Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1.ClC1S[C:15]2[CH:21]=CC=C(Cl)C=2N=1.[OH-:23].[Na+].O>C(O)C>[CH2:21]([O:23][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:5]=2[N:6]=1)[CH3:15]
Reactant: Clc1nc2c(Cl)cccc2s1
Reactant: Clc1cccc2sc(Br)nc12
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1nc2c(Cl)cccc2s1
Yield: 92.9 %

Procedure:
A mixture (20.87 g, 0.1 mole) of 2-bromo-4-chlorobenzothiazole and 2,4-dichlorobenzothiazole and 94% sodium hydroxide (4.68 g, 0.11 mole) in 95% ethanol (200 c.c.) was heated under reflux for 1 hour. After cooling, water (250 c.c.) was added to the reaction solution, followed by ice-cooling. The deposited crystals were filtered and washed with water to obtain 19.86 g of 2-ethoxy-4-chlorobenzothiazole. Yield 92.9%, purity 98.9%, m.p. 43°-45° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:25]2[C@@H:29]([CH2:30][C:31]([O:33]C)=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:39])([F:38])[F:37])=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][C@H:10]1[CH3:24].[OH-].[Li+]>C1COCC1.O>[Br:1][C:2]1[CH:3]=[C:4]([N:25]2[C@@H:29]([CH2:30][C:31]([OH:33])=[O:32])[C@H:28]([CH3:35])[C:27]([C:36]([F:37])([F:38])[F:39])=[N:26]2)[CH:5]=[CH:6][C:7]=1[O:8][C@@H:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([Cl:21])=[CH:19][N:18]=[C:17]([O:22][CH3:23])[CH:16]=2)[CH2:11][C@H:10]1[CH3:24]
Reactant: COC(=O)C[C@H]1[C@H](C)C(C(F)(F)F)=NN1c1ccc(O[C@@H]2CCN(c3cc(OC)ncc3Cl)C[C@H]2C)c(Br)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: COc1cc(N2CC[C@@H](Oc3ccc(N4N=C(C(F)(F)F)[C@@H](C)[C@@H]4CC(=O)O)cc3Br)[C@H](C)C2)c(Cl)cn1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100.5 %

Procedure:
To a stirred solution of methyl 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetate (44 mg, 0.069 mmol) in THF (2.0 mL) and water (0.2 mL) at rt was added 1.0M aqueous lithium hydroxide (0.2 mL, 0.200 mmol). After stirring at rt for 4.5 h, the reaction mixture was partially evaporated to remove most of the THF. The remaining solution was partitioned between water (50 mL) and Hex (15 mL). The aqueous layer was acidified to pH 2 by dropwise addition of 1M HCl, and then extracted with CH2Cl2 (3×30 mL). The combined organic extracts were dried (Na2SO4) and concentrated. The residue was dried under vacuum to afford 2-((4S,5S)-1-(3-bromo-4-(((3R,4R)-1-(5-chloro-2-methoxypyridin-4-yl)-3-methylpiperidin-4-yl)oxy)phenyl)-4-methyl-3-(trifluoromethyl)-4,5-dihydro-1H-pyrazol-5-yl)acetic acid (43 mg, 100% yield) as a white solid: LC-MS [M+H] 619, 621. 1H NMR (500 MHz, CD2Cl2) δ 7.97 (s, 1H), 7.36 (d, J=2.8 Hz, 1H), 7.02 (dd, J=9.0, 2.8 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.30 (s, 1H), 4.41 (m, 1H), 4.02 (dt, J=3.9, 8.3 Hz, 1H), 3.86 (s, 3H), 3.54 (m, 2H), 3.28 (m, 1H), 2.90 (m, 1H), 2.84 (dd, J=16.5, 3.1 Hz, 1H), 2.18 (m, 2H), 1.86 (m, 2H), 1.35 (d, J=7.1 Hz, 3H), 1.17 (d, J=6.7 Hz, 3H). Analytical HPLC (Zorbax method, 50% Solvent B start): RT=8.55 min, HI: 100%. hGPR40 EC50=45 nM.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[C:13]([S:14][C:15]2[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=2)=[N:12][C:11]2[C:6]1=[N:7][CH:8]=[N:9][C:10]=2[NH2:27].C(N(CC)CC)C.[C:35](Cl)(=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]>C(Cl)Cl>[NH2:27][C:10]1[N:9]=[CH:8][N:7]=[C:6]2[C:11]=1[N:12]=[C:13]([S:14][C:15]1[C:23]([N:24]([CH3:26])[CH3:25])=[CH:22][C:18]3[O:19][CH2:20][O:21][C:17]=3[CH:16]=1)[N:5]2[CH2:4][CH2:3][CH2:2][NH:1][C:35](=[O:40])[C:36]([CH3:39])([CH3:38])[CH3:37]
Reactant: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCN)OCO2
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cc2c(cc1Sc1nc3c(N)ncnc3n1CCCNC(=O)C(C)(C)C)OCO2

Procedure:
9-(3-Aminopropyl)-8-(6-(dimethylamino)benzo[d][1,3]dioxol-5-ylthio)-9H-purin-6-amine (60 mg, 0.155 mmol), triethylamine (17 mg, 24 μL, 0.170 mmol), pivaloyl chloride (19 mg, 19 μL, 0.155 mmol) in CH2Cl2 (3 mL) was stirred for 2 h at rt. The mixture was dried under reduced pressure and the residue purified by preparatory TLC (CH2Cl2:MeOH—NH3(7N), 20:1) to give MRP-I-29 (65 mg, 89%). 1H NMR (600 MHz, CDCl3): δ 8.30 (s, 1H), 7.65 (t, J=6.2 Hz, 1H), 6.77 (s, 1H), 6.50 (s, 1H), 6.39 (br s, 2H), 5.90 (s, 2H), 4.26 (t, J=6.0 Hz, 2H), 3.04 (q, J=6.0 Hz, 2H), 2.68 (s, 6H), 1.83-1.87 (m, 2H), 1.27 (s, 9H); 13C NMR (150 MHz, CDCl3): δ 178.8, 154.9, 152.9, 151.9, 148.3, 147.5, 146.6, 144.7, 119.8, 119.7, 109.5, 102.5, 101.7, 45.3, 40.3, 38.8, 34.8, 28.9, 27.7; (ESI) m/z [M+H]+ calcd. for C22H30N7O3S, 472.2131. found 472.2128.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][C:3]1=[O:9].[OH:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]=O.[NH2:23][C:24]1[CH:28]=[CH:27][NH:26][N:25]=1>>[OH:11][C:12]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][C:13]=1[CH:14]1[C:4]2[C:3](=[O:9])[C:2]([CH3:10])([CH3:1])[CH2:7][CH2:6][C:5]=2[NH:23][C:24]2=[CH:28][CH:27]=[N:26][N:25]12
Reactant: Nc1cc[nH]n1
Reactant: O=Cc1cc([N+](=O)[O-])ccc1O
Reactant: CC1(C)CCC(=O)CC1=O
Product: CC1(C)CCC2=C(C1=O)C(c1cc([N+](=O)[O-])ccc1O)n1nccc1N2

Procedure:
4,4-Dimethyl-1,3-cyclohexanedione, 2-hydroxy-5-nitrobenzaldehyde and 3-aminopyrazole were processed as described in General Procedure A to provide the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[C:4]1[CH:9]=[CH:8][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([OH:23])=O)[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:6][CH:5]=1.C(N1C=CN=C1)([N:28]1C=CN=C1)=O.N>CN(C=O)C.C(Cl)Cl>[F:24][C:3]([F:2])([F:25])[C:4]1[CH:5]=[CH:6][C:7]([C:10]2[C:11]3[CH2:18][CH2:17][CH:16]([O:19][CH2:20][C:21]([NH2:28])=[O:23])[C:12]=3[CH:13]=[N:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: O=C(O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: N
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)COC1CCc2c(-c3ccc(C(F)(F)F)cc3)cncc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
To a solution of (rac)-2-(4-(4-(trifluoromethyl)phenyl)-6,7-dihydro-5H-cyclopenta[c]pyridin-7-yloxy)acetic acid hydrochloride (example 99) (34.6 mg, 0.093 mmol) in DMF (1 mL) was added N,N-triethylamine (31 μL, 0.22 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol). The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min to give a 1:1 mixture of starting material and product. The residue was dissolved in CH2Cl2, dried (Na2SO4) and evaporated. The oil was again dissolved in DMF (1 mL) and N,N-triethylamine (15.5 μL, 0.11 mmol) and 1,1′-carbonyldiimidazole (18.0 mg, 0.11 mmol) were added. The reaction was stirred at room temperature for 2 h, cooled (0°) and treated with aq. 25% ammonia solution (0.87 mL, 5.55 mmol) and evaporated after 30 min at room temperature. The solution was evaporated, dried in vacuo and purified by flash chromatography (20 g SiO2, Telos-cartridge, 3% MeOH in CH2Cl2) to give the title compound (15 mg, 48%) as off-white solid. MS: 337.1 (M+H+).
Reaction SMILES: [N+:1]([CH:4]=[C:5]1[NH:9][CH2:8][CH2:7][S:6]1)([O-:3])=[O:2].[C:10](#[N:12])C.CN.Cl.[CH3:16][N:17]([CH2:19][C:20]1[O:24][C:23]([CH2:25]Cl)=[CH:22][CH:21]=1)[CH3:18]>C(C(C)=O)C(C)C>[CH3:16][N:17]([CH2:19][C:20]1[O:24][C:23]([CH2:25][S:6][CH2:7][CH2:8][NH:9][C:5]([NH:12][CH3:10])=[CH:4][N+:1]([O-:3])=[O:2])=[CH:22][CH:21]=1)[CH3:18]
Reactant: CN(C)Cc1ccc(CCl)o1
Reactant: O=[N+]([O-])C=C1NCCS1
Reactant: CC#N
Agent: CN
Agent: Cl
Solvent: CC(=O)CC(C)C
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Reaction time: 0.5 h

Procedure:
Combine 2-nitromethylene-thiazolidine (1.25 kg, 8.53 mol) and acetonitrile (2.15 L). Add methylamine (0.85 kg). While maintaining the temperature of the reaction at below 35° C., add a solution of 5-[(dimethylamino)methyl]-2-(chloromethyl)-furan hydrochloride as obtained in Example 4.1, maintained at 50° C. to 60° C. to prevent crystallization. During the first hour, add about half to the solution. During the second hour, add about a quarter of the solution. During the third hour, add about an eighth of the solution. During the fourth and fifth hours, add the remainder of the solution. Add methylamine during the addition of 5-[(dimethylamino)methyl]-2-(chloromethyl)-furan hydrochloride. Add methylamine (0.18 kg) at the beginning of the addition and then seven more 0.18 kg portions, one portion about every 30 minutes, during about the first 3.5 hours of the addition. When the reaction is complete, add aqueous 32% sodium acetate solution. Separate the layers and extract the aqueous layer twice with acetonitrile (3.4 L). Combine the organic layers and evaporate in vacuo to obtain a residue. Combine the residue and methyl isobutyl ketone (2.8 L) and partially evaporate in vacuo before combining with methyl isobutyl ketone (15 L). Extract with aqueous 10% potassium carbonate solution. Separate the layers and extract the aqueous layer with methyl isobutyl ketone. Combine the organic layers extract with water. Evaporate the organic layer in vacuo to give a residue. Recrystallize the residue from methyl isobutyl ketone to give the title compound.
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:13]=1[CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]2)=[C:2]=S.C(OC1CC2C(CC=1)=CC=CC=2N=C=S)C.[N:35]([CH2:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=1)=[O:40])=[N+]=[N-].N(CC(C1C=CC(C(F)(F)F)=CC=1)=O)=[N+]=[N-]>>[CH3:47][C:44]1[CH:43]=[CH:42][C:41]([C:39]2[O:40][C:2]([NH:1][C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:13]=3[CH2:12][CH:11]([NH:14][S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]4)=[N:35][CH:38]=2)=[CH:46][CH:45]=1
Reactant: Cc1ccc(C(=O)CN=[N+]=[N-])cc1
Reactant: CS(=O)(=O)NC1CCc2cccc(N=C=S)c2C1
Agent: CCOC1=CCc2cccc(N=C=S)c2C1
Agent: [N-]=[N+]=NCC(=O)c1ccc(C(F)(F)F)cc1
Product: Cc1ccc(-c2cnc(Nc3cccc4c3CC(NS(C)(=O)=O)CC4)o2)cc1
Yield: 64.4 %

Procedure:
The title compound was prepared using the procedure as described in Example 1H, substituting the product of Example 23C (128 mg, 0.453 mmol) for the product of Example 1F and the product of Example 9A (95 mg, 0.544 mmol) for the product of Example 1G. The crude product was purified by flash chromatography eluting with 2% to 5% CH3OH/CH2Cl2 followed by 100% EtOAc which gave 116 mg (64%) of the title compound as a tan solid. 1H NMR (DMSO-d6) δ 9.13 (s, 1H), 7.61 (d, J=7.5 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.30 (s, 1H), 7.23 (m, 3H), 7.11 (t, J=7.8 Hz, 1H), 6.85 (d, J=7.5 Hz, 1H), 3.58 (m, 1H), 3.11 (m, 1H), 2.99 (s, 3H), 2.87 (m, 2H), 2.56 (m, 1H), 2.31 (s, 3H), 2.01 (m, 1H), 1.66 (m, 1H); MS (ESI+) m/z 398 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH2:9][C:10]([C:16]2[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[CH:17]=2)(O)[C:11]([F:14])([F:13])[F:12])=[CH:4][C:3]=1[CH3:25].S(Cl)(Cl)=O.N1C=CC=CC=1.Cl>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:24])[CH:9]=[C:10]([C:16]2[CH:17]=[C:18]([Cl:23])[CH:19]=[C:20]([Cl:22])[CH:21]=2)[C:11]([F:13])([F:14])[F:12])=[CH:4][C:3]=1[CH3:25]
Reactant: Cc1cc(C(=O)CC(O)(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Agent: Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1Br
Temperature: 80 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a solution of 0.3 g of 1-(4-bromo-3-methylphenyl)-3-(3,5-dichlorophenyl)-3-hydroxy-4,4,4-trifluorobutane-1-one synthesized under Synthetic Example 1 in 3 g toluene, 0.391 g of thionyl chloride and 0.104 g of pyridine were added at room temperature and the mixture was stirred for 1 hour at 80° C. After the end of reaction, the reaction solution was cooled to room temperature, added with toluene and 2N hydrochloric acid and separated, and then an organic layer was washed with water and dried with anhydrous magnesium sulfate to distill off the solvent under reduced pressure. The resulting residue, which although contains mixed geometrical isomers, was purified using silica gel column chromatography that was eluted with ethyl acetate-hexane (1:10), and 0.244 g of aimed product was obtained as yellow solid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[N:29][CH:30]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]([OH:14])CO)[C:3]=12.C(O)(=O)C.I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:15]([C:17]3[C:18]([O:36][CH2:37][CH3:38])=[C:19]([C:25]4[CH:26]=[CH:27][C:28]([C:31]([N:33]([CH3:35])[CH3:34])=[O:32])=[N:29][CH:30]=4)[C:20]([CH3:24])=[C:21]([Cl:23])[CH:22]=3)[CH3:16])[N:9]=[C:10]([CH:11]=[O:14])[C:3]=12
Reactant: CCOc1c(C(C)n2nc(C(O)CO)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(C(C)n2nc(C=O)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccc(C(=O)N(C)C)nc1
Reaction time: 2 h
Yield: 89.3 %

Procedure:
To a solution of 5-(3-{1-[4-amino-3-(1,2-dihydroxyethyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]ethyl}-5-chloro-2-ethoxy-6-methylphenyl)-N,N-dimethylpyridine-2-carboxamide (70 mg, 0.13 mmol) in tetrahydrofuran (0.98 mL) and water (0.59 mL) was added acetic acid (1.9 μL, 0.034 mmol) and sodium periodate (83 mg, 0.39 mmol) at 0° C. After stirring for 2 h, the reaction mixture was diluted with water, and extracted with dichloromethane. The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated to give the desired product (0.059 g, 90%). LCMS calculated for C25H27ClN7O3 (M+H)+: m/z=508.2; Found: 508.1.
Reaction SMILES: [CH:1]([OH:3])=O.C(OC(=O)C)(=O)C.[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14]>C1COCC1>[F:11][C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH:14][CH:1]=[O:3]
Reactant: Nc1ccccc1F
Reactant: O=CO
Solvent: CC(=O)OC(C)=O
Solvent: C1CCOC1
Product: O=CNc1ccccc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 100.7 %

Procedure:
Formic acid (3 g) was added dropwise to acetic anhydride (5.4 g) which had been cooled to 0° C. The mixture was stirred at 0° C. for 15 minutes and then heated to 55° C. for 2 hours. The mixture was cooled to ambient temperature. THF (5 ml) and a solution of 2-fluoroaniline (2.22 g) in THF (15 ml) were added and the mixture was stirred at ambient temperature for 2 hours. The mixture was evaporated to give 2'-fluoroformanilide (2.8 g) which was used without further purification.
Reaction SMILES: [ClH:1].C1(OC)C=CC=CC=1.[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]([CH2:19][C@H:20]([NH:26]C(=O)OC(C)(C)C)[C:21]2[NH:25][N:24]=[N:23][N:22]=2)=[CH:11]1>C(OCC)(=O)C>[ClH:1].[NH:25]1[C:21]([C@@H:20]([NH2:26])[CH2:19][C:12]2[C:13]3[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10][CH:11]=2)=[N:22][N:23]=[N:24]1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1c[nH]c2ccccc12)c1nnn[nH]1
Agent: Cl
Solvent: COc1ccccc1
Solvent: CCOC(C)=O
Product: N[C@@H](Cc1c[nH]c2ccccc12)c1nnn[nH]1
Reaction time: 1 h

Procedure:
Ethyl acetate (30 mL) was saturated with HCl gas at 0° C. at which point anisole (7.4 mL) was added followed by (S)-[2-(1H-indol-3-yl)-1-(1 H-tetrazol-5-yl)ethyl]carbamic acid, 1,1-dimethylethyl ester (1.24 g., 3.77 mmol.) dissolved in ethyl acetate (7 mL). The resulting solution was stirred at 0° for one hour at which time TLC showed that no starting material remained. The reaction mixture was evaporated and chased with methylene chloride and ether and finally pumped to 0.95 g. of (S)-α-(1 H-tetrazol-5-yl)-1 H-indol-3-ethanamine, hydrochloride as a light brown solid.
Reaction SMILES: C([C@@H]([C@H](C(O)=O)O)O)(O)=O.[NH:11]1[CH2:21][CH2:20][CH2:19][C@@H:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:12]1.C(=O)(O)[O-].[Na+].[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35]2)=[CH:30][CH:29]=1>ClCCl>[CH2:17]([O:16][C:14]([C@@H:13]1[CH2:19][CH2:20][CH2:21][N:11]([C:38]([C:34]2([C:31]3[CH:30]=[CH:29][C:28]([Cl:27])=[CH:33][CH:32]=3)[CH2:35][CH2:36][CH2:37]2)=[O:39])[CH2:12]1)=[O:15])[CH3:18]
Reactant: CCOC(=O)[C@@H]1CCCNC1
Reactant: O=C(Cl)C1(c2ccc(Cl)cc2)CCC1
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl (R)-nipecotate L-tartrate (15.0 g, 48.8 mmol) was added to a stirred mixture of dichloromethane and saturated sodium bicarbonate solution (100 mL each) at 0° C. After 10 min 1-(4-chloro-phenyl)-cyclobutanecarbonyl chloride (11.13 g, 48.8 mmol) was slowly added at 0° C. The reaction was then allowed to stir for 2 h at room temperature. The organic layer was separated and the aqueous layer was washed once with dichloromethane (100 mL). The organic material was combined and washed once with water (100 mL), dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (2:1) to give 9.2 g of the amidester as a thick clear gum; C19H24ClNO3, LRMS (m/z)=350 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6].[F:13][C:14]([F:25])([F:24])[C:15]1[CH:16]=[C:17](B(O)O)[CH:18]=[CH:19][CH:20]=1.N1C=CC=CC=1>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[F:13][C:14]([F:25])([F:24])[C:15]1[CH:20]=[C:19]([NH:1][C:2]2[CH:3]=[C:4]([CH:10]=[CH:11][CH:12]=2)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: CCOC(=O)c1cccc(N)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)c1cccc(Nc2cccc(C(F)(F)F)c2)c1
Yield: 59.3 %

Procedure:
A solution of ethyl 3-aminobenzoate (0.300 g; 1.82 mmol), 3-(trifluoromethyl)phenylboronic acid (0.690 g; 3.63 mmol), copper acetate (0.660 g, 3.63 mmol) and pyridine (0.293 mL, 3.63 mmol) in dichloromethane (3 mL) was stirred at room temperature for 18 hours and filtered through celite and concentrated under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate (2×200 mL). The organic layers were washed with brine, dried and concentrated under reduced pressure. The crude material was purified by flash chromatography on silica gel (eluent 5 to 40% ethyl acetate in heptane) to afford 0.334 g (60%) of ethyl 3-(3-(trifluoromethyl)phenylamino)benzoate.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[SH:19])([CH3:12])[CH3:11].C([O-])([O-])=O.[K+].[K+].C(O)CO>[Cu]I.CC(O)C>[CH:10]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[S:19][C:2]1[CH:3]=[C:4]([O:8][CH3:9])[CH:5]=[CH:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: COc1cccc(I)c1
Reactant: CC(C)c1ccccc1S
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: COc1cccc(Sc2ccccc2C(C)C)c1
Yield: 93.3 %

Procedure:
The general procedure in example 39 was followed. 3-Iodoanisole (234 mg, 1.0 mmol), 2-Isopropylbenzenethiol (90% purity, 168 μL, 1.0 mmol), CuI (10 mg, 0.05 mmol), K2CO3 (276 mg, 2.0 mmol), ethylene glycol (111 μL, 2.0 mmol) and 2-Propanol (1.0 mL) were used to obtain the 3-(2-isopropylphenyl)sulfanylanisole (241 mg, 93% yield) as colorless liquid. Column chromatographic solvent (hexane/ethyl acetate=40/1). Rf=0.3 (hexane/ethyl acetate=40/1). 1H NMR (CDCl3, 300 MHz) δ 7.29-7.36 (m, 3 H), 7.09-7.17 (m, 2 H), 6.67-6.73 (m, 3 H), 3.72 (s, 3 H), 3.54 (hept, 1 H, J=6.9 Hz), 1.22 (s, 3 H), 1.19 (s, 3 H). 13C NMR (CDCl3, 75 MHz) δ 160.1, 150.9, 139.0, 134.5, 132.1, 129.9, 128.9, 126.8, 126.3, 121.4, 114.4, 111.9, 55.6, 31.1, 24.0. IR (neat, cm−1) 3060, 2962, 2867, 2834, 2362, 2343. MS (EI) m/z (relative intensity) 258 (100), 241 (30), 225 (30). HRMS (EI), Cald. for C16H18OS 258.1078; Found 258.1080.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C)C=O>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1](=[O:3])[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][CH:9]=1
Reactant: COC(OC)N(C)C
Reactant: CC(=O)c1cccnc1
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1cccnc1
Yield: 72 %

Procedure:
A solution of 125 g of 3-acetylpyridine and 138 g of N,N-dimethylformamide-dimethylacetal in dry dimethyl-formamide was refluxed for 3 h, after which the solution was evaporated to dryness and the product triturated with ether to give N,N-dimethyl-3-oxo-3-(3-pyridinyl)-prop-1-enamine in 72% yield. To a solution of 10.2 g of this product in 2-methoxyethanol 3.2 g of hydrazine were added under nitrogen and the mixture was heated. After 2 h the solvent was removed in vacuo to give quantitatively 3-(lH-pyrazol-3-yl)pyridine, which was dissolved in dimethylformamide. To this solution 22.8 g of N-bromosuccinimide were added in small portions over a period of 30 min, maintaining the temperature at 0°-5° C. The mixture was stirred for 3 h, poured into water, extracted with ethyl acetate, dried over sodium sulfate and evaporated to dryness, to obtain crude 3-(4-bromo-1H-pyrazol-3-yl)pyridine. To a solution of 13.5 g of this product in 190 ml of acetonitrile were added 17.5 g of methyl iodide under nitrogen, after which the solution was refluxed for 3 h. After cooling the crystalline material was filtered to give 3-(4-bromo-1H-pyrazol-3-yl)-1-methylpyridinium iodide in 71% yield. 15.6 g of this product was suspended in methanol and 5.7 g of sodium borohydride were added in small portions over 20 min at 0° C. After 1 h of stirring glacial acetic acid was added and the pH was adjusted to 6. The solvent was removed in vacuo, the residue suspended in brine and basified, and the product extracted with ethyl acetate. After drying over sodium sulfate and evaporation to dryness 3-(4-bromo-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine was obtained in 93% yield, and converted into its fumaric salt, which was recrystallized from methanol to give 3-(4-bromo-1H-pyrazol-3-yl)-1,2,5,6-tetrahydro-1-methylpyridine (E)-2-butenedioate. mp 228° C.
Reaction SMILES: [F:1][C:2]1[C:3](I)=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.C[C:11]([N:13](C)C)=O>[C-]#N.[Zn+2].[C-]#N>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:11]#[N:13]
Reactant: Cc1cccc(F)c1I
Reactant: CC(=O)N(C)C
Agent: [C-]#N
Agent: [Zn+2]
Product: Cc1cccc(F)c1C#N
Temperature: 80 °C

Procedure:
A 10 L round bottom flask equipped with adapter, thermocouple and stir bar was charged with DMA (6 L) and degassed under vacuum and purged with N2 three times. To the mixture was added palladium tetrakis triphenylphosphine (87.5 g, 72.0 mmol) and the mixture was degassed under vacuum and purged with N2 three times. The reaction was heated to 80° C. for 30 min. 3-Fluoro-2-iodotoluene (575 g, 2.4 mol) and zinc cyanide (171.7 g, 1.46 mol) were added and the mixture was degassed under vacuum and purged with N2 three times. The reaction mixture was heated to 80° C. for 16 h and then allowed to cool to RT. The solution was added to a 2.0 L aqueous solution of 1N NH4OH, which was extracted three times with 1.5 L EtOAc, washed with 2 L brine, dried over Na2SO4, filtered and concentrated. The crude product was treated with mCPBA in cooled DCM and then purified by chromatography (PE/EA=10:1) to get the title compound.