Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:32]=[CH:31][C:8]([CH2:9][C:10]2[C:19]3[C:14](=[C:15]([I:21])[C:16]([OH:20])=[CH:17][CH:18]=3)[O:13][C:12](=[O:22])[C:11]=2[C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:7][CH:6]=1.[NH:33]1[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[C:11]1[C:12](=[O:22])[O:13][C:14]2[C:19]([C:10]=1[CH2:9][C:8]1[CH:31]=[CH:32][C:5]([O:4][CH2:3][CH2:2][N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:6][CH:7]=1)=[CH:18][CH:17]=[C:16]([OH:20])[C:15]=2[I:21]
Reactant: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCBr)cc2)c1-c1ccc(Cl)cc1Cl
Reactant: C1CCNC1
Solvent: C1CCOC1
Product: O=c1oc2c(I)c(O)ccc2c(Cc2ccc(OCCN3CCCC3)cc2)c1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Yield: 100 %

Procedure:
To a stirred suspension 4-(4-(2-Bromoethoxy)-benzyl)-3-(2,4-dichlorophenyl)-7-hydroxy-8-iodo-chromen-2-one (1.90 g, 2.94 mmol) in anhydrous THF (20 mL) was added pyrrolidine (1.46 mL, 17.6 mmol), and the resulting yellow solution was heated at 85° C. for 1.5 h. The resultant mixture was cooled to room temperature and the solvent was removed in vacuo. The resultant residue was dissolved in CH2Cl2, washed with H2O and brine and dried (MgSO4). The organic phase was concentrated in vacuo. The resultant residue was purified using flash chromatography (200 g silica gel, 12:1→9:1→85:15 CH2Cl2:MeOH) to afford the title compound as a yellow solid (1.87 g, 100%). 1H NMR (300 MHz, CDCl3) δ 7.50 (d, J=2.0 Hz, 1H), 7.32 (d, J=8.8 Hz, 1H), 7.26 (dd, J=2.0, 8.0 Hz, 1H), 7.12 (d, J=8.0 Hz, 1H), 6.95–6.86 (m, 3H), 6.77–6.70 (m, 2H), 4.30 (t, J=5.0 Hz, 2H), 4.00 (d, J=15.5 Hz, 1H), 3.76 (d, J=15.5 Hz, 1H), 3.25 (t, J=5.0 Hz, 2H), 3.19–3.04 (m, 4H), 2.04–1.91 (m, 4H); MS (ESI) m/z 635.6 (M)+; HPLC tR 5.85 min.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:26])[C:5]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34](B(O)O)=[CH:35][C:30]=2[CH2:29][CH2:28]1.C(N(CC)CC)C.N1C=CC=CC=1>C(Cl)Cl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([N:3]3[C:4](=[O:26])[C:5]([CH2:11][C:12]4[CH:17]=[CH:16][C:15]([C:18]5[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=5)=[CH:14][CH:13]=4)=[C:6]([CH2:8][CH2:9][CH3:10])[N:7]=[C:2]3[CH3:1])=[CH:35][C:30]=2[CH2:29][CH2:28]1
Reactant: CCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: OB(O)c1ccc2c(c1)CCO2
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCCc1nc(C)n(-c2ccc3c(c2)CCO3)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of 4′-[(2-methyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (2.0 g), 2,3-dihydro-1-benzofuran-5-ylboronic acid (2.0 g), triethylamine (4.0 mL), pyridine (2.0 mL) and molecular sieves 4 A (4.0 g) in methylene chloride (30 mL) was added copper(II) acetate (2.0 g), and the mixture was stirred at room temperature for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow viscous substance (2.26 g, 84%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1/[CH:37]=[CH:38]/[CH2:39]O.C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:39]/[CH:38]=[CH:37]/[C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][C:31]=1[CH2:30][C:26]1[NH:27][CH:28]=[CH:29][N:25]=1)=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1ccccc1Cc1ncc[nH]1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C=C/c2ccccc2Cc2ncc[nH]2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycarbonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 215 mg (1 mM) of (E)-3-{2-(1-imidazolylmethyl)phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled to room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 528 mg (100%).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](OC)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.ClC1C2C(=[C:20]([O:25]C)C=CC=2)N=CC=1>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:25][CH3:20])[CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: COc1cccc2c(Cl)ccnc12
Reactant: COc1ccc2c(Cl)ccnc2c1
Product: COc1ccc2nccc(Cl)c2c1

Procedure:
4-Chloro-7-methoxyquinoline and 4-Chloro-8-methoxy-quinoline: Lauer; J. Am. Chem. Soc.; 68; 1946; 1268);
Reaction SMILES: O1CCCC1.[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][C:7]1=O.[CH2:16]([NH2:19])[CH2:17][CH3:18].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C>[CH2:6]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH:7]1[NH:19][CH2:16][CH2:17][CH3:18]
Reactant: CCCN
Reactant: O=C1Cc2ccccc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCNC1Cc2ccccc2C1
Yield: 67.6 %

Procedure:
A tetrahydrofuran (150 mL) solution of 2-indanone (11.0 g, 92 mmol), propyl amine (12 mL, 146 mmol), sodium triacetoxy borohydride (35.0 g, 165 mmol), and acetic acid (5 mL) was stirred at ambient temperature for 1 hour. The solution was then heated at reflux temperature for 2 hours. After cooling, the solvent was evaporated and the residue taken up in concentrated hydrochloric acid (40 mL). The acidic solution was washed with diethyl ether and then basified (10M sodium hydroxide). Extraction of the aqueous layer with ether, drying over anhydrous sodium carbonate and removal of the solvent yielded 10.9 g of the title compound as a yellow oil (75%).:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH2:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.[CH3:43][NH:44][OH:45].CCN(CC)CC>CN(C=O)C.C(Cl)Cl>[CH3:43][N:44]([OH:45])[C:22](=[O:23])[C:21]1[CH:25]=[CH:26][C:18]([CH2:17][CH2:16][CH2:15][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:19][CH:20]=1
Reactant: CNO
Reactant: O=C(O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(O)C(=O)c1ccc(CCCc2ccccc2OCc2ccccc2)cc1
Reaction time: 3 h
Yield: 36.1 %

Procedure:
A mixture of 4-(3-(2-benzyloxyphenyl)propyl]benzoic acid (1.0 g), 1-HOBT (0.39 g) and DCCI (0.595 g) in DMF (10 ml) was stirred for 3 hours, then added to a solution of N-methylhydroxylamine HCl (0.24 g) and Et3N (0.29 g) in CH2Cl2 (10 ml) and stirred for 70 hours. The product was extracted in 2N aqueous KOH and washed with ethyl acetate. The aqueous solution was acidified with concentrated HCl and extracted with diethyl ether. The solvent was evaporated and the residue subjected to flash chromatography on silica gel (using diethyl ether:methanol (95:5) as eluant) to give N-methyl-N-hydroxy-4-(3-(2-benzyloxyphenyl)propyl)benzamide as a gum (0.39 g).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[Se:4][C:3]=1[C:11]([NH2:13])=[O:12].S(=O)(=O)(O)O.N.[CH:20](O)=O>>[C:7]([C:5]1[Se:4][C:3]2[C:11](=[O:12])[NH:13][CH:20]=[N:1][C:2]=2[CH:6]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)c1cc(N)c(C(N)=O)[se]1
Reactant: O=CO
Agent: N
Agent: O=S(=O)(O)O
Product: CC(C)(C)c1cc2nc[nH]c(=O)c2[se]1
Yield: 80 %

Procedure:
To a solution of 3-amino-5-(tert-butyl)selenophene-2-carboxamide (1 g) in formic acid (10 mL) was added concentrated sulfuric acid (5 mL) slowly for 10 min at rt. The mixture was refluxed for 1.5 h and allowed to rt. The mixture was poured into ice cold water and basified with ammonia solution. The solution was extracted with chloroform (3×200 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as a yellow color solid (900 mg, 80%), mp 240-242° C. 1H NMR (400 MHz, CDCl3): δ 12.61 (1H, br s), 8.16 (1H, s), 7.34 (1H, s), 1.46 (9H, s); LC-MS (negative ion mode): m/z 253, 255 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:10]([CH2:12][NH2:13])[OH:11].C(N(CC)CC)C>C(#N)C>[Br:1][C:2]1[C:3]([NH:13][CH2:12][CH2:10][OH:11])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: NCCO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: OCCNc1nc(Cl)ncc1Br

Procedure:
In analogy to compound 1.1, a solution of 0.34 g (1.49 mmol) of 5-bromo-2,4-dichloropyrimidine in 5 ml of acetonitrile is reacted with 0.1 ml (1.61 mmol) of ethanolamine in the presence of 0.25 ml (1.81 mmol) of triethylamine. Recrystallization from hexane/ethyl acetate 7/3 results in 0.28 g (74% of theory) of the product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:31]([OH:34])(=O)=[O:32])[C:6](=[CH:27][C:28]=1[O:29][CH3:30])/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1.[CH2:35]([NH:38][CH2:39][CH2:40][CH3:41])[CH2:36][CH3:37]>>[CH2:35]([N:38]([CH2:39][CH2:40][CH3:41])[S:31]([C:5]1[C:6](=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)/[CH:7]=[CH:8]/[C:9]1[N:17]([CH3:18])[C:16]2[C:15](=[O:19])[N:14]([CH2:20][CH2:21][CH3:22])[C:13](=[O:23])[N:12]([CH2:24][CH2:25][CH3:26])[C:11]=2[N:10]=1)(=[O:34])=[O:32])[CH2:36][CH3:37]
Reactant: CCCn1c(=O)c2c(nc(/C=C/c3cc(OC)c(OC)cc3S(=O)(=O)O)n2C)n(CCC)c1=O
Reactant: CCCNCCC
Product: CCCN(CCC)S(=O)(=O)c1cc(OC)c(OC)cc1/C=C/c1nc2c(c(=O)n(CCC)c(=O)n2CCC)n1C
Yield: 39.9 %

Procedure:
Substantially the same procedure as in Example 2 was repeated using 1.00 g (1.96 mmol) of Compound 1 obtained in Example 1 and 2.68 ml (19.6 mmol) of dipropylamine. The resulting crude crystals were recrystallized from cyclohexane/toluene to give 450 mg (yield 40%) of Compound 3 as a pale yellow powder.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH2:9][N:10]([CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36](O)=[O:37].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl.C([O-])(O)=O.[Na+]>[NH:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[C:36]([N:14]1[CH2:15][CH2:16][CH:11]([N:10]([CH2:9][C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][N:4]=2)[CH2:17][C:18]2[C:23]([CH:24]([CH3:26])[CH3:25])=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:12][CH2:13]1)=[O:37]
Reactant: O=C(O)c1nc2ccccc2[nH]1
Reactant: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCNCC2)c(C)c1
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cnc(CN(Cc2ncccc2C(C)C)C2CCN(C(=O)c3nc4ccccc4[nH]3)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 53.7 %

Procedure:
A mixture of the (3,5-dimethyl-pyridin-2-ylmethyl)-(3-isopropyl-pyridin-2-ylmethyl)-piperidin-4-yl-amine (211 mg, 0.60 mmol), 1H-benzimidazole-2-carboxylic acid (107 mg, 0.66 mmol), HOBT (97 mg, 0.72 mmol), EDCI (142 mg, 0.72 mmol), and DIPEA (142 mg, 0.72 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was then diluted with CH2Cl2 (25 mL) and saturated NaHCO3 (3×20 mL). The organic layer was dried (MgSO4), filtered, and concentrated to afford a yellow oil. Purification by radial chromatography on silica gel (2 mm plate; using CH2Cl2/MeOH/NH4OH; 100:1:1→25:1:1) afforded the product as a white foam (160 mg, 54%). 1H NMR (CDCl3) δ 0.93 (t, 2H, J=6.9 Hz), 1.69-1.92 (m, 2H), 2.09 (br t, 3H, J=14.7 Hz), 2.18 (s, 3H), 2.27 (s, 3H), 2.68-2.83 (m, 2H), 2.87-2.94 (m, 1H), 3.04-3.13 (m, 1H), 3.79 (d, 2H, J=5.1 Hz), 3.86 (s, 2H), 4.94 (d, 1H, J=13.5 Hz), 6.16 (d, 1H, J=12.9 Hz), 7.15 (dd, 1H, J=7.8, 4.8 Hz), 7.25 (s, 1H), 7.31 (d, 2H, J=3.9 Hz), 7.50 (d, 2H, J=6.6 Hz), 7.82 (br s, 1H), 8.19 (s, 1H), 8.34 (dd, 1H, J=4.7, 1.2 Hz). 13C NMR (CDCl3) δ 18.31, 18.53, 23.60, 23.68, 27.35, 27.42, 28.66, 44.20, 47.20, 54.34, 57.35, 112.35, 121.26, 123.22, 125.11, 132.31, 133.26, 133.61, 133.92, 139.10, 143.52, 144.45, 145.85, 146.09, 146.64, 154.45, 156.28, 159.23. ES-MS m/z 497 [M+H]+. Anal. Calcd. for C30H36N6O.—0.8CH2Cl2: C, 65.52; H, 6.71; N, 14.88. Found: C, 65.54; H, 6.62; N, 15.11.
Reaction SMILES: C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.[CH3:12][C:13]1([CH3:23])[C:18](=[CH2:19])[CH2:17][CH2:16][CH:15]([CH3:20])[CH:14]1[CH2:21][OH:22]>C(Cl)Cl>[CH3:23][C:13]1([CH3:12])[C:18](=[CH2:19])[CH2:17][CH2:16][CH:15]([CH3:20])[CH:14]1[CH:21]=[O:22]
Reactant: C=C1CCC(C)C(CO)C1(C)C
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=C1CCC(C)C(C=O)C1(C)C
Reaction time: 2 h

Procedure:
Prepared according to the method described, starting from 13.0 g (0.06 mol) of PCC in 70 ml of CH2Cl2 and a solution of 6.45 g (0.038 mol) of 2,2,6-trimethyl-3-methylene-1-cyclohexanemethanol (obtained according to example 3a.) in 30 ml of CH2Cl2. After stirring for 2 h and treating as described, 5.58 g of a colorless oil, containing 80% of the desired aldehyde (2 isomers, cis/trans ~9:1) and a secondary product of no interest, were obtained.
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].[NH2:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH:22]=O>C1COCC1>[NH2:18][C:19]1[C:20]([F:27])=[C:21]([CH:24]=[CH:25][CH:26]=1)[CH2:22][N:6]1[CH2:5][CH2:4][N:3]([C:8]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[O:9])[C@H:2]([CH3:1])[CH2:7]1
Reactant: C[C@@H]1CNCCN1C(=O)OCc1ccccc1
Reactant: Nc1cccc(C=O)c1F
Solvent: C1CCOC1
Product: C[C@@H]1CN(Cc2cccc(N)c2F)CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 108.8 %

Procedure:
To a room temperature solution of (R)-benzyl 2-methylpiperazine-1-carboxylate (1.7 g, 7.2 mmol, 1.0 equiv) and 3-amino-2-fluorobenzaldehyde (1.0 g, 7.2 mmol, 1.0 equiv) in THF (10 mL) was added NaHB(OAc)3 (3.84 g, 18.1 mmol, 2.5 equiv) as a solid in one portion. After stirring at room temperature for 1.5 h, the reaction was complete, as determined by LCMS. The remaining reducing reagent was quenched by the careful addition of aq. satd. NaHCO3, and the mixture was diluted with EtOAc. The layers were separated and the organic layer was washed with aq. satd. NaHCO3 and brine, dried over sodium sulfate and concentrated in vacuo to provide (R)-benzyl 4-(3-amino-2-fluorobenzyl)-2-methylpiperazine-1-carboxylate (2.8 g, >100% mass recovery). The material was used without further purification. LCMS m/z (APCI)=358.5 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26]([OH:28])=O)=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:29]([N:31]1[CH2:35][CH2:34][S:33][CH2:32]1)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.Cl.C(C1C=C(Cl)C(N2CCN([C@@H]3CN[C@H](C(N4CCSC4)=O)C3)CC2)=[N:46]C=1)(O)=O.[Cl-].[NH4+].CN1CCOCC1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]3[C:24]([Cl:25])=[CH:23][C:22]([C:26](=[O:28])[NH2:46])=[CH:21][N:20]=3)[CH2:15][CH2:14]2)[CH2:10][C@H:9]1[C:29]([N:31]1[CH2:35][CH2:34][S:33][CH2:32]1)=[O:30])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1cnc(N2CCN([C@@H]3CN[C@H](C(=O)N4CCSC4)C3)CC2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1C[C@@H](N2CCN(c3ncc(C(=O)O)cc3Cl)CC2)C[C@H]1C(=O)N1CCSC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@@H](N2CCN(c3ncc(C(N)=O)cc3Cl)CC2)C[C@H]1C(=O)N1CCSC1
Reaction time: 4 h

Procedure:
3-{(2S,4S)-1-tert-Butoxycarbonyl-4-[4-(5-carboxy-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine [product of Example 217 (1), 2.63 g] and ammonium chloride (0.54 g) were dissolved in DMF (30 mL), and N-methylmorpholine (1.1 mL), HOBT (1.53 g) and EDC hydrochloride (1.15 g) were successively added thereto. The mixture was stirred at room temperaturte for 4 hr. The reaction mixture was concentrated under reduced pressure, and saturated aqueous sodium hydrogencarbonate solution was added to the residue. The mixture was extracted with ethyl acetate. The extract washed with brine and dried. The solvent was evaporated under reduced pressure to give 3-{(2S,4S)-1-tert-butoxycarbonyl-4-[4-(5-carbamoyl-3-chloro-2-pyridyl)-1-piperazinyl]-2-pyrrolidinylcarbonyl}-1,3-thiazolidine (2.50 g) as a white solid.
Reaction SMILES: [OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1.[Cl:31][C:32]1[CH:33]=[C:34]([N:38]=[C:39]=[O:40])[CH:35]=[CH:36][CH:37]=1.O>CN(C=O)C>[OH:1][C@:2]1([C@:28]2([CH3:29])[C@H:14]([C@H:15]3[C:25](=[CH:26][CH2:27]2)[C@:23]2([CH3:24])[C:18](=[CH:19][C:20](=[O:30])[CH2:21][CH2:22]2)[CH2:17][CH2:16]3)[CH2:13][CH2:12]1)[C:3](=[O:11])[CH2:4][N:5]1[CH2:6][CH2:7][N:8]([C:39]([NH:38][C:34]2[CH:35]=[CH:36][CH:37]=[C:32]([Cl:31])[CH:33]=2)=[O:40])[CH2:9][CH2:10]1
Reactant: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCNCC1
Reactant: O=C=Nc1cccc(Cl)c1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@]12CCC(=O)C=C1CC[C@@H]1C2=CC[C@@]2(C)[C@H]1CC[C@]2(O)C(=O)CN1CCN(C(=O)Nc2cccc(Cl)c2)CC1
Reaction time: 1 h

Procedure:
17α-Hydroxy-21-(1-piperazinyl)pregna-4,9(11)-diene-3,20-dione (EXAMPLE 6A, 5.00 g) is treated in DMF (20 ml) with m-chlorophenylisocyanate (1.84 g) for 3 days. The mixture is poured into water (200 ml). After 1 hr, the liquid is decanted. The solid is dissolved in methylene chloride and is extracted with aqueous sodium bicarbonate The phases are separated and the organic phase is dried over sodium sulfate and concentrated. The concentrate is chromatographed on silica gel (3% methanol in methylene chloride to 4%) to give the title compound which is crystallized from hot ethyl acetate.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:11]([C:12]([O:14]CC)=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1.O.[OH-].[Li+]>C1COCC1.O>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:18]=[C:17]([O:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)[C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: CCOC(=O)c1cnc(Nc2nc(C)cs2)cc1Oc1cccc2ccccc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1csc(Nc2cc(Oc3cccc4ccccc34)c(C(=O)O)cn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
Ethyl 6-(4-methylthiazol-2-ylamino)-4-(naphthalen-1-yloxy)nicotinate (1.00 g, 2.47 mmol) was dissolved in THF (5 mL). A solution of lithium hydroxide hydrate (0.207 g, 4.93 mmol) in water (1 mL) was added, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated, 2M HCl was added to adjust the pH to 3. The reaction mixture was filtered to obtain the desired product (0.61 g, 65.5% yield) as a white solid. 1H NMR (d6-DMSO) δ 10.85 (bs, 1H), 8.76 (s, 1H), 8.06 (d, 1H), 7.88-7.93 (m, 2H), 7.55-7.65 (m, 3H), 7.35 (d, 1H), 6.58 (s, 1H), 6.32 (s, 1H), 2.14 (s, 3H).
Reaction SMILES: [OH-].[Na+].[OH:3][C@H:4]1[CH2:8][N:7]([C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[C@H:6]([CH:19]=[CH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[CH2:5]1.Cl[CH2:26][C:27]([CH3:29])=[CH2:28].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1>[CH3:23][CH:22]([CH3:24])[CH2:21][CH:20]=[CH:19][C@@H:6]1[CH2:5][C@@H:4]([O:3][CH2:28][C:27]([CH3:29])=[CH2:26])[CH2:8][N:7]1[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10]
Reactant: C=C(C)CCl
Reactant: CC(C)CC=C[C@@H]1C[C@@H](O)CN1C(=O)OCc1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: C=C(C)CO[C@@H]1C[C@@H](C=CCC(C)C)N(C(=O)OCc2ccccc2)C1
Temperature: 120 °C

Procedure:
After adding 0.04 g of tetrabutylammonium bromide to 8 ml of 50% aqueous solution of sodium hydroxide, the mixture is heated to 120° C. Thereto is dropwise added a solution of 0.40 g of benzyl (2S,4R)-4-hydroxy-2-(4-methyl-1-pentenyl)-1-pyrrolidinecarboxylate and 0.65 ml of 3-chloro-2-methyl-1-propene in 0.8 ml of toluene over a period of 5 minutes. The mixture thus obtained is heated under reflux for 30 minutes with stirring. The reaction mixture is cooled to ambient temperature, toluene and water are added, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and then the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=10:1) to obtain 0.31 g of benzyl (2S,4R)-2-(4-methyl-1-pentenyl)-4-[(2-methyl-2-propenyl)oxy]-1-pyrrolidinecarboxylate as a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[N:7]([CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20](Br)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].[N:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CC#N.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6](=[O:24])[N:7]([CH3:8])[CH:9]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[N:18]([C:20]([C:28]4[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=4)=[CH:21][N:22]=3)[N:19]=2)[CH2:10]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(Br)n3n2)C1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CN(C(=O)OC(C)(C)C)C1CCN(c2ccc3ncc(-c4ccncc4)n3n2)C1
Temperature: 150 °C
Yield: 25.7 %

Procedure:
A mixture of [1-(3-bromo-imidazo[1,2-b]pyridazin-6-yl)-pyrrolidin-3-yl]-methyl-carbamic acid tert-butyl ester (100 mg, 0.25 mmol), 4-pyridinylboronic acid (40 mg, 0.33 mmol), K2CO3 (104 mg, 0.75 mmol) and dichlorobis(triphenylphosphine)palladium(II) (8.8 mg, 0.013 mmol) in MeCN/water (3.2 ml/0.8 ml) was heated in a microwave at 150° C. for 15 min. The water layer was removed and the organic layer was diluted with MeCN and filtered. The filtrate was subjected to preparative HPLC to give the titled compound (25.3 mg). 1H NMR (400 MHz, METHANOL-d4) δ ppm 1.50-1.55 (m, 9H) 2.22-2.32 (m, 2H) 2.89 (s, 3H) 3.46-3.57 (m, 2H) 3.72-3.80 (m, 2H) 4.91 (t, J=7.61 Hz, 1H) 6.95 (d, J=9.92 Hz, 1H) 7.77 (d, J=9.70 Hz, 1H) 8.11 (s, 1H) 8.23-8.27 (m, 2H) 8.53-8.58 (m, 2H). LRMS (ESI) m/z 395.2 [(M+H)]+, calc'd for C21H26N6O2: 394.48.