Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:6]([C@H:24]([CH2:27][CH3:28])[CH2:25][OH:26])[C:5]1=[O:29])[CH:2]=[CH2:3].O>C(Cl)Cl>[CH2:1]([C@@:4]1([CH3:30])[CH2:9][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[C@@H:7]([C:17]2[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=2)[N:6]([C@@H:24]([CH2:27][CH3:28])[CH:25]=[O:26])[C:5]1=[O:29])[CH:2]=[CH2:3]
Reactant: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](CC)CO)C1=O
Solvent: ClCCl
Solvent: O
Product: C=CC[C@@]1(C)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@H](C=O)CC)C1=O

Procedure:
To a solution of 218 mg (0.49 mmol) of (3S,5R,6S)-3-allyl-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-hydroxybutan-2-yl)-3-methylpiperidin-2-one (Example 91, Step B) in a mixture of water (13.20 μL, 0.733 mmol) and DCM (4883 μL) was added 1,1,1,-tris(acetoxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)one (“Dess Martin periodinane”) (311 mg, 0.733 mmol) at ambient temperature. The reaction was monitored by LCMS, and several small portions of additional periodinane were added until the reaction was complete. The reaction was quenched (2 mL, 1 M Na2S2O3), extracted (2×DCM), and the combined organic layers were washed with sat. NaHCO3 solution (2×), sat NaCl solution, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. Purification of the residue by flash chromatography on silica gel (eluent: 20 to 35% EtOAc/hexanes, gradient elution) provided the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:12][CH2:11][CH2:10][C:9]2=[O:13])[CH:5]=[CH:4][C:3]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[C:30]3[CH:29]=[C:28]4[C:31]5([CH2:37][O:38][C:27]4=[CH:26][C:25]=3[CH2:24][CH2:23]2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]5)=[O:21])=[CH:16][CH:15]=1.[CH:39]1(Br)[CH2:43][CH2:42][CH2:41][CH2:40]1>>[CH:39]1([N:34]2[CH2:35][CH2:36][C:31]3([C:28]4[C:27](=[CH:26][C:25]5[CH2:24][CH2:23][N:22]([C:20]([C:17]6[CH:18]=[CH:19][C:14]([C:3]7[CH:4]=[CH:5][C:6]([N:8]8[CH2:12][CH2:11][CH2:10][C:9]8=[O:13])=[CH:7][C:2]=7[CH3:1])=[CH:15][CH:16]=6)=[O:21])[C:30]=5[CH:29]=4)[O:38][CH2:37]3)[CH2:32][CH2:33]2)[CH2:43][CH2:42][CH2:41][CH2:40]1
Reactant: BrC1CCCC1
Reactant: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCNCC2)CO4)cc1
Product: Cc1cc(N2CCCC2=O)ccc1-c1ccc(C(=O)N2CCc3cc4c(cc32)C2(CCN(C3CCCC3)CC2)CO4)cc1

Procedure:
The title compound was prepared from 5-[2'-methyl-4'-(2-oxopyrrolidin-1-yl)biphenyl-4-carbonyl]-2,3,6,7-tetrahydrospiro[furo[2,3-f]indole-3,4'-piperidine] (E18) and cyclopentyl bromide using a similar procedure to Example 19, as a white powder (22%).
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.[CH3:15][N:16]=[C:17]=[S:18]>C(O)C>[CH3:15][NH:16][C:17](=[S:18])[NH:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cc2ccccn2)cc1
Reactant: CN=C=S
Solvent: CCO
Product: CNC(=S)Nc1ccc(Cc2ccccn2)cc1
Yield: 77.4 %

Procedure:
A solution of 2-(4-aminobenzyl)pyridine (3.8 g) and methyl isothiocyanate (2.0 g) in ethanol (100 ml) was heated under reflux for 2 hours. Evaporation of the solvent gave a residue which was triturated with diethyl ether to give a precipitate. The precipitate was collected by filtration and dried to give 2-[4-(3-methylthioureido)benzyl]pyridine (4.11 g).
Reaction SMILES: I[C:2]([F:6])=[C:3]([F:5])[F:4].C([Li])(CC)C.Cl[Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>C(OCC)C>[F:6][C:2]([Si:13]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])=[C:3]([F:5])[F:4]
Reactant: CCO[Si](Cl)(OCC)OCC
Reactant: FC(F)=C(F)I
Agent: [Li]C(C)CC
Solvent: CCOCC
Product: CCO[Si](OCC)(OCC)C(F)=C(F)F
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
A dry 3-neck round bottom flask with nitrogen and stir-bar is charged with approximately (9.5 mL, 14.5 g at −78° C., 0.12 mol) iodotrifluoroethylene and 200 mL diethylether pre-cooled to −78° C. Sec-butyl lithium (89 mL, 1.4 M solution, 0.12 mol) is added dropwise over 1 hour. Solution is allowed to stir for 5 minutes at −78° C. Chlorotriethoxysilane (24.35 mL, 0.12 mol) is added over 5 minutes at −78° C. The solution is allowed to warm slowly and allowed to stir overnight. A clear yellow solution remains. Fractional distillation is used to purify the product.
Reaction SMILES: FC(F)(F)C(OC(=O)C(F)(F)F)=[O:4].[CH2:14]([N:16]1[C:24]2[C:19](=[N:20][CH:21]=[CH:22][C:23]=2[CH3:25])[N:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][Si:33]([CH:40]([CH3:42])[CH3:41])([CH:37]([CH3:39])[CH3:38])[CH:34]([CH3:36])[CH3:35])=[CH:28][CH:27]=2)[C:17]1=[O:43])[CH3:15].OO.NC(N)=O.[Cl-].[Cl-].[Ca+2].C([O-])(O)=O.[Na+]>CCOC(C)=O>[CH2:14]([N:16]1[C:24]2[C:19](=[N+:20]([O-:4])[CH:21]=[CH:22][C:23]=2[CH3:25])[N:18]([C:26]2[CH:31]=[CH:30][C:29]([O:32][Si:33]([CH:34]([CH3:35])[CH3:36])([CH:37]([CH3:39])[CH3:38])[CH:40]([CH3:42])[CH3:41])=[CH:28][CH:27]=2)[C:17]1=[O:43])[CH3:15]
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Reactant: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2nccc(C)c21
Agent: NC(N)=O
Agent: O=C([O-])O
Agent: OO
Solvent: CCOC(C)=O
Product: CCn1c(=O)n(-c2ccc(O[Si](C(C)C)(C(C)C)C(C)C)cc2)c2c1c(C)cc[n+]2[O-]

Procedure:
Trifluoroacetic anhydride (3.92 mL) was added to a suspenstion of 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (4 g) and urea hydrogen peroxide (2.74 g) in EtOAc (20 mL) at 0° C. The mixture was stirred at room temperature under a dry atmosphere (CaCl2 tube) overnight. The mixture was neutralized with sat. NaHCO3 at 0° C. and extracted with EtOAc. The organic layer was separated, washed with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by column chromatography (NH silica gel, eluted with 0%-100% EtOAc in hexane) to give 1-ethyl-7-methyl-3-(4-{[tris(1-methylethyl)silyl]oxy}phenyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one 4-oxide (250 mg) as colorless crystals.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].[O:25]1[CH:29]=[CH:28][CH:27]=[CH:26]1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[O:25][CH:29]=[CH:28][CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Reactant: c1ccoc1
Product: O=C(c1cn(-c2cccc(-c3cccnc3F)c2)cn1)c1ccco1

Procedure:
This compound is prepared by method C using compound 12i and furane
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1.Cl.[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[NH:30]1>>[CH3:28][C@@H:29]1[CH2:33][CH2:32][C@@H:31]([CH3:34])[N:30]1[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([N:20]3[CH2:25][CH2:24][CH:23]([CH3:26])[CH2:22][CH2:21]3)=[O:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1
Reactant: C[C@@H]1CC[C@@H](C)N1
Reactant: CC1CCN(C(=O)c2ccc(-c3ccc(OCCCCl)cc3)cc2)CC1
Agent: Cl
Product: CC1CCN(C(=O)c2ccc(-c3ccc(OCCCN4[C@H](C)CC[C@H]4C)cc3)cc2)CC1

Procedure:
The product from Example 9A and (2R,5R)-2,5-dimethylpyrrolidine hydrochloride were processed as described in Example 10F to provide the title compound.
Reaction SMILES: [OH-].[Na+].[C:3]([CH2:5][CH:6]1[CH2:9][CH:8]([C:10]([O:12]C)=[O:11])[CH2:7]1)#[N:4]>CO>[C:3]([CH2:5][CH:6]1[CH2:9][CH:8]([C:10]([OH:12])=[O:11])[CH2:7]1)#[N:4]
Reactant: COC(=O)C1CC(CC#N)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: N#CCC1CC(C(=O)O)C1
Reaction time: 3 h

Procedure:
An aqueous solution of sodium hydroxide (1M, 295 ml) was added dropwise over a period of 30 minutes to a stirred solution of methyl 3-cyanomethylcyclobutane carboxylate (21.0 g, 0.20 mol) in methanol (300 ml). After 3 hours, the reaction mixture was washed with hexane (2×75 ml) and the aqueous phase acidified with aqueous hydrochloric acid (2M, 150 ml) to pH5. The aqueous was extracted with ethyl acetate (2×100 ml) and the combined extracts dried, filtered and evaporated to a yellow oil (21 g). The crude product was purified by chromatography on flash silica eluting with diethyl ether to give the title compound as an oil.
Reaction SMILES: O[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22].O=P(Cl)(Cl)[Cl:25]>>[Cl:25][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH:16]3[CH2:20][CH2:19][O:18][CH2:17]3)=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:21]#[N:22]
Reactant: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1O
Reactant: O=P(Cl)(Cl)Cl
Product: N#Cc1cnc2cc(OC3CCOC3)c([N+](=O)[O-])cc2c1Cl
Temperature: 105 °C
Reaction time: 2.5 h
Yield: 92.7 %

Procedure:
To a single-neck reaction flask (100 ml) were added 4-hydroxy-6-nitro-7-(tetrahydrofuran-3-yl-oxy)quinoline-3-carbonitrile (1.8 g, 3 mmol) and POCl3 (10 mL) under argon atmosphere. The mixture was warmed to the temperature of 105° C. The reaction mixture was stirred for 2.5 hr. Then the reaction was stopped. The resultant mixture was rotary-evaporated to dryness. DCM (20 mL) was added to dissolve the resultant mixture. The solution was poured into a cooled mixture solution of DCM (200 mL) and saturated K2CO3 solution (60 mL). The resultant mixture was stirred for 10 min. The solution was extracted and the aqueous layer was discarded. The DCM layer was washed with water (150 mL) and staturated NaCl solution (150 mL), successively. The resultant substance was dried over MgSO4 for half-hour, filtered, rotary-evaporated to dryness, and dried in vacuo to give a yellow solid (1.771 g). Yield: 92.7%.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.N1C=CC=CC=1.[C:14](Cl)(=[O:22])[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(N(C)C)=O>[SH:7][C:4]1[S:3][C:2]([NH:1][C:14]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:22])=[N:6][N:5]=1
Reactant: Nc1nnc(S)s1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: c1ccncc1
Solvent: CC(=O)N(C)C
Product: O=C(Nc1nnc(S)s1)Oc1ccccc1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
61 g of 2-amino-5-mercapto-1,3,4-thiadiazole were dissolved in 230 ml of dimethylacetamide, and 40.8 ml of pyridine were added thereto. The resulting solution was cooled to a temperature not higher than 0° C., and 79 g of phenyl chlorocarbonate were added dropwise thereto. After completion of the dropwise addition, the solution was stirred for 1.5 hours at a temperature not higher than 0° C., and the reaction mixture was then poured into 1 liter of ice-water. Precipitated crystals were collected by filtration and recrystallized from acetonitrile to obtain the desired product.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7].[O:8]=[C:9]1[NH:18][C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][CH:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH2:26][CH2:25]1>>[O:8]=[C:9]1[N:18]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]#[N:7])[C:17](=[O:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]1[CH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([O:30][CH:31]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH2:26][CH2:25]1
Reactant: N#CCCCCBr
Reactant: O=c1[nH]c(=O)n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c2ccccc12
Product: N#CCCCCn1c(=O)c2ccccc2n(CCCCN2CCC(OC(c3ccccc3)c3ccccc3)CC2)c1=O
Yield: 66.3 %

Procedure:
Using the method similar to that in Example 61 and 5-bromovaleronitrile (1.09 ml, 9.31 mmol) instead of benzyl bromide and starting from 2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl]-1,2,3,4-tetrahydroquinazoline (3.00 g, 6.20 mmol) obtained in Example 2, a free salt of the title compound (2.32 g, 66%) was obtained as an oil.
Reaction SMILES: [BrH:1].C[O:3][C:4](=[O:14])[C@H:5]([CH:7]([CH2:12][CH3:13])[C:8]([O:10][CH3:11])=[O:9])[NH2:6].S>O.[OH-].[Cu+2].C(=O)([O-])[O-].[Cu+2]>[BrH:1].[NH2:6][C@@H:5]([C@@H:7]([C:8]([O:10][CH3:11])=[O:9])[CH2:12][CH3:13])[C:4]([OH:14])=[O:3]
Reactant: CCC(C(=O)OC)[C@H](N)C(=O)OC
Agent: [Cu+2]
Agent: Br
Agent: O=C([O-])[O-]
Solvent: O
Product: CC[C@H](C(=O)OC)[C@H](N)C(=O)O
Reaction time: 119 h
Yield: 76 %

Procedure:
The crude material of (2S,3S)-dimethyl-3-ethylaspartate hydrobromide (27.2 g) of Example 6 was suspended in water (200.0 mL) and filtered. The filter cake was washed with water (300.0 mL) 2nd the combined aqueous solution were diluted with methanol (500.0 mL). To this solution was added copper(II) carbonate copper(II) hydroxide (76.4 g, 345.5 mmol) and the resulting green suspension was mechanically stirred in a Morton flask (2.0 L) for 119 h. The suspension was saturated with hydrogen sulfide for 1 h, then the resulting black suspension was filtered through celite. The filter cake was washed with an aqueous solution of methanol (70%, 1800.0 mL). The combined filtrate and washings were concentrated in vacuo to give the amino acid salt (19.6 g) which was used for further reaction without purification.
Reaction SMILES: [CH:1]([Mg]Cl)([CH3:3])[CH3:2].C([Li])CCC.[Br:11][C:12]1[C:17]([CH3:18])=[CH:16][C:15](Br)=[CH:14][C:13]=1[CH3:20].C([Cu])#N.[Li+].[Cl-].BrCC=C>O1CCCC1.CCCCCC>[CH2:3]([C:15]1[CH:14]=[C:13]([CH3:20])[C:12]([Br:11])=[C:17]([CH3:18])[CH:16]=1)[CH:1]=[CH2:2]
Reactant: CC(C)[Mg]Cl
Reactant: Cc1cc(Br)cc(C)c1Br
Agent: N#C[Cu]
Agent: [Cl-]
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CCc1cc(C)c(Br)c(C)c1
Temperature: -40 °C
Reaction time: 0.17 h

Procedure:
To a solution of isopropylmagnesium chloride (6.15 mL of a 2 M solution in tetrahydrofurane) in tetrahydrofurane (75 mL) is added dropwise at 0° C. n-butyllithium (15.4 mL of a 1.6 M solution in n-hexane). The mixture is stirred for 10 minutes, a solution of 2,5-dibromo-1,3-dimethylbenzene (5 g) in tetrahydrofurane (75 mL) is added within 10 minutes. The mixture is stirred for 2 hours, cooled to −40° C. and then CuCN×LiCl (5.5 mL of a 1 M solution in tetrahydrofurane) is added dropwise. After stirring for 5 minutes 3-bromopropene (6.6 mL) is added dropwise, the mixture is stirred for 1 hour, warmed to room temperature and stirred for further 12 hours. Then the reaction is quenched by addition of saturated aqueous NH4Cl solution. The mixture is extracted with diethylether, the organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (dichloromethane) to give the title compound. Yield: 3.76 g; LC (method 8): tR=0.83 min; Mass spectrum (ESI+): m/z=225 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:30]([CH3:32])[CH3:31])[C:17]4[CH2:22][CH2:21][CH:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1>C(=O)=O.CO>[Cl:1][C:2]1[N:3]=[CH:4][N:5]([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]3[N:15]=[C:16]([N:30]([CH3:31])[CH3:32])[C:17]4[CH2:22][CH2:21][C@H:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:18]=4[N:19]=3)=[CH:9][C:8]=2[O:33][CH3:34])[CH:6]=1
Reactant: COc1cc(Nc2nc3c(c(N(C)C)n2)CCC3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1
Agent: O=C=O
Solvent: CO
Product: COc1cc(Nc2nc3c(c(N(C)C)n2)CC[C@@H]3c2ccc(F)cc2)ccc1-n1cnc(Cl)c1

Procedure:
A racemic mixture of N2-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)-7-(4-fluorophenyl)-N4,N4-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 46) was purified using chiral SFC to afford peak A (Example 46A) and peak B (Example 46B). SFC Method: Chiralpak OJ-H (4.6×250 mm, 5 μM), 35% methanol (0.1% diethylamine) in CO2, 35° C., flow rate 2.0 mL/min for 14 min, absorbance 268 nm, injection 5 μL of 2 mg/mL solution in methanol (multiple stacked injections), tR (peak A)=4.3 min, tR (peak B) 10.8 min. The absolute stereochemistry of individual enantiomers (Examples 46A and 46B) was not determined LC-MS and 1H NMR analytical data for the separated enantiomers was identical to the racemate (Example 46).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=1.[CH:12]1([N:15]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)[CH2:14][CH2:13]1.C(N(C(C)C)C(C)C)C>ClCCl>[CH:12]1([N:15]2[CH2:21][CH2:20][CH2:19][N:18]([C:2]3[N:7]=[CH:6][C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][N:3]=3)[CH2:17][CH2:16]2)[CH2:14][CH2:13]1
Reactant: C1CNCCN(C2CC2)C1
Reactant: COC(=O)c1cnc(Cl)nc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cnc(N2CCCN(C3CC3)CC2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97.3 %

Procedure:
A solution of methyl 2-chloropyrimidine-5-carboxylate (200 mg, 1.16 mmol) in dichloromethane (4.00 mL) was added to a stirred solution of 1-cyclopropyl-1,4-diazepane (247 mg, 1.16 mmol) and N-ethyl-N-propan-2-ylpropan-2-amine (0.902 mL, 5.22 mmol) in dichloromethane (4.00 mL) at 25° C. The resulting solution was stirred at ambient temperature for 18 h. The reaction mixture was evaporated to dryness and redissolved in MeOH (20 mL) and the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7M NH3/MeOH and evaporated to dryness to afford methyl 2-(4-cyclopropyl-1,4-diazepan-1-yl)pyrimidine-5-carboxylate (312 mg, 97%) as a cream solid. This was used directly with no further purification.
Reaction SMILES: C(O[C:4]([C:6]1[C:7]([N:18]([CH3:23])[CH2:19][CH2:20][C:21]#[N:22])=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([F:16])=[C:11]([F:17])[CH:10]=2)=[O:5])C.CC([O-])(C)C.[K+].C(O)(=O)C.C(O)C.O>O1CCCC1>[C:21]([CH:20]1[CH2:19][N:18]([CH3:23])[C:7]2[N:8]=[C:9]3[CH:10]=[C:11]([F:17])[C:12]([F:16])=[CH:13][C:14]3=[CH:15][C:6]=2[C:4]1=[O:5])#[N:22]
Reactant: CCOC(=O)c1cc2cc(F)c(F)cc2nc1N(C)CCC#N
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(=O)O
Solvent: O
Solvent: CCO
Product: CN1CC(C#N)C(=O)c2cc3cc(F)c(F)cc3nc21
Yield: 98.1 %

Procedure:
A solution of 19.17 g of 3-ethoxycarbonyl-6,7-difluoro-2-[N-methyl-N-(b-cyanoethyl)amino]quinoline in 50 cm3 of tetrahydrofuran is introduced in the course of 60 minutes into a solution, cooled to -10° C. of 8.74 g of potassium tert-butylate in 200 cm3 of tetrahydrofuran. The suspension obtained is stirred, still at -10° C., for a further 30 minutes 4 cm3 of glacial acetic acid are then introduced. The tetrahydrofuran is evaporated off under reduced pressure (20 pKa). The crude reaction mixture is taken up with 200 cm3 of an aqueous-alcoholic ethanol/water (70/30 vol/vol) mixture. The precipitate obtained is filtered off, washed twice with 50 cm3 of water and then dried under reduced pressure (20 kPa). 16.1 g of 3--cyano-7,8-difluoro-1-methyl-4-oxo-1,2,3,4-tetrahydrobenzo[b][1,8]naphthyridine are isolated in the form of a golden-yellow solid, melting point 144° C.
Reaction SMILES: [O:1]1CCO[CH:2]1[CH2:6][N:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][C:11]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:13]=2)[C:8]1=[O:21].Cl>O1CCCC1.O>[O:21]=[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[C:11]([C:17]([O:19][CH3:20])=[O:18])[CH:10]=2)[CH:15]=[CH:16][N:7]1[CH2:6][CH:2]=[O:1]
Reactant: COC(=O)c1ccc2ccn(CC3OCCO3)c(=O)c2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2ccn(CC=O)c(=O)c2c1
Temperature: 65 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
To a solution of methyl 2-(1,3-dioxolan-2-ylmethyl)-1-oxo-1,2-dihydroisoquinoline-7-carboxylate (0.23 g, 0.8 mmol) in tetrahydrofuran (5 mL) was added 1.0 M hydrochloric acid in water (9.0 mL). The reaction mixture was heated to 65° C. and stirred overnight. The mixture was cooled to rt, water was added and the mixture was extracted with DCM (2×). The combined organic phases were then washed with water, and brine, dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by flash silica gel chromatography (30% to 100% EtOAc/hexanes) to afford methyl 1-oxo-2-(2-oxoethyl)-1,2-dihydroisoquinoline-7-carboxylate (0.11 g, 56%). LC-MS: (FA) ES+ 246.
Reaction SMILES: C([O:8][C:9]1[C:14]([Cl:15])=[CH:13][C:12]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][C:10]=1[Cl:27])C1C=CC=CC=1>[Pd].C1COCC1>[Cl:15][C:14]1[CH:13]=[C:12]([NH:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])[CH:11]=[C:10]([Cl:27])[C:9]=1[OH:8]
Reactant: COC(=O)c1ccccc1Nc1cc(Cl)c(OCc2ccccc2)c(Cl)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1Nc1cc(Cl)c(O)c(Cl)c1
Reaction time: 3 h

Procedure:
Palladium on carbon (10% by mass of 10% by wt Pd, 50 mg) was cautiously added to a deoxygenated stirring solution of methyl 2-(4-(benzyloxy)-3,5-dichlorophenylamino)benzoate (0.520 g, 1.3 mmol) in THF (15 mL). The mixture was subjected to three cycles of evacuation and purging with hydrogen gas, before being stirred under an atmosphere of hydrogen gas. After 3 h, the reaction was purged with nitrogen, filtered through Celite™ (eluent: THF) and concentrated in vacuo to afford methyl 2-(3,5-dichloro-4-hydroxyphenylamino)benzoate as a white solid that was used without further purification.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[C:23]([C:26]1[CH:27]=[C:28](B(O)O)[CH:29]=[CH:30][CH:31]=1)(=[O:25])[CH3:24]>>[F:8][C:7]1[CH:6]=[CH:5][C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)=[CH:3][C:2]=1[C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([C:23](=[O:25])[CH3:24])[CH:31]=1
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: CC(=O)c1cccc(B(O)O)c1
Product: CC(=O)c1cccc(-c2cc(-c3cnc4c(F)c(C(C)(C)O)ccn34)ccc2F)c1
Yield: 11 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 3-acetylbenzeneboronic acid were coupled in the same way as in Example 30 to give 1-{2′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-3-yl}ethanone as an off-white solid (14 mg, 11%): m/z (ES+) 407 [MH+].
Reaction SMILES: CO[C:3]([C:5]1[C:6]([OH:31])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10](=[O:22])[C:9]([C:23]1[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=1)=[CH:8]2)=[O:4].[NH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].C[O-].[Na+]>C([O-])(O)=O.[Na+]>[CH2:15]([N:11]1[C:12]2[C:7](=[C:6]([OH:31])[C:5]([C:3]([NH:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:4])=[N:14][CH:13]=2)[CH:8]=[C:9]([C:23]2[CH:28]=[CH:27][C:26]([C:29]#[N:30])=[CH:25][CH:24]=2)[C:10]1=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: COC(=O)c1ncc2c(cc(-c3ccc(C#N)cc3)c(=O)n2Cc2ccccc2)c1O
Reactant: NCCC(=O)O
Agent: C[O-]
Agent: O=C([O-])O
Agent: [Na+]
Product: N#Cc1ccc(-c2cc3c(O)c(C(=O)NCCC(=O)O)ncc3n(Cc3ccccc3)c2=O)cc1
Temperature: 25 °C
Yield: 59.4 %

Procedure:
A mixture of 1-benzyl-3-(4-cyano-phenyl)-5-hydroxy-2-oxo-1,2-dihydro-[1,7]-naphthyridine-6-carboxylic acid methyl ester (40 mg, 0.097 mmol), β-alanine (694 mg, 7.8 mmol) and NaOMe solution (11.7 mL, 5.8 mmol, 0.5 M in MeOH) was refluxed for 16 h. After the mixture was cooled to r.t., the solvent was evaporated in vacuo. The residue was partitioned between EtOAc and water. 1 M HCl was added with vigorous stirring until pH was about 2. The organic layer was dried over MgSO4 and concentrated. The crude solid obtained was dissolved in saturated NaHCO3 and washed several times with ether. The aqueous layer was acidified to pH about 2, and the resulting precipitate was isolated by filtration to give 27 mg of the title compound. MS: (−) m/z 467.24 (M−1).