Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:16]2[CH2:21][C:20]([CH3:23])([CH3:22])[CH2:19][C:18]([CH3:25])([CH3:24])[CH2:17]2)[C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:26]([N:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B(O)O)([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[OH:15][C:12]1[CH:11]=[CH:10][C:9]([C:8](=[C:16]2[CH2:17][C:18]([CH3:25])([CH3:24])[CH2:19][C:20]([CH3:23])([CH3:22])[CH2:21]2)[C:5]2[CH:4]=[CH:3][C:2]([C:34]3[N:33]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:37]=[CH:36][CH:35]=3)=[CH:7][CH:6]=2)=[CH:14][CH:13]=1
Reactant: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(Br)cc2)CC(C)(C)C1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(-c3cccn3C(=O)OC(C)(C)C)cc2)CC(C)(C)C1
Temperature: 25 °C
Yield: 71.9 %

Procedure:
To a round-bottomed flask were added 4-[(4-bromophenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenol (14) (0.127 g, 0.32 mmoL), 1-N-BOC-pyrrole-2-boronic acid (0.21 g, 1.0 mmoL), tetrakis(triphenylphosphine)palladium (0) (0.033 g, 0.029 mmoL), 2 M Na2CO3 (3 mL), and ethylene glycol dimethyl ether (8 mL). The stirred reaction mixture was heated at reflux overnight under a nitrogen atmosphere. The oil bath was removed and the reaction mixture was allowed to cool at RT. The reaction mixture was transferred to a separatory funnel and partitioned between H2O and EtOAc. The organic phase was separated, dried over MgSO4, filtered, and the filtrate was concentrated in vacuo to give an orange-brown oil. The crude product was purified by flash chromatography on silica gel with a hexanes:EtOAc gradient (100:0 to 80:20) to give 111 mg (72%) of compound 18 as an off-white solid. 1H NMR (400 MHz, DMSO-d6): δ 0.88 (s, 12 H), 1.24 (m, 11 H), 1.92 (s, 2 H), 1.94 (s, 2 H), 6.19 (m, 1 H), 6.23 (m, 1 H), 6.65 (d, J=8.5 Hz, 2 H), 6.92 (d, J=8.4 Hz, 2 H), 7.09 (d, J=8.1 Hz, 2 H), 7.21 (d, J=8.0 Hz, 2 H), 7.31 (m, 1 H), 9.27 (s, 1 H). LCMS (ESI): m/z 508 (M+Na)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([CH2:7][C:8](OCC)=[O:9])[C:3]1=[O:13].[CH3:14][NH2:15]>O>[CH3:14][NH:15][C:8](=[O:9])[CH2:7][N:4]1[CH2:5][CH2:6][CH:2]([OH:1])[C:3]1=[O:13]
Reactant: CCOC(=O)CN1CCC(O)C1=O
Reactant: CN
Solvent: O
Product: CNC(=O)CN1CCC(O)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
1.0 g of ethyl (R/S)-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetate is treated with 10 ml of a 40% solution of methylamine in water. After stirring at room temperature for 1 hour, the mixture is evaporated. The residue is shaken five times with acetonitrile in order to remove the water, whereupon in each case it is again evaporated. The residue is treated with diethyl ether. By filtration there is isolated N-methyl-2-(3-hydroxy-2-oxo-1-pyrrolidinyl)acetamide of melting point 129°-130.5°.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:9](Br)=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[CH:11]=[CH:10][C:9]([C:13]#[N:14])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5]
Reactant: CN(C)C=O
Reactant: CNC(=O)c1cc(Br)ccc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: CNC(=O)c1cc(C#N)ccc1N
Yield: 48 %

Procedure:
A mixture of 2-Amino-5-bromo-N-methylbenzamide (100.0 mg, 0.4365 mmol), zinc cyanide (51.26 mg, 0.4365 mmol), Pd(PPh3)4 (75.67 mg, 0.06548 mmol) in DMF (1.5 mL) was flushed with nitrogen and irradiated in a microwave reactor at 150° C. for 5 minutes. The reaction mixture was poured into water and extracted by ethyl acetate. The combined organic layers were washed with water and brine, concentrated in vacuo and purified on an ISCO Combiflash unit to isolate the desired product (37.0 mg, 48% yield).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[C:11]([O:24]C)[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]2[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]2)=[C:8]([NH2:26])[N:7]=1)[CH2:2][CH2:3][CH3:4].I[CH2:28][CH2:29][CH2:30][CH3:31]>>[NH2:26][C:8]1[N:7]=[C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])[N:14]=[C:13]2[C:9]=1[NH:10][C:11](=[O:24])[N:12]2[CH2:15][CH2:16][CH2:17][CH:18]1[CH2:23][CH2:22][N:21]([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:20][CH2:19]1
Reactant: CCCCI
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCC3CCNCC3)c2n1
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCCC3CCN(CCCC)CC3)c2n1

Procedure:
Prepared similarly to Example 14 from 2-(butyloxy)-8-(methyloxy)-9-[3-(4-piperidinyl)propyl]-9H-purin-6-amine and 1-iodobutane.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:21]=[CH:20][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[N:40]=[C:41]=[O:42]>C(Cl)Cl>[F:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[NH:40][C:41]([NH:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[CH:17]=[CH:18][C:19]([C:22]([N:24]5[CH2:28][CH2:27][CH2:26][CH2:25]5)=[O:23])=[CH:20][CH:21]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1)=[O:42]
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1
Solvent: ClCCl
Product: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(C(=O)N5CCCC5)cc4)sc23)c(F)c1)Nc1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
To a solution of 126 (125 mg, 0.288 mmol) in DCM (6 mL) was added the 2,4-difluorophenyl isocyanate (134 mg, 0.865 mmol) and the reaction mixture was stirred at RT overnight. The reaction mixture was then concentrated and the resultant solid was triturated with acetone and collected by filtration to give title compound 127 (100 mg, 59% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 9.37 (s, 1H), 8.61 (s, 1H), 8.51 (d, J=5.48 Hz, 1H), 8.14 (s, 1H), 8.04 (m, 1H), 7.94 (m, 2H), 7.76 (m, 1H), 7.64 (m, 2H), 7.45 (t, J=8.99 Hz, 1H), 7.35 (m, 1H), 7.22 (m, 1H), 7.06 (m, 1H), 6.63 (d, J=5.48 Hz, 1H), 3.48-3.37 (m, 4H), 1.85 (m, 4H). MS (m/z)=589.546 (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:23][S:24]([C:27]([F:30])([F:29])[F:28])(=[O:26])=[O:25])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17](Cl)[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)=[O:35])[CH3:32]>CN1CCCC1=O.O>[CH2:31]([O:33][C:34]([CH:36]1[CH2:41][CH2:40][N:39]([C:17]2[CH:16]=[C:15]([C:9]([OH:14])([C:10]([F:12])([F:11])[F:13])[CH:8]([C:7]3[CH:6]=[CH:5][C:4]([O:23][S:24]([C:27]([F:28])([F:29])[F:30])(=[O:25])=[O:26])=[CH:3][C:2]=3[Cl:1])[CH3:22])[CH:20]=[CH:19][N:18]=2)[CH2:38][CH2:37]1)=[O:35])[CH3:32]
Reactant: CC(c1ccc(OS(=O)(=O)C(F)(F)F)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(C(O)(C(C)c3ccc(OS(=O)(=O)C(F)(F)F)cc3Cl)C(F)(F)F)ccn2)CC1

Procedure:
Trifluoro-methanesulfonic acid 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenyl ester (Example 135-Step 1, 1.0 g) and piperidine-4-carboxylic acid ethyl ester (0.773 mL) in 1-methyl-2-pyrrolidon (10 mL) were heated at 220° C. in a microwave oven for 30 minutes. The reaction mixture was then diluted with water (100 mL), extracted twice with ethyl acetate. The combined organic phases were washed with brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography (70 g silica gel, heptane/acetic acid isopropylester 80/20 to 70/30) to give the title compound as light yellow viscous oil (119 mg). MS (m/e)=619.2 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](/[CH:18]=[CH:19]/[C:20]2[C:28]3[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=3)[NH:22][N:21]=2)[CH:13]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:29][C:25]1[CH:24]=[C:23]2[C:28]([C:20](/[CH:19]=[CH:18]/[C:14]3[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=3)=[N:21][NH:22]2)=[CH:27][CH:26]=1
Reactant: O=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Reactant: O=C1Cc2cc(Br)ccc2N1
Product: O=C1Nc2ccc(Br)cc2C1=Cc1ccc2c(/C=C/c3cccnc3)n[nH]c2c1
Yield: 82.3 %

Procedure:
The title compound (E:Z=1:4, 73 mg, 83%) was synthesized as a dark yellow solid according to the method described for Example A67 (oil temp 75° C., reflux 2 h) using 5-bromoindolin-2-one (44.5 mg, 0.21 mmol) and (E)-3-(2-(pyridin-3-yl)vinyl)-1H-indazole-6-carbaldehyde (49.8 mg, 0.2 mmol). 1H NMR (400 MHz, DMSO-d6): δ 13.60 (s, 1H), 10.84 (s, 1H), 8.99 (s, 1H), 8.91 (s, 1H), 8.48 (d, J=4.4 Hz, 1H), 8.30 (d, J=8.4 Hz, 1H), 8.19 (d, J=8.0 Hz, 1H), 8.16-8.10 (m, 3H), 8.04 (s, 1H), 7.71 (d, J=16.8 Hz, 1H), 7.59 (d, J=17.2 Hz, 1H), 7.43 (dd, J=7.6 Hz, J=4.8 Hz, 1H), 7.39 (dd, J=8.0 Hz, J=1.2 Hz, 1H); MS ESI 443.3 [M+H]+, calcd for [C23H15BrN4O+H]+ 443.1.
Reaction SMILES: [CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]=[O:13])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Li][CH3:15].[NH4+].[Cl-]>C(OCC)C>[CH2:1]([C:5]1[CH2:10][CH:9]([CH3:11])[CH:8]([CH:12]([OH:13])[CH3:15])[CH2:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)CC1=CCC(C=O)C(C)C1
Reactant: [Li]C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(C)CC1=CCC(C(C)O)C(C)C1
Temperature: -20 °C
Yield: 94 %

Procedure:
4-Isobutyl-6-methylcyclohex-3-enecarbaldehyde 3b (23 g, 130 mmol) was dissolved in diethyl ether (200 ml). The solution was cooled to −20° C. under nitrogen and MeLi (1.6M, 100 ml, 160 mmol) added over 30 min with stirring. The temperature was allowed to rise to −5° C. and the reaction stirred at this temperature for 1 h. The reaction mixture was poured slowly, and under nitrogen, onto a vigorously stirred mixture of sat. NH4Cl (150 ml) and ice (100 g). After stirring for 15 min the phases were separated and the lower aqueous layer extracted with diethyl ether (100 ml). The organic phases were combined, washed with water (100 ml), dried (Na2SO4) and concentrated in vacuo to give 24 g of a light yellow oil. The crude oil was purified by flash chromatography (MTBE/hexane 1:3) to give 4b as a 3:2 mixture of diastereomers (18 g, 72% yield, colorless oil, >99% pure). Subsequent distillation provided 12.5 g of olfactory pure product.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[N:28]=[C:29]=[O:30]>>[CH3:20][C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[NH:28][C:29](=[O:30])[NH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:16]3[C:11](=[CH:12][N:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([NH2:19])=[O:18])=[CH:6][CH:7]=1
Reactant: NC(=O)c1[nH]c2cnccc2c1-c1ccc(N)cc1
Reactant: Cc1ccc(C)c(N=C=O)c1
Product: Cc1ccc(C)c(NC(=O)Nc2ccc(-c3c(C(N)=O)[nH]c4cnccc34)cc2)c1

Procedure:
87 mg of solid yellow 3-{4-[3-(2,5-dimethylphenyl)ureido]phenyl}-1H-pyrrolo-[2,3-c]pyridine-2-carboxamide are prepared as described in Example 1 starting with 3-(4-aminophenyl)-1H-pyrrolo[2,3-c]pyridine-2-carboxamide and 2,5-dimethylphenyl isocyanate.
Reaction SMILES: [CH2:1]([CH:3]1[CH2:7][C:6](=O)[CH2:5][CH:4]1[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:2].CC(O)=O.[CH2:18]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH2:26]([N:25]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]1[CH2:5][CH:4]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:3]([CH2:1][CH3:2])[CH2:7]1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)C1CC(=O)CC1CC
Reactant: c1ccc(CNCc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)C1CC(N(Cc2ccccc2)Cc2ccccc2)CC1CC
Temperature: 0 °C
Reaction time: 20 h
Yield: 71.7 %

Procedure:
A round-bottom flask was charged with ethyl 2-ethyl-4-oxocyclopentanecarboxylate (95.9 g, 521 mmol) and DCE (1.8 L). The solution was cooled to about 0° C. and AcOH (45 mL, 780 mmol) and dibenzylamine (120 mL, 625 mmol) were added drop-wise, resulting in the formation of a thick suspension. The reaction mixture was warmed to about 10° C. by removing the cooling bath and additional DCE (500 mL) was added. Sodium triacetoxyborohydride (166 g, 781 mmol) was added portion-wise and the reaction mixture was stirred at room temperature for about 20 h. The reaction mixture was slowly poured into saturated aqueous NaHCO3 (1.5 L) with stirring followed by the portion-wise addition of solid NaHCO3 (175 g, 2083 mmol). The mixture was stirred for about 2 h and the organic layer was separated, dried over anhydrous Na2SO4, and concentrated to dryness under reduced pressure. The crude yellow oil was purified by flash column chromatography using EtOAc/heptane as eluant (0-20% EtOAc) to yield ethyl 4-(dibenzylamino)-2-ethylcyclopentanecarboxylate (136.6 g, 72%) as a white solid: LC/MS (Table 2, Method a) Rt=3.26 min; MS m/z: 366 (M+H)+.
Reaction SMILES: [CH3:1][C@H:2]1[C@@H:11]2[CH2:12][CH2:13][C:14]3([CH3:18])[O:16][O:17][C@:10]42[C@H:5]([C@@H:6]([CH3:20])[C@@H:7]([OH:19])[O:8][C@@H:9]4[O:15]3)[CH2:4][CH2:3]1.[CH2:21](OC(OCC)OCC)[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C(O)C>[CH3:21][CH2:22][O:19][C@H:7]1[O:8][C@@H:9]2[O:15][C:14]3([CH3:18])[O:16][O:17][C@@:10]42[C@@H:5]([CH2:4][CH2:3][C@@H:2]([CH3:1])[C@@H:11]4[CH2:12][CH2:13]3)[C@H:6]1[CH3:20]
Reactant: CCOC(OCC)OCC
Reactant: C[C@H]1[C@@H](O)O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]1[C@@]24OO3
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CCO[C@H]1O[C@@H]2OC3(C)CC[C@H]4[C@H](C)CC[C@@H]([C@H]1C)[C@@]24OO3
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
Dihydroartemisinin (50 mg) was dissolved in dry ethanol (3 ml). Add 2 ml of triethylorthoformate and (25 mg) of p-toluenesulphonic acid. The reaction mixture was stirred at room temperature (20° C.) for 30 min. 50 ml of water was added in the reaction mixture The reaction product was extracted by dichloromethane (30 mil×3). The dichloromethane extract was dried over anhydrous sodium sulphate and evaporation of solvent under vacuum at 40° C. and yielded the arteether (52 mg).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1OC.[Cl-].[Al+3].[Cl-].[Cl-].CO[C:16]1[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=1)[C:19](Cl)=[O:20]>ClCCl>[C:19]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:20])[C:18]1[CH:22]=[CH:23][CH:24]=[CH:16][CH:17]=1
Reactant: COc1ccccc1Br
Reactant: COc1cccc(C(=O)Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
60.6 g (324.2 mmol) of 2-bromoanisole was added dropwise to a dichloromethane (350 ml) solution containing 51.8 g (388.6 mmol) of aluminum chloride and 55.31 g (324.3 mmol) of 3-methoxybenzoyl chloride which was cooled to 0° C. After addition, the resulting mixture was stirred for 2 hours. After a reaction, the reaction solution was washed with water, the solvent was removed, and the obtained product was purified by column chromatography to obtain a benzophenone derivative represented by the following formula (47) as 67.7 g (210.7 mmol, yield of 65%) of a yellow solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([C:22]3[N:23]([CH3:28])[N:24]=[CH:25][C:26]=3[Br:27])[CH:15]=2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+].Cl.CCOC(C)=O>C(O)C>[Br:27][C:26]1[CH:25]=[N:24][N:23]([CH3:28])[C:22]=1[C:16]1[CH:15]=[C:14]([NH:13][C:11]([NH:10][C:6]2[CH:7]=[CH:8][CH:9]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:5]=2)=[O:12])[CH:19]=[CH:18][C:17]=1[O:20][CH3:21]
Reactant: COc1ccc(NC(=O)Nc2cccc(C(C)=O)c2)cc1-c1c(Br)cnn1C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc(NC(=O)Nc2cccc(C(C)O)c2)cc1-c1c(Br)cnn1C
Reaction time: 8 h
Yield: 62.2 %

Procedure:
Compound 17 (30.2 mg, 0.07 mmol, see Example 1.24) was dissolved in ethanol (5 mL). Sodium Borohydride (3.1 mg, 0.08 mmol) was added under Argon gas. The reaction was stirred overnight and found to be complete by TLC and LC/MS. The mixture was worked up with 1N Hydrogen Chloride solution (10 mL) and EtOAc (2×15 mL). The organic layers were combined and washed with water, dried over Na2SO4, filtered, and the solvent removed under reduced pressure. The residue was then purified by HPLC to afford 19.4 mg (63%) of Compound 94: LCMS m/z (%)=445 (M+H79Br, 25), 447 (M+H81Br, 25). 1H NMR (400 MHz, CDCl3) δ: 7.34 (dd, J1=8 Hz, J2=2 Hz, 1H), 7.26 (s, 1H), 7.20 (s, 1H), 7.14 (s, 1H), 7.11 (d, J=8 Hz, 1H), 7.09 (s, 1H), 7.06 (t, 1H), 6.95 (d, J=4 Hz, 1H), 6.85 (d, J=8 Hz, 1H), 6.76 (d, J=8 Hz, 1H), 4.65 (m, 1H), 3.59 (s, 3H), 3.49 (s, 3H), 1.27 (d, J=4 Hz, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:15][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:5]=[C:6]([Cl:14])[C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.P(Cl)(Cl)(Cl)(Cl)[Cl:23]>C1C=CC=CC=1>[Cl:23][CH:16]([CH2:15][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:6]([Cl:14])[CH:5]=1)[C:17]([O:19][CH2:20][CH3:21])=[O:18]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CCOC(=O)CCc1cc(Cl)c(C2CCCCC2)c(Cl)c1
Solvent: c1ccccc1
Product: CCOC(=O)C(Cl)Cc1cc(Cl)c(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a mixture of 23.8 g. (0.077 moles) of ethyl β-(3,5-dichloro-4-cyclohexylphenyl)propionate in 35 ml. of benzene is added 19.2 g. (0.092 moles) of phosphorous pentachloride in small portions over 11/2 hours. The mixture is stirred for 20 hours and then poured into an ice-cold mixture. The reaction mixture is extracted with petroleum ether which is then washed with cold 10% sodium bicarbonate solution followed by water. On drying, the mixture is evaporated in vacuo to ethyl α-chloro-β-(3,5-dichloro-4-cyclohexylphenyl)propionate.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:32])([F:31])[C:4]=2[CH:3]=1)[CH2:12][CH2:11][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=O)=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:9][CH2:8]3.Cl.[NH2:34][OH:35].C([O-])(=O)C.[Na+]>C(O)C>[Cl:1][C:2]1[S:6][C:5]2[C:7]3([O:28][CH2:29][C:30]([F:31])([F:32])[C:4]=2[CH:3]=1)[CH2:8][CH2:9][N:10]([CH2:13][C:14]1[C:15]([CH3:27])=[N:16][N:17]([C:19]2[C:24]([CH:25]=[N:34][OH:35])=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:18]=1)[CH2:11][CH2:12]3
Reactant: NO
Reactant: Cc1nn(-c2ncccc2C=O)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: Cc1nn(-c2ncccc2C=NO)cc1CN1CCC2(CC1)OCC(F)(F)c1cc(Cl)sc12
Yield: 50.8 %

Procedure:
To a solution of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde (0.210 g, 0.438 mmol) in ethanol (3 mL) are added hydroxylamine hydrochloride (0.038 g, 0.526 mmol) and sodium ethanoate (0.044 g, 0.526 mmol) and the mixture is stirred at reflux for 1 h. The solvent is evaporated and the residue is extracted with ethyl acetate and water. The organic layer is separated, dried over magnesium sulfate, filtered and the solvent is evaporated in vacuo. The residue is purified by basic reverse phase HPLC to yield 0.110 g of 2-[4-[(2-chloro-4,4-difluoro-spiro[5H-thieno[2,3-c]pyran-7,4′-piperidine]-1′-yl)methyl]-3-methyl-pyrazol-1-yl]pyridine-3-carbaldehyde oxime. MS (m/z): 494 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20])=[CH:16][CH:15]=[N:14]1.[N+:26]([O-])([OH:28])=[O:27].C(=O)([O-])O.[Na+]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:9])[F:11])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:17]([O:18][CH:19]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH3:20])=[C:16]([N+:26]([O-:28])=[O:27])[CH:15]=[N:14]1
Reactant: CCOC(=O)C(C)Oc1ccnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reactant: O=[N+]([O-])O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)C(C)Oc1c([N+](=O)[O-])cnn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 0.25 h
Yield: 49 %

Procedure:
17 g (0.05 mol) of 1-(2,6-dichloro-4-trifluoromethyl-phenyl)-5-(1-ethoxycarbonyl-ethoxy)-pyrazole are dissolved in 50 ml of acetic anhydride, and 10 ml of concentrated nitric acid are added dropwise with stirring at 0°-10° C. within 15 minutes. The reaction batch is stirred for a further 1 hour at room temperature and then poured onto ice water. After neutralization of the mixture using sodium hydrogen carbonate, the organic components are extracted with methylene chloride. The methylene chloride phase is dried over sodium sulphate and concentrated in vacuo. The crude yield of oily reaction product is 17 g. After trituration with petroleum ether, 10.8 g (49% of theory) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-5-(1-ethoxycarbonyl-ethoxy)-4-nitro-pyrazole are obtained in the form of oily crystals.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[C:11]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)(=O)[CH3:12]>>[F:2][C:3]1[CH:4]=[C:5]([NH:9][N:10]=[C:11]([C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH3:12])[CH:6]=[CH:7][CH:8]=1
Reactant: CC(=O)c1cccs1
Reactant: NNc1cccc(F)c1
Agent: Cl
Product: CC(=NNc1cccc(F)c1)c1cccs1

Procedure:
This compound is prepared from commercial 3-fluorophenylhydrazine hydrochloride (Aldrich) and from commercial 2-acetylthiophene (Aldrich), according to the procedure 1.
Reaction SMILES: [CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][C:8](=[O:20])[NH:7][CH2:6]1)=[O:4].[CH3:21][O:22][C:23]1[CH:38]=[CH:37][C:26]([CH:27](O)[C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][CH:29]=2)=[CH:25][CH:24]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][O:2][C:3]([C@H:5]1[C@H:10]([C:11]2[CH:16]=[C:15]([F:17])[C:14]([F:18])=[CH:13][C:12]=2[F:19])[CH2:9][C:8](=[O:20])[N:7]([CH:27]([C:26]2[CH:37]=[CH:38][C:23]([O:22][CH3:21])=[CH:24][CH:25]=2)[C:28]2[CH:29]=[CH:30][C:31]([O:34][CH3:35])=[CH:32][CH:33]=2)[CH2:6]1)=[O:4]
Reactant: COC(=O)[C@@H]1CNC(=O)C[C@H]1c1cc(F)c(F)cc1F
Reactant: COc1ccc(C(O)c2ccc(OC)cc2)cc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)[C@@H]1CN(C(c2ccc(OC)cc2)c2ccc(OC)cc2)C(=O)C[C@H]1c1cc(F)c(F)cc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 6.6 g (23 mmol) of the product of Step C in 100 mL of acetic acid was added 6.11 g (25 mmol) of 4,4′-dimethoxybenzhydrol followed by 5 mL of concentrated sulfuric acid and the resulting solution was stirred at ambient temperature for 18 h. The solution was then concentrated and cooled 0° C. before quenching with ice water (100 mL). The resulting mixture was extracted with three 300-mL portions of ethyl acetate, and the organic phases combined and washed sequentially with water, saturated aqueous sodium bicarbonate solution, and saturated aqueous brine (200 mL each). The organic phase was dried over magnesium sulfate, filtered, and evaporated in vacuo to yield a viscous oil. The crude material was purified by flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate/hexanes gradient) to give methyl-trans-1-[bis(4-methoxyphenyl)methyl]-6-oxo-4-(2,4,5-trifluorophenyl)piperidine-3-carboxylate as a colorless solid. LC/MS 536.2 (M+23).