Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:24][C:25](=[O:43])[C@@H:26]([NH:31][C:32](=[O:42])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]([OH:23])=[O:22])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3].C(=O)([O-])[O-].[K+:48].[K+].C(#N)C>CO.O>[K+:48].[NH2:1][C:2]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([CH2:19][C@H:20]([NH:24][C:25](=[O:43])[C@@H:26]([NH:31][C:32](=[O:42])[CH2:33][O:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=3[CH3:41])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:21]([O-:23])=[O:22])=[CH:15][CH:14]=2)=[O:11])[CH2:6][CH2:5]1)=[O:3]
Reactant: Cc1ccccc1OCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(OC(=O)N2CCC(C(N)=O)CC2)cc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Solvent: CO
Product: Cc1ccccc1OCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](Cc1ccc(OC(=O)N2CCC(C(N)=O)CC2)cc1)C(=O)[O-]
Temperature: 20 °C
Yield: 199.9 %

Procedure:
A suspension of Example 27 (10 g) in methanol (150 ml) was warmed to reflux to obtain a clear solution. To this was added a solution of potassium carbonate (1.16 g) in water (7.5 ml). After heating under reflux for two minutes the solvents were evaporated in vacuo to give a crisp foam. To this was added acetonitrile (100 ml) and the mixture was warmed to reflux, during which time the foam collapsed and started to crystallise. After ten minutes the mixture was allowed to cool to 20° C. then filtered under reduced pressure, washed with acetonitrile (25 ml) and ether (50 ml) to give the title compound as a white solid (10.65 g, 100%). The product is believed to be isolated in the form of its monohydrate. Solubility in water: >250 mg/ml.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[C:6]([F:13])([F:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8].O.C(Cl)(Cl)(Cl)F>CS(C)=O>[N:1]([C:6]([F:13])([F:12])[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)C(F)(F)Br
Agent: [Na+]
Solvent: O
Solvent: FC(Cl)(Cl)Cl
Solvent: CS(C)=O
Product: CCOC(=O)C(F)(F)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Powdered sodium azide (19.5 g, 0.3 mol) was added in portions, over 5 minutes, to a stirred solution of ethyl 2-bromo-2,2-difluoroacetate (50.74 g, 0.25 mol) in dry dimethyl sulfoxide (250 mL). After stirring at room temperature for 18 hours, the mixture was poured into water (750 mL) and extracted with methylene chloride (4×100 mL). The combined extracts were washed with water (4×100 mL), dried over anhydrous magnesium sulfate, then filtered, and the filtrate was distilled at atmospheric pressure through an indented (10 cm.) distillation column, at a bath temperature of 77° C., until no more methylene chloride distilled. 1H NMR spectroscopy (CDCl3 ; (CH3)4Si internal standard) of the colorless residue showed a mixture of methylene chloride (31 mol %) and the azido ester (69 mol%); 4.53 (q, 2H, CH2), 1.44 (t, 3H, CH3). This corresponds to a yield of 34.44 g (83.4%) of the azido ester. The pure product was obtained as a colorless liquid by distillation under vacuum; bp 68° C./100 mm. 19F NMR (CDCl3, CFCl3 internal standard) φ 84.8 (s). Anal. Calcd. for C4H5F2N3O2 : C, 29.10; H, 3.05; N, 25.45; F, 23.02. Found: C, 28.80; H, 3.15; N, 25.36; F, 23.15.
Reaction SMILES: S(=O)(=O)(O)O.S([O-])([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]CCCCCC)(=O)=O.[Na+].[C:24](=[O:27])([O-])[O-:25].[Na+].[Na+].[CH2:30](O)[CH3:31]>S(=O)(=O)(O)O.C1C=CC=CC=1>[OH:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][C:24]([O:25][CH2:30][CH3:31])=[O:27]
Reactant: CCO
Reactant: CCCCCCCCCCCCOS(=O)(=O)[O-]
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCOC(=O)CCCC#CCO
Temperature: 20 °C
Reaction time: 8 h

Procedure:
A mixture of 20 g of 7-(α-tetrahydropyranyloxy)-5-heptynoic acid, 12 g of ethanol, 50 cc of benzene and 2 drops of concentrated sulfuric acid was refluxed under nitrogen for 3 hours and after letting the mixture return to room temperature, 20 cc of 12.5% sulfuric acid, 30 cc of ethanol and traces of sodium lauryl sulfate were added thereto. The mixture was stirred overnight at 20° C and was then neutralized with sodium carbonate. The mixture was extracted with ether and the ether extracts were dried and the solvent was evaporated off under reduced pressure. The residue was rectified to obtain 8.5 g of ethyl 7-hydroxy-5-heptynoate identical of that of Step E of Example I.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([OH:51])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2].ClC(Cl)(Cl)C(=N)O[CH:60]([CH3:62])[CH3:61].FC(F)(F)S(O)(=O)=O>>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:52])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([OH:50])[CH:46]([O:51][CH:60]([CH3:62])[CH3:61])[CH2:45]2)[CH:7]([CH3:53])[CH:6]([OH:54])[CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CC(C)OC(=N)C(Cl)(Cl)Cl
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(O)C3)C(C)C(O)CC1=O)C(C)CC2OC
Agent: O=S(=O)(O)C(F)(F)F
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC(C)C)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C

Procedure:
To a solution of 17-ethyl-1,14-dihydroxy-12-[2'-(3",4"-dihydroxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (110 mg in 1.5 ml 33% methylene chloride in cyclohexane), isopropyl trichloroacetimidate (52 μl neat) was added and the reagents allowed to mix for 5 minutes. Trifiuoromethanesulfonic acid (2 μl neat) was added slowly via syringe and the mixture stirred at room temperature. After 3 hours the reaction was quenched by the addition of saturated sodium bicarbonate and extracted with ethyl acetate (3×5 ml). The combined organics were washed with brine and dried over magnesium sulfate. Purification of the concentrate by preparative TLC on silica gel (ethyl acetate: hexane (1:1)+1% methanol) gave the title compounds (15 mg 4"-ether; 16 mg 3"-ether).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11])N.N([O-])=O.[Na+].[S:18](=[O:20])=[O:19].O.[ClH:22]>NC1C=CC=CC=1.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:18]([Cl:22])(=[O:20])=[O:19])[CH:7]=[C:8]([O:12][CH3:13])[C:9]=1[O:10][CH3:11]
Reactant: O=S=O
Reactant: Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Solvent: Nc1ccccc1
Product: COc1cc(S(=O)(=O)Cl)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3,4,5-Trimethoxybenzenesulfonyl chloride was synthesized from 3,4,5-trimethoxyaniline according to the procedure described in G. Pifferi and R. Monguzzi, Journal of Pharmaceutical Sciences, 1973, 62, 1393. In this procedure the aniline was dissolved in concentrated hydrochloric acid and to the resulting mixture was added a solution of aqueous sodium nitrite at 0° C, the resulting mixture containing the desired diazonium salt was added at 5° C. to a saturated solution of sulfur dioxide in glacial acetic acid containing substoichiometric amount of cuprous chloride. The mixture was stirred at ambient temperature for 3 h, poured into cold water, and the product extracted with dichloromethane. The solvent was evaporated and the solid residue was recrystallized from hexanes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][N:27]=[C:28]=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1.[NH3:30]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]=[C:10]2[CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH:27][C:28]([NH2:30])=[S:29])[CH2:21][CH2:20]2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(Cn2c(CC3CCN(CCN=C=S)CC3)nc3ccccc32)cc1
Reactant: N
Solvent: CO
Product: NC(=S)NCCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
A mixture of 25 parts of 1-[(4-fluorophenyl)methyl]-2-[[1-(2-isothiocyanatoethyl)-4-piperidinyl]methyl]-1H-benzimidazole and 160 parts of methanol saturated with ammonia was stirred overnight at room temperature. The reaction mixture was evaporated, yielding 25 parts (100%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]ethyl]thiourea (449).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH:7][C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][C:9]=2[C:17]([OH:19])=[O:18])=[CH:3][CH:2]=1.N1C=CC=CC=1.FC(F)(F)C(O[C:31]1[C:36]([F:37])=[C:35]([F:38])[C:34]([F:39])=[C:33]([F:40])[C:32]=1[F:41])=O>CN(C)C=O>[F:37][C:36]1[C:31]([O:18][C:17]([C:9]2[NH:10][C:11]3[C:16]([C:8]=2[NH:7][C:4]2[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=2)=[CH:15][CH:14]=[CH:13][CH:12]=3)=[O:19])=[C:32]([F:41])[C:33]([F:40])=[C:34]([F:39])[C:35]=1[F:38]
Reactant: O=C(O)c1[nH]c2ccccc2c1Nc1ccncc1
Reactant: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: O=C(Oc1c(F)c(F)c(F)c(F)c1F)c1[nH]c2ccccc2c1Nc1ccncc1
Yield: 39.7 %

Procedure:
Stir under N2 a suspension of 3-(4-pyridinylamino)-1H-indole-2-carboxylic acid (0.2 g, 0.78 mmol) in dimethylformamide, add pyridine (0.13 mL, 1.6 mmol) and then add dropwise pentafluorophenyl trifluoroacetate (0.31 g, 1.13 mmol). Stir the reaction overnight at ambient temperature and quench into water. Extract the aqueous mixture with ethyl acetate, wash with 5% aqueous potassium carbonate, brine and dry over MgSO4. Concentrate under vacuum to afford a crude solid, which is triturated with ether to obtain 0.13 g (41%) of the title compound: MS 420(M+H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[C:16]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:12]([OH:14])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:34][O:35][C:36]1[CH:47]=[C:46]2[C:39]([NH:40][CH:41]=[C:42]2[CH2:43][CH2:44][NH2:45])=[CH:38][CH:37]=1.C(Cl)CCl.CO>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:16]1[CH:15]=[C:11]([CH:10]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:12]([NH:45][CH2:44][CH2:43][C:42]1[C:46]2[C:39](=[CH:38][CH:37]=[C:36]([O:35][CH3:34])[CH:47]=2)[NH:40][CH:41]=1)=[O:14])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(O)c1cc(OCc2ccccc2)c(OCc2ccccc2)c(OCc2ccccc2)c1
Reactant: COc1ccc2[nH]cc(CCN)c2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: ClCCCl
Product: COc1ccc2[nH]cc(CCNC(=O)c3cc(OCc4ccccc4)c(OCc4ccccc4)c(OCc4ccccc4)c3)c2c1

Procedure:
2g was synthesized by the condensation of 1b (480 mg, 1.09 mmol) and 5-methoxy tryptamine (248 mg, 1.308 mmol) using standard EDC coupling method and was isolated as white solid (565 mg, 84%) by elution with 0.5% methanol in chloroform. Rf: 0.517 (1.6% methanol in chloroform); mp: 125-128° C.;
Reaction SMILES: [NH:1]1[C:5]2=[N:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][CH:14](O)[CH:15]=[CH:16][C:17]3[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=3)=[CH:8][CH:9]=[C:4]2[CH2:3][CH2:2]1.[C:25](O)(=[O:28])[CH2:26]C.[C:30]([CH3:40])(OCC)([O:34]CC)[O:31][CH2:32][CH3:33]>>[CH2:32]([O:31][C:30](=[O:34])[CH2:40][CH:16]([C:17]1[CH:18]=[N:19][C:20]([CH3:23])=[N:21][CH:22]=1)[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11][CH2:10][C:7]1[N:6]=[C:5]2[N:1]([C:25](=[O:28])[CH3:26])[CH2:2][CH2:3][C:4]2=[CH:9][CH:8]=1)[CH3:33]
Reactant: CCC(=O)O
Reactant: Cc1ncc(C=CC(O)CCCCc2ccc3c(n2)NCC3)cn1
Reactant: CCOC(C)(OCC)OCC
Product: CCOC(=O)CC(C=CCCCCc1ccc2c(n1)N(C(C)=O)CC2)c1cnc(C)nc1
Temperature: 25 °C
Yield: 37 %

Procedure:
A solution of the allylic alcohol 23-9 (0.402 g, 1.24 mmol) in (EtO)3CMe (20 mL) was treated with 1 uL propionic acid. The yellow solution was heated at reflux until complete by 1 cms. The solution was cooled to room temperature, concentrated, and purified by PCTLC (4 mm, 0-10% MeOH/CHCl3) which provided 0.198 g (37% yield) of 23-10.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7](Cl)[CH:8]=2)[N:3]=1.[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH2:18].[NH2:23][CH2:24][CH2:25][CH2:26][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17][NH:18][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:23][CH2:24][CH2:25][CH2:26][N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)[CH:8]=2)[N:3]=1
Reactant: Clc1ccc2nc(Cl)ccc2c1
Reactant: NCCCN1CCOCC1
Reactant: COc1ccccc1CN
Product: COc1ccccc1CNc1ccc2cc(NCCCN3CCOCC3)ccc2n1

Procedure:
The title compound, MS: m/e=407.5 (M+H+), was prepared in accordance with the general method of example 1 from 2,6-dichloroquinoline, 2-methoxybenzylamine and 4-(3-aminopropyl)morpholine.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=1)[C:16]#[N:17].C(N(CC)CC)C>C(Cl)Cl>[CH:12]([C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][N:20]=1)[C:16]#[N:17])=[O:11]
Reactant: N#Cc1ccnc(CO)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: N#Cc1ccnc(C=O)c1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a cooled solution of oxalyl chloride (13.2 mL, 150 mmol) in anhydrous DCM (86 mL) under nitrogen atmosphere at −78° C. was added DMSO (21.2 mL dropwise over 20 minutes. The mixture was stirred for 15 minutes at (−78° C.) before 2-hydroxymethyl-isonicotinonitrile (4.0 g, 30 mmol) dissolved in anhydrous DCM (60 mL) was added dropwise to the reaction mixture over 5 minutes. The reaction was stirred for 2 hrs at −78° C. maintaining a nitrogen atmosphere. A white solid precipitate formed and the temperature was raised to (−55° C.) and triethylamine (6.15 mL, 450 mmol) was added dropwise for over 15 minutes, cooling bath was removed allowing the mixture to warm to room temperature over 2 hrs. The mixture was diluted with DCM (400 mL) and washed with brine (2×50 mL). The aqueous phase was extracted with DCM (3×50 mL). The combined organic layers were combined and concentrated in vacuo. A buff white solid was isolated that was used without any further purification. Single peak in LC-MS analysis, (yield taken to be quantitative), m/z (LC-MS, ESP), RT=2.53 mins, (M+H)=133.0.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:25])=[C:19]([OH:24])[CH:20]=[CH:21][C:22]=3[CH3:23])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH2:15][NH:16][C:17]3[C:18]([CH3:25])=[C:19]([CH:20]=[CH:21][C:22]=3[CH3:23])[O:24][CH2:33][C:34]([O:36][CH:37]([CH3:39])[CH3:38])=[O:35])[CH:11]=[C:12]([CH3:14])[CH:13]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CNc2c(C)ccc(O)c2C)cc(-c2cccc(F)c2)c1
Reactant: CC(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(CNc2c(C)ccc(OCC(=O)OC(C)C)c2C)cc(-c2cccc(F)c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 69.3 %

Procedure:
To a solution of 3-[[3-(3-fluorophenyl)-5-methyl-phenyl]methylamino]-2,4-dimethyl-phenol (168 mg, 0.50 mmol, 1.0 eq) in DMF (10 mL) was added Cs2CO3 (245 mg, 0.75 mmol, 1.5 eq). The reaction mixture was stirred at room temperature for 30 min then isopropyl bromoacetate (109 mg, 0.6 mmol, 1.2 eq) was added. The reaction mixture was stirred at room temperature for a further 1 h then poured into water and extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo. The residue was purified by column chromatography (petroleum ether: EtOAc, 40:1 to 30:1) to give the title compound as a colorless oil (151 mg, 69%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26](S(C)=O)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:34]([O:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][CH:43]([NH2:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([CH3:37])([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][N:27]=[C:26]([NH:50][CH:43]([C:44]5[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=5)[CH2:42][CH2:41][NH:40][C:39]([O:38][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:51])[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CS(=O)c1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1
Reactant: CC(C)(C)OC(=O)NCCC(N)c1ccccc1
Product: CC(C)(C)OC(=O)NCCC(Nc1nccc(-c2cnc3c(NC4CCC(NC(=O)OC(C)(C)C)CC4)nccn23)n1)c1ccccc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of {4-[3-(2-methanesulfinyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (from Example 48 supra) (170 mg, 0.36 mmol) and compound (3-amino-3-phenyl-propyl)-carbamic acid tert-butyl ester (from Example 53 supra) (361 mg, 1.44 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 50:1 to 30:1) to afford crude (4-{3-[2-(3-tert-butoxycarbonylamino-1-phenyl-propylamino)-pyrimidin-4-yl]-imidazo[1,2-a]pyrazin-8-ylamino}-cyclohexyl)-carbamic acid tert-butyl ester. (Yield 110 mg).
Reaction SMILES: [C:1]1([CH2:7][C:8]2[N:17]=[CH:16][CH:15]=[CH:14][C:9]=2[C:10](OC)=[S:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].C(O)(=[O:22])C>CN(C)C=O.O>[OH:22][C:8]1[C:9]2[CH:14]=[CH:15][CH:16]=[N:17][C:10]=2[S:11][C:7]=1[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(=S)c1cccnc1Cc1ccccc1
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Oc1c(-c2ccccc2)sc2ncccc12
Temperature: 25 °C
Reaction time: 4 h
Yield: 93 %

Procedure:
A suspension of 12.9 g (50 mmol) of methyl 2-phenylmethylthionicotinate and 2.6 g (110 mmol) of sodium hydride in 100 mL of dry N,N-dimethylformamide was stirred for 4 hours at room temperature. The solution was diluted with 200 mL water and acidified with glacial acetic acid. The precipitate was collected, washed with water, and dried to afford 10.6 g (93%) of a white crystalline solid to be used in the next step.
Reaction SMILES: [C:1]1([C:7]2([C:10]([C:12]3[CH:22]=[CH:21][CH:20]=[CH:19][C:13]=3[C:14](OCC)=[O:15])=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[NH2:24][NH2:25]>C(O)C>[C:1]1([C:7]2([C:10]3[C:12]4[C:13](=[CH:19][CH:20]=[CH:21][CH:22]=4)[C:14](=[O:15])[NH:25][N:24]=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: NN
Reactant: CCOC(=O)c1ccccc1C(=O)C1(c2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: O=c1[nH]nc(C2(c3ccccc3)CC2)c2ccccc12
Temperature: 75 °C
Reaction time: 8 h
Yield: 93.2 %

Procedure:
A solution of (2-(ethoxycarbonyl)phenyl)zinc(II) bromide (2.2 mL, 1.1 mmol) was added to a mixture of 1-phenylcyclopropanecarbonyl chloride (0.200 g, 1.1 mmol) and Pd(PPh3)4 (0.0644 g, 0.056 mmol) in THF (1.1 mL), stirred for 2 hours, diluted with EtOAc, washed with 1N HCl and brine, dried (Na2SO4), filtered, and chromatographed (20% Et2O/hexanes) to give 216.2 mg of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate. A mixture of impure ethyl 2-(1-phenylcyclopropanecarbonyl)benzoate (0.216 g, 0.735 mmol) and hydrazine hydrate (0.13 mL, 2.298 mmol) in ethanol (3 mL) was stirred at 75° C. overnight, and concentrated to give 179.7 mg of impure 4-(1-phenylcyclopropyl)phthalazin-1(2H)-one, which was treated with O-(diphenylphosphoryl)hydroxylamine using a method similar to that described in Example 1B to give impure 2-amino-4-(1-phenylcyclopropyl)phthalazin-1(2H)-one.
Reaction SMILES: CC1N=C(C#CC(C2CCNCC2)O)C=CC=1.[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]#[C:26]/[CH:27]=[C:28]2\[CH2:29][NH:30][CH2:31][CH2:32][CH2:33]\2)[N:20]=1.Cl[C:35]1[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=[C:37]([CH3:44])[N:36]=1>>[CH3:44][C:37]1[N:36]=[C:35]([N:30]2[CH2:31][CH2:32][CH2:33]/[C:28](=[CH:27]\[C:26]#[C:25][C:21]3[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[N:20]=3)/[CH2:29]2)[C:40]([N+:41]([O-:43])=[O:42])=[CH:39][CH:38]=1
Reactant: Cc1cccc(C#C/C=C2/CCCNC2)n1
Reactant: Cc1ccc([N+](=O)[O-])c(Cl)n1
Agent: Cc1cccc(C#CC(O)C2CCNCC2)n1
Product: Cc1cccc(C#C/C=C2\CCCN(c3nc(C)ccc3[N+](=O)[O-])C2)n1

Procedure:
The title compound was prepared as described for the compound of Example 237 but starting from Compound 310c or 311c instead of compound 237a and using 2-chloro-6-methyl-3-nitropyridine instead of 2-bromo-3-nitropyridine. After the work-up, the residue was purified by automated flash liquid chromatography (SP1™-Biotage) eluting with PE-EtOAc gradient from PE-EtOAc 7:3 to 6:4 affording the title products. Example 310:18%. Example 310: 11%
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=O)=[CH:6][CH:5]=1)([O-])=O.[CH:13]1[CH:18]=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=C[CH:14]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=[O:35].[Li+].[OH-].Cl>CCOC(C)=O.C1COCC1.O>[OH:35][C@H:5]1[C:6]2=[N:1][CH:4]=[CH:12][CH:11]=[C:7]2[C:8](=[O:10])[CH2:18][CH2:13][CH2:14]1
Reactant: CC(C)OC(=O)N=NC(=O)OC(C)C
Reactant: O=C(O)c1ccc([N+](=O)[O-])cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: O=C1CCC[C@@H](O)c2ncccc21
Temperature: 0 °C
Reaction time: 8 h

Procedure:
In a 1 L round-bottomed flask was (S)-9-hydroxy-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-5-one (19.14 g, 108 mmol) (obtained by enzyme reduction of the diketone) in THF (300 mL) to give a light orange solution. 4-Nitrobenzoic acid (27.1 g, 162 mmol) and Ph3P (42.5 g, 162 mmol) were added under nitrogen, and the mixture was cooled to 0° C. Diisopropyl azodicarboxylate (31.9 mL, 162 mmol) was added dropwise. The mixture was allowed to gradually warm to rt and stirred overnight (5:00 pm). The color changed to tan. 15 h: LCMS showed complete conversion. 80 ml water was added followed by LiOH (7.76 g, 324 mmol). The mixture was stirred at rt for 2 h (some LiOH was not completely dissolved). 2 h: LCMS showed complete conversion (product/dehydrated ˜7/1 by intergration). THF was stripped off and the remaining mixture was slowly acidified with 40 ml concentrated HCl (12N). 300 ml EtOAc was added. The mixture was shaken in a 1L separating funnel. (10 ml hexane was added for better separation). The layers were separated and the organic layer was extracted with water (2×50 mL). The combined aqueous layers were washed with EtOAc (4×100 mL). The tan aqueous solution was then basified slowly with 50 mL ION NaOH and was extracted with EtOAc (4×150 mL). The aqueous layer was saturated with NaCl and extracted with EtOAc (2×100 mL). The combined tan organic layers (TLC showed desired product, dehydrated product and some baseline) were washed with brine, dried and concentrated to a tan oil (crude weight: 19.24 g, 100%), which was directly used in the next step. MS(ESI)[M+H+]=178.24.