Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].Cl[C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>>[CH2:22]([O:21][C:19]([NH:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17])=[O:20])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(Cl)OCc1ccccc1
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)OCc1ccccc1

Procedure:
The same operation as in Example (40a) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained by the method described in Example (112d) (0.5 g, 2.05 mmol) and benzyl chloroformate (0.5 mL, 3.50 mmol), to obtain 0.73 g of the title compound as a colorless oily substance (93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[NH4+].C([BH3-])#[N:28].[Na+]>CO>[C:1]([O:5][C:6](=[O:21])[CH2:7][O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH:14]([NH2:28])[C:13]=2[CH:12]=[C:11]([Cl:19])[C:10]=1[F:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: [BH3-]C#N
Reactant: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)COc1c(F)c(Cl)cc2c1CCCC2N
Yield: 95.3 %

Procedure:
To a stirred and ice cold solution of (3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (1.32 g, 4.01 mmol) and ammonium acetate (4.7 g, 61.0 mmol) in methanol (21 mL) was added sodium cyanoborohydride (504 mg, 8.02 mmol) under nitrogen. After 10 minutes of stirring at room temperature, the reaction mixture was heated at reflux for 4 hours. The solvent was removed under reduced pressure and to the residue was added saturated sodium bicarbonate solution (10 mL). The resulting solution was extracted with dichloromethane (25 mL×3). The organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to afford (5-amino-3-chloro-2-fluoro-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid tert-butyl ester (1.26 g, 98%), which is used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH:22]=O)=[CH:4][C:3]=1[F:24].[N:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH2:31]>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]2[O:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:20])([CH3:21])[CH3:19])=[O:16])[CH2:10][C@H:9]2[CH2:22][NH:31][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][N:25]=2)=[CH:4][C:3]=1[F:24]
Reactant: Nc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](C=O)C1
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(F)c2)[C@H](CNc2ccccn2)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 61.3 %

Procedure:
To a solution of tert-butyl (6R,7R)-7-(4-chloro-3-fluorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (150 mg) and pyridin-2-amine (79 mg) in THF (1.3 mL) and methanol (0.1 ml) was added borane-2-picoline complex (90 mg), and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, the residue was stirred in 1 M aqueous hydrochloric acid solution, and neutralized with saturated aqueous sodium hydrogen carbonate solution, and the mixture was extracted with ethyl acetate. The extract was washed with distilled water and brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (112 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:23])[N:9]([CH2:11][C:12]3[C:13]([CH3:22])=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)[N:10]=[C:4]2[C:3]=1[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1)#[N:31].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.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>[CH3:22][C:13]1[C:12]([CH2:11][N:9]2[C:8](=[O:23])[N:5]3[CH:6]=[CH:7][C:2]([C:35]4[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[CH:33][CH:34]=4)=[C:3]([C:24]4[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=4)[C:4]3=[N:10]2)=[CH:17][CH:16]=[C:15]([C:18]([F:21])([F:20])[F:19])[N:14]=1
Reactant: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(Cl)ccn2c1=O
Reactant: N#Cc1ccc(B(O)O)cc1
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: [Na+]
Solvent: Cc1ccccc1
Product: Cc1nc(C(F)(F)F)ccc1Cn1nc2c(-c3ccncc3)c(-c3ccc(C#N)cc3)ccn2c1=O
Temperature: 100 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one (135 mg, 0.32 mmol), 4-cyanophenylboronic acid (189 mg, 1.29 mmol), and 2.0 M aqueous sodium carbonate (0.70 mL) in toluene (2.5 mL) was added (Ph3P)4Pd (55 mg, 0.048 mmol) in one portion, and the resulting yellow mixture was vigorously stirred under argon at 100° C. for 1.5 h. Analysis by HPLC/MS indicated about 30% of the starting 7-chloro-2-((2-methyl-6-(trifluoromethyl)pyridin-3-yl)methyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one remained. Additional catalyst (35 mg, 0.030 mmol) was added. The reaction mixture was stirred at 100° C. for 2 h more. After cooling to room temperature, the reaction mixture was partitioned between EtOAc and water. The EtOAc layer was washed with water, then saturated aqueous NaCl twice, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified using a silica gel cartridge (40 g) eluted with a gradient of EtOAc (0-80%) in hexanes to afford the desired product, which was dissolved in acetonitrile, frozen and lyophilized to afford 80 mg of the title compound as a light yellow powder. HPLC/MS: retention time=2.39 min, [M+H]+=487.2.
Reaction SMILES: [F:1][CH:2]([F:12])[CH:3]1[CH2:6][CH:5]([C:7]([O:9]CC)=[O:8])[CH2:4]1.[OH-].[Na+]>C1COCC1.O>[F:1][CH:2]([F:12])[CH:3]1[CH2:6][CH:5]([C:7]([OH:9])=[O:8])[CH2:4]1
Reactant: CCOC(=O)C1CC(C(F)F)C1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)C1CC(C(F)F)C1
Reaction time: 16 h
Yield: 71.2 %

Procedure:
To a stirred solution of Intermediate 252A (0.2 g, 1.122 mmol) in THF (5 mL) was added NaOH (0.112 g, 2.81 mmol) in water (2 mL) at RT. After 16 h, THF was removed under a reduced pressure and the pH of aqueous solution was adjusted to 3 using a 1.0 N aq. solution of HCl and extracted with ethyl acetate (3×10 mL). The combined organic layer was washed with water, brine, dried over Na2SO4, filtered and the filtrate concentrated to afford Intermediate 252B as yellow liquid (0.12 g, 71%, mixture of cis and trans isomers). The crude product was used in a subsequent reaction without further purification. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.01-12.22 (m, 1H), 5.84-6.32 (m, 1H), 2.97-3.13 (m, 1H), 2.59-2.77 (m, 1H), 2.06-2.32 (m, 4H).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:8]2[CH:11]([CH3:12])[C:10](=[O:13])[NH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:20]1([CH3:32])[CH:25]=[CH:24][C:23]([S:26]([N:29]=[C:30]=[O:31])(=[O:28])=[O:27])=[CH:22][CH:21]=1>>[C:14]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]2[CH:11]([CH3:12])[C:10](=[O:13])[N:9]2[C:30]([NH:29][S:26]([C:23]2[CH:24]=[CH:25][C:20]([CH3:32])=[CH:21][CH:22]=2)(=[O:28])=[O:27])=[O:31])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Reactant: CC1C(=O)NN1C(c1ccccc1)c1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)N2C(=O)C(C)N2C(c2ccccc2)c2ccccc2)cc1
Yield: 64 %

Procedure:
Following the procedure of Example 2 and using 1-(diphenylmethyl)-4-methyl-1,2-diazetidin-3-one (prepared according to Example 1B.) and p-toluenesulfonylisocyanate there is obtained 1.15 g (64%) of the title compound having a melting point of 155°-159° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[F:25][C:26]1[C:34]([OH:35])=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2>>[F:25][C:26]1[C:34]([O:35][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]4[CH2:23][CH2:22][N:21]([CH3:24])[CH2:20][CH2:19]4)=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][N:3]=2)=[CH:33][CH:32]=[C:31]2[C:27]=1[CH:28]=[C:29]([CH3:36])[NH:30]2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCN(C)CC1
Reactant: Cc1cc2c(F)c(O)ccc2[nH]1
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCCCN1CCN(C)CC1
Yield: 69.5 %

Procedure:
Using an analogous procedure to that described in Example 237, 4-chloro-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (106 mg, 0.30 mmol), (prepared as described for the starting material in Example 176), was reacted with 4-fluoro-5-hydroxy-2-methylindole (60 mg, 0.36 mmol), (prepared as described for the starting material in Example 237), to give 4-(4-fluoro-2-methylindol-5-yloxy)-6-methoxy-7-(3-(4-methylpiperazin-1-yl)propoxy)quinazoline (100 mg, 70%).
Reaction SMILES: CO[C:3](=[O:19])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[CH3:20][NH:21][C:22]([NH2:24])=[O:23].C[O-].[Mg+2].C[O-].CO>>[C:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([NH:24][C:22]([NH:21][CH3:20])=[O:23])=[O:19])=[CH:16][CH:15]=1)#[N:18]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Reactant: CNC(N)=O
Agent: C[O-]
Agent: [Mg+2]
Solvent: CO
Product: CNC(=O)NC(=O)C(CC1CCCC1)c1ccc(C#N)cc1
Yield: 16.3 %

Procedure:
A mixture of 2-(4-cyano-phenyl)-3-cyclopentyl-propionic acid methyl ester (257 mg, 1.0 mmol) and methyl urea (148 mg, 2.0 mmol) in a solution of magnesium methoxide in methanol (7.4 wt %, 2.0 mL, 1.40 mmol) was heated to reflux for 48 h. The reaction mixture was then concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 70/30 ethyl acetate/hexanes) afforded 1-[2-(4-cyano-phenyl)-3-cyclopentyl-propionyl]-3-methyl-urea (48.8 mg, 16.3%) as a white solid: mp 61-65° C.; FAB-HRMS m/e calcd for C17H21N3O2 (M+H)+300.1712 found 300.1722.
Reaction SMILES: [CH3:1][C:2]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([O:23]CC)=[O:22])[CH:18]=[N:17]1)[NH:10][C:9]2=O.[CH3:32][NH:33][CH3:34]>>[CH3:31][C:27]1[CH:28]=[CH:29][CH:30]=[C:2]([CH3:1])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[C:11]([N:16]1[CH:20]=[C:19]([C:21]([OH:23])=[O:22])[CH:18]=[N:17]1)[N:10]=[C:9]2[N:33]([CH3:34])[CH3:32]
Reactant: CCOC(=O)c1cnn(-c2nc3ccc(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: CNC
Product: Cc1cccc(C)c1CNc1ccc2nc(-n3cc(C(=O)O)cn3)nc(N(C)C)c2c1

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and dimethylamine in step E. MS (ESI/CI): predicted mass C23H24N6O2, 416.20.
Reaction SMILES: [NH2:1][CH2:2][C:3]([OH:5])=[O:4].[CH2:6]([CH:9]([CH2:13][CH2:14][CH3:15])[C:10](Cl)=[O:11])[CH2:7][CH3:8].[OH-].[Na+]>O>[CH2:6]([CH:9]([CH2:13][CH2:14][CH3:15])[C:10]([NH:1][CH2:2][C:3]([OH:5])=[O:4])=[O:11])[CH2:7][CH3:8]
Reactant: NCC(=O)O
Reactant: CCCC(CCC)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCCC(CCC)C(=O)NCC(=O)O
Temperature: 25 °C
Reaction time: 3 h
Yield: 58.7 %

Procedure:
In 63 ml of water was dissolved 6.93 g of glycine, and under ice-cooling, 15 g of 2-n-propyl-n-pentanoyl chloride and 13 ml of a 36% sodium hydroxide solution were alternately added dropwise. After completion of the dropwise addition, the mixture was stirred at room temperature for 3 hours to conduct the reaction, adjusted a pH thereof to about 2 with a 1 N hydrochloric acid, and precipitated crystals were collected by filtration. The crystals were dissolved in ethyl acetate, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. Crystals obtained by condensing the solvent under reduced pressure were recrystallized from hexane-ethyl acetate to give 10.9 g (Yield: 59%) of the title compound as colorless needle crystals.
Reaction SMILES: [CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[OH:17])[CH2:2][CH2:3][CH3:4].[CH2:23]([CH:25]1[O:27][CH2:26]1)Cl.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([C:5]1[O:6][C:7]2[CH:22]=[CH:21][CH:20]=[CH:19][C:8]=2[C:9]=1[C:10](=[O:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[O:17][CH2:23][CH:25]1[O:27][CH2:26]1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1oc2ccccc2c1C(=O)c1ccccc1O
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCCCc1oc2ccccc2c1C(=O)c1ccccc1OCC1CO1

Procedure:
A mixture of 7.5 g. (0.025 mol.) of 2-n-butyl-3-(2'-hydroxybenzoyl)benzofuran, 25 ml. of epichlorohydrin and 15.0 g. of potassium carbonate in 150 ml. of ethanol was refluxed for three hours. After cooling the reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was dissolved in water and the aqueous solution was extracted with methylene chloride. The extracts were combined, dried (Na2SO4) and concentrated to give an oily residue that was chromatographed on alumina with chloroform as the eluant to give 2-n-butyl-3-[2'-(2,3-epoxy)propoxybenzoyl]benzofuran.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3([OH:34])[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH2:17])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12.[C:35]1([C@@H:41]2[CH2:43][C@H:42]2[C:44](Cl)=[O:45])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>N1C=CC=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([CH2:20][C:21]3([OH:34])[CH2:22][CH2:23][N:24]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:25][CH2:26]3)[N:9]=[C:10]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:44]([C@@H:42]4[CH2:43][C@H:41]4[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:45])=[C:13]([O:18][CH3:19])[CH:12]=3)[C:3]=12
Reactant: O=C(Cl)[C@@H]1C[C@H]1c1ccccc1
Reactant: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1N
Solvent: c1ccncc1
Product: COc1cc(-c2nn(CC3(O)CCN(C(=O)OC(C)(C)C)CC3)c3ncnc(N)c23)ccc1NC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 76.5 %

Procedure:
To a mixture of tert-butyl 4-{[4-amino-3-(4-amino-3-methoxyphenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00017 mol) in pyridine (4 mL) was added trans-2-phenyl-cyclopropane carbonyl chloride (0.035g, 0.00019 mol) at −5° C. The mixture was stirred at −5° C. for 10 minutes then warmed up to room temperature to stir for 1 hours. The mixture was quenched with an aqueous 1N solution of sodium hydroxide. Pyridine was removed under reduced pressure. The residue was partitioned between water and dichloromethane (50 mL). The organic layer was washed with water. The solvents were removed under reduced and the residue was purified by RP-HPLC (Hypersilprep HS C18, 8μm, 250×21.1 mm; 5%-100% over 35 min with 0.1 M ammonium acetate, 21 mL/min) to yield trans tert-butyl 4-{[4-amino-3-(3-methoxy-4-{[(2-phenylcyclopropyl)carbonyl]amino}phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl]methyl}-4-hydroxy-1-piperidinecarboxylate (0.08 g, 0.00013 mol). RP-HPLC (Delta Pak C18, 5 μm, 300 A, 15 cm; 5%-85% acetonitrile-0.1M ammonium acetate over 10 min, 1 mL/min) Rt 10.7 min. MS: MH+ 614.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[CH:11][S:10][C:9]=2[CH2:13][OH:14])=[CH:4][CH:3]=1.C1C(=O)N([Cl:22])C(=O)C1>CN(C)C=O>[Cl:22][C:11]1[S:10][C:9]([CH2:13][OH:14])=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[CH:12]=1
Reactant: OCc1sccc1-c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Product: OCc1sc(Cl)cc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed [3-(4-chlorophenyl)thiophen-2-yl]methanol (500 mg, 2.23 mmol, 1.00 equiv), N,N-dimethylformamide (10 mL), NCS (300 mg, 2.25 mmol, 1.01 equiv). The resulting solution was stirred for 2 h at 25° C. The reaction was then quenched by the addition of 20 ml of water. The resulting solution was extracted with 2×20 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×50 mL of brine. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with PE/EA (30/1-10/1). This resulted in 350 mg (55%) of [5-chloro-3-(4-chlorophenyl)thiophen-2-yl]methanol as a white solid.
Reaction SMILES: [C:1](Cl)(=[O:4])[CH:2]=[CH2:3].[CH3:6][N:7]([CH3:37])[CH:8]1[CH2:11][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH2:36])[CH2:9]1>C(Cl)Cl.CO.C(Cl)Cl>[CH3:37][N:7]([CH3:6])[CH:8]1[CH2:9][N:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([NH:20][C:21]3[N:26]=[C:25]([C:27]4[CH:28]=[N:29][N:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=45)[CH:24]=[CH:23][N:22]=3)=[CH:14][C:13]=2[NH:36][C:1](=[O:4])[CH:2]=[CH2:3])[CH2:11]1
Reactant: COc1cc(N2CC(N(C)C)C2)c(N)cc1Nc1nccc(-c2cnn3ccccc23)n1
Reactant: C=CC(=O)Cl
Solvent: ClCCl
Solvent: CO
Product: C=CC(=O)Nc1cc(Nc2nccc(-c3cnn4ccccc34)n2)c(OC)cc1N1CC(N(C)C)C1
Reaction time: 0.5 h
Yield: 65.9 %

Procedure:
A solution of acryloyl chloride (49 μL, 0.60 mmol) in CH2Cl2 (2.77 mL) was added dropwise over 5 minutes to 4-(3-dimethylaminoazetidin-1-yl)-6-methoxy-N-(4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-yl)benzene-1,3-diamine (Intermediate 156, 246 mg, 0.57 mmol) in CH2Cl2 (8.3 mL), which was cooled in an ice/CH3OH bath. The mixture was stirred for 0.5 h asn was then diluted with 10% CH3OH/CH2Cl2. The resulting solution was washed with sat. NaHCO3, dried (MgSO4) and concentrated in vacuo. Purification by FCC, eluting with 0-5% methanolic ammonia in CH2Cl2 gave the title compound (182 mg, 66%) as a yellow solid after trituration with diethyl ether; 1H NMR: 2.09 (6H, s), 3.04-3.12 (1H, m), 3.55-3.60 (2H, m), 3.83 (3H, s), 3.96 (2H, t), 5.67 (1H, dd), 6.18 (1H, dd), 6.26 (1H, s), 6.48 (1H, dd), 7.05 (1H, td), 7.20 (1H, d), 7.41-7.46 (1H, m), 7.71 (1H, s), 8.00 (1H, s), 8.29 (1H, d), 8.43 (1H, br d), 8.75 (1H, s), 8.77 (1H, d), 9.29 (1H, s); m/z: ES+ MH+ 485.69.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][C:4]#[CH:5].C(Cl)(=O)C(Cl)=O.[CH2:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>ClCCl.CN(C=O)C>[CH2:14]([O:6][C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OCc1ccccc1
Reactant: C#CCCC(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C#CCCC(=O)OCc1ccccc1
Reaction time: 1.5 h
Yield: 134.9 %

Procedure:
To a solution in dichloromethane (25 mL) containing a few drops DMF of 4-pentynoic acid (2.49 g, 23.4 mmol) was added oxalyl chloride (2.2 mL, 25 mmol). The reaction mixture was stirred for 1.5 hours and benzyl alcohol (3.9 mL, 38 mmol) was added via syringe. The reaction mixture was stirred for 6 hours and then was extracted with saturated aqueous sodium carbonate. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to give 4-pentynoic acid benzyl ester (5.94 g) as a yellow liquid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO.[Br-:18].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC>C(Cl)Cl>[Br:18][CH2:2][C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][NH:12][C:13](=[O:15])[CH3:14])=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)NCCc1ccc(C(C)=O)cc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: ClCCl
Solvent: CO
Product: CC(=O)NCCc1ccc(C(=O)CBr)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
In a round-bottomed flask, N-[2-(4-acetyl-phenyl)-ethyl]-acetamide (7.23 g, 35.2 mmol) was dissolved in methylene chloride (120 ml), and methanol (60 ml). Tetrabutylammonium tribromide (17.0 g, 35.2 mmol) was added to this solution in one portion, and the mixture was allowed to stir overnight at room temperature. The volatiles were then removed in vacuo to afford an oil, which was then resuspended in 100 ml of methylene chloride and extracted with 125 ml of saturated aqueous sodium bicarbonate. The aqueous extracts were reextracted with methylene chloride (3×100 ml), and the combined organic extracts were then washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude oil was purified by column chromatography (silica gel; methylene chloride to 7% methanol/methylene chloride), and the resulting material was washed with 110 ml of water to afford 8.27 g (83% yield) of pure product as a white solid. LRMS ([M−1]−)=283.0, 284.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH2:19]>ClCCl>[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][NH:19][C:10](=[O:12])[CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: NCc1cccs1
Reactant: COc1ccccc1CC(=O)O
Solvent: ClCCl
Product: COc1ccccc1CC(=O)NCc1cccs1
Reaction time: 1 h

Procedure:
N,N'-Carbonyldiimidazole (8.1 g) is added to a stirred solution of 2-(2-methoxyphenyl)acetic acid (8.3 g) in anhydrous dichloromethane (80 cc), cooled to +5° C.; stirring of the reaction mixture is continued for 1 hour and a half and (2-thienyl)methylamine (5.1 cc) is then added. Stirring of the reaction mixture is continued for 1 hour at +5° C. and then for 2 hours at ambient temperature. The reaction mixture is then washed with distilled water (2×40 cc); the organic solution is dried over magnesium sulphate and concentrated to dryness under reduced pressure (2.7 kPa). The solid residue obtained is washed with isopropyl ether (30 cc), drained and dried. N-(2-Thienyl)methyl-2-(2-methoxyphenyl)acetamide (10.5 g) melting at 84° C. is obtained.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)(=[NH:3])[NH2:2].[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[CH:26]([C:32](OCC)=[O:33])[C:27](OCC)=[O:28]>C1(C)C=CC=CC=1>[S:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[N:19]=[C:18]1[C:26]1[C:32]([OH:33])=[N:3][C:1]([CH:4]2[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]2)=[N:2][C:27]=1[OH:28]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=N)N)CC1
Reactant: CCOC(=O)C(C(=O)OCC)c1nc2ccccc2s1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2nc(O)c(-c3nc4ccccc4s3)c(O)n2)CC1
Temperature: 120 °C
Yield: 68.2 %

Procedure:
A mixture of tert-butyl 4-carbamimidoylpiperidine-1-carboxylate (35 g, 153.98 mmol, 1.00 equiv) and 1,3-diethyl 2-(1,3-benzothiazol-2-yl)propanedioate (49.7 g, 169.43 mmol, 1.10 equiv) in toluene (500 ml) was heated overnight at 120° C. in an oil bath under nitrogen. After cooled to room temperature, the solid was collected by filtration. 45 g of tert-butyl 4-[5-(1,3-benzothiazol-2-yl)-4,6-dihydroxypyrimidin-2-yl]piperidine-1-carboxylate was obtained as a light yellow solid. MS m/z [M+H]+ (ESI): 429.