Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13](S(CC3C=CC=CC=3)(=O)=O)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28].[NH2:29][CH:30]1[CH2:35][CH2:34][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:32][CH2:31]1>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[CH2:17][C:16]2[C:11](=[N:12][C:13]([NH:29][CH:30]3[CH2:31][CH2:32][N:33]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH2:34][CH2:35]3)=[N:14][CH:15]=2)[NH:10][C:9]1=[O:28]
Reactant: CCOC(=O)N1CCC(N)CC1
Reactant: O=C1Nc2nc(S(=O)(=O)Cc3ccccc3)ncc2CN1c1ccccc1Cl
Solvent: CO
Product: CCOC(=O)N1CCC(Nc2ncc3c(n2)NC(=O)N(c2ccccc2Cl)C3)CC1
Temperature: 150 °C
Reaction time: 1 h
Yield: 54.8 %

Procedure:
Sulfone 9.1 (1.0 g, 2.41 mmol) was taken up in 5 mL ethyl 4-amino-1-piperidinecarboxylate (29 mmol) and stirred at 150° C. After 1 hour, the reaction slurry was cooled to room temperature, poured into 50 mL methanol, and filtered to collect a white solid. The solid was washed with an additional 50 mL methanol and dried in vacuo to yield 0.569 g of 3-(2-chlorophenyl)-7-(1-ethoxycarbonylpiperidin-4-ylamino)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)[N:8]1[CH:19]([CH3:21])[S:20][C:7]1=[C:6]([C:22]([O:24]CC)=[O:23])[C:5]2=[O:27].[OH-].[K+].C(O)(C)(C)C>O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:18])[C:11]=1[N:12]1[CH2:13][CH2:14][NH:15][CH2:16][CH2:17]1)[N:8]1[CH:19]([CH3:21])[S:20][C:7]1=[C:6]([C:22]([OH:24])=[O:23])[C:5]2=[O:27]
Reactant: CCOC(=O)c1c2n(c3c(F)c(N4CCNCC4)c(F)cc3c1=O)C(C)S2
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: O
Product: CC1Sc2c(C(=O)O)c(=O)c3cc(F)c(N4CCNCC4)c(F)c3n21
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
To 0.5 g of ethyl 6,8-difluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate was added 10 ml of 5% solution of potassium hydroxide in a 3:1 mixture of tert-butanol and water and the mixture was stirred at 60° C. for 30 minutes. tert-Butanol was evaporated therefrom in vacuo and the residue was neutralized with acetic acid. After cooling, the crystals separated out therefrom were collected by filtration, washed with water and then washed with acetone and ether to give 0.43 g of the title product, m.p. 260° C. (decompn.).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12](O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]([O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH:17]1[O:19][CH2:18]1>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1>[OH:19][CH:17]([CH2:16][O:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:18][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:18][CH:17]([OH:19])[CH2:16][O:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CCCCOCC1CO1
Reactant: Oc1ccc(Cc2ccc(O)cc2)cc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Product: CCCCOCC(O)Cc1ccc(Cc2ccc(CC(O)COCCCC)cc2)cc1

Procedure:
bis(p-Hydroxyphenyl)methane (153 g; 67% pure, containing polynuclear homologues), butyl glycidyl ether (232.5 g), and benzyltrimethylammonium chloride (3.85 g) were stirred and heated slowly to 100°, when a mildly exothermic reaction commenced and the temperature rose to 110°. The mixture was kept at 110° for 41/2 hours, 120° for 1 hour, and 150° for 11/2 hours. The product had an epoxy value of 0.19 equiv./kg.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([N:8]([CH3:22])[C:9]2[CH:20]=[CH:19][CH:18]=[C:17]([CH3:21])[C:10]=2[O:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[O:7])=[CH:4][C:3]=1[C:25]1[CH:26]=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]=1[CH3:31].[C:34](Cl)(=O)[C:35](Cl)=O.C(O)C>C(Cl)Cl.CN(C=O)C>[CH2:34]([O:15][C:14](=[O:16])[CH2:13][CH2:12][O:11][C:10]1[C:17]([CH3:21])=[CH:18][CH:19]=[CH:20][C:9]=1[N:8]([C:6](=[O:7])[C:5]1[CH:23]=[CH:24][C:2]([Cl:1])=[C:3]([C:25]2[CH:26]=[N:27][C:28]([C:32]#[N:33])=[CH:29][C:30]=2[CH3:31])[CH:4]=1)[CH3:22])[CH3:35]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(C#N)ncc1-c1cc(C(=O)N(C)c2cccc(C)c2OCCC(=O)O)ccc1Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCOc1c(C)cccc1N(C)C(=O)c1ccc(Cl)c(-c2cnc(C#N)cc2C)c1
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a solution of 3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionic acid (160 mg, 0.35 mmol) in DCM (15 mL) was added oxalyl chloride (45.2 μL, 0.52 mmol) and 1 drop of DMF. The solution was stirred for 30 minutes before addition of ethanol (5 mL). The solution was stirred for a further 30 minutes at which time the solvent was evaporated and the residue purified by preparative TLC [eluent: 50% ethyl acetate in hexane] to yield 3-(2-{[4-chloro-3-(6-cyano-4-methyl-pyridin-3-yl)-benzoyl]-methyl-amino}-6-methyl-phenoxy)-propionic acid ethyl ester 16-1 (125 mg). MS [M+H]: 492.4; tR=5.45 min. (method 4).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:5]2[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.[CH2:29]([CH2:33][C:34](=O)[CH3:35])[C:30]([CH3:32])=O>C1(C)C=CC=CC=1>[CH2:11]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([N:1]3[C:34]([CH3:35])=[CH:33][CH:29]=[C:30]3[CH3:32])=[CH:10][CH:9]=2)[C:5]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[C:6]1[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CC(=O)CCC(C)=O
Reactant: CCOC(=O)c1c(-c2ccccc2)c2cc(N)ccc2n1Cc1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1c(-c2ccccc2)c2cc(-n3c(C)ccc3C)ccc2n1Cc1ccccc1
Yield: 89.2 %

Procedure:
A mixture of ethyl 5-amino-1-benzyl-3-phenyl-1H-indole-2-carboxylate (0.93 g, 2.5 mmol), acetonylacetone (2.5 mL, 21.3 mmol), and toluene (25 mL) was heated at reflux under nitrogen using a Dean-Stark trap for 6 h. The reaction was cooled and concentrated. The residue was then purified by flash silica gel chromatography (hexanes/ethyl acetate 4/1) to afford 1.0 g (89%) of ethyl 1-benzyl-5-(2,5-dimethyl-1H-pyrrol-1-yl)-3-phenyl-1H-indole-2-carboxylate as a white solid: 1H NMR (CDCl3) δ 0.99 (t, J=7.1 Hz, 3 H), 2.00 (s, 6 H), 4.15 (q, J=7.1 Hz, 2 H), 5.83 (s, 2 H), 5.86 (s, 2 H), 7.10-7.51 (m, 13 H); MS (ESI) m/z (MH+) 449; Anal. calcd for C30H28N2O2.0.25 H2O: C, 79.53; H, 6.34; N, 6.18. Found: C, 79.67; H, 6.40; N, 5.91.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([F:10])=[C:7]([OH:9])[CH:8]=1)[CH3:2].N1C=CN=C1.[C:16]([Si:20]([CH3:23])([CH3:22])Cl)([CH3:19])([CH3:18])[CH3:17].C(OCC)C>CN(C=O)C.O>[C:16]([Si:20]([O:9][C:7]1[CH:8]=[C:3]([CH2:1][CH3:2])[CH:4]=[CH:5][C:6]=1[F:10])([CH3:23])[CH3:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CCc1ccc(F)c(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCc1ccc(F)c(O[Si](C)(C)C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 85.3 %

Procedure:
To a 40 ml solution of 16.4 g of 5-ethyl-2-fluorophenol in DMF there were added 9.16 g of imidazole and 19.4 g of t-butyldimethylchlorosilane, and the reaction mixture was stirred at room temperature for 18 hours. After then adding 500 ml of diethyl ether and 500 ml of water to the reaction mixture, the organic layer was washed twice with 100 ml of water and once with 100 ml of saturated aqueous sodium chloride in that order and then dried over anhydrous magnesium sulfate, the desiccant was filtered out, and the filtrate was concentrated under reduced pressure. The residue was distilled to obtain the target compound (25.38 g) as a colorless liquid (boiling point: 133-135° C., 20 mmHg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5](Br)=[CH:6][N:7]=1.[C:20]12(P(C34CC5CC(CC(C5)C3)C4)CCCC)[CH2:29]C3CC(CC(C3)[CH2:21]1)C2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH2:1][C:2]1[C:3]([C:9]2[CH:18]=[CH:17][C:12]([C:13]([O:15][CH3:16])=[O:14])=[C:11]([F:19])[CH:10]=2)=[N:4][C:5]([CH:29]2[CH2:20][CH2:21]2)=[CH:6][N:7]=1
Reactant: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Reactant: COC(=O)c1ccc(-c2nc(Br)cnc2N)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1ccc(-c2nc(C3CC3)cnc2N)cc1F
Temperature: 100 °C
Yield: 472.9 %

Procedure:
To methyl 4-(3-amino-6-bromopyrazin-2-yl)-2-fluorobenzoate (for synthesis see Example 34, Step 2) (300 mg, 0.920 mmol) in toluene (10 mL) and water (1 mL) was added potassium cyclopropyl trifluoroborate (408 mg, 2.76 mmol), di(1-adamantyl)-n-butylphosphine (66.0 mg, 0.184 mmol), cesium carbonate (1499 mg, 4.60 mmol), and palladium(II) acetate (20.65 mg, 0.092 mmol). The reaction mixture was heated in heating block at 100° C. overnight. The reaction mixture was quenched with sat. NH4Cl and extracted with ethyl acetate. The organic extracts were combined, washed with brine, dried over sodium sulfate, filtered and evaporated. The crude was purified by flash chromatography (0 to 80% EtOAc in heptane) yielding methyl 4-(3-amino-6-cyclopropylpyrazin-2-yl)-2-fluorobenzoate (250 mg, 90%). LCMS (m/z): 288.2 (MH+), 0.756 min.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C:11]2[N:20](COCCOC)[C:19](=[O:27])[C:18]3[C:13](=[CH:14][C:15](I)=[CH:16][CH:17]=3)[N:12]=2)[CH:10]=1)=[O:5])C.O=C1C2C(=CC(C3C=CC=CC=3)=CC=2)N=C(N2C=C(C(O)=O)C=N2)N1.[Cl:54][C:55]1[CH:60]=[CH:59][C:58](B(O)O)=[CH:57][CH:56]=1>>[Cl:54][C:55]1[CH:60]=[CH:59][C:58]([C:15]2[CH:14]=[C:13]3[C:18]([C:19](=[O:27])[NH:20][C:11]([N:9]4[CH:10]=[C:6]([C:4]([OH:3])=[O:5])[CH:7]=[N:8]4)=[N:12]3)=[CH:17][CH:16]=2)=[CH:57][CH:56]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(I)ccc3c(=O)n2COCCOC)c1
Agent: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccc(Cl)cc4)ccc3c(=O)[nH]2)c1

Procedure:
The titled compound was prepared in a manner analogous to Example 184, steps C-E using 1-[7-iodo-3-(2-methoxy-ethoxymethyl)-4-oxo-3,4-dihydro-quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (Intermediate from Example 184, product from step B) and 4-chlorophenylboronic acid in step C. MS (ESI): mass calcd. for C18H11ClN4O3, 366.1; m/z found, 367.0 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 12.99 (br s, 2H), 8.97 (d, J=0.6 Hz, 1H), 8.28 (s, 1H), 8.20 (d, J=8.3 Hz, 1H), 7.97 (s, 1H), 7.87 (d, J=8.5 Hz, 2H), 7.83 (dd, J=8.3, 1.7 Hz, 1H), 7.63-7.58 (m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10](=O)[CH2:11]Br)[S:7][CH:6]=1)=[O:4].[CH:14]([NH2:16])=[O:15]>>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[N:16]=[CH:14][O:15][CH:11]=2)[S:7][CH:6]=1)=[O:4]
Reactant: COC(=O)c1csc(C(=O)CBr)c1
Reactant: NC=O
Product: COC(=O)c1csc(-c2cocn2)c1
Temperature: 170 °C

Procedure:
5-(2-Bromo-acetyl)-thiophene-3-carboxylic acid methyl ester (0.4 g, 1.52 mmol) was dissolved in formamide (2 mL) and the tube purged with nitrogen and then sealed. The mixture was heated at 170° C. for 20 minutes. The resultant solution was diluted with HCl (1 M) and water and washed with ethyl acetate. The organic phase was evaporated then purified by chromatography on a silica II cartridge, eluting with 2:1 pentane:DCM to neat DCM, to give the side product, 5-oxazol-4-yl-thiophene-3-carboxylic acid methyl ester as white solid (0.049 g). LCMS m/z 251.35 [M+MeCN+H]+ R. T.=3.07 min (Analytical Method 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[C:11]([C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)#[N:12].C([O-])([O-])=O.[K+].[K+]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:19][C:16]2[CH:17]=[CH:18][C:13]([C:11]#[N:12])=[CH:14][CH:15]=2)=[C:6]([CH:7]=[O:8])[CH:9]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=Cc1cc(Cl)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: N#Cc1ccc(Oc2ccc(Cl)cc2C=O)cc1
Yield: 85.2 %

Procedure:
In a manner similar to the method described in Example 50a, 5-chloro-2-fluoro-benzaldehyde (2 g, 12.8 mmol) (Beta Pharma) was reacted with 4-cyanophenol (1.67 g, 14 mmol) and K2CO3 in N,N-dimethylacetamide to give 4-(4-chloro-2-formyl-phenoxy)-benzonitrile as a light yellow solid (Yield 2.81 g, 85%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:14]1[N:18]2[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[N:22][C:17]2=[N:16][CH:15]=1)CCC>>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([C:14]2[N:18]3[CH:19]=[CH:20][C:21]([C:23]([F:24])([F:25])[F:26])=[N:22][C:17]3=[N:16][CH:15]=2)=[N:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Reactant: Cc1ccc(Br)nc1
Product: Cc1ccc(-c2cnc3nc(C(F)(F)F)ccn23)nc1

Procedure:
2-Bromo-5-methylpyridine (1.29 g, 7.5 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (3.8 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with dichloromethane containing 1% methanol, then crystallisation from toluene/isohexane, gave 3-(5-methylpyridin-2-yl)-7-trifluoromethyl-imidazo[1,2-α]pyrimidine as a yellow solid: δH (400 MHz, CDCl3) 10.48 (1H, d, J 7), 8.50-8.52 (1H, m), 8.46 (1H, s), 7.72 (1H, d, J 8), 7.61-7.65 (1H, m), 7.31 (1H, d, J 7); m/z (ES+) 279 (M++H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][CH:11]=1)[CH2:7][NH2:8])([O-:3])=[O:2].[O:12]=[C:13](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N:8]([CH2:7][C:6]1[CH:9]=[CH:10][CH:11]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)=[C:13]=[O:12]
Reactant: NCc1cccc([N+](=O)[O-])c1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=C=NCc1cccc([N+](=O)[O-])c1
Temperature: 75 °C
Reaction time: 3 h
Yield: 126.4 %

Procedure:
3-Nitro-benzylamine (2.3 g, 15.1 mmol) was dissolved in anhydrous dioxane (50 ml) under N2 atmosphere. Diphosgene (2.2 ml, 18.2 mmol) was added, a precipitate formed which dissolved upon heating to 75° C. The reaction was stirred at 75° C. for 3 h, cooled and evaporated to dryness giving 3.4 g of crude material which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7]([NH2:9])=[O:8].[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15](=O)[CH2:16]Br)=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:20]=[CH:19][C:14]([C:15]2[N:9]=[C:7]([C:3]3[S:4][CH:5]=[CH:6][C:2]=3[Cl:1])[O:8][CH:16]=2)=[CH:13][CH:12]=1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Reactant: NC(=O)c1sccc1Cl
Product: Clc1ccc(-c2coc(-c3sccc3Cl)n2)cc1

Procedure:
The title compound was prepared from 3-chloro-thiophene-2-carboxamide (0.100 g, 1.03 mmol) and 4-chloro-phenacyl bromide (0.200 g, 0.856 mmol) by a procedure similar to Example 101 as a white solid (0.006 g, 3.2%). 1H NMR (Acetone-d6): 8.45 (s, 1H), 7.80 (d, J=6.6 Hz, 2H), 7.70 (d, J=6.0 Hz, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.08 (d, J=6.0 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14](=[O:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:10][CH:9]=2)=[C:4]([CH3:21])[CH:3]=1.[BH4-].[Na+].C1(N)CCCCC1>C(Cl)CCl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([CH:14]([OH:20])[CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:12][CH:13]=2)=[C:4]([CH3:21])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1-c1ccc(C(=O)CCC(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Solvent: NC1CCCCC1
Product: Cc1cc(Cl)ccc1-c1ccc(C(O)CCC(=O)O)cc1
Yield: 96 %

Procedure:
Prepared analogous to Example 25 by reduction of 4-(4'-chloro-2'-methyl-4-biphenylyl)-4-oxo-butyric acid (m.p. 153°-154° C.) with sodium borohydride. Yield: 96%. Melting point of the cyclohexylamine salt: 139°-140° C. (from ethylene chloride/ethyl acetate 5:1).
Reaction SMILES: [NH2:1][C:2]1[C:3]([F:19])=[C:4]([NH:9][S:10]([C:13]2[N:14]=[CH:15][N:16]([CH3:18])[CH:17]=2)(=[O:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].F[C:21]1[C:26]([C:27]2[N:35]=[CH:34][N:33]=[C:32]3[C:28]=2[N:29]=[CH:30][N:31]3[CH:36]2[CH2:41][CH2:40][CH2:39][CH2:38][O:37]2)=[CH:25][CH:24]=[CH:23][N:22]=1>O>[F:19][C:3]1[C:2]([NH:1][C:21]2[C:26]([C:27]3[N:35]=[CH:34][N:33]=[C:32]4[C:28]=3[N:29]=[CH:30][N:31]4[CH:36]3[CH2:41][CH2:40][CH2:39][CH2:38][O:37]3)=[CH:25][CH:24]=[CH:23][N:22]=2)=[C:7]([F:8])[CH:6]=[CH:5][C:4]=1[NH:9][S:10]([C:13]1[N:14]=[CH:15][N:16]([CH3:18])[CH:17]=1)(=[O:12])=[O:11]
Reactant: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(N)c2F)c1
Reactant: Fc1ncccc1-c1ncnc2c1ncn2C1CCCCO1
Solvent: O
Product: Cn1cnc(S(=O)(=O)Nc2ccc(F)c(Nc3ncccc3-c3ncnc4c3ncn4C3CCCCO3)c2F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 82 %

Procedure:
The N-(3-amino-2,4-difluorophenyl)-1-methyl-1H-imidazole-4-sulfonamide (45 mg, 0.16 mmol) prepared at Step 5 and the 6-(2-fluoropyridin-3-yl)-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (43 mg, 0.14 mmol) prepared at Step 7 were added and dissolved, and lithium (bistrimethylsilyl) amide (1.0M solution in THF) was applied slowly at 0° C. After stirring the reactant at room temperature for 1 hour, completing the reaction, pouring water, and extracting with ethylacetate, the organic layer was dried with sulfuric anhydride magnesium and vacuum concentrated, and then refined by means of column chromatography, so that 65 mg of the target compound, N-(2,4-difluoro-3-(3-(9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)pyridin-2-ylamino)phenyl)-1-methyl-1H-imidazole-4-sulfonamide (percentage yield: 82%), was obtained.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([CH3:9])=[CH:4][C:3]=1[OH:10].Br[CH2:12][C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1)=[O:14]>>[CH3:22][O:21][C:17]1[CH:16]=[C:15]([C:13](=[O:14])[CH2:12][O:10][C:3]2[CH:4]=[C:5]([CH3:9])[CH:6]=[C:7]([CH3:8])[C:2]=2[CH3:1])[CH:20]=[CH:19][CH:18]=1
Reactant: Cc1cc(C)c(C)c(O)c1
Reactant: COc1cccc(C(=O)CBr)c1
Product: COc1cccc(C(=O)COc2cc(C)cc(C)c2C)c1
Yield: 88 %

Procedure:
Using 2,3,5-trimethylphenol and 2-bromo-1-(3-methoxyphenyl)ethanone, the title compound was synthesized in the same manner as in Reference Example 159. Yield 88%. Oily matter.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[S:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[S:31]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:35]4[S:29][C:30](=[S:31])[NH:32][C:33]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][N:19]=[C:18]([F:22])[CH:17]=3)[CH:6]=2)[CH2:2][CH2:3]1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Solvent: CCO
Solvent: C1CCNCC1
Product: O=C1NC(=S)SC1=Cc1cnn2c(NC3CC3)cc(-c3ccnc(F)c3)nc12
Temperature: 80 °C
Reaction time: 2 h
Yield: 36.4 %

Procedure:
To 7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde 30 mg, 0.1 mmol) in EtOH (1 mL) was added piperidine (13 μL, 0.1 mmol), and rhodanine (13 mg, 0.1 mmol). The reaction was stirred at 80° C. for 2 hours. The solid formed was isolated by filtration, washed with water then ethanol. The recovered solid was further purified by washing with 20% methanol/dichloromethan to provide 15 mg of 5-((7-(cyclopropylamino)-5-(2-fluoropyridin-4-yl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2-thioxothiazolidin-4-one (35%). LCMS (M+1=413)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][NH:7][CH2:6][CH2:5]2.[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18](O)=[O:19])([CH3:14])[CH3:13]>>[CH:12]([O:15][C:16]1[CH:24]=[CH:23][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:21][C:17]=1[C:18]([N:7]1[CH2:6][CH2:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[CH2:8]1)=[O:19])([CH3:14])[CH3:13]
Reactant: Cc1ccc2c(c1)CCNC2
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: Cc1ccc2c(c1)CCN(C(=O)c1cc(S(C)(=O)=O)ccc1OC(C)C)C2

Procedure:
Prepared in analogy to example 1.1 from 6-methyl-1,2,3,4-tetrahydro-isoquinoline (CA [42923-76-2]) and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([NH:13][CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClC(Cl)C>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([N:13]([CH2:25][C:24]2[CH:27]=[CH:28][C:21]([Cl:20])=[CH:22][CH:23]=2)[CH2:14][CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)CCNC1CCN(C(=O)OC(C)(C)C)C1
Reactant: O=Cc1ccc(Cl)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: COC(=O)CCN(Cc1ccc(Cl)cc1)C1CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-(2-methoxycarbonyl-ethylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester (0.73 g, 2.68 mmol) in dichloroethane (10.0 mL) was added 4-chlorobenzaldehyde (0.42 g, 2.95 mmol), sodium triacetoxy borohydride (1.71 g, 8.04 mmol) and catalytic acetic acid and the resulting mixture was stirred at room temperature overnight. The reaction mixture was concentrated, dissolved in dichloromethane and washed with saturated aqueous sodium bicarbonate. The combined organics were washed with brine and dried over sodium sulfate. The crude product was purified on silica using gradient elution from hexane/ethyl acetate (15%) to hexane/ethyl acetate (50%). 1H-NMR (CDCl3) δ: 1.35 (9H, s), 1.80 (1H, m), 1.90 (1H, m), 2.40 (2H, t), 2.85 (2H, t), 3.00-3.80 (7H, m), 4.70 (1H, d), 7.20 (4H, m). ESI-MS m/z: 397 (M+1), UV retention time: 1.99 min.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][NH:15][C:16](=O)[O:17]C3C=CC=CC=3)=[CH:9][CH:8]=2)[N:5]=[C:4]([C:25]([F:28])([F:27])[F:26])[C:3]=1[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH2:45])(=[O:44])=[O:43])=[N:40][CH:41]=1>>[Cl:35][C:36]1[CH:37]=[CH:38][C:39]([S:42]([NH:45][C:16]([NH:15][CH2:14][CH2:13][C:10]2[CH:11]=[CH:12][C:7]([N:6]3[C:2]([CH3:1])=[C:3]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[C:4]([C:25]([F:26])([F:27])[F:28])=[N:5]3)=[CH:8][CH:9]=2)=[O:17])(=[O:43])=[O:44])=[N:40][CH:41]=1
Reactant: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)Oc2ccccc2)cc1
Reactant: NS(=O)(=O)c1ccc(Cl)cn1
Product: Cc1c(-c2ccccc2)c(C(F)(F)F)nn1-c1ccc(CCNC(=O)NS(=O)(=O)c2ccc(Cl)cn2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 1 of Example 42 from phenyl 2-{4-[5-methyl-4-phenyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl}ethylcarbamate (step 7 of Example 52) and 5-chloro-2-pyridinesulfonamide: MS (ESI) m/z 564 [M+H]+, 562 [M−H]−, 1H-NMR (CDCl3) δ 78.54 (1H, s), 7.96-7.90 (2H, m), 7.47-7.19 (7H, m), 6.91-6.79 (2H, m), 6.65 (1H, br.s) 5.98 (1H, br.s), 3.44 (2H, t, J=6.6 Hz), 2.83 (2H, t, J=6.7 Hz), 2.20 (3H, s).
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:40])[CH2:7][C:8]1[N:9]=[C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:37][CH3:38])([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:34])([CH3:33])[CH3:32])=[C:24]([CH3:36])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:39])[S:11][CH:12]=1)C.Cl>CO>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[S:11][CH:12]=[C:8]([CH2:7][C:6]([OH:40])=[O:5])[N:9]=2)=[C:14]([CH3:39])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([CH2:28][CH2:29][CH:30]([OH:35])[C:31]([CH3:33])([CH3:34])[CH3:32])=[C:24]([CH3:36])[CH:23]=1)[CH2:37][CH3:38])[CH3:21]
Reactant: CCOC(=O)Cc1csc(-c2ccc(C(CC)(CC)c3ccc(CCC(O)C(C)(C)C)c(C)c3)cc2C)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2nc(CC(=O)O)cs2)c(C)c1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.3 %

Procedure:
A 2 N sodium hydroxide aqueous solution (0.12 mL) was added to a solution of [2-(4-{1-ethyl-1-[4-(3-hydroxy-4,4-dimethyl-pentyl)-3-methyl-phenyl]-propyl}-2-methyl-phenyl)-thiazol-4-yl]-acetic acid ethyl ester (Example 69-(2); 34.0 mg, 0.0635 mmol) in methanol (0.85 mL) at room temperature, and the mixture was stirred at room temperature for 4.5 hours. The mixture was acidified with dilute hydrochloric acid aqueous solution, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure to give the title compound (32 mg, 100%).