Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[SH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17]Cl>CC(C)=O>[Cl:13][C:14]([F:20])([F:19])[CH2:15][CH2:16][CH2:17][S:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1
Reactant: Sc1nccs1
Reactant: FC(F)(Cl)CCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: FC(F)(Cl)CCCSc1nccs1
Temperature: 25 °C
Yield: 96.4 %

Procedure:
Solid anhydrous potassium carbonate (9.33 g) was added in two portions to a stirred mixture of 2-mercaptothiazole (7.90 g), 1,4-dichloro-1,1-difluorobutane (9.70 g) and acetone (150 ml) under a nitrogen atmosphere, and the resultant mixture heated at the reflux temperature for 4 hours. After cooling to the ambient temperature the solid component was removed by filtration and washed with acetone (2×50 ml) and the combined washings and filtrate concentrated by evaporation of the solvent under reduced pressure. Diethyl ether (150 ml) was added to the residue and the resultant solution washed with aqueous potassium carbonate solution (2×100 ml) and with water (100 ml). After drying over anhydrous magnesium sulfate the solution was concentrated by removal of the solvent by evaporation under reduced pressure to yield 2-(4-chloro-4,4-difluorobutylthio)thiazole (13.98 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[CH:11][N+:12]([O-])=O)=[CH:6][CH:5]=1.[H][H]>[Pd].C(O)C.C(O)(=O)C>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH2:12])=[CH:6][CH:5]=1
Reactant: COC(=O)c1ccc(C=C[N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)c1ccc(CCN)cc1
Yield: 103.9 %

Procedure:
Palladium on carbon (10%, 50 mg) was added to a solution of 4-(2-nitrovinyl)benzoic acid methyl ester (228 mg) in 5 mL of ethyl alcohol and 2 mL of acetic acid. The reaction vessel was saturated with hydrogen and stirred under a 1 atm hydrogen atmosphere for 20 h. The vessel was saturated with nitrogen and filtered through celite. Evaporation of the solvents gave 205 mg of crude 4-(2-amino-ethyl)-benzoic acid methyl ester.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:30]2[C:31]([CH2:34][CH2:35][C:36]3[CH:41]=[CH:40][C:39]([O:42][CH2:43][CH2:44]O)=[CH:38][CH:37]=3)=[CH:32][O:33][C:29]=2[CH:28]=[CH:27][CH:26]=1)(=O)C.[NH2:46][C:47]([CH3:52])([CH2:50][OH:51])[CH2:48][OH:49].NCCO>>[C@@H:6]1([O:24][C:25]2[C:30]3[C:31]([CH2:34][CH2:35][C:36]4[CH:37]=[CH:38][C:39]([O:42][CH2:43][CH2:44][NH:46][C:47]([CH2:50][OH:51])([CH3:52])[CH2:48][OH:49])=[CH:40][CH:41]=4)=[CH:32][O:33][C:29]=3[CH:28]=[CH:27][CH:26]=2)[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]1[OH:4]
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2cccc3occ(CCc4ccc(OCCO)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CC(N)(CO)CO
Solvent: NCCO
Product: CC(CO)(CO)NCCOc1ccc(CCc2coc3cccc(O[C@@H]4O[C@H](CO)[C@@H](O)[C@H](O)[C@H]4O)c23)cc1

Procedure:
The title compound was prepared in a similar manner to that described in Example 21 using 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-(2-[4-(2-hydroxyethoxy)phenyl]ethyl)benzofuran and 2-amino-2-methyl-1,3-propanediol instead of 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-3-{2-[4-(3-hydroxypropoxy)phenyl]ethyl}benzofuran and 2-aminoethanol, respectively.
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:3][CH2:2]1.[CH:25](=O)[CH:26]([CH3:28])[CH3:27].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C.O>[CH2:25]([N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([N:16]3[CH2:24][C:23]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=4[CH2:17]3)=[O:15])=[CH:9][CH:8]=2)[CH2:5][CH2:6]1)[CH:26]([CH3:28])[CH3:27]
Reactant: O=C(Nc1ccc(C2=CCNCC2)cc1)N1Cc2ccncc2C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(C)CN1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 20 mL scintillation vial were mixed N-(4-(1,2,3,6-tetrahydropyridin-4-yl)phenyl)-1H-pyrrolo[3,4-c]pyridine-2(3H)-carboxamide (100 mg, 0.312 mmol), isobutyraldehyde (0.343 mmol), and sodium triacetoxyborohydride (0.43 mmol) in anhydrous dichloroethane (4 ml). The reaction mixture was stirred overnight at room temperature. This mixture was diluted with water and the resulting suspension was stirred again overnight at room temperature. The solid was filtered through a 30 mL plastic disposable Buchner funnel, and the collected solid was washed with water, dried for 2 hours, washed with ether, and dried again to provide the title compound. 1H NMR (400 MHz, DMSO-d6, Temp=90° C.) δ ppm 8.58 (s, 1H), 8.47 (d, J=5.0 Hz, 1H), 8.18 (m, 1H), 7.50 (m, 2H), 7.38 (d, J=5.1 Hz, 1H), 7.30 (m, 2H), 6.03 (m, 1H), 4.80 (m, 4H), 3.06 (m, 2H), 2.61 (t, J=5.6 Hz, 2H), 2.44 (m, 2H), 2.17 (d, J=7.2 Hz, 2H), 1.82 (m, 1H), 0.89 (d, J=6.6 Hz, 6H); MS (ESI(+)) m/e 377 (M+H).
Reaction SMILES: Br[C:2]1[C:3]([N:22]2[CH2:26][C@H:25]([OH:27])[C@H:24]([OH:28])[CH2:23]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([Cl:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[N:29]1[CH:34]=[C:33](B(O)O)[CH:32]=[N:31][CH:30]=1>>[Cl:20][C:17]([F:19])([F:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:7](=[O:8])[C:6]2[CH:21]=[C:2]([C:33]3[CH:34]=[N:29][CH:30]=[N:31][CH:32]=3)[C:3]([N:22]3[CH2:26][C@H:25]([OH:27])[C@H:24]([OH:28])[CH2:23]3)=[N:4][CH:5]=2)=[CH:11][CH:12]=1
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(Br)c1
Reactant: OB(O)c1cncnc1
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1cnc(N2C[C@@H](O)[C@@H](O)C2)c(-c2cncnc2)c1

Procedure:
The title compound was prepared in an analogous fashion to that described in Example 244 using 5-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-6-(cis-3,4-dihydroxypyrrolidin-1-yl)nicotinamide (Stage 249.1) and pyrimidin-5-ylboronic acid to afford a white solid. UPLC-MS (Condition 3) tR=0.87 min, m/z=478.1 [M+H]+, m/z=476.1 [M−H]−; 1H-NMR (400 MHz, DMSO-d6) δ ppm 3.05 (dd, J=11.00, 4.40 Hz, 2H) 3.26 (dd, J=10.64, 5.26 Hz, 2H) 3.94-4.02 (m, 2H) 4.88 (d, J=4.65 Hz, 2H) 7.34 (d, J=9.05 Hz, 2H) 7.81-7.90 (m, 2H) 8.10 (d, J=2.20 Hz, 1H) 8.79 (d, J=2.20 Hz, 1H) 8.88 (s, 2H) 9.20 (s, 1H) 10.18 (s, 1H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][N:32]3COCC[Si](C)(C)C)=[CH:28][CH:27]=2)=[CH:22][CH:21]=1.C(OCC)(=O)C>O1CCCC1>[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:34]=[C:33]3[C:29]([C:30]([NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])=[N:31][NH:32]3)=[CH:28][CH:27]=2)=[CH:24][CH:25]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(-c3ccc(F)cc3)ccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC(=O)Nc1n[nH]c2cc(-c3ccc(F)cc3)ccc12
Temperature: 66 °C

Procedure:
8.1 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 580 mg of N-[6-(4-fluorophenyl)-1-[[2-(trimethylsilyl)ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 30 cm3 of tetrahydrofuran, and the reaction medium is heated at about 66° C. for 22 hours. The heating is then stopped, 75 cm3 of ethyl acetate are added and the resulting mixture is washed with 50 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 50 cm 3 of saturated aqueous sodium chloride solution. The organic phase is separated out after settling of the phases has taken place, dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (2 kPa; 50° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 2.5 cm), eluting with a cyclohexane/ethyl acetate mixture (40/60 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.). The residue is taken up in 10 cm3 of diisopropyl ether, filtered and washed successively with 5 cm3 of diisopropyl ether and 2×3 cm3 of ethyl acetate; after drying (90 Pa; 50° C.), 250 mg of N-[6-(4-fluorophenyl)-1H-indazol-3-yl]butanamide are thus obtained in the form of a white product melting at 232° C.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12]([C:14]2[S:18][CH:17]=[N:16][CH:15]=2)=[O:13])[CH3:10])=[CH:4][CH:3]=1.C(NC(C)C)(C)C.[CH:26]1([O:30][C:31]2[N:36]=[CH:35][C:34]([C:37]#[CH:38])=[CH:33][N:32]=2)[CH2:29][CH2:28][CH2:27]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.C1COCC1>[CH:26]1([O:30][C:31]2[N:32]=[CH:33][C:34]([C:37]#[C:38][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([NH:11][C:12]([C:14]4[S:18][CH:17]=[N:16][CH:15]=4)=[O:13])[CH3:10])=[CH:4][CH:3]=3)=[CH:35][N:36]=2)[CH2:27][CH2:28][CH2:29]1
Reactant: C#Cc1cnc(OC2CCC2)nc1
Reactant: CC(Cc1ccc(I)cc1)NC(=O)c1cncs1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CC(Cc1ccc(C#Cc2cnc(OC3CCC3)nc2)cc1)NC(=O)c1cncs1
Temperature: 0 °C

Procedure:
100 mg (0.27 mmol) thiazole-5-carboxylic acid (2-(4-iodophenyl)-1-methylethyl)-amide (I76) are added to 2.0 mL THF and cooled down to 0° C. 2.87 mg (4.00 μmol) bis(triphenylphosphine)palladium dichloride, 1.02 mg (5.00 μmol) CuI, 90.6 μL (0.65 mmol) diisopropylamine and finally 51.5 mg 2-cyclobutoxy-5-ethynyl-pyrimidine (I25.7) are added and the reaction mixture is stirred at r.t. over night. The solvent is removed in vacuo and the residue is dissolved in EtOAc and washed with diluted ammonia solution (1×) and water (2×). The organic layer is dried with MgSO4 and the solvent is removed in vacuo. The crude product is purified by HPLC (MeOH/H2O/TFA).
Reaction SMILES: [CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]#[N:24])=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:27])[C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N-:34]=[N+:35]=[N-:36].[Na+].[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]3[CH:26]=[CH:25][C:20]([O:21][CH2:22][C:23]4[NH:36][N:35]=[N:34][N:24]=4)=[CH:19][CH:18]=3)[CH:15]=2)[N:10]([CH3:27])[C:9]=1[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(OCC#N)cc3)ccc21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1c(-c2ccccc2)c(Cc2ccccc2)c2cc(-c3ccc(OCc4nnn[nH]4)cc3)ccc21

Procedure:
The desired product was prepared using a procedure similar to step 6 of example 3. Thus, [4-(3-benzyl-1-methyl-2-phenyl-1H-indol-5-yl)-phenoxy]-acetonitrile (0.137 g, 0.320 mmol) was reacted with NaN3 (0.104 g, 1.598 mmol) and NH4Cl (0.085 g, 1.598 mmol) in DMF (5 ml) to give the product (0.102 g, 0.216 mmol, 68%) as a pale-yellow solid, dec. 194-197° C. 1H NMR (DMSO-d6) δ 3.59 (s, 3H), 4.01 (s, 2H), 5.46 (s, 2H), 7.03-7.09 (m, 5H), 7.13-7.17 (m, 2H), 7.39-7.53 (m, 9H), 7.55 (d, J=1.2 Hz, 1H), 16.75 (broad s, 1H); IR (solid) 3020, 2920, 1605, 1520, 1480, 1450, 1370 and 1240 cm−1; [ESI(−)], m/z 470 (M−H)−; Anal. Calcd. for C30H25N5O: C, 76.41; H, 5.34; N, 14.85; Found: C, 76.35; H, 5.28; N, 14.90.
Reaction SMILES: [CH3:1][N:2]1[C:6](=[O:7])[C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[N:4]=[C:3]1SC.[NH4+:25].[I-]>N.CCO>[NH2:25][C:3]1[N:2]([CH3:1])[C:6](=[O:7])[C:5]2([C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[O:10][CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:8]2)[N:4]=1
Reactant: CSC1=NC2(CC(c3ccccc3)Oc3ccccc32)C(=O)N1C
Reactant: [NH4+]
Agent: N
Agent: [I-]
Solvent: CCO
Product: CN1C(=O)C2(CC(c3ccccc3)Oc3ccccc32)N=C1N
Yield: 11 %

Procedure:
A solution of 1′-methyl-2′-(methylthio)-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (50 mg, 0.148 mmol) and NH4I (42.9 mg, 0.296 mmol) in NH3/EtOH (4 mL, 1.5 N) is heated at 110° C. in a tube under microwave reactor for 2-2.5 h. After cooling, the mixture is concentrated in vacuo to give a residue, which is purified by preparative TLC to afford 2′-amino-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (5 mg, 10%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31].C(N(C(C)C)CC)(C)C.[Cl-].[CH3:42][N:43]([CH:45]=[O:46])[CH3:44]>>[CH3:42][N:43]([CH3:44])[C:45]([NH:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][O:28][CH2:29][CH3:30])=[O:24])[C:5]1=[O:31])=[O:46]
Reactant: CN(C)C=O
Reactant: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCN)c1=O
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N(C)C)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 1-(2-aminoethyl)-N-[2-(ethyloxy)ethyl]-7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.02 g, 0.047 mmol) and diisopropyl ethylamine (0.041 mL, 0.24 mmol) in DMF (5 mL) under nitrogen was treated with N,N-dimethyl carbonyl chloride (0.0043 mL, 0.047 mmol) at ambient temperature. After 2 h, an additional 0.001 mL of the chloride was added and the was stirred at ambient temperature for an additional 6 h. The reaction was concentrated in vacuo and the resulting residue suspended in DMSO and water, filtered, then washed with water and Et2O before drying in vacuo to provide the title compound as an off-white solid: 1H NMR (400 MHz, DMSO-D6) δ ppm 1.1 (t, J=7.0 Hz, 3 H), 2.7 (s, 6 H), 3.3 (d, J=7.0 Hz, 2 H), 3.5 (q, J=7.0 Hz, 2 H), 3.5 (s, 4 H), 4.1 (s, 2 H), 4.2 (t, J=6.1 Hz, 2 H), 6.6 (m, 1 H), 7.1 (t, J=8.9 Hz, 2 H), 7.4 (dd, J=8.8, 5.5 Hz, 2 H), 8.3 (s, 1 H), 8.5 (s, 1 H), 10.4 (s, 1 H); ES+ MS: 500 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([CH3:21])([CH3:20])[C:10]([O:12]CC2C=CC=CC=2)=[O:11])=[N:6][CH:7]=1>[Pd].CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C:9]([CH3:21])([CH3:20])[C:10]([OH:12])=[O:11])=[N:6][CH:7]=1
Reactant: CC(C)(Oc1ccc(F)cn1)C(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: CC(C)(Oc1ccc(F)cn1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of benzyl 2-(5-fluoro-2-pyridyloxy)-2-methylpropionate (2.6 g, 9.2 mmol) and 10% palladium on carbon (0.26 mg) in 20 mL MeOH was degassed and filled with hydrogen using a balloon. After stirring at room temperature for 3 h, the reaction mixture was filtered through CELITE diatomaceous earth and washed with MeOH (20 mL), and the filtrate was concentrated to dryness to give the title compound. 1H NMR (500 MHz, CD3OD): δ 7.91 (d, 1H), 7.48 (ddd, 1H), 6.78 (dd, 1H), 1.65 (s, 6H). LC-MS: m/e 200 (M+H)+ (2.6 min).
Reaction SMILES: O.[NH2:2][NH2:3].C(O)C.Cl.[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1[C:14](=O)[CH3:15]>O>[NH2:8][N:9]1[CH:13]=[CH:12][CH:11]=[C:10]1/[C:14](=[N:2]/[NH2:3])/[CH3:15]
Reactant: NN
Reactant: CC(=O)c1cccn1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: C/C(=N\N)c1cccn1N
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.6 %

Procedure:
Under a nitrogen atmosphere, hydrazine monohydrate (530 g) was added to ethanol (1.7 L) over 55 minutes. To the mixture was added 1-(1-amino-1H-pyrrol-2-yl)ethanone hydrochloride (170 g) over 20 minutes. The mixture was stirred for 10 minutes at room temperature and heated to refluxing temperature over 55 minutes, and refluxed for 15 minutes. After cooling the mixture under a water bath, water (1.7 L) was added to the mixture (30 to 31° C.). Ethanol was evaporated off, and the resulting mixture was extracted with chloroform (0.85×4 mL). The combined organic extract was washed with brine (1.3 L). The brine was extracted with chloroform (0.85 L). The combined organic extract was dried over anhydrous magnesium sulfate, and evaporated to give (1E)-1-(1-amino-1H-pyrrol-2-yl)ethanone hydrazone as a brown crystal (112 g).
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][NH:19][N:18]=1)=[O:15].Br[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=1[C:36]([F:39])([F:38])[F:37]>C1COCC1.CS(C)=O>[F:11][C:12]1[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=1[C:14]([NH:16][C:17]1[CH:21]=[CH:20][N:19]([CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[C:36]([F:37])([F:38])[F:39])[N:18]=1)=[O:15]
Reactant: O=C(Nc1cc[nH]n1)c1ccccc1F
Reactant: COc1ccc(CBr)c(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Product: COc1ccc(Cn2ccc(NC(=O)c3ccccc3F)n2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 M lithium bis(trimethylsilyl)amide (100 μl, 0.1 mmol, Aldrich) was slowly added to a solution of 2-fluoro-N-1H-pyrazol-3-ylbenzamide (for a preparation see Intermediate 43) (20.5 mg, 0.1 mmol) in THF (400 μl). The resulting solution was then transferred to a solution of 1-(bromomethyl)-4-(methyloxy)-2-(trifluoromethyl)benzene 24.7 mg, 0.1 mmol, JRD Fluorochemicals Ltd) in THF (200 μl) and stirred for 2 h under nitrogen at ambient temperature. The mixture was diluted with DMSO (0.6 ml) and purified by MDAP using the Sunfire C18 column (Method D) using Acetonitrile-Water with a TFA modifier. The solvent was removed under a stream of nitrogen to give the title compound (27 mg). LCMS (System 4)
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH2:6][CH2:7][CH2:8][CH:9]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=1)[C:10](O)=[O:11])[CH3:2].C(=O)(O)[O-].[Na+]>C1COCC1>[C:20]([C:17]1[CH:16]=[CH:15][C:14]([CH2:13][CH:9]([CH2:10][OH:11])[CH2:8][CH2:7][CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:22])=[CH:19][CH:18]=1)#[N:21]
Reactant: CCOC(=O)CCCCC(Cc1ccc(C#N)cc1)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CCCCC(CO)Cc1ccc(C#N)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
34.42 ml of a 1 M borane-THF complex solution (34.42 mmol) are added dropwise to a solution of 6.64 g (22.94 mmol) of 2-(4-cyanobenzyl)heptanedioic acid 7-ethyl ester from Example 109A in 260 ml of THF at −10° C. After warming to 0° C., the mixture is stirred at this temperature for 2 hours. After the reaction is complete, saturated sodium bicarbonate solution is added to the reaction mixture, and the solvent is concentrated to dryness. The residue is taken up in dichloromethane, dried over sodium sulfate and again freed of solvent. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: ethyl acetate/cyclohexane 1:8→1:2). 5.84 g (88% yield, 20.19 mmol) of a colorless solid are obtained.
Reaction SMILES: C([O-])(O)=O.[Na+].[ClH:6].[CH:7]([N:20]1[CH2:23][C:22]([CH:25]2[CH2:27][CH2:26]2)(O)[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.COCCN(S(F)(F)[F:38])CCOC>C(OCC)(=O)C>[ClH:6].[CH:7]([N:20]1[CH2:23][C:22]([CH:25]2[CH2:27][CH2:26]2)([F:38])[CH2:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Reactant: COCCN(CCOC)S(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: FC1(C2CC2)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Yield: 60.5 %

Procedure:
Saturated NaHCO3 (100 ml) was added to a suspension of 1-Benzhydryl-3-cyclopropylazetidin-3-ol hydrochloride (7.78 g, 24.50 mmol) in ethyl acetate (100 ml). The mixture was transferred to a separating funnel and shaken vigorously until all of the solid had dissolved. The organic layer was separated and the aqueous layer extracted further with ethyl acetate (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to an oil. The oil was dissolved in dichloromethane (100 ml) and cooled to −78° C. [bis(2-methoxyethyl)amino]sulfur trifluoride (5.98 g, 27.05 mmol, 5.0 ml) was added dropwise and the solution stirred for 30 mins at −78° C. and then warmed to 0° C. and stirred for a further 1 hr. Reaction was quenched with Saturated NaHCO3 (50 ml) and brine (50 ml) and the aqueous layer extracted with dichloromethane (50 ml). The combined organic extracts were dried (Na2SO4) and concentrated to give a yellow oil. The crude was purified on silica gel, eluting with 5% ethyl acetate/petrol. The resulting alcohol was dissolved in ether (100 ml) and the solution cooled to 0° C. A solution of HCl in ether (2M, 25 ml) was then added dropwise over 5 minutes. The HCl salt precipitated from solution. The resulting slurry was stirred at 0° C. for an additional 10 minutes then filtered. The filter cake was washed with ether (20 ml) and the solid dried under vacuum. This furnished the product as a white solid (4.71 g, 61%). 1H NMR d4-MeOH δ 0.30-0.52 (4H, m), 1.22 (1H, brs), 4.01-4.23 (4H, m), 5.50-5.60 (1H, brs), 7.13-7.46 (10H, m); ES+282.
Reaction SMILES: [Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][C@@H:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13][C@@H:12]2O)=[N:6][C:7]=1[CH2:8][CH3:9].C(C1C(NC2C3C(=CC=[C:40]([O:43]C)C=3)CC2)=NC(CC)=CN=1)C>>[Br:1][C:2]1[N:3]=[C:4]([CH2:21][CH3:22])[C:5]([NH:10][CH:11]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:43][CH3:40])[CH:18]=3)[CH2:13][CH2:12]2)=[N:6][C:7]=1[CH2:8][CH3:9]
Reactant: CCc1nc(N[C@@H]2c3ccccc3C[C@@H]2O)c(CC)nc1Br
Reactant: CCc1cnc(CC)c(NC2CCc3ccc(OC)cc32)n1
Product: CCc1nc(NC2CCc3ccc(OC)cc32)c(CC)nc1Br

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(5-bromo-3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 3,6-diethyl-N-(6-methoxy-2,3-dihydro-1H-inden-1-yl)pyrazin-2-amine and making non-critical variations provided the title compound as a oil: 1H NMR (CDCl3) δ 1.27–1.31, 1.86, 2.58, 2.75, 2.83, 2.85, 2.97, 3.80, 4.54, 5.67, 6.83–6.88, 7.20; HRMS (FAB) calcd for C18H22BrN3O+H 376.1025, found 376.1020. Anal. Calcd for C18H22BrN3O: C, 57.45; H, 5.89; N, 11.17; Br, 21.23. Found: C, 56.15; H, 5.65; N, 10.83.
Reaction SMILES: C(O[CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:7][CH2:6]1)C.[CH3:20][O:21][C:22](=[C:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)[O:23][Si](C)(C)C>C(Cl)Cl.FC(F)(F)S(O[Si](C)(C)C)(=O)=O>[C:15]([O:14][C:13]([NH:12][CH2:11][CH:8]1[CH2:7][CH2:6][N:5]([CH2:4][C:28]2([C:22]([O:21][CH3:20])=[O:23])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH2:10][CH2:9]1)=[O:19])([CH3:16])([CH3:17])[CH3:18]
Reactant: CCOCN1CCC(CNC(=O)OC(C)(C)C)CC1
Reactant: COC(O[Si](C)(C)C)=C1CCOCC1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)C1(CN2CCC(CNC(=O)OC(C)(C)C)CC2)CCOCC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 130.8 %

Procedure:
To a stirred solution of tert-butyl {[1-(ethoxymethyl)piperidin-4-yl]methyl}carbamate (4 g, 14 mmol, step 1 of Example 8) and [methoxy(tetrahydro-4H-pyran-4-ylidene)methoxy](trimethyl)silane (2.9 g, 13 mmol, step 2 of Example 8) in CH2Cl2 (30 mL) was added dropwise trimethylsilyl trifluoromethanesulfonate (0.24 mL, 1.3 mmol) at 0° C., and the resulting mixture was stirred at room temperature for 12 h. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (150 mL), extracted with CH2Cl2 (30 mL×2), and the combined organic layer was dried over sodium sulfate and filtered. Removal of the solvent gave a residue, which was chromatographed on a column of silica gel eluting with ethyl acetate/hexane (1:1) to give 6.3 g (64%) of the title compound as clear colorless oil.