Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:28])[CH:20]=[CH:21][C:22]4[S:23][CH:24]=[C:25]([Br:27])[CH:26]=4)[C@@H:15]([CH3:29])[C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.C1(O)C=CC=CC=1.C([O-])(=O)C.[NH4+:42]>>[NH2:42][C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH2:12][N:13]3[CH2:18][CH2:17][N:16]([C:19](=[O:28])[CH:20]=[CH:21][C:22]4[S:23][CH:24]=[C:25]([Br:27])[CH:26]=4)[C@@H:15]([CH3:29])[C:14]3=[O:30])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1
Reactant: C[C@H]1C(=O)N(Cc2ccc3c(Cl)ccnc3c2)CCN1C(=O)C=Cc1cc(Br)cs1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Oc1ccccc1
Product: C[C@H]1C(=O)N(Cc2ccc3c(N)ccnc3c2)CCN1C(=O)C=Cc1cc(Br)cs1
Temperature: 120 °C
Yield: 62.2 %

Procedure:
(S)-1-(4-Chloroquinolin-7-ylmethyl)-4-[3-(4-bromothiophen-2-yl)acryloyl]-3-methyl piperazin-2-one (0.50 g, 0.9 mmol) is treated with phenol (˜2 g) and ammonium acetate (0.5 g, 6.4 mmol) and heated to 120° C. in a sealed vessel for 1 hour. Upon cooling, the solution is partitioned between 2 N NaOH and ethyl acetate. The organic layer is separated and washed with fresh 2 N NaOH (3×100 mL) and water. The organic layer is concentrated and the residue is purified by reverse phase HPLC (gradient elution of 10% of 0.1% aqueous TFA/acetonitrile to 100% acetonitrile) to give the title compound (0.22 g, 0.56 mmol). MS m/z: [M+H]+=485, 487, Cl pattern. 1H NMR (CD3OD, 300 MHz) δ8.2-8.4 (m, 2H), 7.7-7.8 (m, 2H), 7.6 (d, 1H), 7.5 (s, 1H), 7.3 (s, 1H), 6.9-7.0 (m, 1H), 6.7 (d, 1H), 5.0-5.1 (m, 1H), 4.9 (q, 2H), 4.3-4.4 (m, 1H), 3.5-3.7 (m, 2H), 3.3-3.4 (m, 2H), 1.5 (d, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][CH:23]=[CH:22][C:4]=1[C:5]([NH:7][C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([S:18](Cl)(=[O:20])=[O:19])=[CH:10][CH:9]=1)=[O:6].[N:26]([CH:29]([CH3:31])C)=[C:27]=[O:28]>C(N(CC)CC)C>[C:27]([N:26]1[CH2:29][CH2:31][CH:5]([NH:7][S:18]([C:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:22]=[CH:23][CH:24]=[CH:25][C:3]=3[O:2][CH3:1])=[CH:9][CH:10]=2)(=[O:20])=[O:19])[CH2:4][CH2:3]1)(=[O:28])[CH2:9][CH2:8][CH3:17]
Reactant: CC(C)N=C=O
Reactant: COc1ccccc1C(=O)Nc1ccc(S(=O)(=O)Cl)c2ccccc12
Solvent: CCN(CC)CC
Product: CCCC(=O)N1CCC(NS(=O)(=O)c2ccc(NC(=O)c3ccccc3OC)c3ccccc23)CC1

Procedure:
The title compound was prepared following the general procedure in Scheme 5, beginning with 4-(2-methoxy-benzoylamino)-naphthalene-1-sulfonyl chloride, and substituting butyric chloride and triethylamine for 2-isocyanato-propane. LC/MS m/z 508 (M−H)−, 510 (M+H)+.
Reaction SMILES: C[O-].[Na+].[O:4]1[CH:8]=[N:7][N:6]=[C:5]1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]#[N:17])=[CH:11][CH:10]=1.[N:18]([C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[F:31])=[N+:19]=[N-:20]>CO>[F:31][C:22]1[CH:23]=[C:24]([C:27]([F:29])([F:30])[F:28])[CH:25]=[CH:26][C:21]=1[N:18]1[C:16]([NH2:17])=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([C:5]3[O:4][CH:8]=[N:7][N:6]=3)=[CH:10][CH:11]=2)[N:20]=[N:19]1
Reactant: [N-]=[N+]=Nc1ccc(C(F)(F)F)cc1F
Reactant: N#CCc1ccc(-c2nnco2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(-c2ccc(-c3nnco3)cc2)nnn1-c1ccc(C(F)(F)F)cc1F
Reaction time: 1 h
Yield: 36.8 %

Procedure:
To a stirred and ice-cooled solution of sodium methoxide (0.158 g, 2.9252 mmol) in methanol (25 ml), commercial 2-[4-(1,3,4-oxadiazol-2-yl)phenyl]acetonitrile (0.430 g, 2.3401 mmol) and 1-azido-2-fluoro-4-trifluoromethyl-benzene (0.400 g, 1.9501 mmol) are added under a nitrogen atmosphere. The reaction mixture is kept at 0° C. for 1 h, and then allowed to attain spontaneously room temperature overnight. The reaction mixture is concentrated, added water (30 ml), and extracted with ethylacetate (3×100 ml). The combined organic layers are dried over MgSO4, filtered and evaporated, to afford a pink solid (0.74 g, 97% mass balance). The crude residue is purified by column chromatography over silica gel (230-400 mesh), eluting with 50% ethylacetate in petroleum ether, to obtain the title compound as a yellow solid (0.280 g, 37% yield). M.p. 184.6-186.1° C. LC-ESI-HRMS of [M+H]+ shows 391.0927 Da. Calc. 391.093046 Da, dev. −0.9 ppm.
Reaction SMILES: C([CH:3]([C:23]([OH:25])=[O:24])[N:4]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=1[CH3:22])[S:5]([C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=[O:7])=[O:6])C.[OH-].[Na+]>C(O)C.O1CCOCC1>[Cl:21][C:17]1[C:16]([CH3:22])=[C:15]([N:4]([S:5]([C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)(=[O:6])=[O:7])[CH2:3][C:23]([OH:25])=[O:24])[CH:20]=[CH:19][CH:18]=1
Reactant: CCC(C(=O)O)N(c1cccc(Cl)c1C)S(=O)(=O)c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)N(CC(=O)O)c2cccc(Cl)c2C)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 88.3 %

Procedure:
35.8 g of ethyl N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine was dissolved in 157 mL of ethanol and 157 mL of 1,4-dioxane, and 157 mL of a 1 M aqueous sodium hydroxide solution was added thereto, followed by stirring at 60° C. overnight. The reaction liquid was cooled to room temperature, and then concentrated under reduced pressure. The residue was dissolved in water, acidified by addition of 1 M hydrochloric acid, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to obtain 29.3 g of N-(3-chloro-2-methylphenyl)-N-[(4-methylphenyl)sulfonyl]glycine.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[C:5]([F:11])=[CH:4][C:3]=1[N+:12]([O-])=O.[H][H]>CO.[Pd]>[Cl:1][C:2]1[C:7]([O:8][CH3:9])=[C:6]([Cl:10])[C:5]([F:11])=[CH:4][C:3]=1[NH2:12]
Reactant: [H][H]
Reactant: COc1c(Cl)c(F)cc([N+](=O)[O-])c1Cl
Agent: [Pd]
Solvent: CO
Product: COc1c(Cl)c(N)cc(F)c1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
72.0 g of 2,4-dichloro-5-fluoro-3-methoxynitrobenzene (0.30 mol) and 2.65 g of Pd/C in 500 ml of methanol were hydrogenated under 3 Mpa (hydrogen pressure) at 60° C. for 3 hours. The reactant was cooled to room temperature. The catalyst was filtered out, and the solvent was evaporated to give 58.5 g of 2,4-dichloro-5-fluoro-3-methoxyaniline (0.279 mol) in 92.9% yield.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18](O)=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1.O[N:23]1C2C=CC=CC=2N=N1.C(OC(N1CCC(CN)CC1)=O)(C)(C)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][C:14]([C:18]([NH2:23])=[O:19])=[CH:13][C:12]=3[CH:21]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCO3)cc1
Reactant: On1nnc2ccccc21
Agent: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ccc(-c2ccc3c(c2)C=C(C(N)=O)CCO3)cc1
Yield: 172.5 %

Procedure:
To 7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxylic acid (1402 mg, 5.00 mmol) dissolved in DMF (30 ml) were added at 0° C. 1-hydroxybenzotriazole (743 mg, 5.50 mmol), [1-(tert-butoxycarbonyl)piperidin-4-yl]methylamine (1393 mg, 6.50 mmol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (1438 mg, 7.50 mmol), and the resulting mixture was stirred at room temperature for 61 hours. The reaction mixture was concentrated under reduced pressure, ethyl acetate (100 ml) was added to the residue, and the resulting mixture was washed successively with water (10 ml×3), a 10% aqueous solution of potassium hydrogensulfate (10 ml×3), an aqueous saturated solution of sodium bicarbonate (10 ml×3) and an aqueous saturated solution of sodium chloride (10 ml). The organic layer was dried with anhydrous magnesium sulfate and then was concentrated under reduced pressure, and the residue was subjected to column chromatography (silica gel 80 g, ethyl acetate/hexane 1/2→1/1). The objective fractions were concentrated under reduced pressure to obtain N-[1-(tert-butoxycarbonyl)piperidin-4-yl]methyl]-7-(4-methylphenyl)-2,3-dihydro-1-benzooxepine-4-carboxamide (2409 mg).
Reaction SMILES: [S:1]([OH:5])([OH:4])(=[O:3])=[O:2].[NH2:6][C:7]([NH:9][C:10]([NH2:12])=[NH:11])=[NH:8].C[O-].[Na+:15].NC(NC(N)=N)=N>CO>[S:1]([O-:5])([O-:4])(=[O:3])=[O:2].[Na+:15].[Na+:15].[NH2:8][C:7]([NH:9][C:10]([NH2:12])=[NH:11])=[NH:6]
Reactant: O=S(=O)(O)O
Agent: C[O-]
Agent: N=C(N)NC(=N)N
Agent: [Na+]
Solvent: CO
Product: O=S(=O)([O-])[O-]

Procedure:
Biguanide was prepared fresh by refluxing anhydrous biguanide sulfate in a methanol solution of freshly prepared sodium methylate by the method of Slotta et al. (Slotta, K. H., Tschesche, R., Ber. Dtsch. Chem. Ges. 1929, B62, 1390-1398). The biguanide was used in solution as prepared for all of the reactions. Because sodium sulfate formed in the preparation of biguanide did not interfere with subsequent reactions, it was not necessary to separate it from the biguanide. Ethyl malonamate used in the preparation of Ib (see Example I below) was prepared as follows by methods of Galat and Marguery (Galat, A., J. Am. Chem. Soc. 1948, 70, 2596 and Marguery, M. F., Bull. Soc. Chem. France 1905, 33, 541; J. Recherces Centr. Nalt. Recherche Sci., Labs. Bellevue (Pairs) 1959, 47, 147), through Chem. Abstr. 1962, 56, 4744g.): Diethyl malonate was converted to the mono-potassium salt of the half-ester. The latter was converted to ethyl malonyl chloride, which in turn was reacted with anhydrous ammonia in ice-cold ether to form ethyl malonamate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:15])=[C:6]([C:8]2[C:12]([NH2:13])=[CH:11][N:10]([CH3:14])[N:9]=2)[CH:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26](Cl)=[O:27])=[C:19]2[N:18]=1.C(N(CC)CC)C>ClCCl>[Cl:16][C:17]1[CH:22]=[CH:21][N:20]2[N:23]=[CH:24][C:25]([C:26]([NH:13][C:12]3[C:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[CH3:15])=[N:9][N:10]([CH3:14])[CH:11]=3)=[O:27])=[C:19]2[N:18]=1
Reactant: O=C(Cl)c1cnn2ccc(Cl)nc12
Reactant: Cc1ccc(Cl)cc1-c1nn(C)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(Cl)cc1-c1nn(C)cc1NC(=O)c1cnn2ccc(Cl)nc12
Reaction time: 16 h
Yield: 86.8 %

Procedure:
To a solution of 3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-amine (182.9 mg, 0.4826 mmol, 1.2 equiv) in dichloromethane (5 mL) was added 5-chloropyrazolo[1,5-a]pyrimidine-3-carbonyl chloride (91.2 mg, 0.411 mmol, 1.0 equiv) and triethylamine (0.30 mL, 2.2 mmol, 5.2 equiv) at room temperature. After 16 hours, the reaction mixture was partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 143.1 mg (87%) of 5-chloro-N-(3-(5-chloro-2-methylphenyl)-1-methyl-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide which was carried forward without purification. LCMS (ESI) m+H=401.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([NH:9][C:10](=[O:17])[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:4]([Cl:18])[CH:3]=1.Cl[CH2:20][CH2:21][O:22][CH2:23][CH2:24]Cl.[I-].[K+]>C(O)C>[Cl:18][C:4]1[CH:3]=[C:2]([N:1]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[CH:7]=[C:6]([CH3:8])[C:5]=1[NH:9][C:10](=[O:17])[CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: ClCCOCCCl
Reactant: Cc1cc(N)cc(Cl)c1NC(=O)CC1CCCC1
Agent: [I-]
Agent: [K+]
Solvent: CCO
Product: Cc1cc(N2CCOCC2)cc(Cl)c1NC(=O)CC1CCCC1
Temperature: 170 °C
Yield: 41 %

Procedure:
N-(4-Amino-2-chloro-6-methyl-phenyl)-2-cyclopentyl-acetamide (830 mg), bis-(2-chloroethyl)ether (3.35 mL) and potassium iodide (470 mg) were mixed in absolute ethanol (33 mL) and heated to 170° C. for 1 hour in a sealed microwave process vial. The crude mixture was concentrated in vacuo and purified by flash chromatography to furnish 390 mg (41%) of the title compound as a white solid. LC-MS (m/z) 337 (MH+); tR=2.61, (UV, ELSD) 97%, 99%. 1H NMR (500 MHz, DMSO-d6): 1.22 (m; 2H), 1.51 (m, 2H), 1.61 (m, 2H), 1.77 (m, 2H), 2.11 (s, 3H), 2.25 (m, 1H), 2.26 (m, 2H), 3.10 (m, 4H), 3.71 (m, 4H), 6.80 (d, 1H), 6.84 (d, 1H), 9.18 (s, 1H).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1S(C)=O.[OH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1.C1CCN2C(=NCCC2)CC1>O1CCOCC1>[Br:1][C:2]1[C:3]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[N:4][C:5]([NH2:11])=[N:6][C:7]=1[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=1
Reactant: OCc1ccccn1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1COCCO1
Product: Nc1nc(OCc2ccccn2)c(Br)c(-c2ccco2)n1

Procedure:
From 5-bromo-4-furan-2-yl-6-methanesulfinyl-pyrimidin-2-yl amine, 2-(hydroxymethyl)pyridine and DBU in dioxane. 349 (M{81Br}+H+, 98), 347 (M{79Br}+H+, 100).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[NH:12][CH2:11][C:10]3=[CH:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1.[CH3:19][C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][C:28]=1[Br:29])[C:23](Cl)=[O:24].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[C:4]([O:17][CH3:18])=[CH:5][C:6]2[N:12]([C:23]([C:22]3[CH:26]=[CH:27][C:28]([Br:29])=[C:20]([CH3:19])[CH:21]=3)=[O:24])[CH2:11][C:10]3=[CH:13][CH:14]=[CH:15][N:9]3[CH2:8][C:7]=2[CH:16]=1
Reactant: Cc1cc(C(=O)Cl)ccc1Br
Reactant: COc1cc2c(cc1OC)NCc1cccn1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc2c(cc1OC)N(C(=O)c1ccc(Br)c(C)c1)Cc1cccn1C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.5 %

Procedure:
To a solution of 7,8-dimethoxy-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine of Step B (3.20 g) in dichloromethane (20 mL) was added 3-methyl-4-bromo benzoyl chloride (3.4 g, 1.1 equiv) and triethylamine (2.0 g, 1.5 equiv) and the mixture was stirred at room temperature overnight. The solvent was then removed in vacuo and the residue chromatographed on silica gel eluting with a solvent gradient from 5 to 50% ethyl acetate in petroleum ether to provide the title compounds as a yellow crystalline solid (3.5 g), m.p. 165-168° C.
Reaction SMILES: C([Li])CCC.[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][CH:11]=1.C(=O)=O.CC(C)=O.[Cl:21][CH2:22][C:23](N(OC)C)=[O:24].Cl>O1CCCC1>[Br:6][C:7]1[CH:8]=[C:9]([C:12]#[N:13])[S:10][C:11]=1[C:23](=[O:24])[CH2:22][Cl:21]
Reactant: CON(C)C(=O)CCl
Reactant: N#Cc1cc(Br)cs1
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: N#Cc1cc(Br)c(C(=O)CCl)s1
Temperature: 25 °C
Yield: 21.7 %

Procedure:
Butyllithium (2.5 M solution in hexanes; 14.5 mL, 36.3 mmol) was added under nitrogen over approximately 5 min to a solution of 4-bromo-thiophene-2-carbonitrile (5.95 g, 31.6 mmol) in 300 mL of anhydrous tetrahydrofuran at dry ice-acetone temperature. After the addition, the reaction was stirred at dry ice-acetone temperature for 30 min. 2-Chloro-N-methoxy-N-methyl acetamide (4.80 g, 32.7 mmol) in 40 mL of anhydrous tetrahydrofuran was then added dropwise over 30 min. After the addition, the reaction was stirred at dry ice-acetone temperature for 4 h. 6 M HCl (36 mL) was added and the reaction allowed to warm to room temperature. The reaction was concentrated under reduced pressure to remove the tetrahydrofuran. The residue was partitioned between ethyl acetate and water. Saturated sodium chloride was added to aid in the separation of an emulsion. The organic layer was separated, washed with water, saturated sodium chloride, dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was purified on 800 g of silica gel (230-400 mesh) using a gradient of 30% methylene chloride in hexane to 60% methylene chloride in hexane as the eluent. Isolation of the major component gave 4-bromo-5-(chloroacetyl)thiophene-2-carbonitrile (1.81 g, 22%) as a white solid, mp 126-128° C.; MS (ESI) m/z 262.
Reaction SMILES: [C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21]O)=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2].CN(C=O)C.S(Cl)([Cl:32])=O.[Na+].[Cl-]>ClCCl>[C:1]([N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[CH:7]([CH2:14][C:15]2[C:20]([CH2:21][Cl:32])=[CH:19][C:18]([Cl:23])=[CH:17][N:16]=2)[C:6]1=[O:24])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CO)c2cccnc21
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Cc2ncc(Cl)cc2CCl)c2cccnc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
To a solution of 5 (5.8 g, 16.8 mmol) in dichloromethane (30 mL) was added DMF (60 μL) and thionyl chloride (2.2 g) at 5° C. The mixture was stirred for 30 min at this temperature followed by addition of 5% aqueous NaCl (30 mL). The organic layer was separated and washed with 5% aqueous NaCl (30 mL). The solvent was removed and the residue was dissolved in heptane (20 mL). The solution was stirred for 10 min and the product was precipitated. The suspension was cooled to 0° C. and filtered to give 6 (5.8 g, 93%) as a solid: 1H NMR (CDCl3, 400 MHz): δ 8.36 (d, J=2.3 Hz, 1H), 8.13 (dd, J=5.1, 1.4 Hz, 1H), 7.65 (d, J=2.3 Hz, 1H), 7.19 (om, 1H), 6.78 (dd, J=7.3, 5.2 Hz, 1H), 4.58 (m, 2H), 4.06 (m, 1H), 3.66 (dd, J=16.3, 4.6 Hz, 1H), 3.32 (dd, J=16.3, 7.5 Hz, 1H), 1.75 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ 178.06, 159.45, 154.58, 147.39, 145.73, 136.87, 132.47, 130.42, 130.11, 123.77, 117.03, 58.51, 43.37, 42.25, 33.69, 28.82.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:23])([CH3:22])[C@H:16]23)=[O:11])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:25][O:24][C:4]1[CH:3]=[C:2]([O:1][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][C:10]([C:12]1[S:19][C:18]([CH3:20])=[C:17]2[C:13]=1[CH2:14][C@H:15]1[C:21]([CH3:22])([CH3:23])[C@H:16]12)=[O:11]
Reactant: ClCC1CO1
Reactant: COc1cc(O)ccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: CCOCC
Product: COc1cc(OCC2CO2)ccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 9 h
Yield: 66.2 %

Procedure:
A solution of 3-(4-hydroxy-2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (600 mg, 1.68 mmol, Intermediate 20) in isopropanol (10 mL) and 3 N aq. NaOH (6 mL) is treated with epichlorohydrine (631 mg, 5.05 mmol). The reaction mixture is stirred at rt for 9 h before it is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(2-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (459 mg) as an almost colourless oil; LC-MS: tR=1.13 min, [M+1]+=413.28.
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([N:29]4[CH2:34][CH2:33][O:32][CH2:31][CH2:30]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: C1COCCN1
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Product: CC(C)Nc1nccn2c(-c3ccnc(N4CCOCC4)n3)cnc12

Procedure:
Isopropyl-[3-(2-morpholin-4-yl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-amine was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and morpholine. LC-MS: [M+H]+ 340.3.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=1)=O.C(N(CC)CC)C.ClC(OC)=O>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:10][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([O:18][CH3:19])[CH:13]=2)=[C:2]([OH:1])[CH:7]=1
Reactant: COc1cccc(C(=O)c2ccc(OC)cc2O)c1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1cccc(Cc2ccc(OC)cc2O)c1
Reaction time: 0.8 h
Yield: 97.6 %

Procedure:
The title compound was synthesized by referring to Tetrahedron Lett., 1995, (30), 5335. To a solution of (2-hydroxy-4-methoxyphenyl)(3-methoxyphenyl)methanone (5.2 g) in tetrahydrofuran (100 ml) were sequentially added triethylamine (3.0 g) and methyl chloroformate (2.2 g) on an ice bath, the solution was stirred for 48 minutes, and then the reaction mixture was filtered. To a solution of sodium borohydride (3.0 g) in water (50 ml) was added dropwise the above-mentioned filtrate on an ice bath, and the solution was stirred for 1 hour and 10 minutes. The reaction solution was concentrated in vacuo, extracted with ethyl acetate, then sequentially washed with water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (4.8 g).
Reaction SMILES: [Cl:1][C:2]1[C:43]([C:44]([F:47])([F:46])[F:45])=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]([CH2:26][CH:27]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH:16](COCC)[C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:11]=1.C([SiH](CC)CC)C.C(O)(C(F)(F)F)=O>ClCCl>[Cl:1][C:2]1[C:43]([C:44]([F:47])([F:45])[F:46])=[CH:42][CH:41]=[CH:40][C:3]=1[CH2:4][N:5]([CH2:26][CH:27]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][C:17]2[NH:21][N:20]=[N:19][N:18]=2)[CH:11]=1
Reactant: CCOCC(c1cccc(OCCCN(Cc2cccc(C(F)(F)F)c2Cl)CC(c2ccccc2)c2ccccc2)c1)c1nnn[nH]1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: FC(F)(F)c1cccc(CN(CCCOc2cccc(Cc3nnn[nH]3)c2)CC(c2ccccc2)c2ccccc2)c1Cl
Reaction time: 8 h
Yield: 43.4 %

Procedure:
To a stirring solution of (2-chloro-3-trifluoromethyl-benzyl)-(2,2-diphenyl-ethyl)-{3-[3-(ethoxymethyl-1,2,3,4-tetrazol-5-ylmethyl)-phenoxy]-propyl}-amine (mixture of regioisomers, 125 mg, 0.19 mmol) in dichloromethane (11 ml) was added triethylsilane (116 mg, 1.08 mmol). The reaction mixture was treated with TFA (3 ml) and then stirred overnight. Solvent was removed and the residue was purified by preparative HPLC (YMC CombiPrep PDS, 75×30 mm, 25 mL/min, acetonitrile:water, UV detection at 254 nm) to afford 50 mg (44%) the title compound as a yellow oil. MS (ESI) 607.0(M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:10][C:11]([OH:13])=[O:12])[CH:5]=[C:6]([CH3:9])[C:7]=1[OH:8].S(=O)(=O)(O)O.[CH3:19]O>>[CH3:19][O:12][C:11](=[O:13])[CH2:10][C:4]1[CH:5]=[C:6]([CH3:9])[C:7]([OH:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(CC(=O)O)cc(C)c1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)Cc1cc(C)c(O)c(C)c1
Temperature: 70 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
A solution of (3,5-dimethyl-4-hydroxy-phenyl)-acetic acid (5a) (12.4 g, 0.069 mmol) in methanol (300 mL) was treated with concentrated sulfuric acid (6.25 mL). The resulting solution was heated to 70° C. overnight. At this time, the reaction was cooled to room temperature. The reaction was concentrated under vacuum. The residue was diluted with ethyl acetate (700 mL) and was washed with water (2×250 mL). The organics were dried over magnesium sulfate, filtered and concentrated under vacuum to give an orange solid. The solid was slurried in 10% ethyl acetate/petroleum ether and was stirred for 1 h. The solid was collected by filtration, washed with 10% ethyl acetate/petroleum ether, and dried under vacuum overnight. The residue was purified by column chromatography using silica gel eluted with 10-15% ethyl acetate in petroleum ether to afford (3,5-dimethyl-4-hydroxy-phenyl)-acetic acid methyl ester (6a) (1.93 g, 86%) as an off-white solid; EI(+)-HRMS m/z calcd for C11H14O3 (M+) 194.0943, found 191.0942. Molecular Weight=194.2324; Exact Mass=194.0943