Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:35][CH3:36])=[C:16]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]([CH2:32][CH2:33][OH:34])[CH3:31])=[O:29])[CH:23]=4)[C:17]([CH3:21])=[C:18](Cl)[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12.[CH3:37][N:38](C)C(=O)C>[Zn].[C-]#N.[Zn+2].[C-]#N>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH:12]([C:14]3[C:15]([O:35][CH3:36])=[C:16]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:30]([CH2:32][CH2:33][OH:34])[CH3:31])=[O:29])[CH:23]=4)[C:17]([CH3:21])=[C:18]([C:37]#[N:38])[CH:19]=3)[CH3:13])[N:9]=[C:10]([CH3:11])[C:3]=12
Reactant: CC(=O)N(C)C
Reactant: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(Cl)c(C)c1-c1ccnc(C(=O)N(C)CCO)c1
Agent: [C-]#N
Agent: [Zn+2]
Agent: [Zn]
Product: COc1c(C(C)n2nc(C)c3c(N)ncnc32)cc(C#N)c(C)c1-c1ccnc(C(=O)N(C)CCO)c1
Temperature: 120 °C

Procedure:
The above catalyst (0.05 mL) was added to a mixture of 4-{3-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-5-chloro-2-methoxy-6-methylphenyl}-N-(2-hydroxyethyl)-N-methylpyridine-2-carboxamide (from Example 19) (4.0 mg, 0.0078 mmol), zinc (0.22 mg, 0.0034 mmol) and zinc cyanide (0.92 mg, 0.0078 mmol) in N,N-dimethylacetamide (0.1 mL). The mixture was degassed and then the reaction was heated at 120° C. for 1.5 hours. The crude mixture was applied on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product. The product was isolated as a racemic mixture. LCMS calculated for C26H29N8O3 (M+H)+: m/z=501.2; Found: 501.2
Reaction SMILES: [CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[C:14]([F:19])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:21]1[CH:26]=[CH:25][N:24]=[C:23]2[N:27]([CH2:31][C:32]3[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=3)[N:28]=[C:29]([CH3:30])[C:22]=12.ClCCl>BrC1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]([C:12]1[CH:17]=[CH:16][C:15]([O:18][C:21]2[CH:26]=[CH:25][N:24]=[C:23]3[N:27]([CH2:31][C:32]4[CH:33]=[CH:34][C:35]([O:38][CH3:39])=[CH:36][CH:37]=4)[N:28]=[C:29]([CH3:30])[C:22]=23)=[C:14]([F:19])[CH:13]=1)[C:9](=[O:11])[CH3:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N(Cc1ccccc1)c1ccc(O)c(F)c1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Solvent: ClCCl
Product: COc1ccc(Cn2nc(C)c3c(Oc4ccc(N(Cc5ccccc5)C(C)=O)cc4F)ccnc32)cc1
Temperature: 150 °C
Yield: 74.4 %

Procedure:
To a stirred solution of N-benzyl-N-(3-fluoro-4-hydroxyphenyl)acetamide (34 mg, 0.13 mmol) and 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (29 mg, 0.1 mmol) (prepared in Example 43, step E) in 400 μL bromobenzene in a capped reaction vial was added DMAP (25 mg, 0.20 mmol). The solution was heated to 150° C. overnight. The reaction was cooled to ambient temperature and loaded onto a Biotage 12S column with dichloromethane and eluted with ethyl acetate to provide the desired product as a tan solid (38 mg, 74% yield).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[C:11]([NH2:15])([CH3:14])([CH3:13])[CH3:12].[Cl-].[Na+]>CN(C)C=O>[C:11]([NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9])([CH3:14])([CH3:13])[CH3:12]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: CC(C)(C)N
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 1-fluoro-2-nitro-benzene (1 g, 7.1 mmol) in dimethylformamide (15 mL) was added tert-butyl amine (0.82 mL, 7.81 mmol) at room temperature, and the reaction mixture stirred for 12 hours at room temperature under nitrogen. Upon completion, the reaction mixture was poured into a saturated aqueous solution of sodium chloride (50 mL) and extracted with ethyl acetate (50 mL). The organic layer was dried over anhydrous sodium sulfate, concentrated in vacuo, and the residue was purified via flash column chromatography (silica, 1% ethyl acetate in hexane) to give tert-butyl-(2-nitrophenyl)-amine as an orange oil. MS (ES) m/z 195.2
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][NH2:14].[C:15]([C:17]([C:24]#[N:25])=[C:18]([CH:21]1[CH2:23][CH2:22]1)OC)#[N:16].[H-].[Na+]>CO>[NH2:25][C:24]1[N:13]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:9])([F:11])[F:10])=[CH:5][C:4]=2[Cl:12])[N:14]=[C:18]([CH:21]2[CH2:23][CH2:22]2)[C:17]=1[C:15]#[N:16]
Reactant: COC(=C(C#N)C#N)C1CC1
Reactant: NNc1c(Cl)cc(C(F)(F)F)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(C2CC2)nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c1N

Procedure:
A solution of 2,6-dichloro-4-trifluoromethylphenylhydrazine (3.8 g) and 1,1-dicyano-2-cyclopropyl-2-methoxyethylene (2.23 g) in methanol (30 ml) was stirred and treated with sodium hydride (80%, 30 mg). After 4 hours the solution was evaporated in vacuo and the residue was dissolved in ethyl acetate (40 ml), treated with charcoal and washed with water. The organic phase was evaporated in vacuo, the residual oil was dissolved in petroleum ether and crystals of 5-amino-4-cyano-3-cyclopropyl-1-(2,6-dichloro-4-trifluoromethylphenyl)pyrazole, m.p. 197-199° C., were obtained.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.CC([O-])(C)C.[K+].Cl[C:13]1[C:18]([C:19]([NH:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=2)=[O:20])=[C:17]([CH3:30])[CH:16]=[C:15]([N:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)[N:14]=1.O>C1COCC1>[F:29][C:25]1[CH:24]=[C:23]([CH2:22][NH:21][C:19]([C:18]2[C:13]([O:1][CH:2]3[CH2:5][O:4][CH2:3]3)=[N:14][C:15]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)=[CH:16][C:17]=2[CH3:30])=[O:20])[CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(N2CCOCC2)nc(Cl)c1C(=O)NCc1cccc(F)c1
Reactant: OC1COC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(N2CCOCC2)nc(OC2COC2)c1C(=O)NCc1cccc(F)c1
Temperature: 50 °C
Yield: 83.9 %

Procedure:
A solution of 209 mg (2.82 mmol) 3-hydroxy-oxetane in THF (6 ml) was treated with 316 mg (2.81 mmol) KOtBu and was heated at 50° C. for 15 min. After cooling to RT a solution of 205 mg (0.56 mmol) 2-chloro-N-[(3-fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-pyridine-3-carboxylic acid amide (synthesis is described in section a) of example 9) in THF (3 ml) was added and the mixture was heated at 80° C. for 8 h. The mixture was then poured into water and extracted with EtOAc. The organic layer was washed with water and brine, dried over Na2SO4 and concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 7:3) provided 190 mg (0.47 mmol, 84%) N-[(3-Fluorophenyl)-methyl]-4-methyl-6-morpholin-4-yl-2-(oxetan-3-yloxy)-pyridine-3-carboxylic acid amide (example 317). [M+H]+ 402.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([C:24]#N)[CH:21]=[CH:20][N:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].C(O)C.[OH-:29].[Na+].[OH2:31]>>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([C:24]([OH:31])=[O:29])[CH:21]=[CH:20][N:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOc1ccc(-c2nc(-c3cc(C#N)ccn3)cs2)cc1OCC
Reactant: [OH-]
Reactant: O
Agent: [Na+]
Solvent: CCO
Product: CCOc1ccc(-c2nc(-c3cc(C(=O)O)ccn3)cs2)cc1OCC

Procedure:
A mixture of 500 mg of 2-(3,4-diethoxyphenyl)-4-(4-cyano-pyridyl)thiazole, 20 ml of ethanol and 17 ml of a 4% aqueous sodium hydroxide solution was refluxed for 16 hours with heating. The reaction mixture was allowed to stand. Then, 200 ml of water was added thereto. The mixture was extracted with 80 ml of dichromethane two times. The aqueous layer was made acidic (pH=about 3) with concentrated hydrochloric acid and extracted with 150 ml of ethyl acetate three times. The ethyl acetate layer was dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from ethyl acetate to obtain 290 mg of 2-(3,4-diethoxyphenyl)-4-(4-carboxy-2-pyridyl)thiazole.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([CH2:7]O)=[CH:5][N:6]=1.S(Cl)(Cl)=O.C(N(CC)CC)C.[NH:20]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]2([C:32]3=[CH:33][C:34]4[O:38][CH2:37][O:36][C:35]=4[CH:39]=[C:31]3[O:30][CH2:29]2)[C:21]1=[O:40].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[Cl:1][C:2]1[S:3][C:4]([CH2:7][N:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[C:22]3([C:32]4=[CH:33][C:34]5[O:38][CH2:37][O:36][C:35]=5[CH:39]=[C:31]4[O:30][CH2:29]3)[C:21]2=[O:40])=[CH:5][N:6]=1
Reactant: OCc1cnc(Cl)s1
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: O=C1N(Cc2cnc(Cl)s2)c2ccccc2C12COc1cc3c(cc12)OCO3
Temperature: 0 °C
Reaction time: 1 h
Yield: 3.9 %

Procedure:
To a solution of (2-chloro-1,3-thiazol-5-yl)methanol (0.30 g, 2.00 mmol) in anhydrous CH2Cl2 (20.0 mL) was added thionyl chloride (0.50 g, 4.20 mmol) followed by triethylamine (0.40 g, 4.00 mmol) at 0° C. After stirring at 0° C. for one hour and ambient temperature for one hour, the reaction mixture was diluted with CH2Cl2 (50.0 mL) and extracted with water (2×20 mL). The organic phase was dried over Na2SO4 and filtered. The filtrate was concentrated in vacuo to dryness. The residue was dissolved in methyl-ethyl ketone (10.0 mL) followed by the additions of spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one (0.36 g, 2.00 mmol) and cesium carbonate (1.95 g, 6.00 mmol). The reaction mixture was heated at 70° C. overnight, cooled, filtered and the filtrate was concentrated in vacuo to dryness. The residue was subjected to column chromatography to yield the title compound (0.032 g, 3.4%) as a colorless solid: mp 195-198° C.; 1H NMR (300 MHz, DMSO-d6) δ 7.81 (s, 1H), 7.39-6.93 (m, 5H), 6.66 (s, 1H), 6.15-6.12 (m, 1H), 5.89 (d, 2H), 5.10 (s, 2H), 4.70 (dd, 2H); MS (ES+) m/z 413.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)C(C)C)(C)C>>[Br:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ncccc1Br
Reactant: C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Product: Brc1cccnc1N1CCNCC1
Temperature: 200 °C

Procedure:
A mixture of 3-bromo-2-chloropyridine (0.96 g, 5 mmol, Aldrich), piperazine (0.86 g, 10 mmol, Aldrich) and N,N-diisopropylethylamine (1 mL, 5.8 mmol, Aldrich) was heated in a microwave synthesizer for 40 min at 200° C. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel, eluting with 10% MeOH in dichloromethane to give the title compound as a white amorphous solid. MS (ESI, pos. ion) m/z: 242 (M+1).
Reaction SMILES: Br[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1.[CH3:31][NH:32][CH3:33].O>C(O)C>[CH3:31][N:32]([CH3:33])[CH:2]1[C:11]2[C:6](=[N:7][C:8]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:10]=2)[N:5]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)N1CCC(Br)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reactant: CNC
Solvent: CCO
Solvent: O
Product: CN(C)C1CCN(C(=O)OC(C)(C)C)c2nc(-c3ccccc3)c(-c3ccccc3)nc21
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 8-bromo-2,3-diphenyl-7,8-dihydropyrido[2,3-b]pyrazine-5(6H)-carboxylate (Intermediate H) (500 mg, 1.072 mmol) in ethanol (10 ml) was added 40% dimethylamine in water (0.407 ml, 3.22 mmol) and the mixture was left to stir under an atmosphere of nitrogen overnight. The solvent was concentrated in vacuo. The crude product was purified by chromatography on silica eluting with EtOAc in iso-hexane to affore the title compound;
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:17])[CH:5]=[CH:6][C:7]=1[CH2:8][CH2:9][CH2:10][CH2:11][N:12]1[CH:16]=[CH:15][N:14]=[N:13]1.[H-].[Na+].Cl[CH2:21][C:22]1[C:23]([CH3:39])=[N:24][C:25]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][C:29]=2[F:38])=[CH:26][CH:27]=1.O>CN(C)C=O>[F:38][C:29]1[CH:30]=[C:31]([C:34]([F:36])([F:37])[F:35])[CH:32]=[CH:33][C:28]=1[C:25]1[N:24]=[C:23]([CH3:39])[C:22]([CH2:21][O:17][C:4]2[CH:5]=[CH:6][C:7]([CH2:8][CH2:9][CH2:10][CH2:11][N:12]3[CH:16]=[CH:15][N:14]=[N:13]3)=[C:2]([CH3:1])[CH:3]=2)=[CH:27][CH:26]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2F)ccc1CCl
Reactant: Cc1cc(O)ccc1CCCCn1ccnn1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(-c3ccc(C(F)(F)F)cc3F)nc2C)ccc1CCCCn1ccnn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
A solution of 153 mg (0.66 mmol) 3-methyl-4-(4-[1,2,3]triazol-1-yl-butyl)phenol in 8.0 ml N,N-dimethylformamide was treated at 0° C. with 26 mg (0.66 mmol) of 60% sodium hydride and stirred at 0° C. for 30 min. Then 200 mg (0.66 mmol) 3-Chloromethyl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyridine were added and stirred continued at r. t. over night. After addition of 16 ml water, the precipitate was isolated, washed thoroughly with water and diisopropylether. The residue was dried at 40° C. to give 250 mg (76%) of the title compound as light brown powder.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([OH:20])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2].CS(O[CH2:28][CH2:29][O:30][CH3:31])(=O)=O.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:21][CH3:22])=[C:17]([O:20][CH2:28][CH2:29][O:30][CH3:31])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:7][CH:8]=1)#[CH:2]
Reactant: C#Cc1cccc(Nc2ncnc3cc(OC)c(O)cc23)c1
Reactant: COCCOS(C)(=O)=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: C#Cc1cccc(Nc2ncnc3cc(OC)c(OCCOC)cc23)c1
Temperature: 25 °C
Yield: 42.9 %

Procedure:
A solution of 4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-ol (2.9 g, 0.01 mol), 2-methoxyethyl methane sulfonate (4.6 g, 0.03 mol, 3 equiv), and cesium carbonate (9.9 g, 0.03 mol, 3 equiv) in DMF (100 ml) was heated to 60° C. for 12 hours. The reaction mixture was cooled to room temperature and poured into cold water, the solid was filtrated and dried to give 1.5 g product. MS (ESI) m/z: 350 (M+1).
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH3:6].[P:10]([Cl:20])(Cl)([O:12][C:13]1[CH:18]=[CH:17]C=[CH:15][CH:14]=1)=[O:11].[CH2:21](Cl)Cl>>[C:2]1([O:3][C:4](=[O:9])[C:5]([NH2:8])([CH3:7])[CH2:6][CH3:21])[CH:17]=[CH:18][CH:13]=[CH:14][CH:15]=1.[P:10]([Cl:20])(=[O:11])([O-:12])[O-:3]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: ClCCl
Reactant: COC(=O)C(C)(C)N
Agent: Cl
Product: CCC(C)(N)C(=O)Oc1ccccc1
Product: O=P([O-])([O-])Cl
Yield: 95.2 %

Procedure:
This is synthesised according to Standard procedure 4, using 2-aminoisobutyrate methyl ester hydrochloride (583.5 mg, 3.75 mmol), phenyl dichlorophosphate (791.1 mg, 3.75, 560 μL), and TEA (758.9 mg, 7.5 mmol, 1045 μL) in DCM (20 mL), to yield 1.041 g (95.2%) of crude product used without further purification.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][CH2:39][N:40]2[CH2:46][C:45]3[CH:47]=[C:48](/[CH:51]=[CH:52]/[C:53](O)=[O:54])[CH:49]=[N:50][C:44]=3[NH:43][C:42](=[O:56])[CH2:41]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[O:5][C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]=1[CH3:9])[C:53](=[O:54])/[CH:52]=[CH:51]/[C:48]1[CH:49]=[N:50][C:44]2[NH:43][C:42](=[O:56])[CH2:41][N:40]([CH2:39][CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:46][C:45]=2[CH:47]=1
Reactant: CNCc1oc2ccccc2c1C
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCCN1CCOCC1)CC(=O)N2
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCCN2CCOCC2)CC(=O)N3)oc2ccccc12
Yield: 78 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzofuran-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(3-morpholin-4-yl-propyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.28 g, 78%) was prepared as an off-white powder: 1H NMR (300 MHz, DMSO-d6) δ 10.74-10.54 (m, 2H), 8.61 (s, 1H), 8.29 (s, 1H), 7.63-7.47 (m, 3H), 7.34-7.23 (m, 3H), 5.03-4.80 (m, 2H), 4.02 (br s, 2H), 3.87-3.79 (m, 4H), 3.65 (br s, 2H), 3.48-3.38 (br s, 4H), 3.20-2.93 (m, 5H), 2.72-2.57 (br s, 2H), 2.26 (s, 3H), 1.95 (s, 2H); MS (ESI) m/e 518 (M+H)+.
Reaction SMILES: C(=O)=O.[CH3:4][NH:5][CH3:6].[C:7]([OH:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>C1CCCCC1>[CH3:4][NH2+:5][CH3:6].[C:7]([O-:26])(=[O:25])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]/[CH:15]=[CH:16]\[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CNC
Agent: O=C=O
Solvent: C1CCCCC1
Product: CCCCCCCC/C=C\CCCCCCCC(=O)[O-]
Product: C[NH2+]C
Temperature: 60 °C

Procedure:
While cooling with dry ice, 0.9 kg of dimethylamine (20 mol) from a reservoir bottle was condensed into a cold trap. A 10 l Büchi stirred autoclave with gas inlet tube, stirrer, internal thermometer and pressure equalizer was initially charged with 3.5 kg of cyclohexane and 5.65 kg of technical-grade oleic acid (20 mol), which were heated to 60° C. until the mixture became homogeneous. By slowly thawing the cold trap, gaseous dimethylamine was passed through the gas inlet tube into the stirred autoclave. In a strongly exothermic reaction, the oleic acid N,N-dimethylammonium salt formed.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.CCOCC.[C:22]([Cl:32])(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>>[ClH:32].[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)=[N:9]2)=[O:31])=[CH:24][CH:25]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CN1CCC(c2n[nH]c3ccccc23)CC1
Solvent: CCOCC
Product: COc1ccc(C(=O)n2nc(C3CCN(C)CC3)c3ccccc32)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A solution of 3.0 g of 3-(1-methyl-4-piperidinyl)-1H-indazole in 10 ml of p-anisoyl chloride was heated at 100° C. for 3 hr. The reaction mixture was cooled to ambient temperature, ether was added and the solid was collected. The solid, suspended in ether, was stirred for 16 hr. The mixture was filtered, and dried. Recrystallization from ethanol (twice) yielded 4.0 g (74.4%) of product, mp 235°-237° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([O:23][CH2:24][CH3:25])([C@@H:10]([NH:14][C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[CH2:11][CH2:12][CH3:13])[C:5]([O:7][CH2:8]C)=[O:6])[CH3:2].O.OS(O)(=O)=O>O(C(C)C)C(C)C>[CH2:24]([O:23][C:4]([O:3][CH2:1][CH3:2])([C@@H:10]([NH:14][C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[CH2:11][CH2:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6])[CH3:25]
Reactant: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OCC
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)OC(C)C
Product: CCC[C@H](N[C@@H](C)c1ccccc1)C(OCC)(OCC)C(=O)OC

Procedure:
A diastereomeric mixture of (S)-ethyl 2,2-diethoxy-3-(((S)-1-phenylethyl)amino)hexanoate (6.4 g, d.r.: 85:15) was dissolved in 100 mL iPr2O and 2 mL water were added. The mixture was acidified to pH=2.21 with 50% H2SO4 and the resulting organic phase was concentrated to half its volume (50 mL). 1 mL water was added, and the mixture was acidified again to pH=2.22 with 50% H2SO4. The aqueous phase was combined with the aqueous phase from the previous extraction (V=1.5 mL) and extracted with 11 mL DIPET (diisopropyl ether) after adjusting the pH to 2.17 with 5M NaOH. The combined organic phases were concentrated (V=40 mL), 1 mL water was added and the mixture was acidified to pH=2.18 with 50% H2SO4. The organic phase was separated and the solvent was removed in vacuo to yield a 98:2 (syn:anti) mixture of diastereomers (37.5 mL solution, assay: 28%, 76% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6]Br.[Mg].[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH2:19][CH2:20][CH2:21][N:22]=[C:14]3[C:13](=[O:23])[C:12]=2[CH:11]=1.[NH4+].[Cl-]>CCOCC.ClCCl>[ClH:9].[Cl:9][C:10]1[CH:18]=[CH:17][C:16]2[N:15]3[CH2:19][CH2:20][CH2:21][N:22]=[C:14]3[C:13]([OH:23])([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:12]=2[CH:11]=1
Reactant: COCCCCBr
Reactant: O=C1C2=NCCCN2c2ccc(Cl)cc21
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Product: COCCCCC1(O)C2=NCCCN2c2ccc(Cl)cc21
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 132.5 %

Procedure:
A Grignard reagent was prepared from 4-methoxybutyl bromide (5 g) and magnesium (0.72 g) in dry ether (25 ml). After cooling with an ice-bath, under a blanket of nitrogen, a solution of 8-chloro-3,4-dihydropyrimido[1,2-a]indol-10(2H)-one (2.2 g) in dichloromethane (25 ml) was added slowly. When addition was complete the mixture was stirred at room temperature for 3 hours. It was poured onto saturated aqueous NH4Cl, the layers were separated and the aqueous phase extracted with dichloromethane. The combined organic phases were washed with water and dried (MgSO4). Filtration and evaporation gave an orange solid, which was triturated with boiling ethyl acetate, cooled, filtered and the crystals were washed with hexane. The crystals were suspended in boiling ethanol and acidified with ethanolic HCl. Evaporation of the solution gave a solid which crystallised from isopropanol. Two crops were combined and dried at 50°/1 mm to give pure 8-chloro-10-hydroxy-10-(4-methoxybutyl)-2,3,4,10-tetrahydropyrimido[1,2-a]indole, hydrochloride quarter hydrate (2.28 g) as buff-cream crystals, m.p. 218°-221° (dec).
Reaction SMILES: CC#N.C(=O)=O.[CH2:7]([N:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1)[C:8]#[CH:9].C([Mg]Cl)(C)C.CON(C)[C:24](=[O:26])[CH3:25]>C1COCC1>[N:10]1([CH2:7][C:8]#[C:9][C:24](=[O:26])[CH3:25])[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1
Reactant: C#CCN1CCOCC1
Reactant: CON(C)C(C)=O
Agent: CC(C)[Mg]Cl
Agent: O=C=O
Solvent: CC#N
Solvent: C1CCOC1
Product: CC(=O)C#CCN1CCOCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.1 %

Procedure:
To a cooled (−40° C., CH3CN/CO2) solution of 4-(2-propyn-1-yl)morpholine (2.2 g, 17.58 mmol) in THF (5 mL) was added dropwise via. syringe under N2 a solution of 2 M isopropylmagnesium chloride in THF (10 mL, 20.00 mmol). The reaction was stirred for 1 hr then a solution of N-methoxy-N-methylacetamide (2.2 mL, 20.69 mmol) in THF (5 mL) was added in one portion. The reaction was stirred for 2 hr (allowed to slowly warm to RT), quenched with aq. NH4Cl, extracted with EtOAc, washed with brine, dried (Na2SO4), filtered and evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 80% EtOAc in hexanes). The pure fractions were combined and evaporated to dryness to give the product 5-(4-morpholinyl)-3-pentyn-2-one (2.09 g, 12.50 mmol, 71.1% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 3.62-3.57 (m, 4H), 3.56 (s, 2H), 2.49-2.43 (m, 4H), 2.34 (s, 3H). MS(ES)+ m/e 168.0 [M+H]+.