Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]#[N:17])=[C:12]([F:18])[CH:11]=1)(=O)OCC)C.[H-].[Na+].[CH3:21][C:22]1[N:23]=[C:24]([C:33]2[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=2)[S:25][C:26]=1[C:27](=O)[CH2:28][CH2:29][CH2:30][CH3:31]>O1CCCC1>[F:18][C:12]1[CH:11]=[C:10](/[CH:9]=[C:27](/[C:26]2[S:25][C:24]([C:33]3[CH:34]=[CH:35][C:36]([C:39]([F:41])([F:42])[F:40])=[CH:37][CH:38]=3)=[N:23][C:22]=2[CH3:21])\[CH2:28][CH2:29][CH2:30][CH3:31])[CH:15]=[CH:14][C:13]=1[C:16]#[N:17]
Reactant: CCCCC(=O)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Reactant: CCOP(=O)(Cc1ccc(C#N)c(F)c1)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCC/C(=C\c1ccc(C#N)c(F)c1)c1sc(-c2ccc(C(F)(F)F)cc2)nc1C
Yield: 98.2 %

Procedure:
1.0 g (4-Cyano-3-fluoro-benzyl)-phosphonic acid diethyl ester was dissolved in 50 ml tetrahydrofuran and cooled in an ice bath. At 0° C. 103 mg sodium hydride were added and the mixture stirred for fifteen minutes. Then 1.2 g 1-[4-Methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-pentan-1-one, dissolved in 20 ml tetrahydrofuran, were added dropwise. The cooling bath was removed and the reaction mixture stirred at room temperature for two hours. Then 1.0 g (4-Cyano-3-fluoro-benzyl)-phosphonic acid diethyl ester and 103 mg sodium hydride were added and the reaction mixture stirred for an additional hour. Then 20 ml water were added and the mixture extracted five times with portions of 25 ml ethyl acetate. The combined organic layers were dried over MgSO4, then the solvent was removed in vacuo to obtain 1.6 g 2-Fluoro-4-{(E)-2-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-hex-1-enyl}-benzonitrile as a yellow oil.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:13]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:14]=2[O:15][CH2:16][C@@H:17]2[CH2:20][CH2:19][N:18]2C(OC(C)(C)C)=O)=[O:12])/[N:7]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.O.[C:48]1([CH3:58])[CH:53]=[CH:52][C:51]([S:54]([OH:57])(=[O:56])=[O:55])=[CH:50][CH:49]=1>C(Cl)Cl.CCOC(C)=O>[C:48]1([CH3:58])[CH:49]=[CH:50][C:51]([S:54]([OH:57])(=[O:55])=[O:56])=[CH:52][CH:53]=1.[NH:18]1[CH2:19][CH2:20][C@H:17]1[CH2:16][O:15][C:14]1[CH:28]=[CH:29][C:30]([C:32]([F:33])([F:34])[F:35])=[CH:31][C:13]=1[C:11](/[N:10]=[C:8]1\[S:9][C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])=[CH:6][N:7]\1[CH2:36][CH:37]([CH3:38])[CH3:39])=[O:12]
Reactant: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCN1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cn1cc(C(C)(C)C)s/c1=N\C(=O)c1cc(C(F)(F)F)ccc1OC[C@@H]1CCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the product of Example 12B (0.33 g, 0.58 mmol) in CH2Cl2 (4 mL) was added trifluoroacetic acid (2 mL, 26 mmol). This mixture stirred at ambient temperature for 2 h then was concentrated under reduced pressure and purified via column chromatography (SiO2, 100% CH2Cl2 to 9:1:0.1 CH2Cl2:CH3OH:NH4OH). The material was dissolved in hexanes/EtOAc (1 mL/2 mL) and one equivalent of p-toluenesulfonic acid monohydrate in 1 mL EtOAc was added. Solids precipitated immediately and the p-toluenesulfonic acid salt of the title compound was isolated via filtration (0.13 g, 0.20 mmol, 35% yield). 1H NMR (300 MHz, CD3OD) δ ppm 0.99 (dd, J=6.8, 2.4 Hz, 6H), 1.39 (s, 9H), 2.24-2.34 (m, 1H), 2.36 (s, 3H), 2.58-2.80 (m, 2H), 4.04-4.20 (m, 4H), 4.35-4.42 (m, 1H), 4.49-4.56 (m, 1H), 4.86-4.95 (m, 1H), 7.18-7.25 (m, 3H), 7.34 (d, J=8.5 Hz, 1H), 7.68-7.71 (m, 2H), 7.79 (dd, J=8.6, 1.9 Hz, 1H), 8.38 (d, J=2.4 Hz, 1H); MS (DCI/NH3) m/z 470 (M+H)+. Anal. calculated for C23H30F3N3O2S.1.5 C7H8O3S.1.2H2O: Calc: C, 53.69; H, 5.97; N, 5.61. Found: 53.38; H, 6.13; N, 5.91.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][C:4]([C:9]3[O:10][C:11]4[C:12](=[C:14]([C:18]([O:20]C)=[O:19])[CH:15]=[CH:16][CH:17]=4)[N:13]=3)([CH2:5][CH2:6]1)[CH2:3][CH2:2]2.O.[OH-].[Li+]>C1COCC1.O>[N:1]12[CH2:2][CH2:3][C:4]([C:9]3[O:10][C:11]4[C:12](=[C:14]([C:18]([OH:20])=[O:19])[CH:15]=[CH:16][CH:17]=4)[N:13]=3)([CH2:7][CH2:8]1)[CH2:5][CH2:6]2
Reactant: COC(=O)c1cccc2oc(C34CCN(CC3)CC4)nc12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cccc2oc(C34CCN(CC3)CC4)nc12
Temperature: 25 °C
Reaction time: 6 h
Yield: 108.8 %

Procedure:
A mixture of methyl 2-(quinuclidin-4-yl)benzoxazole-4-carboxylate (233 mg, 0.81 mmol), lithium hydroxide monohydrate (51 mg, 1.22 mmol) and THF/water (2:1, 15 mL) was stirred at room temperature for 6 h. The reaction mixture was concentrated, and washed with brine (10 mL), the precipitate which formed was filtered, washed with hexanes and dried to afford 2-(quinuclidin-4-yl)benzoxazole-4-carboxylic acid (240 mg, 108%) as a brown solid: 1H NMR (500 MHz, DMSO-d6) δ 7.80 (d, J=8.0 Hz, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 2.83-2.81 (m, 6H), 1.89-1.84 (m, 6H); MS (ESI+) m/z 273 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC1C=CC(S(O[CH2:48][C@H:49]2[O:51][CH2:50]2)(=O)=O)=CC=1.C1(O)C=CC=CC=1>CN(C=O)C>[Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:8]=[CH:9][C:10]([N:13]3[CH:17]=[C:16]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:48][C@@H:49]5[CH2:50][O:51]5)=[CH:20][CH:19]=4)[N:15]=[C:14]3[CH2:25][O:26][CH2:27][CH3:28])=[CH:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CO2)cc1
Reactant: CCOCc1nc(-c2ccc(O)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Product: CCOCc1nc(-c2ccc(OC[C@@H]3CO3)cc2)cn1-c1ccc(Oc2ccc(Cl)cc2)cc1

Procedure:
A mixture of 4-{1-[4-(4-chloro-phenoxy)-phenyl]-2-ethoxymethyl-1H-imidazol-4-yl}-phenol (0.21 g, 0.5 mmol, 1.0 eq.) and Cs2CO3 (0.49 g, 1.5 mmol, 3.0 eq.) in DMF (2 mL) was stirred and preheated to 80° C. The reaction mixture was then treated with a solution of (2S)-(+)-glycidyl tosylate (0.17 g, 0.75 mmol, 1.5 eq.) in 1 mL of DMF dropwise, and further stirred at 80° C. for ˜30 min following completion of the addition. Analysis of the reaction by TLC and LC/MS showed that the starting phenol had been consumed and the desired alkylated-phenol was the major product. The reaction was then cooled and diluted with EtOAc and washed with brine. The organic phase was dried with Na2SO4 and evaporated in vacuo. The crude alkylated-phenol was then purified by flash column chromatography over silica gel (EtOAc/hexanes ˜1:3).
Reaction SMILES: Cl.[CH2:2]([S:5]([CH2:8][C:9]1[N:10]=[C:11]([NH2:14])[S:12][CH:13]=1)(=[O:7])=[O:6])[CH2:3][CH3:4].Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1.C1COCC1>[C:19]1([O:18][C:16](=[O:17])[NH:14][C:11]2[S:12][CH:13]=[C:9]([CH2:8][S:5]([CH2:2][CH2:3][CH3:4])(=[O:6])=[O:7])[N:10]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCCS(=O)(=O)Cc1csc(N)n1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CCCS(=O)(=O)Cc1csc(NC(=O)Oc2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a cooled (0° C.) solution of 4-(propylsulfonylmethyl)thiazol-2-amine HCl-salt (3.99 g, 15.5 mmol) and DMAP (5 mol %, 95 mg) in pyridine (30 mL) was added a solution of phenyl chloroformate (1 eq, 1.96 mL) in THF (30 mL) drop wise. The reaction mixture was stirred at room temperature overnight and poured onto ice/water. The mixture was allowed to warm to room temperature and the solids were filtered off. The solids were washed with water, 10% aq. sodium bicarbonate, and dried in vacuo affording the title phenyl carbamate (1.22 g, 51% yield) as a solid.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=O)[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C([O-])(=O)C.[Na+].Cl.[NH2:30][NH:31][C:32]([NH2:34])=[O:33]>C(O)C>[N:1]1[C:10]2[C:9](=[CH:8][C:7]([CH2:11][N:12]3[C:16]4=[N:17][C:18]([C:21](=[N:30][NH:31][C:32]([NH2:34])=[O:33])[CH3:22])=[CH:19][CH:20]=[C:15]4[N:14]=[N:13]3)=[CH:6][CH:5]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: NNC(N)=O
Reactant: CC(=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CC(=NNC(N)=O)c1ccc2nnn(Cc3ccc4ncccc4c3)c2n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 48.3 %

Procedure:
To a solution of example 208 (0.070 g, 0.230 mmol) in ethanol (2 ml), sodium acetate (0.018 g, 0.230 mmol) and semicarbazide hydrochloride (0.026 g, 0.230 mmol) were added and stirred at RT for 12 h. The reaction mixture was concentrated and the residue was washed with bicarbonate solution, dichloromethane and dried under vacuum to afford the title compound as a yellow solid (0.040 g, 48%). M.P.: 249-250° C. 1H-NMR (δ ppm, DMSO-d6, 400 MHz): 9.70 (s, 1H), 8.88 (d, J=2.8 Hz, 1H), 8.54 (d, J=8.9 Hz, 1H), 8.45 (d, J=8.9 Hz, 1H), 8.37 (d, J=8.2 Hz, 1H), 8.01 (s, 1H), 7.99 (d, J=8.6 Hz, 1H), 7.81 (dd, J=8.6, 1.3 Hz, 1H), 7.53 (dd, J=8.2, 4.1 Hz, 1H), 6.78 (br s, 2H), 6.14 (s, 2H), 2.35 (s, 3H).
Reaction SMILES: C([Li])CCC.CN(C)[CH2:8][CH2:9]NC.[Cl:13][C:14]1[CH:21]=C[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=1.IC>CCCCCC.C1COCC1>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([CH:18]=[O:19])=[C:8]([CH3:9])[CH:21]=1
Reactant: CNCCN(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CI
Product: Cc1cc(Cl)ccc1C=O
Temperature: -23 °C
Reaction time: 0.25 h

Procedure:
A solution of n-butyllithium in hexane (30.4 ml, 2.5M) was added dropwise with stirring under nitrogen to a solution of N,N,N'-trimethylethylenediamine (7.9 g) in dry THF (150 ml) at -15 to -20° C. After the addition the mixture was stirred at -23° C. for 15 minutes and then 4-chlorobenzaldehyde (10.0 g) was added dropwise at -15 to -20° C. After the addition the mixture was stirred at -23° C. for 15 minutes and then more n-butyllithium in hexane (85.4 ml, 2.5M) was added dropwise at -15° C. The mixture was stirred at -23° C. for 3 hours, cooled to -40° C. and iodomethane (60.6 g) added at -40° to -20° C. After the addition, the mixture was stirred at -40° C. for 5 minutes and then allowed to warm up to ambient temperature and then stirred at that temperature for 30 minutes. The mixture was carefully poured into ice cold 10% hydrochloric acid (2 1) and left standing for 64 hours. The mixture was extracted with diethyl ether to give an oil which was distilled twice under vacuum to give 4-chloro-2-methylbenzaldehyde, b.p. 105°-110° (15 mmHg) which was sufficiently pure for synthetic use in Example 40.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:19]2[CH2:25][C:24]([F:27])([F:26])[CH2:23][CH2:22][NH:21][C:20]2=[O:28])[CH2:12][CH:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:36](Cl)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>ClCCl>[C:36]([N:16]1[CH2:15][CH2:14][CH:13]([CH2:12][N:11]([C@@H:19]2[CH2:25][C:24]([F:27])([F:26])[CH2:23][CH2:22][NH:21][C:20]2=[O:28])[S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)(=[O:9])=[O:10])[CH2:18][CH2:17]1)(=[O:43])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: O=C1NCCC(F)(F)C[C@H]1N(CC1CCNCC1)S(=O)(=O)c1ccc(Cl)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1NCCC(F)(F)C[C@H]1N(CC1CCN(C(=O)c2ccccc2)CC1)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.7 %

Procedure:
4-Chloro-N-((R)-5,5-difluoro-2-oxo-azepan-3-yl)-N-piperidin-4-ylmethyl-benzenesulfonamide (0.04 g, 0.09 mmol) and triethylamine (19 mg, 0.18 mmol) were dissolved in dichloromethane (1.5 ml). Then benzoyl chloride (0.018 g, 0.13 mmol) was added and the mixture was stirred overnight at room temperature. The reaction mixture was partitioned between aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was dried (MgSO4) and concentrated under reduced pressure. The residue was purified over silica gel (heptane/ethyl acetate 1:1) to yield 29 mg (58%) of the title compound;
Reaction SMILES: [Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH2:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH:13]1([CH2:16][C:17](O)=[O:18])[CH2:15][CH2:14]1.C(N(CC)CC)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[Li+].[OH-]>C(Cl)Cl.O>[Br:1][C:2]1[C:3]([F:12])=[C:4]2[C:10]([NH:11][C:17](=[O:18])[CH2:16][CH:13]3[CH2:15][CH2:14]3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: O=C(O)CC1CC1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: O=C(CC1CC1)Nc1c[nH]c2ncc(Br)c(F)c12
Temperature: 25 °C
Reaction time: 42 h
Yield: 75.2 %

Procedure:
A mixture of 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (200 mg, 0.869 mmol, Example 1, Step H), 2-cyclopropylacetic acid (218 mg, 2.17 mmol), triethylamine (606 μL, 4.35 mmol), and BOP-Cl (203 mg, 2.17 mmol) in CH2Cl2 (10 mL) was stirred at room temperature for 42 hours. Then 2M LiOH. H2O (3 mL) was added, and the mixture was stirred for 18 hours. The mixture was then diluted with CH2Cl2 (50 mL). The layers were separated, and the organic layer was dried (MgSO4), filtered, and concentrated in vacuo to provide N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-cyclopropylacetamide (204 mg, 75% yield) as a solid. 1H NMR (400 MHz, (CD3)2SO) δ 12.04 (s, 1H), 9.40 (s, 1H), 8.34 (d, 1H), 7.61 (s, 1H), 2.24 (d, 2H), 1.10-1.03 (m, 1H), 0.52-0.47 (m, 2H), 0.24-0.20 (m, 1H); LCMS (APCI+) m/z (M+H)+, Retention time=2.92 minutes (Method 2).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.[Cl-].[Cl-].[Cl-].[Al+3].Cl>ClCCl.CN(C)C=O.ClCCCl>[O:1]1[CH2:8][CH2:9][CH2:10][C:11](=[O:13])[C:7]2[CH:6]=[CH:5][CH:4]=[CH:3][C:2]1=2
Reactant: O=C(O)CCCOc1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Solvent: CN(C)C=O
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1CCCOc2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of phenol (3.16 g, 33.6 mmol) in acetonitrile, was added ethyl 4-bromobutyrate (4.8 ml, 33.6 mmol), potassium carbonate (4.64 g, 33.6 mmol) and tetrabutylammonium iodide (370 mg, 1 mmol). The reaction mixture was stirred vigorously and heated to reflux for 2 days before being cooled, filtered, dried (MgSO4) and concentrated in-vacuo to yield 4-phenoxy-butyric acid ethyl ester. 4-Phenoxy-butyric acid ethyl ester was hydrolyzed to its corresponding carboxylic acid using sodium hydroxide mediated hydrolysis to yield 4-phenoxy-butyric acid. To a solution of 4-phenoxy-butyric acid (7.67 g, 29.6 mmol) in anhydrous dichloromethane was added oxalyl chloride (4.4 ml, 50.3 mmol) and one drop of dimethyl formamide and the reaction mixture stirred at room temperature for 30 minutes. Reaction mixture was concentrated in-vacuo and the residue dissolved in 1,2-dichloroethane (90 ml). This solution was added drop wise to a suspension of aluminum trichloride (4.73 g, 35.5 mmol) in 1,2-dichloroethane (50 ml) at 0° C. Reaction mixture was left stirring in ice bath which rose to room temperature overnight. The reaction mixture was poured over conc. hydrochloric acid (30 ml) stirred into 100 g ice, and then stirred for a further 90 minutes until the ice fully melted. The aqueous phase was washed with dichloromethane 3 times, before the organics were combined, dried (Na2SO4) and concentrated in-vacuo. Purification by triturating with diethyl ether gave 3,4-dihydro-2H-benzo[b]oxepin-5-one.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5](O)=O.[NH2:8][C:9]1[C:14]([NH2:15])=[CH:13][CH:12]=[CH:11][N:10]=1.Cl.N>>[OH:1][CH2:2][CH2:3][CH2:4][C:5]1[NH:8][C:9]2[C:14]([N:15]=1)=[CH:13][CH:12]=[CH:11][N:10]=2
Reactant: O=C(O)CCCO
Reactant: Nc1cccnc1N
Agent: Cl
Agent: N
Product: OCCCc1nc2cccnc2[nH]1
Temperature: 150 °C
Reaction time: 4 h
Yield: 66.4 %

Procedure:
0.83 g of 4-hydroxybutyric acid (prepared as described in Preparation 32) was added to 0.77 g of 2,3-diaminopyridine, and the resulting mixture was stirred at 150° C. for 4 hours. At the end of this time, the reaction mixture was treated with 3 N aqueous hydrochloric acid and subsequently made alkaline by the addition of aqueous ammonia. The aqueous mixture was evaporated to dryness under reduced pressure, and then the resulting residue was purified by column chromatography through silica gel, using a 5:1 by volume mixture of ethyl acetate and methanol as the eluent. The product was crystallized by trituration with ethyl acetate, to give 0.83 g of the title compound, melting at 151-153° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][NH:5][C:6]([NH2:8])=[NH:7].C(NC1N=[C:17]([C:19]2[C:20]([CH:28]([CH3:30])[CH3:29])=[N:21][N:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=23)[CH:16]=[CH:15]N=1)(C)C>>[CH:28]([C:20]1[C:19]([C:17]2[CH:16]=[CH:15][N:8]=[C:6]([NH:5][CH2:4][CH2:3][CH2:2][OH:1])[N:7]=2)=[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][N:22]2[N:21]=1)([CH3:30])[CH3:29]
Reactant: CC(C)Nc1nccc(-c2c(C(C)C)nn3ccccc23)n1
Reactant: N=C(N)NCCCO
Product: CC(C)c1nn2ccccc2c1-c1ccnc(NCCCO)n1

Procedure:
3-[4-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-ylamino]-propan-1-ol was prepared from 3-dimethylamino-1-(2-isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-propenone and N-(3-hydroxy-propyl)-guanidine following the method used in Step 4 of the synthesis of Isopropyl-[4-(2-isopropylpyrazolo[1,5-a]pyridin-3-yl)-pyrimidin-2-yl]-amine (Example 66), except preparative-HPLC purification was used in the place of recrystallization (166 mg, 18%). 1H-NMR (250 MHz, DMSO-d6) δ 8.85 (d, J=7.0 Hz, 1H), 8.44-8.22 (m, 3H), 7.59 (t, J=7.0 Hz, 1H), 7.18-7.05 (m, 2H), 4.07 (broad s, 1H), 3.79 (sept, J=6.9 Hz, 1H), 3.58-3.33 (m, 4H), 1.77 (pent, J=6.6 Hz, 2H), 1.37 (d, J=6.5 Hz, 6H); LC/MS 312.3 m/z (M+H+). Compound 1134.
Reaction SMILES: [C:1]1(B(O)O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18](Br)=[CH:17][C:16]=1[N+:22]([O-:24])=[O:23].C(=O)([O-])[O-].[K+].[K+]>O.C1COCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[N+:22]([C:16]1[CH:17]=[C:18]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[CH:19]=[CH:20][C:15]=1[C:9]1[C:10]2[C:5](=[CH:4][CH:3]=[CH:2][CH:1]=2)[CH:6]=[CH:7][CH:8]=1)([O-:24])=[O:23]
Reactant: OB(O)c1cccc2ccccc12
Reactant: O=[N+]([O-])c1cc(Br)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cc(-c2cccc3ccccc23)ccc1-c1cccc2ccccc12

Procedure:
2.4 g (2.1 mmol) of Pd(PPh3)4 are added to a well-stirred, degassed suspension of 67.8 g (190 mmol) of 1-naphthylboronic acid, 53.3 g (190 mmol) of 2,5-dibromonitrobenzene and 137.9 g (648.5 mmol) of potassium carbonate in a mixture of 250 ml of water and 250 ml of THF, and the mixture is heated under reflux for 20 h. After cooling, the organic phase is separated off, washed three times with 200 ml of water and once with 200 ml of saturated, aqueous sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo in a rotary evaporator. The grey residue is recrystallised from hexane. The deposited crystals are filtered off with suction, washed with a little MeOH and subsequently dried in vacuo; yield: 86.1 g, 71% of theory; purity: 98.4% according to HPLC.
Reaction SMILES: [C:1]1(=[O:7])[NH:5][C:4](=[O:6])[CH2:3][CH2:2]1.[BH4-].[Na+].Cl.[OH-].[K+].[CH:13](O)([CH3:15])[CH3:14]>>[O:7]=[C:1]1[CH2:2][CH2:3][CH:4]([O:6][CH:13]([CH3:15])[CH3:14])[NH:5]1
Reactant: O=C1CCC(=O)N1
Reactant: CC(C)O
Agent: Cl
Agent: [BH4-]
Agent: [K+]
Product: CC(C)OC1CCC(=O)N1
Temperature: -10 °C
Reaction time: 2 h

Procedure:
To a mixture of 28.64 g of succinimide in 1200 cm3 of isopropanol cooled to -10° C., 32.8 g of sodium borohydride is added, with agitaton for 4 hours, while maintaining the temperature at -10° to 0° C. Every 15 minutes 15 drops of a 2M solution of hydrochloric acid in isopropanol is added. Operating at 0° to +2° C., the reactional mixture is then taken to pH 2-3 by the addition of a 2N solution of hydrochloric acid in isopropanol, then agitated for 2 hours at the same temperature. Neutralization is then done by the addition of a saturated solution of potassium hydroxide in isopropanol, operating at -°C. The isopropanol is evaporated off under reduced pressure, and after extracting with chloroform, filtering and evaporating off the solvent under reduced pressure, 20.5 g of the expected product is obtained, m.p. 68° to 71° C.
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1.CC(NCCC#N)CC1C=CC=CC=1.Cl>CCCCCC.C(O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C@H:11]([CH2:14][CH2:15][NH:16][C:17](=[O:19])[CH3:18])[C:8]=32)=[N:3]1
Reactant: CC(=O)NCCC1CCc2ccc3nn(C)cc3c21
Agent: CC(Cc1ccccc1)NCCC#N
Agent: Cl
Solvent: CCO
Solvent: CCCCCC
Product: CC(=O)NCC[C@H]1CCc2ccc3nn(C)cc3c21
Yield: 51.4 %

Procedure:
N-[2-(2-Methyl-2,6,7,8-tetrahydrocyclopenta[e]indazol-8-yl)ethyl]acetamide (about 70 mg) was fractionated by high performance liquid chromatography (instrument: Prep LC 2000 (manufactured by Nihon Waters K.K.), column: CHIRALPAK AD (50 mm ID×500 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 80 mL/min, column temperature: room temperature, sample concentration: 1.0 mg/mL (hexane/ethanol=90/10), injection amount: about 35 mg). A fraction solution containing an optically active compound having a longer retention time under the above-mentioned high performance liquid chromatography conditions was concentrated. The concentrate was re-dissolved in ethanol, and concentrated to dryness. Hexane was further added, and the mixture was concentrated to dryness again to give the title compound (36 mg, 99% ee). The enantiomer excess (ee) was measured by high performance liquid chromatography (column: CHIRALPAK AD-H (4.6 mm ID×250 mm L, manufactured by Dicel Chemical Industries, Ltd.), mobile phase: hexane/ethanol=90/10, flow rate: 1.0 mL/min, column temperature: room temperature, sample concentration: 1 mg/mL (hexane/ethanol=90/10), injection volume: 10 μL).
Reaction SMILES: [CH3:1][NH2:2].[CH:3]1[C:8](=[O:9])[C:7]([OH:10])=[CH:6]O[C:4]=1[CH2:11][OH:12]>O>[OH:12][CH2:11][C:4]1[N:2]([CH3:1])[CH:6]=[C:7]([OH:10])[C:8](=[O:9])[CH:3]=1
Reactant: CN
Reactant: O=c1cc(CO)occ1O
Solvent: O
Product: Cn1cc(O)c(=O)cc1CO

Procedure:
A solution of 40% methylamine in water is added to a solution of kojic acid dissolved in hot distilled water. The pH of this solution is adjusted to 9.8 by the addition of HCl solution. The mixture is kept under reflux overnight and then decolorized with activated charcoal. The solvent is removed under reduced pressure. The white product is obtained upon recrystallization from hot water.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([S:7]C(=O)C)[CH2:4][C@H:3]1[C:11]([NH2:13])=[O:12].C[O-].[Na+].[ClH:17]>CO>[ClH:17].[CH3:1][N:2]1[CH2:6][C@@H:5]([SH:7])[CH2:4][C@H:3]1[C:11]([NH2:13])=[O:12]
Reactant: CC(=O)S[C@H]1C[C@@H](C(N)=O)N(C)C1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CN1C[C@@H](S)C[C@H]1C(N)=O
Reaction time: 0.08 h

Procedure:
(2S,4S)-1-Methyl-2-aminocarbonyl-4-acetylthiopyrrolidine (201 mg) was dissolved in methanol (2.4 ml), and a solution of sodium methoxide (54 mg) in methanol (1.2 ml) was added thereto at room temperature under nitrogen stream, followed by stirring at the same temperature for 5 minutes. To the reaction mixture, conc. hydrochloric acid (240 mg) was added, and the solvent was removed. The residue was dissolved in a mixture of chloroform and methanol (4:1) and dried over magnesium sulfate. Removal of the solvent gave (2S,4S)-1-methyl-2-aminocarbonyl-4-mercaptopyrrolidine hydrochloride.