Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][C@@H:15]([OH:17])[CH2:14][O:13]1)=[O:11].C(N(CC)C(C)C)(C)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>ClCCl>[CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]([N:12]1[CH2:16][C@@H:15]([O:17][S:29]([CH3:28])(=[O:31])=[O:30])[CH2:14][O:13]1)=[O:11]
Reactant: COC(=O)c1ccccc1C(=O)N1C[C@@H](O)CO1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccccc1C(=O)N1C[C@@H](OS(C)(=O)=O)CO1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100 %

Procedure:
2-[(R)-4-Hydroxyisoxazolidine-2-carbonyl]benzoic acid methyl ester (prepared by the method of Martin et al., Tetrahedron Lett., 2007, 47, 7635) (3.50 g, 14.0 mmol) was dissolved in dichloromethane (100 mL) and N,N-diisopropylethylamine (3.55 mL, 20.3 mmol), then methanesulfonyl chloride (1.40 mL, 18.5 mmol) was added and the mixture was stirred at room temperature for 18 hours. The mixture was washed with 0.1M HCl solution (100 mL), dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow oil (5.00 g, 100%). δH (DMSO-d6) 7.92-7.46 (4H, m), 4.28 (1H, m) 4.17-4.14 (2H, m), 4.06-3.92 (2H, m), 3.82 (3H, s), 3.31 (3H, s). LCMS (ES+) RT 1.45 minutes, 330 (M+H)+ (pH 3).
Reaction SMILES: [CH2:1]([NH:8][C:9]([C:11]1[S:12][CH:13]=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O>C(#N)C.C(OCC)(=O)C>[CH2:1]([NH:8][C:9]([C:11]1[S:12][C:13]([Br:17])=[CH:14][C:15]=1[CH3:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccsc1C(=O)NCc1ccccc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Cc1cc(Br)sc1C(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.9 %

Procedure:
A mixture of N-benzyl-3-methylthiophene-2-carboxamide (6.63 g, 28.66 mmol) and N-bromosuccinimide (5.10 g, 28.66 mmol) in anhydrous acetonitrile (70 mL) was stirred at ambient temperature for 18 h, and diluted with ethyl acetate (200 mL). The organic layer was washed with saturated aqueous sodium bicarbonate (4×100 mL) and brine (100 mL), dried over sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with ethyl acetate/hexanes to afford the title compound as a colorless solid (6.48 g, 73%): 1H NMR (300 MHz, CDCl3) δ 7.40-7.29 (m, 5H), 6.87 (s, 1H), 5.95 (br s, 1H), 4.59 (d, J=5.7 Hz, 2H), 2.47 (s, 3H); MS (ES+) m/z 310.2 (M+1), 312.2 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:7][O:6][C:5](=[S:8])[N:4]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-])=O)[CH2:3]1.[Cl-].[NH4+].O>C(O)C.[Fe]>[NH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[CH2:9][N:4]1[CH2:3][C:2]([CH3:19])([CH3:1])[CH2:7][O:6][C:5]1=[S:8]
Reactant: CC1(C)COC(=S)N(Cc2ccccc2[N+](=O)[O-])C1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: CC1(C)COC(=S)N(Cc2ccccc2N)C1
Temperature: 25 °C
Yield: 63.2 %

Procedure:
5,5-Dimethyl-3-(2-nitrobenzyl)-[1,3]-oxazinan-2-thione (1.06 g, 3.79 mmol), iron powder (1.06 g, 19.0 mmol), ammonium chloride (0.10 g, 1.87 mmol) were suspended in ethanol (20 ml) and water (10 ml) and heated to reflux for one hour. After cooling to room temperature, the reaction mixture was filtered with suction and extracted with ethyl acetate. The organic layer was washed with a saturated brine and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to obtain 3-(2-aminobenzyl)-5,5-dimethyl-[1,3]-oxazinan-2-thione (0.60 g).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[CH:12]=[N:13][C:14]([C:15]#[N:16])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1.CN(C)C=CC(C1SC=CC=1)=[O:22]>>[S:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[CH:12]=[N:13][C:14]([C:15]([NH2:16])=[O:22])=[C:10]3[N:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: N#Cc1ncn2c(-c3ccsc3)ccnc12
Reactant: CN(C)C=CC(=O)c1cccs1
Product: NC(=O)c1ncn2c(-c3ccsc3)ccnc12

Procedure:
3-Dimethylamino-1-(3-thienyl)-2-propen-1-one (prepared as described in Example 2) can be substituted for 3-dimethylamino-1-(2-thienyl)-2-propen-1-one in the procedure of Example 6, to produce 4-(3-thienyl)imidazo[1,5-a]pyrimidine-8-carboxamide.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][NH:7][CH:8]=1)([O-:3])=[O:2].[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@@:17]1([CH2:21][N:22]2[CH:26]=[N:25][CH:24]=[N:23]2)[C@H:19]([CH3:20])[O:18]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[C@:17]([OH:18])([C@H:19]([N:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:8]=[N:7]1)[CH3:20])[CH2:21][N:22]1[CH:26]=[N:25][CH:24]=[N:23]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: O=[N+]([O-])c1cn[nH]c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C[C@@H](n1cc([N+](=O)[O-])cn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 180 °C
Yield: 74.6 %

Procedure:
4-Nitropyrazole (0.5 g, 4.42 mmol) and 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)methyl)-1H-1,2,4-triazol (0.93 g, 3.68 mmol) were suspended in N,N-dimethylformamide (20 mL), and anhydrous potassium carbonate (0.61 g, 4.44 mmol) was added thereto, followed by heating at 180° C. for 5 minutes by microwave irradiation while stirring. After completion of the reaction, the resulting mixture was extracted with ethyl acetate (200 mL), and the extract was washed successively with saturated ammonium chloride (200 mL) and brine (200 mL). The organic layer was dried over anhydrous magnesium sulfate and concentrated by evaporation under a reduced pressure. The resulting residue was purified by silica gel chromatography to obtain the title compound (1.0 g, yield 75%).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15](=[O:36])[NH:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([CH2:29][N:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH2:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([NH:16][CH:17]1[C:26]2[C:21](=[CH:22][C:23]([C:27]([CH2:29][N:30]3[CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]3)=[CH2:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19][CH2:18]1)=[O:36]
Reactant: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=C(CN1CCCCC1)c1ccc2c(c1)CCCC2NC(=O)CC1CCCCN1
Temperature: 25 °C

Procedure:
To a solution of 2-{[6-(1-piperidin-1-ylmethyl-vinyl)-1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl]-methyl}-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 (2 mL) was added TFA (2 mL). The mixture was stirred at RT, concentrated in vacuo. The crude was neutralized with 10% Na2CO3 until the aqueous phase is basic, extracted with CH2Cl2three times. The organic solution was dried over Na2SO4 filtered and concentrated in vacuo to provide the title compound. MS (ESI): 396 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])=[CH:4][C:3]=1[CH:15]=[O:16].[OH:17][CH2:18][CH2:19][CH2:20]O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:16]1[CH2:20][CH2:19][CH2:18][O:17][CH:15]1[C:3]1[CH:4]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: Cc1ccccc1-c1ccc(O)c(C=O)c1
Reactant: OCCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: Cc1ccccc1-c1ccc(O)c(C2OCCCO2)c1
Yield: 89 %

Procedure:
A solution of 4-hydroxy-2′-methyl-biphenyl-3-carbaldehyde (18.8 mmol) in toluene (100 mL) was added 1,3-dihydroxypropane (65.7 mmol) and p-toluenesulfonic acid (cat) and heated at reflux overnight in a Dean-Stark set-up. The reaction was cooled and washed with a solution of Na2CO3 (aq, 1 M). Evaporation in vacuo gave the title product as brown oil in 89% yield. 1H-NMR (CDCl3) δ 9.61 (bs, 1H), 7.34-7.10 (m, 6H), 6.87 (d, 1H), 5.77 (s,1H), 4.13-4.07 (m, 2H), 3.95-3.86 (m, 2H), 2.20 (s, 3H), 2.18-1.96 (m, 1H), 1.40 (d, 1H).
Reaction SMILES: C([O:8][C@H:9]1[C@H:14]([O:15]CC2C=CC=CC=2)[C@@H:13]([O:23]CC2C=CC=CC=2)[C@@:12]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[C:35]([CH2:40][C:41]3[S:42][C:43]([C:46]4[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=4)=[CH:44][CH:45]=3)[CH:34]=2)([O:31]C)[O:11][C:10]1([CH2:55]O)[CH2:53][OH:54])C1C=CC=CC=1>CO.C(OCC)(=O)C.[Pd]>[F:52][C:49]1[CH:48]=[CH:47][C:46]([C:43]2[S:42][C:41]([CH2:40][C:35]3[CH:34]=[C:33]([C@@:12]45[O:11][C@@:10]([CH2:53][OH:54])([CH2:55][O:31]4)[C@@H:9]([OH:8])[C@H:14]([OH:15])[C@H:13]5[OH:23])[CH:38]=[CH:37][C:36]=3[CH3:39])=[CH:45][CH:44]=2)=[CH:51][CH:50]=1
Reactant: CO[C@@]1(c2ccc(C)c(Cc3ccc(-c4ccc(F)cc4)s3)c2)OC(CO)(CO)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc([C@]23OC[C@](CO)(O2)[C@@H](O)[C@H](O)[C@H]3O)cc1Cc1ccc(-c2ccc(F)cc2)s1
Reaction time: 16 h
Yield: 13.7 %

Procedure:
[(3S,4S,5R,6S)-3,4,5-tribenzyloxy-6-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-2-(hydroxymethyl)-6-methoxy-tetrahydropyran-2-yl]methanol 9j (130 mg, 0.17 mmol) was dissolved in 10 mL methanol, followed by addition of a solution (4 mL) of 2 M hydrochloric in ethyl acetate and Palladium/carbon (260 mg, 20%). The mixture was exchanged with H2 three times and stirred for 16 hours. Thereafter, the reaction mixture was filtered. The filtrate was concentrated under reduced pressure and the resulting residue was purified by HPLC to obtain the title compound (1S,2S,3S,4R,5S)-5-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methyl-phenyl]-1-(hydroxymethyl)-6,8-dioxabicyclo[3.2.1]octane-2,3,4-triol 9 (11 mg, white solid), yield: 13.8%. MS m/z (ESI): 473.2 [M+1]; 1H NMR (400 MHz, CD3OD): δ 7.57-7.56 (m, 2H), 7.48 (d, 1H), 7.39-7.37 (m, 1H), 7.19 (d, 1H), 7.15 (d, 1H), 7.10-7.06 (m, 2H), 6.67 (d, 1H), 4.18 (d, 3H), 3.88-3.81 (m, 2H), 3.73-3.68 (m, 2H), 3.65-3.62 (m, 2H), 2.33 (s, 3H).
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[C:19]3[O:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>C(Cl)Cl>[C:1]1([CH2:7][O:8][C:9]2[C:19]3[O:18][CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20])[CH2:14][C:13]=3[CH:12]=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(COc2cccc3c2OCCNC3)cc1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCOc2c(cccc2OCc2ccccc2)C1
Reaction time: 1 h

Procedure:
9-[(Phenylmethyl)oxy]-2,3,4,5-tetrahydro-1,4-benzoxazepine (Preparation 60) (7.01 g, 27.5 mmol) and BOC2O (7.01 ml, 30.2 mmol) were dissolved in DCM (100 ml) and left at room temperature for one hour then evaporated and biotage chromatographed in 5% EtOAc in hexane to remove excess BOC2O and changing to 15% EtOAc in iso-hexane to elute the title compound (8.25 g) as a white solid. MS (ES): C21H25NO4 requires 355; found 256 [M+H−100]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][CH:9]=O)=[CH:4][CH:3]=1.[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH:22]([CH3:24])[CH3:23])=C(Cl)[N:13]=1>>[Cl:11][C:12]1[N:20]=[C:19]2[C:15]([N:16]=[CH:17][N:18]2[CH2:21][CH:22]([CH3:24])[CH3:23])=[C:9]([NH:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1
Reactant: O=CNc1ccc(Cl)cc1
Reactant: CC(C)Cn1cnc2c(Cl)nc(Cl)nc21
Product: CC(C)Cn1cnc2c(Nc3ccc(Cl)cc3)nc(Cl)nc21

Procedure:
Was prepared according to Example 3 from N-(4-chloro-phenyl)-formamide and 2,6-dichloro-9-isobutyl-9H-purine.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:11])[CH:10]=1)[C:5]([OH:7])=O.[CH3:12][Li]>CCOCC>[Br:11][C:9]1[CH:8]=[C:4]([C:5](=[O:7])[CH3:12])[CH:3]=[C:2]([Br:1])[CH:10]=1
Reactant: [Li]C
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Solvent: CCOCC
Product: CC(=O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,5-dibromobenzoic acid (2.5 g, 8.9 mmol) in Et2O (30 mL) at 0° C. was added methyl lithium (1.6M in diethyl ether; 12.3 mL, 19.6 mmol) was added dropwise. The reaction was warmed to room temperature and stirred for 2 hours. Acidic work-up, followed by silica gel chromatography, gave 1-(3,5-dibromo-phenyl)-ethanone.
Reaction SMILES: C([O:3][C:4](=O)/[C:5](/[C:12]1[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=1)=[CH:6]/[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])C.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>>[CH3:21][S:18]([C:15]1[CH:16]=[CH:17][C:12](/[C:5](=[CH:6]\[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])/[CH2:4][OH:3])=[CH:13][CH:14]=1)(=[O:19])=[O:20]
Reactant: CCOC(=O)/C(=C/CCC(C)C)c1ccc(S(C)(=O)=O)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Product: CC(C)CC/C=C(/CO)c1ccc(S(C)(=O)=O)cc1
Yield: 89.3 %

Procedure:
Reduction of (E)-2-(4-methanesulfonyl-phenyl)-6-methyl-hept-2-enoic acid ethyl ester (320 mg, 1.09 mmol) with DIBAL in toluene (1.98 mL, 2.4 mmol) following the method of example 54e gives the title compound as an amorphous solid (275 mg). MS (m/e): 283 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(O)(=O)C.[NH2:12][C:13]1[N:18]=[CH:17][N:16]=[C:15]2[N:19]([CH:30]3[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]3)[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([NH2:28])=[C:24]([F:29])[CH:23]=3)[C:14]=12.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[NH2:28][C:25]1[CH:26]=[CH:27][C:22]([C:21]2[C:14]3[C:15](=[N:16][CH:17]=[N:18][C:13]=3[NH2:12])[N:19]([CH:30]3[CH2:35][CH2:34][CH:33]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH2:32][CH2:31]3)[N:20]=2)=[CH:23][C:24]=1[F:29]
Reactant: Nc1ccc(-c2nn(C3CCC(=O)CC3)c3ncnc(N)c23)cc1F
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1CCN(C2CCC(n3nc(-c4ccc(N)c(F)c4)c4c(N)ncnc43)CC2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 283.3 %

Procedure:
N-methylpiperazine (3.6 g, 0.036 mol) and acetic acid (2.17 g, 0.036 mol) were added to a suspension of 4-[4-amino-3-(4-amino-3-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]-1-cyclohexanone (Intermediate R) (4.1 g, 0.012 mol) in dichloroethane (200 mL). Sodium triacetoxyborohydride (3.32 g, 0.016 mol) was then added portionwise to the reaction suspension. The reaction mixture was stirred at room temperature for 18 h. Additional sodium triacetoxyborohydride (1.79 g, 0.084 mol and 1.28 g, 0.06 mol) was added in two batches over 5 days. The reaction mixture was filtered, washed with dichloroethane (100 mL) and the filtrate was concentrated under reduced pressure to give 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a yellow solid (14.5 g, 0.034 mol). The yellow solid was purified and the cis/trans isomers were separated by flash column chromatography on silica gel using dichloromethane/methanol/ammonium hydroxide (93:5:2) as the eluent to give trans 3-(4-amino-3-fluorophenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (lower running component) as a white solid (115 mg, 0.27 mmol). 1H NMR (DMSO-d6, 400 MHz) 8.19 (s, 1H), 7.18 (m, 2H), 6.88 (m, 1H), 5.46 (s, 2H), 4.60 (m, 1H), 2.35 (br m, 4H), 2.14 (s, 3H), 1.95 (br m, 6H), 1.44 (m, 2H), 1.26 (m, 4H), 0.86 (m, 2H). TLC (dichloromethane/methanol/ammonium hydroxide=95:5) Rf 0.31.
Reaction SMILES: [CH3:1][NH2:2].[O:3]=[C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH2:8][CH2:7][CH:6]=[CH:5]1>C1C=CC=CC=1.C(O)C>[CH3:1][NH:2][CH:6]1[CH2:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:4](=[O:3])[CH2:5]1
Reactant: O=C1C=CCCc2ccccc21
Reactant: CN
Solvent: CCO
Solvent: c1ccccc1
Product: CNC1CCc2ccccc2C(=O)C1
Reaction time: 0.5 h
Yield: 99.3 %

Procedure:
A solution of 22.7 g of monomethylamine in 160 ml of benzene was added to a solution of 40 g of 5-oxo-8,9-dihydro [5H] benzocycloheptene in 400 ml of ethanol and the mixture was stirred for 2 1/2 hours and was evaporated to dryness to obtain 47.5 g of 7-methylamino-5-oxo-6,7,8,9-tetrahydro [5H] benzocycloheptene which was used as is for the next step.
Reaction SMILES: [CH3:1][Zn]C.[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]=[O:10])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[I:4][C:5]1[CH:12]=[CH:11][C:8]([CH:9]([OH:10])[CH3:1])=[C:7]([N+:13]([O-:15])=[O:14])[CH:6]=1
Reactant: O=Cc1ccc(I)cc1[N+](=O)[O-]
Reactant: C[Zn]C
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(O)c1ccc(I)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 48.2 %

Procedure:
Titanium(IV) isopropoxide (1.2 mL, 4.04 mmol) was dissolved in anhydrous dichloromethane (8 mL) under a nitrogen atmosphere. The solution was cooled to 0° C. and dimethylzinc (2 M in toluene, 8.67 mL, 17.34 mmol) was added dropwise. The mixture was stirred at 0° C. for 45 minutes followed by addition of 4-iodo-2-nitrobenzaldehyde (800 mg, 2.89 mmol). The mixture was stirred at 0° C. for 36 hours, then quenched by 1 M HCl (CAUTION: vigorous gas evolution!) and extracted with ethyl either (50 mL) three times. The combined organic phase was washed with water (50 mL), saturated NaHCO3 solution (50 mL) and brine (50 mL), dried over Na2SO4, concentrated in vacuo, and purified by column chromatography to yield racemic (RS)-1-(4-Iodo-2-nitrophenyl)ethanol (408 mg, 48%). 1H NMR (400 MHz, CDCl3): δ 8.21 (dd, 1 H, J=1.8 and 5.3 Hz, Ph-H), 7.96 (m, 1 H, Ph-H), 7.58 (d, 1 H, J=8.3 Hz, Ph-H), 5.38 (q, 1 H, J=6.1 Hz, Ph-CH), 2.34 (br s, 1 H, OH), 1.54 (d, 3 H, J=6.1 Hz, CH3); 13C NMR (100 MHz, CDCl3): δ 147.98 (C), 142.49 (CH), 140.68 (C), 132.77 (CH), 131.31 (CH), 91.60 (C), 65.40 (CH), 24.28 (CH3).
Reaction SMILES: Br[C:2]1[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=1[NH2:4].[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][CH:18]=1>>[F:11][C:12]([F:23])([F:22])[C:13]1[CH:18]=[C:17]([C:2]2[CH:8]=[C:7]([CH2:9][CH3:10])[CH:6]=[CH:5][C:3]=2[NH2:4])[CH:16]=[CH:15][CH:14]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCc1ccc(N)c(Br)c1
Product: CCc1ccc(N)c(-c2cccc(C(F)(F)F)c2)c1

Procedure:
2-bromo-4-ethylaniline and 3-trifluoromethylbenzene boronic acid can be combined to form 2-(3-trifluoromethylphenyl)-4-ethylaniline,
Reaction SMILES: C(O[C:5](=[O:7])C)(=O)C.[C:8]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:13]=[CH:12][C:11]([C:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[CH:20][CH:19]=2)=[CH:15][CH2:16][NH2:17])=[CH:10][CH:9]=1>C(O)=O>[C:21]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:20]=[CH:19][C:18]([C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:9][CH:10]=2)=[CH:15][CH2:16][NH:17][CH:5]=[O:7])=[CH:23][CH:22]=1
Reactant: NCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1
Reactant: CC(=O)OC(C)=O
Solvent: O=CO
Product: O=CNCC=C(c1ccc(-c2ccccc2)cc1)c1ccc(-c2ccccc2)cc1

Procedure:
Acetic anhydride (1ml) was added to a solution of 1, 1 -di(4-biphenylyl)- 3 -amino-prop-1-ene (1g) in 99% formic acid (5ml) and the mixture was refluxed for 1 hour then poured onto ice. The solid was collected, washed with water, dried and then recrystallised from benzene/ n - propanol to furnish 1, 1-di (4 -biphenyly)-3-formamido-prop-1-ene (m.p. 171°- 173° C). This compound, reduced with lithium aluminium/hydride in ether/tetrahydrofuran at - 30° C, afforded 1, 1-di(4-biphenylyl)-3-methylamino-prop- 1-ene identical with that described in Example 4.
Reaction SMILES: [H-].[Na+].CN(C=O)C.[F:8][C:9]([F:13])([F:12])[CH2:10][OH:11].F[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=2[N:25]=1>O>[F:8][C:9]([F:13])([F:12])[CH2:10][O:11][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[C:21]1[O:22][C:23]2[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:24]=2[N:25]=1
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: FC(F)(F)COc1cnccc1-c1nc2cc(C(F)(F)F)ccc2o1
Temperature: 25 °C
Yield: 75.1 %

Procedure:
A mixture of 0.06 g of 55% sodium hydride (in oil) and 2 ml of DMF was stirred at room temperature. To the mixture, a mixture solution of 0.13g of 2,2,2-trifluoroethanol and 0.5 ml of DMF was added. The mixture solution was stirred at the same temperature for 15 minutes, and then 0.28 g of 2-(3-fluoropyridin-4-yl)-5-(trifluoromethyl)benzoxazole was stirred at room temperature for one hour. Water was added to the reaction mixture, which followed by extraction with ethyl acetate twice. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.27 g of 2-[3-(2,2,2-trifluoroethyl)oxypyridin-4-yl]-5-(trifluoromethyl)benzoxazole (hereinafter, referred to as “active compound 39”).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.[CH3:11][NH2:12]>>[CH3:11][NH:12][C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CN
Product: CNc1ccc([N+](=O)[O-])nc1
Yield: 80 %

Procedure:
Using analogous procedures to those described in the portion of Note [9] immediately above that is concerned with the preparation of starting materials, 5-bromo-2-nitropyridine was reacted with methylamine to give 5-methylamino-2-nitropyridine in 80% yield; 1H NMR: (DMSOd6) 2.51 (s, 3H), 7.02 (m, 1H), 7.43 (br s, 1H), 7.86 (m, 1H), 8.13 (d, 1H); Mass Spectrum: M−H− 152; which in turn was converted into 5-(N-tert-butoxycarbonyl-N-methylamino)-2-nitropyridine in 51% yield; 1H NMR: (CDCl3) 1.52 (s, 9H), 3.4 (s, 3H), 7.98 (m, 1H), 8.24 (m, 1H), 8.6 (m, 1H); which in turn was converted into 2-amino-5-(N-tert-butoxycarbonyl-N-methylamino)pyridine in 100% yield; 1H NMR: (CDCl3) 1.42 (br s, 9H), 3.19 (s, 3H), 4.39 (br s, 2H), 6.46 (d, 1H), 7.3 (m, 1H), 7.94 (m, 1H); Mass Spectrum: M+H+ 224; and which in turn was converted into N-[5-(N-tert-butoxycarbonyl-N-methylamino) pyridin-2-yl]-2-[4-(6,7-dimethoxyquinazolin-4-yloxy)phenyl]acetamide; Mass Spectrum: M+H+ 546.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2=[O:31].C(=O)(O)[O-].[K+].Br[CH2:38][C:39]1[O:40][C:41](=[O:45])[O:42][C:43]=1[CH3:44]>CN(C)C=O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:38][C:39]3[O:40][C:41](=[O:45])[O:42][C:43]=3[CH3:44])[CH2:14][CH2:13]1)[N:8]1[CH:18]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:19][C:7]1=[C:6]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:5]2=[O:31]
Reactant: Cc1oc(=O)oc1CBr
Reactant: CCOC(=O)c1c2n(c3cc(N4CCNCC4)c(F)cc3c1=O)C(c1ccccc1)S2
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c2n(c3cc(N4CCN(Cc5oc(=O)oc5C)CC4)c(F)cc3c1=O)C(c1ccccc1)S2
Temperature: 0 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
Ethyl 6-fluoro-4-oxo-1-phenyl-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate (3.0 g) and 0.82 g of potasium bicarbonate were suspended in 50 ml of N,N-dimethylformamide, 1.58 g of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one was dropped thereinto with ice cooling, and the mixture was stirred for 3 hours. After the reaction, the mixture was poured over into ice water and the crystals separated out therefrom were collected by filtration. They were then dissolved in chloroform, the solution was washed with water, and evaporated/dried in vacuo. The resulting oily residue was purified by a column chromatography (silica gel/methanolchloroform [1:50]) to give 2.47 g of desired product, mp, 223°-226° C. (decompn.).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[C:9]1([C:15]2[CH:22]=[CH:21][C:18]([CH2:19][OH:20])=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+]>>[C:15]1([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH:16]=[CH:17][C:18]([CH2:19][O:20][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=2)=[CH:21][CH:22]=1
Reactant: Clc1cncc(Cl)n1
Reactant: OCc1ccc(-c2ccccc2)cc1
Agent: [H-]
Agent: [Na+]
Product: Clc1cncc(OCc2ccc(-c3ccccc3)cc2)n1
Yield: 61.8 %

Procedure:
The title compound was prepared according to the procedure of example 4, step 1 starting from 2,6-dichloropyrazine (444 mg, 3.00 mmol),p-phenylbenzyl alcohol (607 mg, 3.30 mmol) and NaH (55% in mineral oil, 144 mg, 3.30 mmol). Recrystallization from hexane gave 0.55 g (88%) of the title compound: mp 86-87° C. MS m/z: 297 (M+H)+. Anal. (C17H13ClN2O) C, H, N.