Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:32][CH3:33])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=3)[CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14][CH2:13]2)=[N:10][CH:11]=1)=[O:5])[CH3:2].C(=O)([O-])[O-].[K+].[K+].ClC(OC(Cl)C)=O>ClCCCl>[CH2:32]([N:3]([CH2:1][CH3:2])[C:4]([C:6]1[CH:7]=[N:8][C:9]([C:12]2([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([OH:31])[CH:26]=3)[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]2)=[N:10][CH:11]=1)=[O:5])[CH3:33]
Reactant: CCN(CC)C(=O)c1cnc(C2(c3cccc(O)c3)CCN(Cc3ccccc3)CC2)nc1
Agent: CC(Cl)OC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCCl
Product: CCN(CC)C(=O)c1cnc(C2(c3cccc(O)c3)CCNCC2)nc1
Temperature: 25 °C
Yield: 101.1 %

Procedure:
To a stirring solution of 2-[1-Benzyl-4-(3-hydroxy-phenyl)-piperidin-4-yl]-pyrimidine-5-carboxylic acid diethylamide (105 mg, 0.24 mmol) in 5 mL 1,2-dichloroethane at room temperature was added potassium carbonate (K2CO3) (331 mg, 2.4 mmol) and 1-chloroethyl chloroformate (0.16 mL, 1.44 mmol). The mixture was refluxed for 24 hours, cooled to room temperature, filtered and concentrated. The resulting residue was taken up in 15 mL MeOH and refluxed for 24 hours. The mixture was cooled to room temperature and concentrated under reduced pressure to yield 86 mg (91%) of the desired amine. 1HNMR (400 MHz, CD3OD) δ 8.78 (s, 2H), 7.04 (t, 1H), 6.82-4.79 (comp, 2H), 6.54 (d, 1H), 3.55-3.32 (comp, 2H), 3.33-3.29 (comp, 2H), 2.99-2.93 (comp, 4H), 2.68 (t, 2H), 2.21 (t, 2H), 1.24-1.15 (comp, 6H); MS (M+1) 355.3
Reaction SMILES: [N+:1]([C:4]1[CH:29]=[CH:28][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([O:24]CC)=[O:23])=[CH:6][CH:5]=1)([O-:3])=[O:2].O1CCCC1.O.[OH-].[Li+].Cl>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8](=[O:27])[CH2:9][NH:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:21])=[CH:17][C:18]=3[Cl:20])[NH:13][C:12]=2[C:22]([OH:24])=[O:23])=[CH:28][CH:29]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1[nH]c2cc(Cl)cc(Cl)c2c1NCC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(CNc1c(C(=O)O)[nH]c2cc(Cl)cc(Cl)c12)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Yield: 95.2 %

Procedure:
Mix 3-[(4-nitrophenacyl)amino]-2-carbethoxy-4,6-dichloroindole (161 mg, 0.381 mmol), tetrahydrofuran (20 ml) and water (20 mL). Add lithium hydroxide monohydrate (64 mg, 1.52 mmol) and stir overnight. Heat at reflux for 4 hours, cool to room temperature and pour onto 1N hydrochloricacid (100 mL). Collect the resulting solid by filtration and air dry to give the title compound (148 mg, 99%); mp 270°-72° C.
Reaction SMILES: [CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([NH:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[O:19])[CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C(C1C=CC(NC(=O)NCCC(OCC)=O)=CC=1)CCCCCCC>>[CH2:1]([C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([C:18]([NH:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:19])[CH2:13][CH2:12]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCc1ccc2c(c1)CCN2C(=O)NCCC(=O)OCC
Agent: CCCCCCCCc1ccc(NC(=O)NCCC(=O)OCC)cc1
Product: CCCCCCCCc1ccc2c(c1)CCN2C(=O)NCCC(=O)O
Yield: 84 %

Procedure:
When the product of Step D was substituted for ethyl 3-(3-(4-octylphenyl)ureido)propanoate in Example 11, Step B, the identical process afforded the title compound in 84% yield, as a colourless solid. 1H-NMR (CDCl3) 7.68 (d, 1H, J=8.7 Hz); 6.94 (m, 2H); 5.24 (t, 1H, J=5.9 Hz); 3.86 (t, 2H, J=8.7 Hz); 3.58 (q, 2H, J=5.9 Hz); 3.11 (t, 2H, J=8.5 Hz); 2.67 (t, 2H, J=5.8 Hz); 2.5 (t, 2H, J=8 Hz); 1.54 (m, 2H); 1.25 (m, 10H); 0.86 (t, 3H, J=6.8 Hz).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20]Br)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1.[N:22]1([C:28](=[O:30])[CH3:29])[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[CH:13]=[CH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][N:25]4[CH2:26][CH2:27][N:22]([C:28](=[O:30])[CH3:29])[CH2:23][CH2:24]4)=[CH:16][C:11]=3[S:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: BrCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Reactant: CC(=O)N1CCNCC1
Product: CC(=O)N1CCN(CCCOc2ccc3c(-c4ccc(Br)cc4)nsc3c2)CC1

Procedure:
In analogy to example 3.1, 3-(4-Bromo-phenyl)-6-(3-bromo-propoxy)-benzo[d]isothiazole and 1-Piperazin-1-yl-ethanone were converted to yield 1-(4-{3-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-propyl}-piperazin-1-yl)-ethanone as colorless oil, MS: 474 (MH+, 1Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.[OH:13]O.[OH-].[Na+]>CC(O)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-:13])=[CH:8][CH:7]=[CH:6]2
Reactant: OO
Reactant: COc1ccc2ncccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: COc1ccc2c(ccc[n+]2[O-])c1
Temperature: 70 °C
Yield: 54.4 %

Procedure:
To a solution of 6-methoxyquinoline (2.00 g, 12.6 mmol) in AcOH (10 mL) was added H2O2 (30% in water, 1.9 mL, 18.9 mmol), the mixture was heated to 70° C. for 21 hours. The mixture was basified with 2M NaOH to pH 8-9 and extracted with CH2Cl2 (200 mL), the combined organic layer was washed with brine (50 mL), dried over Na2SO4, filtered and concentrated to give the crude product, which was purified by silica gel column (EtOAc/MeOH=10/1) to give 6-methoxyquinoline 1-oxide (1.20 g, 55%) as a solid.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[C:8]([N+:9]([O-])=O)=[CH:7][CH:6]=[C:5]([Cl:12])[C:4]=1[CH:13]1[CH2:20][N:16]2[CH2:17][CH2:18][N:19]=[C:15]2[CH2:14]1.[H][H]>O.[Ni]>[BrH:1].[NH2:9][C:8]1[C:3]([Cl:2])=[C:4]([CH:13]2[CH2:20][N:16]3[CH2:17][CH2:18][N:19]=[C:15]3[CH2:14]2)[C:5]([Cl:12])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Cl)c(C2CC3=NCCN3C2)c1Cl
Reactant: [H][H]
Agent: [Ni]
Agent: Br
Solvent: O
Product: Nc1ccc(Cl)c(C2CC3=NCCN3C2)c1Cl

Procedure:
A solution of 6-(2,6-dichloro-3-nitrophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo[1,2-a]imidazole hydrobromide (2.3 g.) in water (70 ml.) is shaken with hydrogen in the presence of a Raney nickel catalyst (0.5 g.) at laboratory temperature and atmospheric pressure until uptake of hydrogen ceases. The mixture is filtered, the filtrate is evaporated to dryness and the residue is dissolved in hot ethanol (200 ml.). The solution is concentrated to 20 ml. by distillation and then cooled and filtered. There is thus obtained as solid residue 6-(3-amino-2,6-dichlorophenyl)-2,3,6,7-tetrahydro-5H-pyrrolo-[1,2-a]imidazole hydrobromide, m.p. 275°-277° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:18])[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:6][CH:5]=1.CS(C)=O.C(N(CC)CC)C.N1C=CC=CC=1.S(=O)(=O)=O>ClCCl.C(OCC)(=O)C.O>[C:12]1([CH2:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([C:3]([O:2][CH3:1])=[O:19])=[CH:9][CH:8]=2)=[O:18])[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(C(O)Cc2ccccc2)cc1
Agent: O=S(=O)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1ccc(C(=O)Cc2ccccc2)cc1
Temperature: 5 °C

Procedure:
33 g methyl-4-(1-hydroxy-2-phenylethyl)benzoate (prepared as described by Berk et al.; J. Org. Chem. 1988, 53, 5791) is dissolved in 200 mL of dichloromethane. The solution is cooled to 0-10° C. To this is added DMSO (10 eq) and triethylamine (1.5 eq) followed by addition of 1.5 eq of pyridine-sulphur trioxide-complex. The reaction is stirred overnight at RT 200 ml of water is added. Then ethyl acetate is added and the organic layer is separated, dried, and concentrated to obtain the crude compound. It is purified by column chromatography to obtain the desired compound.
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1>O1CCCC1>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:20][CH2:19][C:18]1[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1)=[O:4]
Reactant: COc1ccc(CN)cc1
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Solvent: C1CCOC1
Product: COc1ccc(CNC(=O)c2ccccc2N)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 100 %

Procedure:
Isatoic anhydride (10.0 g) was suspended in tetrahydrofuran (150 ml) and treated dropwise with 4-methoxybenzylamine (9.61 ml). The reaction mixture was stirred at room temperature for 20 hours and then the solvent was distilled off under reduced pressure to give a crude crystal (17.8 g, about 100%) of the title compound. Recrystallization from ethyl acetate-isopropyl ether yielded a colorless crystal, melting point 104 to 105° C.
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].CCN(C(C)C)C(C)C.[C:18](Cl)(=[O:36])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]>C1COCC1>[OH:1][N:2]1[C:6](=[O:7])[CH2:5][CH2:4][C:3]1=[O:8].[C:18]([OH:36])(=[O:1])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH3:35]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1.33 g. of N-hydroxy succinimide (11.56 mmole) and DIEA (1.5 ml, 8.62 mmole) were dissolved in 50 ml of anhydrous THF and gently stirred at 0° C. under nitrogen atmosphere. To this were added dropwise and during 1 h a solution of stearoyl chloride (2.35 g, 7.7 mmole) in 50 ml of anhydrous THF. After, the mixture was stirred at 0° C. for 2 h and overnight at room temperature. Solvent was removed under reduced pressure and the remaining white solid was redissolved in 200 ml of DCM. The organic phase were washed with DDW (2×100 ml), dried over anhydrous MgSO4, filtered and evaporated to dryness. The reaming solid was dissolved in 100 ml of ethyl acetate and 200 ml of hexane and kept at −20° C. overnight. The resulting white crystals were collected by filtration and dried in vacuum over NaOH-pellets. The crystallized product was free from unreacted acid chloride as determined by 1H-NMR. The remaining filtrate was also evaporated to yield the product contaminated with 10% of the starting acid as determined by 1H-NMR.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:12][CH2:13][N:14]1[CH2:18][CH2:17][CH2:16][C@H:15]1[CH3:19])[CH:6]=[CH:5]2.[C:20]([C:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1)#[N:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C(O)(C)C.C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:19][C@@H:15]1[CH2:16][CH2:17][CH2:18][N:14]1[CH2:13][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:25]3[CH:26]=[CH:27][C:22]([C:20]#[N:21])=[CH:23][CH:24]=3)[CH:3]=2)[N:8]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@@H]1CCCN1CCc1ccc2cc(Br)ccc2n1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: C[C@@H]1CCCN1CCc1ccc2cc(-c3ccc(C#N)cc3)ccc2n1
Temperature: 25 °C

Procedure:
The product from Example 42D (160 mg, 0.5 mmol), 4-cyanophenylboronic acid (0.75 mmol), and dichlorobis(triphenylphosphine)palladium (II) (35.1 mg, 0.05 mmol) were combined in isopropyl alcohol (5.0 mL) and 0.2 M K3PO4 aq. solution (5.0 mL, 1.0 mmol) and heated at 60° C. for 24 hours. The reaction mixture was allowed to cool to room temperature and diluted with ethyl acetate (20 mL). The organic phase was separated, washed with 5% NaHCO3 (25 mL×3), 25% brine (25 mL), dried over Na2SO4, filtered, and the filtrate concentrated to dryness. The residue was purified by column chromatography (heptane:acetone:CH2Cl2:TEA (60:40:5:1) to provide the title compound. The title compound was treated with one equivalent of L-tartaric acid in IPA:ethanol to give the tartrate salt. mp 164° C.; MS (ESI) 342 (M+H)+; 1H NMR (DMSO-d6) δ 8.40 (1H, d), 8.38 (1H, d), 8.12 (1H, d), 8.06 (1H, d), 8.04 (2H, d), 7.98 (2H, d), 7.58 (1H, d), 4.05 (2H, s), 3.63 (1H, m), 3.50 (1H, m), 3.33 (2H, t), 3.15 (2H, m), 2.88 (1H, m), 2.09 (1H, m), 1.86 (2H, m), 1.55 (1H, m), 1.29 (3H, d).
Reaction SMILES: Br[CH2:2][CH2:3][NH:4][C:5](=[O:16])[C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=1[N+:13]([O-:15])=[O:14].[Cl:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)[C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C>O>[Cl:17][C:18]1[CH:33]=[CH:32][C:21]2[N:22]([CH:26]3[CH2:27][CH2:28][N:29]([CH2:2][CH2:3][NH:4][C:5](=[O:16])[C:6]4[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:7]=4[N+:13]([O-:15])=[O:14])[CH2:30][CH2:31]3)[C:23](=[O:25])[NH:24][C:20]=2[CH:19]=1
Reactant: O=C(NCCBr)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=c1[nH]c2cc(Cl)ccc2n1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)CC(C)C
Product: O=C(NCCN1CCC(n2c(=O)[nH]c3cc(Cl)ccc32)CC1)c1ccc(F)cc1[N+](=O)[O-]

Procedure:
A mixture of 7.3 parts of N-(2-bromoethyl)-4-fluoro-2-nitrobenzamide, 6.2 parts of 5-chloro-1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one, 5.2 parts of sodium carbonate and 80 parts of 4-methyl-2-pentanone is stirred and refluxed overnight. The reaction mixture is cooled, water is added and the layers are separated. The aqueous phase is extracted with 4-methyl-2-pentanone. The combined organic phases are washed with water, dried, filtered and evaporated. The residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue is crystallized from 2-propanone. The product is filtered off and dried, yielding 1 part of N-{2-[4-(5-chloro-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)-1-piperidinyl]-ethyl}-4-fluoro-2-nitrobenzamide.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])/[CH:5]=[C:6](/[CH:8]=[CH:9]/[C@@H:10]1[CH2:12][C@@:11]1([C:14]1[CH:15]=[C:16]([CH2:25][CH2:26][CH:27]([OH:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C:17]2[O:21][CH2:20][C:19]([CH3:23])([CH3:22])[C:18]=2[CH:24]=1)[CH3:13])\[CH3:7])[CH3:2].OC(CCCC)CCC1C2OCC(C)(C)C=2C=C([C@@]2(C)C[C@H]2/C=C/C(/C)=C/C(O)=O)C=1.ClCCl.C[N+]1([O-])CCOCC1>[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC.C(#N)C>[CH2:1]([O:3][C:4](=[O:33])/[CH:5]=[C:6](/[CH:8]=[CH:9]/[C@@H:10]1[CH2:12][C@@:11]1([C:14]1[CH:15]=[C:16]([CH2:25][CH2:26][C:27](=[O:32])[CH2:28][CH2:29][CH2:30][CH3:31])[C:17]2[O:21][CH2:20][C:19]([CH3:22])([CH3:23])[C:18]=2[CH:24]=1)[CH3:13])\[CH3:7])[CH3:2]
Reactant: CCCCC(O)CCc1cc([C@@]2(C)C[C@H]2/C=C/C(C)=C/C(=O)OCC)cc2c1OCC2(C)C
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCCCC(O)CCc1cc([C@@]2(C)C[C@H]2/C=C/C(C)=C/C(=O)O)cc2c1OCC2(C)C
Agent: CCC[N+](CCC)(CCC)CCC
Solvent: CC#N
Solvent: ClCCl
Product: CCCCC(=O)CCc1cc([C@@]2(C)C[C@H]2/C=C/C(C)=C/C(=O)OCC)cc2c1OCC2(C)C

Procedure:
Following General Procedure F and using (E)-3-((E)-2-{(1S,2S)-2-[7-(3-hydroxy-heptyl)-3,3-dimethyl-2,3-dihydro-benzofuran-5-yl]-2-methyl-cyclopropyl}-vinyl)-but-2-enoic acid ethyl ester (Compound 38, 0.019 g, 0.042 mmol), dichloromethane (2.5 mL), acetonitrile (0.5 mL), 4A° molecular sieves powder (0.15 g), tetra-n-propylammoniumperruthenate (0.012 g) and N-methylmorpholine-N-oxide (0.07 g, 0.6 mmol), the title compound was obtained (0.012 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH2:18])[CH:17]=1)=[CH:5]2.[C:21]([C:24]1[CH:29]=[CH:28][C:27]([N:30]=[C:31]=[S:32])=[CH:26][CH:25]=1)([OH:23])=[O:22].C(OCC)(=O)C>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[F:11])[NH:7][C:6]([C:12]1[CH:13]=[CH:14][C:15]([O:19][CH3:20])=[C:16]([NH:18][C:31](=[S:32])[NH:30][C:27]3[CH:26]=[CH:25][C:24]([C:21]([OH:23])=[O:22])=[CH:29][CH:28]=3)[CH:17]=1)=[CH:5]2
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Reactant: O=C(O)c1ccc(N=C=S)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NC(=S)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
The product from Example 3, 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine, (0.274 g, 1.0 mmol) was mixed with 4-carboxyphenyl isothiocyanate (0.183 g, 1.0 mmol) in tetrahydrofuran (10 mL) and was heated briefly to 50° C. and then allowed to stand overnight at room temperature. The tetrahydrofuran was boiled off on the rotary evaporator (no vacuum) to give a solid. Ethyl acetate (5 mL) was added, and the mixture was allowed to stand overnight at room temperature. The insoluble material was collected by filtration and was a mixture. All material from the reaction mixture was taken up in tetrahydrofuran/ethyl acetate and more 4-carboxyphenyl isothiocyanate (0.020 g, 0.11 mmol) was added and the solvent was boiled off on the rotary evaporator. Ethyl acetate was added to the solid and the mixture allowed to stand overnight at room temperature. The insoluble material was collected by filtration (0.191 g), mp 201-203° C.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1.[NH2:14][C:15]1[CH:16]=[C:17]2[C:21]3=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]3[C@H:19]3[CH2:28][CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][C@@H:18]23)[CH:23]=1>>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:14][C:15]2[CH:16]=[C:17]3[C:21]4=[C:22]([CH2:24][O:25][CH2:26][CH2:27][N:20]4[C@H:19]4[CH2:28][CH2:29][NH:30][CH2:31][C@@H:18]34)[CH:23]=2)=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1
Reactant: O=Cc1ccc(F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(N)cc3c1N2CCOC3
Product: Fc1ccc(CNc2cc3c4c(c2)[C@@H]2CNCC[C@@H]2N4CCOC3)c(C(F)(F)F)c1

Procedure:
Using 4-fluoro-2-(trifluoromethyl)benzaldehyde and following the procedures described in EXAMPLE 126, tert-butyl (7bR,11aS)-6-amino-1,2,7b,10,11,11a-hexahydro-4H—[1,4]oxazepino[6,5,4-hi]pyrido[4,3-b]indole-9(8H)-carboxylate from EXAMPLE 56, Part B was converted into the title compound of EXAMPLE 131. 1H NMR(CDCl3) δ 7.61 (dd, 1H, J=8.4, 5.5 Hz), 7.40 (dd, 1H, J=8.8, 2.8 Hz), 7.19 (td, 1H, J=8.3, 2.6 Hz), 6.35 (d, 1H, J=2.2 Hz), 6.19 (d, 1H, J=2.2 Hz), 4.56 (ABq, 2H, JAB=14.3 Hz), 4.44 (s, 2H), 4.22 (app d, 1H, J=12.8 Hz), 3.92 (broad s, 1H), 3.71 (app t, 1H), 3.38-3.28 (m, 2H), 3.22-3.02 (m, 4H), 2.65 (app t, 1H), 2.53 (app t, 1H), 2.10-2.00 (m, 2H). LRMS (ES)+: 422.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][CH2:9][CH2:10][CH2:11][SH:12])[CH:2]=1.[N+:13]([CH:16]=[C:17](SC)SC)([O-:15])=[O:14]>C(O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][N:8]2[CH2:9][CH2:10][CH2:11][S:12][C:17]2=[CH:16][N+:13]([O-:15])=[O:14])[CH:2]=1
Reactant: SCCCNCc1cccnc1
Reactant: CSC(=C[N+](=O)[O-])SC
Solvent: CCO
Product: O=[N+]([O-])C=C1SCCCN1Cc1cccnc1
Yield: 48.4 %

Procedure:
A mixture of N-(3-pyridylmethyl)3-aminopropanethiol (1.8 g), 1-nitro-2,2-bis(methylthio)ethylene (1.7 g) and ethanol (40 ml) was heated under reflux for 5 hours under a nitrogen stream. After the reaction, about 2/3 by volume of ethanol was distilled off under reduced pressure. Ether was added little by little to the reaction mixture to precipitate crystals. The crystals were collected by filtration, and washed with a mixture of ethanol and ether to give the desired 3-(3-pyridylmethyl)2-nitromethylenetetrahydro 2H 1,3 thiazine (1.2 g).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:28]([CH3:41])[C:29]([NH:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([F:39])[C:34]=1[Cl:40])=[O:30])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])(C(C)(C)C)(C)C.Cl.C([O-])(O)=O.[Na+]>CO>[Cl:40][C:34]1[C:35]([F:39])=[CH:36][CH:37]=[CH:38][C:33]=1[CH2:32][NH:31][C:29](=[O:30])[N:28]([C@H:10]([CH2:9][OH:8])[CH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:41]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@@H](CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1)CO[Si](C)(C)C(C)(C)C
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](CO)CCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of (S)-tert-butyl 4-(5-(tert-butyldimethylsilyloxy)-4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)pentanoyl)piperazine-1-carboxylate (4.2 g, 6.8 mmol, 1.0 equiv.) in MeOH (35 mL), was added HCl (2N, 0.68 mL, 1.36 mmol, 0.2 equiv.). The reaction was stirred at RT for 1 h. NaHCO3 (1.1 g, 13.6 mmol, 2.0 equiv) was added to quench the reaction. The solvents were removed. The residue was dissolved in EtOAc (100 mL). The salt was filtered off and the filtrate was concentrated to give (S)-tert-butyl 4-(4-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-5-hydroxypentanoyl)piperazine-1-carboxylate (3.4 g, quant.). LRMS (M+H+) m/z 501.2.
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[CH:4]=1.BrCC1CCCCO1.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:40]3[C:31](=[CH:32][C:33]4[O:38][CH2:37][CH2:36][O:35][C:34]=4[CH:39]=3)[O:30][CH2:29]2)[C:21]1=[O:41]>>[N:7]1[O:8][N:9]=[C:5]2[CH:4]=[C:3]([CH2:2][N:20]3[C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[C:22]4([C:40]5[C:31](=[CH:32][C:33]6[O:38][CH2:37][CH2:36][O:35][C:34]=6[CH:39]=5)[O:30][CH2:29]4)[C:21]3=[O:41])[CH:11]=[CH:10][C:6]=12
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCCO3
Reactant: BrCc1ccc2nonc2c1
Agent: BrCC1CCCCO1
Product: O=C1N(Cc2ccc3nonc3c2)c2ccccc2C12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 5-(bromomethyl)-2,1,3-benzooxadiazole to replace 2-(bromomethyl)tetrahydro-2H-pyran, and 2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2″(1′H)-one, 1′-(2,1,3-benzoxadiazol-5-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (44%) as a colorless solid: mp 164-166° C.; 1H NMR (300 MHz, CDCl3) δ7.86 (d, J=9.3 Hz, 1H), 7.75 (s, 1H), 7.43-7.37 (m, 1H), 7.25-7.19 (m, 2H), 7.08 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.8 Hz, 1H), 6.53 (s, 1H), 6.23 (s, 1H), 5.13 (d, J=16.2 Hz, 1H), 4.95 (d, J=9.0 Hz, 1H), 4.94 (d, J=16.2 Hz, 1H), 4.70 (d, J=9.0 Hz, 1H), 4.24-4.10 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 177.7, 155.3, 149.0, 148.7, 144.8, 141.4, 139.7, 138.4, 132.0, 131.4, 129.0, 124.3, 124.0, 120.6, 117.8, 113.9, 111.4, 108.8, 99.6, 80.1, 64.5, 63.9, 58.0, 44.0; MS (ES+) m/z 427.9 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([O:17]C)=[O:16])=[CH:12][S:13][CH:14]=1.[OH-].[K+]>C(O)C.O.O>[F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]1[C:11]([C:15]([OH:17])=[O:16])=[CH:12][S:13][CH:14]=1
Reactant: COC(=O)c1cscc1Nc1ccc(I)cc1F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cscc1Nc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 82.9 %

Procedure:
A mixture of methyl 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylate (0.74 g, 1.96 mmol) in the solution of potassium hydroxide (0.3 g) in ethanol/water (4 ml/4 ml) was heated up to 60° C. and stirred at this temperature for 30 min. The mixture was cooled to room temperature, diluted with 4 ml of water and extracted with ether. The water layer was acidified with 1 N HCl to pH 2, the product precipitated and was filtered off, washed several times with water and dried in vacuo to afford 4-[(2-fluoro-4-iodophenyl)amino]thiophene-3-carboxylic acid (0.59 g, 83%). 1H NMR (d6-DMSO): 13.20 (s, 1H), 9.13 (s, 1H), 8.35 (d, 1H), 7.62 (dd, 1H), 7.48-7.38 (m, 2H), 7.11 (s, 1H); MS (EI) for C11H7FINO2S: 362 (MH−).