Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:32]=[CH:31][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[S:30][CH2:29][CH2:28][CH2:27][S:26]3)=[CH:21][CH:20]=2)=[CH:9][CH:8]=1.C([Li])CCC.[CH3:38][Ge:39](Cl)([CH3:41])[CH3:40].O>O1CCCC1.CCCCCC.C(OCC)(=O)C>[CH3:38][Ge:39]([CH3:41])([CH3:40])[C:2]1([C:7]2[CH:32]=[CH:31][C:10]([O:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4([Ge:39]([CH3:41])([CH3:40])[CH3:38])[S:26][CH2:27][CH2:28][CH2:29][S:30]4)=[CH:21][CH:20]=3)=[CH:9][CH:8]=2)[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: C[Ge](C)(C)Cl
Reactant: c1cc(C2SCCCS2)ccc1OCCCCCCOc1ccc(C2SCCCS2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: C[Ge](C)(C)C1(c2ccc(OCCCCCCOc3ccc(C4([Ge](C)(C)C)SCCCS4)cc3)cc2)SCCCS1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
A suspension of 8.11 g (16.0 mmol) 1,6-bis[4-(1,3-dithian-2-yl)phenoxy]hexane in 50 ml anhydrous tetrahydrofuran (THF) was prepared under argon in a dry 250-ml three-necked flask with 50 ml dropping funnel, internal thermometer, magnetic stirrer and septum. The suspension was cooled to −10° C. and 14.1 ml of a 2.5 molar solution of n-butyl lithium (35.2 mmol) in hexane added dropwise over a period of 10 min such that the internal temperature did not exceed 0° C. The brown solution was then stirred for 3 h at −10° C. and a solution of 4.90 g (32.0 mmol) trimethylgermanium chloride in 20 ml anhydrous THF added dropwise to it at −5° C. within 5 min. The reaction mixture was stirred for a further 24 h at room temperature. 50 ml water and 150 ml ethyl acetate were then added and the resultant phases separated. The organic phase was washed twice with 50 ml each time and the combined aqueous phases were re-extracted with 50 ml ethyl acetate. Finally, the combined organic phases were washed with 80 ml saturated aqueous NaCl solution and dried over anhydrous sodium sulphate. After separating off the desiccant, the reaction mixture was concentrated on the rotary evaporator and the product dried to constant weight under fine vacuum. 10.9 g (92% of the theoretical value) 1,6-bis{4-[2-(trimethylgermyl)-1,3-dithian-2-yl]phenoxy}hexane was obtained as a pale-yellowish solid (m.p.: 147-153° C.).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=1[CH:4]=O.[SH:11][CH2:12][C:13](=[O:15])[CH3:14].CCN(CC)CC.O>CS(C)=O>[C:13]([C:12]1[S:11][C:2]2[CH:9]=[CH:8][CH:7]=[C:6]([I:10])[C:3]=2[CH:4]=1)(=[O:15])[CH3:14]
Reactant: O=Cc1c(F)cccc1I
Reactant: CC(=O)CS
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CC(=O)c1cc2c(I)cccc2s1
Temperature: 80 °C
Yield: 60.6 %

Procedure:
A mixture of 2.53 g (10.1 mmol) of 2-fluoro-6-iodo benzaldehyde, 1.0 g (11.1 mmol) of mercapto-2-propanone and 3.5 mL (2.5 g, 25 mmol) of Et3N in 15 mL of DMSO was heated to 80° C. overnight. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water (2 times), brine and dried over MgSO4. After evaporation of the solvents, the crude product was purified over silica gel column chromatography to afford 1.85 g (6.12 mmol, yield: 61%) of 2-acetyl-4-iodo benzo[b]thiophene as an orange powder. 1H-NMR (CDCl3), δ: 7.97 (s, 1H), 7.83 (d, J=7.9 Hz, 2H), 7.16 (t, J=7.9 Hz, 1H), 2.70 (s, 3H).
Reaction SMILES: O=[C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)O1.[H-].[Na+]>C1COCC1>[C:16]1([C:4]2[C:5]3[CH2:4][C:16]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:2]=3[C:7]([C:8]#[N:9])=[C:6]([N:10]3[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]3)[CH:5]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)oc1=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: N#Cc1c(N2CCCCC2)cc(-c2ccccc2)c2c1-c1ccccc1C2

Procedure:
A mixture of 2-oxo-6-phenyl-4-(piperidin-1-yl)-2H-pyran-3-carbonitrile (280 mg), indanone-1 (132 mg) and NaH (36 mg) in THF was stirred for <5 min. After completion, the reaction solvent was evaporated under vacuum to dryness and crude solid was quenched with ice water and subsequently neutralized with dil. HCl, finally purified by column chromatography using ethylacetate-hexane as eluent. White solid; mp 156-156° C.; ESIMS 351 (M++1); IR (KBr) 2214 cm−1 (CN);
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([OH:18])[CH2:10][CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7][CH2:6]2)[CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:1]1([CH2:4][C:5]2([OH:18])[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(CC2CC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: OC1(CC2CC2)CCNCC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of compound 14B (1 eq.) in DCM, was added TFA (10 eq.), the reaction mixture was stirred at room temperature for about 2 hours, when LCMS detected no s.m. The reaction mixture was concentrated to afford the desired product 14C. The crude product was used for the next step directly without further purification. LC-MS: m/z 156.2 (M+H)+
Reaction SMILES: [CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18]O)[C@@H:14]([OH:15])[C@H:12]1[OH:13].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.CC1N=CN=C2C=1NC=N2.[I:54]I>O1C=CC=C(O)C1>[CH3:1][C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C@@H:11]1[O:17][C@H:16]([CH2:18][I:54])[C@@H:14]([OH:15])[C@H:12]1[OH:13]
Reactant: II
Reactant: Cc1ncnc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Agent: Cc1ncnc2nc[nH]c12
Agent: OC1=CC=COC1
Agent: c1c[nH]cn1
Product: Cc1ncnc2c1ncn2[C@@H]1O[C@H](CI)[C@@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The reaction is carried out according to Example 5 starting from 6-Methyl-9-(β-D-ribofuranosyl)purine (2a in Table VII) (108 mg, 0.41 mmol), triphenylphosphine (361 mg, 1.36 mmol), and imidazole (185 mg, 2.70 mmol) in M-PYROL (2 ml). Hassan et al., Convenient Synthesis of 6-Methylpurine and Related Nucleosides, Nucleosides, Nucleotides, & Nucleic Acids, 19, 1123-1134 (2000). Iodine beads (1-3 mm) (339 mg, 1.33 mmol) are added over 10 min. The resulting red solution is stirred at room temperature for 4 h at which time TLC indicated complete reaction. No further addition of reagents is required. After aqueous workup and purification by preparative TLC as described for per Example 5, pure 2b (93 mg, 61%) crystallized from 1:1 H2O/MeCN as a white solid.
Reaction SMILES: [C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([OH:32])[C:26]([CH3:34])([CH3:33])[CH2:25]1)(=[O:22])[C:2]1[C:3](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:14])([CH3:13])[N:10]([OH:15])[C:9]([CH3:17])([CH3:16])[CH2:8]1)=[O:5].[CH2:35]([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[CH3:36].[O-]O>O.[Mo]=O>[C:4]([O:6][CH:7]1[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([O:15][CH:35]([CH3:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:9]([CH3:17])([CH3:16])[CH2:8]1)(=[O:5])[C:3]1[C:2](=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:1]([O:23][CH:24]1[CH2:29][C:28]([CH3:31])([CH3:30])[N:27]([O:32][CH:35]([CH3:36])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:26]([CH3:34])([CH3:33])[CH2:25]1)=[O:22]
Reactant: CC1(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(O)C(C)(C)C2)CC(C)(C)N1O
Reactant: CCc1ccccc1
Agent: O=[Mo]
Agent: [O-]O
Solvent: O
Product: CC(ON1C(C)(C)CC(OC(=O)c2ccccc2C(=O)OC2CC(C)(C)N(OC(C)c3ccccc3)C(C)(C)C2)CC1(C)C)c1ccccc1
Temperature: 110 °C
Yield: 88 %

Procedure:
The compound is prepared from 40.0 g of di-(1-oxyl-2,2,6,6-tetramethylpiperidin-4-yl) phthalate, 200 ml of ethylbenzene, and 2.0 g of molybdenum oxide which are heated to 110° C. (nitrogen atmosphere). Thereafter, 65 g of 70% t-butyl hydroxperoxide in water is added dropwise over one hour. The reaction mixture is refluxed for 3 hours after the hydroperoxide addition is complete. The crude product is chromatographed on silica gel (9:1 hexane: ethyl acetate) to give 51.0 g (88% yield) of a soft glassy product.
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11](=[O:13])[CH3:12].[H-].[Na+].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C)C=O>[CH2:16]([O:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[CH:5]=[C:4]([CH3:10])[C:3]=1[C:11](=[O:13])[CH3:12])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CC(=O)c1c(C)cc(C)c(C)c1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)c1c(C)cc(C)c(C)c1OCc1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 78.7 %

Procedure:
In N,N-dimethylformamide (8 mL) was dissolved 2.00 g (11.2 mmol) of 1-(2-hydroxy-3,4,6-trimethylphenyl)ethanone obtained in Example 622 (2). To the solution was added in an ice bath 0.488 g (11.2 mmol) of 60% sodium hydride, and after stirring in an ice bath for 10 minutes, 1.92 g (11.2 mmol) of benzyl bromide was gradually added dropwise and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, and extracted with ethyl acetate. The organic layer was successively washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed, and the obtained residue was purified by silica gel column chromatography (Wako gel C-100, hexane-ethyl acetate, gradient) to obtain 2.36 g (8.81 mmol, Yield: 78.7%) of 1-[2-(benzyloxy)-3,4,6-trimethylphenyl]ethanone.
Reaction SMILES: [F:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19](O)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[N:66]1[CH:71]=[CH:70][CH:69]=[C:68]([CH2:72][NH2:73])[CH:67]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[C@@H:11]([CH3:12])[CH2:10][N:9]([C:13]3[S:14][C:15]([C:19]([NH:73][CH2:72][C:68]4[CH:67]=[N:66][CH:71]=[CH:70][CH:69]=4)=[O:20])=[C:16]([CH3:18])[N:17]=3)[C:8]2=[O:22])=[CH:23][CH:24]=1
Reactant: NCc1cccnc1
Reactant: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(N2C[C@H](C)N(Cc3ccc(F)cc3)C2=O)sc1C(=O)NCc1cccnc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
To a solution of (S)-2-(3-(4-fluorobenzyl)-4-methyl-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylic acid (0.11 g, 0.30 mmol) in anhydrous tetrahydrofuran (3.0 mL) was added 1-hydroxybenzotriazole (HOBt) (0.08 g, 0.60 mmol), 2-(1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU) (0.19 g, 0.60 mmol), N,N-diisopropylethylamine (0.23 g, 1.80 mmol) and pyridin-3-ylmethanamine (0.05 g, 0.45 mmol). The resulting mixture was stirred at ambient temperature for 16 h and concentrated in vacuo. The residue was diluted in ethyl acetate (100 mL), washed with saturated aqueous sodium bicarbonate solution (20 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated in vacuo and the residue was purified by column chromatography eluted with 2-8% methanol in dichloromethane to afford the title compound as a colorless solid (0.09 g, 70%): mp 67-70° C. (hexanes/diethyl ether); 1H NMR (300 MHz, DMSO-d6) δ 8.57 (t, J=5.9 Hz, 1H), 8.53 (d, J=1.9 Hz, 1H), 8.45 (dd, J=4.8, 1.5 Hz, 1H), 7.72-7.69 (m, 1H), 7.40-7.34 (m, 3H), 7.18 (dd, J=8.8, 8.8 Hz, 2H), 4.59 (d, J=15.6 Hz, 1H), 4.40 (d, J=5.9 Hz, 2H), 4.30 (d, J=15.6 Hz, 1H), 4.19 (dd, J=10.1, 9.1 Hz, 1H), 3.80-3.69 (m, 1H), 3.55 (dd, J=10.1, 6.2 Hz, 1H), 2.47 (s, 3H), 1.22 (d, J=6.2 Hz, 3H); 13C NMR (75 MHz, DMSO-d6) δ161.5 (d, 1JC-F=244 Hz), 161.8, 157.2, 154.9, 151.2, 148.8, 148.0, 135.1, 135.1, 133.1 (d, 4JC-F=3 Hz), 130.0 (d, 3JC-F=8 Hz), 123.5, 117.6, 115.4 (d, 2JC-F=21 Hz), 49.4, 48.6, 43.7, 40.4, 18.4, 17.1; MS (ES+) m/z 439.9 (M+1).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:5](=[O:19])[O:6][C:7]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[C:11]([O:17][CH3:18])[C:8]=2[C:9]=1[CH3:10].[F:20][C:21]([F:35])([F:34])[C:22]1[CH:23]=[C:24]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH:25]=[CH:26][CH:27]=1>C(O)(C)C>[CH3:18][O:17][C:11]1[C:8]2[C:9]([CH3:10])=[C:4]([CH2:3][CH2:2][N:31]3[CH2:30][CH2:29][N:28]([C:24]4[CH:25]=[CH:26][CH:27]=[C:22]([C:21]([F:34])([F:35])[F:20])[CH:23]=4)[CH2:33][CH2:32]3)[C:5](=[O:19])[O:6][C:7]=2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Reactant: COc1cc(OC)c2c(C)c(CCCl)c(=O)oc2c1
Solvent: CC(C)O
Product: COc1cc(OC)c2c(C)c(CCN3CCN(c4cccc(C(F)(F)F)c4)CC3)c(=O)oc2c1
Yield: 47 %

Procedure:
Process B; starting materials: 3-(2-chloroethyl)-5,7-dimethoxy-4-methyl-2H-1-benzopyran-2-one (Example 39) and 1-(3-trifluoromethylphenyl)piperazine; yield 47%; m.p. 138°-139° C. (from isopropanol).
Reaction SMILES: [C:1]1([C:7]2[S:15][C:14]3[C:13]([NH:16][C:17]4[CH:18]=[C:19]5[C:23](=[CH:24][CH:25]=4)[NH:22][CH:21]=[C:20]5[CH:26]=O)=[N:12][CH:11]=[N:10][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([BH3-])#N.[Na+].[Cl-].[NH4+].Cl>C(Cl)Cl.[I-].[Zn+2].[I-]>[CH3:26][C:20]1[C:19]2[C:23](=[CH:24][CH:25]=[C:17]([NH:16][C:13]3[C:14]4[S:15][C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][C:9]=4[N:10]=[CH:11][N:12]=3)[CH:18]=2)[NH:22][CH:21]=1
Reactant: O=Cc1c[nH]c2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc12
Agent: Cl
Agent: [BH3-]C#N
Agent: [Cl-]
Solvent: ClCCl
Product: Cc1c[nH]c2ccc(Nc3ncnc4cc(-c5ccccc5)sc34)cc12
Temperature: 25 °C
Yield: 30.4 %

Procedure:
To a suspension of 5-(6-phenyl-thieno[3,2-d]pyrimidin-4-ylamino)-1H-indole-3-carbaldehyde (75 mg, 0.203 mmol) in 5 mL of methylene chloride was added zinc iodide (97 mg, 0.303) and sodium cyanoborohydride (97 mg, 1.522 mmol). The reaction mixture was refluxed for 24 hours and then cooled to ambient temperature and poured into an ice-cooled mixture of saturated ammonium chloride. The solution was then neutralized with 6N HCl and extracted with ethyl acetate (3×, 50 mL). The organic extracts were dried over magnesium sulfate and concentrated in vacuo. The residue was chromatographed using a Biotage Autoflash 40 system and 1% MeOH/CH2Cl2 to produce the title compound (22 mg, 31% yield). RP18-HPLC RT: 6.071 minutes; API MS: 357.10 (M+1); MP: 221-223° C.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22]Br.[CH3:24][O:25][P:26]([O:29]C)[O:27][CH3:28]>>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)[C:3]=1[CH2:22][P:26](=[O:29])([O:27][CH3:28])[O:25][CH3:24]
Reactant: Cc1ccc(-c2c(CBr)c(C)nc3sc4c(c23)CCCC4)cc1
Reactant: COP(OC)OC
Product: COP(=O)(Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCCC3)OC

Procedure:
A solution of (2-methyl-4-(p-tolyl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl)bromomethane (0.309 g; 0.8 mmol) in trimethylphosphite (8 mL) was heated at reflux for 18 h. The volatiles were removed under reduced pressure and the remaining residue was used in the next step without further purification.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[C:14]1[C:28]([O:30]C(C)(C)C)=[O:29]>ClCCl>[Cl:8][C:9]1[CH:10]=[C:11]([CH:35]=[CH:36][C:37]=1[Cl:38])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([N:22]2[CH2:23][CH2:24][O:25][CH2:26][CH2:27]2)=[C:14]1[C:28]([OH:30])=[O:29]
Reactant: CC(C)(C)OC(=O)c1c(N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1c(N2CCOCC2)c2ccccc2n1Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.6 %

Procedure:
Trifluoroacetic acid (5 ml) was added to a solution of t-butyl N-(3,4-dichlorobenzyl)-3-morpholinoindole-2-carboxylate (293 mg) in dichloromethane (10 ml) and the reaction stirred at ambient temperature overnight. The reaction was concentrated in vacuo and the residue purified by column chromatography using 20% ethyl acetate:iso-hexane as eluent to afford the product as a brown solid (125 mg, 30%); NMR d (CD3SOCD3) 3.10 (t, 4H), 3.83 (t, 4H), 5.36 (s, 2H), 7.01 (t, 1H), 7.12 (m, 2H), 7.46 (m, 2H), 7.58 (m, 2H), M/z(−) 404.2 (M−H+).
Reaction SMILES: C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].N[C@H:23]([CH2:36]O)[C@@H:24](C1C=CC(S(C)(=O)=O)=CC=1)O.C(=O)([O-])[O-].[K+].[K+]>CO.CC(C)=O.C1(C)C=CC=CC=1>[CH3:24][C:23]1([CH3:36])[NH:18][C@H:5]([CH2:4][OH:19])[C@@H:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[O:7]1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CC(C)=O
Product: CC1(C)N[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)O1
Temperature: 80 °C

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in 500 mL of methanol reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C. to quantitatively yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.36 g, 0.3480 moles) in solution. Toluene (500 mL) and acetone (500 mL) replace methanol which distills off. Addition of potassium carbonate (6.9 g, 0.0696 moles) with heating at 75-85° C. for 12-18 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of potassium carbonate (19.0 g, 0.1914 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the crude product. Filtration, washing with water (250 mL) then drying yields (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].C(OCC)C.[CH:17]([Mg]Br)([CH3:19])[CH3:18].Cl>[Cu]Cl.O>[F:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4](=[O:5])[CH:17]([CH3:19])[CH3:18]
Reactant: O=C(Cl)c1ccc(F)cc1F
Reactant: CC(C)[Mg]Br
Agent: Cl[Cu]
Agent: Cl
Solvent: O
Solvent: CCOCC
Product: CC(C)C(=O)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 83 %

Procedure:
To a mixture of 120 g (0.68 mmol) of 2,4-difluorobenzoyl chloride, 3.7 g (37 mmol) of copper (I) chloride, and 400 ml of diethyl ether was added dropwise 442 ml of diethyl ether containing 130.2 g (0.88 mol) of isopropylmagnesium bromide at -25° C. over 4 hours. The temperature was elevated up to -5° C., and the mixture was stirred at that temperature for 30 minutes. To the reaction mixture were added dropwise 150 ml of water and then 120 ml of 6N hydrochloric acid. The organic layer was separated, washed successively with 5% hydrochloric acid, a saturated sodium chloride aqueous solution, a saturated sodium carbonate aqueous solution, and a saturated sodium chloride aqueous solution, and dried. The solvent was removed by distillation under reduced pressure, and the residue was distilled under reduced pressure to obtain 104.3 g (83%) of 1-(2,4-difluorophenyl)-2-methylpropan-1-one as a colorless oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[CH:21]=[CH:20][C:19]4[CH:28]=[CH:29][CH:30]=[CH:31][C:18]3=4)[CH2:13][CH2:12]2)=[CH:4][CH:3]=1.[C:32](OC(=O)C)(=[O:34])[CH3:33]>>[C:32]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14](=[C:17]3[C:18]4[CH:31]=[CH:30][CH:29]=[CH:28][C:19]=4[CH:20]=[CH:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]3=4)[CH2:13][CH2:12]2)=[CH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(CCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Product: CC(=O)Nc1ccc(CCCN2CCC(=C3c4ccccc4C=Cc4ccccc43)CC2)cc1
Yield: 92.9 %

Procedure:
This was prepared from 1-(4-Aminophenyl)-3-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-piperidinyl]propane (compound 8) and acetic anhydride. Yield 92.9%
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]=[O:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[Cl-].[NH4+]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH2:13][OH:14])=[C:11]([CH3:15])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: Cc1nnn(-c2ccc(F)cc2)c1C=O
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nnn(-c2ccc(F)cc2)c1CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.9 %

Procedure:
To a solution of 3-(4-fluoro-phenyl)-5-methyl-3H-[1,2,3]triazole-4-carbaldehyde (2.28 g, 11 mmol) in MeOH (180 mL) was added sodiumborohydride (210 mg, 6.0 mmol) at 0° C., and the resulting mixture stirred at 0° C. for 30 min, The mixture was then poured into saturated ammonium chloride solution and extracted with ethyl acetate and the combined organic extracts washed with brine, dried over sodium sulphate, filtered and evaporated to afford the title compound (2.05 g, 89%) as a white solid. MS: m/e=208.2 [M]+.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=O.[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][CH:14]=1.CC([O-])=O.C([BH3-])#N.[Na+]>CO>[Cl:12][C:13]1[CH:19]=[CH:18][C:16]([NH:17][CH2:1][C:3]2[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=2)=[CH:15][CH:14]=1
Reactant: O=Cc1ccc(C(=O)O)cc1
Reactant: Nc1ccc(Cl)cc1
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(O)c1ccc(CNc2ccc(Cl)cc2)cc1
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 102.4 %

Procedure:
4-Formylbenzoic acid (15 g, 100 mmol) was suspended in methanol (500 mL) and 4-chloroaniline (12.7 g, 100 mmol) was added. The resulting suspension was heated at reflux temperature for 30 minutes and subsequently cooled to approximately 35° C. Acetic cid glacial (50 mL) was added followed by sodium cyanoborohydride (4.96 g, 80 mmol) in portions. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated in vacuo to approximately 150 mL by rotary evaporation. Water (150 mL) was added and the resulting suspension was stirred at room temperature for 16 hours. Filtration, washing with water and drying afforded 26.8 g (100%) 4-[(4-chlorophenylamino)-methyl]benzoic acid as a solid.
Reaction SMILES: [Mg].Br[C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=1.Cl[P:12](=[O:20])(Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>BrCCBr.O1CCCC1>[CH3:10][O:9][C:6]1[CH:7]=[CH:8][C:3]([P:12](=[O:20])([C:3]2[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][CH:4]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:5]=1
Reactant: O=P(Cl)(Cl)c1ccccc1
Reactant: COc1ccc(Br)cc1
Agent: [Mg]
Solvent: BrCCBr
Solvent: C1CCOC1
Product: COc1ccc(P(=O)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 70 °C
Yield: 92.6 %

Procedure:
A slurry of magnesium (133.7 g, 5.50 mol), tetrahydrofuran (988 g), and 1,2-dibromoethane (0.1 g, 0.5 mmol) was refluxed for 20 min. under a blanket of nitrogen. 4-Bromoanisole (1002 g, 5.357 mol) was added by drop over 6 h at a rate to maintain 70° C. The reaction mixture was heated for an additional hour. Dichlorophenylphosphine oxide (479.4 g, 2.459 mol) was added by drop to maintain a temperature of 35° C. over 5 h. The reaction mixture was worked up to give bis(4-methoxyphenyl)phenylphosphine oxide (770.8 g, 93% yield) as a viscous amber oil. 31P NMR: (d6-DMSO) δ 30.2 (s).