Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O-:4])([O-])=O.[K+].[K+].FC1C=C(OC)C=C(F)C=1CBr.[CH3:19][O:20][C:21]1C(C)=[CH:25][C:24]([N:28]2[C:33](=[O:34])[N:32]([CH2:35][C:36]3[C:41]([F:42])=[CH:40][C:39](F)=[CH:38][C:37]=3[F:44])[C:31]3[CH:45]=[CH:46][CH:47]=[CH:48][C:30]=3[S:29]2(=[O:50])=[O:49])=[CH:23][C:22]=1C.C[N:53](C=O)C>>[F:44][C:37]1[CH:38]=[C:39]([O:4][CH3:1])[CH:40]=[C:41]([F:42])[C:36]=1[CH2:35][N:32]1[C:31]2[CH:45]=[CH:46][CH:47]=[CH:48][C:30]=2[S:29](=[O:50])(=[O:49])[N:28]([C:24]2[CH:25]=[N:53][C:21]([O:20][CH3:19])=[CH:22][CH:23]=2)[C:33]1=[O:34]
Reactant: CN(C)C=O
Reactant: COc1c(C)cc(N2C(=O)N(Cc3c(F)cc(F)cc3F)c3ccccc3S2(=O)=O)cc1C
Reactant: O=C([O-])[O-]
Agent: COc1cc(F)c(CBr)c(F)c1
Agent: [K+]
Product: COc1cc(F)c(CN2C(=O)N(c3ccc(OC)nc3)S(=O)(=O)c3ccccc32)c(F)c1

Procedure:
The title compound (58 mg, 0.13 mmol) was prepared from (IntA15) (76 mg, 0.25 mmol), K2CO3 (104 mg, 0.75 mmol) and 2,6-difluoro-4-methoxybenzyl bromide (71 mg, 0.30 mmol) in DMF (2 mL) using the methods of (115).
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:2]([F:26])([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[C:13]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)n3)cccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)n3)cccc2s1

Procedure:
A solution of 4-[6-(4-trifluoromethyl-phenyl)-pyrazin-2-yloxy]-benzothiazol-2-ylamine (42 mg, 0.11 mmol), acetic anhydride (50 uL, 0.53 mmol) and pyridine (2 mL) was heated at 70° C. for 18 h. The solution was concentrated under a N2 stream and the resulting solid was purified by prep LC (10-90% CH3CN/H2O modified with 0.1% TFA) to give N-{4-[6-(4-trifluoromethyl-phenyl)-pyrazin-2-yloxy]-benzothiazol-2-yl}-acetamide as a white solid [MS (ESI, pos. ion) m/z: 431 (M+1)].
Reaction SMILES: [NH:1]([CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1)[NH2:2].[Cl:18][C:19]1[N:24]=[C:23](Cl)[C:22]([C:26]([NH:28][C:29]2[C:34]([Cl:35])=[CH:33][CH:32]=[CH:31][C:30]=2[Cl:36])=[O:27])=[CH:21][N:20]=1.C(N(CC)CC)C>C1COCC1>[Cl:18][C:19]1[N:20]=[C:21]([NH:2][NH:1][CH2:3][CH2:4][CH:5]2[CH2:6][CH2:7][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:9][CH2:10]2)[C:22]([C:26](=[O:27])[NH:28][C:29]2[C:30]([Cl:36])=[CH:31][CH:32]=[CH:33][C:34]=2[Cl:35])=[CH:23][N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CCNN)CC1
Reactant: O=C(Nc1c(Cl)cccc1Cl)c1cnc(Cl)nc1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CCNNc2nc(Cl)ncc2C(=O)Nc2c(Cl)cccc2Cl)CC1
Temperature: 25 °C
Reaction time: 66 h

Procedure:
A solution of 618 mg (2.5 mmol) of tert-butyl 4-(2-hydrazinylethyl)piperidine-1-carboxylate in 10 mL THF was cooled to 0° C. and treated sequentially with 763 mg (2.3 mmol) of 2,4-dichloro-N-(2,6-dichlorophenyl)pyrimidine-5-carboxamide and 355 μl (2.5 mmol) of triethylamine. The resulting yellow slurry was warmed to room temperature and stirred for 66 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (20 mL) and extracted with CH2Cl2 (3×30 mL). The combined organic layers were dried over Na2SO4, filtered, and the filtrate was purified by chromatography on silica gel (CH2Cl2:MeOH, 99.5:0.5 grading to CH2Cl2:MeOH, 98:2) to give the title compound 92. 1H-NMR (CDCl3) δ 1.08-1.23 (m, 3H), 1.45 (s, 9H), 1.58-1.66 (m, 2H), 1.72-1.79 (m, 2H), 2.61-2.75 (m, 2H), 3.87 (t, J=7.1 Hz, 2H), 3.99-4.14 (m, 4H), 7.24 (t, J=8.4 Hz, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.48 (s, 1H), 8.40 (s, 1H). Mass Spectrum (ESI) m/e=543.1 (M+1).
Reaction SMILES: [OH:1][C@H:2]1[CH2:23][CH2:22][C@@:21]2([CH3:24])[CH:4]([CH2:5][CH2:6][C:7]3[C:8]4[C@:17]([CH3:25])([CH2:18][CH2:19][C:20]=32)[C@@H:11]([C@@H:12]([CH3:16])[CH2:13][CH:14]=O)[CH2:10][CH:9]=4)[C:3]1([CH3:27])[CH3:26].[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:14][CH2:13][C@@H:12]([C@@H:11]3[C@:17]4([CH3:25])[C:8]([C:7]5[CH2:6][CH2:5][C@@H:4]6[C@:21]([C:20]=5[CH2:19][CH2:18]4)([CH3:24])[CH2:22][CH2:23][C@H:2]([OH:1])[C:3]6([CH3:27])[CH3:26])=[CH:9][CH2:10]3)[CH3:16])[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: C[C@@H](CC=O)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)C1CC3
Reactant: c1ccc(N2CCNCC2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: C[C@@H](CCN1CCN(c2ccccc2)CC1)[C@H]1CC=C2C3=C(CC[C@@]21C)[C@@]1(C)CC[C@H](O)C(C)(C)[C@@H]1CC3

Procedure:
(20S)-3β-hydroxy-4,4,20-trimethyl-pregna-8,14-dien-21-carbaldehyde was treated with N-phenylpiperazin and sodium tris(acetoxy)borohydride as described in Example 9d). (20S)-20-[(4-phenylpiperazin-1-yl)ethyl]-4,4-dimethyl-5α-pregna-8,14-dien-3β-ol was isolated as a white solid.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][C:14]1[N:18]([CH3:19])[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=1.CCN(C(C)C)C(C)C.[CH3:33][C:34]1[C:35]([CH2:40][N:41]([CH2:48][C:49]2[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][N:50]=2)[CH:42]2[CH2:47][CH2:46][NH:45][CH2:44][CH2:43]2)=[N:36][CH:37]=[CH:38][CH:39]=1>CN(C=O)C>[CH3:19][N:18]1[C:17]2[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=2[N:15]=[C:14]1[NH:13][C:1]([N:45]1[CH2:46][CH2:47][CH:42]([N:41]([CH2:48][C:49]2[C:54]([CH3:55])=[CH:53][CH:52]=[CH:51][N:50]=2)[CH2:40][C:35]2[C:34]([CH3:33])=[CH:39][CH:38]=[CH:37][N:36]=2)[CH2:43][CH2:44]1)=[O:2]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(N)nc2ccccc21
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2nc3ccccc3n2C)CC1
Yield: 26.8 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (80.1 mg, 0.494 mmol), 2-amino-1-methylbenzimidazole (70.8 mg, 0.481 mmol), and DIPEA (0.17 mL, 0.97 mmol) in DMF (5 mL) was stirred at room temperature for 2.5 h. To this solution was added DIPEA (0.17 mL, 0.97 mmol) and COMPOUND 249 (149 mg, 0.479 mmol), and the resultant solution was stirred at 60° C. overnight. The solution was concentrated to dryness, treated with saturated aqueous NaHCO3 (30 mL), and extracted with CH2Cl2 (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by flash chromatography on silica gel (CH2Cl2/MeOH/NH4OH, 92:4:4) provided COMPOUND 290 (62 mg, 27%) as a white solid. 1H NMR (CDCl3) δ 1.63-1.76 (m, 2H), 1.80-2.05 (m, 2H), 2.10 (s, 6H), 2.43-2.80 (m, 3H), 3.54 (s, 3H), 3.83 (s, 4H), 4.61 (br s, 1H), 4.90 (br s, 1H), 7.04-7.20 (m, 6H), 7.36 (d, 2H, J=7.2 Hz), 8.35 (d, 2H, J=1.2 Hz); 13C NMR (CDCl3) 18.43, 27.22, 28.22, 42.96, 45.27, 55.07, 58.34, 108.42, 110.29, 122.33, 122.36, 122.72, 129.12, 131.10, 133.84, 138.37, 146.25, 154.51, 157.80, 163.72; ES-MS m/z 506 (M+Na). Anal. Calcd. for C28H33N7O.0.9H2O: C, 67.28; H, 7.02; N, 19.62. Found: C, 67.19; H, 6.97; N, 19.50.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.[C-:25]#[N:26].[Na+]>O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][O:17][CH3:18])=[CH:11][C:10]=1[CH2:19][C:25]#[N:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: COCOc1ccc(OCc2ccccc2)c(CBr)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COCOc1ccc(OCc2ccccc2)c(CC#N)c1
Reaction time: 13 h
Yield: 91.2 %

Procedure:
To a mixture of 1-benzyloxy-2-bromomethyl-4-methoxymethoxybenzene (0.30 g) and dimethyl sulfoxide (3 mL) was added an aqueous solution (0.3 mL) of sodium cyanide (0.05 g) at room temperature and the mixture was stirred for 13 hrs. To the reaction mixture was added water and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give 2-(2-benzyloxy-5-methoxymethoxyphenyl)acetonitrile as a colorless oil (0.23 g, 92%).
Reaction SMILES: [ClH:1].Cl.Cl.[CH3:4][N:5]1[CH2:10][CH2:9][NH:8][CH:7]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:6]1.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26](Cl)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]>C(N(CC)CC)C>[ClH:17].[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]([CH2:25][C:26]([N:8]2[CH2:9][CH2:10][N:5]([CH3:4])[CH2:6][CH:7]2[CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[O:27])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CN1CCNC(CN2CCCC2)C1
Reactant: O=C(Cl)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)Cc2ccc(Cl)c(Cl)c2)C(CN2CCCC2)C1
Yield: 127.3 %

Procedure:
The procedure described in Example 17, but using 1.0 g of 1-methyl-3-(pyrrolidin-1-ylmethyl )piperazine trihydrochloride, 2.1 ml of triethylamine and 0.8 g of 3,4-dichlorophenylacetyl chloride, to afford 1.01 g of the title compound, melting at 223°-227° C. (dec.).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[CH:5]=2.[ClH:13].O.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1.C(O)(=O)C>C(O)(C)C>[ClH:13].[CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1)=[CH:8][CH:7]=[C:6]([O:11][CH3:12])[CH:5]=2
Reactant: O=C1CCNCC1
Reactant: COc1ccc2cc(C)[nH]c2c1
Agent: Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CC(C)O
Product: COc1ccc2c(C3=CCNCC3)c(C)[nH]c2c1
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
A mixture of 2 g of 2-methyl-6-methoxy-1H-indole, 4 g of the hydrochloride of 4-piperidone monohydrate and 40 ml of acetic acid was stirred at 100° C. under an inert atmosphere for 90 minutes and the mixture was cooled and poured into a solution of 150 g of ice and 80 ml of 22° Be ammonium hydroxide. The mixture was extracted with ethyl acetate and the organic phase was washed with water, dried over magnesium sulfate and evaporated to dryness and reduced pressure. The residue was empasted with hot ethyl acetate and the mixture was cooled and vacuum filtered. The product was washed with ethyl acetate and dried under reduced pressure to obtain 2.5 g of raw product which was dissolved in 50 ml of hot isopropanol. The solution was cooled and made acidic by dropwise addition of an isopropanol solution of gaseous hydrogen chloride. The mixture stood overnight after crystallization was induced and was vacuum filtered. The product was washed with isopropanol and was dried under reduced pressure to obtain 2.25 of 2-methyl-6-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indole hydrochloride melting at 270° C.
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[OH:5].[H-].[Na+].[CH3:17]I>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[CH:4]([C:6]1[O:7][CH:8]=[CH:9][CH:10]=1)[O:5][CH3:17]
Reactant: CI
Reactant: OC(c1ccco1)c1ccccc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(c1ccco1)c1ccccc1Cl
Reaction time: 1 h
Yield: 89.8 %

Procedure:
A soluton of (±) 2-(2-chloro-α-hydroxybenzyl)furan [prepared as described in (j) above] (31.3 g.) in dimethylformamide (100 ml.) was treated with sodium hydride (4.1 g.) with ice cooling. Methyl iodide (28.4 g.) was added to the stirred solution over 15 minutes at 15°-30° C. with ice cooling and the mixture was allowed to stand at ambient temperature for 1 hour. The mixture was then diluted with diethyl ether (300 ml.) and filtered. The filtrate was washed with water (3 × 500 ml.), dried over sodium sulphate and evaporated to give a light red oil, which was distilled to give (±) 2-(2-chloro-α-methoxybenzyl)furan (30 g.), b.p. 115° C./0.1 mm.Hg.
Reaction SMILES: C(O[CH:4]=[C:5]([C:11](=[O:22])[C:12]1[CH:17]=[C:16]([F:18])[C:15]([F:19])=[C:14]([Cl:20])[C:13]=1F)[C:6]([O:8][CH2:9][CH3:10])=[O:7])C.ClC1C(F)=C(C=C(F)C=1F)C(CC(OCC)=O)=O.[NH2:41][C:42]1[C:47]([Cl:48])=[CH:46][C:45]([F:49])=[C:44]([NH:50][C:51]([CH3:54])([CH3:53])[CH3:52])[N:43]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(Cl)(Cl)Cl>[C:51]([NH:50][C:44]1[N:43]=[C:42]([N:41]2[C:13]3[C:12](=[CH:17][C:16]([F:18])=[C:15]([F:19])[C:14]=3[Cl:20])[C:11](=[O:22])[C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4]2)[C:47]([Cl:48])=[CH:46][C:45]=1[F:49])([CH3:54])([CH3:52])[CH3:53]
Reactant: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1F
Reactant: CC(C)(C)Nc1nc(N)c(Cl)cc1F
Agent: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn(-c2nc(NC(C)(C)C)c(F)cc2Cl)c2c(Cl)c(F)c(F)cc2c1=O
Temperature: 90 °C
Reaction time: 0.42 h

Procedure:
To 3 ml chloroform solution of ethyl 3-ethoxy-2-(3-chloro-2,4,5-trifluorobenzoyl)acrylate prepared from 0.84 g of ethyl 3-chloro-2,4,5-trifluorobenzoylacetate by normal process was added 0.65 g of 2-amino-6-(t-butylamino)-3-chloro-5-fluoropyridine. The solution was concentrated under reduced pressure to obtain yellow solid residue. To this residue were added 0.7 g of anhydrous potassium carbonate and 3 ml of N,N-dimethylformamide, and the mixture was stirred at 90° C. for 25 minutes and allowed to cool. The solution was separated by adding 40 ml of chloroform and 300 ml of distilled water, and the chloroform layer was washed twice with 300 ml of distilled water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and allowed to stand. The precipitate was collected by filtration, washed with ethanol and diisopropylether successively to obtain 1.06 g of the title compound as a pale yellow powder.
Reaction SMILES: [CH2:1](N)[CH:2]([CH3:4])[CH3:3].[CH2:6]([N:8]([CH2:29][CH3:30])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH2:27])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH3:7]>C(O)C>[CH2:29]([N:8]([CH2:6][CH3:7])[CH2:9][CH:10]([N:12]1[C:25]2[CH:24]=[C:23]([C:26](=[S:28])[NH:27][CH2:1][CH:2]([CH3:4])[CH3:3])[CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH3:11])[CH3:30]
Reactant: CC(C)CN
Reactant: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(N)=S)cc21
Solvent: CCO
Product: CCN(CC)CC(C)N1c2ccccc2Sc2ccc(C(=S)NCC(C)C)cc21
Reaction time: 16 h

Procedure:
Isobutylamine (2.50 cc) is added to a solution of 10-[(2RS)-1-diethylamino-2-propyl]-2-phenothiazinecarbothioamide (1.86 g) in absolute ethanol (25 cc). The mixture is brought to 150° C. for 16 hours and then concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 50° C. The residue obtained is purified by chromatography on a column (height: 16.5 cm; diameter: 2.8 cm) silica gel (0.04-0.06 mm) with a slight excess presof sure of nitrogen (40 kPa), eluting with mixtures of cyclohexane and ethyl acetate in proportions (by volume) of 80:20 (1.5 liters) and 50:50 (1 liter), collecting 50-cc fractions. Fractions 4 to 15 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. to give 10-[(2RS)-1-diethylamino-2-propyl]-N-(2-methylpropyl)-2-phenothiazinecarbothioamide (1.3 g).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1.[NH4+].[Cl-]>C(Cl)Cl>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)(=[O:32])=[O:31])=[C:26]([CH3:34])[CH:25]=1
Reactant: Cc1cc(Br)ccc1S(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(Br)ccc1S(=O)(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,1-dimethylethyl 1-piperazinecarboxylate (1.86 g, 9.99 mmol, supplier Aldrich) and DIPEA (2.62 ml, 14.98 mmol) in dry DCM (20 ml) at 0° C. under argon was added 4-bromo-2-methylbenzenesulfonyl chloride (2.96 g, 10.99 mmol) and the resulting yellow solution allowed to warm to rt, then stirred at rt for 18 h. Semi-saturated NH4Cl (40 ml) was added, then the aq extracted with DCM (30 ml). The combined organics were passed through a hydrophobic frit, then concentrated in vacuo to give the title compound as a yellow gum that became a solid on standing (4.72 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:11][NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]3[C:31]4[C:30]5[CH:29]=[CH:28][C:27]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:26][C:25]=5[NH:24][C:23]=4[C:22]([C:37]([O:39][CH3:40])=[O:38])=[N:21][N:20]=3)[C:14]=2[CH3:41])=[C:6]([CH:10]=1)[C:7](O)=[O:8].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5]([CH2:11][N:12]([C:13]3[C:14]([CH3:41])=[C:15]([C:19]4[C:31]5[C:30]6[CH:29]=[CH:28][C:27]([O:32][CH2:33][CH2:34][O:35][CH3:36])=[CH:26][C:25]=6[NH:24][C:23]=5[C:22]([C:37]([O:39][CH3:40])=[O:38])=[N:21][N:20]=4)[CH:16]=[CH:17][CH:18]=3)[C:7]2=[O:8])=[CH:4][CH:3]=1
Reactant: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)nnc(-c3cccc(NCc4ccc(Cl)cc4C(=O)O)c3C)c12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)[nH]c1c(C(=O)OC)nnc(-c3cccc(N4Cc5ccc(Cl)cc5C4=O)c3C)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 17.5 %

Procedure:
A solution of 5-chloro-2-((3-(4-(methoxycarbonyl)-7-(2-methoxyethoxy)-5H-pyridazino [4,5-b]indol-1-yl)-2-methylphenylamino)methyl)benzoic acid (0.227 g, 0.394 mmol), BOP (0.366 g, 0.827 mmol), and N-methylmorpholine (0.273 mL, 2.482 mmol) in DMF (3.94 mL) under nitrogen was heated at 45° C. After 6 hr, the reaction was cooled to room temperature, dissolved in EtOAc (100 mL) and washed with water (3×25 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated in vacuo to give a residue which was purified by flash chromatography using an ISCO 24 g column eluting with 0-5% MeOH/CH2Cl2. Appropriate fractions were collected and concentrated in vacuo to give the desired product (0.0384 g, 0.069 mmol, 17.5% yield) as a light orange solid.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=[O:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:30](Br)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CN(C)C=O>[CH2:30]([O:2][C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)=[O:3])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: BrCc1ccccc1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)OCc3ccccc3)(CC1)CC2
Reaction time: 1 h
Yield: 79.8 %

Procedure:
(2S,4S)-1-[[N-(4-Carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.0 mg) was dissolved in N,N-dimethylformamide (1.0 mL) and cesium carbonate (45.3 mg) was added to the solution. Benzyl bromide (17.5 mg) in N,N-dimethylformamide (0.5 mL) was then added while the mixture was chilled in an ice bath and the mixture was stirred for 1 hour. Subsequently, water was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: dichloromethane:methanol=10:1) to give (2S,4S)-1-[[N-(4-benzyloxycarbonyl bicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (30.6 mg).
Reaction SMILES: [C:1]12([CH2:11][CH2:12][C:13]3[NH:17][C:16]([C:18]4[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=4[CH3:24])=[N:15][C:14]=3[C:27](O)=[O:28])[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([NH2:39])[CH:36]=[CH:35][C:34]=1[F:40]>>[CH3:30][O:31][C:32](=[O:41])[C:33]1[CH:38]=[C:37]([NH:39][C:27]([C:14]2[N:15]=[C:16]([C:18]3[C:19]([CH3:26])=[N:20][C:21]([CH3:25])=[CH:22][C:23]=3[CH3:24])[NH:17][C:13]=2[CH2:12][CH2:11][C:1]23[CH2:10][CH:5]4[CH2:4][CH:3]([CH2:9][CH:7]([CH2:6]4)[CH2:8]2)[CH2:2]3)=[O:28])[CH:36]=[CH:35][C:34]=1[F:40]
Reactant: Cc1cc(C)c(-c2nc(C(=O)O)c(CCC34CC5CC(CC(C5)C3)C4)[nH]2)c(C)n1
Reactant: COC(=O)c1cc(N)ccc1F
Product: COC(=O)c1cc(NC(=O)c2nc(-c3c(C)cc(C)nc3C)[nH]c2CCC23CC4CC(CC(C4)C2)C3)ccc1F

Procedure:
5-(2-Adamantan-1-yl-ethyl)-2-(2,4,6-trimethyl-pyridine-3-yl)-1H-imidazole-4-carboxylic acid (Example 182) was reacted with 5-amino-2-fluoro-benzoic acid methyl ester according to the procedure of Example 20, step d to afford 5-{[5-(2-adamantan-1-yl-ethyl)-2-(2,4,6-trimethyl-pyridine-3-yl)-1H-imidazole-4-carbonyl]-amino}-2-fluoro-benzoic acid methyl ester. The ester was hydrolysed following the procedure of Example 36, step d, to afford the title compound as a white solid. 1H NMR (300 MHz, d6-DMSO) 12.50 (1H, br s), 9.67 (1H, s), 8.15 (1H, d), 7.71 (1H, m), 7.03 (2H, m), 2.99 (2H, m), 2.42 (3H, s), 2.25 (3H, s), 2.09 (3H, s), 1.92 (3H, br s), 1.60 (6H, m), 1.50 (6H, br s), 1.42 (2H, m). The acid was converted to the N-methyl-D-glucamine salt and lyophilised from water/dioxan. Found: C, 53.44; H, 7.81; N, 8.03%. C38H52FN5O8.7.0 mols H2O requires: C, 53.57; H, 7.81; N, 8.22%.
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[C:5](=[O:29])[N:6]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:26])=[O:25])[C:19]([O:21]CC)=[O:20])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C1COCC1.CO.O>[F:3][C:4]1[C:5](=[O:29])[N:6]([CH2:16][CH2:17][C@@:18]([CH3:28])([S:24]([CH3:27])(=[O:25])=[O:26])[C:19]([OH:21])=[O:20])[CH:7]=[CH:8][C:9]=1[C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: CCOC(=O)[C@@](C)(CCn1ccc(-c2ccccc2)c(F)c1=O)S(C)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: C[C@@](CCn1ccc(-c2ccccc2)c(F)c1=O)(C(=O)O)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.9 %

Procedure:
Potassium hydroxide (120 mg, 2.14 mmol) was added to a solution of ethyl (2R)-4-(3-fluoro-2-oxo-4-phenylpyridin-1(2H)-yl)-2-methyl-2-(methylsulfonyl)butanoate (131 mg, 0.33 mmol) in THF:methanol:water (2:2:1, 10 mL) and the reaction was stirred at RT overnight. The reaction was concentrated, and the residue was dissolved in aqueous 1N sodium hydroxide (20 mL), washed with ethyl acetate (3×20 mL), acidified using concentrated HCl, and extracted with ethyl acetate (3×50 mL). The combined organics were dried (MgSO4), filtered, and concentrated to afford the title compound as a white solid (88.4 mg, 72.7%). LC-MS m/z 383.0 (M+1). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59 (s, 3 H) 2.13-2.30 (m, 1 H) 3.17 (s, 3 H) 3.93-4.23 (m, 2 H) 6.43 (t, J=6.93 Hz, 1 H) 7.44-7.56 (m, 3 H) 7.57-7.66 (m, 3 H).