Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([C:18]3[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=3)=[CH:12][C:13](=[O:17])[O:14]2)=[CH:9][CH:8]=1)(=O)=O.C(N(CC)CC)C.[C]=O>CS(C)=O>[O:17]=[C:13]1[CH:12]=[C:11]([C:18]2[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=2)[C:10]2[C:15](=[CH:16][C:7]([C:13]([O:14][CH3:15])=[O:17])=[CH:8][CH:9]=2)[O:14]1
Reactant: O=c1cc(-c2cccnc2)c2ccc(OS(=O)(=O)C(F)(F)F)cc2o1
Agent: [C]=O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(-c3cccnc3)cc(=O)oc2c1
Temperature: 25 °C

Procedure:
To a mixture of 2-oxo-4-pyridin-3-yl-2H-chromen-7-yl trifluoromethanesulfonate (6.4 g, 17.24 mmol) in DMSO (100 mL) stirred at room temperature, triethylamine (4.85 mL, 34.5 mmol) was added. The reaction was then purged twice with carbon monoxide and palladium dichloride-(dppf)-dichloromethane (2.82 g, 3.45 mmol) was added. The mixture was purged once again with carbon monoxide and the reaction was stirred overnight at 65° C. under carbon monoxide atmosphere. After cooling, the reaction was quenched by the addition of an aqueous saturated ammonium chloride solution. The aqueous layer was extracted (3×) with ethyl acetate and the combined organic extracts were dried over MgSO4, filtered and concentrated. The crude residue obtained was purified by column chromatography (acetone/CH2Cl2, 10:90). MS (+ESI) 282.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([CH3:26])[N:21]=4)=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:6][N:5]2[CH:27]=1.[C:28](Cl)(=[O:31])[CH2:29][CH3:30]>CN(C)C(=O)C.C(=O)([O-])O.[Na+]>[CH3:26][C:22]1[N:21]=[C:20]([C:18]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([O:10][C:7]3[CH:8]=[CH:9][C:4]4[N:5]([CH:27]=[C:2]([NH:1][C:28](=[O:31])[CH2:29][CH3:30])[N:3]=4)[CH:6]=3)[CH:12]=2)=[O:19])[CH:25]=[CH:24][CH:23]=1
Reactant: Cc1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)cn4c3)c2)n1
Reactant: CCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CCC(=O)Nc1cn2cc(Oc3cccc(NC(=O)c4cccc(C)n4)c3)ccc2n1
Temperature: 25 °C
Reaction time: 10 h
Yield: 40.4 %

Procedure:
To a solution of N-{3-[(2-aminoimidazo[1,2-a]pyridin-6-yl)oxy]phenyl}-6-methylpyridine-2-carboxamide (300 mg, 0.835 mmol) in N,N-dimethylacetamide (5 mL) was added propionyl chloride (72.6 μL, 0.836 mmol), and the mixture was stirred at room temperature for 10 hr. The reaction mixture was diluted with aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and filtrated. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH silica gel, 0%→100% ethyl acetate-hexane) to give the title compound (140 mg, 40%) as a white solid.
Reaction SMILES: [CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][OH:19])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:20]([Si:24]([CH3:27])([CH3:26])Cl)([CH3:23])([CH3:22])[CH3:21].N1C=CN=C1>C(Cl)Cl>[CH2:1]([N:8]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH:10]([CH2:18][O:19][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([CH3:27])[CH3:26])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1Cc2ccccc2N(Cc2ccccc2)C1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCC1Cc2ccccc2N(Cc2ccccc2)C1
Yield: 95.1 %

Procedure:
11.6 g of 1-benzyl-3(R,S)-hydroxymethyl-1,2,3,4-tetrahydroquinoline (Example 29e), 8.54 g of tert-butyldimethylchlorosilane and 4.05 g of imidazole are stirred in 120 ml of methylene chloride at room temperature for 20 h. The precipitate is then filtered off and the crude product obtained after concentration of the filtrate is purified over 900 g of silica gel (mobile phase Z). 16 g of the title compound are obtained as a yellowish oil: Rf (Z)=0.66.
Reaction SMILES: Br[C:2]1[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=1.[NH:15]1[C:23]2[C:18](=[CH:19][C:20](B(O)O)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH:15]1[C:23]2[C:18](=[CH:19][C:20]([C:2]3[N:6]=[C:5]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[S:4][N:3]=3)=[CH:21][CH:22]=2)[CH:17]=[CH:16]1
Reactant: CC(C)(C)OC(=O)Nc1nc(Br)ns1
Reactant: OB(O)c1ccc2[nH]ccc2c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)Nc1nc(-c2ccc3[nH]ccc3c2)ns1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44 %

Procedure:
To a mixture of tert-butyl (3-bromo-1,2,4-thiadiazol-5-yl)carbamate (100 mg, 0.359 mmol) and indole-5-boronic acid (57.9 mg, 0.359 mmol) in 1,4-dioxane (5 mL) was added Pd(PPh3)4 (20.77 mg, 0.017 mmol) and 1M aq K2CO3 solution (0.539 mL, 0.539 mmol). N2 gas was purged for 15 min. After 15 min, the reaction was heated at reflux for 4 h. The reaction mixture was cooled to RT and treated with H2O (5 mL), extracted with EtOAc (25 mL). The aqueous layer was back extracted with EtOAc (25 mL). The combined organic layers were dried over anhydrous Na2SO4 and concentrated. The crude was further purified by silica gel column chromatography (eluent: 10% EtOAc in petroleum ether) to afford tert-butyl (3-(1H-indol-5-yl)-1,2,4-thiadiazol-5-yl)carbamate (50 mg, 44.2%) as an off white solid. MS (ESI, pos. ion) m/z: 261 (M+1); 1H NMR (400 MHz, DMSO-d6): δ 12.40 (s, 1H), 11.31 (s, 1H), 8.35 (s, 1H), 7.91 (dd, J=1.2 Hz & 8.4 Hz, 1H), 7.46 (d, J=8.4 Hz, 1H), 7.41-7.40 (m, 1H), 6.35 (s, 1H), 1.52 (s, 9H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][NH:8][C:7](=[O:11])[N:6]=1)(=[O:3])[CH3:2].C(O[C@H:16]1[O:38][C@@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:17]1[O:18][C:19](=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)(=O)C.C[Si](N[Si](C)(C)C)(C)C.Cl[Si](C)(C)C.Cl[Sn](Cl)(Cl)Cl>CC#N>[C:19]([O:18][C@H:17]1[C@@H:27]([O:28][C:29](=[O:36])[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@H:37]([CH2:39][O:40][C:41](=[O:48])[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[O:38][C@@H:16]1[N:8]1[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:6][C:7]1=[O:11])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)Nc1cc[nH]c(=O)n1
Reactant: CC(=O)O[C@H]1O[C@@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: CC#N
Product: CC(=O)Nc1ccn([C@H]2O[C@@H](COC(=O)c3ccccc3)[C@H](OC(=O)c3ccccc3)[C@@H]2OC(=O)c2ccccc2)c(=O)n1
Yield: 69.3 %

Procedure:
To a mixture of N4 -acetylcytosine (0.18 g, 1.19 mmol) and compound 2 (0.50 g, 0.99 mmol) in anhydrous MeCN (30 ml) were successively added HMDS (0.17 ml, 0.79 mmol), ClSiMe3 (0.10 ml, 0.79 mmol) and SnCl4 (0.14 ml, 1.19 mmol). The resulting clear solution was refluxed for one hour. Then the solvent was evaporated and the residue dissolved in EtOAc (100 ml), washed with NaHCO3 and H2O. After evaporation of the solvent the residue was purified on a silica gel column using EtOAc/petroleum ether (70%) to give pure 7 (0.41 g, 70%) as a white foam.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].CI.[C:14](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1cc(Br)ccc1F
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1cc(Br)ccc1F
Temperature: 50 °C
Yield: 93.6 %

Procedure:
A mixture of 5-bromo-2-fluorobenzoic acid (25 g, 0.11 mol), methyl iodide (8.5 mL, 0.14 mol), and potassium carbonate (31 g, 0.23 mol) in DMF (200 mL) was heated to 50° C. for 18 hr. The cooled reaction mixture was diluted with EtOAc (200 mL) and the organic phase was washed with a saturated aqueous NaCl solution (4×). The organic phase was then dried over sodium sulfate and evaporated to dryness to give 24 g of methyl 5-bromo-2-fluorobenzoate as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.[N:29]([C:32]1[CH:37]=[CH:36][N:35]=[CH:34][CH:33]=1)=[C:30]=[O:31]>C(Cl)Cl>[N:35]1[CH:36]=[CH:37][C:32]([NH:29][C:30]([N:9]2[CH2:10][CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:8]2[C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[F:28])=[O:31])=[CH:33][CH:34]=1
Reactant: O=C=Nc1ccncc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: ClCCl
Product: CC(C)(C)CC1CN(C(=O)Nc2ccncc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 89.6 %

Procedure:
A mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (39.4 mg, 0.093 mmol) and 4-isocyanatopyridine (Princeton, 27.8 mg, 0.231 mmol) in CH2Cl2 (5 mL) was stirred at rt for 7.5 hrs then more 4-isocyanatopyridine (Princeton, 23.6 mg, 0.196 mmol) was added. After and additions 16 hrs, the reaction mixture was then concentrated and purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-3-cyano-4-(2,2-dimethyl-propyl)-pyrrolidine-1-carboxylic acid pyridin-4-ylamide (45.3 mg, 89.5%). HRMS (ES+) m/z Calcd for C28H26Cl2F2N4O+H [(M+H)+]: 543.1525; Found: 543.1525.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[F:13].Br[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1>>[Br:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]#[N:12])=[CH:7][N:8]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:4][C:3]=1[F:13]
Reactant: Fc1cccc(CBr)c1
Reactant: N#Cc1c[nH]c2cc(Br)c(F)cc12
Product: N#Cc1cn(Cc2cccc(F)c2)c2cc(Br)c(F)cc12

Procedure:
The title compound was prepared as described in Example 28A using 6-bromo-5-fluoro-1H-indole-3-carbonitrile in place of 6-bromo-1H-pyrrolo[3,2-b]pyridine-3-carbonitrile and using 1-(bromomethyl)-3-fluorobenzene in place of 4-(bromomethyl)tetrahydro-2H-pyran.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:28])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]3)[S:17][C:10]=12.[O:29]([C:36]1[CH:44]=[CH:43][CH:42]=[CH:41][C:37]=1[C:38](O)=[O:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[F:1][C:2]1[CH:3]=[C:4]([NH:28][C:38](=[O:39])[C:37]2[CH:41]=[CH:42][CH:43]=[CH:44][C:36]=2[O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]#[C:19][CH2:20][N:21]3[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]3)[S:17][C:10]=12
Reactant: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(N)cc4F)c3s2)CC1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Product: CN1CCN(CC#Cc2cc3nccc(Oc4ccc(NC(=O)c5ccccc5Oc5ccccc5)cc4F)c3s2)CC1
Yield: 67 %

Procedure:
Prepared from 3-fluoro-4-(2-(3-(4-methylpiperazin-1-yl)prop-1-ynyl)thieno[3,2-b]pyridin-7-yloxy)aniline (Example 17, Step B) and 2-phenoxybenzoic acid according to the procedure of Example 89. The crude was purified by silica gel flash column chromatography (10% MeOH in CH2Cl2) to afford 25 mg (67%) of the desired product. LRMS (ESI pos) m/e 593.3 (M+1). 1H-NMR (400 MHz, CDCl3) δ 8.92 (s, 1H), 8.48 (d, 1H), 8.36 (d, 1H), 7.87 (dd, 1H), 7.58 (s, 1H), 7.46 (t, 3H), 7.29 (m, 3H), 7.21 (d, 1H), 7.17 (m, 2H), 6.91 (d, 1H), 6.51 (dd, 1H), 3.60 (s, 2H), 2.52-2.71 (m, 8H), 2.32 (s, 3H); 19F NMR (376 MHz, CDCl3) δ −126.7.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+].Cl[CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.Cl>CS(C)=O.C(=O)(O)[O-].[Na+].O>[O:7]([CH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1)[C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(O)c1ccc(CCl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)c1ccc(COc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
Phenol 2 (4.706 g, 50.0 mmol) and KOH (6.172 g, 110 mmol) were combined in dimethyl sulfoxide (DMSO) (250 ml). 4-Chloromethylbenzoic acid 1 (8.530 g, 50.0 mmol) was added. The mixture was stirred at room temperature overnight. The mixture was then poured into H2O and acidified with concentrated HCl. The solution was then extracted and concentrated to give a solid. The solid was dissolved in an aqueous sodium bicarbonate solution, then washed with ethyl acetate. The aqueous mixture was then acidified with dilute HCl forming a precipitate which was filtered and dried to give about 3.7 g of 4-phenoxymethylbenzoic acid 3.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][CH2:6][O:7][CH3:8])[CH3:2].C(O)(=O)C.[N:13]#[C:14][NH2:15].C([O-])(=O)C>>[CH3:8][O:7][CH2:6][CH2:5][CH2:4][N:3]([CH2:1][CH3:2])[C:14]([NH2:15])=[NH:13]
Reactant: N#CN
Reactant: CCNCCCOC
Agent: CC(=O)[O-]
Solvent: CC(=O)O
Product: CCN(CCCOC)C(=N)N
Temperature: 90 °C
Yield: 50 %

Procedure:
3.00 g (25.6 mmol) of N-ethyl-3-methoxypropylamine and 1.54 g (25.6 mmol) of acetic acid were placed in a 50 ml two neck flask. While heating the flask in a 90° C. oil bath, 1.08 g (25.6 mmol) of cyanamide was added. After 12 hours of the reaction, the product was purified by a silica gel column chromatography (eluent, chloroform/ethanol=1/2 containing 0.5% acetic acid) to obtain 2.80 g of the title compound (wax-like, 12.8 mmol, 50.0% in yield) in the form of acetate. Results of the analysis of this compound are as follows.
Reaction SMILES: B(Br)(Br)Br.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22]C)[CH:18]=3)[CH:13]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:8][CH:7]=1>C(Cl)Cl>[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([OH:22])[CH:18]=3)[CH:13]2[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][S:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:8][CH:7]=1
Reactant: CCCCCCSCCCCCCCCCCC1c2ccc(OC)cc2CCC1c1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCCCCCSCCCCCCCCCCC1c2ccc(O)cc2CCC1c1ccc(F)cc1
Temperature: -70 °C
Reaction time: 16 h

Procedure:
Boron tribromide (0.66 ml. of a molar solution in methylene chloride) was added to a stirred solution of the (1RS,2RS)-2-p-fluorophenyl-1-(10-hexylthiodecyl)-1,2,3,4-tetrahydro-6-methoxynaphthalene thus obtained (0.11 g.) in methylene chloride (4 ml.) which was cooled to -70° C., and the mixture was allowed to warm up to laboratory temperature, stirred at that temperature for 16 hours and then poured onto ice (20 g.). The mixture was extracted three times with methylene chloride (10 ml. each time) and the combined extracts were washed with saturated aqueous sodium bicarbonate solution (5 ml.) and then with water, dried and evaporated to dryness. The residue was purified by chromatography on a silica gel column using toluene as eluent. There was thus obtained as an oil (1RS,2RS)-2-p-fluorophenyl-1-(10-hexylthiodecyl)-1,2,3,4-tetrahydronaphth-6-ol, the structure of which was confirmed by proton magnetic resonance and mass spectroscopy.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:12]([CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:30][CH:29]=2)([CH2:13][O:14]C(=O)C2C=CC=CC=2[N+]([O-])=O)[CH2:11][O:10][C:9]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+]>CO.C1COCC1>[C:1]([O:5][C:6]([N:8]1[C:12]([CH2:26][CH2:27][C:28]2[CH:29]=[CH:30][C:31]([O:34][CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:33]=2)([CH2:13][OH:14])[CH2:11][O:10][C:9]1([CH3:43])[CH3:42])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(CCc2ccc(OCc3ccccc3)cc2)(COC(=O)c2ccccc2[N+](=O)[O-])COC1(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1C(CO)(CCc2ccc(OCc3ccccc3)cc2)COC1(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
To a solution of 4-[2-(4-benzyloxy-phenyl)-ethyl]-2,2-dimethyl-4-(2-nitro-benzoyloxymethyl)-oxazolidine-3-carboxylic acid tert-butyl ester (80 mg, 0.13 mmol) in methanol (1 ml) and THF (1 ml) is added K2CO3 (1.5 mg, 0.076 eq), the reaction mixture is stirred overnight at room temperature. The reaction mixture is concentrated to dryness and 4-[2-(4-benzyloxy-phenyl)-ethyl]-4-hydroxymethyl-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (51 mg, 85%) is isolated as a white solid after flash chromatography (Ethyl acetate/Hexane (1/4)).
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:11]2[CH:10]=[CH:9][C:5]([CH2:6][CH2:7][NH2:8])=[CH:4][C:3]=2[O:2]1.Cl[C:15]1[C:16]2[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=2[N:18]=[C:19]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)[N:20]=1>>[N:23]1[CH:24]=[CH:25][CH:26]=[C:21]([C:19]2[N:20]=[C:15]([NH:8][CH2:7][CH2:6][C:5]3[CH:9]=[CH:10][C:11]4[O:12][CH2:13][CH2:1][O:2][C:3]=4[CH:4]=3)[C:16]3[C:29]([CH3:30])=[C:28]([CH3:31])[S:27][C:17]=3[N:18]=2)[CH:22]=1
Reactant: Cc1sc2nc(-c3cccnc3)nc(Cl)c2c1C
Reactant: NCCc1ccc2c(c1)OCCO2
Product: Cc1sc2nc(-c3cccnc3)nc(NCCc3ccc4c(c3)OCCO4)c2c1C

Procedure:
With the procedure of Example 1, the reaction of 3,4-ethylenedioxyphenethylamine with 4-chloro-2-(pyridin-3-yl)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine yields 2-(pyridin-3-yl)-4-(3,4-ethylenedioxyphenethylamino)-5,6-dimethyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]2[CH:14]=[C:13]([O:15][CH3:16])[C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2)[CH:4]=1.[NH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:20][O:19][C:11]1[CH:10]=[C:9]([C:5]2[CH:4]=[C:3]([CH2:2][N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)[CH:8]=[CH:7][N:6]=2)[CH:14]=[C:13]([O:15][CH3:16])[C:12]=1[O:17][CH3:18]
Reactant: COc1cc(-c2cc(CCl)ccn2)cc(OC)c1OC
Reactant: C1CNCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chloromethyl-2-(3,4,5-trimethoxyphenyl)pyridine (13.52 g) and piperazine (11.89 g) were dissolved in DMF (100 mL), and to the solution potassium carbonate (15.89 g) was added. The mixture was stirred at room temperature for 5 hours. After the reaction mixture was concentrated under reduced pressure, chloroform was added to the residue, and the mixture was washed with water, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform:methanol=20:1 to chloroform:ammonia-saturated methanol=10:1) to obtain a free base of the title compound.
Reaction SMILES: [C:1]([CH:3]([CH:9]1[CH2:11][CH2:10]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].O1[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])S1(=O)=O.Cl>C1(C)C=CC=CC=1.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:26]([O:25][C:23]([NH:20][CH2:21][CH2:22][C:3]([C:1]#[N:2])([CH:9]1[CH2:10][CH2:11]1)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[O:24])([CH3:29])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C(C#N)C1CC1
Reactant: CC(C)(C)OC(=O)N1CCOS1(=O)=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C#N)(CCNC(=O)OC(C)(C)C)C1CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of ethyl cyano(cyclopropyl)acetate (27 g) obtained in Step A of Example 103 in toluene (400 mL) were added cesium carbonate (88 g), tetrabutylammonium bromide (5.8 g) and tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (40 g), and the mixture was stirred overnight at room temperature. The reaction mixture was neutralized with 0.5 M hydrochloric acid (400 mL), and extracted with ethyl acetate. The obtained organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (45 g).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][O:8][CH2:9][N:10]=[C:11]=[S:12].[C:13]([C:15]1[CH:20]=[CH:19][C:18]([O:21][C:22]2[CH:26]=[C:25]([CH3:27])[NH:24][N:23]=2)=[C:17]([C:28]([F:31])([F:30])[F:29])[CH:16]=1)#[N:14].Cl>C(OCC)(=O)C>[CH3:7][O:8][CH2:9][NH:10][C:11]([N:24]1[C:25]([CH3:27])=[CH:26][C:22]([O:21][C:18]2[CH:19]=[CH:20][C:15]([C:13]#[N:14])=[CH:16][C:17]=2[C:28]([F:29])([F:30])[F:31])=[N:23]1)=[S:12]
Reactant: Cc1cc(Oc2ccc(C#N)cc2C(F)(F)F)n[nH]1
Reactant: COCN=C=S
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: COCNC(=S)n1nc(Oc2ccc(C#N)cc2C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
Potassium carbonate (0.23 g, 1.7 mmol) and methoxymethyl isothiocyanate (0.15 g, 1.5 mmol) were added to a solution of 3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole (0.40 g, 1.5 mmol) in ethyl acetate (10 ml), and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate (10 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/10), to give a white solid of N-methoxymethyl-3-(4-cyano-2-trifluoromethylphenyloxy)-5-methylpyrazole-1-carbothioamide (0.18 g, yield: 32.4%) mp: 89-90° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.84 (s, 3H), 3.44 (s, 3H), 5.13 (d, J=6.2 Hz, 2H), 5.98 (m, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.84 (dd, J=2.0 and 8.7 Hz, 1H), 8.01 (d, J=2.0 Hz, 1H), 8.95-9.30 (m, 1H).
Reaction SMILES: C[O:2][C:3]([CH:5]1[CH2:10][CH2:9][N:8]([C:11]2[C:16]([Cl:17])=[CH:15][CH:14]=[CH:13][N:12]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Na+]>C1COCC1.CO>[Cl:17][C:16]1[C:11]([N:8]2[CH2:9][CH2:10][CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: COC(=O)C1CCN(c2ncccc2Cl)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1CCN(c2ncccc2Cl)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of the ester from step (a) above (1.77 g, 6.9 mmol) and 5N NaOH (4 mL) in THF/MeOH (20 mL/30 mL) mixture was stirred at room temperature for 16 h. The organic solvent was removed in vacuo, the aqueous solution was acidified with 10% HCl to pH 2 and then lyophilized to give the title compound, which was used in the next step without additional purification. MS (ESI, pos. ion) m/z: 241 (M+1).
Reaction SMILES: CO[C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([F:13])([F:12])[F:11])=[O:4].[CH3:15][O:16][P:17]([CH3:21])(=[O:20])[O:18][CH3:19]>>[CH3:15][O:16][P:17]([CH2:21][C:3]([C:5]1[CH:6]=[N:7][N:8]([CH3:14])[C:9]=1[C:10]([F:11])([F:12])[F:13])=[O:4])(=[O:20])[O:18][CH3:19]
Reactant: COC(=O)c1cnn(C)c1C(F)(F)F
Reactant: COP(C)(=O)OC
Product: COP(=O)(CC(=O)c1cnn(C)c1C(F)(F)F)OC

Procedure:
This material was obtained in analogy to example step A] from 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid methyl ester (3.3. g) and methyl-phosphonic acid dimethyl ester (3.934 g) to give [2-(1-methyl-5-trifluoromethyl-1H-pyrazol-4-yl)-2-oxo-ethyl]-phosphonic acid dimethyl ester (4.48 g) as a white solid. MS (ESI): 301.0 (MH+).