])C.[OH-].[K+]>C1COCC1.O>[C:4]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]([C:20]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)=[O:21])=[CH:12]1)([OH:5])=[O:3]
Reactant: CCOC(=O)CCCCCn1cc(C(=O)c2cccc3ccccc23)c2ccccc21
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)CCCCCn1cc(C(=O)c2cccc3ccccc23)c2ccccc21
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a solution of 2 (5.0 g, 12 mmol) in a mixture of THF/H2O (1:1) was added potassium hydroxide (1.7 g) and the mixture was stirred at 60° C. for 1 h. The THF was removed under vacuum, the aqueous solution acidified to pH 1 by the addition of hydrochloric acid solution (1N) and extracted by ethyl acetate (3×100 ml). The combined organic phases were washed by water (100 ml), brine solution (100 ml), dried over sodium sulphate, filtered and concentrated to dryness. The crude product obtained was dissolved in ethyl acetate (10 ml) and the Hapten-A precipitated by the addition of a mixture of ether/hexane as a white solid, filtered and dried under high vacuum to give Hapten-A (3.6 g, 78%).
Reaction SMILES: [CH:1]([C@@H:3]1[CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][N:4]1C(OC(C)(C)C)=O)=O.[NH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1>>[N:20]1([CH2:1][C@@H:3]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH2:5][NH:4]2)[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccccc2C[C@H]1C=O
Product: c1ccc2c(c1)CN[C@H](CN1CCCC1)C2

Procedure:
Following a procedure analogous to that for the synthesis of Example 107, (S)-tert-butyl 3-formyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (57 mg, 0.22 mmol) and pyrrolidine (16 mg, 0.22 mmol) provided a crude oil which was used without purification in preparation of Example 111. MS(ESI+) m/z 217.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.CO[CH:10](OC)[CH2:11]Br.Br>C(O)C>[N:1]1[CH:10]=[CH:11][N:3]2[CH:4]=[CH:5][N:6]=[CH:7][C:2]=12
Reactant: Nc1cnccn1
Reactant: COC(CBr)OC
Agent: Br
Solvent: CCO
Product: c1cn2ccnc2cn1
Temperature: 25 °C
Yield: 68.7 %

Procedure:
2-Aminopyrazine (100 mg, 1.1 mmol) and bromoacetaldehyde dimethylacetal (253 mg, 1.6 mmol) were dissolved in ethanol (4.5 ml), hydrobromic acid (48%, 0.5 ml) added and the mixture was heated under reflux for 18 h. The solution was allowed to cool to room temperature then pre-adsorbed directly onto silica. Purification by silica gel chromatography eluting with dichloromethane and 1% conc. ammonia on a gradient of methanol (1-4%) gave imidazo[1,2-α]pyrazine (90 mg, 72%) as a white crystalline solid: δH (360 MHz, CDCl3) 6.70 (1H, s), 7.82 (1H, s), 7.88 (1H, d, J 4), 8.29 (1H, d, J 4), 9.12 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]([CH3:25])[CH2:14][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:16][NH2:17]>>[CH3:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:17][CH2:16][CH:15]([C:18]1[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[CH2:14][CH:13]([CH3:25])[CH3:12])=[O:6]
Reactant: Cc1cccc(C(=O)O)c1C
Reactant: Cc1ccc(C(CN)CC(C)C)cn1
Product: Cc1ccc(C(CNC(=O)c2cccc(C)c2C)CC(C)C)cn1

Procedure:
From 2,3-dimethylbenzoic acid and 4-methyl-2-(6-methylpyridin-3-yl)-pentylamine. LCMS (MH+): m/z=325.0, tR (minutes, Method A)=1.38
Reaction SMILES: Cl.[CH2:2]([N:5]=[C:6]([NH2:21])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([NH2:20])=[NH:19])[N:9]=1)[CH2:3][CH3:4].[Na].[CH:23]([CH:25]([CH2:31][CH3:32])[C:26](OCC)=O)=[O:24]>CO>[CH2:2]([N:5]=[C:6]([NH2:21])[NH:7][C:8]1[CH:13]=[CH:12][N:11]=[C:10]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]2[N:20]=[C:23]([OH:24])[C:25]([CH2:31][CH3:32])=[CH:26][N:19]=2)[N:9]=1)[CH2:3][CH3:4]
Reactant: CCCN=C(N)Nc1ccnc(CCCCC(=N)N)n1
Reactant: CCOC(=O)C(C=O)CC
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CCCN=C(N)Nc1ccnc(CCCCc2ncc(CC)c(O)n2)n1

Procedure:
A mixture of 5-(4-[2-propylguanidino]pyrimid-2-yl)valeramidine hydrochloride (0.4 g.) and the sodium salt of ethyl 2-formylbutyrate (1.5 g.) in MeOH (5 ml.) was heated under reflux for 4 hours. The solvent was evaporated in vacuo and the residue was partitioned between water (pH 7) and EtOAc. The EtOAc layer was separated, dried (MgSO4) and evaporated in vacuo to give 2-[4-(4-(2-propylguanidino]pyrimid-2-yl)butyl]-5-ethyl-4-hydroxypyrimidine as an oil (0.13 g.) which was characterised by conversion to the bis hydrogen maleate salt (0.11 g.), m.p. 140°-142°.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([OH:18])([C:14]([F:17])([F:16])[F:15])[C:10]([F:13])([F:12])[F:11])=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH:28]1[C:33]([O:35][CH3:36])=[O:34]>C(#N)C>[F:11][C:10]([F:13])([F:12])[C:9]([C:6]1[CH:7]=[CH:8][C:3]([CH2:2][N:30]2[CH2:31][CH2:32][NH:27][CH:28]([C:33]([O:35][CH3:36])=[O:34])[CH2:29]2)=[CH:4][CH:5]=1)([OH:18])[C:14]([F:17])([F:16])[F:15]
Reactant: COC(=O)C1CNCCN1
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)C1CN(Cc2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CCN1
Yield: 25.1 %

Procedure:
2-(4-(Bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (4.61 mmol, 1.553 g), potassium carbonate (13.82 mmol, 1.910 g) and methyl piperazine-2-carboxylate dihydrochloride (4.61 mmol, 1 g) were combined and stirred at room temperature overnight in acetonitrile (25 mL). The reaction mixture was filtered and the solid washed with ethyl acetate. The organic was concentrated under reduced pressure. The resulting residue was purified by silica column chromatography (eluant dichloromethane/methanol/ammonia 95/5/0.5) to afford the title compound (464 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:4][C:3]=1[Cl:15].C(N(CC)CC)C.Cl[C:24]([CH3:28])([CH3:27])[C:25]#[CH:26].CCCCCC>O1CCOCC1.O.[Cu]Cl>[Cl:15][C:3]1[CH:4]=[C:5]([CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:6]=[CH:7][C:2]=1[NH:1][C:24]([CH3:28])([CH3:27])[C:25]#[CH:26]
Reactant: CCOC(=O)C(C)c1ccc(N)c(Cl)c1
Reactant: C#CC(C)(C)Cl
Agent: Cl[Cu]
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: O
Product: C#CC(C)(C)Nc1ccc(C(C)C(=O)OCC)cc1Cl
Yield: 50.8 %

Procedure:
9.3 g of Ethyl 2-(4-amino-3-chlorophenyl)propionate were dissolved in a mixture of 100 ml of dioxane and 30 ml of water. 1.0 g of copper(I) chloride and 10 ml of triethylamine were further added to the solution. 6.3 g of 3-chloro-3-methyl-1-butyn was added dropwise thereto with stirring under nitrogen atmosphere. The mixture was reacted at 5° C. for 2 hours, followed by addition of a mixture of hexane and water and then separation of the organic layer. The organic layer was washed with water and saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate, then the solvent was distilled off. The residue was purified by column chromatography on silica gel (eluted with benzene) to give 6.1 g of ethyl 2-[3-chloro-4-(1,1-dimethyl-2-propynylamino)phenyl]propionate (Compound 1).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2].[CH:13]1([C:16](Cl)=[O:17])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][C:8]([C:16]([CH:13]3[CH2:15][CH2:14]3)=[O:17])=[CH:9][CH:10]=2)[CH2:5][C:4]1=[O:12])[CH3:2]
Reactant: CCN1C(=O)Cc2ccccc21
Reactant: O=C(Cl)C1CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCN1C(=O)Cc2cc(C(=O)C3CC3)ccc21

Procedure:
In a manner similar to Preparation J1., 10 g. (62 mmoles) of 1-ethyloxindole, 7.2 ml. (78.8 mmoles) of cyclopropylcarbonyl chloride and 51 g. (380 mmoles) of aluminum chloride in 200 ml. of carbon disulfide gave 3.75 of the desired product.
Reaction SMILES: [CH:1]([CH:4]1[NH:9][CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:19])=[O:18])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2].Cl[C:22]1[N:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[C:25]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][N:23]=1.CCN(C(C)C)C(C)C>CS(C)=O.O>[CH:1]([CH:4]1[N:9]([C:22]2[N:27]=[C:26]([C:28]([F:30])([F:31])[F:29])[C:25]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:24][N:23]=2)[CH2:8][CH2:7][N:6]2[C:10]3[CH:16]=[C:15]([S:17]([CH3:20])(=[O:18])=[O:19])[CH:14]=[CH:13][C:11]=3[N:12]=[C:5]12)([CH3:3])[CH3:2]
Reactant: CC(C)C1NCCn2c1nc1ccc(S(C)(=O)=O)cc12
Reactant: CCOC(=O)c1cnc(Cl)nc1C(F)(F)F
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(N2CCn3c(nc4ccc(S(C)(=O)=O)cc43)C2C(C)C)nc1C(F)(F)F
Temperature: 100 °C
Reaction time: 2 h
Yield: 54.7 %

Procedure:
To a solution of 1-isopropyl-7-(methylsulfonyl)-1,2,3,4-tetrahydrobenzo[4,5]imidazo[1,2-a]pyrazine (5.0 mg, 0.02 mmol, prepared according to example 1) in DMSO (1 mL) was added ethyl 2-chloro-4-(trifluoromethyl)pyrimidine-5-carboxylate (8.7 mg, 0.03 mmol), DIEA (6.6 mg, 0.05 mmol) under N2. The mixture was stirred at 100° C. for 2 h. The mixture was diluted with water (5 mL) and extracted with EtOAc (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over anhydrous Na2SO4, filtered, concentrated and then purified by preparative TLC to afford a racemic mixture of ethyl 2-(1-isopropyl-7-(methylsulfonyl)-3,4-dihydrobenzo[4,5]imidazo[1,2-a]pyrazin-2(1H)-yl)-4-(trifluoromethyl)pyrimidine-5-carboxylate (5.6 mg, 64% yield) as a white solid. LC-m/z 512.2 [M+H]+. 1H NMR (CDCl3 400 MHz): δ 8.98 (s, 1H), 8.07-7.98 (m, 1H), 7.93-7.83 (m, 2H), 6.16 (d, J=6.4 Hz, 1H), 5.53-5.41 (m, 1H), 4.43-4.32 (m, 3H), 4.28-4.16 (m, 1H), 3.92-3.79 (m, 1H), 3.09 (s, 3H), 2.61-2.46 (m, 1H), 1.40 (s, 3H), 1.38-1.32 (m, 3H), 1.08 (d, J=6.8 Hz, 3H).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[NH:15][C:14]4[CH2:19][CH:20]5[NH:24][CH:23]([C:13]=4[C:12]=3[C:11]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]5)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1CCC[C@H]1C(O)=O.I[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O.[Cu](I)I>[C:1]1([S:7]([C:10]2[CH:18]=[CH:17][C:16]3[N:15]([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:14]4[CH2:19][CH:20]5[NH:24][CH:23]([C:13]=4[C:12]=3[C:11]=2[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:22][CH2:21]5)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2[nH]c3c(c12)C1CCC(C3)N1
Reactant: Ic1ccccc1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)c1c(S(=O)(=O)c2ccccc2)ccc2c1c1c(n2-c2ccccc2)CC2CCC1N2
Temperature: 115 °C
Yield: 50.4 %

Procedure:
To a solution of the product of step C (100 mg, 0.27 mmol) in dimethylsulfoxide (2 mL) was added copper iodide (51 mg, 0.02 mmol), L-proline (6.2 mg, 0.05 mmol), iodobenzene (33 μL, 0.29 mmol) and potassium carbonate (75 mg, 0.54 mmol). The resulting mixture was heated to 115° C. for 40 h, diluted with water and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was purified by flash chromatography (SiO2, 3:2 hexanes/ethyl acetate) to give tert-butyl 2-phenylsulfonyl-5-phenyl-5,6,7,8,9,10-hexahydro-7,10-epiminocyclohepta[b]indole-carboxylate (70 mg, 50%) as a white solid: 1H NMR (CDCl3, 300 MHz) δ 8.26 (s, 1H), 7.95-7.98 (m, 2H), 7.63 (d, J=8.7 Hz, 1H), 7.42-7.54 (m, 6H), 7.21-7.26 (m, 3H), 5.33 (br s, 1H), 4.65 (br s, 1H), 2.20-2.33 (m, 3H), 2.00-2.06 (m, 1H), 1.60-1.69 (m, 2H), 1.40 (s, 9H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[Br:9]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.[W]>[Br:9][CH2:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([F:1])[CH:7]=1
Reactant: Cc1ccnc(F)c1
Reactant: O=C1CCC(=O)N1Br
Agent: [W]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cc(CBr)ccn1
Temperature: 25 °C
Yield: 28.4 %

Procedure:
The mixture of 2-Fluoro-4-methyl-pyridine (10 g, 90 mmol), N-bromosuccinimide (19.2 g, 108 mmol), and benzoyl peroxide (2.18 g, 9 mmol) in carbon tetrachloride (100 ml) was refluxed for 5 hr under a light of 500 W tungsten light. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated in vacuo to give a brown oil, which was purified by silica gel column chromatography (eluent, ether:hexane (1:9)) to afford 4.85 g (28%) of a pale brown oil; 1H NMR (200 MHz, CDCl3) δ: 4.40 (2H, s), 6.95 (1H, m), 7.19 (1H, m), 8.18 (1H, d, J=5.2 Hz); m/z (EI): 189 (M+), 191 (M+2+).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12](O)[N:7]2[N:6]=1)=[N+:2]=[N-:3].P(Cl)(Cl)([Cl:18])=O>N1C=CC=CC=1>[N:1]([CH2:4][C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([Cl:18])[N:7]2[N:6]=1)=[N+:2]=[N-:3]
Reactant: Cc1cc(O)n2nc(CN=[N+]=[N-])nc2n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: Cc1cc(Cl)n2nc(CN=[N+]=[N-])nc2n1
Temperature: 50 °C
Reaction time: 4.5 h

Procedure:
2-Azidomethyl-5-methyl[1.2.4]-triazolo[1,5-a]-pyrimidin-7-ol (3.1 g) are suspended in 20 ml of freshly distilled phosphorus oxychloride and 1.1 ml of pyridine and stirred at 50° C. for 4.5 hours. The phosphorus oxychloride is evaporated in a vacuum and the residue is taken up in 40 ml of ethyl acetate and 40 ml of water. The resulting suspension is stirred in an ice bath for 45 minutes. The product is filtered off under suction and dried in a vacuum at 40° C. There are obtained 2.1 g of 2-azidomethyl-7-chloro-5-methyl[1.2.4]triazolo[1,5-a]pyrimidine as white crystals of melting point 130°-132° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8]O)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.S(Cl)(C)(=O)=O.C([O-])([O-])=O.[K+].[K+].[Li+].[Br-:28]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][Br:28])[CH:5]=[N:6][CH:7]=1
Reactant: [Br-]
Reactant: OCc1cncc(Br)c1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: BrCc1cncc(Br)c1
Reaction time: 2 h

Procedure:
To a solution of 5-bromo-3-pyridylmethanol [see Kauffman, T., and Fischer, H. (1973) Chem. Ber. 106, 220-227.1] (0.525 gms, 2.79 mmol) in methylene chloride (2.6 mls) at 0° C. is added pyridine (0.26 mls, 3.21 mmol) then mesyl chloride (0.25 mls, 3.23 mmol). After stirring 2 hours, K2CO3 (0.88 gms, 6.37 mmol) is added. Stirring is continued for one hour and the ice bath is removed. The mixture is diluted with methylene chloride and washed with saturated aqueous NaHCO3. The organic layer is dried over Na2SO4 and evaporated to a viscous residue (>0.6 gms). The residue is dissolved in methylene chloride (8.8 mls) and tetrahydrofuran (4.4 mls) without further purification or characterization. LiBr powder (0.46 gms, 5.53 mmol) is introduced and the reaction is immersed in an oil bath (80° C.) for one hour. The crude mixture is concentrated and resolvated with ethyl acetate. Any remaining residue is pulverized and rinsed with methylene chloride. Combined organics are dried over Na2SO4 and evaporated to a solid (0.7 gms, 2.79 mmol; 100%). 1H NMR (CDCl3, 300 MHz) δ 8.65 (s, 1H), 8.55 (s, 1H), 7.90 (s, 1H), 4.45 (s, 2H).
Reaction SMILES: C(Cl)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4]C=1.[C:10]([O:13][C:14](=[O:16])[CH3:15])(=[O:12])[CH3:11]>>[C:10]([O:13][C:14](=[O:16])[C:15]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1)(=[O:12])[C:11]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)OC(C)=O
Reactant: O=C(Cl)c1ccccc1
Product: O=C(OC(=O)c1ccccc1)c1ccccc1

Procedure:
300 g of benzoyl chloride (2.13 mol) are mixed with 91 g of acetic anhydride (0.89 mol) and the mixture is heated to 100° to 120° C. The resultant acetyl chloride is removed by distillation under reduced pressure (400 mbar) and, upon completion of the reaction, excess benzoyl chloride is removed by distillation at about 7 mbar. The residue consists of pure benzoic anhydride. Yield: 200 g (=99% of theory) of benzoic anhydride.
Reaction SMILES: [C:1]1([N:7]2[CH:11]=[CH:10][CH:9]=[C:8]2[CH:12]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].O.NN>C(O)CO>[CH3:12][C:8]1[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1cccn1-c1ccccc1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCO
Solvent: O
Product: Cc1cccn1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.7 %

Procedure:
A mixture of 1-phenylpyrrole-2-carbaldehyde (700 mg, 4.1 mmol), potassium hydroxide (490 mg, 12.3 mmol) and hydrazine hydrate (0.8 mL, 12.3 mmol) in ethylene glycol (15 mL) was stirred at ambient temperature for 30 min and then slowly heated to 150° C. and maintained for 2 h. The reaction mixture was allowed to cool to ambient temperature, poured into ice-water and extracted with diethyl ether. The organic layer was washed with water, brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the crude compound. Purification by column chromatography over silica gel (60-120 mesh) using petroleum ether as eluent to afford 2-methyl-1-phenyl-pyrrole (430 mg, 66%) as a yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH:13]([CH3:24])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1.[Cl:33][Si](C)(C)C>CC(CC)=O>[ClH:33].[CH3:32][N:2]([CH3:1])[C:3]1([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:8][CH2:7][C:6](=[CH:9][C:10]([NH:12][CH:13]([CH3:24])[CH2:14][C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[NH:17][CH:16]=2)=[O:11])[CH2:5][CH2:4]1
Reactant: C[Si](C)(C)Cl
Agent: CC(Cc1c[nH]c2ccccc12)NC(=O)C=C1CCC(c2ccc(F)cc2)(N(C)C)CC1
Solvent: CCC(C)=O
Product: Cl
Reaction time: 1.5 h

Procedure:
The less polar diastereoisomer of 2-[4-dimethylamino-4-(4-fluorophenyl)cyclohexylidene]-N-[2-(1H-indol-3-yl)-1-methylethyl]acetamide (150 mg, 0.39 mmol) was dissolved in ethyl methyl ketone (10 ml), and chlorotrimethylsilane (0.075 ml, 0.59 mmol) was added. After 1.5 h it was possible to isolate the hydrochloride as a colourless solid in a yield of 63% (115 mg) with an m.p. of 188-191° C. (Example 21).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]([C:18](=[O:21])[CH2:19]Cl)[C:11]1[CH:16]=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=1.[Cl-].[Al+3].[Cl-].[Cl-].ClC1C=CC=CC=1Cl.Cl>O>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[C:4]([F:9])[C:3]=1[N:10]1[C:11]2[C:16](=[CH:15][C:14]([CH3:17])=[CH:13][CH:12]=2)[CH2:19][C:18]1=[O:21]
Reactant: Cc1ccc(N(C(=O)CCl)c2c(F)cc(F)cc2Cl)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Clc1ccccc1Cl
Solvent: O
Product: Cc1ccc2c(c1)CC(=O)N2c1c(F)cc(F)cc1Cl
Temperature: 25 °C

Procedure:
To a mixture of 100 g (0.3 mol) of N-(2′-chloro-4′,6′-difluorophenyl)-N-chloroacetyl-4-methylaniline and 103 g (0.78 mol) of aluminum chloride is added 400 ml of 1,2-dichlorobenzene. The reaction is heated to 140° for 2 hours. The reaction is cooled to room temperature and added to a mixture of 100 ml of concentrated HCl and 700 ml water (cooled to 0-5° in a dry ice/acetone bath). The mixture is extracted twice with 400 ml of methylene chloride. The combined organic layers are washed with 600 ml of 3N HCl. The organic layer is stirred with 66 g of magnesium sulfate and 33 g of charcoal (DARCO G-60). The solids are filtered off and the solvents are evaporated under reduced pressure to give a tan solid which is recrystallized from ethanol to give N-(2′-chloro-4′,6′-difluorophenyl)-5-methyloxindole, mp 137-140°.
Reaction SMILES: [CH3:1][C:2]([CH3:41])([CH3:40])[CH2:3][CH2:4][NH:5][C:6](=[O:39])[CH2:7][CH2:8][CH:9]([CH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1)[C:10]([C:31]#[N:32])=[CH:11][C:12]1[CH:17]=[C:16]([O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]([O:25][CH2:26][CH3:27])=[CH:14][C:13]=1[N+:28]([O-])=O.[NH4+].[Cl-:43].Cl>CO.[Zn]>[ClH:43].[NH2:32][C:31]1[C:10]([CH:9]([CH:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[CH2:8][CH2:7][C:6]([NH:5][CH2:4][CH2:3][C:2]([CH3:41])([CH3:40])[CH3:1])=[O:39])=[CH:11][C:12]2[C:13](=[CH:14][C:15]([O:25][CH2:26][CH3:27])=[C:16]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH:17]=2)[N:28]=1
Reactant: [Cl-]
Reactant: CCOc1cc([N+](=O)[O-])c(C=C(C#N)C(CCC(=O)NCCC(C)(C)C)C2CCOCC2)cc1Oc1ccccc1
Agent: Cl
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CCOc1cc2nc(N)c(C(CCC(=O)NCCC(C)(C)C)C3CCOCC3)cc2cc1Oc1ccccc1

Procedure:
To a solution of 5-cyano-6-(4-ethoxy-2-nitro-5-phenoxy-phenyl)-4-(tetrahydro-pyran-4-yl)-hex-5-enoic acid (3,3-dimethyl-butyl)-amide (160 mg, 0.28 mmol) in methanol was added Zn (0.4 g) and NH4Cl (0.10 g). The resulting mixture was treated under μW at 95° C. for 20 min, filtered through Celite® and concentrated. The resulting crude product was purified by chromatography (silica gel, 0-2% methanol in methylene chloride) to yield a white solid that was converted to the HCl salt of the title compound by reacting with 1M HCl in diethyl ether.
Reaction SMILES: C([O:3][C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[O:11][CH2:12][C@H:13]1[CH2:15][O:14]1)=O.[OH-].[K+]>O1CCOCC1>[Br:10][C:8]1[CH:7]=[CH:6][C:5]2[O:11][CH2:12][C@H:13]([CH2:15][OH:14])[O:3][C:4]=2[CH:9]=1
Reactant: O=COc1cc(Br)ccc1OC[C@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Product: OC[C@H]1COc2ccc(Br)cc2O1
Reaction time: 1 h

Procedure:
Preparation according to Preparation 8 using 5-bromo-2-[(2R)-oxiran-2-ylmethoxy]phenyl formate (7.0 g, 25 mmol), dioxane (30 ml) and KOH (10%, 15 ml), stirred for 1 h. Purification on flash column chromatography (Isooctane/EtOAc). Crude yield: 3.7 g. MS m/z (rel. intensity, 70 eV) 245 (M+, 97) 244 (M+, bp), 189 (48), 188 (50) 79 (39).