Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][CH2:10]Cl.O1CCCC1.[F:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][C:19]=1[OH:27]>C(OCC)(=O)C>[F:17][C:18]1[CH:26]=[CH:25][C:21]([CH2:22][OH:24])=[CH:20][C:19]=1[O:27][CH2:8][O:9][CH3:10]
Reactant: COCCl
Reactant: O=C(O)c1ccc(F)c(O)c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COCOc1cc(CO)ccc1F
Temperature: 0 °C
Reaction time: 2 h
Yield: 94 %

Procedure:
Triethylamine (1.07 mL) and methoxymethyl chloride (2.24 mL) were added to tetrahydrofuran (10 mL) solution of 4-fluoro-3-hydroxybenzoic acid (1.0 g), and stirred at 0° C. for 2 hours. Ethyl acetate was added to the reaction liquid which then was washed with water and saturated brine, dried over anhydrous magnesium sulfate, the solvent therein was concentrated under reduced pressure and the residue was dissolved in tetrahydrofuran (20 mL). Lithiumaluminium hydride (360 mg) was added, stirred at 0° C. for an hour, ethyl acetate was added and the insoluble matter was removed, followed by washing with saturated brine and drying over anhydrous magnesium sulfate. Concentrating the solvent under reduced pressure, the title compound (1.14 g, 94%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:18][O:19][CH2:20][CH2:21][NH:22][CH2:23][CH2:24][O:25][CH3:26]>C(O)CCC>[CH3:18][O:19][CH2:20][CH2:21][N:22]([CH2:23][CH2:24][O:25][CH3:26])[C:2]1[CH:3]=[C:4]([NH2:8])[N:5]=[CH:6][N:7]=1
Reactant: Nc1cc(Cl)ncn1
Reactant: COCCNCCOC
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: COCCN(CCOC)c1cc(N)ncn1
Temperature: 180 °C
Reaction time: 24 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.3 g, 2.32 mmol) and diisopropylethylamine (0.30 g, 2.32 mmol) were suspended in n-butanol and then 2-methoxy-N-(2-methoxyethyl)ethanamine 6-1 (0.31 g, 2.32 mmol) was added. The reaction was stirred at 180° C. for 24 hours. The solvent was removed under reduced pressure and the product 6-2 was purified on a silica column. 1H-NMR (DMSO): 7.91 ppm (s, 1H); 6.10 ppm (2H); 5.51 ppm (s, 1H); 3.45 ppm (m, 4H); 3.45 ppm (m, 4H); 3.25 ppm (s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]2=1.CCCCC.[H-].[Na+].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CN(C=O)C>[CH2:23]([N:11]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:15])[C:5]=2[C:4]2[C:12]1=[CH:13][CH:14]=[C:2]([F:1])[CH:3]=2)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: BrCc1ccccc1
Reactant: O=C1CCCc2[nH]c3ccc(F)cc3c21
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCC
Product: O=C1CCCc2c1c1cc(F)ccc1n2Cc1ccccc1
Reaction time: 0.17 h
Yield: 66 %

Procedure:
6-Fluoro-1,2,3,9-tetrahydro-4H-carbazol-4-one (0.3938 g, 0.0019 mol) is added to a slurry of pentane-washed NaH (0.0970 g, 0.0024 mol) in DMF (3 mL) and after stirring for 10 min, benzyl bromide (0.28 mL, 0.0024 mol) is added. After stirring for 4 h at room temperature, the mixture is partitioned between water and ethyl acetate. The combined organic layers are dried over sodium sulfate and concentrated to dryness. The resulting solids are chromatographed on silica gel (200 mL) using dichloromethane/heptane (60/40 to 80/20 to 100/0) to give 0.3681 g (65%) of the title compound. An aliquot is recrystallized from ethyl acetate/heptane; MS (ESI+) for C19H16FNO m/z 294.2 (M+H)+; IR (drift) 1634, 1523, 1483, 1466, 1447, 1357, 1254, 1138, 900, 868, 803, 799, 759, 729, 700 cm−1; 1H NMR (CDCl3) δ2.22, 2.59, 2.88, 5.32, 6.95, 7.01, 7.15, 7.30, 7.96. Anal. Calcd for C19H16FNO: C, 77.80; H, 5.50; N, 4.78. Found: C, 77.65; H, 5.39; N, 4.69.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([CH:8]=O)[C:5]([F:10])=[CH:4][CH:3]=1.[NH2:11][C@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14].[BH4-].[Na+]>CO>[Br:1][C:2]1[N:7]=[C:6]([CH2:8][NH:11][C@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][OH:14])[C:5]([F:10])=[CH:4][CH:3]=1
Reactant: CC(C)[C@@H](N)CO
Reactant: O=Cc1nc(Br)ccc1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)[C@H](CO)NCc1nc(Br)ccc1F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
6-bromo-3-fluoropicolinaldehyde (4.0 g, 19.61 mmol) and (R)-2-amino-3-methylbutan-1-ol (2.281 mL, 20.59 mmol) were dissolved in methanol (100 mL) and stirred at ambient temperature for 1 hour and 15 minutes. Sodium borohydride (0.742 g, 19.61 mmol) was added and the mixture was stirred for another 1 hour and 30 minutes. The volume of the reaction mixture was reduced, and the mixture was quenched with 200 mL 1.0 N NaOH, and extracted with 200 mL dichloromethane (2×). The organic phase was extracted with 1.0 N HCl and partitioned. The aqueous phase was separated, neutralized with 3.0 N NaOH, extracted with EtOAc, organic phase separated and washed with brine. The organic phase was dried over Na2SO4, filtered, and concentrated to obtain the title compound as an orange solid. MS (ESI+) m/z 291.0 (M+H); 1H NMR (300 MHz, DMSO-d6) δ 7.69 (t, J=8.8, 1H), 7.60 (dd, J=8.6, 3.7, 1H), 4.42 (t, J=5.2, 1H), 3.92-3.75 (m, 2H), 3.43 (dt, J=10.7, 4.8, 1H), 2.34-2.24 (m, 1H), 2.08 (s, 1H), 1.87-1.71 (m, 1H), 0.83 (dd, J=8.5, 6.9, 6H).
Reaction SMILES: C(N[C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])(C)(C)C.[CH3:12][CH:13]([CH:15]([NH2:19])[CH:16]([CH3:18])[CH3:17])[CH3:14].C(N(CC)CC)C.C(Cl)(=O)C(C)(C)C>>[CH3:12][CH:13]([CH:15]([NH:19][C:6](=[O:11])[C:7]([CH3:10])([CH3:9])[CH3:8])[CH:16]([CH3:18])[CH3:17])[CH3:14]
Reactant: CC(C)C(N)C(C)C
Reactant: CC(C)(C)NC(=O)C(C)(C)C
Agent: CC(C)(C)C(=O)Cl
Solvent: CCN(CC)CC
Product: CC(C)C(NC(=O)C(C)(C)C)C(C)C
Yield: 98 %

Procedure:
In a fashion similar to the preparation of LtBu,tBuH, treatment of 2,4-dimethylpentan-3-amine (14.0 mL, 100 mmol) and triethylamine (14.9 mL, 105 mmol) with pivaloyl chloride (8.9 mL, 100 mmol) afforded LtBu,CHiPr2H as white crystalline solid (19.53 g, 98%) upon sublimation at 65° C./0.05 Torr: mp 107-109° C.
Reaction SMILES: BrC1C=CC(C(Cl)=O)=CC=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][C:22]=1[O:23][CH3:24])[N:19]=[CH:18][N:17]=[C:16]2[O:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:36][CH:35]=1>C1(C)C=CC=CC=1.C(O)C>[Br:33][C:34]1[CH:35]=[CH:36][C:37]([C:40]([N:42]=[C:43]=[S:44])=[O:41])=[CH:38][CH:39]=1.[Br:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([NH:42][C:43]([NH:30][C:29]2[CH:31]=[CH:32][C:26]([O:25][C:16]3[C:15]4[C:20](=[CH:21][C:22]([O:23][CH3:24])=[C:13]([O:12][CH3:11])[CH:14]=4)[N:19]=[CH:18][N:17]=3)=[CH:27][CH:28]=2)=[S:44])=[O:41])=[CH:36][CH:35]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Agent: O=C(Cl)c1ccc(Br)cc1
Agent: O=C(N=C=S)c1ccc(Br)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=S)NC(=O)c4ccc(Br)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
4-Bromo-1-benzenecarbonyl isothiocyanate was prepared using commercially available 4-bromo-1-benzenecarbonyl chloride (80 mg) as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-bromo-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (53 mg, yield 58%).
Reaction SMILES: [Cl:1][C:2]1[CH:31]=[CH:30][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:29]=[CH:28][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:18][C:17]=3[Cl:27])=[CH:13][CH:12]=2)=[O:10])=[CH:4][CH:3]=1.[OH-].[Na+].O>C1COCC1.C(Cl)Cl.Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][CH2:7][NH:8][C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:15][C:16]3[CH:21]=[CH:20][C:19]([CH2:22][C:23]([OH:25])=[O:24])=[CH:18][C:17]=3[Cl:27])=[CH:28][CH:29]=2)=[O:10])=[CH:30][CH:31]=1
Reactant: COC(=O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C(O)Cc1ccc(Oc2ccc(C(=O)NCCc3ccc(Cl)cc3)cc2)c(Cl)c1
Reaction time: 2 h
Yield: 59.4 %

Procedure:
Methyl 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetate (33 mg, 0.0720 mmol) was diluted with THF (500 μL) followed by the addition NaOH (0.144 ml, 0.720 mmol) and 100 μL of water. After stirring for 2 hours, the reaction was diluted with DCM and 2N HCl. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated to yield 2-(4-(4-((4-chlorophenethyl)carbamoyl)phenoxy)-3-chlorophenyl)acetic acid (19 mg, 59.4% yield) as a white solid. 1H NMR (400 MHz, CDCl3/CD3OD) δ 7.65 (d, 2H), 7.42 (m, 1H), 7.25 (d, 2H), 7.20 (d, 1H), 7.15 (d, 2H), 7.05 (d, 1H), 6.85 (d, 2H), 3.65 (1, 2H), 3.60 (s, 2H), 2.90 (t, 2H).
Reaction SMILES: [F:1][CH:2]([F:21])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH2:16])[CH3:15])=[CH:6][CH:5]=[N:4]1.Cl[C:23]1[N:31]=[C:30]([NH2:32])[N:29]=[C:28]2[C:24]=1[N:25]=[CH:26][NH:27]2.C(N(C(C)C)C(C)C)C>C(#N)C>[F:21][CH:2]([F:1])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]3[N:19]([CH3:20])[CH:18]=[CH:17][C:11]3=[N:12][C:13]=2[C@@H:14]([NH:16][C:23]2[N:31]=[C:30]([NH2:32])[N:29]=[C:28]3[C:24]=2[N:25]=[CH:26][NH:27]3)[CH3:15])=[CH:6][CH:5]=[N:4]1
Reactant: Nc1nc(Cl)c2nc[nH]c2n1
Reactant: C[C@H](N)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: C[C@H](Nc1nc(N)nc2[nH]cnc12)c1nc2ccn(C)c2cc1-c1ccnn1C(F)F
Temperature: 120 °C

Procedure:
(S)-1-(6-(1-(Difluoromethyl)-1H-pyrazol-5-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethanamine (172 mg, 0.590 mmol), 6-chloro-9H-purin-2-amine (100 mg, 0.590 mmol), and N-ethyl-N-isopropylpropan-2-amine (0.31 mL, 1.8 mmol) were combined in acetonitrile (6 mL). The reaction mixture was heated in a microwave reactor at 120° C. for 2 hours and then concentrated. The residue was taken up in DMF and was purified by preparative HPLC (acid mode) eluting with 5-20% ACN in water. The fractions containing the desired compound were combined and concentrated in vacuo. The residue was further purified by preparative HPLC (basic mode) eluting with 25-35% ACN in water. The fractions containing the desired product were combined and concentrated in vacuo to give the title compound as a white solid. 1H NMR (500 MHz, CD3OD) δ ppm 1.58 (d, J=6.83 Hz, 3 H), 3.87 (s, 3 H), 5.94-6.01 (m, 1 H), 6.64 (d, J=2.93 Hz, 1 H), 6.87 (d, J=2.44 Hz, 1 H), 7.46-7.76 (m, 2 H), 7.93 (s, 1 H), 8.18 (s, 1 H); ESI-MS m/z [M+H]+ calc'd for C19H18F2N10, 425; found 425.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]([C:10]1[C:11](Cl)=[N:12][C:13]([S:17][CH3:18])=[N:14][C:15]=1[Cl:16])=O.C(N(CC)C(C)C)(C)C.[NH2:29][NH2:30]>C1COCC1.C(OCC)(=O)C.O>[Cl:16][C:15]1[N:14]=[C:13]([S:17][CH3:18])[N:12]=[C:11]2[NH:29][N:30]=[C:8]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[C:10]=12
Reactant: NN
Reactant: CSc1nc(Cl)c(C(=O)c2ccccc2Cl)c(Cl)n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CSc1nc(Cl)c2c(-c3ccccc3Cl)n[nH]c2n1
Temperature: 25 °C

Procedure:
To a mixture of (2-chlorophenyl)-(4,6-dichloro-2-methylsulfanylpyrimidin-5-yl)-methanone (875 mg, 2.62 mmol) and N,N-diisopropyl ethyl amine (0.69 mL, 1.5 eq) in THF (20 mL) at 0° C. was added a solution of hydrazine (83 μL, 1 eq) in THF (20 mL) dropwise with stirring. After addition was complete, the reaction was gradually warmed to room temperature over 2 hours. Analysis by TLC indicated that there was still starting material remaining. Additional 3 mL of a solution of hydrazine (17 μL) in THF (10 mL) was added dropwise to the reaction mixture, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (150 mL) and water (50 mL). The organic layer was separated, washed with water (4×50 mL) and brine (1×50 mL), dried over magnesium sulfate, filtered and concentrated to give the title compound (867 mg, (M+H)+=311).
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:16]=[C:17](Cl)[CH:18]=[C:19]([C:21]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:24]=[C:23]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:22]=4)[CH:20]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.[N:40]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH:43]=[CH:42][C:41]=1[C:50]1[CH:55]=[CH:54][C:53](B(O)O)=[CH:52][CH:51]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.C(=O)([O-])[O-].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C(O)CCC.C1(C)C=CC=CC=1>[CH:1]1[C:14]2[C:5](=[CH:6][C:7]3[C:12]([C:13]=2[C:15]2[CH:20]=[C:19]([C:21]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[CH:24]=[C:23]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)[N:22]=4)[CH:18]=[C:17]([C:53]4[CH:52]=[CH:51][C:50]([C:41]5[CH:42]=[CH:43][C:44]6[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=6)[N:40]=5)=[CH:55][CH:54]=4)[CH:16]=2)=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1
Reactant: OB(O)c1ccc(-c2ccc3ccccc3n2)cc1
Reactant: Clc1cc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)cc(-c2c3ccccc3cc3ccccc23)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CCCCO
Solvent: Cc1ccccc1
Solvent: O
Product: c1ccc(-c2cc(-c3ccccc3)nc(-c3cc(-c4ccc(-c5ccc6ccccc6n5)cc4)cc(-c4c5ccccc5cc5ccccc45)c3)n2)cc1
Temperature: 95 °C
Reaction time: 2 h

Procedure:
In a stream of argon, 517 mg (0.996 mmol) of 2-[5-(anthracen-9-yl)-3-chlorophenyl]-4,6-diphenylpyrimidine, 299 mg (1.20 mmol) of 4-(quinolin-2-yl)phenylboronic acid and 4.5 mg (20 μmol) of palladium acetate and 29.6 mg (60 μmol) of 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl were suspended in a toluene (4.5 mL)/n-butanol (0.5 mL) mixed solvent, and the suspension was heated to 95° C. 800 μL (2.40 mmol) of an aqueous 3.0M potassium carbonate solution was gradually dropwise added to the mixture, and the mixture was stirred at that temperature for 2 hours. Then the reaction mixture was left to be cooled to room temperature, and water was added to the reaction mixture. Then the deposited solid was collected by filtration to give 645 mg of target 2-[5-(anthracen-9-yl)-4′-(quinoline-2-yl) biphenyl-3-yl]-4,6-diphenylpyrimidine as a white solid (yield, 94%).
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:23]=[CH:22][C:17]([C:18]([O:20]C)=[O:19])=[CH:16][CH:15]=3)=[CH:9][CH:10]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1.[OH-].[K+]>O>[CH3:1][C:2]1([CH3:26])[C:11]2[C:6](=[CH:7][C:8](/[CH:12]=[CH:13]/[C:14]3[CH:15]=[CH:16][C:17]([C:18]([OH:20])=[O:19])=[CH:22][CH:23]=3)=[CH:9][CH:10]=2)[C:5]([CH3:25])([CH3:24])[CH2:4][CH2:3]1
Reactant: COC(=O)c1ccc(/C=C/c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC1(C)CCC(C)(C)c2cc(/C=C/c3ccc(C(=O)O)cc3)ccc21
Temperature: 70 °C
Yield: 90.4 %

Procedure:
In a 50 mL round bottom flask was charged methyl 4-((E)-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)vinyl)benzoate 10 (0.30 g, 0.86 mmol) in 20 mL and water (2 mL) and KOH was added (193 mg, 3.44 mmol). The suspension was heated for 6 h at 70° C. Methanol was removed in vacuo, water (20 mL) was added and the solution washed with diethyl ether (2×30 mL). The aqueous solution was carefully acidified to pH=1 using a solution of HCl 1N and extracted with diethyl ether (3×100 ml). The organic layer was dried over MgSO4, filtered and evaporated to yield to 4-((E)-2-(1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalen-6-yl)vinyl)benzoic acid 12 (0.26 g, 90% yield) as a white solid.
Reaction SMILES: CC([NH:5][S:6]([C:9]1[C:10]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=2)=[N:11][C:12]([S:15][CH3:16])=[N:13][CH:14]=1)(=[O:8])=[O:7])(C)C>FC(F)(F)C(O)=O>[CH3:24][C:20]1[CH:19]=[C:18]([NH:17][C:10]2[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][N:13]=[C:12]([S:15][CH3:16])[N:11]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CSc1ncc(S(=O)(=O)NC(C)(C)C)c(Nc2cccc(C)c2)n1
Solvent: O=C(O)C(F)(F)F
Product: CSc1ncc(S(N)(=O)=O)c(Nc2cccc(C)c2)n1
Yield: 100 %

Procedure:
N-(1,1-Dimethylethyl)-4-[(3-methylphenyl)amino]-2-(methylthio)-5-pyrimidinesufonamide (200 mg, 0.55 mmol) was dissolved in trifluoroacetic acid (TFA) (15 mL) and refluxed for 1 hour. The TFA was removed under reduced pressure to yield a crude solid which was crystallized from ethanol and water to yield 170 mg (0.55 mmol, 100%) of white needles, m.p. 183.5°-184.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][NH:25][CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:21])=[O:20])=[N:11]3)=[N:8][C:4]=2[CH:3]=1.FC(F)(F)S(O[CH2:36][C:37]([F:40])([F:39])[F:38])(=O)=O>>[Cl:1][C:2]1[CH:29]=[CH:28][C:5]2[N:6]([C@@H:23]3[CH2:27][CH2:26][N:25]([CH2:36][C:37]([F:40])([F:39])[F:38])[CH2:24]3)[C:7]([CH2:9][N:10]3[C:14]4=[CH:15][N:16]=[CH:17][CH:18]=[C:13]4[C:12]([S:19]([CH3:22])(=[O:20])=[O:21])=[N:11]3)=[N:8][C:4]=2[CH:3]=1
Reactant: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCNC2)c2cnccc12
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Product: CS(=O)(=O)c1nn(Cc2nc3cc(Cl)ccc3n2[C@@H]2CCN(CC(F)(F)F)C2)c2cnccc12

Procedure:
The title compound was prepared in analogy to Example 2-19 by using (R)-1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2,2,2-trifluoroethyl trifluoromethanesulfonate instead of (S)-1-((5-chloro-1-(pyrrolidin-3-yl)-1H-benzo[d]imidazol-2-yl)methyl)-3-(methylsulfonyl)-1H-pyrazolo[3,4-c]pyridine and 2,2,2-trifluoroethyl trifluoromethanesulfonate.
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+]>[Fe].O>[OH2:2].[OH2:2].[OH2:2].[OH2:2].[OH2:2].[O-:3][Si:1]([O-:4])=[O:2].[Na+:6].[Na+:6]
Reactant: [O-][Si]([O-])([O-])[O-]
Agent: [Fe]
Agent: [Na+]
Solvent: O
Product: O=[Si]([O-])[O-]
Temperature: 75 °C
Reaction time: 0.75 h

Procedure:
A sodium metasilicate pentahydrate liquor was prepared by blending a sodium silicate solution with an SiO2 /Na2O ratio of 3.22 with caustic solution. The mole ratio of Na2O: O:SiO2 :H2O of the liquor was 0.99:1.00:4.97 and the liquor was maintained at 75°C to prevent any crystallization until the test was started. The liquor (97.5 pbw) was cooled to 70°C and 2.5 pbw of seed particles were added. The seed was less than 200 mesh and had a composition similar to the liquor. The temperature of the liquor fell until the crystallization began. The crystallization began after about 45 minutes and continued for about 60 minutes until the cake was hard to the touch. Evolution of heat of crystallization continued for about 30 minutes more. The cake was allowed to equilibrate for 60 minutes and then ground in a jaw crusher. The total processing time prior to crushing was 3 hours and 15 minutes. The cake and resulting material had to be passed through the jaw crusher 6 times before all of the material was reduced to below 20 mesh. In the process a large percentage of fines were produced and the product was dusty. The product contained about 1.5% iron.
Reaction SMILES: Br.[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[NH:7][CH:8]=1.Br[CH2:11][C:12]([C:14]1[S:15][CH:16]=[CH:17][CH:18]=1)=[O:13]>C(N(CC)CC)C.C(O)C>[Br:2][C:3]1[CH:4]=[N:5][C:6](=[O:9])[N:7]([CH2:11][C:12](=[O:13])[C:14]2[S:15][CH:16]=[CH:17][CH:18]=2)[CH:8]=1
Reactant: O=c1ncc(Br)c[nH]1
Reactant: O=C(CBr)c1cccs1
Agent: Br
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(Cn1cc(Br)cnc1=O)c1cccs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 5-bromopyrimidin-2-one hydrobromide (780 mg) and 2-bromoacetylthiophene (633 mg) in triethylamine (1 ml) and ethanol (20 ml) was stirred at ambient temperature for 11/2 hours. A solution formed within 10 minutes but a suspension subsequently resulted. This was chilled in ice, and the collected solid was crystallised from acetone to give the title pyrimidinone: yield 293 mg; m.p. 173°-175° C. dec; λmaxEtOH 259.5 nm (ε 9470), 287 nm (ε 6830), 332 nm (ε 2780).
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[OH-].[Ca+2].[OH-].[C:12](Cl)(=O)[CH2:13][CH2:14][CH2:15]CC.N>C(Cl)Cl.C(C(C)=O)C>[C:3]([CH2:2][C:1]([O:7][CH3:8])=[O:6])(=[O:4])[CH2:5][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)CC(C)=O
Agent: N
Agent: [Ca+2]
Agent: [OH-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: CCCCCC(=O)CC(=O)OC
Yield: 95.8 %

Procedure:
Under the same conditions as in Example 1, 116 g (1.0 mol) of methyl acetoacetate in a mixture of 520 ml of methylene chloride and 30 ml of methyl ethyl ketone were reacted with 77.8 g (1.05 mol) of calcium hydroxide and 148.0 g (1.1 mol) of hexanoyl chloride. The pH in the subsequent reaction with ammonia was adjusted to 9.2. This gave 165 g (GC purity 78.5%) of methyl hexanoylacetate (yield 75.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[C:14](OCC)=[O:15])=[CH:5][CH:4]=1.[H-].C([Al+]CC(C)C)C(C)C.Cl>O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[O:13][N:12]=[CH:11][C:10]=2[CH2:14][OH:15])=[CH:7][CH:8]=1
Reactant: CCOC(=O)c1cnoc1-c1ccc(OC)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc(-c2oncc2CO)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
To a solution of ethyl 5-(4-methoxyphenyl)isoxazole-4-carboxylate (8.56 g) in tetrahydrofuran (100 ml) was gently added diisobutylaluminum hydride (1.0 M tetrahydrofuran solution, 80 ml) at 0° C. and the mixture was stirred at room temperature for 30 min. The reaction mixture was poured into dilute hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated to give 5-(4-methoxyphenyl)-4-isoxazolylmethanol (6.87 g, yield 97%) as colorless crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point: 57–58° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12](OC)=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=1)=[O:18].[Li+].[OH-].[NH2:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([NH:43][C:44]1[NH:48][N:47]=[N:46][N:45]=1)=[O:13])[O:8][CH2:7][CH2:6][CH:5]2[N:16]([C@H:31]1[CH2:36][CH2:35][C@H:34]([C:37]([CH3:39])([CH3:40])[CH3:38])[CH2:33][CH2:32]1)[C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]([F:29])([F:28])[F:30])=[CH:22][CH:21]=1)=[O:18]
Reactant: Nc1nnn[nH]1
Reactant: COC(=O)c1cc2c(cc1Br)C(N(C(=O)Nc1ccc(OC(F)(F)F)cc1)[C@H]1CC[C@H](C(C)(C)C)CC1)CCO2
Agent: [Li+]
Agent: [OH-]
Product: CC(C)(C)[C@H]1CC[C@H](N(C(=O)Nc2ccc(OC(F)(F)F)cc2)C2CCOc3cc(C(=O)Nc4nnn[nH]4)c(Br)cc32)CC1

Procedure:
Enantiomer A of methyl 6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]chromane-7-carboxylate (25 mg) was saponified with aqueous LiOH and then coupled to 5-amino tetrazole following the procedure described (Step D., Example 1/2) to give 6-bromo-4-[(trans-4-tert-butylcyclohexyl)({[4-(trifluoromethoxy)phenyl]amino}carbonyl)amino]-N-1H-tetrazol-5-ylchromane-7-carboxamide. HPLC/MS: m/z=680.2 (M+1), Rt=2.55 min. 1H NMR (DMSO-d6): δ 12.58 (1H, br s), 8.61 (1H, s), 7.47 (2H, dd, J=2.5 Hz, 8.5 Hz), 7.29 (1H, s), 7.21 (2H, d, J=8.5 Hz), 7.05 (1H, s), 4.71 (1H, m), 4.40 (1H, dt, J=2.5 Hz, 10.5 Hz), 4.25 (1H, t, J=10.5 Hz), 3.93 (1H, m), 2.77 (1H, m), 2.02 (1H, m), 1.90-1.67 (6H, m), 1.29-1.03 (4H, m), 0.88 (9H, s).