Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(Br)(Br)Br.[ClH:5].C[O:7][C:8]1[CH:39]=[CH:38][C:11]2[C@@H:12]3[C@H:16]([CH2:17][CH2:18][C:10]=2[CH:9]=1)[N:15]=[C:14]([NH:19][CH2:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([CH2:27][NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])[CH2:23][CH2:22]1)[CH2:13]3.C(N(CC)CC)C.CO>ClCCl>[ClH:5].[OH:7][C:8]1[CH:39]=[CH:38][C:11]2[C@@H:12]3[C@H:16]([CH2:17][CH2:18][C:10]=2[CH:9]=1)[N:15]=[C:14]([NH:19][CH2:20][C@H:21]1[CH2:22][CH2:23][C@H:24]([CH2:27][NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])[CH2:25][CH2:26]1)[CH2:13]3
Reactant: COc1ccc2c(c1)CC[C@@H]1N=C(NC[C@H]3CC[C@H](CNS(=O)(=O)c4ccccc4)CC3)C[C@H]21
Agent: BrB(Br)Br
Agent: Cl
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=S(=O)(NC[C@H]1CC[C@H](CNC2=N[C@H]3CCc4cc(O)ccc4[C@H]3C2)CC1)c1ccccc1
Reaction time: 1 h

Procedure:
A solution of boron tribromide (3.4 mmol) in dichloromethane (3.4 mL) was added to a solution of N-[[trans-4-[[(cis-3a,4,5,9b-tetrahydro-7-methoxy-1H-benz[e]indol-2-yl)amino]methyl]cyclohexyl]methyl]benzenesulfonamide hydrochloride (8) (0.37 g, 0.714 mmol) and triethylamine (0.235 mL, 1.69 mmol) in dichloromethane (20 mL) at 0° C. The resultant mixture was stirred at 0° C. for 1 h, and stirring was continued at room temperature for an additional 1 h. The mixture was cooled on an ice bath and methanol was added. After stirring for several minutes, the solvents were evaporated In vacuo. The residue was purified by preparative HPLC on a C18 reverse phase column, eluted with waterlacetonitrile/trifluoroacetic acid (˜50:50:0.1). The product was dissolved in a minimum amount of methanol and converted to the hydrochloride salt with ethanolic hydrogen chloride. The solvents were evaporated in vacuo to give N-[[trans-4-[[(cis-3a,4,5,9b-tetrahydro-7-hydroxy-1H-benz[e]indol-2-yl)amino]methyl]cyclohexyl]methyl]benzenesulfonamide hydrochloride as a colorless solid (0.15 g, 42%). NMR (DMSO-d6): δ 0.67-0.98 (m, 4 H), 1.21-1.50 (m, 2 H), 1.58-1.97 (m, 6 H), 2.50-2.75 (m, 5 H), 3.03-3.23 (m, 2 H), 3.31-3.46 (m, 1 H), 3.55-3.67 (m, 1 H), 4.17-4.33 (m, 1 H), 6.53 (s, 1 H), 6.64 (d, 1 H), 6.99 (d, 1 H), 7.52-7.83 (m, 6 H), 9.34 (br s, 1 H), 9.76 (br s, 1 H) and 10.24 (br s, 1 H); MS 468 (M+H)+ (FIG. 4).
Reaction SMILES: [F:1][CH:2]([F:5])[CH2:3]Cl.[C:6]1(=[O:12])[NH:10][C:9](=[O:11])[CH2:8][CH2:7]1.C(=O)([O-])[O-].[K+].[K+]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[F:1][CH:2]([F:5])[CH2:3][N:10]1[C:6](=[O:12])[CH2:7][CH2:8][C:9]1=[O:11]
Reactant: FC(F)CCl
Reactant: O=C1CCC(=O)N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: CN(C)C=O
Product: O=C1CCC(=O)N1CC(F)F
Temperature: 120 °C
Reaction time: 16 h
Yield: 88.1 %

Procedure:
An amount of 40.9 g (0.39 mol) of 2,2-difluoro-1-chloroethane, 3.22 g (9.9 mmol) of tetra(n-butyl)ammonium bromide, 95 g of N,N-dimethylformamide and 20 g (0.19 mol) of succinimide are treated with 83.6 g (0.599 mol) of potassium carbonate. The reaction mixture is stirred in an autoclave under pressure at 120° C. for 16 h. After the end of the reaction, cooling is carried out to ambient temperature and the reaction mixture is subsequently filtered. The filter residue is washed with dichloromethane and the solvent is removed under vacuum. The oil is once more treated with 30 ml of water and extracted twice with 30 ml of dichloromethane. The combined organic phases are dried and the solvent is removed under vacuum. An amount of 27.3 g of 1-(2,2-difluoroethyl)pyrrolidine-2,5-dione with a purity of 93% is obtained. This corresponds to a yield of 77.8% of theory.
Reaction SMILES: [C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1)([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[Na+].[Na+].[Cl:22][CH2:23][C:24](Cl)=[O:25]>CC(C)=O>[C:1]([Si:5]([CH3:15])([CH3:14])[O:6][C:7]1[CH:8]=[CH:9][C:10]([NH:13][C:24](=[O:25])[CH2:23][Cl:22])=[CH:11][CH:12]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(N)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(NC(=O)CCl)cc1
Reaction time: 1 h
Yield: 85 %

Procedure:
4-(tert-Butyl-dimethyl-silanyloxy)-phenylamine (2.23 g, 10 mmol) was dissolved in acetone (25 ml). After addition of Na2CO3 (3.2 g, 30 mmol), chloroacetylchloride (0.96 ml, 12 mmol) was added dropwise. After 1 hour at room temperature, the reaction mixture was quenched with H2O (100 ml) and the aqueous phase was extracted with CH2Cl2 (3×10 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was chromatographed over silica gel (hexane-ethyl acetate 9:1 then hexane-ethyl acetate 4:1) to provide N-[4-(tert-Butyl-dimethyl-silanyloxy)-phenyl]-2-chloro-acetamide (2.55 g, 71%) as a colorless solid, m.p. 107°-108° C. and MS: m/e=299 (M+).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26](=[O:37])[NH:27][C:28]4[CH:36]=[CH:35][C:31]([C:32](O)=[O:33])=[CH:30][CH:29]=4)=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(O[N:55]1N=N[C:57]2[CH:58]=[CH:59][CH:60]=[CH:61][C:56]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.N1C=CC=CC=1CN>CN1C(=O)CCC1>[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[N:12]=[C:11]([N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:27][C:28]4[CH:29]=[CH:30][C:31]([C:32](=[O:33])[CH2:61][C:60]5[CH:59]=[CH:58][CH:57]=[CH:56][N:55]=5)=[CH:35][CH:36]=4)=[O:37])=[CH:21][CH:20]=3)[N:8]=2)[CH2:3][CH2:2]1
Reactant: O=C(Nc1ccc(C(=O)O)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(=O)Cc2ccccn2)cc1)Nc1ccc(-c2nc(N3CCOCC3)nc(N3CCOCC3)n2)cc1
Yield: 15.7 %

Procedure:
To the solution of 4-(3-(4-(4,6-dimorpholino-1,3,5-triazin-2-yl)phenyl)ureido)benzoic acid (50 mg; 0.099 mmol), Hunig's base (103 μL, 0.594 mmol), HBTU (188 mg, 0.495 mmol) in 2 mL of NMP was reacted according to example 68 with pyridin-2-ylmethanamine (43 mg, 0.396 mmol). Evaporated the solvent and purified by HPLC to give the product (9 mg, 15% yield); MS (ESI) m/z=596.6.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH2:9].[C:10](O)(=[O:14])[C:11]([CH3:13])=O>>[CH3:1][N:2]1[C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:9]=[C:11]([CH3:13])[C:10]1=[O:14]
Reactant: CC(=O)C(=O)O
Reactant: CNc1ccccc1N
Product: Cc1nc2ccccc2n(C)c1=O

Procedure:
Reaction between N-methyl-1,2-phenylene-diamine and pyruvic acid gave after recrystallisation (EtOH) the title compound;
Reaction SMILES: [C:1]([O:4][CH:5]([O:7][C:8](=[O:29])[C@H:9]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19](=[O:28])[N:20]([CH3:27])[C:21](=[O:26])[N:22]([CH3:25])[C:23]=2[CH3:24])=[CH:14][CH:13]=1)[NH2:10])[CH3:6])(=[O:3])[CH3:2].[Cl:30][C:31]1[CH:39]=[CH:38][CH:37]=[C:36]([CH3:40])[C:32]=1[C:33](Cl)=[O:34]>>[C:1]([O:4][CH:5]([O:7][C:8](=[O:29])[C@H:9]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[C:19](=[O:28])[N:20]([CH3:27])[C:21](=[O:26])[N:22]([CH3:25])[C:23]=2[CH3:24])=[CH:16][CH:17]=1)[NH:10][C:33]([C:32]1[C:36]([CH3:40])=[CH:37][CH:38]=[CH:39][C:31]=1[Cl:30])=[O:34])[CH3:6])(=[O:3])[CH3:2]
Reactant: Cc1cccc(Cl)c1C(=O)Cl
Reactant: CC(=O)OC(C)OC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Product: CC(=O)OC(C)OC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(C)cccc1Cl

Procedure:
N-[(2-chloro-6-methylphenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester was prepared from 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine 1-(acetoxy)ethyl ester and 2-chloro-6-methylbenzoyl chloride using the general procedures described in example 33 and was obtained as a white solid: mp 84-88° C. ES-HRMS m/e calcd for C28H30ClN3O7 (M+Na) 578.1664, found 578.1665.
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[Cl:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([NH2:10])=[O:9].[OH-].[Na+]>OS(O)(=O)=O>[Cl:5][C:6]1[C:14]([N+:1]([O-:4])=[O:2])=[CH:13][CH:12]=[C:11]([Cl:15])[C:7]=1[C:8]([NH2:10])=[O:9]
Reactant: O=[N+]([O-])O
Reactant: NC(=O)c1c(Cl)cccc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)c1c(Cl)ccc([N+](=O)[O-])c1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.3 %

Procedure:
A solution of 12 g of fuming HNO3 (d=1.52) in 11 ml of concentrated H2SO4 is added at room temperature over a period of 30 minutes to a solution of 30.4 g of 2,6-dichlorobenzoic acid amide in 60 ml of concentrated H2SO4 (d=1.83). After stirring for 2 hours at room temperature, the reaction mixture is added to ice/H2O and adjusted to a pH of ~ 6 with 30% NaOH and the precipitating crystals are isolated by filtration, affording 28.7 g of 2,6-dichloro-3-nitrobenzoic acid amide (m.p. 163°-165° C.).
Reaction SMILES: C(O[C:4]([N:6]1[CH2:18][C@H:17]2[C@H:9]([CH2:10][C:11]3[C:16]2=[CH:15][C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:12]=3[CH3:25])[CH2:8][CH2:7]1)=O)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:4][N:6]1[CH2:18][C@H:17]2[C@H:9]([CH2:10][C:11]3[C:16]2=[CH:15][C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][C:12]=3[CH3:25])[CH2:8][CH2:7]1
Reactant: CCOC(=O)N1CC[C@H]2Cc3c(C)cc(-c4ccccc4)cc3[C@H]2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ccccc2)cc2c1C[C@@H]1CCN(C)C[C@H]21
Temperature: 20 °C
Reaction time: 2 h
Yield: 60 %

Procedure:
To a solution of cis-8-methyl-6-phenyl-1,2,4,4a,9,9a-hexahydro-3-aza-fluorene-3-carboxylic acid ethyl ester (20 mg, 0.060 mmol) in THF (1.0 mL) was added LiAlH4 (4.5 mg, 0.12 mmol) under Ar. The reaction mixture was stirred at 20° C. for 2 h then refluxed for 4 h. The reaction was cooled to 20° C. and quenched by addition of H2O and 1M NaOH. The quenched reaction mixture was extracted with CH2Cl2. The combined organic solution was dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed in silica gel column (Hex/EtOAc 1/1) to obtain the title compound (10 mg, 0.036 mmol): MS (ES) 278.2 (M+H).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([CH2:7][OH:8])[N:3]=1.[Cl:9][CH:10]([CH:13]=O)[CH:11]=O>C(O)(=O)C>[Cl:9][C:10]1[CH:11]=[N:1][C:2]2[N:6]([N:5]=[C:4]([CH2:7][OH:8])[N:3]=2)[CH:13]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: O=CC(Cl)C=O
Solvent: CC(=O)O
Product: OCc1nc2ncc(Cl)cn2n1
Temperature: 80 °C

Procedure:
To a slurry of (5-amino-1H-[1,2,4]triazol-3-yl)-methanol (28.5 g, 150 mmol, from step 6 of example A(1)) in acetic acid was added chloromalonaldehyde (16 g, 150 mmol). The mixture was heated to 80° C. for 4 hours. Upon cooling of the reaction, the product crystallized out as a white solid (25.5 g, 92%). 1H NMR (300 MHz, DMSO-d6): δ 4.67 (s, 2 H), 5.62 (s, 1 H), 8.94 (d, J=2.45 Hz, 1 H), 9.81 (d, J=2.45 Hz, 1 H).
Reaction SMILES: [C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([NH:17][C:18]([CH:20]2[CH2:24][CH2:23][CH2:22][O:21]2)=[O:19])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2].C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:4][CH:5]([CH2:41][O:42][C:43](=[O:45])[CH3:44])[CH2:6][NH:7][C:8]([C:10]1[C:15]([I:16])=[C:14]([N:17]2[CH2:22][CH2:23][CH2:24][CH:20]([OH:21])[C:18]2=[O:19])[C:13]([I:25])=[C:12]([C:26]([NH:28][CH2:29][CH:30]([O:36][C:37](=[O:39])[CH3:38])[CH2:31][O:32][C:33](=[O:35])[CH3:34])=[O:27])[C:11]=1[I:40])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(CNC(=O)c1c(I)c(NC(=O)C2CCCO2)c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c1I)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)OCC(CNC(=O)c1c(I)c(C(=O)NCC(COC(C)=O)OC(C)=O)c(I)c(N2CCCC(O)C2=O)c1I)OC(C)=O

Procedure:
To a stirred solution of N,N'-bis[2,3-bis(acetyloxy)propyl]-2,4,6-triiodo-5-[[(tetrahydro-2-furanyl)carbonyl]amino]-1,3-benzenedicarboxamide (0.25 g, 0.26 mmol) (the title compound of Example 19) in dry CH2Cl2 (5 mL) was added triethyl amine (0.01 mL). The solution was cooled to 0°-5°, and to this was added dropwise a solution of dimethylboron bromide in CH2Cl2 (0.12 g, 0.5 mL/2 mMol solution in CH2CL2). After stirring the mixture at 0°-5° for 6-8 hours, the mixture was added to a vigorously stirred solution of aqueous saturated sodium bicarbonate (5 mL). After stirring for 5 minutes, ethyl acetate (50 mL) and water (10 mL) were added. The organic layer was separated, washed with water, dried over anhydrous sodium sulfate, and concentrated in vacua to yield the omega-bromo-alpha-hydroxypentanoyl anilide as an off-white fluffy solid (260 mg).
Reaction SMILES: [C:1]([CH2:5][S:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:8]=1[CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])([O:3]C)=[O:2].[Li+].[OH-]>CO.O>[C:1]([CH2:5][S:6][C:7]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[N:9]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=2)[C:8]=1[CH2:25][C:26]([CH3:32])([CH3:31])[C:27]([O:29][CH3:30])=[O:28])([OH:3])=[O:2]
Reactant: COC(=O)CSc1c(CC(C)(C)C(=O)OC)n(Cc2ccc(Cl)cc2)c2ccc(O)cc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C(C)(C)Cc1c(SCC(=O)O)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of diester from Step 3 (4.5 g, 9.46 mmol) in MeOH (90 mL) there was added 1N LiOH (50 mL) and the mixture was stirred for 1 hour at r.t. It was then diluted with H2O and extracted twice with Et2O. The aqueous fraction was then acidified with 6N HCl and extracted 4 times with Et2O. These extracts were washed 4 times with H2O, dried and evaporated to yield the title compound as a thick oil.
Reaction SMILES: [S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]1=2.[C:10](Cl)(=[O:12])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)Cl>[S:1]1[CH2:5][CH2:4][C:3]2[CH:6]=[C:7]([C:10](=[O:12])[CH3:11])[CH:8]=[CH:9][C:2]1=2
Reactant: c1ccc2c(c1)CCS2
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CC(=O)c1ccc2c(c1)CCS2
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 78.5 %

Procedure:
To a solution of 2,3-dihydro-benzo[b]thiophene (1.88 g, 13.8 mmol) in methylene chloride (20 mL) at −10° C. was added dropwise a solution of acetyl chloride (1.85 mL, 25.9 mmol) and aluminum chloride (1.84 g, 13.8 mmol) in methylene chloride (20 mL) keeping the temperature below −6° C. during the addition period. After the addition is complete the reaction mixture was stirred for an additional 30 min at −10° C. and then added ice (40 mL) and concentrated hydrochloric acid (6 mL) and extracted with methylene chloride (3×20 mL), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (80 g column, 10% diethyl ether/hexanes) afforded 1-(2,3-dihydro-benzo[b]thiophen-5-yl)-ethanone (1.93 g, 78%) as a clear colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])=[O:17])[CH2:11][CH2:10]1.ClC1C=C(C=CC=1)C(OO)=[O:40]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1([S:22]([C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:33])([F:32])[F:34])=[CH:29][CH:30]=2)(=[O:24])=[O:23])[CH2:14][CH2:13][CH:12]([NH:15][S:16]([C:18]([CH3:21])([CH3:20])[CH3:19])(=[O:40])=[O:17])[CH2:11][CH2:10]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)S(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Product: CC(C)(C)S(=O)(=O)NC1CCC(c2cc(F)ccc2F)(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Reaction time: 1 h

Procedure:
The product from Example 65 (110 mg, 0.21 mmol) in dichloromethane (2 ml) was treated with m-chloroperoxybenzoic acid (86 mg, 0.25 mmol, 50% w/w) and stirred for 1 hour. The reaction was diluted with dichloromethane (25 ml) and washed with sodium bisulfite (30 ml, 10% solution), saturated sodium bicarbonate (30 ml) and brine (20 ml), dried over magnesium sulfate, evaporated and purified by silica gel chromatography eluting the desired product with ethyl acetate/hexane mixtures, 80 mg. 1H NMR δ(ppm) (CDCl3), 7.66 (2H, d, J=7.5 Hz), 7.53 (2H, d, J=7.5 Hz), 7.08-7.04 (2H, m), 6.90-6.78 (1H, m), 4.32 (1H, d, J=7.9 Hz), 3.64-3.55 (1H, m), 2.62-2.53 (2H, m), 2.48-2.38 (2H, m), 2.21-1.98 (2H, m), 1.65-1.54 (2H, m), 1.40 (9H, s), MS MH=540.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([C:15]#[CH:16])[C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[CH:11][C:10]=1[Cl:22])(C)(C)C>C(Cl)Cl.C(O)(C(F)(F)F)=O>[NH2:7][CH2:8][C:9]1[C:10]([Cl:22])=[CH:11][C:12]([NH:17][S:18]([CH3:21])(=[O:20])=[O:19])=[C:13]([C:15]#[CH:16])[CH:14]=1
Reactant: C#Cc1cc(CNC(=O)OC(C)(C)C)c(Cl)cc1NS(C)(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C#Cc1cc(CN)c(Cl)cc1NS(C)(=O)=O
Reaction time: 12 h
Yield: 74.3 %

Procedure:
A dried 25 ml of two-neck round bottom flask was filled with argon gas and the solution of (2-chloro-5-ethynyl-4-methanesulfonylamino-benzyl)-carbamic acid t-butyl ester (182.6 mg, 0.51 mmol) in methylenechloride was put into the flask. To the solution were added 5-6 drops of CF3COOH and stirred for 12 hours. After confirming the completion of the reaction with TLC, the resulting solution was concentrated under reduced pressure using toluene to yield brown syrup (98.1 mg, 114.23%).
Reaction SMILES: C(=O)(O)[O-].[NH4+].[CH2:6]([N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20])[CH2:7][N:8]([CH2:13][C:14]([O-:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11].[NH4+].[Fe:27]>>[Fe:27].[CH2:7]([N:8]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][C:10]([OH:12])=[O:11])[CH2:6][N:17]([CH2:22][C:23]([OH:25])=[O:24])[CH2:18][C:19]([OH:21])=[O:20]
Reactant: O=C([O-])CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [Fe]
Agent: O=C([O-])O
Agent: [NH4+]
Product: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O

Procedure:
passing through the ore deposit an aqueous leach solution comprising essentially from about 0.3 to 5 grams per liter of ammonium bicarbonate, sufficient ferric ammonium EDTA to provide from about 3 to 100 ppm of iron, with an EDTA:Fe ratio of at least 1.25:1, and from about 0.1 to 3 grams per liter of H2O2, the leach solution having a pH of between 7.4 and 9.5, the leach solution converting any tetravalent uranium it contacts to the hexavalent state which readily dissolves in the leach solution,
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12](Cl)(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]2[CH2:26][CH:25]([N:27]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:28][C@H:29]([OH:46])[CH2:30][O:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH2:39][C:40]4[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=4)=[CH:34][CH:33]=3)[CH2:24]2)=[CH:19][CH:18]=1.C(N(CC)CC)C.O>C(Cl)Cl>[CH2:47]([N:27]([CH2:28][C@H:29]([OH:46])[CH2:30][O:31][C:32]1[CH:33]=[CH:34][C:35]([O:38][CH2:39][C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)=[CH:36][CH:37]=1)[CH:25]1[CH2:24][N:23]([C:20]2[CH:19]=[CH:18][C:17]([NH:16][S:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[CH:7][CH:8]=3)(=[O:14])=[O:13])=[CH:22][CH:21]=2)[CH2:26]1)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CCCCOc1ccc(S(=O)(=O)Cl)cc1
Reactant: Nc1ccc(N2CC(N(Cc3ccccc3)C[C@H](O)COc3ccc(OCc4ccccc4)cc3)C2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCOc1ccc(S(=O)(=O)Nc2ccc(N3CC(N(Cc4ccccc4)C[C@H](O)COc4ccc(OCc5ccccc5)cc4)C3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4-Butoxybenzenesulfonyl chloride (0.20 g, 0.79 mmol) was added to a solution of (2S)-1-{[1-(4-amino-phenyl)-azetidin-3-yl]-benzyl-amino}-3-(4-benzyloxy-phenoxy)-propan-2-ol (which was obtained in Example 401) (0.37 g, 0.727 mmol) and triethylamine (0.56 mL, 3.99 mmol) in anhydrous methylene chloride (7 mL). The reaction was stirred at room temperature overnight. The solution was then treated with water (30 mL) followed by extraction with ethyl acetate (3×30 mL). The organic extract was dried with anhydrous sodium sulfate, filtered and concentrated to afford a crude solid. The desired product was isolated using silica gel flash chromatography to give 90 mg of an off-white solid; 1H NMR (300 MHz, CDCl3) δ 0.99(t, 3H, J=5.04 Hz), 1.47(m, 2H), 1.78(m, 2H), 2.69(m, 2H), 3.08(brs, 1H), 3.65(m, 3H), 3.78(m, 2H), 3.87(m, 4H), 3.95(t, 2H, J=6.45 Hz), 5.01 (s, 2H), 6.01(s, 1H), 6.29(d, 2H, J=8.73 Hz), 6.86(m, 10H), 7.35(m, 8H), 7.56(d, 2H, J=8.94 Hz). MS (ES) m/z: 722.1 (MH+); Anal. Calcd. for C42H47N3O6S: C, 69.88; H, 6.56; N, 5.82. Found: C, 68.91; H, 6.38; N, 5.55.
Reaction SMILES: FC(F)(F)C(O)=O.[N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C@H:26]([NH:30]C(OC(C)(C)C)=O)[C:27]([OH:29])=[O:28])=[CH:21][CH:20]=2)=[CH:10][CH:9]=1>C1COCC1>[NH2:30][C@@H:26]([CH2:25][C:22]1[CH:23]=[CH:24][C:19]([O:18][C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]=[CH:9][CH:10]=2)=[CH:20][CH:21]=1)[C:27]([OH:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: N[C@@H](Cc1ccc(Oc2ccnc3ccccc23)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 119.4 %

Procedure:
Trifluoroacetic acid (5.5 g) is added dropwise to a stirred suspension of (S)-3-[4-(quinolin-4-yloxy)-phenyl]-2-tert-butoxycarbonylamino-propionic acid (0.76 g, 1.88 mmol) in THF (2 mL) while cooling with an ice bath. The mixture is stirred at rt for 3 days, then it is concentrated under reduced pressure. The residue is treated with ethyl ether to give the title compound (0.692 g, 87%) as a trifluoroacetic acid salt.
Reaction SMILES: Br[C:2]1[CH:23]=[C:22]2[C:5]([CH2:6][C:7]3([C:15]42[N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]4)[CH2:12][CH2:11][CH:10]([O:13][CH3:14])[CH2:9][CH2:8]3)=[CH:4][CH:3]=1.C([O-])(=O)C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[K+].[K+].Br[C:54]1[CH:59]=[CH:58][N:57]=[C:56]([C:60]#[C:61][CH3:62])[CH:55]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.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>[CH3:14][O:13][CH:10]1[CH2:11][CH2:12][C:7]2([C:15]3([N:19]=[C:18]([NH2:20])[C:17]([CH3:21])=[N:16]3)[C:22]3[C:5](=[CH:4][CH:3]=[C:2]([C:54]4[CH:59]=[CH:58][N:57]=[C:56]([C:60]#[C:61][CH3:62])[CH:55]=4)[CH:23]=3)[CH2:6]2)[CH2:8][CH2:9]1
Reactant: COC1CCC2(CC1)Cc1ccc(Br)cc1C21N=C(C)C(N)=N1
Reactant: CC#Cc1cc(Br)ccn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: O
Product: CC#Cc1cc(-c2ccc3c(c2)C2(N=C(C)C(N)=N2)C2(CCC(OC)CC2)C3)ccn1
Temperature: 110 °C
Reaction time: 0.25 h
Yield: 8.5 %

Procedure:
(1r,4r)-6′-Bromo-4-methoxy-5″-methyl-3′H-dispiro[cyclohexane-1,2″-indene-1′,2″-imidazol]-4″-amine (Example 19, 75 mg, 0.20 mmol), potassium acetate (39.1 mg, 0.40 mmol), bis(pinacolato)diboron (55.7 mg, 0.22 mmol) and PdCl2(dppf)-CH2Cl2 adduct (8.14 mg, 9.97 μmol) were taken up in dioxane (2 mL) in a microwave vial. The reaction vessel was sealed and heated at 110° C. for 30 min and then at 120° C. for 15 min in a Biotage Initiator. After cooling, K2CO3 (55 mg, 0.40 mmol), Pd(Ph3P)4 (11.5 mg, 9.97 μmol), and water (0.3 mL) were added followed by 4-bromo-2-(prop-1-ynyl)pyridine (Intermediate 33, 39 mg, 0.20 mmol) in dioxane (1 mL). The reaction vessel was sealed and heated at 110° C. for 30 min in a Biotage Initiator. After cooling, the mixture was filtered and concentrated in vacuo. The product was purified by flash chromatography using a gradient of EtOAc in heptane (0-100%), then EtOAc:MeOH (9:1) followed by preparative chromatography to give the title compound (7 mg, 9% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 0.96 (m, 1 H), 1.12-1.29 (m, 2 H), 1.39-1.50 (m, 3 H), 1.83 (m, 2 H), 2.08 (s, 3 H), 2.18 (s, 3 H), 2.90-3.13 (m, 3 H), 3.20 (s, 3 H), 6.56 (s, 2 H), 6.89 (d, 1 H), 7.42 (d, 1 H), 7.50 (dd, 1 H), 7.58 (d, 1 H), 7.62 (dd, 1 H), 8.49 (d, 1 H); MS (MM−ES+APCI)+m/z 413 [M+H]+.