Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[C:33](Cl)(=[O:37])[CH2:34][CH2:35][CH3:36]>>[NH2:8][C:9]1[C:14]([C:15](=[O:16])[C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([C:33](=[O:37])[CH2:34][CH2:35][CH3:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Reactant: CCCC(=O)Cl
Solvent: O=C(O)C(F)(F)F
Product: CCCC(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and butyryl chloride (Aldrich) to give 1-[4-[4-amino-5-(5-fluoro-2-methoxy-benzoyl)-pyrimidin-2-ylamino]-piperidin-1-yl]-butan-1-one. MS (M+H)+, 416.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[C:9]([C@@H:21]([OH:31])[C@@H:22]([NH:24][C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH3:23])[CH:10]=[CH:11][C:12]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.N1C=CC=CC=1.O>C(OCC)(=O)C>[CH2:14]([O:13][C:12]1[CH:11]=[CH:10][C:9]([C@@H:21]([OH:31])[C@@H:22]([NH:24][C:25](=[O:30])[C:26]([F:27])([F:28])[F:29])[CH3:23])=[CH:8][C:7]=1[NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C[C@H](NC(=O)C(F)(F)F)[C@H](O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1

Procedure:
Methanesulfonyl chloride (14 mL) was added to a mixture of N-[(1S,2R)-2-(3-amino-4-benzyloxyphenyl)-2-hydroxy-1-methylethyl]-2,2,2-trifluoroacetamide (62 g) and pyridine (34 mL) in ethyl acetate (558 mL) at room temperature with stirring, and the mixture was stirred at 40° C. for 1 hr. Ethyl acetate and water were added to the reaction mixture. The organic layer was separated, washed successively with 1 mol/L hydrochloric acid, water and brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized from n-hexane/ethyl acetate to afford the title compound (42 g).
Reaction SMILES: [CH2:1]([OH:6])[C:2]#[C:3][CH2:4][CH3:5].[S:7](Cl)([C:10]1[CH:16]=[CH:15][C:13]([CH3:14])=[CH:12][CH:11]=1)(=[O:9])=[O:8].[OH-].[K+]>C1COCC1>[CH3:14][C:13]1[CH:15]=[CH:16][C:10]([S:7]([O:6][CH2:1][C:2]#[C:3][CH2:4][CH3:5])(=[O:9])=[O:8])=[CH:11][CH:12]=1
Reactant: CCC#CCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCC#CCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
To a solution of 2-Pentyn-1-ol (60 g, 0.71 mol) in THF (420 mL) cooled to −5° C., tosyl chloride (142.9 g, 0.75 mol) and KOH (79.9 g, 1.42 mol) were added and the reaction mixture was stirred at room temperature for 1 h. After completion of starting material, the reaction mixture was extracted with ethyl acetate (300 mL×2), washed with water (100 mL×2), brine (50 mL×2) and dried over Na2SO4. The combined organic extracts were evaporated under reduced pressure to obtain the crude product which was purified by column chromatography (100-200 mesh silica gel, 20% EtOAc-hexane) to furnish pent-2-ynyl 4-methylbenzenesulfonate (110 g, 64%) as a light red liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6].[Br:19]Br>C(Cl)Cl>[NH2:1][C:2]1[C:16]([Br:19])=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:3]=1[CH2:4][N:5]([CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH3:6]
Reactant: BrBr
Reactant: COc1ccc(N)c(CN(C)C2CCCCC2)c1
Solvent: ClCCl
Product: COc1cc(Br)c(N)c(CN(C)C2CCCCC2)c1

Procedure:
2-Amino-3-bromo-N-cyclohexyl-5-methoxy-N-methyl-benzylamine was prepared from 2-amino-N-cyclohexyl-5-methoxy-N-methylbenzylamine and bromine analogous to Example 9. Proof of structure by IR- and UV-spectra. IR-spectrum (methylenechloride):
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.C(N(CC)CC)C.[C:14]1([CH:24]=O)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1.[CH2:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH2:29][CH2:28][C:27]1=O>C(O)C>[C:14]1([CH:24]2[C:31]3[C:30]4[CH:29]=[CH:28][CH:27]=[CH:26][C:35]=4[CH2:34][CH2:33][C:32]=3[NH:1][C:2]3=[N:3][N:4]=[N:5][N:6]23)[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: Nc1nnn[nH]1
Reactant: O=C1CCc2ccccc2C1
Reactant: O=Cc1cccc2ccccc12
Solvent: CCN(CC)CC
Solvent: CCO
Product: c1ccc2c(c1)CCC1=C2C(c2cccc3ccccc23)n2nnnc2N1
Yield: 5.4 %

Procedure:
To a solution of 5-aminotetrazole (0.850 g, 10.0 mmole) and triethylamine (0.250 ml, 1.8 mmole) in hot ethanol (25 ml) was added 1-naphthaldehyde (1.36 ml, 10.0 mmole) followed by 2-tetralone (1.32 ml, 10.0 mmole). The mixture is refluxed for 72 h after which time a small amount of powdery precipitate is observed. Upon cooling the reaction to room temperature, it was filtered and washed with ethyl ether to provide the desired product (0.189 g, 5.1%) as a tan powder. 1H NMR (400 MHz; DMSO-d6) δ 10.9 (bs, 1H); 9.0 (bs, 1H); 8.05-7.85 (m, 2H); 7.77 (at, 1H, J=7.0 Hz); 7.65 (at, 2H, J=7.0 Hz); 7.42 (at, 1H, J=7.4 Hz); 7.14 (d, 1H, J=7.4 Hz); 7.0-6.75 (m, 3H); 3.0-2.6 (m, 4H). LC MS shows MH+ at 352; 2M+H at 703 and 2M+Na at 725.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[NH:11][CH2:10][C@@H:9]1[CH3:15])=[O:7])([CH3:4])(C)C.[CH2:16](N(CC)CC)[CH3:17].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C(#N)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:13][C@@H:12]([CH3:14])[N:11]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:10][C@@H:9]1[CH3:15])=[O:7])[CH2:4][CH2:16][CH3:17]
Reactant: CCN(CC)CC
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: BrCc1ccccc1
Solvent: CC#N
Product: CCCCOC(=O)N1C[C@@H](C)N(Cc2ccccc2)C[C@@H]1C

Procedure:
To an acetonitrile (40 ml) solution of 4.5 g (21.0 mmol.) of trans-1-tert-butoxycarbonyl-2,5-dimethyl piperazine and 5.9 ml (42.3 mmol.) of triethylamine was added, at room temperature, 3.2 ml (26.9 mmol.) of benzyl bromide. The mixture was heated for 24 hours under reflux. The solvent was distilled off under reduced pressure. To the residue was added water. The mixture was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution, which was dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane 10%) to give the object compound as a pale yellow oily product. The yield was 5.17 g (81%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1.C(N(CC)CC)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.ClCCl>[F:12][C:13]([F:24])([F:23])[C:14]1[CH:19]=[CH:18][C:17]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=2)=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Reaction time: 48 h

Procedure:
A flask was charged with methyl 4-hydroxybenzoate (500 mg, 3.29 mmol), copper (II) acetate (895 mg, 4.93 mmol), 4-trifluoromethylphenylboronic acid (2.50 g, 13.15 mmol), and 4 angstrom molecular sieves (500 mg). Dichloromethane (33 mL) and triethylamine (1.83 mL, 13.15 mmol) were added, and the reaction mixture was stirred rapidly, open to air. After 48 h, the reaction mixture was filtered and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 10% EtOAc in hexanes, then 10 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 297.5 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 8.07-8.05 (m, 2H), 7.63 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 7.06-7.04 (m, 2H), 3.92 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[CH:7][C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.C(C1C=C(C)C(=[C:42]([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)C=1)(C)(C)C.O>C(OCC)C>[C:1]([C:5]1[CH:6]=[C:7]([CH:42]([C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[C:8]2[CH2:9][C:10]3[C:15]([C:16]=2[CH:17]=1)=[CH:14][C:13]([C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:12][CH:11]=3)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=CC(C(C)(C)C)=CC1=C(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)ccc1C2
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Solvent: CCCCCC
Product: CC(C)(C)c1ccc2c(c1)-c1cc(C(C)(C)C)cc(C(c3ccccc3)c3ccccc3)c1C2
Temperature: 25 °C

Procedure:
In a 200 ml three-necked flask equipped with a magnetic stirrer chip and three-way cock thoroughly purged with nitrogen, 3.01 g of 3,6-di-tert-butyl-fluorene (10.8 mmol) was dissolved in 80 ml of dehydrated diethyl ether in a nitrogen atmosphere. To the solution, 7.6 ml of a n-butyl lithium/hexane solution (1.56M: 11.9 mmol) was gradually added dropwise in an ice bath and stirred at room temperature over night. To the reaction solution, 50 ml of a solution prepared by dissolving 4.86 g of 3-tert-butyl-1-methyl-6,6-diphenyl fulvene (16.2 mmol) in 50 ml of dehydrated diethyl ether was added and stirred with refluxing for 13 days. To the reaction mixture, 30 ml of distilled water was gradually added dropwise in an ice bath, and thereafter diethyl ether was added to separate an organic phase. The organic phase was washed with distilled water and saturated brine. The organic phase was dried with anhydrous magnesium sulfate, thereafter the drying agent was filtered off and the solvent was distilled off from the filtrate under reduced pressure to give red solid. The red solid was re-crystallized using ethanol and dried under reduced pressure, and thereby the aimed compound was obtained in an amount of 4.42 g (7.63 mmol) as a pale yellow solid (yield: 71%).
Reaction SMILES: [OH-].[NH4+:2].[Br:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6](Cl)=[O:7]>C(Cl)Cl>[Br:3][C:4]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][C:5]=1[C:6]([NH2:2])=[O:7]
Reactant: COc1ccc(Br)c(C(=O)Cl)c1
Reactant: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: COc1ccc(Br)c(C(N)=O)c1

Procedure:
A 30% ammonium hydroxide solution (56 mL) is added dropwise to a solution of 2-bromo-5-methoxybenzoyl chloride in methylene chloride at 0° C. After the addition is complete, the reaction mixture is filtered to obtain a solid which is air-dried and recrystallized from a methanol/water solution to give the title product as a white solid, mp 158°-159° C.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8](B1OC(C)(C)C(C)(C)O1)[CH:7]=[CH:6]2.[Cl:23][C:24]1[CH:25]=[C:26]([CH2:30][N:31]2[CH:35]=[CH:34][N:33]=[C:32]2[CH3:36])[N:27]=[N:28][CH:29]=1>>[ClH:23].[F:22][CH:2]([F:1])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[CH:9]=[C:8]([C:24]1[CH:25]=[C:26]([CH2:30][N:31]3[CH:35]=[CH:34][N:33]=[C:32]3[CH3:36])[N:27]=[N:28][CH:29]=1)[CH:7]=[CH:6]2
Reactant: CC1(C)OB(c2ccc3cc(C(F)F)ccc3c2)OC1(C)C
Reactant: Cc1nccn1Cc1cc(Cl)cnn1
Product: Cc1nccn1Cc1cc(-c2ccc3cc(C(F)F)ccc3c2)cnn1
Product: Cl

Procedure:
The title compound, MS: m/e 351.4 (M+H+), was prepared from 2-(6-difluoromethyl-naphthalen-2-yl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane and 5-chloro-3-(2-methyl-imidazol-1-yl-methyl)-pyridazine.
Reaction SMILES: CN(C)[CH:3]=[C:4]1[C:9](=O)[CH:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[CH2:7][CH2:6][CH2:5]1.[N+]([O-])(O)=O.[N+]([O-])(O)=O.[CH3:27][O:28][C:29]1[CH:30]=[C:31]([NH:41][C:42]([NH2:44])=[NH:43])[CH:32]=[CH:33][C:34]=1[N:35]1[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]1>>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:9]3[N:44]=[C:42]([NH:41][C:31]4[CH:32]=[CH:33][C:34]([N:35]5[CH:39]=[C:38]([CH3:40])[N:37]=[CH:36]5)=[C:29]([O:28][CH3:27])[CH:30]=4)[N:43]=[CH:3][C:4]=3[CH2:5][CH2:6][CH2:7]2)=[CH:12][CH:13]=1
Reactant: COc1cc(NC(=N)N)ccc1-n1cnc(C)c1
Reactant: CN(C)C=C1CCCC(c2ccc(F)cc2)C1=O
Solvent: O=[N+]([O-])O
Product: COc1cc(Nc2ncc3c(n2)C(c2ccc(F)cc2)CCC3)ccc1-n1cnc(C)c1

Procedure:
The title compound was prepared from 6-[1-dimethylamino-methylidene]-2-(4-fluoro-phenyl)-cyclohexanone (143 mg, 0.53 mmol) and N-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine dinitrate (195 mg, 0.53 mmol) using in analogous manner the procedure described in example 45b). Obtained as an off-white solid (71 mg, 31%). MS ISP (m/e): 430.5 [(M+H)+]. mp 191-193° C.
Reaction SMILES: O.[Cl-].[NH4+].[Br:4][C:5]1[CH:6]=[C:7]([C:11]23[O:17][CH:16]2[CH2:15][O:14][CH2:13][CH2:12]3)[CH:8]=[CH:9][CH:10]=1.[N-:18]=[N+:19]=[N-:20].[Na+]>CO>[N:18]([C@@:11]1([C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([Br:4])[CH:6]=2)[CH2:12][CH2:13][O:14][CH2:15][C@@H:16]1[OH:17])=[N+:19]=[N-:20]
Reactant: Brc1cccc(C23CCOCC2O3)c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: [N-]=[N+]=N[C@@]1(c2cccc(Br)c2)CCOC[C@@H]1O
Temperature: 25 °C
Yield: 108.1 %

Procedure:
Water (88 mL) and ammonium chloride (11.7 g) were added to a solution of (±)-6-(3-bromophenyl)-3,7-dioxa-bicyclo[4.1.0]heptane (17.5 g) in methanol (700 mL), followed by stirring at room temperature. Then, sodium azide (32.1 g) was added, followed by stirring at 80° C. for eight hours. After returning to room temperature, the excess of methanol was evaporated under reduced pressure. The residual aqueous layer was extracted with chloroform three times, and the organic layers were dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to obtain the title compound (22.1 g).
Reaction SMILES: [C:1]([CH2:3][CH2:4][CH2:5][CH2:6][CH:7](/[CH:20]=[CH:21]/[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])[CH2:8][CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)#[N:2].[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:29]([C:33]1[CH:34]=[CH:35][C:36]([CH2:37][O:28][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2/[CH:21]=[CH:20]/[CH:7]([CH2:6][CH2:5][CH2:4][CH2:3][C:1]#[N:2])[CH2:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:18][CH:19]=2)=[CH:39][CH:40]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)CCCCC#N)cc1
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(C(C)(C)C)cc2)CCCCC#N)cc1
Yield: 92 %

Procedure:
A solution of 1.70 g (3.38 mmol, 75% pure) of methyl 4-{7-cyano-3-[2-(2-hydroxyphenyl)vinyl]heptyl}benzoate from Example 95A in 20 ml of dry acetonitrile is mixed with 1.53 g (7.76 mmol) of 4-(tert-butyl)benzyl bromide and 1.4 g (10.13 mmol) of anhydrous potassium carbonate and heated to reflux for 12 hours. The mixture is then filtered and the filtrate is concentrated to dryness. The resulting crude product is taken up on silica gel and purified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 10:1). 1700 mg (3.12 mmol, 96% purity, 92% yield) of an oil are obtained.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][NH:6][C:7]1[C:12]([CH3:13])=[CH:11][CH:10]=[CH:9][C:8]=1[N+:14]([O-])=O)C>[Pd].C(O)C>[CH3:13][C:12]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:7]=1[NH:6][CH2:5][C:4](=[O:3])[NH:14]2
Reactant: CCOC(=O)CNc1c(C)cccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1cccc2c1NCC(=O)N2

Procedure:
A mixture of N-(6-methyl-2-nitrophenyl)glycine ethyl ester (XV, EXAMPLE 17, 675 mg), ethanol (60.0 ml) and palladium on carbon (10%, 150 mg) is hydrogenated (48 psi) at 20°-25° for 3.5 hr. The mixture is filtered, the residue washed with ethanol, and the combined filtrates are concentrated to give the title compound, mp 168°-171°; IR (mineral oil) 3382, 2955, 2925, 1671, 1490, 1444, 1393, 1295 and 770 cm-1 ; NMR (CDCl3) 8.68, 6.79, 6.6-6.75, 4.04, 3.76 and 2.17 δ; MS (m/z) 162 and 133.
Reaction SMILES: C([Li])CCC.Br[C:7]1[S:11][C:10]2[CH:12]=[C:13]([CH3:16])[CH:14]=[CH:15][C:9]=2[C:8]=1[Br:17].O>CCOCC>[Br:17][C:8]1[C:9]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:10]=2[S:11][CH:7]=1
Reactant: Cc1ccc2c(Br)c(Br)sc2c1
Agent: [Li]CCCC
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2c(Br)csc2c1
Reaction time: 1 h
Yield: 66.5 %

Procedure:
A solution of n-butyl lithium (22.3 ml. of 1.6 M solution in hexane) was added dropwise to a stirred solution of 2,3-dibromo-6-methylbenzo[b]thiophene (11.76 g.) in dry ether (150 ml.) at 0° under an atmosphere of dry nitrogen. The resulting solution was stirred at 0° for 1 hour and then water (50 ml.) was added. The mixture was stirred for a few minutes and then the ether layer was separated, dried (Na2SO4) and evaporated to give an oil. The oil was distilled to give 3-bromo-6-methylbenzo[b]thiophene (5.80 g.), b.p. 112°-114° C. @ 0.2 m.m., m.p. 51°-53° C. (from methanol).
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:10]([O:15][CH2:16][CH3:17])(=[O:14])[C:11]([O-])=[O:12].[O-]CC.[Na+]>C(O)C>[C:8]([CH:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[C:11](=[O:12])[C:10]([O:15][CH2:16][CH3:17])=[O:14])#[N:9]
Reactant: CCOC(=O)C(=O)[O-]
Reactant: N#CCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(=O)C(C#N)c1ccccc1

Procedure:
A mixture of 117.1 g. (1.0m.) of phenylacetonitrile and 326 ml. (2.4m.) of ethyl oxalate is added to an ethanol solution of sodium ethoxide (prepared by dissolving 23.8 g., 1.08m. of sodium in 500 ml. of absolute ethanol) and refluxed two hours. After cooling, diluting with 2500 ml. of water and extracting with ether, the solution is acidified with acetic acid. The solid is removed and washed with water to give ethyl 3-cyano-3-phenylpyruvate, m.p. 127°-129° C.
Reaction SMILES: [F-:1].[K+].Cl[C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14].O>CN(C=O)C>[F:1][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([CH:10]([F:12])[F:11])[C:5]=1[CH:13]=[O:14]
Reactant: [F-]
Reactant: Cn1nc(C(F)F)c(C=O)c1Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nc(C(F)F)c(C=O)c1F
Temperature: 150 °C
Reaction time: 3 h
Yield: 99.4 %

Procedure:
96.3 g (1660 mmol) of spray-dried potassium fluoride were carefully dried under high vacuum. 129.2 g (664 mmol) of 5-chloro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (II-1) in 1 L of DMF were added. The reaction mixture was heated to 150° C. with rapid stirring. The reaction is complete after 3 hours (GC check). The reaction mixture is cooled down to room temperature and bulked with water to a total volume of 4 L. The reaction mixture is washed twice with 2000 ml of ethyl acetate each time. The combined organic phases were subsequently washed with saturated sodium chloride solution, dried over sodium sulphate and concentrated to obtain 117.6 g (90% of theory, purity 90%) of 5-fluoro-1-methyl-3-difluoromethyl-1H-pyrazole-4-carbaldehyde (IV-1) in the form of a brown solid which is further reacted without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:16][CH2:17][CH2:18][O:19][CH3:20])=[C:9]([O:12][CH2:13][CH2:14][Cl:15])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[C:21]([C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26])#[CH:22]>>[ClH:1].[Cl:15][CH2:14][CH2:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:16][CH2:17][CH2:18][O:19][CH3:20])[N:5]=[CH:4][N:3]=[C:2]2[NH:26][C:25]1[CH:27]=[CH:28][CH:29]=[C:23]([C:21]#[CH:22])[CH:24]=1
Reactant: C#Cc1cccc(N)c1
Reactant: COCCOc1cc2ncnc(Cl)c2cc1OCCCl
Product: C#Cc1cccc(Nc2ncnc3cc(OCCOC)c(OCCCl)cc23)c1
Product: Cl

Procedure:
The title product was prepared from 4-chloro-6-(2-chloro-ethoxy)-7-(2-methoxyethoxy)-quinazoline (399 mg, 1.26 mmol) and 3-ethynyl-aniline (147 mg, 1.26 mmol) as described for Example 29. (515 mg; 94%; M.P. 215°-225° C. (dec); LC-MS: 398 (MH+); anal. RP18-HPLC RT: 4.85 min.).
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][C:14]1[O:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.[CH3:21][O:22][CH2:23][CH2:24][CH2:25][NH2:26]>>[CH3:21][O:22][CH2:23][CH2:24][CH2:25][NH:26][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][CH:6]=1)[N:3]=[C:2]([NH:20][CH2:19][C:17]1[O:18][C:14]([CH3:13])=[CH:15][CH:16]=1)[CH:11]=[CH:10]2
Reactant: COCCCN
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: Cc1ccc(CN)o1
Product: COCCCNc1ccc2nc(NCc3ccc(C)o3)ccc2c1

Procedure:
The title compound, MS: m/e=326.1 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 5-methyl-2-furanmethanamine and 3-methoxypropylamine.
Reaction SMILES: [C:1]12([C:11]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:21][Si]([N-][Si](C)(C)C)(C)C.[K+].IC.C(OCC)(=O)C>C1COCC1>[C:1]12([C:11]3[CH:15]=[C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:13]([CH3:21])[CH:12]=3)[CH2:2][CH:3]3[CH2:9][CH:7]([CH2:6][CH:5]([CH2:4]3)[CH2:10]1)[CH2:8]2
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)c[nH]1
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C23CC4CC(CC(C4)C2)C3)cn1C
Reaction time: 4 h
Yield: 298.2 %

Procedure:
Preparation C6, Step 1. Ethyl 3-(adamant-1-yl)-pyrrole-5-carboxylate (0.20 g, 0.7 mmol, 1 eq) was dissolved in THF (20 mL). Potassium bis(trimethylsilyl)amide (0.5 M in Tol, 1.62 mL, 0.81 mmol, 1.1 eq) was added thereto followed by iodomethane (.0.102 mL, 1.6 mmol, 2.2 eq). The next day, the same amounts of potassium bis(trimethylsilyl)amide and iodomethane were again added to drive the reaction to completion. In 4 h, the reaction was finished. Ethyl acetate was added (100 mL) and the organic layer was washed with water (2×), brine, dried (MgSO4) and stripped to yield 600 mg of ethyl 3-(adamant-1-yl)-1-methylpyrrole-5-carboxylate, which was used as is in the next step. MS found: (M+H)+=288.16.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH3:11])[CH2:5][Cl:6].[Cl:13]Cl>C(Cl)Cl.[Fe]>[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([CH:7]=[C:8]([Cl:13])[C:9]=1[CH2:10][CH3:11])[CH2:5][Cl:6].[Br:1][C:2]1[C:3]([Cl:12])=[C:4]([C:7]([Cl:13])=[CH:8][C:9]=1[CH2:10][CH3:11])[CH2:5][Cl:6]
Reactant: ClCl
Reactant: CCc1ccc(CCl)c(Cl)c1Br
Agent: [Fe]
Solvent: ClCCl
Product: CCc1c(Cl)cc(CCl)c(Cl)c1Br
Product: CCc1cc(Cl)c(CCl)c(Cl)c1Br

Procedure:
A mixture of 54 parts of 3-bromo-2-chloro-4-ethylbenzyl chloride and 3 parts of iron filings at 90°-95°C is treated with chlorine in the absence of light until there is no additional gain in weight, then cooled and diluted with methylene chloride. The mixture is filtered, and the filtrate is washed with water and dilute sodium bisulfite, then dried and concentrated. The residue is chromatographed and 3-bromo-2,5-dichloro-4-ethylbenzyl chloride and a small amount of 3-bromo-2,6-dichloro-4-ethylbenzyl chloride are isolated as two of the fractions.