Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][CH2:4][CH2:5][N:6]=1.[CH3:7][C:8]([CH3:12])=[CH:9][CH2:10]Br.[CH3:13][O-:14].[Na+]>C(#N)C>[CH3:13][O:14][C:2]1([CH3:1])[N:6]([CH2:10][CH:9]=[C:8]([CH3:12])[CH3:7])[CH2:5][CH2:4][O:3]1
Reactant: CC(C)=CCBr
Reactant: CC1=NCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CC#N
Product: COC1(C)OCCN1CC=C(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 84 %

Procedure:
8.5 g (0.1 mol) of 2-methyloxazoline and 14.9 g (0.1 mol) of 3-methyl-2-butenyl bromide were stirred in 50 ml of acetonitrile at 20° to 25° C. for 2 hours and, after adding 20 ml of a 5 N sodium methylate solution, the mixture was stirred at room temperature for a further 3 hours. The solution was filtered and, after stripping off the solvent, the residue was distilled. 15.6 g (84 mmols, 84%) of 2-methoxy-2-methyl-3-(3-methyl-2-butenyl)-oxazolidine of boiling point 96°-99° C./20 mm Hg were obtained.
Reaction SMILES: [OH-].[K+].[CH3:3]C1C=CC(S(N(N=O)C)(=O)=O)=CC=1.C(O)CO.CCOCC.[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[C:38]([CH3:46])=[C:37]([OH:47])[C:36]3=[O:48])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1>CO>[NH:26]1[C:30]2[CH:31]=[C:32]([N:35]3[CH:39]([CH:40]4[CH2:45][CH2:44][CH2:43][CH2:42][CH2:41]4)[C:38]([CH3:46])=[C:37]([O:47][CH3:3])[C:36]3=[O:48])[CH:33]=[CH:34][C:29]=2[N:28]=[CH:27]1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Reactant: CC1=C(O)C(=O)N(c2ccc3nc[nH]c3c2)C1C1CCCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: OCCO
Solvent: CCOCC
Product: COC1=C(C)C(C2CCCCC2)N(c2ccc3nc[nH]c3c2)C1=O

Procedure:
The compound was synthesized starting from KOH (15 eq in water), diazald (8 eq), ethylene glycol/Et2O (1/2 v/v, 30 ml), 1-(1H-Benzo[d]imidazol-6-yl)-5-cyclohexyl-3-hydroxy-4-methyl-1H-pyrrol-2(5H)-one (1.00 g, 3.22 mmol, 1 eq) and MeOH (10 ml); yield: 0.250 g (25%); MS m/z: 326.1 [M+H]+; 1H-NMR: (400 MHz, DMSO-D6) δ: 1.05 (d, 3H), 1.40 (d, 2H), 1.65-1.60 (m, 4H), 2.05 (s, 3H), 4.03 (s, 3H), 4.40 (s, 1H), 7.05 (s, 1H), 7.62 (s, 1H), 7.63 (s, 1H), 7.82 (s, 1H); HPLC (METHOD [A]): rt 11.25 min (98.78%)
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[CH:12][C:11]([C:14]([OH:16])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(C1NC=CN=1)(C1NC=CN=1)=O.[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH2:44])[CH:38]=1)([CH3:32])([CH3:31])[CH3:30]>C1COCC1.CCOC(C)=O>[C:29]([O:33][C:34](=[O:45])[NH:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[C:39]([CH2:43][NH:44][C:14]([C:11]2[CH:12]=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=2)=[O:16])[CH:38]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: CC(C)(C)OC(=O)NCc1cccc(CN)c1
Reactant: O=C(O)c1cnc(-c2cccc(F)c2)nc1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCc1cccc(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 60 °C
Reaction time: 12 h
Yield: 81.5 %

Procedure:
To a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid (0.5 g, 2.25 mmol) in THF (25 mL) is added carbonyl diimidazole (0.5 g, 2.7 mmol) and heated at 60° C. for 2 hours. The mixture is cooled to room temperature and (3-aminomethyl-benzyl)-carbamic acid tert-butyl ester (0.67 mL, 2.7 mmol) is added. The mixture is stirred for 12 h, diluted with EtOAc (100 mL), washed with brine (2×50 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue is purified by flash chromatography eluting with 20%-80% EtOAc/heptane to afford [3-({[2-(3-fluoro-phenyl)-pyrimidine-5-carbonyl]-amino}-methyl)-benzyl]-carbamic acid tert-butyl ester (0.8 g, 80%) as a solid. MS: 437 (M+H); 1H NMR (300 MHz, DMSO-d6): δ 1.35 (s, 9H), 4.13 (d, J=6.1 Hz, 2H), 4.54 (d, J=5.9 Hz, 2H), 7.27-7.48 (m, 4H), 7.62 (m, 1H), 8.16 (m, 1H), 8.31 (m, 1H), 9.32 (s, 2H), 9.43 (m, 1H).
Reaction SMILES: O[C@H:2]([C:37]1[C:65]([F:66])=[CH:64][C:40]2[N:41]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[C:42]([C@@H:44]3[CH2:48][CH2:47][CH2:46][N:45]3[C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])=[N:43][C:39]=2[CH:38]=1)[CH2:3][CH2:4][C@@H:5]([C:7]1[C:35]([F:36])=[CH:34][C:10]2[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[C:12]([C@@H:14]3[CH2:18][CH2:17][CH2:16][N:15]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:13][C:9]=2[CH:8]=1)O.C(N(CC)CC)C.S(Cl)(C)(=O)=O.[C:79]([C:83]1[CH:89]=[CH:88][C:86]([NH2:87])=[CH:85][CH:84]=1)([CH3:82])([CH3:81])[CH3:80]>C(Cl)Cl.CCOC(C)=O>[C:79]([C:83]1[CH:84]=[CH:85][C:86]([N:87]2[C@@H:2]([C:37]3[C:65]([F:66])=[CH:64][C:40]4[N:41]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:62])([CH3:61])[CH3:63])[C:42]([C@@H:44]5[CH2:48][CH2:47][CH2:46][N:45]5[C:49]([O:51][C:52]([CH3:53])([CH3:54])[CH3:55])=[O:50])=[N:43][C:39]=4[CH:38]=3)[CH2:3][CH2:4][C@@H:5]2[C:7]2[C:35]([F:36])=[CH:34][C:10]3[N:11]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:31])([CH3:32])[CH3:33])[C:12]([C@@H:14]4[CH2:18][CH2:17][CH2:16][N:15]4[C:19]([O:21][C:22]([CH3:24])([CH3:23])[CH3:25])=[O:20])=[N:13][C:9]=3[CH:8]=2)=[CH:88][CH:89]=1)([CH3:82])([CH3:80])[CH3:81]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc([C@@H](O)CC[C@H](O)c3cc4nc([C@@H]5CCCN5C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c4cc3F)c(F)cc2n1COCC[Si](C)(C)C
Reactant: CC(C)(C)c1ccc(N)cc1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1c1nc2cc([C@H]3CC[C@H](c4cc5nc([C@@H]6CCCN6C(=O)OC(C)(C)C)n(COCC[Si](C)(C)C)c5cc4F)N3c3ccc(C(C)(C)C)cc3)c(F)cc2n1COCC[Si](C)(C)C
Temperature: -20 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a solution of di-tert-butyl (2S,2′S)-2,2′-{[(1S,4S)-1,4-dihydroxybutane-1,4-diyl]bis(6-fluoro-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-benzimidazole-5,2-diyl)}dipyrrolidine-1-carboxylate (100 mg, 0.10 mmol) in CH2Cl2 (1 mL) at −20° C. was added triethylamine (0.044 mL, 0.31 mmol) followed by mesyl chloride (0.018 mL, 0.23 mmol) and the solution stirred at −20° C. for 1 hour. 4-tert-Butyl aniline (0.083 mL, 0.52 mmol) was added in one portion, and the solution was allowed to warm to room temperature overnight, with stirring. The solution was diluted with EtOAc, washed with 1N HCl, H2O, and brine, dried (Na2SO4), filtered and concentrated. Purification by flash chromatography (0-50% EtOAc/hexane) gave the title compound (46 mg, 0.04 mmol, 41%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:4][C:5]2[C:10]([CH:11]=1)=[C:9]([OH:12])[CH:8]=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=2.O.O.O.C([O-])(=O)C.[Na+:28].[N+:29]([C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][CH:40]=1)[C:35](Cl)=[O:36])([O-:31])=[O:30].[OH-].[Na+:42].Cl>O.C(OCC)C>[OH:12][C:9]1[CH:8]=[C:7]([S:13]([OH:16])(=[O:15])=[O:14])[CH:6]=[C:5]2[C:10]=1[CH:11]=[C:2]([NH:1][C:35](=[O:36])[C:34]1[CH:38]=[CH:39][CH:40]=[C:32]([N+:29]([O-:31])=[O:30])[CH:33]=1)[C:3]([S:17]([OH:20])(=[O:19])=[O:18])=[CH:4]2.[Na:28][Na:42]
Reactant: Nc1cc2c(O)cc(S(=O)(=O)O)cc2cc1S(=O)(=O)O
Reactant: [Na+]
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Product: O=C(Nc1cc2c(O)cc(S(=O)(=O)O)cc2cc1S(=O)(=O)O)c1cccc([N+](=O)[O-])c1
Product: [Na][Na]
Reaction time: 0.08 h

Procedure:
A 41.0 g portion of recrystallized 3-amino-5-hydroxy-2,7-naphthalenedisulfonic acid and 16.5 g of sodium acetate trihydrate is dissolved in 250 ml of distilled water, then 44.55 g of m-nitrobenzoyl chloride is added all at once along with 120 ml of 1N sodium hydroxide and a small amount of diethyl ether. The resulting mixture is shaken for 5 minutes and another 120 ml of 1N sodium hydroxide is added and the mixture is shaken for 1/2 hour. The latter addition and shaking is repeated two more times. The resulting mixture is acidified to Congo Red indicator paper with concentrated hydrochloric acid and is allowed to stand at 5° C for 17 hours. The solution is filtered and the filtrate is allowed to stand until a precipitate forms. The precipitate is stirred with about 400 ml of diethyl ether and is collected to give 5-hydroxy-3-m-nitrobenzamido-2,7-naphthalenedisulfonic acid, disodium salt.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5](=[O:27])[NH:6][C:7]1[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:11]=1.[CH3:30][C@H:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[N:41]2[CH:42]=[C:43]([O:46][C@H:47]3[C:56]4[C:51](=[CH:52][CH:53]=[CH:54][CH:55]=4)[C@@H:50]([NH2:57])[CH2:49][CH2:48]3)[CH:44]=[CH:45][C:40]2=[N:39][N:38]=1.CCN(C(C)C)C(C)C>O1CCOCC1>[C:12]([C:10]1[CH:11]=[C:7]([NH:6][C:5]([NH:57][C@@H:50]2[C:51]3[C:56](=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@H:47]([O:46][C:43]3[CH:44]=[CH:45][C:40]4[N:41]([C:37]([N:32]5[CH2:33][CH2:34][CH2:35][CH2:36][C@@H:31]5[CH3:30])=[N:38][N:39]=4)[CH:42]=3)[CH2:48][CH2:49]2)=[O:27])[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][C@@H:23]([CH3:26])[CH2:24][OH:25])[CH:17]=2)[N:9]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: C[C@H]1CCCCN1c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H](CO)Oc1cccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CCCC[C@@H]5C)n4c3)c3ccccc32)c1
Temperature: 70 °C
Reaction time: 6.75 h
Yield: 58.9 %

Procedure:
A solution of Intermediate 152c (59 mg, 0.13 mmol) in 1,4-dioxane (1.3 mL) was treated with Intermediate 81d (44 mg, 0.12 mmol) and DIPEA (0.025 mL, 0.14 mmol) and the mixture was stirred at 70° C. for 6.75 h then at 50° C. for 64 h. The cooled solution was concentrated in vacuo, and the residue was partitioned between DCM and water. The phases were separated and the aqueous layer was extracted with DCM (×2). The combined organic phase was washed with brine, dried (Na2SO4) and concentrated in vacuo to a brown gum. The gum was purified by FCC, using 0-10% MeOH in DCM to give the title compound as a pale yellow glass (49 mg, 61%). LCMS (Method 3): Rt 3.74 min, m/z 693.5 [MH+].
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:20][C:21]([CH3:23])=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClC(Cl)C.C(O)(=O)C>[CH:21]([NH:1][C:2]1[C:10]2[N:9]=[C:8]([C:11]([N:13]3[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]3)=[O:12])[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1)([CH3:23])[CH3:20]
Reactant: CN1CCN(C(=O)c2nc3c(N)cccc3[nH]2)CC1
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CC(C)Nc1cccc2[nH]c(C(=O)N3CCN(C)CC3)nc12
Temperature: 25 °C
Reaction time: 16 h
Yield: 61.1 %

Procedure:
To a solution of (4-amino-1H-benzoimidazol-2-yl)-(4-methyl-piperazin-1-yl)-methanone (Example 43; 50 mg, 0.19 mmol) in dichloroethane (10 mL), was added acetone (0.07 mL, 0.96 mmol) and acetic acid (10 drops), followed by NaBH(OAc)3 (203 mg, 0.96 mmol). The reaction mixture was stirred at room temperature for 16 h, and then was quenched with satd aq NaHCO3 (5 mL). The aqueous layer was extracted with CHCl3 (10 mL), and the combined organic layers were dried (Na2SO4) and then concentrated under reduced pressure. The crude product was purified on silica gel (10 g; 0-10% methanol (2 M NH3)/CH2Cl2) to give 35 mg of the title compound (60%). MS (ESI): mass calculated for C16H23N5O, 301.39; m/z found, 302.3 [M+H]+. 1H NMR (400 MHz, CDCl3): 11.11-11.07 (s, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.76 (d, J=7.8 Hz, 1H), 6.37 (d, J=7.8 Hz, 1H), 4.80-4.65 (m, 2H), 3.92-3.78 (m, 2H), 2.56-2.53 (m, 4H), 2.36 (s, 3H), 1.85-1.81, (m, 1H), 1.32 (d, J=6.3 Hz, 6H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[N-:10]=[N+:11]=[N-:12].[Na+].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[OH:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]2[NH:12][N:11]=[N:10][N:2]=2)=[CH:4][CH:5]=1
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Oc1ccc(-c2nnn[nH]2)cc1
Reaction time: 8 h
Yield: 83 %

Procedure:
Into the same device as used in Example 1 were placed 1.19 g (0.010 mole) of paracyanophenol, 1.95 g (0.030 mole) of sodium azide, 4.13 g (0.030 mole) of triethylamine hydrochloride and 12 ml of toluene. The mixture wasreacted for 8 hours in the same manner as in Example 1, giving 1.34 g (0.0083 mole) of 5-(4-hydroxyphenyl)-1H-tetrazole (yield 82.7% based on paracyanophenol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH2:14])=[CH:4][CH:3]=1.[CH3:15][C:16]([CH3:23])=[CH:17][CH2:18][CH2:19][C:20](=O)[CH3:21]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[NH:14][CH:20]([CH3:21])[CH2:19][CH2:18][CH:17]=[C:16]([CH3:23])[CH3:15])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1N
Reactant: CC(=O)CCC=C(C)C
Product: CC(C)=CCCC(C)Nc1c(C)noc1-c1ccc(Br)cc1

Procedure:
Prepared according to the procedure described in Example 24, Step 1, using 5-(4-bromo-phenyl)-3-methyl-isoxazol-4-ylamine and 6-methyl-hept-5-en-2-one.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5](Br)=[CH:4][N:3]=1.CCO[C:13]([S-:15])=[S:14].[K+].O.OS(O)(=O)=O>CN(C=O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]2[S:15][C:13](=[S:14])[NH:8][C:6]=2[N:7]=1
Reactant: Nc1ncc(Br)c(N)n1
Reactant: CCOC(=S)[S-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1ncc2sc(=S)[nH]c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 89 %

Procedure:
A solution of 2,4-diamino-5-bromo-pyrimidine (9.5 g, 50 mmol, 1.0 eq) and potassium ethyl xanthogenate (16 g, 100 mmol. 2 eq) in DMF (300 ml) was heated up to reflux for 10 hours under N2. The reaction solution was cooled down to room temperature and water (600 ml) was added. The pH of the solution was then adjusted to about 5 using H2SO4 (2 ml) and the resulting suspension was stirred at 50-60° C. for 30 min., cooled to about 30° C., filtered and washed with water. The product was dried under vacuum at 50-60° C. to give 8.2 g (89%) of 5-amino-3H-thiazolo[4,5-d]pyrimidin-2-thione as a yellow solid. 1H NMR (400 MHz, d6-DMSO). δ 6.91 (s, 2H, ex. D2O), 8.34 (s, 1H), 12.3 (br, 1H, ex. D2O); MS (+)-ES [M+H]+ m/z 185.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([Cl:19])=[O:18])[CH:12]=1)=[O:5])[CH3:2].[CH2:20]([O:23][C:24](=[O:34])[C:25]1[CH:33]=[CH:32][CH:31]=[C:27]([C:28](O)=[O:29])[CH:26]=1)[CH:21]=[CH2:22].S(Cl)(Cl)=O.CN(C=O)C>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:8][O:9][C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17](=[O:18])[CH2:25][C:24]([OH:34])=[O:23])[CH:12]=1)=[O:5])[CH3:2].[CH2:20]([O:23][C:24](=[O:34])[C:25]1[CH:33]=[CH:32][CH:31]=[C:27]([C:28]([Cl:19])=[O:29])[CH:26]=1)[CH:21]=[CH2:22]
Reactant: C=CCOC(=O)c1cccc(C(=O)O)c1
Reactant: CCOC(=O)c1ncoc1-c1cccc(C(=O)Cl)c1
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: C=CCOC(=O)c1cccc(C(=O)Cl)c1
Product: CCOC(=O)c1ncoc1-c1cccc(C(=O)CC(=O)O)c1
Temperature: 90 °C

Procedure:
The 5-(3-carboxyacetyl-phenyl)-oxazole-4-carboxylic acid ethyl ester was prepared from 5-(3-chlorocarbonyl-phenyl)-oxazole-4-carboxylic acid ethyl ester [prepared by the following sequence: i.) A mixture of isophthalic acid monoallyl ester (8.2 g), thionyl chloride (4.4 mL) and DMF (0.1 mL) in toluene (50 mL) was heated to 90° C. for 2 h. The mixture was evaporated in vacuum to give 3-chlorocarbonyl-benzoic acid allyl ester (9.0 g) as a light-yellow oil. ii.) To a solution of this material (9.0 g) and isocyano-acetic acid ethyl ester (4.4 mL) in THF (60 mL) was added at 0° C. Et3N (14.0 mL). The mixture was stirred at 20° C. for 2.5 h and then evaporated in vacuum. The residue was partitioned between EtOAc and brine and the organic layer was dried and evaporated in vacuum. The residual oil was chromatographed on silica gel using EtOAc/hexane as eluent to give 5-(3-allyloxycarbonyl-phenyl)-oxazole-4-carboxylic acid ethyl ester (6.9 g) as a pale-yellow oil. iii.) This material (6.9 g) was subjected to the palladium-catalysed allylester cleavage according to general procedure G (method b) to give 5-(3-carboxy-phenyl)-oxazole-4-carboxylic acid ethyl ester (6.9 g) as light brown crystals, mp 190-192° C. iv.) This carboxylic acid (2.6 g) was heated with thionyl chloride in toluene and the resulting carboxylic acid chloride was used directly in the next step.] (2.8 g) and bis(trimethylsilyl)malonate with n-BuLi in ether at −60° C. to 0° C. according to general procedure K (method c2). The crude material was transformed into the title compound by stirring in isopropenyl acetate and conc. H2SO4 according to general procedure L (method a). Obtained as pale-yellow crystals (1.4 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>CC#N>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1
Reactant: COc1ccc(C=O)cc1O
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccc(C=O)cc1OCCN1CCOCC1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxy-4-methoxybenzaldehyde (8.56 g, 56.26 mmol) in CH3CN (50 ml) was added K2CO3 (17.1 g) with CH3CN (20 ml), followed 20 minutes later by N-(2-chloroethyl)morpholine hydrochloride (11.52 g). The reaction mixture was refluxed overnight, and then was cooled to room temperature, filtered, and the solvent was stripped to give, as an amber oil, 4-methoxy-3-[2-(4-morpholinyl)ethoxy]benzaldehyde.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.CCN(C(C)C)C(C)C.Cl.[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH2:35]>CN(C=O)C>[CH3:27][O:28][C:29](=[O:36])[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][NH:35][C:2]1[C:3]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2oc(-c3ccccc3)cc12
Reactant: COC(=O)CCCCCN
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)CCCCCNc1ncnc2oc(-c3ccccc3)cc12
Temperature: 160 °C
Reaction time: 4 h

Procedure:
Heat 2.0 g (8.67 mmol) 4-chloro-6-phenylfuro[2,3-d]pyrimidine and 6.04 ml (34.7 mmol) DIEA in 5 ml DMF to 160° C. Add 3.15 g (17.34 mmol) 6-aminohexanoic acid methyl ester hydrochloride and stir for 4 h at 160° C. After cooling, add the mixture to ice water and extract three times with ethyl acetate. Combine the organic phases and wash with saturated ammonium chloride solution, dry over magnesium sulphate and concentrate under vacuum. Add methanol to the oil residue. Filter off the precipitated solid with suction, wash with methanol again and dry the solid at high vacuum. 1.85 g (57.2% of theor.) of the target compound is obtained.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:34]([NH:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=2)(=[O:36])=[O:35])[CH:31]=[CH:32][CH:33]=1>>[N:40]1[CH:41]=[CH:42][CH:43]=[CH:44][C:39]=1[CH2:38][NH:37][S:34]([C:30]1[CH:29]=[C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])[CH:33]=[CH:32][CH:31]=1)(=[O:36])=[O:35]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NCc2ccccn2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NCc2ccccn2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-N-pyridin-2-ylmethyl-benzenesulfonamide (example B.6) according to general procedure II. Yellow solid. MS (ISP) 619.3 [(M−H−]; mp 229° C.
Reaction SMILES: [Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18](O)=[O:19])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:34])([F:33])[F:32])[CH:25]=2)=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:49]([NH2:52])[CH2:50][CH3:51]>CN(C=O)C.O>[Cl:1][C:2]1[CH:36]=[CH:35][C:5]([CH2:6][N:7]2[C:15]3[C:14](=[O:16])[N:13]([CH2:17][C:18]([NH:52][CH2:49][CH2:50][CH3:51])=[O:19])[C:12](=[O:21])[N:11]([CH3:22])[C:10]=3[N:9]=[C:8]2[O:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][C:31]([F:33])([F:34])[F:32])[CH:25]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(=O)n(CC(=O)O)c(=O)c2c1nc(Oc1cccc(OC(F)(F)F)c1)n2Cc1ccc(Cl)cc1
Reactant: CCCN
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: O
Product: CCCNC(=O)Cn1c(=O)c2c(nc(Oc3cccc(OC(F)(F)F)c3)n2Cc2ccc(Cl)cc2)n(C)c1=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 47 %

Procedure:
2-(7-(4-Chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)acetic acid (0.25 g, 0.48 mmol, Example 361) and CDI (0.93 g, 0.57 mmol) were combined in DMF (4 mL) and stirred at room temperature for 20 min. Propan-1-amine was added and the reaction was stirred at room temperature for 3 h. The reaction was diluted with water (100 mL) and extracted with ethyl acetate (3×75 mL). The combined extracts were washed with 1N lithium chloride (2×75 mL), dried with magnesium sulfate, filtered and evaporated under reduced pressure to a white solid. Solid was purified using a 25 g silica gel flash column eluted with 1% methanol/DCM to give 2-(7-(4-chlorobenzyl)-3-methyl-2,6-dioxo-8-(3-(trifluoromethoxy)phenoxy)-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-propylacetamide (0.13 g, 47% yield) as a white solid. LCMS retention time=4.070 min and 99% purity, LCMS MH+ 566. 1H NMR (DMSO-d6) δ 7.99 (t, NH), 7.60 (t, 1H, J=8 Hz), 7.48-7.52 (m, 1H), 7.39-7.46 (m, 5H), 7.32 (d, 1H, J=8 Hz), 5.42 (s, 2H), 4.42 (s, 2H), 3.31 (s, 3H), 3.00 (dd, 2H, J=8 Hz and 16 Hz), 1.34-1.45 (m, 2H), 0.83 (t, 3H, J=8 Hz).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].[Cl:5][C:6]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28]OS(C)(=O)=O)=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9]>C(O)CCC.C(OCC)(=O)C>[C:1]([OH:9])(=[O:2])[CH3:3].[Cl:5][C:6]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][CH2:28][NH:4][CH2:3][CH2:1][OH:2])=[CH:22][C:7]=1[C:8]([NH:10][CH2:11][C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][CH:14]([CH2:15]3)[CH2:13]1)[CH2:19]2)=[O:9]
Reactant: NCCO
Reactant: CS(=O)(=O)OCCCc1ccc(Cl)c(C(=O)NCC23CC4CC(CC(C4)C2)C3)c1
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: CC(=O)O
Product: O=C(NCC12CC3CC(CC(C3)C1)C2)c1cc(CCCNCCO)ccc1Cl
Temperature: 100 °C

Procedure:
Ethanolamine (0.07 ml) was added to a suspension of 2-chloro-5-[3-[(methylsulfonyl)oxy]propyl]-N-(tricyclo[3.3.1.13,7]dec-1-ylmethyl)-benzamide (Example 6e, 0.170 g) in n-butanol (5 ml) and heated at 100° C. in a sealed tube for 12 h. On cooling to ambient temperature the solution was diluted with ethyl acetate and extracted twice with saturated aqueous sodium hydrogencarbonate solution and once with brine, dried over magnesium sulfate and concentrated under reduced pressure. Purification by preparative reverse phase HPLC (eluting with a gradient of acetonitrile in 0.1% aqueous ammonium acetate/25-95%) gave the title compound as the acetate salt (0.070 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:14][C:15]([NH2:17])=[S:16])[CH:5]=[CH:6][C:7]=1[N:8]1[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]1.Br[CH:19]1[CH2:24][CH2:23][CH2:22][CH:21]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=2[Cl:32])[C:20]1=O>>[Cl:32][C:26]1[CH:27]=[C:28]([Cl:31])[CH:29]=[CH:30][C:25]=1[CH:21]1[C:20]2[N:17]=[C:15]([NH:14][C:4]3[CH:5]=[CH:6][C:7]([N:8]4[CH:12]=[C:11]([CH3:13])[N:10]=[CH:9]4)=[C:2]([F:1])[CH:3]=3)[S:16][C:19]=2[CH2:24][CH2:23][CH2:22]1
Reactant: Cc1cn(-c2ccc(NC(N)=S)cc2F)cn1
Reactant: O=C1C(Br)CCCC1c1ccc(Cl)cc1Cl
Product: Cc1cn(-c2ccc(Nc3nc4c(s3)CCCC4c3ccc(Cl)cc3Cl)cc2F)cn1

Procedure:
The title compound was prepared from [3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-thiourea (109 mg, 0.44 mmol) and crude 2-bromo-6-(2,4-dichloro-phenyl)-cyclohexanone (350 mg, ca. 0.5 mmol) using in analogous manner the procedure described in example 1b). Obtained as a light-brown solid (118 mg, 57%). MS ISP (m/e): 473.1 [(M+H)+]. mp 136-139° C.