Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][O:35]CC1C=CC=CC=1)[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH:25]C(=O)C1C=CC=CC=1)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>ClCCl>[OH:8][C@H:9]1[C@H:13]2[O:14][CH2:15][C@:10]1([CH2:34][OH:35])[O:11][C@H:12]2[N:16]1[CH:24]=[N:23][C:22]2[C:17]1=[N:18][CH:19]=[N:20][C:21]=2[NH2:25]
Reactant: O=C(Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(COCc3ccccc3)CO[C@@H]1[C@@H]2OCc1ccccc1)c1ccccc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Solvent: CO
Product: Nc1ncnc2c1ncn2[C@@H]1O[C@@]2(CO)CO[C@@H]1[C@@H]2O
Temperature: -78 °C
Reaction time: 4 h

Procedure:
To a stirred solution of nucleoside 61 (0.80 g, 1.42 mmol) in anhydrous dichloromethane (30 cm3) at −78° C. was dropwise during 30 min added BCl3 (1 M solution in hexane: 11.36 cm3, 11.36 mmol). The mixture was stirred for 4 h at −78° C., additional BCl3 (1M solution in hexane, 16.0 cm3, 16.0 mmol) was added drop-wise, and the mixture was stirred at −78° C. for 3 h. Then the temperature of the reaction mixture was raised slowly to room temperature and stirring was continued for 30 min. Methanol (25.0 cm3) was added at −78° C., and the mixture was stirred at room temperature for 12 h. The mixture was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography using dichloromethane/methanol (92:8, v/v) as eluent to give nucleoside 61A as a white solid material (0.332 g, 84%). δH ((CD3)2SO) 8.22 (1H, s, 8-H), 8.15 (1H, s, 2-H), 7.33 (2H, s, NH2), 5.89 (1H, s, 1′-H), 5.83 (1H, d, J 4.2, 3′-OH), 5.14 (1H, t, J 5.9, 5′-OH), 4.14 (1H, s, 2′-H), 4.25 (1H, d, J 4.2, 3′-H), 3.92 (1H, d, J 7.8, 1″-Ha), 3.81-3.41 (3H, m, 5′-Ha, 5′-Hb, 1″-Hb). δC ((CD3)2SO) 155.90 (C-6), 152.64 (C-2), 148.35 (C-4), 137.72 (C-8), 118.94 (C-5), 88.48, 85.17 (C-1′, C-4′), 79.09, 71.34, 69.83, 56.51 (C-2′, C-3′, C-1″, C-5′). FAB-MS m/z 280 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([OH:17])=O)[CH:11]=2)[C:6]1=[O:18].[N:23]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:22]=[CH:21][CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:13](=[O:14])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:15]([NH:30][CH2:29][CH2:28][NH+:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:17])[CH:11]=2)[C:6]1=[O:18]
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Reactant: NCCN1CCCC1
Product: O=C(NCC[NH+]1CCCC1)c1ccc2c(c1)C(=O)N(Cc1ccccc1Cl)C2=O
Product: [Cl-]

Procedure:
2-(2-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-pyrrolidin-1-yl-ethylamine (100 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 121 mg (85%) was obtained by following the procedure described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C@@H:5]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[NH2:6].C(N(C(C)C)CC)(C)C.[Br:30][C@H:31]([CH3:35])[C:32](Cl)=[O:33]>ClCCl>[Br:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][C@H:5]([NH:6][C:32](=[O:33])[C@H:31]([Br:30])[CH3:35])[C:7]([O:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)=[O:8]
Reactant: C[C@@H](Br)C(=O)Cl
Reactant: N[C@@H](Cc1ccccc1Br)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](Br)C(=O)N[C@@H](Cc1ccccc1Br)C(=O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Introduce 25.7 g of benzyl (S)-2-bromophenylalaninate and 150 ml of dichloromethane into a reactor, then bring the temperature of the reaction mixture to 0° C. and add 20 ml of diisopropylethylamine followed by 13.2 g of (2R)-2-bromopropionyl chloride. Subsequently, bring the mixture to ambient temperature. After stirring for 1 hour at that temperature, wash the mixture with water and then with dilute acetic acid solution, and evaporate off the solvents to yield the title compound.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)(OC(C)(C)C)=O.[ClH:21].Cl.N1C=CC=CC=1OC1CCNCC1.C(O)C>C(OCC)C>[ClH:21].[ClH:21].[N:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccncc2)CC1
Agent: Cl
Agent: c1ccc(OC2CCNCC2)nc1
Solvent: CCO
Solvent: CCOCC
Product: c1cc(OC2CCNCC2)ccn1

Procedure:
Prepared from 1-Boc-4-(pyridin-4-yloxy)piperidine using methods substantially equivalent to those described for the synthesis of 4-(pyridin-2-yloxy)piperidine dihydrochloride, using ethanol in place of ethyl acetate. The product was isolated by trituration with diethyl ether.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1.[CH:39](=O)[CH:40]([CH3:42])[CH3:41].[BH4-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:39]([N:1]([CH2:3][CH:4]([CH3:13])[CH3:5])[CH2:2][CH2:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]([NH:14][C:15](=[O:38])[CH2:16][CH:17]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[NH:18][S:19]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:29])[F:30])[CH:23]=3)(=[O:21])=[O:20])[CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1)[CH:40]([CH3:42])[CH3:41]
Reactant: CC(C)C=O
Reactant: NCCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)CN(CCc1ccc2c(c1)OCCC2NC(=O)CC(NS(=O)(=O)c1cccc(C(F)(F)F)c1)c1ccccc1)CC(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of N-[7-(2-aminoethyl)-chroman-4-yl]-3-phenyl-3-(3-trifluoromethylbenzenesulfonylamino)-propionamide (Example 208, 50 mg, 0.09 mmol) in dry CH2Cl2 (8 mL) was added isobutyraldehyde (83 L, 0.9 mmol) and HOAc (1 drop). The resulting mixture was stirred at RT under N2 After 3 h, MS showed the formation of imine; NaBH4 (17 mg, 0.45 mmol) was then added. The resulting mixture was stirred for 18 h. Quenched with minimum amount of sat. NaHCO3. The organic layer was isolated, dried over MgSO4 and evaporated in vacuo. The crude product was purified by chromatography on silica gel. Elution with CH2Cl2:MeOH mixture (97:3) gave final compound. MS m/z: 660.31 (M+H). Calc'd. for Calc'd. for C35H44F3N3O4S-659.82.
Reaction SMILES: C[N:2](C)[CH:3]=[C:4]([C:13]1[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=1)[C:5]([C:7]1[S:8][C:9]([Cl:12])=[CH:10][CH:11]=1)=O.O.NN.C([N:27](CC)CC)C>C(O)C.O>[Cl:12][C:9]1[S:8][C:7]([C:5]2[C:4]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([S:19][CH3:20])[N:14]=3)=[CH:3][NH:2][N:27]=2)=[CH:11][CH:10]=1
Reactant: CCN(CC)CC
Reactant: CSc1nccc(C(=CN(C)C)C(=O)c2ccc(Cl)s2)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: CSc1nccc(-c2c[nH]nc2-c2ccc(Cl)s2)n1
Yield: 81 %

Procedure:
To a mixture of 3-(dimethylamino)-1-(5-chloro-2-thienyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]prop-2-en-1-one (1 eq, 96 mmol) in 300 mL ethanol was added dropwise hydrazine hydrate (1.5 eq, 144 mmol) and then triethylamine (1.5 eq, 144 mmol). The mixture was heated under reflux for 2 h and then overnight at room temperature. The solvent was then slowly poured in 1 L of water. The resulting precipitate was filtered and dried to afford 24 g of 4-[3-(5-chloro-2-thienyl)-1H-pyrazol-4-yl]-2-(methylsulfanyl)pyrimidine (80% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](O)=O)=[C:4]([C:12](=[O:22])[C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[CH:3]=1.O.NN.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:8][CH2:9][O:22][CH:12]2[C:13]2[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=2)=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1C(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: O=[N+]([O-])c1ccc(C2OCCc3ccc(Cl)cc32)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
17.6 g (55 mM) of 4-chloro-2-(4-nitrobenzoyl)-phenylacetic acid and 8 ml of 85% hydrazine hydrate were refluxed in 340 ml of ethanol for 4 hours. The reaction mixture was cooled, acidified with 115 ml of 1 M hydrochloric acid and evaporated. The residue was mixed with 50 ml of water, the crystals were filtered and dried. The resulting hydrazone derivative was dissolved in 300 ml of anhydrous dichloromethane and treated with a solution of 13.4 g (65 mM) of dicyclohexylcarbodiimide in 210 ml of anhydrous dichloromethane. The reaction mixture was stirred at room temperature overnight, then the precipitated crystals were filtered and washed with dichloromethane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]3[CH2:10][CH2:11][CH:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:13][C:7]=3[C:6]=2[CH:19]=1.[O:20]1[CH:24]=[CH:23][C:22]([C:25]([Cl:27])=[O:26])=[CH:21]1>>[ClH:27].[CH2:15]([N:14]([CH2:17][CH3:18])[CH:12]1[CH2:11][CH2:10][C:8]2[O:9][C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:25]([C:22]4[CH:23]=[CH:24][O:20][CH:21]=4)=[O:26])=[CH:19][C:6]=3[C:7]=2[CH2:13]1)[CH3:16]
Reactant: CCN(CC)C1CCc2oc3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccoc1
Product: CCN(CC)C1CCc2oc3ccc(NC(=O)c4ccoc4)cc3c2C1
Product: Cl
Yield: 69.4 %

Procedure:
Beginning with 0.100 gm (0.30 mMol) 8-amino-1,2,3,4-tetrahydro-2-diethylaminodibenzofuran and 0.052 gm (0.40 mMol) furan-3-carbonyl chloride, 0.081 gm (69%) of the title compound were recovered as an off-white solid by the procedure described in Example 17.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[CH:4][C:3]=1[F:12].ClC1C=CC=C(C(OO)=[O:21])C=1>ClCCl>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N+:8]([O-:21])=[CH:9]2)=[CH:4][C:3]=1[F:12]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Fc1cc2ccncc2cc1Cl
Solvent: ClCCl
Product: [O-][n+]1ccc2cc(F)c(Cl)cc2c1
Temperature: 25 °C
Yield: 67.6 %

Procedure:
25 g (137.7 mmol) of 7-chloro-6-fluoro-isoquinoline (4) were dissolved in 500 ml of dichloromethane. At room temperature, 50.9 g (206.5 mmol) of m-chloro perbenzoic acid (70%) were added and the mixture was stirred at room temperature until complete conversion is achieved. For workup, the precipitate was filtered off and washed with dichloromethane. The filtrate was washed twice with sodium bicarbonate solution. The layers were separated and the aqueous phase was extracted twice with dichloromethane. The organic phases were dried with magnesium sulfate and evaporated. The so obtained solid material (18.4 g) was used without further purification. Rt=0.87 min (Method C). Detected mass: 198.1/200.1 (M+H+).
Reaction SMILES: [ClH:1].[CH:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[CH2:12][CH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26]Br)=[CH:22][CH:21]=1.C([O-])([O-])=O.[K+].[K+]>>[ClH:1].[F:19][C:20]1[CH:29]=[CH:28][C:23]([O:24][CH2:25][CH2:26][N:16]2[CH2:17][CH2:18][CH:13]([CH2:12][C:3]3[CH:4]=[CH:5][C:6]4[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=4[CH:2]=3)[CH2:14][CH2:15]2)=[CH:22][CH:21]=1
Reactant: c1cc2c(cc1CC1CCNCC1)CCCC2
Reactant: Fc1ccc(OCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Fc1ccc(OCCN2CCC(Cc3ccc4c(c3)CCCC4)CC2)cc1

Procedure:
The title compound was prepared from 4-((5,6,7,8-tetrahydro-2-naphthyl)methyl)piperidine hydrochloride (250 mg, 940 μmol), 2-(4-fluorophenoxy)ethyl bromide (216 mg, 987 μmol) and K2CO3 (266 mg, 1.93 mmol) as a colorless solid (220 mg): mp 181-183° C.; 1H NMR (CDCl3) 1.60-2.12 (m, 9H), 2.54 (d, J=7.2 Hz, 2H), 2.65-2.81 (m, 6H), 3.20-3.55 (m, 2H), 3.59-3.71 (m, 2H), 4.52 (t, J=4.2 Hz, 2H), 6.77-7.01 (m, 7H), 12.55 (bs, 1H); Anal. Calcd for C24H31ClFNO: C, 71.36; H, 7.74; N, 3.47. Found: C, 71.30; H, 7.78; N, 3.39.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16](Br)[CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[CH3:22][C:23]1([CH3:32])[CH2:28][CH2:27][C:26](B(O)O)=[CH:25][CH2:24]1.[C:33]([O-:36])([O-])=[O:34].[Na+].[Na+]>C1(C)C=CC=CC=1.CCO.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:11]([O:36][C:33]([C:11]1([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([C:26]3[CH2:27][CH2:28][C:23]([CH3:32])([CH3:22])[CH2:24][CH:25]=3)[CH:15]=2)[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:34])([CH3:14])([CH3:12])[CH3:10]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(N)c(Br)c2)CC1
Reactant: CC1(C)CC=C(B(O)O)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)CC=C(c2cc(C3(C(=O)OC(C)(C)C)CCNCC3)ccc2N)CC1
Temperature: 85 °C
Reaction time: 36 h
Yield: 65.7 %

Procedure:
A solution of 250 mg (0.704 mmol) 4-(4-amino-3-bromo-phenyl)-piperidine-1-carboxylic acid tert-butyl ester (as prepared in Example 61, step (c)) in 6 mL toluene and 3 mL EtOH was treated with 119 mg (0.774 mmol) 4,4-dimethyl-cyclohex-1-enylboronic acid and 2.81 mL (5.63 mmol) 2.0 M Na2CO3. The mixture was degassed via sonication, placed under Ar, treated with 56.9 mg (0.0493 mmol) Pd(PPh3)4, and heated to 85° C. for 27 h and allowed to stand at RT for 36 h. The mixture was diluted with EtOAc (15 mL) and washed with water (1×15 mL). The combined aqueous layers were extracted with EtOAc (15 mL), and the combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a Varian MegaBond Elut 50-gm column with 10-15% EtOAc-hexane afforded 89.0 mg (33%) of the title compound as a tan solid: Mass spectrum (ESI, m/z): Calcd. for C20H29N2O2, 329.2 (M—C4H9+2H), found 329.2.
Reaction SMILES: OC[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:5][CH:4]=1.[OH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46]C1C=CC(B(O)O)=CC=1>>[OH:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([S:15]([C:18]3[CH:19]=[C:20]4[C:25](=[C:26]([CH3:28])[CH:27]=3)[N:24]=[CH:23][C:22]([C:29]([NH2:31])=[O:30])=[C:21]4[NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([O:39][CH3:40])[CH:34]=3)(=[O:17])=[O:16])[CH:10]=2)=[CH:7][CH:8]=1
Reactant: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CO)cc5)c4)cc23)c1
Reactant: OCCCCCc1ccc(B(O)O)cc1
Product: COc1cccc(Nc2c(C(N)=O)cnc3c(C)cc(S(=O)(=O)c4cccc(-c5ccc(CCCCCO)cc5)c4)cc23)c1

Procedure:
The title compound was synthesized in a manner analogous to that described for Intermediate 64, using 4-(5-hydroxypentyl)phenylboronic acid in place of 4-(hydroxymethyl)phenylboronic acid. ES/MS calcd. for C35H36N3O5S+ 610.2. Found m/z=610.3 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH2:12][P:13]([O:17]Cl)([O:15]Cl)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4].[CH3:21][OH:22].C(N(CC)CC)C.[Cl:30][C:31]1[CH:32]=[C:33]([OH:37])[CH:34]=[CH:35][CH:36]=1>CCOCC>[F:1][C:2]([F:20])([F:19])[C:3]([N:5]([CH:12]([O:22][CH3:21])[P:13]([OH:17])([O:15][O:37][C:33]1[CH:34]=[CH:35][CH:36]=[C:31]([Cl:30])[CH:32]=1)=[O:14])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:4]
Reactant: CO
Reactant: CCOC(=O)CN(CP(=O)(OCl)OCl)C(=O)C(F)(F)F
Reactant: Oc1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CCOC(=O)CN(C(=O)C(F)(F)F)C(OC)P(=O)(O)OOc1cccc(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 67.2 %

Procedure:
A solution of ethyl N-trifluoroacetyl-N-(dichlorophosphonomethyl)glycinate (8.25 g, 0.025 mole) in 100 ml. of ether was cooled to 0° C. and treated with a solution of methanol (1.01 ml, 0.025 mole) and triethylamine (3.49 ml, 0.025 mole) in 100 ml. of ether. After two hours, the mixture was filtered and the filtrate was cooled to 0° C. and treated with a solution of m-chlorophenol (3.21 g, 0.025 mole) and triethylamine (3.49 ml, 0.025 mole) in 100 ml. of ether. The resulting solution was stirred overnight at 25° C., filtered and the filtrate concentrated in vacuo. The residue was extracted into petroleum ether and the resulting solution was concentrated in vacuo to yield ethyl N-trifluoroacetyl-N-(methoxy(m-chlorophenoxy)phosphonomethyl)glycinate as a yellow oil (7.55 g), ND =1.4803.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=[O:6].[Br:12]C(Cl)(Cl)C(Cl)(Cl)Br.O>O1CCCC1>[Br:12][C:3]1[C:2]([Cl:1])=[C:10]([F:11])[CH:9]=[CH:8][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: ClC(Cl)(Br)C(Cl)(Cl)Br
Reactant: O=C(O)c1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(F)c(Cl)c1Br
Temperature: -75 °C
Reaction time: 8 h
Yield: 93.5 %

Procedure:
n-Butyl lithium (2.5M solution, 76 ml) was added to a stirred solution of diisopropylamine (2.8 ml) in dry tetrahydrofuran (THF) at -75° C., and maintained at -30° C. for a further 1 hour, to produce lithium diisopropylamide (LDA). After re-cooling to -75° C., a solution of 3-chloro-4-fluorobenzoic acid (14.4 g) in dry THF was added over 1 hour, and stirring was continued overnight at -75° C. A solution of 1,2-dibromotetrachloroethane (42.77 g) in dry THF was then added over 20 minutes, stirring was continued for 2 hours at -70° C. then at room temperature for 4 hours. Water was added, the organic and aqueous phases were separated and the aqueous phase was washed with ether, then acidified with hydrochloric acid solution and extracted with dichloromethane. The dichloromethane extract was dried (arthydrous magnesium sulphate) and the solvent evaporated to give 2-bromo-3-chloro4-fluorobenzoic acid (19.54 g) as a beige solid, NMR (DMSO-D6) 7.55(t,1H), 7.75(dd,1H), 13.8(brs,1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].CN(C)C1C=CC=CC=1.[Br:29][CH2:30][C:31](Br)=[O:32]>ClCCl>[Br:29][CH2:30][C:31]([NH:1][C:2]1[C:3]([O:15][CH2:16][CH2:17][O:18][CH3:19])=[N:4][C:5]([CH3:14])=[CH:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13])=[O:32]
Reactant: O=C(Br)CBr
Reactant: COCCOc1nc(C)cc(OCC(F)(F)F)c1N
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COCCOc1nc(C)cc(OCC(F)(F)F)c1NC(=O)CBr

Procedure:
3-Amino-2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridine (1.39 g, 4.96 mmol) was dissolved in dichloromethane (15 mL). N,N-dimethylaniline (0.76 g, 6.27 mmol) was added to the solution. Under stirring on an ice bath, bromoacetyl bromide (1.16 g, 5.75 mmol) in dichloromethane (5 mL) was added dropwise to the mixture, followed by stirring at the same temperature for 30 minutes. The reacion mixture was directly subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate=5/1→n-hexane/acetone=1/1) for purification, to thereby yield 2-bromo-N-[2-[(2-methoxyethyl)oxy]-6-methyl-4-[(2,2,2-trifluoroethyl)oxy]pyridin-3-yl]acetamide as a colorless solid (1.98 g, 99%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:21]([N:22]=1)=[CH:20][C:7]1[CH2:8][CH2:9][N:10](C(OC(C)(C)C)=O)[CH2:11][CH2:12][C:6]=1[CH:5]=2.FC(F)(F)C(O)=O>C(Cl)Cl>[CH3:1][C:2]1[O:3][C:4]2[C:21]([N:22]=1)=[CH:20][C:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12][C:6]=1[CH:5]=2
Reactant: Cc1nc2cc3c(cc2o1)CCN(C(=O)OC(C)(C)C)CC3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1nc2cc3c(cc2o1)CCNCC3
Yield: 114.2 %

Procedure:
1,1-Dimethylethyl 2-methyl-5,6,8,9-tetrahydro-7H-[1,3]oxazolo[4,5-h][3]benzazepine-7-carboxylate (1.1 g) was exposed to trifluoroacetic acid (5 ml) in DCM (5 ml) for 90 min at 25° C. After elimination of volatiles under reduced pressure the residue was partitioned between aqueous Na2CO3 (2M) and DCM. The organic layer was collected and the aqueous phase extracted twice with DCM. The combined DCM layers were concentrated to give the title compound (0.84 g) as an off-white solid.
Reaction SMILES: Cl.[C:2]([S:21][CH2:22][CH2:23][NH2:24])([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:25][C:26]1[C:34]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:33]2[C:29]([CH:30]=[C:31]([C:44](O)=[O:45])[NH:32]2)=[CH:28][CH:27]=1.N1(O)C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C.CN(C)C=O.C(N(CC)CC)C>[CH3:25][C:26]1[C:34]([NH:35][S:36]([C:39]2[S:40][CH:41]=[CH:42][CH:43]=2)(=[O:38])=[O:37])=[C:33]2[C:29]([CH:30]=[C:31]([C:44]([NH:24][CH2:23][CH2:22][S:21][C:2]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)=[O:45])[NH:32]2)=[CH:28][CH:27]=1
Reactant: Cc1ccc2cc(C(=O)O)[nH]c2c1NS(=O)(=O)c1cccs1
Reactant: NCCSC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc2cc(C(=O)NCCSC(c3ccccc3)(c3ccccc3)c3ccccc3)[nH]c2c1NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 48 h
Yield: 90.7 %

Procedure:
To a mixture of 2-(tritylthio)ethylamine hydrochloride (0.44 g), triethylamine (0.17 mL) and N,N-dimethylformamide (15 mL) were added 6-methyl-7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (0.34 g), 1H-1,2,3-benzotriazol-1-ol (0.21 g) and N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (0.26 g) under ice-cooling, and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained oil was crystallized from ethyl acetate-hexane to give the title compound (585 mg, yield 91%) as colorless prism crystals. melting point 245-246° C.