Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6](C(C2C=CC(C)=CC=2)=O)=[CH:5][CH:4]=[C:3]1[CH3:16].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20](S(O)(=O)=O)=[CH:19][CH:18]=1.[C:28](=[O:31])(O)[O-].[Na+]>>[CH3:1][N:2]1[CH:6]=[C:5]([C:28]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)=[O:31])[CH:4]=[C:3]1[CH3:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C([O-])O
Reactant: Cc1ccc(C(=O)c2ccc(C)n2C)cc1
Agent: [Na+]
Product: Cc1ccc(C(=O)c2cc(C)n(C)c2)cc1

Procedure:
A 1.0g sample of 1,2-dimethyl-5-p-toluoylpyrrole in 10g of dried p-toluenesulfonic acid heated at 105° C for 1 hour. The solution is then poured into sodium bicarbonate solution and extracted into chloroform. The chloroform is evaporated in vacuo and the residue is recrystallized from ethyl acetate to give 1,2-dimethyl-4-p-toluoylpyrrole as a tan solid; m.p. 117°-119° C.
Reaction SMILES: C(O[C:4]([CH2:6][C:7]1[CH2:11][C:10](=[O:12])[NH:9][N:8]=1)=O)C.[C-:13]#[N:14].[Na+].C[OH:17]>N>[NH2:14][C:13]([CH2:4][CH2:6][C:7]1[CH2:11][C:10](=[O:12])[NH:9][N:8]=1)=[O:17]
Reactant: CO
Reactant: CCOC(=O)CC1=NNC(=O)C1
Reactant: [C-]#N
Agent: N
Agent: [Na+]
Product: NC(=O)CCC1=NNC(=O)C1
Temperature: 45 °C

Procedure:
A mixture of 3-(ethoxycarbonylmethyl)-2-pyrazolin-5-one (1 g, 5.8 mmol) and NaCN (28 mg, 0.58 mmol) in 30 ml of 9M ammonia in MeOH was heated to 45° C. in sealed tube for 3 days. After cooling, the solvent was evaporated and the residue was suspended in water. The precipitated solid was collected by filtration.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[S:10][C:11]([C:15]([OH:17])=[O:16])=[C:12]([CH3:14])[N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Si](C=[N+]=[N-])(C)(C)[CH3:19]>C1COCC1.CO>[CH3:19][O:16][C:15]([C:11]1[S:10][C:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[N:13][C:12]=1[CH3:14])=[O:17]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: Cc1nc(NC(=O)OC(C)(C)C)sc1C(=O)O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1sc(NC(=O)OC(C)(C)C)nc1C
Reaction time: 6 h

Procedure:
2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid (0.52 g) was dissolved in THF: MeOH (2:1, 10 mL) and 2 eq of TMSCHN2 (2M sln in hex) was added at RT and stirred for 6 h. All volatiles were removed in vacuum by rotavap and the residue was dried in vacuum to give 2-tert-Butoxycarbonylamino-4-methyl-thiazole-5-carboxylic acid methyl ester (0.52 g). This was used in the next reaction without further purification. 1H NMR (400 MHz, CDCl3) 3.83 (s, 3H), 2.65 (s, 3H), 1.54 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[C:5](=O)[CH:6]([CH3:16])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=1)=O)[CH3:2].BrC1C=C(C(=O)CC)C=CC=1.C(OCC)(=O)C(OCC)=O.[CH3:40][NH:41][NH2:42]>CO>[CH2:1]([O:3][C:4]([C:5]1[N:41]([CH3:40])[N:42]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[C:6]=1[CH3:16])=[O:18])[CH3:2].[CH2:1]([O:3][C:4]([C:5]1[C:6]([CH3:16])=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Br:15])[CH:10]=2)[N:41]([CH3:40])[N:42]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(=O)C(C)C(=O)c1cccc(Br)c1
Reactant: CNN
Agent: CCC(=O)c1cccc(Br)c1
Solvent: CO
Solvent: CCOC(=O)C(=O)OCC
Product: CCOC(=O)c1c(C)c(-c2cccc(Br)c2)nn1C
Product: CCOC(=O)c1nn(C)c(-c2cccc(Br)c2)c1C
Temperature: 65 °C

Procedure:
4.00 g (8.02 mmol) of 4-(3-bromo-phenyl)-3-methyl-2,4-dioxo-butyric acid ethyl ester (synthesized from 3′-bromopropiophenone and diethyl oxalate, following a procedure described in Ksander, Gary M.; McMurry, John E.; Johnson, Mark. A method for the synthesis of unsaturated carbonyl compounds. Journal of Organic Chemistry (1977), 42(7), 1180-5) were dissolved in 12.20 ml of MeOH and 0.37 g (8.02 mmol) of methylhydrazine were added. The reaction was heated under reflux (65° C.) for 1 h. Then the reaction was partitioned between chilled aqueous 1N HCl/EtOAc (3×). The organic phase was washed with aqueous 1N HCl, with aqueous sat. NaCl, dried (Na2SO4) and evaporated. The crude product was purified by flash chromatography (SiO2, n-heptane/EtOAc 99:1) to give 0.61 g of 5-(3-bromo-phenyl)-2,4-dimethyl-2H-pyrazole-3-carboxylic acid ethyl ester as yellow oil (MS: 323.2 MH+, Br) and 1.731 g of 5-(3-bromo-phenyl)-1,4-dimethyl-1H-pyrazole-3-carboxylic acid ethyl ester as yellow oil (MS: 323.2 MH+, Br).
Reaction SMILES: C([Li])(C)(C)C.[CH2:6]([N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].CN(CCN(C)C)C.[CH:34](N1CCCCC1)=[O:35].Cl>C(OCC)(=O)C.C(OCC)C>[CH2:6]([N:12]1[C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([CH:34]=[O:35])[C:20]=2[S:19][C:18]2[C:13]1=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: O=CN1CCCCC1
Reactant: CCCCCCN1c2ccccc2Sc2ccccc21
Agent: CN(C)CCN(C)C
Agent: Cl
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCCCCN1c2ccccc2Sc2c(C=O)cccc21
Reaction time: 16 h
Yield: 48.8 %

Procedure:
38.6 ml of tert-butyllithium solution (1.4M in hexane) were slowly added dropwise at -78° under argon and while stirring to a solution of 11.80 g (41.6 mmol) of 10-hexyl-phenothiazine in 125 ml of abs. diethyl ether and 12.5 ml of N,N,N,N-tetramethylethylenediamine. The reaction mixture was stirred at -75° for 16 hours, brought slowly to 0°, treated with 6.92 ml (1.5 eq.) of N-formylpiperidine, stirred at 0° for 1 hour and then poured into ice, 100 ml of 0.1N hydrochloric acid solution and 250 ml of ethyl acetate. The organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on 1 kg of silica gel with ethyl acetate/hexane (1:1), whereupon 6.33 g (48.8%) of 10-hexyl-phenothiazine-4-carbaldehyde were obtained as a light yellowish oil. IR (film): 3064w, 2927m, 2854m, 2731w, 1689s, 1561m, 1455s, 1388w, 1336m, 1286m, 1259s, 1052w, 784m, 750m, 724m.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[NH:12][C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:25])([CH3:24])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1.C(N(CC)CC)C.[CH3:34][C:35]1[CH:36]=[C:37]([S:41](Cl)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1.O>ClCCl>[Br:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([S:41]([C:37]4[CH:36]=[C:35]([CH3:34])[CH:40]=[CH:39][CH:38]=4)(=[O:43])=[O:42])[C:13](=[O:26])[N:14]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([CH3:24])([CH3:25])[C:22]#[N:23])=[CH:17][CH:16]=4)[C:5]=3[C:4]=2[CH:3]=1
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C#N)c1ccc(-n2c(=O)[nH]c3cnc4ccc(Br)cc4c32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: Cc1cccc(S(=O)(=O)n2c(=O)n(-c3ccc(C(C)(C)C#N)cc3)c3c4cc(Br)ccc4ncc32)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-(4-(8-bromo-2-oxo-2,3-dihydro-1H-imidazo[4,5-c]quinolin-1-yl)phenyl)-2-methylpropanenitrile (Intermediate 1, 50 mg 0.12 mmol) and triethylamine (24.2 mg, 0.24 mmol) in dichloromethane (6 ml) was added 3-methylbenzene-1-sulfonyl chloride (36 mg, 0.18 mmol) at 0° C. The reaction was stirred at RT for 3 hours. The reaction mixture was poured into cold water and organic layer was separated. The aqueous layer was extracted with dichloromethane. The combined organic layer was washed with brine dried over sodium sulfate and evaporated to dryness. The crude product was purified by column chromatography (silica gel, 2% acetone in chloroform) to obtain the title compound. Yield: 22 mg (32%); 1H NMR (DMSO d6, 300 MHz): δ 9.44 (s, 1H), 8.01 (s, 2H), 7.98 (s, 1H), 7.813-7.841 (d, 2H, J=8.4 Hz), 7.70-7.77 (m, 3H), 7.56-7.66 (m, 2H), 6.76-6.766 (d, 1H, J=1.8 Hz), 2.405 (s, 3H), 1.776 (s, 6H); MS: m/z 561 (M+).
Reaction SMILES: [CH:1]1([NH2:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N:8]([C:19]1([N:25]=[C:26]=[O:27])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[N:9][C:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CCCCC>[N:8]([C:19]1([NH:25][C:26]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:27])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1)=[N:9][C:10]1([NH:16][C:17]([NH:7][CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: NC1CCCCC1
Reactant: O=C=NC1(N=NC2(N=C=O)CCCCC2)CCCCC1
Solvent: CCCCC
Product: O=C(NC1CCCCC1)NC1(N=NC2(NC(=O)NC3CCCCC3)CCCCC2)CCCCC1
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4.22 grams (.0426 moles) of cyclohexylamine in 20 ml pentane in a 125 ml erlenmeyer flask, cooled to 5° C. in an ice bath, was slowly added a solution of 5.78 grams (.0213 moles) of 1,1'-azobis (1-isocyanatocyclohexane) in 20 ml of pentane. During the addition, a solid product formed. After the addition was complete, the reaction was stirred an additional 30 minutes at 0°-5° C. The reaction mixture was filtered and the filter cake washed with pentane and dried. The dry white solid weighed 5.4 grams (54% crude yield) and melted at 105°-109° C. with decomposition. The infrared spectrum of the product contained a strong carbonyl band at 1655 cm-1 and NH bands at 3200 cm-1 to 3440 cm-1.
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([CH2:6][C:7]2[CH2:11][C:10]([CH2:14][OH:15])([CH2:12][OH:13])ON=2)=[CH:4][CH:3]=1.C(O)(=O)C.O>O1CCCC1.O.[Pt](=O)=O>[OH:13][CH2:12][C:10]1[CH:11]=[C:7]([CH2:6][C:5]2[CH:16]=[CH:17][C:2]([F:1])=[CH:3][CH:4]=2)[O:15][CH:14]=1
Reactant: OCC1(CO)CC(Cc2ccc(F)cc2)=NO1
Agent: O=[Pt]=O
Solvent: O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: OCc1coc(Cc2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 5.5 h
Yield: 63.2 %

Procedure:
67.9 g of 3-(p-fluorobenzyl)-5,5-bis-(hydroxymethyl)-isoxazoline are taken up in 400 ml of tetrahydrofuran, 80 ml of glacial acetic acid and 40 ml of water, and 1.5 g of platinum(IV) oxide hydrate are added. Hydrogenation is carried out for 5-6 hours at 25°-30° C., a slightly exothermic reaction taking place (cooling). When the absorption of hydrogen is complete, the catalyst is filtered off, the filtrate is evaporated down and the residue is stirred in 400 ml of methylene chloride with 400 ml of 10% strength hydrochloric acid for 1 hour at room temperature. The organic phase is separated off, washed neutral, dried over sodium sulfate and evaporated down. Purification by column chromatography over silica gel with toluene/acetone 9/1 as the eluent gives 37 g of 3-hydroxymethyl-5-(p-fluorobenzyl)-furan of melting point 45°-47° C. ##STR13##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22]([CH2:25][C:26]3[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=3)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C(=O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[C:14]([N:19]3[CH2:24][CH2:23][N:22]([CH2:25][C:26]4[CH:27]=[N:28][N:29]([CH3:31])[CH:30]=4)[CH2:21][CH2:20]3)=[N:15][CH:16]=[CH:17][N:18]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: Cn1cc(CN2CCN(c3nccnc3Cl)CC2)cn1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cn1cc(CN2CCN(c3nccnc3-c3ccc(F)c(Cl)c3)CC2)cn1
Temperature: 110 °C
Yield: 57.8 %

Procedure:
Add 3-chloro-4-fluorobenzeneboronic acid (71 mg, 0.41 mmol) to a mixture of 3′-chloro-4-(1-methyl-1H-pyrazol-4-ylmethyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyrazinyl (104 mg, 0.34 mmol), potassium carbonate (113 mg, 0.82 mmol) and tetrakis(triphenyl-phosphine)palladium(0) (0.002 g, 0.002 mmol) in N,N-dimethylacetamide (2 mL) and water (1 mL). Purge with nitrogen and heat overnight at 110° C. Cool to room temperature, add water (10 mL), extract with DCM (3×20 mL), combine and purify using high pH reverse phase HPLC to give title compound (76 mg, 57.7%). MS (ES): m/z=387 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14].O>N1C=CC=CC=1>[C:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 93.7 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy-benzoic acid (3.0 g, 18.05 mmol) in pyridine (7 mL) was added acetic anhydride (2.05 mL, 21.66 mmol) and the reaction mixture was stirred at room temperature for 16 h. Water was added and the mixture was extracted with ethyl acetate, washed with water, brine and dried over anhydrous Na2SO4. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid (3.52 g, 94%). To a solution of 4-acetoxy-3,5-dimethyl-benzoic acid (6.02 g, 28.91 mmol) in CH2Cl2 (80 mL), oxalyl chloride (5.04 mL, 57.83 mmol) was added slowly, followed by a drop of dimethyl formamide. The reaction mixture was stirred at room temperature for 2 h. The solvent was removed and acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester was dried under vacuum (6.37 g, 97%). To a solution of N,N,N,N-tetramethyl guanidine (2.77 mL, 22.078 mmol) in CH3CN (50 mL), a solution of 6,8-dimethoxy-isochroman-1,3-dione (4.46 g, 20.07 mmol) in CH3CN (100 mL) was added slowly at <0° C. (bath temperature −20° C.) in 30 min. Then, Et3N was added in one portion, followed by a solution of acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester (6.37 g, 28.1 mmol) in CH3CN (50 mL) and stirred for 30 min. at <0+ C. The reaction mixture was stirred at room temperature for 16 h, then heated to reflux for 3 h. After cooling to room temperature, the reaction mixture was quenched with 1 N HCl. The precipitated solid was filtered off to give a mixture of acetic acid 4-(6,8-dimethoxy-1,3-dioxo-isochroman-4-carbonyl)-2,6-dimethyl-phenyl ester and acetic acid 4-(6,8-dimethoxy-1-oxo-1H-isochromen-3-yl)-2,6-dimethyl-phenyl ester (6.0 g).
Reaction SMILES: C1N2CCN(CC2)C1.[Li]CCCC.[F:14][C:15]1[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=1.CN([CH:24]=[O:25])C>CCOCC.O.CCOC(C)=O>[F:14][C:15]1[C:16]([CH:24]=[O:25])=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)C=O
Reactant: Fc1cccnc1
Agent: C1CN2CCN1CC2
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: O
Product: O=Cc1ncccc1F
Temperature: -70 °C
Reaction time: 0.75 h

Procedure:
To a stirred solution of DABCO (262.4 g, 2342 mmol) in anhydrous Et2O (2.1 L) at −25° C. in a 10 L 3-neck round bottom flask was added n-BuLi (2.5 M in hexane, 938 mL, 2342 mmol). The mixture was stirred between −25° C. to −10° C. for 45 min. and then cooled to −70° C. To the above solution was added 3-fluoropyridine (206.7 g, 2129 mmol) dropwise, and the reaction was stirred between −70° C. to −60° C. for 1.5 h before DMF (344 mL, 4258 mmol) was added. The progress of the reaction was monitored by TLC (5% EtOAc in Petroleum ether). After 1 h stirring at −70° C., water (800 mL) was added, and the reaction was allowed to warm to rt. The layers were separated, and the aqueous layer was extracted with DCM (5×1 L). The combined organic layers were washed with brine and dried over sodium sulfate. After removal of solvent the initially obtained product was purified by silica gel chromatography using a gradient of EtOAc in hexane to give the title compound as pale yellow oil. 1H-NMR (400 MHz, CDCl3): δ ppm 10.21 (s, 1H), 8.63 (t, J=2.2 Hz, 1H), 7.54-7.57 (m, 2H). MS (ESI pos. ion) m/z: 126.0 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22](Br)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[F:27][C:28]1[CH:33]=[CH:32][C:31](OB(O)O)=[CH:30][CH:29]=1.O>O1CCCC1.C(=O)([O-])O.[Na+].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>[C:1]([O:5][C:6](=[O:26])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:31]3[CH:32]=[CH:33][C:28]([F:27])=[CH:29][CH:30]=3)=[CH:21][N:20]=2)[N:15]=1)([CH3:9])[CH3:8])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(Br)cn2)cs1
Reactant: OB(O)Oc1ccc(F)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: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCOc2ccc(-c3ccc(F)cc3)cn2)cs1
Yield: 60.5 %

Procedure:
Under nitrogen atmosphere, 2-[(4-{2-[(5-bromopyridin-2-yl)oxy]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester (486 mg) synthesized in Example 100-1 and 4-fluorophenylboric acid (297 mg) were dissolved in tetrahydrofuran (10 mL) and sodium hydrogen carbonate (1 mol/l, 10 mL), tetrakis(triphenylphosphine)palladium (245 mg) was added, and the mixture was refluxed for 4.5 hr. The reaction mixture was cooled, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; hexane:ethyl acetate=10:1 to 5:1) to give the title compound (304 mg) as a pale-yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][N:9]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]2[CH:19]=[CH:20][CH:21]=[CH:22][C:3]=12.N1C=CC=CC=1.[C:29](OC(=O)C)(=[O:31])[CH3:30]>O>[C:15]([O:14][C:12]([N:9]1[CH2:8][CH2:7][C:6]2[N:5]=[C:4]3[CH:19]=[CH:20][CH:21]=[CH:22][C:3]3=[C:2]([NH:1][C:29](=[O:31])[CH3:30])[C:11]=2[CH2:10]1)=[O:13])([CH3:17])([CH3:18])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccccc3c(N)c2C1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Nc1c2c(nc3ccccc13)CCN(C(=O)OC(C)(C)C)C2
Yield: 56.8 %

Procedure:
10-Amino-2-t-butoxycarbonyl-1,2,3,4-tetrahydro-benzo[b][1,6]-naphthyridine (0.77 g, 2.59 mmol) was added to pyridine (1.0 g, 12.7 mmol). Acetic anhydride (0.53 g, 5.18 mmol) was added to the mixture, followed by refluxing for 7.5 hours. Then, water was added thereto and the resulting mixture was extracted with chloroform. The chloroform layer was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain the desired compound (0.5 g, 1.47 mmol, 57%).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][N+:9]([O-:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[C@@H:24]([CH:25]=[O:26])[CH2:23][O:22][C@@H:21]([CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[C:12]([O:16][C:17]([N:19]1[C@@H:24]([C@@H:25]([OH:26])[C@@H:8]([N+:9]([O-:11])=[O:10])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:23][O:22][C@@H:21]([CH2:27][CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]2)[CH2:20]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1C=O
Reactant: O=[N+]([O-])CCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1C[C@H](CCC2CCCCC2)OC[C@@H]1[C@@H](O)[C@H](Cc1ccccc1)[N+](=O)[O-]
Temperature: 0 °C
Yield: 63.8 %

Procedure:
Add 1-phenyl-2-nitroethane (91 mg, 0.61 mmol) to a solution of 2-(S)-(2-cyclohexylethyl)-5-(R)-formylmorpholine-4-carboxylic acid tert-butyl ester (164 mg, 0.50 mmol) in dry tetrahydrofuran (6 mL). Cool to 0° C. and add tetrabutylammonium fluoride (0.25 mL of a 1 M solution in tetrahydrofuran, 0.25 mmol) and refrigerate the solution overnight. Dilute with ethyl acetate, wash with cold saturated aqueous sodium chloride (50 mL), dry (sodium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 2.5:97.5 ethyl acetate:dichloromethane) to give the desired compound as a white foam (152 mg, 63%).
Reaction SMILES: [CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([OH:18])=O)([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2].C(Cl)(=O)C(Cl)=O.[CH3:25][NH2:26]>C(Cl)Cl.CN(C=O)C>[CH2:1]([S:3]([CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]([NH:26][CH3:25])=[O:18])([CH2:12][CH2:13]1)[CH2:10][CH2:9]2)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)CCC12CCC(C(=O)O)(CC1)CC2
Reactant: CN
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCS(=O)(=O)CCC12CCC(C(=O)NC)(CC1)CC2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Carboxylic acid 10-4 (810 mg, 2.96 mmol) was dissolved in 12 mL of anhydrous methylene chloride under nitrogen atmosphere, treated with oxalyl chloride (2M in methylene chloride, 4.4 mL, 8.8 mmol) and subsequently with 5 drops of DMF. The reaction was stirred at room temperature under nitrogen atmosphere for 90 min, then evaporated and placed under vacuum for 20 min. The acid chloride was dissolved in anhydrous methylene chloride (12 mL), cooled in an ice-bath, and then treated dropwise with a solution of methylamine (2M in THF, 8.9 mL, 17.8 mmol). Upon addition of the amine, the cooling bath was removed and the reaction stirred at ambient temperature for 30 min. The mixture was diluted with 200 mL of methylene chloride and washed with 1N aqueous HCl, saturated aqueous sodium bicarbonate, and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated. The residue was subjected to chromatography on silica gel eluting with a gradient from 0 to 3.5% methanol in methylene chloride to give 4-[2-(ethylsulfonyl)ethyl]-N-methylbicyclo[2.2.2]octane-1-carboxamide 10-5 as a white powder. MS (ESI+)=288 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH2:12])[O:7][C:6]=2[CH:13]=1.Cl[CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:28]=[C:27]2[C:22]([CH:23]=[CH:24][C:25](=[O:29])[O:26]2)=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C.[I-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH:8]([CH2:11][NH:12][CH2:15][CH2:16][CH2:17][O:18][C:19]3[CH:20]=[CH:21][C:22]4[CH:23]=[CH:24][C:25](=[O:29])[O:26][C:27]=4[CH:28]=3)[O:7][C:6]=2[CH:13]=1
Reactant: NCC1COc2ccc(Cl)cc2O1
Reactant: O=c1ccc2ccc(OCCCCl)cc2o1
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=c1ccc2ccc(OCCCNCC3COc4ccc(Cl)cc4O3)cc2o1
Yield: 8.5 %

Procedure:
2,3-Dihydro-7-chloro-1,4-benzodioxin-2-methanamine (1.72 g, 8.62 mmole), 7-(3-chloropropoxy)coumarin (1.88 g, 7.88 mmole), diisopropylethylamine (7.5 ml, 43.1 mmole) and sodium iodide (1.37 g, 9.14 mmole) were combined in 200 ml of DMF and heated at 80°-100° C. for 3 days under a nitrogen atmosphere. The solvent was then removed in vacuum and the residue was column chromatographed on silica gel using first 0.5% methanol/dichloromethane and then 1% methanol/dichloromethane as eluant. The product-containing fractions were combined and concentrated in vacuum, during which procedure the free base began to come out of solution. This material was collected by filtration and recrystallized from isopropanol with addition of 4N HCl/isopropanol to give 0.27 g of white solid, monohydrochloride, m.p. 235°-242° C.
Reaction SMILES: Br[C:2]1[C:10]2[C:9]([Cl:11])=[N:8][CH:7]=[N:6][C:5]=2[NH:4][CH:3]=1.C([Li])CCC.CC1C=CC(S([C:27]#[N:28])(=O)=O)=CC=1>C1COCC1>[Cl:11][C:9]1[N:8]=[CH:7][NH:6][C:5]2=[N:4][CH:3]=[C:2]([C:27]#[N:28])[C:10]=12
Reactant: Cc1ccc(S(=O)(=O)C#N)cc1
Reactant: Clc1ncnc2[nH]cc(Br)c12
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1cnc2[nH]cnc(Cl)c1-2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of anhydrous THF (40 ml) containing 5-Bromo-4-chloro-7H-pyrrolo[2,3-c]pyrimidine D3 (1 g) was added nBu-Li (2.5M, 5.2 ml, 12.9 mmol) dropwise at −78° C. under nitrogen. After this addition the resulting solution was stirred for 1 hour at −78° C. before adding 4-methylbenzenesulfonyl cyanide (935 mg, 5.2 mmol) and the resulting solution stirred for 1 hour at −78° C. and then allowed to warm up to room temperature overnight. The reaction was quenched with a saturated NH4Cl solution at 0° C., extracted with EtOAc (100 ml) and organic layer was washed with 5% NaHCO3 solution, dried Na2SO4, filtered and concentrated in vacuo to afford a yellow solid. Purified by flash chromatography on silica gel eluting with Pet Eth/EtOAc 1/2 to give the desired product D42 as a yellow solid in 350 mg. LCMS [MH+] 179.0 @1.17 min (5 min run)