Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:9]1[C:14](=[O:15])[C:13](I)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[C:10]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C([O-])([O-])=O.[Na+].[Na+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1>COCCOC.O.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>[C:1]([N:9]1[C:14](=[O:15])[C:13]([C:29]2[C:24]([F:23])=[N:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][N:11]([CH2:17][CH2:18][CH2:19][CH2:20][Cl:21])[C:10]1=[O:22])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1cccnc1F
Reactant: O=C(c1ccccc1)n1c(=O)c(I)cn(CCCCCl)c1=O
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: O
Solvent: COCCOC
Product: O=C(c1ccccc1)n1c(=O)c(-c2cccnc2F)cn(CCCCCl)c1=O
Yield: 54.3 %

Procedure:
3-Benzoyl-1-(4-chloro-butyl)-5-iodo-1H-pyrimidine-2,4-dione (Prep129, 614 mg, 1.42 mmol) was dissolved in degassed DME-water solution (5-1, 35 ml). 2-Fluoro-pyridine 3-boronic acid (250 mg, 1.77 mmol), Na2CO3 (301 mg, 2.84 mmol), 2-(dicyclohexylphosphino)biphenyl (99 mg, 0.28 mmol) and Pd(PPh3)4 (328 mg, 0.28 mmol) were added and the mixture was refluxed for 3 hours. The solvents were evaporated under vacuum and the crude was partitioned between ethyl acetate and water. The organic phase was dried (Na2SO4) and evaporated; the crude (0.9 g, yellow oil) was purified by flash chromatography with ethyl acetate-petroleum ether (1-1) to give the title compound as yellow oil (310 mg, 54% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:36])[CH3:35]>ClCCl>[C:34]([NH:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8](=[O:24])[C:9]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[CH:12]=[CH:11][C:10]=2[NH:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)=[CH:4][CH:3]=1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(CNC(=O)c2cc([N+](=O)[O-])ccc2NC2CCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.8 %

Procedure:
To a mixture of N-(4-aminobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide (126 mg) and triethylamine (0.119 mL) in anhydrous dichloromethane (20 mL) was added acetyl chloride (33.5 mg). After stirring for 2 hours at ambient temperature, the mixture was washed with an aqueous saturated sodium bicarbonate solution, water and brine. The resultant was dried over magnesium sulfate and evaporated in vacuo. The residue was purified by a silica gel column chromatography eluting with 10% methanol in chloroform. The obtained product was triturated with diisopropyl ether to give N-(4-acetamidobenzyl)-2-(cyclopentylamino)-5-nitrobenzamide as yellow powders (135 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[O:12])[CH:10]=1)[C:5](O)=[O:6].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[NH2:45][C@@H:46]([CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1)[C@H:47]([OH:61])[CH2:48][NH:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:60])([F:59])[F:58])[CH:52]=1.CCN(C(C)C)C(C)C.O1C2C=CC=CC=2C=C1CNC(=O)OC(C)(C)C>C(Cl)Cl.C(OCC)(=O)C>[OH:61][C@H:47]([CH2:48][NH:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[C:53]([C:57]([F:58])([F:59])[F:60])[CH:52]=1)[C@@H:46]([NH:45][C:5](=[O:6])[C:4]1[CH:8]=[C:9]([C:11]([N:13]2[CH2:17][CH2:16][CH2:15][C@@H:14]2[C:18]2[S:19][CH:20]=[C:21]([CH3:23])[N:22]=2)=[O:12])[CH:10]=[C:2]([CH3:1])[CH:3]=1)[CH2:62][C:63]1[CH:68]=[CH:67][CH:66]=[CH:65][CH:64]=1
Reactant: Cc1cc(C(=O)O)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Reactant: N[C@@H](Cc1ccccc1)[C@H](O)CNCc1cccc(C(F)(F)F)c1
Agent: CC(C)(C)OC(=O)NCc1cc2ccccc2o1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc(C(=O)N[C@@H](Cc2ccccc2)[C@H](O)CNCc2cccc(C(F)(F)F)c2)cc(C(=O)N2CCC[C@@H]2c2nc(C)cs2)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
To (R)-3-methyl-5-(2-(4-methylthiazol-2-yl)pyrrolidine-1-carbonyl)benzoic acid (330 mg, 1 mmol) in CH2Cl2 at rt, EDCI (269 mg, 1.4 mmol) and HOBT (162 mg, 1.20 mmol) were added and stirred at rt for 20 min. In a separate flask (2R,3S)-3-amino-4-phenyl-1-(3-(trifluoromethyl)benzylamino)butan-2-ol was taken in CH2Cl2 and treated with DIPEA (2 ml). After 20 min, flask containing acid was cooled to 0° C. and the amine was added to it. Reaction mixture was stirred at rt for 16 h. Then reaction mixture was diluted with ethyl acetate, washed with sodium bicarbonate, water, brine and dried. Crude residue was purified by column chromatography to yield 60% of desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[C:12]3[CH:15]=[N:16][N:17]([C:18]4[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH:21]=[CH:22][CH:23]=4)[C:11]=3[N:10]=[C:9]2[C:29]2[CH:34]=[CH:33][C:32](B3OC(C)(C)C(C)(C)O3)=[CH:31][CH:30]=2)=[CH:4][CH:3]=1.[NH2:44][C:45]1[CH:50]=[CH:49][C:48](Br)=[CH:47][N:46]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O.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]>[NH2:44][C:45]1[N:46]=[CH:47][C:48]([C:32]2[CH:33]=[CH:34][C:29]([C:9]3[N:8]([C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=4)[C:13](=[O:14])[C:12]4[CH:15]=[N:16][N:17]([C:18]5[CH:19]=[C:20]([NH:24][S:25]([CH3:28])(=[O:26])=[O:27])[CH:21]=[CH:22][CH:23]=5)[C:11]=4[N:10]=3)=[CH:30][CH:31]=2)=[CH:49][CH:50]=1
Reactant: CC1(C)OB(c2ccc(-c3nc4c(cnn4-c4cccc(NS(C)(=O)=O)c4)c(=O)n3-c3ccc(Cl)cc3)cc2)OC1(C)C
Reactant: Nc1ccc(Br)cn1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc(-n2ncc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccc(N)nc5)cc4)nc32)c1
Temperature: 100 °C

Procedure:
In the last step, a solution of N-(3-{5-(4-chloro-phenyl)-4-oxo-6-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)phenyl]-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl}-phenyl)-methane sulfonamide (5, 0.5 g, 0.89 mmol) in N,N-dimethylformamide (15 mL) is degassed with argon for 0.5 h. Then 2-amino-5-bromopyridine (0.21 g, 1.22 mmol), cesium carbonate (0.53 g, 1.618 mmol), Pd(dppf)2Cl2 (0.03 g, 0.04 mmol) are added and the resulting solution is degassed with argon for 0.5 h. The reaction mixture is then heated at 100° C. for 6 h. The reaction mixture is cooled to rt and diluted with water and extracted with ethyl acetate (3×). The combined organic layer is washed with brine, dried over Na2SO4, concentrated, and purified by preparative HPLC to afford N-{3-[6-[4-(6-amino-pyridin-3-yl)-phenyl]-5-(4-chloro-phenyl)-4-oxo-4,5-dihydro-pyrazolo[3,4-d]pyrimidin-1-yl]-phenyl}-methane sulfonamide, as a pale yellow solid. 1H NMR (CD3OD, 400 MHz) δ 8.34 (s, 1H), 8.27 (s, 1H), 8.15 (m, 2H), 7.90 (d, 1H), 7.60 (m, 5H), 7.4 (m, 2H), 7.34 (m, 2H), 7.2 (d, 1H), 7.0 (d, 1H), 2.99 (s, 3H); LC-MS calculated for C29H22ClN7O3S (M+H+) 584.1, found 584.1.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH:13]=O)[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.[CH3:21][C:22]1([CH3:28])[CH2:27][O:26][CH2:25][CH2:24][NH:23]1.Cl.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH2:12][CH2:13][N:23]3[CH2:24][CH2:25][O:26][CH2:27][C:22]3([CH3:28])[CH3:21])[N:8]2[CH3:11])=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1
Reactant: Cn1c(CC=O)nc2c(N3CCOCC3)nc(Cl)nc21
Reactant: CC1(C)COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: Cn1c(CCN2CCOCC2(C)C)nc2c(N3CCOCC3)nc(Cl)nc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 28 %

Procedure:
To a solution of (2-chloro-9-methyl-6-morpholin-4-yl-9H-purin-8-yl)acetaldehyde (119 mg, 0.40 mmol) in DCE (10 mL) was added 3,3-dimethylmorpholine.HCl (61 mg, 0.40 mmol), triethylamine (0.06 mL, 0.40 mmol) and powdered 4 Å molecular sieves. After stirring at room temperature for 4 h, sodium triacetoxyborohydride (171 mg, 0.80 mmol) was added and the resulting mixture stirred for a further 16 h. The reaction mixture was filtered through Celite®, loaded onto an Isolute® SCX-2 cartridge, the cartridge was washed with MeOH then the desired product eluted with 2 M NH3/MeOH in DCM. The resulting residue was purified by column chromatography (Si—PCC, 0-7% MeOH in DCM) to give the title compound as a pale yellow oil (44 mg, 28%). LCMS (Method H): RT=2.45 min, [M+H]+ 395.5
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([OH:10])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.Br[CH2:12][CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:16][CH:15]([CH3:17])[CH2:14][CH2:13][CH2:12][O:10][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][CH:7]=1)[NH:1][N:2]=[CH:3]2
Reactant: CC(C)CCCBr
Reactant: Oc1ccc2[nH]ncc2c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)CCCOc1ccc2[nH]ncc2c1
Temperature: 60 °C
Reaction time: 9 h
Yield: 36.9 %

Procedure:
To a solution of the 1H-indazol-5-ol (100 mg, 0.745 mmol) obtained in Reference Example 4 in N,N-dimethylformamide (2 ml) were added 1-bromo-4-methylpentane (0.109 ml, 0.745 mmol), tetrabutylammonium iodide (28 mg, 0.1 mmol) and potassium carbonate (103 mg, 0.745 mmol), and the resulting mixture was heated to 60° C. After 9 hours, the mixture was poured into water (20 ml) and extracted with ethyl acetate (20 ml×2). The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate) to obtain 5-[(4-methylpentyl)oxy]-1H-indazole (60 mg, 37%).
Reaction SMILES: C[C:2]1[O:3]C(=O)C2SC=C[C:6]=2[N:7]=1.[NH2:12][C:13]1C(C)=CC=CC=1>C(O)(=O)C>[CH3:2][N:7]([C:13]([N:12]=[N:12][C:2]([N:7]([CH3:6])[CH3:13])=[O:3])=[O:3])[CH3:6]
Reactant: Cc1ccccc1N
Reactant: Cc1nc2ccsc2c(=O)o1
Solvent: CC(=O)O
Product: CN(C)C(=O)N=NC(=O)N(C)C
Yield: 45.9 %

Procedure:
2-Methyl-thieno[3,2-d][1,3]oxazin-4-one (12.7 g, 76 mmol) and o-toluidine (16.2 mL, 152 mmol) were combined in acetic acid (175 mL) and refluxed for 3 hours. The reaction was concentrated and the residue was partitioned between ethyl acetate and water. The two phase mixture was treated with sodium bicarbonate until the aqueous layer was basic and the phases were then separated. The aqueous phase was extracted with ethyl acetate and the combined organic layer was washed with water and brine, dried over sodium sulfate and concentrated to leave a black oil. This residue was purified by flash chromatography on silica gel (60×200 mm). Elution with 20% ethyl acetate/hexane gave 16.2 g of impure product and 3 g of uncyclized diamide biproduct. The impure product was chromatographed a second time as above but with 10% and 15% ethyl acetate/hexane elution. In this fashion 9.2 g (47%) of 2-methyl-3-(2-methylphenyl)-3H-thieno[3,2-d]pyrimidin-4-one was isolated as a light yellow solid. 1H NMR δ7.70 (d, J=5.3 Hz, 1 H), 7.39-7.30 (m, 3 H), 7.29 (d, J=5.3 Hz, 1 H), 7.13 (d, J=7.8 Hz, 1 H), 2.15 (s, 3 H), 2.10 (s, 3 H).
Reaction SMILES: [C@@H:1]12[C:10](=O)[O:9][C:7](=[O:8])[C@@H:2]1[CH2:3][CH:4]=[CH:5][CH2:6]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O1CCCC1.O.C(Cl)(Cl)Cl>O1CCCC1>[OH:8][CH2:7][C@H:2]1[C@@H:1]([CH2:10][OH:9])[CH2:6][CH:5]=[CH:4][CH2:3]1
Reactant: O=C1OC(=O)[C@@H]2CC=CC[C@H]12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Product: OC[C@@H]1CC=CC[C@@H]1CO
Temperature: 0 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A solution of 25 g of cis-4-cyclohexene-1,2-dicarboxylic acid anhydride in 140 ml of tetrahydrofuran is instilled in a suspension of 10 g of lithium aluminum hydride in 140 ml of tetrahydrofuran at room temperature and the mixture is then stirred for 3 hours at reflux temperature. It is cooled to 0° C. a mixture of tetrahydrofuran/water (1+1) is instilled slowly, stirred for 30 minutes, mixed with 150 ml of chloroform, filtered and the filtrate is concentrated by evaporation in a vacuum. The residue is distilled at 0.2 mm/Torr and 150° C. on a bulb tube. After recrystallization of the distillate from toluene/pentane, 21 g of cis-1,6-dihydroxymethyl-3-cyclohexene is obtained as colorless crystals, melting point 33°-35° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][CH:5]([CH2:7][OH:8])[CH2:4][O:3]1.[OH-].[K+].I[CH:13]([CH3:15])[CH3:14]>CS(C)=O.O>[CH:13]([O:8][CH2:7][C@@H:5]1[CH2:4][O:3][C:2]([CH3:9])([CH3:1])[O:6]1)([CH3:15])[CH3:14]
Reactant: CC(C)I
Reactant: CC1(C)OCC(CO)O1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)OC[C@@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 2,2-dimethyl-1,3-dioxolane-4-methanol (2 g), in DMSO (50 mL), powdered potassium hydroxide was added portionwise at 0° C. then warmed to room temperature, 2-Iodo-propane (43 mL) was added to the mixture at 0° C. then stirred for 72 h at room temperature. The reaction mixture was diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O then brine (×2) and dried (MgSO4), filtered and evaporated to give the subtitle compound as clear, colourless oil. Yield: 2 g
Reaction SMILES: [OH:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:13])[CH3:12])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:25](OC(=O)C)(=[O:27])[CH3:26]>N1C=CC=CC=1>[C:25]([O:1][C@@H:2]([C@@H:9]([NH:14][C:15]([C@H:17]1[O:19][C@@H:18]1[C:20]([O:22][CH2:23][CH3:24])=[O:21])=[O:16])[CH2:10][CH:11]([CH3:12])[CH3:13])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](O)c1ccccc1
Solvent: c1ccncc1
Product: CCOC(=O)[C@H]1O[C@@H]1C(=O)N[C@@H](CC(C)C)[C@H](OC(C)=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
In pyridine (0.6 mL) was dissolved ethyl (2S,3S)-3-[[1-(S)-[α-(R)-hydroxybenzyl]-3-methylbutyl]carbamoyl]-oxirane-2-carboxylate (300 mg, 0.894 mmol.). To the resulting solution was added acetic anhydride (0.085 ML, 0.901 mml.) under chilling with ice. The mixture was stirred for 18 hours at room temperature, and extracted with ether (8 mL, 3 portions) after addition of water (10 mL). The organic portion was washed successively with water, 1N hydrochloric acid, and an aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate=2/1), to give the titled compound as a slightly brownish crystalline product (267 mg, yield: 79%),
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:13]([CH2:20]Br)[NH:12][C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[N:26]=2)=[N:10]1.[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH:35]1[C:40]([OH:42])=[O:41]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:10]=[C:11]([C:22]2[S:23][CH:24]=[C:25]([CH2:27][C:28]([NH:30][CH:31]([CH3:33])[CH3:32])=[O:29])[N:26]=2)[NH:12][C:13]([CH2:20][N:34]2[CH2:39][CH2:38][O:37][CH2:36][CH:35]2[C:40]([OH:42])=[O:41])=[C:14]1[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: CCOC(=O)C1=C(CBr)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2nc(CC(=O)NC(C)C)cs2)=NC1c1ccc(F)cc1Br
Yield: 49 %

Procedure:
Ethyl 4-(2-bromo-4-fluorophenyl)-6-(bromomethyl)-2-(4-(2-(isopropylamino)-2-oxo ethyl)thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (1.2 g, 2 mmol) was reacted with morpholine-3-carboxylic acid (0.39 g, 3 mmol) according to the procedure as described in Example 1, Step C to give the title compound as a yellow solid (0.64 g, 49%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:9][CH2:10][NH:11][CH2:12][CH:13]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>C(Cl)Cl.CN(C1C=CN=CC=1)C.[NH4+].[Cl-].O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][N:11]([S:22]([CH3:21])(=[O:24])=[O:23])[CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(C2=CCNCC2)cc1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CS(=O)(=O)N1CC=C(c2ccc(Cl)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine (645 mg, 3.33 mmol) was dissolved in DCM (20 ml) and then DMAP (40.7 mg, 0.333 mmol), triethylamine (1.858 ml, 13.33 mmol), and methane sulfonylchloride (0.286 ml, 3.67 mmol) were added. The reaction was stirred 1 h at rt, then diluted with DCM and saturated NH4Cl/water (1:1). The aqueous phase was extracted with DCM (×2) and the combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated. The resulting residue was purified by column chromatography on a Biotage™ 50 g column by eluting with 10% to 100% EtOAc:Hexane to provide the desired product. LC-MS: calculated for C12H14ClNO2S 271.04 observed m/e: 271.91 (M+H)+ (Rt 1.15/2 min).
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][O:9][P:8]1([NH:14][CH2:15][CH2:16][Br:17])=[O:13])=O.B(F)(F)F.CCOCC>O1CCCC1.C(Cl)(Cl)Cl.CC(C)=O.CO.O>[Br:3][CH2:4][CH2:5][N:7]1[CH2:12][CH2:11][CH2:10][O:9][P:8]1([NH:14][CH2:15][CH2:16][Br:17])=[O:13]
Reactant: O=C(CBr)N1CCCOP1(=O)NCCBr
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: O=P1(NCCBr)OCCCN1CCBr
Temperature: 25 °C

Procedure:
Sodium borohydride (1.5 g) was added to the solution of 6.6 g (18.1 mM) of (+)-3-bromoacetyl-2[(2-bromoethyl)-amino]-2-oxo-1,3,2-oxazaphosphorinane {[α]D25 =+32.7° MeOH} in 45 mL of tetrahydrofuran at ambient temperature and then was added a solution of 5.2 mL of boron trifluoride etherate in 15 mL of tetrahydrofuran. The resulting suspension was stirred at room temperature until completed and then 15 mL of water was added. Following the isolation procedure described in Example II 5.7 g (90%) of the colorless crystalline product was obtained, mp. 93°-94.5° C.; 31P-NMR (CHCl3) δ 11.2 ppm(100%), [α]D25 =+37.86 (c 16 MeOH); TLC (CHCl3 -acetone 3:1) Rf 0.2; MS as in example II
Reaction SMILES: [CH:1]1([CH:7]([NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][CH:24]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:20])([F:19])[F:18])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:32][NH:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[Cl-].[NH4+]>CN(C)C=O.C(N(CC)CC)C>[CH:1]1([CH:7]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([C:27]([N:33]([CH3:32])[CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])=[O:28])=[CH:30][CH:31]=2)[C:8]2[S:16][C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:17]([F:18])([F:19])[F:20])[CH:14]=3)[C:9]=2[CH3:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCNC
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)sc2cc(C(F)(F)F)cnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)CCN(C)C(=O)c1ccc(NC(c2sc3cc(C(F)(F)F)cnc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 72.2 %

Procedure:
To a mixture of 4-({cyclohexyl[3-methyl-6-(trifluoromethyl)thieno[3,2-b]pyridin-2-yl]methyl}amino)benzoic acid (343 mg) synthesized above, ethyl 3-(methylamino)propanoate (151 mg), 1-hydroxybenzotriazole monohydrate (176 mg), triethylamine (321 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (221 mg), and the mixture was stirred at room temperature for 2.5 days. Saturated aqueous ammonium chloride solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30-70% ethyl acetate/hexane) to give the title object compound (310 mg, 72%) as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([OH:21])=O)=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25]1)=[O:23].[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[NH:9][C:10]1[N:15]2[N:16]=[CH:17][C:18]([C:19]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:21])=[C:14]2[N:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:25][CH2:26][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:28][CH2:29]1)=[O:23]
Reactant: CCS(N)(=O)=O
Reactant: Cc1ccc(F)c(Nc2c(C(=O)N3CCC(c4ccccc4)CC3)cnc3c(C(=O)O)cnn23)c1
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cc(C)ccc3F)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 24.6 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(2-fluoro-5-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (87 mg, 0.18 mmol) obtained in step 2 and ethanesulfonamide (94 mg, 0.90 mmol), the title compound (25 mg, 25%) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([N:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)[S:11][C:7]=2[C:6]([C:18]([OH:20])=O)=[CH:5][CH:4]=1.C(Cl)(=O)C(Cl)=O.[CH3:27][C:28]1[C:32]([NH2:33])=[C:31]([CH3:34])[O:30][N:29]=1>CN(C)C=O.ClCCl.C(N(CC)CC)C>[CH3:27][C:28]1[C:32]([NH:33][C:18]([C:6]2[C:7]3[S:11][C:10]([N:12]4[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]4)=[N:9][C:8]=3[C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[O:20])=[C:31]([CH3:34])[O:30][N:29]=1
Reactant: Cc1noc(C)c1N
Reactant: COc1ccc(C(=O)O)c2sc(N3CCCCC3)nc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2c(C)noc2C)c2sc(N3CCCCC3)nc12
Yield: 9.1 %

Procedure:
Starting from 4-methoxy-2(piperidin-1-yl)benzothiazole-7-carboxylic acid (0.24 g), oxalyl chloride (2.0 ml), dichloromethane (20 ml) and dimethylformamide (1 drop), followed by 3,5-dimethylisoxazol-4-amine (0.10 g), triethylamine (0.25 ml) and dichloromethane (20 ml). Purification by flash chromatography (eluent 5% methanol in dichloromethane) yielded the title compound as a white solid (29 mg). TLC Rf 0.49 (ethyl acetate); MS found M+1 387.
Reaction SMILES: [CH3:1][C:2]1[CH2:6][CH2:5][C:4]([P:8](=[O:15])([O:12][CH2:13][CH3:14])[O:9][CH2:10][CH3:11])([CH3:7])[N:3]=1.[P:16]([O-:23])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19].Cl.C([O-])(O)=O.[Na+].[Na+].[Cl-].C([O-])([O-])=O.[Na+].[Na+]>C(OCC)C>[CH2:10]([O:9][P:8]([C:4]1([CH3:7])[CH2:5][CH2:6][C:2]([P:16]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:23])([CH3:1])[NH:3]1)([O:12][CH2:13][CH3:14])=[O:15])[CH3:11]
Reactant: CCOP(=O)(OCC)C1(C)CCC(C)=N1
Reactant: CCOP([O-])OCC
Agent: Cl
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: CCOCC
Product: CCOP(=O)(OCC)C1(C)CCC(C)(P(=O)(OCC)OCC)N1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
Diethyl 2,5-dimethyl-1-pyrrolin-5-yl)phosphonate prepared in step 1 above (4.87 g; 0.0208 mol) is placed in a 250 ml two-necked round-bottomed flask and diethyl phosphite (5.89 g; 0.043 mol) is added dropwise thereto. The reaction is stirred at room temperature for 5 days. The reaction mixture is treated with 0.1 M HCl solution to pH=1 and is then extracted with diethyl ether. The aqueous phase obtained is: treated by addition of NaHCO3 to pH=10. The amine is salted out by adding NaCl and a large excess of Na2CO3 with stirring, in the presence of diethyl ether. The aqueous phase is then extracted with diethyl ether, after which the organic phase is dried over anhydrous Na2SO4. After filtration and evaporation under vacuum, the title compound is obtained in the form of an orange oil (3.41 g, 44%).