Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]([OH:14])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[C:19](Cl)(=[O:21])[CH3:20].Cl>C(=S)=S.C(Cl)(Cl)Cl>[C:19]([C:7]1[CH:6]=[C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[CH:13]=[C:9]([C:10]([OH:12])=[O:11])[C:8]=1[OH:14])(=[O:21])[CH3:20]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)c1ccc(O)c(C(=O)O)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Solvent: ClC(Cl)Cl
Product: CC(=O)c1cc(C(C)(C)C)cc(C(=O)O)c1O
Temperature: 0 °C
Reaction time: 20 h
Yield: 48.7 %

Procedure:
A vigorously stirred solution of 5-tert-butyl-salicyclic acid (3.88 g) in carbon disulphide (80 ml) was treated portionwise with anhydrous aluminium chloride (8.8 g). The mixture was brought cautiously to the reflux temperature and treated with acetyl chloride (3.45 g) dropwise during 15 minutes. The mixture was heated at reflux with vigorous stirring for 20 hours and then the mixture was added to a mixture of chloroform (80 ml), ice (100 g) and concentrated hydrochloric acid (20 ml), and stirred for a further one hour. The organic layer was then separated, washed with water (3 × 20 ml), and dried over anhydrous sodium sulphate, and the solvent was removed in vacuo. The resulting solid was recrystallized from ethyl acetate, to give 3-acetyl-5-tert-butylsalicylic acid (2.3 g), m.p. 159°-161° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Br:11])[CH2:7][C@:6]1([C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]1[CH3:18])[CH2:5]2.[O:19]=[C:20]1[N:24]([CH2:25][C:26](O)=[O:27])[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[N:21]1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=1.C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Br:11][C:10]1[CH:9]=[C:8]2[C:4]([CH2:5][C@@:6]3([C:15](=[O:16])[NH:14][C:13](=[O:17])[N:12]3[CH3:18])[CH2:7]2)=[CH:3][C:2]=1[NH:1][C:26](=[O:27])[CH2:25][N:24]1[C:23]2[CH:29]=[CH:30][CH:31]=[CH:32][C:22]=2[N:21]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)[C:20]1=[O:19]
Reactant: CN1C(=O)NC(=O)[C@@]12Cc1cc(N)c(Br)cc1C2
Reactant: O=C(O)Cn1c(=O)n(-c2ccccn2)c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN1C(=O)NC(=O)[C@]12Cc1cc(Br)c(NC(=O)Cn3c(=O)n(-c4ccccn4)c4ccccc43)cc1C2
Temperature: 40 °C
Reaction time: 18 h

Procedure:
To a stirred mixture of (S)-5′-amino-6′-bromo-3-methyl-spiro[imidazolidine-4,2′-indane]-2,5-dione (50 mg, 0.161 mmol, described in Intermediate 18) and (2-oxo-3-pyridin-2-yl-2,3-dihydro-1H-benzimidazol-1-yl)acetic acid (52 mg, 0.193 mmol, described in Intermediate 16) in DMF (1 mL) were added N,N-diisopropylethylamine (0.028 mL, 0.161 mmol), followed by PyBOP (126 mg, 0.242 mmol). The reaction mixture was heated to 40° C. for 5 h, then PyBOP (126 mg, 0.242 mmol) was added and heating was continued for 18 h. The cooled mixture was purified by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H-90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and concentrated to give the title compound. MS: m/z=563 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:22])[CH3:21].[I-].[K+]>C(OCC)(=O)C.[I-].[K+].CN(C)C=O>[CH:20]([O:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH3:12])[C:5]([O:7][CH3:8])=[O:6])([CH3:22])[CH3:21]
Reactant: COC(=O)c1ccc(C)c(O)c1
Reactant: CC(C)Br
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(C)c(OC(C)C)c1
Temperature: 25 °C
Yield: 95.1 %

Procedure:
To a mixture of methyl 3-hydroxy-4-methylbenzoate (5.28 g, 31.8 mmol), potassium carbonate (6.59 g, 47.7 mmol) and N,N-dimethylformamide (50 mL) were added 2-bromopropane (3.58 mL, 38.2 mmol) and potassium iodide (0.53 g, 3.18 mmol) with stirring at room temperature, and the mixture was stirred at 80° C. for 7 hr. 2-Bromopropane (1.79 mL, 19.1 mmol) and potassium iodide (0.27 g, 1.59 mmol) were added to the reaction mixture, and the mixture was further stirred at 80° C. for 15 hr. The reaction mixture was cooled, and diluted with ethyl acetate. The mixture washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=19/1-hexane/ethyl acetate=4/1) to give the title compound (6.3 g, yield 96%) as a colorless oil. MS (ESI+): 209 (M+H).
Reaction SMILES: [O:1]=[C:2]1[CH2:23][O:22][C:21]2[C:4](=[CH:5][C:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][C:7]=3[CH:20]=2)[NH:3]1.Br[CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[F:32][C:28]1[CH:27]=[C:26]([CH:31]=[CH:30][CH:29]=1)[CH2:25][N:3]1[C:4]2=[CH:5][C:6]3[CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8][C:7]=3[CH:20]=[C:21]2[O:22][CH2:23][C:2]1=[O:1]
Reactant: Fc1cccc(CBr)c1
Reactant: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)OCC(=O)N3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCc2cc3c(cc2CC1)N(Cc1cccc(F)c1)C(=O)CO3
Temperature: 50 °C
Reaction time: 16 h

Procedure:
To a solution of 500 mg of t-butyl 3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate in 10 ml of DMF were added 250 μl of 1-(bromomethyl)-3-fluorobenzene and 800 mg of cesium carbonate, followed by stirring at 50° C. for 16 hours under an argon atmosphere. The reaction mixture was cooled to room temperature, and water added, followed by extraction with ethyl acetate twice. The combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. The solvent was evaporated and the residue was purified by silica gel chromatography (elution solvent: HEX-EtOAc) to obtain 609 mg of t-butyl 4-(3-fluorobenzyl)-3-oxo-3,4,6,7,9,10-hexahydro[1,4]oxazino[2,3-h][3]benzazepine-8(2H)-carboxylate.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:34][C:35]1[CH:36]=[C:37]([OH:42])[CH:38]=[CH:39][C:40]=1[Cl:41].[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:60][CH2:59][CH:58](O)[CH2:57][CH2:56]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:45])[CH3:44]>C(OCC)C>[C:43]([O:47][C:48]([N:50]1[CH2:55][CH2:54][C:53]2([CH2:60][CH2:59][CH:58]([O:42][C:37]3[CH:38]=[CH:39][C:40]([Cl:41])=[C:35]([Cl:34])[CH:36]=3)[CH2:57][CH2:56]2)[CH2:52][CH2:51]1)=[O:49])([CH3:46])([CH3:44])[CH3:45]
Reactant: Oc1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCC(O)CC2)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC2(CCC(Oc3ccc(Cl)c(Cl)c3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 55.4 %

Procedure:
Diisopropylazo dicarboxylate (315 mg, 1.56 mmol) in diethyl ether (2 mL) was added slowly to an ice cooled solution of triphenylphosphine (582 mg, 2.22 mmol) in diethyl ether (5 mL). The reaction mixture was stirred for 20 min. 3,4-Dichlorophenol (290 mg, 1.78 mmol) in diethyl ether (2 mL) was added and stirred 30 min at 0° C. and 9-hydroxy-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester (400 mg, 1.48 mmol) in diethylether (5 mL) was added and the mixture stirred at room temperature over night. Evaporation followed by flash chromatography (heptane/ethylacetate 9:1) gave 340 mg (56%) of 9-(3,4-dichloro-phenoxy)-3-aza-spiro[5.5]undecane-3-carboxylic acid tert-butyl ester.
Reaction SMILES: [NH2:1][CH:2]([P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6].[C:19]1([S:25](Cl)(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.C(OCC)(=O)C>[C:19]1([S:25]([NH:1][CH:2]([P:3](=[O:10])([O:7][CH2:8][CH3:9])[O:4][CH2:5][CH3:6])[P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])(=[O:27])=[O:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOP(=O)(OCC)C(N)P(=O)(OCC)OCC
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CCOP(=O)(OCC)C(NS(=O)(=O)c1ccccc1)P(=O)(OCC)OCC
Reaction time: 4 h

Procedure:
To a solution of tetraethyl (aminomethylene)bis(phosphonate) (661 mg) in pyridine (2 ml) were added benzenesulfonyl chloride (0.35 ml) and then 4-(dimethylamino)pyridine (50 mg) at ambient temperature with stirring. After stirring for 4 hours at the same temperature, the reaction mixture was diluted with ethyl acetate (20 ml). The mixture was washed with 1N hydrochloric acid four times, water and saturated aqueous hydrogen bicarbonate solution successively. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure. The residue was subjected to column chromatography on silica gel (20 g) eluted with a mixture of chloroform and methanol (20:1 V/V) to give tetraethyl (phenylsulfonylaminomethylene)bis(phosphonate) as a yellow syrup (364 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[C:4]([CH2:10]Cl)[N:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CN(C=O)C>[N:12]([CH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:8]#[N:9])=[CH:6][CH:5]=1)=[N+:13]=[N-:14]
Reactant: [N-]=[N+]=[N-]
Reactant: N#Cc1ccc(CCl)nc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(CN=[N+]=[N-])nc1Cl
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-chloro-6-chloromethyl-3-cyanopyridine (600 mg, 3.21 mmol) and sodium azide (229 mg, 3.53 mmol) in DMF (12 mL) were stirred at 50° C. for 30 min. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was washed with water (2 times) and brine, dried (Na2SO4) and evaporated in vacuo. The residue was purified by chromatography on silica (chloroform) to give the title compound as an oil:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14])[CH:5]=[O:6].C1COCC1.[C:22]1([Mg]Br)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(OCC)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:6])[CH:7]=[C:8]([O:15][CH3:16])[C:9]=1[O:10][CH2:11][CH2:12][O:13][CH3:14]
Reactant: COCCOc1c(Br)cc(C=O)cc1OC
Reactant: Br[Mg]c1ccccc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: COCCOc1c(Br)cc(C(O)c2ccccc2)cc1OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 1l round bottomed flask with a stirring bar and an argon inlet was added 3-bromo-4-(2-methoxyethoxy)-5-methoxybenzaldehyde (12.00 g, 41.50 mmol) and dry THF (150 mL). This solution was cooled in an ice bath and phenylmagnesiumbromide in diethyl ether (16.6 mL of a 3.0 M solution, 49.81 mmol) was added with a syringe. The resulting solution was stirred for 1 h at 0° C. The reaction was quenched with aqueous NH4Cl solution. The mixture was diluted with EtOAc and the layers were separated. The organic phase was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. This material was chromatographed on 400g of silica gel using 30/70 EtOAc-hexane as eluant. There was obtained 1-(3-bromo-4-(2-methoxyethoxy)-5-methoxyphenyl)-1-phenylmethanol as an oil. 1H NMR (CDCl3): δ2.29 (d, j=4Hz, 1H); 3.44 (s, 3H); 3.74 (t, j=4 Hz, 2H); 3.82 (s, 3H); 4.13 (t, j=4 Hz, 2H); 5.75 (d, j=4Hz, 1H); 6.88 (s, 1H); 7.12 (s, 1H); 7.35 (m, 5H).
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2)=CSC=1C(OC)=O.C(OCC)(OCC)OCC.[F:49]C1C=CC=CC=1N>C(O)(=O)C>[F:49][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:10]=2[N:9]=[CH:8]1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: Nc1ccccc1F
Agent: COC(=O)c1scc(-c2ccccc2)c1N
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1F
Yield: 26 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-phenylthiophene-2-carboxylate (100 mg, 0.43 mmol), triethyl orthoformate (1.0 ml), 2-fluoroaniline (88.6 mg, 0.8 mmol), and acetic acid (0.12 ml) were used to give 36 mg (0.11 mmol, 26% yield) of the title compound.
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:29][F:30])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:12]=2[CH3:28])[CH2:5][O:4]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO>[F:1][CH2:2][C:3]1([CH2:29][F:30])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:39])[C:12]=2[CH3:28])[CH2:7][O:8]1
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a toluene/methanol (10:1) (20 ml) solution of the 2-(((4-((2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (305 mg, 700 mmol) obtained in the step (7d), a toluene/methanol (10:1) (5 ml) solution of 3-chloroperbenzoic acid (167 mg, 630 μmol as the content was regarded as 65%) was added dropwise at −50° C. to −60° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (215 mg, yield: 68%) as a light yellow foam.
Reaction SMILES: [C:1]([O:7][CH3:8])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].C([Li])CCC.CCCCCC.[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[CH:28][CH:29]=2)[C:24]=1[CH2:35][CH2:36][CH:37]=[O:38]>O1CCCC1>[Cl:22][C:23]1[CH:32]=[C:31]([Cl:33])[C:30]2[C:25](=[CH:26][C:27]([Cl:34])=[CH:28][CH:29]=2)[C:24]=1[CH2:35][CH2:36][CH:37]([OH:38])[CH2:5][C:3](=[O:4])[CH2:2][C:1]([O:7][CH3:8])=[O:6]
Reactant: O=CCCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Reactant: COC(=O)CC(C)=O
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC(=O)CC(=O)CC(O)CCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Temperature: 5 °C
Reaction time: 0.33 h
Yield: 88.5 %

Procedure:
A solution of methyl acetoacetate (0.088 g, 0.76 mmole) in dry tetrahydrofuran (2 ml) was added dropwise (5 minutes) to a mixture of sodium hydride (0.036 g, 0.75 mmole) in tetrahydrofuran (3 ml) under nitrogen and with cooling (ice bath). After stirring at about 5° C. for 20 minutes, a solution of n-butyl lithium in hexane (0.55 ml, 0.77 mole) was added dropwise (5 minutes) and the mixture stirred at 5° C. for 30 minutes. The ice bath was replaced by a dry ice-acetone bath and a solution of 3-(2,4,7-trichloronaphthalen-1-yl)propanal (0.20 g, 0.7 mmole) in tetrahydrofuran (5 ml) was added (5 minutes). The reaction mixture was stirred at -70° C. for about 10 minutes and at room temperature for 5 hours and then poured into ice water containing 0.5 ml conc. HCl. After extraction with ether, the ether extracts were combined, washed with cold water and brine and dried over MgSO4. The solution was filtered and concentrated in vacuo to give 0.25 g of the title compound as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[F:15][CH:16]([F:33])[C:17]1[CH:21]=[C:20]([NH2:22])[N:19]([C:23]2[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=2[CH:25]=[CH:26][CH:27]=[N:28]3)[N:18]=1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:22][C:20]2[N:19]([C:23]3[CH:32]=[CH:31][CH:30]=[C:29]4[C:24]=3[CH:25]=[CH:26][CH:27]=[N:28]4)[N:18]=[C:17]([CH:16]([F:33])[F:15])[CH:21]=2)(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1cc(C(F)F)nn1-c1cccc2ncccc12
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(C)(C)c1ccc(S(=O)(=O)Nc2cc(C(F)F)nn2-c2cccc3ncccc23)cc1
Temperature: 80 °C
Yield: 50 %

Procedure:
A mixture of 4-t-butylbenzene-1-sulfonyl chloride (0.070 g, 0.30 mmol), 3-(difluoromethyl)-1-(quinolin-5-yl)-1H-pyrazol-5-amine (0.045 g, 0.17 mmol), and DMAP (0.020 g, 0.17 mmol) in pyridine (2 mL) was heated at 80° C. for 5 h with stirring. After cooling to room temperature, the reaction mixture was concentrated in vacuo. The crude residue was purified by flash chromatography (SiO2, 5% methanol in ethyl acetate), followed by reverse phase HPLC(C18 column, acetonitrile-H2O with 0.1% TFA as eluent) to give the title compound as a white solid (0.040 g, 0.085 mmol, 53%). 1H NMR (400 MHz, CD3OD) δ 8.88 (dd, J=2.0, 4.0 Hz, 1H), 8.15 (d, J=8.0 Hz, 1H), 7.77 (dd, J=7.2, 8.4 Hz, 1H), 7.63 (dddd, J=0.8, 1.6, 1.2, 7.2 Hz, 1H), 7.53-7.43 (m, 5H), 7.31 (dd, J=0.8, 7.2 Hz, 1H), 6.71 (t, J=54.8 Hz, 1H), 6.42 (s, 1H), 1.35 (s, 9H); MS: (ES) m/z calculated for C23H23F2N4O2S [M+H]+ 457.2. found 457.2.
Reaction SMILES: [CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]1([C:7]([F:10])([F:9])[F:8])[CH2:6][O:5]1.[NH2:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2>CCCCCC.C(OCC)(=O)C>[CH3:1][C:2]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([CH3:11])[CH2:3][C:4]([C:7]([F:10])([F:9])[F:8])([OH:5])[CH2:6][NH:18][C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[CH:21]=[CH:22][C:23]([CH3:29])=[N:24]2
Reactant: Cc1ccc2c(N)cccc2n1
Reactant: CC(C)(CC1(C(F)(F)F)CO1)c1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1ccc2c(NCC(O)(CC(C)(C)c3ccccc3)C(F)(F)F)cccc2n1
Yield: 58.8 %

Procedure:
Analogously to Example 1, 500 mg (2.05 mmol) of 2-(2-methyl-2-phenylpropyl)-2-(trifluoromethyl)oxirane and 650 mg (4.10 mmol) of 5-amino-2-methylquinoline are reacted. After chromatography on silica gel with hexane-ethyl acetate (0–70%), 485 mg of product is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[Cl:11].[NH2:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15].O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH2:13][Si:14]([CH3:17])([CH3:16])[CH3:15])=[O:7])=[CH:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1ccc(Br)c(Cl)c1
Reactant: C[Si](C)(C)CN
Solvent: O
Solvent: ClCCl
Product: C[Si](C)(C)CNC(=O)c1ccc(Br)c(Cl)c1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 99.8 %

Procedure:
To a suspension of 4-bromo-3-chlorobenzoic acid (25.00 g, 106.2 mmol) in CH2Cl2 (320 mL) was added N,N-dimethyl aminopyridine (1.95 g), followed by N-ethyl-N-dimethylamine propylcarbodiimide hydrochloride (22.39 g) in small portions. After 30 min at room temperature, aminomethyl trimethylsilane (11.2 g, 7.87 mL, 108 mmol) was added while maintaining the temperature at 20° C. After stirring over night, water was added and the organic layer was separated. The aqueous layer was extracted twice with CH2Cl2 and the combined organic phases were dried and evaporated in vacuum. The residue was purified by flash chromatography on silica gel to give the title compound (34.00 g, 100%).
Reaction SMILES: [CH2:1](O)[CH:2]=[CH2:3].[CH3:5][S:6][CH3:7].[F:8][B-:9]([F:12])([F:11])[F:10].[H+]>>[F:8][B-:9]([F:12])([F:11])[F:10].[CH2:1]([S+:6]([CH3:7])[CH3:5])[CH:2]=[CH2:3]
Reactant: C=CCO
Reactant: CSC
Agent: F[B-](F)(F)F
Agent: [H+]
Product: C=CC[S+](C)C
Reaction time: 144 h

Procedure:
Into a 3-neck 5-liter flask were weighed 1161.6 g (20 moles) of allyl alcohol, 950 g (15.3 moles) of dimethyl sulfide, and 1829 g (10 moles) of 48% aqueous tetrafluoroboric acid. The flask was attached to a large (1.5 liter) capacity Dean-Stark trap (initially filled with dimethyl sulfide) which was attached to a condenser. Reflux was started and an aqueous phase began to accumulate at the bottom of the Dean-Stark trap, displacing dimethyl sulfide back into the reaction mixture. Reflux was continued for six days. At the end of this period, the rate of accumulation of aqueous phase had become very small. The aqueous phase was drained into a tared bottle and weighed; the net weight of the aqueous phase was 1136.7 g. Excess dimethyl sulfide and allyl alcohol were allowed to distill at atmospheric pressure into the Dean-Stark trap until the temperature in the flask had reached 100° C. At this point, the flask was connected to a dry ice trap and vacuum was applied. The mixture in the flask was evaporated at 70° C. under magnetic stirring for one hour, with the pressure decreasing to a final value of 200 Pa. The yield of nonvolatile product was 1952 g. The nonvolatile product (identified as VII) was a viscous liquid containing a small amount of crystals. It showed no signs of further crystallization on standing at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1.[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=1[C:21](Cl)=[O:22].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[CH3:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:21]([C:20]3[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=3[F:18])=[O:22])=[N:15][CH:16]=2)=[CH:4][C:5]2[O:9][CH:8]=[N:7][C:6]=2[CH:10]=1
Reactant: O=C(Cl)c1ccccc1F
Reactant: Cc1cc2ncoc2cc1-c1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc2ncoc2cc1-c1ccc(NC(=O)c2ccccc2F)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
To a solution of 5-(5-methylbenzoxazol-6-yl)-2-pyridylamine (44) (26.6 mg, 0.12 mmol) in 2 ml DCM was added 2-fluorobenzoyl chloride (29 μl, 0.24 mmol) followed by addition of DIEA (105 μl). The resulting brown solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (180 μl) at r.t. for 40 min before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 24.1 mg N-[5-(5-methylbenzoxazol-6-yl)(2-pyridyl)](2-fluorophenyl)carboxamide (45) as off-white solid. (yield: 57.8%, purity>95%).
Reaction SMILES: O.[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([NH2:19])=[C:13]([O:20][CH3:21])[CH:12]=2)=[C:5](Cl)[N:4]=1>[Hg](Cl)Cl.[Zn].C(O)(=O)C>[NH2:2][C:3]1[N:8]=[C:7]([NH2:9])[C:6]([CH2:10][C:11]2[CH:12]=[C:13]([O:20][CH3:21])[C:14]([NH2:19])=[C:15]([O:17][CH3:18])[CH:16]=2)=[CH:5][N:4]=1
Reactant: COc1cc(Cc2c(N)nc(N)nc2Cl)cc(OC)c1N
Agent: Cl[Hg]Cl
Agent: [Zn]
Solvent: CC(=O)O
Solvent: O
Product: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1N
Reaction time: 8 h

Procedure:
A solution of 0.1 g. of mercury (II) chloride in 2 ml. of water and 1.5 g. of zinc powder was added to a solution of 1.5 g. of 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-6-chloropyrimidine in 15.5 ml. of glacial acetic acid and the mixture was boiled under reflux with stirring overnight. Then, the mixture was filtered while hot and the zinc powder washed with 5 ml. of acetic acid. The combined filtrates were added dropwise with stirring at a temperature below 20° C. to 40 ml. of concentrated ammonia. Then, the mixture was stirred at 20° C. for an additional hour and the solid material was removed by filtration under vacuum, washed with water, dried, recrystallized from methanol and there was obtained 2,4-diamino-5-(4-amino-3,5-dimethoxy-benzyl)-pyrimidine having a melting point of 214° C.