Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3](SC)=[C:4]1[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]2[C:6](=[CH:7][C:8]([F:21])=[CH:9][CH:10]=2)[C:5]1=[O:22].CSC(SC)=C1C(=O)C(CCCC)(CCCC)C2C(=CC=CC=2)C1=O.[NH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=1[S:57]([NH2:60])(=[O:59])=[O:58].NC1C=CC(OCC2C=CC=CC=2)=CC=1S(N)(=O)=O>>[O:58]=[S:57]1(=[O:59])[C:52]2[CH:53]=[CH:54][CH:55]=[CH:56][C:51]=2[NH:50][C:3]([C:4]2[C:13](=[O:14])[C:12]([CH2:18][CH2:19][CH3:20])([CH2:15][CH2:16][CH3:17])[C:11]3[C:6]([C:5]=2[OH:22])=[CH:7][C:8]([F:21])=[CH:9][CH:10]=3)=[N:60]1
Reactant: CCCC1(CCC)C(=O)C(=C(SC)SC)C(=O)c2cc(F)ccc21
Reactant: Nc1ccccc1S(N)(=O)=O
Agent: CCCCC1(CCCC)C(=O)C(=C(SC)SC)C(=O)c2ccccc21
Agent: Nc1ccc(OCc2ccccc2)cc1S(N)(=O)=O
Product: CCCC1(CCC)C(=O)C(C2=NS(=O)(=O)c3ccccc3N2)=C(O)c2cc(F)ccc21

Procedure:
The title compound was prepared according to the procedure of Example 5D, substituting the compound of Example 14H for the compound of Example 5C, and also substituting 2-aminobenzenesulfonamide for the compound of Example 2D. 1H NMR (300 MHz, DMSO-d6): δ 0.58 (m, 2 H) 0.67 (m, 6 H) 0.93 (m, 2 H) 2.01 (m, 2 H) 2.17 (m, 2 H) 7.72 (m, 7 H) 13.48 (s, 1-H).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:32]=[CH:31][C:6]2[NH:7][C:8]([C:13]3[C:14](=[O:30])[C@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:16]4[C:21]([C:22]=3[OH:23])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[N:9][S:10](=[O:12])(=[O:11])[C:5]=2[CH:4]=1.N1C=CC=CC=1.[C:39]([NH:42][C:43]1[CH:44]=[C:45]2[C:50](=[CH:51][CH:52]=1)[CH:49]=[C:48]([S:53](Cl)(=[O:55])=[O:54])[CH:47]=[CH:46]2)(=[O:41])[CH3:40]>CC(C)=O>[OH:23][C:22]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C@@:15]([CH3:29])([CH2:24][CH2:25][CH:26]([CH3:28])[CH3:27])[C:14](=[O:30])[C:13]=1[C:8]1[NH:7][C:6]2[CH:31]=[CH:32][C:3]([NH:2][S:53]([C:48]3[CH:49]=[C:50]4[C:45](=[CH:46][CH:47]=3)[CH:44]=[C:43]([NH:42][C:39](=[O:41])[CH3:40])[CH:52]=[CH:51]4)(=[O:55])=[O:54])=[CH:4][C:5]=2[S:10](=[O:12])(=[O:11])[N:9]=1
Reactant: CC(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CC(=O)Nc1ccc2cc(S(=O)(=O)Cl)ccc2c1
Agent: Cl
Solvent: c1ccncc1
Solvent: CC(C)=O
Product: CC(=O)Nc1ccc2cc(S(=O)(=O)Nc3ccc4c(c3)S(=O)(=O)N=C(C3=C(O)c5ccccc5[C@@](C)(CCC(C)C)C3=O)N4)ccc2c1
Yield: 61 %

Procedure:
A mixture of Example 39H (23.8 mg, 0.050 mmol), pyridine (31.6 mg, 0.40 mmol) and 6-acetylamino-2-naphthalenesulfonyl chloride (56.7 mg, 0.20 mmol, prepared by the procedure as described in J. Med. Chem., 1995, 38, 8, p. 1344-1354) in acetone (1.5 mL) was stirred at rt for 18 h. The reaction mixture was evaporated in vacuo and partitioned between ethyl acetate and 1 N HCl. The organic phase was separated, dried (MgSO4), filtered, and evaporated in vacuo. The residue was purified by chromatography on silica gel eluting with 99:1 dichloromethane/methanol to provide the title compound (20.8 mg, 61% yield). 1H NMR (300 MHz, DMSO-d6) δ 0.38 m, 1 H) 0.66 (d, J=7.35 Hz, 3 H) 0.68 (d, J=6.99 Hz, 3H) 0.80 m, 1 H) 1.30 m, 1 H) 1.53 (s, 3 H) 2.02 m, 1 H) 2.10 (s, 3 H) 2.18 (m, 1 H) 7.52 m, 4 H) 7.69 m, 4 H) 7.99 (d, J=8.82 Hz, 1 H) 8.07 (d, J=8.82 Hz, 1 H) 8.11 (d, J=8.09 Hz, 1H) 8.38 (s, 2 H) 10.32 (s, 1 H) 10.87 (s, 1 H) 13.72 (s, 1 H).
Reaction SMILES: [CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([OH:26])=O)[CH:20]=2)[S:5]([C:8]2[C:13]([CH3:14])=[CH:12][C:11]([O:15][CH3:16])=[CH:10][C:9]=2[CH3:17])(=[O:7])=[O:6])[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.Cl.[CH3:59][O:60][CH:61]1[CH2:64][N:63]([CH2:65][C:66]2[CH:71]=[CH:70][C:69]([CH2:72][NH:73][CH3:74])=[CH:68][CH:67]=2)[CH2:62]1>C(Cl)Cl>[CH:1]1([N:4]([CH2:18][C:19]2[O:23][CH:22]=[C:21]([C:24]([N:73]([CH2:72][C:69]3[CH:68]=[CH:67][C:66]([CH2:65][N:63]4[CH2:64][CH:61]([O:60][CH3:59])[CH2:62]4)=[CH:71][CH:70]=3)[CH3:74])=[O:26])[CH:20]=2)[S:5]([C:8]2[C:9]([CH3:17])=[CH:10][C:11]([O:15][CH3:16])=[CH:12][C:13]=2[CH3:14])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: CNCc1ccc(CN2CC(OC)C2)cc1
Reactant: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)O)co2)C2CC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(C)c(S(=O)(=O)N(Cc2cc(C(=O)N(C)Cc3ccc(CN4CC(OC)C4)cc3)co2)C2CC2)c(C)c1

Procedure:
The title compound was prepared according to general procedure BH using 5-({cyclopropyl[(4-methoxy-2,6-dimethylphenyl)sulfonyl]amino}methyl)furan-3-carboxylic acid (45 mg, 0.12 mmol), EDCI (32 mg, 0.168 mmol), HOBt (24 mg, 0.18 mmol), DIPEA (0.04 mL, 0.24 mmol), 1-{4-[(3-methoxyazetidin-1-yl)methyl]phenyl}-N-methylmethanamine dihydrochloride (37 mg, 0.14 mmol) and DCM (10 mL).
Reaction SMILES: Cl.Cl.[CH2:3]1[C@@H:8]2[CH2:9][NH:10][CH2:11][CH2:12][N:7]2[CH2:6][CH2:5][O:4]1.[Cl:13][C:14]1[C:19]([F:20])=[C:18](Cl)[N:17]=[C:16]([CH3:22])[N:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:13][C:14]1[N:15]=[C:16]([CH3:22])[N:17]=[C:18]([N:10]2[CH2:11][CH2:12][N:7]3[C@H:8]([CH2:3][O:4][CH2:5][CH2:6]3)[CH2:9]2)[C:19]=1[F:20]
Reactant: C1CN2CCOC[C@@H]2CN1
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(Cl)c(F)c(N2CCN3CCOC[C@@H]3C2)n1
Reaction time: 2 h

Procedure:
To a mixture of (9aS)-octahydropyrazino[2,1-c][1,4]oxazine dihydrochloride (23.28 g, 108.2 mmol) in DCM (360 mL) was added 4,6-dichloro-5-fluoro-2-methylpyrimidine (19.59 g, 108.2 mmol) and N,N-diisopropylethylamine (68 mL, 390.4 mmol). The mixture was stirred for 2 h, and the resulting solution was diluted with DCM (100 mL) and washed with saturated aq. NaHCO3 (200 mL). The aqueous phase was extracted with a fresh portion of DCM (100 mL), and this organic phase was washed with saturated aq. NaHCO3 (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give (9aS)-8-(6-chloro-5-fluoro-2-methyl-4-pyrimidinyl)octahydropyrazino[2,1-c][1,4]oxazine as a light yellow oil that was used without further purification. LCMS: (M+H)+: 287.1.
Reaction SMILES: Cl.C([N:9]1[CH2:18][CH2:17][C:16]2[C:15]([C:19]3[CH:23]=[C:22]([CH3:24])[S:21][CH:20]=3)=[N:14][C:13]([CH:25]([CH3:27])[CH3:26])=[N:12][C:11]=2[CH2:10]1)C1C=CC=CC=1.[Cl:28]C(OC(Cl)=O)C>ClCCCl>[ClH:28].[CH:25]([C:13]1[N:14]=[C:15]([C:19]2[CH:23]=[C:22]([CH3:24])[S:21][CH:20]=2)[C:16]2[CH2:17][CH2:18][NH:9][CH2:10][C:11]=2[N:12]=1)([CH3:27])[CH3:26]
Reactant: Cc1cc(-c2nc(C(C)C)nc3c2CCN(Cc2ccccc2)C3)cs1
Reactant: CC(Cl)OC(=O)Cl
Agent: Cl
Solvent: ClCCCl
Product: Cc1cc(-c2nc(C(C)C)nc3c2CCNC3)cs1
Temperature: 95 °C

Procedure:
A solution of 7-benzyl-2-isopropyl-4-(5-methyl-thiophen-3-yl)-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine hydrochloride (0.133 g) in 1,2-dichloroethane (7 mL) was treated with 1-chloroethylchloroformate (0.105 mL). The mixture was heated at 95° C. for 16 h, concentrated, dissolved in MeOH, and heated at 50° C. for an additional 2 h. The mixture was concentrated and chromatographed on SiO2 (2 M NH3 in MeOH/CH2Cl2). MS (ESI): exact mass calcd. for C15H19N3S, 273.13; m/z found, 274.3 [M+H]+. 1H NMR (MeOH-d4): 7.81-7.80 (m, 1H), 7.36-7.35 (m, 1H), 4.42 (s, 2H), 3.55 (t, J=6.0, 2H), 3.25 (t, J=6.0, 2H), 3.19 (m, 1H), 2.55 (s, 3H), 1.35 (d, J=7.2, 6H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29](Br)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1.[CH3:34][CH:35]([CH3:48])[CH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42](B(O)O)=[CH:41][CH:40]=1>>[CH3:1][O:2][C:3](=[O:33])[CH2:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[CH:16]=[C:15]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=3[Cl:24])[N:14]=[C:13]2[CH2:25][C:26]2[CH:31]=[CH:30][C:29]([C:42]3[CH:41]=[CH:40][C:39]([CH2:38][CH2:37][CH2:36][CH:35]([CH3:48])[CH3:34])=[CH:44][CH:43]=3)=[CH:28][CH:27]=2)=[CH:8][CH:7]=1
Reactant: CC(C)CCCc1ccc(B(O)O)cc1
Reactant: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1
Product: COC(=O)CNc1ccc(-n2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(-c3ccc(CCCC(C)C)cc3)cc2)cc1

Procedure:
{-4-[2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-imidazol-1-yl]-phenylamino}-acetic acid methyl ester (500 mg, 0.91 mmol) was coupled with 4-(4-methylpentyl)phenyl boronic acid according to general procedure G to give (4-{4-(2,4-dichloro-phenyl)-2-[4′-(4-methyl-pentyl)-biphenyl-4-ylmethyl]-imidazol-1-yl}-phenylamino)-acetic acid methyl ester.
Reaction SMILES: [Li]N([Si](C)(C)C)[Si](C)(C)C.C1COCC1.[NH:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]([O:23][CH2:24][CH3:25])=[O:22].[NH2:26]OP(=O)(C1C=CC=CC=1)C1C=CC=CC=1>CN(C=O)C>[NH2:26][N:16]1[CH:20]=[CH:19][N:18]=[C:17]1[C:21]([O:23][CH2:24][CH3:25])=[O:22]
Reactant: CCOC(=O)c1ncc[nH]1
Reactant: NOP(=O)(c1ccccc1)c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCOC(=O)c1nccn1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.8 %

Procedure:
Alternative procedure using 1M LiN(TMS)2 as base: A 1M THF solution of LiHMDS (19.62 ml, 19.62 mmol) was added dropwise to a solution of ethyl 1H-imidazole-2-carboxylate (2.5 g, 17.84 mmol) in DMF (119 ml) at 0° C. The reaction was stirred at 0° C. for 10 minutes. A DMF (119 ml) suspension of (aminooxy)diphenylphosphine oxide (4.99 g, 21.41 mmol) was added. After stirring for 10 minutes, the ice bath was removed, and stirring was continued at room temperature. After 3 hrs, the starting material was completely consumed. Water was added portion-wise to the reaction mixture until complete dissolution of the suspension. The clear solution was concentrated to dryness under reduced pressure. Ethyl acetate was added to the solid, forming a yellow suspension. The suspension was stirred for 15 minutes and filtered. The solid was washed with ethyl acetate and dichloromethane, successively. The collected organic wash was concentrated. The crude product was dissolved in 10% MeOH/DCM (10 ml) and was chromatographed on a prepacked silica gel column (Isco prep: 0-5% MeOH-DCM over 20 minutes. The product began eluting around 7 minutes (˜2% MeOH/DCM). The desired ethyl 1-amino-1H-imidazole-2-carboxylate (2.57 g, 16.56 mmol, 93% yield) was obtained as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:20])[CH2:10][CH2:9]4)[CH2:6][CH2:5][C:4]=2[C:3]=1[CH3:21].[C:22]12(O)[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2.B(F)(F)F.CCOCC>CCCCC>[C:22]12([C:19]3[C:2]([OH:1])=[C:3]([CH3:21])[C:4]4[CH2:5][CH2:6][C@@H:7]5[C@@H:16]([C:17]=4[CH:18]=3)[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]5[CH2:9][CH2:10][C:11]3=[O:20])[CH2:31][CH:26]3[CH2:27][CH:28]([CH2:30][CH:24]([CH2:25]3)[CH2:23]1)[CH2:29]2
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: Cc1c(O)ccc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Agent: FB(F)F
Solvent: CCOCC
Solvent: CCCCC
Product: Cc1c(O)c(C23CC4CC(CC(C4)C2)C3)cc2c1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 65.2 %

Procedure:
To a suspension of the known 3-hydroxy-4-methylestra-1,3,5(10)-trien-17-one (ref. Kaneko et al., 1964; Chemical Abstracts Registry Number [68969-90-4], 30 mg, 0.11 mmol) and 30 mg (0.197 mmol) of 1-adamantanol in 1 mL of anhydrous pentane was added 0.02 mL of boron trifluoride diethyl etherate while cooling with an ice bath and stirring. After stirring at 0° C. for 15 min. the reaction was stirred at room temperature for 45 min. Ice was added and the white solid that formed was filtered, washed with water and dried over P2O5. The crude product was purified by chromatography (silica gel eluted with 7% ethyl acetate in hexanes) to give 30 mg of pure product (68% yield). After recrystallization from methylene chloride-hexanes the product had: m.p. 262-263° C.; 1H NMR(CDCl3) δ 0.90 (s, 3H, CH3), 2.13 (s, 3H, CH3), 2.7 (m, 2H, CH2), 7.11 (s, 1H, Ar—H); 13C NMR (CDCl3) δ 11.02, 13.70, 21.44, 26.22, 26.67, 27.54, 28.95 (3×C), 31.56, 35.84, 36.60, 36.98 (3×C), 37.63, 40.82 (3×C), 44.60, 47.91, 50.34, 121.41, 121.51, 131.45, 133.32, 150.79, 221.49. (Anal. calc'd. for C29H39O2: C, 83.21; H, 9.15. Found: C, 83.45; H, 8.94.)
Reaction SMILES: C([Li])CCC.CCCCCC.[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([Br:30])[CH:26]=2)[CH2:21]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([CH:37]=[O:38])[CH:32]=1>O1CCCC1>[C:12]([O:16][C:17]([NH:19][CH:20]1[CH2:29][CH2:28][C:27]2[CH2:26][C:25]([CH:37]([C:33]3[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=3)[OH:38])([Br:30])[CH:24]=[CH:23][C:22]=2[CH2:21]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)NC1CCc2cc(Br)ccc2C1
Reactant: O=Cc1cccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)OC(=O)NC1CCC2=C(C=CC(Br)(C(O)c3cccnc3)C2)C1
Temperature: -70 °C
Reaction time: 1.5 h

Procedure:
8.8 ml of a solution of n-butyl lithium in hexane (2.5 mol) was dropped to a solution of 3.25 g of 2-tert.butoxycarbonylamino-6-bromo-1,2,3,4-tetrahydro-naphthaline in 50 ml of absolute tetrahydrofurane cooled to -70° C. and stirring was continued for 1.5 hours at -50° C. Subsequently, 1.1 g of pyridine-3-aldehyde were dropped into the mixture at -70° C. After stirring for one hour, the reaction mixture was poured on ice and extracted with ethyl acetate. The organic Phase was washed with water, dried and evaporated. The obtained residue was recrystallised from cyclohexane/ethyl acetate.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([SH:8])=[N:4]1.[CH:9](N(C(C)C)CC)(C)C.CI>CO>[OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][C:5]([S:8][CH3:9])=[N:4]1
Reactant: CCN(C(C)C)C(C)C
Reactant: OC[C@@H]1CSC(S)=N1
Solvent: CI
Solvent: CO
Product: CSC1=N[C@H](CO)CS1
Yield: 59 %

Procedure:
To a mixture solution of 4.88 g of 4(R)-hydroxymethyl-2-mercapto-1,3-thiazoline [Compound (5)] and 22.8 ml of diisopropylethylamine in 65 ml of dry methanol was added 14.00 g of methyl iodide under refluxing condition, and the reaction mixture was refluxed for 1 hour. After removal of the solvent under reduced pressure, the resulting residue was dissolved in ethyl acetate and the organic layer was washed with saturated sodium bicarbonate solution, water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under reduced pressure and the resulting residue was purified by silica gel column chromatography (chloroform-acetone) to give 3.14 g (59%) of 4(R)-hydroxymethyl-2-methylthio-1,3-thiazoline [Compound (6)].
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH:7]2[CH2:9][O:8]2)=[CH:5][S:4][C:3]=1[C:10]#[N:11].[OH:12][CH2:13][C@H:14]1[NH:19][CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:15]1>CCO>[C:10]([C:3]1[S:4][CH:5]=[C:6]([CH:7]([OH:8])[CH2:9][N:19]2[CH2:18][CH2:17][N:16]([C:20]([O:22][C:23]([CH3:24])([CH3:25])[CH3:26])=[O:21])[CH2:15][C@H:14]2[CH2:13][OH:12])[C:2]=1[CH3:1])#[N:11]
Reactant: CC(C)(C)OC(=O)N1CCN[C@H](CO)C1
Reactant: Cc1c(C2CO2)csc1C#N
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(C(=O)OC(C)(C)C)C[C@H]2CO)csc1C#N
Temperature: 140 °C

Procedure:
A mixture of 3-methyl-4-(oxiran-2-yl)thiophene-2-carbonitrile (1.3 g, 7.9 mmol) and tert-butyl (3S)-3-(hydroxymethyl)piperazine-1-carboxylate (2.0 g, 9.5 mmol) in 5 mL of EtOH was heated in a microwave apparatus at 140° C. for 90 minutes and then cooled down. The reaction mixture was concentrated, and the residue was purified by column chromatography (DCM:MeOH=10:1) to afford the title compound.
Reaction SMILES: [C:1]1([C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4])[OH:2].C(=O)([O-])[O-].[K+].[K+].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.O>CN(C)C=O>[Cl:22][C:19]1[CH:18]=[N:17][C:16]([O:2][C:1]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])=[N:21][CH:20]=1
Reactant: Clc1cnc(Cl)nc1
Reactant: Oc1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Oc1ccccc1Oc1ncc(Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.4 %

Procedure:
To a mixture of 6.0 grams (0.055 mole) catechol and 7.0 grams of potassium carbonate stirring in 45 ml of dimethylformamide, 7.0 grams of 2,5-dichloropyrimidine was added and the mixture stirred at room temperature overnight followed by heating at 80° for 4 hours. Excess water was added to the reaction mixture, and the aqueous mixture extracted with 300 ml of ethyl ether. The ether extract was washed with H2O (2X), brine, dried (magnesium sulfate), filtered, and the solvent removed to yield a yellow oil which slowly crystallized. From a 1-chlorobutane/cyclohexane mixture, the crude solid was recrystallized to give 6.0 grams of product, m.p. 131°-139°; ir (Nujol): 2.90-3.30 (OH), 12.80, 13.30 microns.
Reaction SMILES: Br[CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH2:2][C:3]1[CH:18]=[CH:17][C:6]2[N:7]=[C:8]([C:10]3[C:14]([CH3:15])=[N:13][NH:12][C:11]=3[NH2:16])[S:9][C:5]=2[CH:4]=1)[CH3:21]
Reactant: Cc1n[nH]c(N)c1-c1nc2ccc(CBr)cc2s1
Reactant: CNC
Product: Cc1n[nH]c(N)c1-c1nc2ccc(CN(C)C)cc2s1

Procedure:
The title compound (24 mg) was prepared starting from 40 mg of 4-(6-bromomethylbenzothiazol-2-yl)-5-methyl-2H-pyrazol-3-ylamine and excess dimethylamine. MS (m/z, ES+): 288.1 (M+1, 20%), 243.1 (M-(CH3)2N, 100%).
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[CH2:25]([O:32][C:33]([NH:35][CH2:36][CH2:37][B-](F)(F)F)=[O:34])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.[K+].C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH2:37][CH2:36][NH:35][C:33](=[O:34])[O:32][CH2:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: O=C(NCC[B-](F)(F)F)OCc1ccccc1
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(Cn2c(=O)n3ncnc3c3cc(CCNC(=O)OCc4ccccc4)cnc32)cc1
Temperature: 80 °C
Yield: 0 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (30 mg, 0.078 mol), potassium (2-(benzyloxycarbonylamino)ethyl)trifluoroborate (30 mg, 0.11 mol), cesium carbonate (122 mg, 0.38 mmol), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) DCM complex (5 mg, 0.01 mol), toluene (0.75 ml) and degassed water (0.25 ml) were added in order. The mixture was heated at 80° C. for 16 hours, concentrated under a stream of nitrogen, diluted with DMF (1.5 mL), filtered and purified by HPLC to afford 6 mg (12%) of 204 as a white solid.
Reaction SMILES: [OH:1][C:2]1([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH2:14]([N:5]1[CH2:6][CH2:7][C:2]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)([OH:1])[CH2:3][CH2:4]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: BrCc1ccccc1
Reactant: OC1(c2ccccc2)CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: OC1(c2ccccc2)CCN(Cc2ccccc2)CC1
Reaction time: 2 h
Yield: 62.8 %

Procedure:
4-Hydroxy-4-phenylpiperidine (0.5 g, 2.8 mmol), benzylbromide (0.5 g, 3 mmol) and potassium carbonate (0.8 g, 6 mmol) were dissolved in DMF (5 mL) and stirred for 2 hours. The mixture was diluted with ethyl acetate and washed with a solution of saturated aqueous sodium carbonate solution then dried over magnesium sulphate, filtered and the solvent removed by evaporation under vacuum. The resulting solid was recrystallised from pentane to give the title compound as a white solid (0.47 g). LCMS m/z 268.3 [M+H]+. R.T.=2.37 min (Analytical Method 4).
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[C:6]([Cl:17])=[CH:7][N:8]=[C:9]2[C:14]=1[N:13]=[C:12]([O:15][CH3:16])[CH:11]=[CH:10]2.[Cl-].[NH4+]>CN(C)C=O>[Cl:17][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:5]=1[C:2]#[N:3])=[N:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2
Reactant: COc1ccc2ncc(Cl)c(Br)c2n1
Reactant: N#C[Cu]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1ccc2ncc(Cl)c(C#N)c2n1
Temperature: 130 °C
Reaction time: 8 h
Yield: 60.9 %

Procedure:
Copper(I) cyanide (39.3 g, 0.44 mol, 1.2 eq) is added at room temperature to a stirred solution of 8-bromo-7-chloro-2-methoxy-[1,5]naphthyridine (100 g, 0.37 mol, 1.0 eq) in N,N-dimethylformamide (1.5 L). After 8 hours stirring at 130° C., the reaction mixture is cooled down to room temperature and treated with a saturated ammonium chloride aqueous solution (1.5 L). The aqueous layer is separated and extracted with ethyl acetate (2×1.5 L). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is washed with ethanol (20 mL) to afford 3-chloro-6-methoxy-[1,5]naphthyridine-4-carbonitrile as an off-white solid (49.5 g, 62% yield).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([C:15]([CH3:25])=[CH:16][CH:17]=[CH:18][C:19]([CH3:24])=[CH:20][C:21]([O-:23])=[O:22])[CH:8]=[C:9]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:26][CH2:27]OC(C)=O>>[C:1]([C:5]1[CH:6]=[C:7]([CH:15]([CH3:25])[CH2:16]/[CH:17]=[CH:18]/[C:19](/[CH3:24])=[CH:20]/[C:21]([O:23][CH2:26][CH3:27])=[O:22])[CH:8]=[C:9]([C:11]([CH3:12])([CH3:13])[CH3:14])[CH:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(C)=O
Reactant: CC(C=CC=C(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1)=CC(=O)[O-]
Product: CCOC(=O)/C=C(C)/C=C/CC(C)c1cc(C(C)(C)C)cc(C(C)(C)C)c1

Procedure:
Compound 13 was prepared from 12 in a similar manner as described for compound 7: TLC (5% EtOAc-95% hexanes) Rf 0.88; 1H-NMR (CDCl3) δ1.30 (m, 6H, CH2CH3 +CH3), 1.34 (s, 18H, 6(CH3)), 2.20, (s, 3H, CH3), 2.40 (m, 2H, CH2), 2.85 (m, 1H, CH), 4.14 (m, 2H, CH2CH3), 5.62 (s, 1H, =CH), 6.03 (m, 2H, =CH), 7.00 (d, J=I Hz, 2H, Ar-H), 7.24 (t, J=1 Hz, 1H, Ar-H).
Reaction SMILES: CC1C=CC=C([N+]([O-])=O)C=1C(OC(=O)C1C([N+]([O-])=O)=CC=CC=1C)=O.[OH:26][C@H:27]([C@H:32]([NH:36][C:37](=[O:98])[C@H:38]([NH:60][C:61](=[O:97])[C@H:62]([NH:67][C:68](=[O:96])[CH2:69][C@@H:70](O)/[CH:71]=[CH:72]/[CH2:73][CH2:74][S:75][C:76]([C:89]1[CH:94]=[CH:93][CH:92]=[CH:91][CH:90]=1)([C:83]1[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=1)[C:77]1[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=1)[CH2:63][CH:64]([CH3:66])[CH3:65])[CH2:39][S:40][C:41]([C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)([C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH:33]([CH3:35])[CH3:34])[CH2:28][C:29]([OH:31])=[O:30]>CN(C1C=CN=CC=1)C.C(Cl)Cl.C(Cl)Cl.C1COCC1>[OH:26][C@@H:27]1[CH2:28][C:29](=[O:31])[O:30][C@H:70](/[CH:71]=[CH:72]/[CH2:73][CH2:74][S:75][C:76]([C:83]2[CH:88]=[CH:87][CH:86]=[CH:85][CH:84]=2)([C:89]2[CH:90]=[CH:91][CH:92]=[CH:93][CH:94]=2)[C:77]2[CH:82]=[CH:81][CH:80]=[CH:79][CH:78]=2)[CH2:69][C:68](=[O:96])[NH:67][C@H:62]([CH2:63][CH:64]([CH3:65])[CH3:66])[C:61](=[O:97])[NH:60][C@H:38]([CH2:39][S:40][C:41]([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:48]2[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=2)[C:37](=[O:98])[NH:36][C@@H:32]1[CH:33]([CH3:34])[CH3:35]
Reactant: CC(C)C[C@@H](NC(=O)C[C@@H](O)/C=C/CCSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)N[C@H](C(C)C)[C@@H](O)CC(=O)O
Agent: CN(C)c1ccncc1
Agent: Cc1cccc([N+](=O)[O-])c1C(=O)OC(=O)c1c(C)cccc1[N+](=O)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Product: CC(C)C[C@H]1NC(=O)C[C@@H](/C=C/CCSC(c2ccccc2)(c2ccccc2)c2ccccc2)OC(=O)C[C@@H](O)[C@@H](C(C)C)NC(=O)[C@@H](CSC(c2ccccc2)(c2ccccc2)c2ccccc2)NC1=O
Yield: 46.7 %

Procedure:
To a solution of 2-methyl-6-nitrobenzoic anhydride (MNBA) (32.7 mg, 0.095 mmol) and DMAP (22.5 mg, 0.184 mmol) in CH2Cl2 (20 mL) was added dropwise a solution of acid 5C (76 mg, 0.075 mmol) in CH2Cl2/THF (2:1, 66 mL) over 3 hours. After a further 12 h the reaction was quenched by the addition of 1M HCl (30 mL). The organic phase was separated (extracting with CH2Cl2) and washed with sat NaHCO3 (30 mL), followed by brine (30 mL). The combined organic phase was dried (MgSO4), filtered and concentrated in vacuo to give a yellow oil. Purification by column chromatography on silica gel (eluent 40% EtOAc/Hexane) gave 6C (35 mg, 0.035 mmol, 47%) as a yellow oil.