Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=2)=[N:4][CH:3]=1.[Br:16]NC(=O)CCC(N)=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:16][CH2:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=2)=[N:4][CH:3]=1
Reactant: Cc1cnc(-c2ccc([N+](=O)[O-])cc2)o1
Reactant: NC(=O)CCC(=O)NBr
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccc(-c2ncc(CBr)o2)cc1
Yield: 65.3 %

Procedure:
To a stirred solution of 5-methyl-2-(4-nitrophenyl)oxazole (3.2 g, 15.68 mmol) and benzoyl peroxide (10 mg, catalytic) in carbon tetrachloride (20 mL), was added N-bromo succinamide (2.77 g, 15.68 mmol). The mixture was heated to reflux for 9 h, filtered and the residue was washed with carbon tetrachloride. The combined filtrates were washed with water, sodium bicarbonate solution, brine, dried over anhydrous sodium sulphate and concentrated in vacuo. The crude product was purified over silica gel (60-120 mesh) with 30% ethyl acetate/hexane as eluent to afford 5-(bromomethyl)-2-(4-nitro-phenyl)-oxazole (2.9 g, 65%) as a solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].[C:10](OC(=N)C(Cl)(Cl)Cl)([CH3:13])([CH3:12])[CH3:11].B(F)(F)F.CCOCC.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C1CCCCC1.CCCCCC.C(OCC)(=O)C>[C:10]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=Cc1cccc(O)c1
Reactant: CC(C)(C)OC(=N)C(Cl)(Cl)Cl
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCCCC1
Solvent: CCOCC
Product: CC(C)(C)Oc1cccc(C=O)c1
Reaction time: 1 h
Yield: 31.6 %

Procedure:
Ex-654A) 3-Hydroxybenzaldehyde (4.08 g, 33.4 mmol) was slurried in 50 mL of anhydrous CH2Cl2 and added to t-butyl-2,2,2-trichloroacetimidate (25.0 g, 114 mmol) in 200 mL of anhydrous cyclohexane with an additional 50 mL of CH2Cl2 used in transfer. The mixture was stirred under nitrogen until uniform, then boron trifluoride diethyl etherate (0.50 μL, 4 mmol) was added via syringe and stirring was continued for 1 h. Powdered sodium bicarbonate (50 g, 0.6 mol) was added, and the solution was filtered through a silica gel plug, washing the plug with hexane. The solvent was evaporated to give crude product 3.54 g (59%) as an amber oil (85% pure by GC analysis). Chromatography on silica gel eluting with 0-10% ethyl acetate in hexane gave 1.88 g (32%) of pure 3-t-butoxybenzaldehyde product as a colorless oil. 1H NMR (C6D6) δ9.59 (s, 1H), 7.44 (br s, 1H), 7.20 (d t, 1H), 6.92 (m, 2H), 1.07 (s, 9H).
Reaction SMILES: C([C:3]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:4]=1[O:5][CH:6]([CH2:10][CH2:11][CH2:12][CH3:13])[C:7](O)=O)=O.C(=O)([O-])[O-].[K+].[K+].C(OC(=O)C)(=O)C>>[N+:18]([C:16]1[CH:15]=[CH:14][C:4]2[O:5][C:6]([CH2:10][CH2:11][CH2:12][CH3:13])=[CH:7][C:3]=2[CH:17]=1)([O-:20])=[O:19]
Reactant: CCCCC(Oc1ccc([N+](=O)[O-])cc1C=O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: CCCCc1cc2cc([N+](=O)[O-])ccc2o1

Procedure:
23.4 g of 2-(2-formyl-4-nitro-phenoxy)hexanoic acid and 2.3 g of potassium carbonate were charged into a 200 ml reactor containing 80 g of acetic anhydride.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]4[N:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1.CS(O[CH2:31][C@H:32]([O:34]C1CCCCO1)[CH3:33])(=O)=O>>[CH3:1][N:2]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:18][C:19]4[N:24]=[CH:23][C:22]([O:25][CH2:31][C@@H:32]([OH:34])[CH3:33])=[CH:21][CH:20]=4)[CH:16]=3)[N:11]=[CH:10][N:9]=2)=[N:3]1
Reactant: C[C@H](COS(C)(=O)=O)OC1CCCCO1
Reactant: Cn1ccc(Nc2ncnc3ccc(Oc4ccc(O)cn4)cc23)n1
Product: C[C@H](O)COc1ccc(Oc2ccc3ncnc(Nc4ccn(C)n4)c3c2)nc1

Procedure:
Using 6-({4-[(1-methyl-1H-pyrazol-3-yl)amino]quinazolin-6-yl}oxy)pyridin-3-ol obtained in Example 6-3) and (2R)-2-(tetrahydro-2H-pyran-2-yloxy)propyl methanesulfonate, and in the same manner as in Example 26-1) and 26-2), the entitled compound (42 mg) was obtained as a pale yellow amorphous solid.
Reaction SMILES: ClC(Cl)(Cl)COC(=O)[N:6]([CH:16]1[CH2:20][CH:19]([C:21]([N:23]2[CH2:28][CH2:27][N:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[C:35]#[N:36])[CH2:25][CH2:24]2)=[O:22])[N:18]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:39]=2[F:45])[CH2:17]1)[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=1[F:15].C(O)(=O)C>CO.[Zn]>[F:45][C:39]1[C:40]([F:44])=[CH:41][CH:42]=[CH:43][C:38]=1[CH2:37][N:18]1[CH2:17][CH:16]([NH:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][C:9]=2[F:15])[CH2:20][CH:19]1[C:21]([N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:35]#[N:36])[CH2:25][CH2:24]1)=[O:22]
Reactant: N#Cc1ccccc1N1CCN(C(=O)C2CC(N(Cc3ccc(F)cc3F)C(=O)OCC(Cl)(Cl)Cl)CN2Cc2cccc(F)c2F)CC1
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: N#Cc1ccccc1N1CCN(C(=O)C2CC(NCc3ccc(F)cc3F)CN2Cc2cccc(F)c2F)CC1
Reaction time: 0.5 h
Yield: 7.7 %

Procedure:
{1-(2,3-Difluoro-benzyl)-5-[4-(2-cyano-phenyl)-piperazine-1-carbonyl]-pyrrolidin-3-yl}-(2,4-difluoro-benzyl)-carbamic acid 2,2,2-trichloro-ethyl ester (0.13 mmol) and Zn (0.068 g, 1.04 mmol) was dissolved in MeOH (5 ml), and PH was adjust to 5-6 using acetic acid. The mixture was heated to reflux and stirred for 30 min. After removal of methanol, the residue was purified by HPLC to afford final product (5.5 mg, 0.01 mmol) as yellow oil in 8% yield. MS m/e=552.4 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br-].[CH:12]1([Zn+])[CH2:14][CH2:13]1>C1COCC1.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>[CH:12]1([C:2]2[CH:3]=[C:4]([F:10])[C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH2:14][CH2:13]1
Reactant: N#Cc1ncc(Br)cc1F
Reactant: [Zn+]C1CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: C1CCOC1
Product: N#Cc1ncc(C2CC2)cc1F
Temperature: 80 °C

Procedure:
To solution of 5-bromo-3-fluoropicolinonitrile (603 mg, 3.0 mmol) and Pd(PPh3)4 (173 mg, 0.15 mmol) in 10 mL of THF was added cyclopropyl zinc bromide (0.5 M, 10 mL) under N2. After being heated 80° C. for 4 h, the mixture was cooled to room temperature and quenched with sat. NH4Cl (aq). The mixture was extracted with EtOAc (3×) and the combined organic layers were washed with sat. NaHCO3 (aq.) and brine, dried (MgSO4), and concentrated. The crude product was purified by silica gel chromatography (elution with 0-8% EtOAc/Hex) to afford 5-cyclopropyl-3-fluoropicolinonitrile (406 mg).
Reaction SMILES: [C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:18](=O)[CH:19](Br)[CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOCC.[BH4-].[Na+].CO>O>[C:1]([N:9]1[C:17]2[CH:16]=[CH:15][CH:14]=[C:13]3[CH:18]=[CH:19][CH2:20][CH:11]([C:12]=23)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1c2cccc3c2C(CC1Br)CN3C(=O)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: CO
Product: O=C(c1ccccc1)N1CC2CC=Cc3cccc1c32
Reaction time: 0.58 h

Procedure:
A suspension of 5 g. of 1-benzoyl-4-bromo-5-keto-1,2,2a,3,4,5-hexahydrobenz[cd]indole was prepared in 200 ml. of ether. 2 g. of sodium borohydride and 50 ml. of methanol were added and the reaction mixture stirred for 35 minutes. The reaction mixture was then diluted with water and the aqueous layer extracted with ethyl acetate. The ethyl acetate layer was separated, washed with water and with saturated aqueous sodium chloride. The organic layer was dried and the solvent removed by evaporation to dryness. Thin layer chromatography indicated that the resulting residue was a single spot material and consisted of 1-benzoyl-4-bromo-5-hydroxy-1,2,2a,3,4,5-hexahydrobenz[cd]indole. The residue was dissolved in 50 ml. of acetic acid. 10 g. of zinc dust were added and the resulting mixture refluxed for 13/4 hours under a nitrogen atmosphere. Thin layer chromatography of an aliquot indicated that one major spot was present. The reaction mixture was filtered and the filtrate poured over ice. The resulting aqueous mixture was made basic with 14 N aqueous ammonium hydroxide. The alkaline layer was then extracted with ethyl acetate. The ethyl acetate extract was separated, washed with water and with saturated aqueous sodium chloride and then dried. Evaporation of the solvent yielded a residue which was shown by thin layer chromatography to consist of one major spot with a small spot corresponding to starting material. A chloroform solution of the residue was filtered through florisil and the residue obtained after the evaporation of chloroform in vacuo was crystallized from methanol to yield crystalline 1-benzoyl-1,2,2a,3-tetrahydrobenz[cd]indole melting at 89°-91° C.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[CH2:42]([NH:46][CH3:47])[CH:43]([CH3:45])[CH3:44]>C(Cl)Cl.CN(C=O)C>[CH2:42]([N:46]([CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1)[CH3:47])[CH:43]([CH3:45])[CH3:44]
Reactant: CNCC(C)C
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)CN(C)Cc1cc(-c2cccc(C3=Nc4cc(OCC(F)(F)F)c(C(F)(F)F)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with isobutyl-methyl-amine in DMF according to the general procedure of Example 288. Obtained as a light brown solid (199 mg, 69%).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9](OS(C(F)(F)F)(=O)=O)=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1.[CH2:23]([OH:26])[C:24]#[CH:25]>CN(C)C=O.C(N(CC)CC)C>[CH3:1][S:2][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:25]#[C:24][CH2:23][OH:26])=[C:10]([O:13][CH3:14])[CH:11]=2)[N:6]=[CH:5][N:4]=1
Reactant: C#CCO
Reactant: COc1cc2c(SC)ncnc2cc1OS(=O)(=O)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc2c(SC)ncnc2cc1C#CCO
Yield: 16.6 %

Procedure:
4-(methylthio)-6-methoxy-7-(trifluoromethanesulphonyloxy)quinazoline (1.0 g, 2.82 mmol) in dimethylformamide (30 ml) was reacted with propargyl alcohol (0.51 ml, 8.75 mmol) in the presence of bisdichloro(triphenylphosphine) palladium (100 mg, 0.14 mmol) copper (I) iodide (40 mg) and triethylamine (1.7 ml, 0.0124 mmol) at 90° C. for 2.5 hours under argon. The solvent was evaporated in vacuo, water and hydrochloric acid (2.0 N) were added, and the mixture was extracted with ethyl acetate. Purification by flash chromatography on silica gel, eluting with 7.5% methanol in dichloromethane, yielded 4-(methylthio)-6-methoxy-7-(3-hydroxyprop-1-ynyl)quinazoline (122 mg, 17% yield):
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.N1C=CC=CC=1.[C:64](Cl)(=[O:71])[C:65]1[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=1>ClCCl>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:64](=[O:71])[C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: O=C(Cl)c1ccccc1
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)c4ccccc4)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the FR-900506 substance (9.7 mg) in dichloromethane (0.2 ml) and pyridine (0.1 ml) was added benzoyl chloride (50 μl) at room temperature, and the mixture was stirred at room temperature for 2 hours. The solvent was removed from the reaction mixture under reduced pressure to give a crude oil. This oil was purified on silica gel thin layer chromatography (developing solvent:diethyl ether and hexane, 2:1 v/v) to afford 17-allyl-12-[2-(4-benzoyloxy-3-methoxycyclohexyl)-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (8.0 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([C:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH:18]=3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C([SiH](CC)CC)C.[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29]>>[F:26][C:27]([F:32])([F:31])[C:28]([OH:30])=[O:29].[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([C:8]([CH:13]3[CH2:14][CH2:15][NH:16][CH2:17][CH2:18]3)=[CH:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(C3=CCNCC3)c[nH]c2c1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc2c(C3CCNCC3)c[nH]c2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 67 %

Procedure:
To a mixture of 2.4 gm (9.9 mMol) 6-nitro-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole in 10.0 mL trifluoroacetic acid were added 1.65 mL (10.4 mMol) triethylsilane. After an initial exotherm, the reaction was allowed to stir for 18 hours at ambient temperature. At this point an additional 0.5 mL triethylsilane were added and the reaction mixture stirred for 24 hours. The reaction mixture was then concentrated under reduced pressure. The residue was crystallized from ethanol to give 2.4 gm (67%) of the title compound.
Reaction SMILES: C1C=C[NH+]=CC=1.Br[Br-]Br.[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:19]1[CH2:18][CH2:17][CH2:16][C:15](=[O:32])[C:14]2=1.[Br-].[Li+].C(=O)([O-])[O-].[Li+].[Li+]>C1COCC1.CN(C=O)C>[Cl:10][C:11]1[CH:12]=[C:13]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1)[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([OH:32])[C:14]2=1
Reactant: O=C1CCCc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Br-]
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: Oc1cccc2c1c1cc(Cl)ccc1n2Cc1ccc(F)cc1
Temperature: 75 °C
Reaction time: 3.5 h
Yield: 73 %

Procedure:
Pyridinium bromide perbromide (0.6155 g, 0.0019 mol) is added to a solution of 6-chloro-9-(4-fluorobenzyl)-1,2,3,9-tetrahydro-4H-carbazol-4-one in THF (2.2 mL) and DMF (1.5 mL) and the mixture is heated to 75° C. After stirring for 3.5 h, the THF is removed under reduced pressure and the residue is partitioned between dichloromethane and brine. The combined organic layers are washed with dilute sodium thiosulfate/brine and the aqueous layer is backwashed with dichloromethane. The combined organic layers are dried over magnesium sulfate and concentrated under reduced pressure to give a residue. A mixture of the resulting residue, lithium bromide (0.3077 g, 0.0036 mol), lithium carbonate (0.2376 g, 0.0032 mol) and DMF (6 mL) is heated at 120° C. for two hours. The DMF is removed under high vacuum and the residue is partitioned between dichloromethane and water. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The residue is chromatographed on silica gel (125 mL) using dichloromethane (100%) to give 0.3773 g (73%) of the title compound. An aliquot is recrystallized from dichloromethane/hexane; MS (ESI−) for C19H13ClFNO m/z 324.1 (M−H)−; IR (drift) 1510, 1468, 1444, 1335, 1297, 1263, 1232, 1218, 1147, 1116, 832, 822, 791, 778, 745 cm−1; 1H NMR (CDCl3) δ5.37, 5.43, 6.59, 6.94, 7.07, 7.23, 7.33, 8.31. Anal. Calcd for C19H13ClFNO: C, 70.05; H, 4.02; N, 4.30; Cl, 10.88. Found: C, 68.51; H, 3.96; N, 4.27.
Reaction SMILES: [CH:1]1([CH:7]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])=[O:27])=[CH:22][CH:21]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CCCCCC.C(O)C.CO.[OH-].[Na+]>O1CCCC1>[CH:1]1([CH:7]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([C:26]([N:28]([CH3:36])[CH2:29][CH2:30][C:31]([OH:33])=[O:32])=[O:27])=[CH:24][CH:25]=2)[C:8]2[O:9][C:10]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][C:11]=3[C:12]=2[CH3:13])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2oc3ccc(F)cc3c2C)C2CCCCC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1c(C(Nc2ccc(C(=O)N(C)CCC(=O)O)cc2)C2CCCCC2)oc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Ethyl 3-{[(4-{[cyclohexyl(5-fluoro-3-methyl-1-benzofuran-2-yl)methyl]amino}phenyl)carbonyl](methyl)amino}propanoate (564 mg) synthesized in Example A45(2) was fractionated by high performance liquid chromatography (column: CHIRALPAK AD (50 mm ID×500 mL, manufactured by Daicel Chemical Industries, Ltd., mobile phase:hexane/ethanol (400/600), flow rate: 60 mL/min, column temperature: 30° C.). The fraction containing an optically active form having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated to give an amorphous form (273 mg, 99.9% ee). To a mixture of the obtained amorphous form, methanol (5 mL) and tetrahydrofuran (5 mL) was added 1N aqueous sodium hydroxide solution (1.00 mL), and the mixture was stirred at room temperature for 1.5 hr, and concentrated under reduced pressure. The residue was dissolved in water (10 mL), and 1N hydrochloric acid (1.00 mL) was added at 0° C. The resulting precipitate was collected by filtration to give the title object compound (248 mg, 47%, 99.9% ee) as a white solid.
Reaction SMILES: [C:1]([N:9]1[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:25])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:15][CH:14]=1.C1C=CC=CC=1.CO>O(CC)CC>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2([OH:25])[CH2:20][CH2:21][N:22]([CH2:10][CH2:11][NH:9][C:1](=[O:8])[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:23][CH2:24]2)=[CH:15][CH:14]=1
Reactant: O=C(c1ccccc1)N1CC1
Reactant: OC1(c2ccc(Cl)cc2)CCNCC1
Solvent: c1ccccc1
Solvent: CCOCC
Solvent: CO
Product: O=C(NCCN1CCC(O)(c2ccc(Cl)cc2)CC1)c1ccccc1

Procedure:
A mixture of 0.74 parts of 1-(benzoyl)aziridine, 1.06 parts of 4-(4- chlorophenyl)-4-piperidinol, 5.4 parts of benzene and 0.4 parts of methanol is stirred and refluxed for 2 hours. The reaction mixture is cooled. Upon the addition of 1,1'-oxybisethane, the product is precipitated. After stirring for 15 minutes, the product is filtered off and dried, yielding 1.1 parts of N-{2-[4-(4-chlorophenyl)-4-hydroxy-1-piperidinyl] ethyl} benzamide; mp. 169° C.
Reaction SMILES: [C:1]([CH2:9][C:10](=O)[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[NH3:13]>C(O)C>[C:1]([CH:9]=[C:10]([NH2:13])[CH3:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: N
Reactant: CC(=O)CC(=O)c1cccnc1
Solvent: CCO
Product: CC(N)=CC(=O)c1cccnc1
Temperature: 50 °C
Reaction time: 72 h
Yield: 91 %

Procedure:
7.5 g of nicotinoyl-acetone are dissolved in 45 ml of anhydrous ethanol and, after adding 20 ml of ammonia, the mixture is then stirred for 3 days at 50° C in an autoclave. Concentrating the clear solution leaves an oil which becomes solid after a short time. After recrystallisation from toluene, 2-nicotinoyl-1-methylvinylamine (melting point 82°) is obtained in a 91% yield.
Reaction SMILES: [OH:1][C@H:2]([CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[CH2:3][N:4]1[CH2:9][CH2:8][C:7]2[NH:10][C:11]([CH:14]=O)=[C:12]([CH3:13])[C:6]=2[C:5]1=[O:16].[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1[CH2:34][C:35](=[O:41])[NH:36]2.N1CCCCC1>C(O)C>[F:24][C:25]1[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=1[C:32]1[CH:40]=[CH:39][CH:38]=[C:37]2[C:33]=1/[C:34](=[CH:14]/[C:11]1[NH:10][C:7]3[CH2:8][CH2:9][N:4]([CH2:3][C@H:2]([OH:1])[CH2:17][N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[C:5](=[O:16])[C:6]=3[C:12]=1[CH3:13])/[C:35](=[O:41])[NH:36]2
Reactant: O=C1Cc2c(cccc2-c2cccc(F)c2F)N1
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1c(/C=C2\C(=O)Nc3cccc(-c4cccc(F)c4F)c32)[nH]c2c1C(=O)N(C[C@H](O)CN1CCOCC1)CC2
Temperature: 25 °C
Yield: 73 %

Procedure:
(R)-5-(2-Hydroxy-3-morpholin-4-yl-propyl)-3-methyl-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde if (50 mg, 0.156 mmol), 4-(2,3-difluoro-phenyl)-1,3-dihydro-indol-2-one 3d (34.3 mg, 0.14 mmol) and piperidine (7.7 μL, 0.078 mmol) were dissolved in 0.3 mL of ethanol under stirring at room temperature. The reaction system was stirred at 80° C. in an oil bath in dark for 2 hours. The reaction was completed until TLC showed the disappearance of starting materials, and the oil bath was removed. The reaction system was naturally cooled down to room temperature to precipitate solids. The resulting solids were filtered to give the title compound 2-[(Z)-4-(2,3-difluoro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-5-[(R)-2-hydroxy-3-morpholin-4-yl-propyl]-3-methyl-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one 3 (56 mg, yield 73%) as a yellow solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([OH:17])=O)[CH3:14])=[O:11])[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.[C:19]([O:23][C:24](=[O:31])[C@H:25]([CH2:27][CH2:28][CH2:29][CH3:30])[NH2:26])([CH3:22])([CH3:21])[CH3:20]>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:12][C@H:13]([C:15]([NH:26][C@@H:25]([CH2:27][CH2:28][CH2:29][CH3:30])[C:24]([O:23][C:19]([CH3:20])([CH3:21])[CH3:22])=[O:31])=[O:17])[CH3:14])=[O:11])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: CCCC[C@H](N)C(=O)OC(C)(C)C
Reactant: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)O
Agent: Cl
Product: CCCC[C@H](NC(=O)[C@H](C)NC(=O)Cc1cc(F)cc(F)c1)C(=O)OC(C)(C)C

Procedure:
Following General Procedure D and using N-(3,5-difluorophenylacetyl)-L-alanine (from Example B2 above) and the norleucine tert-butyl ester hydrochloride, the title compound was prepared as a semi-solid. The reaction was monitored by tlc (Rf=0.41 in 50% EtOAc/hexanes) and the product was purified by flash chromatography using 50% EtOAc/hexanes as the eluent, followed by preparative plate chromatography using 50% EtOAc/hexanes as the eluent. NMR data was as follows: