Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:3]=1[C:4]([O:6]CC(O)=O)=O.[OH-:16].[Na+:17].[CH2:18]([OH:20])[CH3:19]>>[Cl:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:2]([Cl:1])[C:3]=1[C:4]([CH2:19][C:18]([O-:16])=[O:20])=[O:6].[Na+:17]
Reactant: O=C(O)COC(=O)c1c(Cl)cccc1Cl
Reactant: CCO
Reactant: [OH-]
Agent: [Na+]
Product: O=C([O-])CC(=O)c1c(Cl)cccc1Cl
Reaction time: 1.75 h

Procedure:
To a stirred solution of 6.0 grams (0.024 mole) of carboxymethyl 2,6-dichlorobenzoate (the compound of Example X) in 100 ml of ethanol was added a solution of 0.9 gram (0.022 mole) of sodium hydroxide in 50 ml of ethanol. The reaction mixture was stirred for 1.75 hours during which time a solid precipitate formed. The solid was collected by filtration and washed with ethanol. The filtrate was concentrated to a volume of 50 ml, and a second crop of solid was collected by filtration. The solids were combined to give 3.7 grams of sodium 2,6-dichlorobenzoylacetate; mp 241° (decomposes). The nmr and the ir spectra were consistent with the proposed structure.
Reaction SMILES: [ClH:1].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5].[S:14]([O-:18])([O-:17])(=[O:16])=[O:15].[Mg+2:19]>O>[Cl-:1].[Mg+2:19].[S:14]([OH:18])([O-:17])(=[O:16])=[O:15].[OH:2][CH:3]1[O:11][C@H:10]([CH2:12][OH:13])[C@@H:8]([OH:9])[C@H:6]([OH:7])[C@H:4]1[NH2:5]
Reactant: O=S(=O)([O-])[O-]
Reactant: Cl
Agent: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: [Mg+2]
Solvent: O
Product: O=S(=O)([O-])O
Product: [Cl-]

Procedure:
Example 1 was repeated using 1655 g of purified water, 431.5 g (2 moles) of glucosamine hydrochloride and 120.3 g (1 mole) of magnesium sulfate instead of the sodium sulfate. After freeze drying, glucosamine sulfate magnesium chloride was obtained as a white powder in a yield of 530 g (96% of theoretical).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31]>>[CH2:1]([O:8][C:9]([NH:11][CH2:12][C:13]([CH3:18])([CH3:17])[C:14]([NH:19][C@@H:20]1[CH2:26][CH2:25][C:24]2[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=2[NH:22][C:21]1=[O:31])=[O:16])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N[C@@H]1CCc2ccccc2NC1=O
Reactant: CC(C)(CNC(=O)OCc1ccccc1)C(=O)O
Product: CC(C)(CNC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCc2ccccc2NC1=O

Procedure:
Prepared from 3-(benzyloxycarbonylamino)-2,2-dimethylpropanoic acid and 3(R)-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step E) by the procedure described in Example 1, Step F. 1H NMR (200MHz, CDCl3): 1.19 (s,6H), 1.90 (m,1H), 2.6-3.0 (n,3H), 3.26 (d,6Hz,2H), 4.46 (m,1H), 5.07 (s,2H), 5.7 (br t,1H), 6.62 (d,7Hz,1H), 6.97 (d,8Hz,1H), 7.1-7.3 (m,3H), 7.3 (s,5H), 8.14 (br s,1H). FAB-MS: calculated for C23H27N3O4 409; found 410 (M+H,100%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[ClH:6].[NH2:7][CH2:8][C:9]([NH:11][CH3:12])=O.[C:13](=[O:16])([O-])[O-].[Na+].[Na+].[C:19](=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CN(C=O)C>[Cl:6][C:9]1[N:11]([CH3:12])[CH:19]=[N:7][C:8]=1[CH:13]=[O:16]
Reactant: Cl
Reactant: CNC(=O)CN
Reactant: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: Cn1cnc(C=O)c1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Phosphoryl trichloride (1 mL, 11 mmol) was added slowly to a 0° C. solution of DMF (22 mL), followed by 2-amino-N-methylacetamide hydrochloride (2.5 g, 20 mmol). The mixture was warmed at room temperature and stirred at 60° C. before phosphoryl trichloride (35 mL, 390 mmol) was added slowly. The solution was stirred at 90° C. overnight. After cooling to room temperature, the mixture was poured into ice/water (500 mL). Solid sodium carbonate was added until pH 6-7 was reached. The mixture was extracted with DCM (4×150 mL). The organic extracts were combined, dried over MgSO4, filtered, evaporated, and dried in vacuo. The residue was dissolved in water (10 mL) and 1,4-dioxane (20 mL) before potassium carbonate (10 g, 72.3 mmol) was added. The mixture was stirred at 60° C. for 4 hours. The mixture was evaporated to dryness. The residue was treated with 50% EtOAc/Et2O (250 mL). The solid was removed by filtration. The filtrate was recovered, evaporated, and dried in vacuo, affording 5-chloro-1-methyl-1H-imidazole-4-carbaldehyde (476 mg, 23% yield). The product was used without further purification.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.BrC[C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20].[C:24]([O-])([O-])=O.[K+].[K+]>CCO>[C:19]([C:18]1[CH:17]=[CH:16][C:23]([CH2:24][N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)=[CH:22][CH:21]=1)#[N:20]
Reactant: N#Cc1cccc(CBr)c1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCN(Cc2ccc(C#N)cc2)CC1
Yield: 84.9 %

Procedure:
A solution of tert-butyl piperazine-1-carboxylate (334, 1 g, 5.37 mmol), 3-(bromomethyl)benzonitrile (335, 1.26 g, 6.45 mmol) and K2CO3 (1.48 g, 10.74 mmol) in EtOH (20 mU was refluxed for four hours. The reaction mixture was then concentrated, diluted with EtOAc (20 ml.) and washed with water (20 mL). The organic phase was separated, dried with Na2SO4, filtered and concentrated. Crude product was purified by flash chromatography using the gradient 10%-25% EtOAc in hexanes as an eluent to afford the title compound 336 (1.374 g 85%). MS: calc: 301.3; found: 302.1 (M+H)
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5]([NH2:7])=[O:6].CC1(C)C(C)(C)OB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>[Pd].O>[C:5]([C:4]1[C:3]([CH3:11])=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([NH:30][C:31]([C:33]2[CH:37]=[CH:36][S:35][CH:34]=2)=[O:32])[CH:24]=[CH:23]3)[CH:10]=[CH:9][CH:8]=1)(=[O:6])[NH2:7]
Reactant: Cc1c(Br)cccc1C(N)=O
Reactant: CC1(C)OB(c2ccc3cc(NC(=O)c4ccsc4)ccc3c2)OC1(C)C
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1c(C(N)=O)cccc1-c1ccc2cc(NC(=O)c3ccsc3)ccc2c1
Temperature: 25 °C
Yield: 29.2 %

Procedure:
3-bromo-2-methylbenzamide (12.5 mg, 0.0584 mmol), N-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)naphthalen-2-yl)thiophene-3-carboxamide (45.8 mg, 0.121 mmol), Fibercat palladium catalyst (Johnson-Matthey, 31.9 mg), and K2CO3 (2 M in water, 0.15 ml, 0.30 mmol) were combined in a microwave reaction vessel and 1,4-dioxane (0.7 ml) was added. The reaction tube was sealed and heated in the microwave (CEM microwave) at 60 Watts and 80 C for 10 minutes and then cooled to room temperature. The reaction was diluted with water (5 ml) and extracted with dichloromethane (3×10 ml) and EtOAc (10 ml). The organic extracts were combined, dried over magnesium sulfate, filtered, concentrated, and purified on HPLC (10%->95% MeCN/water with 0.1% TFA) to afford title compound (6.6 mg, 29%). MS (ESI pos. ion) m/z: 387 (M+H). Calc'd Exact Mass for C23H18N2O2S: 386.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5].[NH2:10][C:11]1[N:16]=[C:15](Cl)[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1>CN1C(=O)CCC1.O>[NH2:10][C:11]1[N:16]=[C:15]([NH:1][C@@H:2]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:3][CH2:4][OH:5])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][C:26]#[N:27])=[CH:21][C:20]=2[F:28])=[C:13]([CH3:29])[N:12]=1
Reactant: CCCC[C@H](N)CCO
Reactant: Cc1nc(N)nc(Cl)c1Cc1ccc(CC#N)cc1F
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC[C@@H](CCO)Nc1nc(N)nc(C)c1Cc1ccc(CC#N)cc1F
Temperature: 150 °C
Reaction time: 8 h

Procedure:
(S)-3-Aminoheptan-1-ol (0.135 g) was added to a stirred solution of the product from step (iii) (0.12 g) in NMP (2 mL). The mixture was heated at 150° C. for 48 h, and then at 170° C. for a further 8 h. The mixture was allowed to cool, diluted with water (10 mL) and the aqueous extracted with EtOAc. The combined organic phase was dried and evaporated. The crude product was purified by column chromatography, to give the subtitle compound, 0.11 g.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C@H:8]([CH2:23][CH2:24][S:25][CH3:26])[C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[CH3:28][I:29]>>[I-:29].[C:1]([O:5][C:6]([NH:7][C@@H:8]([C:9]([NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=1)=[O:10])[CH2:23][CH2:24][S+:25]([CH3:28])[CH3:26])=[O:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: CI
Reactant: COc1ccc(CNC(=O)[C@@H](CCSC)NC(=O)OC(C)(C)C)cc1OC
Product: COc1ccc(CNC(=O)[C@@H](CC[S+](C)C)NC(=O)OC(C)(C)C)cc1OC
Product: [I-]
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of (R)-tert-butyl(1-((3,4-dimethoxybenzyl)amino)-4-(methylthio)-1-oxobutan-2-yl)carbamate (2 g, 5 mmol) and methyl iodide (24 ml, 381 mmol) was stirred at RT for 48 hrs. The solvent was then evaporated off and the residue was triturated with ether and dried under high vacuum. Yield 2 g. LCMS (Method J) RT 0.64 min, m/z 413.1 (M+); 1H NMR (400 MHz, chloroform-d) δ 1.40 (s, 9H), 2.08-2.21 (br s, 1H), 2.55-2.70 (br s, 1H), 3.06 (s, 3H), 3.23 (s, 3H), 3.70-3.80 (br s, 1H), 3.85 (s, 3H), 3.89 (s, 3H), 4.34 (m, 2H), 4.45-4.55 (br s, 1H), 6.07 (d, J=6.8, 1H) 6.79 (d, J=8, 1H), 6.91 (m, 1H), 7.26 (s, 1H), 8.16 (s, 1H). The crude reaction product was used directly in the next step.
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:23]2[CH:30]=[CH:29][C:26]([C:27]#[N:28])=[CH:25][CH:24]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[CH2:7]2.[C:31]([N:50]1[CH:54]=[C:53]([CH:55]=O)[CH:52]=[N:51]1)([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.N1CCCC1>CO>[CH3:1][C:2]1[C:3]([C:23]2[CH:24]=[CH:25][C:26]([C:27]#[N:28])=[CH:29][CH:30]=2)=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:11][C:12]1[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=[CH:14][CH:13]=1)[C:8](=[O:22])[C:7]2=[CH:55][C:53]1[CH:52]=[N:51][N:50]([C:31]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:54]=1
Reactant: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2
Reactant: O=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Solvent: CO
Solvent: C1CCNC1
Product: Cc1c(-c2ccc(C#N)cc2)ccc2c1N(Cc1cccc3ccccc13)C(=O)C2=Cc1cnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Temperature: 70 °C
Yield: 62.1 %

Procedure:
To a suspension of 4-(7-methyl-1-naphthalen-1-ylmethyl-2-oxo-2,3-dihydro-1H-indol-6-yl)-benzonitrile (300 mg, 0.773 mmol) and 1-trityl-1H-pyrazole-4-carbaldehyde (303 mg, 0.928 mmol) in methanol (5 ml) was added pyrrolidine (0.323 ml, 3.87 mmol). The reaction mixture was heated at 70° C. overnight. After cooled to room temperature, the reaction mixture formed a precipitate. The solid was collected and washed with cold methanol to give the title compound of 13B as a bright yellow solid (340 mg, 63.2% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=2)[CH2:4][C@H:3]1[O:22][CH2:23][CH3:24].[Cl:25][C:26]1[N:27]=[C:28]([C:33](O)=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CC(N(C)C)=O.ClCCl>[Cl:25][C:26]1[N:27]=[C:28]([C:33]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[O:9][C:10]([CH2:20][CH3:21])=[C:11]([C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:14])[N:12]=3)[CH2:4][C@H:3]2[O:22][CH2:23][CH3:24])=[O:34])[NH:29][C:30]=1[CH2:31][CH3:32]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1CC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC(=O)N(C)C
Solvent: ClCCl
Product: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)oc1CC
Yield: 50.4 %

Procedure:
The same operation as in Example (106d) was performed using butyl cis(±)-2-(4-amino-3-ethoxypiperidin-1-yl)-5-ethyl-1,3-oxazole-4-carboxylate obtained in Example (115b) (0.89 g, 2.63 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (85% content, 0.2 g, 1 mmol), WSC hydrochloride (0.5 g, 2.5 mmol), HOBt (0.2 g, 1.5 mmol), dichloromethane (5 mL) and DMA (3 mL), to obtain 0.25 g of the title compound as a colorless amorphous solid (49%).
Reaction SMILES: [C:1]([CH2:5][C:6]1(C(OC)=O)[C@@H:10]([CH:11]=[CH:12][CH:13]([OH:19])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:9][C@H:8](C(OC)=O)[C:7]1=[O:24])([O:3]C)=[O:2].[OH-].[Na+].Cl>O.CO>[OH:19][CH:13]([CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:12]=[CH:11][C@@H:10]1[CH2:9][CH2:8][C:7](=[O:24])[C@H:6]1[CH2:5][C:1]([OH:3])=[O:2]
Reactant: CCCCCC(O)C=C[C@H]1C[C@H](C(=O)OC)C(=O)C1(CC(=O)OC)C(=O)OC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCCC(O)C=C[C@@H]1CCC(=O)[C@H]1CC(=O)O

Procedure:
A suspension of dimethyl trans-1-(carbomethoxymethyl)-5-(3-hydroxy-1-octenyl)-2-oxo-1,3-cyclopentanedicarboxylate (26.24 g), described in Example 42, in a solution of sodium hydroxide (12 g) in 70 ml of water and 80 ml of methanol is heated at reflux for 2 hr. The reaction mixture is cooled, acidified to pH 6 with 2N HCl. The resulting oil is extracted with ether. The ether extract is washed with water, dried (MgSO4) and the solvent removed. The residue is subjected to chromatography on silica gel (850 g). Elution with methanol-chloroform (1:9) yields the title compound, νmaxfilm 3350, 1727 cm-1. The corresponding methyl ester of the title compound, prepared by treatment with diazomethane, has νmaxfilm 3412, 1737 cm-1.
Reaction SMILES: O.C(O)(=O)CC(CC(O)=O)(C(O)=O)O.C(=O)([O-])[O-].[K+].[K+].[CH3:21][C:22]1[CH:23]=[C:24]([CH:30]=[CH:31][C:32]=1[CH2:33][CH2:34][S:35][Si](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:25]([N:27]([CH3:29])[CH3:28])=[O:26]>CO>[SH:35][CH2:34][CH2:33][C:32]1[CH:31]=[CH:30][C:24]([C:25]([N:27]([CH3:28])[CH3:29])=[O:26])=[CH:23][C:22]=1[CH3:21]
Reactant: Cc1cc(C(=O)N(C)C)ccc1CCS[Si](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: Cc1cc(C(=O)N(C)C)ccc1CCS
Reaction time: 1 h
Yield: 98.8 %

Procedure:
Citric acid monohydrate (110 mg, 0.523 mmol) and potassium carbonate (52.8 mg, 0.382 mmol) were added to a solution of 3,N,N-trimethyl-4-(2-triphenylsilanylsulfanyl-ethyl)-benzamide (767 mg, 1.59 mmol) in MeOH (27 ml) at room temperature, and the mixture was stirred for one hour. The reaction mixture was concentrated under reduced pressure, and the residue was then dissolved in dichloromethane. The organic layer was washed with water, and then dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to give 4-(2-mercapto-ethyl)-3,N,N-trimethyl-benzamide (351 mg, 99%).
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.C(N([CH2:16][CH3:17])CC)C.[CH3:18]O>>[CH:16]([NH:6][C:5]1[CH:7]=[CH:8][C:9]2[O:10][CH2:1][O:2][C:3]=2[CH:4]=1)([CH3:17])[CH3:18]
Reactant: CCN(CC)CC
Reactant: CO
Reactant: Nc1ccc2c(c1)OCO2
Product: CC(C)Nc1ccc2c(c1)OCO2
Yield: 85 %

Procedure:
To a solution of 3,4-(methylenedioxy)aniline (9.0 g), and 9-iodopropane (5.9 mL) in methanol (100 mL) was added triethylamine (8.2 mL). The mixture was refluxed for 50 h, and then concentrated in vacuo. The residue was taken with 1:1 hexane/EtOAc (180 mL), washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by chromatography (3:1 hexane/EtOAc) to yield the title compound as an oil (10.1 g, 85%). 1H NMR (CDCl3): 6.64 (d, J=8.3, 1H), 6.23 (d, J=2.2, 1H), 6.03 (dd, J=2.2, 8.3, 1H), 5.85 (s, 2H), 3.51 (m, 1H), 3.19 (br s, 1H), 1.18 (d, J=6.1, 6H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH:4]1[CH2:9][NH:8][CH2:7][CH2:6][NH:5]1.[C:10]1([C:16](Cl)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(N([CH2:35][CH3:36])CC)C>C(Cl)Cl>[C:16]([O:1][CH2:2][CH2:3][CH:4]1[CH2:9][N:8]([C:16]([C:36]2[CH:35]=[CH:28][CH:23]=[CH:24][CH:25]=2)([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH2:7][CH2:6][NH:5]1)([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN(CC)CC
Reactant: OCCC1CNCCN1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Product: c1ccc(C(OCCC2CN(C(c3ccccc3)(c3ccccc3)c3ccccc3)CCN2)(c2ccccc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.3 %

Procedure:
To a mixture of 255 mg (1.96 mmol) of (±) 2-(2-hydroxyethyl)piperazine and 1.25 g (4.50 mmol) of triphenylmethyl chloride in 5.0 ml of methylene chloride was added 550 ml (3.95 mmol) of triethylamine in one portion and the mixture was stirred at room temperature overnight under a nitrogen atmosphere. The reaction was diluted with 5 mL of methylene chloride and washed with water (3×5 ml) and the layers separated. The aqueous layer was extracted with 10 mL of methylene chloride. The organic layers were combined and washed with 15 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to an orange foam. Flash chromatography on 75 g of silica gel using a gradient elution of 1:9 v/v ethyl acetate/hexane to 1:9 v/v ethanol/ethyl acetate yielded 401 mg (33%) of a foam.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([OH:18])=[O:17])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:31]1[CH2:36][CH2:35][O:34][C:32]1=[O:33]>CC(C)=O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]=[C:7]([O:9][C:10]3[CH:21]=[CH:20][C:13]([O:14][CH:15]([CH3:19])[C:16]([O:18][CH:31]4[CH2:36][CH2:35][O:34][C:32]4=[O:33])=[O:17])=[CH:12][CH:11]=3)[S:8][C:4]=2[CH:3]=1
Reactant: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)O
Reactant: O=C1OCCC1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(Oc1ccc(Oc2nc3ccc(Cl)cc3s2)cc1)C(=O)OC1CCOC1=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
21 g (0.06 mole) of 2-[4-(6-chloro-2-benzthiazolyloxy)-phenoxy]-propionic acid were initially taken together with 10.4 g (0.075 mole) of potassium carbonate in 100 ml of acetone and the mixture was stirred for approx. 1/2 hour at 45° C., a thick paste being formed. 11.6 g (0.07 mole) of 2-bromobutyrolactone in 50 ml of acetone were then added dropwise in the course of 1/2 hour. When the addition was complete, the reaction mixture became highly fluid; the conversion was followed by means of thin-layer chromatography and was approx. 70% after 5 hours. Altogether, the mixture was stirred for 16 hours at approx. 50° C. After cooling, the salt was filtered off, the acetone was removed by distillation and the residue was taken up in approx. 200 ml of toluene and washed with water and saturated sodium bicarbonate solution. After drying, the toluene was removed by distillation and the residue remaining was dried in vacuo (0.05 mbar) for one hour at approx. 70° C. The product remaining after drying was 22 g (91.3% of theory) of a very viscous oil, which was identified by 1H nuclear magnetic resonance spectroscopy as 2-oxotetrahydrofuran-3-yl 2-[4-(6-benzthiazolyloxy)-phenoxy]-propanoate. ##STR12##
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([CH2:15][CH:16]=[CH2:17])[C:12]([OH:14])=O)=[CH:5]2.[CH3:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[C:26]([N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH:11]([CH2:15][CH:16]=[CH2:17])[C:12]([NH:22][C:21]1[CH:23]=[CH:24][C:25]([C:26]([N:28]3[CH2:29][CH2:30][CH2:31][CH2:32]3)=[O:27])=[C:19]([CH3:18])[CH:20]=1)=[O:14])=[CH:5]2
Reactant: Cc1cc(N)ccc1C(=O)N1CCCC1
Reactant: C=CCC(C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: C=CCC(C(=O)Nc1ccc(C(=O)N2CCCC2)c(C)c1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Prepared by saponification of ethyl rac.-2-(1-tert-butoxycarbonyl-1H-5-chloroindol-2-yl)pent-4-enoate to rac.-2-(5-chloro-1H-indol-2-yl)pent-4-enoic acid analogously to Example 1f and subsequent amide coupling analogously to Example 1g with 3-methyl-4-(pyrrolidin-1-ylcarbonyl)aniline, TBTU, diisopropylethylamine in tetrahydrofuran. C25H26ClN3O2 (435.96); mass spectrum: (M+H)+=435.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH2:21].[CH2:27](OC(OCC)OCC)C>C(O)(C)C>[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[NH:21][CH:27]=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5]
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Reactant: COc1ccc(N)cc1Br
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Product: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(Br)c2)c(Cl)cc1Cl
Yield: 23.1 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (900 mg, 3.46 mmol) in 100 mL of iso-propanol was added 3-bromo-4-methoxyaniline (700 mg, 3.46 mmol). This mixture was heated to reflux and triethylorthoformate (3.3 mL, 19.8 mmol) was added dropwise. The reaction mixture was heated at reflux for 6 hours. The mixture was filtered while still warm and the collected white solid was washed with iso-propanol to give 376 mg of 3-bromo-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, mp >250° C.; MS (ES) m/z 467.7, 469.9, 471.7 (M−H)−
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27][CH2:26]4)=[N:21][NH:22]3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:41](Br)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11](/[CH:14]=[CH:15]/[C:16]2[CH:24]=[C:23]3[C:19]([C:20]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:29][CH2:30]4)=[N:21][N:22]3[CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1CCC(c2n[nH]c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1CCC(c2nn(Cc3ccccc3)c3cc(/C=C/C4CCN(C(=O)OC(C)(C)C)CC4)ccc23)CC1
Reaction time: 0.33 h

Procedure:
A solution of 4{-2-[3-(1-tert-butoxycarbonylmethyl-piperidin-4-yl)-1H-indazol-6-yl]-(E)-vinyl}-piperidine-1-carboxylic acid tert-butyl ester (152 mg, 0.29 mmol) in dry DMF (2 ml) under nitrogen was treated with sodium hydride (5 mg of a 60% dispersion in oil, 0.37 mmol) and stirred at +23° for 20 min. The solution was treated with a solution of benzyl bromide in dry DMF (0.1 ml of 3.14M solution, 0.314 mmol; Aldrich). The resulting mixture was stirred at +23° for 24 h and concentrated in vacuo. The residue was dissolved in dichloromethane (100 ml) and the solution washed with water (2×25 ml). The dried (MgSO4) organic layer was concentrated in vacuo onto silica (Merck 9385); purification by flash chromatography eluting with ether--cyclohexane (1:1) gave the title compound as a white foam (102 mg).