Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C=O.[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][NH:21][CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7].[CH2:36](Cl)Cl.CO.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CC(O)=O>[F:3][C:4]1[C:27]([NH:28][S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])=[CH:26][CH:25]=[C:24]([F:35])[C:5]=1[C:6]([NH:8][C:9]1[CH:10]=[C:11]2[C:17]([C:18]3[CH2:19][CH2:20][N:21]([CH3:36])[CH2:22][CH:23]=3)=[N:16][NH:15][C:12]2=[N:13][CH:14]=1)=[O:7]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCNCC4)c3c2)c1F
Reactant: ClCCl
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]nc(C4=CCN(C)CC4)c3c2)c1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62 %

Procedure:
37% Aqueous formaldehyde (100 μL) was added to a solution of 2,6-difluoro-3-(propylsulfonamido)-N-(3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)benzamide (22 mg, 0.046 mmol) in 5:1 CH2Cl2/MeOH (6 mL), followed by a drop of AcOH. After 5 minutes, sodium triacetoxyborohydride (49 mg, 5 equiv) was added, and the reaction mixture was stirred for 2 hours at ambient temperature. The reaction mixture was quenched with MeOH, concentrated, and purified by silica gel chromatography (10:90:1 MeOH/CHCl3/NH4OH) to afford 2,6-difluoro-N-(3-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-pyrazolo[3,4-b]pyridin-5-yl)-3-(propylsulfonamido)benzamide as a white solid (14 mg, 62%). 1H NMR (400 MHz, CD3OD) δ 8.90-8.88 (m, 1H), 8.62-8.60 (m, 1H), 7.70-7.63 (m, 1H), 7.17-7.11 (m, 1H), 6.57-6.53 (m, 1H), 3.35-3.31 (m, 2H), 3.14-3.09 (m, 2H), 2.90-2.83 (m, 4H), 2.49 (s, 3H), 1.92-1.82 (m, 2H), 1.08-1.04 (m, 3H); m/z (APCI-pos) M+1=491.0.
Reaction SMILES: [O:1]=[C:2]1[C@@:6]([N:12]2[CH:16]=[CH:15][CH:14]=[CH:13]2)([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:17])[NH:3]1.[Cl:18][C:19]([Cl:24])([Cl:23])[C:20](Cl)=[O:21].O.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C>[O:1]=[C:2]1[C@@:6]([N:12]2[CH:13]=[CH:14][CH:15]=[C:16]2[C:20](=[O:21])[C:19]([Cl:24])([Cl:23])[Cl:18])([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:5][C:4](=[O:17])[NH:3]1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CCOC(=O)[C@@]1(n2cccc2)CC(=O)NC1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(=O)[C@@]1(n2cccc2C(=O)C(Cl)(Cl)Cl)CC(=O)NC1=O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of ethyl (R)-2,5-dioxo-3-(pyrrol-1-yl)pyrrolidine-3-carboxylate (767 mg) in ethyl acetate (10 ml) was added trichloroacetyl chloride (1.1 ml) and this solution was heated under reflux overnight. This reaction mixture was allowed to cool to room temperature, and thereto was added trichloroacetyl chloride (1.1 ml) and this mixture was heated under reflux for 3 hours. This reaction mixture was allowed to water-cooling to room temperature and the residual trichloroacetyl chloride was decomposed carefully with saturated aqueous sodium bicarbonate solution. After the aqueous layer was confirmed to be alkali, this mixture was extracted with ethyl acetate (5 ml) three times and the combined extract was washed sequentially with water and saturated brine, dried over magnesium sulfate, filtered and then concentrated to give a crude product as oil. This was purified by a flash column chromatography (n-hexane:ethyl acetate=1:1) to give ethyl (R)-2,5-dioxo-3-(2-trichloroacetylpyrrol-1-yl)pyrrolidine-3-carboxylate (1.17 g, 94%).
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1Cl.[CH2:14]([N:17]([CH2:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1)[CH2:18][CH2:19][CH3:20])[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:3](=[O:13])[N:4]([C:9]([CH3:12])([CH3:11])[CH3:10])[N:5]=[CH:6][C:7]=1[N:27]([CH2:26][C:25]1[CH:29]=[CH:30][C:22]([CH2:21][N:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19][CH3:20])=[CH:23][CH:24]=1)[CH3:28]
Reactant: CC(C)(C)n1ncc(Cl)c(Cl)c1=O
Reactant: CCCN(CCC)Cc1ccc(CNC)cc1
Product: CCCN(CCC)Cc1ccc(CN(C)c2cnn(C(C)(C)C)c(=O)c2Cl)cc1

Procedure:
The compounds as identified in Table 15 were prepared in the synthetic manner and after-treatment similar to those in Example 8 except that the 4,5-dichloro-2-alkyl- 3(2H)pyridazinones with R1 and R2 as identified in Table 15 were used instead of the starting 4,5-dichloro-2-t-butyl-3(2H)pyridazinone used in Example 8, and the N-alkylbenzylamines with R3, Y1, Y2 and Y3 as identified in Table 15 were used instead of the starting 4-di-n-propylaminomethyl-N-methylbenzylamine. In the NMR data, only the characteristic absorptions are given in Table 15.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[F:27][C:28]1[CH:29]=[C:30]([C:34]#[CH:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:13])([F:15])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:35]#[C:34][C:30]1[CH:31]=[CH:32][CH:33]=[C:28]([F:27])[CH:29]=1
Reactant: C#Cc1cccc(F)c1
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Product: O=C(N1CCc2ccc(Cl)c(C#Cc3cccc(F)c3)c2CC1)C(F)(F)F
Yield: 62.4 %

Procedure:
Use a method similar to the General Procedure 3 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (425 mg, 1 mmol) with (3-fluorophenyl)-ethyne (241 mg, 2 mmol). Purify by chromatography on silica gel eluting with isohexane/EtOAc (1:0 to 1:1 gradient over 40 min) to give 7-chloro-6-(3-fluoro-phenylethynyl)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (247 mg, 64%). MS (ES+) m/z: 396 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]1[CH:19]=[C:18]2[C@:13]([CH3:21])([CH2:14][CH2:15][C:16](=[O:20])[CH2:17]2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C@@H:7]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:34])([F:33])[F:32])=[O:23])[CH2:6][CH2:5]1.Cl>O1CCOCC1>[CH3:1][CH:2]1[CH2:19][C:18]2[C@:13]([CH3:21])([CH2:14][CH2:15][C:16](=[O:20])[CH:17]=2)[C@@H:12]2[C@@H:3]1[C@H:4]1[C@@:8]([CH2:10][CH2:11]2)([CH3:9])[C@@H:7]([C:22]([NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:33])[F:34])=[O:23])[CH2:6][CH2:5]1
Reactant: CC1C=C2CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)Nc4ccccc4C(F)(F)F)CC[C@H]3[C@H]12
Agent: Cl
Solvent: C1COCCO1
Product: CC1CC2=CC(=O)CC[C@]2(C)[C@H]2CC[C@]3(C)[C@@H](C(=O)Nc4ccccc4C(F)(F)F)CC[C@H]3[C@H]12

Procedure:
A solution of the compound from Step B (5-3) (0.057 g, 0.12 mmol), dioxane (0.5 mL) and 1.0 N HCl solution (0.5 mL) was heated to 50° C. for 2 hr. The reaction was then concentrated to yield the desired product as an 8:1 mixture of epimers at C-7.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH2:16][CH:15]2[CH:11]([CH2:12][NH:13][CH2:14]2)[CH2:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:18]1[CH:19]=[CH:20][C:21]2[N:22]([C:24]([C:27]([Cl:30])([F:29])[F:28])=[N:25][N:26]=2)[N:23]=1>>[CH2:2]([N:9]1[CH2:10][CH:11]2[CH2:12][N:13]([C:18]3[CH:19]=[CH:20][C:21]4[N:22]([C:24]([C:27]([Cl:30])([F:29])[F:28])=[N:25][N:26]=4)[N:23]=3)[CH2:14][CH:15]2[CH2:16]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(CN2CC3CNCC3C2)cc1
Reactant: FC(F)(Cl)c1nnc2ccc(Cl)nn12
Agent: Cl
Product: FC(F)(Cl)c1nnc2ccc(N3CC4CN(Cc5ccccc5)CC4C3)nn12
Yield: 66 %

Procedure:
A mixture of 2-benzylhexahydropyrrolo[3,4-c]pyrrole hydrochloride and 6-chloro-3-[chloro(difluoro)methyl]-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by an analogous method to Example 331 to give 6-(5-benzylhexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl)-3-[chloro(difluoro)methyl][1,2,4]triazolo[4,3-b]pyridazine in 66% yield.
Reaction SMILES: [NH:1]([C:3]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1)[NH2:2].[C:21]([O-])([O-])(OCC)[CH3:22].S(=O)(=O)(O)O>C(O)C>[CH3:21][C:22]1[N:4]2[C:5]3[C:10]([C:11]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)=[N:12][C:3]2=[N:1][N:2]=1)=[CH:9][C:8]([O:19][CH3:20])=[CH:7][CH:6]=3
Reactant: COc1ccc2nc(NN)nc(-c3ccccc3)c2c1
Reactant: CCOC(C)([O-])[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: COc1ccc2c(c1)c(-c1ccccc1)nc1nnc(C)n12

Procedure:
In the next place, to a solution of 2.0 g of 2-hydrazino-4-phenyl-6-methoxyquinazoline in 100 ml of ethanol were added 3.5 g of ethyl orthoacetate and 0.5 ml of concentrated sulfuric acid. The resulting mixture was refluxed for 3 hours and then the solvent was removed under reduced pressure. To the residue was added ammonia water to basify, and the mixture was extracted with chloroform. The extract was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo. To the residue was added ethanol and the crystallized product was collected by filtration, and dried to give 1-methyl-5-phenyl-7-methoxy-s-triazolo[4,3-a]quinazoline as slightly yellow needles, m.p. 251° - 252° C.
Reaction SMILES: S(C)C.ClCCl.[F:7][C:8]1[CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[C:11]2[O:16][CH:15]([C:17](O)=[O:18])[CH2:14][CH2:13][C:12]=2[CH:20]=1>O1CCCC1>[F:7][C:8]1[CH:9]=[C:10]([N+:21]([O-:23])=[O:22])[C:11]2[O:16][CH:15]([CH2:17][OH:18])[CH2:14][CH2:13][C:12]=2[CH:20]=1
Reactant: O=C(O)C1CCc2cc(F)cc([N+](=O)[O-])c2O1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CSC
Product: O=[N+]([O-])c1cc(F)cc2c1OC(CO)CC2
Yield: 103.9 %

Procedure:
A 1M solution of (CH3)2S.BH3 in dichloromethane (0.28 mol) was added dropwise to a mixture of intermediate 13-b (0.25 mol) in tetrahydrofuran (800 ml), stirred under N2 flow. About 60 ml of the solvent was removed by distillation. The reaction mixture was stirred and refluxed for 2 h. The mixture was cooled, decomposed with CH3OH (20 ml), poured out into H2O/NaOH and this mixture was extracted with CH2Cl2. The separated organic layer was washed with water, dried (MgSO4), filtered and the solvent was evaporated, yielding 59 g of (±)-6-fluoro-3,4-dihydro-8-nitro-2H-1-benzopyran-2-methanol (104% crude residue) (interm. 14-b).
Reaction SMILES: Br[C:2]1[C:3](=[O:32])[C:4]2[C:9]([C:10]=1[C:11]1[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=1)=[CH:8][CH:7]=[C:6]([O:19][CH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:24][CH2:23]1)[CH:5]=2.O1CCN(CCOC2C=C3C(C(C4C=CC=CC=4)=C(Br)C3=O)=CC=2)CC1.[CH3:59][O:60][C:61]1[N:66]=[C:65](B(O)O)[CH:64]=[CH:63][CH:62]=1>>[F:17][C:15]1[CH:16]=[C:11]([C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:19][CH2:20][CH2:21][CH:22]4[CH2:23][CH2:24][N:25]([S:28]([CH3:31])(=[O:30])=[O:29])[CH2:26][CH2:27]4)=[CH:7][CH:8]=3)[C:3](=[O:32])[C:2]=2[C:64]2[CH:65]=[N:66][C:61]([O:60][CH3:59])=[CH:62][CH:63]=2)[CH:12]=[C:13]([F:18])[CH:14]=1
Reactant: CS(=O)(=O)N1CCC(CCOc2ccc3c(c2)C(=O)C(Br)=C3c2cc(F)cc(F)c2)CC1
Reactant: COc1cccc(B(O)O)n1
Agent: O=C1C(Br)=C(c2ccccc2)c2ccc(OCCN3CCOCC3)cc21
Product: COc1ccc(C2=C(c3cc(F)cc(F)c3)c3ccc(OCCC4CCN(S(C)(=O)=O)CC4)cc3C2=O)cn1
Yield: 59 %

Procedure:
The procedure of Step 7 of Example 1 was repeated except for using 2-bromo-3-(3,5-difluorophenyl)-6-{2-[1-(methylsulfonyl)piperidin-4-yl]ethoxy}-1H-inden-1-one obtained in Step 3 as a starting material instead of 6-(2-morpholinoethoxy)-2-bromo-3-phenyl-1H-inden-1-one, 6-methoxypyridinylboronic acid instead of 3-pyridinylboronic acid, and being purified by silica gel column chromatography (EtOAc/CH2Cl2=1:1) to obtain the title compound (59%).
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH2:8][OH:9])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][CH:11]=2)[N:3]=1.C(N(C(C)C)C(C)C)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[CH3:1][C:2]1[C:7]([CH2:8][O:9][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:6][CH:5]=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([F:17])([F:19])[F:18])=[CH:12][CH:11]=2)[N:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.60 g (9.7 mmol) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-methanol (example 1M]) were dissolved in 50 ml MeCl2 and cooled down to 0° C. 2.55 ml=1.93 g (14.6 mmol) of N-ethyl diisopropylamine was added, followed by 0.85 ml=1.25 g (10.7 mmol) of methane sulfonylchloride, drop by drop. After stirring for 30 min. at ambient temperature, the reaction mixture was poured into crashed ice and extracted twice with MeCl2. The combined organic phases were washed with water and brine, dried over anhydrous magnesium sulfate and evaporated. This gave 3.44 g of crude title compound as yellow solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11](C2C=C(Cl)C=CC=2Cl)[C@H](C)CCN2CCCCC2CS(C)(=O)=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.ClC1C=CC(S(N(C2C=C(Cl)C=CC=2Cl)[C@H](C)CCBr)(=O)=O)=CC=1.[K+].[Br-]>>[C:5]1([S:8]([NH2:11])(=[O:10])=[O:9])[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: C[C@H](CCN1CCCCC1CS(C)(=O)=O)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: C[C@H](CCBr)N(c1cc(Cl)ccc1Cl)S(=O)(=O)c1ccc(Cl)cc1
Agent: [Br-]
Agent: [K+]
Product: NS(=O)(=O)c1ccccc1
Yield: 6 %

Procedure:
4-chloro-N-2,5-dichlorophenyl)-N-3-(2-carboxymethyl-3-thiazolidinyl)-1(R)-methylpropyl)-benzenesulfonamide was prepared analogous to 4-chloro-N-(2,5-dichlorophenyl)-N-(3-(2-((methylsulfonyl)methyl)-1-piperidinyl)-1(R)-methylpropyl)benzenesulfonamide by reacting 4-chloro-N-[2,5-dichlorophenyl]-N-[(R)-1-methyl-3-bromopropyl]benzenesulfonamide with 2-carboxymethyl-3-thiazolidine. Yield=6%; White powder: IR (KBr) 1747, 1467, 1352, 1166, 1094, 622 cm−1; MS (ESI+), 537 (M+H)+.
Reaction SMILES: [H-].[Na+].[C:3]([O:11][CH2:12][CH3:13])(=[O:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[C:15]1[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][N:16]=1.Cl>O1CCOCC1.[Cu](Cl)Cl.C(OCC)(=O)C.O>[Cl:21][C:20]1[C:15]([CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[C:3]([O:11][CH2:12][CH3:13])=[O:10])=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: CCOC(=O)CC(=O)OCC
Reactant: Clc1cccnc1Cl
Agent: Cl[Cu]Cl
Agent: Cl
Agent: [H-]
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C(=O)OCC)c1ncccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.4 %

Procedure:
8.73 g of sodium hydride (55% oil dispersion) was suspended in 100 ml of 1,4-dioxane. Into this, 32.03 g of diethyl malonate was added dropwise over a period of about 1 hour at 60° C. under a nitrogen atmosphere. The mixture was stirred at the same temperature further for 0.5 hours, then, to the mixture was added 8.26 g of copper chloride (I). Thereafter, into the mixture, a solution prepared by dissolving 12.23 g of 2,3-dichloropyridine in 50 ml of 1,4-dioxane was added dropwise at 80° C. The mixture was stirred for 22.5 hours under reflux with heating. The reaction mixture was allowed to cool to room temperature, and to the reaction mixture was added 15 ml of concentrated hydrochloric acid. To the mixture were added water and ethyl acetate, and the mixture was filtrated through celite. The filtrate was liquid-separated. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. 46.65 g of the resultant residue was subjected to silica gel column chromatography, to obtain 3.90 g of diethyl (3-chloro-2-pyridyl)malonate.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(OCC)(=O)C.[CH3:29][N:30]1CCCC1=O>[Cu+]>[C:29]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])(=[O:10])=[O:9])=[CH:4][CH:3]=1)#[N:30]
Reactant: N#Cc1cccc(OCCNS(=O)(=O)c2ccc(Br)cc2)c1
Reactant: CN1CCCC1=O
Agent: [Cu+]
Solvent: CCOC(C)=O
Product: N#Cc1ccc(S(=O)(=O)NCCOc2cccc(C#N)c2)cc1
Temperature: 140 °C
Reaction time: 8 h

Procedure:
300 mg (0.84 mmol) of 3-[2-(4-bromobenzenesulfonylamino)ethoxy]benzonitrile was dissolved in 1 ml of N-methylpyrrolidone. 76 mg (0.84 mmol) of copper (I) cyamide was added to the solution, and they were stirred at 140° C. overnight. The crude product was obtained by the treatment with ethyl acetate as the extractant in an ordinary manner. After the silica gel column chromatography, the title compound was obtained.
Reaction SMILES: [CH3:1][N:2]([CH:21]([CH3:23])[CH3:22])[CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[C:14][Si](C)(C)C)=[CH:10][CH:11]=2)[C:6]([CH3:20])([CH3:19])[CH2:5][CH2:4]1.CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[C:13]([C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[CH:3]([N:2]([CH:21]([CH3:22])[CH3:23])[CH3:1])[CH2:4][CH2:5][C:6]2([CH3:19])[CH3:20])#[CH:14]
Reactant: CC(C)N(C)C1CCC(C)(C)c2cc(C#C[Si](C)(C)C)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: C#Cc1ccc2c(c1)C(C)(C)CCC2N(C)C(C)C
Yield: 80 %

Procedure:
Following general procedure E and using 1-(methyl-iso-propylamino)-4,4-dimethyl-6-trimethylsilanylethynyl-1,2,3,4-tetrahydro-naphthalene (Intermediate 28, 0.14 g, 0.45 mmol), methanol (5 mL), potassium carbonate (0.61 g, 4.41 mmol) and ethyl acetate the title compound (0.092 g, 80%) was obtained as an oil.
Reaction SMILES: [CH3:1][C:2]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N+:16]#[C-:17])(=[O:8])=[O:7])([CH3:4])[CH3:3].O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[Cl-].[NH4+]>C1COCC1.C1CCCCC1>[CH3:4][C:2]([NH:5][S:6]([C:9]1[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:16][CH:17]=1)(=[O:8])=[O:7])([CH3:1])[CH3:3]
Reactant: [C-]#[N+]c1ccccc1CS(=O)(=O)NC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)NS(=O)(=O)c1c[nH]c2ccccc12
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 90 %

Procedure:
A solution of 25.2 g (0.10 mol) of N-(1,1-dimethylethyl)-2-isocyanobenzenemethanesulfonamide in 600 mL anhydrous THF was cooled to -70° C. under nitrogen atmosphere and treated with 147 mL (0.22 mol) 1.5M lithium diisopropylamide mono(tetrahydrofuran) in cyclohexane at such a rate as to keep the temperature under -60° C. The mixture was stirred at -70° C. for 15 minutes then warmed to 0° C. Saturated ammonium chloride solution (75 mL) was then added and the product was extracted with two 200 mL portions of ethyl acetate. The organic extract was washed with 10% HCl, brine, dried (MgSO4) and evaporated in vacuo. The resulting residue was triturated with ether/n-butyl chloride and collected by filtration to afford 22.7 g of the title compound, m.p. 157°-158° C.
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:26])[C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18]3[CH:23]=[C:22]([NH2:24])[N:21]=[C:20]([NH2:25])[N:19]=3)[CH:12]=2)=[CH:5][CH:4]=1.[Cl:27][C:28]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=[CH:30][CH:29]=1.Cl.CO.CCOC(C)=O>CCO.O.CCOC(C)=O.CO>[ClH:27].[ClH:1].[NH2:25][C:20]1[N:19]=[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[C:10]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([NH:2][C:28]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=[CH:30][CH:29]=3)=[CH:4][CH:5]=2)=[O:26])[CH:23]=[C:22]([NH2:24])[N:21]=1
Reactant: Clc1ccnc2ccccc12
Reactant: Nc1ccc(NC(=O)c2cccc(Nc3cc(N)nc(N)n3)c2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: CCOC(C)=O
Product: Nc1cc(Nc2cccc(C(=O)Nc3ccc(Nc4ccnc5ccccc45)cc3)c2)nc(N)n1
Temperature: 20 °C

Procedure:
To a solution of compound B6 (150 mg, 0.37 mmol) in EtOH (15 mL) and H2O (7.5 mL) was added 4-chloroquinoline (73 mg, 0.45 mmol) and stirred until it dissolved, then 2 drops of c.HCl was added. The reaction mixture was refluxed for 20 h, diluted with EtOAc, brought to boil and cool to 20° C. The resulting precipitate was filtered and stirred in aqueous NH3 (20 ml) to convert to free base. This new precipitate was filtered and chromatographed (neutral Al2O3, 0-7% DCM/MeOH) to give pure free base of the product. This was then converted to HCl salt by using 1.25 M HCl in MeOH to give Cpd. FF2 (139 mg, 70%); m.p (MeOH/EtOAc)>300° C. 1H NMR [(CD3)2SO] δ 14.25 (br, 1H, N+H), 12.00 (br, 1H, N+H), 10.95 (s, 1H, NH), 10.53 (s, 1H, NH), 9.93 (s, 1H, NH), 9.05 (d, J=8.5 Hz, 1H, ArH), 7.51 (d, J=7.0 Hz, 1 H, ArH), 8.06-8.00 (m, 5H, ArH), 7.95-7.91 (br m, 2H, NH2), 7.81 (d d, J=7.6, 1.4 Hz, 1H, ArH), 7.71 (d, J=7.6 Hz, 1H, ArH), 7.58 (s, 2H, NH2), 7.57-7.47 (m, 5 H, ArH), 6.78 (d, J=7.0 Hz, 1H, ArH), 6.78 (d, J=7.0 Hz, 1H, ArH), 5.46 (s, 1H, ArH); HRMS (FAB+) calc. for C26H23N8O (M+1) m/z 463.1995, found 463.1992.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH2:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:19](OC(=O)C)(=[O:21])[CH3:20]>C(Cl)Cl.C(OCC)(=O)C>[Br:1][C:2]1[CH:11]=[CH:10][C:5]([O:6][CH2:7][CH2:8][NH:9][C:19](=[O:21])[CH3:20])=[CH:4][CH:3]=1
Reactant: CC(=O)OC(C)=O
Reactant: NCCOc1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NCCOc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67.4 %

Procedure:
To a solution of 2-(4-bromophenoxy)ethanamine (500 mg, 2.3 mmol) in CH2Cl2 (20 mL) was added triethylamine (700 mg, 6.9 mmol) and acetic anhydride (470 mg, 4.6 mmol). The reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo to give a yellow residue. The crude product was diluted with ethyl acetate (20 mL), washed with 1N HCl followed by saturated sodium bicarbonate, dried over sodium sulfate and concentrated in vacuo to give N-[2-(4-bromophenoxy)ethyl]acetamide (400 mg, 67%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.39 (d, 2H), 6.76 (d, 2H), δ 5.89 (m, 1H), 4.00 (m, 2H), 3.67 (m, 2H), δ 2.01 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([CH:27]=C)=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.[O:29]1CCOCC1.I([O-])(=O)(=O)=O.[Na+]>O.[Os](=O)(=O)(=O)=O>[F:1][C:2]1[C:3]([C:8]2([CH2:12][N:13]([C:21]3[N:22]=[N:23][C:24]([CH:27]=[O:29])=[CH:25][CH:26]=3)[C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:11][CH2:10][CH2:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=Cc1ccc(N(CC2(c3ncccc3F)CCC2)C(=O)OC(C)(C)C)nn1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: CC(C)(C)OC(=O)N(CC1(c2ncccc2F)CCC1)c1ccc(C=O)nn1
Reaction time: 2 h
Yield: 41 %

Procedure:
t-Butyl (1-(3-fluoropyridin-2-yl)cyclobutyl)methyl(6-vinylpyridazin-3-yl)carbamate (3.4 g, 8.84 mmol) was added as a dioxane (100 mL) solution to a mixture of sodium periodate (10.8 g, 50.5 mmol) and 4% osmium tetraoxide solution (6.5 mL) in H2O (30 mL) at 0° C. The reaction was stirred for 2 h. The reaction mixture was filtered through a pad of celite and washed with EtOAc. The organic layer was washed with satd. aq. NaHCO3, brine and dried over sodium sulfate, filtered, and concentrated. Silica gel chromatography provided a colorless oil (1.4 g, 41%), (m/z [M+H]=387.2).