Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[O:11][N:10]=[C:9]([CH2:12][N:13]3[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([C:22](O)=[O:23])[C:16]=4[N:15]=[C:14]3[C:25](=[O:36])[NH:26][CH:27]3[CH2:32][CH2:31][N:30]([CH:33]([CH3:35])[CH3:34])[CH2:29][CH2:28]3)[CH:8]=2)=[CH:4][CH:3]=1.[NH:37]1[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]1>>[CH:33]([N:30]1[CH2:31][CH2:32][CH:27]([NH:26][C:25]([C:14]2[N:13]([CH2:12][C:9]3[CH:8]=[C:7]([C:5]4[S:6][C:2]([Cl:1])=[CH:3][CH:4]=4)[O:11][N:10]=3)[C:17]3[CH:18]=[CH:19][CH:20]=[C:21]([C:22]([N:37]4[CH2:42][CH2:41][CH:40]([OH:43])[CH2:39][CH2:38]4)=[O:23])[C:16]=3[N:15]=2)=[O:36])[CH2:28][CH2:29]1)([CH3:35])[CH3:34]
Reactant: OC1CCNCC1
Reactant: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)O)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1
Product: CC(C)N1CCC(NC(=O)c2nc3c(C(=O)N4CCC(O)CC4)cccc3n2Cc2cc(-c3ccc(Cl)s3)on2)CC1

Procedure:
1-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-4-(4-hydroxy-piperidine-1-carbonyl)-1H-benzoimidazole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide was prepared by a procedure according to example 22 starting from 670 mg (1.10 mmol) 1-[5-(5-chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-(1-isopropyl-piperidin-4-ylcarbamoyl)-1H-benzoimidazole-4-carboxylic acid and 124.0 mg (1.21 mmol) piperidin-4-ol. The title compound was obtained as its formiate. Subsequent transformation to the corresponding acetate gave a white amorphous solid.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]3[C:24](=[O:25])[C:23]4=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]4[C:21]3=[O:30])=[C:18]([C:31]([O:33]C(C)(C)C)=[O:32])[N:17]=[CH:16]2)[C@@H:6]1[Cl:38])(=[O:3])[CH3:2]>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][O:11][C:12](=[O:14])[CH3:13])[O:8][C@@H:7]([N:15]2[C:19]([N:20]3[C:21](=[O:30])[C:22]4=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]4[C:24]3=[O:25])=[C:18]([C:31]([OH:33])=[O:32])[N:17]=[CH:16]2)[C@@H:6]1[Cl:38])(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)OC(C)(C)C)c2N2C(=O)c3ccccc3C2=O)[C@H](Cl)[C@@H]1OC(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N2C(=O)c3ccccc3C2=O)[C@H](Cl)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound (34) obtained in step (2) above (1.50 g) was dissolved in a mixture of trifluoroacetic acid-dichloromethane (1:4) (25 ml), and the solution so obtained was allowed to stand at room temperature overnight so that there occurred de-esterification of compound (34). The resulting reaction solution was concentrated to leave a solid. This solid was then washed with diethyl ether to yield the titled compound (35) (1.31 g) which was insoluble in diethyl ether (1.31 g). Yield: 97%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21])C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[CH3:6][NH:7][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:18][CH2:19][CH2:20][OH:21]
Reactant: CN(CCc1ccccc1OCCCO)C(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCCc1ccccc1OCCCO
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
{2-[2-(3-Hydroxypropoxy)phenyl]ethyl}N-methylcarbamic acid tert-butyl ester (0.587 g, 1.90 mmol) was dissolved in dichloromethane (5 ml). The solution was cooled to 0° C. Trifluoroacetic acid (5 ml) was added. The reaction mixture was stirred for 30 min at 0° C. Dichloromethane (50 ml) was added. A saturated aqueous solution of sodium hydrogen carbonate (50 ml) was added dropwise. Solid sodium hydrogen carbonate was added, until pH 7 was obtained. The phases were separated. The aqueous solution was extracted with dichloromethane (3×70 ml). The aqueous phase was made basic to pH 14 with a 20% aqueous sodium hydroxide solution. It was extracted with tert-butyl methyl ether (3×100 ml). The tert-butyl methyl ether extracts were combined and dried over magnesium sulfate. The solvent was removed in vacuo to give 227 mg of crude 342-(2-methylaminoethyl)phenoxy]propan-1-ol. The crude product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:14]=1[NH2:29])=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].C1COCC1.CC#N.[C:38]1([N:44]=[C:45]=[O:46])[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(Cl)Cl>[CH2:1]([C@H:3]([NH:10][C:11]([C:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:16]=[C:15]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:14]=1[NH:29][C:45]([NH:44][C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)=[O:46])=[O:12])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH3:2]
Reactant: CC[C@H](NC(=O)c1c(N)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Reactant: O=C=Nc1ccccc1
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CC#N
Product: CC[C@H](NC(=O)c1c(NC(=O)Nc2ccccc2)c(-c2ccccc2)nc2ccccc12)c1ccccc1
Temperature: 40 °C
Yield: 46.1 %

Procedure:
1.5 g (3.9 mmol) of (S)-N-(α-ethylbenzyl)-3-amino-2-phenylquinoline-4-carboxamide (compound of Description 2) were dissolved in 30 ml of dry CH2Cl2, 10 ml of dry THF and 10 ml of dry CH3CN. 0.47 ml (4.3 mmol) of phenylisocyanate dissolved in 10 ml of CH2Cl2 were added and the reaction mixture heated to 40° C. for 4 hours. After cooling of the reaction mixture, the precipitate was collected by filtration and washed with CH2Cl2 to yield 0.9 g of the title compound.
Reaction SMILES: [CH:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br)([CH3:3])[CH3:2].[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH:1]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)([CH3:3])[CH3:2]
Reactant: CC(C)OCCCCCCCCCBr
Reactant: C1CCNCC1
Product: CC(C)OCCCCCCCCCN1CCCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
Mix 9-bromononanyl isopropyl ether (730 mg, 2.75 mmol) and piperidine (1 mL, 10 mmol) and stir at room temperature overnight. Add additional piperidine (5 mL) and heat at 100° C. for 4 hours. Partition between ethyl ether and 5N sodium hydroxide. Separate the organic phase and extract the aqueous phase with ethyl ether (2×30 mL). Combine the organic phases and dry (MgSO4). Evaporate the solvent in vacuo to yield 510 mg yellow oil. Purify by silica gel chromatography (ethyl acetate followed by 10% MeOH/ethyl acetate) to yield 380 mg (51%) of the title compound as a pale yellow oil.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]3([C:44](O)=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1.[CH3:47][S:48]([NH2:51])(=[O:50])=[O:49]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH2:21][CH2:22][NH:23][C:24]1[N:29]=[C:28]([O:30][CH3:31])[N:27]=[C:26]([C:32]2[CH:33]=[C:34]([C:38]3([C:44]([NH:51][S:48]([CH3:47])(=[O:50])=[O:49])=[O:45])[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)[CH:35]=[CH:36][CH:37]=2)[CH:25]=1
Reactant: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)O)CCOCC3)c2)n1
Reactant: CS(N)(=O)=O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1nc(NCCc2ccc(Cl)cc2Cl)cc(-c2cccc(C3(C(=O)NS(C)(=O)=O)CCOCC3)c2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.4 %

Procedure:
N-(3-dimethylaminopropyl)-N-ethylcarbodiimide hydrochloride (60.4 mg, 0.31 mmol) is added to a stirred ice cold solution of 4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carboxylic acid [150 mg, 0.3 mmol, Example 80(a)], methanesulfonamide (30 mg, 0.31 mmol) and 4-dimethylaminopyridine (38.5 mg, 0.3 mmol) in dry DCM under nitrogen and the reaction mixture is stirred overnight, while warming to room temperature. The mixture is concentrated in vacuo, the residue is dissolved in ethyl acetate, washed with 0.1N HCl, brine and water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by chromatography (SiO2 packed column), eluting with ethyl acetate/heptane to afford N-[4-(3-{6-[2-(2,4-dichloro-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenyl)-tetrahydro-pyran-4-carbonyl]-methanesulfonamide [65 mg, Example 80(b)]. LCMS: RT=2.54 minutes; MS: 579, 581 (M+H); 1H NMR (300 MHz, CDCl3): □8 (1H, s), 7.85 (1H, d, J=3.5 Hz), 7.45 (3H, m), 7.2 (2H, s), 6.4 (1H, s), 5.38 (1H, b), 4 (3H, s), 3.65-3.9 (6H, m), 3.2 (3H, s), 3.08 (2H, t, J=3.5 Hz), 2.45 (2H, b), 2.18 (2H, m). IC50<1 nM
Reaction SMILES: [ClH:1].Cl.[NH:3]1[CH:7]=[CH:6]N=[C:4]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.[S:14]1C=CN=C1>>[ClH:1].[S:14]1[CH:6]=[CH:7][N:3]=[C:4]1[CH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1
Reactant: c1c[nH]c(C2CCNCC2)n1
Reactant: c1cscn1
Agent: Cl
Product: c1csc(C2CCNCC2)n1

Procedure:
Prepared similarly as in the case of 4-(1H-imidazol-2-yl)piperidine dihydrochloride using 1,3-thiazole instead of 1-(diethoxymethyl)-1H-imidazole in Step A. 1H NMR (400 MHz, D2O): 8.24 (m, 1 H), 7.90(m, 1H), 3.77-3.68 (m, 1H), 3.57 (br. d, J=13 Hz, 2H), 3.19 (br. t, J=13 Hz, 2H), 2.42 (br. d, J=13 Hz, 21), 2.11-2.01 (m, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[CH3:10].[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)([OH:13])=[O:12].C(=O)([O-])[O-].[Na+].[Na+].[C:29](OC(=O)C)(=[O:31])[CH3:30].Cl>COCCOC.O>[C:29]([NH:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([C:17]2[CH:18]=[CH:19][C:14]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[C:3]([CH3:10])[CH:4]=1)(=[O:31])[CH3:30]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc(CN)ccc1Br
Reactant: O=C(O)c1ccc(B(O)O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: CC(=O)NCc1ccc(-c2ccc(C(=O)O)cc2)c(C)c1
Reaction time: 16 h

Procedure:
4-Bromo-3-methylbenzylamine (EP 532266) (7.36 g, 0.037 mol) was dissolved in 1,2-dimethoxyethane (DME) (180 ml), with stirring, and was treated with 4-carboxyphenyl boronic acid (6.14 g, 0.037 mol), followed by a solution of sodium carbonate (17.65 g, 0.167 mol) in water (180 ml). The reaction mixture was then flushed with argon and tetrakistriphenylphosphinepalladium (O) (1.00 g) was added. The reaction mixture was then heated to reflux under argon. After 16 h, the reaction mixture was allowed to cool and the DME was removed by evaporation under reduced pressure. The aqueous residue was then diluted with water (~200 ml) and extracted with EtOAc (2×150 ml). The aqueous layer was then treated with acetic anhydride (6.98 ml, 0.074 mol) and stirred for 1 h at room temperature. The resulting pale brown solution was then filtered through kieselguhr to give a pale yellow solution which was acidified to pH5 using conc. HCl to give an off white precipitate which was filtered off, washed with water and dried in vacuo to give the title compound as an off white solid (5.85 g, 56%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1CCCCCCC(=O)CC(O)(C(OC)=O)CC(OC)=O.ClC1C=C(Cl)C=CC=1[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C:49](=[O:62])[CH2:50][C:51]([OH:61])([C:57]([O:59]C)=O)[CH2:52][C:53]([O:55]C)=[O:54]>>[F:1][C:2]([F:34])([F:33])[C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][C@@H:49]1[O:62][C:57](=[O:59])[C@@:51]([CH2:52][C:53]([OH:55])=[O:54])([OH:61])[CH2:50]1
Reactant: COC(=O)CC(O)(CC(=O)CCCCCCc1ccc(Cl)cc1Cl)C(=O)OC
Reactant: COC(=O)CC(O)(CC(=O)CCCCCCc1ccc(C(F)(F)F)cc1C(F)(F)F)C(=O)OC
Product: O=C(O)C[C@]1(O)C[C@H](CCCCCCc2ccc(C(F)(F)F)cc2C(F)(F)F)OC1=O

Procedure:
Following the procedures described in examples 1 (g) and 2, substituting ±methyl 11-[2,4-Bis (trifluoromethyl)phenyl]-3-hydroxy-3-methoxycarbonyl-5-oxo-undecanoate for ± methyl 11(2,4-dichlorophenyl )-3-hydroxy-3-methoxycarbonyl-5-oxo-undecanoate, gave the title compound as a solid, m.p. 70°-73° C.
Reaction SMILES: CS(C)=O.[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17](/[CH:20]=[CH:21]/[N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1.[BH4-].[Na+]>C(O)(=O)C>[F:5][C:6]1[CH:7]=[CH:8][C:9]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][N+:22]([O-:24])=[O:23])=[CH:16][CH:15]=2)=[N:10][CH:11]=1
Reactant: O=[N+]([O-])/C=C/c1ccc(COc2ccc(F)cn2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: O=[N+]([O-])CCc1ccc(COc2ccc(F)cn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.7 %

Procedure:
To a dimethyl sulfoxide (49 mL) solution of 5-fluoro-2-(4-((E)-nitro-vinyl)-benzyloxy)-pyridine (2.9 g, 10.6 mmol) described in Manufacturing Example 56-1-3 and acetic acid (2.9 mL) was added sodium borohydride (642 mg, 17 mmol) at room temperature while cooling appropriately. This mixture was stirred for 1 hour at room temperature. This mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by NH-silica gel column chromatography (heptane:ethyl acetate=10:1) to obtain the title compound (1.63 g, 56%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1.[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1F)[CH:14]=[O:15]>CC(N(C)C)=O>[F:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:14]=[O:15]
Reactant: COc1ccc(O)cc1
Reactant: O=Cc1ccc(F)c(F)c1
Solvent: CC(=O)N(C)C
Product: COc1ccc(Oc2ccc(C=O)cc2F)cc1
Temperature: 110 °C
Reaction time: 0.25 h

Procedure:
4.9 g (40 mmol) of 4-methoxy-phenol and 4.4 ml (40 mmol) of 3,4-difluorobenzaldehyde were dissolved in 40 ml DMA and stirred in a microwave (CEM Explorer) for 15 minutes at 110° C., then filtered through basic Alox, washed with DMF and concentrated by rotary evaporation. The residue was separated through a KG column with a gradient (cyclohexane+10-25% ethyl acetate) and concentrated by rotary evaporation.
Reaction SMILES: [Cl:1]N1C2C=CC=CC=2N=N1.[F:11][C:12]([F:29])([F:28])[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([C:19]2[N:24]3[N:25]=[CH:26][CH:27]=[C:23]3[N:22]=[CH:21][CH:20]=2)[CH:14]=1.C(Cl)(Cl)Cl.[OH-].[Na+]>C(Cl)Cl>[Cl:1][C:27]1[CH:26]=[N:25][N:24]2[C:19]([C:15]3[CH:14]=[C:13]([C:12]([F:28])([F:11])[F:29])[CH:18]=[CH:17][CH:16]=3)=[CH:20][CH:21]=[N:22][C:23]=12
Reactant: FC(F)(F)c1cccc(-c2ccnc3ccnn23)c1
Reactant: Cln1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1cccc(-c2ccnc3c(Cl)cnn23)c1
Temperature: 25 °C

Procedure:
A 3.3 g. portion of N-chlorobenzotriazole is added to a solution of 5.26 g. of 7-(α,α,α-trifluoro-m-tolyl)pyrazolo[1,5-a]pyrimidine in 50 ml. of chloroform producing an exothermic reaction. The mixture is refluxed on a steam bath for 15 minutes, cooled to room temperature and then poured into an ice-cold solution of 2.5 N sodium hydroxide. The organic layer is separated, dried over sodium sulfate and passed through a hydrous magnesium silicate column. The effluent is heated to reflux and hexane is added giving a solid. The solid is dissolved in methylene chloride re-processed through the column and precipitated from refluxing solution with hexane giving crystals of the desired product, m.p. 155°-157° C.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH2:17][F:18])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.CCN(CC)CC.[CH3:30][S:31](Cl)(=[O:33])=[O:32].CCOC(C)=O>CN(C=O)C>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][C@H:12]3[C@@H:16]([CH2:17][F:18])[CH2:15][N:14]([S:31]([CH3:30])(=[O:33])=[O:32])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: NC(=O)c1cnn2cc(Br)cc2c1N[C@@H]1CNC[C@@H]1CF
Reactant: CS(=O)(=O)Cl
Agent: I
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1C[C@H](CF)[C@H](Nc2c(C(N)=O)cnn3cc(Br)cc23)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58.2 %

Procedure:
A solution of 6-bromo-4-(((3S,4S)-4-(fluoromethyl)pyrrolidin-3-yl)amino) pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide salt (894 mg, 2.846 mmol) and Et3N (1.399 mL, 10.04 mmol) in DMF (10 mL) was added METHANESULFONYL CHLORIDE (0.293 mL, 3.76 mmol) and the resulting mixture was stirred at RT for 30 minutes. To the reaction mixture was then added 150 mL of EtOAc and the mixture was washed with 50 mL×2 of 10% LiCl solution, 50 mL of brine and then dried over Na2SO4. Filtration and concentration afforded a crude product which was triturated with MeOH and the resulting solid collected and dried under vacuum to afford the title compound (0.719 g, 90% yield). MS (ES+) m/z: 434.1, 436.1 (M+H); HPLC: 89.6%, retention time: 2.348 min (analytical HPLC Method H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=1.[OH-].[K+]>CS(C)=O.O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([O:1][C:2]2[CH:3]=[C:4]([CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH:5]=[CH:6][CH:7]=2)=[CH:16][CH:17]=1)#[N:20]
Reactant: CCOC(=O)Cc1cccc(O)c1
Reactant: N#Cc1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)Cc1cccc(Oc2ccc(C#N)cc2)c1
Yield: 49.3 %

Procedure:
A solution of ethyl 3-hydroxyphenylacetate (28 g, 0.15 mole) and 4-fluorobenzonitrile (25 g, 0.21 mole) in dimethylsulfoxide (150 ml) was stirred with 87% potassium hydroxide (10 g, 0.15 mole) at 75-80° C. for 80 minutes under nitrogen. The resulting mixture was allowed to cool, diluted with water (1000 ml), and extracted with diethyl ether (2×50 ml). The organic solution was washed with water (100 ml), dried (MgSO4), concentrated in vacuo and the residue eluted on silica gel (500 g) with ethyl acetate: hexane (0 to 1:6). A solution of the product in diethyl ether (125 ml) was washed with 1N NaOH (15 ml) to remove some residual phenol, dried (K2CO3 and MgSO4), and concentrated in vacuo to give ethyl 3-(4-cyanophenyloxy)phenylacetate (20.8 g). 1H NMR (DMSO-d6, 300 MHz) δ: 1.18 (t, J=7 Hz, 3H, CH3), 3.71 (s, 2H, Ar CH2), 4.08 (q, J=7 Hz, 2H, ester CH2), 7.02-7.13 (m, 4H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.42 (t, J=8 Hz, 1H, Ar), 7.85 (d, J=9 Hz, 2H, Ar). Anal. Calculated for C17H15NO3: C, 72.58; H, 5.37; N, 4.98. Found: C, 72.67; H, S.43; N, 4.94.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:12]([C:15]1[CH:16]=[C:17]([CH:21]=[CH:22][CH:23]=1)[C:18](O)=[O:19])(=[O:14])[CH3:13].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH:11][C:18](=[O:19])[C:17]1[CH:21]=[CH:22][CH:23]=[C:15]([C:12](=[O:14])[CH3:13])[CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(=O)c1cccc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)c1cccc(C(=O)NCCNC(=O)OC(C)(C)C)c1
Reaction time: 2.5 h

Procedure:
N-(t-Butoxycarbonyl)ethylenediamine 2 (5 mmol, 800 mg) was weighed directly into a clean dry flask, which was then tightly stoppered. 3-Acetylbenzoic acid 3 (5 mmol, 820 mg) was added directly to the amine in the flask. Under an inert atmosphere dry dimethylformamide (15 mL) was added to the flask. Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (5 mmol, 2.21 g) was added to the solution, and subsequently N-methylmorpholine (15 mmol, 1.51 g, 1.7 mL) was added to the solution, and the mixture was allowed to stir for 2-3 hrs. The reaction mixture was quenched by the addition of 15 mL of water to the reaction flask, and partitioned between water (300 mL) and ethyl acetate (300 mL). The organic phase was washed successively with saturated sodium bicarbonate (200 mL), water (4×300 mL), and brine (200 mL) and then dried over anhydrous sodium sulfate. Filtering off the drying agent and concentration of the organic phase to ˜10-15 mL yielded a tan solid. Hexanes (˜30 mL) were added and the mixture gently heated to reflux. Upon cooling semicrystalline product was precipitated as a white powder. The product was collected by filtration and dried. Yield 775 mg, 51%.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:19])[NH:5][C:6](=[O:18])[N:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:8]=1)#[N:2].S(OC)(O[CH3:24])(=O)=O>[OH-].[Na+]>[C:1]([C:3]1[C:4](=[O:19])[N:5]([CH3:24])[C:6](=[O:18])[N:7]([NH:9][C:10]2[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:11]=2[CH3:17])[CH:8]=1)#[N:2]
Reactant: Cc1cccc(C)c1Nn1cc(C#N)c(=O)[nH]c1=O
Reactant: COS(=O)(=O)OC
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1Nn1cc(C#N)c(=O)n(C)c1=O

Procedure:
To a mixture of 5-cyano-1-(2,6-dimethylanilino)-2,4-pyrimidinedione (0.1 mol) and 80 ml of 5% sodium hydroxide solution, with stirring, is slowly added dimethyl sulfate (0.1 mol). The reaction mixture is stirred for about 2-4 hours and then filtered, washed with water and dried to yield 5-cyano-1-(2,6-dimethylanilino)-3-methyl-2,4-pyrimidinedione.
Reaction SMILES: [Cl-].O[NH3+:3].[C:4](=[O:7])([O-])[OH:5].[Na+].CS(C)=O.[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]4[C:46]([C:51]#[N:52])=[CH:47][CH:48]=[CH:49][CH:50]=4)=[CH:41][CH:40]=3)[C:20](=[O:37])[N:21]([CH2:24][C:25]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]>C(Cl)(Cl)Cl>[CH2:13]([C:15]1[S:53][C:18]2[N:19]([CH2:38][C:39]3[CH:44]=[CH:43][C:42]([C:45]4[CH:50]=[CH:49][CH:48]=[CH:47][C:46]=4[C:51]4[NH:3][C:4](=[O:7])[O:5][N:52]=4)=[CH:41][CH:40]=3)[C:20](=[O:37])[N:21]([CH2:24][C:25]([C:27]3[CH:36]=[CH:35][C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[CH:28]=3)=[O:26])[C:22](=[O:23])[C:17]=2[CH:16]=1)[CH3:14]
Reactant: O=C([O-])O
Reactant: CCc1cc2c(=O)n(CC(=O)c3ccc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Reactant: [NH3+]O
Agent: [Cl-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: ClC(Cl)Cl
Product: CCc1cc2c(=O)n(CC(=O)c3ccc4ccccc4c3)c(=O)n(Cc3ccc(-c4ccccc4-c4noc(=O)[nH]4)cc3)c2s1
Temperature: 40 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
A mixture of hydroxylammonium chloride (0.83 g), sodium hydrogencarbonate (1.26 g) and dimethyl sulfoxide (10 mL) was stirred at 40° C. for 30 min, 4′-{[6-ethyl-3-[2-(2-naphthyl)-2-oxoethyl]-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl]methyl}biphenyl-2-carbonitrile (0.84 g) was added, and the mixture was stirred at 90° C. for 16 hr. The reaction mixture was diluted with chloroform, washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography and dissolved in methylene chloride (30 mL). N,N′-Carbonyldiimidazole (0.24 g) and then 1,8-diazabicyclo[5.4.0]undec-7-ene (0.21 mL) were added, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was diluted with chloroform, washed successively with saturated aqueous potassium hydrogensulfate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was dissolved in methylene chloride (50 mL), iodine acid (0.84 g) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by preparative HPLC to give the title compound as colorless crystals (0.26 g, 19%).