Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[N:12]=[N:11][C:10]([C:13]2[CH:14]=[C:15]([C:19]3[N:20]=[CH:21][N:22]([C:24]([N:26]([CH:28]4[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]4)[CH3:27])=[O:25])[CH:23]=3)[CH:16]=[CH:17][CH:18]=2)=[N:9]1)C1C=CC=CC=1.C1CCCCC=1>[Pd]>[N:11]1[NH:12][N:8]=[N:9][C:10]=1[C:13]1[CH:14]=[C:15]([C:19]2[N:20]=[CH:21][N:22]([C:24]([N:26]([CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)[CH3:27])=[O:25])[CH:23]=2)[CH:16]=[CH:17][CH:18]=1
Reactant: CN(C(=O)n1cnc(-c2cccc(-c3nnn(Cc4ccccc4)n3)c2)c1)C1CCCCC1
Agent: [Pd]
Solvent: C1=CCCCC1
Product: CN(C(=O)n1cnc(-c2cccc(-c3nn[nH]n3)c2)c1)C1CCCCC1
Temperature: 80 °C
Yield: 22.1 %

Procedure:
A stirred mixture of 4-(3-(2-benzyl-2H-tetrazol-5-yl)phenyl)-N-cyclohexyl-N-methyl-1H-imidazole-1-carboxamide (256 mg, 0.58 mmol), 10% palladium on carbon (30.9 mg, 0.029 mmol) and cyclohexene (1.175 ml, 11.6 mmol) was heated at 80° C. in a sealed tube. Then the reaction was cooled to room temperature, filtered through a celite pad and evaporated to dryness. The remaining oil was purified by chromatography over silica using a mixture of dichloromethane/methanol (90:10). Homogenous fractions were pooled and evaporated and the residual oil was crystallised from diethyl ether to give the product as an off-white powder, (45 mg, 21%).
Reaction SMILES: [F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([C:13]([NH:16][C:17](=[O:23])[C:18]([O:20]CC)=O)([CH3:15])[CH3:14])[CH2:9][C:8]2=[O:24])=[CH:4][CH:3]=1.[Li+].[CH3:28][Si]([N-][Si](C)(C)C)(C)C.CI>CN(C=O)C>[F:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]3[C:9](=[C:18]([OH:20])[C:17](=[O:23])[N:16]([CH3:28])[C:13]3([CH3:14])[CH3:15])[C:8]2=[O:24])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(=O)NC(C)(C)C1CCN(Cc2ccc(F)cc2)C(=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)C(O)=C2C(=O)N(Cc3ccc(F)cc3)CCC2C1(C)C
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of ethyl ({1-[1-(4-fluorobenzyl)-2-oxopiperidin-4-yl]-1-methyethyl}amino)(oxo)acetate (1.2 g, 3.3 mmol) in anhydrous DMF (10 mL) under an atmosphere of nitrogen was added LiHMDS (1M in THF, 3.5 mL, 3.5 mmol). After stirring at 0° C. for 15 min, methyl iodide (0.47 g, 3.3 mmol) was added to the reaction mixture. After stirring for an additional 15 min, more LiHMDS (1M in THF, 3.5 mmol, 3.5 mmol) was added. After another 2 h, an additional portion of LiHMDS (1M in THF, 3.5 mL, 3.5 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was concentrated under vacuum. The residual material was purified using reverse phase HPLC on a C18 stationary phase eluting with a gradient of 5%-95% acetonitrile (0.1% TFA) in H2O (0.1% TFA) to afford the title compound as an oil 1H NMR (400 MHz, CDCl3) δ 7.27 (m, 2H), 7.04 (t, J=8.6 Hz, 2H), 4.67 (d, J=14.7 Hz, 1H), 4.52 (d, J=14.7 Hz, 1H), 3.33 (d, J=6 Hz, 2H), 3.31 (s, 3H), 2.84 (m, 1H), 1.93 (m, 1H), 1.64 (m, 1H), 1.37 (s, 3H), 1.13 (s, 3H) ppm. ES MS M+1=333.
Reaction SMILES: [N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH2:10])=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1.[C:13]([O:17][C:18]([N:20]1[CH2:25][CH2:24][C:23](=O)[CH2:22][CH2:21]1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C1COCC1>[N:1]1([C:6]2[CH:12]=[CH:11][C:9]([NH:10][CH:23]3[CH2:24][CH2:25][N:20]([C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH2:21][CH2:22]3)=[CH:8][CH:7]=2)[CH:5]=[N:4][N:3]=[N:2]1
Reactant: Nc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(-n3cnnn3)cc2)CC1
Reaction time: 20 h
Yield: 98.3 %

Procedure:
To a solution of 4-(1H-tetrazol-1-yl)aniline (2 g, 12.4 mmol) and 1-tert-butoxycarbonyl-4-piperidone (3.71 g, 18.6 mmol) in THF (15 ml) were added acetic acid (1.42 ml, 24.8 mmol) and sodium triacetoxyborohydride (4 g, 18.6 mmol), successively, under ice cooling, and the mixture was stirred for 20 hours. To the mixture was added sodium triacetoxyborohydride (4 g, 18.6 mmol), and the mixture was stirred at room temperature for 20 hours. To the mixture was added saturated aqueous solution of sodium hydrogencarbonate (100 ml), and the mixture was stirred at room temperature for 1 hour. The mixture was extracted with ethyl acetate (100 ml), and the organic layer was washed with saturated sodium chloride solution (50 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. To the concentrate was added diisopropyl ether (20 ml), and the resulting precipitates were collected by filtration to give the titled compound (4.2 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.[Li]CCCC.[Cl:14][C:15]1[CH:26]=[CH:25][C:18]([C:19](N(OC)C)=[O:20])=[CH:17][N:16]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:19]([C:18]2[CH:17]=[N:16][C:15]([Cl:14])=[CH:26][CH:25]=2)=[O:20])=[CH:4][CH:3]=1
Reactant: Clc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1ccc(Cl)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(c1ccc(Cl)cc1)c1ccc(Cl)nc1
Reaction time: 1 h
Yield: 78.7 %

Procedure:
To a solution of 4-chlorobromobenzene (33.88 g, 177 mmol) in THF (200 mL), a solution of BuLi (118 mL, 142 mmol, 1.2 M solution in hexane) was added at −78° C. The mixture was stirred for 1 h and a solution of compound A (23.6 g, 118 mmol) in THF (100 mL) was added to it dropwise. The mixture was stirred for additional 1 h, quenched with saturated NH4Cl solution and extracted with ethyl acetate (300 mL). The organic layer was dried (Na2SO4), filtered and evaporated. The crude product was purified using column chromatography to obtain 23.4 g (79%) of compound B as light yellow solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]([CH3:32])([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:30])[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][C:21]=2[CH3:29])[CH2:13][CH2:12]1.CCN(C(C)C)C(C)C.[CH3:42][C:43]1[NH:52][C:51]2[C:50]3[CH:53]=[CH:54][CH:55]=[CH:56][C:49]=3[NH:48][CH2:47][CH2:46][C:45]=2[N:44]=1>ClCCl.CN(C=O)C>[CH3:7][C:8]([CH3:32])([CH3:31])[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17](=[O:30])[CH2:18][CH2:19][C:20]2[CH:28]=[CH:27][C:23]([C:24]([N:48]3[CH2:47][CH2:46][C:45]4[N:44]=[C:43]([CH3:42])[NH:52][C:51]=4[C:50]4[CH:53]=[CH:54][CH:55]=[CH:56][C:49]3=4)=[O:26])=[CH:22][C:21]=2[CH3:29])[CH2:13][CH2:12]1
Reactant: Cc1nc2c([nH]1)-c1ccccc1NCC2
Reactant: Cc1cc(C(=O)O)ccc1CCC(=O)N1CCN(CCC(C)(C)C)CC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2c([nH]1)-c1ccccc1N(C(=O)c1ccc(CCC(=O)N3CCN(CCC(C)(C)C)CC3)c(C)c1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
Oxalyl chloride (0.049 ml, 0.55 mmol) was added slowly to a solution of 4-{3-[4-(3,3-dimethyl-butyl)-piperazin-1-yl]-3-oxo-propyl}-3-methyl-benzoic acid from Example E44 (100 mg, 0.28 mmol) in dichloromethane (10 ml) and few drops of DMF. The mixture was stirred for 1 h at room temperature then concentrated in vacuo and azeotroped with toluene. The residue was redissolved in dichloro-methane (10 ml) and DIEA (0.144 ml, 0.84 mmol) then 2-methyl-1,4,5,6-tetrahydro-1,3,6-triaza-benzo[e]azulene from Example E5 (55 mg, 0.28 mmol) was added. The mixture was stirred for 20 h at room temperature then washed with saturated NaHCO3 then brine, dried and concentrated in vacuo. The residue was purified by preparative HPLC (eluant; 0.5% 35% ammonia:9.5% methanol:90% dichloro-methane) to give a white fluffy solid identified as the title compound (42 mg, 28%).
Reaction SMILES: [CH2:1]([N:8]([CH2:10][CH:11]([C:13]1[CH:20]=[CH:19][C:17]([OH:18])=[C:15]([OH:16])[CH:14]=1)[OH:12])C)C1C=CC=CC=1.[H][H]>O.S(=O)(=O)(O)O.[Pd]>[CH3:1][NH:8][CH2:10][CH:11]([C:13]1[CH:20]=[CH:19][C:17]([OH:18])=[C:15]([OH:16])[CH:14]=1)[OH:12]
Reactant: CN(Cc1ccccc1)CC(O)c1ccc(O)c(O)c1
Reactant: [H][H]
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: O
Product: CNCC(O)c1ccc(O)c(O)c1

Procedure:
Benzyladrenaline 2 is dissolved in about 10 ml of water and about 5 ml of 18% sulfuric acid (pH: about 5.5), about 50 mg of palladium-charcoal (10%) are added and the mixture is hydrogenated at about 60° C. under 2 bar of hydrogen pressure. It is then evaporated down to about half its volume, about 20 ml of methanol are added and the mixture is cooled. The crystalline product (adrenaline sulphate 3) is filtered off and dried.
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1C1CCCCC1)=[CH:8][CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[C:5]=2Cl.C1(B(O)O)C=CC=CC=1.[Li+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C1(C)C=CC=CC=1.CCO>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=2)[CH:10]=[CH:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: OB(O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a mixture of methyl 2-bromo-7-chloro-3-cyclohexyl-1H-indole-6-carboxylate (841.8 mg, 2.27 mmol), phenylboronic acid (409 mg, 3.35 mmol), Pd(PPh3)4 (267 mg, 0.231 mmol), LiCl (188 mg, 4.44 mmol) and Na2CO3 (589 mg, 5.56 mmol) under N2 at r.t. in a re-usuable sealed tube was charged with a mixture of PhMe/EtOH (10 ml/10 ml) and then water (6.6 ml). The sealed tube was closed and the reaction mixture stirred at 60° C. for 3 hr, left standing at r.t. overnight, and then re-stirred at 60° C. for 2 hr 40 min. After cooling to r.t., the mixture was partitioned between CH2Cl2 and H2O (50 ml/50 ml). The organic layer was separated and evaporated to give a residue, which was purified by Biotage flash chromatography (gradient elution, 0 to 20% EtOAc/Hexane) to gave 1H-indole-6-carboxylic acid, 7-chloro-3-cyclohexyl-2-phenyl-, methyl ester (755 mg, 90%). 1H NMR (500 MHz): (CD3OD) δ 7.77 (d, J=8.3, 1H), 7.61 (d, J=8.3, 1H), 7.58-7.52 (overlapping m, 4H), 7.47 (m, 1H), 3.95 (s, 3H), 2.92 (m, 1H), 2.03 (m, 2H), 1.88-1.78 (overlapping m, 5H), 1.38 (m, 3H); Analytical HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Flow Rate=5 ml/min, Column: Xterra MS C18 S7 3.0×50 mm; LC/MS: (ES+) m/z (M+H)+=368.06, 370.03, HPLC Rt=2.085 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([C:15]([C:17]2[CH:22]=[CH:21][C:20]([N:23]3[C@H:27]([CH2:28][OH:29])[CH2:26][CH2:25][S:24]3(=[O:31])=[O:30])=[CH:19][CH:18]=2)=[O:16])[CH2:11][CH2:10]1.S(C1C=CC(C)=CC=1)(O[CH3:36])(=O)=O>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:10][CH2:11][N:12]([C:15]([C:17]2[CH:18]=[CH:19][C:20]([N:23]3[C@H:27]([CH2:28][O:29][CH3:36])[CH2:26][CH2:25][S:24]3(=[O:30])=[O:31])=[CH:21][CH:22]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4[C@H](CO)CCS4(=O)=O)cc3)CC2)c(C)c1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Product: COC[C@@H]1CCS(=O)(=O)N1c1ccc(C(=O)N2CCN(c3ccc(C)cc3C)CC2)cc1

Procedure:
Using (S)-[4-(2,4-dimethylphenyl)piperazin-1-yl][4-(3-hydroxymethyl-1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl]methanone (480 mg) described in Example 32 and methyl tosylate (0.16 mL) and by the reaction and treatment in the same manner as in Example 36, the title compound (177 mg) was obtained.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][C:6]([OH:8])=[O:7])([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:14](O)[CH3:15]>>[CH2:14]([CH:5]([CH2:4][N+:1]([O-:3])=[O:2])[C:6]([OH:8])=[O:7])[CH3:15]
Reactant: O=C(O)CC[N+](=O)[O-]
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCC(C[N+](=O)[O-])C(=O)O

Procedure:
To a solution of 2 gr of 3-nitropropionic acid (41) in 30 mL of ethanol add catalytic amount of concentrated sulphuric acid (0.8 mL) and reflux overnight. Then add water and extracted with ethylacetate. The organic layer was washed with saturated sodium bicarbonate solution, saturated sodium chloride and water. Purification from column gives ethyl 3-nitropropionic acid (26) as pale yellow liquid with boiling point 92° C. at 2.5 torr.
Reaction SMILES: [C:1]1([C:8]([O:10]C)=[O:9])([C:4]([O:6][CH3:7])=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+].O>CO>[CH3:7][O:6][C:4]([C:1]1([C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1)=[O:5]
Reactant: COC(=O)C1(C(=O)OC)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)C1(C(=O)O)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Dimethyl 1,1-cyclopropanedicarboxylate (5 ml) was mixed with NaOH (1.4 g) in MeOH (40 ml)/water (4 ml). The reaction mixture was stirred at RT overnight and the solvent was evaporated. To the residue was added ether (50 ml), water (50 ml) and extracted once. The aqueous layer was acidified with 6N HCl and extracted three times with ether, the combined organic layer was washed with brine, dried and evaporated to give 1-(methoxycarbonyl)cyclopropanecarboxylic acid (4 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH3:16]>>[NH2:16][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14]
Reactant: CC(C(N)=O)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: N
Product: CC(C(N)=O)c1ccc(N)c([N+](=O)[O-])c1

Procedure:
By an original process, 2-(4'-chloro-3'-nitro-phenyl) propionamide (I), thus obtained, is treated with ammonia in an alcohol solution to furnish 2-(4'-amino-3'-nitro-phenyl) propionamide (II) which, when hydrolyzed in an acid medium, is transformed into 2-(4'-amino-3'-nitro-phenyl) propionic acid (III). This, when treated with 2,5-dimethoxytetrahydrofuran (a mixture of cis/trans isomers) produces 2-(3'-nitro-4'-[1"-pyrrolyl] phenyl) propionic acid (A). Catalytic hydrogenation of the latter in the presence of palladium on activated charcoal produces 2-(3'-amino-4'-[1"-pyrrolyl] phenyl) propionic acid (B).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=2)[N:10]=1.[F:27][C:28]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:29]=1[CH2:30][OH:31]>>[F:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH:17]=3)[N:10]=2)=[C:2]([O:31][CH2:30][C:29]2[CH:32]=[C:33]([F:37])[C:34]([F:36])=[CH:35][C:28]=2[F:27])[CH:7]=1
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3F)n2)c1
Reactant: OCc1cc(F)c(F)cc1F
Product: CS(=O)(=O)Cc1cccc(Nc2ncnc(-c3ccc(F)cc3OCc3cc(F)c(F)cc3F)n2)c1

Procedure:
Starting with 4-(2,4-difluorophenyl)-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine (70 mg; 0.184 mmol), intermediate 42.1, and 2,4,5-trifluorobenzyl alcohol (123 mg; 0.736 mmol), example 75 was prepared analogously to the procedure for the preparation of example 42.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][NH:11][CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:1]([NH:5][S:6]([C:9]1[CH:13]=[CH:12][N:11]([CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[CH:10]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1cc[nH]c1
Reactant: BrCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)NS(=O)(=O)c1ccn(CC2CCCCC2)c1
Yield: 40.9 %

Procedure:
To a solution of compound 27d (29.4 g, 146 mmol), bromocyclohexylmethane (30.9 g, 175 mmol), K2CO3 (40.2 g, 291 mmol) in dry DMF (300 mL) was heated at 85° C. overnight, quenched with water and extracted with EA twice. The combined organic layers were washed with water (3×) and brine, concentrated and purified by CC (PE/EA=2/1) to give compound 27e (17.8 g, 41%) as a solid.
Reaction SMILES: [CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21]CC3C=CC=CC=3)=[C:17]([F:29])[CH:16]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[CH2:1]([C:8]1[NH:13][C:12](=[O:14])[C:11]([C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([F:29])[CH:16]=2)=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(OCc2ccccc2)c(F)c1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c(Cc2ccccc2)ncc1-c1ccc(O)c(F)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 81.3 %

Procedure:
A suspension of 2-benzyl-5-(4-(benzyloxy)-3-fluorophenyl)pyrimidin-4(3H)-one (0.284 g, 0.735 mmol) in trifluoroacetic acid (3 mL) was stirred at 40° C. for 2 hours and then at room temperature for 16 hours. The reaction mixture was concentrated to dryness and then purified by flash column chromatography, eluting with 20:1 dichloromethane/MeOH. The desired product (0.177 g, 81%) was obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) δ 12.89 (br s, 1H), 9.98 (s, 1H), 8.08 (s, 1H), 7.58 (dd, J=2.3, 13.3 Hz, 1H), 7.39-7.30 (m, 5H), 7.28-7.22 (m, 1H), 6.96 (dd, J=8.2, 9.4 Hz, 1H), 3.89 (s, 2H). LRMS (ESI pos) m/e 297 (M+1).
Reaction SMILES: I[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+].[Br:10][C:11]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:12]=1[CH2:13][CH:14]1[CH2:19][CH2:18][N:17]([C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:16][CH2:15]1>CN(C)C=O>[Br:10][C:11]1[CH:33]=[CH:32][C:31]([O:34][CH2:2][CH3:3])=[CH:30][C:12]=1[CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([C:20](=[O:29])[CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])[CH2:18][CH2:19]1
Reactant: CCI
Reactant: O=C(Cc1ccccc1Cl)N1CCC(Cc2cc(O)ccc2Br)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1ccc(Br)c(CC2CCN(C(=O)Cc3ccccc3Cl)CC2)c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
Iodoethane (311.9 mg, 2.000 mmol) and potassium carbonate (500.0 mg, 3.619 mmol) were added to a solution (3 ml) of 4-(2-bromo-5-hydroxybenzyl)-1-[(2-chlorophenyl)-acetyl]piperidine (400.0 mg, 0.952 mmol) in N,N-dimethylformamide, and the resulting mixture was stirred at 60° C. for 3 hours. The reaction was terminated by adding water (20 ml), followed by extraction with diethyl ether. The extract layer was washed with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then distilled under reduced pressure to remove the solvent, whereby the title compound (426.7 mg, 0.952 mmol) was quantitatively obtained.
Reaction SMILES: [CH2:1]([S:3](Cl)(=[O:5])=[O:4])[CH3:2].[NH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13]([CH2:17][C:18]([O:20]C)=[O:19])[C:12]([CH3:22])=[C:11]2[O:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1>>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[C:8]([NH:7][S:3]([CH2:1][CH3:2])(=[O:5])=[O:4])[CH:9]=3)[N:13]([CH2:17][C:18]([OH:20])=[O:19])[C:12]=2[CH3:22])=[CH:25][CH:26]=1
Reactant: COC(=O)Cn1c(C)c(Oc2ccc(Cl)cc2)c2cc(N)ccc21
Reactant: CCS(=O)(=O)Cl
Product: CCS(=O)(=O)Nc1ccc2c(c1)c(Oc1ccc(Cl)cc1)c(C)n2CC(=O)O

Procedure:
The title compound was prepared by the method of example 7 step (iii) using ethanesulfonyl chloride and the product from example 7 step (ii). Yield 155 mg
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH2:13])[CH:10]=[CH:9][C:4]=1[C:5](OC)=[O:6].Cl.[NH2:15][OH:16].[OH-].[K+]>CO>[NH2:13][C:11]1[CH:10]=[CH:9][C:4]([C:5]([NH:15][OH:16])=[O:6])=[C:3]([O:2][CH3:1])[CH:12]=1
Reactant: COC(=O)c1ccc(N)cc1OC
Reactant: NO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1cc(N)ccc1C(=O)NO
Yield: 46.4 %

Procedure:
Methyl 2-methoxy-4-aminobenzoate (10 g, 55.25 mmol) and hydroxylamine hydrochloride (15.36 g, 221 mmol) were taken up in MeOH (80 ml) and a solution of KOH (15.4 g, 275 mmol) in MeOH (55 ml) was added carefully. The resultant mixture was stirred at reflux for 36 hrs. The volatiles were removed in vacuo. The residue was taken up in 1M NaOH (50 ml) and washed with ethyl acetate (EtOAc, 50 ml). Concentrated HCl was added slowly until precipitation of a solid (pH was 10). The solid was filtered off, washed with H2O, then methyl-tert-butyl ether (MTBE) and dried under vacuum. 1H NMR showed the solid contained approx. 1/3 molar equivalent of ethyl acetate. The solid was taken up in 1M NaOH (100 ml) and the EtOAc was removed in vacuo. Concentrated HCl was added carefully until precipitation of a solid (pH was 8). The solid was collected by filtration, washed with H2O, then MTBE and dried under vacuum to give 4.67 g (47%) of the title compound as a dark red solid.
Reaction SMILES: C([N:8]1[CH2:17][CH2:16][C:15]2[C:14](=[O:18])[NH:13][CH:12]=[N:11][C:10]=2[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[N:11]1[C:10]2[CH2:9][NH:8][CH2:17][CH2:16][C:15]=2[C:14](=[O:18])[NH:13][CH:12]=1
Reactant: O=c1[nH]cnc2c1CCN(Cc1ccccc1)C2
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: O=c1[nH]cnc2c1CCNC2
Reaction time: 72 h
Yield: 96 %

Procedure:
7-Benzyl-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4(3H)-one (1.5 g, 6.2 mmol) was dissolved in methanol (25 mL) and palladium hydroxide was added (1.5 g, 20% wt). The mixture was shaken on a Parr Shaker under H2(g) atmosphere (60 PSI) for 3 days. The mixture was filtered through celite and evaporated to give 0.9 g of material as a yellow solid (96%), which was used as such for the next step.
Reaction SMILES: Cl[C:2]1[C:3]([C:23]#[N:24])=[N:4][CH:5]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15]3=[O:21])[C@H:9]2[CH3:22])[N:7]=1.Cl.[CH:26]1([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:43]=[CH:42][C:40]([NH2:41])=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1>O1CCOCC1.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:26]1([N:31]2[CH2:36][CH2:35][CH:34]([C:37]3[CH:43]=[CH:42][C:40]([NH:41][C:2]4[C:3]([C:23]#[N:24])=[N:4][CH:5]=[C:6]([N:8]5[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]6[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[C:15]6=[O:21])[C@H:9]5[CH3:22])[N:7]=4)=[CH:39][CH:38]=3)[CH2:33][CH2:32]2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: Nc1ccc(C2CCN(C3CCCC3)CC2)cc1
Reactant: C[C@@H]1[C@H](N2CCCN(C)C2=O)CCCN1c1cnc(C#N)c(Cl)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1[C@H](N2CCCN(C)C2=O)CCCN1c1cnc(C#N)c(Nc2ccc(C3CCN(C4CCCC4)CC3)cc2)n1
Temperature: 115 °C
Reaction time: 1 h

Procedure:
The mixture of 3-chloro-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (405) (60 mg, 0.17 mmol), 4-(1-cyclopentylpiperidin-4-yl)aniline hydrochloride (304) (58 mg, 0.21 mmol), fine-powder cesium carbonate (230 mg, 0.68 mmol), Pd(OAc)2(11 mg, 0.05 mmol), BINAP (31 mg, 0.05 mmol) in 15 mL dioxane was degassed with nitrogen stream for 3 min. It was then stirred in 115° C. bath in nitrogen atmosphere for 1 hour. The mixture was cooled to RT, diluted with 100 mL EtOAc, and filtered. The filtrate was concentrated in vacuo and subjected to silica flash column using 0 to 10% MeOH in chloroform to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carbonitrile (406). It was dissolved in 10 mL MeOH and 2 mL DMSO. To it were added one NaOH solid bead (about 100 mg), Et3N (60 μL), and then 0.5 mL 30% H2O2. The mixture was stirred at RT for 30 min, diluted with 10 mL MeCN, stirred for 5 min, and concentrated on rotavap. The residue was diluted with 150 mL EtOAc, washed with water ×3, dried, concentrated in vacuo, acidified with 0.2 mL TFA, and directly subjected to reverse phase prep HPLC using 5 mM HCl (aq) and neat MeCN as mobile phases to isolate 3-(4-(1-cyclopentylpiperidin-4-yl)phenylamino)-5-((2R,3R)-2-methyl-3-(3-methyl-2-oxotetrahydropyrimidin-1(2H)-yl)piperidin-1-yl)pyrazine-2-carboxamide (407) as HCl salt (58 mg, 59%). LC-MS (ESI): m/z (M+1) 575.8. UV: λ=268, 277, 306, 336, 372 nm. Proton NMR (CD3OD): δ 7.64 (1H, s), 7.61 (2H, d, J=8.5 Hz), 7.20 (2H, d, J=8.5 Hz), 4.93 (1H, m), 4.56-4.30 (3H, m), 3.71 (2H, m), 3.55 (1H, m), 3.38 (3H, m), 3.13 (2H, m), 3.06 (1H, m), 2.97 (3H, s), 2.84 (1H, m), 2.25-1.65 (18H, m), 1.20 (3H, d, J=6.5 Hz) ppm.