Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#N.[Na+].[CH3:4][C:5]1([CH3:18])[CH2:14][C:13]2[C:8](=[CH:9][C:10]([CH3:17])=[C:11]([OH:16])[C:12]=2[CH3:15])[CH:7]=[N:6]1>>[CH3:18][C:5]1([CH3:4])[N:6]=[CH:7][C:8]2[CH:9]=[C:10]([CH3:17])[C:11]([OH:16])=[C:12]([CH3:15])[C:13]=2[CH2:1][CH2:14]1
Reactant: [C-]#N
Reactant: Cc1cc2c(c(C)c1O)CC(C)(C)N=C2
Agent: [Na+]
Product: Cc1cc2c(c(C)c1O)CCC(C)(C)N=C2
Yield: 8 %

Procedure:
The product from the previous reaction (4.9 g, 24 mmol) is treated with NaCN as described above for compound 38. The resulting crude, cyclized imine is purified by FC (19:1 CH2Cl2/MeOH, then 9:1 CH2Cl2 /MeOH) to afford a dark orange semi-solid (370 mg, 8%). 1H NMR (CDCl3) 7.50 (s, 1), 7.00 (s, 1), 3.34 (br s, 1), 3.00-2.95 (m, 2), 2.18 (s, 3), 2.13 (s, 3), 2.00-1.95 (m, 2), 1.41 (s, 6); 13C NMR (CDCl3) 173.41, 156.30, 143.13, 141.14, 127.66, 125.74, 112.00, 57.81, 36.79, 28.50, 28.41, 16.73, 12.38; MS (MW=217.3, EI, eE=70 eV) m/z 217 (M+), 161 (base peak)
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:23]2[CH2:24][CH2:25][CH2:26][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: OCCN1CCCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(CCO)CC2)cc1
Temperature: 95 °C
Yield: 91.7 %

Procedure:
Fluoronitrobenzene (2.03 g, 14.4 mmol) is dissolved in water (10 ml), and then potassium carbonate (2.4 g, 17.3 mmol) and 1-(2-hydroxyethyl)-homopiperazine are added. The medium is heated at 95° C. for 4 hours and then cooled to room temperature and filtered. A dark orange-coloured powder is recovered which is placed in the oven (3.5 g, yield=91.7%).
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[N:16]1C=C[CH:19]=[CH:18][CH:17]=1.C(N)C=C>C(Cl)Cl.CN(C=O)C.C1COCC1>[CH2:17]([NH:16][C:7]([C:5]1[S:6][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:9])[CH:18]=[CH2:19]
Reactant: c1ccncc1
Reactant: O=C(O)c1ccc(Cl)s1
Agent: O=C(Cl)C(=O)Cl
Solvent: C=CCN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: C=CCNC(=O)c1ccc(Cl)s1
Temperature: -20 °C
Reaction time: 1.5 h

Procedure:
Part A: To a cooled (−30° C.) solution of 16.26 g (0.1 mol) of 5-chlorothiophene-2-carboxylic acid in 75 ml of CH2Cl2 were added 0.15 mol (75 mL, 1.5 eq) of oxalyl chloride 2M solution in CH2Cl2 followed by 4 drops of DMF. The mixture was stirred for 1.5 h. Volatiles were evaporated to yiled the acid chloride as a yellow oil. The crude acid chloride obtained (0.1 mol) was mixed with 41 mL of pyridine and 41 mL of THF. The mixture was cooled to −20° C. and 7.5 mL (0.1 mol) of allylamine was added. The temperature was allowed to increase to ambient and stirring continued for 3 h. Volatiles were evaporated and 300 mL of water added. The yellow precipitate was collected and washed with water. Purified by ISCO system flash chromatography (120 g cartridge loading with CH2Cl2 gradient elution 0% to 100% B over 30 min; (A=CH2Cl2, B=10% MeOH)) to yield 15.7 mg of the N-allyl-5-chlorothiophene-2-carboxamide as a solid. TR=2.67 min (Shimadzu Phenomenex S5 ODS 4.6×50 mm Luna flow rate 2.5 ml/mn; detection at 220 nM; gradient elution 0% to 100% B over 4 min; (A=10% MeOH, 90% H2O, 0.2% H3PO4& B=90% MeOH, 10% H2O, 0.2% H3PO4).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([CH:11]2[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14][CH:13]3[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][N:12]23)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.O>C(Cl)Cl>[C:1]([N:23]1[CH2:22][CH2:21][CH:13]2[N:12]([CH:11]([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:20]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[CH2:14]2)[CH2:25][CH2:24]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: c1ccc(C2c3ccccc3CC3CCNCCN32)cc1
Solvent: O
Solvent: ClCCl
Product: CC(=O)N1CCC2Cc3ccccc3C(c3ccccc3)N2CC1
Reaction time: 1 h

Procedure:
3.08 of acetyl chloride diluted with 10 ml of methylene chloride was added dropwise to a solution of 9.9 g (7 RS,12aRS)-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline in 100 ml of methylene chloride. The reaction mixture was stirred for 1 hour, then wasted twice with water, then dried with magnesium sulphate and concentrated to dryness to give (7RS,12aRS)-3-acetyl-1,2,3,4,5,7,12,12a-octahydro-7-phenyl-1,4-diazepino[1,7-b]isoquinoline (M.P. 145°-147°).
Reaction SMILES: [NH:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:5][CH2:4]1)[NH2:2].O.[F:20][C:21]([F:25])([F:24])[CH:22]=O>CCO>[F:20][C:21]([F:25])([F:24])[CH:22]=[N:2][NH:1][CH:3]1[CH2:4][CH2:5][N:6]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:7][CH2:8]1
Reactant: O=CC(F)(F)F
Reactant: NNC1CCN(C(=O)OCc2ccccc2)CC1
Solvent: CCO
Solvent: O
Product: O=C(OCc1ccccc1)N1CCC(NN=CC(F)(F)F)CC1
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a stirred solution of 109 (4 g, 8.38 mmol) in EtOH (42 ml) was added trifluoroacetaldehyde hydrate (0.648 ml, 8.38 mmol) and the resulting solution was allowed to stir for 3 h at 70° C. The solvent was evaporated and AcOEt was added to the residue and the organic layer was washed with 1N HCl then with brine, dried over MgSO4, filtrated and concentrated. Crude 110 was obtained as yellow oil and was used as is for the next step. LRMS (ESI): calc. 329.3; found 330.2 (MH)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:44])[N:14]([CH2:25][C:26]([NH:28][CH:29]([CH:41]([CH3:43])[CH3:42])[CH:30]([OH:40])[C:31]([F:39])([F:38])[C:32](=[O:37])[NH:33][CH2:34][CH2:35][CH3:36])=[O:27])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:45](N)[CH2:46][C:47]1C=CC=[CH:49][CH:48]=1.Cl>O>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13](=[O:44])[N:14]([CH2:25][C:26]([NH:28][CH:29]([CH:41]([CH3:43])[CH3:42])[CH:30]([OH:40])[C:31]([F:38])([F:39])[C:32](=[O:37])[NH:33][CH2:34][CH2:35][C:36]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[O:27])[C:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])=[CH:16][CH:17]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCCc1ccccc1
Reactant: CCCNC(=O)C(F)(F)C(O)C(NC(=O)Cn1c(-c2ccccc2Cl)ccc(NC(=O)OCc2ccccc2)c1=O)C(C)C
Agent: Cl
Solvent: O
Product: CC(C)C(NC(=O)Cn1c(-c2ccccc2Cl)ccc(NC(=O)OCc2ccccc2)c1=O)C(O)C(F)(F)C(=O)NCCc1ccccc1

Procedure:
2-[3-Benzyloxycarbonylamino-6-(2-chlorophenyl)-2-oxo-1,2-dihydro-1-pyridyl]-N-[3,3-difluoro-2-hydroxy-1-isopropyl-3-(N-propylcarbamoyl)propyl]acetamide was treated with phenethylamine using a method similar to that described in Example 1.h. except that the reaction mixture was diluted with water, and the pH was adjusted to 6-7 with 10% hydrochloric acid; the mixture was evaporated; and the residue was partitioned between ethyl acetate and water. The organic phase was washed (10% hydrochloric acid, brine), dried and evaporated. Purification by trituration from ether afforded the amide; TLC: Rf =0.34, chloroform:methanol (40:1).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:38])[C@@H:6]([NH2:37])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:36])[CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[O:27])[CH2:22][CH2:21]2)[CH2:12]1)=[O:10])[CH3:3].[CH3:39][O:40][CH2:41][CH2:42][C:43](O)=[O:44].ON1C2C=CC=CC=2N=N1.C(N=C=NCCCN(C)C)C>CN(C)C=O.O>[CH2:2]([O:4][C:5](=[O:38])[C@@H:6]([NH:37][C:43](=[O:44])[CH2:42][CH2:41][O:40][CH3:39])[CH2:7][NH:8][C:9]([C@@H:11]1[CH2:16][CH2:15][CH2:14][N:13]([C:17](=[O:36])[CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][N:23]([C:26]([O:28][CH2:29][C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[O:27])[CH2:24][CH2:25]2)[CH2:12]1)=[O:10])[CH3:3]
Reactant: COCCC(=O)O
Reactant: CCOC(=O)[C@@H](N)CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@H](CNC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OCc3ccccc3)CC2)C1)NC(=O)CCOC
Temperature: 0 °C

Procedure:
To a mixture of N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-amino-β-alanine ethyl ester hydrochloride (1 g), 3-methoxypropionic acid (0.17 ml) and 1-hydroxybenztriazole (0.24 g) in N,N-dimethylformamide (10 ml) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (0.33 ml) under stirring at 0° C. After stirring at ambient temperature for overnight, the mixture was poured into water and extracted with ethyl acetate. The extract washed with water, brine and dried over MgSO4, and evaporated in vacuo. The residue was purified by column chromatography on silica gel eluting with (CHCl3:MeOH=100:1) to give N-[(R)-1-{3-(1-benzyloxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-2(S)-(3-methoxypropionyl)amino-β-alanine ethyl ester (0.59 g) as an oil.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40](Cl)=[O:41]>ClCCl>[Cl:35][CH2:36][CH2:37][CH2:38][CH2:39][C:40]([NH:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([NH:9][C:10](=[O:27])[C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[N:13][C:12]=2[O:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([S:25][CH3:26])[CH:20]=2)[CH2:5][CH2:4]1)=[O:41]
Reactant: O=C(Cl)CCCCCl
Reactant: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](N)CC2)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CSc1cccc(Oc2ncc(F)cc2C(=O)N[C@H]2CC[C@H](NC(=O)CCCCCl)CC2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
N-(trans-4-Amino-cyclohexyl)-5-fluoro-2-(3-methylsulfanyl-phenoxy)-nicotinamide hydrochloride (400 mg, 1.065 mmol) was dissolved in dichloromethane (6 ml) and triethylamine (445 μl, 3.20 mmol) was added followed by dropwise addition of 5-chlorovaleryl chloride (151 μl, 1.172 mmol). The reaction was stirred under nitrogen at room temperature for 4 h. The reaction mixture was quenched with sat. sodium hydrogen carbonate solution (10 ml) and extracted with dichloromethane (3×15 ml). The combined organic extracts were dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by column chromatography, eluting with 95:5 dichloromethane/methanol, clean fractions were combined and the solvent was removed under reduced pressure to obtain the title compound (220 mg) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1.C1COCC1.[Br:24]N1C(C)(C)C(=O)N(Br)C1=O>CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+].[O-]S([O-])=O.[Na+].[Na+].O>[NH2:1][C:2]1[C:7]2=[C:8]([Br:24])[CH:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH2:17][OH:18])[CH:14]=[CH:15][CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: Nc1ncnn2c(-c3cccc(CO)c3)ccc12
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: Nc1ncnn2c(-c3cccc(CO)c3)cc(Br)c12
Reaction time: 1 h
Yield: 191.9 %

Procedure:
The product from step 1 (1.54 g, 6.4 mmol) was dissolved in 18 mL of 1:1 DMF:THF. The mixture was cooled to −20° C. (internal temperature) and 1,3-dibromo-5,5-dimethylhydantoin (0.92 g, 3.2 mmol) was added in 4 equal portions over 40 minutes. The mixture was stirred for an additional 1 hour during which the internal temp rose to −5° C. A solid mass formed, which was diluted with a mixture of 15 mL of 2M Na2CO3, 10 mL of sat. Na2SO3 and 60 mL of water and the mixture was stirred for an additional 30 minutes. The solid was collected by filtration, washed with water and dried in a vacuum oven at 40° C. to give 1.96 g (95%) of the title compound as a tan solid. 1H-NMR (DMSO-d6) 8.10 (bs, 1H), 7.94 (s, 2H), 7.86 (d, 1H), 7.40 (t, 1H), 7.29 (d, 1H), 7.17 (s, 1H), 6.84 (bs, 1H), 5.22 (t, 1H), 4.56 (d, 2H); LC-MS [M+H]+=319.3, 321.1, RT=2.29 min.
Reaction SMILES: C([O:8][C:9](=O)[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:12][C:11]=1[Cl:24])C1C=CC=CC=1.CC(C[AlH]CC(C)C)C.C1(C)C=CC=CC=1>C1COCC1>[CH2:17]([O:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][OH:8])=[C:11]([Cl:24])[CH:12]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(OCc1ccccc1)c1ccc(OCc2ccccc2)cc1Cl
Agent: CC(C)C[AlH]CC(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OCc1ccc(OCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 4-Benzyloxy-2 chloro-benzoic acid benzyl ester from Step A with DIBAL-H 1M in toluene (2.2 eq) in THF were stirred at room temperature for 3 hours. The quenched with tartrate saturated solution and extracted with ethyl acetate. Concentrated to dryness and purified by chromatography to afford the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([C:38]([OH:40])=O)[CH:36]=[CH:37][C:29]1=2.CCN(C(C)C)C(C)C.[NH2:50][C@@H:51]1[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[C@@H:53]([C:64]([O:66][CH3:67])=[O:65])[CH2:52]1>CN(C=O)C.O>[O:28]1[CH2:33][CH2:32][O:31][C:30]2[CH:34]=[C:35]([C:38]([NH:50][C@@H:51]3[CH2:56][CH2:55][N:54]([C:57]([O:59][C:60]([CH3:61])([CH3:62])[CH3:63])=[O:58])[C@@H:53]([C:64]([O:66][CH3:67])=[O:65])[CH2:52]3)=[O:40])[CH:36]=[CH:37][C:29]1=2
Reactant: O=C(O)c1ccc2c(c1)OCCO2
Reactant: COC(=O)[C@H]1C[C@H](N)CCN1C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)[C@H]1C[C@H](NC(=O)c2ccc3c(c2)OCCO3)CCN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.1 %

Procedure:
BOP (6.59 g, 14.9 mmol) was added to a solution of 2,3-dihydrobenzo[b][1,4]dioxine-6-carboxylic acid (2.68 g, 14.9 mmol) and DIEA (5.3 mL, 30 mmol) in DMF (50 mL). Then (2R,4R)-1-tert-butyl 2-methyl 4-aminopiperidine-1,2-dicarboxylate (3.5 g, 13.5 mmol) was added to the mixture and the resulting solution was stirred at room temperature for 18 hours. Water (100 mL) was added to quench the reaction, and extracted with ethyl acetate (2×100 mL), organic layers were dried over MgSO4, and concentrated under reduced pressure. The residue was purified by Companion (ReadySep, 120 g, silica gel packed) with ethyl acetate/heptane from 20-50% to give the amide as off-white solid 5.4 g (95%). LC-MC: 421.2 (t=2.4 min).
Reaction SMILES: [CH:1]([C:4]1([CH3:18])[N:8]2[C:9](=[O:16])[C:10]3[C:15]([C:7]2=[N:6][C:5]1=[O:17])=[CH:14][CH:13]=[CH:12][CH:11]=3)([CH3:3])[CH3:2].[CH3:19][NH:20][CH3:21]>O1CCCC1>[CH:1]([C:4]1([CH3:18])[NH:8][C:7]([C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[C:9]([N:20]([CH3:21])[CH3:19])=[O:16])=[N:6][C:5]1=[O:17])([CH3:2])[CH3:3]
Reactant: CNC
Reactant: CC(C)C1(C)C(=O)N=C2c3ccccc3C(=O)N21
Solvent: C1CCOC1
Product: CC(C)C1(C)NC(c2ccccc2C(=O)N(C)C)=NC1=O
Temperature: 50 °C
Reaction time: 16 h
Yield: 91.3 %

Procedure:
To a cold solution of 180 g of 3-isopropyl-3-methyl-5H-imidazo[2,1-a]isoindole-2-(3H),5-dione in 300 ml of dry tetrahydrofuran in a pressure bottle is added 68 g of dimethylamine. The bottle is sealed and the mixture heated to 50° C. with stirring for 16 hours. The mixture is cooled, and the contents of the bottle transferred to a flask. The solvent is then removed in vacuo. The crystalline residue is then suspended in ether, filtered, washed with ether, and air-dried to give 195 g of o-(5-isopropyl-5-methyl-4-oxo-2-imidazolin-2-yl)-N,N-dimethylbenzamide, melting point 144°-146° C. This product is recrystallized from acetonitrile to give an analytically pure product, melting point 147°-150° C.
Reaction SMILES: [C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:46]([O:47][Si](C(C)(C)C)(C)C)[CH:41]6[CH:42]([O:43][CH2:44][CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:55]([CH3:57])[CH3:56])=[O:16])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(OCC)(=O)C>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[C:1]1([CH:7]([O:14][C:15]([C:17]23[C:28]4([CH:30]=[O:31])[CH2:29][CH:20]([C:21]2([CH2:33][O:34][C:35]25[CH:46]([OH:47])[CH:41]6[CH:42]([O:43][CH2:44][CH3:45])[CH:37]([CH:38]([O:40]6)[O:39]2)[O:36]5)[CH2:22][CH:23]2[CH:27]4[CH2:26][CH2:25][CH:24]2[CH3:32])[CH:19]=[C:18]3[CH:55]([CH3:56])[CH3:57])=[O:16])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC1C2OC3(OCC45CC6C(C)CCC6C6(C=O)CC4C=C(C(C)C)C65C(=O)OC(c4ccccc4)c4ccccc4)OC2OC1C3O
Temperature: 25 °C
Reaction time: 1.33 h

Procedure:
Compound (27) was mixed with in 70 μl of 1M tetrabutylammonium fluoride-tetrahydrofuran solution and stirred at room temperature. After 80 minutes, the reaction solution was mixed with 15 ml of ethyl acetate and washed with 10 ml of sodium phosphate buffer (10 mM, pH 5.97) and then with 10 ml of water twice. After the washing, the ethyl acetate layer was dried over anhydrous sodium sulfate, filtered for removal of solids and concentrated in vacuo to give a crude reaction product. The reaction product was further subjected to silica gel column chromatography (Kieselgel 60, Merck, 1.5φ×15 cm) and eluted with n-hexane-ethyl acetate (3:1) to give 21.2 mg of compound (28) as a colorless oily substance.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].C(O[CH:18](N(C)C)[N:19]([CH3:21])[CH3:20])(C)(C)C>CN(C=O)C>[CH3:18][N:19]([CH3:21])/[CH:20]=[CH:1]/[C:2]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: CN(C)C(OC(C)(C)C)N(C)C
Reactant: Cc1cc([N+](=O)[O-])ccc1C#N
Solvent: CN(C)C=O
Product: CN(C)/C=C/c1cc([N+](=O)[O-])ccc1C#N
Temperature: 70 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
A mixture of 2-methyl-4-nitrobenzonitrile (5.0 g, 31 mmol) and tert-butoxybis(dimethylamino)methane (12.2 mL, 59 mmol) in dry DMF (8 mL) was stirred at 70° C. for 2 h under N2. After cooling to rt, DMF was removed in vacuo and the crude product was triturated with hexanes/EtOAc (5:1). The solid was collected by filtration and washed with hexane to give Intermediate 1A (6.5 g, 97%) as black solid. 1H NMR (400 MHz, CDCl3) δ 2.97 (s, 6H), 5.36 (d, J=13.2 Hz, 1H), 7.16 (d, J=13.6 Hz, 1H), 7.52 (d, J=8.8 Hz, 1H), 7.60 (m, 1H), 8.11 (d, J=1.8 Hz, 1H).
Reaction SMILES: C1(C)C=CC(S(N[C@H](C2C=CC=CC=2)[C@@H](C2C=CC=CC=2)N)(=O)=O)=CC=1.C(O)(C)C.CC(C)([O-])C.[K+].[Cl:37][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)=[O:40]>C(O)(C)C>[Cl:37][CH2:38][CH:39]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[OH:40]
Reactant: O=C(CCl)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: Cc1ccc(S(=O)(=O)N[C@H](c2ccccc2)[C@H](N)c2ccccc2)cc1
Agent: [K+]
Solvent: CC(C)O
Product: OC(CCl)c1ccccc1
Temperature: 25 °C
Yield: 93.6 %

Procedure:
A solution of di-μ-chlorodichlorobis(pentamethylcyclopentadienyl)dirhodium (III) (155 mg, 0.025 mmol) and (1R,2R)-N-(p-toluenesulfonyl)-1,2-diphenylethylenediamine (36.6 mg, 0.1 mmol) in isopropyl alcohol (25.0 ml) was heated at 80° C. for 20 minutes while stirring. After cooling the solution to room temperature, a 0.1 M potassium tert-butoxide isopropyl alcohol solution (2.5 ml, 0.25 mmol) and an isopropyl alcohol solution (22.5 ml) of 2-chloroacetophenone (773.0 mg, 5.0 mmol) as a reaction substrate were added thereto, followed by stirring at room temperature for 14 hours. After completion of the reaction, the solvent was removed by evaporation, and the residue was purified by silica gel column chromatography to give a desired compound, (+)-2-chloro-1-phenylethanol (732.9 mg; yield: 93.6%; optical purity: 97.5% ee).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([C:9]([Cl:13])=[CH:10][C:11]=1[Cl:12])[NH2:8])[CH:2]=C.[C:14]1(=O)OC(=O)C2=CC=CC=C12.C(OC1C=C(C(F)=CC=1Cl)N)C=C.C1(=O)NC(=O)C2=CC=CC=C12.NC1(F)C2CC(C)OC2=C(Cl)C=C1>>[NH2:8][C:7]1[C:6]2[CH2:14][CH:1]([CH3:2])[O:4][C:5]=2[C:11]([Cl:12])=[CH:10][C:9]=1[Cl:13]
Reactant: C=CCOc1cc(N)c(Cl)cc1Cl
Reactant: O=C1OC(=O)c2ccccc21
Agent: C=CCOc1cc(N)c(F)cc1Cl
Agent: CC1CC2C(=C(Cl)C=CC2(N)F)O1
Agent: O=C1NC(=O)c2ccccc21
Product: CC1Cc2c(N)c(Cl)cc(Cl)c2O1

Procedure:
4-amino-5,7-dichloro-2,3-dihydro-2-methylbenzofuran (38A) was prepared as an orange oil in four steps from 3-(allyloxy)-4,6-dichloroaniline and phthalic anhydride by the procedures described for preparing Example 19 from 19A, followed by hydrazinolysis of the phthalimide intermediate as described for the preparation of 37A.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[CH3:28][C:29]1[C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1>>[CH3:28][C:29]1[C:34]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:33][N:32]=[C:31]([NH2:44])[N:30]=1
Reactant: Cc1nc(N)ncc1B1OC(C)(C)C(C)(C)O1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Cc1nc(N)ncc1-c1nc(N2CCOCC2)c2sc(CN3CCN(S(C)(=O)=O)CC3)cc2n1

Procedure:
2-Chloro-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (225 mg) was coupled to 4-methyl-5-(4, 4,5,5-tetramethyl (1,3,2-dioxaborolan-2-yl))pyrimidine-2-ylamine via General Procedure A to yield 42 mg of 379. MS (Q1) 505.2 (M)+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.Br[CH2:22]/[C:23](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[N:24]\[O:25][CH3:26]>>[CH3:26][O:25]/[N:24]=[C:23](/[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)\[CH2:22][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CO/N=C(\CBr)c1ccccc1
Reactant: CCOC(=O)CCc1ccc(-c2ccc(O)cc2)cc1
Product: CO/N=C(\COc1ccc(-c2ccc(CCC(=O)O)cc2)cc1)c1ccccc1

Procedure:
Compound 115 was synthesized from ethyl 3-(4′-hydroxybiphenyl-4-yl)propanoate (0.27 g, 1 mmol) and (1Z)-2-bromo-N-methoxy-1-phenylethanimine (0.23 g, 1 mmol) by following the procedure described in scheme 39. (0.2 g, 49.8%) purity: 99.5%.