Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH:16]([CH3:17])[CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=[C:4]([CH:18]([CH:20]([CH3:26])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:19])[CH:3]=1.Cl.[N:28]1([CH2:34][CH2:35][CH2:36][C:37](O)=[O:38])[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH3:26][CH:20]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH:18]([C:4]1[CH:3]=[C:2]([O:1][C:37](=[O:38])[CH2:36][CH2:35][CH2:34][N:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[C:7]2[C:8]3[CH:16]([CH3:17])[CH2:15][S:14][C:9]=3[C:10]([CH3:13])([CH3:12])[O:11][C:6]=2[CH:5]=1)[CH3:19]
Reactant: O=C(O)CCCN1CCCCC1
Reactant: CCCCCC(C)C(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2C(C)CS1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: ClCCl
Product: CCCCCC(C)C(C)c1cc(OC(=O)CCCN2CCCCC2)c2c(c1)OC(C)(C)C1=C2C(C)CS1

Procedure:
A combination of 2.4 g. (6.4 mmole) of 1,2-dihydro-9-hydroxy-7-(3-methyl-2-octyl)-1,4,4,-trimethyl-4H-thieno[2,3-c][1]benzopyran, 1.33 g. (6.4 mmole) of γ-piperidinobutyric acid hydrochloride, 1.40 g. (6.75 mmole) of dicyclohexylcarbodiimide and 125 ml. of methylene chloride was stirred at room temperature for 18 hours. The reaction mixture was cooled and the byproduct of dicyclohexylurea was removed by filtration. The methylene chloride was distilled off on a rotary evaporator to give a colorless, foamy residue, which was purified on 80 g. of magnesium silicate (60-100 mesh) using a graded methanol/chloroform solvent system. The fractions were monitored by thin layer chromatography, and the appropriate fractions were combined to give 1.23 g. (37%) of the desired material as a golden gum. The infrared and nuclear magnetic resonance spectra were in agreement with the desired product.
Reaction SMILES: [Br:1]Br.[F:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([F:10])[C:5]=1[OH:11].O.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>C(=S)=S.Br>[Br:1][C:8]1[CH:9]=[C:4]([F:3])[C:5]([OH:11])=[C:6]([F:10])[CH:7]=1
Reactant: BrBr
Reactant: Oc1c(F)cccc1F
Agent: Br
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: S=C=S
Product: Oc1c(F)cc(Br)cc1F
Reaction time: 16 h
Yield: 23 %

Procedure:
A solution of bromine (1.6 g) in dry carbon disulphide (10 cm3) was added over 5 minutes to a solution of 2,6-difluorophenol (1.3 g) in dry carbon disulphide (10 cm3). To the stirred reaction mixture was added 5 drops of 48% hydrogen bromide solution. The mixture was heated for 2 hours at the reflux temperature, then allowed to stand at the ambient temperature (ca 22° C.) for 16 hours. After a further period of heating (4 hours) the mixture was allowed to stand for 24 hours before being poured into water (20 cm3). To the mixture was added saturated sodium metabisulphite solution (30 cm3). The layers were separated, and the organic phase was washed with saturated sodium hydrogen carbonate solution (20 cm3) and water (20 cm3). The organic layer was dried over anhydrous sodium sulphate then evaporated under reduced pressure to give an oil which solidified. The crude product was distilled in a Kugelrohr apparatus at an oven temperature of 100° C. under reduced pressure (ca 20 mm Hg). The distillate crystallised to give 4-bromo-2,6-difluorophenol as a white solid (0.48 g).
Reaction SMILES: CC1(C)CC=C(C2SC=CN=2)C2C=C(C#CC3C=CC(C(O)=O)=CC=3)C=CC1=2.[CH3:29][C:30]1([CH3:59])[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]2[CH:35]=[C:34]([C:46]#[C:47][C:48]3[CH:58]=[CH:57][C:51]([C:52]([O:54]CC)=[O:53])=[CH:50][CH:49]=3)[CH:33]=[CH:32][C:31]1=2>>[CH3:29][C:30]1([CH3:59])[CH2:39][CH:38]=[C:37]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:36]2[CH:35]=[C:34]([C:46]#[C:47][C:48]3[CH:49]=[CH:50][C:51]([C:52]([OH:54])=[O:53])=[CH:57][CH:58]=3)[CH:33]=[CH:32][C:31]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccccc2)=CCC3(C)C)cc1
Agent: CC1(C)CC=C(c2nccs2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Product: CC1(C)CC=C(c2ccccc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of 4-[(5,6-dihydro-5,5-dimethyl-8-(2-thiazolyl)-2-naphthalenyl)ethynyl]benzoic acid (Compound 30a), 27.0 mg (0.07 mmol) of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-phenyl-2-naphthalenyl)ethynyl]benzoate (Compound 1a) was converted into the title compound (colorless solid) using 5.9 mg (0.14 mmol) of LiOH in H2O. PMR (d6-DMSO): δ1.31 (6H, s), 2.35 (2H, d, J=4.5 Hz), 6.05 (1H, t, J=J=J=4.5 Hz), 7.00 (1H, s), 7.33 (2H, d, J=6.2 Hz), 7.44 (4H, m), 7.59 (2H, d, J=8.1 Hz), 7.90 (2H, d, J=8.1 Hz).
Reaction SMILES: O.[C:2]1([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=[C:4]([OH:5])[CH:3]=1.[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18](Cl)(=[O:20])=[O:19])[CH:17]=1.C([O-])(O)=O.[Na+]>C(OCC)C>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([O:22][CH3:23])=[C:16]([S:18]([O:5][C:4]2[CH:3]=[C:2]([OH:10])[CH:9]=[C:7]([CH3:8])[CH:6]=2)(=[O:19])=[O:20])[CH:17]=1
Reactant: Cc1cc(O)cc(O)c1
Reactant: COc1ccc(Br)cc1S(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: COc1ccc(Br)cc1S(=O)(=O)Oc1cc(C)cc(O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 1.25 g (8.76 mmol) of orcinol monohydrate and 2.50 g (8.76 mmol) of 5-bromo-2-methoxybenzenesulfonyl chloride in 25 mL of diethyl ether was added 25 mL of saturated aqueous NaHCO3 and the biphasic mixture stirred vigorously at ambient temperature for 3 days. The layers were separated and the aqueous layer extracted with 2×30 mL of ethyl acetate. The combined organic layers were washed with 50 mL of brine, dried (Na2SO4) and concentrated to 1.92 g (59%) of the desired product as a pale yellow crystalline solid: 1H-NMR (300 MHz; CDCl3) δ 7.93 (d, 1 H, J=2.5 Hz), 7.69 (dd, 1 H, J=8.9, 2.5 Hz), 6.98 (d, 1 H, J=8.9 Hz), 6.54 (br s, 1 H), 6.51 (br s, 1 H), 6.41 (t, 1 H, J=2.2 Hz), 3.98 (s, 3 H) and 2.24 (s, 3 H).
Reaction SMILES: [CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH2:19])[O:15][C:14]1=[O:20])[CH3:2].[C:21](OC(=O)C)(=[O:23])[CH3:22]>N1C=CC=CC=1>[CH2:1]([C:3]1[CH:12]=[CH:11][C:6]2[N:7]=[C:8]([CH3:10])[NH:9][C:5]=2[C:4]=1[N:13]1[CH2:17][CH:16]([CH2:18][NH:19][C:21](=[O:23])[CH3:22])[O:15][C:14]1=[O:20])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc2nc(C)[nH]c2c1N1CC(CN)OC1=O
Solvent: c1ccncc1
Product: CCc1ccc2nc(C)[nH]c2c1N1CC(CNC(C)=O)OC1=O
Reaction time: 2 h

Procedure:
A mixture of (±)-3-(5'-1-Ethyl-2-methylbenzimidazolyl)-5-(aminomethyl)oxazolidin-2-one (XL, EXAMPLE 71, 0.100 g) in pyridine (2 ml) and acetic anhydride (1 ml) is stirred under nitrogen for 2 hrs. The mixture is then concentrated under reduced pressure to give the title compuond, no further purification is necessary by analysis, mp 217°-218°. NMR (CDCl3 /DMF-d7, 300 MHz) 7.74, 7.52, 4.80, 4.27, 3.93, 3.58, 2.61 and 1.38 δ; CMR (DMF-d7, 75.47 MHz) 13.06, 14.67, 22.2, 38.65, 42.2, 72.01, 101.7, 109.34, 109.96, 114.57, 132.5, 134.2, 143.3, 153.5, 155.7 and 171.7 δ.
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH2:21])[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[CH:23]([C:26]1[CH:27]=[C:28]2[C:33](=[CH:34][CH:35]=1)[CH2:32][C:31](=O)[CH2:30][CH2:29]2)([CH3:25])[CH3:24]>>[CH3:1][C:2]([N:10]1[CH:14]=[C:13]([NH:15][C:16](=[O:22])[CH:17]([NH:21][CH:31]2[CH2:30][CH2:29][C:28]3[C:33](=[CH:34][CH:35]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:27]=3)[CH2:32]2)[CH2:18][CH2:19][CH3:20])[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CC(C)c1ccc2c(c1)CCC(=O)C2
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1
Product: CCCC(NC1CCc2cc(C(C)C)ccc2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
2-Amino-pentanoic acid [1-(1,1-dimethyl-2-pyrrolidin-1-yl-ethyl)-1H-imidazol-4-yl]-amide was reacted with 6-Isopropyl-3,4-dihydro-1H-naphthalen-2-one to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 19.5, 19.6, 24.2, 26.6, 26.7, 28.2, 28.4, 29.6, 30.6, 33.9, 36.3, 36.5, 37.2, 53.4, 53.7, 56.0, 59.1, 60.3, 60.8, 67.3, 104.6, 124.1, 126.7, 126.8, 129.5, 129.6, 131.1, 132.1, 135.7, 136.0, 137.3, 146.7, 146.8, 172.4, 172.6; MS m/z 480.5 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:14])=[O:13].[H-].[Na+].[C:33]([O:37][C:38](=[O:41])[CH2:39]Br)([CH3:36])([CH3:35])[CH3:34]>CN(C=O)C.CCOCC>[CH3:1][O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:39][C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:41])[C:5]=1[N:11]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[S:12]([C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1)(=[O:13])=[O:14]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: COC(=O)c1cccc(O)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.1 %

Procedure:
To a solution of 0.40 g (0.94 mmol) of the product of Example 37 in 10 mL of DMF was added 0.047 g (1.171 mmol) of a 60% suspension of sodium hydride in minena oil. The resulting mixture was stirred at room temperature for 0.5 h and then 0.277 mL (1.873 mmol) of t-butylbromoacetate was added in one portion. Th reaction mixture was stirred for an additional 18 h and then diluted with ether, washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was triturated with ether-hexanes to provide 0.423 g (83%) of the desired product as a white solid. Electrospray Mass Spec: 524.3 (M+H)+
Reaction SMILES: C(C1C=CC2N(C=CN=2)C=1)(OCC)=O.[C:15]([N:19]1[C:23]([NH2:24])=[C:22]([C:25]([NH2:27])=[O:26])[C:21]([CH2:28][C:29]2[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=2)=[N:20]1)([CH3:18])([CH3:17])[CH3:16].[CH:35]1([N:40]2[C:44](N)=[C:43](C(N)=O)[C:42]([CH2:49]C)=N2)[CH2:39]CCC1>>[C:15]([N:19]1[C:23]2=[N:24][C:49]([C:42]3[CH:39]=[CH:35][N:40]=[CH:44][CH:43]=3)=[N:27][C:25](=[O:26])[C:22]2=[C:21]([CH2:28][C:29]2[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=2)[NH:20]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Reactant: CC(C)(C)n1nc(Cc2ccncc2)c(C(N)=O)c1N
Agent: CCOC(=O)c1ccc2nccn2c1
Product: CC(C)(C)n1[nH]c(Cc2ccncc2)c2c(=O)nc(-c3ccncc3)nc1-2
Yield: 84 %

Procedure:
Following a procedure substantially similar to that described in Example 16, part c, but substituting ethyl isonicotinate for 6-carboethoxyimidazo[1,2-a]pyridine and 1-tert-butyl-3-(4-pyridylmethyl)-5-amino-1H-pyrazole-4-carboxamide for 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide there was obtained 1-tert-butyl-3-(4-pyridylmethyl)-6-(4-pyridyl)-pyrazolo[3,4-d]pyrimidin-4-one in 84% yield as a white powder, m.p. 233°-235° C.
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[C:7]=1[NH:13][CH2:14][C:15]1[C:16]([NH:23][CH3:24])=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=1.C(N(CC)CC)C.[Cl-].[NH4+]>O1CCCC1>[F:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([F:5])[C:7]=1[N:13]1[CH2:14][C:15]2[C:16](=[N:17][C:18]([S:21][CH3:22])=[N:19][CH:20]=2)[N:23]([CH3:24])[C:1]1=[O:2]
Reactant: CNc1nc(SC)ncc1CNc1c(F)cccc1F
Reactant: O=C(Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CSc1ncc2c(n1)N(C)C(=O)N(c1c(F)cccc1F)C2
Reaction time: 1 h
Yield: 87.4 %

Procedure:
A stirred solution, cooled in ice, of 0.7 ml (1.3 mmol) of phosgene (20% in toluene) in 5 ml of tetrahydrofuran was treated dropwise with a solution of 210 mg (0.71 mmol) of 5-(2,6-difluorophenyl)aminomethyl-4-methylamino-2-methylthiopyrimidine and 0.2 ml (1.4 mmol) of triethylamine in 5 ml of tetrahydrofuran. The mixture was stirred for 1 hour. To the mixture were added 20 ml of tetrahydrofuran and 20 ml of saturated aqueous ammonium chloride solution and the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 200 mg (87%) of 3-(2,6-difluorophenyl)-7-methylthio-3,4-dihydro-1-methylpyrimido[4,5-d]pyrimidin-2(1H)-one as a white solid. [Mass spectrum (ESI) MH+ =323].
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6].[CH2:10]([NH:13][CH2:14][CH2:15][CH3:16])[CH2:11][CH3:12]>>[CH2:10]([N:13]([CH2:14][CH2:15][CH3:16])[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][N:9]=1)[C:5]#[N:6])[CH2:11][CH3:12]
Reactant: N#Cc1ccnc(Cl)c1
Reactant: CCCNCCC
Product: CCCN(CCC)c1cc(C#N)ccn1
Temperature: 100 °C

Procedure:
2-Chloroisonicotinonitrile (1.0 g) and dipropylamine (10 mL) were placed in a sealed heavy wall tube and heated to 100° C. for 18 h. The mixture was removed from heat and cooled to room temperature. The dipropylamine was removed under reduced pressure and the residue chromatographed on silica gel using 2% ethyl acetate in hexanes as eluent to give 1.06 g of the title compound: MS (ESI+) for C12H17N3 m/z 204.1 (M+H)+.
Reaction SMILES: C(OC(OCC)[C:5]([CH:21]=O)([CH2:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=1)[C:6]#[N:7])C.[NH2:26][C:27]([NH2:29])=[NH:28]>C(O)C>[NH2:29][C:27]1[N:28]=[C:6]([NH2:7])[C:5]([CH2:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)=[CH:21][N:26]=1
Reactant: N=C(N)N
Reactant: CCOC(OCC)C(C#N)(C=O)Cc1cc(OC)c(OC)c(OC)c1
Solvent: CCO
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reaction time: 8 h
Yield: 67.2 %

Procedure:
α-Diethoxymethyl-α-formyl-β-(3,4,5-trimethoxyphenyl) propionitrile (35.1 g, 0.10 mol) was added to an ethanolic solution of guanidine (from 0.35 mol of guanidine hydrochloride). The mixture was heated at reflux for a total of 6.5 hours during which time enough ethanol was allowed to boil off to bring the reaction temperature up to 85°. The dark solution was allowed to cool and stand overnight. The mixture was filtered, and the solid was washed with cold ethanol and dried to yield crude product (24.4 g, 84.1%). Purification was effected by dissolving the crude product in hot aqueous acetic acid and reprecipitation with concentrated ammonium hydroxide. The precipitate was washed twice with water, once with cold acetone, and dried to yield 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine (19.5 g, 67.2%), m.p. 197°-198° C. (identity confirmed by nmr). The acetone was concentrated in vacuo to dryness yielding additional though somewhat less pure trimethoprim (2,5 g, 8.6%, m.p. 194°-196° C.).
Reaction SMILES: [CH2:1]1[O:12][CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([NH2:11])[CH:6]=2)[O:3][CH2:2]1.[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][CH:15]=1>C(OCC)(=O)C>[Cl:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([NH:11][C:7]2[CH:8]=[CH:9][CH:10]=[C:5]([CH:4]3[O:3][CH2:2][CH2:1][O:12]3)[CH:6]=2)=[O:19])=[CH:16][CH:15]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: Nc1cccc(C2OCCO2)c1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc(C2OCCO2)c1)c1ccc(Cl)cc1
Yield: 78 %

Procedure:
A solution of 3-aminobenzaldehyde ethylene acetal (10 g, 60.5 mmol) and TEA (7.35 g, 72.6 mmol) in ethyl acetate (100 mL) at 0° C. is treated dropwise with 4-chlorobenzoyl chloride (9.44 mL, 72.6 mmol) during 30 min. The reaction mixture is stirred at RT for 3 h before dilution with EtOAc. The medium is washed twice with sat. aq. NaHCO3 (100 mL) and once with brine (100 mL). The organic layer is dried over MgSO4, filtered and evaporated. The residual oil is triturated with ethyl acetate and the resulting crystalline material is filtered to give the title compound (14.33 g, 78%) as a slightly pink solid; LC-MS B: tR=0.86 min; [M+H]+=304.03.
Reaction SMILES: C1O[C:4]2([CH2:9][CH2:8][CH:7]([NH:10][C:11]3[C:16](Cl)=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][N:12]=3)[CH2:6][CH2:5]2)[O:3]C1.[ClH:21]>O1CCCC1.C1(C)C=CC=CC=1>[Cl:21][C:11]1([NH:10][CH:7]2[CH2:8][CH2:9][C:4](=[O:3])[CH2:5][CH2:6]2)[CH:16]=[C:15]([CH2:18][CH3:19])[N:14]=[CH:13][NH:12]1
Reactant: CCc1ncnc(NC2CCC3(CC2)OCCO3)c1Cl
Reactant: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CCC1=CC(Cl)(NC2CCC(=O)CC2)NC=N1

Procedure:
70 g (0.235 mol) of 4-(5-chloro-6-ethylpyrimidin-4-ylamino) cyclohexanone ethylene ketal (starting material for Example C) were stirred at 50° C. for 8 hours in a mixture of 250 ml of tetrahydrofuran and 250 ml of 2N hydrochloric acid. For work-up, the mixture was diluted with 250 ml of toluene, and the organic phase was extracted by stirring with sodium carbonate solution and water. Stripping off the solvent mixture gave 53.4 g (90% of theory) of product, which can be reacted without further purification.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]1[CH:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][CH:38]=1)=[O:36]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]([C:37]3[CH:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][CH:38]=3)=[O:36])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Reactant: CCc1ccc(C(=O)CCCCCBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCc1ccc(C(=O)CCCCCN2CCC(CNC(=O)c3cc(Cl)c(N)cc3OC)CC2)cc1
Yield: 22.9 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (1.1 g) as starting compound, potassium carbonate (1.0 g) and 6-bromo-1-(4-ethylphenyl)-1-hexanone (0.94 g) were reacted and treated in the same manner as in Example 172 to give 0.34 g of 4-amino-5-chloro-N-((1-(6-(4-ethylphenyl)-6-oxohexyl)piperidin-4-yl)methyl)-2-methoxybenzamide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Li]CCCC.[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23](OC)=[C:22]([C:28]3[CH:33]=[CH:32][C:31]([S:34][CH3:35])=[CH:30][CH:29]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1.[NH2-].[Li+]>C1(C)C=CC=CC=1>[F:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]2[C:24](=[O:25])[C:23]([N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)=[C:22]([C:28]3[CH:29]=[CH:30][C:31]([S:34][CH3:35])=[CH:32][CH:33]=3)[CH:21]=[N:20]2)=[CH:15][CH:14]=1
Reactant: COc1c(-c2ccc(SC)cc2)cnn(-c2ccc(F)cc2)c1=O
Reactant: C1CCNCC1
Agent: [Li+]
Agent: [Li]CCCC
Agent: [NH2-]
Solvent: Cc1ccccc1
Product: CSc1ccc(-c2cnn(-c3ccc(F)cc3)c(=O)c2N2CCCCC2)cc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 95.1 %

Procedure:
To a slightly heterogeneous solution of piperidine (99.7 mg, 1.17 mmol) and toluene (8 mL) cooled to −78° C. was slowly added dropwise an n-BuLi solution (0.235 mL, 0.59 mmol, 2.5 M in hexanes). After stirring at −78° C. for 10 minutes, the cooling bath was removed and the mixture stirred an additional 1 hour at 23° C. The 2-(4-fluorophenyl)-4-methoxy-5-[4-(methylthio)phenyl]-3(2H)-pyridazinone (400 mg, 1.17 mmol) was dissolved in portions in toluene (3×6-7 mL aliquots) with a heat gun and cooled to 0° C. prior to transfer via syringe to the lithium amide solution (cooled to −78° C.). The addition was made slowly along the interior wall of the reaction vessel. This reaction mixture was stirred overnight, slowly warming to 23° C. as the cooling bath evaporated. The reaction was quenched with water and diluted with a large excess of ethyl acetate. The layers were separated, and the ethyl acetate layer washed with additional water and brine and dried over MgSO4, filtered, and concentrated in vacuo. The residue was chromatographed (flash silica gel, ethyl acetate/hexanes 1:2) to provide 440 mg (95%) of 2-(4-fluorophenyl)-5-[4-(methylthio)phenyl]4-piperidino-3(2H)-pyridazinone.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1.[F:32][C@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)=[C:11]([C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:31]=[CH:30][C:27]([CH2:28][N:35]4[CH2:36][CH2:37][C@@H:33]([F:32])[CH2:34]4)=[CH:26][CH:25]=3)[N:20]=2)[N:10]=[N:9]1
Reactant: O=Cc1ccc(-c2noc(-c3nnn(-c4ccccc4F)c3-c3ccncc3)n2)cc1
Reactant: F[C@H]1CCNC1
Product: Fc1ccccc1-n1nnc(-c2nc(-c3ccc(CN4CC[C@@H](F)C4)cc3)no2)c1-c1ccncc1

Procedure:
The title compound was prepared following the procedure described for Example 94, but starting from 4-(5-(1-(2-fluorophenyl)-5-(pyridin-4-yl)-1H-1,2,3-triazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde, obtained as described in Example 113, Step 1, (200 mg; 0.48 mmol) and (S)-3-fluoropyrrolidine (121 mg; 0.97 mmol) to give Example 160 as a white solid. 1H NMR: (CDCl3, 400 MHz) δ 8.73-8.70 (2H, m), 8.05 (2H, d, J=8.03 Hz), 7.63-7.52 (2H, m), 7.47 (2H, d, J=8.0 Hz), 7.39-7.34 (3H, m), 7.18 (1H, t, J=9.1 Hz), 5.27-5.08 (1H, m), 3.72 (2H, s), 2.92-2.70 (3H, m), 2.49 (1H, q, J=7.4 Hz), 2.22-2.02 (2H, m). LC/MS (Method C): 486 (M+H)+. HPLC (Method F) Rt 3.99 min (Purity: 99.5%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC1C(O)=C(F)C(F)=C(F)C=1F.C(Cl)CCl.[NH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>ClCCl>[C:40]1([NH:39][C:20](=[O:22])[C@H:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: Nc1ccccc1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(N[C@@H](Cc1ccccc1)C(=O)Nc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Nα -Benzyloxycarbonyl-L-phenylalanine (4.95 g, 16.5 mmol) was dissolved in dichloromethane (70 ml) and the solution was cooled to 0° C. and stirred during the addition of pentafluorophenol (3.35 g, 18.2 mmol), followed by EDC (3.49 g, 18.2 mmol). The mixture was allowed to warm to room temperature, stirred for a further 1 hour then cooled back to 0° C. Aniline (3.85 g, 41.4 mmol) was added dropwise and the mixture was warmed to room temperature then stirred overnight. The solution was washed twice with 1M sodium carbonate, twice with 1M hydrochloric acid and finally with brine before drying over anhydrous magnesium sulphate. The solution was filtered and evaporated to a white solid which was recrystallised from ethyl acetate-hexane. Yield: 2.57 g (41%). 1H-NMR; δ (CDCl3), 7.87 (1H, br s), 7.43-7.03 (15H, br m), 5.62 (1H, m), 5.08 (2H, s), 4.59 (1H, s) and 3.15 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].CN(C)C=O>ClCCl>[N:23]1([CH2:22][CH2:21][O:18][C:14]2[CH:13]=[C:12]([C:10]3[CH:9]=[CH:8][C:4]4[N:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]=4[N:11]=3)[CH:17]=[CH:16][CH:15]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Nc1ncnc2ccc(-c3cccc(O)c3)nc12
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Nc1ncnc2ccc(-c3cccc(OCCN4CCCC4)c3)nc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 14.9 %

Procedure:
To a 4 mL screw-cap vial was added 3-(4-aminopyrido[3,2-d]pyrimidin-6-yl)phenol (100 mg; 0.32 mmol) followed by 1-(2-chloroethyl)pyrrolidine hydrochloride (CAS 7050-67-1) (1.1 equiv., 0.35 mmol, 59 mg) cesium carbonate (5 equiv., 1.57 mmol, 513 mg) and dimethylformamide (0.6 mL). The reaction was capped at shaken at 80° C. overnight. The reaction was cooled to room temperature, diluted with dichloromethane, and washed with water. Organic phase was concentrated, then purified by reverse phase HPLC yielding 16 mg of desired product. 1H NMR (400 MHz, DMSO) δ 8.48-8.39 (m, 2H), 8.15-8.08 (m, 2H), 8.00-7.89 (m, 3H), 7.47-7.40 (t, J=7.9 Hz, 1H), 7.12-7.03 (dd, J=8.1, 2.3 Hz, 1H), 4.27-4.18 (t, J=5.9 Hz, 2H), 2.90-2.81 (t, J=5.9 Hz, 2H), 2.59-2.53 (m, 4H), 1.76-1.66 (m, 4H). LCMS M/Z (M+H)=336.