Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]2[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=2[CH2:24][O:25][CH3:26])=[O:15])[C:5]2[CH:10]=[N:9][N:8]([CH:11]([CH3:13])[CH3:12])[C:6]=2[N:7]=1.[CH3:29][C:30]1([CH3:41])[CH2:35][C:34](B(O)O)=[CH:33][C:32]([CH3:40])([CH3:39])[NH:31]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.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>[CH:11]([N:8]1[C:6]2[N:7]=[C:2]([C:34]3[CH2:33][C:32]([CH3:40])([CH3:39])[NH:31][C:30]([CH3:41])([CH3:29])[CH:35]=3)[CH:3]=[C:4]([C:14]([NH:16][CH2:17][C:18]3[C:19](=[O:28])[NH:20][C:21]([CH3:27])=[CH:22][C:23]=3[CH2:24][O:25][CH3:26])=[O:15])[C:5]=2[CH:10]=[N:9]1)([CH3:13])[CH3:12]
Reactant: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Br)nc2c1cnn2C(C)C
Reactant: CC1(C)C=C(B(O)O)CC(C)(C)N1
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: O
Solvent: C1COCCO1
Product: COCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(C2=CC(C)(C)NC(C)(C)C2)nc2c1cnn2C(C)C
Temperature: 100 °C
Yield: 44 %

Procedure:
To a stirred solution of 6-bromo-1-isopropyl-N-((4-(methoxymethyl)-6-methyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-1H-pyrazolo[3,4-b]pyridine-4-carboxamide (0.06 g, 0.133 mmol) and (2,2,6,6-tetramethyl-1,2,3,6-tetrahydropyridin-4-yl)boronic acid (0.043 g, 0.160 mmol) in dioxane/water mixture (1.5 mL+0.5 mL), Na2CO3 (0.5 g, 0.5 mmol) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.008 g, 0.007 mmol) was added and argon was purged again for 10 min. Reaction mass was heated at 100° C. for 2 h. On completion, reaction mixture was diluted with water and extracted with 10% MeOH/DCM. Combined organic layers were dried over Na2SO4 and solvent removed under reduced pressure to obtain crude material which was purified by column chromatography over silica gel to afford the desired product (44% yield). LCMS: 507.25 (M+1)+; HPLC: 99.64% (@ 254 nm) (Rt; 5.159); 1H NMR (DMSO-d6, 400 MHz) δ 11.68 (bs, 1H), 8.91 (t, 1H), 8.26 (s, 1H), 7.77 (s, 1H), 6.80 (s, 1H), 6.09 (s, 1H), 5.24-5.18 (m, 1H), 4.51 (s, 2H), 4.35 (d, 2H, J=4.4 Hz), 3.32 (3H merged in DMSO peak), 2.43 (s, 2H), 2.17 (s, 3H), 1.49 (d, 6H, J=6 Hz), 1.24 (s, 6H), 1.14 (s, 6H).
Reaction SMILES: [CH2:1]([OH:7])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6].[Li].[CH3:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].C(O)C>C1COCC1>[CH2:1]([O:7][CH2:9]/[CH:10]=[CH:11]/[CH:12]=[CH:13]/[CH3:14])/[CH:2]=[CH:3]/[CH:4]=[CH:5]/[CH3:6]
Reactant: CCCCCC
Reactant: C/C=C/C=C/CO
Agent: [Li]
Solvent: C1CCOC1
Solvent: CCO
Product: C/C=C/C=C/COC/C=C/C=C/C

Procedure:
A mixture of 10 g of the polymer from Example 17, 2.2 ml of sorbyl alcohol (2,4-hexadienol) and 0.1 g of lithium metal in 100 ml of THF was refluxed under nitrogen for 18 hours. The mixture was then cooled and a 10-ml portion was poured into 100 ml of hexane containing 2 ml of ethanol to obtain the solid product. To further purify, it was redissolved in 10 ml of THF and suction filtered through a fine frit into 100 ml of water. The precipitated solid was collected and dried.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]([O:12][CH2:13][CH3:14])(=[O:11])[CH:9]=[CH2:10].C(N(CC)CC)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>[N:4]1[CH:3]=[C:2]([CH:10]=[CH:9][C:8]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=[N:6][CH:5]=1
Reactant: C=CC(=O)OCC
Reactant: Brc1cncnc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)C=Cc1cncnc1
Temperature: 150 °C
Reaction time: 6 h
Yield: 71.9 %

Procedure:
A mixture of 5-bromopyrimidine (5.93 g), ethyl acrylate (5.08 g), palladium acetate (0.112 g), triphenyl phosphine (0.23 g) and triethylamine (4.5 g) was stirred at 150° C. in a pressure vessel for 6 hours. After cooling overnight, water (50 ml) was added to the dark residue, and the product was extracted into toluene. Drying, charcoaling and evaporation gave a pale oil, which was triturated with pet ether to obtain ethyl 3-(5-pyrimidyl)acrylate (4.78 g). 1H-NMR (CDCl3) δ 1.36 (3H,t), 4.27 (2H,q), 6.59 (1H,d), 7.62 (1H,d), 8.88 (2H,s), 9.20 (1H,s).
Reaction SMILES: [Cl:1][C:2]1[NH:11][C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([C:26]([C:28]2[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=2)=[O:27])=[CH:24][CH:23]=1>CN(C=O)C.O>[Cl:1][C:2]1[N:11]([CH2:32][C:31]2[CH:30]=[CH:29][C:28]([C:26](=[O:27])[C:25]3[CH:36]=[CH:37][C:22]([Cl:21])=[CH:23][CH:24]=3)=[CH:35][CH:34]=2)[C:10]2[C:9](=[O:12])[N:7]([CH3:8])[C:6](=[O:13])[N:5]([CH3:14])[C:4]=2[N:3]=1
Reactant: Cn1c(=O)c2[nH]c(Cl)nc2n(C)c1=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1c(=O)c2c(nc(Cl)n2Cc2ccc(C(=O)c3ccc(Cl)cc3)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.2 %

Procedure:
To a solution of 8-chlorotheophylline (2.15 g) in DMF (20 ml) was added potassium carbonate (1.66 g) as well as 4-(4-chlorobenzoyl)benzyl bromide (3.10 g) and the mixture was stirred at room temperature for 20 hours. This reaction mixture was diluted with water and extracted with ethyl acetate. The extract was washed with saturated aqueous NaCl solution and dried over anhydrous sodium sulfate. The solvent was then distilled off and the residue was washed with ether to provide the title compound as white powder (3.34 g, 75%). 1H-NMR (CDCl3) 6: 3.41(3H,s), 3.57(3H,s), 5.64(2H,s), 7.41-7.52(4H,m), 7.68-7.80(4H,m).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][OH:7].[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11](Cl)[N:10]=1>O1CCOCC1.CCCCCC.C(OCC)(=O)C>[Cl:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([O:7][CH2:6][C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[N:10]=1
Reactant: OCc1cccs1
Reactant: Clc1cccc(Cl)n1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Clc1cccc(OCc2cccs2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.3 %

Procedure:
K-t-BuO (1.70 g, 15.1 mmol) was added portionwise to a stirred mixture of 2-thiophenemethanol (2.14 g, 18.7 mmol) and 2,6-dichloropyridine (2.13 g, 14.4 mmol) in dioxane (3 mL) at room temperature. An exotermic reaction started and more dioxane (3 mL) was added. After 3 h of stirring at room temperature, the reaction mixture was passed through a column of silica using n-hexane/ethyl acetate (85:15) as eluent. A second purification on silica (16×4 cm) using n-hexane/ethyl acetate (9:1) furnished 3.0 g (93%) of the title compound as a light beige oil. HRMS m/z calcd for C10H8ClNOS (M)+ 225.0015, found 225.0022. Anal. (C10H8ClNOS) C, H, N.
Reaction SMILES: CO[C:3]1[C:7](OC)=[N:6][S:5](=[O:10])[N:4]=1.[NH:11]([C:15]1[S:16][CH:17]=[C:18]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:19]=1)[C:12]([NH2:14])=[NH:13].[NH3:25]>>[NH2:25][C:3]1[C:7]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C:18]2[N:19]=[C:15]([NH:11][C:12]([NH2:14])=[NH:13])[S:16][CH:17]=2)=[N:6][S:5](=[O:10])[N:4]=1
Reactant: N
Reactant: COC1=NS(=O)N=C1OC
Reactant: N=C(N)Nc1nc(CCCCN)cs1
Product: N=C(N)Nc1nc(CCCCNC2=NS(=O)N=C2N)cs1

Procedure:
When a methanolic solution of 3,4-dimethoxy-1,2,5-thiadiazole 1-oxide is successively treated with 4-(2-guanidinothiazol-4-yl)butylamine [prepared according to the procedure described in U.S. Pat. No. 4,165,377] and excess anhydrous ammonia according to the general procedure described in Example 35, the title compound is thereby produced.
Reaction SMILES: CN(C=O)C.CS(O[CH2:11][C:12]1[O:16][N:15]=[C:14]([C@@H:17]2[CH2:21][CH2:20][CH2:19][N:18]2[C:22](=[O:37])[C:23]([F:36])([F:35])[C:24]2([OH:34])[CH2:29][C:28]([CH3:31])([CH3:30])[CH2:27][C:26]([CH3:33])([CH3:32])[CH2:25]2)[CH:13]=1)(=O)=O.[N:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[OH:44].C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[F:36][C:23]([F:35])([C:24]1([OH:34])[CH2:25][C:26]([CH3:32])([CH3:33])[CH2:27][C:28]([CH3:31])([CH3:30])[CH2:29]1)[C:22]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1[C:14]1[CH:13]=[C:12]([CH2:11][N:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]2=[O:44])[O:16][N:15]=1)=[O:37]
Reactant: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(COS(C)(=O)=O)on2)C1
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: CC1(C)CC(C)(C)CC(O)(C(F)(F)C(=O)N2CCC[C@H]2c2cc(Cn3ccccc3=O)on2)C1
Temperature: 50 °C
Yield: 53.4 %

Procedure:
To a DMF (1.0 mL) solution of the compound (30 mg) obtained in Example 3-(5) and pyridin-2-ol (12 mg), K2CO3 (35 mg) was added and the mixture was stirred at 50° C. for an hour. To the reaction mixture, DMSO (1.0 ml) was added and after filtering off the insoluble matter, the filtrate was purified by reverse-phase preparative HPLC to give Compound 54 (2.0 mg, colorless oil) and Compound 60 (16.0 mg, colorless oil.)
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[C:17]([N:18]2[N:22]=[CH:21][CH:20]=[N:19]2)=[CH:16][CH:15]=[CH:14][C:13]=1[CH3:23])=[O:11].F[C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1>>[CH3:9][C@@H:8]1[CH2:7][CH2:6][CH2:5][N:4]([C:10]([C:12]2[C:17]([N:18]3[N:22]=[CH:21][CH:20]=[N:19]3)=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:23])=[O:11])[C@@H:3]1[CH2:2][NH:1][C:25]1[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][N:26]=1
Reactant: Fc1ccc(C(F)(F)F)cn1
Reactant: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CN
Product: Cc1cccc(-n2nccn2)c1C(=O)N1CCC[C@@H](C)[C@H]1CNc1ccc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A264 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(2-methyl-6-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2-fluoro-5-(trifluoromethyl)pyridine. ESI-MS (m/z): 459 [M+1]+. 1H NMR (500 MHz, CD3OD) δ 8.35-6.55 (m, 8H), 5.10-2.85 (m, 5H), 2.43-0.75 (m, 11H).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[Cl-:4].[CH2:5]([Al+:9]CC(C)C)[CH:6]([CH3:8])[CH3:7]>C1(C)C=CC=CC=1>[Cl:4][Al:9]([O:3][CH2:1][CH3:2])[CH2:5][CH:6]([CH3:8])[CH3:7]
Reactant: CCO
Reactant: CC(C)C[Al+]CC(C)C
Reactant: [Cl-]
Solvent: Cc1ccccc1
Product: CCO[Al](Cl)CC(C)C
Temperature: 50 °C

Procedure:
A solution of 23.75 g (0.516 mol) of absolute ethanol in 350 ml of absolute toluene is added dropwise during 1 hour to a solution of 91.1 g (0.516 mol) of diisobutylaluminum chloride in 350 ml of absolute toluene at 0° C. and under a protective gas atmosphere (argon). Thereafter, the mixture is warmed at 50° C. for 1 hour and cooled to 5° C., to yield the chloro-ethoxy-isobutyl-aluminum starting material.
Reaction SMILES: S(Cl)(Cl)=O.[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([OH:13])=[O:12].[CH3:14]O>>[N:5]1[CH:10]=[CH:9][N:8]=[CH:7][C:6]=1[C:11]([O:13][CH3:14])=[O:12]
Reactant: CO
Reactant: O=C(O)c1cnccn1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cnccn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Thionyl chloride (0.146 L, 1998 mmol) was added to methanol (1.5 L) dropwise at −5° to 0° C. over a period of 1 hour and was stirred at this temperature for 30 minutes. The solution was allowed to warm to room temperature whereupon 2-pyrazine carboxylic acid (62 g, 500 mmol) was added. The mixture was cautiously heated at reflux for 6 h and allowed to cool to room temperature overnight. LCMS indicated that the reaction was complete. The solvents were removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and saturated sodium bicarbonate solution (500 mL). The aqueous phase was extracted with ethyl acetate (3×500 mL), the combined organic extracts were washed with water (250 mL), brine (250 mL), dried over anhydrous sodium sulfate and concentrated in vacuo to afford a crude solid. The solid was recrystalised from ˜500 ml of 1:1 pentane:cyclohexane, decanting the hot solution twice off a dark viscous oil. Care was taken to minimise the amount of product oiling out upon cooling affording as cream needles. The mothor liquors were concentrated in vacuo and the residue recrystalised from the same solvent (˜200 mL) affording a second crop, as buff needles. Analysis by LCMS and NMR indicates that both materials are consistant with desired product and of comaparable purity. Both batches were combined to afford product in 42.8 g as beige needles.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].[N:6]([C:14]([CH3:19])([CH3:18])[C:15]([O-:17])=O)=[N:7][C:8]([CH3:13])([CH3:12])[C:9]([O-:11])=O.C[O-].[Na+].O>CO>[N:7]([C:8]([CH3:12])([CH3:13])[C:9]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:11])=[N:6][C:14]([CH3:19])([CH3:18])[C:15]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:17]
Reactant: CCCCN
Reactant: CC(C)(N=NC(C)(C)C(=O)[O-])C(=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCCCNC(=O)C(C)(C)N=NC(C)(C)C(=O)NCCCC
Temperature: 10 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
34.9 Grams of n-butylamine is mixed with 50 g of 2,2'-azobis (2-methyl propionate), and 10 g of 28% sodium methoxide solution in methanol is dropwise added thereto with stirring, followed by conducting a reaction at room temperature with stirring for 6 hours and keeping standing overnight. 100 Milliliter of water is added to the reaction solution and cooled to 10° C. to precipitate crystals. The crystals are recovered by filtration and dried to give 58.0 g (yield 85.5%) of 2,2'-azobis [N-butyl-2-methyl propionamide] as pale yellow crystal. The solubility is shown in Table 1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].[NH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1>>[N+:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8](=[O:11])[CH2:9][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: C1COCCN1
Reactant: O=C(CBr)c1ccc([N+](=O)[O-])cc1
Product: O=C(CN1CCOCC1)c1ccc([N+](=O)[O-])cc1

Procedure:
Reaction of 4-nitrophenacyl bromide with morpholine affords the novel intermediate 1-(4-nitrophenyl)-2-morpholinylethanone which when reduced yields the novel sunscreen 1-(4-aminophenyl)-2-morpholinylethanone.
Reaction SMILES: C(OC(N[C@@H](C(O)=O)CO)=O)(C)(C)C.[ClH:15].[NH2:16][C@@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:18]1.C(OC(N[C@H](C(O)=O)CO)=O)(C)(C)C>>[ClH:15].[NH2:16][C@H:17]1[C:23](=[O:24])[NH:22][C:21]2[CH:25]=[CH:26][CH:27]=[CH:28][C:20]=2[O:19][CH2:18]1
Reactant: N[C@H]1COc2ccccc2NC1=O
Agent: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: CC(C)(C)OC(=O)N[C@H](CO)C(=O)O
Agent: Cl
Product: N[C@@H]1COc2ccccc2NC1=O

Procedure:
(R)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt was prepared from N-t-butyloxycarbonyl-D-serine by the procedures described in Itoh, et al., Chem. Pharm. Bull. 1986, 34, 1128-1147 for the preparation of (S)-3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one hydrochloride salt from N-t-butyloxycarbonyl-L-serine.
Reaction SMILES: [CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:15]3[CH:20]=[CH:19][C:18](Br)=[CH:17][CH:16]=3)=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2].[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(N(CC)CC)C>C1COCC1.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.[Cu](I)I>[CH2:1]([N:3]([CH2:22][CH3:23])[C:4]1[CH:13]=[C:12]2[C:7]([C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:31]#[C:30][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:17][CH:16]=3)=[CH:9][C:10](=[O:14])[O:11]2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: CCN(CC)c1ccc2c(-c3ccc(Br)cc3)cc(=O)oc2c1
Reactant: C#Cc1ccccc1
Agent: I[Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN(CC)c1ccc2c(-c3ccc(C#Cc4ccccc4)cc3)cc(=O)oc2c1

Procedure:
After charging 7.4 parts of 7-diethylamino-4-[(p-bromphenyl)]coumarin synthesized by a known method, 2.4 parts of phenylacetylene, 0.46 parts of tetrakis(triphenylphosphine)palladium(0), 0.038 parts of copper iodide and 20 ml of triethylamine in 40 ml of THF, the mixture was refluxed for 9 hours. The reaction mixture was filtered and washed with THF, and the obtained filtrate was concentrated and then diluted with water and filtered. The obtained cake was recrystallized from methanol. Upon drying under reduced pressure there was obtained 2.2 parts of 7-diethylamino-4-[4-(phenylethynyl)phenyl]coumarin having a melting point of 136-138° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:34])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([NH:26][C:27](=[O:33])[CH2:28][CH2:29][CH2:30][CH2:31][Cl:32])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C)C=O>[ClH:32].[CH3:3][N:4]([CH:13]1[CH2:18][CH2:17][N:16]([C:19](=[O:34])[C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][C:27]3=[O:33])[CH:21]=2)[CH2:15][CH2:14]1)[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(NC(=O)CCCCCl)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(CCc1ccccc1)C1CCN(C(=O)c2cccc(N3CCCCC3=O)c2)CC1
Product: Cl
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 77.3 %

Procedure:
230 mg of sodium hydride was added, under ice-cooling, to a solution of 2.2 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(5-chlorovalerylamino)benzoyl]piperidine in 20 ml of dimethylformamide. The mixture was stirred at the same temperature for 30 minutes. The reaction mixture was poured into ice water. The mixture was extracted with methylene chloride. The extract was washed with a saturated aqueous sodium chloride solution, dried with magnesium sulfate, and concentrated under reduced pressure. The residue was purified by a silica gel column chromatography (eluant: methylene chloride/methanol=100/3 to 20/1) and then converted into a hydrochloride. The hydrochloride was solidified from ethanol-diethyl ether to obtain 1.7 g of 4-[N-methyl-N-(2-phenylethyl)amino]-1-[3-(2-oxo-1-piperidinyl)benzoyl]piperidine hydrochloride as a white amorphous.
Reaction SMILES: Cl[C:2]1[N:10]=[CH:9][N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[C:11]1[CH:12]=[C:13]([CH:20]=[CH:21][C:22]=1[CH3:23])[C:14]([NH:16][CH:17]1[CH2:19][CH2:18]1)=[O:15].[CH:24]1([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25]1.[CH3:30]N(C=O)C>>[CH:17]1([NH:16][C:14](=[O:15])[C:13]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:11]([N:6]3[CH:5]=[N:4][C:3]4[C:7]3=[N:8][CH:9]=[N:10][C:2]=4[O:29][C:24]3[CH:30]=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:12]=2)[CH2:19][CH2:18]1
Reactant: CN(C)C=O
Reactant: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Cl)ncnc21
Reactant: OC1CCCC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-n1cnc2c(Oc3ccccc3)ncnc21
Temperature: 150 °C

Procedure:
To a solution of 3-(6-Chloro-purin-9-yl)-N-cyclopropyl-4-methyl-benzamide (Example 4B) (21 mg, 0.064 mmol) in DMF (0.2 ml) was added cyclopentanol (59 □1, 0.64 mmol). The mixture was heated with microwave at 150° C. for 30 minutes. It was cooled to RT and then purified by PTLC or HPLC to give the desired as a white solid (10 mg, 0.027 mmol, 41%). HPLC tR=2.09 min; MS m/z 386 [M+H]+.
Reaction SMILES: O[CH2:2]/[CH:3]=[C:4](/[CH2:6][CH2:7]/[CH:8]=[C:9](/[CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])\[CH3:10])\[CH3:5].CC(CCC=C(C)CCC=C(C)C)=CCN1C(=O)C2C(=CC=CC=2)C1=O.P(Br)(Br)[Br:44]>C(OCC)C>[CH2:2]([Br:44])[CH:3]=[C:4]([CH2:6][CH2:7][CH:8]=[C:9]([CH2:11][CH2:12][CH:13]=[C:14]([CH3:16])[CH3:15])[CH3:10])[CH3:5]
Reactant: CC(C)=CCC/C(C)=C/CC/C(C)=C/CO
Reactant: BrP(Br)Br
Agent: CC(C)=CCCC(C)=CCCC(C)=CCN1C(=O)c2ccccc2C1=O
Solvent: CCOCC
Product: CC(C)=CCCC(C)=CCCC(C)=CCBr

Procedure:
A solution of 2.00 g (9.0 mmol) of (E,E)-farnesol in 20 ml of dry diethyl ether at 0° C. under argon in the dark was treated dropwise with a solution of 735 1 (4.0 mmol, 0.45 eq.) of PBr3 in 4 ml of dry diethyl ether. The resultant mixture was stirred at 0° C. for one hour, then quenched with H2O and separated. The organic phase was washed with 15 ml of NaHC03, 15 ml of H2O, and 15 ml of brine, dried over MgSO4 and evaporated to provide 2.47 g of crude farnesyl bromide as a clear oil.
Reaction SMILES: C(O)(=O)C(O)=O.[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][NH:14][CH2:13]1.[CH3:19][N:20]=[C:21]=[O:22].C(N(CC)CC)C>O1CCCC1.O>[F:7][C:8]1[CH:9]=[C:10]([CH:16]=[CH:17][CH:18]=1)[O:11][CH:12]1[CH2:15][N:14]([C:21]([NH:20][CH3:19])=[O:22])[CH2:13]1
Reactant: CN=C=O
Reactant: Fc1cccc(OC2CNC2)c1
Agent: O=C(O)C(=O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CNC(=O)N1CC(Oc2cccc(F)c2)C1
Reaction time: 3 h
Yield: 66.9 %

Procedure:
A stirred mixture of 5.4 g (0.02 mole) of 3-(3-fluorophenoxy)-azetidine oxalate and 1.7 g (0.022 mole) of methyl isocyanate in 20 ml of tetrahydrofuran was treated with 5 ml of triethylamine then stirring was continued for 3 hr. The reaction was diluted with water and the fine crystalline precipitate obtained was collected by filtration and dried at 60° C. under vacuum to yield 3 g (66.9%) of product, m.p. 155°-156° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:30][CH3:31].O>CN(C)C=O>[CH2:30]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([NH2:13])=[O:12])=[C:5]2[S:14]([N:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1)(=[O:16])=[O:15])[CH3:31]
Reactant: CCI
Reactant: NC(=O)c1[nH]c2ccc(O)cc2c1S(=O)(=O)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc2[nH]c(C(N)=O)c(S(=O)(=O)N3CCOCC3)c2c1
Reaction time: 1 h

Procedure:
To a solution of 5-hydroxy-3-(morpholin-4-ylsulfonyl)-1H-indole-2-carboxamide from Example 50 (32 mg, 0.098 mmol) in 1 mL of dimethylformamide was added cesium carbonate (95 mg, 0.29 mmol) and iodoethane (0.0094 mL, 0.12 mmol). After one hour, 0.5 mL of water was added to solubilize the material, and the resulting mixture was purified by preparative reversed phase HPLC to provide the titled product as a white solid. Proton NMR for the product was consistent with the titled compound. HRMS (ES) exact mass calculated for C15H20N3O5S (M+H+): 354.1118. Found 354.1094.
Reaction SMILES: [C:1]([C:4]1[N:5]=[C:6]([CH2:24][CH3:25])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1Cl)(=[O:3])[NH2:2].[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH2:29][CH2:28]1.C(N(C(C)C)CC)(C)C.CN(C)C=O>C(OCC)(=O)C>[C:1]([C:4]1[N:5]=[C:6]([CH2:24][CH3:25])[C:7]([O:11][CH:12]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13]2)=[N:8][C:9]=1[NH:37][C:36]1[CH:35]=[CH:34][C:33]([N:30]2[CH2:29][CH2:28][N:27]([CH3:26])[CH2:32][CH2:31]2)=[CH:39][CH:38]=1)(=[O:3])[NH2:2]
Reactant: CCc1nc(C(N)=O)c(Cl)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCN(C)CC3)cc2)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 120 °C
Reaction time: 22 h
Yield: 31.7 %

Procedure:
A mixture of tert-butyl 3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (790 mg), 4-(4-methylpiperazin-1-yl)aniline (448 mg), diisopropylethylamine (729 μL), and N,N-dimethylformamide (5.53 mL) was stirred at 120° C. for 22 hours. The reaction mixture was left to be cooled and then diluted with ethyl acetate, and the organic phase was washed with water, a saturated aqueous sodium hydrogen carbonate solution, and saturated brine in this order, and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform:methanol:28% aqueous ammonia=1:0:0-30:1:0.1), and then washed with diisopropyl ether to obtain tert-butyl 3-[(5-carbamoyl-3-ethyl-6-{[4-(4-methylpiperazin-1-yl)phenyl]amino}pyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (355 mg) as a pale yellow solid.