Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2]1([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)C(C)C)C.Cl[C:24]1[N:25]=[C:26]([S:32][CH3:33])[N:27]=[N:28][C:29]=1[C:30]#[N:31]>O1CCOCC1>[CH3:33][S:32][C:26]1[N:27]=[N:28][C:29]([C:30]#[N:31])=[C:24]([N:11]2[CH2:10][CH:9]=[C:8]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH2:13][CH2:12]2)[N:25]=1
Reactant: C1=C(c2ccccc2)CCNC1
Reactant: CSc1nnc(C#N)c(Cl)n1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CSc1nnc(C#N)c(N2CC=C(c3ccccc3)CC2)n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 56.7 %

Procedure:
A solution of 130 mg (0.66 mmol) of 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride in 5 ml of dioxane was treated at room temperature with 0.23 ml (1.32 mmol) of N-ethyl-diisopropylamine and, thereupon, with 112 mg (0.60 mmol) of crude 5-chloro-3-methylsulfanyl-[1,2,4]triazine-6-carbonitrile. The reaction mixture was stirred at 50° C. during 18 hours. For the working-up, the solution was evaporated under reduced pressure and the residue was chromatographed on silica gel with a 2:1 mixture of hexane and ethylacetate as the eluent. There were obtained 120 mg (0.34 mmol, 64.5% of theory) of 3-methylsulfanyl-5-(4-phenyl-3,6-dihydro-2H-pyridin-1-yl)-[1,2,4]triazine-6-carbonitrile in the form of an orange powder; MS: [M+H]+=310.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9](Cl)(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1.[NH2:14][C:15]1[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=1[CH3:20]>N1C=CC=CC=1>[Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([S:9]([NH:14][C:15]2[C:16]([CH3:22])=[N:17][N:18]([CH3:21])[C:19]=2[CH3:20])(=[O:11])=[O:10])=[C:4]([Cl:13])[CH:3]=1
Reactant: O=S(=O)(Cl)c1c(Cl)cc(Br)cc1Cl
Reactant: Cc1nn(C)c(C)c1N
Solvent: c1ccncc1
Product: Cc1nn(C)c(C)c1NS(=O)(=O)c1c(Cl)cc(Br)cc1Cl
Yield: 89 %

Procedure:
Prepared from 4-bromo-2,6-dichlorobenzenesulfonyl chloride (5.0 g, 15.4 mmol) and 4-amino-1,3,5-trimethyl-1H-pyrazole (1.93 g, 15.4 mmol) in pyridine (35 ml) according to the method of intermediate 1, to give the title compound as an orange solid (5.64 g, 13.7 mmol, 89%). δH (D-6 DMSO, 300K) 9.75 (1H, s), 8.00 (2H, s), 3.57 (3H, s), 1.93 (3H, s), 1.72 (3H, s). m/z (ES+, 70V) 413.9 (MH+).
Reaction SMILES: [CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:1]1[C:11]2[C:10](=[C:12]3[CH2:17][CH2:16][N:15]([CH2:23][CH2:24][C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:14][CH2:13]3)[C:9]3[CH:18]=[CH:19][CH:20]=[CH:21][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)CCBr
Reactant: c1ccc2c(c1)COc1ccccc1C2=C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCN1CCC(=C2c3ccccc3COc3ccccc32)CC1
Temperature: 80 °C
Reaction time: 2 h
Yield: 85.5 %

Procedure:
A mixture of 3.61 g of 4-(dibenz[b,e]oxepin-11(6H)-ylidene)piperidine, 2.6 g of ethyl 3-bromopropionate, 1.8 g of potassium carbonate and 25 ml of N,N-dimethylformamide was stirred at 80° C. for 2 hrs. After cooling, water was added to the reaction mixture and extracted with ether. The ether layer was washed with water and extracted with hydrochloric acid. The aqueous layer was made alkaline with potassium carbonate and extracted with ether. The ether layer was washed with water, dried and concentrated to give 4.2 g of yellowish brown liquid, which was purified by column chromatography on silica gel (eluent: chloroform) to give 3.9 g of pale yellow liquid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH3:23])[CH2:18]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:24]([NH2:28])[CH:25]([CH3:27])[CH3:26]>CO>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH3:23])[C:20]([NH:28][CH2:24][CH:25]([CH3:27])[CH3:26])=[O:22])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)CN
Reactant: C[C@@H]1C[C@@H]([C@H](CC2CCCCC2)NC(=O)OC(C)(C)C)OC1=O
Solvent: CO
Product: CC(C)CNC(=O)[C@H](C)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 8 h

Procedure:
A solution of 290 mg (0.93 mmole) of (3R, 5S)-5-[(1S)-1-(t-butoxycarbonyl)amino-2-cyclohexylethyl]-3-methyldihydrofuran-2(3H)-one (prepared as described in Preparation 2) in 3 ml of methanol was mixed with 3 ml of isobutylamine, and the mixture was allowed to stand overnight at room temperature. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure, and the residue was triturated with hexane to afford 340 mg of the title compound as colorless crystals, melting at 125°-126° C.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=3)(=[O:20])=[O:19])=[CH:14][CH:15]=2)[C:10]([CH3:28])=[N:9]1)=O)(C)(C)C.I[Si](C)(C)C>C(Cl)(Cl)Cl>[F:27][C:23]1[CH:22]=[C:21]([S:18]([NH:17][C:13]2[CH:12]=[C:11]3[C:16](=[CH:15][CH:14]=2)[NH:8][N:9]=[C:10]3[CH3:28])(=[O:19])=[O:20])[CH:26]=[CH:25][CH:24]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Agent: C[Si](C)(C)I
Solvent: ClC(Cl)Cl
Product: Cc1n[nH]c2ccc(NS(=O)(=O)c3cccc(F)c3)cc12
Yield: 59 %

Procedure:
3-Fluoro-N-(3-methyl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 6 from 1.35 g of N-(N-tert-butoxycarbonyl-3-methyl-1H-indazol-5-yl)-3-fluorobenzenesulfonamide, 13.5 ml of chloroform and 0.47 ml of iodotrimethylsilane. 0.6 g of 3-fluoro-N-(3-methyl-1H-indazol-5-yl)-benzenesulfonamide is thus obtained in the form of a white foam melting at 120° C. (analysis: C14H12FN3O2S.0.39CH2Cl2 % calculated, C, 55.07; H, 3.96; F, 6.22; N, 13.76; O, 10.48; S, 10.50. % found C, 54.99; H, 2.70; N, 13.81; S, 10.18).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([S:17][CH3:18])=[N:8][C:9]2[C:14]([C:15]=1[OH:16])=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:5])C.Cl>[OH-].[Na+]>[CH3:18][S:17][C:7]1[NH:8][C:9]2[C:14]([C:15](=[O:16])[C:6]=1[C:4]([OH:5])=[O:3])=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: CCOC(=O)c1c(SC)nc2ccccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CSc1[nH]c2ccccc2c(=O)c1C(=O)O
Yield: 85 %

Procedure:
4-Hydroxy-2-methylsulfanyl-quinoline-3-carboxylic acid ethyl ester (8 g, 30 mmol) was heated under reflux in NaOH solution (10%, 100 mL) for 1.5 h. After cooling, the mixture was acidified with concentrated HCl to pH 4. The resulting solid was collected via filtration, washed with water (100 mL) and MeOH (100 mL) to give 2-methylsulfanyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid (A-16) as a white solid (6 g, 85%). 1H NMR (CDCl3) δ 16.4 (br s, 1H), 11.1 (br s, 1H), 8.19 (d, J=8 Hz, 1H), 8.05 (d, J=8 Hz, 1H), 7.84 (t, J=8, 8 Hz, 1H), 7.52 (t, J=8 Hz, 1H), 2.74 (s, 3H); ESI-MS 235.9 m/z (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([O:16]C)=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1.[OH-].[Li+].CO>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][CH:6]1[C:10]2[NH:11][C:12]([C:14]([OH:16])=[O:15])=[CH:13][C:9]=2[CH2:8][CH2:7]1
Reactant: COC(=O)c1cc2c([nH]1)C(Cc1cccc(Br)c1)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c([nH]1)C(Cc1cccc(Br)c1)CC2
Yield: 10 %

Procedure:
The title compound was synthesized from methyl 6-(3-bromobenzyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (0.151 g, 0.45 mmol) and lithium hydroxide (0.193 g, 4.6 mmol in 2 mL water), according to General Procedure 7. A 1:1 mixture of methanol (MeOH) and THF (4 mL) was used. The resulting product was purified by reverse phase HPLC, eluting with a gradient of 40-100% MeOH: water (with 0.1% formic acid) to afford a light pink solid: 0.014 g (10% yield). 1H NMR (400 MHz, METHANOL-d4) δ ppm 2.03-2.13 (m, 1H), 2.37-2.46 (m, 4H), 2.68 (dd, J1=13.28 Hz, J2=8.88 Hz, 1H), 3.08 (dd, J1=13.52 Hz, J2=4.73 Hz, 1H), 6.56 (s, 1H), 7.10-7.12 (m, 1H), 7.17 (t, J=7.74 Hz, 1H), 7.32-7.35 (m, 2H); LCMS-MS (ESI−) 318.0 (M−H); HPLC (UV=96.26%), (ELSD=100%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18](C3CCOCC=3)[CH:17]=2)[C:12]([C:28]([NH2:30])=[O:29])=[CH:11][N:10]=1.[CH3:31][OH:32]>[Pd]>[NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9]1[N:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([CH:2]3[CH2:3][CH2:4][O:32][CH2:31][CH2:7]3)=[CH:20][CH:21]=2)[C:12]([C:28]([NH2:30])=[O:29])=[CH:11][N:10]=1
Reactant: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1cccc(C2=CCOCC2)c1
Reactant: CO
Agent: [Pd]
Product: NC(=O)c1cnc(N[C@@H]2CCCC[C@@H]2N)nc1Nc1ccc(C2CCOCC2)cc1

Procedure:
The title compound was prepared from Example 175 using standard catalysis hydrogenation by treating the solution of Example 175 in methanol with 10% Pd/C under H2 balloon for overnight. MS found for C22H30N6O2 as (M+H)+ 411.4. UV λ=243, 296 nm.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][N:5]([C:7]2[N:12]=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[C:15]([F:23])[CH:14]=3)[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=2)[CH:6]=1.[NH2:28][C:29]1[CH:34]=[CH:33][C:32](B2OC(C)(C)C(C)(C)O2)=[CH:31][N:30]=1>>[F:23][C:15]1[CH:14]=[C:13]([C:11]2[CH:10]=[C:9]([C:24]([F:27])([F:26])[F:25])[N:8]=[C:7]([N:5]3[CH:6]=[C:2]([C:32]4[CH:33]=[CH:34][C:29]([NH2:28])=[N:30][CH:31]=4)[N:3]=[CH:4]3)[N:12]=2)[CH:18]=[CH:17][C:16]=1[C:19]([F:22])([F:21])[F:20]
Reactant: Fc1cc(-c2cc(C(F)(F)F)nc(-n3cnc(Br)c3)n2)ccc1C(F)(F)F
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cn(-c3nc(-c4ccc(C(F)(F)F)c(F)c4)cc(C(F)(F)F)n3)cn2)cn1

Procedure:
The title compound was prepared from 2-(4-bromo-imidazol-1-yl)-4-(3-fluoro-4-trifluoromethyl-phenyl)-6-trifluoromethyl-pyrimidine (example 35) (0.23 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as a yellow solid (0.065 g, 28%). MS (ISP) 469.2 [(M+H)+]; mp 309° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH3:9].C(Br)C.[NH3:13].O=O>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]#[N:13]
Reactant: N
Reactant: Cc1c(Cl)cccc1Cl
Agent: O=O
Solvent: CCBr
Product: N#Cc1c(Cl)cccc1Cl
Yield: 82.3 %

Procedure:
270 g of this catalyst was charged into the same fluidized bed reactor as used in Example 1. The catalyst layer was kept at 390° C. To the catalyst layer were fed air, 2,6-dichlorotoluene containing 2% of ethyl bromide, and ammonia at rates of 71.6 N liters, 25.0 g, and 17 N liters per hour, respectively. The ratio of 2,6-dichlorotoluene:oxygen:ammonia was 1.0:4.2:5.0. 2,6-dichlorobenzonitrile was obtained in an amount of 21.5 g per hour. The quantity of unreacted 2,6-dichlorotoluene was 1.6 g. Conversion was 94.5%, yield was 82.3%, and selectivity was 87.1%.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:10]2[C:5](=[CH:6][C:7]([N+:15]([O-:17])=[O:16])=[C:8]([NH:11]C(=O)C)[CH:9]=2)[NH:4][C:3]1=[O:18].I[CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25].C([O-])([O-])=O.[K+].[K+]>>[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][C:7]=1[N+:15]([O-:17])=[O:16])[N:4]([CH2:21][CH2:22][CH2:23][C:24]([F:27])([F:26])[F:25])[C:3](=[O:18])[C:2]2([CH3:1])[CH3:19]
Reactant: CC(=O)Nc1cc2c(cc1[N+](=O)[O-])NC(=O)C2(C)C
Reactant: FC(F)(F)CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)C(=O)N(CCCC(F)(F)F)c2cc([N+](=O)[O-])c(N)cc21
Yield: 65.6 %

Procedure:
Analogously to general procedure (I) N-(3,3-dimethyl-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl)-acetamide (2 g) is alkylated in a high pressure reaction vessel using 1-iodo-4,4,4-trifluoro-butane (3.62 g; 15.2 mmol) and K2CO3 (2.1 g; 15.2 mmol) at 60° C. for 3 days. After aqueous work-up and purification by RP chromatography the pure material (1.92 g) is de-acetylated in MeOH (200 ml) using DBU (1.6 ml) at reflux. After aqueous work-up 5-amino-3,3-dimethyl-6-nitro-1-(4,4,4-trifluoro-butyl)-1,3-dihydro-indol-2-one (1.65 g) is obtained and used without further purification.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][C:2]1=[O:7].[C:8]1([CH:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:15][C:16](O)=[O:17])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.C(Cl)CCl>ClCCl>[C:19]1([CH:14]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:15][C:16]([N:4]2[CH2:5][CH2:6][NH:1][C:2](=[O:7])[CH2:3]2)=[O:17])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)CC(c1ccccc1)c1ccccc1
Reactant: O=C1CNCCN1
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C1CN(C(=O)CC(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.8 %

Procedure:
To a solution of piperazin-2-one (100 m g, 1 mmol), 3,3-diphenylpropanoic acid (226 mg, 1 mmol) was added EDC (382 mg, 2 mmol) in dichloromethane (5 mL). The solution was stirred at room temperature overnight and concentrated in vacuo. The residue was diluted with EtOAc, and the mixture was washed consecutively with saturated aqueous NaHCO3 and brine. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The crude material was purified by flash column chromatography (2:98 MeOH/DCM) to give the desired 4-(3,3-diphenylpropanoyl)piperazin-2-one product (compound 4) (246 mg, 80%) as a white powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:12][C:13]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: O=C(O)Cc1ccccc1Br
Product: O=C(O)Cc1ccccc1Nc1ccc(Cl)cc1Cl

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid was condensed with 2,4-dichloroaniline to yield 2-[(2,4-dichlorophenyl)amino]phenylacetic acid.
Reaction SMILES: C[O:2][C:3](=[O:38])[CH:4]([CH2:13][CH2:14][C:15](=[O:37])[NH:16][O:17][C:18]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH2:5][C:6]([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7].[OH-].[Na+]>CO.O>[C:9]([O:8][C:6](=[O:7])[CH2:5][CH:4]([CH2:13][CH2:14][C:15](=[O:37])[NH:16][O:17][C:18]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:3]([OH:38])=[O:2])([CH3:12])([CH3:10])[CH3:11]
Reactant: COC(=O)C(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)CC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)CC(CCC(=O)NOC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the compound of example 65 (2.27 g, 4.39 mmol) in a mixture of methanol/water (4:1, 50 mL) was added a solution of sodium hydroxide (1N, 9 mL). The resulting mixture was stirred for 24 h at room temperature. The solvent was evaporated and the residue was partitioned between water and ether. The alkaline phase acidified using HCl (6N) and extracted with ethyl acetate followed by drying over sodium sulfate, filtration and evaporation. The product was converted to an off-white foam under high vacuum. 1H-NMR(CDCl3, 400 MHz: 1.42(s, 9H); 1.59(m, 3H); 1.88-2.54(m, 4H); 7.33(m, 15H); 7.46(s, broad, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O.[OH-].[Na+]>>[Br:9][C:5]1[CH:6]=[C:7]2[NH:8][C:14]([C:13]3[CH:17]=[CH:18][CH:19]=[C:11]([Cl:10])[CH:12]=3)=[N:1][C:2]2=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: O=C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Product: Clc1cccc(-c2nc3ncc(Br)cc3[nH]2)c1
Temperature: 170 °C
Reaction time: 2 h
Yield: 69.2 %

Procedure:
A mixture of 2,3-diamino-5-bromopyridine (Compound of Reference Example 1) (1.32 g), 3-chlorobenzoic acid (1.10 g) and polyphosphoric acid (30 g) was stirred at 170° C. for 2 hours. The mixture was poured onto ice, neutralized with 8N-sodium hydroxide and extracted with ethyl acetate-tetrahydrofuran (3:1, v/v). The organic layer was washed with water and dried with MgSO4. The solvent was distilled off under reduced pressure, and resulting crystals were collected by filtration to obtain 6-bromo-2-(3-chlorophenyl)-1H-imidazo[4,5-b]pyridine (1.50 g, 69%).
Reaction SMILES: [OH:1][C:2]1[C:7]2[C@@:8]3([OH:45])[C@@:21]([O:25][CH3:26])([C@H:22]([OH:24])[CH2:23][C:6]=2[CH:5]=[C:4]([CH3:46])[C:3]=1[C:47]([O:49][CH3:50])=[O:48])[C:20](=[O:27])[C:19]1[C:10](=[CH:11][C:12]2[C:13](=[O:43])[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)=[CH:15][C:16](=[O:29])[C:17]=2[C:18]=1[OH:28])[C:9]3=[O:44].[Br:51]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)Cl>[Br:51][C:5]1[C:6]2[CH2:23][C@@H:22]([OH:24])[C@:21]3([O:25][CH3:26])[C@:8]([OH:45])([C:7]=2[C:2]([OH:1])=[C:3]([C:47]([O:49][CH3:50])=[O:48])[C:4]=1[CH3:46])[C:9](=[O:44])[C:10]1[C:19](=[C:18]([OH:28])[C:17]2[C:16](=[O:29])[CH:15]=[C:14]([NH:30][C@@H:31]4[C@H:36]([O:37][CH3:38])[C@H:35]([OH:39])[C@@H:34]([O:40][CH3:41])[C@H:33]([CH3:42])[O:32]4)[C:13](=[O:43])[C:12]=2[CH:11]=1)[C:20]3=[O:27]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1c(C)cc2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1c(C)c(Br)c2c(c1O)[C@]1(O)C(=O)c3cc4c(c(O)c3C(=O)[C@]1(OC)[C@H](O)C2)C(=O)C=C(N[C@H]1O[C@@H](C)[C@H](OC)[C@@H](O)[C@H]1OC)C4=O
Temperature: 75 °C
Yield: 35.8 %

Procedure:
To a solution of (6R,6aS,14aR)-methyl 1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (50 mg, 0.072 mmol) in chloroform (1 mL) was added N-bromosuccinimide (13 mg, 0.072 mmol) followed by benzoyl peroxide (1-2 mg). The reaction mixture was refluxed at 75° C. for 1 h. After cooled to room temperature, the reaction mixture was diluted with chloroform (10 mL) and washed with saturated sodium bicarbonate (5 mL). The aqueous layer was further extracted with chloroform (2×10 mL). The combined organics were dried (Na2SO4), filtered and concentrated. The crude material was purified by preparative TLC (silica gel, 95:5 chloroform/methanol) and semi-preparative HPLC to afford (6R,6aS,14aR)-methyl 4-bromo-1,6,8,14a-tetrahydroxy-11-((2S,3R,4R,5R,6S)-4-hydroxy-3,5-dimethoxy-6-methyltetrahydro-2H-pyran-2-ylamino)-6a-methoxy-3-methyl-7,9,12,14-tetraoxo-5,6,6a,7,9,12,14,14a-octahydrobenzo[a]tetracene-2-carboxylate (20 mg, 36%) as a dark red solid: 1H NMR (500 MHz, CDCl3) δ 14.22 (s, 1H), 11.62 (br s, 1H), 8.19 (s, 1H), 6.85 (d, J=9.0 Hz, 1H), 5.88 (s, 1H), 5.29 (s, 1H), 4.99 (s, 1H), 4.72 (s, 1H), 4.68 (d, J=8.5 Hz, 1H), 3.88 (s, 3H), 3.79 (s, 3H), 3.76-3.65 (m, 2H), 3.61 (s, 3H), 3.55 (d, J=6.5 Hz, 1H), 3.45 (d, J=20.5 Hz, 1H), 3.41 (s, 3H), 3.38-3.31 (m, 1H), 3.13 (t, J=9.5 Hz, 1H), 2.59 (s, 3H), 2.48 (d, J=4.5 Hz, 1H), 1.36 (d, J=6.0 Hz, 3H); MS (ESI+) m/z 776 (M+H); HPLC >99% (AUC), tR 14.64 min.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:16])([F:15])[F:14])[NH2:8])(=[O:4])=[O:3].Cl.C1(C)C=CC=CC=1.[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl>C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:8]=[C:26]=[O:25])[CH:9]=[CH:10][C:11]=1[O:12][C:13]([F:14])([F:15])[F:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1cc(N)ccc1OC(F)(F)F
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1cc(N=C=O)ccc1OC(F)(F)F
Reaction time: 8 h

Procedure:
To 3-methylsulfonyl-4-trifluoromethoxyaniline (2.0 mmol, 500 mg) dissolved in ethyl acetate (6 mL) was added 3 N hydrochloric acid in ethyl acetate (5 mL) followed by concentration in vacuo. The residue was treated with toluene (3×5 mL) and each time concentrated in vacuo. To the residue was added toluene (10 mL) and diphosgene (6 mmol, 0.73 mL) under a nitrogen atmosphere and the suspension was gently refluxed for 2 hours. Additional diphosgene (6 mmol, 0.73 mL) was added and refluxing was continued overnight. The reaction mixture was concentrated in vacuo to afford 3-methylsulfonyl-4-trifluoromethoxyphenyl isocyanate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:13][CH2:12][C@H:11]([CH2:14][CH:15]2[CH:19]([C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=4)[N:23]=[CH:22][C:21]=3[O:32]CC3C=CC=CC=3)OC(=O)[O:16]2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]>[Pd].CO.C(N(CC)CC)C>[C:1]([O:5][C:6](=[O:41])[NH:7][C@H:8]1[CH2:9][CH2:10][C@H:11]([CH2:14][CH:15]([OH:16])[CH2:19][C:20]2[C:29]3[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[N:28]=3)[N:23]=[CH:22][C:21]=2[OH:32])[CH2:12][CH2:13]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1ccc2ncc(OCc3ccccc3)c(C3OC(=O)OC3C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: COc1ccc2ncc(O)c(CC(O)C[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
10% Palladium on activated carbon (976 mg, 0.91 mmol, 0.3 eq) is added at room temperature to a stirred solution of {trans-4-[5-(3-benzyloxy-6-methoxy-[1,5]naphthyridin-4-yl)-2-oxo-[1,3]dioxolan-4-ylmethyl]-cyclohexyl}-carbamic acid tert-butyl ester (1.70 g, 3.02 mmol, 1.0 eq) in methanol (200 mL), followed by several drops of triethylamine. The resulting mixture is stirred under hydrogen flow (1 bar) at room temperature for 1 hour. The catalyst is then removed by filtration and the solution is concentrated to afford {trans-4-[2-hydroxy-3-(3-hydroxy-6-methoxy-[1,5]naphthyridin-4-yl)-propyl]-cyclohexyl}-carbamic acid tert-butyl ester as a white solid (890 mg, 68% yield).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:26][N:25]([CH2:27][C:28](N)=[O:29])[CH2:24]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].BrCCO[CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1>CN(C=O)C>[CH:1]([N:4]1[C:8]([C:9]2[S:10][C:11]3[CH2:12][CH2:13][O:14][C:15]4[CH:22]=[C:21]([CH:23]5[CH2:24][N:25]([CH2:27][CH2:28][O:29][CH:35]6[CH2:40][CH2:39][CH2:38][CH2:37][O:36]6)[CH2:26]5)[CH:20]=[CH:19][C:16]=4[C:17]=3[N:18]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CC(N)=O)C3)ccc1-2
Reactant: BrCCOC1CCCCO1
Solvent: CN(C)C=O
Product: CC(C)n1ncnc1-c1nc2c(s1)CCOc1cc(C3CN(CCOC4CCCCO4)C3)ccc1-2

Procedure:
The title compound was prepared by a similar method to 2-{3-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-8-yl]-azetidin-1-yl}-acetamide using 2-(2-bromoethoxyl)tetrahydro-2H-pyran instead of 2-bromoacetamide and DMF instead of THF and performing the reaction at 60° C. The title compound was isolated as an amber gum (104 mg, 29%). LCMS: RT=3.24, 3.35 min, [M+H]+=496