Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[N:20]=3)[CH:17]=2)[N:12]=[CH:11][CH:10]=1)C1C=CC=CC=1>[Pd].CCO.CCOC(C)=O>[F:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([F:32])[C:25]=1[C:21]1[N:20]=[C:19]([C:16]2[CH:17]=[C:18]3[C:13](=[CH:14][CH:15]=2)[N:12]=[CH:11][CH:10]=[C:9]3[OH:8])[CH:24]=[CH:23][CH:22]=1
Reactant: Fc1cccc(F)c1-c1cccc(-c2ccc3nccc(OCc4ccccc4)c3c2)n1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: Oc1ccnc2ccc(-c3cccc(-c4c(F)cccc4F)n3)cc12
Reaction time: 72 h
Yield: 70 %

Procedure:
To a solution of 4-(benzyloxy)-6-(6-(2,6-difluorophenyl)pyridin-2-yl)quinoline (1.0 equiv.) in 1:1 EtOH/EtOAc, at a concentration of 0.1 M, was added 10% palladium on carbon (0.1 eq.). The resultant heterogeneous solution was put under an atmosphere of hydrogen and was stirred for 72 hours. At this time the mixture was filtered through a pad of celite eluting with EtOAc. The volatiles were removed in vacuo yielding 6-(6-(2,6-difluorophenyl)pyridin-2-yl)quinolin-4-ol (70%). LCMS (m/z): 335.0 (MH+); LC Rt=3.09 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14]C1CO1)[N:9]=[CH:8][CH:7]=[C:6]2[O:18][C:19]1[C:20]([C:29](=[O:31])[CH3:30])=[N:21][C:22]2[C:27]([CH:28]=1)=[CH:26][CH:25]=[CH:24][CH:23]=2.F[C:33](F)(F)[C:34]([OH:36])=O.[OH-:39].[Na+].O>C(Cl)Cl>[OH:39][CH:33]([CH2:34][OH:36])[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[C:20]([C:29](=[O:31])[CH3:30])=[N:21][C:22]4[C:27]([CH:28]=3)=[CH:26][CH:25]=[CH:24][CH:23]=4)=[CH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: [OH-]
Reactant: O=C(O)C(F)(F)F
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCC1CO1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C(C)=O)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
1-[3-(6-Methoxy-7-oxiranylmethoxy-quinolin-4-yloxy)-quinolin-2-yl]-ethanone (compound 394) (150 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min. The mixture was then stirred at room temperature for 4 hr. The reaction solution was brought to 0° C. and was stirred. The reaction solution was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added thereto, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (140 mg, yield 90%).
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[C:1]([C:4]1[O:5][C:6]2[C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][N:29]3[CH2:28][CH2:27][N:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=4[O:19][CH3:18])[CH2:31][CH2:30]3)=[CH:11][CH:10]=[CH:9][C:7]=2[CH:8]=1)(=[O:3])[NH2:2]
Reactant: NC(=O)c1cc2cccc(OCC3CO3)c2o1
Reactant: COc1ccccc1N1CCNCC1
Solvent: CCO
Product: COc1ccccc1N1CCN(CC(O)COc2cccc3cc(C(N)=O)oc23)CC1

Procedure:
There was suspended 1.2 g (0.005 mole) of 2-carbamoyl-7-(2,3-epoxypropoxy)benzofuran in 15 ml of ethanol, and thereto 1.1 g (0.0055 mole) of 1-(2-methoxyphenyl)piperazine was added. Thereafter, the mixture was refluxed with heating for 2 hours. After completion of the reaction, the solvent was distilled away from the reaction mixture under reduced pressure, and then the resultant residue was crystallized from chloroform and petroleum ether.
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[Br:20][C:21]1[CH:22]=[N:23][C:24]([Cl:29])=[C:25]([CH:28]=1)[C:26]#[N:27].Cl.O1[CH2:36][CH2:35]OCC1>O1CCOCC1>[ClH:29].[Br:20][C:21]1[CH:28]=[C:25]([C:26]#[N:27])[C:24]([N:18]([CH2:22][CH2:21][CH2:28][CH2:25][CH2:24][CH2:35][CH3:36])[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)=[N:23][CH:22]=1
Reactant: C1COCCO1
Reactant: N#Cc1cc(Br)cnc1Cl
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Agent: Cl
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(Br)cc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained by using, as starting materials, 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 5-bromo-2-chloronicotinonitrile synthesized in reference to patent reference [WO0224694] and the like, and by operations similar to those of Example 265-1 and Example 265-2, was dissolved in dioxane, an excess amount of 4 mol/L hydrochloric acid-dioxane was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was concentrated under reduced pressure, azeotroped with diethyl ether, and the precipitated solid was collected by filtration to give the title compound as a white solid.
Reaction SMILES: C1(C)C=CC=CC=1OP([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])(OC1C=CC=CC=1C)=O.[OH-].[CH2:26]([N+](C)(C)C)C1C=CC=CC=1.CO.[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:49]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=[C:50]2C=O)(=[O:48])=[O:47])=[CH:42][CH:41]=1.[Cl-].[Na+]>C1COCC1>[Br:39][C:40]1[CH:45]=[CH:44][C:43]([S:46]([N:49]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[CH:51]=[C:50]2/[CH:26]=[CH:18]\[C:19]([O:21][CH2:22][CH3:23])=[O:20])(=[O:48])=[O:47])=[CH:42][CH:41]=1
Reactant: C[N+](C)(C)Cc1ccccc1
Reactant: CCOC(=O)CP(=O)(Oc1ccccc1C)Oc1ccccc1C
Reactant: O=Cc1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOC(=O)/C=C\c1cc2ccccc2n1S(=O)(=O)c1ccc(Br)cc1
Temperature: -70 °C
Reaction time: 0.25 h

Procedure:
To a solution of 0.4 mL of ethyl di-o-tolylphosphonoacetate in 15 mL of THF was added 0.67 g of a 40% benzyltrimethylammonium hydroxide-methanol solution under cooling in a dry ice-acetone bath, and the resulting mixture was stirred at −70° C. for 15 minutes. To the solution, a solution of 0.47 g of 1-[(4-bromophenyl)sulfonyl]-1H-indole-2-carbaldehyde in 5 mL of THF was added, the resulting mixture was stirred at −70° C. for 1.5 hours and under cooling in an ice-methanol bath for 1 hour. To the solution, 50 mL of saturated aqueous sodium chloride solution was added, the mixture was extracted with 100 mL of ethyl acetate, the extract was washed with water and saturated aqueous sodium chloride solution and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate-hexane=1:5) to obtain 0.53 g of ethyl (2Z)-3-{1-[(4-bromophenyl)sulfonyl]-1H-indol-2-yl}acrylate as a pale yellow syrup. ESI−: 432, 434
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[C:12]([O:16][CH3:17])(=[O:15])[CH:13]=[CH2:14].Cl>O>[C:3]([CH2:2][N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:14][CH2:13][C:12]([O:16][CH3:17])=[O:15])([OH:5])=[O:4]
Reactant: C=CC(=O)OC
Reactant: O=C(O)CNCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)CCN(CC(=O)O)CC(=O)O
Reaction time: 6 h
Yield: 96 %

Procedure:
133 g (1.00 mol) of iminodiacetic acid were dissolved in 530 ml of water, and the solution was adjusted to pH 7.0 with 40.5 g (1.00 mol) of solid NaOH. 86.0 g (1.00 mol) of methyl acrylate were added dropwise to this solution at 20° C., and the mixture was then stirred for 6 h. The methyl acrylate content after this time had fallen to 0.6% of the initial amount, and the pH was adjusted to 2 by adding 98.5 ml of concentrated HCl. Methyl N,N-bis(carboxymethyl)-3-aminopropionate separated out as colorless precipitate overnight at 5° C. Filtering off and drying resulted in 210 g (corresponding to a yield of 96% of theory) of a pure product of melting point 141° C.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([N:1]5[CH:5]=[CH:4][CH:3]=[N:2]5)=[CH:11][CH:10]=4)=[O:20])[CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: O=C(Nc1ccc(-n2cccn2)cc1)OCC(Cl)(Cl)Cl
Solvent: O
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(-n2cccn2)cc1)N1CCN(c2nc(-c3ccccc3)cs2)CC1

Procedure:
A solution of 2,2,2-trichloroethyl [4-(1H-pyrazol-1-yl)phenyl]carbamate (200 mg, 0.598 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (147 mg, 0.598 mmol), diisopropylethylamine (0.208 ml, 1.20 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate) to give the desired product as a solid. The solid was recrystallized from ethyl acetate to give 73.6 mg (28.6%) of the desired product as a solid.
Reaction SMILES: Br[C:2]1[N:3]([CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2.C([O-])([O-])=O.[Na+].[Na+].[C:35]1(B(O)O)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:25]([O:24][C:22](=[O:23])[CH2:21][N:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([O:19][CH3:20])=[O:18])[CH:5]=2)[C:10]([CH:11]2[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]2)=[C:2]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)OC(C)(C)C)c2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3)n(CC(=O)OC(C)(C)C)c2c1
Temperature: 80 °C
Yield: 88 %

Procedure:
To a solution of methyl 2-bromo-1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-1H-indole-6-carboxylate in dioxane (0.06 M) was added bis(triphenylphosphine)palladium(II) dichloride (0.2 eq) at RT under a nitrogen atmosphere. Then aqueous Na2CO3 (2 M; 4 eq) followed by phenylboronic acid (2.5 eq) were added and the reaction was heated to 80° C. for 2 h. The reaction mixture was allowed to cool and concentrated in vacuo. DCM was added and the organic phase washed with H2O, brine and dried over Na2SO4 before being filtered and concentrated in vacuo. The crude material was purified by automated FC (SiO2; 95:5 EtOAc/PE) to afford the title compound (88%). (ES+) m/z 448 (M+H)+
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:14][CH:15](O)[CH:16]=[CH2:17].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>COC(OC)(C)C>[CH2:14]([CH:9]1[CH2:8][C:7]2[C:11](=[CH:12][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:5][CH:6]=2)[C:10]1=[O:13])[CH:15]=[CH:16][CH3:17]
Reactant: CC(C)c1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: O
Product: CC=CCC1Cc2ccc(C(C)C)cc2C1=O
Yield: 38 %

Procedure:
A solution of 11.2 g of 6-isopropyl-1-indanone, 13.3 ml of 3-buten-2-ol and 110 mg of p-toluenesulfonic acid in 110 ml of 2,2-dimethoxy-propane was boiled under reflux for 89 hours on a water separator filled with molecular sieve (0.4 nm, 2 mm pearl shaped). The reaction mixture was subsequently concentrated in a vacuum and purified by column chromatography on silica gel (hexane/diethyl ether 5:1). In addition to 6.6 g of educt, there were obtained 5.6 g (38%) of (RS)-2-(2-buten-1-yl)-6-isopropyl-1-indanone as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[CH:4][C:3]=1[F:9].Cl[CH2:11][CH:12]=O>>[Br:1][C:2]1[N:7]2[CH:11]=[CH:12][N:8]=[C:6]2[CH:5]=[CH:4][C:3]=1[F:9]
Reactant: Nc1ccc(F)c(Br)n1
Reactant: O=CCCl
Product: Fc1ccc2nccn2c1Br
Temperature: 100 °C
Reaction time: 18 h
Yield: 89 %

Procedure:
A mixture of 6-bromo-5-fluoropyridin-2-ylamine (25 mg, 0.13 mmol) and chloroacetaldehyde (0.1 mL, 50 wt. % in water) in IMS (2 mL) was stirred at 100° C. in a sealed tube for 18 hours, then cooled to room temperature and loaded onto an Isolute® SCX-2 cartridge (5 g). The desired product was washed with MeOH then eluted with 2 M NH3 in MeOH to give 5-Bromo-6-fluoroimidazo[1,2-a]pyridine as a yellow oil (25 mg, 89%). 1H NMR (400 MHz, CHCl3-d): δ 7.84 (s, 1 H); 7.76 (m, 1 H); 7.61 (ddd, J=9.73, 4.67, 0.71 Hz, 1 H); 7.21-7.16 (m, 1 H).
Reaction SMILES: [I:1][C:2]1[C:3]([O:20][CH2:21][CH2:22][O:23][Si](C)(C)C)=[CH:4][C:5]([CH:17]([CH3:19])[CH3:18])=[C:6]([CH:16]=1)[O:7][C:8]1[C:9]([NH2:15])=[N:10][C:11]([NH2:14])=[N:12][CH:13]=1>CC(O)=O.C1COCC1.O>[NH2:14][C:11]1[N:10]=[C:9]([NH2:15])[C:8]([O:7][C:6]2[C:5]([CH:17]([CH3:18])[CH3:19])=[CH:4][C:3]([O:20][CH2:21][CH2:22][OH:23])=[C:2]([I:1])[CH:16]=2)=[CH:13][N:12]=1
Reactant: CC(C)c1cc(OCCO[Si](C)(C)C)c(I)cc1Oc1cnc(N)nc1N
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1cc(OCCO)c(I)cc1Oc1cnc(N)nc1N
Yield: 84.2 %

Procedure:
5-[5-Iodo-2-isopropyl-4-(2-trimethylsilanyloxy-ethoxy)-phenoxy]-pyrimidine-2,4-diamine (0.38 g, 0.69 mmol) in a solution of HOAc/THF/H2O in a ratio of 3:1:1.95 ml) was heated at 65° C. for 16 hrs. The pH of the reaction mixture was adjusted to pH=9 and extracted into methylene chloride. The combined eatracts was dried over Na2SO4, filtered and concentrated. Flash chromatography on silica (5% MeOH in methylene chloride with 0.1% NH40H) gave 2-[4-(2,4-Diamino-pyrimidin-5-yloxy)-2-iodo-5-isopropyl-phenoxy]-ethanol (0.25 g, 86% ) as a white solid. (M+H)=431
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.Cl[C:35]([CH2:37][O:38]C(=O)C)=[O:36]>>[OH:38][CH2:37][C:35]([NH:1][CH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[C:28]5[O:27][CH2:26][O:25][C:24]=5[CH:23]=[CH:22][C:21]=4[O:29][CH2:30][CH:31]4[CH2:33][CH2:32]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1)=[O:36]
Reactant: N[C@H]1CC[C@@H](NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1
Reactant: CC(=O)OCC(=O)Cl
Product: O=C(CO)NC1CCC(NC(=O)c2c[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from cis-4-(5-cyclopropylmethoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (4-amino-cyclohexyl)-amide (example A141) and acetic acid chlorocarbonyl-methyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH:11]=O)=[CH:3]1.[CH3:13][NH2:14]>CO>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][NH:14][CH3:13])=[CH:3]1
Reactant: Cn1cc(C=O)c2ccccc21
Reactant: CN
Solvent: CO
Product: CNCc1cn(C)c2ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-methylindole-3-carboxaldehyde (10.0 g, 62.8 mmole) in MeOH (100 mL) was added a solution of 2.0 M CH3NH2 in MeOH (126 mL, 252.0 mmole). The reaction was stirred at RT for 2 hrs, then was concentrated to a light yellow oil. This oil was dissolved in EtOH (300 mL), and NaB3H4 (2.38 g, 62.8 mmole) was added. After 2 hrs the reaction was concentrated to a slurry and dissolved in 1.0 N NaOH (75 mL). The aqueous solution was extracted with Et2O (2×200 mL) and the combined organic fractions were dried over Na2SO4 and concentrated. Flash chromatography on silica gel (9:1 CHCl3/MeOH containing 5% NH4OH) and drying in high vacuum left the title compound (10.1 g, 92%) as a faintly yellow oil: MS (ES) m/e 175 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][CH2:4][CH2:5][OH:6])[CH3:2].Cl[C:8]([CH3:12])([CH3:11])[C:9]#[CH:10]>C1COCC1.Cl[Cu]>[CH3:11][C:8]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][OH:6])([CH3:12])[C:9]#[CH:10]
Reactant: C#CC(C)(C)Cl
Reactant: CCNCCO
Agent: Cl[Cu]
Solvent: C1CCOC1
Product: C#CC(C)(C)N(CC)CCO
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 14.3 ml (146.3 mmol) 2-Ethylaminoethanol in 60 ml THF were added 362 mg (3.7 mmol) CuCl, followed by 7.5 g (73.1 mmol) 3-Chloro-3-methyl-1-butyne. The solution was stirred at RT for 2 h, the solvent was removed and the residue dissolved in ether/2M HCl. The phases were separated and after addition of Na2CO3 to the aqueous phase (pH9), it was extracted with ether. The ether phase was dried over Na2SO4 and concentrated. Distillation by Kugelrohr yielded 2-[(1,1-Dimethyl-prop-2-ynyl)-ethyl-amino]-ethanol as colorless oil, MS: 155 (M).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].C1(O)C=CC=CC=1.C1(C(C2C=CC=C(C)C=2C)C)C=CC=CC=1.[C:32](=[O:34])=[O:33]>O>[C:32]([OH:34])(=[O:33])[C:2]1[C:1](=[CH:6][CH:5]=[CH:4][CH:3]=1)[OH:7]
Reactant: [O-]c1ccccc1
Reactant: O=C=O
Agent: Cc1cccc(C(C)c2ccccc2)c1C
Agent: [Na+]
Solvent: O
Solvent: Oc1ccccc1
Product: O=C(O)c1ccccc1O

Procedure:
In a pressure reaction vessel were charged 100 g of sodium phenolate, 40 g of phenol and 400 g of 1-phenyl-1-(2,3-dimethylphenyl)-ethane, and a reaction was allowed to proceed at 170° C. and at a carbon dioxide pressure of 10 kg/cm2 (G) for 2 hours, with stirring. The reaction mixture was cooled and charged into 500 ml of water, followed by separation into the reaction medium layer and the water layer at 90° C. The water layer was extracted with 50 g of xylene, and the phenol was recovered with an aqueous sodium hydroxide solution from the reaction medium and extraction medium layers. After recovery of phenol, the water layer was made acid with dilute sulfuric acid to give 94.3 g of salicylic acid, with neither p-hydroxybenzoic acid nor isophthalic acid being detected as an isomer. The yield based on sodium phenolate was 90.2%, and the recovered phenol was 57 g, with the selectivity being 98.5%.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1.[CH2:24]([OH:29])[C:25]([CH3:28])([CH3:27])[CH3:26].[H-].[Na+]>CN(C=O)C>[F:1][C:2]([F:23])([F:22])[CH2:3][N:4]1[C:9](=[O:10])[C:8]([O:29][CH2:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[N:5]1
Reactant: CS(=O)(=O)c1ccc(-c2cnn(CC(F)(F)F)c(=O)c2Cl)cc1
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)COc1c(-c2ccc(S(C)(=O)=O)cc2)cnn(CC(F)(F)F)c1=O
Reaction time: 8 h
Yield: 79.9 %

Procedure:
2-(2,2,2-Trifluoroethyl)-4-chloro-5-[4-(methylsulfonyl)phenyl]-3(2H)-pyridazinone (150 mg, 0.41 mmol), prepared in Example 193E, and neopentyl alcohol (43 mg, 0.49 mmol) were dissolved in DMF (2 mL) and NaH (25 mg, 0.62 mmol, 60% in mineral oil) was added with shaking and left overnight. The reaction mixture was carefully quenched with saturated NH4Cl solution, diluted with ethyl acetate and extracted with 1 N HCl, twice, then water, 3 times, and then dried over MgSO4. After filtration of the drying agent and concentration of the filtrate in vacuo, the residue was purified by chromatography on silica gel (Biotage 40S) eluted with 2:1 hexanes-ethyl acetate. The product fractions were combined and evaporated to provide the title compound (yield: 137 mg, 76%). mp 145-146° C. 1H NMR (300 MHz, DMSO-d6) δ 0.76 (s, 9H), 3.28 (s, 3H), 4.06 (s, 2H), 5.02 (q, J=9 Hz, 2H), 7.88 (d, J=8 Hz, 2H), 8.04 (d, J=8 Hz, 2H), 8.13 (s, 1H). MS (DCI/NH3) m/z 419 (M+H)+, 436 (M+NH4)+. Anal. calc. for C18H21F3N2O4S: C, 51.67; H, 5.06; N, 6.69. Found: C, 51.47; H, 5.12; N, 6.48.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1.[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH2:26]>>[ClH:1].[NH2:22][CH2:23][CH:24]([OH:27])[CH2:25][NH:26][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[CH:3]=1
Reactant: COc1ccc(-c2cc(Cl)c3ccc(OC)cc3n2)cc1
Reactant: NCC(O)CN
Product: COc1ccc(-c2cc(NCC(O)CN)c3ccc(OC)cc3n2)cc1
Product: Cl

Procedure:
The title compound, m.p. 190-205° C. and MS: m/e=353 (M+), was prepared from 4-chloro-7-methoxy-2-(4-methoxy-phenyl)-quinoline and 1,3-diamino-2-propanol.
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH:14]=O)[CH:12]=2)[NH:7][CH:6]=1.[CH2:17]([O:21][C:22]([NH:24][NH2:25])=[O:23])[CH:18]([CH3:20])[CH3:19]>CO>[CH2:17]([O:21][C:22]([NH:24][N:25]=[CH:14][C:11]1[CH:12]=[C:13]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:4][CH2:3][N:2]([CH3:16])[CH3:1])=[O:23])[CH:18]([CH3:20])[CH3:19]
Reactant: CC(C)COC(=O)NN
Reactant: CN(C)CCc1c[nH]c2ccc(C=O)cc12
Solvent: CO
Product: CC(C)COC(=O)NN=Cc1ccc2[nH]cc(CCN(C)C)c2c1
Reaction time: 6 h
Yield: 85.3 %

Procedure:
A 100 ml flask is charged with 3-(2-dimethylamino-ethyl)-1H-indole-5-carbaldehyde (Reference Example 9; 2.16 g, 10 mmol), methanol (50 ml), and hydrazinecarboxylic acid isobutyl ester (1.32 g, 10 mmol). This mixture is heated at reflux, and after 6 hours the conversion is 70% by NMR. Heating is continued over night, and removal of the solvent gives the crude product, which is then filtered over a pad of silica (40 g) with the following eluent: CH2Cl2:methanol: NEt3 90:10:1 (v:v:v), ca. 700 ml. Removal of the solvent gives the product (2.82 g, 85%) as a pale yellow residue which is pure by NMR. 1H-NMR (CDCl3, 300 MHz) δ 0.93 (d, 6H, J=6.5 Hz, CH(CH3)2); 1.96 (m, 1H, CH(CH3)2); 2.22 (s, 6H, N(CH3)2); 2.52, 2.78 (2 m, 2H each, CH2CH2NHMe2); 3.97 (d, 2H, J=6.5 Hz, OCH2); 6.85 (s, 1H, H-2); 7.04 (d, 1H, J=7.6 Hz, H-7); 7.41 (dd, 1H, J=1.5 Hz, H-6); 7.61 (bs, 1H, H-4); 7.86 (br s, 1H, N═CH); 9.43 (br s, 1H, NH); 9.82 (br s, 1H, H-1). 13C-NMR (CDCl3, 75 MHz) δ 19.36 (CH(CH3)2); 23.59 (CH2); 28.39 (CH(CH3)2); 45.53 (N(CH3)2); 60.32 (CH2NMe2); 71.87 (OCH2); 112.20 (C-7); 114.21 (C-3); 119.35 (C-4); 120.58 (C-6); 123.41 (C-2); 125.17 (C-5); 127.48 (C-9); 137.76 (C-8); 146.80 (N═CH); 154.91 (NC═O).
Reaction SMILES: C([N:3](CC)CC)C.[CH2:8]([C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1[CH:12]=CC(O)=O)[CH3:9].[CH2:21]([O:23]C(Cl)=O)[CH3:22].[N-]=[N+]=[N-].[Na+]>CC(C)=O.O>[CH2:8]([C:10]1[NH:3][C:21](=[O:23])[C:22]2[C:19]([CH:20]=1)=[CH:18][CH:17]=[CH:11][CH:12]=2)[CH3:9]
Reactant: CCOC(=O)Cl
Reactant: CCN(CC)CC
Reactant: CCc1ccccc1C=CC(=O)O
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCc1cc2ccccc2c(=O)[nH]1
Reaction time: 0.17 h

Procedure:
88.3 g (0.87 mole) of triethylamine in 100 ml of absolute acetone were added dropwise to 128 g (0.73 mole) of 2-ethylcinnamic acid in 1200 ml of absolute acetone. The whole was stirred for 10 minutes and 94.6 g (0.87 mole) of chloroformic acid ethyl ester in 100 ml of absolute acetone were added dropwise with stirring. After 1 hour, a concentrated solution of 65 g (1 mole) of sodium azide in a small amount of water was added dropwise and stirring was continued for 30 minutes. The major part of the solvent was removed at room temperature under reduced pressure and the residue was poured onto ice. Extraction was effected with methylene chloride and the organic phase was washed with water and dried carefully over MgSC4. This solution of the acid azide was added dropwise into 350 ml of boiling diphenyl ether, during which time the methylene chloride was simultaneously distilled off. The whole was further heated for 1 hour under reflux and then the solvent was removed under reduced pressure. The residue was recrystallized from ethanol. M.p. 139° to140° C.