Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:25])[C:13]2[CH:18]=[CH:17][C:16]([CH:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].Br[C:27]1[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([Cl:36])[CH:28]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12]([C:13]2[CH:14]=[CH:15][C:16]([CH:19]3[CH2:24][CH2:23][N:22]([C:27]4[CH:35]=[CH:34][C:30]([C:31]([OH:33])=[O:32])=[C:29]([Cl:36])[CH:28]=4)[CH2:21][CH2:20]3)=[CH:17][CH:18]=2)=[O:25])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCNCC3)cc2)c1
Reactant: O=C(O)c1ccc(Br)cc1Cl
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CC(C)(C)c1cccc(NC(=O)c2ccc(C3CCN(c4ccc(C(=O)O)c(Cl)c4)CC3)cc2)c1

Procedure:
4-{4-[4-(3-tert-Butyl-phenylcarbamoyl)-phenyl]-piperidin-1-yl}-2-chloro-benzoic acid was synthesized from N-(3-tert-butyl-phenyl)-4-piperidin-4-yl-benzamide and 4-bromo-2-chloro-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above.
Reaction SMILES: [Br:1][C:2]1[C:11]([OH:12])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13].C(OC([N:21]1[CH2:26][CH2:25][CH2:24][C@@H:23](OS(C)(=O)=O)[CH2:22]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>CO.O>[Br:1][C:2]1[C:11]([O:12][C@H:23]2[CH2:24][CH2:25][CH2:26][NH:21][CH2:22]2)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][NH:6][C:7]2=[O:13]
Reactant: O=c1[nH]ccc2c(Br)c(O)ccc12
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H](OS(C)(=O)=O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: O=c1[nH]ccc2c(Br)c(O[C@H]3CCCNC3)ccc12
Reaction time: 1 h

Procedure:
The crude 5-bromo-6-hydroxy-2H-isoquinolin-1-one (93 mg) was mixed with (R)-3-methanesulphonyloxypiperidine-1-carboxylic acid tert-butyl ester (500 mg, 4.3 mol eq), potassium carbonate (700 mg, 12 mol eq) and N, N-dimethylformamide (2 ml). The mixture was microwaved at 150° C. for 20 minutes. Water was added to the mixture and the crude product extracted out into ethyl acetate. The organic phase was washed with brine and dried (MgSO4). The organics were concentrated in vacuo then purified by prep-HPLC. Dichloromethane and trifluoroacetic acid (3:1, 2 ml) were added and the mixture stirred for 1 h then concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column using methanol and eluted with 2M ammonia in methanol to afford (S)-5-bromo-6-(piperidin-3-yloxy)-2H-isoquinolin-1-one. The residue was purified by prep-HPLC (1.8 mg), El-MS: m/z=323.5 and 323.5 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[C:23](=O)[CH2:24][N:25]([CH3:29])[S:26](=[O:28])(=[O:27])[C:21]=4[CH:20]=[CH:19]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.[NH2:32][OH:33]>N1C=CC=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][CH2:17][N:18]3[C:22]4[C:23](=[N:32][OH:33])[CH2:24][N:25]([CH3:29])[S:26](=[O:28])(=[O:27])[C:21]=4[CH:20]=[CH:19]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: CN1CC(=O)c2c(ccn2CCCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CN1CC(=NO)c2c(ccn2CCCCN2CCN(c3ccc(F)cc3)CC2)S1(=O)=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 88.4 %

Procedure:
A suspension of 174 mg (0.4 mmol) of Compound 23 and 111 mg (1.6 mmol) of hydroxylamine hydrochloride in 10 ml of pyridine was stirred for 24 hours over an oil bath of 80° C. Post-treatment and purification were conducted in a similar manner as in Example 21, whereby 159 mg of the title compound were obtained (yield: 88%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[F:40])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([O:29]CC)=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].O.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:32][C:33]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:34]=1[F:40])[CH2:10][C:11]([N:13]1[CH2:22][C:21]2[N:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[C:18]([C:27]([OH:29])=[O:28])=[CH:17][C:16]=2[CH2:15][CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc2c(nc1C(F)(F)F)CN(C(=O)C[C@@H](Cc1cc(F)ccc1F)NC(=O)OC(C)(C)C)CC2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCc2cc(C(=O)O)c(C(F)(F)F)nc2C1)Cc1cc(F)ccc1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the product from Step A above (92 mg, 0.161 mmol) in 1.2 mL of 3:2:1 tetrahydrofuran/methanol/water was treated with lithium hydroxide monohydrate (10 mg) and the solution was stirred at room temperature for 18 h. The volatiles were removed under a stream of nitrogen, and the residue was dissolved in 4 mL of water. The solution was acidified by portionwise addition of citric acid monohydrate, and the product was extracted into ethyl acetate. The combined organic extracts were dried over magnesium sulfate and concentrated to afford the title compound as a white foam.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:39][C:40]([CH3:42])=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO.O>[C:1]([O:5][C@@H:6]([C:10]1[C:30]([CH3:31])=[CH:29][C:13]2[N:14]=[C:15]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([N:23]4[CH2:28][CH2:27][N:26]([CH:40]([CH3:42])[CH3:39])[CH2:25][CH2:24]4)[CH:18]=3)[S:16][C:12]=2[C:11]=1[C:32]1[CH:33]=[CH:34][C:35]([Cl:38])=[CH:36][CH:37]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cccc(N4CCNCC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: CC(C)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc2nc(-c3cccc(N4CCN(C(C)C)CC4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-(piperazin-1-yl)phenyl)benzo[d]thiazol-6-yl)acetic acid (30 mg, 0.055 mmol) in MeOH (1 mL) was added acetone (0.20 mL), acetic acid (0.08 mL), and sodium triacetoxyborohydride (58 mg, 0.27 mmol). Stirred at rt for 18 h then 60° C. for 3 h (reaction not to completion). H2O added (1 mL) and purified using reverse phase HPLC, eluting by 2-100% acetonitrile in H2O with 0.1% TFA to give the product. 1H NMR (400 MHz, CD3OD) δ 7.83 (s, 1H), 7.68 (m, 2H), 7.58 (m, 3H), 7.43 (t, J=8 Hz, 1H), 7.21 (d, J=8 Hz, 1H), 5.25 (s, 1H), 4.02 (m, 2H), 3.60 (m, 4H), 3.12 (m, 3H), 2.61 (s, 3H), 1.43 (d, J=7 Hz, 6H), 0.97 (s, 9H). LCMS-ESI+: calc'd for C33H39ClN3O3S: 592.2 (M+H+); Found: 592.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[C:11]=1[OH:12])[C:5]([O:7][CH3:8])=[O:6].[C:18](=O)([O-])[O-].[K+].[K+].COS(=O)(=O)OC.O>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:13][C:14]([F:15])([F:16])[F:17])[C:11]=1[O:12][CH3:18])[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1cc(Cl)c(O)c(OC(F)(F)F)c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: COS(=O)(=O)OC
Solvent: O
Product: COC(=O)c1cc(Cl)c(OC)c(OC(F)(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.2 %

Procedure:
Methyl 3-chloro-4-hydroxy-5-trifluoromethoxybenzoate (2.64 g) was dissolved in N,N-dimethylformamide (15 mL), and potassium carbonate (3.60 g) and dimethylsulfuric acid (1.64 mL) were added to the solution, and then the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution and the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=9:1) to obtain the title compound (1.70 g) as a colorless oily substance.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[O:15][C:14]([S:16]([Cl:19])(=[O:18])=[O:17])=[CH:13][CH:12]=2)[CH:4]=1)[CH3:2].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH2:27]>>[ClH:19].[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:26][NH:27][S:16]([C:14]1[O:15][C:11]([C:5]2[CH:4]=[C:3]([CH2:1][CH3:2])[C:8](=[O:9])[NH:7][C:6]=2[CH3:10])=[CH:12][CH:13]=1)(=[O:18])=[O:17]
Reactant: CCc1cc(-c2ccc(S(=O)(=O)Cl)o2)c(C)[nH]c1=O
Reactant: NCc1ccccn1
Product: CCc1cc(-c2ccc(S(=O)(=O)NCc3ccccn3)o2)c(C)[nH]c1=O
Product: Cl
Yield: 78 %

Procedure:
5-(5-Ethyl-2-methyl-6-oxo-1,6-dihydropyridin-3-yl)furan-2-sulfonyl chloride as prepared above is reacted with (pyridin-2-yl)methylamine as described in Step 5, Example 24 to give the title compound as a solid (78% yield). LC/MS: RT 2.21 min; m/e 374 (M+H).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[OH:14])[CH2:3][CH2:2]1.[O:16]1[CH2:18][C@H:17]1[CH2:19]OS(C1C=CC=C([N+]([O-])=O)C=1)(=O)=O.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[CH:1]1([NH:4][C:5](=[O:15])[C:6]2[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][C:7]=2[O:14][CH2:19][C@@H:17]2[CH2:18][O:16]2)[CH2:2][CH2:3]1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)OC[C@@H]2CO2)c1
Reactant: COc1ccc(C(=O)NC2CC2)c(O)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)NC2CC2)c(OC[C@@H]2CO2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 112.4 %

Procedure:
A mixture of N-cyclopropyl-2-hydroxy-4-methoxybenzamide (700 mg, 3.38 mmol), (2S)-oxiran-2-ylmethyl3-nitrobenzenesulfonate (876 mg, 3.38 mmol) and Cs2CO3 (1.31 g, 4.05 mmol) in DMF (12 mL) was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel flash chromatography (0-80% ethyl acetate in petroleum ether) to give the subtitled compound (1.0 g).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:7][N:6]=[N:5]1.C(N(CC)CC)C.Br[CH2:27][C:28]([O:30][CH2:31][CH3:32])=[O:29]>O1CCCC1>[C:28]([CH2:27][NH:1][CH2:2][CH2:3][N:4]1[C:8]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[N:7][N:6]=[N:5]1)([O:30][CH2:31][CH3:32])=[O:29]
Reactant: COc1ccc(CSc2nnnn2CCN)cc1
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CNCCn1nnnc1SCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 62 %

Procedure:
To a solution of 15.0 g. (56 mmol) of 1-(2-aminoethyl)-5-[(4-methoxybenzyl)thio]-1H-tetrazole in 70 ml. of dry tetrahydrofuran was added 7.7 ml. (56 mmol) of triethylamine, and 6.2 ml. (56 mmol) of ethyl bromoacetate. After stirring at room temperature for 15 hours, the mixture was filtered, and the filtrate was evaporated in vacuo to dryness. The residue was dissolved in 70 ml. of chloroform and decolorized with charcoal. The filtrate was chromatographed on silica gel, eluting with a gradient of 0-15% ethyl acetate in chloroform. Fractions containing product by thin layer chromatography were pooled and evaporated to dryness to give 12.5 g. (62% yield) of 1-[2-[[(carbethoxy)methyl]amino]ethyl]-5-[(4-methoxybenzyl)thio]-1H-tetrazole as a brown oil.
Reaction SMILES: O=[C:2](C1C=CN=CC=1)CC(OCC)=O.[OH:15][C:16]1[C:21]([CH2:22][O:23]C)=[CH:20][C:19]([CH3:25])=[CH:18][C:17]=1[C:26](=[O:28])[CH3:27].CC(C)([O-])C.[K+]>C1COCC1.C(OCC)(=O)C.Cl[Pd]Cl>[C:26]([C:17]1[C:16]([OH:15])=[C:21]([C:22](=[O:23])[CH3:2])[CH:20]=[C:19]([CH3:25])[CH:18]=1)(=[O:28])[CH3:27]
Reactant: COCc1cc(C)cc(C(C)=O)c1O
Reactant: CCOC(=O)CC(=O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1cc(C)cc(C(C)=O)c1O

Procedure:
A mixture of a bromo derivative 1 (324 mg, 1 mmol), (R)-(+)-α-methylbenzylamine 2 (122 mg, 1 mmol), potassium t-butoxide (225 mg, 2 mmol) and PdCl2 (dppf) (35 mg, 0.05 mmol) in THF was stirred at refluxing temperature for 20 hours over a nitrogen atmosphere. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over Na2SO4. The ethyl acetate layers was concentrated in vacuo and the residue was subjected to column chromatography (silica gel, ethylacetate) to give the required product 3. 1H NMR (300 MHz, CDCl3), δ 8.78 (br s, 2H), 8.21 (s, 1H), 7.92 (d, J=5.9 Hz, 2H), 7.4-7.26 (m, 5H), 6.90 (s, 1H), 6.50 (d, J=5.5 Hz, 1H, —NH), 6.27 (s, 1H), 4.60 (m, 1H), 2.23 (s, 3H), 1.71 (d, J=6.9 Hz, 311). MS (m/z)=357.13 (m+1).
Reaction SMILES: [C:1]([OH:6])(=O)[C:2]([CH3:4])=[O:3].S(Cl)(Cl)=O.[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[CH:15][C:14]=1[C:20]([F:23])([F:22])[F:21])#[N:12]>CC(N(C)C)=O.CCOCC>[C:11]([C:13]1[CH:19]=[CH:18][C:16]([NH:17][C:1](=[O:6])[C:2](=[O:3])[CH3:4])=[CH:15][C:14]=1[C:20]([F:21])([F:22])[F:23])#[N:12]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CC(=O)C(=O)O
Solvent: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CC(=O)N(C)C
Product: CC(=O)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
Pyruvic acid (3.0 mL; 43 mmol) and thionyl chloride (3.1 mL; 43 mmol) were added simultaneously via syringes to a stirring solution of 4-cyano-3-trifluoromethyl-aniline (1.00 g; 5.38 mmol) in 20 mL of dry DMA at room temperature. After 10 minutes, the reaction mixture was diluted with ether and extracted 3 times with saturated NaHCO3 and 4 times with cold saturated brine. The organic layer was dried with MgSO4 and concentrated by rotary evaporation. The product was purified by silica gel chromatography (ethyl acetate/hexanes [1/1]). Yield 1.11 g (81%); mp 147-148° C.; MS (FAB+) 257 (M+1); 1H NMR δ 9.12 (s, 1H), 8.15 (s, 1 H), 8.01 (d, J=8.5), 7.84 (d, J=8.5, 1 H), 2.59 (s, 3 H); 13C NMR δ 195.66, 157.71, 140.29, 135.90, 134.2, 122.01, 121.85, 117.44, 115.12, 105.55,23.92; 19F NMR δ-62.76. IR: 3330, 3112, 3065, 1719, 1540. UV: λmax 214, 248, 288. Anal. Calculated for C11H7F3N2O2: C, 51.57; H, 2.75; N, 10.94. Found: C, 51.69; H, 2.81; N, 10.86.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4](Cl)[C:3]=1[C:13]1[C:22](=[O:23])[N:21]([CH3:24])[C:20]2[N:19]=[C:18]([NH:25][C:26]3[C:31]([N+:32]([O-])=O)=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:35])[N:17]=[CH:16][C:15]=2[N:14]=1.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:32][C:31]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:35])[C:26]=1[NH:25][C:18]1[N:17]=[CH:16][C:15]2[N:14]=[C:13]([C:3]3[CH:4]=[C:5]([O:10][CH3:11])[CH:6]=[C:7]([O:8][CH3:9])[CH:2]=3)[C:22](=[O:23])[N:21]([CH3:24])[C:20]=2[N:19]=1
Reactant: COc1cc(OC)c(Cl)c(-c2nc3cnc(Nc4c(C)cccc4[N+](=O)[O-])nc3n(C)c2=O)c1Cl
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: COc1cc(OC)cc(-c2nc3cnc(Nc4c(C)cccc4N)nc3n(C)c2=O)c1
Yield: 44 %

Procedure:
To a solution of 6-(2,6-dichloro-3,5-dimethoxyphenyl)-8-methyl-2-(2-methyl-6-nitrophenylamino)pteridin-7(8H)-one (200 mg, 0.38 mmol) in ethanol (50 mL) and water (2 mL) was added iron powder (210 mg, 3.8 mmol) and ammonium chloride (450 mg, 8 mmol). The mixture was refluxed for 2 h. The solvents were evaporated, and the residue was diluted with brine and dichloromethane. The solid was filtered off, and the filtrate was extracted with dichloromethane (50 mL*6). The organic layers were combined, dried over sodium sulfate, filtered and concentrated to give the title compound (70 mg, 38%). MS (ES+) C22H20Cl2N6O3 requires: 486, 488. found: 487, 489 [M+H]+. 1H-NMR (500 MHz, CDCl3) δ ppm 8.83 (s, 1H), 7.09 (t, 1H, J=8.0 Hz), 6.74-6.71 (m, 2H), 6.65 (s, 1H), 3.94 (s, 6H), 3.85 (br. s., 2H), 3.63-3.59 (br, 3H), 2.25 (s, 3H).
Reaction SMILES: [CH:1]1([C@H:7]([NH:9][CH2:10][C:11]([CH3:14])([CH3:13])O)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:17].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]=[C:28]=[S:29]>>[ClH:17].[Cl:19][C:20]1[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=1[N:27]=[C:28]1[N:9]([C@@H:7]([CH:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[CH3:8])[CH2:10][C:11]([CH3:14])([CH3:13])[S:29]1
Reactant: O=S(Cl)Cl
Reactant: C[C@@H](NCC(C)(C)O)C1CCCCC1
Reactant: S=C=Nc1cccc(Cl)c1Cl
Product: C[C@H](C1CCCCC1)N1CC(C)(C)SC1=Nc1cccc(Cl)c1Cl
Product: Cl

Procedure:
(1R)-1-Cyclohexyl-1-ethylamine was reacted with 1,2-epoxy-2-methylpropane according to Method B5b to give N-((1R)-1-cyclohexyl-1-ethyl)-N-(2,2-dimethyl-2-hydroxyethyl)amine. N-((1R)-1-Cyclohexyl-1-ethyl)-N-(2,2dimethyl-2-hydroxyethyl)amine was reacted with SOCl2 followed by 2,3-dichlorophenyl isothiocyanate according to Method C2f to afford 2-(2,3-dichlorophenylimino)-3-((1R)-1-cyclohexyl-1-ethyl)-5,5-dimethyl-1,3-thiazolidine HCl salt.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][CH2:6][C:7]([NH2:10])([CH3:9])[CH3:8]>N1C=CC=CC=1>[CH3:8][C:7]([NH2:10])([CH3:9])[CH2:6][NH:5][C:3]([NH:2][CH3:1])=[O:4]
Reactant: CC(C)(N)CN
Reactant: CN=C=O
Solvent: c1ccncc1
Product: CNC(=O)NCC(C)(C)N
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 34.7 %

Procedure:
A reaction mixture of 5.7 g (1 mol) of methyl isocyanate and 20 ml of pyridine was stirred at 0° C. for 5 minutes and slowly added into a solution of 20 g (0.23 mol) 1,2-diamino-2-methylpropane in 30 ml of pyridine. The reaction mixture was warmed to 20° C. and stirred for 1 hour. Evaporation of the solvent in vacuo gave 11.6 g (90%) of product which was identified by NMR and IR spectroscopy.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.ClCCl.[CH:10]1([N:16]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:17](=O)[N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.[NH3:38].CO>C1COCC1>[CH:10]1([N:16]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)[C:17]([N:18]([CH:25]2[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]2)[CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)=[NH:38])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: N
Reactant: O=C(N(C1CCCCC1)C1CCCCC1)N(C1CCCCC1)C1CCCCC1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CO
Solvent: ClCCl
Product: N=C(N(C1CCCCC1)C1CCCCC1)N(C1CCCCC1)C1CCCCC1

Procedure:
A solution of dicyclohexylamine (3.9 mL, 19 mmol) and triethylamine (6 mL, 43 mmol) in THF (64 mL) was added dropwise to a stirred solution of triphosgene (1.99 g, 6.7 mmol) in THF (35 mL) at room temperature. The reaction mixture was stirred overnight. Then, a solution of dicyclohexylamine (3.9 mL, 18 mmol) and triethylamine (6 mL, 43 mmol) in THF (37 mL) was added. The reaction mixture was stirred overnight at reflux temperature. The reaction mixture was filtered and the filtrate was evaporated to dryness, yielding tetracyclohexylurea as a yellow solid. Yield: 4.5 g (65%). A solution of oxalyl chloride in dichloromethane (1.1 mL, 13 mmol) was added to a stirred solution of the urea (4.5 g, 11 mmol) in THF (50 mL). The reaction mixture was evaporated to dryness after overnight heating to reflux. A solution of ammonia in methanol (5 mL, 35 mmol, 7 M) was added to a solution of the formed solid in THF (40 mL). The reaction mixture was heated to reflux overnight and evaporated to dryness. The product was neutralized and treated with aqueous sodium hydroxide solution. The organic layer was extracted with diethyl ether and dried over magnesium sulfate. Crystallization from hexanes yielded the desired guanidine as a brown solid. Yield: 2.9 g (64%). 13C NMR (CDCl3, 75 MHz): δ 25.4, 26.2, 31.8, 58.0, 156.2 ppm.
Reaction SMILES: Br[C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1.[C:19](B1OC(C)(C)C(C)(C)O1)([CH3:21])=[CH2:20].C(=O)([O-])[O-].[Na+].[Na+].COCCOC>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.O>[CH3:21][C:19]([C:2]1[C:11]2[O:10][CH2:9][CH2:8][N:7]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][C:5]=2[S:4][CH:3]=1)=[CH2:20]
Reactant: CC(C)(C)OC(=O)N1CCOc2c(Br)csc2C1
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
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: COCCOC
Solvent: O
Product: C=C(C)c1csc2c1OCCN(C(=O)OC(C)(C)C)C2
Temperature: 85 °C
Reaction time: 12 h
Yield: 91.5 %

Procedure:
A mixture of tert-butyl 8-bromo-2,3-dihydrothieno[2,3-f][1,4]oxazepine-4(5H)-carboxylate (334 mg) obtained in Example 1, steps 1-3, isopropenylboronic acid pinacol ester (168 mg), saturated aqueous sodium carbonate solution (6 ml), tetrakis(triphenylphosphine)palladium (32.5 mg) and DME (9 ml) was stirred at 85° C. for 12 hr under a nitrogen atmosphere, and poured into water, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (solvent gradient; 0→30% ethyl acetate/hexane) to give the title compound (270 mg, 91.5%) as an oil.
Reaction SMILES: [H-].[Na+].P(=O)([O-])O[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:13]=[C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][N:15]3[CH:21]=2)=[CH:8][CH:7]=1.[N+:24]([C:27]1[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=1)([O-:26])=[O:25].C(Cl)Cl.CO>C1COCC1>[CH3:20][C:17]1[CH:18]=[CH:19][C:14]2[N:15]([CH:21]=[C:12]([C:9]3[CH:10]=[CH:11][C:6](/[CH:5]=[CH:31]/[C:30]4[CH:33]=[CH:34][C:27]([N+:24]([O-:26])=[O:25])=[CH:28][CH:29]=4)=[CH:7][CH:8]=3)[N:13]=2)[CH:16]=1
Reactant: Cc1ccc2nc(-c3ccc(CO[PH](=O)[O-])cc3)cn2c1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc2nc(-c3ccc(/C=C/c4ccc([N+](=O)[O-])cc4)cc3)cn2c1
Yield: 24.2 %

Procedure:
Prepared as described in the Alkene Formation section using sodium hydride (60% dispersion in mineral oil, 7 mg, 0.307 mmol), diethyl[4-(6-methylimidazo[1,2-a]pyridin-2-yl)benzyl phosphonate (100 mg, 0.279 mmol) and 4-nitrobenzaldehyde (42 mg, 0.279 mmol) in THF (5 ml) to give the title compound (24 mg, 24%) as a yellow solid after work-up and flash chromatography (100:1 DCM/MeOH).
Reaction SMILES: [CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](OCC)=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:27][NH2:28].O>C(O)C>[CH2:1]([N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]([NH:27][NH2:28])=[O:16])[CH2:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: CCOC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Solvent: O
Solvent: CCO
Product: NNC(=O)[C@H]1CC[C@H](N(Cc2ccccc2)Cc2ccccc2)CC1
Temperature: 150 °C
Reaction time: 8 h

Procedure:
A solution of 13B (750 mg, 2.134 mmol) in ethanol (5 mL) was treated with hydrazine.H2O (1.036 mL, 21.34 mmol), stirred at 80° C. for 2 h. No product was observed so more hydrazine.H2O (1.036 mL, 21.34 mmol) was added, and the solution was stirred at 150° C. in sealed tube overnight. Upon cooling, water was added and the resulting white solid was collected by filtration, washed with water and air dried to provide 14A (754 mg, >quantitative yield) as a white solid. MS (ES): m/z=338.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ ppm 7.16-7.40 (m, 10H); 6.58 (br. s, 1H); 3.76 (br. s, 2H); 3.55 (s, 4H); 2.42-2.51 (m, 1H); 1.79-1.97 (m, 5H); 1.25-1.42 (m, 4H).