Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]([CH2:15][CH3:16])[C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([SH:13])[N:7]=[C:6]([CH3:14])[N:5]=1)[CH3:2].[Sn].[OH-].[Na+]>Cl>[NH2:10][C:9]1[C:4]([N:3]([CH2:1][CH3:2])[CH2:15][CH3:16])=[N:5][C:6]([CH3:14])=[N:7][C:8]=1[SH:13]
Reactant: CCN(CC)c1nc(C)nc(S)c1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCN(CC)c1nc(C)nc(S)c1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5 g of the crystals of 4-diethylamino-6-mercapto-2-methyl-5-nitropyrimidine and 7.0 g of metal tin were mixed well, and 50 ml of concentrated hydrochloric acid was slowly added to the mixture under cooling. After the addition, the reaction mixture was stirred at room temperature for 3 hours. Then 3N solution of sodium hydroxide was added to the mixture, while cooling with ice, and the pH of the mixture was adjusted to 8-9 to obtain an oily substance. The oily substance was extracted with 200 ml of ethyl acetate, and the organic layer was dried over magnesium sulphate anhydride. Then the solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixture of chloroform and n-hexane to obtain crystals of 5-amino-4-diethylamino-6-mercapto-2-methylpyrimidine (3.9 g).
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]12[CH2:15][CH2:14][C:11]([C:16]3[CH:21]=[C:20]([O:22][CH:23]4[CH2:28][CH2:27][CH2:26][CH2:25][O:24]4)[CH:19]=[C:18]([F:29])[CH:17]=3)([CH2:12][CH2:13]1)[O:10][CH2:9]2)(=O)=O.[C-:30]#[N:31].[Na+]>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].CS(C)=O.CCOC(C)=O>[F:29][C:18]1[CH:17]=[C:16]([C:11]23[CH2:14][CH2:15][C:8]([CH2:7][CH2:6][C:30]#[N:31])([CH2:13][CH2:12]2)[CH2:9][O:10]3)[CH:21]=[C:20]([O:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)[CH:19]=1
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: N#CCCC12CCC(c3cc(F)cc(OC4CCCCO4)c3)(CC1)OC2
Temperature: 85 °C
Reaction time: 18 h
Yield: 92.2 %

Procedure:
A mixture of 2-(1-(3-fluoro-5-((tetrahydro-2H-pyran-2-yl)oxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethyl methanesulfonate (0.45 g, 1.05 mmol), NaCN (0.309 g, 6.30 mmol), and Bu4NI (0.039 g, 0.105 mmol) in DMSO (10 mL) was stirred at 85° C. for 18 h, then was cooled to rt and diluted with EtOAc (10 mL). The organic phase was washed with water (3×), dried (MgSO4), filtered, and concentrated in vacuo. The residual crude oil was chromatographed (SiO2; gradient from 0% to 30% EtOAc/hexane over 10 min) to give the title compound (0.348 g, 0.968 mmol, 92% yield) as a clear oil. 1H NMR (CDCl3) δ: 6.86 (t, J=1.8 Hz, 1H), 6.74 (dt, J=10.1, 1.9 Hz, 1H), 6.69 (dt, J=10.6, 2.3 Hz, 1H), 5.40 (t, J=3.2 Hz, 1H), 3.93-3.86 (m, 1H), 3.85-3.81 (m, 2H), 3.62 (dtd, J=11.4, 4.1, 1.4 Hz, 1H), 2.32 (dd, J=8.6, 7.3 Hz, 2H), 2.07-1.96 (m, 4H), 1.88-1.80 (m, 2H), 1.79-1.55 (m, 10H); 19F NMR (CDCl3) δ: −111.9.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]([O:8]CC)=O.[CH2:11]([NH2:14])[CH2:12][NH2:13]>C1(C)C=CC=CC=1>[NH2:13][CH2:12][CH2:11][NH:14][C:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)=[O:8]
Reactant: NCCN
Reactant: CCOC(=O)c1cccs1
Solvent: Cc1ccccc1
Product: NCCNC(=O)c1cccs1

Procedure:
A mixture of ethyl thiophene-2-carboxylate (12.0 g.) and ethylenediamine (15.4 ml.) was heated at 95°-100° C. for 48 hours. Excess ethylenediamine was removed under reduced pressure and the residue was dissolved in water (150 ml.). The insoluble material [bis(carboxamide)derivative] was removed by filtration. Evaporation of the filtrate gave a residue which was dissolved in toluene (50 ml.). The mixture was evaporated to give N-(2-aminoethyl)-thiophene-2-carboxamide as an oil (12.0 g.) essentially pure by TLC (Rf 0.90; SiO2 : 10% v/v methanol in chloroform as eluant) which was used without purification.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].O.[CH:8](/[C:17]1[C:26]([CH3:27])=[C:25]([O:28]C(=O)C)[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]>CO>[CH:8](/[C:17]1[CH:26]([CH3:27])[C:25](=[O:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[CH:9]/[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCC/C=C\c1nc2ccccc2c(OC(C)=O)c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCC/C=C\C1=Nc2ccccc2C(=O)C1C
Temperature: 25 °C
Reaction time: 13 h
Yield: 85.3 %

Procedure:
205 mg (1.49 mmols) of potassium carbonate and 2 ml of water were added to a solution of 483 mg (1.49 mmols) of 2-(cis-1-nonenyl)-3-methyl-4-acetoxyquinoline, 1 ml of water and 30 ml of methanol and stirred at room temperature for 13 hours. Thereafter, the solution was treated and purified in the same manner as in Example 2 to obtain 360 mg (yield 86%) of 2-(cis-1-nonenyl)-3-mehtyl-4-quinolone.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=O)[CH:8]([CH2:14][C:15]([OH:17])=O)[CH2:7][CH2:6]2)#[N:2].O.[NH2:19][NH2:20]>C(O)(=O)C>[C:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:9]3[CH:8]([CH2:14][C:15](=[O:17])[NH:19][N:20]=3)[CH2:7][CH2:6][C:5]=2[CH:4]=1)#[N:2]
Reactant: NN
Reactant: N#Cc1ccc2c(c1)CCC(CC(=O)O)C2=O
Solvent: CC(=O)O
Solvent: O
Product: N#Cc1ccc2c(c1)CCC1CC(=O)NN=C21

Procedure:
A solution of 6-cyano-1-oxo-1,2,3,4-tetrahydro-2-naphthyl acetic acid (5.0 g) in 50% hot aqueous acetic acid was treated with hydrazine hydrate (1.0 ml ) and heated under reflux for 2 hours. The precipitated solid was filtered off and washed with water to give 8-cyano-4,4a,5,6-tetrahydrobenzo[h]cinnolin-3[2H]-one (1.2 g; m.p. 292°-5°); ν(Nujol mull) 3500, 3225, 2225, 1685, 1615, and 1586; δ(DMSO-d6) 1.55 (1H,m,5-H), 2.14 (1H,m,5-H) 2.40 (2H,m,4-H), 2.78 (3H,m,4a,6-H), 7.65 (lH,m,9-H), 7.71 (lH, s, 7-H), 8.12 (1H,d,10-H), 11.04 (1H,s,NH).
Reaction SMILES: [NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23](C4NC=CN=4)=[O:24])[CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1.[NH:36]1[CH2:39][CH2:38][CH2:37]1>C1COCC1>[NH2:1][C:2]1[C:31]([Cl:32])=[CH:30][C:5]([C:6]([NH:8][CH2:9][C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][CH:17]3[CH2:22][CH2:21][N:20]([C:23]([N:36]4[CH2:39][CH2:38][CH2:37]4)=[O:24])[CH2:19][CH2:18]3)[CH2:11]2)=[O:7])=[C:4]([O:33][CH2:34][CH3:35])[CH:3]=1
Reactant: C1CNC1
Reactant: CCOc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CN(CC2CCN(C(=O)c3ncc[nH]3)CC2)CCO1
Solvent: C1CCOC1
Product: CCOc1cc(N)c(Cl)cc1C(=O)NC[C@H]1CN(CC2CCN(C(=O)N3CCC3)CC2)CCO1
Temperature: 25 °C
Yield: 41.1 %

Procedure:
A solution of (S)-4-amino-5-chloro-2-ethoxy-N-[{4-[(1-imidazolecarbonyl-4-piperidinyl)-methyl]-2-morpholinyl}methyl]benzamide (Example 206) (1.07 g) and azetidine (0.25 g) in THF (15 ml) was heated to reflux for 19 hours with stirring. After cooling to room temperature, the reaction solution was dried under reduced pressure to be solidified, and the residue was purified by silica gel column chromatography (eluent: chloroform/methanol=10/1) to give the titled compound (0.43 g) as a white solid. Melting point 166-168° C. (recrystallized from EA/H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:13]3[CH:14](O)[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]2[CH2:20][CH2:19]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][C:24]([CH:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[O:25])[CH3:22].CP(C)C.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1(C)C=CC=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:13]3[CH:14]([C:26]([C:32]([O:34][CH2:35][CH3:36])=[O:33])([C:24]([O:23][CH2:21][CH3:22])=[O:25])[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH2:15][CH2:16][C:12]=3[N:11]=[C:10]2[CH:18]2[CH2:20][CH2:19]2)=[CH:6][CH:7]=1
Reactant: OC1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)OCC
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: CP(C)C
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)OCC)(C(=O)OCC)C1CCc2nc(C3CC3)n(Cc3ccc(Cl)cc3)c21
Temperature: -78 °C
Reaction time: 0.75 h

Procedure:
To a solution of Intermediate 30 (95 mg) and triethylmethanetricarboxylate (0.140 ml) in toluene (1.5 ml) and tetrahydrofuran (1.5 ml), stirred at RT under an inert atmosphere of nitrogen, was added trimethylphosphine, 1M in toluene (0.658 ml). The resulting solution was cooled to −78° C. and diisopropyl azodicarboxylate (0.130 ml) was added dropwise via syringe and the reaction was stirred at −78° C. for 45 mins. The reaction mixture was removed from the cold bath and allowed to warm to RT and stirred under N2 atmosphere overnight. Reaction mixture concentrated in vacuo. The residue was taken up in DCM (20 ml) and washed with water (20 mL). The 2 phases were separated, the organic extract was dried (hydrophobic frit) and concentrated under vacuum. The residue was purified on silica using a cyclohexane:ethyl acetate 0-100% gradient. The desired fractions were combined and concentrated under vacuum to give the title compound (146 mg). LC/MS MH+503, Rt 3.37 min (5 minute run).
Reaction SMILES: [CH2:1]([N:4]1[C@H:9]([CH3:10])[CH2:8][N:7]([C@@H:11]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@@H:6]([CH3:24])[CH2:5]1)[CH:2]=[CH2:3].C1(C)C=CC(C([C@@](C(O)=O)(O)[C@@](C(C2C=CC(C)=CC=2)=O)(O)C(O)=O)=O)=CC=1>C(O)C>[CH2:1]([N:4]1[C@@H:9]([CH3:10])[CH2:8][N:7]([C@H:11]([C:19]2[CH:23]=[CH:22][S:21][CH:20]=2)[C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)[C@H:6]([CH3:24])[CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCN1C[C@H](C)N([C@@H](c2ccsc2)c2cccc(O)c2)C[C@H]1C
Agent: Cc1ccc(C(=O)[C@](O)(C(=O)O)[C@@](O)(C(=O)O)C(=O)c2ccc(C)cc2)cc1
Solvent: CCO
Product: C=CCN1C[C@@H](C)N([C@H](c2ccsc2)c2cccc(O)c2)C[C@@H]1C
Yield: 7.7 %

Procedure:
(±)-3-((R*)-((2S*,5R*)-4-Allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol (2.74 g, 8.0 mmol, Example 63) was added to a solution of 6.18 g (16 mmol) of (-)-di-p-toluoyl-L-tartaric acid in 20 mL of absolute ethanol. The mixture was warmed to complete solution, cooled and allowed to crystallize at room temperature. After four recrystallizations, the salt was dissolved in 20 mL of 1N aqueous sodium hydroxide, and the solution was titrated to pH 8 with 6N hydrochloric acid. The precipitated amine was collected by filtration and recrystallized from absolute ethanol to give 0.21 g of (-)-3-((S)-((2R,5S)-4-allyl-2,5-dimethyl-1-piperazinyl)(3-thienyl)methyl)phenol as white crystals, mp 193°-194° C. [α]D20 =-3.2° (ethyl acetate, c=1.4). HPLC on β-cyclodextrin with methanoh0.1M ammonium acetate/1:1 gave one peak at tR =7.8 min. Calc. for C20H26N2OS: C, 70.14; H, 7.65: N, 8.18: S, 9.36. Found: C, 70.24; H, 7.69; N, 8.23; S, 9.42.
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH2:12][C@H:11]([OH:15])[CH2:10]3)[S:8][C:4]=2[CH:3]=1.ClCCl.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30]>C(OCC)C>[CH3:28][S:29]([O:15][C@H:11]1[CH2:12][CH2:13][CH2:14][N:9]([C:7]2[S:8][C:4]3[CH:3]=[C:2]([Br:1])[CH:17]=[CH:16][C:5]=3[N:6]=2)[CH2:10]1)(=[O:31])=[O:30]
Reactant: CS(=O)(=O)Cl
Reactant: O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CS(=O)(=O)O[C@H]1CCCN(c2nc3ccc(Br)cc3s2)C1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
In a 20 mL scintillation vial equipped with a magnetic stirbar was added (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-ol (Reference Example 7, 1.15 g, 3.67 mmol). Dichloromethane (10 mL) was then added to the reaction vial to give a solution. To this stirred solution was added 2.5 equivalents of triethylamine (1.279 mL, 9.18 mmol). The reaction vial was capped with a septum and vented to a bubbler. The vial was placed in an ice water bath. To this stirred, 0° C. solution was added dropwise 2.0 equivalents of methanesulfonyl chloride (0.572 mL, 7.34 mmol). The reaction mixture was stirred for 10 minutes at 0° C., then the ice bath was removed and stirring was continued at room temperature overnight. The reaction mixture was washed with water, then dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give an oil that was purified by column chromatography on an Analogix IntelliFlash-280 (Analogix SF10-4g [2 connected in series], 100% dichloromethane). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was treated with diethyl ether. This suspension was filtered to collect (S)-1-(6-bromobenzo[d]thiazol-2-yl)piperidin-3-yl methanesulfonate. 1H NMR (300 MHz, CDCl3) δ ppm 1.68-1.81 (m, 1H), 1.94-2.16 (m, 3H), 3.06 (s, 3H), 3.51-3.68 (m, 2H), 3.85-3.90 (m, 2H), 4.86-4.93 (m, 1H), 7.37-7.39 (m, 2H), 7.69-7.71 (m, 1H); MS (DCI/NH3) m/z 391 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[I-:19].[NH4+].OO>C(O)(=O)C>[NH2:1][C:2]1[C:3]([I:19])=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:14])([F:15])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: [I-]
Agent: OO
Agent: [NH4+]
Solvent: CC(=O)O
Product: C[C@]1(c2cc(N)c(I)cc2F)N=C(N)OCC1(F)F
Reaction time: 8 h

Procedure:
A solution of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate A8.5) (500 mg, 1.9 mmol) and ammonium iodide (308 mg, 2.1 mmol) in acetic acid (9.6 ml) was treated at room temperature with an aqueous solution of hydrogen peroxide (35%, 0.19 ml, 2.1 mmol). After stirring overnight 50% of the starting material was left. Another equivalent of ammonium iodide and hydrogen peroxide was added and stirring continued at room temperature overnight. For the workup, the reaction mixture was filtered, the filtrate treated with sodium thiosulphate, then extracted with ethyl acetate (3×). The combined organic layers were washed with a saturated solution of sodium hydrogen carbonate, then dried over sodium sulphate and evaporated at reduced pressure. In order to eliminate residual acetic acid, the crude product was dissolved in dichloromethane and extracted again with a saturated solution of sodium hydrogen carbonate. The crude product was purified by chromatography on an Isolute flash NH2 column using a gradient of heptane/ethyl acetate=100/0 to 0/100 as the eluent. The (R)-4-(5-amino-2-fluoro-4-iodo-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine was obtained as a yellow solid (415 mg, 56% of theory). MS (ISP): m/z=386.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:14]([O:16][C:17](=[O:26])[C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[C:20](Br)[CH:19]=1)[CH3:15].C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([C:17]([O:16][CH2:14][CH3:15])=[O:26])[CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cc(Br)ccc1Cl
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(N2CCN(C(=O)OC(C)(C)C)CC2)ccc1Cl
Temperature: 100 °C
Yield: 97.2 %

Procedure:
Piperazine-1-carboxylic acid tert-butyl ester (106 mg), 3-bromo-6-chlorobenzoic acid ethyl ester (125 mg), cesium carbonate (220 mg), palladium acetate (5 mg) and R-BINAP (22 mg) were combined in toluene (2 ml) and heated at 100° C. in a sealed vessel for 48 hr. The cooled reaction was loaded onto a silica column and eluted with iso-hexane/ethyl acetate (4:1) to give the subtitle product (170 mg).
Reaction SMILES: Br[C:2]1[C:18](=[O:19])[N:17]([CH:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C:5]2[N:6]=[C:7]([NH:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[CH3:25][O:26][C:27]1[N:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:20]1([N:17]2[C:5]3[N:6]=[C:7]([NH:11][CH2:12][C:13]([OH:16])([CH3:15])[CH3:14])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:30]3[CH:31]=[N:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=3)[C:18]2=[O:19])[CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: COc1ccc(B(O)O)cn1
Reactant: Cc1nc(NCC(C)(C)O)nc2c1cc(Br)c(=O)n2C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(-c2cc3c(C)nc(NCC(C)(C)O)nc3n(C3CCCC3)c2=O)cn1
Temperature: 110 °C
Yield: 44.2 %

Procedure:
To a solution of 6-bromo-8-cyclopentyl-2-(2-hydroxy-2-methylpropylamino)-4-methyl-pyrido[2,3-d]pyrimidin-7(8H)-one (50 mg, 0.126 mmol), 6-methoxypyridin-3-ylboronic acid (21 mg, 0.137 mmol), potassium carbonate (3 M, 0.06 mL) in DMF (1.2 mL) was added dichlorobis(triphenylphosphine)palladium(II) (4.5 mg, 0.0064 mmol). The mixture was degassed with N2, sealed and heated for 30 min at 110° C. The solvent was removed under reduced pressure. The crude mixture was purified by chromatography to give the title compound (23.6 mg, 44%).
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: O=C(Cl)CCl
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CCl)CC4)cc3)n2)n1C(C)C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 1.89 g, 5 mmol), di-isopropylethylamine (0.956 ml, 5.5 mmol) in DCM (25 ml) was treated at 0° C. with chloroacetyl chloride (0.438 ml, 5.5 mmol). The mixture was stirred at ambient for 2 hours, diluted with DCM (25 ml), washed with aqueous saturated sodium bicarbonate solution (20 ml) and aqueous saturated sodium chloride solution (20 ml). The solution was dried and evaporated at reduced pressure to give the title compound, (1.96 g, 87%). NMR (CDCl3) 8.30 (d, 1H), 7.44 (d, 2H), 7.35 (s, 1H), 6.96 (s, 1H), 6.92 (d, 1H), 6.85 (d, 1H), 5.68-5.56 (m, 1H), 4.12 (s, 2H), 3.83-3.76 (m, 2H), 3.72-3.67 (m, 2H), 3.22-3.11 (m, 4H), 2.59 (s, 3H), 1.48 (d, 6H); m/z 454.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:20][NH2:21]>C(Cl)Cl>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]([NH:20][NH2:21])=[O:11])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(Cl)cc1
Reactant: NN
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC(C(=O)NN)c1ccc(Cl)cc1
Reaction time: 0.5 h
Yield: 72.3 %

Procedure:
1,1-Carbonyldiimidazole (1.60 g, 9.89 mmol) was added to a solution of 2-(tert-butoxycarbonylamino)-2-(4-chlorophenyl)acetic acid (2.57 g, 9.00 mmol) in CH2Cl2 (22.5 mL, 9.00 mmol), and the mixture was stirred for 30 minutes until gas evolution ceased. Hydrazine (0.367 mL, 11.7 mmol) was then added to this solution, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was diluted with CH2Cl2 and washed with NaHCO3 (10%). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by reversed-phase chromatography (Biotage SP4, 40+M, C18, 25% to 100% MeCN/H2O). Fractions containing product were poured into a separatory funnel and extracted with ethyl acetate (3×). The combined organic layers were dried and concentrated to give tert-butyl 1-(4-chlorophenyl)-2-hydrazinyl-2-oxoethylcarbamate as a solid (1.95 g, 72%). LCMS (APCI+) M+H+: 299 (5%); M+H+-Boc: 199 (100%); rt=2.78 minutes. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.30 (s, 4H), 5.85 (d, J=6.6 Hz, 1H), 5.21 (s, 1H), 3.87 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([OH:26])=O.Cl.[F:28][C:29]1[CH:34]=[CH:33][C:32]2[C:35]3([CH2:41][O:42][C:31]=2[CH:30]=1)[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]3>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:14]2[N:13]=[CH:12][C:11]=1[C:24]([N:38]1[CH2:39][CH2:40][C:35]2([C:32]3[CH:33]=[CH:34][C:29]([F:28])=[CH:30][C:31]=3[O:42][CH2:41]2)[CH2:36][CH2:37]1)=[O:26]
Reactant: Fc1ccc2c(c1)OCC21CCNCC1
Reactant: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)O)cnc12
Agent: Cl
Product: CCOC(=O)c1cnn2c(Nc3cc(C)ccc3C)c(C(=O)N3CCC4(CC3)COc3cc(F)ccc34)cnc12
Yield: 75.3 %

Procedure:
In the same manner as in Example 21, step 5 and using 7-(2,5-dimethylphenylamino)-3-ethoxycarbonylpyrazolo[1,5-a]pyrimidine-6-carboxylic acid (0.123 g, 0.347 mmol) obtained in Example 88, step 2 and 6-fluoro-2H-spiro[benzofuran-3,4′-piperidine]hydrochloride (0.079 g, 0.382 mmol), the title compound (0.142 g, 76%) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[N:22]=[CH:21][CH:20]=[CH:19][N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ncccn1
Temperature: 100 °C

Procedure:
A mixture of (RS) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.28 g) and 2-chloropyrimidine was heated at 100° C. for 48 hours. After cooling to room temperature the mixture was column chromatographed (silica gel, 0-10% (9:1 methanol/ammonia) in dichloromethane eluant) to give the title compound (0.42 g) as an oil.
Reaction SMILES: [C:1]([S:4][CH:5]1[N:8]([CH:9](O)[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2].S(Cl)([Cl:27])=O>ClCCl>[C:1]([S:4][CH:5]1[N:8]([CH:9]([Cl:27])[C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)=[O:11])[C:7](=[O:24])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)SC1CC(=O)N1C(O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CC(=O)SC1CC(=O)N1C(Cl)C(=O)OCc1ccc([N+](=O)[O-])cc1
Yield: 99 %

Procedure:
A solution of acid 1 (19.36 g), thionyl chloride (40 ml) and dichloromethane (200 ml) was stirred at 23° for 18 h. The solvent and excess thionyl chloride were evaporated in vacuo at 23° to give acid chloride 2 as an off-white solid, 20.5 g (99% yield). ##STR123##
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([OH:35])=[O:34])(=[O:11])=[O:10])[CH:8]=1)#[N:2].[OH-].[Na+:38]>C(O)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([OH:36])=[C:7]([S:9]([NH:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[S:27]([CH3:30])(=[O:29])=[O:28])=[CH:17][C:16]=2[O:31][CH2:32][C:33]([O-:35])=[O:34])(=[O:10])=[O:11])[CH:8]=1)#[N:2].[Na+:38]
Reactant: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CS(=O)(=O)c1ccccc1-c1ccc(CCNS(=O)(=O)c2cc(C#N)ccc2O)c(OCC(=O)[O-])c1

Procedure:
To a stirred solution of 146 g of [4-[2-(5-cyano-2-hydroxybenzenesulfonylamino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetic acid in 580 mL of ethanol was added 137 mL of 2 mol/L sodium hydroxide solution under ice-cooling, and the solvent was removed under reduced pressure. The residue was suspended with 1.16 L of ethanol, and the mixture was stirred under reflux for an hour, then at room temperature overnight. The obtained white solid was collected by filtration to give 129 g of sodium [4-[2-(5-cyano-2-hydroxybenzenesulfonyl-amino)ethyl]-2′-methanesulfonylbiphenyl-3-yloxy]acetate.