Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(C1C=C2C(C3C=C(C=CC=3)CNC(C3C(=O)N(CC4C=CC(F)=C(F)C=4)C=CC=3)=O)=CNC2=NC=1)#N.CC1(C)C(C)(C)OB([C:46]2[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]3[C:56](=[O:70])[N:57]([CH2:61][C:62]4[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=4)[CH:58]=[CH:59][CH:60]=3)=[O:54])=[CH:48][CH:47]=2)O1.[B].[F:73][C:74]1[CH:75]=[C:76]2[C:82](I)=[CH:81][NH:80][C:77]2=[N:78][CH:79]=1>>[F:73][C:74]1[CH:75]=[C:76]2[C:82]([C:46]3[S:50][C:49]([CH2:51][NH:52][C:53]([C:55]4[C:56](=[O:70])[N:57]([CH2:61][C:62]5[CH:67]=[CH:66][C:65]([F:68])=[C:64]([F:69])[CH:63]=5)[CH:58]=[CH:59][CH:60]=4)=[O:54])=[CH:48][CH:47]=3)=[CH:81][NH:80][C:77]2=[N:78][CH:79]=1
Reactant: CC1(C)OB(c2ccc(CNC(=O)c3cccn(Cc4ccc(F)c(F)c4)c3=O)s2)OC1(C)C
Reactant: Fc1cnc2[nH]cc(I)c2c1
Agent: N#Cc1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: [B]
Product: O=C(NCc1ccc(-c2c[nH]c3ncc(F)cc23)s1)c1cccn(Cc2ccc(F)c(F)c2)c1=O

Procedure:
Except where indicated, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-thiophen-2-ylmethyl]-amide was synthesized as per Example 68, 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid 3-(5-cyano-1H-pyrrolo[2,3-b]pyridin-3-yl)-benzylamide using 1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carboxylic acid [5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-thiophen-2-ylmethyl]-amide as activated boron species and 5-Fluoro-3-iodo-1H-pyrrolo[2,3-b]pyridine as substituted bicyclic heterocycle, to produce the title compound. 1H NMR (400 MHz, CDCl3-MeOH-d4) d ppm 8.570 (d, J=7.0 Hz, 1H) 8.500 (d, J=7.6 Hz, 1H) 8.287 (s, 1H) 7.744 (s, 1H) 7.555 (d, J=6.3 Hz, 1H) 7.186-6.972 (m, 5H) 6.478 (t, J=6.7 Hz, 1H) 5.135 (s, 2H) 4.788 (s, 2H); MS m/z=495.29 M+H.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH:4](O)[N:5](C(C)(C1C=CC=CC=1)C)[C:6]2=[O:13].FC(F)(F)C(O)=O.C([SiH](CC)CC)C.O>[N+](C)([O-])=O.CCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([I:12])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:13]
Reactant: Cc1cc(I)c2c(c1Cl)C(O)N(C(C)(C)c1ccccc1)C2=O
Agent: CC[SiH](CC)CC
Solvent: CCOC(C)=O
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(I)c2c(c1Cl)CNC2=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
In a similar manner to Step 4 of Example 16, 4-chloro-5-methyl-3-hydroxy-7-iodo-2-(1-methyl-1-phenylethyl)isoindolinone (300 mg, 0.679 mmol) was dissolved in nitromethane (5 mL), and the solution was added with trifluoroacetic acid (0.523 mL, 6.79 mmol) and triethylsilane (0.219 mL, 1.36 mmol), followed by stirring at room temperature for 24 hours. The reaction mixture was added with water, ethyl acetate and hexane. The precipitated solid was collected by filtration and washed with hexane and water, followed by drying under reduced pressure to obtain 4-chloro-5-methyl-7-iodoisoindolinone (140 mg, yield 67%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[CH:6]=[CH:5]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:20][CH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[C:18]#[N:19])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(-c3ccccc3C#N)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)(Cl)Cl
Product: N#Cc1ccccc1-c1ccc2cc(CBr)ccc2c1

Procedure:
A mixture of 6.30 g of 6-methyl-2-(2'-cyanophenyl)-naphthalene, 4.60 g of N-bromosuccinimide and 0.085 g of azoisobutyronitrile in 70 ml of carbon tetrachloride is heated at 110° for 4 hours. The cooled reaction mixture is extracted twice with 45 ml of 2N sodium hydroxide solution each time. The aqueous phases are then extracted with 50 ml of CH2Cl2 in each case. The combined organic phases are dried over MgSO4. After removing the solvent in vacuo, the crude product is recrystallised from toluene/hexane and yields 6-bromomethyl-2-(2'-cyanophenyl)-naphthalene, m.p. 171°-172°.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]#[N:9].[Cl:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17](=O)[CH2:16][CH2:15][CH2:14]2.B(F)(F)F.CCOCC>>[NH2:9][C:8]1[C:16]2[CH2:15][CH2:14][C:13]3[CH:12]=[C:11]([Cl:10])[CH:20]=[CH:19][C:18]=3[C:17]=2[N:1]=[C:2]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2
Reactant: N#Cc1ccccc1N
Reactant: O=C1CCCc2cc(Cl)ccc21
Agent: FB(F)F
Solvent: CCOCC
Product: Nc1c2c(nc3ccccc13)-c1ccc(Cl)cc1CC2

Procedure:
2-amino-1-cyano-benzene (5.0 g, 42.3 mmol), 6-chloro-3, 4-dihydro-[2H]-napthalen-1-one (Organon Laboratories) (8.8 g, 48.7 mmol) and boron trifluoride diethyl etherate (1M, 6.4 ml, 52.4 mmol) were treated according to the general procedure described herein to give the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1.C(N(CC)CC)C.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>ClCCl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])=[C:7]([N+:12]([O-:14])=[O:13])[CH:8]=[N:9]2)=[N:4][CH:3]=1
Reactant: NCCCO
Reactant: O=[N+]([O-])c1cnc2cc(Br)cnc2c1Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cnc2cc(Br)cnc2c1NCCCO
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
To a solution of 7-bromo-4-chloro-3-nitro[l,5]naphthyridine (22.53 g, 78.10 g) in dichloromethane (260 mL) at room temperature was added triethylamine (14.2 mL, 102 mmol). The solution was cooled to 0° C. and 3-amino-1-propanol (6.57 mL, 85.9 mmol) was added. The solution was stirred for 20 minutes at room temperature and then was concentrated under reduced pressure to yield a yellow solid. Water (250 mL) was added to the solid, and the mixture was sonicated for 10 minutes. The solid was isolated by filtration, washed with water, and dried at 70° C. under vacuum to afford 22.60 g of 3-[(7-bromo-3-nitro[1,5]naphthyridin-4-yl)amino]propan-1-ol as a yellow powder.
Reaction SMILES: O.[OH-].[Li+].[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([O:28]C)=[O:27])[CH:24]=3)[C:19]([S:30]([CH3:32])=[O:31])=[CH:18]2)=[N:15][CH:16]=1>O.C1COCC1.O>[F:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[N:13][C:14]([N:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([C:26]([OH:28])=[O:27])[CH:24]=3)[C:19]([S:30]([CH3:32])=[O:31])=[CH:18]2)=[N:15][CH:16]=1
Reactant: COC(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Lithium hydroxide monohydrate (0.34 g, 8.05 mmol) in water (2 mL) was added to an ice-cooled suspension of methyl ester 51d) (2.2 g, 5.37 mmol) in THF/water (1:1; 40 mL) and the resulting mixture was stirred at room temperature for 16 h. The solvent was removed under vacuum and the remnant was dissolved in water (20 mL) and washed with ethyl acetate (2×20 mL). The aqueous phase was acidified with sodium hydrogen sulfate and extracted with dichloromethane (2×50 mL). The organic layers were dried over sodium sulfate and evaporated. White solid. Yield: 1.8 g (85% of theory). HPLC-MS (method 5): Rt=2.6 min; m/z [M+H]+=396
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH2:8][CH:9]([CH2:11][CH2:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:20]([OH:22])=O.[CH3:23][C:24]([C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([NH2:32])[C:27]=1[OH:33])=[O:25]>>[C:24]([C:26]1[C:27]([OH:33])=[C:28]([NH:32][C:20]([C:3]2[CH:4]=[CH:5][C:6]3[O:10][CH:9]([CH2:11][CH2:12][CH2:13][C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[CH2:8][C:7]=3[C:2]=2[Cl:1])=[O:22])[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:23]
Reactant: CC(=O)c1cccc(N)c1O
Reactant: O=C(O)c1ccc2c(c1Cl)CC(CCCc1ccccc1)O2
Product: CC(=O)c1cccc(NC(=O)c2ccc3c(c2Cl)CC(CCCc2ccccc2)O3)c1O
Yield: 93 %

Procedure:
Following the process described in example 1 (point K), starting from 4-chloro-2-(3-phenylpropyl)-2,3-dihydrobenzofuran-5-carboxylic acid and 3-amino-2-hydroxyacetophenone, the title compound was prepared (93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([O:24]C)=[O:23])=[CH:12][CH:11]=2)[C:7]2[C:26]([C:30]([O:32]C)=[O:31])=[CH:27][CH:28]=[CH:29][C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>CO>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]([OH:24])=[O:23])=[CH:14][CH:15]=2)[C:7]2[C:26]([C:30]([OH:32])=[O:31])=[CH:27][CH:28]=[CH:29][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)OC)c2n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Temperature: 80 °C
Reaction time: 3 h
Yield: 82.3 %

Procedure:
To a solution of methyl 2-ethoxy-1-[(2′-methoxycarbonylbiphenyl-4-yl)methyl]benzimidazole-7-carboxylate (0.7 g) in methanol (10 ml) was added 1N NaOH (5 ml) and the mixture was stirred at 80° C. for 3 hours. After evaporation of the methanol, the aqueous residue was neutralized with 1N hydrochloric acid to give crystals. The crystals were recrystallized from methanol-chloroform to afford colorless crystals (0.54 g, 83%), m.p. 213-215° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:21])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([NH:16][CH2:17][CH:18]3[CH2:20][CH2:19]3)=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[CH3:22][C:23]1[O:24][C:25]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:26][C:27]=1[C:28](O)=[O:29]>C1COCC1>[CH:18]1([CH2:17][NH:16][C:14]([C:11]2[CH:12]=[CH:13][C:8]([C:6]3[C:5]([CH3:21])=[CH:4][CH:3]=[C:2]([NH:1][C:28]([C:27]4[CH:26]=[C:25]([C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)[O:24][C:23]=4[CH3:22])=[O:29])[CH:7]=3)=[CH:9][CH:10]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(N)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: Cc1oc(-c2ccccc2)cc1C(=O)O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cc(-c3ccccc3)oc2C)cc1-c1ccc(C(=O)NCC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.3 %

Procedure:
5′-Amino-N-(cyclopropylmethyl)-2′-methyl-1,1′-biphenyl-4-carboxamide (53 mg, 0.189 mmol) and 2-methyl-5-phenyl-3-furoic acid (76.4 mg, 0.378 mmol) were mixed in THF (5 ml) and the mixture shaken in a varian tube for 15 min at room temperature. Carbodiimde resin (500 mg) was added and shaking continued for 18 h. The solution was filtered off and concentrated under vacuum. The residue was dissolved in methanol, filtered through an SCX SPE and the solvent evaporated under vacuum to give N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-methyl-5-phenyl-3-furamide (24 mg, 28%). NMR; δH CDCl3 7.81,(2H, d), 7.64,(2H, d), 7.55-7.53,(2H, m), 7.45,(1H, s), 7.40-7.37,(4H, m), 7.30-7.25,(2H, m), 6.78,(1H, s), 6.26,(1H, t), 3.33,(2H, t), 2.70,(3H, s), 2.22,(3H, s), 1.07,(1H, m), 0.57,(2H, m), 0.28,(2H, m). LCMS: retention time 3.93 min, MH+465.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:22](=[O:24])[CH3:23])[CH2:11][C:12]2[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([BH-](C(CC)C)C(CC)C)(CC)C.[Li+].O.C(O)(=O)C>O1CCCC1.C(OCC)(=O)C>[OH:24][CH:22]([CH3:23])[CH:10]([C:7]1[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=1)[CH2:11][C:12]1[O:16][C:15]([C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:14][CH:13]=1
Reactant: CCOC(=O)c1ccc(CC(C(C)=O)c2ccc([N+](=O)[O-])cc2)o1
Agent: CCC(C)[BH-](C(C)CC)C(C)CC
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(CC(c2ccc([N+](=O)[O-])cc2)C(C)O)o1
Temperature: -78 °C
Yield: 66.4 %

Procedure:
5.48 g of ethyl 5-(2-(4-nitrophenyl)-3-oxobutyl)-2-furancarboxylate was dissolved in 50 ml of tetrahydrofuran, and 16.5 ml of a 1M tetrahydrofuran solution of lithium tri-sec-butylborohydride was added under cooling to -78° C. with stirring, followed by stirring at the same temperature for 2 hours. Water was added to the reaction solution, followed by stirring at room temperature for 30 minutes. Then, the solution was acidified by an addition of acetic acid. Ethyl acetate was added thereto for extraction. The organic layer was washed with a saturated sodium chloride aqueous solution and then dried over anhydrous magnesium sulfate. The drying agent was filtered off, and then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=5/1+1/1) to obtain 3.66 g of the above-identified compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH:5]([OH:12])[CH2:6][NH:7]2.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>ClCCl>[OH:12][CH:5]1[CH2:4][C:3]2[C:8](=[CH:9][CH:10]=[CH:11][C:2]=2[NH:1][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[NH:7][CH2:6]1
Reactant: Nc1cccc2c1CC(O)CN2
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cccc2c1CC(O)CN2
Temperature: -20 °C

Procedure:
5-Amino-1,2,3,4-tetrahydroquinolin-3-ol (36.4 mg, 0.22 mmol) is dissolved in dichloromethane and cooled to −20° C. 4-Trifluoromethylbenzylisocyanate (44.6 mg, 0.22 mmol) is added and the reaction mixture is warmed to room temperature over 4 h. The organic layer is diluted with dichloromethane, washed with aq. NH4Cl and water. The organic phase is dried over magnesium sulfate, filtered and evaporated to dryness. The crude product consists of a mixture of regioisomers and is separated using preparative HPLC with an acetonitrile/water gradient.
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH3:14].[S].II.[SH2:19]>>[CH3:14][C:9]1[C:8]2[NH:7][C:2]3[C:3](=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:15])[S:19][C:13]=2[CH:12]=[CH:11][CH:10]=1
Reactant: S
Reactant: Cc1ccccc1Nc1ccccc1C
Agent: II
Agent: [S]
Product: Cc1cccc2c1Nc1c(C)cccc1S2
Temperature: 210 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Put di(2-tolyl)amine (11.7 g, 59.3 mmol) in a 3-neck 100 mL round-bottom flask. Added elemental sulfur (3.9 g, 121.65 mmol, 2 eq.), crushed iodine (0.44 g, 1.73 mmol, 3 mol %), then o-dichlorobenzene (22 mL). Added an outlet to a dilute bleach solution (for hydrogen sulfide evolution) then put under argon. Refluxed at 180° C. for 4 h. Remove solvent under reduced pressure. Purified with Isco column chromatography using 2% ethyl acetate/98% hexane. Obtained product as white crystals (2 g, 8.8 mmol, 15% yield). Alternatively, put di(2-tolyl)amine (either purified or impure from the aforementioned reaction; 8.9525 g, 45.3 mmol) in a round bottom flask. Added elemental sulfur (2.98 g, 92.9 mmol, 2 eq.) then crushed iodine (3.28 g, 12.9 mmol, 28% mol). Added an outlet to a dilute bleach solution (for hydrogen sulfide) then put under argon. Stirred at 210° C. for 30 min or until no starting material was present by LC/MS. Allowed the reaction cool to about 60° C. then add hexane for extraction. Repeat hot hexane extractions (at least one overnight; minimum time of half an hour for each extraction) of reaction until product was no longer seen in residue (about 4 times). Combined hexane extractions and concentrate in vacuo. Purified resulting residue either through repeated repeated hot hexane/ethanol or isopropanal crystallizations, hot acetone/isopropanol crystallizations (or triturations) or Isco column chromatography using 2% ethyl acetate/98% hexane to obtain product as white crystals (2.92 g, 12.8 mmol, 28% yield).
Reaction SMILES: [CH:1]1([Mg]Br)[CH2:3][CH2:2]1.C1(Br)CC1.[Mg].[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]3[CH:22]=[C:21]([CH:23]=[O:24])[N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1>>[CH3:11][O:12][C:13]1[CH:26]=[CH:25][C:16]2[N:17]3[CH:22]=[C:21]([CH:23]([CH:1]4[CH2:2][CH2:3]4)[OH:24])[N:20]=[C:18]3[S:19][C:15]=2[CH:14]=1
Reactant: Br[Mg]C1CC1
Reactant: COc1ccc2c(c1)sc1nc(C=O)cn12
Agent: BrC1CC1
Agent: [Mg]
Product: COc1ccc2c(c1)sc1nc(C(O)C3CC3)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 56.6 %

Procedure:
A mixture of 3.6 g (0.03 mole) of cyclopropyl magnesium bromide prepared from cyclopropyl bromide and 0.8 g (0.033 mole) of magnesium in 50 ml of dry T.H.F. was added dropwise to a suspension of 3.9 g (0.0177 mole) of 7-methoxy-imidazo[2,1-b]benzothiazole-2carboxaldehyde in 80 ml of dry T.H.F. The mixture was stirred at room temperature for 3 hours and was quenched with saturated aqeous ammonium chloride solution. The mixture was extracted with ethyl acetate and the extracts were dried over magnesium sulfate and evaporated under reduced pressure. The residue was chromatographed on silica gel and eluted with 2% methanol/dichloromethane to obtain 2.75 g (69% yield) of [7-methoxy-imidazo[2,1-b]benzothiazol-2-yl) cyclopropyl methanol as colorless solid melting at 151° to 153° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][C:15]([I:18])=[C:14]([O:19][CH3:20])[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[I:18][C:15]1[CH:16]=[CH:17][C:10]2[O:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[C:11]=2[C:14]=1[O:19][CH3:20]
Reactant: COc1c(I)ccc2oc(C(=O)OC(C)(C)C)c(C)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1c(I)ccc2oc(C(=O)O)c(C)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.4 %

Procedure:
To 140 mg (0.36 mmol) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 3 mL of TFA/dichloromethane (1:1) and the solution was stirred at room temperature for 2.5 h. When the reaction was done, the solvents were removed by vacuum and the residue was triturated with hexane/dichloromethane. Filtration of the suspension gave 120 mg (100% yield) of 5-iodo-4-methoxy-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:11].[H-].[Na+].Br[CH2:15][C:16]([O:18][CH3:19])=[O:17]>CN(C=O)C>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:15][C:16]([O:18][CH3:19])=[O:17])=[CH:4][C:3]=1[F:11]
Reactant: Fc1cc2cc[nH]c2cc1Br
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)Cn1ccc2cc(F)c(Br)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.4 %

Procedure:
6-Bromo-5-fluoro-1H-indole (10 g, 46.7 mmol) was dissolved in DMF (100 mL) and cooled to 0° C. in an ice bath before the addition of sodium hydride, 60% dispersion in mineral oil (3.74 g, 93 mmol) and methyl 2-bromoacetate (8.59 mL, 93 mmol). The ice bath was removed and the reaction mixture was stirred at RT for 1 hour. The reaction mixture was cooled with an ice bath once again then quenched with water (50 mL). The aqueous layer was extracted with DCM (3×200 mL). The organics were combined, passed through a hydrophobic frit and concentrated. The residue was purified by column chromatography on silica gel, eluting with a gradient of 0-40% ethyl acetate in cyclohexane to afford the title compound (10.209 g). LCMS (A): m/z (M+H)+ 286/288, C11H9BrFNO2 requires 285/287 (acidic).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1)([O-])=O>[Ni].ClCCl.CO>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH2:10][N:11]2[CH2:16][CH2:15][S:14](=[O:17])[CH2:13][CH2:12]2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(CN2CCS(=O)CC2)cc1
Agent: [Ni]
Solvent: CO
Solvent: ClCCl
Product: Nc1ccc(CN2CCS(=O)CC2)cc1

Procedure:
1.2 g of Raney nickel are added to a solution of 3.9 g (15 mmol) of 4-(4-nitrophenylmethyl)-thiomorpholine-1-oxide in 10 ml of dichloromethane and 40 ml of methanol. The mixture is hydrogenated under a hydrogen atmosphere. The product is obtained by chromatography on silica gel (dichloromethane/methanol=9:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH:9]1[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([CH2:31][N+:32]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].O>COCCOC>[CH2:15]([CH:9]1[CH2:10][CH:11]([C:31]#[N:32])[CH2:12][CH2:13][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C#N)CC1Cc1ccccc1
Temperature: -10 °C
Reaction time: 2 h
Yield: 76.2 %

Procedure:
To a solution of 2-benzyl-4-oxo-piperidine-1-carboxylic acid tert-butyl ester (15 g, 51.8 mmol) (from SYNTECH) in DME (250 mL) under nitrogen atmosphere was simultaneously added toluene-4-sulfonylmethyl isocyanide (15.2 g, 77.7 mmol, in 250 mL DME) and potassium tert-butoxide (156 mL, 1 M in tert-butanol) over 1 h so that the temperature was kept below −10° C. The solution was stirred at −10° C. for 2 h and then allowed to reach room temperature over 16 h. To the reaction mixture was added H2O (400 mL) and the solution was stirred for 20 min and then extracted with DEE (×3) and EtOAc (×3). The combined organic phases were dried over Na2SO4 and evaporated. The residue was purified by column chromatography using EtOAc/heptane (10-60% gradient EtOAc) to yield tert-butyl 2-benzyl-4-cyanopiperidine-1-carboxylate (11.85 g, 76%). 1H NMR (600 MHz, cdcl3) δ 1.38-1.46 (m, 9H), 1.63-2.14 (m, 4H), 2.62-3.33 (m, 4H), 4.17 (m, 1H), 4.48 (m, 1H), 7.11-7.41 (m, 5H); MS m/z 301 (M+H)+.
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[O:1]=[C:2]1[C@H:6]([CH2:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][N:4]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:3]1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](CNC(=O)OCc2ccccc2)[C@@H](O)C1
Agent: O=[Cr](=O)([O-])Cl
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(=O)[C@H](CNC(=O)OCc2ccccc2)C1
Reaction time: 48 h

Procedure:
Dissolve 1,1-dimethylethyl(3R,4R)-3-hydroxy-4-[({[(phenylmethyl)oxy]carbonyl}amino)methyl]-1-pyrrolidinecarboxylate (1.0 g, 2.85 mmol) in methylene chloride (20 mL). Add PCC (1.23 g, 5.7 mmol) and Florisil (2.5 g) and stir at ambient temperature for 16 hours. Add 3 more equivalents of PCC (1.84 g, 8.55 mmol) and stir for 48 hours. Dilute solution with ether and filter through a pad of celite. The solvent was removed under reduced pressure yielding a crude oil. The crude mixture was purified on silica gel. (0.598 g, 60%). LCMS: m/z 349.4 (MH+).
Reaction SMILES: [C:1]1([C:7]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)=[CH:8][C:9]([OH:11])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.ClC(OCC)=O.[CH3:27][CH:28]([NH2:38])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]>>[CH3:27][CH:28]([NH:38][C:9](=[O:11])[CH:8]=[C:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: O=C(O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Reactant: CCCCCCCCCC(C)N
Agent: CCOC(=O)Cl
Product: CCCCCCCCCC(C)NC(=O)C=C(c1ccccc1)c1ccc([N+](=O)[O-])cc1
Yield: 51 %

Procedure:
The title compound was prepared from 3-phenyl-3-(4-nitrophenyl)propenoic acid via mixed anhydride formation using ethyl chloroformate, followed by reaction with 1-methyldecylamine, substantially according to the procedure of Preparation 21. The product was induced to solidify by trituration under hexane. The solid was recrystallized from hexane, giving a small amount of material which was discarded. The mother liquors were evaporated in vacuo to give an oil which solidified when stirred under acetonitrile. The solid was filtered off, giving a 51% yield of the title compound, m.p. 69°-71° C.