Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.Br[C:28]([CH3:35])([CH3:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:18]=[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)[C:16](=[O:26])[C:8]4[CH:9]=[C:10]([O:15][C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH3:35])[CH3:34])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: O=c1c(Cc2cccnc2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Reactant: CCOC(=O)C(C)(C)Br
Product: CCOC(=O)C(C)(C)Oc1cc2c(=O)c(Cc3cccnc3)cn3c4ccc(Br)cc4c(c1)c23
Yield: 74 %

Procedure:
The procedure of Example 3 was repeated by using 10-bromo-2-hydroxy-5-(3-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (500 mg) and ethyl α-bromoisobutyrate (0.22 ml) to obtain the title compound (470 mg, 74%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH2:8]([C:10]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]3[N:35]=[N:36][N:37]([C:39]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)([C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)[C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)[N:38]=3)=[CH:24][CH:23]=2)[C:17]2[CH2:16][NH:15][CH2:14][CH2:13][C:12]=2[N:11]=1)[CH3:9].C(N(CC)CC)C>ClCCl>[C:1]([N:15]1[CH2:14][CH2:13][C:12]2[N:11]=[C:10]([CH2:8][CH3:9])[CH:19]=[C:18]([O:20][CH2:21][C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]4[N:35]=[N:36][N:37]([C:39]([C:40]5[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=5)([C:46]5[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=5)[C:52]5[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=5)[N:38]=4)=[CH:26][CH:27]=3)[C:17]=2[CH2:16]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCNC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCc1cc(OCc2ccc(-c3ccccc3-c3nnn(C(c4ccccc4)(c4ccccc4)c4ccccc4)n3)cc2)c2c(n1)CCN(C(C)=O)C2
Reaction time: 20 h
Yield: 65.8 %

Procedure:
Acetic anhydride (78 mg) was added to a stirred solution of 2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl) biphenyl-4-yl)methoxy]-1,6-naphthyridine (500 mg) and triethylamine (150 mg) in dichloromethane (10 ml) under an atmosphere of argon. The solution was left to stand for 20 hours and then volatile material was removed by evaporation. The residue was purified by flash chromatography, eluting with a mixture of methanol/ethyl acetate (1:9 v/v), to give 6-acetyl-2-ethyl-5,6,7,8-tetrahydro-4-[(2'-(2-triphenylmethyl-2H-tetrazol-5-yl)biphenyl-4-yl)methoxy]-1,6-naphthyridine (350 mg), m.p. 97°-98° C.; NMR (d6 -DMSO, d4 -acetic acid): 1.25(t,3H), 2.15(s,3H), 2.75(q,2H), 2.9-3.0(m,3H), 3.7(m,2H), 4.5(d,2H), 5.2(s,2H), 6.8-7.7 (complex m,23H), 7.75-7.85(m,1H).
Reaction SMILES: [C:1]([C:4]1[N:5]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:6](=[O:21])[C:7]2[C:12]([C:13]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:11][C:10]([Br:20])=[CH:9][CH:8]=2)(=[O:3])[CH3:2].[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)=[O:36])[CH3:33]>>[CH2:32]([O:34][C:35]([CH:37]1[CH2:42][CH2:41][N:40]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([CH2:22][N:5]3[C:4]([C:1](=[O:3])[CH3:2])=[C:13]([C:14]4[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=4)[C:12]4[C:7](=[CH:8][CH:9]=[C:10]([Br:20])[CH:11]=4)[C:6]3=[O:21])=[CH:24][CH:25]=2)[CH2:39][CH2:38]1)=[O:36])[CH3:33]
Reactant: CC(=O)c1c(-c2ccccc2)c2cc(Br)ccc2c(=O)n1Cc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)C1CCNCC1
Product: CCOC(=O)C1CCN(C(=O)c2ccc(Cn3c(C(C)=O)c(-c4ccccc4)c4cc(Br)ccc4c3=O)cc2)CC1

Procedure:
In the same manner as in Example 423, the title compound was synthesized from 4-(3-acetyl-6-bromo-1-oxo-4-phenyl-1H-isoquinolin-2-ylmethyl)benzoic acid and piperidine-4-carboxylic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.Cl[CH2:21][CH2:22][OH:23]>CN(C)C=O.C[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][CH2:22][OH:23])[CH:10]=2)=[O:8])=[CH:18][CH:19]=1
Reactant: OCCCl
Reactant: COc1ccc(C(=O)c2c[nH]c3ccccc23)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(CCO)c3ccccc23)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
5 g of 3-(p-methoxybenzoyl)indole were dissolved in 30 ml of dimethylformamide containing 1.3 g of sodium methoxide. 1.93 g of 2-chloroethanol was added to the solution followed by stirring at 110° C. for 1 hour. The solution was concentrated under reduced pressure and was extracted with 100 ml of chloroform and 50 ml of water. After evaporating the organic layer to dryness, the residue was recrystallized from ethanol to give 3-(p-methoxybenzoyl)-N-(2-hydroxyethyl)indole (compound 21). (Yield: 51%).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH:11]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)[C:3]=1[C:4]#[N:5].O=[C:19]([CH3:26])[CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[NH2:5][C:4]1[C:3]2[C:2](=[CH:9][CH:8]=[CH:7][C:6]=2[O:10][CH:11]2[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)[N:1]=[C:19]([CH3:26])[C:20]=1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: N#Cc1c(N)cccc1OC1CCCCCC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OC3CCCCCC3)c2c1N

Procedure:
Prepared as in Example 2a from 2-amino-6-(cycloheptyloxy)benzonitrile (Example 32b) and ethyl 3-oxobutanoate as a bright yellow solid (72%). 1H NMR (400 MHz, DMSO-d6) δ 1.32 (t, J=8.0 Hz, 3H), 1.49-1.65 (m, 8H), 1.78-1.87 (m, 2H), 2.04-2.10 (m, 2H), 2.53 (s, 3H), 4.31 (q, J=8.0 Hz, 2H), 4.79 (m, 1H), 6.89 (d, J=8.0 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.49 (t, J=8.0 Hz, 1H), 8.14 (brs, 2H). MS 343 (MH+).
Reaction SMILES: [C:1]([O:5]CC)(=O)[CH:2]=[CH2:3].[CH3:8][C:9]1[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:11][NH:12][C:13]=1[NH2:14]>N1C=CC=CC=1.O>[CH3:8][C:9]1[C:10]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:11][N:12]2[CH2:3][CH2:2][C:1](=[O:5])[NH:14][C:13]=12
Reactant: Cc1c(-c2cccnc2)n[nH]c1N
Reactant: C=CC(=O)OCC
Solvent: c1ccncc1
Solvent: O
Product: Cc1c(-c2cccnc2)nn2c1NC(=O)CC2
Temperature: 25 °C

Procedure:
Ethyl acrylate (0.5 mL) was added to a solution of 4-methyl-3-(pyridin-3-yl)-1H-pyrazol-5-amine (300 mg, 1.72 mmol) in pyridine (4 mL) and water (1 mL) and the resulting mixture heated to reflux overnight. After cooling to rt, the solvent was removed in vacuo and the residue re-crystallized from MeOH to give the desired product: MS (m/z): 229.1 [M+H]+, 1HNMR (400 MHz, CD3OD) δ 8.80 (d, 1 H, J=1.2 Hz), 8.53 (dd, 1 H, J=1.2 Hz, J=4.8 Hz), 8.07-8.09 (m, 1 H), 7.52 (dd, 1 H, J=4.8 Hz, J=8.0 Hz), 4.36 (t, 2 H, J=7.2 Hz), 2.94 (t, 2 H, J=7.2 Hz), 2.13 (s, 3 H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O1CCCCC1[O:20][NH:21][C:22](/[CH:24]=[CH:25]/[C:26]1[CH:31]=[CH:30][C:29](/[CH:32]=[CH:33]/[C:34]([C:36]2[CH:47]=[CH:46][C:39]([CH2:40]OS(C)(=O)=O)=[CH:38][CH:37]=2)=[O:35])=[CH:28][CH:27]=1)=[O:23]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([CH2:40][C:39]2[CH:38]=[CH:37][C:36]([C:34](=[O:35])/[CH:33]=[CH:32]/[C:29]3[CH:30]=[CH:31][C:26](/[CH:25]=[CH:24]/[C:22]([NH:21][OH:20])=[O:23])=[CH:27][CH:28]=3)=[CH:47][CH:46]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: O=C(/C=C/c1ccc(/C=C/C(=O)c2ccc(CN3CCN(Cc4ccccc4)CC3)cc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 31.5 %

Procedure:
1-Benzyl-piperazine (40 mg, 0.22 mmol) was added to a stirred mixture of methanesulfonic acid 4-((E)-3-{4-[(E)-2-(tetrahydro-pyran-2-yloxycarbamoyl)-vinyl]-phenyl}-acryloyl)-benzyl ester (prepared as described in Preparation 5, 90 mg, 0.185 mmol) and TEA (0.052 ml, 0.37 mmol) in DMF (2 ml). The resulting solution was stirred at room temperature for 1 h. The mixture was diluted with water and extracted with hot AcOEt. The organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was triturated with di-isopropylether/DCM, filtered and the resulting powder was suspended in DCM and treated with HCl/Et2O for 1 h. The solid was filtered and washed with DCM to give 28.1 mg of (E)-3-(4-{(E)-3-[4-(4-benzyl-piperazin-1-ylmethyl)-phenyl]-3-oxo-propenyl}-phenyl)-N-hydroxy-acrylamide as its bis-hydrochloride salt.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]([C:14]3[O:15][CH:16]=[CH:17][CH:18]=3)O)[CH:11]=2)=[CH:4][CH:3]=1.CC(C)=[O:25]>O>[Cl:1][C:2]1[CH:22]=[CH:21][C:5]([C:6]2[CH:7]=[CH:8][C:9]([CH2:19][CH3:20])=[C:10]([CH:12]3[C:16](=[O:15])[CH:17]=[CH:18][CH:14]3[OH:25])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CCc1ccc(-c2ccc(Cl)cc2)cc1C(O)c1ccco1
Solvent: O
Product: CCc1ccc(-c2ccc(Cl)cc2)cc1C1C(=O)C=CC1O
Temperature: 55 °C
Reaction time: 25 h

Procedure:
A solution of (4′-chloro-4-ethylbiphen-3-yl)furan-2-ylmethanol (67.18 g, 214.8 mmol) in acetone (1340 ml) and water (235 ml) is heated to 55° C. and 30 drops of polyphosphoric acid are added. The mixture is stirred at 55° C. for 25 hours, then cooled to room temperature. The reaction mixture is concentrated under reduced pressure to remove most of the acetone then ethyl acetate (600 ml) is added, and the reaction mixture is partitioned. The aqueous phase is extracted into ethyl acetate and the organic solutions are combined, washed with saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered and the filtrate is concentrated under reduced pressure. The residue is purified by column chromatography on silica gel to give 5-(4′-chloro-4-ethylbiphen-3-yl)-4-hydroxy-cyclopent-2-enone (59.84 g) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH2:10]([SH:14])[CH2:11][CH2:12][SH:13]>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]2[S:14][CH2:10][CH2:11][CH2:12][S:13]2)[CH:7]=[CH:8][CH:9]=1
Reactant: SCCCS
Reactant: O=Cc1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Clc1cccc(C2SCCCS2)c1
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution of 3-chlorobenzaldehyde (100 mmol) in chloroform (250 mL) is added 1,3-propanedithiol (110 mmol). The mixture is chilled to −10° C. and HCl gas is gently bubbled through the mixture for 20 min. The mixture is stirred at −10° C. for one hour, then allowed to warm to room temperature overnight. The solution is washed with 1 M KOH, water, brine, and dried (K2CO3). After filtering, the organic extract is concentrated in vacuo to afford 2-(3-chlorophenyl)-1,3-dithiane.
Reaction SMILES: C(O[C:4](=[O:37])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:36]=[CH:35][C:12]([CH2:13][C@@H:14]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[N:18][N:17]=2)=[CH:11][CH:10]=1)C.[NH2:38][C:39]1[NH:40][CH2:41][CH2:42][CH2:43][N:44]=1>C(Cl)Cl>[O:37]=[C:4]([NH:38][C:39]1[NH:44][CH2:43][CH2:42][CH2:41][N:40]=1)[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:13][C@@H:14]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[NH:15][C:16]2[N:20]([CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:19]=[N:18][N:17]=2)=[CH:35][CH:36]=1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nnnn2Cc2ccccc2)C(=O)OC(C)(C)C)cc1
Reactant: NC1=NCCCN1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nnnn1Cc1ccccc1
Reaction time: 24 h
Yield: 24.2 %

Procedure:
The ester 5-1 (150 mg) is mixed with 2-amino-1,4,5,6-tetrahydropyrimidine (42 mg) in 5 ml of CH2Cl2 and agitation is carried out at ambient temperature for 24 hours. Evaporation is then carried out under reduced pressure and the dry extract obtained is purified by chromatography, eluting with a CH2Cl2/MeOH/water/AcOH mixture 90/10/1/1. 40 mg of the expected product 5-2 is obtained.
Reaction SMILES: [CH3:1][N:2](C)[CH2:3][CH2:4][CH2:5][CH:6]1[C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2.C(=O)(O)[O-].[Na+].Cl[C:28]([O:30][CH2:31][CH3:32])=[O:29].O>C1(C)C=CC=CC=1>[CH2:31]([O:30][C:28](=[O:29])[N:2]([CH2:3][CH2:4][CH2:5][CH:6]1[C:10]2([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[O:9][C:8]2[CH:17]=[CH:18][CH:19]=[CH:20][C:7]1=2)[CH3:1])[CH3:32]
Reactant: CN(C)CCCC1c2ccccc2OC12CCCCCC2
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)N(C)CCCC1c2ccccc2OC12CCCCCC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred mixture, kept under nitrogen, of 7.85 g of 3-(3-dimethylaminopropyl)-spiro[benzofuran-2(3H),1'-cycloheptane] and 11.7 g of powdered sodium bicarbonate in 250 ml of toluene was added 5.2 ml of ethyl chloroformate. The mixture was refluxed overnight and thereafter an additional 2.6 ml of ethyl chloroformate was added. The mixture was refluxed for another 5 hours and thereafter stirred overnight at room temperature. Water (250 ml) was then added with stirring. The organic phase was separated and washed successively with 2N-hydrochloric acid, water and brine, dried over anhydrous sodium sulfate and concentrated in vacuo to an oil. This material was used as such for subsequent synthesis. The IR, NMR and Mass Spectra were in accord with the designated structure.
Reaction SMILES: C[O-].[Na+].[Cl:4][C:5]1[C:10]([Cl:11])=[C:9]([SH:12])[CH:8]=[CH:7][C:6]=1[NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:19])([F:18])[F:17].[O:23]1[CH:25]([CH2:26][CH3:27])[CH2:24]1.CCOC(C)=O>C1COCC1>[OH:23][CH:25]([CH2:26][CH3:27])[CH2:24][S:12][C:9]1[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:22])[C@:15]([OH:21])([CH3:20])[C:16]([F:17])([F:18])[F:19])=[C:5]([Cl:4])[C:10]=1[Cl:11]
Reactant: CCC1CO1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S)c(Cl)c1Cl)C(F)(F)F
Agent: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(O)CSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Sodium methoxide (0.075 g) was added to a stirred solution of (R)-N-[2,3-dichloro-4-mercaptophenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 35) (0.44 g) in anhydrous THF (10 ml). The reaction mixture was stirred at ambient temperature for 5 minutes and 1,2-epoxybutane (0.11 ml) was added. The mixture was heated under reflux for 2 hours and allowed to cool to ambient temperature. EtOAc (150 ml) was added and the mixture washed with brine (100 ml) and dried. Volatile material was removed by evaporation and the residue was purified on a 20 g silica Mega Bond Elut column eluting with 1-40% EtOAc/isohexane to give the title compound (0.259 g) as an orange solid. NMR: 0.88 (t, 3H), 1.35-1.49 (m, 1H), 1.58 (s, 3H), 2.97-3.08 (m, 1H), 3.53-3.62 (m, 1H), 5.00 (d, 1H), 7.42 (d, 1H), 7.77 (d, 1H), 9.79 (brs, 1H); m/z: 404.
Reaction SMILES: C([O:8][C:9]([CH:11]([CH2:24][CH2:25][C:26]([O:28]CC1C=CC=CC=1)=[O:27])[CH2:12][P:13]([CH3:23])(=[O:22])[O:14]CC1C=CC=CC=1)=[O:10])C1C=CC=CC=1>O.[Pd]>[CH3:23][P:13]([CH2:12][CH:11]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])[C:9]([OH:10])=[O:8])([OH:22])=[O:14]
Reactant: CP(=O)(CC(CCC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Agent: [Pd]
Solvent: O
Product: CP(=O)(O)CC(CCC(=O)O)C(=O)O

Procedure:
2,4-di(benzyloxycarbonyl)buty(methyl)-O-benzylphosphinic acid (0.8 g, 1.6 mmol) in 20 mL of water containing 100 mg of 10% Pd/C was hydrogenated at 40 psi for 4 hours. The mixture was filtered over a pad of Celite and evaporated at high vacuum to give 2-[(methylhydroxyphosphinyl)methyl]pentanedioic acid (4,R=CH3,0.28 g, 78% as a clear and colorless viscous oil. 1H NMR (D2O): 2.5 ppm(m,1H), 2.2 ppm(t,2H), 2.0 ppm (m,1H), 1.7 ppm(m,3H), 1.3 ppm (d, 3H) Elemental Analysis Calculated C7H13O6P.0.2 H2O: C36.92 H 5.93 Found: C37.06 H 6.31
Reaction SMILES: [Li+].[BH4-].[CH:3]1([C@H:6]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:9]([C:18](OC)=[O:19])[C:8](=[O:22])[CH2:7]2)[CH2:5][CH2:4]1>C1COCC1.CCOC(C)=O>[CH:3]1([C@H:6]2[N:10]([C:11]([O:13][C:14]([CH3:15])([CH3:16])[CH3:17])=[O:12])[CH:9]([CH2:18][OH:19])[CH:8]([OH:22])[CH2:7]2)[CH2:4][CH2:5]1
Reactant: COC(=O)C1C(=O)C[C@@H](C2CC2)N1C(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C(CO)C(O)C[C@H]1C1CC1
Temperature: 60 °C
Reaction time: 18 h

Procedure:
LiBH4 (0.5 g, 23.3 mmol) was added to a solution of (5S)-1-tert-butyl 2-methyl 5-cyclopropyl-3-oxopyrrolidine-1,2-dicarboxylate (31) (2.2 g, 7.76 mmol) in THF (20 mL). The reaction mixture was stirred at 60° C. for 18 h after which HPLC indicated that the reaction was compete. The resulting solution was diluted with EtOAc (20 mL) and washed with sat. aq. NaHCO3 (20 mL). The organic phase was dried (Na2SO4), filtered and concentrated under vacuum to give (5S)-tert-butyl 5-cyclopropyl-3-hydroxy-2-(hydroxymethyl)pyrrolidine-1-carboxylate (32). Retention time (min)=1.484 method [1], MS (m/z) 280.2 (M+Na)+.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([S:7]([NH2:10])(=[O:9])=[O:8])=[CH:4][CH:3]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>C(#N)C>[CH3:13][N:14]([CH3:16])[CH:15]=[N:10][S:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][CH:4]=1)(=[O:9])=[O:8]
Reactant: COC(OC)N(C)C
Reactant: NS(=O)(=O)c1ccc(Br)s1
Solvent: CC#N
Product: CN(C)C=NS(=O)(=O)c1ccc(Br)s1

Procedure:
To a stirred mixture of 5-bromothiophene-2-sulfonamide (24.2 g, 0.10 mol) in acetonitrile (100 ml) was added dimethylformamide dimethyl acetal (14 ml) in acetonitrile (125 ml) dropwise over 0.5 hour. After an additional 0.5 hour the solvent was removed in vacuo. The residue was treated with water and the solid that precipitated was collected and dried, 28.7 g., m.p. 103°-105° C. Recrystallization from 1-chlorobutane gave material with m.p. 104°-106° C.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4].[H-].[Na+].[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[CH2:26]Cl.Cl>CN(C)C=O>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:11]([CH2:26][C:25]2[CH:28]=[CH:29][CH:30]=[C:23]([Cl:22])[CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[CH:7][N:6]=1)=[O:4]
Reactant: COC(=O)c1ccc(NCc2cccc(Cl)c2)cn1
Reactant: ClCc1cccc(Cl)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(Cc2cccc(Cl)c2)Cc2cccc(Cl)c2)cn1

Procedure:
To the solution of 1.38 g of 5-(m-chlorobenzylamino)-pyridine-2-carboxylic acid methyl ester in 15 ml of dimethylformamide, 0.12 g of sodium hydride in 2 ml of dimethylformamide are added and the mixture is stirred several minutes. Then 0.97 g of m-chlorobenzyl chloride are added and the mixture is stirred at room temperature for 18 hours. It is made acidic with diluted hydrochloric acid and extracted with diethyl ether. The extract is washed with 10% aqueous potassium bicarbonate and water, dried and evaporated, to yield the 5-[di-(m-chlorobenzyl)-amino]-pyridine-2-carboxylic acid methyl ester.
Reaction SMILES: [C:1]([C:3]([CH3:9])([CH3:8])[C:4]([NH:6][NH2:7])=O)#[N:2].CCN(CC)CC.Cl.[C:18](=[NH:27])(OC)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>CO>[CH3:8][C:3]([C:4]1[NH:6][N:7]=[C:18]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:27]=1)([CH3:9])[C:1]#[N:2]
Reactant: COC(=N)c1ccccc1
Reactant: CC(C)(C#N)C(=O)NN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C#N)c1nc(-c2ccccc2)n[nH]1
Yield: 65 %

Procedure:
2-Cyano-2-methylpropanehydrazide (100 mg, 0.78 mmol) and Et3N (0.1 mL, 0.86 mmol) were added to a solution of methyl benzimidate hydrochloride (100 mg, 0.58 mmol) in dry MeOH (10 mL), and the mixture was heated to reflux for 1 h. The reaction mixture was then concentrated under reduced pressure and the crude product was purified by column chromatography (silica 60-120 mesh, eluant 15% EtOAc in petroleum ether) to get 2-methyl-2-(3-phenyl-1H-1,2,4-triazol-5-yl)propanenitrile (80 mg, yield 51%). 1H NMR (300 MHz, MeOD) δ 7.98-7.95 (m, 2H), 7.52-7.50 (m, 3H), 1.82 (s, 6H). MS (ESI) m/z: Calculated for C12H12N4: 212.11. found: 213.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][CH:8]=2)[S:4][C:3]=1[C:14]([O:16][CH3:17])=[O:15].CO[CH:20](OC)[N:21]([CH3:23])[CH3:22]>CCO>[Cl:13][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[S:4][C:3]([C:14]([O:16][CH3:17])=[O:15])=[C:2]([N:1]=[CH:20][N:21]([CH3:23])[CH3:22])[CH:6]=2)=[CH:12][CH:11]=1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N
Reactant: COC(OC)N(C)C
Solvent: CCO
Product: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C

Procedure:
The title compound was prepared following the procedure described in WO2003033476. Condensation of 2.00 g of methyl 3-amino-5-(4-chlorophenyl)-thiophene-2-carboxylate with dimethylformamide dimethyl acetal for 3 hr in refluxing EtOH yielded 2.52 g (100%) after removal of the volatiles under vacuum. 1H NMR (CDCl3) δ 3.06 (s, 3H), 3.08 (s, 3H), 3.81 (s, 3H), 6.98 (s, 1H), 7.35 (d, J=8.79 Hz, 2H), 7.53 (d, J=8.24 Hz, 2H), 7.69 (s, 1H); 13C NMR (CDCl3) δ 34.31, 40.26, 51.44, 112.43, 122.28, 126.95, 129.09, 132.18, 134.45, 145.79, 156.09, 159.16, 163.22; HPLC (Method #1): 2.45 min retention time; MS (ES): m/z 323 [M+H]+.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@H:28]([CH2:30]OS(C4C=CC=C([N+]([O-])=O)C=4)(=O)=O)[O:27][C:26]3=[O:44])=[CH:21][C:20]=2[F:45])[CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]>CN(C=O)C>[C:5]([N:15]1[CH2:18][CH:17]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:29][C@@H:28]([CH2:30][N:1]=[N+:2]=[N-:3])[O:27][C:26]3=[O:44])=[CH:21][C:20]=2[F:45])[CH2:16]1)([O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:6]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(OCc1ccccc1)N1CC(c2ccc(N3C[C@H](COS(=O)(=O)c4cccc([N+](=O)[O-])c4)OC3=O)cc2F)C1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NC[C@@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 16 h

Procedure:
A mixture of sodium azide (1.44 g, 22.1 mmol) and (R)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-[[(3-nitrophenylsulfonyl)oxy]-methyl]-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 6, 2.60 g, 4.44 mmol) in DMF (30 mL) was stirred for 16 hr, then filtered. The solvent was removed at 38°/0.75 mm and the residue extracted with ethyl acetate (100 mL) and washed with water (3×50 mL) and brine (50 mL). After drying over magnesium sulfate, filtration and evaporation gave a yellow oil. Chromatography over silica gel (150 g, 40-60 μm) eluting with 1-3% methanol-methylene chloride gave the title compound as a pale yellow foam. FAB-HRMS: theory 426.1577 (M+1); meas. 426.1580.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[S:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]([O:23][CH2:24][C:25]([Cl:28])([Cl:27])[Cl:26])=[O:22])=[CH:16][CH:15]=1)[C:7](O)=[O:8])([O-:3])=[O:2].S(Cl)([Cl:31])=O>CN(C)C=O>[Cl:26][C:25]([Cl:28])([Cl:27])[CH2:24][O:23][C:21](=[O:22])[NH:20][C:17]1[CH:18]=[CH:19][C:14]([S:13][C:12]2[CH:11]=[CH:10][C:6]([C:7]([Cl:31])=[O:8])=[CH:5][C:4]=2[N+:1]([O-:3])=[O:2])=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(Nc1ccc(Sc2ccc(C(=O)O)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(Sc2ccc(C(=O)Cl)cc2[N+](=O)[O-])cc1)OCC(Cl)(Cl)Cl

Procedure:
The product from Example 84a (2.0 g, 42.9 mmol) in thionyl chloride (10 mL) containing 1 drop of dimethylformamide and was heated to reflux for 3 hours. Cooled and concentrated under vacuum and dried under high vacuum overnight. The title compound was used without further purification.