Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O)=[O:2].C(N(CC)CC)C.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.[CH3:42][CH:43]([CH3:52])[C:44]([N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1)=[O:45]>ClCCl>[C:44]([N:46]1[CH2:51][CH2:50][N:49]([C:6]([C:5]2[CH:4]=[C:3]([CH:11]=[CH:10][CH:9]=2)[CH:1]=[O:2])=[O:8])[CH2:48][CH2:47]1)(=[O:45])[CH:43]([CH3:52])[CH3:42]
Reactant: O=Cc1cccc(C(=O)O)c1
Reactant: CC(C)C(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C(=O)N1CCN(C(=O)c2cccc(C=O)c2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 99.9 %

Procedure:
To a solution of 3-formylbenzoic acid (750 mg, 5 mmol) in anhydrous dichloromethane (15 mL) was added triethylamine (1.263 g, 12.5 mmol), 1-hydroxybenzotriazole (0.743 g, 5.5 mmol), followed by 1-ethyl-3-(3-dimethylamino propyl)carbodiimide hydrochloride (1.05 g, 5.5 mmol). After the addition, the mixture was stirred at room temperature for 40 mins. Then the mixture was cooled to 0° C. and 2-methyl-1-(piperazin-1-yl)propan-1-one hydrochloride (1.06 g, 5.5 mmol) was added portionwise. After the addition, the mixture was stirred at room temperature overnight. The mixture was diluted with dichloromethane (50 mL), washed with saturated sodium bicarbonate (50 mL×2), 10% citric acid (50 mL), brine (30 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-(4-isobutyrylpiperazine-1-carbonyl)benzaldehyde (1.44 g, yield 95%) as a gum. 1H-NMR (400 MHz, CDCl3) δ (ppm): 1.13-1.14 (d, J=6.8 Hz 6H), 2.80 (s, 1H), 3.46-3.80 (m, 8H), 7.62-7.66 (t, J=7.6 Hz, 1H), 7.69-7.71 (d, J=7.6 Hz, 1H), 7.94 (s, 1H), 7.96-7.99 (dd, J1=7.6 Hz, J2=1.2 Hz, 1H), 10.06 (s, 1H); LC-MS (ESI) m/z: 289 (M+1)+.
Reaction SMILES: CC1C=CC(S([CH2:11][N+:12]#[C-])(=O)=O)=CC=1.CC(C)([O-])C.[K+].[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[C:26](=O)[CH2:25]2.[Br-].[Li+].Cl>C1COCC1.O.CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]2[C:27](=[CH:28][C:29]=1[O:30][CH3:31])[CH:26]([C:11]#[N:12])[CH2:25]2
Reactant: COc1cc2c(cc1OC)C(=O)C2
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: COc1cc2c(cc1OC)C(C#N)C2
Temperature: 0 °C
Yield: 54 %

Procedure:
A solution of TosMIC (0.98 g, 4.98 mmol, 2.3 eq) in THF (3 mL) is poured, over 20 minutes, into a solution of potassium tert-butoxide (1.22 g; 10.9 mmol; 5 eq) in THF (7.5 mL) stirred at 0° C. under nitrogen. Then 200 μL of methanol are added to the mixture and stirring is maintained for 30 minutes at 0° C. In parallel, 3,4-dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7-one (0.39 g, 2.17 mmol, 1 eq), lithium bromide (0.19 g, 2.17 mmol, 1 eq) and THF (2.5 mL) are transferred into a second three-necked flask. After cooling to 0° C. under nitrogen, the solution of TosMIC and potassium tert-butoxide is transferred to the reaction mixture. After returning to ambient temperature, the solution is heated to 40° C. and stirred for 16 hours at that temperature. The mixture is then hydrolysed with a solution of 11N HCl (0.7 mL, 7.73 mmol) in water (2 mL). After evaporating off the THF under reduced pressure, the product is extracted with 5 mL of dichloromethane. The organic phase is washed twice with 2×5 mL of water before being dried. The crude product is purified by column chromatography over silica gel using the binary mixture methylcyclohexane/ethyl acetate 75/25 to obtain the title product in the form of a cream-coloured powder.
Reaction SMILES: CN(C)C1C=CC=CC=1.Cl.[CH3:11][CH:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:24])[Cl:23])=[O:19])[N:15]2[C:26](=[O:29])[CH:27]([NH2:28])[C@H:14]2[S:13]1.[C:30]([CH2:32][C:33](O)=[O:34])#[N:31].C1(N=C=NC2CCCCC2)CCCCC1.Cl>ClCCl.C(N(CC)CC)C>[CH3:11][CH:12]1[CH:17]=[C:16]([C:18]([O:20][CH2:21][C:22]([Cl:25])([Cl:23])[Cl:24])=[O:19])[N:15]2[C:26](=[O:29])[CH:27]([NH:28][C:33](=[O:34])[CH2:32][C:30]#[N:31])[C@H:14]2[S:13]1
Reactant: N#CCC(=O)O
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(N)[C@H]2S1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CN(C)c1ccccc1
Product: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)CC#N)[C@H]2S1
Yield: 84.9 %

Procedure:
A solution of triethylamine (0.9 g) and dimethylaniline (0.15 g) in dichloromethane (20 ml) was added under stirring and ice-cooling to a suspension of 2,2,2-trichloroethyl 2-methyl-7-amino-3-cephem-4-carboxylate hydrochloride (3.82 g) in dried dichloromethane (80 ml). To the mixture were added cyanoacetic acid (0.85 g) and dicyclohexylcarbodiimide (2.25 g), and the mixture was stirred for 1 hour under ice-cooling. To the mixture was added 5% hydrochloric acid (50 ml), and the mixture was stirred for 30 minutes, after which the organic layer was separated, washed in turn with 5% hydrochloric acid, a saturated sodium bicarbonate aqueous solution and a saturated sodium chloride aqueous solution and then dried over magnesium sulfate. The solvent was distilled off to give colorless powder of 2,2,2-trichloroethyl 2-methyl-7-(2-cyanoacetamido)-3-cephem-4-carboxylate (3.5 g), mp 160° to 165° C. (dec.).
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[NH:22][S:23](=[O:29])(=[O:28])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:44][C:45]#[N:46]>CN(C)C=O.C(=O)(O)[O-].[Na+]>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:20][C:21]4[N:22]([CH2:44][C:45]#[N:46])[S:23](=[O:28])(=[O:29])[CH2:24][O:25][C:26]=4[N:27]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NS(=O)(=O)CO4)cc2)CCC1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)N(CC#N)S(=O)(=O)CO4)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
In a 15 mL reaction tube was added tert-butyl(1-(4-(2,2-dioxido-7-phenyl-1H-pyrido[3,2-e][1,3,4]oxathiazin-6-yl)phenyl)cyclobutyl)carbamate (50 mg, 0.099 mmol), potassium carbonate (41 mg, 0.296 mmol) and 2-bromoacetonitrile (0.021 mL, 0.296 mmol) in anhydrous N,N-dimethylformamide (1 mL) to give a yellow suspension. The reaction mixture was stirred at room temperature for one hour. The reaction mixture was allowed to cool to room temperature, diluted with saturated sodium bicarbonate solution (5 mL) and extracted into dichloromethane (3×3 mL). The combined organic phases were dried over Na2SO4, filtered and concentrated to dryness under reduced pressure to give a yellow oil. This was purified by Biotage chromatography (cyclohexane:ethyl acetate, gradient elution from 90:10 to 20:80) to give the desired product as a colourless oil (32 mg, 59% yield). 1H-NMR (500 MHz, CDCl3) δ 8.04 (1H, s), 7.25-7.38 (7H, m), 7.17-7.25 (2H, m), 5.32 (2H, s), 5.05 (1H, br s), 4.73 (2H, s), 2.20-2.65 (4H, m), 2.00-2.18 (1H, m), 1.77-1.90 (1H, m), 1.05-1.55 (9H, br m). LCMS (Method D) RT=1.60 min, M+H+=547.10.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:15][CH2:16][CH:17]=[CH:18][C:19](=[O:21])[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]>[Zn]>[OH:21][C:19]([CH3:20])([CH:18]=[CH:17][CH2:16][CH2:15][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25]
Reactant: CCOC(=O)CBr
Reactant: CC(=O)C=CCCc1ccccc1OCc1ccccc1
Agent: [Zn]
Product: CCOC(=O)CC(C)(O)C=CCCc1ccccc1OCc1ccccc1

Procedure:
Using 2.42 g of 6-(o-benzyloxyphenyl)-3-hexen-2-one, 1.8 ml of ethyl bromoacetate and 1.1 g of zinc, the reaction and the purification of the product were carried out according to the method described in Example 1 (a) affording 2.9 g of ethyl 3-hydroxy-3-methyl-7-(o-benzyloxyphenyl)-4-heptenoate.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:28]=[CH:27][C:23]([C:24]([OH:26])=O)=[CH:22][CH:21]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1.C1C=CC2N(O)N=[N:38]C=2C=1.CCN(CC)CC.CCN=C=NCCCN(C)C.N>ClCCl.O1CCOCC1>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:29]=[CH:30][N:31]=3)[N:17]=[C:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]([NH2:38])=[O:26])=[CH:27][CH:28]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: On1nnc2ccccc21
Reactant: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccc(C(=O)O)cc3)nn3ccnc23)n1
Agent: CCN=C=NCCCN(C)C
Agent: N
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: C[C@H]1CCCN1c1cccc(Nc2cc(-c3ccc(C(N)=O)cc3)nn3ccnc23)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.3 %

Procedure:
To a stirred solution of (S)-4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (90 mg), HOBT (49 mg, 0.365 mmol), Et3N (49 mg, 0.486 mmol) and EDCI (70 mg, 0.365 mmol) in dichloromethane (20 mL) and dioxane (100 mL) was bubbled NH3 gas until saturation and the mixture stirred for 16 h at room temperature. The mixture was filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography (silica gel, 10 g, 200-300 mesh, MeOH:dichloromethane=1:50) to afford (S)-4-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamide (38 mg, 47%) as a yellow solid. 1H NMR (300 MHz, CD3OD): δ 8.74 (s, 1H), 7.94-7.86 (m, 5H), 7.49 (s, 1H), 7.32 (t, 1H, J=8.1 Hz), 6.18 (d, 1H, J=6.0 Hz), 5.98 (d, 1H, J=8.4 Hz), 4.17-4.14 (m, 1H), 3.55-3.49 (m, 1H), 3.38-3.32 (m, 1H), 2.07-1.93 (m, 3H), 1.68 (s, 1H), 1.10 (d, 3H, J=6.0 Hz). LC-MS: [M+H]+, 414, tR=1.505 min, HPLC: 97.48% at 214 nm, 97.67% at 254 nm, tR=6.027 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:10]([Si](C)(C)C)[CH:9]2[C:15]2[CH:20]=[CH:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]4[N:28]=[C:27]([CH:29]5[CH2:31][CH2:30]5)[N:26]([CH3:32])[C:25]=4[CH:33]=3)[C:17](=[O:34])[CH:16]=2)=[CH:4][CH:3]=1.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:15]2[CH:20]=[CH:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]4[N:28]=[C:27]([CH:29]5[CH2:31][CH2:30]5)[N:26]([CH3:32])[C:25]=4[CH:33]=3)[C:17](=[O:34])[CH:16]=2)=[CH:4][CH:3]=1
Reactant: Cn1c(C2CC2)nc2ccc(-n3ccc(C4C(c5ccc(Cl)cc5)C4[Si](C)(C)C)cc3=O)cc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: Cn1c(C2CC2)nc2ccc(-n3ccc(C4CC4c4ccc(Cl)cc4)cc3=O)cc21
Temperature: 100 °C
Yield: 41.5 %

Procedure:
A mixture of 4-((1RS,2RS)-2-(4-chlorophenyl)-3-(trimethylsilyl)cyclopropyl)-1-(2-cyclopropyl-1-methyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (26 mg), TBAF (1.0 M in THF, 0.533 ml) and THF (1 ml) was heated at 100° C. under microwave irradiation for 1 h. The mixture was purified by NH silica gel column chromatography (hexane/EtOAc) to give the title compound (9.2 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1.[F:20][C:21]1[CH:22]=[CH:23][C:24]([O:28][CH3:29])=[C:25]([SH:27])[CH:26]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.[Cu]I>[Cl:1][C:2]1[C:3]2[C:10]([S:27][C:25]3[CH:26]=[C:21]([F:20])[CH:22]=[CH:23][C:24]=3[O:28][CH3:29])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COc1ccc(F)cc1S
Reactant: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)ncnc21
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(F)cc1Sc1cn(COCC[Si](C)(C)C)c2ncnc(Cl)c12
Temperature: 50 °C
Yield: 26 %

Procedure:
4-Chloro-5-iodo-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (200 mg, 0.49 mmol), 5-fluoro-2-methoxybenzenethiol (96 μl, 0.73 mmol), copper(I) iodide (139 mg, 0.73 mmol), potassium carbonate (135 mg, 0.98 mmol) and 2 ml dimethylformamide as solvent according to Preparation 86 but heating the reaction mixture at 50° C. overnight. The residue was purified using SP1® Purification System (0% to 15%, hexane-ethyl acetate) to give 56 mg (26% yield) of the title compound.
Reaction SMILES: [C:1]1([NH:7][NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][C:10]([CH3:17])([CH3:16])[C:11](=O)[CH2:12][C:13]#[N:14]>>[C:10]([C:11]1[CH:12]=[C:13]([NH2:14])[N:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[N:8]=1)([CH3:17])([CH3:16])[CH3:9]
Reactant: NNc1ccccc1
Reactant: CC(C)(C)C(=O)CC#N
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1

Procedure:
Phenyl hydrazine and 4,4-dimethyl-3-oxopentanenitrile were combined according to literature procedures to yield 3-tert-butyl-1-phenyl-1H-pyrazol-5-amine. See WO 2006/071940.
Reaction SMILES: [C:1]([NH2:6])([CH2:4][CH3:5])([CH3:3])[CH3:2].[CH2:7]1[CH2:13][S:10](=[O:12])(=[O:11])[O:9][CH2:8]1>O1CCCC1>[C:1]([NH:6][CH2:8][CH2:7][CH2:13][S:10]([OH:12])(=[O:11])=[O:9])([CH2:4][CH3:5])([CH3:3])[CH3:2]
Reactant: CCC(C)(C)N
Reactant: O=S1(=O)CCCO1
Solvent: C1CCOC1
Product: CCC(C)(C)NCCCS(=O)(=O)O
Temperature: 25 °C

Procedure:
To a solution of tert-amylamine (2.0 g, 23.3 mmol) in tetrahydrofuran (15 mL) was added 1,3-propane sultone (2.76 g, 22.2 mmol). The solution was stirred at reflux for 2 hours. The reaction mixture was cooled to room temperature. The solid product was collected by filtration, washed with acetone (2×25 mL), and dried in vacuo, to afford compound DG (3.3 g, 73%): 1H NMR (D2O, 500 MHz) δ ppm 3.04 (t, 2H, J=7.8 Hz), 2.89 (t, 2H, J=7.8 Hz), 2.87 (t, 2H, J=7.3 Hz), 1.97 (m, 2H), 1.55 (m, 2H), 1.18 (s, 6H), 0.82 (t, 6H, J=7.3 Hz). 13C NMR (D2O, 125 MHz) δ ppm 60.42, 48.17, 39.88, 30.81, 22.23, 21.98, 7.25. ES-MS 208 (M−1).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][CH:3]([C:9]#[N:10])[CH2:2]2.P([S-])(OCC)(OCC)=[S:12]>Cl.C(OCC)(=O)C>[N:1]12[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:4][CH:3]([C:9](=[S:12])[NH2:10])[CH2:2]2
Reactant: CCOP(=S)([S-])OCC
Reactant: N#CC1C[C@@H]2CCCN2C1
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=S)C1C[C@@H]2CCCN2C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 100 ml of 4N solution of hydrogen chloride in ethyl acetate, 5.10 g of a diastereomer mixture of (5S)-1-azabicyclo[3.3.0]octane-3-carbonitrile was dissolved. Then, 7 g of O,O-diethyl dithiophosphate was added, followed by stirring at room temperature for 16 hours. After the solvent was evaporated, the residue was washed with ethyl acetate, followed by drying under reduce pressure, whereby (5S)-1-azabicyclo[3.3.0]octane-3-carbothioamide was obtained. The resulting product was dissolved in 150 ml of isopropanol, 6.3 g of 2-bromo-1-indanone and 3.7 g of calcium carbonate were added, and the mixture was heated under reflux for 5 hours. After cooling, the insoluble matter was removed by filtration and the solvent was evaporated. To the resulting residue, ethyl acetate and 1N hydrochloric acid were added. The aqueous layer was separated, and neutralized with sodium bicarbonate, followed by extraction with chloroform. The extract was dried over anhydrous sodium sulfate. The solvent was evaporated, and the resulting residue was subjected to preparative medium-pressure column chromatography, whereby 0.32 g of a (3R,5S) form compound (Example 63A) and 0.18 g of a (3S,5S) form compound (Example 63B) of 3-(8H-indeno[1,2-d]thiazol-2-yl)-1-azabicyclo[3.3.0]octane was obtained from the fraction eluted with chloroform-methanol-aqueous ammonia (200:10:1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]1[NH:11][C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:28][C:29](=[O:31])[CH3:30].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH2:1]([O:8][CH2:9][C:10]1[N:11]([CH2:28][C:29](=[O:31])[CH3:30])[C:12]([S:18][C:19]2[CH:24]=[C:23]([Cl:25])[CH:22]=[C:21]([Cl:26])[CH:20]=2)=[C:13]([CH:15]([CH3:17])[CH3:16])[N:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)c1nc(COCc2ccccc2)[nH]c1Sc1cc(Cl)cc(Cl)c1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)Cn1c(COCc2ccccc2)nc(C(C)C)c1Sc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.5 %

Procedure:
In 20 ml of acetone was dissolved 5.0 g of the imidazole (101a) and 1.36 g (14.7 mmol) of monochloroacetone, followed by addition of 2.46 g (12.27 mmol) of potassium iodide, and the mixture was stirred at room temperature for 30 minutes. Then, to the mixture was added 2.04 g (14.8 mmol) of potassium carbonate, and the mixture was stirred with heating at 50° C. for 4 hours and worked up. The reaction mixture was distilled off under reduced pressure, and the residue was extracted with methylene chloride. The extract was washed with water, dried and the solvent was distilled off. The residue was purified by silica gel column chromatography (methylene chloride:ethyl acetate=9:1) to provide 3.1 g (yield 54%) of 2-benzyloxymethyl-5-(3,5-dichlorophenylthio)-4-isopropyl-1-acetylmethyl-1H-imidazole (139) as solid.
Reaction SMILES: [SiH:1]([Cl:4])([CH3:3])[CH3:2].[CH2:5]([Cl:9])[C:6](=[CH2:8])[CH3:7]>>[Si:1]([CH2:7][CH:6]([CH2:5][Cl:9])[CH3:8])([CH3:3])([CH3:2])[Cl:4]
Reactant: C[SiH](C)Cl
Reactant: C=C(C)CCl
Product: CC(CCl)C[Si](C)(C)Cl
Temperature: 80 °C
Yield: 83.3 %

Procedure:
In a 100 ml apparatus, there were combined 14.2 g (0.15 mol) of Me2SiHCl and 13.6 g (0.15 mol) of methallyl chloride, followed by 0.05 ml Pt catalyst solution at 21° C. Gentle heating caused a smooth exothermic reaction to 90° C. in 16 in. Reaction was heated at 80° C. until completed (50 min). Vacuum distillation yielded 23.14 g (83.4%) of Me2SiClCH2CHMeCH2Cl.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Br[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]>O.O1CCOCC1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])=[CH:18][CH:19]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCBr
Reactant: Oc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCCCCOc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Temperature: 25 °C
Yield: 75 %

Procedure:
To a mixture of 4-(4-benzyl-morpholin-2-yl)-phenol (1.33 g; 4.94 mmol) in water (10 mL) and 1,4-dioxane (10 mL) was added KOH (0.55 g; 9.88 mmol), 1-bromohexane (1.04 mL; 7.41 mmol) and tetrabutylammonium bromide (0.16 g; 0.49 mmol), the resulting mixture was heated under reflux overnight. After cooling to RT the mixture was concentrated in vacuo, and partitioned between EtOAc and 5% aqueous NaHCO3solution. The organic layer was dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, Et2O: hexanes 1:1) to afford 4-benzyl-2-(4-hexyloxy-phenyl)-morpholine (1.31 g).
Reaction SMILES: [CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:17]([O:19]CC)=[O:18])=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>O1CCCC1.CO>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([C:14]3[CH:15]=[C:16]([CH:22]=[CH:23][C:24]=3[CH3:25])[C:17]([OH:19])=[O:18])=[CH:11][CH:12]=2)[CH:7]=[N:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CCOC(=O)c1ccc(C)c(-c2ccc3c(C(C)C)nncc3c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc(C(=O)O)cc1-c1ccc2c(C(C)C)nncc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of ethyl 3-(1-isopropylphthalazin-6-yl)-4-methylbenzoate (37.5 mg, 0.11 mmol) in tetrahydrofuran (0.3 mL) and methanol (0.15 mL) was treated with 1N aq. sodium hydroxide (0.28 mL, 0.28 mmol) and stirred at RT for 18 h. The reaction mixture was concentrated in vacuo and the residue was taken up in water. The pH was adjusted with 10% HCl solution to ˜7. The precipitate formed was collected via filtration and dried under high vacuum to afford the title compound as a maize-colored solid. MS (ES+): 307.2 (M+H)+.
Reaction SMILES: [S:1]([O:8][C:9]1[C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)[N:16]=[C:17]([NH:18][CH2:19][CH2:20][CH3:21])[C:12]=2[S:11][CH:10]=1)([C:4]([F:7])([F:6])[F:5])(=[O:3])=[O:2].[BH4-].[Na+]>CO>[S:1]([O:8][CH:9]1[C:13]2[N:14]=[C:15]([N:22]3[CH2:27][CH2:26][N:25]([C:28]4[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=4)[CH2:24][CH2:23]3)[N:16]=[C:17]([NH:18][CH2:19][CH2:20][CH3:21])[C:12]=2[S:11][CH2:10]1)([C:4]([F:6])([F:5])[F:7])(=[O:3])=[O:2]
Reactant: CCCNc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c(OS(=O)(=O)C(F)(F)F)csc12
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNc1nc(N2CCN(c3ccc(Cl)cc3)CC2)nc2c1SCC2OS(=O)(=O)C(F)(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 20.1 %

Procedure:
0.050 g (0.12 mmol) of 2-[4-(4-chlorophenyl)piperazin-1-yl]-4-propylaminothieno[3,2-d]pyrimidin-7-ol triflate (IX) is dissolved in 1 mL of methanol and 0.020 g (0.53 mmol) of sodium borohydride is added. The reaction mixture is stirred for 16 hours at ambient temperature, then concentrated by evaporation. The residue is purified by chromatography using HPLC through an RP column (column: Microsorb, RP-C18). Corresponding fractions are combined and lyophilized. 0.013 g of product X (20%) is obtained as a powder. 1H NMR (400 MHz, DMSO): 7.26 (2H, d); 7.00 (2H, d); 5.15-5.09 (1H, m); 3.86-3.79 (4H, m), 3.63-3.55 (2H, m); 3.42-3.33 (2H, m); 3.28-3.22 (4H, m); 3.18-3.11 (1H, m); 1.63-1.52 (2H, m); 0.88 (3H, t).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:12])([CH3:11])[CH2:9][OH:10])=[CH:4][CH:3]=1.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH3:12])([CH3:11])[CH:9]=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(CO)c1ccc(Br)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(C)(C=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 2-(4-bromophenyl)-2-methylpropan-1-ol (10 g, 44 mmol) in dichloromethane (80 mL) was added PCC (14 g, 65 mmol) in portions at 0° C. The resulting solution was stirred at ambient temperature overnight, and then filtered and concentrated in vacuo. The crude residue was purified by flash column chromatography with 1-2% ethyl acetate in hexane to afford the title compound as an off-white solid. 1H NMR (300 MHz, CDCl3) δ 9.49 (s, 1H), 7.52 (d, J=6.3 Hz, 2H), 7.17 (d, J=6.3 Hz, 2H), 1.43 (s, 6H).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH:15]C(=O)C)[NH:4][N:3]=1.C(O)C.[OH-].[Na+]>C(OCC)(=O)C.O>[CH3:1][C:2]1[C:6]([C:7]#[C:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:5]([NH2:15])[NH:4][N:3]=1
Reactant: CC(=O)Nc1[nH]nc(C)c1C#Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1n[nH]c(N)c1C#Cc1ccccc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.6 %

Procedure:
A mixture of N-(3-methyl-4-(phenylethynyl)-1H-pyrazol-5-yl)acetamide (15 g, 63 mmol), ethanol (50 mL) and 25% aq. NaOH solution (50 mL) was stirred at 90° C. for 1 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate and water. The organic phase was washed with water and brine, dried (phase separator cartridge) and concentrated in vacuo. Diethyl ether was added to the residue and the solid was collected by filtration, washed with diethyl ether and dried in vacuo to provide the title compound as a solid (3.3 g).