Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([N:7]([CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:8][CH2:9]Cl)[CH3:6])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(O)(=O)C>C1COCC1>[CH2:1]([O:3][C:4]([C:5]1([CH3:6])[CH2:9][CH2:8][N:7]1[CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:18])[CH3:2]
Reactant: CCOC(=O)C(C)N(CCCl)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCOC(=O)C1(C)CCN1Cc1ccccc1
Temperature: -76 °C
Reaction time: 1 h
Yield: 79.1 %

Procedure:
A solution of 2-[benzyl-(2-chloro-ethyl)-amino]-propionic acid ethyl ester (27.4 g, 1 eq.) in 253 mL of dry THF was cooled to −78° C. under argon. KHMDS (15% w/w in toluene, 170.40 g, 1.25 eq.) was slowly added so that temperature was kept below −76° C. The reaction was stirred for 1 h at −76° C., then warmed to 20° C. and stirred for 1 h. Acetic acid (1.74 mL, 0.3 eq.) was added and the reaction was stirred at 20° C. for 10 min. The reaction was quenched with 50 mL of a saturated aqueous solution of NaHCO3 and partially concentrated under reduced pressure. The crude was extracted three times with DCM. The organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with heptane/EtOAc 100/0 to 90/10) to afford 1-benzyl-2-methyl-azetidine-2-carboxylic acid ethyl ester (18.75 g, yield=79%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](O)=[O:28])=[C:10]1[C:30]([O:32][CH2:33][CH3:34])=[O:31].Cl.[NH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH:22]2[C:27](=[O:28])[NH:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CCOC(=O)CN
Agent: Cl
Product: CCOC(=O)CNC(=O)C1COCCN1CC1=C(C(=O)OCC)C(c2ccc(F)cc2Br)N=C(c2nccs2)N1
Yield: 47 %

Procedure:
4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine-3-carboxylic acid (0.5 g, 0.9 mmol) was reacted with ethyl 2-aminoacetate hydrochloride (0.15 g, 1.1 mmol) according to the procedure as described in Example 53 to give the title compound as a yellow solid (0.27 g, 47%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=[O:11])=O)=[CH:4][CH:3]=1.S(Cl)([Cl:21])=O>CN(C=O)C>[Cl:21][C:6]1([C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:8]2[C:9](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:10](=[O:12])[O:11]1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccccc1C(=O)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Product: O=C1OC(Cl)(c2ccc(Cl)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 100 %

Procedure:
Distilled THF (25 mL) was added to 2-(4-chlorobenzoyl)benzoic acid (1 g, 3.8 mmol) followed by thionyl chloride (0.55 mL, 7.6 mmol) and a catalytic amount of DMF (3 drops). The system was stirred under nitrogen for 4 h at room temperature and monitored by TLC. Removal of the solvent gave 3-chloro-3-(4-chlorophenyl)-3H-isobenzofuran-1-one as a colourless oil (1.06 g, 3.8 mmol, 100%).
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]1[O:14][C:13](=[O:15])[N:12]([C:16]2[CH:21]=[CH:20][C:19]([C:22]3[CH:27]=[CH:26][C:25]([N:28]4[CH2:32][C@H:31]([CH2:33][N:34]5[CH:38]=[C:37]([CH3:39])[N:36]=[N:35]5)[O:30][C:29]4=[O:40])=[CH:24][CH:23]=3)=[CH:18][CH:17]=2)[CH2:11]1)(C(C)(C)C)(C)C.[F-:41].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[F:41][C:23]1[CH:24]=[C:25]([N:28]2[CH2:32][C@H:31]([CH2:33][N:34]3[CH:38]=[C:37]([CH3:39])[N:36]=[N:35]3)[O:30][C:29]2=[O:40])[CH:26]=[CH:27][C:22]=1[C:19]1[CH:20]=[CH:21][C:16]([N:12]2[CH2:11][C@H:10]([CH2:9][OH:8])[O:14][C:13]2=[O:15])=[CH:17][CH:18]=1
Reactant: [F-]
Reactant: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(N5C[C@H](CO[Si](C)(C)C(C)(C)C)OC5=O)cc4)cc3)C(=O)O2)nn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: Cc1cn(C[C@H]2CN(c3ccc(-c4ccc(N5C[C@H](CO)OC5=O)cc4)c(F)c3)C(=O)O2)nn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(5R)-5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-(4′-{(5R)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-2-oxo-1,3-oxazolidin-3-yl}-1,1′-biphenyl-4-yl)-1,3-oxazolidin-2-one (0.016 g, 0.030 mM) was suspended in tetrahydrofuran (0.5 ml) and a 1N solution of tetrabutylammoniumfluoride in tetrahydrofuran (0.03 ml) was added. The reaction was stirred at room temperature for one hour. The cloudy suspension was concentrated as a white residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@:15]3(C)[CH2:20][C:19](=[O:21])[N:18]([CH3:22])[C:17](=[N:23]C(=O)OC(C)(C)C)[NH:16]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1.[C:32](O)([C:34](F)(F)F)=O.C(Cl)Cl>>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C@@:15]3([CH2:32][CH3:34])[NH:16][C:17](=[NH:23])[N:18]([CH3:22])[C:19](=[O:21])[CH2:20]3)[CH:12]=[CH:13][CH:14]=2)[C:5]([OH:8])=[CH:6][CH:7]=1
Reactant: CN1C(=O)C[C@@](C)(c2cccc(-c3cc(Cl)ccc3O)c2)NC1=NC(=O)OC(C)(C)C
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC[C@@]1(c2cccc(-c3cc(Cl)ccc3O)c2)CC(=O)N(C)C(=N)N1
Yield: 60 %

Procedure:
(S)-tert-butyl 4-(3-(3-chloro-6-hydroxyphenyl)phenyl)-1,4-dimethyl-6-oxo-tetrahydropyrimidin-2(1H)-ylidenecarbamate (CF3; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) (23 mg, 0.05 mmol) was treated with 1 mL of 30% TFA/CH2Cl2 at RT for 30 min. The volatiles were removed in vacuo. The residue was redissolved in acetonitrile (5 mL) and evaporated again to afford 17 mg of the crude product as a yellow solid. The crude product was purified via reverse phase HPLC to provide 10 mg (60%) of (S)-6-(3-(3-chloro-6-hydroxy-phenyl)phenyl)-6-ethyl-2-imino-3-methyl-tetrahydropyrimidin-4(1H)-one (CF4; R1=R6=Me, R21=3-chloro-6-hydroxyphenyl) as a white solid. 1H NMR (CDCl3, 300 MHz): 11.4 (br s, 1H), 7.6-4.25 (m, 3H), 7.24-6.84 (m, 3H), 3.68 (br s, 1H), 5.18 (br s, 1H), 3.39 (d, J=16.1 Hz, 1H), 3.20 (s, 3H), 2.95 (d, J=15.8 Hz, 1H), 1.74 (s, 3H). MS (ESI): MH+=344.1. HPLC (A) Rt=5.07 min.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C1(S([N:19]2[C:23]3=[N:24][CH:25]=[CH:26][CH:27]=[C:22]3[C:21]([C:28]3[CH:33]=[CH:32][N:31]=[C:30](Cl)[N:29]=3)=[CH:20]2)(=O)=O)C=CC=CC=1>>[CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH:4][C:30]1[N:29]=[C:28]([C:21]2[C:22]3[C:23](=[N:24][CH:25]=[CH:26][CH:27]=3)[NH:19][CH:20]=2)[CH:33]=[CH:32][N:31]=1
Reactant: Cc1cccc(C)c1N
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2ccnc(Cl)n2)c2cccnc21
Product: Cc1cccc(C)c1Nc1nccc(-c2c[nH]c3ncccc23)n1
Yield: 40 %

Procedure:
Using the procedure of example 1, 2,6-dimethylaniline (98 mg) was reacted with compound 1f (100 mg) to provide compound 35 (34 mg, 40%). 1H NMR (400 MHz, CD3OD) δ 8.40 (d, J=8.0 Hz, 1H), 8.21 (d, J=4.8 Hz, 1H), 8.19 (s, 1H), 8.17 (d, J=5.2 Hz, 1H), 7.50 (d, J=7.2 Hz, 1H), 7.35 (d, J=7.2 Hz, 1H), 7.14 (d, J=5.2 Hz, 2H), 7.03 (t, J=5.2 Hz, 1H), 2.36 (s, 6H). MS (ESI) m/z: 316 (M+H)+.
Reaction SMILES: Cl[S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3].[NH2:22][C:23]1[O:27][N:26]=[C:25]([CH3:28])[C:24]=1[Br:29]>>[Br:29][C:24]1[C:25]([CH3:28])=[N:26][O:27][C:23]=1[NH:22][S:2]([C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]2[O:18][CH2:19][O:20][C:14]=2[C:13]=1[Cl:21])(=[O:4])=[O:3]
Reactant: Cc1noc(N)c1Br
Reactant: O=S(=O)(Cl)c1ccsc1COc1ccc2c(c1Cl)OCO2
Product: Cc1noc(NS(=O)(=O)c2ccsc2COc2ccc3c(c2Cl)OCO3)c1Br
Yield: 47 %

Procedure:
N-(4-bromo-3-methyl-5-isoxazolyl)-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene-3-sulfonamide was prepared in the same manner as described in Example 1 by reaction of 3-chlorosulfonyl-2-[(2-chloro-3,4-methylenedioxyphenoxy)methyl]thiophene with 5-amino-4-bromo-3-methylisoxazole, 47% yield, m.p. 152-154° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][OH:17])=[CH:10][CH:9]=1.C(N(CC)CC)C>ClCCl>[CH3:1][S:2]([O:17][CH2:16][CH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=1)(=[O:4])=[O:3]
Reactant: COc1ccc(CCCO)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(CCCOS(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanesulfonyl chloride (31 mL) was added dropwise to a solution of 3-(4-methoxyphenyl)-1-propanol (50 g) and triethylamine (56 mL) in dichloromethane (800 mL) at 0° C. The resulting mixture was stirred overnight at room temperature. After washing with water, 2% hydrochloric acid and 4% aqueous sodium bicarbonate, the organic solution was dried over sodium sulfate and rotoevaporated to yield crude 3-(4-methoxyphenyl)-1-propyl methanesulfonate as a colourless solid (ca. 83 g). This product and sodium iodide (75 g) in acetone (800 mL) were heated at reflux in the dark for 20 hours. After cooling to room temperature, the reaction mixture was poured into n-hexane/EtOAc/water 1:1:1 (1.5 L) under stirring. The organic layer was washed with water, diluted aqueous sodium metabisulfite and 4% aqueous sodium bicarbonate, then dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by passing it through a short pad of silica gel (eluting with n-hexane/EtOAc 95:5). The title compound was obtained as a pale yellow solid (75 g).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N1CCCCC1>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:39]([NH2:41])=[O:40])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]5[CH2:35][CH2:36][O:4][CH2:37][CH2:38]5)[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCCC5)c4)cc23)CC1
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN5CCOCC5)c4)cc23)CC1
Yield: 14.9 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[5-(1-pyrrolidinylmethyl)-3-thienyl]-1H-indole-7-carboxamide trifluoroacetate, substituting morpholine (70 mg, 0.670 mmol) for piperidine to afford 6.3 mg of the title compound (14.9%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH:8]=[CH:7]2)([O-])=O.C([O-])=O.[NH4+]>CO>[NH2:1][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1)[CH:8]=[CH:7]2
Reactant: O=[N+]([O-])c1ccc2c(ccn2C2CCCCO2)c1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Nc1ccc2c(ccn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
17 g of 5-nitro-1-tetrahydropyran-2-ylindole are dissolved in 170 ml of methanol and then 3 g of 10% Pd-on-charcoal and then, portionwise at 0° C., 20.6 g of ammonium formate are added. After stirring for 1 hour 30 at room temperature, the reaction mixture is filtered and the filtrate is evaporated to dryness. The residue is taken up in 300 ml of ethyl acetate. The solution is washed with 800 ml of water, dried over sodium sulphate and evaporated to dryness. 14.2 g of 5-amino-1-tetrahydropyran-2-ylindole are obtained in the solid form. A sample is purified by chromatography on a column of silica gel eluted with a 3/1 (v/v) cyclohexane/ethyl acetate mixture, to provide (Compound 29). 1H NMR (DMSO): 1.30-2.20 (m, 6H), 3.59-3.93 (m, 2H), 4.72 (m, 2H), 5.41 (dd, J=1.8, 12.0, 1H), 6.16 (d, J=3.2, 1H), 6.52 (dd, J=2.0, 8.6, 1H), 6.66 (d, J=2.0, 1H), 7.20 (d, J=8.6, 1H), 7.27 (d, J=3.2, 1H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11](=[O:18])(OCC)[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].P(Cl)(Cl)(Cl)(Cl)[Cl:20]>C(Cl)Cl.C(Cl)(Cl)(Cl)Cl>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][P:11]([Cl:20])(=[O:18])[O:12][CH2:13][CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOP(=O)(Cl)Cc1ccc([N+](=O)[O-])cc1
Temperature: 30 °C
Reaction time: 24 h
Yield: 84.3 %

Procedure:
This method is a modification of that outlined by Doak and Freedman (Ref. 178). Diethyl (p-nitrophenyl)methylphosphonate (7.16) (1.0 g, 3.6 mmol) in DCM (10 ml) was added dropwise to a solution of PCl5 (0.9 g, 4.32 mmol) in CCl4 (20 ml) under an inert atmosphere. The reaction was stirred at 30° C. and the progress of the chlorination was followed by 31P NMR which showed the reaction was complete after 24 h. Solvent and phosphoryl chloride were removed in vacuo to yield a pale yellow, moisture-sensitive oil (0.8 g, 90%) which was used without further purification. δH (250 MHz, CDCl3) 1.40 (3H, t, J 7.5 Hz, CH3), 3.60 (2H, d, 2JPH 22.5 Hz, Ar--CH2), 4.25-4.43 (2H, m, JHP 8.5 Hz, J 7.5 Hz,CH2), 7.5 (2H, d, J 7.5 Hz, Ar--H), 8.20 (2H, d, J 7.5 Hz, Ar--H); δP (101 MHz, CDCl3) 35.94 (s).
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])=[CH:5][C:6]=1[C:7]1[S:11][C:10]([NH:12][C:13](=[O:15])[CH3:14])=[N:9][C:8]=1[CH3:16].C([Li])CCC.O>C1COCC1>[CH3:16][C:8]1[N:9]=[C:10]([NH:12][C:13](=[O:15])[CH3:14])[S:11][C:7]=1[C:6]1[CH:5]=[C:4]([S:17]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)(=[O:19])=[O:18])[S:3][CH:2]=1
Reactant: CC(=O)Nc1nc(C)c(-c2cc(S(=O)(=O)N3CCOCC3)sc2Br)s1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)Nc1nc(C)c(-c2csc(S(=O)(=O)N3CCOCC3)c2)s1
Temperature: -70 °C
Reaction time: 0.42 h
Yield: 64.5 %

Procedure:
N-{ 5-[2-bromo-5-(morpholin-4-ylsulfonyl)-3-thienyl]-4-methyl-1,3-thiazol-2-yl}acetamide (54 mg; 0.12 mmol; 1 eq) is dissolved in dry THF (5 ml) at −70° C. under an inert atmosphere. n-Butyllithium (0.16 ml; 1.6 M; 0.26 mmol; 2.20 eq) is added slowly and reaction stirred at −70° C. for 25 minutes before being hydrolyzed with water (0.3 ml). Crude material is warmed up to room temperature before being concentrated to dryness. Residue is then taken up with water (2 ml) and EtOAc (10 ml). The organic phases are decanted, dried over MgSO4, filtrated and evaporated. Crude material is purified by flash chromatography on silica gel using cyclohexane/EtOAc (10/90) as eluent, affording expected Compound (46) as an oil (30 mg; 67%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.[CH2:16]=[O:17]>C(O)C>[OH:17][CH2:16][N:11]1[C:10](=[O:13])[CH:9]=[CH:8][C:7]([O:6][C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=2)=[N:12]1
Reactant: O=c1ccc(Oc2ccc(Cl)cc2)n[nH]1
Reactant: C=O
Solvent: CCO
Product: O=c1ccc(Oc2ccc(Cl)cc2)nn1CO
Reaction time: 1 h

Procedure:
Into a solution, at reflux, of 7 g 6-(4-chlorophenoxy)-3-pyridazinone in 100 ml ethanol, there are poured 30 ml of a 20% aqueous formaldehyde solution, and then after 1 hour a further 30 ml. After refluxing for 3 hours, the solution is concentrated to half, and 100 ml water are introduced into the mixture from which 4.5 g of final product are extracted in chloroform. After recrystallisation from benzene, the product melts at 162° C. (with decomposition)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:35][CH3:36])=[C:6]([S:8]([N:11]2[C:16]3[CH:17]=[C:18]([C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=[O:29])=[C:26]([O:33][CH3:34])[CH:25]=4)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])[CH:7]=1.[CH2:37](OC(=O)C1C=CC(N)=CC=1OC)[CH3:38]>>[CH2:37]([O:29][C:28](=[O:30])[C:27]1[CH:31]=[CH:32][C:24]([NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]3[O:14][CH2:13][CH2:12][N:11]([S:8]([C:6]4[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[O:35][CH3:36])(=[O:10])=[O:9])[C:16]=3[CH:17]=2)=[O:22])=[CH:25][C:26]=1[O:33][CH3:34])[CH3:38]
Reactant: CCOC(=O)c1ccc(N)cc1OC
Reactant: COc1cc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)ccc1C(=O)O
Product: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)N(S(=O)(=O)c2cc(Cl)ccc2OC)CCO3)cc1OC

Procedure:
4-{[4-(5-Chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoic acid, MS (ISP): m/e=531.0 (M−H), was prepared as described in example 1, steps 1 to 6. Step 5 was performed using 4-amino-2-methoxy-benzoic acid ethyl ester and yielded 4-{[4-(5-chloro-2-methoxy-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazine-6-carbonyl]-amino}-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step 6.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=[N:11][OH:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:13][CH2:14][CH2:15]Br.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:13][CH2:14][CH2:15][O:12][N:11]=[C:4]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH2:3][O:2][CH3:1]
Reactant: COCC(=NO)c1ccccc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCC(=NOCCBr)c1ccccc1

Procedure:
A mixture of the above oxime (5.5 g, 33 mmol), 1,2-dibromoethane (50 ml), potassium carbonate (12.4 g, 90 mmol) and acetone (100 ml) was heated at reflux for 24 h. The mixture was filtered and the solvent was evaporated from the filtrate in vacuo. The residue was purified by column chromatography on silica gel (80 g, n-heptane/ethyl acetate 20/1) to give 6.6 g of 2-methoxyacetophenone O-(2-bromoethyl)oxime.
Reaction SMILES: [CH2:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16]([CH2:18][CH:19]2[CH2:21][CH2:20]2)=O)=[C:10]([Cl:24])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:34])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([C:8]1[CH:23]=[CH:22][C:11]([O:12][CH2:13][CH2:14][NH:15][C:16](=[S:34])[CH2:18][CH:19]2[CH2:21][CH2:20]2)=[C:10]([Cl:24])[CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CC1CC1)NCCOc1ccc(Cc2ccccc2)cc1Cl
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: S=C(CC1CC1)NCCOc1ccc(Cc2ccccc2)cc1Cl
Reaction time: 0.33 h
Yield: 89 %

Procedure:
A mixture of 500 mg (1.52 mmol) of N-[2-(4-benzyl-2-chlorophenoxy)ethyl]-cyclopropane carboxyamide, 614 mg (1.52 mmol) of a Lawesson's reagent and 20 ml of anhydrous toluene was refluxed by heating with stirring. After 20 minutes, the reaction mixture was cooled and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give 487 mg of N-[2-(4-benzyl-2-chlorophenoxy)ethyl]-cyclopropane thiocarboxyamide as a colorless oily substance nD23.6 1.6041). After one week, the oily substance caked as a white solid (m.p. 90°-92° C. .
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[C:11]([I:12])[C:3]=12.[H-].[Na+].Cl[CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21]>O1CCCC1>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]2[N:9]([CH2:16][O:17][CH2:18][CH2:19][Si:20]([CH3:23])([CH3:22])[CH3:21])[CH:10]=[C:11]([I:12])[C:3]=12
Reactant: C[Si](C)(C)CCOCCl
Reactant: Fc1cnc2[nH]cc(I)c2c1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1cc(I)c2c(Cl)c(F)cnc21
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of Example 263A (2.8 g, 9.44 mmol) in tetrahydrofuran (200 mL) was cooled to 0° C. and sodium hydride (0.34 g, 14.17 mmol) was added. The mixture was stirred at 0° C. for 30 minutes and (2-(chloromethoxy)ethyl)trimethylsilane (2.5 mL, 14.17 mmol) was added. The mixture was warmed to room temperature, stirred for 2 hours, quenched with brine and extracted with ethyl acetate (twice). The organic phase was concentrated and purified by flash chromatography (silica gel, 30% ethyl acetate in hexane) to afford the title compound. MS (ESI+) m/z 427 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:29])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][C@@H:17]([NH:20]C(=O)OC(C)(C)C)[C@@H:16]([OH:28])[CH2:15]2)=[N:4][CH:3]=1.[ClH:30]>C(Cl)Cl.O1CCOCC1>[ClH:30].[ClH:30].[NH2:20][C@@H:17]1[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]2[C:10]3[C:5](=[N:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH:6]=[CH:7][C:8]2=[O:29])[CH2:15][C@@H:16]1[OH:28]
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@@H]1O
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: N[C@@H]1CCN(CCn2c(=O)ccc3ncc(F)cc32)C[C@@H]1O
Reaction time: 2 h

Procedure:
1,1-Dimethylethyl {(3S,4R)-1-[2-(7-fluoro-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl]-3-hydroxy-4-piperidinyl}carbamate (310 mg, 0.7627 mmol) was dissolved in DCM (1 ml) and the solution was treated with 4M hydrogen chloride in 1,4-dioxane (1 ml). Effervescence and formation of a precipitate was observed. After 2 h, the solvents were removed under reduced pressure and the residue was dried under reduced pressure overnight, to give 1-{2-[(3S,4R)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-fluoro-1,5-naphthyridin-2(1H)-one dihydrochloride as an off-white solid (253 mg).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([N:8]2[C:12](=[O:13])[CH2:11][S:10][C:9]2=[O:14])[CH2:4][CH2:3]1.[F:15][C:16]([F:40])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:38])([F:37])[F:36])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25]([CH:29]=O)=[CH:26][CH:27]=2)[CH:22]=[N:21]1>>[F:40][C:16]([F:15])([F:39])[C:17]1[CH:34]=[C:33]([C:35]([F:36])([F:37])[F:38])[CH:32]=[CH:31][C:18]=1[CH2:19][N:20]1[C:28]2[C:23](=[CH:24][C:25](/[CH:29]=[C:11]3/[C:12](=[O:13])[N:8]([N:5]4[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]4)[C:9](=[O:14])[S:10]/3)=[CH:26][CH:27]=2)[CH:22]=[N:21]1
Reactant: CN1CCN(N2C(=O)CSC2=O)CC1
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1
Product: CN1CCN(N2C(=O)S/C(=C\c3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)C2=O)CC1

Procedure:
(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(4-methylpiperazin-1-yl)-1,3-thiazolidine-2,4-dione was prepared from 3-(4-methylpiperazin-1-yl)-thiazolidine-2,4-dione (from Example 349) and [2,4-bis(trifluoromethyl)benzyl]-1H-indazol-5-carbaldehyde (from Example 6) following General Procedure E.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:10]([O:8][C:7](=[O:9])[C@H:2]([CH2:3][CH:4]([CH3:6])[CH3:5])[NH2:1])[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCCCCCCCO
Reactant: CC(C)C[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)[C@@H](N)CC(C)C
Yield: 97.4 %

Procedure:
L-Leucine (5.0 g, 0.038 mol), 1-octanol (5.0 g, 0.038 mol) and p-toluenesulfonic acid monohydrate (8.0 g, 0.042 mol) were suspended in toluene (200 ml) in a flask equipped with a Dean-Stark trap and refluxed for 20 h. Subsequently, the solvent was removed in vacuo and the remaining white solid was dissolved in CHCl3 (150 ml). This solution was extracted with 10%1/sodium carbonate, water and brine and dried Over MgSO4, Evaporation of the solvent in vacuo yielded a colourless oil (9.0 g, 0.037 mol, 97%). 1H NMR (CDCl3): δ=4.18 (t, 2H, 3J=7.0 Hz), 3.63 (dd, 1H, 3JAB=8.4 Hz, 3JAB=5.9 Hz), 1.85 (m, 1H), 1.74-3.18 (m, 6H), 1.37 (s, 10H, 0.99 (t's, 9H); 13C NMR (CDCl3): δ=176.98, 64.82, 52.79, 44.06, 31.64, 29.04, 28.47, 25.76, 24.66, 22.81, 22.51, 21.77, 13.96