Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:19][OH:20])([CH2:17][OH:18])[CH2:15][CH2:14][C:13]1=[O:21].[CH3:22][CH2:23][CH2:24][C:25](=O)[CH2:26][CH2:27][CH3:28].C([BH3-])#N.[Na+]>ClCCl.C(O)(=O)C>[CH3:22][CH2:23][CH2:24][CH:25]([NH:1][C:2]1[CH:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][C:3]=1[N:12]1[C:16]([CH2:17][OH:18])([CH2:19][OH:20])[CH2:15][CH2:14][C:13]1=[O:21])[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)c1ccc(N2C(=O)CCC2(CO)CO)c(N)c1
Reactant: CCCC(=O)CCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCC(CCC)Nc1cc(C(=O)OC)ccc1N1C(=O)CCC1(CO)CO
Temperature: 25 °C
Reaction time: 12 h
Yield: 74.9 %

Procedure:
A solution of 1-(2-amino-4-methoxycarbonylphenyl)-5,5-bis-(hydroxymethyl)pyrrolidin-2-one (0.15 g, 0.51 mmol) from Example 6 in 1 mL of dichloromethane and 0.3 mL of acetic acid was treated with 4-heptanone (0.175 g, 1.53 mmol) and sodium cyanoborohydride (0.05 g, 0.8 mmol). The resulting mixture was stirred at ambient temperature for 12 h after which time addition 4-heptanone (0.175 g, 1.53 mmol), sodium cyanoborohydride (0.05 g, 0.8 mmol) and acetic acid (0.3 mL) were added. Stirring was continued for 12 h. The reaction mixture was quenched with 10 mL of a saturated sodium bicarbonate solution and the mixture was extracted with ethyl acetic (3×50 mL). The combined extracts were dried and concentrated. The residue was purified by chromatography (silica gel; 5% ethanol in ether) to give 0.15 g (75%) of 1-[2-(4-heptylamino)-4-methoxycarbonylphenyl]-5,5-bis-(hydroxymethyl)pyrrolidin-2-one as a white solid, mp 139-140° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[CH:6]=1.[Br:13][C:14]1[CH:15]=[CH:16][C:17](F)=[C:18]([CH:21]=1)[CH:19]=[O:20].C(=O)([O-])[O-].[K+].[K+].Cl>O1CCOCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][C:17]2[CH:16]=[CH:15][C:14]([Br:13])=[CH:21][C:18]=2[CH:19]=[O:20])[CH:6]=1
Reactant: O=Cc1cc(Br)ccc1F
Reactant: COC(=O)Cc1cccc(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COC(=O)Cc1cccc(Oc2ccc(Br)cc2C=O)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 47.6 %

Procedure:
(3-Hydroxy-phenyl)-acetic acid methyl ester (5 g, 30.1 mmol), 5-bromo-2-fluorobenzaldehyde (3.6 mL, 30.1 mmol), and potassium carbonate (8.3 g, 60.2 mmol) were combined in 1,4-dioxane (40 mL) and stirred at 120° C. for 16 hours. Once no starting material was seen by analytical LCMS and tlc, the mixture was worked-up with 10% aqueous HCl and EtOAc, and the crude material was purified by silica gel chromatography to give the desired product as a colorless oil (5 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)=[O:12])=[CH:9][N:10]=2)[N:7]=1.[CH3:22][Mg]Br>O1CCOCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([C:13]3[CH:14]=[CH:15][C:16]4[N:17]([CH:19]=[CH:20][N:21]=4)[CH:18]=3)([OH:12])[CH3:22])=[CH:9][N:10]=2)[N:7]=1
Reactant: C[Mg]Br
Reactant: O=C(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Solvent: C1COCCO1
Product: CC(O)(c1ccc2nccn2c1)c1cnc2ccc(Cl)nn12
Temperature: 90 °C

Procedure:
(6-Chloro-imidazo[1,2-b]pyridazin-3-yl)-imidazo[1,2-a]pyridin-6-yl-methanone (Stage 292.2, 4.0 g, 13.44 mmol) was suspended in dioxane (400 mL) and it was heated at 90° C. When all the material was in solution, it was cooled down to 50° C. and the 3 M methylmagnesium bromide solution (28.8 mL, 40.3 mmol) was added. It was refluxed for 2 h. Then it was cooled down to rt and the precipitate formed was filtered off. It was taken up with EtOAc/MeOH (9:1) and washed with saturated NaHCO3 solution and brine. The organic layer was dried over Na2SO4, filtered and concentrated to give the title compound as a brown solid (tR 0.3 min (conditions 2), MH+=314)
Reaction SMILES: O.[C:2]1([CH3:12])[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:13]1([P:19]([CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]2)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1>ClC1C=CC=CC=1.C(OCC)C>[C:2]1([CH3:12])[CH:3]=[CH:4][C:5]([S:8]([O-:11])(=[O:9])=[O:10])=[CH:6][CH:7]=1.[CH:26]1([PH+:19]([CH:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]2)[CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:27][CH2:28][CH2:29][CH2:30][CH2:31]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: Clc1ccccc1
Solvent: CCOCC
Solvent: O
Product: C1CCC([PH+](C2CCCCC2)C2CCCCC2)CC1
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 77.3 %

Procedure:
1.2 g (12 mmol) p-toluene sulfonic acid monohydrate is dissolved twice in 25 ml chlorobenzene each, and concentrated to dryness in order to remove the water aceotropically. The remaining residue is taken up in 25 ml diethylether and added to 25 ml of a solution of 12 mmol tricyclohexyl phosphine in diethylether. 4.2 g (77%) tricyclohexyl phosphonium p-toluene sulfonate is obtained as a colorless solid, which is filtered off and washed with diethylether.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:12])[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16]1([CH:22]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[N:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH2:33])[CH2:25][CH2:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.O>CS(C)=O>[C:34]1([CH:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[N:23]2[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][CH2:31][CH2:32][NH:33][C:13]([C:3]3[CH:4]=[N:5][C:6]4[C:11]([C:2]=3[OH:1])=[C:10]([OH:12])[CH:9]=[CH:8][CH:7]=4)=[O:15])[CH2:27][CH2:28]2)[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1
Reactant: O=C(O)c1cnc2cccc(O)c2c1O
Reactant: NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Solvent: O
Solvent: CS(C)=O
Product: O=C(NCCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1cnc2cccc(O)c2c1O
Temperature: 25 °C
Reaction time: 6 h
Yield: 41.3 %

Procedure:
N,N'-Carbonyldiimidazole (1.2 g) is added to a solution of 4,5-dihydroxyquinoline-3-carboxylic acid (0.7 g), which is prepared according to the method described in Japanese Patent First Publication No. 65874/1981, in dry dimethyl sulfoxide (30 ml) and the mixture is stirred at room temperature for 30 minutes. 4-(4-Diphenylmethyl-1-piperazinyl)butylamine (2.2 g) is added to the reaction mixture and the mixture is stirred at room temperature for 6 hours, and thereto is added water (about 200 ml), and the mixture is extracted with chloroform. The organic layer is dried over anhydrous magnesium sulfate and the solvent is distilled off. The residue is subjected to silica gel column chromatography, followed by elution with chloroform - methanol (30 : 1). The obtained crystals are recrystallized from isopropyl alcohol to give the desired compound (0.72 g). m.p. 215° to 218° C.
Reaction SMILES: N[C:2]1C=CC2N=CSC=2C=1.[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH:25]1[C:30]([NH:31][NH2:32])=[CH:29][CH:28]=[C:27]([S:33]([NH2:36])(=[O:35])=[O:34])[CH:26]=1.Cl>>[S:11]1[C:22]2[C:14](=[CH:15][CH:16]=[C:17]3[C:21]=2[C:20](=[O:23])[C:19](=[O:24])[NH:18]3)[N:13]=[CH:12]1.[CH3:2][NH:36][S:33]([C:27]1[CH:26]=[CH:25][C:30]([NH:31][N:32]=[C:20]2[C:21]3[C:17](=[CH:16][CH:15]=[C:14]4[C:22]=3[S:11][CH:12]=[N:13]4)[NH:18][C:19]2=[O:24])=[CH:29][CH:28]=1)(=[O:34])=[O:35]
Reactant: Nc1ccc2ncsc2c1
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Agent: O=C1Nc2ccc3ncsc3c2C1=O
Product: CNS(=O)(=O)c1ccc(NN=C2C(=O)Nc3ccc4ncsc4c32)cc1

Procedure:
6H-1-Thia-3,6-diaza-as-indacene-7,8-dione was prepared from 6-aminobenzothiazole according to Procedure A: 1H NMR (DMSO-d6): δ 7.10 (d, J=8.4 Hz, 1H), 8.31 (d, J=8.5 Hz, 1H), 9.35 (s, 1H), 11.19 (s, 1H); ESI-MS m/z 204 (M)−. The title compound was prepared from 6H-1-thia-3,6-diaza-as-indacene-7,8-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>260° C.; 1H NMR (DMSO-d6): δ 2.39 (d, J=5.1 Hz, 3H), 7.12 (d, J=8.4 Hz, 1H), 7.32 (q, J=5.1 Hz, 1H), 7.63 (d, J=8.8 Hz, 2H), 7.76 (d, J=8.7 Hz, 2H), 7.99 (d, J=8.6 Hz, 1H), 9.30 (s, 1H), 11.26 (s, 1H), 12.69 (s, 1H); APCI-MS m/z 387 (M)−. Anal. Calcd for C16H13N5O3S2.0.33H2O: C, 48.85; H, 3.50; N, 17.80; S, 16.30. Found: C, 48.89; H, 3.40; N, 17.67; S, 16.23.
Reaction SMILES: [F:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([CH3:11])[C:8]([OH:10])=O)=[CH:4][CH:3]=1>O>[F:1][C:2]1[CH:3]=[C:4]2[C:5]([CH2:6][CH:7]([CH3:11])[C:8]2=[O:10])=[CH:12][CH:13]=1
Reactant: CC(Cc1ccc(F)cc1)C(=O)O
Solvent: O
Product: CC1Cc2ccc(F)cc2C1=O
Temperature: 95 °C
Reaction time: 1 h

Procedure:
To 932 g polyphosphoric acid at 70° C. (on the steam bath) is added p-fluoro-α-methylhydrocinnamic acid (93.2 g, 0.5 mol) slowly with stirring. The temperature is gradually raised to 95° C., and the mixture is kept at this temperature for 1 hour. The mixture is allowed to cool and added to 2 1. of water. The aqueous layer is extracted with ether, the ether solution is washed twice with saturated sodium chloride solution, 5% Na2CO3 solution, water, and is then dried. The ether filtrate is concentrated with 200 g silica-gel, and is added to a five pound silica-gel column packed with 5% ether-petroleum ether. The column is eluted with 5-10% ether-petroleum ether, to give 6-fluoro-2-methylindanone. Elution is followed by TLC.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:13])=[C:5]([C:9]([CH3:12])=[CH:10][CH:11]=1)[C:6](O)=[O:7])#[N:2].B.O.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:1]([C:3]1[C:4]([CH3:13])=[C:5]([CH2:6][OH:7])[C:9]([CH3:12])=[CH:10][CH:11]=1)#[N:2]
Reactant: Cc1ccc(C#N)c(C)c1C(=O)O
Agent: B
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(C#N)c(C)c1CO
Yield: 37.1 %

Procedure:
A solution of 3-cyano-2,6-dimethylbenzoic acid (8.11 grams, 0.049 mole) in tetrahydrofuran (100 ml) was cooled to 0°. Borane (48.7 grams, 0.049 mole) in tetrahydrofuran was added dropwise over a 20 minute period. The mixture was allowed to come to room temperature, and water was added. Potassium carbonate was added to separate the layers. The aqueous layer was extracted with diethyl ether. The extract was added to the organic phase, which was dried over magnesium sulfate, filtered, and the solvent evaporated to give (3-cyano-2,6-dimethylphenyl)methanol (2.93 grams).
Reaction SMILES: [CH3:1][C:2]1[C:7]2[N:8]=[C:9]([NH:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[O:10][C:6]=2[CH:5]=[C:4]([CH2:19]C(O)=O)[CH:3]=1.F[P-](F)(F)(F)(F)F.N1([O:39][C:40](N(C)C)=[N+:41](C)C)C2N=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.N[C:57]1[CH:62]=[CH:61][N:60]=[C:59]([CH:63]([CH3:70])[CH2:64][C:65]([O:67][CH2:68][CH3:69])=[O:66])[CH:58]=1>CN(C)C=O.O>[CH2:68]([O:67][C:65](=[O:66])[CH2:64][CH:63]([C:59]1[CH:58]=[CH:57][C:62]([NH:41][C:40](=[O:39])[CH2:19][C:4]2[CH:3]=[C:2]([CH3:1])[C:7]3[N:8]=[C:9]([NH:11][C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=4[CH3:18])[O:10][C:6]=3[CH:5]=2)=[CH:61][N:60]=1)[CH3:70])[CH3:69]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CCOC(=O)CC(C)c1cc(N)ccn1
Reactant: Cc1ccccc1Nc1nc2c(C)cc(CC(=O)O)cc2o1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CC(C)c1ccc(NC(=O)Cc2cc(C)c3nc(Nc4ccccc4C)oc3c2)cn1
Reaction time: 1 h

Procedure:
A stirred solution of 2-(4-methyl-2-o-tolylamino-benzoxazol-6-yl)acetic acid (0.13 g, Reference Example 9) in dimethylformamide (5 mL) was treated with O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (0.166 g), diisopropylethylamine (0.153 mL) and then with a solution of ethyl (3RS)-3-(4-aminopyrid-2-yl)butyrate (0.091 g, Reference Example 5) in dimethylformamide (5 mL). After stirring for 1 hour and then standing at room temperature over night the reaction mixture was diluted with water and then extracted with t-butyl methyl ether. The extracts were dried over magnesium sulphate and then evaporated to give (3RS)-3-{5-[2-(4-methyl-2-o-tolylamino-benzoxazol-6-yl)acetylamino]pyrid-2-yl}butyric acid ethyl ester as a gum. A solution of this gum in ethanol was treated with aqueous lithium hydroxide solution (1M) and after stirring at room temperature for 1 hour the mixture was partially evaporated. The residue was acidified to pH 6-7 by addition of concentrated hydrochloric acid. This mixture was extracted with ethyl acetate. The extracts were dried over magnesium sulphate and then evaporated to give the title compound (0.012 g) as a cream solid. MS (ES negative): 457(MH−).
Reaction SMILES: [C:1]1([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH:7][C:8](=[O:29])[O:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][N:18]([C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]O)[CH3:19])[CH2:12][CH2:11]1.[CH3:36][NH:37][C:38]1[CH:50]=[CH:49][C:41]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])=[CH:40][CH:39]=1>>[C:45]([O:44][C:42](=[O:43])[C:41]1[CH:49]=[CH:50][C:38]([N:37]([CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][C:20]([N:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][CH:10]([O:9][C:8](=[O:29])[NH:7][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:11][CH2:12]2)[CH3:19])=[O:28])[CH3:36])=[CH:39][CH:40]=1)([CH3:47])([CH3:46])[CH3:48]
Reactant: CNc1ccc(C(=O)OC(C)(C)C)cc1
Reactant: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCO
Product: CN(CCN1CCC(OC(=O)Nc2ccccc2-c2ccccc2)CC1)C(=O)CCCCCCN(C)c1ccc(C(=O)OC(C)(C)C)cc1
Yield: 25.9 %

Procedure:
The compound (163 mg, 0.338 mmol) obtained in Example 39b was used according to the method described in Example 4g to give a crude aldehyde compound (160 mg). The resulting crude aldehyde compound and the compound (69 mg, 0.334 mmol) obtained in Example 35a were used a to give the title compound (58 mg; yield, 26%) as a white solid according to the method described in Example 18b.
Reaction SMILES: [C:1]1([Mg]Br)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:9][C:10]1[C:17]([Cl:18])=[CH:16][CH:15]=[CH:14][C:11]=1[C:12]#[N:13].[C:19](Cl)(=O)[O:20]C.Cl.C(=O)(O)[O-].[Na+]>C1COCC1.CC(OC)(C)C>[Cl:18][C:17]1[CH:16]=[CH:15][CH:14]=[C:11]2[C:10]=1[NH:9][C:19](=[O:20])[N:13]=[C:12]2[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1cccc(Cl)c1N
Reactant: COC(=O)Cl
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: O=c1nc(-c2ccccc2)c2cccc(Cl)c2[nH]1
Yield: 81.1 %

Procedure:
To 7.10 g of phenylmagnesium bromide (32% THF solution) was added dropwise a solution of 953 mg of 2-amino-3-chlorobenzonitrile in THF (7 ml) at room temperature, followed by heating under reflux for 30 minutes. To the resulting reaction product was added dropwise 885 mg of methyl chlorocarbonate under ice cooling, followed by heating under reflux for 40 minutes. The resulting reaction solution was cooled and poured into 40 ml of 2N-hydrochloric acid, and 8 g of sodium bicarbonate and 20 ml of MTBE were added thereto, followed by stirring. Then, precipitated crystals were collected by filtration to obtain 1.30 g of the titled compound. 1H NMR (DMSO-d6): 7.24(1H, t, J=8.0 Hz), 7.57-7.70 (6H, m), 7.90-7.93 (1H, m), 11.45 (1H,br. s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][NH:10][C:9]2=[O:18])=[CH:4][CH:3]=1.[H-].[Na+].[H][H].[C:23](OC)(=O)C(OC)=O>O.CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:13]3[N:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][N:10]([CH3:23])[C:9]2=[O:18])=[CH:6][CH:7]=1
Reactant: O=C1NCc2cccnc2N1c1ccc(F)cc1
Reactant: COC(=O)C(=O)OC
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN1Cc2cccnc2N(c2ccc(F)cc2)C1=O
Temperature: 170 °C
Yield: 63 %

Procedure:
To a solution of 2.4 g of 1-(p-fluorophenyl)-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine and 15 ml of dimethylformamide was added 0.5 g of approximately 50% sodium hydride, and the mixture was allowed to stand until the evolution of hydrogen ceased. To this was further added 5.9 g of dimethyl oxalate and the resulting mixture was heated at 170° C in a sealed-tube for 12 hours. After the reaction was complete, the solvent was removed from the reaction mixture by distillation under reduced pressure. The residue thus obtained was diluted with water, extracted with ether and dehydrated. The ether solution was concentrated and left to give 1.6 g of 1-(p-fluorophenyl)-3-methyl-2-oxo-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidine as colorless needles, melting at 212° - 213° C.
Reaction SMILES: O1[CH2:6][CH2:5][N:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[NH:13][C:14]#[N:15])[CH2:3][CH2:2]1.[CH3:16][NH:17][CH3:18].ClCCl.[Cl-].[Na+].[OH2:24]>>[CH3:16][N:17]([CH3:18])[C:14]([NH2:15])=[N:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[N:4]1[CH2:5][CH2:6][O:24][CH2:2][CH2:3]1
Reactant: CNC
Reactant: O
Reactant: N#CNc1ccccc1N1CCOCC1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Product: CN(C)C(N)=Nc1ccccc1N1CCOCC1
Reaction time: 0.08 h

Procedure:
A mixture of N-(2-morpholinophenyl)cyanamide (1.5 g) and a 33% ethanolic solution of dimethylamine (12 ml) was heated under reflux for 4 hours. Removal of solvent gave a residue to which was added dichloromethane (100 ml) and brine (50 ml). The mixture was stirred for 5 minutes and the organic layer separated and dried. Removal of the solvent gave 1,1-dimethyl-2-(2-morpholinophenyl)guanidine (m.p. 144°-145° C.) which was recrystallised from hexane.
Reaction SMILES: Br[CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1O.[F:14][C:15]([F:26])([F:25])[C:16]1[CH:24]=[CH:23][C:19]([C:20]([NH2:22])=[O:21])=[CH:18][CH:17]=1.[K+].[Br-].CN(C)C=[O:32]>>[OH:32][CH:2]1[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][S:12][C:4]=2[CH:3]1[NH:22][C:20](=[O:21])[C:19]1[CH:23]=[CH:24][C:16]([C:15]([F:25])([F:26])[F:14])=[CH:17][CH:18]=1
Reactant: NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC1(C)Oc2ccsc2C(O)C1Br
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [K+]
Product: CC1(C)Oc2ccsc2C(NC(=O)c2ccc(C(F)(F)F)cc2)C1O

Procedure:
The title compound was prepared as described in Example 3 starting with 6-bromo-7-hydroxy-5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]pyran (4.5 g, 17.1 mmol) and 4-trifluoromethylbenzamide (7.43 g, 39.3 mmol) in N,N-dimethylformamide (75 mL) to give the product, 1.96 g (31%), as a colorless solid: mp 162°-163° C.; IR (KBr): 3396, 1664, 1534 and 1507 cm-1 ; MS: m/z 372 (MH+); 1NMR (DMSO-d6): δ 1.21 (s, 3H), 1.40 (s, 3H), 3.80 (m, 1H, simplifies to d, J=8.7 Hz, with D2O), 5.01 (m, 1H, simplifies to d, J=8.7 Hz, with D2O), 5.68 (d, J=6.0 Hz, 1H, exchanges with D2O), 6.59 (d, J 5.7 Hz, 1H), 7.31 (d, J=5.7 Hz, 1H), 7.88 (d, J=8.3 Hz, 2H), 8.11 (d, J=8.3 Hz, 2H) and 9.05 (d, J=8.4 Hz, 1H exchanges with D2O).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:20][CH3:21])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=3)[C:6]=2[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][C:29]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1)[NH2:26]>C(O)(=O)C.C1COCC1>[F:22][C:23]1[CH:24]=[C:25]([NH:26][C:2]2[N:3]=[C:4]([NH:20][CH3:21])[C:5]3[CH2:10][CH2:9][CH:8]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([F:18])=[C:13]([F:19])[CH:12]=4)[C:6]=3[N:7]=2)[CH:27]=[CH:28][C:29]=1[N:30]1[C:34]([CH3:35])=[N:33][CH:32]=[N:31]1
Reactant: Cc1ncnn1-c1ccc(N)cc1F
Reactant: CNc1nc(Cl)nc2c1CCC2c1cc(F)c(F)c(F)c1
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CNc1nc(Nc2ccc(-n3ncnc3C)c(F)c2)nc2c1CCC2c1cc(F)c(F)c(F)c1
Temperature: 80 °C

Procedure:
2-Chloro-N-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (65.3 mg, 0.208 mmol) was added to a solution of 3-fluoro-4-(5-methyl-1H-1,2,4-triazol-1-yl)aniline (40 mg, 0.208 mmol) in acetic acid (2 mL) and THF (2.000 mL). The reaction mixture was heated at 80° C. overnight. Partial formation of the desired product was observed. The reaction mixture was heated at 130° C. for 6 h. The crude reaction mixture was purified by preparative HPLC. The appropriate fractions were evaporated to afford N2-(3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine, TFA salt (5.3 mg, 8.99 μmol, 4.32% yield). LC-MS (M+H)+=470.0. 1H NMR (500 MHz, CDCl3) δ ppm 12.17 (1H, s), 8.75 (1H, d, J=1.8 Hz), 8.05 (1H, dd, J=13.7, 2.1 Hz), 7.80 (1H, t, J=8.7 Hz), 7.44-7.65 (1H, m), 6.74-6.99 (2H, m), 5.33-5.66 (1H, m), 4.34-4.67 (1H, m), 3.42-3.74 (2H, m), 3.29 (3H, d, J=4.9 Hz), 2.70-2.99 (2H, m), 2.57 (2H, s), 2.14-2.38 (1H, m).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[CH:7]=[CH:6][C:5]=1[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)([O-])=O.O.Cl>CCO>[CH3:20][N:17]1[CH2:18][CH2:19][CH:14]([NH:13][C:5]2[C:4]([NH2:1])=[CH:9][C:8]([N+:10]([O-:12])=[O:11])=[CH:7][CH:6]=2)[CH2:15][CH2:16]1
Reactant: CN1CCC(Nc2ccc([N+](=O)[O-])cc2[N+](=O)[O-])CC1
Agent: Cl
Solvent: O
Solvent: CCO
Product: CN1CCC(Nc2ccc([N+](=O)[O-])cc2N)CC1
Temperature: 65 °C
Yield: 25.5 %

Procedure:
(2,4-Dinitro-phenyl)-(1-methyl-piperidin-4-yl)-amine 51 (1.50 g, 5.352 mmol) was dissolved in anhydrous EtOH (20 mL) in a 2 neck 250 mL argon purged flask. The reaction vessel was fitted with a condenser and dropping funnel and heated in an oil bath to 65° C. H2O (20 mL), EtOH (40 mL) and aqueous (NH4)2S (50 wt %, 2.55 g, 18.73 mmol) were charged to the dropping funnel and added to the hot reaction mixture dropwise over 30 minutes. The reaction was heated at 75° C. for 2 hours then cooled to room temperature overnight. Mixture was acidified by the addition of aqueous 4M HCl to adjust pH to 2. The reaction mixture was filtered to remove any insoluble material and the filtrate was concentrated under reduced pressure to remove EtOH. The resulting aqueous solution was basified by the addition of aqueous 2M ammonium hydroxide solution to adjust pH to 10. The aqueous solution was diluted with dichloromethane and transferred to a separatory funnel and the organic layer collected. The aqueous layer was further extracted with dichloromethane and the combined organic layers were washed with H2O, brine, and dried over magnesium sulphate, filtered and concentrated to afford a dark red oil. The product was purified using silica gel dry column chromatography with a solvent system of 5% 2M NH3 in methanol/95% dichloromethane to afford an orange solid 52 N1-(1-Methyl-piperidin-4-yl)-4-nitro-benzene-1,2-diamine Yield: 0.342 grams (25.5%). 1H NMR (DMSO) δ: 1.42-1.55 (m, 2H), 1.89-1.93 (m, 2H), 1.97-2.05 (m, 2H), 2.17 (s, 3H), 2.70-2.81 (m, 2H), 3.30-3.42 (m, 1H), 5.20 (br s, 2H), 5.63 (br d, 1H, J=7.4), 6.53 (d, 1H, J=9.0), 7.39 (d, 1H, J=2.9), 7.49 (dd, 1H, J=8.9, 2.7); MS (ESI): 251 (MH+, 100%).
Reaction SMILES: [N+:1]([C:4]1[C:5]([OH:14])=[C:6]([O:12][CH3:13])[CH:7]=[C:8]([CH:11]=1)[CH:9]=[O:10])([O-:3])=[O:2].[CH2:15](I)[CH2:16][CH3:17].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:15]([O:14][C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[CH:11][C:8]([CH:9]=[O:10])=[CH:7][C:6]=1[O:12][CH3:13])[CH2:16][CH3:17]
Reactant: COc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCOc1c(OC)cc(C=O)cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 24 h
Yield: 49.4 %

Procedure:
A mixture of 5-nitrovanillin (10 g), propyl iodide (25 g), potassium carbonate (10 g) and N,N-dimethylformamide (200 ml) is stirred at 100° C. for 24 hours. After cooling, water (500 ml) is added to the reaction mixture, followed by extraction with ethyl acetate (200 ml). The extract solution is washed with water, dried and, then, distilled off under reduced pressure. The residue is purified by means of a silica gel column chromatography (hexane: ethyl acetate=2:1-1:1) to afford 4-propoxy-3-methoxy-5-nitrobenzaldehye (6 g) as a pale yellow oily product. This product is dissolved in acetone (200 ml), and potassium permanganate (18 g) is added to the solution. The mixture is stirred at room temperature overnight. To the reaction mixture are added ethanol (50 ml), water (50 ml) and acetone (200 ml). The whole mixture is stirred for two hours, and filtered off. The filtrate is concentrated under reduced pressure. Precipitating crystals are collected by filtration to give 3-methoxy- 5-nitro-4-propoxy benzoic acid (2.2 g) as colorless crystals. This product is recrystallized from a mixture of ethanol and water to give colorless needles, m.p. 121°-123° C.