Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[CH:7]=1.C1COCC1.C([Li])CCC.[I:28]I>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH3:17])=[CH:11][CH:10]=2)[CH:5]=[C:6]([F:8])[C:7]=1[I:28]
Reactant: CCCc1ccc(-c2cc(F)cc(F)c2)cc1
Reactant: II
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCCc1ccc(-c2cc(F)c(I)c(F)c2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
To a reaction vessel under a nitrogen atmosphere, 3,5-difluoro-4′-propylbiphenyl (T-4) (18.0 g) and THF (200 ml) were added, and cooling was carried out to −74° C. Thereto, a n-butyllithium (1.57 M) n-hexane solution (56.4 ml) was added dropwise in a temperature range of −74° C. to −70° C., and stirring was carried out for another 1 hour. Subsequently, a THF (150 ml) solution of iodine (24.6 g) was added dropwise in a temperature range of −75° C. to −70° C., and stirring was carried out for 6 hours while returning to room temperature. The resultant reaction mixture was poured into ice water (400 ml), and mixing was carried out. Toluene (300 ml) was added to separate layers into an organic layer and an aqueous layer, and an extraction operation was performed. The resultant organic layer was sequentially washed with an aqueous solution of sodium thiosulfate and water, and drying over anhydrous magnesium sulfate was carried out. The resultant solution was concentrated under reduced pressure, and a residue was purified by means of column chromatography (silica gel; heptane), and further purified by recrystallization from Solmix A-11, and thus 3,5-difluoro-4-iodo-4′-propylbiphenyl (T-5) (21.4 g) was obtained. The yield based on compound (T-4) was 77%.
Reaction SMILES: O[CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.S(Cl)([Cl:29])=O>C(Cl)(Cl)Cl>[Cl:29][CH2:2][C:3]1[N:4]=[CH:5][N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: ClC(Cl)Cl
Product: ClCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
The product from Step F is dissolved in chloroform and cooled to 0° C. under nitrogen. Thionyl chloride (molar equivalent) is added slowly via syringe. The reaction is stirred for 30 min, and extracted with sodium bicarbonate solution. The organic phase is dried over magnesium sulfate, filtered and concentrated to provide the title compound.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][N:11]2[CH2:14][C@H:15]([CH2:18][OH:19])[CH2:16][CH2:17][C@H:10]2[CH2:9]1)(OC(C)(C)C)=O.[F:20][C:21]1[CH:22]=[C:23](O)[CH:24]=[C:25]([F:27])[CH:26]=1.[Cl:29][C:30]1[N:31]=[N:32]C(Cl)=[CH:34][CH:35]=1>>[F:20][C:21]1[CH:22]=[C:23]([CH:24]=[C:25]([F:27])[CH:26]=1)[O:19][CH2:18][C@H:15]1[CH2:14][N:11]2[CH2:12][CH2:13][N:8]([C:1]3[N:32]=[N:31][C:30]([Cl:29])=[CH:35][CH:34]=3)[CH2:9][C@@H:10]2[CH2:17][CH2:16]1
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCN2C[C@H](CO)CC[C@H]2C1
Reactant: Oc1cc(F)cc(F)c1
Product: Fc1cc(F)cc(OC[C@@H]2CC[C@H]3CN(c4ccc(Cl)nn4)CCN3C2)c1

Procedure:
A mixture of (7R,9aS)-N-BOC-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (WO 93/25552) and 3,5-difluorophenol were coupled followed by N-BOC deprotection according to Preparation 9. The product from this reaction was coupled with 3,6-dichloropyridazine according to Preparation 3 to give the title compound. mp (—HCl) 254-259° C. 13C NMR (base, CDCl3): δ26.7, 28.9, 36.1, 45.1, 50.4, 54.3, 58.4, 60.3, 71.4, 96.3, 95.0, 98.4, 115.2, 128.8, 146.8, 158.8.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]([C:14]3[N:15]=[C:16]4[CH:22]=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:30])([CH3:29])[CH3:28])[C:17]4=[N:18][CH:19]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1.CN([CH:36]=[O:37])C>>[Cl:6][C:7]1[CH:32]=[CH:31][C:10]2[N:11]([C:14]3[N:15]=[C:16]4[C:22]([CH:36]=[O:37])=[CH:21][N:20]([CH2:23][O:24][CH2:25][CH2:26][Si:27]([CH3:28])([CH3:29])[CH3:30])[C:17]4=[N:18][CH:19]=3)[CH:12]=[N:13][C:9]=2[CH:8]=1
Reactant: C[Si](C)(C)CCOCn1ccc2nc(-n3cnc4cc(Cl)ccc43)cnc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(-n3cnc4cc(Cl)ccc43)cnc21
Temperature: 67.5 °C
Reaction time: 7 h

Procedure:
A solution of DMF at 5° C. was treated with phosphoryl trichloride (483 mg, 3.2 mmol) for 0.5 h. 2-(5-Chloro-benzoimidazol-1-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine (210 mg, 0.52 mmol) was added and the mixture was stirred at 65-70° C. for 7 h. The reaction was cooled and quenched with NaHCO3 (aq) then extracted into ethyl acetate (2×). The organics were washed with water and brine then dried (MgSO4). Purification was by flash chromatography gave 2-(5-chloro-benzoimidazol-1-yl)-5-(2-trimethylsilanylethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde. LCMS: (M+H)+=428.
Reaction SMILES: [CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([OH:18])=[O:17])[CH:9]=[CH:8]2.[N+](=[CH:22][CH3:23])=[N-]>C(OCC)C>[CH3:1][O:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[CH:11]=[C:10]([CH:15]([CH3:19])[C:16]([O:18][CH2:22][CH3:23])=[O:17])[CH:9]=[CH:8]2
Reactant: COCOc1ccc2cc(C(C)C(=O)O)ccc2c1
Reactant: CC=[N+]=[N-]
Solvent: CCOCC
Product: CCOC(=O)C(C)c1ccc2cc(OCOC)ccc2c1
Reaction time: 0.25 h

Procedure:
To a solution of 26 g. of 6-methoxymethyloxy-2-naphthyl-α-methylacetic acid and 500 ml. of diethyl ether are slowly added to a solution comprising of 5.6 g. of diazoethane and 50 ml. of diethyl ether. The reaction mixture is allowed to stand for 15 minutes and then is evaporated under reduced pressure to yield ethyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate. By replacing diazoethane with diazopropane in the above process, propyl 6-methoxymethyloxy-2-naphthyl-α-methylacetate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:17][C:16](=O)[C:15]3[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:16]1[C:15]2[C:10](=[CH:11][C:12]([O:21][CH3:22])=[C:13]([O:19][CH3:20])[CH:14]=2)[N:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:17]=1
Reactant: COc1cc2nc(-c3ccc(Cl)cc3)[nH]c(=O)c2cc1OC
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3ccc(Cl)cc3)nc(Cl)c2cc1OC
Reaction time: 0.17 h
Yield: 86 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6,7-dimethoxyquinazolin-4(3H)-one (200 mg), thionyl chloride (10 mL) and DMF (0.3 mL) was refluxed for 2 h. Solvents were removed under vacuum. The mixture was poured into ice cold water and stirred for 10 min. The solution was basified with ammonia and stirred for 5 min. The solution was extracted with chloroform (3×100 mL) and the combined chloroform layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and evaporated the solvent to give the product as an yellow color solid (180 mg, 86%), mp 204-206° C. 1H NMR (400 MHz, DMSO-d6): δ 8.47 (2H, d, J=8.4 Hz), 7.66 (2H, d, J=8.4 Hz), 7.52 (1H, s), 7.44 (1H, s), 4.08 (3H, s), 4.05 (3H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[C:10]([O:16][CH3:17])(=[O:15])[CH2:11][C:12]([CH3:14])=[O:13]>C1C=CC=CC=1.N1CCCCC1.C(O)(=O)C>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[C:11]([C:12](=[O:13])[CH3:14])[C:10]([O:16][CH3:17])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)CC(C)=O
Reactant: Cc1ccc(C=O)cc1
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: c1ccccc1
Product: COC(=O)C(=Cc1ccc(C)cc1)C(C)=O
Yield: 84.7 %

Procedure:
A solution of 4-methylbenzaldehyde (0.981 ml, 8.32 mmol), methyl acetoacetate (0.898 ml, 8.32 mmol), piperidine (0.041 ml, 0.416 mmol), and acetic acid (0.024 ml, 0.416 mmol) in benzene (12.5 ml) was refluxed with a Dean Stark apparatus for 1 day. The reaction was concentrated; the residue was dissolved in EtOAc, washed with water, sat. NaHCO3, Brine, dried with Na2SO4, filtered, and concentrated. Purification with column chromatography afforded a 2:3 mixture of E/Z isomers of methyl 2-(4-methylbenzylidene)-3-oxobutanoate (1539.1 mg, 7.05 mmol, 84.7% yield) as yellow oil: E=1H NMR (400 MHz, CHLOROFORM-d) d=7.67 (s, 1 H), 7.29 (d, J=8.2 Hz, 2 H), 7.18 (d, J=8.1 Hz, 2 H), 3.83 (s, 3 H), 2.37 (s, 3 H), 2.36 (s, 3 H) LCMS (m/z) ES+=219 (M+1). Z=1H NMR (400 MHz, CHLOROFORM-d) d=7.55 (s, 1 H), 7.33 (d, J=8.2 Hz, 2 H), 7.20 (d, J=8.1 Hz, 2 H), 3.86 (s, 3 H), 2.42 (s, 3 H), 2.38 (s, 3 H); LCMS (m/z) ES+=219 (M+1).
Reaction SMILES: [C:1]([NH:5][S:6]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25]Br)=[CH:21][CH:20]=1.O>CN(C)C(=O)C.CCOC(C)=O>[Br:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][N:5]([C:1]([CH3:4])([CH3:2])[CH3:3])[S:6]([CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)(=[O:8])=[O:7])=[CH:21][CH:20]=1
Reactant: CC(C)(C)NS(=O)(=O)Cc1ccccc1
Reactant: BrCc1ccc(Br)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)N(Cc1ccc(Br)cc1)S(=O)(=O)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.8 %

Procedure:
To a solution of N-tert-butyl-1-phenyl-methanesulfonamide (1 g, 4.39 mmol) in N,N-dimethylacetamide (15 mL) was added sodium hydride (60% in mineral oil) (211 mg, 5.3 mmol) and the reaction was stirred at ambient temperature for 30 minutes. 1-Bromo-4-(bromomethyl)benzene (1.21 g, 4.83 mmol) was then added and the reaction was stirred at 80° C. for 16 hours. Water was added and the reaction was diluted with EtOAc and washed with water (×2) and brine, dried with MgSO4, concentrated and purified by silica gel column chromatography (0-30% EtOAc in heptane) to give N-[(4-bromophenyl)methyl]-N-tert-butyl-1-phenyl-methanesulfonamide (1.18 g, 68% yield). LCMS (m/z) ES+ 397 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][N:14](S(C4C=CC(C)=CC=4)(=O)=O)[C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:43])=[O:42].[OH-].[Li+]>C1COCC1.CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]3[C:16]([C:17]4[CH:18]=[N:19][N:20]([CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=5)[CH:21]=4)=[CH:15][NH:14][C:11]3=[N:12][CH:13]=2)=[CH:4][C:3]=1[NH:40][S:41]([CH3:44])(=[O:42])=[O:43]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(F)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1F
Yield: 48.8 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, N-(2-fluoro-5-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)methanesulfonamide (60 mg, 0.094 mmol) was hydrolyzed with lithium hydroxide (20 mg, 0.474 mmol) in THF/methanol/water (15/5/5 mL) to yield 22 mg (48.8% yield). 1H NMR (CD3OD, 400 MHz): δ 8.467-8.462 (d, 1H), 8.36-8.35 (d, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.84-7.80 (dd, 1H), 7.63-7.57 (m, 1H), 7.44-7.32 (m, 2H), 7.16-7.12 (d, 1H), 7.10-7.02 (m, 2H). MS: m/z=480.3 (M+1), HPLC: 92.50% in method B.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2F)[N:12]=1>CS(C)=O>[NH2:10][C:11]1[N:20]=[C:19]([NH2:21])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][C:17]=2[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[N:12]=1
Reactant: Nc1nc(N)c2c(F)cccc2n1
Reactant: Nc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Nc1nc(N)c2c(Nc3ccccc3)cccc2n1
Yield: 4.8 %

Procedure:
Aniline (Aldrich) (5 g, 50 mmol), sodium hydride (80% disp in mineral oil) (1.5 g, 50 mmol) and 2,4-diamino-5-fluoroquinazoline (4.4 g, 25 mmol) were reacted in 80 ml of dimethyl sulphoxide according to procedure A to give 2,4-diamino-5-anilinoquinazoline (0.3 g, 4.8%, m.p. 279-283° C. (dec)).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([CH3:28])[C:9]2[CH:27]=[CH:26][C:12]3[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][C:11]=3[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH2:29][C:30]1[CH:31]=[CH:32][C:33]([CH3:40])=[C:34]([S:36]([NH2:39])(=[O:38])=[O:37])[CH:35]=1>>[ClH:1].[CH3:40][C:33]1[CH:32]=[CH:31][C:30]([NH:29][C:2]2[N:7]=[C:6]([N:8]([CH3:28])[C:9]3[CH:27]=[CH:26][C:12]4[N:13]([CH3:25])[C:14]([NH:16][CH2:17][CH2:18][C:19]5[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=5)=[N:15][C:11]=4[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[CH:35][C:34]=1[S:36]([NH2:39])(=[O:38])=[O:37]
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Reactant: CN(c1ccc2c(c1)nc(NCCc1ccccc1)n2C)c1ccnc(Cl)n1
Product: Cc1ccc(Nc2nccc(N(C)c3ccc4c(c3)nc(NCCc3ccccc3)n4C)n2)cc1S(N)(=O)=O
Product: Cl

Procedure:
The title compound was prepared following the procedure of example 1 with N5-(2-Chloro-pyrimidin-4-yl)-1,N5-dimethyl-N2-phenethyl-1H-benzoimidazole-2,5-diamine (98 mg, 0.25 mmol) and 5-amino-2-methyl-benzenesulfonamide (46 mg, 0.25 mmol) as a white solid (88 mg, 61%). 1H NMR (400 MHz, d6-DMSO) δ 10.25 (br s, 1H), 9.22 (br s, 1H), 8.44 (s, 1H), 7.87 (d, J=6.8 Hz, 1H), 7.58-7.64 (m, 2H), 7.18-7.41 (m, 10H), 5.75 (d, J=5.6 Hz, 1H), 3.68-3.73 (m, 2H), 3.66 (s, 3H), 3.48 (s, 3H), 2.97 (m, 2H), 2.50 (s, 3H) ppm. MS (ESI) m/z=543 [M+H]+.
Reaction SMILES: C[P:2]([OH:11])([CH2:4][CH2:5][C@H:6](N)C(O)=O)=[O:3].P(Cl)(Cl)Cl.[Cl-:16].[Cl-].[Cl-].[Cl-].[Al+3].[CH2:21]=[CH2:22]>C(O)C>[Cl:16][CH2:6][CH2:5][CH2:4][PH:2](=[O:3])[O:11][CH2:21][CH3:22]
Reactant: [Cl-]
Reactant: C=C
Reactant: CP(=O)(O)CC[C@H](N)C(=O)O
Agent: [Al+3]
Solvent: CCO
Solvent: ClP(Cl)Cl
Product: CCO[PH](=O)CCCCl

Procedure:
Another process of producing phosphinothricin generally comprises converting phosphorus trichloride to an adduct of methylphosphonous trichloride and aluminum tetrachloride (i.e., CH3PCl3.AlCl4). The adduct is reacted with ethylene to form an intermediate adduct, which is then reacted with ethanol to form ethyl 1-(2-chloroethyl)-methylphosphinate. This compound is reacted with potassium hydroxide and ethanol to prepare an ethyl vinylphosphinate precursor. The ethyl vinylphosphinate precursor is subjected to hydroformylation-aminocarbonylation, followed by hydrolysis of the hydroformylation-aminocarbonylation product in the presence of hydrochloric acid to produce phosphinothricin.
Reaction SMILES: ClC1C=C(Cl)C=C(Cl)C=1[O:10][C:11](=O)[CH2:12][C:13](OC1C(Cl)=CC(Cl)=CC=1Cl)=[O:14].[NH2:26]/[C:27](/[CH3:34])=[CH:28]\[C:29]([O:31][CH2:32][CH3:33])=[O:30]>BrC1C=CC=CC=1.CCOC(C)=O>[CH2:32]([O:31][C:29](=[O:30])[C:28]1[C:11]([OH:10])=[CH:12][C:13]([OH:14])=[N:26][C:27]=1[CH3:34])[CH3:33]
Reactant: O=C(CC(=O)Oc1c(Cl)cc(Cl)cc1Cl)Oc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Solvent: CCOC(C)=O
Solvent: Brc1ccccc1
Product: CCOC(=O)c1c(O)cc(O)nc1C
Temperature: 50 °C
Yield: 85.6 %

Procedure:
A mixture of malonic acid (20 g, 192 mmol), 2,4,6-trichlorophenol (72 g, 365 mmol), and phosphorus oxychloride (38 mL, 403.2 mmol) was stirred at reflux for 12 h. The reaction mixture was cooled to 70° C. and poured into ice water. The solid was collected by filtration, washed with water, and air-dried to give malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 95%). A solution of malonic acid bis-(2,4,6-trichloro-phenyl) ester (85 g, 183.6 mmol) and ethyl 3-aminocrotonate (26.1 g, 202 mmol) in bromobenzene (100 mL) was stirred at reflux for 50 min. The reaction mixture was cooled to 50° C. and diluted with EtOAc (260 mL). The solid was collected by filtration, washed with water, and air-dried, to give 4,6-dihydroxy-2-methyl nicotinic acid ethyl ester (31 g, 86%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]1[N:14]=[C:15]2[CH:20]=[C:19]([C:21]([OH:23])=O)[CH:18]=[CH:17][N:16]2[CH:24]=1.C(N(CC)C(C)C)(C)C.[NH2:34][CH2:35][CH:36]1[CH2:38][CH2:37]1.[Cl-].[Na+].O.O>CN(C=O)C>[CH:36]1([CH2:35][NH:34][C:21]([C:19]2[CH:18]=[CH:17][N:16]3[CH:24]=[C:13]([C:3]4[C:4]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=5)=[N:5][O:6][C:2]=4[CH3:1])[N:14]=[C:15]3[CH:20]=2)=[O:23])[CH2:38][CH2:37]1
Reactant: NCC1CC1
Reactant: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)O)cc2n1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc(-c2ccccc2)c1-c1cn2ccc(C(=O)NCC3CC3)cc2n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.8 %

Procedure:
To a solution of 2-(5-methyl-3-phenyl-isoxazol-4-yl)-imidazo[1,2-a]pyridine-7-carboxylic acid (64 mg, 0.2 mmol) in DMF (0.3 mL) was added N,N,N′,N′-tetramethyl-O-(benzotriazol-1-yl)uranium tetrafluoroborate (71 mg, 0.22 mmol), N,N-diisopropyl ethyl amine (129 mg, 1.0 mmol) and aminomethylcyclopropane (19 μL, 0.22 mmol) and the resulting mixture stirred at room temperature for 1 h. The resulting mixture was then poured into a mixture of brine:water (1:1) and extracted with ethyl acetate. The combined organic layers were then washed with brine, dried over sodium sulphate and evaporated to leave a yellow oil. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 25:75) afforded the title compound (55 mg, 74%) which was obtained as a yellow solid. MS: m/e=373.1 [M+H]+.
Reaction SMILES: [N:1]12[Si:6]34[N:7]5[Si:4]61[N:5]3[Si:2]25[N:3]64.[Si:8](=O)=O>>[N:1]12[Si:6]34[N:7]5[Si:4]61[N:5]3[Si:2]25[N:3]64.[SiH4:8].[NH3:1]
Reactant: O=[Si]=O
Agent: N12[Si]34N5[Si]16N3[Si]25N46
Product: N
Product: [SiH4]

Procedure:
Next, a middle silicon nitride layer 12 is deposited onto the first layer 10 of silicon dioxide previously deposited. Silicon nitride is produced from the reaction of silane (SiH4) with nitrogen and ammonia (NH3). The nitride deposition is performed, for example, in a "pancake style"]reactor. Typically, 3.5 minutes is required to deposit 500 Angstroms of Si3N4 at 800° C.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[CH2:12][C@H:11](OS(C)(=O)=O)[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-:18].[Na+]>CC(C)=O.C(OCC)C>[CH2:1]([O:8][C@H:9]1[CH2:12][C@H:11]([I:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [I-]
Reactant: CS(=O)(=O)O[C@H]1C[C@@H](OCc2ccccc2)C1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCOCC
Product: I[C@H]1C[C@H](OCc2ccccc2)C1
Yield: 86 %

Procedure:
A solution of cis-3-benzyloxy-1-methanesulfonyloxycyclobutane (1.25 g, 4.8 mmol) and sodium iodide (2.16 g, 14.4 mmol) in dry acetone (20 ml) was refluxed under nitrogen for 3.5 days. The mixture was cooled and diluted with diethyl ether (150 ml). The suspension was filtered and the filtrate was concentrated. The residue was dissolved in ethyl acetate and filtered through a plug of silica gel, eluting with ethyl acetate to give trans-3-benzyloxy-1-iodocyclobutane (1.19 g, 86%) as an orange oil; 1H NMR (250 MHz, CDCl3) δ 2.54-2.65 (2H, m), 2.94-3.04 (2H, m), 3.85-4.06 (2H, m), 4.40 (2H, s), 7.26-7.38 (5H, m).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:11][N:12]([CH:22]1[CH2:26][CH:25]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]([CH2:33][OH:34])[CH2:23]1)[S:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)(=[O:15])=[O:14].CCN(C(C)C)C(C)C.Cl>C(Cl)Cl>[CH3:11][N:12]([CH:22]1[CH2:26][CH:25]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:24]([CH:33]=[O:34])[CH2:23]1)[S:13]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)(=[O:14])=[O:15]
Reactant: CN(C1CC(CO)C(c2ccccc2)C1)S(=O)(=O)c1ccccc1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CS(C)=O
Product: CN(C1CC(C=O)C(c2ccccc2)C1)S(=O)(=O)c1ccccc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 83 %

Procedure:
To a solution of oxalyl chloride (0.045 mL, 0.50 mmol) in methylene chloride (2 mL) at −70° C. was added dropwise DMSO (0.045 mL, 1.0 mmol). After 15 min, a solution of 1-(RS)-(N-(methyl)-N-(phenylsulfonyl)amino)-3-(SR)-(hydroxymethyl)-4-(SR)-phenylcyclopentane (Higher Rf isomer from Step C) (65 mg, 0.2 mmol) in methylene chloride (2 mL) was added. The reaction was stirred at −70° C. for 1.5 h and then DIPEA (0.35 mL, 2.0 mmol) was added. After a further 10 min, the mixture was allowed to warm to RT for 1 h and was then diluted with methylene chloride and poured into dilute aq. HCl and the layers were separated. The aq. layer was reextracted with a second portion of methylene chloride and the organic layers were each washed with brine, dried over sodium sulfate, combined and concentrated in vacuo. The residue was purified by FC using a gradient of 20 to 30% ethyl acetate in hexanes to give the title product (57 mg) as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14]([OH:16])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:19]([F:26])=[C:20]([CH:23]=[CH:24][CH:25]=1)[CH2:21][NH2:22].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([F:13])[C@H:9]1[C:14](=[O:16])[NH:22][CH2:21][C:20]1[CH:23]=[CH:24][CH:25]=[C:18]([Cl:17])[C:19]=1[F:26])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)O
Reactant: NCc1cccc(Cl)c1F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC[C@H](F)[C@H]1C(=O)NCc1cccc(Cl)c1F
Reaction time: 20 h

Procedure:
To a solution of (2R,3S)-3-fluoro-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (120 mg, 0.514 mmol) in CH2Cl2 (5 mL) were added successively 3-chloro-2-fluorobenzylamine (0.065 mL, 0.514 mmol), HBTU (293 mg, 0.772 mmol) and DIPEA (0.18 mL, 1.03 mmol), and stirring was continued at RT for 20 h. The reaction mixture was then diluted with CH2Cl2, and the organics were washed with 0.1N aqueous HCl (2×), aqueous NaHCO3 (2×) and brine (1×), dried (Phase separator) and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (EtOAc/c-hexane gradient 1:4 to 1:3) to afford the title compound as a white foam. TLC Rf (EtOAc/c-hexane 1:1)=0.62; MS (LC/MS): 397 [M+Na]+, 319 [MH−tBu]+, 275 [MH−Boc]+; tR (HPLC conditions b): 4.72 min.
Reaction SMILES: C(N(CC)CC)C.O.Cl.Cl.[O:11]=[C:12]1[N:21]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)[CH2:20][CH2:19][C:18]2[N:17]=[C:16]([CH2:28][CH2:29][CH3:30])[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:14][C:13]1=2.[CH:36]1([C:39]2[C:44]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[C:43]([F:52])[C:42]([O:53][CH2:54][CH3:55])=[C:41]([CH:56]=O)[CH:40]=2)[CH2:38][CH2:37]1.[Na]>C1COCC1>[CH:36]1([C:39]2[C:44]([C:45]3[CH:50]=[CH:49][C:48]([F:51])=[CH:47][CH:46]=3)=[C:43]([F:52])[C:42]([O:53][CH2:54][CH3:55])=[C:41]([CH2:56][N:25]3[CH2:24][CH2:23][CH:22]([N:21]4[CH2:20][CH2:19][C:18]5[N:17]=[C:16]([CH2:28][CH2:29][CH3:30])[C:15]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[CH:14][C:13]=5[C:12]4=[O:11])[CH2:27][CH2:26]3)[CH:40]=2)[CH2:38][CH2:37]1
Reactant: CCOc1c(C=O)cc(C2CC2)c(-c2ccc(F)cc2)c1F
Reactant: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCNCC1)CC2
Agent: Cl
Agent: [Na]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: CCCc1nc2c(cc1C(=O)OCC)C(=O)N(C1CCN(Cc3cc(C4CC4)c(-c4ccc(F)cc4)c(F)c3OCC)CC1)CC2
Reaction time: 0.17 h
Yield: 93.1 %

Procedure:
Triethylamine (3.26 g) was added to a mixture of ethyl 5-oxo-6-(piperidin-4-yl)-2-propyl-5,6,7,8-tetrahydro-1,6-naphthyridine-3-carboxylate dihydrochloride monohydrate (5.92 g) and 6-cyclopropyl-3-ethoxy-2,4′-difluorobiphenyl-4-carbaldehyde (5.35 g) in THF (100 mL) at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 10 minutes. Sodium triacetoxyhydroborate (6.82 g) was added to the reaction mixture at room temperature. The mixture was stirred at the same temperature under nitrogen atmosphere for 16 hours. The mixture was quenched with saturated sodium hydrogen carbonate aqueous solution at room temperature and extracted with ethyl acetate. The organic layer was separated, washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by a silica gel column chromatography (hexane/ethyl acetate then NH silica gel, hexane/ethyl acetate) to give the title compound (7.98 g)