Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]#[C:19][C:20]1[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.C(O)(=O)C>[Fe].O>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[C:10]([C:18]#[C:19][C:20]2[CH:21]=[C:22]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH:23]=[CH:24][CH:25]=2)[CH:11]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc([N+](=O)[O-])ccc2NC(=O)OC(C)(C)C)c1
Agent: [Fe]
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)Nc1cccc(C#Cc2cc(N)ccc2NC(=O)OC(C)(C)C)c1
Temperature: 60 °C
Yield: 90.5 %

Procedure:
Into the reaction flask was added tert-butyl [3-({2-[(tert-butoxycarbonyl)amino]-5-nitrophenyl}ethynyl)phenyl]carbamate (2.7 g, 6.0 mmol), methanol (70 mL), acetic acid (10 mL), and water (7 mL). Then iron powder (1.8 g, 30 mmol) was added. The reaction mixture was heated at 60° C. for 3 h. After filtration, the cake was rinsed with EtOAc. The filtrate was concentrated and the residue was diluted with NaHCO3 (aq) and EtOAc. After the layers were separated, the organic layer was dried, filtered and concentrated to give the desired product (2.3 g, 91%). LCMS for C24H30N3O4 (M+H)+: m/z=424.2.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:3]=1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([O:23]C)=[O:22].[O-2].[Li+].[Li+].Cl>O1CCOCC1.O>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[CH:20]([CH2:25][CH2:26][CH3:27])[C:21]([OH:23])=[O:22]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Agent: Cl
Agent: [Li+]
Agent: [O-2]
Solvent: C1COCCO1
Solvent: O
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1ccccc1)CCC3
Temperature: 60 °C
Reaction time: 2.5 h
Yield: 47.8 %

Procedure:
To a solution of methyl [2-methyl-4-phenyl-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]pentanoate (0.111 g; 0.292 mmol) in dioxane (4 mL) and water (1 mL) was added a 1N lithium oxide solution (1.8 mL; 1.80 mmol). The reaction mixture was heated at 60° C. for 3 h and 1N lithium oxide solution (0.9 mL; 0.90 mmol) was added again. After 2.5 h at 60° C., the reaction mixture was acidified with 1N HCl (pH˜2) and partially concentrated under reduced pressure. The residue was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over sodium sulphate, filtered and concentrated under reduced pressure. The residue was crystallized from a mixture of ethyl acetate/heptane to afford 0.051 g (48%) of the title compound as a white powder.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([NH2:12])[C:2]=12.[CH3:13][CH2:14][O:15]C(C)=O.O(C(C)C)C(C)C.[NH4+].[OH-]>C(Cl)Cl.CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]2[CH2:7][CH2:8][CH2:9][CH2:10][C@@H:11]([NH:12][C:14](=[O:15])[CH3:13])[C:2]=12
Reactant: CCOC(C)=O
Reactant: NC1CCCCc2cccnc21
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: CC(C)OC(C)C
Solvent: ClCCl
Product: CC(=O)N[C@@H]1CCCCc2cccnc21
Reaction time: 24 h

Procedure:
Following the general procedure, 6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (195 mg, 1.20 mmol), CALB (59 mg), EtOAc (0.48 mL) and iPr2O (4.6 mL) were stirred for 24 hours. The conversion determined from 1H NMR by integration of the peaks at 5.05 ppm (CHNHAc) and 4.34 ppm (CHNH2) was 58%. Flash chromatography of the material on silica gel using 1:10 MeOH:CH2Cl2 followed by 1:1:4 NH4OH:MeOH:CH2Cl2 furnished the (R)—N-(6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl)acetamide ((134 mg, 55%) in 45% ee (chiral GC method: 180° C. for 15 min, ramp rate of 10° C./min to 210° C., hold 10 min, (S)-(−)-enantiomerrt=17.4 min, (R)-(+)-enantiomerrt=17.1 min); [α]D=−10° (c 1.34, CHCl3); 1H NMR (CDCl3, 300 MHz)δ 1.09–1.31 (m, 2H), 1.80–2.03 (m, 3H), 2.06 (s, 3H), 2.24 (d, 1H, J=13.5 Hz), 2.65–2.71 (m, 1H), 2.75–2.85 (m, 1H), 4.96–5.01 (m, 1H), 7.06 (dd, 1H, J=7.0, 4.8 Hz), 7.38 (d, 1H, J=7.0 Hz), 8.11 (br s, 1H), 8.28 (d, 1H, J=4.8 Hz); 13C NMR (CDCl3) δ 24.0, 27.3, 30.1, 34.5, 34.8, 53.8, 122.8, 137.0, 137.5, 145.5, 159.2, 169.6; MS m/z: 205 (M+H+). The unreacted (S)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-ylamine (was isolated in 41% yield (81 mg) and 61% ee (chiral GC, (S)-enantiomerrt=5.81 min, (R)-enantiomerrt=6.00 min)[α]D=+2° (c 1.13, CHCl3); and displayed spectra identical to the starting material: 1H NMR (CDCl3, 300 MHz) δ 1.20–1.35 (m, 1H), 1.36–1.53 (m, 1H), 1.75–2.01 (m, 4H), 2.15 (br s, 2H), 2.69–2.77 (m, 2H), 4.16 (d, 1H, J=8.7 Hz), 6.95–7.06 (m, 1H), 7.32 (d, 1H, J=6.0 Hz), 8.34 (br s, 1H),
Reaction SMILES: [P:1]([O-:6])([O:4][CH3:5])[O:2][CH3:3].[CH:7](=[O:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl>>[OH:14][C@@H:7]([P:1](=[O:6])([O:4][CH3:5])[O:2][CH3:3])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=Cc1ccccc1
Reactant: COP([O-])OC
Agent: Cl
Product: COP(=O)(OC)[C@H](O)c1ccccc1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
The solution of ALB in tetrahydrofuran (0.1 M, 0.40 ml) obtained in Example 1 was concentrated at room temperature for 1 hour under reduced pressure, then 0.4 ml of toluene was added thereto under an argon atmosphere. To this solution was added dimethyl phosphite (37 μl, 0.40 mmol) at room temperature. After stirring for 30 minutes, the reaction vessel was cooled to -40° C., and it was maintained at this temperature for 15 minutes. Benzaldehyde (0.40 mmol) then was added thereto. After reacting for 51 hours, 1N hydrochloric acid was added thereto to stop the reaction. The mixture -was extracted with ethyl acetate (10 ml×three times). The combined extracts were washed with brine and dried over Na2SO4. The solvent was distilled, and the residue was purified by flash column chromatography (acetone/hexane=1/5, on SiO2) to obtain dimethyl (S)-hydroxy-phenylmethylphosphonate as final product in a yield of 90%. The chemical reaction in this Example is shown in chemical formula 27. ##STR21##
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:14]([NH2:16])=[N:13][CH:12]=[N:11][C:10]=3[NH:9][C:8]=2[Si:17]([CH2:22][CH3:23])([CH2:20][CH3:21])[CH2:18][CH3:19])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:38]1[CH2:42][CH2:41][CH2:40][C@H:39]1[C:43](O)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CN(C1C=CN=CC=1)C.CN(C=O)C.C1COCC1.ClCCl>[C:1]1([C:7]2[C:15]3[C:14]([NH:16][CH2:43][C@@H:39]4[CH2:40][CH2:41][CH2:42][O:38]4)=[N:13][CH:12]=[N:11][C:10]=3[NH:9][C:8]=2[Si:17]([CH2:20][CH3:21])([CH2:22][CH3:23])[CH2:18][CH3:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC[Si](CC)(CC)c1[nH]c2ncnc(N)c2c1-c1ccccc1
Reactant: O=C(O)[C@@H]1CCCO1
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Agent: [Al+3]
Solvent: C1CCOC1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC[Si](CC)(CC)c1[nH]c2ncnc(NC[C@@H]3CCCO3)c2c1-c1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a slurry of 4.00 g (12.3 mmol) of 5-phenyl-6-(triethylsilyl)-7-H-pyrrolo[2,3-d]pyrimidin-4-amine, 3.10 g (16.0 mmol) of EDC and 2.50 g (18.5 mmol) of HOBt and catalytic DMAP in 20 ml DMF was added dropwise 1.91 g (14.8 mmol) of (S)-tetrahydro-2-furoic acid at 0° C. The reaction mixture was stirred at 0° C. for 1 h, then was warmed to room temperature and stirred for 30 h. Dichloromethane (500 ml) was added and the mixture was washed with brine (1×), saturated aqueous sodium bicarbonate (1×), and brine (1×). The organic layer was dried over Na2SO4 and filtered. The crude amide was dissolved in 20 ml THF and added to a solution of 700 mg (27.1 mmol) of lithium aluminum hydride in 40 ml THF at 0° C. The slurry was warmed to room temperature and stirred for 1 h, and then to 50° C. and stirred for an additional 2 h. The reaction mixture was cooled to room temperature and poured into ice water. The aqueous material was extracted with ethyl acetate (4×). The combined organic layers were washed with brine (1×), dried over Na2SO4, filtered and purified by chromatography on silica gel (EtOAc:MeOH:Et3N, 9:1:0.1) to give the title compound. 1H-NMR (400 MHz, CDCl3)δ, 0.61 (q, J=7.6 Hz, 6 H), 0.89 (t, J=7.6 Hz, 9 H), 1.48 (m, 1 H), 1.69-1.85 (m, 3 H), 3.59-3.62 (m, 4 H), 3.94 (m, 1 H), 5.03 (s, 1 H), 7.28 (m, 3 H), 7.45 (m, 2 H), 8.33 (s, 1 H), 8.68 (s, 1 H). Mass Spectrum (ESI) m/e=409.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=2[CH:18]=1.B([O-])([O-])O[C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C(O)C.O.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>[F:28][C:27]([F:30])([F:29])[C:24]1[CH:25]=[CH:26][C:21]([C:2]2[CH:3]=[CH:4][C:5]3[S:11](=[O:13])(=[O:12])[CH2:10][CH2:9][C:8]([C:14]([O:16][CH3:17])=[O:15])=[CH:7][C:6]=3[CH:18]=2)=[CH:22][CH:23]=1
Reactant: [O-]B([O-])Oc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)C1=Cc2cc(Br)ccc2S(=O)(=O)CC1
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: [K+]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)C1=Cc2cc(-c3ccc(C(F)(F)F)cc3)ccc2S(=O)(=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
Under argon atmosphere, a mixture of methyl 7-bromo-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (1.00 g), 4-trifluoromethylphenyl borate (0.63 g) and potassium carbonate (0.84 g) in toluene/ethanol/water (30/3/3 ml) was stirred at room temperature for 1 hour. To the mixture was added tetrakistriphenylphosphinepalladium (0.174 g), and the mixture was refluxed for 16 hours, cooled, extracted with ethyl acetate, washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure. The residue was purified with column chromatography (ethyl acetate/hexane=1:2) to give pale yellow crystals of methyl 7-(4-trifluoromethylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (704.7 mg).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:45]([O:46]C(=O)C)[C@@H:44]([O:50]C(=O)C)[C@@H:43]([CH2:54][N:55]2C(=O)C3=CC=CC=C3C2=O)[O:42][C@H:6]1[S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C@H:15]1[CH2:39][CH2:38][C@@:37]2([CH3:40])[C:17](=[CH:18][CH2:19][C@@H:20]3[C@@H:36]2[CH2:35][CH2:34][C@@:33]2([CH3:41])[C@H:21]3[CH2:22][CH2:23][C@@H:24]2[C@H:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:16]1)(=O)C.C(Cl)(Cl)Cl.CO.[NH4+].[OH-].C(Cl)(Cl)Cl>CO.C(N)CCC>[NH2:55][CH2:54][C@H:43]1[O:42][C@@H:6]([S:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14][C@H:15]2[CH2:39][CH2:38][C@@:37]3([CH3:40])[C:17](=[CH:18][CH2:19][C@@H:20]4[C@@H:36]3[CH2:35][CH2:34][C@@:33]3([CH3:41])[C@H:21]4[CH2:22][CH2:23][C@@H:24]3[C@H:25]([CH3:32])[CH2:26][CH2:27][CH2:28][CH:29]([CH3:30])[CH3:31])[CH2:16]2)[C@H:5]([OH:4])[C@@H:45]([OH:46])[C@H:44]1[OH:50]
Reactant: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H]1OC(C)=O
Agent: [NH4+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: CCCCN
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCS[C@@H]5O[C@H](CN)[C@H](O)[C@H](O)[C@H]5O)CC[C@]4(C)[C@H]3CC[C@]12C

Procedure:
A suspension of 6-(5-cholesten-3β-yloxy)hexyl 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-1-thio-β-D-galactopyranoside (710 mg.) in methanol (10 ml.) and n-butylamine (10 ml.) is heated under reflux for 16 hours. The solution is evaporated to a crystalline mass. Chloroform is added and the solid is filtered and washed with chloroform. The combined filtrates are evaporated to a syrup which is put on a column of silica gel and eluted with chloroform-methanol-ammonium hydroxide (80:20:2). The desired fractions are combined and evaporated to a syrup which is triturated with ethyl ether to give crystals (390 mg. 76%); Rf 0.28 (CHCl3 -MeOH-NH4OH, 80:20:2), [α]D27 -29.5° C. (C 1.05, chloroform), m.s.: m/e 665 (M+ +1).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:12][CH:11]=1)[C:6]([OH:8])=O)=[O:4].S(Cl)(Cl)=O.[NH3:34]>C1C=CC=CC=1.C(OCC)(=O)C>[C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][O:19][C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[CH:23]3)=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])(=[O:8])[NH2:34]
Reactant: N
Reactant: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1ccc(OCCOc2ccc3ncccc3c2)cc1)C(N)=O
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 57.5 %

Procedure:
To a solution of 2-(methoxycarbonyl)-3-[4-[2-(6-quinolinoxy)ethoxy]phenyl]propionic acid (2.11 g, 5.29 mmol) in benzene (20 ml) at room temperature is added thionyl chloride (0.76 g, 6.34 mmol). Then the mixture was heated at 80° C. for 90 min. After cooled to room temperature, the solvent is removed under a vacuum. To the residue is added 28% ammonia solution (5.49 ml, 79.30 mmol) at room temperature. The mixture is stirred for 30 min, dissolved in ethyl acetate (20 ml), washed with brine (3×15 ml), dried over sodium sulfate, and concentrated. The crude product is crystallized from ethanol to give title compound (1.20 g, 57%). HRMS calcd for C22H26N2O5: 398.4558. Found: 398.4554. MA calcd for C22H26N2O5: C, 66.32%; H, 6.58%; N, 7.03%. Found: C, 66.44%; H, 6.54%; N, 7.05%
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][CH2:14][O:15][C:16]1[CH:31]=[CH:30][C:19]([CH2:20][CH:21]([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].[CH3:34]I.S([O-])(O)(=O)=O.[Na+]>CN(C)C=O>[CH3:34][C:21]([CH2:20][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH2:13][C:3]2[N:4]=[C:5]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:6][C:2]=2[CH3:1])=[CH:31][CH:30]=1)([C:26]([O:28][CH3:29])=[O:27])[C:22]([O:24][CH3:25])=[O:23]
Reactant: CI
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)C(C)(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Reaction time: 2 h
Yield: 61.9 %

Procedure:
Dimethyl 4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzylmalonate (4.24 g, 10.0 mmol) synthesized according to the method described in WO95/18125 was dissolved in dimethylformamide (40 ml), and sodium hydride (60% in oil, 480 mg, 12.0 mmol) was added at 0° C., which was followed by stirring for 2 hr. Methyl iodide (0.93 ml, 15.0 mmol) was added at room temperature and, 2.5 hours later, 1N sodium hydrogensulfate (100 ml) was added. The mixture was extracted three times with ethyl acetate. The extracted organic layer was washed with brine, dried over sodium sulfate and concentrated to dryness to give a crude title compound, which was purified and concentrated by silica gel column chromatography (developing solvent; hexane:ethyl acetate=10:1→7:1→5:1) to give the title compound (2.71 g, yield 62%) as a white solid.
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.[Br:13][C:14]1[CH:15]=[C:16]([F:22])[C:17]([F:21])=[C:18]([F:20])[CH:19]=1.[C:23](=[O:25])=[O:24].Cl>C1COCC1>[Br:13][C:14]1[C:19]([C:23]([OH:25])=[O:24])=[C:18]([F:20])[C:17]([F:21])=[C:16]([F:22])[CH:15]=1
Reactant: Fc1cc(Br)cc(F)c1F
Reactant: O=C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=C(O)c1c(Br)cc(F)c(F)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 84 %

Procedure:
To a solution of i-Pr2NH (3.65 mL, 25.8 mmol) in THF (50 mL) was added n-BuLi (10.3 mL, 25.8 mmol, 2.50 M solution in hexanes) at 0° C. After stirring for 15 minutes, the reaction mixture was cooled to −78° C. A solution of 5-bromo-1,2,3-trifluorobenzene (5.00 g, 23.7 mmol) in THF (5 mL) was added. The resulting mixture was stirred for 2 hours at −78° C., poured into an excess of freshly crushed dry ice, and stirred for 30 minutes To this mixture was added 10% aqueous HCl to adjust its pH to 1. The resulting mixture was extracted with ether (3×). The combined organic layers were washed with 5% aqueous NaOH (2×). The combined basic aqueous layers were acidified to pH 1 with concentrated HCl, and extracted with ether (2×). The combined organic layers were washed with water, dried over MgSO4, filtered, and concentrated in vacuo to give the desired product (5.06 g, 84%) that was used directly without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]([C:19](OCC)=[O:20])[C:14](OCC)=[O:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>O1CCCC1>[OH:20][CH2:19][CH:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:14][OH:15]
Reactant: CCOC(=O)C(CCCCCOCOCCOC)C(=O)OCC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COCCOCOCCCCCC(CO)CO
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.1 %

Procedure:
A solution of 10.29 g of diethyl 2-[5-(2-methoxyethoxy)methoxypentyl]malonate (prepared as described in Preparation 41) dissolved in 100 ml of tetrahydrofuran was added dropwise to 2.40 g of lithium aluminum hydride dispersed in 100 ml of tetrahydrofuran, whilst ice-cooling (at 5° to 7° C.). The mixture was stirred at room temperature for 3 hours, and then 9.60 ml of a 4% w/v aqueous solution of sodium hydroxide was added dropwise at 5° to 9° C. After stirring the mixture for 30 minutes at room temperature, it was filtered with a Celite filter aid, and the filtrate was concentrated by evaporation under reduced pressure. The residue was subjected to column chromatography through 105 g of silica gel and 6.94 g of the title compound were obtained from the fractions eluted with mixtures of methylene chloride and methanol ranging from 98:2 to 95:5 by volume, as a colorless oil.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH2:4][O:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[C:8]([CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[S:21][C:22]4[CH:28]=[C:27]([O:29][C:30]([F:33])([F:32])[F:31])[CH:26]=[CH:25][C:23]=4[N:24]=3)[C@H:16]([CH2:34][CH2:35][CH2:36][CH3:37])[CH2:15]2)[CH:7]=1.[OH-].[Na+].O1CCCC1.Cl>C(Cl)(Cl)Cl.O.CO>[CH2:34]([C@H:16]1[N:17]([C:20]2[S:21][C:22]3[CH:28]=[C:27]([O:29][C:30]([F:32])([F:33])[F:31])[CH:26]=[CH:25][C:23]=3[N:24]=2)[CH2:18][CH2:19][N:14]([CH2:13][C:8]2[CH:7]=[C:6]([CH:11]=[C:10]([CH3:12])[CH:9]=2)[O:5][CH2:4][C:3]([OH:38])=[O:2])[CH2:15]1)[CH2:35][CH2:36][CH3:37]
Reactant: CCCC[C@@H]1CN(Cc2cc(C)cc(OCC(=O)OC)c2)CCN1c1nc2ccc(OC(F)(F)F)cc2s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: CCCC[C@@H]1CN(Cc2cc(C)cc(OCC(=O)O)c2)CCN1c1nc2ccc(OC(F)(F)F)cc2s1
Temperature: 25 °C
Reaction time: 16 h
Yield: 92 %

Procedure:
A mixture of [3-[(R)-3-butyl-4-(6-trifluoromethoxybenzothiazole-2-yl)-piperazine-1-ylmethyl]-5-methylpheno xy]acetic acid methyl ester (203 mg), 2N sodium hydroxide (0.46 mL), tetrahydrofuran (2 mL) and methanol (2 mL) was stirred at room temperature for 16 hours. To the reaction solution were added water and chloroform. The mixture was neutralized with 2N hydrochloric acid. The reaction solution was extracted with chloroform. The organic layer was washed with brine, and dried over magnesium sulphate. The solvent was evaporated under reduced pressure to give the title compound (182 mg). Yield: 91%.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][CH:9]=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[Li]CCCC.CN([CH:20]=[O:21])C.[BH4-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[S:8][C:9]([CH2:20][OH:21])=[CH:10][CH:11]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2cccs2)s1
Reactant: CN(C)C=O
Agent: [BH4-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1ccc(-c2ccc(Cl)s2)s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 64.8 %

Procedure:
To a solution of 5-chloro-[2,2′]bithiophenyl (3.00 g, 14.9 mmol) in 30 mL of THF at 0° C. is added n-BuLi (9.8 mL of a 1.6M solution in hexanes, 15.7 mmol) dropwise. DMF (2.30 mL, 30 mmol) is added dropwise and the resulting solution is heated at reflux for 1 hour. The solution is diluted with H2O and extracted with Et2O. The organic layer is washed with H2O and saturated NaCl solution, then dried over MgSO4, filtered and concentrated. The crude aldehyde is dissolved in 40 mL of anhydrous MeOH and sodium borohydride (0.85 g, 22.5 mmol) is added portionwise. The mixture is stirred at room temperature for 10 min, then quenched with water. The mixture is diluted with Et2O and the layers separated. The organic layer is washed with H2O, then dried over MgSO4, filtered and concentrated to yield the title compound (2.23 g, 9.66 mmol) which is used in the subsequent step without further purification. 1H NMR (CDCl3, 300 MHz) δ6.95 (d, 1H), 6.90 (m, 2H), 6.86 (d, 1H), 4.82 (s, 2H), 1.88 (bs, 1H).
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]([CH2:13][NH:14]C(=O)OC(C)(C)C)=[CH:11][C:10]([C:22]([F:25])([F:24])[F:23])=[N:9]2)=CC=1.[Cl-].[Al+3].[Cl-].[Cl-].C(OCC)(=O)C.CCCCCC.Cl>C1(C)C=CC=CC=1>[F:25][C:22]([F:23])([F:24])[C:10]1[CH:11]=[C:12]([CH2:13][NH2:14])[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C(F)(F)F)cc2CNC(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: NCc1cc(C(F)(F)F)n[nH]1
Temperature: 55 °C
Reaction time: 2 h

Procedure:
To a stirred solution of tert-butyl (1-(4-methoxybenzyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)methylcarbamate (20 g, 0.052 mol) in toluene (300 mL) cooled to 0° C. was added aluminum chloride (17.34 g, 0.129 mol) portion wise for 30 min. The reaction mixture was slowly heated to 50-60° C. and allowed to stir for 2 h at the same temperature. Progress of the reaction was monitored by TLC (20% ethyl acetate/hexane, Rf˜0.1). On completion of the reaction, the reaction contents were treated with diluted HCl, ice cold water (300 mL) was added and the mixture was extracted with ethyl acetate (2×100 mL). The aqueous layer was basified with sodium hydroxide solution and extracted with ethyl acetate and dried over sodium sulfate and concentrated under reduced pressure to give (3-(trifluoromethyl)-1H-pyrazol-5-yl)methanamine as a brown colored solid (4.6 g, crude). The crude product obtained was used directly for the next step.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:9][C:10]([F:13])([F:12])[F:11])=[C:6]([CH:8]=1)[NH2:7].[CH2:14]([O:16][C:17]([C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26](I)[N:25]=2)[N:21]([CH3:31])[CH:20]=1)=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:14]([O:16][C:17]([C:19]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH:7][C:6]3[CH:8]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=3[O:9][C:10]([F:11])([F:12])[F:13])[N:25]=2)[N:21]([CH3:31])[CH:20]=1)=[O:18])[CH3:15]
Reactant: CCOC(=O)c1cc(-c2ccnc(I)n2)n(C)c1
Reactant: Nc1cc(Br)ccc1OC(F)(F)F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(-c2ccnc(Nc3cc(Br)ccc3OC(F)(F)F)n2)n(C)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 51.9 %

Procedure:
Palladium acetate [Pd(OAc)2] (0.12 g, 0.55 mmol), (±)-BINAP (0.34 g, 0.55 mmol) and dimethylformamide (60 mL) were charged to a round-bottom flask flushed with argon. The flask was evacuated and backfilled with argon. The mixture was stirred under argon for 30 minutes and added to a mixture of 5-bromo-2-trifluoromethoxy aniline (2.0 g, 5.60 mmol), 5-(2-iodo-pyrimidin-4-yl)-1-methyl-1H-pyrrole-3-carboxylic acid ethyl ester (1.44 g, 5.60 mmol), and potassium carbonate (7.70 g, 55.80 mmol) in dimethylformamide (90 mL). The resulting mixture was stirred at 80° C. for 3 hours under argon. After cooling to room temperature, the reaction mixture was filtered on a pad of celite. The solvent was concentrated, the crude solid was purified by flash chromatography on silica gel (eluant: hexane/ethyl acetate 70/30) to afford 1.41 g (52%) of the title compound as white solid.