Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[O:3][C:4]1[CH:9]=[CH:8][C:7](/[CH:10]=[CH:11]/[C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:33]=[CH:32][C:22]([CH2:23][S:24][CH2:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[CH:21][CH:20]=3)[N:16]=2)=[CH:6][CH:5]=1.ClC1C=C(C(OO)=[O:44])C=CC=1>ClCCl.C(OCC)(=O)C>[F:35][C:2]([F:1])([F:34])[O:3][C:4]1[CH:5]=[CH:6][C:7](/[CH:10]=[CH:11]/[C:12]2[O:13][CH:14]=[C:15]([CH2:17][O:18][C:19]3[CH:33]=[CH:32][C:22]([CH2:23][S:24]([CH2:25][CH2:26][N:27]4[CH:31]=[CH:30][N:29]=[N:28]4)=[O:44])=[CH:21][CH:20]=3)[N:16]=2)=[CH:8][CH:9]=1
Reactant: FC(F)(F)Oc1ccc(/C=C/c2nc(COc3ccc(CSCCn4ccnn4)cc3)co2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=S(CCn1ccnn1)Cc1ccc(OCc2coc(/C=C/c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: -30 °C
Reaction time: 1 h
Yield: 74.3 %

Procedure:
To a solution of 101 mg (0.20 mmol) 1-[2-(4-{2-[2-(E)-(4-trifluoromethoxy-phenyl)vinyl]-oxazol-4-ylmethoxy}-benzylsulfanyl)-ethyl]-1H-[1,2,3]triazole in 8 ml dichloromethane at −30° C. were added dropwise during 20 min 54 mg (0.24 mmol) 3-chloro-benzenecarboperoxoic acid dissolved in 2 ml ethyl acetate. After 1 hour stirring at −30° C. the mixture was allowed to warm up over night, diluted with dichloromethane, washed with sodium bicarbonate solution, then with water, dried and evaporated. Elution from silica with ethyl acetate/methanol 9:1 furnished 77 mg (74%) title compound as off-white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[C:7]3[C:12](=[CH:13][C:4]=2[N:3]=[C:2]1[SH:14])[CH:11]=[CH:10][CH:9]=[CH:8]3.[ClH:15].[Cl:16][CH2:17][C:18]1[NH:19][CH2:20][CH2:21][N:22]=1>CN(C)C=O.C1(C)C=CC=CC=1>[ClH:16].[ClH:15].[NH:22]1[CH2:21][CH2:20][N:19]=[C:18]1[CH2:17][S:14][C:2]1[NH:3][C:4]2[CH:13]=[C:12]3[C:7](=[CH:6][C:5]=2[N:1]=1)[CH:8]=[CH:9][CH:10]=[CH:11]3
Reactant: ClCC1=NCCN1
Reactant: Sc1nc2cc3ccccc3cc2[nH]1
Agent: Cl
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: c1ccc2cc3[nH]c(SCC4=NCCN4)nc3cc2c1
Temperature: 25 °C
Yield: 58.1 %

Procedure:
10.0 g of 1H-Naphth[2,3-d]imidazole-2-thiol and 8.0 g of 2-chloromethylimidazoline-hydrochloride were heated for 3 hours at 90° in 50 ml of dimethylformamide. The reaction mixture was cooled to room temperature and then diluted with 200 ml of toluene. The residue was suctioned filtered, washed well with toluene, and crystallised from 700 ml of methanol, with the addition of 300 ml of ether. 10.3 g of 2-[(2-Imidazoline-2-ylmethyl)thio]-1H-naphth[2,3-d]imidazol-dihydrochloride having an m.p. of 227°-228° were obtained.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([CH:21]=O)=[CH:19][N:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:24][O:25][CH2:26][CH2:27][OH:28]>>[OH:28][CH2:27][CH2:26][O:25]/[N:24]=[CH:21]/[C:18]1[N:17]=[C:16]2[N:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)[N:13]=[N:14][C:15]2=[N:20][CH:19]=1
Reactant: NOCCO
Reactant: O=Cc1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: Cl
Product: OCCO/N=C/c1cnc2nnn(Cc3ccc4ncccc4c3)c2n1
Yield: 45 %

Procedure:
The title compound was prepared from 1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazine-6-carbaldehyde and 2-(aminooxy)ethanol hydrochloride in 45% yield using the same procedure as described in the synthesis of example 22. 1H-NMR (400 MHz, CD3OD), δ ppm 9.27 (s, 1H), 8.84 (m, 1H), 8.36 (s, 1H), 8.34 (d, 1H), 8.01 (d, 1H), 8.00 (s, 1H), 7.85 (d, 1H), 7.53 (dd, 1H), 6.20 (s, 2H), 4.39 (t, 2H), 3.87 (t, 2H). LCMS (method B): [MH]+=350, tR=1.94 min.
Reaction SMILES: S(OC)(O[CH3:5])(=O)=O.C(=O)([O-])[O-].[K+].[K+].[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([OH:19])=[O:18].O>CN(C)C=O>[NH2:14][C:15]1[CH:23]=[C:22]([O:24][CH3:25])[CH:21]=[C:20]([O:26][CH3:27])[C:16]=1[C:17]([O:19][CH3:5])=[O:18]
Reactant: COS(=O)(=O)OC
Reactant: COc1cc(N)c(C(=O)O)c(OC)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1c(N)cc(OC)cc1OC
Reaction time: 1 h
Yield: 77.5 %

Procedure:
Dimethyl sulfate (1.04 ml, 11.0 mmol) was added dropwise to a mixture of potassium carbonate (3.34 g, 24.2 mmol) and 2-amino-4,6-dimethoxybenzoic acid (2.56 g, 11.0 mmol) in dimethylformamide (70 ml) at 0° C. The reaction was stirred for 1 hour, then poured into water. The resulting precipitate was filtered, washed with water and dried in vacuo. The filtrate was extracted with ethyl acetate, and the combined organic extracts were dried (magnesium sulphate) and concentrated in vacuo. The combined solids were dried in vacuo to yield methyl 2-amino-4,6-dimethoxybenzoate (1.8 g, 77% yield) as a yellow crystalline solid:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.IC.[CH3:33][Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[N:12]([C@@H:21]([CH2:28][CH3:29])[CH2:22][O:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)[C:11](=[O:30])[CH:10]([CH3:33])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC[C@@H](COCC1CC1)N1C(=O)CC[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CC[C@@H](COCC1CC1)N1C(=O)C(C)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of 0.325 g (0.73 mmol) of (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(cyclopropylmethoxy)butan-2-yl)piperidin-2-one (Example 68, Step B) and iodomethane (0.055 mL, 0.874 mmol) in THF (7.0 mL) was added lithium bis(trimethylsilyl)amide (1M solution in THF, 0.8 mL, 0.8 mmol) at −78° C. The reaction was allowed to warm to R.T., then was quenched with sat. aqueous NH4Cl solution and extracted with EtOAc. The combined organic layers were washed with water and sat. aq. NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated under reduced pressure.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([OH:14])=O)=[CH:2]1.S(Cl)([Cl:17])=O>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[C:3]([C:12]([Cl:17])=[O:14])=[CH:2]1
Reactant: O=C(O)c1coc2ccccc2c1=O
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1coc2ccccc2c1=O
Yield: 90 %

Procedure:
In accordance with the procedure described in Example 5-a), chromone-3-carboxylic acid (3.8 g, 20 mmol) was treated with thionyl chloride (1.73 ml) to obtain the desired compound (3.76 g, 90%).
Reaction SMILES: Br[CH2:2][CH2:3][C:4]#[C:5][Si:6]([CH3:9])([CH3:8])[CH3:7].[NH:10]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[N:11]1.C([O-])([O-])=O.[K+].[K+].C[Si](C)(C)C#CCCN1C2C(=CC=CC=2)C=N1>CC(C)=O.O>[CH3:7][Si:6]([CH3:9])([CH3:8])[C:5]#[C:4][CH2:3][CH2:2][N:11]1[CH:12]=[C:13]2[C:18]([CH:17]=[CH:16][CH:15]=[CH:14]2)=[N:10]1
Reactant: C[Si](C)(C)C#CCCBr
Reactant: c1ccc2[nH]ncc2c1
Agent: C[Si](C)(C)C#CCCn1ncc2ccccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: C[Si](C)(C)C#CCCn1cc2ccccc2n1
Temperature: 150 °C
Yield: 60.9 %

Procedure:
A suspension of (4-bromo-but-1-ynyl)-trimethyl-silane (374 mg, 1.83 mmol), indazole (200 mg, 1.69 mmol) and K2CO3 (459 mg, 3.32 mmol) in acetone (2 mL) was heated at 150° C. for 900 s in a microwave. After the addition of water, acetone was evaporated. The aqueous phase was extracted with DCM. The organic phase was washed with brine, dried over MgSO4, filtered and evaporated to yield 250 mg (1.03 mmol, 62%) of 2-(4-trimethylsilanyl-but-3-ynyl)-2H-indazole and 1-(4-trimethylsilanyl-but-3-ynyl)-1H-indazole.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[O:16][CH3:17])[C:12]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[NH:6][C:5]2=O.O=P(Cl)(Cl)[Cl:21]>>[Br:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:13]2[C:4](=[C:5]([Cl:21])[N:6]=[C:7]3[C:12]=2[CH2:11][CH2:10][CH2:9][CH2:8]3)[CH:3]=1
Reactant: COc1cc2c3c([nH]c(=O)c2cc1Br)CCCC3
Reactant: O=P(Cl)(Cl)Cl
Product: COc1cc2c3c(nc(Cl)c2cc1Br)CCCC3
Temperature: 80 °C

Procedure:
To the product from Step 3, 8-bromo-9-methoxy-1,3,4,5-tetrahydrophenanthridin-6(2H)-one (880 mg, 2.86 mmol) was added POCl3 (6 mL, 64.4 mmol) and the mixture was heated to 80° C. for 3 h. The excess POCl3 was then removed in vacuo, the residue was dissolved in DCM and the pH was adjusted to 5 with 1N NaOH. The organic layer was then dried over Na2SO4 and the solvent was removed in vacuo. The resulting solid was tritrated with ether to yield the title compound as a light yellow solid. LRMS (M+H)+=325.8.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([OH:23])[C:8]2[C:13]([C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)=[O:5])C.[OH-].[Na+]>C1COCC1.C(O)C>[CH2:24]([C:7]1([OH:23])[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:21][CH3:22])[CH:9]=2)[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:6]1[C:4]([OH:5])=[O:3])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccc(OC)cc2C1(O)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)C(O)(Cc1ccccc1)C(C(=O)O)=C2c1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 108 %

Procedure:
1-Benzyl-1-hydroxy-6-methoxy-3-phenyl-1H-indene-2-carboxylic acid ethyl ester (35 mg, 0.087 mmol) prepared in Example 5 was dissolved in THF, and an excess amount of sodium hydroxide dissolved in aqueous ethanol was added thereto in such a way not to cause layer separation. The mixture was stirred for 24 hrs at RT, and the pH was adjusted to 3˜4 using 2N hydrochloric acid. The resulting mixture was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous MgSO4 and concentrated under a reduced pressure, to obtain 35 mg of the titled compound (yield: 100%).
Reaction SMILES: [F:1][C:2]([F:29])([S:25](F)(=[O:27])=[O:26])[C:3]([F:24])([F:23])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:18])([F:17])[C:7]([F:16])([F:15])[C:8]([F:14])([F:13])[C:9]([F:12])([F:11])[F:10].C(N(CC)CC)C.[CH2:37]([NH2:47])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]>O>[CH2:37]([NH:47][S:25]([C:2]([F:29])([F:1])[C:3]([F:23])([F:24])[C:4]([F:22])([F:21])[C:5]([F:20])([F:19])[C:6]([F:17])([F:18])[C:7]([F:15])([F:16])[C:8]([F:13])([F:14])[C:9]([F:11])([F:12])[F:10])(=[O:27])=[O:26])[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCN
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCNS(=O)(=O)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F

Procedure:
50.21 g (100.0 mmol) of perfluorooctanesulfonyl fluoride is added in drops to a mixture of 10.62 g (105.0 mmol) of triethylamine and 15.73 g (100.0 mmol) of decylamine at 80° C. while being stirred vigorously. It is stirred for 2 days at 80° C., the reaction mixture is mixed with 300 ml of water and extracted three times with ethyl acetate. The combined organic extracts are dried on sodium sulfate, filtered and concentrated by evaporation. The residue is chromatographed on silica gel (mobile solvent: dichloromethane/methanol=4/1).
Reaction SMILES: Cl.[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][NH:32][CH2:31]4)=[CH:24][N:23]=3)=[CH:16][CH:15]=2)[CH:7]=1)([CH3:5])([CH3:4])[CH3:3].Cl.F[CH2:39][C:40](C1ON=C(NC(=O)NC2C=CC(NC(=O)C3C=CC(OC4CCNCC4)=CN=3)=CC=2)C=1)(C)[CH2:41]F>>[C:2]([C:6]1[O:10][N:9]=[C:8]([NH:11][C:12](=[O:36])[NH:13][C:14]2[CH:15]=[CH:16][C:17]([NH:20][C:21](=[O:35])[C:22]3[CH:27]=[CH:26][C:25]([O:28][CH2:29][C@@H:30]4[CH2:34][CH2:33][N:32]([CH:40]([CH3:41])[CH3:39])[CH2:31]4)=[CH:24][N:23]=3)=[CH:18][CH:19]=2)[CH:7]=1)([CH3:5])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC[C@@H]4CCNC4)cn3)cc2)no1
Reactant: CC(CF)(CF)c1cc(NC(=O)Nc2ccc(NC(=O)c3ccc(OC4CCNCC4)cn3)cc2)no1
Agent: Cl
Product: CC(C)N1CC[C@@H](COc2ccc(C(=O)Nc3ccc(NC(=O)Nc4cc(C(C)(C)C)on4)cc3)nc2)C1
Yield: 20 %

Procedure:
(R)-N-(4-(3-(5-tert-Butylisoxazol-3-yl)ureido)phenyl)-5-((1-isopropylpyrrolidin-3-yl)methoxy)picolinamide (26 mg, 20%) was prepared using a procedure analogous to that described in Example 20, substituting (R)-N-(4-(3-(5-tert-butylisoxazol-3-yl)ureido)phenyl)-5-(pyrrolidin-3-ylmethoxy)picolinamide hydrochloride from Step 2 of this example for N-(4-(3-(5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-yl)ureido)phenyl)-5-(piperidin-4-yloxy)picolinamide hydrochloride used in Example 20. LC-MS (ESI) m/z 521 (M+H)+.
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][C:10]([CH3:15])([CH2:13]O)[CH2:11][OH:12]>C1(C)C=CC=CC=1>[CH3:9][C:10]1([CH3:15])[CH2:11][O:12][C:3]2([CH2:4][CH2:5][CH2:6][C:1](=[O:8])[CH2:2]2)[O:7][CH2:13]1
Reactant: O=C1CCCC(=O)C1
Reactant: CC(C)(CO)CO
Solvent: Cc1ccccc1
Product: CC1(C)COC2(CCCC(=O)C2)OC1

Procedure:
125 g (630 mmole) 3,3-dimethyl-1,5-dioxa-spiro[5,5]undecan-8-one, which was obtained by the azeotropic acetylation of cyclohexane-1,3-dione with 2,2-dimethylpropane-1,3-diol in toluene as a solvent using p-toluenesulphonic acid as a catalyst, and 59 g (630 mmole) dimethylammonium methylene chloride were stirred at room temperature in 400 ml of dry acetonitrile. After adding 1 ml acetyl chloride the mixture was stirred for a further 3 hours at room temperature, whereupon a clear colourless solution was obtained. 800 ml of dry ether were then added drop-wise to the reaction mixture, whereupon the hydrochloride crystallised out. 158 g of (18) were obtained (98% theoretical).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][CH:6]=1)=[O:4].C([O-])=[O:13].[K+]>CO>[Cl:11][C:8]1[CH:9]=[CH:10][C:5]([C:3](=[O:4])[CH2:2][OH:13])=[CH:6][CH:7]=1
Reactant: O=C[O-]
Reactant: O=C(CBr)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CO
Product: O=C(CO)c1ccc(Cl)cc1

Procedure:
A mixture of 2-bromo-1-(4-chloro-phenyl)-ethanone (100 mmoles) and potassium formate (130 mmoles) in MeOH (100 ml) is stirred at reflux for 3 hours. The reaction mixture is poured onto crushed ice. The solid formed is filtered off, washed with cold MeOH and then dried in vacuo to yield the title product, which is used directly in the next Step.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[S:13][C:12]([C:14](Cl)=[O:15])=[CH:11][CH:10]=1.[CH2:17]([O:19][C:20](=[O:30])[CH2:21][NH:22][C:23]1[C:28]([NH2:29])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:18].C(OC(=O)CNC1C([N+]([O-])=O)=CC=CN=1)C>O1CCCC1.[Pd]>[CH2:17]([O:19][C:20](=[O:30])[CH2:21][NH:22][C:23]1[C:28]([NH:29][C:14]([C:12]2[S:13][C:9]([CH3:8])=[CH:10][CH:11]=2)=[O:15])=[CH:27][CH:26]=[CH:25][N:24]=1)[CH3:18]
Reactant: CCOC(=O)CNc1ncccc1N
Reactant: Cc1ccc(C(=O)Cl)s1
Agent: [Pd]
Agent: CCOC(=O)CNc1ncccc1[N+](=O)[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNc1ncccc1NC(=O)c1ccc(C)s1
Yield: 100.8 %

Procedure:
Under a nitrogen atmosphere, triethylamine (31.41 g, 0.311 mole) and 5-methyl-2-thiophenecarbonyl chloride (50 g, 0.311 mole) were added simultaneously, dropwise, to a stirred and chilled solution of freshly prepared N-[[3-amino]-2-pyridinyl] glycine ethyl ester (0.296 mole) by palladium/carbon reduction of N-[[3-nitro]-2-pyridinyl]glycine ethyl ester (66.98 g, 0.296 mole) in dry tetrahydrofuran (~1 liter). The reaction mixture was stirred at room temperature overnight and the solvent was evaporated under reduced pressure. The residue was partitioned between water and ethyl acetate, the layers separated and the aqueous layer was again extracted with ethyl acetate. The combined organic layers were washed twice with a 5% potassium hydroxide solution, twice with a saturated sodium bicarbonate solution, twice with water, dried over magnesium sulfate, treated with charcoal, filtered, and evaporated under reduced pressure to give 95.3 g of a tan solid in quantitative yield. A 1.5-g portion of the solid was dissolved in hot absolute ethanol, filtered while hot, and brought to its cloud point by addition of water. Cooling to room temperature gave a solid which was collected by filtration, rinsed with water, and dried under high vacuum at room temperature overnight to give 1.11 g of title compound, mp 112°-115° C.
Reaction SMILES: O=[O+][O-].[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[N:15]=[N:14][C:13]([C:16]([CH3:24])=CC3C=CC=CC=3)=[N:12]2)[CH:8]=[CH:9][CH:10]=1.[O:25]=O.[BH4-].[Na+]>CO.ClCCl>[Cl:4][C:5]1[CH:6]=[C:7]([N:11]2[N:15]=[N:14][C:13]([CH:16]([OH:25])[CH3:24])=[N:12]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CC(=Cc1ccccc1)c1nnn(-c2cccc(Cl)c2)n1
Reactant: O=O
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: CC(O)c1nnn(-c2cccc(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
Ozone was bubbled through a solution of 2-(3-chlorophenyl)-5-[1-methyl-2-phenylvinyl]-2H-tetrazole (2.73 g, 9.2 mmol) in methanol (75 mL) and dichloromethane (75 mL) at −78° C. When the color lightened and the starting material had disappeared by TLC, oxygen was bubbled through the mixture for approximately 2-3 minutes. Sodium borohydride (635 mg, 16.8 mmol) was added. The reaction was allowed to warm to room temperature, stirred for 30 minutes and quenched with water (5 mL) and saturated ammonium chloride (5 mL). After removal of the solvent in vacuo, the product was partitioned between dichloromethane and water, dried over sodium sulfate, and the solvent was removed in vacuo. Flash chromatography (15-35% ethyl acetate in hexane) yielded the title compound as a yellow solid (1.795 g, 87%). 1H NMR (CDCl3) δ (ppm): 8.19 (m, 1H), 8.06 (m, 1H), 7.50 (m, 2H), 5.3 (m, 1H), 2.54 (m, 1H), 1.78 (d, 3H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1.[C:25]1([CH3:34])[C:26]([C:31](Cl)=[O:32])=[CH:27][CH:28]=[CH:29][CH:30]=1.C1(C2C=CC=CC=2C(Cl)=O)C=CC=CC=1>>[OH:1][CH2:2][CH2:3][CH:4]1[CH:10]=[CH:9][N:8]([S:11]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:31](=[O:32])[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH3:34])=[CH:16][CH:15]=2)(=[O:13])=[O:12])[C:7]2[CH:21]=[CH:22][CH:23]=[CH:24][C:6]=2[S:5]1
Reactant: Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1
Reactant: Cc1ccccc1C(=O)Cl
Agent: O=C(Cl)c1ccccc1-c1ccccc1
Product: Cc1ccccc1C(=O)Nc1ccc(S(=O)(=O)N2C=CC(CCO)Sc3ccccc32)cc1

Procedure:
Compound 4 as prepared in Example 25 (0.55 g, 1.5 mM) was treated as described in Example 26 with 2-toluoyl chloride (0.3 ml) substituted for 2-phenylbenzoyl chloride to give the desired product m/z (MH+)483
Reaction SMILES: [F:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=[CH:9][N:8]=2)=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH3:23]O>>[CH3:23][O:14][C:13]([C:12]1[C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:17][CH:16]=2)=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CO
Reactant: O=C(O)c1cccnc1Oc1ccc(F)cc1
Agent: O=S(=O)(O)O
Product: COC(=O)c1cccnc1Oc1ccc(F)cc1
Temperature: 0 °C
Yield: 64 %

Procedure:
A mixture of 20.0 g (89.6 mmol) of 2-(4-fluorophenoxy)-3-pyridinecarboxylic acid (for preparation, see: Villani, F. J. et al. J. Med. Chem., 1975, 18,3), 300 mL of methanol, and 5.5 mL of concentrated sulfuric acid was heated to reflux for 2 h. The cooled mixture was poured onto 500 mL of ice cold saturated aqueous sodium hydrogencarbonate solution, and the resulting precipitate was filtered, washed with water, and dreid under vacuum to give 12.9 g (64% yield) of the title compound as a white solid, mp 97-99° C. Anal. Calcd for C13H10NO3F: C, 63.16; H, 4.08; N, 5.67. Found: C, 62.80; H, 4.08; N, 5.50.
Reaction SMILES: Br[C:2]1[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)=[N:4][C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.C(N(CC)CC)C.[C:22]([Si:24]([CH3:27])([CH3:26])[CH3:25])#[CH:23]>[Cu]I.C(#N)C>[CH3:9][NH:8][C:5]1[N:4]=[C:3]([C:10]2[S:11][CH:12]=[CH:13][CH:14]=2)[C:2]([C:23]#[C:22][Si:24]([CH3:27])([CH3:26])[CH3:25])=[CH:7][N:6]=1
Reactant: CNc1ncc(Br)c(-c2cccs2)n1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CNc1ncc(C#C[Si](C)(C)C)c(-c2cccs2)n1
Temperature: 90 °C

Procedure:
A 75 mL thick wall glass tube with a teflon screw cap was charged with 5-bromo-N-methyl-4-(thiophen-2-yl)pyrimidin-2-amine (0.995 g, 3.68 mmol), acetonitrile (9 mL), triethylamine (3.00 ml, 3.68 mmol), dichlorobistriphenylphosphine palladium(II) (0.259 g, 0.368 mmol), copper(I) iodide (0.0351 g, 0.184 mmol), and ethynyltrimethylsilane (0.362 g, 3.68 mmol). The tube was capped and heated to 90° C. for 2 hours. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (gradient elution with 0-100% ethyl acetate-hexane) to afford N-methyl-4-(thiophen-2-yl)-5-(2-(trimethylsilyl)ethynyl)pyrimidin-2-amine. MS m/z=288 [M+H]+. Calc'd for C14H17N3SSi: 287.
Reaction SMILES: [C:1](=[O:14])([O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[O:2][CH:3](Cl)[CH3:4].[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O-:28])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16].[K+].[I-].[Na+]>CN(C=O)C>[C:15]([NH:18][C:19]1[C:20]([I:35])=[C:21]([N:30]([C:32](=[O:34])[CH3:33])[CH3:31])[C:22]([I:29])=[C:23]([C:26]([O:28][CH:3]([O:2][C:1]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:14])[CH3:4])=[O:27])[C:24]=1[I:25])(=[O:17])[CH3:16]
Reactant: CC(Cl)OC(=O)OCc1ccccc1
Reactant: CC(=O)Nc1c(I)c(C(=O)[O-])c(I)c(N(C)C(C)=O)c1I
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1c(I)c(C(=O)OC(C)OC(=O)OCc2ccccc2)c(I)c(N(C)C(C)=O)c1I
Temperature: 50 °C
Reaction time: 168 h

Procedure:
1-Chloroethyl benzyl carbonate (prepared according to Synthesis 1986, 627), (2.36 g, 11.0 mmol) was added at room temperature to a solution of potassium 5-(N-acetylamino)-3-(N-acetyl-N-methylamino)-2,4,6-triiodobenzenecarboxylate (6.66 g, 20 mmol) and sodium iodide (0.15 g, 1 mmol) in dry DMF (50 ml). After stirring at 50° C. for 7 hours and at room temperature for 7 days the solvent was removed at reduced pressure. The residue was dissolved in chloroform (100 ml) and washed four times with a saturated sodium hydrogen carbonate solution and twice with water. After treatment with magnesium sulfate the solution was evaporated to dryness. Yield: 6.8 g. Purity by HPLC: 97% 1H-NMR(DMSO-d6): delta=1.64 (CHCH3); 1.66(N(CH3)COCH3); 2.05 (NCOCH3); 5.23 (CH2); 7.00 (CH); 7.30-7.45 (arom.); 10.12 ppm (NH).
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:20]=[CH:21][CH:22]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:15][C:16]([NH:18][NH2:19])=[S:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[C:23]1([NH:29][C:30]([NH:19][NH:18][C:16]([NH:15][CH2:14][CH2:13][CH2:12][O:11][C:10]2[CH:20]=[CH:21][CH:22]=[C:8]([CH2:7][N:1]3[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]3)[CH:9]=2)=[S:17])=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1
Reactant: O=C=Nc1ccccc1
Product: O=C(NNC(=S)NCCCOc1cccc(CN2CCCCC2)c1)Nc1ccccc1

Procedure:
The compound is prepared by a method analogous to that of Example 9 from N-[3-[3-(1-piperidinylmethyl) phenoxy]propyl]-hydrazine carbothioamide and phenyl isocyanate. The analytical values are summarized in Table I.