Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]4[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=4)[N:11]=3)[N:7](COCC[Si](C)(C)C)[C:6]=2[CH:32]=1.[F:33][C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[Na+].[Na+].O=O>O1CCOCC1.C(OCC)(=O)C.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>[F:33][C:34]1[CH:39]=[CH:38][C:37]([C:2]2[CH:3]=[CH:4][C:5]3[N:9]=[C:8]([C:10]4[CH:14]=[C:13]([CH3:15])[N:12]([CH2:16][C:17]5[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=5)[N:11]=4)[NH:7][C:6]=3[CH:32]=2)=[CH:36][CH:35]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Cc1ccc(Cn2nc(-c3nc4ccc(Br)cc4n3COCC[Si](C)(C)C)cc2C)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: O=O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2nc(-c3nc4ccc(-c5ccc(F)cc5)cc4[nH]3)cc2C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 38.3 %

Procedure:
To a solution of 6-bromo-2-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole (Step 1, 150 mg, 0.29 mmol) in dioxane (5 mL) was added (4-fluorophenyl)boronic acid (49 mg, 0.35 mmol) followed by sodium carbonate solution (2.0 M aq., 0.44 mL, 0.88 mmol), and the resultant mixture was freed from oxygen by bubbling a gentle stream of nitrogen through the solution for 10 min. Tetrakis(triphenylphosphine)palladium(0) (34 mg, 0.03 mmol) was then added and the mixture was refluxed for 5 hr. After being cooled to rt, the mixture was diluted with ethyl acetate (50 mL) and washed with water (1×25 mL). The combined organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting crude material was suspended in dichloromethane (2 mL), TFA (2 mL) was added, and the mixture was stirred at rt for 16 h. The volatiles were removed under reduced pressure and the crude product was purified by HPLC eluting with a gradient from 20% to 80% acetonitrile in water containing 0.1% TFA. The combined fractions were then diluted with ethyl acetate and washed with sat. NaHCO3 solution (1×50 mL), dried (Na2SO4), filtered, and concentrated under reduced pressure to afford the title compound as a light yellow solid (44 mg, 38%): 1H NMR (300 MHz, CD3OD) δ 7.75 (bs, 1H), 7.63-7.69 (m, 3H), 7.52 (dd. 1H), 7.11-7.20 (m, 6H), 6.78 (s, 1H), 5.40 (s, 2H), 2.30 (s, 6H); ES-MS m/z 397.22, HPLC RT (Method B) 3.21 min.
Reaction SMILES: [CH3:1][C:2]1[C:3]([Se:16][C:17]2[CH:25]=[CH:24][C:20]([C:21](O)=O)=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1.C1(C)C=CC=CC=1.S(Cl)([Cl:35])=O>CN(C=O)C>[CH3:1][C:2]1[C:3]([Se:16][C:17]2[CH:25]=[CH:24][C:20]([CH2:21][Cl:35])=[CH:19][N:18]=2)=[CH:4][C:5]2[C:6]([CH3:15])([CH3:14])[CH2:7][CH2:8][C:9]([CH3:13])([CH3:12])[C:10]=2[CH:11]=1
Reactant: Cc1cc2c(cc1[Se]c1ccc(C(=O)O)cn1)C(C)(C)CCC2(C)C
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc2c(cc1[Se]c1ccc(CCl)cn1)C(C)(C)CCC2(C)C

Procedure:
2 g (5 mmol) of 6-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydro-2-naphthylselanyl)nicotinic acid, 20 ml of toluene, 100 μl of DMF and 450 μl of thionyl chloride are introduced into a round-bottomed flask. The reaction medium is refluxed for one hour and evaporated. 100% of the expected acid chloride are collected, this product being used for the rest of the synthesis without further purification.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)[S:7]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)=[C:12]([F:28])[C:11]=1[F:29])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:29][C:11]1[C:12]([F:28])=[C:13]([O:16][C@H:17]2[CH2:21][CH2:20][CH2:19][C@@H:18]2[C:22]2[N:26]([CH3:27])[N:25]=[CH:24][CH:23]=2)[CH:14]=[CH:15][C:10]=1[S:7]([NH:6][C:30]1[CH:35]=[CH:34][N:33]=[CH:32][N:31]=1)(=[O:8])=[O:9]
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2ccc(O[C@H]3CCC[C@@H]3c3ccnn3C)c(F)c2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC[C@@H]1Oc1ccc(S(=O)(=O)Nc2ccncn2)c(F)c1F
Yield: 42 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,3-difluoro-4-{[(1S*,2R*)-2-(1-methyl-1H-pyrazol-5-yl)cyclopentyl]oxy}-N-(pyrimidin-4-yl)benzenesulfonamide (190 mg, 0.32 mmol) prepared in Example 30b, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (58.5 mg, 41%) as a colorless solid.
Reaction SMILES: C[SiH](C)O.C([Si](C=C)(C)Cl)=C.[CH3:12][Si:13]([O:20][SiH3:21])(C)[CH:14]([CH:17]=[CH2:18])[CH:15]=[CH2:16]>C1COCC1>[CH:15]([CH:14]([CH:17]=[CH2:18])[SiH:13]([O:20][SiH3:21])[CH3:12])=[CH2:16]
Reactant: C=CC(C=C)[Si](C)(C)O[SiH3]
Agent: C=C[Si](C)(Cl)C=C
Agent: C[SiH](C)O
Solvent: C1CCOC1
Product: C=CC(C=C)[SiH](C)O[SiH3]

Procedure:
The prepared di-methyl silanol was added into a THF solution along with divinyl methyl chlorosilane with a molar ratio of about 1:1, simultaneously. The reacted product was methyl divinyl siloxy dimethyl silane, which was an AB2 type monomer and represented by previously described chemical formula (1), reproduced below.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:18](O)=[O:19])=[N:14][CH:15]=[CH:16][N:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.CCN(C(C)C)C(C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:18]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[O:19])=[N:14][CH:15]=[CH:16][N:17]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:21]([F:24])([F:22])[F:23]
Reactant: C1COCCN1
Reactant: O=C(O)c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(c1nccnc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)N1CCOCC1
Yield: 59.3 %

Procedure:
To a mixture of 20 mg of 3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyrazine-2-carboxylic acid, 10 mg of morpholine and 20 μl of DIEA in 1.5 mL of CH2Cl2 was added 32 μL of 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate). After 3-4 hours the reaction mixture was directly purified via flash column (65% ethyl acetate in hexane) to afford 14 mg of 4-chloro-N-[3-(morpholine-4-carbonyl)-pyrazin-2-yl]-3-trifluoromethyl-benzenesulfonamide as a white powder. MS: (M+H)/z=451.0.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]1[C:12]([CH3:13])=[CH:11][C:10]([Cl:14])=[CH:9][N:8]=1.[N+](N[C:19]1[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]2[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=2)=[CH:21][N:20]=1)([O-])=O.Cl>O>[Cl:14][C:10]1[CH:11]=[C:12]([CH3:13])[C:7]([NH:6][CH2:5][CH2:4][CH2:3][CH2:2][NH:1][C:19]2[NH:24][C:23](=[O:25])[C:22]([CH2:26][C:27]3[CH:28]=[N:29][C:30]([CH3:33])=[CH:31][CH:32]=3)=[CH:21][N:20]=2)=[N:8][CH:9]=1
Reactant: Cc1ccc(Cc2cnc(N[N+](=O)[O-])[nH]c2=O)cn1
Reactant: Cc1cc(Cl)cnc1NCCCCN
Agent: Cl
Solvent: O
Product: Cc1ccc(Cc2cnc(NCCCCNc3ncc(Cl)cc3C)[nH]c2=O)cn1
Yield: 38.9 %

Procedure:
2-(4-Aminobutylamino)-5-chloro-3-methylpyridine (1.81 g) and 2-nitroamino-5-(6-methylpyrid-3ylmethyl)-4-pyrimidone (1.95 g) were fused together on an oil bath at 140°-50° C. for 2 hr. On cooling the mixture was treated with water and dilute hydrochloric acid and some solid material removed at pH 4. On raising the pH to 5 a precipitate was obtained which on recrystallising twice from dimethyl formamide/water gave 2-[4-(5-chloro-3-methylpyrid-2-ylamino)butylamino]-5-(6-methylpyrid-3-ylmethyl)-4-pyrimidone (1.2 g; 39%) m.p. 202°-3° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1I.[C:14]([Cu])#[N:15]>CN(C=O)C.C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:14]#[N:15]
Reactant: N#C[Cu]
Reactant: FC(F)(F)c1cc(Cl)c(I)c(Br)c1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#Cc1c(Cl)cc(C(F)(F)F)cc1Br
Temperature: 100 °C

Procedure:
1-bromo-3-chloro-2-iodo-5-(trifluoromethyl)benzene (8.0 g, 20.6 mmol) and CuCN (1.9 g, 20.6 mmol) were dissolved in DMF (20 mL) and heated 100° C. After 2 h the temperature was increased to 110° C. After 3 h the reaction was cooled to room temperature, diluted with DCM, filtered, concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([N:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.C([BH3-])#N.[Na+].C(OC)(OC)OC.[CH:40](=O)[CH2:41][CH3:42]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([N:23]2[CH2:24][CH2:25][N:26]([CH2:40][CH2:41][CH3:42])[CH2:27][CH2:28]2)=[O:22])=[CH:19][CH:20]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CCC=O
Reactant: O=C(c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1)N1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CCCN1CCN(C(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The compound (48.8 mg) obtained in Example 32-2 was dissolved in anhydrous methanol (1.0 ml) and then added with sodium cyanoborohydride (16.2 mg), trimethyl orthoformate (21.1 μl), propionaldehyde (13.9 μl), followed by stirring overnight at room temperature under a nitrogen atmosphere. After completion of the reaction, the solvent was distilled off and the residue was then dissolved in chloroform. A saturated aqueous sodium bicarbonate solution was added to the solution, followed by stirring. The resultant solution was subjected to extraction with chloroform and washed with a saturated aqueous sodium bicarbonate solution and saturated saline solution, and then the organic layer was dried with anhydrous sodium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the treated product was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (33.2 mg) of the subject compound as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24][Si]([NH-])(C)C.C[Si]([NH-])(C)C.[K+].[K+].IC.C(OCC)(=O)C.CCCCCCC>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[S:15][C:16]([S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCS(=O)(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Reactant: C[Si](C)(C)[NH-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: CC(C)S(=O)(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)s1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 30 %

Procedure:
To a solution of 0.83 mmol 4-(5-ethanesulfonyl-thiazol-2-yl)-piperazine-1-carboxylic acid tert-butyl ester (Example 32(b)) in 3 ml tetrahydrofuran at −78° C. was added dropwise 1.08 mmol potassium bis(trimethylsilylamide) solution (0.91 M in tetrahydrofuran). After 3 min, a solution of 1.24 mmol iodomethane in 2 ml tetrahydrofuran was added dropwise and stirring continued for 10 min at −78° C. The reaction mixture was then allowed to warm to room temperature and poured onto tetrahydrofuran/ethyl acetate (1:1). The mixture was washed with brine and the organic phase was dried over sodium sulphate and concentrated in vacuo. Chromatography (SiO2, ethyl acetate/heptane) afforded the title compound as a white crystalline solid (yield 30%). MS (m/e): 376.1 (M+H+, 100%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19](C(O)=O)=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33].[CH3:34][S:35](C1C=CC(N)=NC=1)(=[O:37])=[O:36]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([CH2:11][CH2:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][C:19]([S:35]([CH3:34])(=[O:37])=[O:36])=[CH:18][N:17]=1)=[O:14])[N:8]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([F:32])=[CH:28][CH:27]=1)[C:7]2=[O:33]
Reactant: O=C(CCC1c2c(F)cccc2C(=O)N1Cc1ccc(F)cc1)Nc1ccc(C(=O)O)cn1
Reactant: CS(=O)(=O)c1ccc(N)nc1
Product: CS(=O)(=O)c1ccc(NC(=O)CCC2c3c(F)cccc3C(=O)N2Cc2ccc(F)cc2)nc1

Procedure:
The product of Example 11, Part D (0.175 g, 0.529 mmol) and 5-Methanesulfonyl-pyridin-2-ylamine (91 mg, 0.529 mmol) were converted to the title compound in a manner analogous to the method described in Example 27 (159 mg, 62%). 1H NMR (400 MHz, CDCl3) d 8.74 (s, 1H); 8.30 (d, J=8.8 Hz, 1H), 8.18 (d, J=8.8 Hz, 1H), 8.09 (broad s, 1H), 7.69 (d, J=7 Hz, 1H); 7.49-7.44 (m, 1H), 7.33-7.30 (m, 2H), 7.23 (t, J=8.8 Hz, 1H); 7.04 (t, J=8.6 Hz, 2H); 5.25 (d, J=15 Hz, 1H), 4.73 (m, 1H), 4.28 (d, J=15 Hz, 1H), 3.18 (s, 3H); 2.61-2.59 (m, 1H); 2.53-2.50 (m, 1H); 2.04-1.97 (m, 2H). MS: m/z (MH+) 486.
Reaction SMILES: [Br:1][C:2]1[C:11]2[S:12][C:13]([CH3:16])=[C:14]([CH3:15])[C:10]=2[C:9]([C:17]2[CH:22]=[C:21]([CH3:23])[C:20]([OH:24])=[C:19]([CH3:25])[CH:18]=2)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[CH:7]2.O[C@@H:27]([CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:28]([O:30][CH3:31])=[O:29].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1C=CC=CC=1>[CH3:31][O:30][C:28](=[O:29])[C@H:27]([O:24][C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:9]2[C:10]3[C:14]([CH3:15])=[C:13]([CH3:16])[S:12][C:11]=3[C:2]([Br:1])=[C:3]3[C:8]=2[CH:7]=[CH:6][CH:5]=[CH:4]3)=[CH:18][C:19]=1[CH3:25])[CH2:32][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccccc1
Product: COC(=O)[C@@H](Cc1ccccc1)Oc1c(C)cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.8 %

Procedure:
To a solution of 4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2,6-dimethyl-phenol (5.0 g, 12.1 mmol), (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (3.3 g, 18.3 mmol), and triphenylphosphine (4.8 g, 18.3 mmol) in anhydrous benzene (50 mL) at room temperature under nitrogen was added dropwise diethyl azodicarboxylate (2.6 mL, 18.3 mmol) over a period of 25 min. The reaction mixture was heated for 2 h, then stirred at room temperature for 3 days. The crude reaction mixture was adsorbed onto silica gel and chromatographed twice with petroleum ether:ethyl acetate (95:5) to yield the title compound as a white foamy solid (4.5 g, 65%): NMR (DMSO-d6): δ8.18 (d, 1H), 7.64 (ddd, 1H), 7.53-7.43 (m, 2H), 7.38-7.24 (m, 5H), 7.00 (s, 2H), 4.80 (t, 1H), 3.58 (s, 3H), 3.31 (m, 2H), 2.42 (s, 3H), 2.24 (s, 3H), 2.19 (s, 3H), 1.55 (s, 3H); MS(EI): [M+], 1 bromine isotope pattern, 572/574; Anal. Calc. for C32H29BrO3S: C, 67.01; H, 5.10; N, 0.00. Found: C, 66.33; H, 5.09; N, 0.09; Analytical HPLC indicates a major component (94.39%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:13])([F:12])([F:11])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[H-].[Na+].[CH3:19]N(C=O)C.IC>O>[CH3:19][NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([F:11])([F:12])([F:13])([F:10])[F:9])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: CN(C)C=O
Reactant: Nc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CNc1ccc(S(F)(F)(F)(F)F)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a mixture of 4-amino-3-nitro-phenyl sulfur pentafluoride (2.0 g), 60% sodium hydride (oil) (310 mg) and DMF (15 ml) was added dropwise iodomethane (447 μL) while ice-cooling. After that, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was poured water, and the precipitated solid was collected by filtration. The solid was washed with water and dried to give methyl-(2-nitro-4-pentafluorosulfanyl-phenyl)-amine (2.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:14])[C:12]=1[OH:13])[C:5]([O:7][CH2:8][CH3:9])=[O:6].Cl[CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1.[OH-].[K+].[I-].[K+]>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([Cl:14])[C:12]=1[O:13][CH2:16][CH2:17][CH2:18][C:19]1[O:23][N:22]=[C:21]([CH3:24])[CH:20]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1cc(CCCCl)on1
Reactant: CCOC(=O)c1cc(Cl)c(O)c(Cl)c1
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCOC(=O)c1cc(Cl)c(OCCCc2cc(C)no2)c(Cl)c1
Yield: 91.4 %

Procedure:
To a mixture of 10.05 g ethyl 3,5-dichloro-4-hydroxybenzoate and 8.0 g 5-(3-chloropropyl)-3-methylisoxazole in 550 ml dry acetonitrile was added 4.87 g potassium hydroxide and 12.9 g potassium iodide. The reaction mixture was stirred at reflux overnight and then filtered and concentrated in vacuo. The residue was partitioned between ethyl acetate and water and the organic layer concentrated to a yellow oil. The latter was crystallized from ethyl acetate-hexane (1:4) at -50° C. to give 14 g of product, 12 g of which was used directly in the following hydrolysis reaction. A sample of the ester was purified by chromatography on silica to give pure compound, m.p. 49°-50° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:15])[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH3:13])[O:7][C:6]=2[CH:14]=1.[CH3:16][S:17]([O-:19])=[O:18].[Na+].N1CCC[C@H]1C(O)=O>[Cu](I)I.CS(C)=O>[F:15][C:4]1[C:5]2[CH2:10][O:9][CH:8]([CH2:11][NH:12][CH3:13])[O:7][C:6]=2[CH:14]=[C:2]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:3]=1
Reactant: CS(=O)[O-]
Reactant: CNCC1OCc2c(F)cc(Br)cc2O1
Agent: I[Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: [Na+]
Solvent: CS(C)=O
Product: CNCC1OCc2c(F)cc(S(C)(=O)=O)cc2O1
Yield: 9.1 %

Procedure:
Preparation according to Example 17 with a small alteration, no base used. 1-(7-bromo-5-fluoro-4H-1,3-benzodioxin-2-yl)-N-methylmethanamine (0.33 g, 1.2 mmol), sodium methanesulfinate (0.18 g, 1.49 mmol, 85%), copperiodide (23 mg, 0.12 mmol), L-proline (69 mg, 0.60 mmol) and DMSO (6.0 ml) was heated at 140° C. for 45 min. Purification by flash column chromatography (EtOAc/MeOH 4:1) afforded the title compound (30 mg, 10%). The amine was converted into the hydrochloric acid salt and crystallized from MeOH/EtOH/DEE. The crystals were washed thoroughly with DEE. M.p. 234° C. 1H-NMR (400 MHz, MeOH): δ 7.28 (2H, m), δ 5.26 (1H, t, J 4.8 Hz), δ 5.05 (2H, dd, J1 20.4 Hz, J2 16.0 Hz), δ 3.13 (3H, s), δ 2.95 (2H, m), δ 2.47 (3H, s).
Reaction SMILES: [Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)=[C:14]([C:16]([O:18]C)=O)[N:15]=[C:7]3[C:6]=2[CH:28]=1.C[O-].[Na+].C([NH2:35])=O>>[Br:1][C:2]1[C:3]([F:29])=[CH:4][C:5]2[CH:11]3[CH2:12][CH:9]([CH2:10]3)[N:8]3[C:13]([CH:20]([OH:27])[C:21]4[N:25]([CH3:26])[CH:24]=[N:23][CH:22]=4)=[C:14]([C:16]([NH2:35])=[O:18])[N:15]=[C:7]3[C:6]=2[CH:28]=1
Reactant: NC=O
Reactant: COC(=O)c1nc2n(c1C(O)c1cncn1C)C1CC(C1)c1cc(F)c(Br)cc1-2
Agent: C[O-]
Agent: [Na+]
Product: Cn1cncc1C(O)c1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Yield: 66 %

Procedure:
10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was prepared similarly to as described in General Procedure L. Methyl 10-bromo-9-fluoro-3-(hydroxy(1-methyl-1H-imidazol-5-yl)methyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxylate was reacted with sodium methoxide and formamide to afford 127 mg (66% yield) of the crude title compound which was carried forward without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]1[CH:19]=[C:18]([F:20])[CH:17]=[C:16]([F:21])[CH:15]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O.[OH-].[NH4+]>C1COCC1>[CH3:22][O:11][C:10](=[O:12])[C@@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][C:14]1[CH:15]=[C:16]([F:21])[CH:17]=[C:18]([F:20])[CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)C(=O)O
Agent: [K+]
Agent: [NH4+]
Agent: [OH-]
Solvent: COS(=O)(=O)OC
Solvent: C1CCOC1
Product: COC(=O)[C@H](Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
(2S)-2-[(tert-butoxycarbonyl)amino]-3-(3,5-difluorophenyl)propanoic acid (1,5.0 g, 0.017 moles, 1.0 equivalent) and potassium carbonate (2.5 g, 0.018 moles, 1.1 equivalent) are mixed in THF (100 mL). To this heterogeneous mixture is then added dimethyl sulfate (1.6 mL, 2.1 g, 0.017 moles, 1.0 equivalent) and the contents were then stirred at 20-25° overnight. Once the reaction is complete as measured by HPLC, ammonium hydroxide (10%, 20 mL) is added and allowed to stir for 1 hr at which time the contents are extracted with ethyl acetate (3×50 mL). The combined organic phases are washed with water (50 mL) and saline (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure to give the title compound.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([NH:39][S:40]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)(=[O:42])=[O:41])[CH:36]=[N:37][CH:38]=2)O1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:24][S:21]([CH2:20][CH2:19][NH:18][CH:15]1[CH2:16][CH2:17][N:12]([C:8]2[CH:7]=[N:6][C:5]3[C:10]([N:9]=2)=[CH:11][C:2]([C:33]2[CH:34]=[C:35]([NH:39][S:40]([C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=4)(=[O:41])=[O:42])[CH:36]=[N:37][CH:38]=2)=[CH:3][CH:4]=3)[CH2:13][CH2:14]1)(=[O:23])=[O:22]
Reactant: CC1(C)OB(c2cncc(NS(=O)(=O)c3ccccc3)c2)OC1(C)C
Reactant: CS(=O)(=O)CCNC1CCN(c2cnc3ccc(Br)cc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CS(=O)(=O)CCNC1CCN(c2cnc3ccc(-c4cncc(NS(=O)(=O)c5ccccc5)c4)cc3n2)CC1
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A slurry of a 1-(7-bromo-2-quinoxalinyl)-N-[2-(methylsulfonyl)ethyl]-4-piperidinamine (0.48 mmol), N-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3-pyridinyl]benzenesulfonamide (0.53 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.03 mmol) in 1,4-dioxane (4 ml) and 2M solution potassium carbonate (2 ml) was stirred at 100° C. for 3 hours. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (10% methanol/ethyl acetate). The desired fractions were combined and concentrated to give the title compound (15 mg, 6%) as a tan solid. MS(ES)+ m/e 567.4 [M+H]+.
Reaction SMILES: FC1C=C(F)C=CC=1C1C=C(CN2C(=O)C3=CC=CC=C3C2=O)C(=O)N(CC(C)C)N=1.[C:32]([C:35]1[C:36](=[O:59])[N:37]([CH2:49][CH:50]=[CH:51][C:52]2[CH:57]=[CH:56][C:55]([Cl:58])=[CH:54][CH:53]=2)[N:38]=[C:39]([C:41]2[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH3:48])[CH:42]=2)[CH:40]=1)(O)=[O:33]>>[Cl:58][C:55]1[CH:54]=[CH:53][C:52]([CH:51]=[CH:50][CH2:49][N:37]2[C:36](=[O:59])[C:35]([CH2:32][OH:33])=[CH:40][C:39]([C:41]3[CH:46]=[CH:45][C:44]([F:47])=[C:43]([CH3:48])[CH:42]=3)=[N:38]2)=[CH:57][CH:56]=1
Reactant: Cc1cc(-c2cc(C(=O)O)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F
Agent: CC(C)Cn1nc(-c2ccc(F)cc2F)cc(CN2C(=O)c3ccccc3C2=O)c1=O
Product: Cc1cc(-c2cc(CO)c(=O)n(CC=Cc3ccc(Cl)cc3)n2)ccc1F

Procedure:
Following the procedure of Example 1 (8), 4-carboxy-2-(4-chlorocinnamyl)-6-(4-fluoro-3-methylphenyl)-2H-pyridazin-3-one was reacted to yield the title compound as slightly yellow needles (yield: 17.2%).