Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[O:7]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Br[C:24]1[C:29]2=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]2[CH:27]=[CH:26][CH:25]=1>CN(C=O)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>[O:7]([C:14]1[CH:19]=[CH:18][C:17]([C:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH:27]=[CH:26][CH:25]=2)=[CH:16][CH:15]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: OB(O)c1ccc(Oc2ccccc2)cc1
Reactant: O=S1(=O)CCN2C=CC=C(Br)C2=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=S1(=O)CCN2C=CC=C(c3ccc(Oc4ccccc4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 8 h
Yield: 86.6 %

Procedure:
A mixture of sodium carbonate (121 mg), tetrakis(triphenylphosphine)palladium(0) (13.18 mg), (4-phenoxyphenyl)boronic acid (98 mg) and 9-bromo-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg) in DMF (dry) (10 mL) and water (2 mL) was stirred at 80° C. under N2 overnight. NH silica gel was added and the mixture was concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give 9-(4-phenoxyphenyl)-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (116 mg) as a white solid. The solid was crystallized from DMSO (1.5 mL)-EtOH (3 mL) to give the title compound (90.7 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][CH2:22][C:23]1([OH:30])[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][CH2:22][C:23]2([OH:30])[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: CN1CCC(O)(CN)CC1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: CN1CCC(O)(CNC(=O)c2cc([N+](=O)[O-])c(Sc3c(Cl)cncc3Cl)s2)CC1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and 4-(aminomethyl)-1-methylpiperidin-4-ol (14.4 mg, 0.1 mmol). The title compound was obtained as a solid (15.2 mg, 32% yield). MS m/z: 476.87, 478.86 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:21][CH2:20]3)[CH2:16]2)SC)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:32]([NH2:34])[CH3:33]>CO>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]=[C:12]([N:15]2[N:19]=[CH:18][C:17]3([CH2:20][CH2:21][N:22]([CH2:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH2:23][CH2:24]3)[CH2:16]2)[NH:34][CH2:32][CH3:33])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CSC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCN(Cc1ccccc1)CC2
Reactant: CCN
Solvent: CO
Product: CCNC(=NS(=O)(=O)c1ccc(N)cc1)N1CC2(C=N1)CCN(Cc1ccccc1)CC2
Temperature: 25 °C
Yield: 87 %

Procedure:
To a solution of 1.35 g 4-amino-N-[(8-benzyl-2,3,8-triaza-spiro[4.5]dec-3-en-2-yl)-methylsulfanyl-methylene]-benzenesulfonamide in 30 mL MeOH was added 2.26 mL (10 equiv.) of a 70% aqueous solution of ethylamine. The mixture was stirred for a weekend at room temperature and concentrated on silica. Purification with flash column chromatography (DCM→DCM/MeOH 99:1→DCM/MeOH 95:5) yielded 1.16 g (87%) of a pale yellow glass. 1H NMR (400 MHz, CDCl3) δ 1.14 (t, J=7 Hz, 3H), 1.50-1.60 (m, 2H), 1.73-1.84 (m, 2H), 2.11-2.26 (m, 2H), 2.63-2.76 (m, 2H), 3.41-3.53 (m, 2H), 3.79 (s, 2H), 3.98 (s, 2H), 6.62-6.70 (m, 2H), 6.76 (s, 1H), 6.97 (br s, 1H), 7.22-7.36 (m, 5H), 7.67-7.75 (m, 2H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[F:32][C:33]1[CH:34]=[C:35]([CH:37]=[CH:38][C:39]=1[N:40]1[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)[NH2:36]>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:36][C:35]3[CH:37]=[CH:38][C:39]([N:40]4[CH2:41][CH2:42][O:43][CH2:44][CH2:45]4)=[C:33]([F:32])[CH:34]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(N2CCOCC2)c(F)c1
Agent: COC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(N3CCOCC3)c(F)c2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 3-fluoro-4-morpholin-4-yl aniline (Bionet, 132 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]2[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]2)(=[O:21])=[O:20])[C:13]=1[OH:35])=[O:10].[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39]>>[F:36][C:37]([F:42])([F:41])[C:38]([OH:40])=[O:39].[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([S:19]([N:22]2[CH2:23][CH2:24][NH:25][CH2:26][CH2:27]2)(=[O:21])=[O:20])[C:13]=1[OH:35])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2c(Cl)ccc(NC(=O)Nc3ccccc3Br)c2O)CC1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1ccccc1Br)Nc1ccc(Cl)c(S(=O)(=O)N2CCNCC2)c1O
Yield: 49 %

Procedure:
Following the general procedure for Boc deprotection outlined in example 36, N-(2-bromophenyl)-N′-[3-[[4-(tert-butoxycarbonyl)piperazin-1-yl]sulfonyl]4-chloro-2-hydroxyphenyl] urea (10 mg, 0.019 mmol) was stirred in trifluoroacetic acid to form the desired product (5 mg, 49%). 1H NMR (MeOD-d4): δ 8.28 (d, 1H), 7.91 (d, 1H), 7.60 (d, 1H), 7.33 (t, 1H), 7.14 (d, 1H), 7.02 (d, 1H) 3.64 (t, 4H) 3.33 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:19]C.Cl.N1C=CC=CC=1>>[Cl:1][C:2]1[C:10]2[O:9][N:8]=[C:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=3[F:18])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:19]
Reactant: COc1ccc2c(-c3ccc(F)cc3F)noc2c1Cl
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(-c3ccc(F)cc3F)noc2c1Cl
Temperature: 200 °C

Procedure:
A solid mixture of 7.1 g of 7-chloro-3-(2,4-difluorophenyl)-6-methoxy-1,2-benzisoxazole and 27.8 g of pyridine HCl is heated at 200° C. for one hour and the mixture poured into vigorously stirred ice water to precipitate a product. The product is filtered and dried giving 7-chloro-3-(2,4-difluorophenyl)-6-hydroxy-1,2-benzisoxazole which is recrystallized from toluene, mp 186°-190° C.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19]C)=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[Li].O>C1COCC1.O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([OH:19])=[O:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc2c(c1)CCN2Cc1ccccc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)CCN2Cc1ccccc1
Yield: 79 %

Procedure:
A solution of compound 55e (80.2 mg, 0.3 mmol), and LiOH.H2O (50.4 mg, 1.2 mmol) in THF/H2O (1.2/1.2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated and diluted with water. The water layer was acidified with 1N aqueous HCl to pH˜4 and extracted with CH2Cl2. The organic solution was dried over Na2SO4 and concentrated to give 55f (60 mg), which was used in the next reaction without further purification. MS m/z (M+H+) 254.1.
Reaction SMILES: C[C@@H](PC)[C]1[C](P(C2C3C(=CC=CC=3)C=CC=2)C2C3C(=CC=CC=3)C=CC=2)[CH][CH][CH]1.[CH2:31]([C:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C:39]=1[NH:50][C:51](=[O:54])[CH2:52][CH3:53])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.[H][H]>[Rh+].ClC1CCCCC=CC=1.CO>[CH2:31]([C@@H:38]1[C:47]2[C:42](=[CH:43][CH:44]=[C:45]([O:48][CH3:49])[CH:46]=2)[CH2:41][CH2:40][C@@H:39]1[NH:50][C:51](=[O:54])[CH2:52][CH3:53])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: [H][H]
Reactant: CCC(=O)NC1=C(Cc2ccccc2)c2cc(OC)ccc2CC1
Agent: [Rh+]
Agent: CP[C@H](C)[C]1[CH][CH][CH][C]1P(c1cccc2ccccc12)c1cccc2ccccc12
Agent: ClC1=CC=CCCCC1
Solvent: CO
Product: CCC(=O)N[C@H]1CCc2ccc(OC)cc2[C@H]1Cc1ccccc1
Temperature: 50 °C
Reaction time: 0.33 h
Yield: 96.6 %

Procedure:
Chlorocyclooctadiene rhodium(I) dimer (0.802 g, 1.63 mmol, 3.25 mmol of Rh), Josiphos SL-J216-2 (2.199 g, 3.42 mmol), and N-(1-benzyl-7-methoxy-3,4-dihydronaphthalen-2-yl)propionamide (440 g, 1.37 mol) were combined in a metal reactor, and the vessel was inerted with argon. Degassed methanol (4.40 I) was added, then the mixture was stirred under argon at 50° C. for 20 min. The vessel was pressurized with 60 psig of hydrogen and stirred at 55° C. for 40 hrs. HPLC analysis indicated complete conversion and 95.9% ee. The methanol solution of crude reduction product was concentrated and triturated with heptane to yield 428.2 g (yield: 91%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19][CH3:20])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1.ClCCl.ClC1C=CC=C(C(OO)=[O:39])C=1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:9]2[C:17]3[C:12](=[C:13]([CH2:18][S:19]([CH3:20])=[O:39])[CH:14]=[CH:15][CH:16]=3)[NH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Solvent: ClCCl
Solvent: CO
Product: CS(=O)Cc1cccc2c(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
200 mg (0.49 mmol) of the compound from Example 279 were introduced into 20 ml of dichloromethane at 0° C., 120 mg (0.49 mmol) of 70% pure meta-chloroperbenzoic acid were added, and the mixture was stirred at RT for 2 h. 2 ml of methanol were added, and the solution was concentrated. The crude product was purified by preparative HPLC (mobile phase: acetonitrile/water gradient) to result in 134 mg (65% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[O:7][C@@H:8]1[CH2:12][O:11][C@@H:10]2[C@@H:13](OS(C(F)(F)F)(=O)=O)[CH2:14][O:15][C@H:9]12.C(#N)C>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N+:25]([O-:27])=[O:26])=[C:6]([CH:24]=1)[O:7][C@H:8]1[C@H:9]2[O:15][CH2:14][CH2:13][C@H:10]2[O:11][CH2:12]1
Reactant: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@H]2[C@@H]1OC[C@@H]2OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1O[C@@H]1CO[C@@H]2CCO[C@@H]21
Temperature: 25 °C
Reaction time: 240 h

Procedure:
To 4.0 g (9.6 mmol) [(3R,3aR,6S,6aS)-3-(5-fluoro-2-nitro-phenoxy)-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl]trifluoromethanesulfonate (intermediate III.3) in acetonitrile 1.1 g (28.8 mmol) sodium borohydride are added. The reaction mixture is stirred at RT for 10 days. The reaction mixture is evaporated, taken up in ice water, carefully acidified with aqueous 4 mol/l HCl and extracted with EtOAc. The organic phases are pooled, washed with water, dried and evaporated. The residue is purified by FC.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][CH2:10][CH2:11][OH:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br.[OH-].[Na+]>O>[Br:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:12][CH2:11][CH2:10][CH2:9][S:8][C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1
Reactant: Cc1ccc(SCCCO)cc1
Reactant: BrCCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1ccc(SCCCOCCCCCCBr)cc1
Yield: 66 %

Procedure:
3-[(4-Methylphenyl)thio]-1-propanol (4.0 g), 1,6-dibromohexane (16.06 g), 40% sodium hydroxide solution (40 ml) and TAB (1 g) were stirred together at room temperature for 18 h. The mixture was diluted with water (150 ml), extracted with ethyl acetate (2×150 ml), which was dried and evaporated in vacuo to give a colourless oil. Purification by FCC eluting with System A (0:20→1:19) gave the title compound (5.0 g) as a colourless oil. T.l.c. (System A 1:9) Rf 0.53.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH:18]=[C:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1>[Pd]>[CH3:1][C@H:2]1[CH2:30][O:29][C@@:5]2([O:9][C@H:8]3[CH2:10][C@H:11]4[C@@H:16]5[CH2:17][CH2:18][C@H:19]6[CH2:24][C@@H:23]([OH:25])[CH2:22][CH2:21][C@:20]6([CH3:26])[C@H:15]5[CH2:14][CH2:13][C@:12]4([CH3:27])[C@H:7]3[C@@H:6]2[CH3:28])[CH2:4][CH2:3]1
Reactant: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC=C5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C
Agent: [Pd]
Product: C[C@@H]1CC[C@@]2(OC1)O[C@H]1C[C@H]3[C@@H]4CC[C@H]5C[C@@H](O)CC[C@]5(C)[C@H]4CC[C@]3(C)[C@H]1[C@@H]2C

Procedure:
This Δ4, 3-keto steroidal sapogenin, for example diosgenone, is itself preferably prepared by an oxidation of the corresponding Δ5, 3-hydroxy steroidal sapogenin, for example diosgenin, to afford the αβ-unsaturated ketone. It will be noted that the direct reduction of diosgenin using palladium on carbon as a catalyst gives predominantly the 5α-product, tigogenin.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C@H:11]([NH:15][C:16]([N:18]2[C:24](=[O:25])[C@@H:23]([CH2:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])[CH2:22][NH:21][C:20](=[N:36][O:37][CH2:38][CH3:39])[CH2:19]2)=[O:17])[CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(O)(=O)C.O.C(O)(=O)C.O>C(OCC)(=O)C>[C:4]([OH:6])(=[O:5])[CH3:3].[NH2:1][C:2]1[CH:10]=[C:9]([C@H:11]([NH:15][C:16]([N:18]2[C:24](=[O:25])[C@@H:23]([CH2:26][C:27]3[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=3[O:34][CH3:35])[CH2:22][NH:21]/[C:20](=[N:36]\[O:37][CH2:38][CH3:39])/[CH2:19]2)=[O:17])[CH2:12][CH2:13][CH3:14])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCC[C@@H](NC(=O)N1CC(=NOCC)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: CCC[C@@H](NC(=O)N1C/C(=N/OCC)NC[C@H](Cc2cc(Cl)ccc2OC)C1=O)c1ccc(C(=O)O)c(N)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 175.8 %

Procedure:
The reaction mixture was diluted with ethyl acetate (10 ml) and filtered by a glass filter spread with Celite®, and further the residue was washed with ethyl acetate (20 ml). The filtrate and the washings were combined, then successively washed with saturated aqueous ammonium chloride solution and brine, dried over sodium sulfate, then concentrated. The concentrated residue was purified by flash column chromatography to obtain 2-amino-4-[(1R)-1-({[(6S)-6-(5-chloro-2-methoxybenzyl)-3-(ethoxyimino)-7-oxo-1,4-diazepan-1-yl]carbonyl}amino)butyl]benzoic acid (compound 12) (698 mg). To the compound 12 (558 mg) thus obtained, acetic acid (1.1 ml) was added and the mixture was stirred at room temperature for 30 minutes. Then water (2.75 ml) was added, and the mixture was stirred for 10 minutes. Further, acetic acid/water (2/5, 2.5 ml) was added, and the mixture was stirred for 15 minutes, then the mixture was cooled to 0° C. and stirred for 30 minutes. The precipitated crystals were collected by filtration to obtain the title compound (543 mg) as a light yellow crystals.
Reaction SMILES: Cl[C:2]1[CH:10]=CC(C(O)=O)=C[C:3]=1O.[OH:12][C:13]1[CH:14]=[N:15][CH:16]=[C:17]([CH:21]=1)[C:18]([OH:20])=[O:19]>>[CH:2]([O:19][C:18](=[O:20])[C:17]1[CH:21]=[C:13]([OH:12])[CH:14]=[N:15][CH:16]=1)([CH3:10])[CH3:3]
Reactant: O=C(O)c1ccc(Cl)c(O)c1
Reactant: O=C(O)c1cncc(O)c1
Product: CC(C)OC(=O)c1cncc(O)c1

Procedure:
The title compound was synthesized by substituting 4-chloro-3-hydroxybenzoic acid in Example 116A with 5-hydroxy-nicotinic acid. MS (DCI) m/z 182(M+H)+.
Reaction SMILES: CO[C:3]([CH2:5][C:6]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[O:7])=[O:4].C([O-])(=O)C.[Na+].[F:18][C:19]([F:23])([F:22])[C:20]#[N:21].Cl>C(O)C>[OH:7][C:6]1[CH:5]=[C:3]([OH:4])[N:21]=[C:20]([C:19]([F:23])([F:22])[F:18])[C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: N#CC(F)(F)F
Reactant: COC(=O)CC(=O)CC(=O)OC
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: COC(=O)c1c(O)cc(O)nc1C(F)(F)F
Temperature: 0 °C
Yield: 25 %

Procedure:
To a well stirred mixture of 84.35 g (0.484 mol) of dimethyl acetonedicarboxylate, 200 ml of saturated sodium acetate, and 400 ml of ethanol at 70° C. was passed 49 g of trifluoroacetonitrile in 4 hours. The reaction mixture was cooled and poured into a mixture of 100 ml of concentrated HCl and 1000 g of ice. The insoluble material was collected to give 28.7 g (25%) of product: mp 235°-238.5° C. (dec).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[C:7]([CH2:10]O)[CH:8]=[CH:9][C:4]=2[CH2:3][CH2:2]1.O=S(Cl)[Cl:14]>C(Cl)(Cl)Cl>[Cl:14][CH2:10][C:7]1[CH:8]=[CH:9][C:4]2[CH2:3][CH2:2][O:1][C:5]=2[CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc2c(c1)OCC2
Solvent: ClC(Cl)Cl
Product: ClCc1ccc2c(c1)OCC2
Yield: 80 %

Procedure:
To a solution of (2,3-dihydrobenzofuran-6-yl)methanol (13.8 g, 92 mmol) in CHCl3 (200 mL) was slowly added SOCl2 at 0□. The reaction mixture was stirred at reflux for 4 h. After the solvent was removed, saturated NaHCO3 and ethyl acetate were added to the mixture. The organic layer was extracted with ethyl acetate. The combined organic layer was then washed with brine and dried over Na2SO4, filtered and concentrated to afford 6-(chloromethyl)-2,3-dihydrobenzofuran (12.3 g, 80.0% yield). 1H NMR (400 MHz, CDCl3) δ: 7.16 (d, J=7.5, 1H), 6.87 (d, J=7.5, 1H), 6.83 (s, 1H), 4.58 (t, J=8.7, 2H), 4.49 (s, 2H), 3.20 (t, J=8.7, 2H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH2:10])[N:7]([C:11]2[CH:21]=[CH:20][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:13][CH:12]=2)[N:6]=1)([CH3:4])([CH3:3])[CH3:2].N(C1C=CC(C(OCC)=O)=CC=1)N.C(CC#N)(=O)C(C)(C)C.[Cl:44][C:45]1[CH:50]=[CH:49][CH:48]=[C:47]([N:51]=[C:52]=[O:53])[C:46]=1[Cl:54]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:52]([NH:51][C:47]2[CH:48]=[CH:49][CH:50]=[C:45]([Cl:44])[C:46]=2[Cl:54])=[O:53])[N:7]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:20][CH:21]=2)[N:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2N)cc1
Reactant: O=C=Nc1cccc(Cl)c1Cl
Agent: CC(C)(C)C(=O)CC#N
Agent: CCOC(=O)c1ccc(NN)cc1
Product: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc(Cl)c2Cl)cc1
Yield: 48 %

Procedure:
Using General method A, ethyl 4-(3-t-butyl-5-amino-1H-pyrazol-1-yl)benzoate (1 g, 3.09 mmol, prepared from ethyl 4-hydrazinobenzoate and pivaloylacetonitrile by the procedure of Regan, et al., J. Med. Chem., 45, 2994 (2002)) and 1,2-dichloro-3-isocyanato-benzene (0.7 g, 3.71 mmol) were combined to afford ethyl 4-{3-t-butyl-5-[3-(2,3-dichlorophenyl)-ureido]-1H-pyrazol-1-yl}benzoate (0.7 g, 48% yield). 1H NMR (300 MHz, DMSO-d6): δ 9.20 (brs, 1H), 8.77 (brs, 1H), 8.04 (m, 1H), 7.44 (brs, 4H), 7.29-7.26 (m, 2H), 6.36 (s, 1H), 4.31 (q, J=7.2 Hz, 2H), 1.27 (s, 9H), 1.26 (t, J=7.2 Hz, 3H).
Reaction SMILES: C([O:5][C:6](=[O:46])[CH:7]([NH:12][C:13](=[O:45])[C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=1[S:21][S:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=1[C:30](=[O:44])[NH:31][CH:32]([C:37]([O:39]C(C)(C)C)=[O:38])[CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:8][CH:9]([CH3:11])[CH3:10])(C)(C)C.FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>ClCCl>[C:37]([CH:32]([NH:31][C:30]([C:24]1[CH:25]=[C:26]([F:29])[CH:27]=[CH:28][C:23]=1[S:22][S:21][C:15]1[CH:16]=[CH:17][C:18]([F:20])=[CH:19][C:14]=1[C:13]([NH:12][CH:7]([CH2:8][CH:9]([CH3:10])[CH3:11])[C:6]([OH:46])=[O:5])=[O:45])=[O:44])[CH2:33][CH:34]([CH3:36])[CH3:35])([OH:39])=[O:38]
Reactant: CC(C)CC(NC(=O)c1cc(F)ccc1SSc1ccc(F)cc1C(=O)NC(CC(C)C)C(=O)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CC(C)CC(NC(=O)c1cc(F)ccc1SSc1ccc(F)cc1C(=O)NC(CC(C)C)C(=O)O)C(=O)O
Yield: 17.6 %

Procedure:
This compound was prepared according to the procedure described in Example 50 using [S-(R R*)-2-[2-[2-(1-tert-butoxycarbonyl-3-methyl-butylcarbamoyl)-4-fluoro-phenyldisulfanyl]-5-fluorobenzoylamino]-4-methyl-pentanoic acid tert-butyl ester (2.1 g, 3.0 mmol) from Example 28, 25 mL dichloromethane, 25 mL trifluoroacetic acid, and 2.5 mL anisole. The crude product was recrystallized from methanol/water to afford 0.3 g of the title compound, mp 246°-247° C.
Reaction SMILES: N[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)[C:8]4[CH:9]=[C:10]([Cl:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.N([O-])=[O:28].[Na+].[OH-:31].[Na+]>S(=O)(=O)(O)O.O>[Cl:15][C:10]1[CH:11]=[C:12]2[C:7]3=[C:8]([C:16](=[O:31])[C:17]([CH2:19][C:20]4[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=4)=[CH:18][N:6]3[C:5]3[CH:4]=[CH:3][C:2]([OH:28])=[CH:14][C:13]2=3)[CH:9]=1
Reactant: Nc1ccc2c(c1)c1cc(Cl)cc3c(=O)c(Cc4cccnc4)cn2c31
Reactant: O=N[O-]
Reactant: [OH-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=c1c(Cc2cccnc2)cn2c3ccc(O)cc3c3cc(Cl)cc1c32
Reaction time: 0.08 h
Yield: 71 %

Procedure:
10-amino-2-chloro-5-(3-pyridylmethyl)-4H-pyrido[3,2,1-jk]carbazole-4-one (300 mg) obtained in Example 273 was dissolved in a mixed solvent of conc. sulfuric acid (14.6 ml) and water (20 ml) and sodium nitrite (63 mg) dissolved in water (1 ml) was added dropwise in an ice bath. A mixed solvent of conc. sulfuric acid (20 ml) and water (15 ml) was heated under reflux in an argon atmosphere. After adding dropwise thereto the solution previously prepared, the mixture was stirred for 5 minutes and allowed to cool. The mixture was adjusted to pH 9 with 1 N aqueous solution of sodium hydroxide, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous solution of sodium chloride, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was washed with methanol and ether in succession to obtain the title compound (213 mg, 71%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][C@H:5]([NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C:6](=[O:12])[CH2:7][CH2:8][CH:9]([CH3:11])[CH3:10])[CH3:3].[CH:24]([Mg]Br)=[CH2:25]>C1COCC1>[CH3:3][CH:2]([CH2:4][C@H:5]([NH:13][S:14]([C:17]1[C:18]([CH3:23])=[CH:19][CH:20]=[CH:21][CH:22]=1)(=[O:16])=[O:15])[C:6]([OH:12])([CH:24]=[CH2:25])[CH2:7][CH2:8][CH:9]([CH3:10])[CH3:11])[CH3:1]
Reactant: Cc1ccccc1S(=O)(=O)N[C@@H](CC(C)C)C(=O)CCC(C)C
Reactant: C=C[Mg]Br
Solvent: C1CCOC1
Product: C=CC(O)(CCC(C)C)[C@H](CC(C)C)NS(=O)(=O)c1ccccc1C
Temperature: 25 °C
Yield: 95 %

Procedure:
To a stirred 0° C. solution of the resultant compound of Example 7 (79 mg, 0.23 mmol) in dry THF (8 mL) was added vinyl magnesium bromide (1.5 mL of a 1.0 M solution in THF) dropwise. The mixture was warmed (room temperature, 10 hours), quenched (8 mL H2O+2 mL brine), acidified with 0.1M H3PO4 (pH=7), and extracted with ether (3×4 mL). The combined ether phase was washed (4 mL brine), dried (Na2SO4), filtered, and evaporated to give 81 mg (95%) of the desired product as a 4:1 mixture of diastereomers.