Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([OH:25])=[C:7]([C:14]([NH:16][CH2:17][C:18]([O:20]CCCC)=[O:19])=[O:15])[C:8](=[O:13])[N:9]2[CH3:12])=[CH:4][CH:3]=1.C(Cl)(Cl)Cl.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[NH:64]1[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]1.CC(C)([O-])C.[Na+]>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[OH:25][C:6]1[C:5]2[C:10](=[CH:11][C:2]([N:64]3[CH2:69][CH2:68][CH2:67][CH2:66][CH2:65]3)=[CH:3][CH:4]=2)[N:9]([CH3:12])[C:8](=[O:13])[C:7]=1[C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15]
Reactant: CCCCOC(=O)CNC(=O)c1c(O)c2ccc(Br)cc2n(C)c1=O
Reactant: C1CCNCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: Cn1c(=O)c(C(=O)NCC(=O)O)c(O)c2ccc(N3CCCCC3)cc21
Temperature: 80 °C
Reaction time: 15 h
Yield: 46.4 %

Procedure:
A solution of tent-butyl 2-(7-bromo-4-hydroxy-1-methyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)acetate (205 mg, 498 μmol), Pd2dba3.CHCl3 (52 mg, 50 μmol). X-Phos (48 mg, 100 μmol) and piperidine (123 μl, 1246 μmol) in 1,4-dioxane (5 ml) was treated with sodium tert-butoxide (192 mg, 1994 μmol). The reaction was stirred at 80° C. in a sealed tube. After 15 hours, the solution was cooled to 23° C., adsorped onto silica gel, concentrated in vacuo and purified by silica gel chromatography (eluant: 5% methanol/dichloromethane, followed by 5% methanol/dichloromethane+1% AcOH), affording an yellow solid which was 83% pure. The impure solid was purified by RP HPLC (0-100% MeCN/water+1% TFA, 10 min), affording 83 mg (46%) of the product as an yellow solid.
Reaction SMILES: Cl.Cl.[N:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:17]=[CH:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[N:5][CH:4]=1.Cl.[F:19][C:20]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:21]=1[CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C.O>[F:19][C:20]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:21]=1[CH2:22][C:23]1([OH:29])[CH2:28][CH2:27][N:26]([C:11]([C:10]2[C:9]([C:6]3[CH:7]=[CH:8][N:3]=[CH:4][N:5]=3)=[N:17][CH:16]=[CH:15][CH:14]=2)=[O:13])[CH2:25][CH2:24]1
Reactant: O=C(O)c1cccnc1-c1ccncn1
Reactant: OC1(Cc2ccc(F)cc2F)CCNCC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(c1cccnc1-c1ccncn1)N1CCC(O)(Cc2ccc(F)cc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
A suspension of 2-(pyrimidin-4-yl)nicotinic acid dihydrochloride (0.36 g), 4-(2,4-difluorobenzyl)-4-hydroxypiperidine hydrochloride (0.42 g), HATU (0.75 g) and triethylamine (1.1 mL) in DMF (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane), and recrystallized from ethyl acetate/hexane to give the title compound (0.18 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][O:16][Si](C(C)(C)C)(C)C)[CH:6]=[C:5]2[CH2:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:29][CH2:28]1.[CH:37]1([NH:40][C:41](=[O:59])[C:42]2[CH:47]=[C:46](B3OC(C)(C)C(C)(C)O3)[C:45]([CH3:57])=[C:44]([F:58])[CH:43]=2)[CH2:39][CH2:38]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cl-].[Na+].O>[CH:37]1([NH:40][C:41](=[O:59])[C:42]2[CH:47]=[C:46]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:25])([CH3:24])[CH2:15][OH:16])[CH:6]=[C:5]4[CH2:26][N:27]3[CH2:28][CH2:29][N:30]([CH2:33][CH2:34][CH2:35][OH:36])[CH2:31][CH2:32]3)[C:45]([CH3:57])=[C:44]([F:58])[CH:43]=2)[CH2:38][CH2:39]1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)Cn1cc(CN2CCN(CCCO)CC2)c2cc(Br)ccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC(C)(C)CO)cc(CN3CCN(CCCO)CC3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.4 %

Procedure:
A solution of 6-bromo-2-(3-{[tert-butyl(dimethyl)silyl]oxy}-2,2-dimethylpropyl)-4-{[4-(3-hydroxypropyl)piperazin-1-yl]methyl}isoquinolin-1(2H)-one (Example 32a, 1.0 g), N-cyclopropyl-3-fluoro-4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.165 g), potassium carbonate (0.143 g) and Pd-118 (0.034 g) was stirred in DMF (10 mL) at 80° C. under nitrogen for 2 h. The reaction was cooled, diluted with saturated brine and extracted into ethyl acetate (3×30 mL), the combined extracts were washed with brine (3×30 mL), dried, (MgSO4) filtered and evaporated. The residue was dissolved in DCM (20 mL), treated with trifluoroacetic acid (3 mL) and stirred at room temperature for 3 h, evaporated and purified by preparative HPLC (Waters Xbridge column using a 95-5% gradient of aqueous 0.2% ammonia in acetonitrile as eluent) to give the title compound (0.052 g) as a solid.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C@H:17]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18]2)=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCOC(C)=O.[BH4-].[Na+]>CCO.CCCCCCC>[CH2:1]([O:8][C:9](=[O:23])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C@H:17]2[CH2:21][CH2:20][CH:19]([OH:22])[CH2:18]2)=[CH:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC[C@H](c2ccc(NC(=O)OCc3ccccc3)cc2)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CCO
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc([C@H]2CCC(O)C2)cc1)OCc1ccccc1
Yield: 99.6 %

Procedure:
[4-((S)-3-Oxo-cyclopentyl)-phenyl]-carbamic acid benzyl ester (150 mg, 0.5 mmol) was dissolved in EtOH (1 mL) and EtOAc (0.1 mL) to form a clear solution. To this solution was added powder NaBH4 (50 mg) with stirring. The reaction was judged to be complete by TLC (30% EtOAc in heptane). The reaction was quenched by EtOAc (2 mL) and NaHCO3 aq. solution (2 mL). The two layers were separated and the aqueous layer was extracted with EtOAc (2×2 mL). The combined extracts were washed with NaHCO3 aq. (2 mL), brine (2 mL), and dried (K2CO3). The solution was filtered through a silica gel pad, eluted with EtOAc. The filtrate was concentrated to dryness to afford 155 mg (100%) of the title compound as a very white crystalline material. mp 99.0-100.6° C.
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:18])[NH:5][C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2].S(OC)(O[CH3:23])(=O)=O>[OH-].[Na+]>[C:1]([C:3]1[C:4](=[O:18])[N:5]([CH3:23])[C:6](=[O:17])[N:7]([C:9]2[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:16])[CH:8]=1)#[N:2]
Reactant: COS(=O)(=O)OC
Reactant: Cc1cccc(C)c1-n1cc(C#N)c(=O)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Product: Cc1cccc(C)c1-n1cc(C#N)c(=O)n(C)c1=O

Procedure:
To a mixture of 5-cyano-1-(2,6-dimethylphenyl)uracil (0.1 mol) and 80 ml of five percent sodium hydroxide solution, with stirring, is slowly added dimethyl sulfate (0.1 mol). The reaction mixture is stirred for about 2 hours and then filtered, washed with water and dried to yield 5-cyano-1-(2,6-dimethylphenyl)-3-methyluracil, m.p. 198.2°-199.5°.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][O:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].BrN1C(=[O:20])CCC1=O>C(Cl)(Cl)(Cl)Cl>[OH:20][CH:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[C:10](=[O:13])[O:9]1
Reactant: O=C1CCC(=O)N1Br
Reactant: O=C1OCc2ccc([N+](=O)[O-])cc21
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1OC(O)c2ccc([N+](=O)[O-])cc21

Procedure:
A mixture of 6-nitro-1(3H)-isobenzofuranone (8.99 g, 50.0 mmol) and N-bromosuccinimide (8.9 g, 50.0 mmol) in carbon tetrachloride (135 mL) was stirred and heated under reflux for one hour during which time the reaction mixture was exposed to the light from a 275 Watt, 125 Volt Hanovia sunlamp that was situated 8 inches from the flask. After cooling, the succinimide was removed by filtration, and the filtrate was evaporated in vacuo. The oily residue was mixed with water (200 mL), and the mixture was refluxed for one hour to give a clear, colorless solution. On cooling, the Compound 3a crystallized from solution. An analytical sample was prepared by recrystallization from water; m.p. 157°-160° C.; IR 3390 cm-1 (OH), 1770 cm-1 (C=O), 1H NMR (CDCl3 -Me2SO-d6 -D2O) δ6.78 (s, br, 1H, H3), 7.88 (d, 1H, H4, J4,5 =9 Hz), 8.56 (d, 1H, H5, J=9 Hz), 8.62 (s, 1H, H6).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4]([C:7](=[O:14])[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:3][CH:2]=1.[Br:16]Br>C(Cl)(Cl)(Cl)Cl>[Br:16][CH:8]([C:7]([C:4]1[CH:3]=[CH:2][C:1]([CH3:15])=[CH:6][CH:5]=1)=[O:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)CC(=O)c1ccc(C)cc1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)C(Br)C(=O)c1ccc(C)cc1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
20.4 g of ethyl 3-p-tolyl-3-oxopropionate (Helv. Chim. Acta 57, 2205 (1974)) are dissolved in 20 ml of CCl4. A solution of 6 ml of bromine in 30 ml of CCl4 is added dropwise at -5° C. After 1 hour at -5° C., the mixture is stirred at 20° C. for 3 h and then at 60° C. for 1 h. the solvent is removed. The title compound is used further as crude product; yield 34 g.
Reaction SMILES: Cl.[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8]([CH2:13][NH2:14])[CH2:7][CH2:6]2.[CH2:15]([O:22][C:23](Cl)=[O:24])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[OH-].[Na+]>O1CCCC1>[I:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][C@@H:8]([CH2:13][NH:14][C:23](=[O:24])[O:22][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2
Reactant: O=C(Cl)OCc1ccccc1
Reactant: NC[C@H]1CCc2cc(I)ccc2O1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC[C@H]1CCc2cc(I)ccc2O1)OCc1ccccc1
Reaction time: 1 h
Yield: 99.2 %

Procedure:
To a mixture of (R)-6-iodo-chroman-2-methylamine hydrochloride of Example 10 (3.3 g, 10 mmol) and benzylchloroformate (1.57 mL, 11 mmol) in tetrahydrofuran (30 mL) cooled in an ice-water bath was added slowly 1N aqueous sodium hydroxide in 20 minutes. The resulting mixture was stirred for 1 hour. The organic layer was separated and concentrated in vacuo. The aqueous layer was extracted with ethyl acetate (50 mL×2). The combined ethyl acetate layer was combined with the above residue and washed with water (50 mL), brine (50 mL), and dried over anhydrous sodium sulfate. Removal of the solvent in vacuo afforded the crude product as a white solid (4.2 g, 99%). 1H nmr (DMSO d6) δ 1.5-1.6 (m, 2H), 1.9-2.0 (m, 1H), 2.7 (m, 2H), 3.3 (m, 2H), 4.0 (m, 1H), 5.0 (s, 2H), 6.5 (d, 1H), 7.3 (m, 7H), 7.5 (t, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1F
Yield: 48.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (60 mg, 0.094 mmol) was hydrolyzed with lithium hydroxide (20 mg, 0.474 mmol) in THF/methanol/water (15/5/5 mL) to yield 22 mg (48.8% yield). 1H NMR (CD3OD, 400 MHz): δ 8.467-8.462 (d, 1H), 8.36-8.35 (d, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.84-7.80 (dd, 1H), 7.63-7.57 (m, 1H), 7.44-7.32 (m, 2H), 7.16-7.12 (d, 1H), 7.10-7.02 (m, 2H). MS: m/z=480.3 (M+1), HPLC: 92.50% in method B.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[Cl:14][C:15]1[N:20]=[N:19][C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)=[C:17]([OH:32])[CH:16]=1.Cl>O>[Br:1][C:16]1[C:17]([OH:32])=[C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)[N:19]=[N:20][C:15]=1[Cl:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
108 mg (0.607 mmol) of N-bromosuccinimide was added to a N,N-dimethylformamide (2 mL) solution containing 157 mg (0.567 mmol) of 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-4-pyridazinol, and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Water, and then, 4 mol/L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO. 1.05744, developed by hexane:ethyl acetate=2:1) to obtain 123 mg (0.346 mmol, Yield: 61.0%) of 5-bromo-6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3843).
Reaction SMILES: [C:1]1([C:14]([OH:16])=[O:15])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]([OH:13])=O)=[CH:3][CH:2]=1.[NH2:17][CH2:18][C@@H:19]([OH:36])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:28]2[CH:33]=[CH:32][C:31]([Cl:34])=[C:30]([Cl:35])[CH:29]=2)[CH2:23][CH2:22]1.C(N(CC)CC)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN1CCCC1=O>[Cl:35][C:30]1[CH:29]=[C:28]([CH:33]=[CH:32][C:31]=1[Cl:34])[O:27][CH:24]1[CH2:23][CH2:22][N:21]([CH2:20][C@H:19]([OH:36])[CH2:18][NH:17][C:11]([C:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[C:1]([C:14]([OH:16])=[O:15])=[CH:2][CH:3]=2)=[O:13])[CH2:26][CH2:25]1
Reactant: O=C(O)c1ccc(C(=O)O)c2ccccc12
Reactant: NC[C@@H](O)CN1CCC(Oc2ccc(Cl)c(Cl)c2)CC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN1CCCC1=O
Product: O=C(O)c1ccc(C(=O)NC[C@@H](O)CN2CCC(Oc3ccc(Cl)c(Cl)c3)CC2)c2ccccc12
Reaction time: 16 h
Yield: 21 %

Procedure:
To a solution of naphthalene-1,4-dicarboxylic acid (0.100 g), (2R)-1-amino-3-[4-(3,4-dichlorophenoxy)piperidin-1-yl]propan-2-ol (0.147 g) and triethylamine (0.193 mL) in N-methyl-2-pyrolidinone (20 mL) was added PyBrOP (0.258 g). The reaction mixture was stirred for 16 h and the solvent was removed in vacuo. The residue was purified by RPHPLC (Symmetry, 0.1% ammonium acetate/acetonitrile) to afford the title compound as a colourless solid (0.050 g, 20%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)OCC[O:10]2)=[CH:5][CH:4]=1>C1COCC1>[CH3:2][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[O:10])[CH2:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[CH:7][CH:8]=1
Reactant: Cc1ccc(C2(CCCOCCc3ccccc3)OCCO2)cc1
Agent: Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CCCOCCc2ccccc2)cc1

Procedure:
This compound was synthesized as described under 5.c) with 2.3 ml of HCl (1N), 2.05 g (6.3 mmol) of 2-(4-methylphenyl)-2-[3-(phenylethoxy)propyl]-1,3-dioxolane obtained under a) in 50 ml of THF for 3 h to give 1.81 g (99%) of a slightly yellow oil that solidifies at 4° C.
Reaction SMILES: [CH2:1]([C:3]1[NH:4][C:5](=[O:27])[C:6]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:15][CH:14]=2)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=1)[CH3:2].[C:28]([O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)([CH3:31])([CH3:30])[CH3:29].C(N(CC)CC)C.N1C=CC=CC=1>ClCCl.C(OCC)(=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:28]([O:32][C:33]1[CH:38]=[CH:37][C:36]([N:4]2[C:5](=[O:27])[C:6]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:20]([C:25]#[N:26])=[CH:21][CH:22]=[CH:23][CH:24]=4)=[CH:15][CH:14]=3)=[C:7]([CH2:9][CH2:10][CH3:11])[N:8]=[C:3]2[CH2:1][CH3:2])=[CH:35][CH:34]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CCCc1nc(CC)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(C)(C)Oc1ccc(B(O)O)cc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nc(CC)n(-c2ccc(OC(C)(C)C)cc2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reaction time: 48 h
Yield: 66.4 %

Procedure:
To a suspension of 4′-[(2-ethyl-6-oxo-4-propyl-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (0.5 g), 4-tert-butoxyphenylboronic acid (0.54 g), triethylamine (0.97 mL), pyridine (0.57 mL) and molecular sieves 4 A (1 g) in dichloromethane (10 mL) was added copper(II) acetate (0.51 g), and the mixture was stirred for 2 days. The reaction mixture was diluted with ethyl acetate, the insoluble material was filtered off through celite, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.47 g, 66%).
Reaction SMILES: [OH-:1].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.OO>O.C(O)C>[N:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[CH:22]=[CH:21][C:18]([C:19]([NH2:20])=[O:1])=[CH:17][CH:16]=3)[CH2:11][CH2:10]2)=[CH:7][CH:8]=1
Reactant: N#Cc1ccc(N2CCN(c3ccncc3)CC2)cc1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: NC(=O)c1ccc(N2CCN(c3ccncc3)CC2)cc1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A solution of sodium hydroxide (1.0 g) in water (5 ml) was added to a solution of the product of (i) above (1.0 g) in ethanol (10 ml), followed by 30% hydrogen peroxide solution (2.5 ml). The mixture was stirred at 50° C. for 1.5 hours, at room temperature for 1 hour and then evaporated. The residue was triturated with water, the mixture was filtered and the solid was crystallised from n-propanol/water to give the title compound (0.28 g), m.p. 327°-330° C. Found: C,68.31; H,6.59; N,19.78. C16H18N4O requires: C,68.09; H,6.43; N,19.85%.
Reaction SMILES: [C:1]([C:3]1[N:11]=[CH:10][C:9]2[N:8](COCC[Si](C)(C)C)[C:7]3[N:20]=[CH:21][CH:22]=[C:23]([N:24]4[CH2:29][CH2:28][CH2:27][C@H:26]([N:30]([CH2:38][CH3:39])C(=O)OC(C)(C)C)[CH2:25]4)[C:6]=3[C:5]=2[CH:4]=1)#[N:2].Br.[OH-].[Na+].Cl>O1CCOCC1>[CH2:38]([NH:30][C@H:26]1[CH2:27][CH2:28][CH2:29][N:24]([C:23]2[C:6]3[C:5]4[CH:4]=[C:3]([C:1]#[N:2])[N:11]=[CH:10][C:9]=4[NH:8][C:7]=3[N:20]=[CH:21][CH:22]=2)[CH2:25]1)[CH3:39]
Reactant: CCN(C(=O)OC(C)(C)C)[C@H]1CCCN(c2ccnc3c2c2cc(C#N)ncc2n3COCC[Si](C)(C)C)C1
Agent: Br
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Product: CCN[C@H]1CCCN(c2ccnc3[nH]c4cnc(C#N)cc4c23)C1
Temperature: 75 °C
Yield: 62.4 %

Procedure:
(S)-tert-butyl 1-(6-cyano-9-((2-(trimethylsilyl)ethoxy)methyl)-9H-dipyrido[2,3-b;4′,3′-d]pyrrol-4-yl)piperidin-3-yl(ethyl)carbamate (90 mg, 0.15 mmol) was dissolved in 1,4-dioxane (0.3 mL) and then treated with 48% HBr(aq) (0.3 mL) and heated at 75° C. for 15 minutes. The cooled reaction mixture was then basified to pH ˜12 by dropwise addition of 6N sodium hydroxide and then immediately acidified to pH ˜8-9 by dropwise addition of concentrated hydrochloric acid, producing a cloudy precipitate. The solid was collected by centrifugation, dissolved in dimethylsulfoxide (2 mL), and purified by preparative HPLC [5-85% methanol in water (0.1% ammonium hydroxide) over 30 min, 35 mL/min] to afford the title compound as a white solid (30 mg, 40% over two steps). 1H NMR (500 MHz, d6-DMSO) δ 8.94 (s, 1H), 8.45-8.39 (m, 2H), 6.87 (d, J=5.6, 1H), 3.71 (d, J=11.1, 1H), 3.51 (d, J=12.0, 1H), 3.08-2.99 (m, 1H), 2.99-2.90 (m, 1H), 2.80-2.72 (m, 1H), 2.72-2.66 (m, 1H), 2.62 (m, 1H), 2.01 (m, 1H), 1.93 (m, 1H), 1.78 (m, 1H), 1.37 (m, 1H), 1.05 (t, J=7.1, 3H), NH signal not observed. LCMS (Method E): RT=2.576 min, M+H+=321.1.
Reaction SMILES: COC1C=CC(C[N:8]2[C:12](=[O:13])[CH2:11][N:10]([CH2:14][C:15]3[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=3)[S:9]2(=[O:22])=[O:21])=CC=1.[C:25]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:26]>C([SiH](CC)CC)C.O>[OH:31][C:25]([C:27]([F:30])([F:29])[F:28])=[O:26].[O:22]=[S:9]1(=[O:21])[N:10]([CH2:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH2:11][C:12](=[O:13])[NH:8]1
Reactant: COc1ccc(CN2C(=O)CN(Cc3ccncc3)S2(=O)=O)cc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: O=C1CN(Cc2ccncc2)S(=O)(=O)N1
Temperature: 80 °C

Procedure:
The title C compound, 2-(4-methoxybenzyl)-1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one (73 mg, 0.21 mmol) in a mixture of TFA (4.75 mL) and triethylsilane (0.25 mL) in a 20 mL scintillation vial with polyseal cap is heated in an 80° C. oil bath for 16 h. The reaction solvents are removed by overnight evaporation on a Savant SpeedVac system. This gives a white solid which is dissolved in water, filtered through a 0.45 micron PTFE filter disc, and water is removed by lyophilization to give 1,1-dioxo-5-pyridin-4-ylmethyl-1,2,5-thiadiazolidin-3-one TFA salt as an amorphous white solid: [M+1]+=228.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][OH:10])[CH3:2].[CH3:11][N:12]([S:16][C:17]([Cl:20])([Cl:19])[Cl:18])[C:13](F)=[O:14].C(N(CC)CC)C>O1CCOCC1.O>[CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][O:10][C:13](=[O:14])[N:12]([CH3:11])[S:16][C:17]([Cl:20])([Cl:19])[Cl:18])[CH3:2]
Reactant: CCN1C(=O)CSC1=NO
Reactant: CN(SC(Cl)(Cl)Cl)C(=O)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCN1C(=O)CSC1=NOC(=O)N(C)SC(Cl)(Cl)Cl
Reaction time: 0.42 h

Procedure:
To a solution of 1.74 g, 3-ethyl-2-oximino-4-thiazolidinone in 25 ml of dioxane cooled to 20°C was added to a solution 2.53 g of N-methyl-N-(trichloromethanesulfenyl) carbamyl fluoride in 25 ml dioxane. To this mixture was added dropwise with external cooling 1.37 g of triethylamine. After stirring for 25 minutes the solution was diluted with 150 ml of water. The solid product was filtered off, dissolved in ethylacetate, dried and concentrated. Crystallized from acetone. Weight 2.8 g., m.p. 126°-128°C.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)=[CH:7][C:6]=1[C:21]1[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=1.Cl.[F:28][C:29]1([F:35])[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:28][C:29]1([F:35])[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][O:4][C:5]2[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=3)=[CH:7][C:6]=2[C:21]2[N:22]([CH3:26])[N:23]=[CH:24][CH:25]=2)[CH2:31][CH2:30]1
Reactant: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCBr
Reactant: FC1(F)CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cn1nccc1-c1cc(NC(=O)c2cccc(F)c2)ccc1OCCN1CCC(F)(F)CC1
Temperature: 120 °C
Yield: 17.4 %

Procedure:
A mixture of N-[4-(2-bromo-ethoxy)-3-(2-methyl-2H-pyrazol-3-yl)-phenyl]-3-fluoro-benzamide (104 mg, 0.25 mmol), 4,4-difluoropiperidine hydrochloride (43 mg, 0.275 mmol) and potassium carbonate (103 mg, 0.75 mmol) in DMF (2 mL) was heated in microwave at 120° C. for 20 min. The crude was purified by HPLC to give the title compound (20 mg, 18%) as a white solid as TFA salt. 1H NMR (DMSO-d6, 400 MHz) δ 2.10-2.23 (m, 4H), 3.10-3.40 (m, 4H), 3.57 (t, 2H), 3.68 (s, 3H), 4.37 (t, 2H), 6.30 (d, 1H), 7.25 (d, 1H), 7.45 (dt, 1H), 7.50 (d, 1H), 7.57-7.62 (m, 1H), 7.72 (d, 1H), 7.74-7.82 (m, 2H), 7.89 (dd, 1H), 10.3 (s, 1H). Exact mass calculated for C24H25F3N4O2 458.2, found 459.4 (MH+).