Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([O:10]C(=O)C)=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15].C(=O)([O-])[O-].[K+].[K+].O.Cl>CO>[OH:1][C:2]1[C:7]([CH3:8])=[C:6]([CH3:9])[C:5]([OH:10])=[CH:4][C:3]=1[C:14](=[O:16])[CH3:15]
Reactant: CC(=O)Oc1cc(C(C)=O)c(O)c(C)c1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(=O)c1cc(O)c(C)c(C)c1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.3 %

Procedure:
The phenylethanone of Step 2 (500 mg) was dissolved in MeOH (20 mL), and potassium carbonate (1 eq.) was added followed by water (1 mL). The mixture was stirred at room temperature for 1 h, and then was poured into water. The solution was acidified with HCl and a precipitate was formed. The precipitate was collected and air dried to give about 350 mg of 1-(2,5-dihydroxy-3,4-dimethyl-phenyl)-ethanone.
Reaction SMILES: [CH3:1][C:2]1[C:3](N2C=NC=N2)=[N:4][C:5](=[O:8])[NH:6][CH:7]=1.C[O-].[Na+].[C:17](O)(=[O:19])C>CO>[CH3:17][O:19][C:3]1[C:2]([CH3:1])=[CH:7][NH:6][C:5](=[O:8])[N:4]=1
Reactant: CC(=O)O
Reactant: Cc1c[nH]c(=O)nc1-n1cncn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc(=O)[nH]cc1C
Yield: 91.7 %

Procedure:
1.06 g (6 mmol) of 5-methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-one are boiled under reflux with 972 mg (18 mmol) of sodium methylate in 30 ml of anhydrous methanol for 4 hours with exclusion of moisture. The cooled solution is neutralized with acetic acid, concentrated and chromatographed on silica gel using ethyl acetate/methanol 9/1. 770 mg (91.7% of theory) of 4-methoxy-5-methylpyrimidin-2(1H)-one are obtained with melting point 196°-199° C. 1H NMR (270 MHz, d6 -DMSO), δ[ppm]: 11.09 (s, 1H), 7.51 (d, 1H), 3.83 (s, 3H), 1.85 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:25][CH2:24][C@H:23]([CH2:26]O)[O:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CS(OS(C)(=O)=O)(=O)=O.[N-:46]=[N+:47]=[N-:48].[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.CS(C)=O>[CH2:1]([O:8][C:9](=[O:29])[NH:10][C@@H:11]([CH3:28])[CH2:12][N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]3[O:25][CH2:24][C@H:23]([CH2:26][N:46]=[N+:47]=[N-:48])[O:22][C:20]3=2)[CH:15]=[N:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CO)CO3)NC(=O)OCc1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: C1CCOC1
Product: C[C@@H](Cn1ncc2ccc3c(c21)O[C@@H](CN=[N+]=[N-])CO3)NC(=O)OCc1ccccc1
Temperature: 95 °C
Yield: 63.6 %

Procedure:
To a ° C. stirred solution of the alcohol from Step B of Example 1 (0.43 g, 1.08 mmol) in anhydrous tetrahydrofuran (30 mL) was added triethylamine (0.88 g, 8.6 mmol) and methanesulfonic anhydride (0.76 g, 4.4 mmol) under nitrogen atmosphere. After 1 h the volatiles were evaporated. To the residue was added anhydrous DMSO (30 mL) and sodium azide (0.7 g, 11 mmol). The resulting mixture was heated at 85° C. for 3 h, 95° C. for 1 h, cooled, mixed with a saturated aqueous solution of sodium bicarbonate (100 mL) and extracted with ethyl acetate (50 mL×3). Chromatography on silica eluting with a gradient of 15% to 60% ethyl acetate/hexane gave an oil (0.29 g, 63%): LCMS (+APCI) 423 (M+H).
Reaction SMILES: F[C:2]1[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=1.[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[C:15]([O:20][CH3:21])[CH:14]=1)[CH3:12].[OH-].[K+]>C(#N)C>[CH2:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][C:2]2[C:3]([N+:8]([O-:10])=[O:9])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:15]([O:20][CH3:21])[CH:14]=1)[CH3:12]
Reactant: CCc1ccc(O)c(OC)c1
Reactant: O=[N+]([O-])c1ncccc1F
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: CCc1ccc(Oc2cccnc2[N+](=O)[O-])c(OC)c1
Temperature: 80 °C
Yield: 84.2 %

Procedure:
To a stirred solution of 3-Fluoro 2-nitro pyridine (1.6 g, 0.01126 mol) in dry Acetonitrile (20 ml) was added 4-Ethyl-2-methoxy phenol (1.71 g, 11.3 mmol) in dry acetonitrile (10 ml) followed by potassium hydroxide (0.696 g, 12.4 mmol). The reaction mixture was heated to 80° C. and maintained for 2 hours. The solvent was evaporated and taken in ethyl acetate (200 ml). The organic layer was washed with water followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 2.6 g of crude product purified by column chromatography (5% Ethyl acetate in Petroleum ether) to yield: 1.75 g (56%) of title compound.
Reaction SMILES: [Cl:1][C:2]1[C:3](C2OC(C)(C)C(C)(C)O2)=[CH:4][C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.Br[C:33]1[C:34]([CH3:41])=[CH:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.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>[Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([S:9]([N:12]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]3[CH:19]=[CH:20][CH:21]=[CH:22][C:13]2=3)(=[O:11])=[O:10])=[CH:4][C:3]=1[C:33]1[C:34]([CH3:41])=[CH:35][C:36]([C:39]#[N:40])=[N:37][CH:38]=1
Reactant: CC1(C)OC(c2cc(S(=O)(=O)N3CCCCc4ccccc43)c(O)cc2Cl)OC1(C)C
Reactant: Cc1cc(C#N)ncc1Br
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C#N)ncc1-c1cc(S(=O)(=O)N2CCCCc3ccccc32)c(O)cc1Cl
Temperature: 100 °C
Yield: 73.4 %

Procedure:
5-Chloro-2-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-4-(4,4,5,5-tetramethyl-[1,3]dioxolan-2-yl)-phenol (153.0 mg, 0.33 mmol), 5-bromo-4-methyl-pyridine-2-carbonitrile (60 mg, 0.30 mmol), Pd(Ph3P)4 (38 mg, 0.03 mmol) and K2CO3 (138 mg, 1.0 mmol) in a mixture of dioxane (4 mL) and water (0.4 mL) was degassed with N2 for 5 min. The reaction vessel was sealed and then heated at 100° C. for 16 hrs. The mixture was then partitioned between ethyl acetate (20 mL) and water (10 mL). The organic layer was washed with brine (2×10 mL) and dried over MgSO4. After filtration and concentration, the material was purified by TLC plates eluting with ethyl acetate in hexanes (1/3) to give 5-[2-chloro-4-hydroxy-5-(2,3,4,5-tetrahydro-benzo[b]azepine-1-sulfonyl)-phenyl]-4-methyl-pyridine-2-carbonitrile 8-1 as a white solid (100 mg). MS: 453.9 (M+H)+; tR=8.37 min (method 2).
Reaction SMILES: [CH3:1][NH:2][CH3:3].C1(C2CCCCCCCCCC=2)CCCCCCCCNN=1.[C:26]([C:29]12[CH2:38][CH:33]3[CH2:34][CH:35]([CH2:37][C:31]([CH2:39][OH:40])([CH2:32]3)[CH2:30]1)[CH2:36]2)(O)=[O:27]>CN(C=O)C>[OH:40][CH2:39][C:31]12[CH2:37][CH:35]3[CH2:34][CH:33]([CH2:38][C:29]([C:26](=[O:27])[N:2]([CH3:3])[CH3:1])([CH2:36]3)[CH2:30]1)[CH2:32]2
Reactant: O=C(O)C12CC3CC(CC(CO)(C3)C1)C2
Reactant: CNC
Agent: C1=C(C2=NNCCCCCCCC2)CCCCCCCCC1
Solvent: CN(C)C=O
Product: CN(C)C(=O)C12CC3CC(CC(CO)(C3)C1)C2
Temperature: 100 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
In an atmosphere of nitrogen, 10 mmole of 1-carboxy-3-hydroxymethyladamantane obtained by the method of Example 73 was dissolved in 10 ml of DMF. To the mixture, 15 mmole of N,N′-carbodiimidazol in the form of powder was added in one portion. After stirring for 1 hour at the room temperature, 15 mmole of dimethylamine and 15 mmole of diazabicycloundecene were added. The mixture was heated to 100° C. and stirred f or 8 hours. As a result, the conversion of 1-carboxy-3-hydroxymethyladamantane was 99%, and 1-hydroxymethyl-3-(N,N-dimethylcarbamoyl)adamantane (yield 95%) was formed.
Reaction SMILES: [C:1]([CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])([O:3][CH3:4])=[O:2].[C:17](OC(C)=C)(=[O:19])[CH3:18].S(=O)(=O)(O)O>>[C:17]([O:16][C:12]1[CH2:13][CH2:14][CH2:15][C:11]=1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])(=[O:19])[CH3:18]
Reactant: COC(=O)CCCCCCC1CCCC1=O
Reactant: C=C(C)OC(C)=O
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCC1=C(OC(C)=O)CCC1
Temperature: 25 °C

Procedure:
This preparation illustrates methods for preparing 1-acyloxy-2-(carboalkoxy-alkyl)-cyclopent-1-ene. In this example, 26.5 g. of 2-(6-carbomethoxy-hexyl)-1-oxo-cyclopentane is added to 250 ml. of isopropenyl acetate containing 0.4 ml. of concentrated sulfuric acid. The mixture is then slowly distilled for 21/2 hours and then cooled to room temperature and poured into an ice saturated solution of aqueous sodium bicarbonate. The mixture is then extracted with methylene chloride. The methylene chloride extract is washed with water and then washed with saturated brine, then dried over anhydrous sodium sulfate and evaporated to dryness affording a crude residue of 1-acetoxy-2-(6-carbomethoxyhexyl)-cyclopent-1-ene, which is further purified by high vacuum distillation.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=2[N:11]=[C:12](S(C)(=O)=O)[N:13]=1.[NH2:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([CH:23]([CH3:25])[CH3:24])[C:10]=2[N:11]=[C:12]([NH:26][CH:27]([CH2:30][OH:31])[CH2:28][OH:29])[N:13]=1
Reactant: CC(C)n1c(=O)ccc2c(-c3ccccc3F)nc(S(C)(=O)=O)nc21
Reactant: NC(CO)CO
Product: CC(C)n1c(=O)ccc2c(-c3ccccc3F)nc(NC(CO)CO)nc21

Procedure:
The product of Example 52, and serinol were reacted by the procedure of Example 60 to afford the title compound 4-(2-fluoro-phenyl)-2-(2-hydroxy-1-hydroxymethyl-ethylamino)-8-isopropyl-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 1.54 (m, 6H), 3.80 (m, 4H), 4.11 (m, 1H), 5.75 (m, 1H), 6.19 (d, 1H, J=9.8), 6.38 (br s, 1H), 7.01-7.21 (m, 2H), 7.30-7.49 (m, 3H). LC MS (m/e)=373 (MH+).
Reaction SMILES: [CH:1](C1C=C(C=CC=1O)N)([CH3:3])[CH3:2].[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[CH:27]1[C:32]([NH:33][NH2:34])=[CH:31][CH:30]=[C:29]([S:35]([NH2:38])(=[O:37])=[O:36])[CH:28]=1.Cl>>[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][C:21]=1[CH:22]([CH3:24])[CH3:23])[NH:18][C:17](=[O:25])[C:16]2=[O:26].[OH:12][C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:1]([CH3:3])[CH3:2])[C:17](=[O:25])[C:16]2=[N:34][NH:33][C:32]1[CH:27]=[CH:28][C:29]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:30][CH:31]=1
Reactant: CC(C)c1cc(N)ccc1O
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: CC(C)c1cc2c(cc1O)C(=O)C(=O)N2
Agent: Cl
Product: CC(C)N1C(=O)C(=NNc2ccc(S(N)(=O)=O)cc2)c2cc(O)ccc21

Procedure:
5-Hydroxy-6-isopropyl-1H-indole-2,3-dione was prepared from 3-isopropyl-4-hydroxyaniline according to Procedure A: 1H NMR (DMSO-d6): δ 1.12 (d, J=6.8 Hz, 6H), 3.21 (septet, J=6.9 Hz, 1H), 6.62 (s, 1H), 6.82 (s, 1H), 9.51 (s, 1H), 10.61 (s, 1H); ESI−MS m/z 204 (M−H)−. The title compound was prepared from 5-hydroxy-6-isopropyl-1H-indole-2,3-dione and 4-sulfonamidophenylhydrazine hydrochloride according to Procedure G: mp>250° C.; 1H NMR (DMSO-d6): δ 1.12 (d, J=7.0 Hz, 6H), 3.21 (septet, J=6.8 Hz, 1H), 6.62 (s, 1H), 6.97 (s, 1H), 7.21 (s, 2H), 7.45 (d, J=8.9 Hz, 2H), 7.75 (d, J=8.7 Hz, 2H), 9.11 (s, 1H), 10.70 (s, 1H), 12.74 (s, 1H); ESI−MS m/z 373 (M−H)−. Anal. Calcd for C17H18N4O4S: C, 54.53; H, 4.85; N, 14.96; S, 8.56. Found: C, 54.37; H, 4.95; N, 14.84; S, 8.48.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:5]=[C:4]([C:17]2[CH:22]=[CH:21][C:20]([NH:23]C(=O)C)=[CH:19][CH:18]=2)[C:3]=1[C:27]#[N:28].Cl>C(O)C.O>[NH2:1][C:2]1[C:3]([C:27]#[N:28])=[C:4]([C:17]2[CH:18]=[CH:19][C:20]([NH2:23])=[CH:21][CH:22]=2)[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[N:11]=2)[N:7]=1
Reactant: CC(=O)Nc1ccc(-c2nc(SCc3cccc(C)n3)nc(N)c2C#N)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: Cc1cccc(CSc2nc(N)c(C#N)c(-c3ccc(N)cc3)n2)n1
Temperature: 80 °C
Yield: 46.9 %

Procedure:
The compound (5.5 g) of Example 2 was suspended in a mixture of 50 mL of ethanol and 50 mL of water, and to the suspension was added 50 mL of 5N hydrochloric acid, and the resulting mixture was heated at 80° C. for 5 hours under stirring. After cooling the reaction mixture, the ethanol was removed under reduced pressure, and the residue was neutralized with 5N aqueous sodium hydroxide at ice temperature. The resulting crystal was filtrated, and recrystallized with ethanol to give 2.3 g of 4-amino-6-(4-aminophenyl)-2-(6-methylpyridin-2-ylmethylsulfanyl)-pyrimidine-5-carbonitrile as a light yellow powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:28]([CH:32]3[CH2:34][CH2:33]3)([C:29]([NH2:31])=O)[C:27](=[O:35])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:23])([F:22])[F:21])[N:9]=2)[N:7]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1>[NH2:1][C:2]1[C:3]2[C:28]([CH:32]3[CH2:34][CH2:33]3)([C:29]#[N:31])[C:27](=[O:35])[NH:26][C:4]=2[N:5]=[C:6]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[CH:14][CH:15]=3)[N:10]([CH2:17][CH2:18][C:19]([F:25])([F:24])[C:20]([F:21])([F:23])[F:22])[N:9]=2)[N:7]=1
Reactant: NC(=O)C1(C2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: N#CC1(C2CC2)C(=O)Nc2nc(-c3nn(CCC(F)(F)C(F)(F)F)c4ncccc34)nc(N)c21
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
4-amino-5-cyclopropyl-6-oxo-2-[1-(3,3,4,4,4-pentafluorobutyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidine-5-carboxamide, as described in Example 162, (565 mg, 1.201 mmol) was taken up in pyridine (6 mL) and the solution cooled to 0° C. Phosphorous oxychloride (0.896 ml, 9.61 mmol) was then added dropwise and the reaction mixture was warmed to room temperature. After 15 minutes, the pyridine solvent was concentrated in vacuo and the residue taken up in EtOAc. The mixture was then washed with water, brine and dried over sodium sulfate. The residue was purified by silica gel column chromatography using a hexanes/EtOAc gradient to give the title compound, Chiral separation by SFC provided both enantiomers of the title compound. 1H NMR (500 MHz, DMSO-d6): δ 9.07 (1H, d, J=8.07 Hz), 8.69 (1H, d, J=4.42 Hz), 7.44 (1H, dd, J=8.08, 4.48 Hz), 7.16 (2H, s), 4.93 (2H, t, J=6.82 Hz), 3.08-2.95 (2H, m), 1.80-1.73 (1H, m), 0.93-0.88 (1H, m), 0.65 (2H, d, J=8.31 Hz), 0.55-0.48 (1H, m). m/z=479.1 (M+H).
Reaction SMILES: CCN(C(C)C)C(C)C.[F:10][C:11]([F:28])([F:27])[O:12][C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[O:21][C:20](=[O:23])[C:19]([C:24]([OH:26])=O)=[CH:18]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH2:68])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12>CN(C)C=O>[N:53]1[C:54]([C:62]2[CH:63]=[C:64]([NH:68][C:24]([C:19]3[C:20](=[O:23])[O:21][C:22]4[C:17]([CH:18]=3)=[CH:16][CH:15]=[CH:14][C:13]=4[O:12][C:11]([F:10])([F:28])[F:27])=[O:26])[CH:65]=[CH:66][CH:67]=2)=[CH:55][N:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=12
Reactant: Nc1cccc(-c2cn3ccccc3n2)c1
Reactant: O=C(O)c1cc2cccc(OC(F)(F)F)c2oc1=O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc(-c2cn3ccccc3n2)c1)c1cc2cccc(OC(F)(F)F)c2oc1=O
Temperature: 25 °C
Yield: 46.6 %

Procedure:
DIEA (0.035 mL, 0.20 mmol) was added to 8-(trifluoromethoxy)-3-carboxy-coumarin (0.050 g, 0.18 mmol) and HATU (0.076 g, 0.20 mmol) in 1 mL of dimethylformamide (DMF) with constant stirring at room temperature until a clear solution resulted. Subsequently, 3-imidazo[1,2-a]pyridin-2-yl-phenylamine (0.038 g, 0.18 mmol) was added and allowed to react overnight, when a yellow solid precipitated out of solution. The precipitate was filtered and dried under suction and then in vacuo to give 0.039 g of 1541B in a 46% yield: LCMS (ESI) m/z 466 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21](O)=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:28])([CH3:27])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1.C(N1C=CN=C1)([N:32]1C=CN=C1)=O.N>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:29])=[C:6]([C:8]2[N:13]=[C:12]([NH:14][C:15]3[C:20]([C:21]([NH2:32])=[O:22])=[CH:19][N:18]=[CH:17][CH:16]=3)[C:11]3[CH2:24][C:25]([CH3:27])([CH3:28])[CH2:26][C:10]=3[N:9]=2)[CH:7]=1
Reactant: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(=O)O)c2C1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: CC1(C)Cc2nc(-c3cc(Cl)ccc3F)nc(Nc3ccncc3C(N)=O)c2C1
Temperature: 70 °C

Procedure:
A suspension of 4-[2-(5-Chloro-2-fluoro-phenyl)-6,6-dimethyl-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino]-nicotinic acid (25 mg, 60.56 μmol) and Carbonyldiimidazole (20 mg, 121.11 μmol) in dry DMF (3 mL) was heated at 70° C. for 1 h then cooled to r.t. A stream of NH3 gas was passed through the solution for 30 min., giving clean conversion to the amide product. Evaporation of the solution, followed by HPLC purification gave, after lyophilization, the pure amide 62 as the TFA salt (20 mg).
Reaction SMILES: [Br:1]Br.[CH:3]1([S:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[CH3:13])[CH2:5][CH2:4]1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(O)(=O)C.[Cl-].[Na+].O>[Br:1][C:10]1[CH:11]=[CH:12][C:7]([S:6][CH:3]2[CH2:5][CH2:4]2)=[C:8]([CH3:13])[CH:9]=1
Reactant: BrBr
Reactant: Cc1ccccc1SC1CC1
Agent: O=S([O-])([O-])=S
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Cc1cc(Br)ccc1SC1CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 80 %

Procedure:
Bromine (0.42 mL) was added to a solution of 1-(cyclopropylsulfanyl)-2-methylbenzene (1.35 g) in acetic acid (10 mL) under ice-cooling, and the mixture was stirred at room temperature for 17 hours. The reaction solution was ice-cooled and a saturated sodium thiosulfate solution and brine were added, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and filtered. The solvent was then evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) and the solvent was evaporated under reduced pressure. The precipitated solid was filtered and washed with hexane, after which the filtrate was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane only) to give the title compound as a pale yellow oil (1.59 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])[CH:5]=[CH:6][C:7]=1[Cl:8].[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:20])[CH3:19]>>[C:18]([O:22][C:23]([N:25]1[CH2:30][CH2:29][CH:28]([N:15]2[CH2:16][CH2:17][CH:12]([S:9]([C:4]3[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=3)(=[O:11])=[O:10])[CH2:13][CH2:14]2)[CH2:27][CH2:26]1)=[O:24])([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: O=S(=O)(c1ccc(Cl)c(Cl)c1)C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(S(=O)(=O)c3ccc(Cl)c(Cl)c3)CC2)CC1

Procedure:
The product of step 3 was used in a reductive amination with 4-oxo-piperidine-1-carboxylic acid tert-butyl ester following the procedure of Example 2 step a.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([SH:7])=[N:5][N:6]=1.C(=O)([O-])[O-].[K+].[K+].C(O)C.Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>O>[NH2:1][C:2]1[S:3][C:4]([S:7][CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])=[N:5][N:6]=1
Reactant: CCOC(=O)CBr
Reactant: Nc1nnc(S)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)CSc1nnc(N)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.1 %

Procedure:
To a mixture of 3.9 g of 2-amino-5-mercapto-1,3,4-thiadiazole, 4.2 g of potassium carbonate and 50 ml of ethanol was gradually added 5 g of ethyl bromoacetate under ice cooling. Then, the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 200 ml of water followed by extraction with ethyl acetate. After washing with water, the extract was dried over anhydrous magnesium sulfate and the solvent was distilled off. The solid obtained was washed with toluene and dried to obtain 2.7 g of ethyl [(5-amino-1,3,4-thiadiazol-2-yl)thio]-acetate.
Reaction SMILES: C[O:2][C:3](=O)[C@H:4](C)[N:5]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])C1CCCCC1.[H-].C([Al+]CC(C)C)C(C)C.[CH:31]([Mg]Br)=[CH2:32].[C:35]1([CH3:41])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>>[C:15]([O:14][C:12]([NH:5][C@@H:4]([CH2:41][CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]1)[CH:3]([OH:2])[CH:31]=[CH2:32])=[O:13])([CH3:18])([CH3:17])[CH3:16]
Reactant: Cc1ccccc1
Reactant: C=C[Mg]Br
Reactant: COC(=O)[C@H](C)N(C(=O)OC(C)(C)C)C1CCCCC1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Product: C=CC(O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60 %

Procedure:
To a stirred -78° C. solution of Boc-cyclohexylalanine methyl ester (10.2 g, 35.8 mmol) in dry toluene (60 ml) was added diisobutylaluminum hydride (34 ml of a 1.5 M solution in toluene). After 30 min., vinyl magnesium bromide (108 ml of 1 M solution in tetrahydrofuran (THF)) was added. After stirring for 15 hours at 0° C., the mixture was carefully quenched with methanol, treated with Rochelle Salts (22 ml of saturated aqueous solution in 140 ml H2O), and filtered. After extracting the solids 5 times with ethyl acetate, the extracts and filtrate were combined and the organic phase was washed with brine, dried, filtered and evaporated to an oil (10.2 g). Chromatography on silica gel eluting with hexane/ethyl acetate mixtures provided 6.1 g (60%) of the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][C:19]3=[O:24])=[CH:12][CH:13]=1)=[O:6].[BH4-].[Na+].CC(C)=O>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[C:5]([NH:7][C:8]1[CH:9]=[N:10][C:11]([O:14][C:15]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:16]=2[CH2:17][CH2:18][CH:19]3[OH:24])=[CH:12][CH:13]=1)=[O:6]
Reactant: O=C(Nc1ccc(Oc2cccc3c2CCC3=O)nc1)c1ccc(Cl)c(Cl)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(Nc1ccc(Oc2cccc3c2CCC3O)nc1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 69.6 %

Procedure:
After 413 mg of 3,4-dichloro-N1-{6-[(1-oxo-2,3-dihydro-1H-inden-4-yl)oxy]-3-pyridinyl}benzamide was dissolved in a mixed solvent of 4 ml of tetrahydrofuran and 1 ml of water, 23 mg of sodium tetrahydroborate was added and the mixture was stirred at room temperature. After 4 hours, acetone was added to the reaction solution to decompose excess sodium tetrahydroborate. Then, water was added and the solution was extracted with ethyl acetate. The organic (ethyl acetate) layer was washed with a saturated sodium chloride solution, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. To the resulting oily substance, diethyl ether was added and the deposited crystal was isolated by filtration to obtain 289 mg of the titled compound.