Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:8]=[C:9]2[C:13](=[CH:14][CH:15]=1)[NH:12][N:11]=[C:10]2[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[NH:6])C.NNC([CH:27]1[CH2:31][CH2:30][CH2:29][NH:28]1)=O.C[O-].[Na+].O=[C:36]1[CH:40]=C[N:38]=[N:37]1>CO>[F:22][C:19]1[CH:18]=[CH:17][C:16]([C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[C:7]([C:5]4[N:6]=[C:36]([CH2:40][N:28]5[CH2:27][CH2:31][CH2:30][CH2:29]5)[NH:37][N:38]=4)[CH:8]=3)[NH:12][N:11]=2)=[CH:21][CH:20]=1
Reactant: NNC(=O)C1CCCN1
Reactant: CCOC(=N)c1ccc2[nH]nc(-c3ccc(F)cc3)c2c1
Reactant: O=C1C=CN=N1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: Fc1ccc(-c2n[nH]c3ccc(-c4n[nH]c(CN5CCCC5)n4)cc23)cc1
Reaction time: 2 h
Yield: 5 %

Procedure:
A suspension of ethoxy[3-(4-fluorophenyl)(1H-indazol-5-yl)]methanimine hydrochloride (0.500 g, 1.56 mmol) and N-aminopyrrolidin-2-ylcarboxamide (0.606 g, 4.69 mmol) in 4 mL of anhydrous methanol was prepared. An excess of a commercial solution of sodium methoxide in methanol (0.727 mL, 4.37 M) was added. After 2 h, the temperature was raised to reflux and was maintained for 48 hours. The analysis of the mixture showed the formation of the corresponding oxodiazole occurring as a side reaction. The reaction was then quenched with water, the pH adjusted to neutral and the crude product extracted with ethyl acetate. The title compound was purified by preparative HPLC (0.030 g, 5% yield): 1H NMR (CD3OD) δ 8.69 (t, 1H), 8.10–8.02 (m, 3H), 7.68 (d, 1H), 7.05 (t, 2H), 4.52 (t, 1H), 3.17 (m, 2H), 2.39–1.99 (m, 4H), 2.37 (s, 6H), 2.30 (s, 2H), 1.12 (s, 9H); ES-MS (m/z) 349 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][C:3]=1[C:17]([CH3:20])([CH3:19])[CH3:18].[CH2:21](O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:21]([O:15][C:14](=[O:16])[CH2:13][CH2:12][C:5]1[CH:4]=[C:3]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:2]([OH:1])=[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:6]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(C)(C)c1cc(CCC(=O)O)cc(C(C)(C)C)c1O
Reactant: OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(CCC(=O)OCc2ccccc2)cc(C(C)(C)C)c1O

Procedure:
3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid benzyl ester was prepared from 278 g (1 mol) of 3-(4-hydroxy-3,5-di-tert.-butylphenyl)-propionic acid and 108 g (1 mol) benzyl alcohol by azeotropic esterification in toluene with 0.5 g of 4-toluenesulfonic acid. The product was analyzed and the results of this analysis were as follows:
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][C:6]([C:18]3[O:19][C:20]([CH3:23])=[CH:21][CH:22]=3)=[CH:7][CH:8]=2)[N:3]=1.CC1(C)C(C)(C)OB([C:32]2[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:51])[NH:40][C:41]3[CH:46]=[CH:45][C:44]([NH:47][C:48](=[O:50])[CH3:49])=[CH:43][CH:42]=3)=[CH:34][CH:33]=2)O1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(C)C=CC=CC=1>O.CCO>[CH3:23][C:20]1[O:19][C:18]([C:6]2[CH:5]=[C:4]3[C:9]([C:10]([N:12]4[CH2:17][CH2:16][O:15][CH2:14][CH2:13]4)=[N:11][C:2]([C:32]4[CH:33]=[CH:34][C:35]([NH:38][C:39](=[O:51])[NH:40][C:41]5[CH:42]=[CH:43][C:44]([NH:47][C:48](=[O:50])[CH3:49])=[CH:45][CH:46]=5)=[CH:36][CH:37]=4)=[N:3]3)=[CH:8][CH:7]=2)=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1ccc(NC(=O)Nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Cc1ccc(-c2ccc3c(N4CCOCC4)nc(Cl)nc3c2)o1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(NC(=O)Nc2ccc(-c3nc(N4CCOCC4)c4ccc(-c5ccc(C)o5)cc4n3)cc2)cc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 10 %

Procedure:
To a 50 ml, round bottom flask, 2-chloro-7-(5-methyl-furan-2-yl)-4-morpholin-4-yl-quinazoline (0.15 g, 0.00045 mol; prepared as described in Example 2; Scheme 6B), N-(4-(3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)ureido)phenyl)acetamide (0.23 g, 0.00059 mol; prepared according to the methods described in Scheme 9), cesium carbonate (0.44 g, 0.00135 mol), toluene (10 mL), EtOH (4 mL) and water (2 mL) were added. The reaction mixture was degassed with nitrogen for 5-10 min. To the same reaction flask, Pd (PPh3)2Cl2 (0.022 g, 0.0000315 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 3 h. The reaction mixture was cooled to room temperature to get the precipitate. The precipitate was collected by filtration to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 3% MeOH in chloroform). The compound was further purified by flash column chromatography using 230-400 silica gel and 1.5% MeOH in chloroform to yield the title compound [0.0252 g, 10%]. 1H NMR (400 MHz, DMSO-d6): δ 9.86 (s, 1H), 8.92 (s, 1H), 8.67 (s, 1H), 8.42 (d, J=8.8 Hz, 2H), 8.01 (d, J=8.8 Hz, 2H), 7.74 (d, J=8.4 Hz, 1H), 7.61 (d, J=8.8 Hz, 2H), 7.51 (d, J=8.8 Hz, 2H), 7.39 (d, J=8.8 Hz, 2H), 7.17 (d, J=3.2 Hz, 1H), 6.32 (d, J=2.8 Hz, 1H), 3.83 (s, 4H), 3.80 (s, 4H), 2.41 (s, 3H), 2.02 (s, 3H). LC-MS (ESI): Calculated mass: 562.2; Observed mass: 563.1 (RT: 0.64 min).
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:8]=2[OH:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:15](Cl)([Cl:17])[Cl:16].Cl>>[Cl:16][P:15]([Cl:17])[O:14][C:8]1[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:7]=1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClP(Cl)Cl
Reactant: Oc1ccc(Cl)cc1-c1ccccc1
Agent: Cl
Product: Clc1ccc(OP(Cl)Cl)c(-c2ccccc2)c1

Procedure:
79.5 g (0.389 mol) of 2-phenyl-4-chlorophenol were slowly heated to 150° C. with 65.7 g (0.478 mol) of phosphorus trichloride. Hydrogen chloride was evolved at the same time. When the reaction was complete, the mixture was distilled at 0.027 kPa. 80 g (67% of theory relative to the 2-phenyl-4-chlorophenol employed) of the abovementioned substance passed over at a temperature of 145° to 146° C. (see formula sheet, formula V where R1 =2-chloro and R2 =H)
Reaction SMILES: [O:1]=[C:2]1[NH:11][C:10]2[N:9]=[C:8]([O:12][CH:13]([CH3:18])[CH2:14][CH2:15][CH:16]=O)[CH:7]=[CH:6][C:5]=2[CH2:4][CH2:3]1.Cl.[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.CCN(CC)CC.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl>[Cl:20][C:21]1[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][N:31]([CH2:16][CH2:15][CH2:14][CH:13]([CH3:18])[O:12][C:8]2[N:9]=[C:10]3[C:5]([CH2:4][CH2:3][C:2](=[O:1])[NH:11]3)=[CH:6][CH:7]=2)[CH2:30][CH2:29]1
Reactant: Clc1cccc(N2CCNCC2)c1Cl
Reactant: CC(CCC=O)Oc1ccc2c(n1)NC(=O)CC2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CC(CCCN1CCN(c2cccc(Cl)c2Cl)CC1)Oc1ccc2c(n1)NC(=O)CC2
Reaction time: 0.17 h
Yield: 60.1 %

Procedure:
To a solution of 4-(7-oxo-5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yloxy)-pentanal (450 mg, crude) in DCE (10 mL) was added 2,3-dichlorophenyl-piperazine hydrochloride (495 mg, 1.85 mmol) followed by Et3N (0.55 mL, 3.96 mmol). The mixture was stirred for 10 min and then powdered NaBH(OAc)3 (534 mg, 2.52 mmol) was added. The reaction was stirred at room temperature for 2 h and then quenched with saturated NaHCO3. The mixture was extracted with EtOAc (2×). The organic layer was washed with saturated NaHCO3 and brine, dried over Na2SO4 and concentrated to give a foam. Purification by liquid chromatography (4% MeOH/CH2Cl2) gave the title compound as a white foam (507 mg, 1.09 mmol, 61%). MS: APCI: M+1: 463.1 (Exact Mass: 462.16). The enantiomers were separated by chiral HPLC (Chiralcel OD).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].Cl[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:20]([O:19][C:17](=[O:18])[CH2:16][O:11][C:6]1[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=1[CH2:8][CH2:9][CH3:10])[CH3:21]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: CCOC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1O

Procedure:
A mixture of 24.25 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 16.0 ml of ethyl chloroacetate and 26 g anhydrous potassium carbonate in 375 ml of anhydrous acetone was stirred at reflux for 17 hours. The reaction mixture was filtered and the filtrate was concentrated in vacuo to an oil which was crystallized from ethanol to give 27.2 g of (4-acetyl-3-hydroxy-2-propylphenoxy)acetic acid ethyl ester, the titled compound, mp 61°-64°, (78% yield) in two crops.
Reaction SMILES: CC(C)=O.[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.O.[C:36]([OH:46])(=[O:45])[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]>CO>[CH3:5][O:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][NH:16][CH2:17][CH:18]([OH:34])[CH2:19][O:20][C:21]1[CH:22]=[CH:23][CH:24]=[C:25]2[NH:33][C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:26]=12.[C:36]([O-:46])(=[O:45])[CH:37]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[OH:38]
Reactant: O=C(O)C(O)c1ccccc1
Agent: COc1ccccc1OCCNCC(O)COc1cccc2[nH]c3ccccc3c12
Solvent: CC(C)=O
Solvent: O
Solvent: CO
Product: O=C([O-])C(O)c1ccccc1

Procedure:
A suitable reactor is charged with acetone (38 mL). The acetone solution is sequentially charged with carvedilol (11.08 grams) and water (8 mL). Upon addition of the water, the slurry dissolves completely with heating. To the solution, 1N Mandelic acid in methanol (1 Equiv. 27.3 mL.) is added. The resulting mixture is stirred at the range between 17° C. and 35° C., and the solid precipitate is formed over 10 hours to 24 hours. Later, the mixture filtered and the cake is washed with a mixture of acetone and water (10 to 1) at 3 volumes or 33 mL. The cake is then dried under vacuum to a constant weight. The final weight is 8.34 g, 54.5% yield.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]([OH:16])([CH2:14][F:15])[CH2:12][F:13].[CH2:17](Cl)[O:18][CH2:19][CH2:20]OC.CC(=O)OCC>C1COCC1.O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[C:11]([O:16][CH2:17][O:18][CH2:19][CH3:20])([CH2:12][F:13])[CH2:14][F:15]
Reactant: Cc1ccc(Br)c(C(O)(CF)CF)c1
Reactant: COCCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOCOC(CF)(CF)c1cc(C)ccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.9 %

Procedure:
NaH (362 mg, 9.05 mmol) was added to a solution of 2-(2-bromo-5-methylphenyl)-1,3-difluoropropan-2-ol (2.0 g, 7.54 mmol) in THF (10 mL) slowly at 0° C. MEMCl (1.41 g, 11.32 mmol) was added dropwise. The mixture was stirred at rt overnight. The mixture was diluted with H2O and extracted with EA (50 mL×2). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (10:1 to 6:1) to give the product (1.8 g, yield 68%) as colorless oil.
Reaction SMILES: Cl.Cl[CH2:3][C:4]1[N:5]=[C:6]([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[S:7][CH:8]=1.[CH2:14]([NH2:16])[CH3:15]>>[CH:9]1([C:6]2[S:7][CH:8]=[C:4]([CH2:3][NH:16][CH2:14][CH3:15])[N:5]=2)[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN
Reactant: ClCc1csc(C2CCCC2)n1
Agent: Cl
Product: CCNCc1csc(C2CCCC2)n1

Procedure:
Using the procedure of Example 1Q, but replacing 4-(chloromethyl)-2-isopropylthiazole hydrochloride with 4-(chloromethyl)-2-cyclopentylthiazole hydrochloride and replacing 40% aqueous methylamine with 70% aqueous ethylamine provided, after purification of the residue by silica gel chromatography using 5% methanol in chloroform, 1.08 g (50%) of the desired compound.
Reaction SMILES: C(N(CC)CC)C.[NH2:8][CH2:9][CH:10]1[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]2[O:22][C:21]3[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=3[O:19][CH2:18]2)[CH2:12][CH2:11]1.[C:28]([NH:31][C:32]1[CH:37]=[CH:36][C:35]([S:38](Cl)(=[O:40])=[O:39])=[CH:34][CH:33]=1)(=[O:30])[CH3:29].C(OCC)C>ClCCl>[C:28]([NH:31][C:32]1[CH:33]=[CH:34][C:35]([S:38]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C@@H:17]3[O:22][C:21]4[CH:23]=[C:24]([Cl:27])[CH:25]=[CH:26][C:20]=4[O:19][CH2:18]3)[CH2:12][CH2:11]2)(=[O:40])=[O:39])=[CH:36][CH:37]=1)(=[O:30])[CH3:29]
Reactant: NCC1CCN(C[C@H]2COc3ccc(Cl)cc3O2)CC1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1ccc(S(=O)(=O)NCC2CCN(C[C@H]3COc4ccc(Cl)cc4O3)CC2)cc1
Reaction time: 20 h
Yield: 46.4 %

Procedure:
Triethylamine (0.62 ml) was added to a cloudy solution of (S)-4-(aminomethyl)-1-(7-chloro-1,4-benzodioxan-2-ylmethyl)piperidine (0.44 g) and 4-acetamidobenzenesulphonyl chloride (0.65 g) in dichloromethane (22 ml) under nitrogen. The resulting solution was stirred for 20 hours, diluted with dichloromethane (100 ml) and washed with water (100 ml) and brine (100 ml). After drying over anhydrous magnesium sulphate, the mixture was concentrated under reduced pressure to afford an orange oil. Purification by flash chromatography on silica gel eluting with a 15:1 mixture of dichloromethane and methanol gave an orange gum. Trituration with diethyl ether (20 ml) yielded (S)-(-)-4-acetamido-N-{[1-(7-chloro-1,4-benzodioxan-2-ylmethyl)-4-piperidyl]methyl}benzenesulphonamide as a pale orange solid (0.34 g); m.p. 173-176° C., [α]D22 -39.3° (c=0.37, MeOH).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:25][CH2:24][CH2:23][CH2:22]4)=[O:20])=[C:15]([C:26]#[CH:27])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1.[H][H]>O1CCOCC1.O.[Pt]>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]2[NH:6][C:7]([CH:9]([NH:11][C:12](=[O:28])[C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)=[O:20])=[C:15]([CH2:26][CH3:27])[CH:14]=3)[CH3:10])=[N:8][C:4]=2[CH:3]=1
Reactant: C#Cc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Reactant: [H][H]
Agent: [Pt]
Solvent: O
Solvent: C1COCCO1
Product: CCc1cc(C(=O)NC(C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CCCC1
Yield: 99 %

Procedure:
60 mg (0.143 mmol) of N-[1-(5-chloro-1H-benzimidazol-2-yl)ethyl]-3-ethynyl-4-(pyrrolidin-1-ylcarbonyl)benzamide is dissolved in 6.0 mL dioxane/water (1:1), combined with 8.0 mg platinum/activated charcoal and hydrogenated for 7 hours with hydrogen (3 bar). Then the catalyst is filtered off and the solvent is distilled off. Yield: 99%; Rf value: 0.15 (Reversed-phase-8; methanol/5%-NaCl solution=3:2); C23H25ClN4O2 (424.93); mass spectrum: (M−H)-=423/425 (chlorine isotope) and (M+H)+=425/427 (chlorine isotope).
Reaction SMILES: [CH:1]1([N:7]2[C:12](=[O:13])[CH2:11][C:10](=[O:14])[N:9]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[N:31]([CH2:34][C:35]([O:37]CC)=[O:36])=[C:32]=[O:33]>ClCCl>[CH:1]1([N:7]2[C:12](=[O:13])[C:11]([C:32]([NH:31][CH2:34][C:35]([OH:37])=[O:36])=[O:33])=[C:10]([OH:14])[N:9]([CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)[C:8]2=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)CN=C=O
Reactant: O=C1CC(=O)N(C2CCOCC2)C(=O)N1C1CCCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(O)CNC(=O)c1c(O)n(C2CCOCC2)c(=O)n(C2CCCCC2)c1=O
Reaction time: 8 h
Yield: 47.1 %

Procedure:
N-{[3-Cyclohexyl-6-hydroxy-2,4-dioxo-1-(tetrahydro-2H-pyran-4-yl)-1-1,2,3,4-tetrahydro-5-pyrimidinyl]carbonyl}glycine. 1-Cyclohexyl-3-(tetrahydro-2H-pyran-4-yl)-2,4,6(1H,3H,5H)-pyrimidinetrione (900 mg, 3.06 mmoles) and diisopropylethylamine (1.06 mL, 6.12 mmoles) were stirred together in dry dichloromethane (50 mL) and treated with ethyl isocyanatoacetate (360 uL, 3.21 mmoles). The mixture was stirred for under argon overnight, washed twice with 1 molar hydrochloric acid, dried and evaporated. The residue was dissolved in ethanol (15 mL) and treated with 1 molar sodium hydroxide solution (2.0 mL) and 6 molar sodium hydroxide solution (2.0 mL) and stirred for 4 hours. The mixture was partitioned between ethyl acetate and 1 molar hydrochloric acid, the organic solution washed with 1 molar hydrochloric acid, dried and evaporated to a solid. The solid was triturated with diethyl ether, collected, washed with a small amount of diethyl ether and hexane to afford the title compound (570 mg, 47%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s, 1 H), 10.19 (t, J=5.56 Hz, 1 H), 4.83-4.94 (m, 1 H), 4.63 (t, J=11.49 Hz, 1 H), 4.13 (d, J=5.81 Hz, 2 H), 3.93 (dd, J=11.12, 4.04 Hz, 2 H), 3.30-3.37 (m, 2 H), 2.56 (m, 2 H), 2.21-2.33 (m, 2 H), 1.79 (d, J=12.88 Hz, 2 H), 1.61 (s, 3 H), 1.52 (d, J=10.61 Hz, 2 H), 1.28 (q, J=12.97 Hz, 2 H), 1.11-1.18 (m, 1 H).
Reaction SMILES: [CH:1]([C:4]1[C:5]([CH:10]2[CH2:15][C:14](=O)[CH2:13][CH:12]([C:17]3[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2].[OH-].[K+].O.NN.C(Cl)Cl>C(O)COCCO>[CH:1]([C:4]1[C:5]([C@H:10]2[CH2:15][CH2:14][CH2:13][C@@H:12]([C:17]3[C:22]([CH:23]([CH3:25])[CH3:24])=[CH:21][CH:20]=[CH:19][N:18]=3)[NH:11]2)=[N:6][CH:7]=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1cccnc1C1CC(=O)CC(c2ncccc2C(C)C)N1
Agent: NN
Agent: [K+]
Agent: [OH-]
Solvent: OCCOCCO
Solvent: O
Solvent: ClCCl
Product: CC(C)c1cccnc1[C@@H]1CCC[C@H](c2ncccc2C(C)C)N1
Temperature: 100 °C
Yield: 98.5 %

Procedure:
To a solution of 3,3″-diisopropyl-2′,3′,5′,6′-tetrahydro-1′H-[2,2′;6′,2″]terpyridin-4′-one (106 mg, 0.314 mmol) in diethylene glycol (3 mL) were added KOH (352 mg, 6.29 mmol) and hydrazine monohydrate (0.61 mL, 12.6 mmol). The reaction mixture was heated to ˜100° C. for 1 h using a sand bath. After 1 h the temperature was raised to 200° C. for about 45 minutes. CH2Cl2 (50 mL) was added to the remaining mixture and was washed with water (3 times 50 mL). The organic layer was dried (MgSO4), filtered and concentrated to provide 100 mg (99%) of 3,3″-diisopropyl-1′,2′,3′,4′,5′,6′-hexahydro-cis-[2,2′;6′,2″]terpyridine (with some DEG). 1H NMR(CDCl3) δ 1.25 (d, 6H, J=9.3 Hz), 1.57-1.65 (m, 2H), 1.68-1.89 (m, 3H), 2.10-2.14 (m, 1H), 3.19-3.30 (m, 3H), 4.33 (br s, 1H), 7.10 (dd, 2H, J=7.8, 4.5 Hz), 7.53 (d, 2H, J=7.8 Hz), 8.46 (d, 2H, J=4.5 Hz).
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]CC)=[O:8])=[CH:5][C:4]([CH3:12])=[N:3]1.[Cl:13][S:14](O)(=[O:16])=[O:15]>>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([S:14]([Cl:13])(=[O:16])=[O:15])[C:4]([CH3:12])=[N:3]1
Reactant: CCOC(=O)c1cc(C)nn1C
Reactant: O=S(=O)(O)Cl
Product: Cc1nn(C)c(C(=O)O)c1S(=O)(=O)Cl
Temperature: 5 °C
Reaction time: 10 h

Procedure:
Into 200 ml of chlorosulfonic acid, there was added dropwise 50.4 g (0.3 mol) of Ethyl 1,3-dimethyl-5-pyrazole carboxylate under cooling at 5° C. or lower. After heating at 120° C. under stirring for 10 hours, the reaction mixture was poured into ice-water and extracted with ether. After washing with water and drying, evaporation of the solvent gave 49 g of crude 1,3-dimethyl-4-chlorosulfonyl-5-pyrazole carboxylic acid as a solid.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=O)(C)(C)C.BrC[CH2:16][C:17]#[N:18]>>[N:8]1([CH2:6][CH2:16][C:17]#[N:18])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: N#CCCBr
Product: N#CCCN1CCNCC1

Procedure:
The title compound was prepared from 1-tert-butyloxycarbonyl-piperazine and 3-bromopropionitrile in an analogous manner as described in example 21.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].C(N(CC)CC)C.[CH2:19]([C@@H:26]1[CH2:31][C@@H:30]([N:32]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:37])([F:36])[F:35])[CH2:29][CH2:28][NH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>C(Cl)Cl>[CH2:19]([C@@H:26]1[CH2:31][C@@H:30]([N:32]([CH2:39][C:40]2[C:49]3[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=3)[N:43]=[CH:42][CH:41]=2)[C:33](=[O:38])[C:34]([F:36])([F:37])[F:35])[CH2:29][CH2:28][N:27]1[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1
Reaction time: 16 h

Procedure:
67 μl (0.468 mmol) of benzyl chloroformate and 72 μl (0.515 mol) of triethylamine are added to a solution of 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine in 4 ml methylene chloride at 0°, and the mixture is left to stir at this temperature for 16 hours. Then a further 34 μl (0.234 mmol) of benzyl chloroformate and 36 μl (0.257 mmol) of triethylamine are added and stirred at room temperature for 3 hours. This is followed by dilution with methylene chloride, and the organic phase is washed with brine, dried over magnesium sulfate and evaporated to dryness. The oil is chromatographed on silica gel with methylene chloride/methanol/conc. ammonia (1000:50:1). The title compound is obtained as oil. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.61, FD-MS: M+ =561.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:24])([F:23])[F:22].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Cl[C:36]1[CH:41]=[C:40]([NH2:42])[N:39]=[C:38]([NH2:43])[N:37]=1.[C:44]([O-:47])([O-])=[O:45].[K+].[K+]>CN(C=O)C.CO>[F:22][C:21]([F:24])([F:23])[C:44]([OH:47])=[O:45].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[NH:10][C:11]([C:14]3[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=3)[O:20][C:36]3[N:37]=[C:38]([NH2:43])[N:39]=[C:40]([NH2:42])[CH:41]=3)=[N:12][N:13]=2)=[CH:4][C:3]=1[C:21]([F:22])([F:23])[F:24]
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(-c2nnc(Nc3ccc(Cl)c(C(F)(F)F)c3)[nH]2)c1
Reactant: Nc1cc(Cl)nc(N)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Product: Nc1cc(Oc2cccc(-c3nnc(Nc4ccc(Cl)c(C(F)(F)F)c4)[nH]3)c2)nc(N)n1
Product: O=C(O)C(F)(F)F
Temperature: 80 °C
Yield: 46.5 %

Procedure:
3-[5-(4-chloro-3-trifluoromethyl-phenylamino)-4H[1,2,4]triazol-3-yl]-phenol (100 mg, 0.282 mmol) was dissolved in 2 mL of anhydrous DMF in a 5 mL microwave vial. Solid potassium bis(trimethylsilyl)amide (140.6 mg, 0.705 mmol) was added and the reaction mixture was stirred with heating at 80° C. for 15 min, then 4-chloro-2,6-diamino-pyrimidine (44.8 mg, 0.31 mmol) was added, followed by anhydrous K2CO3 (19.5 mg, 0.141 mmol). Then the vial was capped and microwaved at 250° C. for 20 min. Then the reaction mixture was diluted with ca. 1 mL of MeOH, filtered through 0.22 um syringe filter and purified by reverse-phase preparative HPLC in acetonitrile/water system with 0.01% TFA. The product was isolated as a TFA salt (37.8 mg of beige solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[CH:13]=[O:14].CC(=CC)C.Cl([O-])=[O:25].[Na+].P([O-])(O)(O)=O.[Na+]>O.C(OCC)(=O)C.C(O)CCC>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[O:5][C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH3:12])[C:7]=1[C:13]([OH:25])=[O:14]
Reactant: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C=O
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Solvent: CCCCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1nn(C)c(Oc2ccc(Cl)c(Cl)c2)c1C(=O)O
Temperature: 25 °C
Reaction time: 12 h
Yield: 65.4 %

Procedure:
5-(3,4-dichlorophenoxy)-1,3-dimethyl-1H-pyrazole-4-carbaldehyde from Step 1 (492 mg, 0.001726 mol) and 2-methyl-2-butene (300 μL, 0.002832 mol) were stirred in test-butyl alcohol (2.0 mL). A solution of sodium chlorite (400 mg, 0.003538 mol) and sodium dihydrogenphosphate (450 mg, 0.003751 mol) in water (3.0 mL) was added and reaction mixture was stirred for 12 hours at room temperature. Solvent was evaporated and resulting residue was dissolved in ethyl acetate. The organic layer was washed with water, dried over MgSO4 and evaporated to give the title compound (340 mg, 65.5%) as white solid. This material was used in the next step without further purification.