Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[F:10].C([Li])CCC.CN(C)[CH:18]=[O:19].[Cl-].[NH4+]>O1CCCC1>[F:10][C:3]1[CH:4]=[C:5]([O:8][CH3:9])[CH:6]=[CH:7][C:2]=1[CH:18]=[O:19]
Reactant: COc1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: COc1ccc(C=O)c(F)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-bromo-2-fluoro-4-methoxybenzene (3.02 g) in tetra hydrofuran (75 mL) was added n-butyl lithium (2.71 mol/L n-hexane solution, 6.0 mL) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. To this mixture was added N,N-dimethylformamide (1.7 mL) at the same temperature, and the mixture was stirred under ice-cooling for 1 hour. The reaction mixture was poured into a saturated aqueous ammonium chloride solution, and the resulting mixture was extracted with diethyl ether. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=8/1-4/1) to give 2-fluoro-4-methoxybenzaldehyde (1.54 g). The title compound was prepared in a similar manner to that described in Reference Example 45 using this material instead of 4-isobutylbenzaldehyde.
Reaction SMILES: [SH:1][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21]Cl>C(O)C>[Cl:18][C:19]1[CH:26]=[CH:25][CH:24]=[CH:23][C:20]=1[CH2:21][S:1][C:2]1[S:3][C:4]([C:7]([F:10])([F:9])[F:8])=[N:5][N:6]=1
Reactant: FC(F)(F)c1nnc(S)s1
Reactant: ClCc1ccccc1Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: FC(F)(F)c1nnc(SCc2ccccc2Cl)s1
Yield: 64.4 %

Procedure:
9.3 g (0.05 mole) of 2-mercapto-5-trifluoromethyl-1,3,4-thiadiazole, 5.1 g (0.05 mole) of triethylamine and 8.1 g (0.05 mole) of o-chlorobenzyl chloride in 80 ml of absolute ethanol were stirred for 2 hours under nitrogen at 50° C and then poured onto ice. The precipitate was filtered off and purified by low temperature crystallization from petroleum ether. 10 g (64% of theory) of 2-(o-chlorobenzylthio)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 36°-37° C were obtained. A solution of 9.8 g (0.048 mole) of m-chloroperbenzoic acid (85% pure) in 85 ml of methylene chloride was added dropwise to 5 g (0.016 mole) of the above compound in 10 ml of methylene chloride. The mixture was stirred for 4.5 hours under reflux and then mixed successively with a solution of 6.4 g of sodium sulfite in a little water, followed by a solution of 2.7 g of sodium carbonate in a little water, and stirred thoroughly for 15 minutes. The organic phase, after concentration and recrystallization from cyclo-hexane/ethyl acetate, gave colorless crystals. 4.8 g (87% of theory) of 2-(o-chlorobenzylsulfonyl)-5-trifluoromethyl-1,3,4-thiadiazole of melting point 103° C were obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:15]2[C:6](=[N:7][C:8]3[CH2:9][CH2:10][CH2:11][CH2:12][C:13]=3[N:14]=2)[C:5]([CH3:17])([CH3:16])[CH2:4][CH2:3]1.[OH2:19]>C(O)(=O)C>[CH3:1][C:2]1([CH3:18])[CH2:3][CH2:4][C:5]([CH3:17])([CH3:16])[C:6]2[N:7]=[C:8]3[C:13]([CH2:12][CH2:11][CH2:10][C:9]3=[O:19])=[N:14][C:15]1=2
Reactant: O
Reactant: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3
Solvent: CC(=O)O
Product: CC1(C)CCC(C)(C)c2nc3c(nc21)CCCC3=O
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
8.0 g of 1,2,3,4,6,7,8,9-octahydro-1,1,4,4-tetramethylphenazine was dissolved in 30 ml of acetic acid, followed by the dropwise addition of a solution of 4.9 g of chromic acid anhydride in acetic acid (30 ml)/water (4 ml) The obtained mixture was stirred at 80° C. for 30 minutes, cooled by allowing to stand, and poured into water, followed by the extraction with ethyl acetate. The organic phase was washed with a saturated aqueous solution of sodium hydrogencarbonate and a saturated aqueous solution of common salt, dried over anhydrous magnesium sulfate and concentrated in a vacuum. The obtained residue was purified by silica gel chromatography (developer: 20% ethyl acetate/hexane) to give 1.6 g of the title compound as a brown oil.
Reaction SMILES: [F:1][CH2:2][C:3]1[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][N:4]=1.Br[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[F:18]>>[F:1][CH2:2][C@@:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[C@H:7]2[CH2:8][O:9][CH2:10][C@H:6]2[O:5][NH:4]1
Reactant: FCC1=NO[C@@H]2COC[C@H]12
Reactant: Fc1ccccc1Br
Product: FC[C@]1(c2ccccc2F)NO[C@@H]2COC[C@@H]21

Procedure:
Intermediate VI-2: Starting from (3aS,6aS)-rel-3-fluoromethyl-3a,4,6,6a-tetrahydro-furo[3,4-d]isoxazole and 1-bromo-2-fluorobenzene, the product (3S,3aS,6aS)-rel-3-fluoromethyl-3-(2-fluoro-phenyl)-hexahydro-furo[3,4-d]isoxazole was obtained as a light yellow oil. MS: m/z=242.1 [M+H]+.
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1.[C:12]([Si](C)(C)C)#[CH:13]>CO>[C:12]([C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][CH:3]=1)#[CH:13]
Reactant: Brc1cnnc2ccccc12
Reactant: C#C[Si](C)(C)C
Solvent: CO
Product: C#Cc1cnnc2ccccc12

Procedure:
The title compound can be synthesized from 4-ethynylcinnoline and N-(3-cyclopropyl-4-((4-methylpiperazin-1-yl)methyl)phenyl)-3-iodo-4-methylbenzamide in a manner similar to that described for Example 1 (nitro reduction performed in a manner similar to that described for Example 10; 0.25M in MeOH/10% AcOH). 4-ethynylcinnoline is prepared from 4-bromocinnoline and ethynyltrimethylsilane according to the 2 steps procedure described in Example 1.
Reaction SMILES: [CH3:1]I.[OH:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH:7]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[H-].[Na+].[Na+].[Cl-]>CN(C)C=O>[CH3:1][O:3][CH2:4][CH2:5][N:6]1[C:10](=[O:11])[CH:9]([CH3:12])[S:8][CH:7]1[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC1SC(c2cccnc2)N(CCO)C1=O
Reactant: CI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)C(C)SC1c1cccnc1
Reaction time: 1 h
Yield: 48.1 %

Procedure:
Methyl iodide (0.72 g, 5.0 mmol) was added to a solution of 3-(2-hydroxyethyl)-5-methyl-2-(3-pyridyl)-thiazolidin-4-one (1 g, 4.2 mmol) in dry dimethylformamide (5 ml), and 40% sodium hydride (176 mg, 4.4 mmol) was added in limited amounts of the mixture under cooling with ice. Then, cooling with ice was continued for 1 hour. The product mixture was poured into aqueous NaCl, and extracted with ethyl acetate. The extract was washed with water, dried over anhydrous Na2SO4, and filtered. The filtrate was concentrated and subjected to medium-pressure chromatography (hexane-acetone), giving 3-(2-methoxyethyl)-5-methyl-2-(3-pyridyl)-thiazolidin-4-one (0.51 g, 48% yield). NMR (CDCl3) δ [ppm]; 1.62 (0.75 H, d, J=7.1 Hz), 1.66 (2.5 H, d, J=7.1 Hz), 3.28 (2.25 H, s), 3.3 (0.75 H, s), 5.85 (1 H, s) IR (CHCl3) [cm-1 ]; 2935, 1670, 1589, 1576, 1445, 1408, 1300, 1113.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:22])([F:21])[F:20])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1.O.C1(N=C=NC2CCCCC2)CCCCC1.[CH3:39][CH:40]([SH:42])[CH3:41]>ClCCl>[Cl:1][C:2]1[CH:18]=[C:17]([C:19]([F:20])([F:22])[F:21])[CH:16]=[CH:15][C:3]=1[O:4][C:5]1[CH:6]=[C:7]([CH2:11][C:12]([S:42][CH:40]([CH3:41])[CH3:39])=[O:14])[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reactant: CC(C)S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Solvent: O
Product: CC(C)SC(=O)Cc1cccc(Oc2ccc(C(F)(F)F)cc2Cl)c1
Reaction time: 6 h
Yield: 41.2 %

Procedure:
3.3 g of 3-(2'-chloro-4'-trifluoromethylphenoxy)phenylacetic acid was dissolved in 30 ml of dichloromethane, and the resulting solution was cooled to below 10° C. on the water bath. Then, 2.1 g of N,N'-dicyclohexylcarbodiimide (DCC) was added, followed by addition of 0.8 g of 2-propanethiol. The reaction was allowed to proceed at room temperature for about 6 hours. After completion of the reaction, the formed solid substance was filtered off, and the filtrate was subjected to evaporation-removal of the solvent under reduced pressure to obtain a crude product. The thus obtained crude product was subjected to purification by the silica gel column chromatography (elution was performed by using a mixed solvent of toluene and n-hexane). As a result, there was obtained 1.6 g of S-1-methylethyl 3-(2'-chloro-4'-trifluoromethylphenoxy)-phenylthioacetate.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[N:7][C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])=[N:9]2)=[CH:4][CH:3]=1.[OH:25][CH:26]([C:30]#[CH:31])[C:27](O)=[O:28].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>C(Cl)Cl>[OH:25][CH:26]([C:30]#[CH:31])[C:27]([N:22]1[CH2:23][CH2:24][N:19]([C:6]2[C:5]3[C:10](=[CH:11][C:2]([CH3:1])=[CH:3][CH:4]=3)[N:9]=[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[OH:18])[N:7]=2)[CH2:20][CH2:21]1)=[O:28]
Reactant: Cc1ccc2c(N3CCNCC3)nc(-c3ccccc3O)nc2c1
Reactant: C#CC(O)C(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CC(O)C(=O)N1CCN(c2nc(-c3ccccc3O)nc3cc(C)ccc23)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 2-(7-methyl-4-(piperazin-1-yl)quinazolin-2-yl)phenol (75 mg, 0.23 mmol) in 0.78 ml CH2Cl2 were added successively 2-hydroxybut-3-ynoic acid (30 mg, 0.30 mmol), BOP (134 mg, 0.30 mmol), and triethylamine (36 mg, 49 μL, 0.35 mmol). The mixture was stirred at 0° C. for 30 minutes. Purification via silica gel chromatography using 0-100% ethyl acetate/hexanes gave 2-hydroxy-1-(4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazin-1-yl)but-3-yn-1-one. (LC/MS: m/z 403.5 (M+H)+ at 2.34 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH:12](=[O:20])[C:13]1[C:14](=[CH:16][CH:17]=[CH:18][CH:19]=1)[OH:15].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Cl)=[CH:24][CH:23]=1>CCOCC>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][O:15][C:14]2[CH:16]=[CH:17][CH:18]=[CH:19][C:13]=2[CH:12]=[O:20])=[CH:24][CH:23]=1
Reactant: O=Cc1ccccc1O
Reactant: ClCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
Potassium carbonate (33.17 g) and DMF (180 ml) were added to salicylaldehyde (24.42 g), and the mixture was stirred at room temperature for 10 minutes. Then a mixture of 4-chlorobenzyl chloride (33.82 g) and DMF (20 ml) was added at room temperature over 15 minutes, and the mixture was stirred at 60° C. for 3 hours. After completion of the reaction, ether (500 ml) was added, and the mixture was washed with water (400 ml) three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude 2-(4-chlorobenzyloxy)benzaldehyde. The ethanol (200 ml) and hydroxylamine hydrochloride (27.80 g) was added to the crude product, and the mixture was stirred at 80° C. overnight. After completion of the reaction, water (400 ml) was added, and the mixture was extracted with methylene chloride (200 ml) three times, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting crude product was recrystallized from ethyl acetate/n-hexane to give 2-(4-chlorobenzyloxy)benzaldehyde oxime (32.06 g) as colorless crystals. mp. 122.5°-123.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18](Cl)=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:39][C:40]1[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=1[OH:47]>>[CH2:1]([O:8][C:9]1[CH:38]=[CH:37][C:12]([O:13][C:14]2[CH:22]=[CH:21][C:17]([C:18]([NH:39][C:40]3[CH:45]=[C:44]([CH3:46])[CH:43]=[CH:42][C:41]=3[OH:47])=[O:19])=[CH:16][C:15]=2[NH:23][C:24]2[C:25]3[CH:33]=[CH:32][C:31]([CH:34]([CH3:36])[CH3:35])=[N:30][C:26]=3[N:27]=[CH:28][N:29]=2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)Cl)ccc3Oc3ccc(OCc4ccccc4)cc3)ncnc2n1
Reactant: Cc1ccc(O)c(N)c1
Product: Cc1ccc(O)c(NC(=O)c2ccc(Oc3ccc(OCc4ccccc4)cc3)c(Nc3ncnc4nc(C(C)C)ccc34)c2)c1

Procedure:
A solution of the product from Example 43D and 2-Amino-4-methyl-phenol was reacted to provide 4-(4-Benzyloxy-phenoxy)-N-(2-hydroxy-5-methyl-phenyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzamide using the procedure from Example 43E. The material was then deprotected using the procedure from Example 43F to provide the crude title compound which was purified by HPLC with TFA to provide the title compound as a trifluoroacetic acid salt (15 mg, 29%). 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.34 (d, J=6.99 Hz, 6 H) 2.22 (s, 3 H) 3.29 (m, 1 H) 6.79 (m, 4 H) 6.92 (m, 3 H) 7.47 (d, J=1.32 Hz, 1 H) 7.87 (d, J=8.82 Hz, 1 H) 7.97 (dd, J=8.46, 2.21 Hz, 1 H) 8.13 (d, J=2.21 Hz, 1 H) 8.91 (s, 1 H) 9.00 (d, J=8.46 Hz, 1 H) 9.45 (m, 3 H) 11.46 (s, 1 H); MS (ESI+) m/z 522 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].Cl[CH:15](Cl)[O:16]C>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[OH:1][C:2]1[C:11]([CH:15]=[O:16])=[C:10]([O:12][CH3:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(Cl)Cl
Reactant: COC(=O)c1ccc(OC)cc1O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c(C=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
At from 0 to 5° C., a solution of 209.0 g (1.1 mol) of titanium tetrachloride in 150 ml of methylene chloride was added dropwise to a solution of 50.1 g (0.275 mol) of methyl 2-hydroxy-4-methoxybenzoate and 88 g (0.725 mol) of dichloromethoxymethane in 400 ml of methylene chloride, and the mixture was stirred at room temperature overnight. The mixture was then stirred into ice-water and extracted with methylene chloride. The combined organic phases were washed with sodium bicarbonate solution, water and sodium chloride solution and dried, and the solvent was then removed. Silica gel chromatography using cyclohexane/ethyl acetate=1:1 gave 24.5 g (42%) of methyl 2-hydroxy-3-formyl-4-methoxybenzoate in the form of a colorless solid of m.p.: 123–1240° C.
Reaction SMILES: [CH2:1]([S:9]([CH2:12][C:13]([O:15]C)=O)(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[NH4+:18]>CO>[CH2:1]([S:9]([CH2:12][C:13]([NH2:18])=[O:15])(=[O:11])=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCS(=O)(=O)CC(=O)OC
Reactant: [NH4+]
Agent: [OH-]
Solvent: CO
Product: CCCCCCCCS(=O)(=O)CC(N)=O
Reaction time: 24 h

Procedure:
A solution of methyl n-octanesulphonylacetate (35 g, 0.143 mole) in 350 ml of anhydrous methanol was stirred magnetically at room temperature. To this solution was added 24 ml of aqueous ammonium hydroxide (27%, 6.48 g, 0.185 mole) in drops over a period of 30 minutes. The solution was stirred for 24 h and the white precipitate formed was filtered. The solid was recrystallized from hot ethyl acetate to obtain the required acetamide III-50 as a crystalline solid, mp. 140-142° C., 33 g, 97.6%.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[N:12]1[CH:17]=[CH:16][CH:15]=[C:14](B(O)O)[CH:13]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[N+:9]([C:6]1[C:7]([NH2:8])=[C:2]([C:14]2[CH:13]=[N:12][CH:17]=[CH:16][CH:15]=2)[CH:3]=[N:4][CH:5]=1)([O-:11])=[O:10]
Reactant: OB(O)c1cccnc1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: Nc1c(-c2cccnc2)cncc1[N+](=O)[O-]
Yield: 88.8 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LVIII) (6 g, 26 mmol), pyridin-3-ylboronic acid (3.54 g, 29 mmol), 1 N Na2CO3 solution (78 ml) and 1,4-dioxane (150 mL) was degassed with argon thrice. Pd(PPh3)2C12 (927 mg, 5 mmol %) was added to the reaction and the solution was refluxed for 15 h until TLC showed the reaction was complete. The reaction was passed through a pad of Celite® and then concentrated under reduced pressure. The reaction mixture was concentrated and the residue was taken up in EtOAc. The organic extract was washed with water, dried and concentrated under vacuum. The crude product was purified on a silica gel column (100% EtOAc→2:98 MeOH:DCM) to give 5-nitro-3,3′-bipyridin-4-amine (LIX) as a yellow solid (5 g, 23.1 mmol, 87% yield). 1H NMR (CDCl3, 500 MHz,) δ ppm 9.31 (s, 1H), 8.80-8.79 (m, 1H), 8.70 (s, 1H), 8.23 (s, 1H), 7.80-7.73 (m, 1H), 7.52-7.48 (m, 1H). ESIMS found C10H8N4O2 m/z 216.95 (M+H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[S:7][CH:8]=[C:9]([CH2:11]O)[N:10]=1.S(Cl)([Cl:15])=O>>[Cl:15][CH2:11][C:9]1[N:10]=[C:6]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[S:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1csc(-c2cccs2)n1
Product: ClCc1csc(-c2cccs2)n1
Yield: 65 %

Procedure:
In substantially the same manner as in Reference Example 73, 2-(2-thienyl)-4-thiazolylmethanol was allowed to react with thionylchloride to give 4-chloromethyl-2-(2-thienyl)thiazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave colorless needles, mp 54-55° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:8][NH:9][CH2:10]2)=[CH:5][CH:4]=1.[CH2:19]=O>CO.[Ni]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:8][N:9]([CH3:19])[CH2:10]2)=[CH:5][CH:4]=1
Reactant: C=O
Reactant: COc1ccc2c(c1)CNCC2c1ccccc1
Agent: [Ni]
Solvent: CO
Product: COc1ccc2c(c1)CN(C)CC2c1ccccc1

Procedure:
(+)- 7 -methoxy- 4 -phenyl- 1,2,3,4 tetrahydroisoquinoline (2.4 g) was dissolved in methanol (50 ml) and 35% formaldehyde solution (3 ml) was added. The solution was stirred at ambient temperature for two hours when Raney nickel (1 g) was added and the solution hydrogenated at Atmospheric Pressure. The catalyst was removed by filtration, washed with ethanol and the filtrate and washings evaporated under reduced pressure to give the title compound as a colourless oil. Treatment of the title compound with ethereal hydrogen chloride gave its hydrochloride salt (2.3 g), m.p. 242° - 3° C. (dec) (methanol-ether) [α]D25 + 21.8° (water).
Reaction SMILES: C(OC([NH:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]([O:38]CC2C=CC=CC=2)=[O:37])=[CH:32][CH:31]=1)([O:27][CH3:28])=[O:26])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])=O)C1C=CC=CC=1.[H][H]>C(O)(=O)C.O.[C].[Pd]>[NH2:11][CH:12]([CH2:23][CH2:24][P:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([C:36]([OH:38])=[O:37])=[CH:34][CH:35]=1)([O:27][CH3:28])=[O:26])[C:13]([OH:15])=[O:14]
Reactant: COP(=O)(CCC(NC(=O)OCc1ccccc1)C(=O)OCc1ccccc1)Oc1ccc(C(=O)OCc2ccccc2)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CC(=O)O
Product: COP(=O)(CCC(N)C(=O)O)Oc1ccc(C(=O)O)cc1
Yield: 88 %

Procedure:
Next, 1.40 g (2.22 mmol) of benzyl 2-(N-benzyloxycarbonylamino)-4-[4-(benzyloxycarbonyl)phenyl(methyl)phosphono]butanoate was dissolved in 28 mL of a solvent mixture of acetic acid and water at 2:1 and mixed with 200 mg of 5% palladium-carbon and hydrogen gas was introduced at room temperature for 2.2 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated, and the residue was freeze-dried from water to obtain 2-amino-4-[4-carboxyphenyl(methyl)phosphono]butanoic acid (0.62 g, yield 89%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18]O)[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1.[Br-:22]>>[F:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([CH2:17][CH2:18][Br:22])[CH:14]=[CH:15][CH:16]=2)=[CH:4][CH:3]=1
Reactant: OCCc1cccc(OCCCOc2ccc(F)cc2)c1
Reactant: [Br-]
Product: Fc1ccc(OCCCOc2cccc(CCBr)c2)cc1

Procedure:
By following the procedure of example 8 and using the product of Example 140 as starting material the title bromide was prepared.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21](OC)=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2].O.[NH2:28][NH2:29]>>[C:1]([NH:5][CH2:6][CH:7]([OH:26])[CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[C:18]1[N:23]=[N:22][C:21]([NH:28][NH2:29])=[CH:20][CH:19]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: COc1ccc(-c2ccc(OC)nn2)c(OCC(O)CNC(C)(C)C)c1
Solvent: O
Product: COc1ccc(-c2ccc(NN)nn2)c(OCC(O)CNC(C)(C)C)c1

Procedure:
A stirred mixture of 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-methoxypyridazine (0.36 g, 0.001 mole) and hydrazine hydrate (8 ml) was heated under reflux for 2 hours. Excess of hydrazine hydrate was removed under reduced pressure and 6-[2-(3-t-butylamino-2-hydroxypropoxy)-4-methoxyphenyl]-3-hydrazino pyridazine was isolated by crystallisation from ethanol-ether
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([OH:13])=O)[C:4](=[O:15])[CH:3]=1.[NH2:16][C:17]1[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[CH:19][CH:18]=1>>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]([CH:10]([CH3:14])[C:11]([NH:16][C:17]2[CH:29]=[CH:28][C:20]([C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[CH:19][CH:18]=2)=[O:13])[C:4](=[O:15])[CH:3]=1
Reactant: COc1cn(C(C)C(=O)O)c(=O)cc1Br
Reactant: CC(C)(C)OC(=O)c1ccc(N)cc1
Product: COc1cn(C(C)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1Br

Procedure:
571 mg (2.01 mmol) of 2-(4-bromo-5-methoxy-2-oxopyridin-1(2H)-yl)propanoic acid (racemate) and 426 mg (2.21 mmol, 1.1 eq.) of tert-butyl 4-aminobenzoate were reacted according to General Method 5A. Yield: 562 mg (61% of theory)
Reaction SMILES: [NH2:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:3]([C:6]#[N:7])[C:4]#[N:5].C(N(CC)CC)C.[SH2:20]>N1C=CC=CC=1>[NH2:1][C:2]([N:8]1[CH2:12][CH2:11][CH2:10][CH2:9]1)=[C:3]([C:4]#[N:5])[C:6](=[S:20])[NH2:7]
Reactant: S
Reactant: N#CC(C#N)=C(N)N1CCCC1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: N#CC(C(N)=S)=C(N)N1CCCC1
Reaction time: 64 h

Procedure:
A mixture of 93.3 g of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenenitrile, 58.2 g of triethylamine and 400 ml of pyridine was heated at 60°-65° and hydrogen sulfide passed in for 21/2 hours. While continuing the addition of hydrogen sulfide, the temperature of the mixture was increased to 80°, where it was maintained for two and a half hours. The mixture stood for 64 hours at ambient temperature, then was heated at 90° for 21/2 hours. The mixture was concentrated under reduced pressure. The tan solid residue was stirred with 750 ml of ice-water, the cold slurry was filtered and the solid was washed with cold water. The washed solid was recrystallized from 1200 ml of ethanol to give 87.4 g (three crops) of 3-amino-2-cyano-3-(1-pyrrolidinyl)propenethioamide, m.p. 164°. The nmr spectrum was consistent with the assigned structure.