Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11](=[O:16])[CH2:10][NH:9]2)[CH:5]=[C:4]([Cl:17])[C:3]=1[CH:18]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[C:19]#[N:20].[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>N1C=CC=CC=1>[C:28]([N:9]1[CH2:10][C:11](=[O:16])[N:12]([CH3:15])[C:13](=[O:14])[N:8]1[C:6]1[CH:5]=[C:4]([Cl:17])[C:3]([CH:18]([C:21]2[CH:22]=[CH:23][C:24]([Cl:27])=[CH:25][CH:26]=2)[C:19]#[N:20])=[C:2]([Cl:1])[CH:7]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CN1C(=O)CNN(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Solvent: c1ccncc1
Product: CN1C(=O)CN(C(=O)c2ccccc2)N(c2cc(Cl)c(C(C#N)c3ccc(Cl)cc3)c(Cl)c2)C1=O
Reaction time: 8 h
Yield: 20.2 %

Procedure:
To a stirred mixture of 3 parts of 2,6-dichloro-α-(4-chlorophenyl)-4-(3,4,5,6-tetrahydro-4-methyl-3,5-dioxo-1,2,4-triazin-2(1H)-yl)-benzeneacetonitrile and 20 parts of pyridine was added dropwise 1.7 parts of benzoyl chloride during a period of 5 minutes at room temperature and under nitrogen atmosphere. Upon complete addition, stirring was continued overnight at room temperature. The reaction mixture was evaporated in vacuo and the residue was stirred in water. The product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice the column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated in vacuo. The residue was crystallized from 8 parts of acetonitrile. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 0.8 parts (20.2%) of 1-benzoyl-2-[3,5-dichloro-4-[(4-chlorophenyl)cyanomethyl]phenyl]-1,6-dihydro-4-methyl-1,2,4-triazine-3,5(2H,4H)-dione; mp. 148.4° C. (compound 79).
Reaction SMILES: C[N:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[C:4]([N+]([O-])=O)[C:3]1=O.[C:15]([O:19][C:20]([N:22]1[CH2:27]CC(=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N.CO>>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][C:3]2[N:2]=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][C:4]=2[CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: Cn1cc([N+](=O)[O-])cc([N+](=O)[O-])c1=O
Agent: N
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 70 °C

Procedure:
1-Methyl-3,5-dinitro-1H-pyridin-2-one (6.0 g, 30.15 mmol), and 4-oxo-piperidine-1-carboxylic acid tert-butyl ester (6.6 g, 33.15 mmol) were added to a 2 M solution of NH3 in MeOH (225 mL, 452.3 mmol) in a sealed tube. The reaction was heated to 70° C. for 16 h. The solvent was removed and the yellow solid was recrystallized from MeOH affording 3-nitro-7,8-dihydro-5H-[1,6]naphthyridine-6-carboxylic acid tert-butyl ester as tan solid.
Reaction SMILES: [CH3:1][C@@:2]12[C:18](=[O:19])[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2.[I-].[CH3:23][S+](C)C.CC(C)([O-])C.[K+].O>CS(C)=O>[CH3:1][C@@:2]12[C@:18]3([CH2:23][O:19]3)[CH2:17][CH2:16][C@H:15]1[CH2:14][C@@H:13]1[C@H:4]([CH2:5][CH2:6][C@H:7]3[C@@:12]1([CH3:20])[CH2:11][CH2:10][C@H:9]([OH:21])[CH2:8]3)[CH2:3]2
Reactant: C[S+](C)C
Reactant: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@]3(C)C(=O)CC[C@H]3C[C@H]12
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: C[C@@]12CC[C@H](O)C[C@H]1CC[C@@H]1C[C@@]3(C)[C@@H](CC[C@@]34CO4)C[C@H]12
Reaction time: 3 h
Yield: 63 %

Procedure:
To a solution of compound 22 (35 mg, 0.12 mmol) in DMSO (3 mL) was added trimethylsulfonium iodide (204 mg, 1.0 mmol) and potassium tert-butoxide (112 mg, 1.0 mmol) at room temperature. After 3 h, water (20 mL) was added and the product extracted into EtOAc (50 mL×3). The combined extracts were dried, filtered and concentrated. The residue was purified by flash column chromatography (silica gel eluted with 20% EtOAc in hexanes) to afford compound 23 (23 mg, 63%): mp 138-140° C.; [α]D20 −16.7 (c 0.15, CHCl3); 1H NMR (CDCl3) δ 4.06 (s, br, 1H), 2.90 (d, J=5.1 Hz, 1H), 2.61 (d, J=5.1 Hz, 1H), 0.86 (s, 3H), 0.79 (s, 3H); 13C NMR (CDCl3) δ 70.5, 66.6, 54.6, 53.6, 47.1, 42.6, 40.2, 39.2, 36.4, 35.8, 35.1, 32.0, 31.8, 29.1, 28.9, 28.8, 25.9, 24.4, 14.4, 11.2; IR νmax 3435, 1007, 758 cm−1. Anal. Calcd for (C20H32O2): C, 78.90; H, 10.59. Found: C, 78.83; H, 10.77.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]2[CH2:8][C@H:9]3[CH2:20][C@H:10]3[C:11]=2[N:12]([C:14]2[CH:19]=[N:18][CH:17]=[CH:16][N:15]=2)[N:13]=1)=[O:5])C.[Li+].[OH-].Cl>O1CCOCC1.O>[N:15]1[CH:16]=[CH:17][N:18]=[CH:19][C:14]=1[N:12]1[C:11]2[C@@H:10]3[CH2:20][C@@H:9]3[CH2:8][C:7]=2[C:6]([C:4]([OH:5])=[O:3])=[N:13]1
Reactant: CCOC(=O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1nn(-c2cnccn2)c2c1C[C@H]1C[C@@H]21
Temperature: 80 °C
Reaction time: 1 h
Yield: 73.7 %

Procedure:
To a solution of (1aR,5aR)-2-(pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ethyl ester (150 mg, 0.56 mmol) in dioxane (2 mL) was added 1 N LiOH (1.1 mL, 1.11 mmol). The reaction was stirred for 1 h at 80° C., and cooled to room temperature. The reaction was acidified to pH 2 with 4 N HCl and diluted with H2O to form precipitate. The resulting precipitate was collected by filtration, rinsed with water, and then dried to give the title compound as a white solid (100 mg). LCMS m/z=243.3 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 0.43 (td, J=4.5 and 3.4 Hz, 1H), 1.26 (td, J=7.7 and 4.4 Hz, 1H), 2.26-2.33 (m, 1H), 2.70-2.79 (m, 2H), 2.89 (dd, J=16.6 and 6.3 Hz, 1H), 8.60 (dd, J=2.6 and 1.5 Hz, 1H), 8.67 (d, J=2.6 Hz, 1H), 9.17 (d, J=1.4 Hz, 1H), 13.01 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:21])[NH:5][N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2].C([O-])([O-])=O.[K+].[K+].O.[Na+].Br[CH2:31][CH2:32][S:33]([O-:36])(=[O:35])=[O:34]>CN(C=O)C>[OH2:21].[C:1]([C:3]1[C:4](=[O:21])[N:5]([CH2:31][CH2:32][S:33]([OH:36])(=[O:35])=[O:34])[N:6]=[C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]=1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)#[N:2]
Reactant: N#Cc1c(-c2ccccc2)c(-c2ccccc2)n[nH]c1=O
Reactant: O=S(=O)([O-])CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(-c2ccccc2)c(-c2ccccc2)nn(CCS(=O)(=O)O)c1=O
Temperature: 110 °C
Yield: 50.1 %

Procedure:
7.5 grams (0.027 mole) of the product of Example 1 was caused to react with 3.79 grams of K2CO3 in the least amount of water along with 200 mls of DMF. To this mixture was added 5 drops of 18 crown-6-ether. Into this solution was added 5.79 grams (0.027 mole) of 2-bromoethane sulfonic acid sodium salt and the mixture heated to 110° C. for 3 hours. The solution was filtered and the filtrate was distilled at reduced pressure. The residual solid was dissolved in excess water and poured into conc. hydrochloric acid. The solid that precipitated was filtered and washed with water and then air dried. The recovered solid was recrystallized from acetonitrile to give 2.7 grams of a yellow solid which melted at 138°-140° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:14])([F:13])[F:12].[Cl:18][S:19](O)(=[O:21])=[O:20]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([S:19]([Cl:18])(=[O:21])=[O:20])[CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C@:10]([OH:16])([CH3:15])[C:11]([F:13])([F:12])[F:14]
Reactant: O=S(=O)(O)Cl
Reactant: C[C@@](O)(C(=O)Nc1ccccc1Cl)C(F)(F)F
Solvent: CCOC(C)=O
Product: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)cc1Cl)C(F)(F)F
Temperature: 85 °C
Reaction time: 0.25 h

Procedure:
(R)-N-(2-Chlorophenyl)-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Method 74) (13.8 g, 52 mmol) was added in portions to a cooled (0° C.) solution of chlorosulphonic acid (25 ml) over 15 mins and then the mixture was heated to 85° C. After 4.5 h the reaction mixture was cooled in an ice bath and then poured very slowly onto a stirred ice-water mixture. After stirring for 15 mins. the mixture was extracted with ethyl acetate (2×100 ml) and the combined organic layer washed with brine, dried and concentrated to yield a brown oil. This oil was purified by flash column chromatography using 10:1, iso-hexane: ethyl acetate to yield the title compound as a pale yellow solid (11 g, 30 mmol). NMR: 1.6 (s, 3H), 7.55 (dd, 1H), 7.6 (d, 1H), 7.95 (d, 1H), 9.7 (brs, 1H); MS: 364.
Reaction SMILES: [CH3:1][OH:2].[H-].[Na+].Cl[C:6]1[N:7]([CH2:32][CH2:33][CH3:34])[C:8](=[O:31])[C:9]2[NH:10][C:11]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH:19]=3)=[N:12][C:13]=2[N:14]=1>C(OCC)(=O)C>[CH3:1][O:2][C:6]1[N:7]([CH2:32][CH2:33][CH3:34])[C:8](=[O:31])[C:9]2[NH:10][C:11]([C:15]3[CH:16]=[N:17][N:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[CH:19]=3)=[N:12][C:13]=2[N:14]=1
Reactant: CCCn1c(Cl)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Reactant: CO
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCCn1c(OC)nc2nc(-c3cnn(Cc4cccc(C(F)(F)F)c4)c3)[nH]c2c1=O
Temperature: 80 °C
Yield: 53 %

Procedure:
To the mixture of methanol (2 ml) and NaH (45 mg, 1.1 mmol), 2-Chloro-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (50 mg, 0.11 mmol) was added and refluxed for 2 hours at 80° C. Reaction mixture was cooled, diluted with ethyl acetate (10 ml) and quenched with saturated NH4Cl solution. The organic layer was separated and washed with brine (2×10 ml), dried over Na2SO4, filtered and evaporated. The residue obtained was purified by preparative HPLC to obtain pure 2-Methoxy-1-propyl-8-[1-(3-trifluoromethyl-benzyl)-1H-pyrazol-4-yl]-1,7-dihydro-purin-6-one (26 mg, 53%) as an off white solid.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6](=[O:23])[N:7]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:8]([CH3:14])=[N:9]2.[C:24]([CH2:28][C:29](Cl)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(CC)C(C)C)(C)C>C(#N)C>[O:22]=[C:16]1[CH:15]([N:7]2[C:6](=[O:23])[C:5]3[C:10](=[CH:11][CH:12]=[CH:13][C:4]=3[CH2:3][NH:2][C:29](=[O:30])[CH2:28][C:24]([CH3:27])([CH3:26])[CH3:25])[N:9]=[C:8]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: CC(C)(C)CC(=O)Cl
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cccc(CNC(=O)CC(C)(C)C)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 20.1 %

Procedure:
To a stirred mixture of 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.49 g, 1.5 mmol) in acetonitrile (10 mL), was added t-butylacetyl chloride (0.31 mL, 2.2 mmol) and N,N-diisopropyl ethylamine (0.60 mL, 3.7 mmol). The mixture was stirred at room temp for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-3,3-dimethyl-butyramide as a light yellow solid (120 mg, 22% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 5.74 min (98.4%); mp, 212-214° C.; 1HNMR (DMSO-d6)0.96 (s, 9H, 3CH3), 2.08 (s, 2H, CH2Me3), 2.12-2.19 (m, 1H, CHH), 2.57-2.86 (m, 6H, CHCH2, CH3), 4.68-4.85 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.34-7.76 (m, 3H, Ar), 8.11 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.76, 23.28, 29.69, 30.47, 30.58, 41.43, 48.76, 56.47, 117.65, 124.64, 125.42, 133.77, 141.19, 148.42, 154.75, 160.93, 169.51, 170.97, 172.60. LCMS MH=399; Anal Calcd For C21H26N4O4+0.1H2O: C, 63.02; H, 6.60; N, 14.00. Found: C, 62.86; H, 6.70; N, 13.92.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:26])[C:13]2[CH:18]=[CH:17][CH:16]=[N:15][C:14]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Cl>[Pt]=O.C(O)C>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH:14]2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=2)=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2cccnc2-c2cccc(F)c2)c1
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: CC(C)(C)c1cccc(NC(=O)C2CCCNC2c2cccc(F)c2)c1

Procedure:
A mixture of N-(3-tert-butylphenyl)-2-(3-fluorophenyl)nicotinamide (501.2 mg, 1.4 mmol), platinum oxide (51.9 mg, 0.21 mmol), and concentrated HCl (400 μL, 5.2 mmol) in 5 ml, of ethanol was stirred vigorously under hydrogen balloon overnight. The mixture was filtered, and the solids washed with 25 mL of methanol three times. The combined solution was dried under reduced pressure. To the residue was added 30 mL of saturated sodium bicarbonate and 150 mL of EtOAc. The organic layer was separated, and dried over sodium sulfate. Evaporation of solvent gave the crude 2-(3-fluorophenyl)piperidine-3-carboxylic acid (3-tert-butylphenyl)amide as a brown solid, which was taken on directly to the next step. MS: (ES) m/z 355.7 (M+H+).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=1.[N:19]1[CH:24]=[C:23](B(O)O)[CH:22]=[N:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C(OCC)(=O)C.O>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C@H:10]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH3:11])[N:3]=[C:2]([C:23]2[CH:24]=[N:19][CH:20]=[N:21][CH:22]=2)[CH:7]=1
Reactant: C[C@H](Nc1nc(Cl)cc(Cl)n1)c1ccc(F)cc1
Reactant: OB(O)c1cncnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nc(Cl)cc(-c2cncnc2)n1)c1ccc(F)cc1
Temperature: 90 °C
Reaction time: 6 h
Yield: 30.2 %

Procedure:
210 mg of (S)-4,6-dichloro-N-[1-(4-fluorophenyl)ethyl]pyrimidine-2-amine (Reference Example 1), 91 mg of pyrimidine-5-boronic acid, 304 mg of potassium carbonate and 60 mg of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride-dichloromethane complex were added in turn to a degassed mixed solution of 3 ml of 1,4-dioxane and 1 ml of water, and the mixture was stirred at 90° C. for 6 hours under argon atmosphere. The reaction solution was diluted with ethyl acetate. The solution was washed in turn with water and brine and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and then the obtained residue was purified by silica gel column chromatography to obtain 73 mg of (S)-6-chloro-N-[1-(4-fluorophenyl)ethyl]-4,5′-bipyrimidine-2-amine as a white amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:17](OCC)=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C>C(Cl)Cl.C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH:16]([CH2:22][CH2:23][CH2:24][C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:17]=[O:18])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: O=CC(CCCCNS(=O)(=O)c1ccc(Cl)cc1)CCCc1cccnc1
Reaction time: 0.17 h

Procedure:
A solution of 3.5 g (7.7 mmol) of ethyl 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanoate (example 2) in 105 ml methylene chloride is cooled to -78° and to it is added slowly added 15.2 ml (23.6 mmol) of 1.53M solution of diisobutylaluminium hydride in toluene. The solution is stirred at -78° for 10 min and then quenched by slow addition of 10.8 ml methanol. The solution is then allowed to warm to 0° by the removal of the cold bath, and then 350 ml of ether is added followed by 10.8 ml of saturated brine and 7.7 g finely powdered anhydrous sodium sulfate. The cloudy suspension is stirred vigorously at room temperature overnight. The salts are filtered off and washed with methylene chloride (10×20 ml). The filtrate is evaporated to give 6-(p-chlorophenylsulfonamido)-2-[3-(3-pyridyl)propyl]-hexanal.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([NH2:8])[CH:4]=1)[CH3:2].[Cl:9][C:10]1[N:15]=[C:14](Cl)[C:13]([Cl:17])=[CH:12][N:11]=1.C([O-])([O-])=O.[Na+].[Na+].O>C(O)(C)C>[Cl:9][C:10]1[N:15]=[C:14]([NH:8][C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[NH:7][N:6]=2)[C:13]([Cl:17])=[CH:12][N:11]=1
Reactant: CCc1cc(N)n[nH]1
Reactant: Clc1ncc(Cl)c(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: CCc1cc(Nc2nc(Cl)ncc2Cl)n[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of 5-ethyl-1H-pyrazol-3-amine (1.00 g, 6.77 mmol), 2,4,5-trichloropyrimidine (1.24 g, 6.77 mmol) and Na2CO3 (1.79 g, 16.9 mmol) in iso-propanol (15 mL) was stirred in a sealed vial at rt for two days. Water (10 mL) was added. The solid was collected by filtration, washed with water (10 mL) and dried to give 2,5-Dichloro-N-(5-ethyl-1H-pyrazol-3-yl)pyrimidin-4-amine as a light yellow solid; ESMS m/z 258.0 (M+H+).
Reaction SMILES: [CH3:1][O:2][Na].Cl[CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[CH2:7]>CO>[CH3:1][O:2][CH2:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1)=[CH2:7]
Reactant: C=C(CCl)c1ccc([N+](=O)[O-])cc1
Reactant: CO[Na]
Solvent: CO
Product: C=C(COC)c1ccc([N+](=O)[O-])cc1

Procedure:
To a CH3ONa-solution from 6.9 g (0.3 gramatom) Na and 600 ml absolute CH3OH are added 59.3 g (0.3 Mol) 4(1-chloromethyl-ethenyl)-nitrobenzene, the reaction mixture heated under reflux for 2 hours and then evaporated to dryness. The residue is digested with diethylether, the ethereal solution filtered and the filtrate concentrated by evaporation. The residue is then chromatographed on silica gel (eluant n-hexane/diethylether 1:1) to give the title compound in analytically pure form (Rf=0.37 on silica gel with CHCl3).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[CH:17]=[C:16]([Sn:19]([CH3:22])([CH3:21])[CH3:20])[CH:15]=[C:14]([NH2:23])[C:13]=3[CH:12]=[N:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.N1C=CC=CC=1.[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37](Cl)=[O:38])=[N:32]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH3:30][N:31]1[CH:35]=[C:34]([CH3:36])[C:33]([C:37]([NH:23][C:14]2[CH:15]=[C:16]([Sn:19]([CH3:20])([CH3:22])[CH3:21])[CH:17]=[C:18]3[C:13]=2[CH:12]=[N:11][N:10]3[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:9])=[O:8])=[O:38])=[N:32]1
Reactant: Cc1cn(C)nc1C(=O)Cl
Reactant: C[Sn](C)(C)c1cc(N)c2cnn(S(=O)(=O)c3ccccc3)c2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn(C)nc1C(=O)Nc1cc([Sn](C)(C)C)cc2c1cnn2S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(Phenylsulfonyl)-6-(trimethylstannanyl)-1H-indazol-4-amine (250 mg) was dissolved in DCM (10 ml) and pyridine (0.051 ml) was added. 1,4-Dimethyl-1H-pyrazole-3-carbonyl chloride (100 mg) in DCM (5 ml) was added dropwise. The reaction was stirred at RT for 2 h. After this time saturated sodium bicarbonate aq (25 ml) was added and the reaction was stirred vigorously for 5 min before the DCM was passed through a hydrophobic frit then evaporated to dryness. The residue was dissolved in DCM, and then applied to the top of a 20 g silica cartridge preconditioned with cyclohexane. The column was washed with 50% cyclohexane:ether (100 ml), before the compound was eluted with ether, then 5% methanol in ether. The product containing fractions were evaporated to dryness to afford the title compound, 310 mg.
Reaction SMILES: [CH3:1][CH2:2][N:3]([CH:7]([CH3:9])[CH3:8])[CH:4]([CH3:6])[CH3:5].C([N:17]1C[C@@H:21]2[CH2:23][C@H:18]1[CH2:19]N2)(OC(C)(C)C)=O.[C:24](#[N:26])[CH3:25]>>[CH:4]([N:3]1[CH2:2][C@@H:1]2[CH2:9][C@H:7]1[CH2:8][N:26]2[C:24]1[CH:21]=[CH:23][C:18]([NH2:17])=[CH:19][CH:25]=1)([CH3:6])[CH3:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CC#N
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Reaction time: 0.25 h

Procedure:
4-Fluoronitrophenyl (4.00 g, 28.348 mmol), DiPEA (5.89 mL, 60.667 mmol, 2.14 equiv.) and (1S,4S)-2-BOC-2,5-diazabicyclo[2.2.1]heptane (6.02 g, 30.333 mmol, 1.07 equiv.) are mixed in acetonitrile (20 mL). The resulting solution is heated to reflux overnight, after which full conversion has occurred. The solvent is removed under vacuum, and the solid yellow residue is stirred in cyclohexane (50 mL) for 0.25 h, then allowed to settle, the supernatant is discarded, and the process is repeated twice. On the third time, the solid is separated by filtration, allowed to dry under suction, to afford the title compound clean as a yellow solid (8.8 g).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]2[N:11]=[C:10]([C:12]3[CH:17]=[CH:16][N:15]=[CH:14][C:13]=3[OH:18])[O:9][C:6]2=[N:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C.[CH2:32](I)[CH3:33]>O>[CH2:32]([O:18][C:13]1[CH:14]=[N:15][CH:16]=[CH:17][C:12]=1[C:10]1[O:9][C:6]2[C:5]([N:11]=1)=[CH:4][C:3]([C:2]([F:19])([F:1])[F:20])=[CH:8][N:7]=2)[CH3:33]
Reactant: Oc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1cnccc1-c1nc2cc(C(F)(F)F)cnc2o1
Temperature: 60 °C
Yield: 21.8 %

Procedure:
To a mixture of 0.25 g of 4-(6-trifluoromethyl-oxazolo[5,4-b]pyridin-2-yl)pyridin-3-ol, 0.14 g of potassium carbonate and 3 ml of DMF, a mixture of 0.15 g of ethyl iodide and 1 ml of DMF was added at room temperature and stirred while heating at 60° C. for 1.5 hours. To the reaction mixture, 70 mg of potassium carbonate and 53 mg of iodoethane were added, and the reaction solution was stirred while heating at 60° C. for 3.5 hours. The reaction solution was cooled to room temperature, and then water was added to the reaction mixture, followed by extraction with ethyl acetate twice. The combined organic layers were washed with water and a saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 60 mg of 2-(3-ethoxypyridin-4-yl)-6-trifluoromethyl-oxazolo[5,4-b]pyridine (hereinafter, referred to as “active compound 161”).
Reaction SMILES: [C:1](#[N:4])[CH2:2][CH3:3].[P:5]([OH:8])([OH:7])[OH:6]>C(O)C>[NH2:4][C:1]([P:5]([OH:8])([OH:7])=[O:6])([P:5]([OH:8])([OH:7])=[O:6])[CH2:2][CH3:3]
Reactant: CCC#N
Reactant: OP(O)O
Solvent: CCO
Product: CCC(N)(P(=O)(O)O)P(=O)(O)O
Temperature: 150 °C
Yield: 52 %

Procedure:
A mixture of propionitrile (5.5 g, 0.1 mole), phosphorous acid (16.4 g, 0.2 mole), ISOPAR-M (22 g), and wetting agents (0.5 g each) was heated under nitrogen at ambient pressure for 2 hours at 150° C. The product was worked up with ethanol. Colorless crystals of 1-amino-1,1-diphosphono propane (52% yield), m.p. 282° C was obtained.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=O)=[CH:5][CH:6]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C.[NH2:52][CH:53]([CH2:59][CH2:60][C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1)[CH2:54][CH2:55][C:56]([OH:58])=[O:57]>CN(C=O)C.CCOCC>[C:61]1([CH2:60][CH2:59][CH:53]([NH:52][C:13](=[O:15])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[CH2:54][CH2:55][C:56]([OH:58])=[O:57])[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1
Reactant: NC(CCC(=O)O)CCc1ccccc1
Reactant: O=C(O)CCCCCCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: O=C(O)CCC(CCc1ccccc1)NC(=O)CCCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
Phenylheptanoic acid (105 mg 0.51 mmol) and BOP (250 mg, 0.56 mmol) were dissolved in dry DMF 2 mL then DIPEA 200 μL was added. After mixing for 3 min the solution was added to (RS)-4-amino-6-phenyl-hexanoic acid (101) (105 mg, 0.51 mmol) and the solution was stirred at room temperature for 1 hr. Ether was added and the solution was washed twice with 1 M HCl and brine then dried over MgSO4. Removal of solvent gave a white solid 200 mg, which was recrystallised from EtOAc-hexane. 1H NMR (300 MHz, CDCl3) δ 7.30-7.22 (m, 4H), 7.21-7.11 (m, 6H), 6.17 (br, 1H, NH), 4.02 (m, 1H), 2.70-2.53 (m, 4H), 2.38 (m, 2H), 2.22 (m, 2H), 2.00-1.52 (m, 8H), 1.44-1.27 (m, 4H).