Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:12]([CH:13]=[O:14])=[CH:11][C:5]2[C:6]([CH3:10])([CH3:9])[CH2:7][O:8][C:4]=2[CH:3]=1.[Br:15]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:15][C:3]1[C:4]2[O:8][CH2:7][C:6]([CH3:10])([CH3:9])[C:5]=2[CH:11]=[C:12]([CH:13]=[O:14])[C:2]=1[OH:1]
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)COc2cc(O)c(C=O)cc21
Solvent: O
Solvent: ClCCl
Product: CC1(C)COc2c1cc(C=O)c(O)c2Br
Yield: 94.2 %

Procedure:
A solution of 5.27 g (27.4 mmol) of 2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde and 5.86 g (32.9 mmol) of N-bromosuccinimide in 135 ml of methylene chloride was stirred at ambient temperature for 3 h. Water (400 ml) was added. The organic phase was dried and evaporated. The residue was chromatographed on silica gel (150 g) using a gradient from 20:80 (v/v) ether:hexane to 40:60 (v/v) ether:hexane eluent. There was obtained 7.0 g (25.8 mmol, 94%) of 7-bromo-2,3-dihydro-6-hydroxy-3,3-dimethyl-5-benzofurancarboxaldehyde. A sample was crystallized from toluene: mp 152°-154° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6](Cl)[CH:5]=1.[CH3:13][NH:14][CH2:15][CH2:16][CH3:17].C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:5]=[C:6]([N:14]([CH3:13])[CH2:15][CH2:16][CH3:17])[N:7]=[C:8]([Cl:10])[CH:9]=1
Reactant: COC(=O)c1cc(Cl)nc(Cl)c1
Reactant: CCCNC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCCN(C)c1cc(C(=O)OC)cc(Cl)n1
Temperature: 80 °C
Yield: 14.2 %

Procedure:
Mix 2,6-dichloro-isonicotinic acid methyl ester (5 g, 24.2 mmol), methylpropyl-amine (3.2 g, 23.06 mmol), cesium carbonate (10 g, 31.2 mmol), racemic-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (1.5 g, 2.43 mmol), and palladium acetate (0.27 g, 1.21 mmol) in toluene (50 mL). Degas with argon, seal the vessel and heat at 80° C. for 16 h. Cool to room temperature and dilute with diethyl ether (50 mL). Filter through a filtering agent, concentrate, and purify (silica gel chromatography, eluting with 0:100 to 20:80 ethyl acetate:hexanes to give the title compound as an oil (795 mg, 13.5%).
Reaction SMILES: BrC1C=CC([C:8]2([C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[NH:12][CH:11]=[CH:10][S:9]2)=CC=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[NH:43][C:42]([C@@H:44]4[CH2:48][CH2:47][CH2:46][N:45]4[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[N:41][CH:40]=3)=[CH:35][CH:34]=2)O1.C(=O)(O)[O-].[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:52]([O:51][C:49]([N:45]1[CH2:46][CH2:47][CH2:48][C@H:44]1[C:42]1[NH:43][C:39]([C:36]2[CH:37]=[CH:38][C:33]([C:33]3[CH:38]=[CH:37][C:36]([C:11]4[N:12]=[C:8]([C@@H:13]5[CH2:17][CH2:16][CH2:15][N:14]5[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])[S:9][CH:10]=4)=[CH:35][CH:34]=3)=[CH:34][CH:35]=2)=[CH:40][N:41]=1)=[O:50])([CH3:54])([CH3:55])[CH3:53]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1C1(c2ccc(Br)cc2)NC=CS1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)[nH]1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])O
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(-c2ccc(-c3ccc(-c4csc([C@@H]5CCCN5C(=O)OC(C)(C)C)n4)cc3)cc2)[nH]1
Temperature: 80 °C
Reaction time: 5 h
Yield: 117.2 %

Procedure:
A flask charged with Compound 12a (0.46 g, 1.13 mmol), (S)-tert-butyl 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (compound 20a, 0.55 g, 1.25 mmol), PdCl2(dppf) (0.036 g, 0.04 mmol), and sodium bicarbonate (0.33 g, 3.93 mmol) was flushed with nitrogen, then 1,2-dimethoxyethane (6 ml) and distilled water (2 ml) were added as solvent. The reaction mixture was stirred at 80° C. under nitrogen for 5 hours. After cooled to room temperature, the mixture was extracted with ethyl acetate/water, dried over magnesium sulfate, filtered, and then concentrated to give crude compound. The crude compound was purified by column chromatography (ethyl acetate: n-hexane=4:1) to yield a yellow solid (0.47 g).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[Br:15][C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18][N:11]1[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=[C:2]1[Cl:1]
Reactant: BrCc1ccccc1Br
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccccc2Br)n(C)c1=O

Procedure:
8-Chlorotheophylline and 2-bromobenzyl bromide were reacted and purified as described in the General procedure CC, step A, to afford 83A as white crystals in 57%.
Reaction SMILES: [C:1]1([C:7]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:8]([O:10]C)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>O1CCCC1>[C:1]1([C:7]([CH2:15][CH2:16][CH3:17])([CH2:12][CH2:13][CH3:14])[C:8]([OH:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCCC(CCC)(C(=O)OC)c1ccccc1
Solvent: C1CCOC1
Product: CCCC(CCC)(C(=O)O)c1ccccc1
Temperature: 25 °C
Yield: 94.4 %

Procedure:
A solution of the product of Example 1B (7.63 g, 32.61 mmol) and potassium trimethylsilanoate (23.2 g of 90% material, 163 mmol) in tetrahydrofuran (163 mL) was warmed at reflux for 18 hours. The solution was cooled to 25° C. and concentrated in vacuo to remove the tetrahydrofuran. A solution of the residue in water (250 mL) was cooled to 0° C., and adjusted to pH 1 by addition of 4 N HCl solution. The resulting precipitate was collected by filtration, washed with water and dried to give the title compound (6.78 g, 95%). 1H NMR (300 MHz, CDCl3): δ 7.25 (m, 5 H), 1.99 (m, 4 H), 1.12 (m, 4 H), 0.90 (t, J=7.17 Hz, 6 H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][C:3]=1[F:9].[CH2:10]([Sn](CCCC)(CCCC)C=C)[CH2:11]CC.CCOCC.O>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:10]=[CH2:11])=[CH:4][C:3]=1[F:9]
Reactant: Fc1cc(I)ccc1Br
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: CCOCC
Solvent: CN(C)C=O
Product: C=Cc1ccc(Br)c(F)c1
Yield: 53.9 %

Procedure:
A solution of 1-bromo-2-fluoro-4-iodo-benzene (1 g, 3.32 mmol), tributyl(vinyl)tin (0.97 mL, 3.32 mmol) and dichlorobis(triphenylphosphine)palladium(II) (116 mg, 0.17 mmol) in anhydrous DMF (3 mL) was heated in a microwave reactor to 160° C. for 5 minutes. Ether (20 mL) and H2O (5 mL) were added and partitioned. The organic layer was washed with water, brine, dried (MgSO4), filtered, and concentrated. The residue was chromatographed on silica gel eluting with hexanes to provide the title compound as a colorless oil (360 mg, 54%). 1H NMR (300 MHz, CDCl3) δ 5.33 (d, J=9 Hz, 1 H), 5.76 (d, J=18 Hz, 1 H), 6.63 (dd, J=18 Hz, J=9 Hz, 1 H), 7.05 (dd, J=9 Hz, J=1 Hz, 1 H), 7.16 (dd, J=9 Hz, J=1 Hz, 1 H), 7.49 (t, J=9 Hz, 1 H); (DCl/NH3) m/z 201 (M+H)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.O=S(Cl)Cl.[C:10]([C:12]1[CH:17]=[CH:16][C:15]([C:18](=O)[CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:14][CH:13]=1)#[N:11].C(Cl)Cl>O1CCCC1>[C:10]([C:12]1[CH:13]=[CH:14][C:15]([C:18]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)=[CH:19][CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)=[CH:16][CH:17]=1)#[N:11]
Reactant: N#Cc1ccc(C(=O)CCc2ccc(F)cc2)cc1
Reactant: c1c[nH]cn1
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: N#Cc1ccc(C(=CCc2ccc(F)cc2)n2ccnc2)cc1
Reaction time: 0.17 h

Procedure:
Imidazole (0.55 g, 8 mmol) is dissolved in dry tetrahydrofuran. The solution is cooled on icebath and SOCl2 (0.16 ml, 2 mmol) is added dropwise to the cooled solution. The mixture is stirred for 10 min. 1-(4-cyanophenyl)-3-(4-fluorophenyl)-1-propanone (0.34 g, 1.3 mmol) is added and the mixture is stirred in room temperature for 4 days. Methylene chloride is added and tie mixture is washed with water. The organic layer is dried and the solvent is evaporated. The residue contains 35% of the product (1H NMR) as a 9:1 mixture of the isomers. The product is purified by flash chromatography (eluent CH2Cl2 -MeOH 99:1).
Reaction SMILES: C(OC(C1C(=O)[C:14]2[C:9](=[CH:10][C:11](C(=O)C)=C(F)C=2)[N:8](C2C=CC(F)=CC=2)C=1)=O)C.[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([C:42](=O)[CH3:43])[C:39]=3Cl)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][C:53]2C=CC=CC=2)[CH2:30][CH2:29]1>[Ni]>[CH:28]1([N:31]2[C:40]3[C:35](=[CH:36][C:37]([F:45])=[C:38]([CH:42]4[CH2:11][CH2:10][CH:9]([NH2:8])[CH2:14][CH2:43]4)[CH:39]=3)[C:34](=[O:46])[C:33]([C:47]([O:49][CH2:50][CH3:51])=[O:48])=[C:32]2[S:52][CH3:53])[CH2:30][CH2:29]1
Reactant: CCOC(=O)c1cn(-c2ccc(F)cc2)c2cc(C(C)=O)c(F)cc2c1=O
Reactant: CCOC(=O)c1c(Sc2ccccc2)n(C2CC2)c2c(Cl)c(C(C)=O)c(F)cc2c1=O
Agent: [Ni]
Product: CCOC(=O)c1c(SC)n(C2CC2)c2cc(C3CCC(N)CC3)c(F)cc2c1=O

Procedure:
In the described fashion as Example 21 (b and c), replacing ethyl 1-ethyl-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-quinoline carboxylate (9) (A=CH, R10 =C2H5, R=C2H5) with 1-cyclopropyl-2-methylthio-6-fluoro-7-acetyl-1,4-dihydro-4-oxo-3-carboxylate (13) of Example 40 and also replacing the catalyst Raney nickel catalyst in Example 21(c) with pallidium on carbon under an hydrogen atmosphere, one can obtain ethyl 1-cyclopropyl-2-methylthio-6-fluoro-7-(3-aminocyclopentyl)-1,4-dihydro-4-oxo-quinoline-3-carboxylate (16) (A=CH, R11 =CH3, R10 =C2H5, R=cyclopropyl, Z= ##STR137##
Reaction SMILES: [C:1]1([CH3:18])[CH:6]=[CH:5][C:4]([C:7](=O)[C:8]([C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)=O)=[CH:3][CH:2]=1.[Cl:19][C:20]1[CH:21]=[C:22]([NH2:27])[C:23]([NH2:26])=[N:24][CH:25]=1.C1(C2N=C3CCCN(CCC/C=C/CC(O)=O)C3=NC=2C2C=CC=CC=2)C=CC=CC=1>C(O)(=O)C>[Cl:19][C:20]1[CH:25]=[N:24][C:23]2=[N:26][C:8]([C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)=[C:7]([C:4]3[CH:5]=[CH:6][C:1]([CH3:18])=[CH:2][CH:3]=3)[N:27]=[C:22]2[CH:21]=1
Reactant: Nc1cc(Cl)cnc1N
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Agent: O=C(O)C/C=C/CCCN1CCCc2nc(-c3ccccc3)c(-c3ccccc3)nc21
Solvent: CC(=O)O
Product: Cc1ccc(-c2nc3cc(Cl)cnc3nc2-c2ccc(C)cc2)cc1

Procedure:
The title compound was prepared from 1,2-dip-tolylethane-1,2-dione and 5-chloro-pyridine-2,3-diamine analogously to 2,3-dip-tolylpyrido[2,3-b]pyrazine (Intermediate E step 1). Acetic acid is not used in this reaction.
Reaction SMILES: Cl.[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1)=[O:11])(=[O:4])[NH2:3].[CH2:24]([O:26][C:27]1[CH:32]=[C:31]([CH:33]=O)[CH:30]=[C:29]([O:35][CH2:36][CH3:37])[C:28]=1[C:38]1[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=1)[CH3:25].C([BH3-])#N.[Na+].C(N(C(C)C)C(C)C)C>C(O)C.C(O)(=O)C>[C:2]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[C:10]([NH:12][CH:13]1[CH2:14][CH2:15][N:16]([CH2:33][C:31]2[CH:30]=[C:29]([O:35][CH2:36][CH3:37])[C:28]([C:38]3[CH:43]=[CH:42][C:41]([F:44])=[CH:40][CH:39]=3)=[C:27]([O:26][CH2:24][CH3:25])[CH:32]=2)[CH2:17][CH2:18]1)=[O:11])(=[O:4])[NH2:3]
Reactant: CCOc1cc(C=O)cc(OCC)c1-c1ccc(F)cc1
Reactant: COc1cc(OCC(N)=O)cc(C(=O)NC2CCNCC2)c1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)O
Solvent: CCO
Product: CCOc1cc(CN2CCC(NC(=O)c3cc(OC)cc(OCC(N)=O)c3)CC2)cc(OCC)c1-c1ccc(F)cc1

Procedure:
In analogy to the procedure described in example 50k), 3-carbamoylmethoxy-5-methoxy-N-piperidin-4-yl-benzamide hydrochloride (example 250b) was reacted with 2,6-diethoxy-4′-fluoro-biphenyl-4-carbaldehyde (example 102), sodium cyanoborohydride, N-ethyl-diisopropylamine and acetic acid in ethanol at 50° C. to yield the title compound as colorless solid. MS: 580.2 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH2:19].[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]2[O:29][C:28]([C:30](O)=[O:31])=[CH:27][C:26]=2[CH:33]=1>>[CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH:10]([N:13]3[CH2:17][CH2:16][CH2:15][CH:14]3[CH3:18])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[NH:19][C:30]([C:28]1[O:29][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:33][C:26]=2[CH:27]=1)=[O:31]
Reactant: COc1ccc2oc(C(=O)O)cc2c1
Reactant: Cc1cc(N2CCC(N3CCCC3C)C2)ccc1N
Product: COc1ccc2oc(C(=O)Nc3ccc(N4CCC(N5CCCC5C)C4)cc3C)cc2c1

Procedure:
The title compound was prepared in a manner substantially the same as example 1 by coupling 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)-phenylamine with 5-methoxy-benzofuran-2-carboxylic acid. MS: 434.2 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:17]([CH:19]1[O:21][CH2:20]1)Cl.C(=O)([O-])[O-].[K+].[K+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][CH2:17][CH:19]3[O:21][CH2:20]3)=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(c1ccc(Cl)cc1)c1ccc(NCC2CO2)cc1

Procedure:
23.2 g of 4-chloro-4'-aminobenzophenone, 92 g of epichlorohydrin and 7 g of potassium carbonate were heated at reflux for 15 hours. The excess epichlorohydrin was evaporated in vacuo and the solid residue was partitioned between water and chloroform. From the organic phase there was obtained 4-chloro-4'-[(2,3-epoxypropyl)amino]benzophenone which was recrystallized twice from methanol, m.p. 128°-129° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][NH:5][CH:6]=1.C(#N)C.C(N(CC)CC)C.[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21](Cl)=[O:22]>>[F:17][C:18]1[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=1)[C:21]([C:4]1[NH:5][CH:6]=[C:2]([CH3:1])[N:3]=1)=[O:22]
Reactant: O=C(Cl)c1cccc(F)c1
Reactant: Cc1c[nH]cn1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Cc1c[nH]c(C(=O)c2cccc(F)c2)n1
Temperature: 140 °C
Yield: 67.7 %

Procedure:
To a 350 mL pressure vessel was added 4-methylimidazole (17.85 g, 217 mmol, 1 eq.) and a stirbar. Acetonitrile (53 mL, 1022 mmol, 4.7 eq.) was added. Triethylamine (88 mL, 631 mmol, 2.9 eq.) was added and the mixture was stirred until it became homogeneous. 3-Fluorobenzoylchloride (100 g, 631 mmol, 2.9 eq.) was added. Upon addition of the acyl chloride, the mixture became warm and viscous. The vessel was sealed and heated at 140° C. for 2 hours with stirring. During heating, the mixture turned black in color. The vessel was removed from the heat, allowed to cool, and its contents were diluted with acetone (250 mL). The mixture was stirred and transferred to a 2 L round-bottomed flask containing 7% aqueous HCl (1000 mL). Charcoal was added to the flask and the mixture was refluxed at 85° C. for 1 hour. The mixture was allowed to cool slightly and then was filtered through a Celite pad followed by a rinse with 1N HCl (˜200 mL). The filtrate was made alkaline with NH4OH whereupon a solid precipitate formed. The solid was filtered and washed with copious amounts of dilute NH4OH to remove triethylamine hydrochloride salts. The solid was collected and placed under high vacuum, yielding ketone 3 as an off-white solid (30.0 g, 80%). LC/MSD (HP Series 1100 MSD) Expected MW: 204.07, Observed M+H: 205.0, Retention time: 1.48. Analytical HPLC: >95% purity, retention time: 3.00 (8 minute run) 1H NMR, DMSO-d6, Varian 400 MHz δ 13.10 (br s, 1H), 8.28 (m, 2H), 7.60 (m, 1H), 7.52 (m, 1H), 7.30-7.06 (d, 1H), 2.29 (s, 3H).
Reaction SMILES: [CH2:1]([S:4][C:5]1[C:15]2[N:14]3[C:16]([CH2:19][OH:20])=[N:17][N:18]=[C:13]3[CH:12]([CH3:21])[N:11]=[C:10]([C:22]3[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:30][CH3:31])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3].[C:32]1(=[O:39])[O:38][C:36](=[O:37])[CH2:35][CH2:34][CH2:33]1>O>[C:32]([OH:38])(=[O:39])[CH2:33][CH2:34][CH2:35][C:36]([OH:20])=[O:37].[CH2:1]([S:4][C:5]1[C:15]2[N:14]3[C:16]([CH2:19][OH:20])=[N:17][N:18]=[C:13]3[CH:12]([CH3:21])[N:11]=[C:10]([C:22]3[C:27]([CH2:28][CH3:29])=[CH:26][CH:25]=[CH:24][C:23]=3[CH2:30][CH3:31])[C:9]=2[CH:8]=[CH:7][CH:6]=1)[CH2:2][CH3:3]
Reactant: O=C1CCCC(=O)O1
Agent: CCCSc1cccc2c1-n1c(CO)nnc1C(C)N=C2c1c(CC)cccc1CC
Solvent: O
Product: O=C(O)CCCC(=O)O

Procedure:
In a manner similar to Example 12, a mixture of 10-propylthio-4-methyl-1-(hydroxymethyl)-6-(2,6-diethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine and glutaric anhydride was heated on the water bath to give 10-propylthio-4-methyl-1-(hydroxymethyl)-6-(2,6-diethylphenyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine hydrogen glutarate (ester).
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]([C:11]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:12]=1[N+:21]([O-:23])=[O:22])=[O:10])[C:3]([O:5][CH2:6][CH3:7])=[O:4].COC1C(OC)=CC(C(=O)C=CC(OCC)=O)=C([N+]([O-])=O)C=1.BrBr>C(Cl)Cl>[CH3:20][O:19][C:14]1[C:15]([O:17][CH3:18])=[CH:16][C:11]([C:9](=[O:10])[C:8]#[C:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:12]([N+:21]([O-:23])=[O:22])[CH:13]=1
Reactant: CCOC(=O)C(Br)C(Br)C(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Agent: BrBr
Agent: CCOC(=O)C=CC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]
Solvent: ClCCl
Product: CCOC(=O)C#CC(=O)c1cc(OC)c(OC)cc1[N+](=O)[O-]

Procedure:
The procedure as described above in connection with Intermediate 1 was repeated to prepare ethyl 2,3-dibromo-4-(4,5-dimethoxy-2-nitrophenyl)-4-oxobutanoate (337 mg, 100%) in the form of a diastereo mixture as light brown oil (mixing ratio=2:1) from a solution of ethyl 4-(4,5-dimethoxy-2-nitrophenyl)-4-oxo-2-butenoate (199 mg, 0.6 mmol) in methylene chloride (10 ml) and a solution of bromine (0.04 ml) in methylene chloride (5 ml). The diastereo mixture was used in the next reaction without separation.
Reaction SMILES: [F:1][C:2]1[CH:33]=[CH:32][C:5]2[CH:6]([CH2:26][C:27]([O:29]CC)=[O:28])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1.N1C=CC=CC=1NCCCOC1C=CC2C[C@H](CC(OCC)=O)C3C=CC=CC=3CC=2C=1>>[F:1][C:2]1[CH:33]=[CH:32][C:5]2[CH:6]([CH2:26][C:27]([OH:29])=[O:28])[CH2:7][C:8]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=4)=[CH:11][C:9]=3[CH2:10][C:4]=2[CH:3]=1
Reactant: CCOC(=O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2cc(F)ccc21
Agent: CCOC(=O)C[C@H]1Cc2ccc(OCCCNc3ccccn3)cc2Cc2ccccc21
Product: O=C(O)CC1Cc2ccc(OCCCNc3ccccn3)cc2Cc2cc(F)ccc21

Procedure:
According to the procedure of Example 6 (c), except substituting ethyl (±)-10,11-dihydro-7-fluoro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10 -acetate for the ethyl (R)-10,11-dihydro-3-[3-(pyridin-2-ylamino)-1-propyloxy]-5H-dibenzo[a,d]cycloheptene-10-acetate, the title compound was obtained: MS (ES) m/e 421.1 (M+H)+. Anal. Calcd for C25H25FN2O3.0.5 H2O: C, 69.99; H, 6.10; N, 6.52. Found: C, 69.86; H, 5.90; N, 6.35.
Reaction SMILES: [I:1][C:2]1[CH:10]=[C:6]([C:7](O)=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.Cl>O1CCCC1>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:10][C:6]=1[CH2:7][OH:8]
Reactant: O=C(O)c1cc(I)ccc1O
Agent: Cl
Solvent: C1CCOC1
Product: OCc1cc(I)ccc1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 5-iodosalicylic acid (25.0 g, 94.6 mmol) in tetrahydrofuran (500 mL) was cooled to 0° C. With vigorous mixing, borane-methyl sulfide complex (15.1 ml of 10 M solution, 151.0 mmol) was added drop-wise over 0.25 hours. The solution was warmed to room temperature and then heated at reflux for 4 h. A white precipitate formed during the reflux. The solution was cooled to room temperature and 10% aqueous hydrochloric acid (100 mL) was added over 15 min and the solution stirred at room temperature for 2 h. The precipitate dissolved and the solvent was concentrated in vacuo to a volume of approximately 200 mL. The solution was poured into ethyl acetate (300 mL) and washed with water (2×200 mL), saturated sodium bicarbonate (2×200 mL), and saturated ammonium chloride (2×200 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo. The 2-hydroxy-5-iodobenzyl alcohol was isolated as a white solid (21.3 g, 85.2 mmol)from hexanes. (90% yield): mp 105-110° C. 1H NMR (CDCl3/300 MHz) 8.21 (s, 1H), 7.30-7.33 (M, 2H), 6.57 (d, 1H, J=8.3 Hz), 4.97 (bs, 1H), 4.62 (s, 2H). EIHRMS m/z=249.9492 (M+, Calc'd 249.9491).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].[BrH:20].S(=O)(=O)(O)O>C(O)(=O)C>[Br:20][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18]
Reactant: O=C(O)CCCCCCCCCCCCCCCO
Reactant: Br
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O=C(O)CCCCCCCCCCCCCCCBr

Procedure:
A mixture of 18 g. of 16-hydroxyhexadecanoic acid and 160 g. of 30-34% hydrogen bromide in acetic acid is treated with 32 ml. of concentrated sulfuric acid and stirred at ambient temperature for 18 hours. The solution is stirred under reflux for 7 hours and then poured into 500 ml. of ice-water and filtered. A methylene chloride solution of the product is Darco clarified, dried over magnesium sulfate, and evaporated. Crystallization of the residue from ether-petroleum ether and then acetonitrile affords 16-bromohexadecanoic acid as a white solid.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[NH:10][CH2:11][CH:12]2[O:17][CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.O1CCOCC1.C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[NH:14]1[CH2:15][CH2:16][O:17][CH:12]([CH2:11][NH:10][C@@H:8]2[CH2:9][C@H:7]2[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCOC(CN[C@@H]2C[C@H]2c2ccccc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1COCCO1
Product: c1ccc([C@@H]2C[C@H]2NCC2CNCCO2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Chloroform (5 mL) was added to a 200 mL round-bottomed flask containing 1,1-dimethylethyl 2-({[trans-2-phenylcyclopropyl]amino}methyl)-4-morpholinecarboxylate (330 mg, 0.993 mmol) to give a suspension. HCl/1,4-Dioxane (6.20 mL, 24.82 mmol) was added and the mixture stirred 18 hours at room temperature. Upon completion, saturated NaHCO3 was added to the reaction mixture and the mixture was extracted with THF—CHCl3 (2×50 mL). The organics were combined, dried over Na2SO4 and concentrated. The residue was adsorbed onto silica and purified via column chromatography on the ISCO Companion (gradient 0-100% 80:20:2 [CHCl3/MeOH/NH4OH]/CHCl3; 12 g column). The compound was further purified via reverse phase column chromatography on Gilson ((C18 column: 0.1% Formic acid H2O/CH3CN, 95-5%) affording the title compound as an amber oil LC-MS (ES) m/z=233 (M+H)+, 1H NMR (400 MHz, DMSO-d6) δ ppm 1H NMR (400 MHz, DMSO-d6) d 7.22 (t, J=7.58 Hz, 2H), 7.11 (t, J=7.33 Hz, 1H), 7.03 (d, J=8.08 Hz, 2H), 3.63-3.73 (m, 1H), 3.35-3.43 (m, 2H), 2.73-2.81 (m, 1H), 2.52-2.70 (m, 4H), 2.25-2.35 (m, 2H), 2.22 (qd, J=2.40, 4.59 Hz, 1H), 1.76 (ddd, J=2.91, 5.94, 9.09 Hz, 1H), 0.86-1.01 (m, 2H).