Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([C:33]([F:36])([F:35])[F:34])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:37][O:38][CH2:39][C:40](O)=[O:41]>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:30])([F:31])[F:32])[CH:26]=[C:25]([C:33]([F:36])([F:34])[F:35])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:40](=[O:41])[CH2:39][O:38][CH3:37])[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Reactant: COCC(=O)O
Agent: Cl
Product: COCC(=O)N1CC[C@H](OCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (31.8 mg) obtained in Example 25 and methoxyacetic acid (9.2 μl) were reacted and treated in the same manner as in the method described in Example 33 to obtain the title compound.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)=[N:6][NH:5][C:4]1=S)[CH3:2]>[Ni].C(O)C>[CH2:1]([N:3]1[CH:4]=[N:5][N:6]=[C:7]1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:2]
Reactant: CCn1c(-c2ccncc2)n[nH]c1=S
Agent: [Ni]
Solvent: CCO
Product: CCn1cnnc1-c1ccncc1
Temperature: 65 °C
Reaction time: 28 h
Yield: 81 %

Procedure:
4-Ethyl-5-pyridin-4-yl-2,4-dihydro-[1,2,4]triazole-3-thione (4.2 g, 20.4 mmol) was slowly added to Raney nickel (˜40 g, washed three times with 25 mL portions of ethanol) in ethanol (50 mL). The resulting mixture was stirred at 65° C. for approximately 28 hours. The solution mixture was carefully filtered and concentrated in vacuo to yield the title compound (2.88 g, 81.3%). 1H NMR (CDCl3) δ (ppm): 8.81 (d, 2H), 8.33 (s, 1H), 7.62 (d, 2H), 8.18 (q, 2H), 1.51 (t, 3H).
Reaction SMILES: [OH:1][C:2]1[C:15]2[C@:14]34[CH2:16][CH2:17][NH:18][C@@H:8]([C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:21][CH3:22].C([O-])(O)=O.[Na+].[CH:28]1([CH2:31]Br)[CH2:30][CH2:29]1>CN(C=O)C>[CH:28]1([CH2:31][N:18]2[CH2:17][CH2:16][C@@:14]34[C:15]5[C:2]([OH:1])=[C:3]([O:21][CH3:22])[CH:4]=[CH:5][C:6]=5[CH2:7][C@@H:8]2[C@@H:9]3[CH2:10][C@H:11]([CH3:20])[C:12](=[O:19])[CH2:13]4)[CH2:30][CH2:29]1
Reactant: BrCC1CC1
Reactant: COc1ccc2c(c1O)[C@]13CCN[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc2c(c1O)[C@]13CCN(CC4CC4)[C@H](C2)[C@@H]1C[C@H](C)C(=O)C3

Procedure:
A mixture of 18a (5.00 g, 16.6 mmole), NaHCO3 (2.90 g, 34.6 mmole) and cyclopropylmethyl bromide (2.80 g, 20.8 mmole) in DMF (50 ml) was heated at 100° under argon for 2 hours. The mixture was cooled, filtered from insoluble material and the filtrate evaporated in high vacuum. The residue was dissolved in dilute NH4OH and extracted with three portions of toluene. The toluene was evaporated to give 4.89 g (83%) of crystalline 19a-CPM. Two recrystallizations from ethanol gave analytically pure 19a-CPM, mp 176.5°-178°. NMR: δ 6.56, s, 2H (aromatic); 6.17, S, 1H, (hydroxy proton); 4.23, d, 1H, (H-5α, J=12.5 Hz); 3.78 (CH3O--); 1.30, d, (H-5β); 0.87, d, 3H (7α-CH3, J=6.5 Hz),
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26](Br)[CH:25]=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:2].[C:45]1(B(O)O)[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:1]([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[CH:25]=[C:24]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCc3ccccc3)c2)c1CCC(=O)OCC
Reactant: OB(O)c1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCc3ccccc3)cc(-c3ccccc3)c2)c1CCC(=O)OCC
Yield: 88.4 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-benzyloxy-5-bromo-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (260 mg, 0.39 mmol), phenylboronic acid (95 mg, 0.78 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (253 mg, 0.78 mmol) to obtain 4-[3-[6-(5-benzyloxy-biphenyl-3-yloxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (230 mg, 89%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C42H50O7 (M+Na)+ 689.3449. found 689.3447.
Reaction SMILES: Br[C:2]1(Br)[C:7]2=[N:8][C:9]3[C:14]([C:15](=[O:16])[N:6]2[CH:5]([CH3:17])[CH2:4][CH2:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[C:19]1([NH:25][NH2:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[C:19]1([NH:25][N:26]=[C:2]2[C:7]3=[N:8][C:9]4[C:14]([C:15](=[O:16])[N:6]3[CH:5]([CH3:17])[CH2:4][CH2:3]2)=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NNc1ccccc1
Reactant: CC1CCC(Br)(Br)c2nc3ccccc3c(=O)n21
Solvent: CCO
Product: CC1CCC(=NNc2ccccc2)c2nc3ccccc3c(=O)n21
Yield: 75 %

Procedure:
3.74 g (0.01 mole) of 6,6-dibromo-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b)quinazoline and 4.32 g. (0.04 mole) of phenyl hydrazine are heated in 40 ml. of ethanol for 10 hours. The precipitated crystals are filtered after cooling. The filtered product is suspended in 100 ml. water containing 2.72 g. (0.02 mole), sodium acetate, filtered and washed with water. 2.4 g. (75%) orange 6-phenylhydrazono-9-methyl-11-oxo-6,7,8,9-tetrahydro-11H-pyrido[2,1-b]quinazoline are obtained which after recrystallization from ethanol melts at 185°-187° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1.Cl[C:33]([O:35][CH2:36][CH3:37])=[O:34]>>[CH2:36]([O:35][C:33]([N:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:27]5[O:26][CH2:25][O:24][C:23]=5[CH:22]=[CH:21][C:20]=4[O:28][CH2:29][CH2:30][CH3:31])[C:13]=3[NH:12][CH:11]=2)=[O:9])[CH2:3][CH2:2]1)=[O:34])[CH3:37]
Reactant: CCOC(=O)Cl
Reactant: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCNCC4)c[nH]c13)OCO2
Product: CCCOc1ccc2c(c1-c1ncnc3c(C(=O)NC4CCN(C(=O)OCC)CC4)c[nH]c13)OCO2

Procedure:
Starting from 4-(5-propoxy-benzo[1,3]dioxol-4-yl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide (example A177) and ethyl chloroformate the title compound was obtained as colorless solid.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:22]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:27]=3[N:26]=2)[CH2:23][OH:24])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[N:7](S(C1C=CC(C)=CC=1)(=O)=O)[CH:6]=[CH:5]2.C(N)CC(C)C.[OH-].[K+]>CCO>[CH3:1][C:2]1[C:3]([CH:22]([C:25]2[NH:29][C:28]3[CH:30]=[CH:31][C:32]([C:34]#[N:35])=[CH:33][C:27]=3[N:26]=2)[CH2:23][OH:24])=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[CH:5]2
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(CO)c4nc5cc(C#N)ccc5[nH]4)c(C)cc(C)c32)cc1
Agent: CC(C)CCN
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)c2[nH]ccc2c1C(CO)c1nc2cc(C#N)ccc2[nH]1
Temperature: 100 °C
Reaction time: 0.5 h

Procedure:
A mixture of (±)-2-(1-(5,7-dimethyl-1-tosyl-1H-indol-4-yl)-2-hydroxyethyl)-1H-benzo[d]imidazole-5-carbonitrile, isoamylamine (103 mg, 1.18 mmol) and KOH (66.0 mg, 1.18 mmol) in EtOH (2 mL) was stirred at 100° C. for 30 min under microwave irradiation. The reaction mixture was concentrated and the residue was partitioned between EtOAc and sat. aq. NH4Cl. The aqueous layer was extracted with EtOAc. The combined organics were washed with brine, dried over sodium sulfate and concentrated. The residue was purified with reverse phase HPLC (HC-B) to provide the title compound. 1H NMR (400 MHz, ACETONITRILE-d3) 9.18 (br. s., 1H) 7.87 (br. s., 1H) 7.47 (d, J=7.07 Hz, 2H) 7.01 (t, J=2.84 Hz, 1H) 6.85 (s, 1H) 5.79-5.86 (m, 1H) 4.92 (dd, J=8.91, 5.49 Hz, 1H) 4.59 (dd, J=10.99, 9.09 Hz, 1H) 3.92 (dd, J=11.05, 5.49 Hz, 1H) 2.42 (s, 6H). MS (ESI+) m/z 331.3 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:15][CH3:16])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:33])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:3]=1[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH:12]([O:17][CH3:18])[C:13]([NH:15][CH3:16])=[S:33]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CNC(=O)C(OC)c1ccccc1COc1cc(C)ccc1C
Solvent: Cc1ccccc1
Product: CNC(=S)C(OC)c1ccccc1COc1cc(C)ccc1C
Temperature: 80 °C
Reaction time: 2 h
Yield: 112.7 %

Procedure:
A solution of 2-[2-(2,5-dimethylphenoxymethyl)phenyl]-2-methoxy-N-methylacetamide (0.12 g, 0.38 mmol) and Lawesson's reagent (0.14 g, 0.35 mmol) in toluene (5 ml) was heated with stirring at 80° C. for 2 hours. The mixture was cooled to room temperature, and purified by column chromatography on silica gel (n-hexane/ethyl acetate=4/1) to give the desired compound 2-[2-(2,5-dimethylphenoxymethyl)-phenyl]-2-methoxy-N-methylthioacetamide (0.13 g, 100%) as an oil.
Reaction SMILES: S(=O)(=O)(O)O.[N+:6]([O-:9])(O)=[O:7].[CH3:10][N:11]1[C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]([CH3:19])=[N:12]1>>[CH3:10][N:11]1[C:15]([C:16]([OH:18])=[O:17])=[C:14]([N+:6]([O-:9])=[O:7])[C:13]([CH3:19])=[N:12]1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(C(=O)O)n(C)n1
Agent: O=S(=O)(O)O
Product: Cc1nn(C)c(C(=O)O)c1[N+](=O)[O-]

Procedure:
One-hundred twelve g concentrated sulfuric acid is added to 42 ml 90% nitric acid at 70°-80° C., 39 g of 1,3-dimethylpyrazole-5-carboxylic acid is added in portions over one hour such that the temperature does not go over 90° C. After 2.5 hours the reaction mixture is cooled and poured over ice. The resulting percipitate was filtered, dried, and recrystallized in ethanol, mp 141°-142° C.
Reaction SMILES: [CH3:1][C:2]([CH2:6][OH:7])([CH2:4][OH:5])[CH3:3].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH3:39])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1(C)C=CC=CC=1>[CH2:20]([O:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]2[O:7][CH2:6][C:2]([CH3:3])([CH3:1])[CH2:4][O:5]2)=[CH:30][C:29]=1[O:36][CH2:37][CH2:38][CH3:39])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCOc1cc(C=O)ccc1OCc1ccccc1
Reactant: CC(C)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CCCOc1cc(C2OCC(C)(C)CO2)ccc1OCc1ccccc1
Temperature: 25 °C
Yield: 64.8 %

Procedure:
1.45 g (13.9 mmol) of neopentylglycol and 88 mg (0.46 mmol) of p-toluenesulfonic acid monohydrate were added to a solution of 1.25 g (4.63 mmol) of 4-benzyloxy-3-propoxybenzaldehyde in 50 ml of toluene and then refluxed for 1 hour under a water separator. Thereafter, the reaction mixture was cooled to room temperature and partitioned between toluene and a saturated sodium bicarbonate solution, and the organic phase was washed several times with water, dried over magnesium sulfate, filtered and evaporated down. Crystallization of the residue from 10 ml of diethyl ether gave 1.07 g of 2-(4-benzyloxy-3-propoxyphenyl)-5,5-dimethyl-1,3-dioxane.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].[O-][Cl:15].[Na+]>CCO>[Cl:15][C:6]1[C:5]2[C:9](=[CH:10][C:2]([F:1])=[C:3]([N+:11]([O-:13])=[O:12])[CH:4]=2)[NH:8][N:7]=1
Reactant: [O-]Cl
Reactant: O=[N+]([O-])c1cc2cn[nH]c2cc1F
Agent: [Na+]
Solvent: CCO
Product: O=[N+]([O-])c1cc2c(Cl)n[nH]c2cc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 57.6 %

Procedure:
6-Fluoro-5-nitroindazole (850 mg, 4.693 mmol, 1.0 equiv) was dissolved in 20 mL EtOH, NaOCl (10 mL, 164.26 mmol, 35 equiv) was added and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated en vacuo to remove EtOH was then diluted with EtOAc and water. The phases were separated, and the organic phase was washed once with satd. NaHCO3, and once with satd. NaCl. The organic phase was dried over Na2SO4, filtered, and concentrated en vacuo. The residue was purified by flash chromatography (10-100% EtOAc in Hexanes) to provide 583 mg (58%) of the title compound as a light orange solid. MS (ES+) m/e 216 [M+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13]Cl.[OH:21][CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.[I-].[K+].[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34]>CN1CCCC1.O>[C:30]([OH:37])(=[O:36])/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[O:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:11][CH2:12][CH2:13][N:25]1[CH2:26][CH2:27][CH:22]([OH:21])[CH2:23][CH2:24]1
Reactant: OC1CCNCC1
Reactant: ClCCCC(Oc1cc(Cl)ccc1Cl)c1ccccc1
Agent: CN1CCCC1
Agent: O=C(O)/C=C/C(=O)O
Agent: [I-]
Solvent: O
Product: OC1CCN(CCCC(Oc2cc(Cl)ccc2Cl)c2ccccc2)CC1
Reaction time: 4 h
Yield: 45 %

Procedure:
A solution of the product from Example 22 step (b) (0.20 g, 0.61 mmol), 4-hydroxypiperidine (0.185 g, 1.83 mmol) and potassium iodide (0.051 g, 0.31 mmol) in N-methylpyrrolidine was heated to 100° C. in a sealed vessel and stirred for 4 h. The reaction was cooled, poured into water (50 ml) and the mixture extracted with ethyl acetate (3×50 ml). The combined organic extracts were washed with water (3×30 ml), dried (magnesium sulphate) and evaporated. The residue was dissolved in methanol and treated with one equivalent of fumaric acid. This was stirred for ten minutes then the solvent was removed in vacuo. The solid residue was triturated with ethyl acetate and the white solid obtained filtered off and dried to give the title compound (0.140 g, 45%).
Reaction SMILES: [Br:1][CH2:2][CH2:3][C:4]1[CH:9]=[C:8]([Cl:10])[C:7]([OH:11])=[C:6]([Cl:12])[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([O:23][CH3:24])=[O:22]>CC(C)=O>[Br:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([Cl:12])[C:7]([O:11][CH2:20][C:21]([O:23][CH3:24])=[O:22])=[C:8]([Cl:10])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: Oc1c(Cl)cc(CCBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1c(Cl)cc(CCBr)cc1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-(2-bromoethyl)-2,6-dichlorophenol (104 mg) in acetone (1.2 ml) were added potassium carbonate (133 mg) and methyl bromoacetate (73 μl), and the mixture was stirred for 3 hours at room temperature. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. Purification of the residue by medium pressure liquid column chromatography on silica gel (eluent: hexane/ethyl acetate=12/1) gave methyl 2-[4-(2-bromoethyl)-2,6-dichlorophenoxy]acetate (82 mg).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].[Cl:9][C:10]1[N:11]=[N:12][C:13](Cl)=[CH:14][CH:15]=1>C1C=CC=CC=1>[NH2:3][C:4]([CH3:8])([CH3:7])[CH2:5][O:6][C:13]1[N:12]=[N:11][C:10]([Cl:9])=[CH:15][CH:14]=1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(N)CO
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CC(C)(N)COc1ccc(Cl)nn1
Yield: 71.1 %

Procedure:
To a suspension of 1.5 g of 61% sodium hydride in 20 ml of benzene was added dropwise at room temperature 2.7 g of 2-amino-2-methylpropanol, and then a solution of 4.5 g of 3,6-dichloropyridazine in 20 ml of benzene was added. The mixture was refluxed for one hour. The reaction mixture was cooled, washed with water, and dried over magnesium sulfate. The solvent was evaporated to give 4.33 g of 3-(2-amino-2-methylpropoxy)-6-chloropyridazine.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.O.[N:10]([C:13]([CH3:18])([CH3:17])[C:14](Cl)=[O:15])=[N+:11]=[N-:12].[OH-].[Na+]>O1CCOCC1>[OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:14](=[O:15])[C:13]([N:10]=[N+:11]=[N-:12])([CH3:18])[CH3:17])[CH2:5][CH2:4]1
Reactant: OCC1CCNCC1
Reactant: CC(C)(N=[N+]=[N-])C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(N=[N+]=[N-])C(=O)N1CCC(CO)CC1

Procedure:
15 g. (0.13 mole) 4-Hydroxymethylpiperidine are dissolved in 130 ml. water and 30 ml. dioxan and 19.4 g. (0.13 mole) 2-azido-2-methylpropionic acid chloride (according to analogous literature: J.A.C.S., 77, 112/1955) added dropwise thereto. The pH of the solution is kept at 12 to 12.5 by the simultaneous dropwise addition of 2N aqueous sodium hydroxide solution. After ending of the reaction, the reaction mixture is extracted with diethyl ether. After drying with anhydrous sodium sulphate and evaporating, there are obtained 17.8 g. of crude oil, i.e. 60% of theory, which can be used in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:21]=[CH:22][CH:23]=1)[O:5][C:6]1[CH:7]=[CH:8][C:9]2[N:10]([CH:12]=[C:13]([NH:15][C:16]([CH:18]3[CH2:20][CH2:19]3)=[O:17])[N:14]=2)[N:11]=1.[OH:24][C:25]([C:28]1[S:29][C:30]([C:33](O)=[O:34])=[CH:31][N:32]=1)([CH3:27])[CH3:26].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O>[CH:18]1([C:16]([NH:15][C:13]2[N:14]=[C:9]3[CH:8]=[CH:7][C:6]([O:5][C:4]4[CH:3]=[C:2]([NH:1][C:33]([C:30]5[S:29][C:28]([C:25]([OH:24])([CH3:26])[CH3:27])=[N:32][CH:31]=5)=[O:34])[CH:23]=[CH:22][CH:21]=4)=[N:11][N:10]3[CH:12]=2)=[O:17])[CH2:20][CH2:19]1
Reactant: CC(C)(O)c1ncc(C(=O)O)s1
Reactant: Nc1cccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)c1ncc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)c2)s1
Yield: 42.2 %

Procedure:
Using N-[6-(3-aminophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.49 mmol), 2-(1-hydroxy-1-methylethyl)-1,3-thiazole-5-carboxylic acid (96 mg, 0.51 mmol), N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (95 mg, 0.50 mmol), 1-hydroxybenzotriazole (67 mg, 0.50 mmol) and N,N-dimethylformamide (8.0 mL) as starting materials and in the same manner as in Example 318, the title compound (99 mg, 43%) was obtained as a white powder.
Reaction SMILES: COC([C:5]1[N:6]=[C:7]([NH:10][C:11](=[O:26])[CH:12]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)[CH2:13][CH:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[S:8][CH:9]=1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[O:33]1CCC[CH2:34]1>>[Cl:25][C:22]1[CH:21]=[CH:20][C:19]([CH:12]([CH2:13][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18]2)[C:11]([NH:10][C:7]2[S:8][C:9]([CH2:34][OH:33])=[CH:5][N:6]=2)=[O:26])=[CH:24][CH:23]=1
Reactant: COC(=O)c1csc(NC(=O)C(CC2CCCC2)c2ccc(Cl)cc2)n1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: O=C(Nc1ncc(CO)s1)C(CC1CCCC1)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 55.4 %

Procedure:
A solution of 2-[2-(4-chloro-phenyl)-3-cyclopentyl-propionylamino]-thiazole-4-carboxylic acid methyl ester (prepared as in Example 32, 127.7 mg, 0.31 mmol) in tetrahydrofuran (0.4 mL) was added to a slurry of lithium aluminum hydride (15.0 mg, 0.39 mmol) in tetrahydrofuran (2.24 mL) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction was then quenched by the dropwise addition of water. The reaction was then diluted with more water (25 mL) and extracted with ethyl acetate (3×25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 75/25 hexanes/ethyl acetate) afforded 2-(4-chloro-phenyl)-3-cyclopentyl-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide (63.4 mg, 55.4%) as a white solid: mp 115–117° C.; EI-HRMS m/e calcd for C18H21ClN2O2S (M+) 364.1012, found 364.1004.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C1C(=O)N([Br:32])C(=O)C1>CC#N>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[C:14]([Br:15])=[C:13]([Br:16])[N:12]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[C:9]2=[C:10]([Br:32])[N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1
Reactant: O=C1CCC(=O)N1Br
Solvent: CC#N
Product: CCOC(=O)c1nc(Br)c2c(c1O)c(Br)c(Br)n2-c1ccc(F)cc1

Procedure:
Prepared in analogy to that of Example 133(a) from 2,3-dibromo-1-(4-fluoro-phenyl)-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester and NBS in MeCN. The title compound, ESI MS (m/z): 535 (M+H)+.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([N:9]([CH3:21])[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[CH:6]=[C:5]([CH3:22])[C:4]=1[NH:23]C(=O)C.[OH-].[K+]>>[CH3:2][C:3]1[CH:8]=[C:7]([N:9]([CH3:21])[CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]([F:18])([F:19])[F:20])=[CH:15][CH:16]=2)[CH:6]=[C:5]([CH3:22])[C:4]=1[NH2:23]
Reactant: CC(=O)Nc1c(C)cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Product: Cc1cc(N(C)Cc2ccc(C(F)(F)F)cc2)cc(C)c1N
Temperature: 130 °C
Yield: 56.8 %

Procedure:
Concentrated aqueous hydrochloric acid (2 mL) was added to N-{2,6-dimethyl-4-[methyl-(4-trifluoromethyl-benzyl)-amino]-phenyl}-acetamide (0.20 g) and heated to 130° C. for 80 minutes in a sealed microwave process vial. The crude mixture was poured onto solid potassium hydroxide (2 g) mixed with ice. The product was extracted with 1,2-dichloroethane (100 mL), and the organic phase was filtered through solid sodium carbonate (5 g), dried over magnesium sulfate and concentrated in vacuo to furnish 0.10 g (57% yield) of the title compound as a pale brown oil. LC-MS (m/z) 309 (MH+); tR=2.11, (UV, ELSD) 99%, 98%. 1H NMR (500 MHz, DMSO-d6): 2.03 (s, 6H), 2.76 (s, 3H), 3.94 (b, 2H), 4.41 (s, 2H), 6.39 (s, 2H), 7.42 (d, 2H), 7.65 (d, 2H).
Reaction SMILES: Br[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH2:7][CH2:8][N:9]([CH3:11])[CH3:10].CN(CCN(C)C)C.[Li]CCCC.[F:29][C:30]1[C:35]([CH:36]=[O:37])=[CH:34][CH:33]=[CH:32][N:31]=1>C1(C)C=CC=CC=1>[CH3:10][N:9]([CH3:11])[CH2:8][CH2:7][C:6]1[S:5][C:4]2[CH:12]=[CH:13][CH:14]=[CH:15][C:3]=2[C:2]=1[CH:36]([C:35]1[C:30]([F:29])=[N:31][CH:32]=[CH:33][CH:34]=1)[OH:37]
Reactant: O=Cc1cccnc1F
Reactant: CN(C)CCc1sc2ccccc2c1Br
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Product: CN(C)CCc1sc2ccccc2c1C(O)c1cccnc1F
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 25.9 %

Procedure:
To a cooled (−78° C.) solution of [2-(3-bromo-benzo[b]thiophen-2-yl)-ethyl]-dimethyl-amine (400 mg, 1.4 mmol) in anhydrous toluene (16 mL), TMEDA (240 uL, 2.8 mmol) was added followed by nBuLi (1.0 mL, 1.7 mmol, 1.6M in hexanes). The mixture was stirred for 40 min at −78° C. and 2-fluoro-3-pyridine-carbaldehyde (0.70 g, 5.6 mmol) was added. The mixture was stirred for 12 hrs during which the mixture warmed up to room temperature, quenched with 1M HCl (2 mL) and extracted with EtOAc (3×). The combined organic layers were dried (Na2SO4), concentrated and purified by silical gel column chromatography (gradient of DCM/MeOH=98/2 up to 90/10) to afford [2-(2-dimethylamino-ethyl)-benzo[b]thiophen-3-yl]-(2-fluoro-pyridin-3-yl)-methanol (Compound 24-1) (0.12 g) in 26% yield. MH+=331.0.
Reaction SMILES: [NH2:1][CH:2]1[CH2:11][CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3]1.[C:16]1([N:22]=[C:23]=[S:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1C=CC=CC=1>[CH2:11]1[CH:10]2[N:5]([CH2:6][CH2:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=32)[CH2:4][CH2:3][CH:2]1[NH:1][C:23]([NH:22][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[S:24]
Reactant: S=C=Nc1ccccc1
Reactant: NC1CCN2CCc3ccccc3C2C1
Solvent: c1ccccc1
Product: S=C(Nc1ccccc1)NC1CCN2CCc3ccccc3C2C1
Yield: 56.7 %

Procedure:
2-Amino-1,3,4,6,7,11b-hexahydro-2H-benzo[a]quinolizine (0.766 g) and phenyl isothiocyanate (0.563 g) were condensed together in benzene (50 ml) in a manner analogous to that of Example 1 to give the title compound (0.724 g). Crystallization from EtOH/HCl afforded the hydrochloride (0.950 g), m.p. 213.5° C. C20H23N3S.HCl requires C, 64.25; H, 6.47; N, 11.24% Found: C, 63.94; H, 6.56; N, 11.16%.