Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][N:3]1[CH2:12][CH2:11][C:10]2[C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[CH2:7][CH2:6][C:5]=2[CH2:4]1.[Li].N.NC1C=CC=CC=1>C1COCC1>[CH3:2][N:3]1[CH2:12][CH2:11][C@@H:10]2[C@H:5]([CH2:6][CH2:7][C:8]3[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=32)[CH2:4]1
Reactant: CN1CCC2=C(CCc3ccccc32)C1
Agent: Cl
Agent: N
Agent: [Li]
Solvent: Nc1ccccc1
Solvent: C1CCOC1
Product: CN1CC[C@H]2c3ccccc3CC[C@@H]2C1
Yield: 62.3 %

Procedure:
Following the procedure of Example 2, 0.64 g (2.71 mmol) of 1,2,3,4,5,6-hexahydro-3-methyl-benz[f]isoquinoline hydrochloride was reacted with 0.126 g of lithium wire in 100 ml of liquid ammonia, 25 ml of anhydrous THF and 0.25 ml of aniline. Chromatography on flash silica, eluting with 5-10% methanol/dichloromethane, then on alumina, eluting with 25% ethyl acetate/petroleum ether gave 0.340 g (62%) of the title product as a colourless oil. The hydrochloride salt was made using ethereal hydrogen chloride. Upon evaporation of the solvent, the title product hydrochloride was obtained as a white solid, m.p. 277°-285° C. (dec). NMR δ(D2O) 1.52-1.92 (4H, m), 2.63-2.75 (2H, m), 2.86-2.98 (3H, m), 2.92 (3H, s), 3.19 (1H, t of d, J=13 and 3 Hz), 3.56 (1H, m), 7.22-7.28 (3H, m), 7.33-7.36 (1H, m). m/z (CI+, NH3) 202 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([CH2:6][OH:7])=[C:4]([F:12])[C:3]=1[F:13].[Cl:14]/[C:15](=[CH:20]\[C@@H:21]1[C@H:23]([C:24](Cl)=[O:25])[C:22]1([CH3:28])[CH3:27])/[C:16]([F:19])([F:18])[F:17]>>[CH3:1][C:2]1[C:9]([F:10])=[C:8]([F:11])[C:5]([CH2:6][O:7][C:24]([C@H:23]2[C:22]([CH3:28])([CH3:27])[C@H:21]2/[CH:20]=[C:15](\[Cl:14])/[C:16]([F:19])([F:18])[F:17])=[O:25])=[C:4]([F:12])[C:3]=1[F:13]
Reactant: Cc1c(F)c(F)c(CO)c(F)c1F
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Product: Cc1c(F)c(F)c(COC(=O)[C@@H]2[C@H](/C=C(\Cl)C(F)(F)F)C2(C)C)c(F)c1F

Procedure:
In a further aspect of the invention the 4-methyl-2,3,5,6-tetrafluorobenzyl alcohol is reacted with cis-Z 3-(2-chloro-1,1,1-trifluoro-2-propenyl)-2,2-dimethylcyclopropane carbonyl chloride to give tefluthrin.
Reaction SMILES: F[C:2]1[C:7]([C:8]2[N:16]=[C:15]([CH3:17])[N:14]=[C:13]3[C:9]=2[N:10]=[CH:11][N:12]3[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[CH:6][C:5]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[CH:4][N:3]=1.[O:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH:36]1[N:41]1[C:49]2[CH:48]=[CH:47][CH:46]=[C:45]([NH2:50])[C:44]=2[CH:43]=[N:42]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[CH3:17][C:15]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH:18]2[CH2:23][CH2:22][CH2:21][CH2:20][O:19]2)=[C:8]([C:7]2[C:2]([NH:50][C:45]3[C:44]4[CH:43]=[N:42][N:41]([CH:36]5[CH2:37][CH2:38][CH2:39][CH2:40][O:35]5)[C:49]=4[CH:48]=[CH:47][CH:46]=3)=[N:3][CH:4]=[C:5]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)[CH:6]=2)[N:16]=1
Reactant: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2F)c2ncn(C3CCCCO3)c2n1
Reactant: Nc1cccc2c1cnn2C1CCCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1nc(-c2cc(Cc3ccc(S(C)(=O)=O)cc3)cnc2Nc2cccc3c2cnn3C2CCCCO2)c2ncn(C3CCCCO3)c2n1
Reaction time: 0.33 h
Yield: 115.7 %

Procedure:
A mixture of 6-(2-fluoro-5-(4-(methylsulfonyl)benzyl)pyridin-3-yl)-2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (78.5 mg, 0.163 mmol) and 1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (45.5 mg, 0.209 mmol) in THF (1.0 mL) was cooled in an ice/salt bath and treated dropwise with LiHMDS (0.627 mL of a 1.0 M solution in THF). The mixture was stirred for 20 min and then quenched with water (0.1 mL). The mixture was stirred for 3 min and then extracted into EtOAc from saturated aqueous NaHCO3. The EtOAc extracts were dried (MgSO4) and concentrated to give a dark yellow solid (128 mg). This was taken on to the next step without further purification.
Reaction SMILES: [CH2:1]([NH:3]/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1)[CH3:2].[OH:21]O>C(O)(=O)C>[CH2:1]([NH:3]/[C:4](/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[C:5]1\[C:6](=[O:14])[C:7]2[CH:13]=[CH:12][CH:11]=[CH:10][C:8]=2[S:9]\1=[O:21])[CH3:2]
Reactant: OO
Reactant: CCN/C(=C1/Sc2ccccc2C1=O)c1ccccc1
Solvent: CC(=O)O
Product: CCN/C(=C1\C(=O)c2ccccc2S1=O)c1ccccc1

Procedure:
Prepared analogous to Example 1 from (E)-2-[(ethylamino)phenylmethylene]-benzo[b]thiophen-3(2H)-one and aqueous hydrogen peroxide in glacial acetic acid.
Reaction SMILES: [OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:35]=[CH:34][CH:33]=[CH:32][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]5[CH:27]=NN(C)[CH:30]=5)=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1.CN1C=C(B2OC(C)(C)C(C)(C)O2)C=N1>>[OH:1][C@@H:2]1[C@@H:7]([N:8]2[C:17](=[O:18])[C:16]3[C:11](=[C:12]4[CH:35]=[CH:34][CH:33]=[CH:32][C:13]4=[C:14]([CH2:19][C:20]4[CH:21]=[N:22][C:23]([C:26]([CH3:27])=[CH2:30])=[CH:24][CH:25]=4)[CH:15]=3)[N:10]=[CH:9]2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: Cn1cc(-c2ccc(Cc3cc4c(=O)n([C@H]5CCOC[C@@H]5O)cnc4c4ccccc34)cn2)cn1
Agent: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: C=C(C)c1ccc(Cc2cc3c(=O)n([C@H]4CCOC[C@@H]4O)cnc3c3ccccc23)cn1

Procedure:
3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-[(6-isopropenylpyridin-3-yl)methyl]benzo[h]quinazolin-4(3H)-one was prepared by the procedure described for the synthesis of 3-[(3R,4S)-3-Hydroxytetrahydro-2H-pyran-4-yl]-6-{[6-(1-methyl-1H-pyrazol-4-yl)pyridine-3-yl]methyl}benzo[h]quinazolin-4(3H)-one in Example 4, substituting isopropenylboronic acid pinacol ester for 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([OH:17])=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1[CH:19]=[CH:20][C:21]2[N:26](O)[N:25]=[N:24][C:22]=2[CH:23]=1.C1CCC(N=C=NC2CCCCC2)CC1>CN(C=O)C>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[C:11]([C:15]([O:17][N:24]2[C:22]3[CH:23]=[CH:18][CH:19]=[CH:20][C:21]=3[N:26]=[N:25]2)=[O:16])[N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)O
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Reaction time: 24 h
Yield: 84.6 %

Procedure:
Boc-Py-acid, 4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrole-2-carboxylic acid (31 g, 129 mmol) was dissolved in 500 mL DMF, HOBt (17.4 g, 129 mmol) was added followed by DCC (34 g, 129 mmol). The reaction was stirred for 24 h and then filtered dropwise into a well stirred solution of 5 L of ice water. The precipitate was allowed to sit for 15 min at 0° C. and then collected by filtration. The wet cake was dissolved in 500 mL DCM, and the organic layer added slowly to a stirred solution of cold petroleum ether (4° C.). The mixture was allowed to stand at −20° C. for 4 h and then collected by vacuum filtration and dried in vacuo to provide (39 g, 85% yield) of 1,2,3-Benzotriazol-1-yl 4-[(tert-butoxycarbonyl)-amino]-1-methylpyrrole-2-carboxylate as a finely divided white powder. TLC (7:2 benzene/ethyl acetate v/v) Rf 0.61H NMR (DMSO-d6) δ 9.43 (s, 1H), 8.12 (d, 1H, J=8.4 Hz), 7.80 (d, 1H, J=8.2 Hz), 7.64 (t, 1H, J=7.0 Hz), 7.51 (m, 2H), 7.18 (s, 1H), 3.83 (s, 3H), 1.45 (s, 9H), 13C NMR (DMSO-d6) δ 156.5, 153.3, 143.2, 129.6, 129.2, 125.7, 125.2, 124.6, 120.3, 112.8, 110.3, 109.8, 79.5, 36.8, 28.6.; IR (KBr) 3246, 3095, 2979, 1764, 1711, 1588, 1389, 1365, 1274, 1227, 1160, 1101, 999, 824, 748.; FABMS m/e 358.152 (M+H 358.151 calc. for C17H20N5O4).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]([CH3:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:2]=1.[CH:15](OCC)=[O:16].[H-].[Na+]>C(COC)OC>[OH:16][CH2:15][CH:8]([CH:7]([C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(C)c1cccnc1
Reactant: CCOC=O
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Product: CCOC(=O)C(CO)C(C)c1cccnc1

Procedure:
Treatment of ethyl 3-(3-pyridyl)butyrate with ethyl formate and sodium hydride in glyme, followed by acidification gave ethyl 2-(hydroxymethyl)-3-(3-pyridyl)butyrate, m.p. 128°-131°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C:5]1([CH2:9][CH2:10][NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15])[CH2:4][CH2:3][CH2:2]2.S(=O)(=O)(O)[OH:21].N>O>[N:1]12[CH2:2][CH2:3][CH2:4][C:5]1([CH2:9][CH2:10][NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]([NH2:15])=[O:21])[CH2:6][CH2:7][CH2:8]2
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1NCCC12CCCN1CCC2
Agent: N
Solvent: O
Product: NC(=O)c1ccccc1NCCC12CCCN1CCC2
Temperature: -78 °C
Yield: 67 %

Procedure:
2-[(1-Azabicyclo[3.3.0]octan-5-yl)ethylamino]benzonitrile (1.34 g, 5.25 mmol) obtained by Example 27 was mixed with concentrated sulfuric acid (48.2 ml) and water 7.5 ml to react the mixture for 2 hours at 110° C. The reaction mixture was cooled to -78° C., neutralized by 25% ammonia solution, extracted by ethyl acetate, washed by water, dried over anhydrous sodium sulfate, concentrated in vacuo, and crystallized from ethyl acetate to afford the desired compound (961 mg, 67.0%).
Reaction SMILES: C(O)C.[Na].[CH2:5]([N:12]=[CH:13][C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>O>[CH2:5]([N:12]=[CH:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][C:22]([CH3:29])([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:18][CH:19]=1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: Oc1ccc(C=NCc2ccccc2)cc1
Reactant: CCOC(=O)C(C)(C)Br
Agent: [Na]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccc(C=NCc2ccccc2)cc1
Reaction time: 22 h
Yield: 65.7 %

Procedure:
(a) To 50 ml of absolute ethanol is added 0.573 g of sodium, and 5 g of 4-(N-benzylformimidoyl)phenol and then 5.54 g of ethyl 2-bromo-2-methylpropionate are added to the solution under cooling with water. The mixture is refluxed under heating and with stirring for 22 hours. The ethanol is distilled off from the reaction mixture under reduced pressure. After dissolving the residue in 30 ml of benzene, the insolubles are filtered off. The benzene filtrate is washed with water twice, then dried over magnesium sulfate and thereafter the solvent is distilled off. 6.12 g of the resulting oily product is dissolved in ether. After removing the insolubles from the ethereal solution by filtration, the filtrate is concentrated to give 5.06 g of ethyl 2-[4-(N-benzylformimidoyl)phenoxy]-2-methylpropionate in the form of a pale brown oil.
Reaction SMILES: [O:1]=[C:2]1[CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][CH2:5][CH2:4][N:3]1[CH2:14][C:15]([OH:17])=O.Cl.[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][NH:24][CH2:23]2.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[F:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[CH2:25][N:24]([C:15](=[O:17])[CH2:14][N:3]1[CH2:4][CH2:5][CH2:6][C@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:2]1=[O:1])[CH2:23]2
Reactant: O=C(O)CN1CCCC(c2ccccc2)C1=O
Reactant: Fc1ccc2c(c1)CNC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: O=C(CN1CCC[C@H](c2ccccc2)C1=O)N1Cc2ccc(F)cc2C1
Reaction time: 8 h

Procedure:
To a suspension of 2-(2-oxo-3-phenylpiperidin-1-yl)acetic acid (4.43 g, 18.99 mmol; Example 91D) and 5-fluoroisoindoline hydrochloride (3.63 g, 20.89 mmol) in dichloromethane (30 mL) was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine (5.04 mL, 28.5 mmol). After a few minutes, a dark brown solution resulted. The reaction was stirred overnight then poured into 1 N HCl (100 mL). The product was extracted into dichloromethane (3×100 mL). The combined extracts were washed with brine (100 mL), dried over magnesium sulfate and concentrated to give a brownish foam. The foam was dissolved in minimal dichloromethane and was loaded onto a GraceResolv™ 80 g silica gel column (Grace Davison Discovery Sciences) and the product eluted with a gradient of 5% ethyl acetate/hexanes to 100% ethyl acetate/hexanes (Flow=40 mL/minute) over 60 minutes to provide the racemic title compound. Supercritical fluid chromatography using a ChiralPak® OD-H 21×250 mm column eluting using 10% to 50% methanol/CO2 over 20 minutes gave the title compound as the second eluting enantiomer. 1H NMR (300 MHz, CDCl3) δ 7.40-7.11 (m, 6H), 6.97 (dd, J=8.6, 18.0, 2H), 4.84 (dd, J=8.7, 19.3, 4H), 4.44 (dd, J=1.6, 15.7, 1H), 4.05 (d, J=15.7, 1H), 3.81-3.47 (m, 3H), 2.34-1.83 (m, 4H); MS (ESI+) m/z 353.0 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])[N:13]=2)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.Br[CH2:44][C:45]1C(C)=[N:48][O:47][N:46]=1>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][C:15]3[C:45]([CH3:44])=[N:46][O:47][N:48]=3)[N:13]=2)[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1nonc1CBr
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: Cc1nonc1Cn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(bromomethyl)-4-methyl-1,2,5-oxadiazole and isolated as light yellow gum. MS (m/e): 379.3 (MH+).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1.C(N(CC)CC)C.Cl>CS(C)=O>[CH:2]([C:3]1[CH:7]=[C:6]([NH:8][S:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:11])=[O:10])[N:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=1)=[O:1]
Reactant: O=S(=O)(Nc1cc(CO)nn1-c1ccccc1)c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: O=Cc1cc(NS(=O)(=O)c2ccccc2)n(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.9 %

Procedure:
N-[3-(Hydroxymethyl)-1-phenyl-1H-pyrazol-5-yl]benzenesulfonamide (379 mg) and triethylamine (1 mL) were dissolved in dimethyl sulfoxide (5 mL), and sulfur trioxide•pyridine complex (549 mg) was added at room temperature. After stirring at room temperature for 18 hr, 1 mol/L hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate, and the combined extracts were washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=1:1→1:3) to give the title compound as a pale-yellow oil (yield 331 mg, yield 88%).
Reaction SMILES: [OH:1][CH2:2][CH:3]([N:6]1[C:15]2[C:10](=[CH:11][C:12](I)=[CH:13][CH:14]=2)[C:9](=[O:17])[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:7]1)[CH2:4][CH3:5].[CH2:23]([NH:25][C:26]([NH:28][C:29]1[CH:34]=[C:33]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1)=[O:27])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.O.C1(P([Pd-4](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)C=CC=CC=1>[CH2:23]([NH:25][C:26](=[O:27])[NH:28][C:29]1[N:30]=[CH:31][C:32]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[N:6]([CH:3]([CH2:4][CH3:5])[CH2:2][OH:1])[CH:7]=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:9]3=[O:17])=[C:33]([C:35]2[S:36][CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[N:39]=2)[CH:34]=1)[CH3:24]
Reactant: CCOC(=O)c1cn(C(CC)CO)c2ccc(I)cc2c1=O
Reactant: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(B2OC(C)(C)C(C)(C)O2)cn1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CCNC(=O)Nc1cc(-c2nc(C(F)(F)F)cs2)c(-c2ccc3c(c2)c(=O)c(C(=O)OCC)cn3C(CC)CO)cn1
Temperature: 100 °C
Reaction time: 2 h
Yield: 28.9 %

Procedure:
To a suspension of ethyl 1-(1-hydroxybutan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylate (Intermediate 64, 282 mg, 0.78 mmol) and 6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazole-2-yl)pyridine-3-ylboronic acid (Intermediate 17, 350 mg, 0.84 mmol) in 1,4-dioxane (3 mL) was added a solution of cesium carbonate (467 mg, 1.43 mmol) in water (1 mL) followed by tetrakis(triphenylphosphino)palladium(0) (48.7 mg, 0.04 mmol). The reaction mixture was stirred at 100° C. for 2 h, cooled to room temperature, and diluted with water (2 mL). The precipitate that formed was collected by filtration, washed with water and hexanes. Purification via column chromatography (silica, 95:5 methylene chloride/methanol) provided ethyl 6-(6-(3-ethylureido)-4-(4-(trifluoromethyl)thiazol-2-yl)pyridin-3-yl)-1-(1-hydroxybutan-2-yl)-4-oxo-1,4-dihydroquinoline-3-carboxylate as a yellow/orange solid (136 mg, 27%).
Reaction SMILES: [OH:1][C:2]([CH3:33])([CH3:32])[CH2:3][CH2:4][CH2:5][CH2:6]/[CH:7]=[C:8](\[C:10]1[CH:11]=[C:12]([CH:29]=[CH:30][CH:31]=1)[O:13][CH2:14][C:15]1[CH:16]=[C:17]([C:25](OC)=[O:26])[C:18](=[CH:23][CH:24]=1)[C:19](OC)=[O:20])/[CH3:9].[BH4-].[Li+]>>[OH:26][CH2:25][C:17]1[CH:16]=[C:15]([CH:24]=[CH:23][C:18]=1[CH2:19][OH:20])[CH2:14][O:13][C:12]1[CH:11]=[C:10](/[C:8](/[CH3:9])=[CH:7]\[CH2:6][CH2:5][CH2:4][CH2:3][C:2]([CH3:32])([OH:1])[CH3:33])[CH:31]=[CH:30][CH:29]=1
Reactant: COC(=O)c1ccc(COc2cccc(/C(C)=C\CCCCC(C)(C)O)c2)cc1C(=O)OC
Agent: [BH4-]
Agent: [Li+]
Product: C/C(=C/CCCCC(C)(C)O)c1cccc(OCc2ccc(CO)c(CO)c2)c1

Procedure:
In a manner similar to Example 53(e), by reacting 790 mg (1.8 mmol) of dimethyl 4-[3-((Z)-7-hydroxy-1,7-dimethyloct-1-enyl)phenoxymethyl]phthalate (prepared in a manner similar to Example 73(a)) with 118 mg (5.4 mmol) of lithium borohydride, a colourless oil is obtained (m=621 mg; Y=86%).
Reaction SMILES: [Cl-:1].[NH4+].O.[CH3:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C@H:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=2)[CH2:8][CH2:7]1.N>C(O)CC>[CH3:4][NH:5][C@@H:6]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[C@H:9]([C:16]2[CH:17]=[CH:18][C:19]([Cl:23])=[C:20]([Cl:22])[CH:21]=2)[CH2:8][CH2:7]1.[ClH:1]
Reactant: [Cl-]
Agent: CN[C@H]1CC[C@@H](c2ccc(Cl)c(Cl)c2)c2ccccc21
Agent: N
Agent: [NH4+]
Solvent: CCCO
Solvent: O
Product: Cl
Temperature: 25 °C

Procedure:
8.75 g of ammonium chloride are dissolved in 100 ml of n-propanol and 35 ml of water at T=50° C. 50 g of free sertraline base dissolved in 100 ml of n-propanol are added dropwise to the solution thus obtained. It Is heated under reflux and is maintained under agitation under a light nitrogen flow until ammonia is no longer evolved and the pH of the solution becomes slightly acidic. It is cooled to room temperature and is seed crystallized with 0.5 g of sertraline hydrochloride form II. A crystalline solid begins to precipitate and agitation is maintained for 1.5 hours. The solid is filtered, washed and dried under vacuum. 49.3 g of sertraline hydrochloride form II (yield 88%) are obtained.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:6][CH:7]=1.[OH:13][C:14]1[C:26]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>>[OH:13][C:14]1[C:26]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:24]=[C:23]([CH2:31][O:32][C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:3]=3)=[CH:35][CH:34]=2)[C:15]=1[C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: CC(C)(C)OC(=O)c1c(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)ccc(C(F)(F)F)c1O
Reactant: CS(=O)(=O)Nc1cccc(I)c1
Product: CC(C)(C)OC(=O)c1c(COc2ccc(-c3cccc(NS(C)(=O)=O)c3)cc2)ccc(C(F)(F)F)c1O

Procedure:
According to a method similar to Example (31), from N-(3-iodophenyl)methanesulfonamide (134 mg, 0.45 mmol) obtained in Example (35-1) and tert-butyl 2-hydroxy-6-{[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]methyl}-3-(trifluoromethyl)benzoate (250 mg, 0.51 mmol) obtained in Example (22-4), the title compound was obtained as a pale violet powder (20 mg, yield: 8%).
Reaction SMILES: Br[C:2]1(Br)[C:4]2([CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:3]1.[PH2](O)=O>O.C(#N)C>[CH2:3]1[C:4]2([CH2:8][C@@H:7]([C:9]([O:11][CH3:12])=[O:10])[N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:5]2)[CH2:2]1
Reactant: COC(=O)[C@@H]1CC2(CN1C(=O)OC(C)(C)C)CC2(Br)Br
Agent: O=[PH2]O
Solvent: CC#N
Solvent: O
Product: COC(=O)[C@@H]1CC2(CC2)CN1C(=O)OC(C)(C)C
Temperature: 90 °C

Procedure:
To the solution of (6S)-5-tert-butyl 6-methyl 1,1-dibromo-5-azaspiro[2.4]heptane-5,6-dicarboxylate (69 mg, 0.167 mmol) in water (1 mL) and ACN (0.5 mL) were added the hypophosphorous acid (0.078 mL, 0.96 mmol), TEA (0.27 mL, 1.92 mmol) and V-50 (4.5 mg, 0.0167 mmol). The solution was degassed and was heated at 90° C. for 15 hours. After being cooled, the solution was diluted with H2O, extracted with EtOAc (×3) and was dried (Na2SO4), concentrated. The crude product was treated under the conditions above for another 15 hours. After cooled, the solution was diluted with H2O (10 mL) and tuned to pH 4 by adding aq HCl (4 N). The aqueous phase was extracted with EtOAc (×3), dried (Na2SO4). After concentrated under vacuum, the title compound was obtained as colorless oil (20 mg, 42%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:4][N:3]=1.ClC1C=CC=[C:25]([C:29]([O:31]O)=[O:30])C=1>O1CCCC1>[C:29]([O:31][CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]2[N:11]=[C:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[O:13][C:14]=2[CH3:15])=[CH:4][N:3]=1)(=[O:30])[CH3:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Solvent: C1CCOC1
Product: CC(=O)OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.1 %

Procedure:
A mixture of 2-methyl-5-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (18.04 g), 3-chloroperbenzoic acid (18.85 g) and tetrahydrofuran (100 mL) was stirred overnight at room temperature and concentrated. The residue was subjected to silica gel column chromatography to give a colorless oil from a fraction eluted with tetrahydrofuran. A solution of the obtained colorless oil in acetic anhydride (100 mL) was slowly added to acetic anhydride (200 mL) heated to 130° C. and the mixture was stirred for 2 hrs. and concentrated. The residue was dissolved in ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate and then with saturated brine, dried (MgSO4) and concentrated. The residue was subjected to silica gel column chromatography to give [5-(5-methyl-2-phenyl-4-oxazolylmethoxy)-2-pyridylmethyl] acetate (18.09 g, yield 83%) as a colorless oil from a fraction eluted with ethyl acetate-hexane (1:2, volume ratio).
Reaction SMILES: [C:1]([NH:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.N>C(Cl)Cl>[NH:12]1[CH2:13][CH2:14][CH2:15][CH:10]([NH:9][C:1](=[O:8])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCCC(NC(=O)c2ccccc2)C1
Agent: N
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CCCNC1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 105.6 %

Procedure:
A solution of tert-butyl 3-(benzoylamino)piperidine-1-carboxylate (0.120 g) in DCM (5 ml) was treated with trifluoroacetic acid (5 ml) and stirred at room temperature for 6 h. The mixture was concentrated under reduced pressure to give a yellow oil which following neutralisation with aqueous ammonia solution, was purified using SPE (silica, eluting with methanol and 5% aqueous ammonia in methanol) to give the title compound (0.085 g) as an off-white solid.