Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]2)=[O:11])=[CH:4][CH:3]=1.OC(C(F)(F)F)=O.N[C@H](CC1C=CC(Cl)=CC=1)C(N1C[CH2:44][N:43]([C:46]2[CH:51]=[CH:50]C=C[C:47]=2[NH:52]S(C)(=O)=O)CC1)=O.C(N1CCC[C@H]1C=O)(OC(C)(C)C)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[NH:43]1[CH2:44][CH2:50][CH2:51][C@@H:46]1[CH2:47][NH:52][C@H:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)[C:10]([N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH2:14][CH2:13]1)=[O:11]
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@H](N)Cc2ccc(Cl)cc2)CC1
Reactant: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)CCc2ccc(Cl)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC(C)(C)OC(=O)N1CCC[C@H]1C=O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nc1ccccc1N1CCN(C(=O)[C@@H](Cc2ccc(Cl)cc2)NC[C@H]2CCCN2)CC1

Procedure:
Following the procedure of Example 38, Step 3, (2R)-2-{[(2R)-pyrrolidin-2-yl)methyl]amino}-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)amino]phenyl}piperazinyl)propan-1-one was prepared from (2R)-2-amino-3-(4-chlorophenyl)-1-(4-{2-[(methylsulfonyl)-amino]phenyl}piperazinyl)propan-1-one TFA salt (0.6 g, 1.1 mmol) in ClCH2Cl2Cl (10 mL), N-Boc-L-prolinal (Aldrich) (280 mg, 1.4 mmol), and NaBH(OAc)3 (Aldrich) (340 mg , 1.9 mmol). The desired compound (TFA salt) was purified by preparative TLC (60% Hexane, 38% CH2Cl2 and 2% 2N NH3 in MeOH), followed by preparative HPLC (TFA buffer) yielding a white solid (14.8 mg). MS (ESI, pos. ion) m/z: 520 (M+H); MS (ESI, neg. ion) m/z: 518 (M−H). Calc'd for C25H34ClN5O3S: 519.21.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[CH2:8]([N:10]=[C:11]=[O:12])[CH3:9]>O1CCOCC1>[CH2:8]([NH:10][C:11]([NH:1][CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5])=[O:12])[CH3:9]
Reactant: CC(C)(CN)CO
Reactant: CCN=C=O
Solvent: C1COCCO1
Product: CCNC(=O)NCC(C)(C)CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.9 %

Procedure:
To a solution of 3-amino-2,2-dimethylpropan-1-ol (1.03 g, 10 mmol) in dry 1,4-dioxane (20 mL) was added dropwise ethyl isocyanate (0.71 g, 10 mmol) at room temperature under nitrogen. The reaction mixture was then stirred at room temperature under nitrogen overnight. The solvent was removed under reduced pressure to give the title compound as colorless oil (1.74 g, 100%). MS 175 (MH+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([CH2:12]O)[CH:6]=[CH:5]2.S(Cl)([Cl:16])=O>C1C=CC=CC=1>[Cl:16][CH2:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([CH3:1])[CH:3]=2)[CH:8]=1
Reactant: Cc1ccc2cc(CO)ccc2c1
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ccc2cc(CCl)ccc2c1
Reaction time: 1 h

Procedure:
20.3 g. of 6-methyl-2-naphthalenemethanol is dissolved in 100 ml. of dry benzene and to this solution is added 30 ml. of thionyl chloride. The solution is stirred for about one hour and concentrated to yield 2-chloromethyl 6-methylnaphthalene.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])[OH:11].N1C=CN=C1.[C:25]([Si:29]([CH3:32])([CH3:31])Cl)([CH3:28])([CH3:27])[CH3:26].[Cl-].[NH4+]>CN(C)C1C=CN=CC=1.CN(C)C=O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]([C:12]1[CH:17]=[C:16]([Br:18])[CH:15]=[CH:14][C:13]=1[F:19])[O:11][Si:29]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC(c1cc2ccccc2s1)c1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 7 h
Yield: 78 %

Procedure:
To a dimethylformamide (20 ml) solution of 1-benzothien-2-yl(5-bromo-2-fluorophenyl)methanol (5.0 g) were added imidazole (1.3 g), a catalytic amount of 4-(dimethylamino)pyridine and tert-butyldimethylchlorosilane (2.7 g), followed by stirring at room temperature for 7 hours. To the reaction mixture was added a saturated aqueous ammonium chloride solution, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous ammonium chloride solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to obtain [1-benzothien-2-yl(5-bromo-2-fluorophenyl)methoxy](tert-butyl)dimethylsilane (5.22 g, yield: 78.0%).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6](Cl)=[O:7])[CH:3]=[N:2]1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1>>[O:1]1[CH:5]=[C:4]([C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:7])[CH:3]=[N:2]1
Reactant: C1CCNCC1
Reactant: O=C(Cl)c1cnoc1
Product: O=C(c1cnoc1)N1CCCCC1

Procedure:
of melting point 78° to 81° C., prepared from 4-isoxazolecarboxylic acid chloride and piperidine.
Reaction SMILES: C(N(C(C)C)C(C)C)C.Cl.[F:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][O:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:18]=[CH:17][C:13]=1[C:14](Cl)=[O:15].[CH3:44][O:45][CH2:46][CH2:47][NH2:48]>C(Cl)Cl>[F:11][C:12]1[CH:20]=[C:19]([C:21]2[CH:22]=[CH:23][C:24]3[N:25]([C:27]([CH2:30][O:31][C:32]4[C:41]5[C:36](=[CH:37][C:38]([O:42][CH3:43])=[CH:39][CH:40]=5)[N:35]=[CH:34][CH:33]=4)=[N:28][N:29]=3)[CH:26]=2)[CH:18]=[CH:17][C:13]=1[C:14]([NH:48][CH2:47][CH2:46][O:45][CH3:44])=[O:15]
Reactant: COCCN
Reactant: COc1ccc2c(OCc3nnc4ccc(-c5ccc(C(=O)Cl)c(F)c5)cn34)ccnc2c1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCNC(=O)c1ccc(-c2ccc3nnc(COc4ccnc5cc(OC)ccc45)n3c2)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of N-ethyl-N-isopropylpropan-2-amine (0.077 ml, 0.44 mmol) and 2-fluoro-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzoyl chloride-HCl (0.088 g, 0.18 mmol) in DCM (1.25 mL) was added 2-methoxyethanamine (0.023 ml, 0.26 mmol) dropwise. The solution was stirred at room temperature for 5 h. The crude material was concentrated and then triturated with sodium bicarbonate and washed with water. The resultant solid was dissolved in DCM/MeOH and concentrated. The crude material was dissolved in DCM/MeOH and was purified via flash chromatography, eluting with 0-10% MeOH/NH4OH in DCM to yield 2-fluoro-N-(2-methoxyethyl)-4-(3-((7-methoxyquinolin-4-yloxy)methyl)-[1,2,4]triazolo[4,3-a]pyridin-6-yl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:12][CH2:11]1)[NH2:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:13]1(B(O)O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[C:1]([O:5][C:6]([N:8]([CH:10]1[CH2:11][CH2:12]1)[NH:9][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N(N)C1CC1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(C)(C)OC(=O)N(Nc1ccccc1)C1CC1
Temperature: 50 °C
Yield: 45.3 %

Procedure:
A mixture of N-cyclopropyl-hydrazinecarboxylic acid tert-butyl ester (Intermediate 28; 0.111 g, 0.64 mmol), phenylboronic acid (Aldrich; 156 mg, 1.3 mmol), copper(II) acetate (116 mg, 0.64 mmol) and triethylamine (180 μL, 1.3 mmol) in 1,2-dichloroethane (3 mL) was heated in an oil bath at 50° C. for 16 h. The mixture was allowed to cool, and it was then adsorbed onto silica gel and purified by chromatography using an ISCO 40 g column, eluting with 5-40% ethyl acetate/hexanes, to give N-cyclopropyl-N′-phenyl-hydrazinecarboxylic acid tert-butyl ester (72 mg, 45%) as a pale yellow solid.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][C:13]([CH3:16])([CH3:15])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=2)O1.Br[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][C:22]=1[CH3:30].P([O-])([O-])([O-])=O.[K+].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O.C(OCC)(=O)C>[CH3:30][C:22]1[CH:23]=[CH:24][CH:25]=[C:26]([N+:27]([O-:29])=[O:28])[C:21]=1[C:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[CH2:12][C:11]([CH3:18])([CH3:17])[CH:10]=1
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Reactant: CC1(C)C=C(B2OC(C)(C)C(C)(C)O2)CC(C)(C)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: Cc1cccc([N+](=O)[O-])c1C1=CC(C)(C)CC(C)(C)C1
Temperature: 80 °C
Reaction time: 0.33 h
Yield: 99.9 %

Procedure:
A mixture of 4,4,5,5-tetramethyl-2-(3,3,5,5-tetramethylcyclohex-1-enyl)[1,3,2]dioxaborolane (3.96 g, 15 mmol) produced in Example (4b), 2-bromo-3-nitrotoluene (2.48 g, 11.5 mmol), tetrakis(triphenylphosphine)palladium(0) (1.33 g, 1.15 mmol), tripotassium phosphate (3.66 g, 17.3 mmol), 1,2-dimethoxyethane (30 mL) and water (10 mL) was stirred for 10 hours and 20 minutes at an external temperature of 80° C. under a nitrogen atmosphere. Ethyl acetate and water were added to the reaction mixture, and it was filtered through Celite. The filtrate was then extracted with ethyl acetate. The separated organic layer was washed with water and brine in that order and then dried over anhydrous magnesium sulfate. The desiccant was filtered off and the filtrate was concentrated under reduced pressure. The resultant residue was purified by NH silica gel column chromatography (hexane) to give 3.14 g of the title compound as a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[CH:31][C:5]2[NH:6][C:7]([C:12]3[C:13](=[O:30])[C@@:14]([CH2:24][CH2:25][C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:23])[C:15]4[C:20]([C:21]=3[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=4)=[N:8][S:9](=[O:11])(=[O:10])[C:4]=2[CH:3]=1.N1C=CC=CC=1.[CH3:39][S:40](Cl)(=[O:42])=[O:41]>ClCCl>[CH3:29][C:26]([CH3:27])([CH3:28])[CH2:25][CH2:24][C@:14]1([CH3:23])[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]([OH:22])=[C:12]([C:7]2[NH:6][C:5]3[CH:31]=[CH:32][C:2]([NH:1][S:40]([CH3:39])(=[O:42])=[O:41])=[CH:3][C:4]=3[S:9](=[O:11])(=[O:10])[N:8]=2)[C:13]1=[O:30]
Reactant: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(N)ccc3N2)=C(O)c2ccccc21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)CC[C@@]1(C)C(=O)C(C2=NS(=O)(=O)c3cc(NS(C)(=O)=O)ccc3N2)=C(O)c2ccccc21
Yield: 87.2 %

Procedure:
To a solution of the product of Example 49-6 (235.0 g, 0.518 mol) and pyridine (123.0 g, 1.55 mol) in dichloromethane (1645 mL) at 18-20° C. was added methane sulfonyl chloride (89.0 g, 0.777 mol) over 45 minutes. The solution was mixed at RT for 3.5 h then quenched with 1 M HCl (1500 mL). The layers were separated and the organic layer was concentrated under vacuum. The product was crystallized from ethyl acetate/heptane (1/1, 8 volumes) to give the title compound (240.01 g, 87%).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)[CH2:14][CH2:13][CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[F:32][C:30]([F:31])([F:33])[O:29][C:26]1[CH:27]=[CH:28][C:23]([O:22][CH2:21][CH2:20][CH2:19][N:15]2[C:16]3[C:11](=[CH:10][C:9]([OH:8])=[CH:18][CH:17]=3)[CH2:12][CH2:13][CH2:14]2)=[CH:24][CH:25]=1
Reactant: FC(F)(F)Oc1ccc(OCCCN2CCCc3cc(OCc4ccccc4)ccc32)cc1
Agent: [Pd]
Solvent: CCO
Product: Oc1ccc2c(c1)CCCN2CCCOc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.8 %

Procedure:
6-Benzyloxy-1-[3-(4-trifluoromethoxy-phenoxy)propyl]-1,2,3,4-tetrahydro-quinoline (2.13 g) was dissolved in ethanol (10 ml). 10% palladium on carbon (0.2 g) was added thereto and stirred at room temperature under a hydrogen atmosphere for 4 hours. The mixture was filtered through Celite to remove the catalyst, and then the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1) and concentrated under reduced pressure to afford the title compound (1.45 g).
Reaction SMILES: [CH2:1]([N:8]1[C:15](=[O:16])[CH2:14][C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[C:30](Cl)(=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33]>ClCCl>[CH2:1]([N:8]1[C:15](=[O:16])[CH:14]([C:30](=[O:35])[CH2:31][CH:32]([CH3:34])[CH3:33])[C:12](=[O:13])[N:11]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]1=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CC(=O)N(Cc2ccccc2)C(=O)N1Cc1ccccc1
Reactant: CC(C)CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)CC(=O)C1C(=O)N(Cc2ccccc2)C(=O)N(Cc2ccccc2)C1=O
Temperature: 0 °C
Yield: 88.8 %

Procedure:
To a solution of 1,3-dibenzyl barbituric acid 265 mg (0.859 mmol) in dry dichloromethane 2.0 mL under a nitrogen atmosphere, added was pyridine 1.0 mL (12 mmol) and stirred at 0° C. Added was isovaleryl chloride 104 mg (0.858 mmol, 1.00 equivalent) in dichloromethane 1.0 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 3 hours. Added was dichloromethane 50 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 351 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-dibenzyl-5-(3-methyl-1-oxobutyl)barbituric acid 299 mg as colorless viscous oil at first, and in 2 days it turned white plates (88.7% yield).
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.[CH2:7]([O:9][CH:10](OCC)OCC)[CH3:8]>C(Cl)(Cl)(Cl)Cl>[CH2:7]([O:9][CH:10]=[N:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1)[CH3:8]
Reactant: Nc1nnn[nH]1
Reactant: CCOC(OCC)OCC
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC=Nc1nnn[nH]1

Procedure:
A mixture of 10 g of 5-aminotetrazole, 18 g of triethoxymethane and 200 ml of carbon tetrachloride was heated under nitrogen with stirring until distillate appeared. Then, a moderate rate of distillation was maintained for 6 hours with carbon tetrachloride being replaced in the reaction mixture as necessary. At this point, analysis of the crystals present showed complete conversion of aminotetrazole. The white crystals were then filtered from the hot solution and washed briefly with carbon tetrachloride to give a wet cake of 5-(ethoxymethyleneamino)tetrazole which was used immediately as is.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:5][C:6]=1[C:7]([O:9]CC)=[O:8].O.[OH-].[Li+]>CCO.O>[NH2:1][C:2]1[S:3][C:4]([C:12]2[CH:13]=[CH:14][N:15]=[CH:16][CH:17]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: CCOC(=O)c1cc(-c2ccncc2)sc1N
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Nc1sc(-c2ccncc2)cc1C(=O)O
Temperature: 80 °C
Yield: 82.2 %

Procedure:
To a solution of ethyl 2-amino-5-(pyridin-4-yl)thiophene-3-carboxylate (400 mg, 1.53 mmol) in EtOH (50 mL) was added a solution of lithium hydroxide monohydrate (256 mg, 6.1 mmol) in water (5 mL). The reaction mixture was heated to 80° C. for 2 hour. After removal of the solvent, the residue was dissolved in water and the organic materials were extracted with AcOEt (50 mL). The organic layer was discarded, and the aqueous layer was neutralized with 2N HCl aqueous solution to pH=5 or 6, upon with a precipitate formed. The solid was collected by filtration and dried to give the title compound (277 mg, 77%) as an orange solid:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][CH:19]=2)[CH:3]=1.[CH:37]([OH:40])([CH3:39])[CH3:38]>>[CH:37]([O:40][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)[N:5]=[C:4]([C:14]2[CH:15]=[C:16]([C:20]3[CH:25]=[CH:24][C:23]([C:26]([N:28]4[CH2:33][CH2:32][N:31]([CH:34]([CH3:36])[CH3:35])[CH2:30][CH2:29]4)=[O:27])=[CH:22][CH:21]=3)[CH:17]=[N:18][CH:19]=2)[CH:3]=1)([CH3:39])[CH3:38]
Reactant: CC(C)N1CCN(C(=O)c2ccc(-c3cncc(-c4cc(Cl)nc(-c5ccccn5)n4)c3)cc2)CC1
Reactant: CC(C)O
Product: CC(C)Oc1cc(-c2cncc(-c3ccc(C(=O)N4CCN(C(C)C)CC4)cc3)c2)nc(-c2ccccn2)n1

Procedure:
This compound is prepared from {4-[5-(6-chloro-2-pyridin-2-yl-pyrimidin-4-yl)-pyridin-3-yl]-phenyl}-(4-isopropyl-piperazin-1-yl)-methanone (Ex. 1) and isopropanol analogously to Example 2: [M+H]+=523 as a pale yellow solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([CH:24]=O)=[CH:20][CH:19]=3)[N:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]([CH2:36][C:37]([N:39]([CH3:41])[CH3:40])=[O:38])#[N:35].C(O)(=O)C.N1CCCCC1>C(O)C>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[CH:20][C:21]([CH:24]=[C:36]([C:34]#[N:35])[C:37]([N:39]([CH3:41])[CH3:40])=[O:38])=[CH:22][CH:23]=3)[N:15]=2)[N:10]([CH2:26][O:27][CH2:28][CH2:29][Si:30]([CH3:33])([CH3:32])[CH3:31])[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Nc3ccc(C=O)cc3)nc12
Reactant: CN(C)C(=O)CC#N
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)C(=O)C(C#N)=Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cc1
Yield: 56.8 %

Procedure:
To a 25 ml three necked round bottom flask, N-tert-butyl-2-(4-formylphenylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (0.022 g, 0.000047 mol) and 2-cyano-N,N-dimethylacetamide (0.021 g, 0.000187 mol) was taken in ethanol (2 ml). Piperidine acetate (3.3 M solution in water) (0.2 ml) was added dropwise at RT. After completion of the addition, reaction mixture was refluxed overnight. After completion of the reaction, the ethanol was distilled out and water was added to the residue. Aqueous was extracted with ethyl acetate, organic layers were combined, dried over Na2SO4, filtered and concentrated to afford crude product which was purified by triturated with n-pentane. The solid was filtered and dried under vacuum to yield 0.015 g of N-tert-butyl-2-(4-(2-cyano-3-(dimethylamino)-3-oxoprop-1-enyl)phenylamino)-5-((2-(trimethylsilyl)ethoxy)-methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide.
Reaction SMILES: [CH2:1]([Si:4](Cl)(Cl)Cl)[CH:2]=[CH2:3].[C:8]([OH:16])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCCCC>[CH2:1]([Si:4]([O:16][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:15][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[O:15][C:8](=[O:16])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3]
Reactant: C=CC[Si](Cl)(Cl)Cl
Reactant: O=C(O)c1ccccc1
Solvent: CCCCCC
Product: C=CC[Si](OC(=O)c1ccccc1)(OC(=O)c1ccccc1)OC(=O)c1ccccc1
Yield: 74 %

Procedure:
878 g (5 moles) of allyltrichlorosilane and 1000 ml of hexane are placed in the apparatus of Example 1. The reaction with 1855 g of benzoic acid (=15.2 mol) is performed as described in Example 1, as is also the distilling of the raw product. At a pressure of 0.4 mbar and a head temperature of 137° C., 1599 g (3.7 mol) of a colorless liquid is distilled out, which several days later transforms to a sticky-crystalline state. The yield of 74%.
Reaction SMILES: [OH:1][CH:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][NH2:4].[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][C:18](=O)[CH3:19])=[CH:14][CH:13]=1>>[CH3:11][C:12]1[CH:22]=[CH:21][C:15]([O:16][CH2:17][CH:18]([NH:4][CH2:3][CH:2]([OH:1])[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH3:19])=[CH:14][CH:13]=1
Reactant: CC(=O)COc1ccc(C)cc1
Reactant: NCC(O)c1ccccc1
Product: Cc1ccc(OCC(C)NCC(O)c2ccccc2)cc1

Procedure:
The title compound was prepared in the manner described in Example 3 using 2-hydroxy-2-phenylethanamine and (4-methylphenoxy)propan-2-one. Recrystallization from heptane gave the title compound m.p. 87-105. τ(CDCL3) 8.9 (3H, d, J=6 Hz), 7.7 (3H, s), 6.7-7.5 (3H, +2H (disappears with D2O)), 6.2 (2H, m), 5.3 (1H, m), 3.3 (2H, d, J=9 Hz), 2.9 (2H, d, J=9 Hz), 2.7 (5H, m).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH3:11][S:12]([C:15]1[N:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:11][S:12]([C:15]1[CH:16]=[CH:17][C:18]([O:21][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)=[CH:19][N:20]=1)(=[O:14])=[O:13]
Reactant: CS(=O)(=O)c1ccc(O)cn1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Oc2ccc([N+](=O)[O-])cc2)cn1
Temperature: 100 °C
Reaction time: 3 h
Yield: 99.9 %

Procedure:
To a solution of 4-fluoronitrobenzene (4.74 g) and 6-(methylsulfonyl)pyridin-3-ol (6.4 g) in N,N-dimethylformamide (50 mL) was added potassium carbonate (9.3 g), and the mixture was stirred at 100° C. for 3 hr. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained crude product was crystallized from diethyl ether to give the title compound (9.88 g, yield 100%) as a yellow solid.
Reaction SMILES: [CH3:1][C@H:2]1[N:7]([CH3:8])[CH2:6][CH2:5][N:4](C(OC(C)(C)C)=O)[CH2:3]1.[ClH:16]>O1CCOCC1>[ClH:16].[ClH:16].[CH3:8][N:7]1[CH2:6][CH2:5][NH:4][CH2:3][C@H:2]1[CH3:1]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)CCN1C
Agent: Cl
Solvent: C1COCCO1
Product: C[C@@H]1CNCCN1C
Reaction time: 8 h

Procedure:
1,1-Dimethylethyl (3R)-3,4-dimethyl-1-piperazinecarboxylate (2.70 g, 12.6 mmol) in 1N HCl (25 mL) was stirred overnight. Then 4M HCl in 1,4-dioxane (25 mL) was added and the reaction was left to stir overnight. The volatiles were removed in vacuo to provide (2R)-1,2-dimethylpiperazine dihydrochloride as a white solid (2.53 g). LCMS: (M+H)+=115.1.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:10])[NH:4][C:5](=[O:9])[NH:6][C:7]=1[Cl:8].C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]1[CH:31]=[CH:30][C:22]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[CH:21][CH:20]=1.ClCCl.CO>CN(C)C=O>[C:26]([O:25][C:23](=[O:24])[C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:4]2[C:3](=[O:10])[C:2]([CH3:1])=[C:7]([Cl:8])[NH:6][C:5]2=[O:9])=[CH:31][CH:30]=1)([CH3:29])([CH3:28])[CH3:27]
Reactant: Cc1c(Cl)[nH]c(=O)[nH]c1=O
Reactant: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: Cc1c(Cl)[nH]c(=O)n(Cc2ccc(C(=O)OC(C)(C)C)cc2)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 40.3 %

Procedure:
5-Methyl-6-chloropyrimidine-2,4-dione (1.00 g, 6.22 mmol) was dissolved in dimethylformamide (15 mL).To the solution was added cesium carbonate (2.02 g, 6.22 mmol) and t-butyl 4-bromomethylbenzoate (1.69 g, 6.22 mmol). The mixture was stirred at room temperature for 20 hours. The solvent was evaporated under a vacuum at 60° C. The residue was mixed with tetrahydrofuran (50 mL) and methanol (10 mL) and filtered. The filtrate was evaporated in a vacuum to an amber oil. The oil was purified by flash chromatography on silica gel eluting first with dichloromethane then with dichloromethane:methanol (19:1) to give the desired product (0.88 g, 40% yield). 1H-NMR (DMSO-d6) δ 11.8 (s, 1H), 7.85 (d, 2H), 7.34 (d, 2H), 5.22 (s, 2H), 1.88 (s, 3H), 1.51 (s, 9H).