Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([C:14]([OH:16])=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.C(N(CC)CC)C.Cl.[CH3:37][NH:38][O:39][CH3:40]>C1COCC1>[CH3:40][O:39][N:38]([CH3:37])[C:14]([C@@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1)=[O:16]
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](C(=O)O)C1
Reactant: CNOC
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
To a stirred solution of (R)-1-(tert-butoxycarbonyl)piperidine-3-carboxylic acid (233 g, 1.2 mol) in THF (1.2 L) was added carbonyldiimidazole (230 g, 1.42 mol). The mixture was stirred for 1 h under ice-water bath. A suspension of triethylamine (207 mL, 1.41 mol) and N,O-dimethylhydroxylamine hydrochloride (138 g, 1.42 mol) in THF (900 mL) was added. The reaction mixture was allowed to warm to room temperature and stirred overnight. TLC showed the reaction was complete. The solvent was evaporated, and the residue was dissolved in CH2Cl2 (1.2 L) and washed successively with 0.5 N hydrochloride solution, saturated solution of sodium carbonate and brine, dried over anhydrous sodium sulfate and evaporated to give crude compound (R)-tert-butyl 3-(methoxy(methyl)carbamoyl)piperidine-1-carboxylate (250 g, 91%), which was used in the next step directly without purification. 1H NMR (400 MHz, CDCl3): 4.05-4.19 (m, 2H), 3.72 (s, 3H), 3.17 (s, 3H), 2.75-2.85 (m, 2H), 2.65 (t, 1H), 1.90 (d, 1H), 1.60-1.78 (m, 2H), 1.44 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:21]=[CH:20][C:7]([CH2:8][N:9]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].O.NN.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O1CCCC1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][NH2:9])=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: NN
Solvent: O
Solvent: C1CCOC1
Product: NCc1ccc([N+](=O)[O-])cc1
Yield: 82.9 %

Procedure:
2-(4-Nitrobenzyl)isoindoline-1,3-dione (1.6 g, 5.67 mmol) was dissolved in tetrahydrofuran (8 mL). To the solution hydrazine monohydrate (1.7 mL, 22.675 mmol) and p-toluenesulfonic acid monohydrate (108 mg, 0.57 mmol) was added. It was refluxed for 6 h. TLC showed complete consumption of starting material. The mixture was extracted with ethyl acetate and washed with water and brine. The extract was dried over magnesium sulfate and concentrated under reduced pressure. The crude was purified by column chromatography to give (4-nitrophenyl)methanamine (715 mg, 83%).
Reaction SMILES: [C:1]1([N:7]2[CH2:12][CH2:11][CH:10]([NH:13][C:14](=[O:22])OC3C=CC=CC=3)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:24][S:25]([N:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29]1)(=[O:27])=[O:26]>>[CH3:24][S:25]([N:28]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[C:30]2([CH2:31][CH2:32][N:33]([C:14]([NH:13][CH:10]3[CH2:9][CH2:8][N:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:12][CH2:11]3)=[O:22])[CH2:34][CH2:35]2)[CH2:29]1)(=[O:26])=[O:27]
Reactant: O=C(NC1CCN(c2ccccc2)CC1)Oc1ccccc1
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Agent: Cl
Product: CS(=O)(=O)N1CC2(CCN(C(=O)NC3CCN(c4ccccc4)CC3)CC2)c2ccccc21

Procedure:
Compounds of Examples 78 to 83 were obtained by following the same procedure as in Example 77-(2), except that phenyl N-(1-phenyl-4-piperidyl)carbamate and 1-methanesulfonylspiro[indoline-3,4′-piperidine]hydrochloride used in Example 77-(2) were replaced with the corresponding starting material of each desired compound.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[C@H:15]([OH:24])[CH2:16][C@H:17]([OH:23])[CH2:18][C:19]([O:21]C)=[O:20])=[C:11]([C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[C:10]2[C:5]1=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:3].[OH-].[Na+:33].C(O)CCC>C(#N)C>[CH3:3][CH:2]([N:4]1[C:12](/[CH:13]=[CH:14]/[CH:15]([OH:24])[CH2:16][CH:17]([OH:23])[CH2:18][C:19]([O-:21])=[O:20])=[C:11]([C:25]2[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=2)[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]1=2)[CH3:1].[Na+:33]
Reactant: COC(=O)C[C@@H](O)C[C@@H](O)/C=C/c1c(-c2ccc(F)cc2)c2ccccc2n1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Solvent: CCCCO
Product: CC(C)n1c(/C=C/C(O)CC(O)CC(=O)[O-])c(-c2ccc(F)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.2 %

Procedure:
Fluvastatin methyl ester (2.0 g) was added to a mixture of NaOH (1 eq.) and butan-1-ol (15 ml). The mixture was stirred at about 80EC for 2.5 h, after which the starting material was not detected by HPLC. Then, 40 ml of acetonitrile was dripped into the solution. The mixture was then cooled slowly to room temperature and stirred overnight. The product was isolated by filtration under nitrogen, washed with acetonitrile (45 ml) and dried at 50EC in a vacuum oven for 24 h to obtain 1.96 g (96.2%) of fluvastatin sodium Form VII.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)[CH3:3].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][N:2]([CH3:3])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: CN(C)Cc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)Cc1ccccc1N1CCNCC1
Yield: 76 %

Procedure:
To tert-butyl 4-{2-[(dimethylamino)methyl]phenyl}-piperazinecarboxylate (Step 2) (0.68 g, 2.1 mmol) dissolved in CH2Cl2 (12 mL) was added TFA (6 mL). After stirring the reaction at RT for 1 h, the solvent was concentrated in vacuo and the residue was partitioned between CH2Cl2 and satd NaHCO3. The organic layer was washed with brine and the combined aqueous layer were extracted with a mixture of CH2Cl2 and 30% MeOH. The combined organic layer was dried over Na2SO4, filtered and concentrated in vacuo to give dimethyl[(2-piperazinylphenyl)methyl]amine as a yellow oil (0.35 g). MS m/z: 220 (M+H). Calc'd for C13H21N3: 219.33.
Reaction SMILES: C([O-])(=O)C.[Na+].C(O)(=O)C.[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][O:34]C)[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:21][CH:20]=1)=[O:15].C([O-])(O)=O.[Na+]>O1CCOCC1>[Cl:10][C:11]1[CH:12]=[C:13]([CH:39]=[CH:40][C:41]=1[O:42][CH:43]([CH3:45])[CH3:44])[C:14]([NH:16][C@H:17]([CH2:36][CH2:37][OH:38])[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([C:31](=[N:33][OH:34])[CH3:32])[N:28]([CH3:30])[CH:29]=2)=[CH:23][CH:24]=1)=[O:15]
Reactant: CON=C(C)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Agent: CC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: CC(=NO)c1nc(-c2ccc(C[C@@H](CCO)NC(=O)c3ccc(OC(C)C)c(Cl)c3)cc2)cn1C
Temperature: 65 °C
Reaction time: 2 h
Yield: 22.8 %

Procedure:
A mixture of 2-amino-4′-bromoacetophene hydrochloride (10.0 g, 40 mmol), sodium acetate (16.4 g, 200 mmol), acetic acid (11.5 mL, 200 mmol) and compound 2 (19.2 g, 80 mmol) in dioxane (70 mL) was stirred at 65° C. until TLC show no compound 2 left (about 2 h). The reaction mixture was carefully neutralized with saturated NaHCO3 solution, and extracted with ethyl acetate. The organic solution was dried over Na2SO4 and concentrated. Purification with flash column chromatography (EtOAc:Hexs 1:1) gave product 3 (9.11 g, 79%) as white solid.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([NH:16][CH2:17][CH2:18][OH:19])(=[O:15])=[O:14].[H-].[Na+].[Na].[C:25]1(C)C=CC(S(OC)(=O)=O)=CC=1>CN(C=O)C.CCOC(C)=O>[CH3:1][N:2]([CH3:21])[C:3](=[O:20])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[S:13]([N:16]([CH2:17][CH2:18][OH:19])[CH3:25])(=[O:15])=[O:14]
Reactant: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)NCCO
Reactant: COS(=O)(=O)c1ccc(C)cc1
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1c([N+](=O)[O-])cccc1S(=O)(=O)N(C)CCO
Reaction time: 20 h

Procedure:
A solution of N,N-Dimethyl 2-(N-(2-hydroxyethyl)aminosulfonyl]-6-nitrobenzamide (3.97 g, 12.5 mmol) in dry DMF (40 ml) was added slowly to a stirred suspension of 50% NaH (0.60 g, 12.5 mmol) in dry DMF (10 ml) under N2 at 20°-25° C. After formation of the sodium salt was complete, a solution of methyl p-toluenesulfonate (2.40 g, 12.9 mmol) in DMF (4 ml) was added and the reaction mixture stirred at 20°-25° C. for 20 hours and then at 60° C. for 23 hours. The orange solution was mixed with EtOAc (400 ml) and the white solid which formed was filtered off. This precipitate was washed with EtOAc (100 ml). The combined EtOAc solutions were washed with a saturated aqueous NaCl solution, dried (Na2SO4), filtered and concentrated under reduced pressure. Pure product, mp 107°-08° C., 2.5 g (60%) was obtained by flash chromatography over silica gel and elution with a 65% n-butylchloride-35% acetonitrile solvent mixture.
Reaction SMILES: [N+]([C:4]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[C:5]=1[C:6]#[N:7])([O-])=O.[C:15]1([SH:21])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])([O-])=O.[K+].[K+].N1C=CC=CC=1>CN(C=O)C.O>[N+:12]([C:8]1[CH:9]=[CH:10][CH:11]=[C:4]([S:21][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:5]=1[C:6]#[N:7])([O-:14])=[O:13]
Reactant: Sc1ccccc1
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: N#Cc1c(Sc2ccccc2)cccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75.7 %

Procedure:
An ice water bath-cooled mixture of 2.0 g (0.01 mol) of 2,6-dinitrobenzonitrile (Lancaster Synthesis, Inc., Windham, N.H. 03087), 1.06 ml (0.01 mol) of thiophenol, and 1.44 g (0.01 mol) of anhydrous K2CO3 in 50 mL of DMF was stirred for 0.5 h. Pyridine was added to the reaction mixture until it became basic, and was followed by the addition of approximately 100 mL of H2O. The yellow precipitate was collected by filtration, washed with 1N NaOH, water and dried to give 1.94 g (89%) of 2-nitro-6-(phenylthio)benzonitrile as a yellow solid: mp 106°-107° C.
Reaction SMILES: [Bi:1].[C:2]([OH:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5]>>[C:2]([O-:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5].[Bi+3:1].[C:2]([O-:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5].[C:2]([O-:12])(=[O:11])[C:3]1[C:4](=[CH:6][C:7](=[CH:9][CH:10]=1)[OH:8])[OH:5]
Reactant: O=C(O)c1ccc(O)cc1O
Reactant: [Bi]
Product: O=C([O-])c1ccc(O)cc1O
Product: [Bi+3]
Temperature: 50 °C
Reaction time: 5 h

Procedure:
In this process the β-resorcylic acid is dissolved in the hydroalcoholic medium with an increase in the temperature to a temperature of between approximately 40° C. and approximately 60° C., preferably approximately 50° C., and then a bismuth compound is added with stirring; the temperature is raised to a temperature of between approximately 70° C. and approximately 90° C., preferably approximately 80° C., allowing the reaction to continue, advantageously for between 2 and 15 hours, preferably approximately 5 hours. The suspension is filtered off, washed and dried. The product obtained corresponds to a bismuth β-resorcylate containing two bismuth atoms per molecule of acid.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:14]=[C:13]([CH3:15])[NH:12][C:11]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17].[OH-].[Na+]>C(Cl)(Cl)Cl.CO>[Cl:1][C:14]1[C:10]([CH3:9])=[C:11]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[NH:12][C:13]=1[CH3:15]
Reactant: CCOC(=O)c1[nH]c(C)cc1C
Reactant: O=C1CCC(=O)N1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCOC(=O)c1[nH]c(C)c(Cl)c1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N-Chlorosuccinimide (1.77 g, 13.25 mmol) was added to a solution of ethyl 3,5-dimethyl-2-pyrrole carboxylate (2.11 g, 12.62 mmol) in chloroform (45 mL). The reaction mixture was stirred at room temperature for 24 h and then poured into 2 N NaOH. The organic layer was washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a crude solid. The crude solid was dissolved in hot MeOH, cooled to room temperature, and the precipitate was collected by filtration (493 mg, 19%). MS (ES) MH+: 174 for C9H12ClNO2.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([N+:13]([O-])=O)[CH:4]=1)#[N:2].[H][H].[ClH:18]>O.[OH-].[Pd+2].[OH-]>[Cl-:18].[NH2:13][C:5]1[CH:4]=[C:3]([CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8])[CH2:1][NH3+:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc(C#N)cc1[N+](=O)[O-]
Reactant: Cl
Agent: [Pd+2]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc(C[NH3+])cc1N
Product: [Cl-]

Procedure:
18.5 g (0.09 mol) of methyl 4-cyano-2-nitrobenzoate and 0.93 g of palladium hydroxide (20% on charcoal) are suspended in a mixture of 8 ml of concentrated hydrochloric acid (30% strength) and 315 ml of water in a Hastelloy stirred autoclave. Then, the mixture is hydrogenated at a hydrogen pressure of 17 bar until the hydrogen uptake is complete. After the pressure in the autoclave has been released and the catalyst filtered off, the filtrate is evaporated completely. This gives 19.5 g (97% strength) of 3-amino-4-methoxycarbonylbenzylammonium chloride of melting point 200-205° C.
Reaction SMILES: [CH:1]([C:3]1[C:4](=[O:13])[NH:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:2].[H-].[Na+].[CH3:16]I.O>O1CCCC1>[CH3:16][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH:12]=[C:3]([CH:1]=[O:2])[C:4]1=[O:13]
Reactant: O=Cc1cc2ccccc2[nH]c1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c(C=O)cc2ccccc21
Temperature: 25 °C

Procedure:
2.7 Grams of 3-formylcarbostyril was dissolved in 150 ml of tetrahydrofuran, then 0.8 g of oil 50%-sodium hydride was added thereto at a room temperature with stirring. Next, 4.5 g of methyl iodide was added dropwise at a room temperature for 3 hours. The reaction mixture was concentrated under a reduced pussure, the residue thus obtained was poured into water and the crystals precipitated were collected by filtration. Recrystallized from ethanol to obtain 1.7 g of 1-methyl-3-formylcarbostyril in the form of yellow-brownish needle-like crystals.
Reaction SMILES: [Cl:1]C1C=CC2OC3C=CC=CC=3[C@H]3C(=[O:13])N(C)C[C@@H]3C=2C=1.[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[O:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C@@H:29]3[C:30](=[O:34])[N:31]([CH3:33])[CH2:32][C@@H:28]3[C:27]=2[CH:42]=1.[OH-].[K+]>C(O)C>[ClH:1].[Cl:22][C:23]1[CH:24]=[CH:25][C:26]2[O:37][C:36]3[CH:38]=[CH:39][CH:40]=[CH:41][C:35]=3[C@@H:29]([C:30]([OH:34])=[O:13])[C@H:28]([CH2:32][NH:31][CH3:33])[C:27]=2[CH:42]=1
Reactant: CN1C[C@@H]2c3cc(Cl)ccc3Oc3ccccc3[C@H]2C1=O
Reactant: CN1C[C@@H]2c3cc(Cl)ccc3Oc3ccccc3[C@@H]2C1=O
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CNC[C@@H]1c2cc(Cl)ccc2Oc2ccccc2[C@H]1C(=O)O
Product: Cl
Yield: 22 %

Procedure:
The mixture of lactams (VII) and (VIII) (13.6 grams, 45 mmol, trans/cis ratio 1:2.3), obtained as described under E, was dissolved in ethanol (140 ml). To the solution potassium hydroxide was added (43 grams, 811 mmol), whereupon the mixture was heated to reflux for 18 hours. Part of the ethanol (60 ml) was evaporated and water was added (200 mL). The aqueous phase was extracted twice with toluene (100 ml). Subsequently toluene (100 ml) was added to the water phase, followed by concentrated hydrochloric acid to adjust the pH to 1. During the addition of hydrochloric acid the temperature rises to 75° C. The water layer was separated and upon cooling the product crystallized. The crystals were collected by filtration and dried to provide trans-2-chloro-10,11-dihydro-11[(methylamino)methyl]-dibenz[b,f]oxepin-10-carboxylic acid hydrochloride (II) (3.75 grams, 10.6 mmol, 22%).
Reaction SMILES: C(N(CC)CC)C.[OH:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1.Cl[Si:18]([CH3:21])([CH3:20])[CH3:19]>CCOCC>[CH3:19][Si:18]([CH3:21])([CH3:20])[O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:14])=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: C[Si](C)(C)Oc1ccc(C=O)cc1
Reaction time: 0.25 h

Procedure:
Triethylamine (42 ml) is added dropwise to a stirred solution of 4-hydroxybenzaldehyde (33.5 g) and chlorotrimethylsilane (42 ml) in ether (300 ml). After 15 min, the mixture is filtered through diatomaceous earth and the filtrate is concentrated and distilled in vacuo, providing 4-(trimethylsiloxy)benzaldehyde as a colorless oil (43 g). This material is reacted with methoxymethyl triphenylphosphonium chloride and potassium tert-butoxide in THF, using the procedure described in Example 1 (A) above, to provide 1-(2-methoxyethenyl)-4-(trimethylsiloxy)benzene (35%) as a colorless oil after distillation in vacuo, as a mixture of (E) and (Z) isomers. This material (3.0 g) is dissolved in methanol (30 ml) containing methanesulfonic acid (0.4 ml), and the solution is refluxed for 3 hr. Sodium bicarbonate (8 ml of 1.0N solution) is added, and the mixture is concentrated in vacuo. The residue is taken up in ethyl acetate, dried, and concentrated to provide 4-[(2,2-dimethoxy)ethyl]phenol as a pale red oil (2.4 g).
Reaction SMILES: Br.[Br:2][C:3]1[C:4]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[N:5][S:6][CH:7]=1.[Na].C(Cl)(Cl)Cl.[CH3:18][N:19]=[C:20]=[S:21]>C(O)C>[CH3:18][NH:19][C:20]([NH:12][CH2:11][CH2:10][S:9][CH2:8][C:4]1[C:3]([Br:2])=[CH:7][S:6][N:5]=1)=[S:21]
Reactant: CN=C=S
Reactant: NCCSCc1nscc1Br
Agent: Br
Agent: [Na]
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: CNC(=S)NCCSCc1nscc1Br
Yield: 108.8 %

Procedure:
The reaction of 4-bromo-3-(bromomethyl)isothiazole (8.5 g.) with cysteamine (from cysteamine hydrochloride (3.76 g) was performed under conditions similar to those described in Example 57. From the reaction there was obtained 4-bromo-3-[(2-aminoethyl)thiomethyl]isothiazole hydrobromide, which, following recrystallisation from ethanol-ether and acetonitrile, gave needles (4.05 g.) m.p. 111°-112°. The amine base (2.73 g.) was isolated by basification with sodium bydroxide and extraction with chloroform and then dissolved in ethanol and treated with methyl isothiocyanate (0.78 g.) The solution was heated under reflux for 30 minutes, concentrated and the residue triturated with ether to yield the crystalline thiourea (2.9 g.) m.p. 60°-61°. Recrystallisation from isopropyl acetate gave N-methyl-N'-[2-((4-bromo-3-isothiazolyl)methylthio)ethyl]thiourea (2.3 g.) as needles, m.p. 62°-63°.
Reaction SMILES: [C:1]1([CH2:11][C:12]([OH:14])=O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:18])=O.N#N>C(Cl)Cl.CN(C=O)C>[C:1]1([CH2:11][C:12]([Cl:18])=[O:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1cccc2ccccc12
Reactant: O=C(Cl)C(=O)Cl
Agent: N#N
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cccc2ccccc12
Temperature: 0 °C
Reaction time: 12 h
Yield: 99.6 %

Procedure:
1-Naphthylacetylchloride was synthesized from 1-naphthylacetic acid (20.0 g, 107.4 mmol) which was dissolved in CH2Cl2 (200 mL) and the solution was cooled to 0° C. Oxalylchloride (11.20 mL, 128.90 mmol) was added to the solution dropwise over 20 min. under the atmosphere of N2 then followed by one drop of DMF. The mixture was then allowed to warm to room temperature where it was stirred for 12 hours. The reaction mixture was concentrated under vacuum, the resulting residue was redissolved in CH2Cl2 (200 mL) and the solvents were evaporated in vacuo to give 1-naphthylacetylchloride 21.90 g (99%) as a dark oil: 1H-NMR (400 MHz, CDCl3) δ 7.92-7.84 (m, 3H), 7.61-7.42 (m, 4H), 4.58 (s, 2H).
Reaction SMILES: C([O:3][C:4](=[O:37])[C:5]1[CH:10]=[C:9]([Cl:11])[C:8]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:14][CH2:13]2)=[N:7][CH:6]=1)C.O.O[Li].O.Cl>C1COCC1.CCO>[Cl:11][C:9]1[C:8]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[N:21]=[C:20]([N:31]4[CH2:35][CH2:34][CH2:33][CH:32]4[CH3:36])[N:19]=3)[CH2:16][CH2:17]2)=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([OH:37])=[O:3]
Reactant: CCOC(=O)c1cnc(N2CCN(c3cc(-c4ccc(F)cc4)nc(N4CCCC4C)n3)CC2)c(Cl)c1
Agent: Cl
Agent: [Li]O
Solvent: CCO
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCN1c1nc(-c2ccc(F)cc2)cc(N2CCN(c3ncc(C(=O)O)cc3Cl)CC2)n1
Temperature: 55 °C

Procedure:
To a solution of 5-chloro-6-{4-[6-(4-fluoro-phenyl)-2-(2-methyl-pyrrolidin-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-nicotinic acid ethyl ester (427 mg, 0.813 mmol) in THF, add water dropwise until the cloudiness almost persists. To this mixture add LiOH.H2O (350 mg, 8.13 mmol) followed by a small amount of EtOH. Heat the mixture at 55° C. for 2 h, and then concentrate under reduced pressure. Add a small amount of water to the residue, followed by 8.13 mmol of HCl (3M solution). Adjust the final pH to 4 and collect the off-white solid via filtration. Wash the solid with water and dry to afford the title compound.
Reaction SMILES: [C:1]1([CH:7]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=2)[N:31]=1.C(N(C(C)C)C(C)C)C.CN(C)[CH:51]=[O:52]>>[C:9]([OH:8])(=[O:52])/[CH:32]=[CH:33]/[C:35]([OH:37])=[O:36].[C:51]([OH:52])(=[O:8])/[CH:32]=[CH:33]/[C:35]([OH:37])=[O:36].[C:19]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:26]3[CH:27]=[CH:28][C:29]4[N:30]([CH:32]=[C:33]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[N:34]=4)[N:31]=3)[CH2:11][CH2:10]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1cn2nc(Cl)ccc2n1
Reactant: NCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cn2nc(NCCCN3CCC(OC(c4ccccc4)c4ccccc4)CC3)ccc2n1
Product: O=C(O)/C=C/C(=O)O
Temperature: 80 °C
Reaction time: 18.5 h

Procedure:
686 mg of 4-(diphenylmethoxy)-1-piperidinepropanamine and 477 mg of ethyl 6-chloroimidazo[1,2-b]pyridazin-2-carboxylate were dissolved in 7 ml of N,N-dimethylformamide; 0.73 ml of N-ethyldiisopropylamine was added, followed by stirring in an oil bath (80° C.) for 18.5 hours. After cooling, ice water and saline were added, followed by extraction with ethyl acetate-tetrahydrofuran (1:1); the extract was washed with saturated saline and dried with magnesium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (50:5:1). The desired fraction was collected, dissolved in 5 ml of ethyl acetate; a solution of 95 mg of fumaric acid in 5 ml of ethanol was added, followed by concentration. Acetone-ethyl ether (1:2) was added to the residue to cause recrystallization; the crystal precipitate was collected by filtration and washed with ethyl ether to yield 211 mg of the title compound.
Reaction SMILES: C[O-].[Na+].CO.[C:6]([O:13][CH3:14])(=[O:12])[CH2:7][C:8]([O:10][CH3:11])=[O:9].[C:15]([O:20][CH3:21])(=[O:19])/[CH:16]=[CH:17]/[CH3:18].C(O)(=O)C.[Na+].[Cl-]>CO.O>[CH3:18][CH:17]([CH2:16][C:15]([O:20][CH3:21])=[O:19])[CH:7]([C:6]([O:13][CH3:14])=[O:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: C/C=C/C(=O)OC
Reactant: COC(=O)CC(=O)OC
Agent: C[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: COC(=O)CC(C)C(C(=O)OC)C(=O)OC
Reaction time: 2 h
Yield: 89.1 %

Procedure:
To a mixture of 28% NaOMe/methanol (0.25 eq) and dimethyl malonate (1.0 eq) in methanol (1.6 vol) was added methyl crotonate at 70° C. The reaction mixture was stirred at the same temperature for 2 hr. After neutralization with acetic acid (0.25 eq)/water (50/50) at 25° C., the mixture was concentrated under reduced pressure. To the mixture was added 5% aq NaCl (3.82 vol) and extracted with MTBE (2 vol X 2), washed two times with 10% NaCl (2 vol) and concentrated to give the product as an oil (89.1% yield, 95% pure as measured by GC-MS).