Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:5]([O:17][CH3:18])=[CH:6][C:7]([N+:14]([O-])=O)=[C:8]([CH:13]=1)[C:9]([O:11][CH3:12])=[O:10])[CH3:2].[Cl-].[NH4+]>O.CO.[Fe]>[NH2:14][C:7]1[CH:6]=[C:5]([O:17][CH3:18])[C:4]([O:3][CH2:1][CH3:2])=[CH:13][C:8]=1[C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOc1cc(C(=O)OC)c([N+](=O)[O-])cc1OC
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CO
Solvent: O
Product: CCOc1cc(C(=O)OC)c(N)cc1OC
Reaction time: 12 h

Procedure:
A mixture of 17.0 g (66.7 mmol) of methyl 5-ethoxy-4-methoxy-2-nitrobenzoate, 13.1 g (233 mmol) of powdered iron and 17.7 g (334 mmol) of ammonium chloride in 95 mL of water and 245 mL of methanol was refluxed for 4.5 h. An additional 13.1 g of iron was added followed by refluxing for 2.5 h. Then an additional 13.1 g of iron and 17.7 g of ammonium chloride was added and refluxing was continued for 12 h. The reaction was filtered through Celite and methanol was removed from the filtrate. The filtrate was extracted with chloroform and the extracts were treated with Darco, evaporated and dried in vacuo (50° C.).The yield was 11.0 g of methyl 2-amino-5-ethoxy-4-methoxybenzoate as tan crystals: mass spectrum (electrospray, m/e): M+H 225.9.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:14][C:15]2[C:16]([O:22][CH3:23])=[N:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:3]=1.[CH2:24](N(CC)CC)[CH3:25].[B-](F)(F)(F)C=C.[K+]>C(O)(C)C.O1CCCC1>[CH3:23][O:22][C:16]1[C:15]([CH2:14][N:4]2[C:5]3[C:10](=[C:9]([N+:11]([O-:13])=[O:12])[CH:8]=[CH:7][CH:6]=3)[C:2]([CH:24]=[CH2:25])=[N:3]2)=[CH:20][CH:19]=[C:18]([CH3:21])[N:17]=1
Reactant: COc1nc(C)ccc1Cn1nc(I)c2c([N+](=O)[O-])cccc21
Reactant: CCN(CC)CC
Agent: C=C[B-](F)(F)F
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)O
Product: C=Cc1nn(Cc2ccc(C)nc2OC)c2cccc([N+](=O)[O-])c12
Temperature: 90 °C
Yield: 52.7 %

Procedure:
A solution of 3-iodo-1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-1H-indazole (982 mg, 2.31 mmol) in a 4:1 mixture of isopropyl alcohol/tetrahydrofuran (10 mL) was stirred under an argon atmosphere. Argon was bubbled through the solution for 20 minutes. Triethylamine (968 μL, 6.94 mmol), 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (189 mg, 0.231 mmol) and potassium trifluoro(vinyl)borate (659 mg, 6.94 mmol) were added to the solution. The reaction mixture was heated at 90° C. for 24 hour. The mixture was allowed to cool and then filtered through Celite®, rinsing with ethyl acetate. The filtrate was concentrated under reduced pressure. The material was dissolved in ethyl acetate (50 mL), transferred to a reparatory funnel and washed with water and brine. The solution was dried over sodium sulfate, filtered and concentrated under reduced pressure. The material was purified using column chromatography on silica, eluting with 15-20% ethyl acetate in hexanes to give 1-((2-methoxy-6-methylpyridin-3-yl)methyl)-4-nitro-3-vinyl-1H-indazole (395 mg).
Reaction SMILES: [C:1]([NH2:3])#N.[C:4](OCC)(=O)[C:5](OCC)=[O:6].[CH3:14][N:15](C)[CH:16]=[O:17]>>[O:17]=[C:16]1[C:5](=[O:6])[CH:4]([C:1]#[N:3])[CH2:14][NH:15]1
Reactant: N#CN
Reactant: CCOC(=O)C(=O)OCC
Reactant: CN(C)C=O
Product: N#CC1CNC(=O)C1=O

Procedure:
Combination of the starting Benzyl-hydrazine 136 with Oxo-acetic acid ethyl ester 137 gives rise to intermediate (Benzyl-hydrazono)-acetic acid ethyl ester 138, which is chlorinated by treatment with N-chloromethyl succinamide or tertiary butoxy chloride to form intermediate 139. The combination of Intermediate 139 with vinyl benzene 140 forms the ester intermediate 1-Benzyl-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid ethyl ester 141. Saponification of the ester intermediate 141 gives rise to intermediate 1-Benzyl-5-phenyl-4,5-dihydro-1H-pyrazole-3-carboxylic acid 142 that gives rise to the cyanoamine intermediate 143 when heated to high temperatures in anhydrous dimethylformamide. Upon further reaction of intermediate 143 with diethyl oxalate 144 affords the intermediate 2,3-dioxo-4-cyanopyrrolidine 145, which forms intermediate 1-Benzyl-4-hydroxy-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid amide 146 under acidic conditions and an amino group replaces the OH group forming intermediate 4-Amino-1-benzyl-5-oxo-2-phenyl-2,5-dihydro-1H-pyrrole-3-carboxylic acid amide 147. Treatment of Intermediate 147 with dimethylformamide and sodium nitrite forms intermediate 1-Benzyl-4-imino-5-oxo-2-phenyl-4,5-dihydro-1H-pyrrole-3-carboxylic acid amide 148 and a combination with compound But-2-ynedioic acid diethyl ester 149 forms an intermediate 7-Benzyl-9-carbamoyl-6-oxo-8-phenyl-1,2,7-triaza-spiro[4.4]nona-1,3,8-triene-3,4-dicarboxylic acid diethyl ester 150, which converts to intermediate 6-Benzyl-4-carbamoyl-7-oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-2,3-dicarboxylic acid diethyl ester 151. Reflux of intermediate 151 in the presence of the acid gives rise to intermediate 6-Benzyl-7-oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-4-carboxylic acid amide 152. Heating formic acid and ammonium ion mixture in methanol and 10% Pd—C to reflux eliminates the benzyl group forming intermediate 7-Oxo-5-phenyl-6,7-dihydro-pyrazolo[1,5-c]pyrimidine-4-carboxylic acid amide 153. Reflux of 153 in phosphorous oxychloride forms intermediate 7-Chloro-5-phenyl-pyrazolo[1,5-c]pyrimidine-4-carbonitrile 154 and treatment with the appropriate amine represented as Y—NH2 results in a substitution of the chloride ion of 154 with the described amine derivative intermediate 155. Treatment of 155 with NBS forms target compound 7-Amino derivative-3-bromo-5-phenyl-pyrazolo[1,5-c]pyrimidine-4-carbonitrile 156.
Reaction SMILES: C1(N2CCN([C:13]3[N:14]=[C:15]([NH:22][C@H:23]4[CH2:27][CH2:26][CH2:25][C@@H:24]4[NH:28][C:29](=[O:35])OC(C)(C)C)[C:16]4[S:21][CH2:20][CH2:19][C:17]=4[N:18]=3)CC2)C=CC=CC=1.[CH:36]([N:39]([CH:42]([CH3:44])C)[CH2:40]C)([CH3:38])C.Cl.[Cl:46]C1N=C(NC2CCCNC2)C2SCCC=2N=1>CS(C)=O>[CH3:40][N:39]1[CH:36]=[CH:38][CH:44]=[C:42]1[C:29]([N:28]1[CH2:25][CH2:26][CH2:27][CH:23]([NH:22][C:15]2[C:16]3[S:21][CH2:20][CH2:19][C:17]=3[N:18]=[C:13]([Cl:46])[N:14]=2)[CH2:24]1)=[O:35]
Reactant: Clc1nc2c(c(NC3CCCNC3)n1)SCC2
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@@H]1Nc1nc(N2CCN(c3ccccc3)CC2)nc2c1SCC2
Agent: Cl
Solvent: CS(C)=O
Product: Cn1cccc1C(=O)N1CCCC(Nc2nc(Cl)nc3c2SCC3)C1
Temperature: 25 °C
Reaction time: 0.1 h
Yield: 85.6 %

Procedure:
0.462 g (3.7 mmol) of 1-methyl-1H-pyrrol-2-carboxylic acid (VII), 1.4 g (9.7 mmol) of O-(7-azabenzotriazol-1-yl-)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU), and 0.640 mL (3.7 mmol) of diisopropylethylamine are placed in 10 mL of dimethylsulfoxide, then stirred for 0.1 hours at ambient temperature. 0.814 g (3.0 mmol) of (2-chloro-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)piperidin-3-ylamine hydrochloride (VI) and 3.7 mmol of diisopropylethylamine are added, then the mixture is stirred for 16 hours at ambient temperature. Then the reaction mixture is suction filtered through Alox, and the mother liquor is concentrated by evaporation. The residue is combined with 1 N sodium hydroxide solution and extracted with dichloromethane. The organic phase is separated off using a phase separator and evaporated to dryness. The crude product is purified by chromatography through a Biotage silica gel cartridge 40 s with petroleum ether/ethyl acetate 1:1. 0.970 g of product VIII (85%) is obtained.
Reaction SMILES: [CH3:1][C:2]([CH3:22])([CH3:21])[CH2:3][C:4]1[N:9]=[C:8]([CH2:10]O)[CH:7]=[CH:6][C:5]=1[C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[F:20].C(N(CC)CC)C.CS([Cl:34])(=O)=O>ClCCl>[Cl:34][CH2:10][C:8]1[N:9]=[C:4]([CH2:3][C:2]([CH3:22])([CH3:21])[CH3:1])[C:5]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=2[F:20])=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2CC(C)(C)C)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(F)c(-c2ccc(CCl)nc2CC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 64.8 %

Procedure:
To a solution of (6-(2,2-dimethylpropyl)-5-(2-fluoro-5-methoxyphenyl)pyridin-2-yl)methanol (4.00 g) and triethylamine (4.00 g) in dichloromethane (20 mL) was added dropwise methanesulfonyl chloride (3.00 g) at 0° C., and the mixture was stirred at room temperature for 15 hr. Dichloromethane (150 ml) was added to the reaction mixture, and the mixture was washed with saturated brine. The organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.75 g) as a colorless oil.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.S(Cl)(Cl)=O.[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[CH2:28][CH2:27][NH:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.N>C(Cl)Cl.CO>[CH2:18]([C@@H:25]1[CH2:30][C@@H:29]([N:31]([CH2:38][C:39]2[C:48]3[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=3)[N:42]=[CH:41][CH:40]=2)[C:32](=[O:37])[C:33]([F:35])([F:36])[F:34])[CH2:28][CH2:27][N:26]1[C:6](=[O:8])[C:5]1[CH:9]=[CH:10][CH:11]=[C:3]([C:2]([F:1])([F:13])[F:12])[CH:4]=1)[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1
Reactant: O=C(N(Cc1ccnc2ccccc12)[C@H]1CCN[C@H](Cc2ccccc2)C1)C(F)(F)F
Agent: N
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1)N1CC[C@H](N(Cc2ccnc3ccccc23)C(=O)C(F)(F)F)C[C@H]1Cc1ccccc1

Procedure:
106 mg (0.56 mmol) of 3-trifluoromethylbenzoic acid are reacted in analogy to Example 2j first with 58 μl (0.795 mmol) of thionyl chloride and subsequently with 200 mg (0.468 mmol) of (2R*,4S*)-2-benzyl-N-(4-quinolylmethyl)-N-trifluoroacetyl-4-piperidinamine to give the product. TLC: methylene chloride/methanol/conc. ammonia (700:50:1) Rf =0.56, FD-MS: M+ =599.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[N:12]=[C:13]([C:16](Cl)=[O:17])[S:14][CH:15]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[F:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.C(N(CC)CC)C>C1COCC1.C(Cl)Cl>[F:19][CH:20]1[CH2:25][CH2:24][N:23]([C:16]([C:13]2[S:14][CH:15]=[C:11]([C:7]3[S:6][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[N:9][C:8]=3[CH3:10])[N:12]=2)=[O:17])[CH2:22][CH2:21]1
Reactant: FC1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2csc(C(=O)Cl)n2)s1
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1nc(C)c(-c2csc(C(=O)N3CCC(F)CC3)n2)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2′-Acetylamino-4′-methyl-[4,5′]bithiazolyl-2-carbonyl chloride, prepared as in Step I of Example 13, described above (200 mg, 0.66 mmol, 1 eq.), is dissolved in THF (8 ml) and DCM (4 ml). 4-Fluoropyperidine (Flrochem) (95.7 mg; 0.92 mmol; 1.40 eq.) and triethylamine (0.37 ml; 2.65 mmol; 4 eq.) are added and the mixture is stirred overnight at rt. Solvents are evaporated and the crude product is purified by preparative HPLC, affording Compound (48) as a white-off powder (36 mg; 13%). 1H NMR (DMSO-d6, 300 MHz) δ 1.71-2.12 (m, 4H), 2.16 (s, 3H), 2.50 (s, 3H), 3.75 (m, 2H), 4.33 (m, 2H), 4.97 (ttd, J=3, 6, 51 Hz, 1H, —CFH), 8.02 (s, 1H), 12.19 (s, 1H). M− (ESI): 367.13; M+ (ESI): 369.12. HPLC (method A), Rt: 3.04 min (purity: 95.8%).
Reaction SMILES: [C:1]([C:4]1([OH:15])[CH2:9][CH2:8][N:7]([C:10]([O:12]CC)=O)[CH2:6][CH2:5]1)(=O)[CH3:2].[C:16]([N:20]=[C:21]=[O:22])([CH3:19])([CH3:18])[CH3:17].[CH2:23](N(CC)CC)[CH3:24]>C(Cl)(Cl)Cl>[C:16]([N:20]1[C:1](=[CH2:2])[C:4]2([CH2:5][CH2:6][N:7]([C:10]([CH2:23][CH3:24])=[O:12])[CH2:8][CH2:9]2)[O:15][C:21]1=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)N=C=O
Reactant: CCN(CC)CC
Reactant: CCOC(=O)N1CCC(O)(C(C)=O)CC1
Solvent: ClC(Cl)Cl
Product: C=C1N(C(C)(C)C)C(=O)OC12CCN(C(=O)CC)CC2
Yield: 44 %

Procedure:
A mixture containing 4.3 g of 4-acetyl-1-ethoxycarbonyl-4-hydroxypiperidine, 6.0 g of tert-butyl isocyanate and 1 ml of triethylamine is refluxed under nitrogen for 6 hours. After cooling down and adding 50 ml of chloroform to the reaction mixture the organic phase is washed with water to neutral, then the solvent is evaporated under reduced pressure. The crude product obtained as evaporation residue is recrystallized from isopropyl ether to give the title substance in 44% yield, m.p.: 104°-105° C.
Reaction SMILES: [C:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1Cl)=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:21][C:22]1[C:23]([CH3:28])=[CH:24][CH:25]=[CH:26][CH:27]=1>O1CCOCC1>[C:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[CH3:28])=[CH:15][CH:14]=[CH:13][C:12]=2[O:19][CH3:20])(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: Cc1ccccc1N
Reactant: CCCCCC(=O)c1cnc2c(OC)cccc2c1Cl
Solvent: C1COCCO1
Product: CCCCCC(=O)c1cnc2c(OC)cccc2c1Nc1ccccc1C
Yield: 36.7 %

Procedure:
3-hexanoyl-4-chloro-8-methoxyquinoline (5 g, 0.071 mol) and o-toluidine (2 ml, 0.019 mol) were heated under reflux in 1,4-dioxan (50 ml) for 1 hour. The solvent was evaporated and the residue was taken up in dichloromethane, washed with 10% hydrochloric acid, water, sodium hydrogen carbonate solution and brine, dried and evaporated. Trituration with ethyl acetate/ether and recrystallisation from methanol-water gave 3-hexanoyl-4-(2-methylphenylamino)-8-methoxyquinoline as yellow needles (2.53 g, 45.3%), m.p. 94°-6° C.
Reaction SMILES: [H-].[Na+].[OH:3][CH:4]([CH2:18][OH:19])[CH2:5][CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].F[C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[N:30]1[CH:34]=[N:33][C:32]([CH3:35])=[N:31]1.C1C[O:39]CC1>>[OH:3][CH:4]([CH2:18][O:19][C:21]1[CH:26]=[C:25]([N+:27]([O-:29])=[O:28])[CH:24]=[CH:23][C:22]=1[N:30]1[CH:34]=[N:33][C:32]([CH3:35])=[N:31]1)[CH2:5][CH2:6][NH:7][C:15]([C:14]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:8]([OH:39])=[O:17])=[O:16]
Reactant: C1CCOC1
Reactant: Cc1ncn(-c2ccc([N+](=O)[O-])cc2F)n1
Reactant: O=C1c2ccccc2C(=O)N1CCC(O)CO
Agent: [H-]
Agent: [Na+]
Product: Cc1ncn(-c2ccc([N+](=O)[O-])cc2OCC(O)CCNC(=O)c2ccccc2C(=O)O)n1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Sodium hydride (0.827 g, 20.67 mmol) was suspended in THF (10 mL), and then 2-(3,4-dihydroxybutyl)isoindoline-1,3-dione (3.24 g, 13.78 mmol) in THF (20.0 mL) was added. This reaction mixture was stirred at 0° C. for 10 min, followed by the addition of 1-(2-fluoro-4-nitrophenyl)-3-methyl-1H-1,2,4-triazole (2.041 g, 9.19 mmol) in THF (16.0 mL). The mixture was stirred at 0° C. for 1 h and then stirred for an additional 2 h at rt. The reaction was quenched with water and washed with EtOAc. The aqueous layer was acidified to pH 2˜4 and then extracted with EtOAc. The combined EtOAc layers were concentrated in vacuo to get 2-(3-hydroxy-4-(2-(3-methyl-1H-1,2,4-triazol-1-yl)-5-nitrophenoxy)butylcarbamoyl)benzoic acid, which is used as-is in the next step. LC-MS (M+H)+=456.1. 1H NMR (500 MHz, methanol-d4) δ 9.31 (s, 1H), 8.15-8.01 (m, 3H), 7.86-7.76 (m, 2H), 7.51-7.46 (m, 2H), 4.43-4.42 (m, 1H), 4.29-4.27 (m, 1H), 3.91-3.87 (m, 1H), 3.63-3.47 (m, 2H), 2.47 (s, 3H), 2.05-1.98 (m, 1H), 1.87-1.84 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][O:9][CH:10]([O:12][CH2:13][CH3:14])[CH3:11].C(Br)C.[Mg].[C:19]([O:24][CH2:25][CH3:26])(=[O:23])[C:20]([O-])=[O:21]>O.C1COCC1>[CH2:13]([O:12][CH:10]([O:9][CH2:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:20](=[O:21])[C:19]([O:24][CH2:25][CH3:26])=[O:23])[CH3:11])[CH3:14]
Reactant: CCOC(C)OCc1ccccc1Br
Reactant: CCOC(=O)C(=O)[O-]
Agent: [Mg]
Solvent: C1CCOC1
Solvent: CCBr
Solvent: O
Product: CCOC(=O)C(=O)c1ccccc1COC(C)OCC
Temperature: 55 °C
Reaction time: 1 h
Yield: 68.4 %

Procedure:
A mixed solution of 1-bromo-2-(1-ethoxyethyl)oxymethylbenzene (3.11 g, 0.012 mol) and dry THF (10 ml) was added dropwise at 50 to 60° C. over 25 minutes to a solution prepared by adding dry THF (2 ml) and ethyl bromide (0.2 ml) to magnesium (0.44 g, 0.018 mol) in a stream of nitrogen. After completion of the addition, the mixture was stirred at 50 to 60° C. for 1 hour and cooled to room temperature. After cooling, the mixture was added dropwise to a mixed solution of ethyl oxalate (2.63 g, 0.018 mol) and dry THF (30 ml) at below -50° C. over 15 minutes. Then, the mixture was stirred at -50 to -60° C for 1 hour. After completion of the reaction, water (200 ml) was added, and the mixture was extracted with ether (200 ml). The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (ethyl acetate/n-hexane) to obtain ethyl 2-[2-{(1-ethoxyethyl)oxymethyl}phenyl]-2-oxoacetate (2.30 g, Yield: 68.4%) as a colorless oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C@H:5]([CH2:7][OH:8])[NH2:6].C(N(CC)CC)C.Cl[C:18](Cl)([O:20]C(=O)OC(Cl)(Cl)Cl)Cl>ClCCl>[O:20]=[C:18]1[NH:6][C@H:5]([C:4]([O:3][CH3:2])=[O:9])[CH2:7][O:8]1
Reactant: COC(=O)[C@@H](N)CO
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1COC(=O)N1
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
A solution of L-serine methyl ester hydrochloride (3.063 kg) in dichloromethane (24.1 L) at 0° C. was treated with triethylamine (5.908 kg), stirred for 30 minutes, treated with triphosgene (1.949 kg) in dichloromethane (5.356 kg) over 6.5 hours, stirred for 45 minutes, treated with hexanes (12.23 kg), stirred for 55 minutes, and filtered with ethyl acetate (16.013 kg). The filtrate was concentrated to provide a 35% (w/w) solution of the desired product (93.5%, 98% ee) in ethyl acetate. 1H NMR (300 MHz, CDCl3) δ6.55 (br s, 1H), 4.62 (dd, J=9, 9 Hz, 1H), 4.53 (dd, J=4, 9 Hz, 1H), 4.45 (dd, J=4, 9 Hz, 1H), 3.83 (s, 3H).
Reaction SMILES: CS(O[C:6]1[C:16]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:15][CH:14]=[CH:13][C:7]=1[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])(=O)=O.CO.[H][H]>[Pd].C(N(CC)CC)C>[O:17]([C:16]1[CH:6]=[C:7]([CH:13]=[CH:14][CH:15]=1)[CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: [H][H]
Reactant: CC(C(=O)O)c1cccc(Oc2ccccc2)c1OS(C)(=O)=O
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C(=O)O)c1cccc(Oc2ccccc2)c1
Yield: 95 %

Procedure:
To a solution of 33 g. of 2-methane-sulphonyloxy-3-phenoxy-hydratropic acid in 200 ml. of methanol 28 ml. of triethyl amine and 2 g. of a 5% palladium on charcoal catalyst are added at 25° C. The mixture is then hydrogenated under atmospheric pressure until a calculated amount of hydrogen is used up. The catalyst is filtered off and the solution is evaporated. The evaporation residue is taken up in water, acidified with a 20% aqueous hydrochloric acid solution and the separated oil is extracted with chloroform. The chloroform solution is evaporated after drying over sodium sulphate, and the residue is distilled off. 23 g. (95%) of 3-phenoxy-hydratropic acid are obtained, boiling at 190° C. to 192° C. (0.4 mmHg.). nD25 =1.5751. Melting point of the corresponding cyclohexylamine salt amounts to 153° C. to 154° C.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][OH:7].N1C=CN=C1.[C:13]([Si:17]([CH3:20])([CH3:19])Cl)([CH3:16])([CH3:15])[CH3:14].O>O1CCCC1.C(OCC)C>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][O:7][Si:17]([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:20])[CH3:19]
Reactant: OCCCCCBr
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OCCCCCBr
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.1 %

Procedure:
A solution of 28 g of crude 5-bromo-1-pentanol in 144 ml of tetrahydrofuran is mixed with 24 g of imidazole. Then, a solution of 30.3 g of tert-butyldimethylchlorosilane in 46 ml of tetrahydrofuran is added in drops, and it is stirred for 4 hours at room temperature. The reaction mixture is poured into water, shaken out with diethyl ether, the organic phase is washed 4 times with water, dried on sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/diethyl ether. 42 g of the title compound is obtained as a colorless liquid.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)S(O)(=O)=O.[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=1>>[CH3:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][C:24]=1[C:1]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:9]
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccc(C)cc1
Agent: O=S(=O)(O)C(F)(F)F
Product: Cc1ccc(C)c(C(=O)c2ccccc2)c1
Reaction time: 16 h

Procedure:
Benzoic acid (20 g, 0.16 mole), p-xylene (100 mL), and trifluoromethanesulfonic acid (5 mL) were heated at reflux in a 300 mL flask equipped with a Dean-Stark trap. After 16 hours, the mixture was extracted with 100 mL of 6% aqueous sodium hydroxide, washed with water, dried over magnesium sulfate and evaporated to give 15.4 g (0.073 mole) of 2,5-dimethylbenzophenone. The aqueous sodium hydroxide extract was acidified to give 8.1 g (0.066 mole) of unreacted benzoic acid.
Reaction SMILES: [CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.Br[CH2:15][CH2:16][CH3:17]>>[CH3:1][NH:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH2:9][N:10]([CH2:15][CH2:16][CH3:17])[CH2:11][CH2:12][CH:13]=2)[N:7]=1
Reactant: CCCBr
Reactant: CNc1nc(-c2cccnc2)cs1
Product: CCCN1CCC=C(c2csc(NC)n2)C1
Yield: 65 %

Procedure:
The procedure described in Example 1 was repeated, using the N-methyl-4-(3-pyridinyl)-2-thiazolamine prepared in Example 14 and an excess of 1-bromopropane as the reactants. The title compound was purified by column chromatography (65% yield) and converted to its HCl salt by the procedure of Example 2. The resulting salt (mp 138° C.) contained 1.25 molecules of HCl and one molecule of water.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:11][C:12]1[CH:13]=[C:14]([CH:17]=[CH:18][CH:19]=1)[C:15]#[N:16])([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: N#Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#Cc1cccc(Oc2ccccc2[N+](=O)[O-])c1
Temperature: 60 °C
Reaction time: 3 h
Yield: 99.2 %

Procedure:
To a solution of 2-fluoro nitrobenzene (1.41 g, 10 mmol, 1.0 equiv) and 3-hydroxybenzonitrile (1.19 g, 1.0 equiv) in 10 mL of DMF was added K2CO3 (2.76 g, 2 equiv). After stirring at 60° C. for 3 h, the mixture was diluted with EtOAc and washed with H2O. The organic layer was dried over MgSO4, filtered and evaporated to give 3-(2-nitrophenoxy)benzonitrile (2.38 g, 99%). MS found for C13H9N2O3 (M+H)+: 241.