Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[CH2:11]1[CH2:15][O:14][CH2:13][CH2:12]1>>[CH2:1]([C:13]([CH2:12][CH2:11][CH2:15][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])=[O:14])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCC[Mg]Br
Reactant: C1CCOC1
Product: CCCCCCCCC(=O)CCCCCCCC
Reaction time: 3.5 h
Yield: 88 %

Procedure:
To a solution of 4.0 g (14.5 mmol) of the LIVb in 100 mL of THF was added 20 mL (40 mmol) of 2M octylmagnesium bromide in THF dropwise. After stirring 3.5 h, the solution was quenched with saturated NH4Cl, acidified with 1N HCl, and was extracted with EtOAc. The combined organic layers were washed with brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was chromatographed on silica gel. Elution with 7.5% ethyl acetate in hexanes gave 4.86 g (88%) of the bis-octyl ketone LIVc as an oil. 1H NMR (300 Hz, CDCl3): δ 4.55 (s, 2H, CH), 2.64 (dt, 4H, CH2), 1.62 (m, 4H, CH2), 1.42 (s, 6H, CH3), 1.27 (broad s, 20H, CH2), 0.88 (t, 6H, CH3); MS (CI, NH3) m/e 383 (M+1).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:11])([CH3:10])[CH3:9])[CH2:2]1.C(N(CC)CC)C.[C:20]1([S:26](Cl)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[Cl-].[NH4+]>ClCCl>[C:20]1([S:26]([N:1]2[CH2:4][CH:3]([NH:5][C:6](=[O:12])[O:7][C:8]([CH3:9])([CH3:11])[CH3:10])[CH2:2]2)(=[O:28])=[O:27])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 25.7 %

Procedure:
To a stirred suspension of tert-butyl azetidin-3-ylcarbamate (4.61 g, contaminated with diphenylmethane 1:1, ˜13.39 mmoles) in dichloromethane (150 mL), was added triethylamine (3.73 mL, 26.77 mmoles) and benzenesulfonyl chloride (2.57 mL, 20.08 mmoles). The reaction was stirred at room temperature for ˜4 hours and became a solution. Sat. ammonium chloride was added to the mixture and the aqueous phase was extracted with dichloromethane (3×). The combined organic layers were dried over anhydrous magnesium sulphate, filtered and concentrated. The residue was precipitated from dichloromethane/hexanes 1:1 to give the title material (1.073 g, ˜26%) as a solid. The mother liquor was concentrated and the residue was purified on Biotage (0 to 20% acetonitrile in dichloromethane) to afford the title material (2.46 g, ˜58%). 1H NMR 400 MHz CDCl3 δ (ppm): 1.42 (9H, s), 3.60 (2H, br s), 4.06 (2H, dd, J=8.7 and 7.7 Hz), 4.35 (1H, br s), 4.70 (1H, br s), 7.60-7.64 (2H, m), 7.68-7.72 (1H, m), 7.86-7.88 (2H, m).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]([F:32])([F:31])[F:30])=[CH:24][CH:23]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=2)=[N:8][CH:9]=1)([CH3:3])[CH3:2].C([O:37][C:38](=[O:41])[CH2:39]Br)(C)(C)C.C(O)(C(F)(F)F)=O>>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([N:10]([CH2:21][C:22]2[CH:23]=[CH:24][C:25]([O:28][C:29]([F:32])([F:30])[F:31])=[CH:26][CH:27]=2)[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=2)[O:20][CH2:39][C:38]([OH:41])=[O:37])=[N:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CC(C)c1ccc(N(CCCc2cccc(O)c2)Cc2ccc(OC(F)(F)F)cc2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)c1ccc(N(CCCc2cccc(OCC(=O)O)c2)Cc2ccc(OC(F)(F)F)cc2)nc1

Procedure:
Similarly prepared by alkylation of 3-(3-{(5-isopropylpyridin-2-yl)[4-(trifluoromethoxy)benzyl]amino}propyl)phenol with tert-butyl-bromo-acetate followed by standard TFA hydrolysis.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4].[CH2:18]([O:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:27]([O:29][CH2:30][CH3:31])[CH:28]=1)[CH:24]=O)[CH3:19]>CO>[CH2:30]([O:29][C:27]1[CH:26]=[C:23]([CH:22]=[C:21]([O:20][CH2:18][CH3:19])[CH:28]=1)[CH2:24][NH:1][C@@H:2]([CH3:17])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([OH:16])=[C:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[OH:4])[CH3:31]
Reactant: CCOc1cc(C=O)cc(OCC)c1
Reactant: C[C@H](N)[C@H](O)c1ccc(O)c(NS(C)(=O)=O)c1
Solvent: CO
Product: CCOc1cc(CN[C@@H](C)[C@H](O)c2ccc(O)c(NS(C)(=O)=O)c2)cc(OCC)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 53.5 %

Procedure:
Borane-pyridine complex (155 μL, 1.46 mmol) was added to a methanol solution (3.3 mL) of an amine (3) (127 mg, 0.486 mmol) and 3,5-diethoxybenzaldehyde (123 mg, 0.632 mmol) at 40° C. and the mixture was stirred for 2.5 hours. The reaction mixture was allowed to cool to room temperature and extracted after addition of water with a mixed solvent (ethyl acetate: methanol=10:1), and the organic layer was washed with saturated aqueous sodium chloride solution. The organic layer was dried and concentrated, and the crude product obtained was purified by amine silica gel column chromatography (eluant:chloroform:methanol=7:1), to give a desired amine (9) as a yellow solid (114 mg, yield 54%).
Reaction SMILES: [F:1][C:2]([F:42])([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([N+:22]([O-])=O)[CH:19]=[C:18]([N+:25]([O-])=O)[CH:17]=2)=[O:13])=[CH:6][CH:5]=1>CN(C)C=O.O.[Zn]>[F:1][C:2]([F:42])([C:28]1[CH:33]=[CH:32][C:31]([O:34][CH2:35][CH2:36][CH2:37][C:38]([F:41])([F:40])[F:39])=[CH:30][CH:29]=1)[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][C:16]2[CH:21]=[C:20]([NH2:22])[CH:19]=[C:18]([NH2:25])[CH:17]=2)=[O:13])=[CH:6][CH:5]=1
Reactant: O=C(/C=C/c1ccc(OC(F)(F)c2ccc(OCCCC(F)(F)F)cc2)cc1)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Zn]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cc(N)cc(COC(=O)/C=C/c2ccc(OC(F)(F)c3ccc(OCCCC(F)(F)F)cc3)cc2)c1
Yield: 70.1 %

Procedure:
4.99 g (8.38 mmol) of 3,5-dinitrobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}phenyl)prop-2-enoate are dissolved in a mixture of 54 mL of N,N-dimethylformamide and 6 mL water. 13.9 g (51.4 mmol) ferric chloride hexahydrate are added. 5.60 g (85.7 mmol) zinc powder is added portion wise within 60 minutes. The mixture is allowed to react for 2 hours. The reaction mixture is partitioned between ethyl acetate and water and filtrated. The organic phase is washed repeatedly with water, dried over sodium sulfate, filtrated and concentrated under reduced pressure. Filtration of the residue on 200 g silica gel using toluene:ethyl acetate 1:3 as eluent and crystallization from ethyl acetate:hexane mixture yields 3.15 g of 3,5-diaminobenzyl (2E)-3-(4-{difluoro[4-(4,4,4-trifluorobutoxy)phenyl]-methoxy}phenyl)prop-2-enoate as yellow crystals.
Reaction SMILES: [CH2:1]([N:3]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2].CO>C(OCC)(=O)C.[Pd]>[CH2:1]([N:3]([C:14]1[CH:15]=[C:16]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])=[CH:22][CH:21]=2)[CH:17]=[CH:18][CH:19]=1)[C:4]([NH:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])=[O:5])[CH3:2]
Reactant: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(/C=C/C(=O)O)cc2)c1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCCCCCCNC(=O)N(CC)c1cccc(-c2ccc(CCC(=O)O)cc2)c1
Yield: 66 %

Procedure:
A solution of 400 mg (0.98 mmol, 1 eq) of (E)-3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]acrylic acid (prepared in Example 27 g) in 10 mL of ethyl acetate in the presence of 0.2 ml of methanol is stirred for 4 hours at room temperature in the presence of 200 mg (50% by mass) of 10% palladium-on-charcoal under a hydrogen atmosphere. The reaction medium is filtered through Celite and then evaporated to dryness. After crystallization from ethyl ether/pentane, 265 mg of 3-[3′-(1-ethyl-3-heptylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=70° C.). Yield=66%
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[C:11](Cl)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>>[C:11]([C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][C:2](=[O:10])[CH2:3]2)(=[O:17])[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: O=C1Cc2ccccc2N1
Reactant: CCCCCC(=O)Cl
Product: CCCCCC(=O)c1ccc2c(c1)CC(=O)N2

Procedure:
Prepared from 2-indolinone and hexanoic acid chloride
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[Cl:32][C:33]1[CH:34]=[C:35](B(O)O)[CH:36]=[CH:37][CH:38]=1>>[Cl:32][C:33]1[CH:38]=[C:37]([C:12]2[N:13]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:14]=[C:15]3[C:11]=2[CH2:10][CH2:9][NH:8][CH2:17][CH2:16]3)[CH:36]=[CH:35][CH:34]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(-c3ccccc3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Product: Clc1cccc(-c2c3c(nn2-c2ccccc2)CCNCC3)c1
Yield: 27.8 %

Procedure:
The title compound (37.5 mg) was prepared from 192.3 mg of 2-phenyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 176, Step B) and 84.7 mg of 3-chlorophenylboronic acid as in Example 199. MS (ESI): exact mass calculated for C19H18ClN3, 323.12; found, m/z 324.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.32-7.16 (m, 8H), 7.01-6.98 (m, 1H), 3.12-3.08 (m, 2H), 3.05-3.02 (m, 2H), 3.01-2.98 (m, 2H), 2.69-2.66 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)=[CH:5][CH:4]=1.[I:18]I>CO.S([O-])([O-])(=O)=O.[Ag+2]>[I:18][C:8]1[CH:7]=[C:6]([C@H:9]2[CH2:13][CH2:12][C@H:11]([C:14]([O:16][CH3:17])=[O:15])[CH2:10]2)[CH:5]=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: II
Reactant: COC(=O)[C@H]1CC[C@H](c2ccc(OC)cc2)C1
Agent: [Ag+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CO
Product: COC(=O)[C@H]1CC[C@H](c2ccc(OC)c(I)c2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl trans-3-(4-methoxyphenyl)cyclopentanecarboxylate (Step B) 60 mg, 0.256 mmol) in MeOH (2 ml), under nitrogen at RT, was added silver sulfate (80 mg, 0.256 mmol) followed by iodine (65.0 mg, 0.256 mmol). The resulting mixture was stirred at room temperature for 1 hour, then, filtered solids washing with MeOH and concentrated filtrate. The residue was purified by flash column chromatography on silica gel, eluting with EtOAc in hexanes to afford the titled compound. 1H NMR (500 MHz, CDCl3): δ 7.63 (d, J=2.2 Hz, 1H); 7.15 (dd, J=8.4, 2.2 Hz, 1H); 6.75 (d, J=8.4 Hz, 1H); 3.85 (s, 3H); 3.70 (s, 3H); 3.12 (m, 1H); 3.00 (m, 1H); 2.33 (ddd, J=13.2, 8.0, 4.6 Hz, 1H); 2.17-2.10 (m, 2H); 1.94 (m, 1H); 1.83 (m, 1H); 1.61 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1.[Br:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21]Br.C(=O)([O-])[O-].[K+].[K+]>CC(CC)=O>[Br:18][C:19]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:20]=1[CH2:21][O:1][C:2]1[C:7]2=[N:8][CH:9]=[C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:11](=[O:12])[N:6]2[CH:5]=[CH:4][CH:3]=1
Reactant: Clc1ccc(CBr)c(Br)c1
Reactant: CCOC(=O)c1cnc2c(O)cccn2c1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)c1cnc2c(OCc3ccc(Cl)cc3Br)cccn2c1=O
Yield: 108.2 %

Procedure:
To 4.7 g of 9-hydroxy-4-oxo-4H-pyrido[1,2-α]pyrimidine-3-carboxylic acid, ethyl ester, 7.2 g of 2-bromo-4-chlorobenzyl bromide and 200 ml of ethyl methyl ketone is added 3.3 g of anhydrous potassium carbonate. The mixture is stirred and heated under reflux for 18 hours, cooled and filtered. The filtrate is concentrated in vacuo to give 9.5 g of a viscous gum. This is dissolved in 100 ml of chloroform and the chloroform solution is washed with 60 ml of 5% aqueous potassium hydroxide. The chloroform solution is separated, washed with 25 ml of saturated aqueous sodium chloride, dried, and concentrated to give 7.4 g of a viscous gum. This gum is crystallized in 250 ml of 1:1 toluene-Skellysolve E to give 3.6 g of green crystals that sinter at 155° and melt at 162°-165°. A second recrystallization from 225 ml of 2-propanol gives the yellow crystalline named product, m.p. about 167°-169°. The yield is about 2.95 g.
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C@:9]1([F:26])[C@@H:14]2[C@H:10]1[CH:11]=[CH:12][C@@:13]2([NH2:25])[C:15]([O:17]CC1C=CC=CC=1)=[O:16])=[O:8])C>O.O1CCCC1>[NH2:25][C@@:13]1([C:15]([OH:17])=[O:16])[CH:12]=[CH:11][C@@H:10]2[C@H:14]1[C@@:9]2([F:26])[C:7]([OH:8])=[O:6]
Reactant: CCOC(=O)[C@@]1(F)[C@@H]2C=C[C@@](N)(C(=O)OCc3ccccc3)[C@@H]21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: N[C@@]1(C(=O)O)C=C[C@@H]2[C@H]1[C@@]2(F)C(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 42.3 %

Procedure:
Lithium hydroxide hydrate, in an amount of 25 mg, dissolved in 5 mL of water was added to 90 mg of (1R,2S,5R,6R)-2-amino-6-fluoro-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid 2-benzyl ester 6-ethyl ester dissolved in 2 mL of tetrahydrofuran, and the mixture was stirred for 2 hours at room temperature. The solvent was concentrated under reduced pressure. The residue was purified by ion exchange resin (AG 50W-X8 Resin (H type), eluent: water, a 50% aqueous solution of tetrahydrofuran, and a 10% aqueous solution of pyridine), thereby yielding 24 mg of (1R,2S,5R,6R)-2-amino-6-fluoro-bicyclo[3.1.0]hex-3-ene-2,6-dicarboxylic acid.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].[Br:9][CH2:10][C:11](=O)[C:12](=O)[CH2:13][Br:14]>C1C=CC=CC=1>[Br:9][CH2:10][C:11]1[C:12]([CH2:13][Br:14])=[N:8][C:1]2[C:2](=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:7]=1
Reactant: Nc1ccccc1N
Reactant: O=C(CBr)C(=O)CBr
Solvent: c1ccccc1
Product: BrCc1nc2ccccc2nc1CBr
Yield: 93 %

Procedure:
A mixture of 1,2-phenylenediamine (0.1 mole, 10.8 g) and 1,4-dibromo-2,3-butanedione (0.1 mole, 24.4 g) was refluxed in benzene (200 mL) using a Dean-Stark trap for one hour. The reaction mixture was then evaporated to dryness in vacuo and the residue flash chromatographed on silica gel (15:1). Elution with 15% hexane/chloroform afforded 29.38 g of 2,3-bis(bromomethyl)quinoxaline, m.p. 150°-151° C.; 1H NMR (CDCl3, 200 MHz): δ4.92 (s, 4H, CH2), 7.8 (m, 2H, ArH), 8.05 (m, 2H, ArH).
Reaction SMILES: S([CH2:5][CH2:6][C:7]#[C:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(C)(=O)=O.[C:15]1([CH:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:15]1([CH:21]2[CH2:22][CH2:23][N:24]([CH2:5][CH2:6][C:7]#[C:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:25][CH2:26]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CS(=O)(=O)CCC#Cc1ccccc1
Reactant: c1ccc(C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C(#Cc1ccccc1)CCN1CCC(c2ccccc2)CC1
Yield: 48.3 %

Procedure:
A mixture of 1-mesyl-4-phenylbut-3-yne (200 mg, 0.870 mmol), 4-phenylpiperidine (120 mg, 0.744 mmol) and K2CO3 (308 mg, 2.23 mmol) in 10 mL of CH3CN is refluxed for 12 hr. The mixture is filtered and washed with EtOAc (3×15 mL). The filtrate is evaporated in vacuo and is purified by flash chromatography to give the product (104 mg, 41%): mp 65-66° C.; 1H NMR (CDCl3) 1.81 (m, 4 H), 2.26 (m, 2 H), 2.65 (m, 1 H), 2.69 (m, 2 H), 2.76 (m, 2 H), 3.13 (d, J=11 Hz, 2 H), 7.13-7.36 (m, 10 H).
Reaction SMILES: [C:1]([N:8](C#N)[C@H:9]([C:11]([OH:13])=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH2:16]([N:18](CC)CC)C.ClC(OCC(C)C)=O.[BH4-:31].[Na+:32]>C1COCC1.O>[BH4-:31].[Na+:32].[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([CH2:11][OH:13])[CH2:10][C:16]#[N:18])([CH3:5])([CH3:6])[CH3:7]
Reactant: C[C@@H](C(=O)O)N(C#N)C(=O)OC(C)(C)C
Reactant: CCN(CC)CC
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CO)CC#N
Temperature: -10 °C
Reaction time: 0.07 h
Yield: 64 %

Procedure:
A solution of N-Boc cyanoalanine (2 g, 9.3 mmol) in THF (30 mL) was cooled in an ice/NaCl bath to −10° C. and treated with triethylamine (0.94 g, 9.3 mmol) followed by dropwise addition of isobutyl chloroformate (1.35 g, 9.9 mmol). The reaction mixture was stirred for 4 minutes at −10° C. and filtered through a coarse scintered glass funnel. Meanwhile, in another flask, a solution of NaBH4 (0.71 g, 19 mmol) in water (10 mL) was prepared and cooled in an ice/water bath. The filtered solution of the mixed anhydride was added dropwise to the cold NaBH4 solution and the resulting mixture was stirred for 2 hours. The THF was removed on the rotary evaporator and the reaction was acidified with 5% NaHSO4 solution to pH 3 and diluted with ethyl acetate and water. The organics were extracted twice with aqueous NaHCO3 and dried over MgSO4. The solvent was removed to afford 1.2 g (64%) of (S)-(2-Cyano-1-hydroxymethyl-ethyl)-carbamic acid tert-butyl ester; 1H NMR (CDCl3, 400 MHz) δ 1.45 (s, 9H), 2.09-2.17 (m, 1H), 2.73 (d, 1H, J=6.0), 3.76 (dd, 1H, J1=4.7, J2=10.8), 3.80-3.86 (m, 1H), 3.91-3.99 (m, 1H), 4.98-5.07 (m, 1H).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]#[N:13])=[N:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH2:22][C:23]([NH:25][NH2:26])=O)[CH:19]=[CH:20][CH:21]=1>>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([CH:19]=[CH:20][CH:21]=1)[CH2:22][C:23]1[NH:13][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][N:4]=2)=[N:26][N:25]=1
Reactant: N#Cc1ncc2cccnc2c1O
Reactant: COc1cccc(CC(=O)NN)c1
Product: COc1cccc(Cc2nnc(-c3ncc4cccnc4c3O)[nH]2)c1

Procedure:
The title compound was prepared in a similar manner to that described in example 1 from of 8-hydroxy-1,6-naphthyridine-7-carbonitrile (50 mg, 0.29 mmol) and 2-(3-methoxyphenyl)acetic hydrazide (270 mg, 1.5 mmol) as a yellow solid (20 mg, 21%). 1H NMR (CDCl3): δ 9.19 (m, 1 H), 8.91 (s, 1 H), 8.31 (d, J=7.6 Hz, 1 H), 7.63 (m, 1 H), 7.22 (m, 1 H), 7.01-6.97 (m, 2 H), 6.83-6.79 (m, 2 H), 4.23 (s, 2 H), 3.79 (s, 3 H); MS m/z 334 (M+1).
Reaction SMILES: [F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17]O)[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1.[I-:27].[Na+]>CC(C)=O>[F:1][C@:2]12[C@@H:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][CH:14]=[C:15]3[C:16](=[O:19])[CH2:17][I:27])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:26])[CH:4]=[CH:5][C:6](=[O:25])[CH:7]=1
Reactant: [I-]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Agent: [Na+]
Solvent: CC(C)=O
Product: C[C@]12C=CC(=O)C=C1CC[C@H]1[C@@H]3CC=C(C(=O)CI)[C@@]3(C)C[C@H](O)[C@@]12F
Yield: 76.6 %

Procedure:
A solution of 2.0 g of 9-fluoro-11β,21-dihydroxypregna-1,4,16-triene-3,20-dione, 21-methanesulfonate in 100 ml of acetone is refluxed with 3 g of sodium iodide under nitrogen for about 17 hours. The solid is filtered off and washed with 50 ml of acetone. The filtrate is evaporated in vacuo. The residue is redissolved in chloroform-methanol (9:1), washed with water, dried over anhydrous sodium sulfate and evaporated in vacuo to give 2.0 g of the title compound.
Reaction SMILES: [C:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[NH:6][C:5]1=[O:13])([CH3:3])=[CH2:2].Cl[CH2:15][CH:16]1[O:21][CH2:20][CH2:19][N:18]([CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:17]1>>[CH2:22]([N:18]1[CH2:19][CH2:20][O:21][CH:16]([CH2:15][N:6]2[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:4]([C:1]([CH3:3])=[CH2:2])[C:5]2=[O:13])[CH2:17]1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: ClCC1CN(Cc2ccccc2)CCO1
Reactant: C=C(C)n1c(=O)[nH]c2ccccc21
Product: C=C(C)n1c(=O)n(CC2CN(Cc3ccccc3)CCO2)c2ccccc21
Yield: 72.9 %

Procedure:
The condensation of 0.1 mol of 1-isopropenyl-2,3-dihydro-benzimidazol-2-one and 0.1 mol of 2-chloromethyl-4-benzyl-morpholine in accordance with the procedure (a) of Example 1 gives, after evaporation of the solvent under reduced pressure, 30 g of an oil which solidifies slowly. Recrystallization from a 250/25 mixture of isopropyl ether and isopropanol gives 26.5 g of 4-benzyl-2-(1-isopropenyl-2,3-dihydro-benzimidazol-2-on-3-yl-methyl)-morpholine, m.p. 117° C.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[S:8]([C:15]1[CH:20]=[CH:19][C:18]([N+:21]#[N:22])=[CH:17][CH:16]=1)([C:11]([F:14])([F:13])[F:12])(=[O:10])=[O:9].C(O)(=O)C.[OH:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]([CH3:39])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C([O-])(=O)C.[Na+]>O>[S:8]([C:15]1[CH:16]=[CH:17][C:18]([N:21]=[N:22][C:36]2[CH:37]=[CH:38][C:33]([N:32]([CH2:31][CH2:30][CH2:29][CH2:28][OH:27])[CH3:39])=[CH:34][CH:35]=2)=[CH:19][CH:20]=1)([C:11]([F:13])([F:14])[F:12])(=[O:10])=[O:9]
Reactant: N#[N+]c1ccc(S(=O)(=O)C(F)(F)F)cc1
Reactant: CN(CCCCO)c1ccccc1
Agent: CC(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CN(CCCCO)c1ccc(N=Nc2ccc(S(=O)(=O)C(F)(F)F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 38.2 g (0.1 mole) of 4-triflylbenzenediazonium hexafluorophosphate in a 50:50 mixture of glacial acetic acid and water at 0° C. is added 17.9 g (0.1 mole) of N-4-hydroxybutyl-N-methylaniline dropwise. The reaction mixture is stirred at 0° C. for 15 minutes, and 12.3 g (0.15 mole) of sodium acetate is added with stirring. The reaction is stirred at 0° C. for 30 minutes and then warmed to room temperature and stirred for 16 hours. Compound C is collected by filtration and purified by recrystallization from ethanol.
Reaction SMILES: [C:1]1([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:21](C1C=C(B(O)O)C=CC=1)=[O:22]>>[CH:21]([C:5]1[CH:6]=[C:1]([C:7]2[NH:8][C:9]3[CH:10]=[CH:11][CH:12]=[C:13]4[C:19](=[O:20])[NH:18][CH2:17][CH2:16][C:15]=2[C:14]=34)[CH:2]=[CH:3][CH:4]=1)=[O:22]
Reactant: O=Cc1cccc(B(O)O)c1
Reactant: O=C1NCCc2c(-c3ccccc3)[nH]c3cccc1c23
Product: O=Cc1cccc(-c2[nH]c3cccc4c3c2CCNC4=O)c1

Procedure:
In a manner similar to that described above for Compound 12, the tricyclic bromide (381 mg, 1.44 mmol) and 3-formylbenzeneboronic acid (345 mg, 2.16 mmol) were coupled to yield 2-(3-formylphenyl)-3,4,5,6-tetrahydro-1H-azepino[5,4,3-cd]indol-6-one 15, 346 mg (83%), as a tan solid. 1H NMR (300 MHz, d6-DMSO) δ2.86 (m, 2H), 3.16 (m, 2H), 7.01 (t, 1H, J=7.8 Hz), 7.34 (d, 1H, J=7.3 Hz), 7.50 (m, 2H), 7.73 (m, 2H), 7.85 (br t, 1H), 7.94 (s, 1H), 9.88 (s, 1H), 11.50 (brs, 1H).
Reaction SMILES: [OH-].[K+].C(O)(C)(C)C.[CH2:8]1[O:16][C:15]2[CH:14]=[CH:13][C:12]([OH:17])=[CH:11][C:10]=2[O:9]1.[Br:18][CH2:19][CH2:20][CH2:21]Br>O>[Br:18][CH2:19][CH2:20][CH2:21][O:17][C:12]1[CH:13]=[CH:14][C:15]2[O:16][CH2:8][O:9][C:10]=2[CH:11]=1
Reactant: Oc1ccc2c(c1)OCO2
Reactant: BrCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: BrCCCOc1ccc2c(c1)OCO2
Reaction time: 3 h
Yield: 81.7 %

Procedure:
To a solution prepared by dissolving 7.3 g of potassium hydroxide in 7 ml of water and then adding 120 ml of t-butanol are added 15 g of 3,4-methylenedioxyphenol and 88 g of 1,3-dibromopropane and the mixture is stirred for 3 hours under heating at reflux. After completion of the reaction, the solvent is distilled off and benzene is added and washed with water. The benzene layer is dried over anhydrous sodium sulfate and the solvent is distilled off. The residue is subjected to vacuum distillation to give 23 g of 5-(3-bromopropoxy)-1,3-benzodioxole boiling at 120° C./1 mmHg.