Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([S:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8])(=O)C.N1CCCC1.Cl>C(#N)C>[SH:4][CH2:5][CH:6]([CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8]
Reactant: CCOC(=O)c1cccc(NC(=O)C(CSC(C)=O)Cc2ccccc2)c1
Agent: Cl
Solvent: C1CCNC1
Solvent: CC#N
Product: CCOC(=O)c1cccc(NC(=O)C(CS)Cc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 28.1 %

Procedure:
Ethyl 3-[(2-acetylthiomethyl-3-phenylpropionyl)-amino]benzoate (compound of Example 68-(a)-[1]) (2.0 g) is dissolved in a 80% aqueous acetonitrile, and thereto is added pyrrolidine (0.5 g), and the mixture is stirred at room temperature for 30 minutes. The mixture is adjusted to pH 5.0 with 10% hydrochloric acid, and acetonitrile is distilled off under reduced pressure, and the residue is extracted with ethyl acetate (50 ml). The extract is washed with water, and ethyl acetate is distilled off under reduced pressure. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-acetonitrile). The fractions containing the desired compound are collected, and acetonitrile is distilled off under reduced pressure. The aqueous solution is extracted with ethyl acetate (50 ml), and the extract is dried over anhydrous magnesium sulfate, and ethyl acetate is distilled off under reduced pressure to give the title compound (0.5 g) as an oily substance.
Reaction SMILES: O=[C:2]([CH:8]=[CH:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:3][C:4]([O:6][CH3:7])=[O:5].P(Cl)(Cl)(Cl)(Cl)[Cl:19].CO.O>CCCCCC>[Cl:19]/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:3]/[C:4]([O:6][CH3:7])=[O:5].[Cl:19]/[C:2](/[CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:3]\[C:4]([O:6][CH3:7])=[O:5]
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: COC(=O)CC(=O)C=CCCc1ccccc1
Solvent: O
Solvent: CCCCCC
Solvent: CO
Product: COC(=O)/C=C(/Cl)CCCCc1ccccc1
Product: COC(=O)/C=C(\Cl)CCCCc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 17 %
Yield: 25 %

Procedure:
A mixture of methyl 3-keto-7-phenylheptenoate (8 g, 34 mmol) and phosphorus pentachloride (14.1 g, 68 mmol) in hexane (60 mL) is heated under reflux for 2 hours. The solution is cooled in ice and methanol (5 mL) is added slowly. The mixture is stirred at room temperature for 10 minutes and is added to water and is extracted with hexane. The organic layer is dried over MgSO4 and the solvent is removed in vacuo. The residue is dissolved in dichloromethane (70 mL) and 17 mL of 2 M oxalyl chloride is added. The solution is stirred for 2 hours and the solvent is removed in vacuo. The residue is dissolved in dichloromethane and some methanol is added. After stirring for 30 minutes the solvent is removed in vacuo. The residue is chromatographed on silica gel (20:1 hexane:ethyl acetate) to give methyl (E)-3-chloro-7-phenyl-2-heptenoate (2.1 g, 25%) as the first component off the column and methyl (Z)-3-chloro-7-phenyl-2-heptenoate (1.4 g, 17%) as the second component off the column: methyl (E)-3-chloro-7-phenyl-2-heptenoate, 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.58-1.69 (m, 4H), 2.57-2.60 (m, 2H), 2.92-3.04 (m, 2H), 3.68 (s, 3H), 6.06 (s, 1H), 7.12-7.22 (m, 3H), 7.22-7.45 (m, 2H); methyl (Z)-3-chloro-7-phenyl-2-heptenoate, 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.58-1.78 (m, 4H), 2.38-2.50 (m, 2H), 2.57-2.62 (m, 2H), 3.72 (s, 3H), 6.00 (s, 1H), 7.12-7.27 (m, 3H), 7.27-7.38(m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]([CH2:21][OH:22])=[C:10]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13]([CH3:19])([CH3:18])[CH:12]=[C:11]3[CH3:20])=[C:4]([O:23][CH3:24])[CH:3]=1.[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](O)=[O:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC>[NH2:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([O:22][CH2:21][C:9]1[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[O:23][CH3:24])=[CH:17][CH:16]=[C:15]2[C:10]=1[C:11]([CH3:20])=[CH:12][C:13]([CH3:19])([CH3:18])[NH:14]2)=[O:30]
Reactant: COc1cc(F)ccc1-c1ccc2c(c1CO)C(C)=CC(C)(C)N2
Reactant: Nc1cccc(C(=O)O)c1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: c1ccccc1
Product: COc1cc(F)ccc1-c1ccc2c(c1COC(=O)c1cccc(N)c1)C(C)=CC(C)(C)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 42 %

Procedure:
6-(4-Fluoro-2-methoxyphenyl)-5-hydroxymethyl-2,2,4-trimethyl-1,2-dihydroquinoline (Reference Compound No. 4-3, 49.7 mg, 0.15 mmol), 3-aminobenzoic acid (49.0 mg, 0.35 mmol), tri-n-butylphosphine (87.0 μL, 0.35 mmol), and 1,1′-(azodicarbonyl)dipiperidine (89.4 mg, 0.35 mmol) were dissolved in anhydrous benzene (2 mL), and then the mixture was stirred under argon atmosphere at room temperature overnight. Hexane (3 mL)-ethyl acetate (3 mL) were added to the reaction mixture, and unsoluble materials were filtered. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (hexane-ethyl acetate) to give the titled compound (28.0 mg) as a colorless amorphous product. (Yield 42%)
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:12])=[C:7]([F:19])[CH:6]=1)(=O)C.C(N)C1C=CC=CC=1>C(O)C.CCOCC>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[O:12])=[C:7]([F:19])[CH:6]=1
Reactant: CCC(CC)OC(=O)c1ccc(OC(C)=O)cc1F
Solvent: CCO
Solvent: NCc1ccccc1
Solvent: CCOCC
Product: CCC(CC)OC(=O)c1ccc(O)cc1F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
0.5 Gram of the compound obtained in the above (3) was dissolved in 30 ml of ethanol, and 1.5 g of benzylamine was added dropwise thereto. Further, the mixture was stirred at room temperature for one day and diluted with 300 ml of ether, and the diluted mixture was washed with diluted hydrochloric acid and then with water and dried over magnesium sulfate.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]3)[C:12]([C:24]([O:26][CH3:27])=[O:25])=[N:11]2)=[CH:6][C:5]=1[F:28])#[N:3].CCN(C(C)C)C(C)C.Cl[C:39]1[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=1.CCOC(C)=O>CN1C(=O)CCC1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:15](=[O:16])[CH:14]=[C:13]([O:17][CH:18]3[CH2:19][CH2:20][N:21]([C:39]4[N:44]=[CH:43][C:42]([CH2:45][CH2:46][CH3:47])=[CH:41][N:40]=4)[CH2:22][CH2:23]3)[C:12]([C:24]([O:26][CH3:27])=[O:25])=[N:11]2)=[CH:6][C:5]=1[F:28])#[N:3]
Reactant: COC(=O)c1nn(-c2ccc(C#N)c(F)c2)c(=O)cc1OC1CCNCC1
Reactant: CCCc1cnc(Cl)nc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCCc1cnc(N2CCC(Oc3cc(=O)n(-c4ccc(C#N)c(F)c4)nc3C(=O)OC)CC2)nc1
Temperature: 95 °C
Yield: 32.5 %

Procedure:
To a stirring solution of methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate HCl (37.2 mg, 0.10 mmol) in NMP (3 mL) at room temperature under argon was added DIPEA (38.8 mg, 0.30 mmol) and 2-chloro-5-propylpyrimidine (23.5 mg, 0.15 mmol). The resulting reaction mixture was heated at 95° C. under argon overnight. 15 mL of EtOAc was added to the reaction mixture. The reaction mixture was washed with water (15 mL), and brine (15 mL). Organic phase was dried (MgSO4), filtered and concentrated. The crude product was directly purified by preparative HPLC (C18 column; 10-100% methanol in water without TFA) to give methyl 1-(4-cyano-3-fluorophenyl)-6-oxo-4-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-1,6-dihydropyridazine-3-carboxylate (16 mg, white solid, 32%). 1H NMR (400 MHz, CDCl3) δ ppm 0.56-1.12 (m, 3H) 1.37-1.67 (m, 2H) 1.70-2.20 (m, 4H) 2.39 (q, J=7.47 Hz, 2H) 3.64-4.09 (m, 7H) 4.02-4.40 (m, 1H) 4.40-4.95 (m, 1H) 6.31 (s, 1H) 7.45-7.91 (m, 3H) 7.91-8.46 (m, 2H). MS (ESI) 493 (M+H).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[C:7]([NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:8].[C:16]([O:20][C:21]([NH:23][C:24]1([C:27](O)=[O:28])[CH2:26][CH2:25]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>>[C:10]1([NH:9][C:7]([C:3]2[N:2]([NH:1][C:27]([C:24]3([NH:23][C:21](=[O:22])[O:20][C:16]([CH3:18])([CH3:17])[CH3:19])[CH2:26][CH2:25]3)=[O:28])[CH:6]=[CH:5][CH:4]=2)=[O:8])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nn1cccc1C(=O)Nc1ccccc1
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CC1
Product: CC(C)(C)OC(=O)NC1(C(=O)Nn2cccc2C(=O)Nc2ccccc2)CC1
Yield: 95.4 %

Procedure:
The title compound was prepared from 1-amino-N-phenyl-1H-pyrrole-2-carboxamide (0.30 g, 1.5 mmol) and 1-(tert-butoxycarbonylamino)cyclopropanecarboxylic acid (0.30 g, 1.5 mmol) following the experimental procedure described in Preparation 73a. 0.55 g (91% yield) of the desired compound were obtained.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@:6]([OH:26])(/[CH:8]=[CH:9]/[C@@H:10]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]/[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:13]([OH:24])[CH2:12][C@H:11]1[OH:25])[CH3:7].O=O.C1C=C(SSC2N=CC=CC=2)N=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(OCC)(=O)C.CCOC(C)=O.CCCCCC.C1(C)C(C)=CC=CC=1>[CH3:1][CH2:2][CH2:3][CH2:4][CH2:5][C@:6]([OH:26])(/[CH:8]=[CH:9]/[C@@H:10]1[C@@H:14]([CH2:15]/[CH:16]=[CH:17]\[CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C@@H:13]([OH:24])[CH2:12][C@@H:11]1[OH:25])[CH3:7]
Reactant: CCCCC[C@](C)(O)/C=C/[C@@H]1[C@@H](C/C=C/CCCC(=O)O)[C@@H](O)C[C@H]1O
Agent: O=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(SSc2ccccn2)nc1
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCCCC[C@](C)(O)/C=C/[C@@H]1[C@@H](C/C=C\CCCC(=O)O)[C@@H](O)C[C@@H]1O
Reaction time: 2.5 h

Procedure:
A solution of 15-methyl-PGF2α (185 mg.) in 2.5 ml. of an anhydrous, oxygen-free xylene containing 2,2'-dipyridyl disulfide (165 mg.) and triphenylphosphine (196 mg.) is stirred under nitrogen for 2.5 hr. at 25° C. The mixture is diluted with 150 ml. of xylene and heated at reflux for 3 hr. TLC (80 percent EtOAc/hexane) shows essentially a single, less polar product. The xylene is removed by evaporation at reduced pressure to afford a residue which is diluted with ice/water/sodium bicarbonate and ethyl acetate and extracted thoroughly with ethyl acetate. The ethyl acetate extract is washed with brine, dried over anhydrous sodium sulfate and concentrated to afford a residue of (15S)-15-methyl PGF2α, 1,9-lactone. The residue is purified by chromatography on 50 g. of neutral silica packed with 10 percent acetone/methylene chloride and eluted (5 ml. fractions) with 200 ml. of 10 percent acetone/methylene chloride, 1500 ml. of 20 percent acetone/methylene chloride and 1000 ml. of 35 percent acetone/methylene chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].C([O:13][B:14](OCC)[O:15]CC)C.S(=O)(=O)(O)O>C(OCC)C.O>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:14]([OH:15])[OH:13])=[CH:3][CH:4]=1
Reactant: CCOB(OCC)OCC
Reactant: COc1ccc(Br)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: CCOCC
Solvent: O
Product: COc1ccc(B(O)O)cc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
100 ml of a solution of 10 g of p-bromoanisole in anhydrous diethyl ether is added dropwise under reflux to a suspension, under inert gas, of 1.3 g of magnesium turnings in 5 ml of anhydrous diethyl ether, and the mixture is left under reflux for 2 hours. The reaction medium is then poured into a solution of 9.02 ml of triethylborate in 60 ml ofanhydrous ether cooled down to −70° C. After agitation for 1 hour at −70° C., then for 1 hour at ambient temperature, the solution is poured into a mixture containing 11 ml of sulphuric acid and 50 g of ice and water and agitation is carried out for 1 hour. The organic phase is extracted with 100 ml of a saturated aqueous solution of sodium bicarbonate, the aqueous phases are combined, reacidified with 6N hydrochloric acid, extracted with ether, dried and evaporated under reduced pressure. 3.9 g of expected product is obtained.
Reaction SMILES: O[C@H:2]1[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.OC[C@@H]1CCCN1C(OC(C)(C)C)=O.[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([C:43]3[CH:48]=[CH:47][C:46]([O:49][C@@H:50]4CCN(C(OC(C)(C)C)=O)C4)=[CH:45][CH:44]=3)[C:39](=[O:62])[CH:38]=2)=[N:33][CH:34]=1>>[Cl:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([C:43]3[CH:44]=[CH:45][C:46]([O:49][CH2:50][C@@H:3]4[CH2:2][CH2:6][CH2:5][NH:4]4)=[CH:47][CH:48]=3)[C:39](=[O:62])[CH:38]=2)=[N:33][CH:34]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Oc2ccc(-n3ccc(OCc4ccc(Cl)cn4)cc3=O)cc2)C1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O)C1
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Product: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OC[C@@H]2CCCN2)cc1

Procedure:
Example 120 was repeated except that tert-butyl (3S)-3-hydroxypyrrolidine-1-carboxylate was replaced with tert-butyl (2S)-2-(hydroxymethyl)pyrrolidine-1-carboxylate. The resulting compound was used in placed of 4-[(5-chloro-2-pyridinyl)methoxy]-1-(4-{[(3R)-1-(tert-butoxycarbonyl)-3-pyrrolidinyl]oxy}phenyl)-1H-pyridin-2-one which was used in Example 121. Otherwise repeating Example 121, the title compound was obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]([C:9]3[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([OH:29])=O)[CH:25]=2)[CH:20]=[CH:19]1>>[NH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([C:27]([NH:1][C:2]3[CH:17]=[CH:16][C:5]4[N:6]([C:9]5[CH:10]=[CH:11][C:12]([NH:15][C:27]([C:24]6[CH:25]=[C:26]7[C:21]([CH:20]=[CH:19][NH:18]7)=[CH:22][CH:23]=6)=[O:29])=[CH:13][CH:14]=5)[CH:7]=[N:8][C:4]=4[CH:3]=3)=[O:29])[CH:25]=2)[CH:20]=[CH:19]1
Reactant: Nc1ccc(-n2cnc3cc(N)ccc32)cc1
Reactant: O=C(O)c1ccc2cc[nH]c2c1
Product: O=C(Nc1ccc(-n2cnc3cc(NC(=O)c4ccc5cc[nH]c5c4)ccc32)cc1)c1ccc2cc[nH]c2c1

Procedure:
Compound 561 was prepared according to the procedure described in Scheme IV from 5-amino-1-(4-aminophenyl)benzimidazole and indole-6-carboxylic acid. [M+H]+ calcd for C31H22N6O2: 511.19; found: 511.01.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[O:3]1.[F:11][C:12]([F:22])([F:21])[O:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[CH:23](OC)(OC)OC>CCCCCC>[CH3:1][C:2]1([CH3:10])[O:7][C:6](=[O:8])[C:5](=[CH:23][NH:18][C:17]2[CH:19]=[CH:20][C:14]([O:13][C:12]([F:21])([F:22])[F:11])=[CH:15][CH:16]=2)[C:4](=[O:9])[O:3]1
Reactant: COC(OC)OC
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: Nc1ccc(OC(F)(F)F)cc1
Solvent: CCCCCC
Product: CC1(C)OC(=O)C(=CNc2ccc(OC(F)(F)F)cc2)C(=O)O1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
In a 48 mL sealed tube was dissolved 2,2-dimethyl-1,3-dioxane-4,6-dione (0.81 g, 5.6 mmol) in trimethyl orthoformate (5.6 mL). The mixture was heated to 100° C. and stirred for 2 h. To the mixture was added 4-(trifluoromethoxy)aniline (0.76 mL, 5.6 mmol) and it was stirred at 100° C. for 3 hours. The reaction was cooled to RT, diluted with hexane, filtered, and the filtered solids were air dried to yield 2,2-dimethyl-5-((4-(trifluoromethoxy)phenylamino)methylene)-1,3-dioxane-4,6-dione as a light yellow solid. MS [M+H]=332.0; Calc'd 331.2 for C14H12F3NO5.
Reaction SMILES: [S:1]([O:11][C:12]1[C:25]2[C:24](=[O:26])[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:27])[C:16]=2[C:15](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:14][CH:13]=1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[NH:39]([C:15]1[C:16]2[C:17](=[O:27])[C:18]3[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:24](=[O:26])[C:25]=2[C:12]([O:11][S:1]([C:4]2[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=2)(=[O:2])=[O:3])=[CH:13][CH:14]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Cc1ccc(S(=O)(=O)Oc2ccc(OS(=O)(=O)c3ccc(C)cc3)c3c2C(=O)c2ccccc2C3=O)cc1
Reactant: Nc1ccccc1
Product: Cc1ccc(S(=O)(=O)Oc2ccc(Nc3ccccc3)c3c2C(=O)c2ccccc2C3=O)cc1
Yield: 79 %

Procedure:
1-(anilino)-4-tosyloxyanthraquinone was prepared by reaction of 1,4-ditosyloxyanthraquinone with aniline. The isolated and purified creaction product has the structure illustrated below (where "Ts" is ##STR11## The yield was 79% and the m.p. 185°-186° C. Mass spec m/e 469 (M+), 314 (M-C7H7SO2), 155 (C7H7SO2), 91 (C7H7); 1H-NMR (CD2Cl2)δ11.50 (br s, 1H), 8.26-8.12 (m, 2H), 8.02-7.84 (m, 2H), 7.79-7.62 (m, 4H), 7.54-7.13 (m, 7H), 2.31 (s, 3H); IR (Nujol) 1355 cm-1 (asymmetric SO2 stretch), 1184 cm-1 (symmetrical SO2 stretch), 945 cm-1, 872, 840, 822, 810, 800, 788, 755 (S--O--C stretch); UV/VIS max (Xylenes) 500 nm (ε7000).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH2:8][CH:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=2)[C:10]1=[O:23].[CH2:24]([Br:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[Br-:31].[CH2:24]([N+:4]1[CH:5]=[CH:6][C:7]([CH2:8][CH:9]2[CH2:18][CH2:17][C:16]3[C:11](=[CH:12][C:13]([O:21][CH3:22])=[C:14]([O:19][CH3:20])[CH:15]=3)[C:10]2=[O:23])=[C:2]([F:1])[CH:3]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: COc1cc2c(cc1OC)C(=O)C(Cc1ccncc1F)CC2
Product: COc1cc2c(cc1OC)C(=O)C(Cc1cc[n+](Cc3ccccc3)cc1F)CC2
Product: [Br-]

Procedure:
The title compound 133 is prepared according to the procedure reported in Example 38.1 with compound 102 (135.8 mg, 0.43 mmol) and benzyl bromide (87 μL, 0.73 mmol) as reactants. White solid. (Yield 152.1 mg, 72%).
Reaction SMILES: [F:1][C:2]1[CH:37]=[CH:36][C:5]([CH2:6][NH:7][C:8]([C:10]2[N:11]=[C:12]3[C:18]4([NH:21][C:22](=[O:31])[C:23](=[O:30])[N:24]5[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]5)[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]4)[CH2:14][N:13]3[C:32](=[O:35])[C:33]=2[OH:34])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:45](Cl)(=[O:47])[CH3:46].CNC>C(Cl)Cl.CO>[C:45]([N:27]1[CH2:26][CH2:25][N:24]([C:23](=[O:30])[C:22]([NH:21][C:18]23[CH2:19][CH2:20][CH:15]([CH2:16][CH2:17]2)[CH2:14][N:13]2[C:32](=[O:35])[C:33]([OH:34])=[C:10]([C:8]([NH:7][CH2:6][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:37][CH:36]=4)=[O:9])[N:11]=[C:12]32)=[O:31])[CH2:29][CH2:28]1)(=[O:47])[CH3:46]
Reactant: O=C(NC12CCC(CC1)Cn1c2nc(C(=O)NCc2ccc(F)cc2)c(O)c1=O)C(=O)N1CCNCC1
Reactant: CC(=O)Cl
Agent: CNC
Solvent: ClCCl
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(C(=O)C(=O)NC23CCC(CC2)Cn2c3nc(C(=O)NCc3ccc(F)cc3)c(O)c2=O)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.8 %

Procedure:
To a solution of N-(4-fluorobenzyl)-3-hydroxy-4-oxo-10-((oxo(1-piperazinyl)acetyl)amino)-4,6,7,8,9,10-hexahydro-7,10-ethanopyrimido[1,2-a]azepine-2-carboxamide (25 mg, 0.049 mmol) in CH2Cl2 (2 mL) was added triethylamine (0.034 mL, 0.244 mmol), followed by acetyl chloride (0.017 mL, 0.244 mmol) and the resulting mixture stirred at room temperature. After 16 h, the reaction mixture was concentrated to give crude product which was dissolved in methanol (2 mL) and treated with 2M dimethylamine in methanol (0.5 mL). The resulting reaction mixture was stirred at 60° C. for 2 h then cooled and purified by preparative HPLC to afford the title compound as a brown solid (13 mg, 46% yield). 1H NMR (500 MHz, CDCl3) δ: 12.05 (1 H, brs), 8.53 (1 H, brs), 8.48 (1 78, 5.65 Hz), 7.07 (2H, t, J=8.24 Hz), 4.66 (2 H, d, J=5.80 Hz), 4.24 (2 H, d, J=3.05 Hz), 4.18 (1 H, brs), 3.95-4.03 (1 H, m), 3.75 (2 H, brs), 3.46-3.63 (4 H, m), 2.64-2.73 (2 H, m), 2.51-2.58 (1 H, m), 2.11 (3 H, d, J=9.46 Hz), 1.95-2.14 (4 H, m), 1.76-1.82 (2 H, m). LCMS (M+H)=555.56. HPLC purity: >95%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25](F)[CH:24]=2)=[N:4][C:5]([N:8]([CH2:16][CH:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)C(=O)OC(C)(C)C)=[CH:6][CH:7]=1.[CH3:31][O:32][CH2:33][C@H:34]([NH:36][C@H:37]1[CH2:42][CH2:41][C@H:40]([NH2:43])[CH2:39][CH2:38]1)[CH3:35].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[C:3]([C:23]2[C:28]([Cl:29])=[CH:27][N:26]=[C:25]([NH:43][C@H:40]3[CH2:39][CH2:38][C@H:37]([NH:36][C@H:34]([CH3:35])[CH2:33][O:32][CH3:31])[CH2:42][CH2:41]3)[CH:24]=2)=[N:4][C:5]([NH:8][CH2:16][C@@H:17]2[CH2:22][CH2:21][CH2:20][O:19][CH2:18]2)=[CH:6][CH:7]=1
Reactant: COC[C@@H](C)N[C@H]1CC[C@H](N)CC1
Reactant: CC(C)(C)OC(=O)N(CC1CCCOC1)c1ccc(Cl)c(-c2cc(F)ncc2Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: COC[C@@H](C)N[C@H]1CC[C@H](Nc2cc(-c3nc(NC[C@@H]4CCCOC4)ccc3Cl)c(Cl)cn2)CC1
Temperature: 110 °C

Procedure:
To a scintillation vial was added racemic tert-butyl 3,5′-dichloro-2′-fluoro-2,4′-bipyridin-6-yl((tetrahydro-2H-pyran-3-yl)methyl)carbamate (114 mg, 0.250 mmol), trans-N1-((R)-1-methoxypropan-2-yl)cyclohexane-1,4-diamine (70 mg, 0.376 mmol) and DIPEA (0.088 ml, 0.501 mmol) followed by NMP (0.1 ml). The mixture was heated at 110° C. for 60 hr then concentrated in vacuo. The resulting residue was purified by reverse phase prep HPLC and lyophilized. The resulting white solid was free based by dissolving in EtOAc and then washing with 1M NaOH (×3), water (×2), saturated brine (×2), then dried (Na2SO4), filtered and evaporated under reduced pressure. The resulting residue was then purified by chiral separation chromatography to yield 3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((S)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine (mg), LCMS (m/z): 522.1/523.9 (MH+), tR=0.675 min. and 3,5′-dichloro-N2′-(trans-4-((R)-1-methoxypropan-2-yl-amino)cyclohexyl)-N6-(((R)-tetrahydro-2H-pyran-3-yl)methyl)-2,4′-bipyridine-2′,6-diamine (mg) LCMS 522.1/523.9 (m/z): (MH+), retention time=0.675 min.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[S:10][C:5]=2[C:4](=[O:17])[N:3]1[CH:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1.[C:31]([C:35]1[O:36][C:37]([CH2:40]Cl)=[N:38][N:39]=1)([CH3:34])([CH3:33])[CH3:32].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:31]([C:35]1[O:36][C:37]([CH2:40][N:7]2[C:6]3[CH:8]=[C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)[S:10][C:5]=3[C:4](=[O:17])[N:3]([CH:18]3[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]3)[C:2]2=[O:1])=[N:38][N:39]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)c1nnc(CCl)o1
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3cc(-c4ccccc4)sc3c2=O)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)c3sc(-c4ccccc4)cc3n(Cc3nnc(C(C)(C)C)o3)c2=O)CC1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl 4-(2,4-dioxo-6-phenyl-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl)piperidine-1-carboxylate (2.565 g, compound B50) and 2-tert-butyl-5-(chloromethyl)-1,3,4-oxadiazole (1050 mg, compound D29) in dry DMF (50 ml) is added potassium carbonate (829 mg). The mixture is stirred for 3 h at 100° C. and subsequently poured into ice-cold water. After stirring for 5 min the resulting precipitate is filtered off and dried in vacuo to afford the title compound as a solid
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[F:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN1CCCC1=O>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([F:44])=[C:22]([NH:21][C:7]([C:6]5[C:2]([CH3:1])=[N:3][O:4][CH:5]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Reactant: Cc1nocc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: Cc1nocc1C(=O)Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)ccc1F
Yield: 65.5 %

Procedure:
Using 3-methylisoxazole-4-carboxylic acid (127 mg, 1.0 mmol), N,N-dimethylformamide (2 drops), tetrahydrofuran (10 mL), oxalyl chloride (0.172 mL, 2.0 mmol), N-methylpyrrolidone (5 mL) and N-[6-(3-amino-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (164 mg, 0.50 mmol), and in the same manner as in Example 173, the title compound (143 mg, yield 65%) was obtained.