Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH2:12])[CH3:11])[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1.Cl[C:21]1[N:29]=[CH:28][N:27]=[C:26]2[C:22]=1[N:23]=[CH:24][N:25]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>CC(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C@@H:10]([NH:12][C:21]3[N:29]=[CH:28][N:27]=[C:26]4[C:22]=3[N:23]=[CH:24][NH:25]4)[CH3:11])[N:7]([C:13]3[N:14]([CH3:18])[N:15]=[CH:16][CH:17]=3)[C:6]=2[CH:19]=1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Reactant: C[C@H](N)c1nc2ccc(F)cc2n1-c1ccnn1C
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H](Nc1ncnc2[nH]cnc12)c1nc2ccc(F)cc2n1-c1ccnn1C
Temperature: 80 °C
Reaction time: 16 h
Yield: 57.4 %

Procedure:
A mixture of (S)-1-[6-fluoro-1-(2-methyl-2H-pyrazol-3-yl)-1H-benzoimidazol-2-yl]-ethylamine, (0.093 g, 0.36 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.119 g, 0.50 mmol) and DIPEA (0.12 mL, 0.65 mmol) in IPA (2 mL) was stirred at 80° C. in a sealed tube for 16 h. After cooling, the reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO2, 0-8% (2M ammonia in methanol) in DCM). The product was dissolved in methanol (4 mL) and treated with HCl/dioxane (4M, 0.6 mL, 2.4 mmol) then stirred for 30 minutes. The resulting mixture was concentrated in vacuo and residue loaded onto an Isolute® SCX-2 cartridge and washed with MeOH. The product was eluted with 2M NH3/MeOH then concentrated in vacuo to give 417 as a white solid (0.078 g, 58%). LCMS (Method K): RT 2.79, 2.95 min [M+H]+ 378.0. 1H NMR (DMSO-d6, 400 MHz): δ 12.91-12.00 (1H, m), 8.30-7.81 (3H, m), 7.78-7.71 (1H, m), 7.50 (1H, s), 7.23-7.03 (1H, m), 7.03-6.92 (1H, m), 6.69-6.51 (1H, m), 5.60-5.22 (1H, m), 3.62-3.55 (3H, m), 1.65-1.54 (3H, m). Signals split due to presence of rotamers/tautomers
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12].Cl[C:18]1[CH:23]=[CH:22][N:21]=[CH:20][C:19]=1[N+:24]([O-:26])=[O:25].CCN(C(C)C)C(C)C>C(O)(C)C>[CH3:1][CH:2]1[CH2:7][CH2:6][N:5]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N+:24]([O-:26])=[O:25])[CH2:4][CH:3]1[NH:8][P:9](=[O:16])([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12]
Reactant: CCOP(=O)(NC1CNCCC1C)OCC
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(NC1CN(c2ccncc2[N+](=O)[O-])CCC1C)OCC
Temperature: 70 °C
Yield: 52 %

Procedure:
To a solution of diethyl 4-methylpiperidin-3-ylphosphoramidate (1.0 equiv.) in isopropyl alcohol was added 4-chloro-3-nitropyridine (2.0 equiv.) and DIEA (1.1 equiv.). The reaction was heated to 70° C. for 18 h, then quenched with water and extracted with ethyl acetate. The organics were dried and concentrated under vacuo. The crude was purified via ISCO (ethyl acetate and hexanes) to yield diethyl 4-methyl-1-(3-nitropyridin-4-yl)piperidin-3-ylphosphoramidate in 52% yield. LCMS (m/z): 373.0 (MH+), Rt=1.93 min.
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][N:19]([CH:22]4[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]4)[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[CH:4][CH:3]=1.[C:31]1([CH2:37][C:38]([N:40]=[C:41]=[O:42])=[O:39])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>O1CCCC1.CCCCCC>[CH3:28][N:25]1[CH2:24][CH2:23][CH:22]([N:19]2[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]3[CH:8]=[C:7]([O:6][C:5]4[CH:4]=[CH:3][C:2]([NH:1][C:41]([NH:40][C:38](=[O:39])[CH2:37][C:31]5[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=5)=[O:42])=[CH:30][CH:29]=4)[CH:12]=[CH:11][N:10]=3)=[O:15])[CH2:21][CH2:20]2)[CH2:27][CH2:26]1
Reactant: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(N)cc4)ccn3)CC2)CC1
Reactant: O=C=NC(=O)Cc1ccccc1
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CN1CCC(N2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)NC(=O)Cc5ccccc5)cc4)ccn3)CC2)CC1
Reaction time: 8 h
Yield: 66 %

Procedure:
To a solution of 4-(4-aminophenoxy)-2-{[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonylamino}pyridine (80.7 mg) in tetrahydrofuran (4.0 ml) was added a solution of 2-phenylacetyl isocyanate in hexane (0.25 M, 1.96 ml) at room temperature, followed by stirring overnight. The reaction mixture was partitioned between ethyl acetate and a saturated aqueous solution of sodium hydrogencarbonate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5) to provide the titled compound (73.7 mg, 66%) as white powder.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][CH:3]=[N:2]1.Cl[C:7]1[S:26][C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]=2[CH:8]=1>>[N:1]1([C:12]2[N:13]=[C:14]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N+:23]([O-:25])=[O:24])[CH:18]=3)[C:9]3[CH:8]=[CH:7][S:26][C:10]=3[N:11]=2)[CH:5]=[CH:4][CH:3]=[N:2]1
Reactant: c1cn[nH]c1
Reactant: O=[N+]([O-])c1cccc(CNc2ncnc3sc(Cl)cc23)c1
Product: O=[N+]([O-])c1cccc(CNc2nc(-n3cccn3)nc3sccc23)c1

Procedure:
Following the procedure of Example 97, the reaction of pyrazole with 6-chloro-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(pyrazol-1-yl)-4-(3-nitrobenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:13][CH:12]([CH3:14])[CH2:11][C@H:3]([NH:2][S:23]([CH3:22])(=[O:25])=[O:24])[C:4]([O:6][C:7]([CH3:8])([CH3:9])[CH3:10])=[O:5]
Reactant: CC(C)C[C@H](N)C(=O)OC(C)(C)C
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)C[C@H](NS(C)(=O)=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
(S)-tert-Butyl 2-amino-4-methylpentanoate hydrochloride (1.53 g, 6.84 mmol) was dissolved in dichloromethane and triethylamine (3.15 mL, 22.57 mmol). Methanesulfonyl chloride (0.638 mL, 8.21 mmol) was added dropwise, and the reaction stirred at room temperature for 1 hour. The reaction was quenched with saturated aqueous NaHCO3 and extracted with dichloromethane (3×50 mL). The solvent was removed in vacuo to give (S)-tert-butyl 4-methyl-2-(methylsulfonamido)pentanoate: 1H NMR (300 MHz, CDCl3) δ ppm 4.71 (d, J=9.7, 1H), 3.98 (td, J=9.5, 5.5, 1H), 2.92 (s, 3H), 1.84 (dt, J=13.1, 6.6, 1H), 1.54 (s, 9H), 1.44-1.48 br s, 1H), 0.96 (dd, J=6.6, 2.4, 6H); MS (ESI−) m/z 264 (M−H)−. (S)-tert-Butyl 4-methyl-2-(methylsulfonamido)pentanoate was dissolved in 10 mL of 4 N HCl in dioxane and stirred at room temperature overnight. The solvent was removed under a stream of nitrogen and under high vacuum to give (S)-4-methyl-2-(methylsulfonamido)pentanoic acid: 1H NMR (300 MHz, CDCl3) δ ppm 4.86 (d, J=9.6, 1H), 4.17 (td, J=9.6, 4.8, 1H), 3.18-3.07 (m, 1H), 2.99 (s, 3H), 1.96-1.80 (m, 1H), 1.64 (dddd, J=23.4, 13.9, 9.1, 5.0, 2H), 1.40 (t, J=7.3, 1H), 0.98 (dd, J=6.6, 3.3, 6H).
Reaction SMILES: Cl[C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1.CC(C)([O-])C.[K+].[CH2:22]([OH:26])[CH2:23][CH2:24][CH3:25]>>[CH2:22]([O:26][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[C:7]1[NH:8][CH2:9][CH2:10][N:11]=1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCO
Reactant: Clc1c(C2=NCCN2)sc2ccccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Product: CCCCOc1c(C2=NCCN2)sc2ccccc12

Procedure:
A solution of 0.1 g (0.42 mmol) of 2-(3-chlorobenzo[b]thiophen-2-yl)-4,5-dihydro-1H-imidazole and 56 mg (0.5 mmol) of potassium tert.-butoxide in 2 ml of absolute n-butanol was heated for 3 d. After cooling the mixture was filtered, the filter rinsed with dichloromethane, and the filtrate concentrated under reduced pressure. The title compound was obtained from the residue after column chromatography on silica gel with dichloromethane/ethanolic ammonia gradient.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:5]2=[N:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C>[C:14]([Si:11]([CH3:13])([CH3:12])[N:8]1[C:5]2=[N:6][CH:7]=[C:2]([C:4]3[CH:5]=[N:6][CH:7]=[CH:2][CH:3]=3)[CH:3]=[C:4]2[CH:10]=[CH:9]1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)n1ccc2cc(Br)cnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(-c3cccnc3)cnc21
Temperature: 25 °C
Yield: 113.4 %

Procedure:
To a solution of 19 (1.77 g, 0.0057 mol), 3-diethylpyridyl borane (1.0 g, 0.0068 mol) in 80 mL of DME, was added PdCl2(Ph3P)2 (320 mg, 0.455 mmol) and aqueous 2M sodium carbonate (8.5 mL, 0.017 mol) under nitrogen. The reaction mixture was refluxed for 3 h. Cooled to rt and diluted with ethyl acetate and washed with brine. The organic layer was dried and concentrated to an oil that was subjected to flash chromatography (30% EtOAc-70% hexanes) to give 1 g (57%) of the desired material 20. 1H NMR CDCl3 8.9 (s, 1H), 8.5 (d, 1H), 8.4 (d, 1H), 8.0 (d, 1H), 7.9 (d, 1H), 7.5 (d, 1H), 7.2 (d, 1H), 6.5 (d, 1H), 0.85 (s, 9H), 0.55 (s, 6H).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([CH2:14][CH2:15][NH2:16])[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][C:12]#[CH:13].C(N(CC)C(C)C)(C)C.[OH:26][CH:27]([CH2:31][C:32]1[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=1)[C:28](O)=[O:29].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[OH:26][CH:27]([CH2:31][C:32]1[CH:33]=[CH:34][C:35]([CH3:38])=[CH:36][CH:37]=1)[C:28]([NH:16][CH2:15][CH2:14][C:6]1[CH:7]=[CH:8][C:9]([O:10][CH2:11][C:12]#[CH:13])=[C:4]([O:3][CH3:2])[CH:5]=1)=[O:29]
Reactant: C#CCOc1ccc(CCN)cc1OC
Reactant: Cc1ccc(CC(O)C(=O)O)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C#CCOc1ccc(CCNC(=O)C(O)Cc2ccc(C)cc2)cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(3-Methoxy-4-prop-2-ynyloxy-phenyl)-ethylamine hydrochloride (11.5 g, 47 mmol) and N,N-diisopropylethylamine (23 g, 0.18 mol) are dissolved in 100 ml of N,N-dimethylformamide. To this solution 2-hydroxy-3-p-tolyl-propionic acid (8.1 g, 45 mmol) and (benzotriazol-1-yloxy)-tris-(dimethylamino)-phosphonium hexafluorophosphate (22 g, 49 mmol) are added successively. The reaction mixture is stirred for 16 hours at room temperature, subsequently poured on ice-water and extracted several times with ethyl acetate. The combined organic layer is washed with brine, dried over sodium sulfate and evaporated in vacuum. The remaining oil is purified by chromatography on silicagel (ethyl acetate/hexane 1:1) to afford 2-hydroxy-N-[2-(3-methoxy-4-prop-2-ynyloxy-phenyl)-ethyl]-3-p-tolyl-propionamide (E1.16).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[CH:4][N:3]=1.[OH-].[NH4+:12]>>[CH3:10][O:9][CH2:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH2:12])[CH:7]=1
Reactant: [NH4+]
Reactant: COCc1cc(Cl)ncn1
Agent: [OH-]
Product: COCc1cc(N)ncn1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of 4-chloro-6-(methoxymethyl)pyrimidine (1.2 g, 7.57 mmol) and ammonium hydroxide (20 ml) was heated in a sealed tube for 3 hours. The mixture was cooled to ambient temperature and concentrated. The residue was triturated with ether to afford 6-(methoxymethyl)pyrimidin-4-amine (0.50 g, 3.59 mmol, 48% yield) as a pale yellow solid. 1H NMR (400 MHz, CDCl3) δ ppm 8.47 (1 H, s), 6.55 (1 H, s), 5.12 (2 H, br. s.), 4.38 (2 H, s), 3.45 (3 H, s). MS (LC/MS) R.T.=0.42;
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[Cl:17])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][NH2:13])[CH2:7]1.[CH2:18]([N:25]=[C:26]=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>ClCCl>[CH2:18]([NH:25][C:26]([NH:13][CH2:12][CH:8]1[O:9][CH2:10][CH2:11][N:6]([CH2:5][C:4]2[CH:14]=[CH:15][C:16]([Cl:17])=[C:2]([Cl:1])[CH:3]=2)[CH2:7]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reactant: O=C=NCc1ccccc1
Solvent: ClCCl
Product: O=C(NCc1ccccc1)NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Reaction time: 72 h

Procedure:
To a stirred solution of Intermediate 3 (0.025 g) in dichloromethane (1 ml) was added benzylisocyanate (16.8 pt). The mixture was stirred at 22° C. for 18 h before tris-(2-aminoethyl)amine polystyrene (Argonaut Technologies, 0.04 g @ 3.85 mmol/g) was added. Stirring was continued for a further 72 h before the mixture was poured onto a 1 g solid phase extraction (Isolute SCX sulphonic acid) cartridge. The cartridge was washed with methanol before eluting with 10% 0.880 ammonia solution in methanol. The basic fraction was evaporated in vacuo to give a pale yellow solid. The solid was purified by eluting through a 1 g silica solid phase extraction cartridge (Varian Bondelut) eluting sequentially with dichloromethane, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a white solid (0.031 g). LC/MS (System A) Rt 2.22 min, Mass Spectrum m/z 408 [MH+].
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19].CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[CH:30]=[N:31][C:32]([CH3:38])=[N:33]2)(=O)=O>>[CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([CH2:12][CH:13]3[CH2:18][CH2:17][N:16]([CH2:25][CH2:26][O:27][C:28]4[CH:37]=[CH:36][CH:35]=[C:34]5[C:29]=4[CH:30]=[N:31][C:32]([CH3:38])=[N:33]5)[CH2:15][CH2:14]3)[C:6]=2[O:5][CH2:4][C:3]1=[O:19]
Reactant: CN1C(=O)COc2c(CC3CCNCC3)cccc21
Reactant: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Product: Cc1ncc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5C)CC3)cccc2n1

Procedure:
The title compound was prepared from 4-methyl-8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-(methanesulphonyloxy)ethoxy)-2-methylquinazoline in a similar manner to Example 1.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]Cl)[CH:10]=2)=[CH:5][CH:4]=1.C[O:22][C:23](=[O:35])[CH2:24][C:25]1[C:26]2[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][C:27]=2[S:28][CH:29]=1.COC(=O)CC1C2C=CC(OCC3C=CC(OCC4C=CC(C(F)(F)F)=CC=4)=CC=3)=CC=2SC=1>>[F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][O:8][C:9]2[CH:10]=[C:11]([CH:12]=[CH:13][CH:14]=2)[CH2:15][O:34][C:31]2[CH:32]=[CH:33][C:26]3[C:25]([CH2:24][C:23]([OH:35])=[O:22])=[CH:29][S:28][C:27]=3[CH:30]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)Cc1csc2cc(O)ccc12
Reactant: FC(F)(F)c1ccc(COc2cccc(CCl)c2)cc1
Agent: COC(=O)Cc1csc2cc(OCc3ccc(OCc4ccc(C(F)(F)F)cc4)cc3)ccc12
Product: O=C(O)Cc1csc2cc(OCc3cccc(OCc4ccc(C(F)(F)F)cc4)c3)ccc12

Procedure:
The title compound was prepared from compounds 6B and 5C in a manner analogous to compound 5F. MS m/z 487 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1O)=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2].C1(C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:30].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[Cl:30])=[CH:13][CH:12]=[CH:11][C:10]=2[C:17]([F:20])([F:19])[F:18])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cnc2c(C(F)(F)F)cccc2c1Cl
Temperature: 0 °C

Procedure:
4-Hydroxy-8-(trifluoromethyl)-3-quinolinecarboxylic acid ethyl ester (compound of formula (V)), 11.27 g, 39.55 mmol) was taken into toluene (125 mL), then POCl3 (7.4 mL, 79.08 mmol) was added and the mixture was refluxed for 1.5 hours. The reaction was carefully poured into ice-water with vigorous stirring, then added carefully added saturated NaHCO3 until the solution was neutral. Dilute with ethyl acetate and separate the layers. The organic layer was dried over MgSO4, filtered and concentrated. The resulting material was passed through a short silica gel plug using 10% ethyl acetate in hexane. Concentration and drying under high vacuum yielded 9.93 g of the title compound as a white solid.
Reaction SMILES: S(=O)(=O)(O)O.[Br:6][C:7]1[CH:8]=[C:9](C(O)=O)[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=1.[N-:19]=[N+]=[N-].[Na+]>C(Cl)(Cl)Cl>[NH2:19][C:9]1[C:10]2[O:14][CH2:13][CH2:12][C:11]=2[CH:15]=[C:7]([Br:6])[CH:8]=1
Reactant: O=C(O)c1cc(Br)cc2c1OCC2
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Nc1cc(Br)cc2c1OCC2
Yield: 12.8 %

Procedure:
Concentrated sulfuric acid (8.8 ml) was added over 5 min to a stirred mixture of 5-bromo-2,3 -dihydrobenzofuran-7-carboxylic acid (0.55 g, 2.3 mmol) in chloroform (27 ml) at 45° C. Sodium azide (0.737 g, 11.3 mmol) was then added portion-wise over 0.5 h and the temperature was maintained for a further 1 h after which time the mixture was poured onto ice (100 g) and extracted with chloroform (2×50 ml). The aqueous phase was basified to pH 12 with 40% sodium hydroxide solution and extracted with chloroform (2×50 ml). The extract was dried (Na2SO4), concentrated, and the residue purified by column chromatography over silica gel eluting with a gradient of acetone/toluene to give the title compound (D14) as a solid (63 mg, 13%), MH+ 214/216.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6](=[S:8])[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]2[CH2:13][CH2:14][CH2:15][C:3]1=2.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Cl)=[CH:27][CH:26]=1.C(O)=O>O.C(O)(C)C>[F:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:8][C:6]2[N:5]([CH2:9][C:10]([OH:12])=[O:11])[C:4]3[CH2:13][CH2:14][CH2:15][C:3]=3[C:2](=[O:1])[N:7]=2)=[CH:27][CH:26]=1
Reactant: O=C(O)Cn1c2c(c(=O)[nH]c1=S)CCC2
Reactant: Fc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Solvent: CC(C)O
Product: O=C(O)Cn1c(SCc2ccc(F)cc2)nc(=O)c2c1CCC2
Temperature: 40 °C
Yield: 96.5 %

Procedure:
(4-oxo-2-thioxo-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-1-yl)acetic acid (30.0 g, 1.0 eq) was slurried in a mixture of water (162 mL) and isopropyl alcohol (30 mL). KOH solution (50% aqueous, 28.3 g, 1.90 eq) was added followed by a water line wash (15 mL) resulting in a solution. Then K2CO3 (2.75 g, 0.15 eq) was charged and the solution was heated to 40±3° C. Thereafter 4-fluorobenzyl chloride (18.2 g, 0.95 eq) was added, followed by a line wash of isopropyl alcohol (18 mL) and the reaction mixture was stirred at 40±3° C. until the reaction was deemed complete (˜2.5 hours). The reaction mixture was cooled to 20±3° C. and formic acid (3.1 g, 0.5 eq) was added resulting in crystallisation of the product within 30 minutes. A second charge of formic acid (10.4 g, 1.7 eq) was added over 1 hour and the slurry was stirred at 20±3° C. for at least one hour. The slurry was filtered to isolate the product, which was washed twice with a mixture of water (48 mL) and isopropyl alcohol (12 mL), then with isopropyl alcohol (60 mL) and dried in vacuo at 50° C. to yield the title compound as an off-white solid (40.6 g, 92%). 1H NMR (d6 DMSO) δ 1.95 (2H, m), 2.57 (2H, t), 2.85 (2H, t), 4.4 (2H, s), 4.7 (2H, s), 7.15 (2H, dd), 7.45 (2H, dd), ˜13.6 (1H, vbrs).
Reaction SMILES: C([O:3][C:4](=[O:31])[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[CH2:28][C@H:27]([CH3:29])[O:26][C@H:25]([CH3:30])[CH2:24]4)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)C.[OH-].[Na+].C(O)C.Cl>O.O1CCCC1>[CH3:30][C@H:25]1[O:26][C@@H:27]([CH3:29])[CH2:28][N:23]([C:20]2[CH:19]=[CH:18][C:17]([N:14]3[CH2:13][CH2:12][N:11]([C:8]4[CH:9]=[CH:10][C:5]([C:4]([OH:31])=[O:3])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)=[CH:22][CH:21]=2)[CH2:24]1
Reactant: CCOC(=O)c1ccc(N2CCN(c3ccc(N4C[C@@H](C)O[C@@H](C)C4)cc3)CC2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: C[C@@H]1CN(c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)cc2)C[C@H](C)O1
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid ethyl ester (2.46 g) and 1.0 mol/l sodium hydroxide solution (11.6 ml) in a mixed solvent of ethanol (50 ml) and tetrahydrofuran (125 ml) was refluxed for 33 hours, during which period additional 1.0 mol/l sodium hydroxide solution (24 ml) was added to the mixture. After cooling to ambient temperature, the reaction mixture was poured into cold water, and the mixture was adjusted to pH 2 with 1.0 mol/l hydrochloric acid. The resulting precipitates were filtered, washed with water and dried to give 4-[4-[4-(cis-2,6-dimethylmorpholin-4-yl)phenyl]piperazin-1-yl]benzoic acid (1.05 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[O:16][C:17]=1[CH3:18])[CH:6]=O.[CH3:24][O:25][C:26]([CH2:28]P(OC)(OC)=O)=[O:27]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[O:11][CH2:12][C:13]1[N:14]=[C:15]([C:19]2[O:20][CH:21]=[CH:22][CH:23]=2)[O:16][C:17]=1[CH3:18])[CH:6]=[CH:28][C:26]([O:25][CH3:24])=[O:27]
Reactant: COC(=O)CP(=O)(OC)OC
Reactant: COc1cc(C=O)ccc1OCc1nc(-c2ccco2)oc1C
Product: COC(=O)C=Cc1ccc(OCc2nc(-c3ccco3)oc2C)c(OC)c1
Yield: 90 %

Procedure:
According to the same manner as that described in Reference Example 1, 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]benzaldehyde was reacted with trimethyl phosphonoacetate to give methyl 3-methoxy-4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]cinnamate (yield: 90%). This product was recrystallized from dichloromethane-diethyl ether. Colorless prisms, mp: 129-130° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][CH:11]=O)=O.C([O-])=O.[NH4+].C([NH2:19])=O>>[N:10]1[C:9]2[CH:8]=[CH:7][S:6][C:5]=2[C:3](=[O:2])[NH:19][CH:11]=1
Reactant: COC(=O)c1sccc1NC=O
Reactant: NC=O
Agent: O=C[O-]
Agent: [NH4+]
Product: O=c1[nH]cnc2ccsc12
Temperature: 140 °C
Yield: 72 %

Procedure:
In a 125 mL round-bottomed flask 3-formylamino-thiophene-2-carboxylic acid methyl ester (5 g, 27.0 mmol), ammonium formate (5.11 9, 81.0 mmol), and formamide (6.40 mL, 162 mmol) were combined and heated at 140° C. After 10 hours the reaction mixture was cooled to room temperature and filtered. The crystalline solid was washed with water and dried in vacuo to afford 2.96 g (72%) of 3H-thieno[3,2-d]pyrimidin-4-one. 1H NMR (400 MHz, DMSO) d 8.10 (m, 2H), 7.34 (m, 1H). LC-MS: 153 (MH′); HPLC RT: 1.21 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([N+:22]([O-])=O)=[CH:20][CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([O:5][C:6]([N:8]([C:16]1[C:21]([NH2:22])=[CH:20][CH:19]=[C:18]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:17]=1)[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc(-c2ccccc2)ccc1N

Procedure:
A solution of di-tert-butyl(3-nitro-6-phenylpyridin-2-yl)imidodicarbonate (378 mg, 0.910 mmol) and MeOH (18.1 mL) was treated with 10% palladium on carbon (˜20 mg) and fitted with a hydrogen balloon. After 30 min the reaction was filtered through celite and concentrated to afford a residue which was used in the next reaction without purification. MS cal'd 386 (M+H)+, exp 386 (M+H)+.