Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[S:2]1(=[O:33])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:27][CH3:28])[CH2:3]1.[OH-].[Na+].C(O)(=O)C>C(O)C>[O:33]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:29][CH2:30][CH2:31][CH3:32])([CH2:27][CH3:28])[CH2:3]1
Reactant: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CCCCC1(CC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Yield: 90 %

Procedure:
1,1-Dioxo-3-butyl-3-ethyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 5; 0.34 g) and sodium hydroxide (0.3 g) were dissolved in ethanol and the mixture was heated to reflux for 1 hour. Acetic acid (1 ml) was added and the solvent was removed at reduced pressure. The residue was partitioned between DCM/H2O and the organic layer was separated and dried. Trituration of the residue with n-hexane gave the title compound 0.29 g (90%) as a solid. NMR (500 MHz, CDCl3): 0.7–0.8 (m, 6H), 1.0–1.7 (m, 8H), 3.1–3.2 (m, 2H), 3.6 (br s, 2H), 4.6 (s, 2H), 6.9–7.1 (m, 4H), 7.2 (m, 2H), 7.5 (s, 1H).
Reaction SMILES: [CH3:1][CH2:2][N:3]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)=[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:26][CH2:25][N:24]([C:27]4[CH:32]=[CH:31][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@@H:44]([CH2:54][S:55][C:56]6[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=6)[CH2:45][CH2:46][N:47]6[CH2:52][CH2:51][CH:50]([OH:53])[CH2:49][CH2:48]6)=[C:39]([S:62]([C:65]([F:68])([F:67])[F:66])(=[O:64])=[O:63])[CH:38]=5)(=[O:36])=[O:35])=[CH:29][CH:28]=4)[CH2:23][CH2:22]3)[CH:16]=2)[C:5]([C:69]([OH:71])=[O:70])=[C:4]1[CH3:72].CC(C)N=C=NC(C)C.O[CH2:83][P:84](=[O:89])([O:87]C)[O:85]C.C[Si](Br)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(OCC)(=O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]2[N:3]([CH2:2][CH3:1])[C:4]([CH3:72])=[C:5]([C:69]([O:71][CH2:83][P:84](=[O:85])([OH:89])[OH:87])=[O:70])[C:6]=2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([N:21]3[CH2:22][CH2:23][N:24]([C:27]4[CH:28]=[CH:29][C:30]([NH:33][S:34]([C:37]5[CH:42]=[CH:41][C:40]([NH:43][C@H:44]([CH2:45][CH2:46][N:47]6[CH2:48][CH2:49][CH:50]([OH:53])[CH2:51][CH2:52]6)[CH2:54][S:55][C:56]6[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=6)=[C:39]([S:62]([C:65]([F:66])([F:67])[F:68])(=[O:63])=[O:64])[CH:38]=5)(=[O:36])=[O:35])=[CH:31][CH:32]=4)[CH2:25][CH2:26]3)[CH:16]=2)=[CH:9][CH:10]=1
Reactant: COP(=O)(CO)OC
Reactant: CCn1c(C)c(C(=O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Agent: C[Si](C)(C)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCn1c(C)c(C(=O)OCP(=O)(O)O)c(-c2cccc(N3CCN(c4ccc(NS(=O)(=O)c5ccc(N[C@H](CCN6CCC(O)CC6)CSc6ccccc6)c(S(=O)(=O)C(F)(F)F)c5)cc4)CC3)c2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 70.9 %

Procedure:
To a solution of BM-957 (100 mg, 0.09 mmol), DIC (18 mg, 0.14 mmol) and DMAP (20 mg, 0.14 mmol) in DCM (2 mL) was added dimethyl (hydroxymethyl)phosphonate (40 mg, 0.28 mmol). The solution was stirred for 6 hours at room temperature until no BM-957 was observed by TLC. The reaction mixture was diluted with ethyl acetate (50 mL), washed with saturated NaHCO3 solution (50 mL), brine (50 mL) and dried over sodium sulfate. The solvent was removed in vacuo to give crude product which was used for next step without purification. The resulting residue was dissolved in DCM (5 mL) and followed by adding TMSBr (248 uL, 1.9 mmol). The solution was stirred at room temperature for 20 h until no starting material was observed by MS. The reaction mixture was concentrated in vacuo and the residue was purified by HPLC to give the pure product 8 (salt with TFA, 74 mg, yield 68% over two steps). The gradient ran from 60% of solvent A and 40% of solvent B to 20% of solvent A and 80% of solvent B in 40 min. 1H NMR (300 M Hz, CD3OD): δ 7.92 (s, 1H), 7.73-7.70 (m, 2H), 7.34-6.82 (m, 17H), 4.28 (d, J=8.6 Hz, 2H), 4.06-3.35 (m, 14H), 3.20-2.92 (m, 5H), 2.65 (s, 3H), 2.24-1.67 (m, 6H), 1.10 (t, J=7.0 Hz, 3H). MS (ESI): m/z 1259.50 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12](Cl)=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[CH2:26]([NH:28][CH3:29])[CH3:27]>CN(C=O)C>[N:1]1([C:6]2[CH:25]=[CH:24][C:9]([CH2:10][C:11]3[C:12]([N:28]([CH2:26][CH3:27])[CH3:29])=[N:13][C:14]4[C:19]([C:20]=3[Cl:21])=[CH:18][C:17]([Br:22])=[CH:16][CH:15]=4)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: CCNC
Reactant: Clc1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Solvent: CN(C)C=O
Product: CCN(C)c1nc2ccc(Br)cc2c(Cl)c1Cc1ccc(-n2cccn2)cc1
Temperature: 80 °C

Procedure:
A mixture of 3-(4-(1H-pyrazol-1-yl)benzyl)-6-bromo-2,4-dichloroquinoline (Intermediate 6: step c, 0.100 g, 0.231 mmol), N-ethylmethylamine (1.5 mL) and DMF (0.5 mL) were heated in a sealed tube at 80° C. for 8 hours, cooled to room temperature, evaporated in vacuo, diluted with acetonitrile and filtered. The filtrate was evaporated in vacuo and chromatographed (EtOAc/Heptane) to provide the title compound.
Reaction SMILES: [O:1]=[C:2]1[C:10]2([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:20])([F:19])[F:18])[CH2:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:21][C:22]([OH:24])=O.[NH2:25][C:26]1[N:31]=[CH:30][C:29]2[CH2:32][C:33]3([CH2:43][C:28]=2[CH:27]=1)[C:41]1[C:36](=[N:37][CH:38]=[CH:39][CH:40]=1)[NH:35][C:34]3=[O:42].C1CN(C(Cl)=[N+]2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1>[O:42]=[C:34]1[NH:35][C:36]2=[N:37][CH:38]=[CH:39][CH:40]=[C:41]2[C:33]21[CH2:32][C:29]1[CH:30]=[N:31][C:26]([NH:25][C:22](=[O:24])[CH2:21][N:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[C:10]4([CH2:15][CH2:14][N:13]([CH2:16][C:17]([F:18])([F:19])[F:20])[CH2:12][CH2:11]4)[C:2]3=[O:1])=[CH:27][C:28]=1[CH2:43]2
Reactant: O=C(O)CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21
Reactant: Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Agent: ClC(N1CCCC1)=[N+]1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CN1C(=O)C2(CCN(CC(F)(F)F)CC2)c2ccccc21)Nc1cc2c(cn1)CC1(C2)C(=O)Nc2ncccc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 2-oxo-1′-(2,2,2-trifluoroethyl)-spiro[indoline-3,4′-piperidine]-1-acetic acid (79 mg, 0.23 mmol, described in Intermediate 11), (±)-3-amino-5,7-dihydrospiro[cyclopenta[c]pyridine-6,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (71 mg, 0.28 mmol, described in Intermediate 3), N,N,N′,N′-bis(tetramethylene)chloroformamidinium hexafluorophosphate (153 mg, 0.46 mmol), and N,N-diisopropylethylamine (0.20 mL, 1.15 mmol) in THF (2 mL) is stirred at ambient temperature for 18 h. The reaction mixture is purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions are combined and made basic with saturated aqueous NaHCO3. The resulting mixture is extracted with EtOAc (3×20 mL), and the combined organic extracts are washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo to provide the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:9])[CH2:7][OH:8])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:17][CH:18]=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:9])[CH2:7][O:8][C:13]1[N:14]=[N:15][C:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[F:25])=[CH:17][CH:18]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)CO
Reactant: Fc1ccccc1-c1ccc(Br)nn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)COc1ccc(-c2ccccc2F)nn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
37.6 mg (0.285 mmol) of hydroxyacetic acid tert-butyl ester were dissolved in 10 ml of DMF, 12.4 mg of sodium hydride (55% in mineral oil) were added, and the mixture was stirred at room temperature for 15 min. Then 60 mg (0.237 mmol) of 3-bromo-6-(2-fluoro-phenyl)-pyridazine in 2 ml of DMF were added, and the reaction mixture was stirred at 60° C. for 5 h and at 120° C. for 5 h. After evaporation to dryness, the crude product was directly employed in the subsequent step.
Reaction SMILES: [CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]Br.[NH2:18][C:19]1[CH:29]=[CH:28][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][CH:20]=1>CN(C)P(N(C)C)(N(C)C)=O>[CH3:1][C:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CCCCCCCCCCCCBr
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCOC(=O)c1ccc(NCCCCCCCCCCCCC(C)(C)C)cc1

Procedure:
A solution of 10 g. of 13,13-dimethyltetradecyl bromide and 10.8 g. of ethyl 4-aminobenzoate in 75 ml. hexamethylphosphoramide is heated at 110° C. for 17 hours. The cooled solution is diluted with 100 ml. water, filtered, and the residue is washed in portions with 100 ml. 50% ethanol-water. After drying, the product is crystallized from ethanol to yield ethyl 4-(13,13-dimethyltetradecyl)aminobenzoate as colorless crystals.
Reaction SMILES: [CH:1]1([C:4]2[C:5]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:6]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([O:27]CC)=[O:26])=[CH:19][CH:18]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CCO>[CH:1]1([C:4]2[C:5]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:6]([O:16][C:17]3[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26])=[CH:19][CH:18]=3)[C:7]3[C:12]([CH:13]=2)=[CH:11][C:10]([O:14][CH3:15])=[CH:9][CH:8]=3)[CH2:3][CH2:2]1
Reactant: CCOC(=O)/C=C/c1ccc(Oc2c(-c3ccccc3)c(C3CC3)cc3cc(OC)ccc23)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc2c(Oc3ccc(/C=C/C(=O)O)cc3)c(-c3ccccc3)c(C3CC3)cc2c1
Yield: 96.7 %

Procedure:
Ethyl ester (154) (0.21 g, 0.45 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.19 g (96%) of the title compound (155) as a white solid. 1H NMR (400 MHz, CDCl3): δ 0.75-0.85 (m, 4H), 1.60-1.70 (m, 1H), 3.92 (s, 3H), 6.22 (d, J=15.9 Hz, 1H), 6.60 (d, J=8.6 Hz, 2H), 7.02 (dd, J1=9.2 Hz, J2=2.4 Hz, 1H), 7.13 (d, J=2.2 Hz, 1H), 7.18-7.30 (m, 8H), 7.62 (d, J=15.9 Hz, 1H), 7.68 (d, J=8.9 Hz, 1H). LCMS (APCI): m/z 437 (M+H)+, m/z 435 (M−H)−.
Reaction SMILES: [O:1]=[C:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([NH:5][CH3:6])=[O:4].Cl>CO.C(Cl)Cl>[OH:1][C@@H:2]([C:7]([CH3:10])([CH3:9])[CH3:8])[C:3]([NH:5][CH3:6])=[O:4]
Reactant: CNC(=O)C(=O)C(C)(C)C
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)[C@@H](O)C(C)(C)C

Procedure:
The experiment was carried out in an analogous manner to Example 1. The asymmetric hydrogenation of 55.0 g (0.384 mol) of 2-keto-3,3,N-trimethyl-butyramide in 270 ml of methanol and 30 ml of methylene chloride in the presence of a catalyst prepared from 296 mg (0.384 mmol) of [Ru(OAc)2((S)-BIPHEMP)] and 31 ml of a 0.025 molar methanolic hydrochloric acid solution gave, after crystallization, 34.4 g (62%) of (S)-2-hydroxy-3,3,N-trimethyl-butyramide, m.p.=60-62° C., [α]=−59.9° (c=1, CHCl3), ee=99.2%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.[CH:9]12[CH2:22][CH:13]([N:14]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][NH:11][CH2:10]2.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:11]2[CH2:12][CH:13]3[CH2:22][CH:9]([N:14]3[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Reactant: Brc1ccc(I)cc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C2CC1CN(c1ccc(Br)cc1)C2
Temperature: 60 °C
Reaction time: 3 h
Yield: 28.1 %

Procedure:
In a 48 mL sealed tube were placed 1-bromo-4-iodobenzene (1498.3 mg, 5.30 mmol), tert-butyl 3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1000.0 mg, 5.04 mmol), Pd2(dba)3 (138.6 mg, 0.15 mmol), XantPhos (262.7 mg, 0.45 mmol), and sodium t-butoxide (1454.2 mg, 15.13 mmol) in toluene (36 ml). The reaction mixture was stirred at 60° C. for 3 h. Then it was cooled to room temperature. Then it was quenched with water and the organic layers were extracted with EtOAc (3×10 mL). The combined organic layers were washed with water (2×10 mL) and brine (1×10 mL), dried (Na2SO4), concentrated, and purified by flash chromatography (100% Hexane to 100% EtOAc) to give 500.0 mg (28%) of tert-butyl 3-(4-bromophenyl)-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.OC1SC=CC=1.[OH:15][C:16]1[C:20]([CH3:21])=[CH:19][S:18][C:17]=1[C:22]([O:24][CH3:25])=[O:23]>C(Cl)(Cl)(Cl)Cl>[Cl:1][C:17]1([C:22]([O:24][CH3:25])=[O:23])[C:16](=[O:15])[C:20]([CH3:21])=[CH:19][S:18]1
Reactant: COC(=O)c1scc(C)c1O
Reactant: O=C1CCC(=O)N1Cl
Agent: Oc1cccs1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)C1(Cl)SC=C(C)C1=O

Procedure:
N-Chlorosuccinimide (0.027 mol) was added to a stirred solution of the hydroxythiophen of (c) above (3 g) in 8 ml of carbon tetrachloride.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:24])[C:15]2[CH:20]=[CH:19][C:18]([N:21]([CH3:23])[CH3:22])=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[OH:25][CH2:26][CH2:27][O:28][C:29]1[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O>>[CH3:22][N:21]([CH3:23])[C:18]1[CH:19]=[CH:20][C:15]([C:14]([NH:13][C:6]2[CH:7]=[CH:8][C:9]3[NH:10][C:32]([C:31]4[CH:34]=[CH:35][CH:36]=[C:29]([O:28][CH2:27][CH2:26][OH:25])[CH:30]=4)=[N:1][C:4]=3[CH:5]=2)=[O:24])=[CH:16][CH:17]=1
Reactant: CN(C)c1ccc(C(=O)Nc2ccc([N+](=O)[O-])c([N+](=O)[O-])c2)cc1
Reactant: O=Cc1cccc(OCCO)c1
Product: CN(C)c1ccc(C(=O)Nc2ccc3[nH]c(-c4cccc(OCCO)c4)nc3c2)cc1

Procedure:
Compound 219 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-dimethylaminobenzamide and 3-(2-hydroxyethyloxy)benzaldehyde. [M+H]+ calcd for C24H24N4O3: 417.19; found: 416.94.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([CH3:11])=[CH:4][C:3]=1[N+:12]([O-])=O.Cl.[OH-].[Na+]>C(O)C>[NH2:12][C:3]1[CH:4]=[C:5]([CH3:11])[CH:6]=[C:7]([NH2:8])[C:2]=1[Cl:1]
Reactant: Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(N)c(Cl)c(N)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
4-chloro-3,5dinitrotoluene (9.0gm.) is dissolved in 50% ethanol (30 ml.). Electrolytically reduced iron powder (14.2 gm.) is added and the stirred reaction mixture heated to reflux. Concentrated HCl (1 ml.) in 50% ethanol (5 ml.) is added dropwise and refluxing continued for one hour. The reaction mixture is allowed to cool slightly and made basic (pH 8) with 20% NaOH, then the iron removed by filtration. The filtrate is taken to dryness under reduced pressure and the residue extracted with hot Skellysolve "B" (700 ml.). The product precipitates in long needles that were collected by filtration (4.57 gm., m.p. 114--115.5°, 70% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([Cl:31])[N:20]=[C:19]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)([O:3]C)=[O:2].C[S-].[K+]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]2[C:22]([CH2:23][O:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH3:30])=[C:21]([Cl:31])[N:20]=[C:19]2[CH2:32][CH2:33][CH2:34][CH3:35])=[CH:13][CH:12]=1)([OH:3])=[O:2]
Reactant: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)OC)cc1
Agent: C[S-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(COCOCCOC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1
Yield: 80 %

Procedure:
A solution of 3.15 g of 1-[(2'-carbomethoxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole and 2.77 g of potassium methanethiolate in 125 mL of dimethylformamide was stirred at 125° for 4 hours. After cooling the solvent was removed in vacuo, and the residue was dissolved in water. The resulting aqueous solution was washed with diethyl ether, adjusted to pH 3 employing 10% hydrochloric acid, and extracted with methylene chloride. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was recrystallized from chlorobutane to afford 2.45 g of 1-[(2'-carboxybiphenyl-4-yl)methyl]-2-butyl-4-chloro-5-(2-methoxyethoxymethoxymethyl)imidazole. NMR (200 MHz, CDCl3) δ7.95 (d, 1H); 7.57 (t, 1H); 7.46 (t, 1H); 7.38 (m, 3H); 7.05 (d, 2H); 5.22 (s, 2H); 4.64 (s, 2H); 4.48 (s, 2H); 3.58 (m, 4H); 3.40 (s, 3H); 2.54 (t, 2H); 1.60 (quint., 2H); 1.32 (sext., 2H); 0.84 (t, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9](C)[C:10](O)=O)C=[CH:6][C:7]=1[F:8].[C:14](Cl)(=[O:18])[C:15](Cl)=O.[Al+3].[Cl-].[Cl-].[Cl-]>CN(C=O)C.C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]2[C:15](=[CH:6][C:7]=1[F:8])[C:14](=[O:18])[CH2:10][CH2:9]2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C(=O)O)c1ccc(F)c(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C1CCc2cc(F)c(F)cc21
Temperature: 0 °C
Reaction time: 24 h

Procedure:
To a solution of 3,4-difluorophenyl propionic acid (30.45 g; 163.6 mmol) and 2 drops of DMF in CH2Cl2 (200 mL) was added oxalyl chloride (41.4 g, 327 mmol) over 20 min. The resulting solution was stirred for 24 hr and concentrated in vacuo (chased 1×PhMe, ca. 100 mL). The residue was dissolved in CS2 (300 mL), cooled to 0° C. and AlCl3 (76.4 g, 573 mmol) was added over 10 min. The mixture was stirred 30 min at 0° C., then heated under reflux for 4 hr. Upon cooling to room temperature the solution was carefully poured onto crushed ice, the carbon disulfide layer was separated and the aqueous layer extracted with EtOAc. Combined organics were dried over MgSO4 and the concentrated in vacuo. The residue was purified by flash chromatography (EtOAc/hexanes), affording the title compound as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.50 (t, 1H, J=8.0 Hz), 7.24 (t, 1H, J=6.6 Hz), 3.09 (t, 2H, J=5.5 Hz), 2.72-2.69 (m, 2H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:13])[NH:10][CH:11]=[CH2:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(C)C=CC=CC=1.N1([CH:30]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=2)[CH2:31][CH3:32])C2C=CC=CC=2N=N1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(OCC)(=O)C>[CH2:1]([O:8][C:9](=[O:13])[NH:10][C@H:11]1[C:35]2[C:34](=[CH:39][CH:38]=[C:37]([C:40]([F:41])([F:42])[F:43])[CH:36]=2)[NH:33][C@@H:30]([CH2:31][CH3:32])[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CNC(=O)OCc1ccccc1
Reactant: CCC(Nc1ccc(C(F)(F)F)cc1)n1nnc2ccccc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CC[C@H]1C[C@@H](NC(=O)OCc2ccccc2)c2cc(C(F)(F)F)ccc2N1
Temperature: 70 °C
Reaction time: 2 h

Procedure:
A one liter, four neck flask under nitrogen atmosphere was charged with N-vinyl-carbamic acid benzyl ester (27.66 g, 156 mmol, 1.0 equiv) and dry toluene (500 mL). (1-Benzotriazol-1-yl-propyl)-(4-trifluoromethyl-phenyl)-amine (50.0 g, 156 mmol, 1.0 equiv) and p-toluenesulfonic acid monohydrate (297 mg, 1.56 mmol, 0.01 equiv) were added, and the mixture heated to 70° C. After 2 h, the mixture was cooled to room temperature and transferred to a separatory funnel. Ethyl acetate (500 mL) was added. The mixture was washed 1×200 mL 1 N NaOH, 1×200 mL H2O, 1×200 mL brine, and dried (MgSO4). The mixture was filtered and the solids washed 1×50 mL ethyl acetate. The filtrate was concentrated to approximately 250 mL. 500 mL toluene were added, and the mixture concentrated to approximately 500 mL. 500 mL n-heptane were added, the slurry was stirred 1 h, filtered through a Buchner funnel, and dried. cis-(2-Ethyl-6-trifluoromethyl-1,2,3,4-tetrahydro-quinolin4-yl)-carbamic acid benzyl ester was isolated as a white powder (45.04 g, 76%): mp 155-157° C.; 1H NMR (DMSO-d6, 400 MHz) δ0.92 (t, 3H, J=7.5 Hz), 1.5 (m, 3H), 2.00 (m, 1H), 3.35 (m, 1H), 4.77 (m, 1H), 5.07 (d, 1H, J=12.5 Hz), 5.15 (d, 1H, J=12.5 Hz), 6.35 (s, 1H), 6.61 (d, 1H, J=8.5 Hz), 7.12 (s, 1H), 7.18 (dd, 1H, J=1.9, 8.5 Hz), 7.4 (m, 5H), 7.70 (d, 1H, J=9.1 Hz); 13C NMR (DMSO-d6, 100 MHz) δ157.03, 149.02, 137.79, 128.82, 128.23, 128.03, 125.9 (q, J=270 Hz), 125.06, 123.50, 121.73, 115.2 (q, J=31.7 Hz), 113.33, 65.85, 52.09, 47.83, 34.02, 28.68, 9.93; DEPT spectrum: quaternary carbons δ157.03, 149.02, 137.79, 125.9, 121.73, 115.2; CH carbons δ128.82, 128.23, 128.03, 125.06, 123.50, 113.33, 52.09, 47.83; CH2 carbons δ65.85, 34.02, 28.68; CH3 carbon δ9.93; IR (drifts) 3430 (m), 3303 (s), 2951 (m), 1686 (vs), 1542 (vs), 1088 (vs); MS (APCI+) m/z (rel. intensity) 379 (M+H+, 53), 228 (100); Anal. Calcd for C20H21N2O2F3: C, 63.48; H, 5.59; N, 7.40; Found: C, 63.69; H, 6.06, N, 7.36.
Reaction SMILES: [C:1]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[N:14](CC2C=CC(OC)=CC=2)[C:13]1=[O:38])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].O.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(C(C(C([O-])=O)O)O)([O-])=O.[K+].[Na+]>C(#N)C.C(OCC)(=O)C>[C:1]([NH:11][CH:12]1[N:18]=[C:17]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:16]2[CH:25]=[CH:26][CH:27]=[CH:28][C:15]=2[NH:14][C:13]1=[O:38])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: COc1ccc(CN2C(=O)C(NC(=O)OCc3ccccc3)N=C(c3ccccc3)c3ccccc32)cc1
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(NC1N=C(c2ccccc2)c2ccccc2NC1=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A suspension of (±) 3-[N-carbobenzyloxy]amino-2,3-dihydro-1-[4-methoxybenzyl]-2-oxo-5-phenyl-1H-1,4-benzodiazepine (0.58 g, 1.15 mmol, from step 5 of Example 1) in a mixture of acetonitrile (3.3 mL), water (1.2 mL) and ammonium cerium(IV) nitrate (3.1 g) was vortexed vigorously for 5 minutes. The resultant clear orange solution was stirred at room temperature for 20 minutes and add dropwisely into a mixture of saturated sodium potassium tartrate solution (40 mL), water (27 mL), and ethyl acetate (190 mL). The resultant mixture was stirred at room temperature for 1.5 hour, and the organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated under vacuo. The residue was subjected to column chromatography on silica gel eluting with 2% methanol in chloroform. Collection and concentration of appropriate fraction provided the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][NH:6][C:7]1[C:12]([NH:13][C:14](=O)[C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:11][CH:10]=[CH:9][N:8]=1)[CH3:2].[O-][Si]([O-])=O.[Mg+2]>C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][N:6]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:12]2[N:13]=[C:14]1[C:15]1[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=1)[CH3:2]
Reactant: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(Br)cc1
Agent: O=[Si]([O-])[O-]
Agent: [Mg+2]
Solvent: ClCCl
Product: CCOC(=O)Cn1c(-c2ccc(Br)cc2)nc2cccnc21

Procedure:
N-[3-[(4-bromobenzoyl)amino]-2-pyridinyl]glycine ethyl ester (4.6 g, 0.012 mole) was heated in glass in a 190° C. oil bath for 1/2 hour. The melt was cooled and methylene chloride (150 ml) added. The solution was twice treated with 25 g of Florisil® and filtered. The filtrate was concentrated in vacuo and the residue recrystallized from isopropyl ether-ethanol to give 2.1 g (49%) of a white flocculent solid, mp 138°-139° C.