Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH2:20]([O:22][C:23](=O)[O:24]CC)[CH3:21].C([N-]C(C)C)(C)C.[Li+].C(NC(C)C)(C)C.C([Li])CCC.C(O)(=O)C>O1CCCC1>[CH2:20]([O:22][C:23]([CH2:1][C:2]1[CH:10]=[C:9]([O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:24])[CH3:21]
Reactant: CCOC(=O)OCC
Reactant: Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: CC(=O)O
Product: CCOC(=O)Cc1cc(OCCN2CCOCC2)ccc1C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2-methyl-4-(2-morpholin-4-yl-ethoxy)-benzoic acid (3.58 g, 13.5 mmole) and diethylcarbonate (2.40 g, 20.4 mmole) in tetrahydrofuran (30 mL) is added dropwise to a solution of lithium diisopropylamide (30.0 mmole) at −78° C. (freshly prepared from diisopropylamine (3.04 g, 30.0 mmole) and n-butyllithium (18.8 mL of 1.6M in hexanes, 30.1 mmole) in tetrahydrofuran (20 mL)) over 15 minutes. This mixture is allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture is cooled with an ice bath then glacial acetic acid (3.1 mL, 54.0 mmole) is added dropwise. The tetrahydrofuran evaporated in vacuo and the mixture is then extracted with ethyl acetate (3×25 mL). The ethyl acetate layer is dried over sodium sulfate, filtered and evaporated. This is purified by HPLC (acetonitrile-water without trifluoroacetic acid and dried to give, 2.81 g, (61%), MS (ESI): m/z 338.1 (M+H).
Reaction SMILES: [CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH2:9])[CH3:2].[CH2:10]([S:12]([C:15]1[CH:16]=[C:17]([C:25](Cl)=[O:26])[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=1)(=[O:14])=[O:13])[CH3:11]>>[CH2:1]([N:3]1[CH2:7][CH2:6][CH2:5][CH:4]1[CH2:8][NH:9][C:25]([C:17]1[C:18]2[O:23][CH2:22][CH2:21][O:20][C:19]=2[CH:24]=[C:15]([S:12]([CH2:10][CH3:11])(=[O:14])=[O:13])[CH:16]=1)=[O:26])[CH3:2]
Reactant: CCN1CCCC1CN
Reactant: CCS(=O)(=O)c1cc2c(c(C(=O)Cl)c1)OCCO2
Product: CCN1CCCC1CNC(=O)c1cc(S(=O)(=O)CC)cc2c1OCCO2
Yield: 60.1 %

Procedure:
In a similar manner 58 g of 1-ethyl-2-aminomethylpyrrolidine was reacted with 131 g of 7-ethylsulfonyl-1,4-benzodioxane-5-carbonyl chloride to give, after treatment and purification, 103.5 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide (M.P.: 118°-119° C.; yield: 60.2%). 100 g of the base produced was dissolved in 220 ml of acetone and then the solution was filtered on carbon black and a solution of 9.5 g of hydrochloric acid in acetone was added. The resulting hydrochloride crystals were dried off, washed with acetone and then dried. 96 g of N-(1-ethyl-2-pyrrolidylmethyl)-7-ethylsulfonyl-1,4-benzodioxane-5-carboxamide hydrochloride was produced (M.P.: 148°-150° C.; yield: 88.2%).
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[Li+].CC([N-]C(C)C)C.[CH3:21][O:22][C:23]1[CH:39]=[CH:38][C:26]([CH2:27][N:28]2[CH:32]=[C:31]([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH:30]=[N:29]2)=[CH:25][CH:24]=1.CN(C)[CH:42]=[O:43]>C1COCC1.CCOC(C)=O>[CH:42]([C:32]1[N:28]([CH2:27][C:26]2[CH:25]=[CH:24][C:23]([O:22][CH3:21])=[CH:39][CH:38]=2)[N:29]=[CH:30][C:31]=1[C:33]([O:35][CH2:36][CH3:37])=[O:34])=[O:43]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)c1cnn(Cc2ccc(OC)cc2)c1C=O
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 60.2 %

Procedure:
According to Scheme 17 Step 1: Butyl lithium 2.5 M (16.9 mmol, 8.45 mL) was added to a solution of diisopropylamine (16.9 mmol, 2.37 mL) in THF (10 mL) at −78° C. and the reaction mixture was stirred at −78° C. for 5 minutes and then at room temperature. To the resulting LDA solution was added at −78° C. a solution of ethyl 1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (7.68 mmol, 2 g) in THF (30 mL) and the reaction mixture was stirred for 5 minutes at −78° C. N,N-Dimethylformamide (61.5 mmol, 4.73 mL) was added and then the reaction mixture was stirred at room temperature. The reaction mixture was diluted with AcOEt and was washed with a saturated aqueous solution of NH4Cl. The combined organic phases were dried over MgSO4, were filtered and were evaporated. The crude mixture was purified by flash chromatography over silica gel using cyclohexane/AcOEt (100:0 to 80:20) as eluent to yield ethyl 5-formyl-1-(4-methoxybenzyl)-1H-pyrazole-4-carboxylate (4.62 mmol, 1.33 g, 60%).
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:27])[N:7]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[CH3:28][N:29]([CH3:46])[CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[C:33](B2OC(C)(C)C(C)(C)O2)[CH:32]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.O>[CH3:28][N:29]([CH2:30][C:31]1[CH:32]=[C:33]([C:2]2[CH:11]=[C:10]3[C:5]([C:6](=[O:27])[N:7]([CH2:20][C:21]([NH:23][CH:24]([CH3:26])[CH3:25])=[O:22])[C:8]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=4)=[N:9]3)=[CH:4][CH:3]=2)[CH:34]=[CH:35][CH:36]=1)[CH3:46]
Reactant: COc1cccc(-c2nc3cc(Cl)ccc3c(=O)n2CC(=O)NC(C)C)c1
Reactant: CN(C)Cc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cccc(-c2nc3cc(-c4cccc(CN(C)C)c4)ccc3c(=O)n2CC(=O)NC(C)C)c1
Temperature: 80 °C

Procedure:
An oven dried flask was charged with 2-[7-chloro-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (INTERMEDIATE IV.11) (38.5 mg, 0.10 mmol), dimethyl-[3-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)benzyl]amine (INTERMEDIATE XI.1) (40 mg, 0.15 mmol) and K3PO4(69 mg, 0.33 mmol) followed by mixture of DMF: H2O (4:1, 5 mL) and purged with argon for a minimum of 10 minutes. CombiPhos™-Pd catalyst (CombiPhos Catalysts Inc., Princeton, N.J.) (1 mole %) was added and the mixture was heated at 80° C. for 18 h. The solvent was removed under vacuum and the residue was dissolved in methanol, filtered and purified by preparative HPLC to give 2-[7-(3-dimethylaminomethylphenyl)-2-(3-methoxyphenyl)-4-oxo-4H-quinazolin-3-yl]-N-isopropylacetamide (EXAMPLE 8a) as a colorless oil.
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:56])[C@H:10]([CH2:35][CH2:36][CH2:37][NH:38]C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[N:11]([C:13](=[O:34])[C@H:14]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[NH:15]C(OC(C)(C)C)=O)[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1CCCCC1.[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66]>CN(C)C=O>[F:63][C:64]([F:69])([F:68])[C:65]([OH:67])=[O:66].[CH2:1]([NH:8][C:9](=[O:56])[C@H:10]([CH2:35][CH2:36][CH2:37][NH2:38])[N:11]([C:13](=[O:34])[C@H:14]([CH2:23][C:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][CH:25]=1)[NH2:15])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OC(C)(C)C)[C@@H](CCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCNCC1
Product: CN(C(=O)[C@@H](N)Cc1cccc2ccccc12)[C@@H](CCCN)C(=O)NCc1ccccc1

Procedure:
Boc-β-(1-Naphthyl)alanyl-Nδ-Fmoc-Nα-methylornithine benzylamide (B) (28 mg) was deprotected in teo steps-i) 20% piperidine in dimethylformamide and ii) trifluoroacetic acid exposure to afford a white solid: HPLC (method A); 1H NMR (400 MHz, D2O) δ1.59 (m, 2H), 1.77 (m, 1H), 1.89 (m, 1H), 2.38 (s, 3H), 3.0 (t, 2H), 3.60 (dd, 1H), 3.82 (dd, 1H), 4.39 (d, 2H), 4.92 (t, 1H), 5.01 (dd, 1H), 7.36-7.50 (m, 12H), 7.75 (m, 2H), 7.99 (t, 1H),8.10 (d, 1H), and 8.18 (d, 1H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:11]=[CH:10][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1.[C-]#N.[Na+].[CH3:15][N:16](C)C=O>O>[S:7]1[CH:8]=[CH:9][C:5]2[CH:4]=[C:3]([CH2:2][C:15]#[N:16])[CH:11]=[CH:10][C:6]1=2
Reactant: CN(C)C=O
Reactant: BrCc1ccc2sccc2c1
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Product: N#CCc1ccc2sccc2c1
Yield: 55 %

Procedure:
In a round bottom flask was placed 5-bromomethyl-benzo[b]thiophene (5.27 g, 23.20 mmol), sodium cyanide (1.59 g, 32.49 mmol) and N,N-dimethylformamide (50 mL) and it was stirred for 24 h at 25° C. After this time, the reaction mixture was dissolved in water (30 mL) and extracted with ethyl acetate (3×30 mL), dried over sodium sulfate and purified on an AnaLogix Intelliflash system (120 g column, 3% ethyl acetate/hexanes to 20% ethyl acetate/hexanes) to afford benzo[b]thiophen-5-yl-acetonitrile (2.23 g, 55%) as a yellow solid.
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:10])[CH2:6][C:7]([CH3:9])=O)[CH:2]=[CH2:3].[NH3:11]>C(O)C>[CH2:1]([NH:4][C:5](=[O:10])/[CH:6]=[C:7](\[NH2:11])/[CH3:9])[CH:2]=[CH2:3]
Reactant: N
Reactant: C=CCNC(=O)CC(C)=O
Solvent: CCO
Product: C=CCNC(=O)/C=C(/C)N
Reaction time: 8 h
Yield: 82.7 %

Procedure:
Acetoacetic allylamide (111.4 g, 0.79 mole) is dissolved in ethanol (80 ml) and thereto is passed ammonia gas, while the temperature is controlled below 30° C. by cooling with a water bath. After passing ammonia gas for about 3 hours, colorless crystals precipitate. The reaction mixture is allowed to stand at 0° C. overnight. The precipitates are separated by filtration and washed with diethyl ether to give the title compound (91.5 g, yield 82.7%) as colorless prisms, m.p. 143°-144° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25][C:26](=[O:28])[CH3:27])=[CH:18][C:17]=2[O:29]C(=O)C)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].C(O)C.Cl>O>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:33])[C:16]2[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[C:19]([NH:25][C:26](=[O:28])[CH3:27])=[CH:18][C:17]=2[OH:29])[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1cc(OC(C)=O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1cc(O)c(C(=O)NC2CCN(Cc3ccccc3)CC2)cc1[N+](=O)[O-]
Yield: 86 %

Procedure:
A mixture of N-(1-benzylpiperid-4-yl)-2-acetoxy-4-acetamido-5-nitrobenzamide (1.4 g; 0.0031 moles) [prepared by the procedure described in Example 1], sodium hydroxide (0.3 g; 0.0062 moles), water (25 ml) and ethanol (12.5 ml) was boiled under reflux for 3 hours. Then the mixture was diluted with water, neutralized with diluted hydrochloric acid and the solid filtered off, washed with water and diethyl ether to give 1.1 g of N-(1-benzylpiperid-4-yl)-2-hydroxy-4-acetamido-5-nitrobenzamide, m.p. 220°-222° C.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:31]=[CH:30][CH:29]=[CH:28][C:12]=1[C:13]([NH:15][C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27])=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:32]I>CN(C)C=O>[CH3:32][N:15]([C:13](=[O:14])[C:12]1[CH:28]=[CH:29][CH:30]=[CH:31][C:11]=1[O:10][CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][C:17]=1[O:26][CH3:27]
Reactant: COC(=O)c1ccc(NC(=O)c2ccccc2OCc2ccccc2)c(OC)c1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(N(C)C(=O)c2ccccc2OCc2ccccc2)c(OC)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (60% oil suspension, 88.3 mg) in N,N-dimethylformamide (6 ml) was added a solution of methyl 4-(2-benzyloxybenzoyl)amino-3-methoxybenzoate (600 mg) in N,N-dimethylformamide (4 ml) and the mixture was stirred at 0° C. for 1 hour. Methyl iodide (0.14 ml) was added dropwise to the above solution and the mixture was stirred at 0° C. for 30 minutes. The reaction temperature was raised to ambient temperature over 30 minutes and the reaction was quenched with 1 N hydrochloric acid, and then the resulting solution was extracted with ethyl acetate. Drying, filtering and removal of solvents afforded a crude product. The crude product was purified by column chromatography (eluent; hexane:ethyl acetate=3:1) to give methyl 4-(N-methyl-2-benzyloxybenzoylamino)-3-methoxybenzoate (650 mg).
Reaction SMILES: [Cl-].[Cl-].[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH:28]2[C:33]([F:35])([F:34])[CH2:32][CH2:31][NH:30][CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6].C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.C(Cl)Cl>[CH2:3]([C:7]1[N:8]=[N:9][C:10]([O:26][CH2:27][CH:28]2[C:33]([F:35])([F:34])[CH2:32][CH2:31][N:30]([CH3:38])[CH2:29]2)=[CH:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16]([O:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)=[CH:15][CH:14]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCc1nnc(OCC2CNCCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCc1nnc(OCC2CN(C)CCC2(F)F)cc1-c1ccc(OC2CCCCC2)cc1
Reaction time: 0.08 h
Yield: 64.6 %

Procedure:
A suspension of 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-piperidin-3-ylmethoxy)-pyridazine dichloride (0.17 mmol, 90 mg), 37% paraformaldehyde (0.4 mmol, 32 mg), and 1 drop of acetic acid in 5 mL of DCM was stirred for 5 min then added sodium triacetoxyborohydride (0.4 mmol, 85 mg) and continued stirring for 0.5 h at room temperature. Quenched with water, solvent was evaporated; the residue was diluted with ethyl acetate, and then washed with saturated NaHCO3 solution, brine. The organic layer was dried (Na2SO4), filtered and concentrated under reduced pressure. The resultant residue was purified by column chromatography using 5% methanolic solution of ammonia (2.0 M ammonia in methanol) in DCM to get 3-butyl-4-(4-cyclohexyloxy-phenyl)-6-(4,4-difluoro-1-methyl-piperidin-3-ylmethoxy)-pyridazine (52 mg).
Reaction SMILES: [F:1][CH:2]([F:25])[O:3][C:4]1[N:8]([CH3:9])[N:7]=[C:6]([N:10]2[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[N:11]2)[CH:5]=1.S(Cl)([Cl:29])(=O)=O>ClCCl>[Cl:29][C:5]1[C:6]([N:10]2[C:14]([NH:15][C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])=[C:13]([N+:22]([O-:24])=[O:23])[CH:12]=[N:11]2)=[N:7][N:8]([CH3:9])[C:4]=1[O:3][CH:2]([F:1])[F:25]
Reactant: Cn1nc(-n2ncc([N+](=O)[O-])c2NC(=O)C(F)(F)F)cc1OC(F)F
Reactant: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: Cn1nc(-n2ncc([N+](=O)[O-])c2NC(=O)C(F)(F)F)c(Cl)c1OC(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.79 g (2.1 mmol) N-[1-(5-Difluoromethoxy-1-methyl-3-pyrazolyl)-4-nitro-5-pyrazolyl]-2,2,2-trifluoroacetamide was suspended in 35 ml dichloromethane and treated with 0.17 ml sulfuryl chloride. The mixture was stirred for one hour at room temperature and concentrated.
Reaction SMILES: [C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([O:9]C)=[O:8])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>C(O)C.O>[C:1]([O:5][CH:6]([C:11]1[N:15]([CH3:16])[N:14]=[C:13]([C:17]2[S:18][CH:19]=[CH:20][N:21]=2)[C:12]=1[C:22]1[CH:23]=[CH:24][C:25]2[O:30][CH2:29][CH2:28][CH2:27][C:26]=2[CH:31]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc3c(c2)CCCO3)c(-c2nccs2)nn1C
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2nccs2)c(-c2ccc3c(c2)CCCO3)c1C(OC(C)(C)C)C(=O)O
Yield: 90.9 %

Procedure:
A mixture of methyl 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]acetate (8h) (50 mg, 0.11 mmol) and potassium hydroxide (55 mg, 0.45 mmol) in a mixture of ethanol (1.0 mL) and water (1.0 mL) was refluxed overnight. The mixture was concentrated in vacuo. Water (2 mL) was added to the residue and the aqueous layer was washed with ethyl acetate (2 mL), acidified with 1M hydrochloric acid until pH 3 and extracted with ethyl acetate (2×3 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide 2-(tert-butoxy)-2-[4-(3,4-dihydro-2H-1-benzopyran-6-yl)-1-methyl-3-(1,3-thiazol-2-yl)-1H-pyrazol-5-yl]acetic acid (example 8) (45 mg, 0.10 mmol, 93%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[NH:11][C@@H:10]([CH3:15])[CH2:9]2)[N:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[C:25](Cl)(=[O:27])[CH3:26].C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][N:5]=[C:6]([N:8]2[CH2:13][C@@H:12]([CH3:14])[N:11]([C:25](=[O:27])[CH3:26])[C@@H:10]([CH3:15])[CH2:9]2)[CH:7]=1
Reactant: CC(=O)Cl
Reactant: C[C@@H]1CN(c2cc(Cl)ncn2)C[C@H](C)N1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1[C@H](C)CN(c2cc(Cl)ncn2)C[C@@H]1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
To a solution of 4-chloro-6-((3S,5R)-3,5-dimethylpiperazin-1-yl)pyrimidine(1, 10.29 g, 45.4 mmol) and DIEA (8.80 g, 68.1 mmol. 1.50 equiv.) in 100 ml DCM was added acetyl chloride (4.03 ml, 56.7 mmol, 1.25 equiv.) at room temperature portionwise over 10 min. The reaction was stirred at room temperature for another 30 min. Aqueous NaHCO3 was added to the reaction and the organic layer was washed with NahCO3 (100 ml×2) followed by saturated aqueous NaCl solution. The organic layer was dried over Organic layer was dried over NacSO4. Removal of solvent left a yellow oil. This oily material was triturated in diethyl ether to afford a white solid. The solid was collected by filtration and the washed with diethyl ether again. The solid was dried under vacuum and was weighted at 11.95 g. The yield is 98.2%. LC/MS (M+1=269.1).
Reaction SMILES: [O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH3:7])=[O:5].[CH3:10][Si:11]([CH3:16])([CH3:15])[CH2:12]CO.P([O-])([O-])([O-])=O>CN(C)C1C=CN=CC=1.C1(C)C=CC=CC=1>[O:1]=[C:2]([CH2:8][CH3:9])[CH2:3][C:4]([O:6][CH2:7][CH2:10][Si:11]([CH3:16])([CH3:15])[CH3:12])=[O:5]
Reactant: C[Si](C)(C)CCO
Reactant: CCC(=O)CC(=O)OC
Agent: CN(C)c1ccncc1
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Product: CCC(=O)CC(=O)OCC[Si](C)(C)C

Procedure:
1.26 ml (10.0 mmol) of methyl 3-oxovalerate, 2.87 ml (20.0 mmol) of 2-trimethylsilylethanol and 122 mg (1.0 mmol) of 4-dimethylaminopyridine were heated under reflux in 20 ml of toluene overnight. A phosphate buffer solution was added to the obtained reaction liquid. After the extraction with ethyl acetate, the organic layer was washed with saturated aqueous salt solution and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by the silica gel chromatography (hexane/ethyl acetate=10/1) to obtain the title compound.
Reaction SMILES: [C:1]([C:3]1[C:4]([SH:13])=[C:5]([CH:8]=[C:9]([C:11]#[N:12])[CH:10]=1)[C:6]#[N:7])#[N:2].[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:21][S:20][C@@H:19]1Br)(=[O:16])[CH3:15].[Hg](C#N)C#N>>[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[CH2:21][S:20][C@H:19]1[S:13][C:4]1[C:3]([C:1]#[N:2])=[CH:10][C:9]([C:11]#[N:12])=[CH:8][C:5]=1[C:6]#[N:7])(=[O:16])[CH3:15]
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)SC[C@H]1OC(C)=O
Reactant: N#Cc1cc(C#N)c(S)c(C#N)c1
Agent: N#C[Hg]C#N
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](Sc2c(C#N)cc(C#N)cc2C#N)SC[C@H]1OC(C)=O
Yield: 17 %

Procedure:
If the procedure described in Preparation I is followed starting from 4.8 g (258.10-3 mol) of 3,5-dicyano-2-mercaptobenzonitrile (Example 17a), 9.71 g (258.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide and 6.57 g (8.6.10-3 mol) of mercuric cyanide (Hg(CN)2), 2 g (yield: 17%) of the expected product are obtained after crystallization from ether.
Reaction SMILES: I[C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:16])=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1.C(NC(C)C)(C)C.C#CCC.Cl.[CH2:29]1[CH2:33][O:32][CH2:31][CH2:30]1>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I.O>[OH:32][CH2:31][CH2:30][C:29]#[C:33][C:2]1[CH:15]=[C:14]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([OH:16])=[CH:10][C:11]=3[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc2c(c1)CCc1cc(I)ccc1-2
Reactant: C1CCOC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: C#CCC
Solvent: O
Solvent: CC(C)NC(C)C
Product: OCCC#Cc1ccc2c(c1)CCc1cc(O)ccc1-2
Reaction time: 1.5 h

Procedure:
9.0 g (24.6 mmol) of 7-iodo-9,10-dihydrophenanthren-2-ol are initially introduced in 100 ml of THF, 1.0 g (1.43 mmol) of bis(triphenylphosphine)-palladium(II) chloride, 0.3 g (1.58 mmol) of copper(I) iodide and 11 ml of diisopropylamine are added, and a solution of 3.0 g (42.8 mmol) of 1-butyne in 20 ml of THF is subsequently added dropwise with cooling at max. 30° C. The batch is left to stir at room temp. for 1.5 h, added to water and acidified using 2 N hydrochloric acid. The aqueous phase is separated off and extracted three times with ethyl acetate. The combined org. phases are washed with water, dried over sodium sulfate, and the solvent is removed in vacuo. The crude product is filtered through silica gel with dichloromethane/ethyl acetate (3:1) and recrystallised from toluene, giving 7-(4-hydroxybut-1-ynyl)-9,10-dihydrophenanthren-2-ol as a colourless solid.
Reaction SMILES: C([N:8]1[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:10]=[C:9]1[CH2:23][O:24][CH2:25][CH3:26])C1C=CC=CC=1.Cl>>[CH2:25]([O:24][CH2:23][C:9]1[NH:10][C:11]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[N:8]=1)[CH3:26]
Reactant: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)n1Cc1ccccc1
Agent: Cl
Product: CCOCc1nc(C(=O)OCC)c(C(=O)OCC)[nH]1

Procedure:
Following a procedure similar to that described in Preparation 42(iv), but using 4.37 g of diethyl 1-benzyl-2-ethoxymethylimidazole-4,5-dicarboxylate [prepared as described in step (i) above], 3.49 g of the hydrochloride of the title compound were obtained as crystals, melting at 60°-61° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:8]2[NH:9][C:10]3[C:15]([CH:16]=2)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=3)[O:6][CH:7]=1.[Na+].[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([O-:32])=[O:31])=[CH:26][CH:25]=1>CN(C)C=O>[Br:23][C:24]1[CH:29]=[CH:28][C:27]([S:30]([CH2:2][C:3]2[N:4]=[C:5]([C:8]3[NH:9][C:10]4[C:15]([CH:16]=3)=[CH:14][C:13]([O:17][C:18]([F:21])([F:20])[F:19])=[CH:12][CH:11]=4)[O:6][CH:7]=2)(=[O:32])=[O:31])=[CH:26][CH:25]=1
Reactant: O=S([O-])c1ccc(Br)cc1
Reactant: FC(F)(F)Oc1ccc2[nH]c(-c3nc(CCl)co3)cc2c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=S(=O)(Cc1coc(-c2cc3cc(OC(F)(F)F)ccc3[nH]2)n1)c1ccc(Br)cc1

Procedure:
A solution of 2-(4-chloromethyl-oxazol-2-yl)-5-trifluoromethoxy-1H-indole (0.3 g, 0.95 mmol) and 4-bromo-benzenesulfinic acid sodium salt (0.92 g, 3.8 mmol) in N,N-dimethyl formamide (10 ml) was stirred for 16 h at 60° C. After cooling the mixture was poured on water (20 ml) and extracted with ethyl acetate (3×20 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. Chromatography on silica gel (ethyl acetate/iso-hexanes 1:1) yielded the title compound as tan solid. Yield 0.28 g (59%)
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.O.[NH2:13][NH2:14]>N1C=CC=CC=1>[F:9][C:8]([F:11])([F:10])[C:5]1[CH:6]=[CH:7][C:2]([NH:13][NH2:14])=[CH:3][CH:4]=1
Reactant: FC(F)(F)c1ccc(Cl)cc1
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: NNc1ccc(C(F)(F)F)cc1
Temperature: 180 °C
Yield: 20 %

Procedure:
A mixture of 4-chlorobenzotrifluoride (1.08 g), hydrazine hydrate (1.8 g, 6 molar equivalents) and pyridine (5 ml) was heated in an autoclave (purged with argon) for 6 hours at 180° C. The mixture was cooled, the excess hydrazine decanted and the organic phase evaporated in vacuo. The residue was crystallised from petroleum ether to give the title compound in 20% yield. It was shown that 20% of the starting material had been consumed, thus indicating that the reaction had occurred with high selectivity.