Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13]1[CH2:12][CH2:11][C:10](=[O:17])[O:9][C:8]=1[CH:7]=[CH:6]2>C(O)C.C(OCC)(=O)C>[OH:2][C:3]1[CH:4]=[C:5]2[C:14](=[CH:15][CH:16]=1)[C:13]1[CH2:12][CH2:11][C:10](=[O:17])[O:9][C:8]=1[CH:7]=[CH:6]2
Reactant: COc1ccc2c3c(ccc2c1)OC(=O)CC3
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C1CCc2c(ccc3cc(O)ccc23)O1
Yield: 70.2 %

Procedure:
Starting with 4.84 g (21.2 mmol) of 1,2-dihydro-8-methoxy-3H-naphtho[2,1-b]pyran-3-one from the preceding example, the title compound (3.19 g; 70.3%) was obtained as an off-white solid, mp 189°-199° C. (recrystallized from ethanol-ethyl acetate), using the procedure of example 221.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([OH:34])[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[F:35][C:36]1[CH:41]=[CH:40][C:39](O)=[CH:38][CH:37]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:13]([O:20][C:21]1[CH:26]=[CH:25][C:24]([CH2:27][CH:28]([O:34][C:39]2[CH:40]=[CH:41][C:36]([F:35])=[CH:37][CH:38]=2)[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:23][CH:22]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)C(O)Cc1ccc(OCc2ccccc2)cc1
Reactant: Oc1ccc(F)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCc2ccccc2)cc1)Oc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.3 %

Procedure:
A solution of diethyl azodicarboxylate (40% toluene solution, 6.40 ml) in toluene (3.0 ml) was added dropwise at room temperature to a solution of ethyl 3-(4-benzyloxyphenyl)lactate (10.0 g) obtained from Reference example 24(a), 4-fluorophenol (4.15 g) and triphenylphosphine (10.6 g) in toluene (10 ml). The reaction mixture was stirred for 2 hours at room temperature and then concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column (eluant; dichloromethane/ethyl acetate=3/2) to afford the target compound (7.00 g) as a colorless oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[N:8]=[C:9]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=2[N:12]=1>>[N:1]1([C:7]2[N:8]=[C:9]([NH:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[S:13][C:11]=3[N:12]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(Cl)nc2s1
Reactant: c1cn[nH]c1
Product: O=[N+]([O-])c1cc2c(NCc3ccccc3)nc(-n3cccn3)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 2-chloro-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-6-nitro-4-benzylamino-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]4[NH:22][N:21]=[C:20]([CH:23]5[CH2:25][CH2:24]5)[N:19]=4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:26]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[N:29][C:28]=1[C@:33]([OH:37])([C:35]#[CH:36])[CH3:34].C(NC(C)C)(C)C>CN(C=O)C>[CH:23]1([C:20]2[N:19]=[C:18]([C:12]3[N:8]4[CH2:9][CH2:10][O:11][C:5]5[CH:4]=[CH:3][C:2]([C:36]#[C:35][C@@:33]([OH:37])([C:28]6[N:29]=[CH:30][CH:31]=[CH:32][N:27]=6)[CH3:34])=[CH:26][C:6]=5[C:7]4=[N:14][C:13]=3[C:15]([NH2:17])=[O:16])[NH:22][N:21]=2)[CH2:25][CH2:24]1
Reactant: NC(=O)c1nc2n(c1-c1nc(C3CC3)n[nH]1)CCOc1ccc(Br)cc1-2
Reactant: C#C[C@@](C)(O)c1ncccn1
Solvent: CN(C)C=O
Solvent: CC(C)NC(C)C
Product: C[C@@](O)(C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(-c3nc(C4CC4)n[nH]3)n1CCO2)c1ncccn1
Yield: 41.6 %

Procedure:
3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-10-[(3R)-3-hydroxy-3-pyrimidin-2-yl-but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was prepared similarly according to General Procedure E with slight modification. 10-bromo-3-(3-cyclopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide was reacted with (2R)-2-pyrimidin-2-ylbut-3-yn-2-ol in a solution of DMF (1.3 mL/mmol) and diisopropylamine (2.6 mL/mmol) to afford 36.7 mg (41.6% yield). M+1=483.2. 1H NMR (400 MHz, DMSO-d6) δ 8.89 (d, J=4.8 Hz, 2H), 8.57 (d, J=2.2 Hz, 1H), 8.30 (br s, 1H), 7.72 (br s, 1H), 7.49 (t, J=4.8 Hz, 1H), 7.35 (dd, J=8.5, 2.3 Hz, 1H), 7.05 (d, J=8.5 Hz, 1H), 6.14 (s, 1H), 5.00-4.77 (m, 2H), 4.58-4.50 (m, 2H), 2.13-2.03 (m, 1H), 1.88 (s, 3H), 1.03-0.96 (m, 2H), 0.94-0.86 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]([F:23])([F:22])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1>>[F:12][C:13]([F:22])([F:23])[C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:1][C:2]2[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=2)=[CH:16][CH:15]=1
Reactant: FC(F)(F)c1ccc(CCl)cc1
Reactant: Nc1ccc(O)c(C(=O)O)c1
Product: O=C(O)c1cc(NCc2ccc(C(F)(F)F)cc2)ccc1O
Yield: 50.3 %

Procedure:
By following the similar procedure in Synthesis Example 1 by using 5-aminosalicylic acid (500 mg, 3.26 mmole) and 4-(trifluoromethyl)benzyl chloride (760 mg, 3.92 mmole), 510 mg (50% yield) of 5-(4-(trifluoromethyl)benzyl)aminosalicylic acid was obtained as a white solid.:mp>188° C. (decompose).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[CH2:10][CH2:11][NH:12][CH2:13][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN([CH2:18][C:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[NH:21][CH:20]=1)C>C1(C)C=CC=CC=1>[C:1]1([CH2:7][CH2:8][C:9]2[CH2:14][CH2:13][N:12]([CH2:18][C:19]3[C:23]4[C:22](=[CH:27][CH:26]=[CH:25][CH:24]=4)[NH:21][CH:20]=3)[CH2:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CN(C)Cc1c[nH]c2ccccc12
Reactant: C1=C(CCc2ccccc2)CCNC1
Solvent: Cc1ccccc1
Product: C1=C(CCc2ccccc2)CCN(Cc2c[nH]c3ccccc23)C1
Yield: 25 %

Procedure:
To a solution of 4-(2-phenylethyl)-1,2,3,6-tetrahydropyridine (prepared by the method of Oediger and Joop, Leibigs. Ann. Chem., 972, 764, 21) (400 mg, 2.2 mmol) in dry toluene (10ml) was added gramine (370 mg, 2.1 mmol) and the reaction heated at reflux overnight. The solvent was evaporated and the residue chromatographed on silica gel eluting with 2% Et3N/EtOAc to give a solid which was recrystallised twice from toluene to yield the title compound as a white solid (160 mg, 25%), m.p. 138-140° C.; (Found: C, 83.59; H, 7.71; N, 8.89. C22H24N2 requires C, 83.50; H, 7.64; N, 8.85%); δH (CDCl3) 2.13 (2H, br s, tetrahydropyridinyl CH2), 2.25 (2H, t, J 8.3 Hz, PhCH2CH2), 2.64-2.73 (4H, m, tetrahydropyridinyl CH2, PhCH2CH2), 3.05 (2H, br s, tetrahydropyridinyl CH2), 3.81 (2H, s, NCH2Ar), 5.40 (1H, br s, tetrahydropyridyl CH), 7.11-7.28 (8H, m, ArH), 7.36 (1H, d, J 7.9 Hz, ArH), 7.72 (1H, d, J 7.9 Hz, ArH), and 8.12 (1H, br s, NH); m/z (CI+, NH3) 317 (M+1)+.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])[C:11]([NH2:25])=[N:10][CH2:9][CH2:8]1)=[O:6])[CH3:3].[H-].[Na+].[N:28]1[CH:33]=[CH:32][C:31]([C:34](=O)[CH2:35][C:36](OCC)=[O:37])=[N:30][CH:29]=1>O1CCCC1.C1(C)C=CC=CC=1>[CH2:2]([O:4][C:5]([N:7]1[CH2:13][CH:12]([N:14]2[C:15](=[O:24])[C:16]3[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:22]2=[O:23])[C:11]2=[N:25][C:34]([C:31]3[CH:32]=[CH:33][N:28]=[CH:29][N:30]=3)=[CH:35][C:36](=[O:37])[N:10]2[CH2:9][CH2:8]1)=[O:6])[CH3:3]
Reactant: CCOC(=O)CC(=O)c1ccncn1
Reactant: CCOC(=O)N1CCN=C(N)C(N2C(=O)c3ccccc3C2=O)C1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)N1CCn2c(nc(-c3ccncn3)cc2=O)C(N2C(=O)c3ccccc3C2=O)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44.9 %

Procedure:
To a suspension of 33.00 g (89.97 mmol) of (+/−)-5-amino-6-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-2,3,6,7-tetrahydro-[1,4]diazepine-1-carboxylic acid ethyl ester hydrochloride (1:1) in 300 mL of tetrahydrofuran was added 6.47 g (161.94 mmol) of sodium hydride (60% in oil), the reaction mixture was stirred at room temperature for 1 h and 17.47 g (89.97 mmol) of ethyl 3-(pyrimidin-4-yl)-3-oxopropionate dissolved in 300 mL of toluene was added. The resulting solution was evaporated to remove tetrahydrofuran, heated under reflux and 5.00 mL of glacial acetic acid was added. The reaction mixture was stirred under reflux for 12 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in dichloromethane, washed with a saturated aqueous solution of ammonium chloride, saturated aqueous sodium chloride, dried over sodium sulfate and evaporated to dryness. The residue was triturated with diethyl ether and filtered to afford 18.60 g (45%) of the product as a brown powder. The compound was used as such in the next step.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][N:7]([CH2:9][CH2:10][CH:11]=O)[CH:8]=1)([O-:3])=[O:2].[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH2:19][CH2:18]2.[BH4-].[Na+]>CO>[CH3:13][O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[N:20]([CH2:11][CH2:10][CH2:9][N:7]1[CH:8]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=[N:6]1)[CH2:19][CH2:18]2
Reactant: O=CCCn1cc([N+](=O)[O-])cn1
Reactant: COc1ccc2c(c1)CCN2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc2c(c1)CCN2CCCn1cc([N+](=O)[O-])cn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(4-nitro-1H-pyrazol-1-yl)propanal (200 mg, 1.18 mmol) in MeOH (12.0 mL), 5-methoxyindoline (176 mg, 1.18 mmol) was added. This reaction mixture was stirred at rt for 1 h, then NaBH4 (121 mg, 3.20 mmol) was added and stirred for another 30 min at rt. The reaction mixture was quenched with water and extracted with EtOAc (2×). The combined org. layers were dried (MgSO4), filtered and the solvent was removed under reduced pressure to yield 5-methoxy-1-(3-(4-nitro-1H-pyrazol-1-yl)propyl)indoline, which was used in the next step without further purification. LC-MS conditions B: tR=0.56 min, [M+H]+=303.15.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][N:17]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.F[B-](F)(F)F.C[N+](C)=C(N(C)C)ON1C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:1][CH2:2][C:3]1[O:7][N:6]=[C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[C:4]=1[CH2:14][O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:22])=[CH:18][N:17]=1
Reactant: O=C(O)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Reactant: NC1CCOCC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(NC1CCOCC1)c1ccc(OCc2c(-c3ccccn3)noc2CO)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
To a solution of 6-(5-hydroxymethyl-3-pyridin-2-yl-isoxazol-4-ylmethoxy)-nicotinic acid (70 mg, 0.21 mmol) in DMF (5 mL) was added 4-aminotetrahydropyrane (30 mg, 0.30 mmol), N,N,N′,N′-tetramethyl-O-(benzotriazole-1-yl)-uronium tetrafluoroborate (96 mg, 0.30 mmol) and N,N-diisopropyl ethylamine (0.15 mL, 0.84 mmol). The reaction mixture was stirred overnight at room temperature. After evaporation of the solvent the residue was partitioned (ethyl acetate/aqueous saturated sodium bicarbonate solution) and the organic phase was dried (Na2SO4) and concentrated. Chromatography (silica, dichloromethane:methanol=100:0 to 97:3) afforded the title compound (42 mg, 48%) as a white solid. MS: m/e=411.2 [M+H]+.
Reaction SMILES: FC(F)(F)C(O)=O.O.C(OC([N:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]2[CH:24]=[N:25][CH:26]=[C:27]([Br:29])[CH:28]=2)[C@@H:18]([C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH2:17]1)=O)(C)(C)C>ClCCl>[Br:29][C:27]1[CH:28]=[C:23]([CH2:22][N:19]2[CH2:20][CH2:21][NH:16][CH2:17][C@@H:18]2[C:30]2[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=2)[CH:24]=[N:25][CH:26]=1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cncc(Br)c2)[C@@H](c2ccc(F)cc2)C1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc([C@H]2CNCCN2Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 200.3 %

Procedure:
A mixture of trifluoroacetic acid and water (TFA:water=19:1, 10 mL) was added to a solution of (S)-4-(5-bromo-pyridin-3-ylmethyl)-3-(4-fluoro-phenyl)-piperazine-1-carboxylic acid tert-butyl ester (300 mg, 0.67 mmol) in 3 mL of dichloromethane and the resulting mixture stirred at ambient temperature for 1.5 h, and then the volatiles were removed in vacuo to leave 470 mg of product. LC/MS: Retention time, 2.13 min; (M+H)=351.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[CH3:14][Si:15]([CH2:18][CH2:19][O:20][CH2:21]Cl)([CH3:17])[CH3:16]>>[C:1]1([C:7]2[N:8]=[CH:9][N:10]([CH2:21][O:20][CH2:19][CH2:18][Si:15]([CH3:17])([CH3:16])[CH3:14])[CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2c[nH]cn2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Product: C[Si](C)(C)CCOCn1cnc(-c2ccccc2)c1
Yield: 65.5 %

Procedure:
Reaction of 4-phenylimidazole (400 mg, 2.78 mmol), NaH (60%, 108 mg, 2.70 mmol), and SEMCl (520 uL/2.94 mmol) followed by column chromatography on silica gel (hexane/EtOAC 1:1) gave the title compound (500 mg, 67%) as a yellow oil. 1H NMR (300 MHz, CDCl3) δ 0.00 (s, 9H), 0.92 (t, 2H, J=9.0 Hz), 3.54 (t, 2H, J=9.0 Hz), 5.27 (s, 2H), 7.17 (s, 1H), 7.37–7.47 (m, 3H), 7.56 (d, 2H, J=9.0 Hz), 7.68 (s, 1H). ES-MS m/z 275 (M+H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+].[N:25]#[C:26][NH2:27]>C(O)C.C(OCC)(=O)C>[NH2:27][C:26]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]2[N:11]=[C:12]([NH:15][C:16](=[O:18])[CH3:17])[S:13][CH:14]=2)=[CH:4][CH:3]=1)=[NH:25]
Reactant: N#CN
Reactant: CC(=O)Nc1nc(CCc2ccc(N)cc2)cs1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC(=O)Nc1nc(CCc2ccc(NC(=N)N)cc2)cs1
Temperature: 25 °C
Yield: 59.6 %

Procedure:
To a suspension of N-(4-(2-(4-aminophenyl)ethyl)-1,3-thiazol-2-yl)acetamide (26 g) in ethanol (500 ml) was added 4N hydrogen chloride in ethyl acetate (25 ml) and cyanamide (6.3 g). The mixture was refluxed for 26 hours. The reaction mixture was cooled to ambient temperature and poured into a mixture of ethyl acetate (500 ml) and saturated sodium hydrogen carbonate solution (500 ml). The resulted precipitate was collected by filtration and washed with water (300 ml) and ethanol (300 ml) to give N-{4-[2-(4-{[amino(imino)methyl]amino}phenyl)ethyl]-1,3-thiazol-2-yl}acetamide (18 g) as white crystals.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O-])=O)=[CH:16][CH:15]=1.[Na+].C(O)CO>CN1CCCC1=O.CCOC(C)=O>[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)[O-])cc1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: OCCO
Product: Cc1ccc(Sc2n[nH]c(=O)c3ccccc23)cc1
Yield: 75.1 %

Procedure:
A mixture of 4-chlorophthalazin-1(2H)-one (0.233 g, 1.29 mmol) and sodium 4-methylbenzenesulfinate (0.460 g, 2.58 mmol) in ethane-1,2-diol (0.29 mL, 5.19 mmol) and methyl-2-pyrrolidinone (2.6 mL) was microwaved at 230° C. for 30 minutes, diluted with EtOAc, washed with water and brine, dried (Na2SO4), filtered, and chromatographed (15% EtOAc/DCM) to give 0.260 g of impure title compound as a white solid: MS (APCI+) M/Z 269 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35]>>[CH2:1]([O:8][NH:9][C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[NH:18][CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][OH:35])=[O:27])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F
Reactant: NCCCCO
Product: O=C(NCCCCO)c1cc(CNc2ccccc2C(=O)NOCc2ccccc2)ccc1F

Procedure:
Prepared by a similar procedure as described for the preparation of Example 499, starting from 5-[(2-benzyloxycarbamoyl-phenylamino)methyl]-2-fluoro-benzoic acid (Example 498) and 4-amino-butan-1-ol.
Reaction SMILES: C(N[N:5]1[CH2:10][CH2:9][C:8]2([CH:15]([CH3:16])[C:14](=[O:17])[C:13]3[CH:18]=[C:19]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:20]=[CH:21][C:12]=3[O:11]2)[CH2:7][CH2:6]1)(=O)C.[ClH:26]>CO>[ClH:26].[CH3:16][CH:15]1[C:8]2([CH2:7][CH2:6][NH:5][CH2:10][CH2:9]2)[O:11][C:12]2[CH:21]=[CH:20][C:19]([S:22]([CH3:25])(=[O:24])=[O:23])=[CH:18][C:13]=2[C:14]1=[O:17]
Reactant: CC(=O)NN1CCC2(CC1)Oc1ccc(S(C)(=O)=O)cc1C(=O)C2C
Agent: Cl
Solvent: CO
Product: CC1C(=O)c2cc(S(C)(=O)=O)ccc2OC12CCNCC2

Procedure:
The product of Step B (0.5 g) in CH3OH (15 mL) and 6N HCl (15 mL) was heated at reflux for 10 hours. The reaction was concentrated to dryness and the residue flushed with ethanol (4 times) and then toluene to yield 0.5 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][CH:12]=1)[C:7]([OH:9])=O.C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:26][C:27]1[CH:28]=[C:29]([CH:46]=[CH:47][CH:48]=1)[O:30][C:31]1[CH:32]=[CH:33][C:34]2[N:35]([CH:37]=[C:38]([NH:40][C:41]([CH:43]3[CH2:45][CH2:44]3)=[O:42])[N:39]=2)[N:36]=1>CN(C)C=O.CN1CCCC1=O>[CH:43]1([C:41]([NH:40][C:38]2[N:39]=[C:34]3[CH:33]=[CH:32][C:31]([O:30][C:29]4[CH:28]=[C:27]([NH:26][C:7](=[O:9])[C:6]5[CH:10]=[CH:11][CH:12]=[C:4]([O:3][C:2]([F:1])([F:14])[F:13])[CH:5]=5)[CH:48]=[CH:47][CH:46]=4)=[N:36][N:35]3[CH:37]=2)=[O:42])[CH2:44][CH2:45]1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Reactant: O=C(O)c1cccc(OC(F)(F)F)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C(Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1)c1cccc(OC(F)(F)F)c1
Yield: 53.3 %

Procedure:
Using 3-(trifluoromethoxy)benzoic acid (120 mg, 0.58 mmol), oxalyl chloride (60 μL, 0.68 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (130 mg, 54%) was obtained as a white powder.
Reaction SMILES: [C:1]([C:5]1[O:9][C:8]([C:10]2[C:11]([NH2:29])=[N:12][CH:13]=[C:14]([C:16]3[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[N:17]=3)[N:15]=2)=[N:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].CC1(C)[O:35][C@@H:34]([C:36]([O-])=[O:37])[CH2:33][O:32]1.[K+]>>[NH2:29][C:11]1[N:12]=[CH:13][C:14]([C:16]2[N:20]([CH2:21][CH3:22])[N:19]=[C:18]([CH:23]3[CH2:28][CH2:27][N:26]([C:33](=[O:32])[C@H:34]([OH:35])[CH2:36][OH:37])[CH2:25][CH2:24]3)[N:17]=2)=[N:15][C:10]=1[C:8]1[O:9][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[N:6][N:7]=1
Reactant: CC1(C)OC[C@H](C(=O)[O-])O1
Reactant: CCn1nc(C2CCNCC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Agent: [K+]
Product: CCn1nc(C2CCN(C(=O)[C@H](O)CO)CC2)nc1-c1cnc(N)c(-c2nnc(C(C)(C)C)o2)n1
Yield: 40 %

Procedure:
3-(5-(Tert-butyl)-1,3,4-oxadiazol-2-yl)-5-(1-ethyl-3-(piperidin-4-yl)-1H-1,2,4-triazol-5-yl)pyrazin-2-amine was reacted with potassium (R)-2,2-dimethyl-1,3-dioxolane-4-carboxylate, using a similar procedure than described in Example 10 to provide the title compound (0.145 g, 40%) as a solid. 1H NMR Spectrum (400 Hz, DMSO-d6, 30° C.): 1.45 (12H, m), 1.60 (2H, m), 1.98 (2H, m), 2.85 (1H, m), 3.00 (1H, m), 3.17 (1H, m), 3.45 (1H, s), 3.55 (1H, s), 4.05 (1H, m), 4.35 (2H, m), 4.60 (2H, m), 4.70 (1H, m), 4.85 (1H, m), 7.90 (2H, m), 8.85 (1H, s); Mass Spectrum [M+H]+=486.
Reaction SMILES: [S:1]1[C:5]([C:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)=[O:7])=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2.[CH3:25][O:26][CH2:27][CH2:28][CH2:29][CH2:30][Mg]Cl.[NH4+].[Cl-]>C1COCC1>[S:1]1[C:5]([C@:6]([C@@H:8]2[CH2:13][CH2:12][CH2:11][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:9]2)([OH:7])[CH2:30][CH2:29][CH2:28][CH2:27][O:26][CH3:25])=[CH:4][C:3]2[CH:21]=[CH:22][CH:23]=[CH:24][C:2]1=2
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)c2cc3ccccc3s2)C1
Reactant: COCCCC[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCC[C@@](O)(c1cc2ccccc2s1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 88 %

Procedure:
A solution of (R)-tert-butyl 3-(benzo[b]thiophene-2-carbonyl)piperidine-1-carboxylate (146 mg, 0.423 mmol) in dry THF (5 mL) was cooled to −70° C. A solution of 1.34 M 4-methoxybutylmagnesium chloride in THF (630 μL, 2 equiv) was added slowly. After 10 min, the reaction mixture was allowed to warm up to rt slowly and stirred for another 2 h. Sat'd aq NH4Cl (20 mL) was added and the mixture was extracted with ether (2×40 mL). The combined ether layers were washed with brine (20 mL) and dried over Na2SO4. After concentration, the crude product was purified by chromatography on a 12-g silica cartridge eluted with a gradient from 0 to 35% EtOAc in hexanes to afford (R)-tert-butyl 3-((S)-1-(benzo[b]thiophen-2-yl)-1-hydroxy-5-methoxypentyl)piperidine-1-carboxylate (160.7 mg, 88%).
Reaction SMILES: Cl.CO.[N:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[CH:6][C:5]=1[CH2:13][OH:14].CS[C:17]1[S:18][CH2:19][CH2:20][N:21]=1>C(OCC)C>[S:18]1[CH2:19][CH2:20][N:21]=[C:17]1[N:11]1[CH2:10][CH2:9][N:8]2[N:4]=[C:5]([CH2:13][OH:14])[CH:6]=[C:7]2[CH2:12]1
Reactant: CSC1=NCCS1
Reactant: OCc1cc2n(n1)CCNC2
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: OCc1cc2n(n1)CCN(C1=NCCS1)C2

Procedure:
Hydrogen chloride (2 mol/l) solution in diethyl ether (0.7 ml) was added to the methanol (20 ml) solution of (4,5,6,7-tetrahydropyrazolo[1,5-a]pyrazin-2-yl)-methanol (1.08 g) and 2-methylsulfanyl-4,5-dihydrothiazole (1.03 g). The reaction mixture was refluxed for 4 days. The mixture was quenched with small amount of saturated potassium carbonate solution, dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The residue was applied to silica-gel column chromatography, then the column was eluted with 10% methanol in chloroform. The titled compound was obtained as a white solid (1.49 g, 89%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C([Li])CCC.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O1CCCC1.C(OCC)(=O)C.[Cl-].[Zn+2].[Cl-]>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:6][NH:7]2
Reactant: CCOC(=O)CBr
Reactant: COc1cccc2[nH]ccc12
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Zn+2]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1c[nH]c2cccc(OC)c12
Reaction time: 2 h

Procedure:
To a solution of 2.94 gm (20 mmol) of 4-methoxyindole in 150 ml of tetrahydrofuran was added slowly 13 ml of n-butyl lithium (1.6M in hexane; 20 mmol) followed by the slow addition of 20 ml of zinc chloride (1.0M in ethyl ether; 20 mmol) at 0-5° C. The cooling bath was removed and the solution stirred for 2 hours and then treated with 2.1 ml (25 mmol) of ethyl bromoacetate for 19 hours, diluted with ethyl acetate, washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with a gradient hexane/10-50% ethyl ether to give starting material (40%) and then product, 2.3 gm, 50%, as an oil. 1H NMR (CDCl3) δ: 1.25 (t, 3H), 3.85 (s, 3H), 3.90 (s, 2H), 4.10 (q, 2H), 6.45 (d, 1H), 6.90 (d, 1H), 6.95 (s, 1H), 7.05 (t, 1H), 8.00 (br s, 1H).