Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:3]=1[C:4]([NH:6][CH2:7][CH:8]([CH3:15])[CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].[N:21]([O-])=O.[Na+].[OH-].[Na+].C(O)(=O)C>O.Cl>[Cl:20][C:17]1[CH:18]=[CH:19][C:2]2[N:1]=[N:21][N:6]([CH2:7][CH:8]([CH3:15])[CH2:9][N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)[C:4](=[O:5])[C:3]=2[CH:16]=1
Reactant: O=N[O-]
Reactant: CC(CNC(=O)c1cc(Cl)ccc1N)Cn1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(Cn1ccnc1)Cn1nnc2ccc(Cl)cc2c1=O

Procedure:
A solution of 5.86 g of 2-amino-5-chloro-N-[3-(1H-imidazol-1-yl)-2-methylpropyl]benzamide in 30 ml of water and 8.3 ml of concentrated hydrochloric acid was cooled in an ice bath and a solution of 1.42 g of sodium nitrite in 10 ml of water was added dropwise. The mixture was stirred, treated for 50 minutes with 10 ml of 10N sodium hydroxide, stirred for 50 minutes and acetic acid was added until a pH of 6-7 was reached. The product was extracted into methylene chloride and the organic layer was washed with water, dried over magnesium sulfate and concentrated. Treatment with ethyl ether resulted in crystals of the desired product, mp 100°-102° C. A sample was converted to the hydrochloride salt, mp 185°-188° C.
Reaction SMILES: [C:1]([C:4]1([CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:26])[CH2:14][CH2:15][CH2:16][CH2:17][C:18]2([C:23]([OH:25])=[O:24])[CH2:22][CH2:21][CH2:20][CH2:19]2)[CH2:8][CH2:7][CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+]>CC(O)C.O.[BH4-].[Na+]>[C:23]([C:18]1([CH2:17][CH2:16][CH2:15][CH2:14][CH:13]([OH:26])[CH2:12][CH2:11][CH2:10][CH2:9][C:4]2([C:1]([OH:3])=[O:2])[CH2:8][CH2:7][CH2:6][CH2:5]2)[CH2:19][CH2:20][CH2:21][CH2:22]1)([OH:25])=[O:24]
Reactant: O=C(CCCCC1(C(=O)O)CCCC1)CCCCC1(C(=O)O)CCCC1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: O=C(O)C1(CCCCC(O)CCCCC2(C(=O)O)CCCC2)CCCC1
Reaction time: 23 h
Yield: 105 %

Procedure:
To a mixture of 1-[9-(1-carboxycyclopentyl)-5-oxononyl]-1-cyclopentanecarboxylic acid (4.70 g, 11.5 mmol) in iPrOH (30 mL) and H2O (30 mL) was added NaOH (1.10 g, 27 mmol). To the resulting clear solution, NaBH4 (0.242 g, 6.4 mmol) was added. After 23 h, TLC analysis revealed the reaction to be incomplete, and an additional portion of NaBH4 (0.036 g, 0.95 mmol) was added. Stirring was continued for 17 h and then, the reaction mixture was concentrated in vacuo. The remaining residue was dissolved in H2O (80 mL) and washed with Et2O (20 mL). The aqueous layer was acidified with aqueous HCl (6M, 15 mL) and then extracted with Et2O (3×50 mL). The combined organic layers were washed with brine (2×50 mL), dried (Na2SO4) and concentrated in vacuo to give 1-[9-(1-carboxycyclopentyl)-5-hydroxynonyl]-1-cyclo-pentanecarboxylic acid (4.45 g, 98%, contains 7% (w/w) Et2O) as a thick, slightly hazy, light yellow oil. 1H NMR (CDCl3): δ=3.56 (br s, 1H), 2.16-2.10 (m, 4H), 1.65-1.60 (m, 12H), 1.51-1.18 (m, 16H). 13C NMR (CDCl3): δ=184.1 (2×), 71.1, 54.2 (2×), 39.4 (2×), 37.1 (2×), 36.1 (2×), 35.7 (2×), 26.0 (2×), 25.8 (2×), 25.03 (2×), 25.00 (2×).
Reaction SMILES: [ClH:1].CO[C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[CH2:9][CH:8]([NH2:13])[CH2:7]2.[CH3:14][O:15]C1C=CC=C2C=1CCC2=O>>[ClH:1].[CH3:14][O:15][C:5]1[CH:4]=[CH:12][CH:11]=[C:10]2[C:6]=1[CH2:7][CH:8]([NH2:13])[CH2:9]2
Reactant: COc1cccc2c1CCC2=O
Reactant: COc1ccc2c(c1)CC(N)C2
Agent: Cl
Product: COc1cccc2c1CC(N)C2

Procedure:
This compound was prepared in the same manner as [5-(methyloxy)-2,3-dihydro-1H-inden-2-yl]amine hydrochloride from 4-(methyloxy)-2,3-dihydro-1H-inden-1-one.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:9]([NH:11][C:12]([NH:14][C:15]1[S:16][C:17]2[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][C:21](C3C=NC(B(O)O)=NC=3)=[CH:20][C:18]=2[N:19]=1)=[O:13])[CH3:10].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>CN(C=O)C.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl>[Cl:8][C:5]1[N:4]=[CH:3][C:2]([C:21]2[CH:22]=[C:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:17]3[S:16][C:15]([NH:14][C:12]([NH:11][CH2:9][CH3:10])=[O:13])=[N:19][C:18]=3[CH:20]=2)=[CH:7][N:6]=1
Reactant: Clc1ncc(Br)cn1
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(B(O)O)nc3)cc(-c3ccccn3)c2s1
Agent: Cl[Pd]Cl
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2cc(-c3cnc(Cl)nc3)cc(-c3ccccn3)c2s1
Temperature: 80 °C
Yield: 49.9 %

Procedure:
To a solution of 5-bromo-2-chloropyrimidine (6.80 g, 35.1 mmol) in DMF (40 mL) was added [5-[2-(ethylcarbamoylamino)-7-(2-pyridyl)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]boronic acid (10 g, 29.24 mmol) and aqueous solution of K3PO4 (9.3 g, 43.86 mmol). The reaction mixture was degassed by purging N2 for 15 min followed by addition of bis(triphenylphosphine)palladium (II) chloride (3.10 g, 4.4 mmol). The reaction mixture was again degassed for 10-15 min then heated up to 80° C. for 2 h. After completion of reaction (by TLC), solvent was evaporated under reduced pressure, 50 mL water added followed by extraction with EtOAc (3×200 mL). The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 60-120 M silica-gel by using 5% MeOH: DCM to obtain an off white solid compound that was triturated with ether (4.80 g). Further product was obtained by repeating the extraction (1.20 g) giving a combined total product yield of 6.0 g (50%). 1H NMR (DMSO-d6): δ 1.12 (t, J=7.20 Hz, 3H), 3.20 (m, 2H), 6.83 (br s, 1H), 7.46 (m, 1H), 8.0 (m, 1H), 8.17 (s, 1H), 8.40 (s, 1H), 8.50 (d, J=8.0 Hz, 1H), 8.82 (d, J=4.0 Hz, 1H), 9.35 (s, 2H) and 10.61 (br s, 1H). MS: 411.16 [M+H]+.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[H-].[H-].[H-].[H-].[Li+].[Al+3].[Br:11][C:12]1[CH:28]=[CH:27][C:15]2[O:16][CH2:17][C:18]3[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=3[CH:20]([C:21]#[N:22])[C:14]=2[CH:13]=1.[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>CCOCC.O>[NH2:22][CH2:21][CH:20]1[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[CH2:17][O:16][C:15]2[CH:27]=[CH:28][C:12]([Br:11])=[CH:13][C:14]1=2
Reactant: N#CC1c2ccccc2COc2ccc(Br)cc21
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: CCOCC
Product: NCC1c2ccccc2COc2ccc(Br)cc21
Reaction time: 0.08 h
Yield: 48.9 %

Procedure:
A solution of AlCl3 (1.0 g, 7.5 mmol) in dry ether (10 ml) was added rapidly to a solution of LiAlH4 (0.5 g, 13.2 mmol) in dry ether (13 ml). After 5 minutes, a suspension of 2-bromo-11-cyano-6,11-dihydrodibenz[b,e]oxepin (2.0 g, 6.7 mmol) in dry ether (100 ml) was added to the mixture of hydride. The reaction mixture was stirred for 4.5 hours. Water and Rochelle Salt were added to the reaction mixture. The mixture was poured into ether. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel to give 11-aminomethyl-2-bromo-6,11-dihydrodibenz[b,e]oxepin (48.9%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[NH:8][CH:7]=1)[CH3:2].CN(C=O)C.[H-].[Na+].[CH3:24][O:25][P:26]([CH2:30][CH2:31][CH2:32]Br)(=[O:29])[O:27][CH3:28]>C1COCC1.O.C(OCC)(=O)C>[CH3:24][O:25][P:26]([CH2:30][CH2:31][CH2:32][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:6][C:14]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH:7]=[C:6]2[CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:16])(=[O:29])[O:27][CH3:28]
Reactant: COP(=O)(CCCBr)OC
Reactant: CCOC(=O)Cc1c[nH]c2ccc(O)cc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)Cc1cn(Cc2ccccc2)c2ccc(OCCCP(=O)(OC)OC)cc12
Reaction time: 0.17 h
Yield: 142.7 %

Procedure:
5-Hydroxy-1H-indole-3-acetic acid ethyl ester (560 mg. 1,8 mmol) was dissolved in 25 mL of THF and 75 mL of DMF and 80 mg (2.0 mmol) of 60% NaH/mineral oil added. After 0.17 hours, 465 mg (2.0 mmol) of (3-bromopropyl)phosphonic acid dimethyl ester was added and stirring maintained for 3.0 hours. The mixture was diluted with water and ethyl acetate, the organic layer separated, washed with water, brine and dried (Na2SO4). The solution was evaporated at reduced pressure and the residue chromatographed on florisil eluting with a gradient, 1% MeOH/methylene chloride→3% MeOH/methylene chloride, to give 590 mg (71% yield) of [3-[[3-(2-ethoxy-2-oxoethyl)-1-(phenylmethyl)-1H-indol-5-yl]oxy]propyl]phosphonic acid dimethyl ester.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@@H:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([O:13]CC2C=CC=CC=2)=[O:12])=[O:8])[CH2:3][CH2:2]1.[H][H]>CO.[Pd]>[O:1]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C@@H:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:11]([OH:13])=[O:12])=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C(O)[C@H](Cc1ccccc1)OC(=O)N1CCOCC1
Yield: 97 %

Procedure:
A solution of benzyl 2(S)-morpholinocarbonyloxy-3-phenylpropionate (300 mg) in methanol (20 ml) was hydrogenated over 10% palladium on carbon (30 mg) at 3 atmospheric pressure of hydrogen for 1 hour. The solution was filtered and concentrated in vacuo to give 2(S)-morpholinocarbonyloxy-3-phenylpropionic acid (220 mg) as an oil.
Reaction SMILES: C(OC(=O)C[C@@H](N1C=[CH:28][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:26]1)C(N[C@@H](CC1C=CC=CC=1)CO)=O)C1C=CC=CC=1.[CH2:43]([O:50][C:51](=[O:72])[CH2:52][C@@H:53]([NH:64][C:65](OC(C)(C)C)=O)[C:54]([NH:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[OH:63])=[O:55])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C1(C2C=CC=CC=2)C=CC(C2CC(OC)OC2OC)=CC=1>C(O)(=O)C>[CH2:43]([O:50][C:51](=[O:72])[CH2:52][C@@H:53]([N:64]1[CH:65]=[CH:26][C:27]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[CH:28]1)[C:54]([NH:56][C@@H:57]1[CH2:62][CH2:61][CH2:60][CH2:59][C@H:58]1[OH:63])=[O:55])[C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CC(=O)OCc1ccccc1)C(=O)N[C@@H]1CCCC[C@H]1O
Reactant: O=C(C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Agent: COC1CC(c2ccc(-c3ccccc3)cc2)C(OC)O1
Solvent: CC(=O)O
Product: O=C(C[C@H](C(=O)N[C@@H]1CCCC[C@H]1O)n1ccc(-c2ccc(-c3ccccc3)cc2)c1)OCc1ccccc1
Yield: 41 %

Procedure:
As described in Example 1(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(R)-(3-(biphenyl-4-yl)-1H-pyrrol-1-yl)succinamic acid benzyl ester, 3(R)-t-butoxycarbonylamino-N-(2(R)-hydroxycyclohex-1(R)-yl)succinamic acid benzyl ester and 3-biphenyl-4-yl-2,5-dimethoxy-tetrahydrofuran (prepared as described in Example 1(a)) were condensed in acetic acid to furnish in 41% yield 3(R)-[3-(biphenyl-4-yl)-1H-pyrrol-1-yl]-N-(2(R)-hydroxycyclohex-1(R)-yl)succinamic acid benzyl ester as an amorphous off-white solid. 1H NMR (CDCl3): δ 7.63-7.54 (m, 6H), 7.45 (t, 2H, J=7.5 Hz), 7.36-7.26 (m, 6H) 1H), 6.76 (t, 1H, J=2.4 Hz), 6.58 (s, 1H), 5.46 (d, 1H, J=7.0 Hz), 5.15-5.10 (m, 3H), 3.61-3.55 (m, 1H), 3.49 (dd, 1H, J=5.5, 16.6 Hz), 3.27-3.21 (m, 1H), 3.06 (dd, 1H, J=8.3, 16.7 Hz), 2.04-1.98 (m, 1H), 1.85-1.78 (m, 1H), 1.71-1.51 (m, 2H), 1.32-1.02 (m, 4H). Anal. Calculated for C33H34N2O4.H2O: C, 73.31; H, 6.71; N, 5.18. Found: C, 72.93; H, 6.72; N, 4.93.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([CH3:32])=[CH:23][C:24]([O:30][CH3:31])=[C:25]([CH:29]=4)[C:26](O)=[O:27])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.[CH3:33][C:34]1[CH:35]=[N:36][C:37]([C:40]2([NH2:43])[CH2:42][CH2:41]2)=[N:38][CH:39]=1.C(N(CC)CC)C>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[CH:19][C:18]([C:21]4[CH:29]=[C:25]([C:26](=[O:27])[NH:43][C:40]5([C:37]6[N:36]=[CH:35][C:34]([CH3:33])=[CH:39][N:38]=6)[CH2:42][CH2:41]5)[C:24]([O:30][CH3:31])=[CH:23][C:22]=4[CH3:32])=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)O)c(OC)cc3C)cc12
Reactant: Cc1cnc(C2(N)CC2)nc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(C(=O)NC4(c5ncc(C)cn5)CC4)c(OC)cc3C)cc12
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)-2-methoxy-4-methylbenzoic acid (0.04 g, 0.092 mmol, 1 eq), 1-(5-methylpyrimidin-2-yl)cyclopropanamine (130 mg, crude), Py-Bop (0.062 g, 0.12 mmol, 1.3 eq) in DMF at ambient temperature under nitrogen was added triethylamine (0.028 g, 0.3 mmol, 3 eq). The clear mixture was stirred at ambient temperature for 12 h. The mixture was concentrated, diluted with water and extracted with EtOAc. The organic layer was further washed with water, dried over sodium sulphate and concentrated. The product obtained was purified by preparative HPLC. Yield: 0.025 g (49%). 1H NMR (400 MHz, CD3OD): δ 8.50 (d, J=0.8 Hz, 2H), 8.01-7.96 (m, 2H), 7.92 (s, 1H), 7.63 (d, J=8.5 Hz, 1H), 7.59 (d, J=1.3 Hz, 1H), 7.34 (dd, J=1.9, 8.4 Hz, 1H), 7.30-7.25 (m, 2H), 7.15 (s, 1H), 4.08 (s, 3H), 2.96 (s, 3H), 2.37 (s, 3H), 2.29 (s, 3H), 1.80-1.69 (m, 2H), 1.52-1.43 (m, 2H). 19F NMR (376.47 MHz, CD3OD): δ−113.45 LCMS: (ES+) m/z=565.2 (M+H)+
Reaction SMILES: P([O-])([O-])([O-])=O.[N+](C1C=CC(C[O:14][C:15]([C:17]2[N:18]3[CH:21]([S:22][CH:23]=2)[C:20]([CH:25](OC(=O)C)[C:26]2[CH:48]=[CH:47][C:29]4[O:30][C:31]5[CH:46]=[CH:45][CH:44]=[CH:43][C:32]=5[C:33](=[O:42])[N:34]([CH2:35][C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)[C:28]=4[CH:27]=2)(Br)[C:19]3=[O:53])=[O:16])=CC=1)([O-])=O>C1COCC1.[Pd]>[CH2:35]([N:34]1[C:33](=[O:42])[C:32]2[CH:43]=[CH:44][CH:45]=[CH:46][C:31]=2[O:30][C:29]2[CH:47]=[CH:48][C:26](/[CH:25]=[C:20]3/[C@@H:21]4[N:18]([C:19]/3=[O:53])[C:17]([C:15]([OH:16])=[O:14])=[CH:23][S:22]4)=[CH:27][C:28]1=2)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(=O)OC(c1ccc2c(c1)N(Cc1ccccc1)C(=O)c1ccccc1O2)C1(Br)C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CSC21
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCOC1
Product: O=C(O)C1=CS[C@@H]2/C(=C/c3ccc4c(c3)N(Cc3ccccc3)C(=O)c3ccccc3O4)C(=O)N12
Reaction time: 3 h
Yield: 24 %

Procedure:
A 0.5M phosphate buffer solution (pH 6.5) was added to a solution of 6-[acetoxy-(10-benzyl-11-oxo-10,11-dihydro-dibenzo[b,f][1,4]oxazepin-8-yl)-methyl]-6-bromo-7oxo-4-thia-1-aza-bicyclo[3.2.0]hept-2-ene-2-carboxylic acid 4-nitro-benzyl ester (0.210 g, 0.273 mmole) in THF, followed by 10% Pd—C (0.0546 g). The reaction mixture then was hydrogenated at 40 psi for three hours. Filtered through a celite pad and removed the THF by rotary evaporation, extracted the mixture with ethyl acetate and washed with water and brine. Dried the organic layer with sodium sulfate and filtered and concentrated. Dissolved the NaHCO3 with minimal amount of distal water and added it to the reaction mixture along with a small amount of ethyl acetate until the pH value reaches 7–8, evaporated the ethyl acetate. Purified with reverse phase column (MCI Gel CHP20P) with varying amounts of acetonitrile (0%-20%) in water. Removed the acetonitrile and water by rotary evaporation, and freeze-dried the compound. Obtained the desired material (yellow solid) in 24% yield.Mp: 179° C. 1H NMR (DMSO) δ 1.755–1.825 (s, 1H), 2.497–2.506 (d, 2H), 5.243–5.434 (m, 2H), 6.516–6.770 (m, 1H), 7.039–7.792 (m, 11H).
Reaction SMILES: [CH2:1]1[CH:3]([C:4]([NH2:6])=[NH:5])[CH2:2]1.Cl.C(N(CC)CC)C.Cl[C:16](=[CH2:19])[C:17]#[N:18]>C(O)C>[CH:3]1([C:4]2[N:6]=[C:17]([NH2:18])[CH:16]=[CH:19][N:5]=2)[CH2:2][CH2:1]1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)C1CC1
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Nc1ccnc(C2CC2)n1
Temperature: 25 °C
Yield: 26.7 %

Procedure:
Cyclopropylcarbamidine hydrochloride (1.0 g, 8.3 mmol) was dissolved in ethanol (25 mL) and triethylamine (1.26 g, 12.5 mmol), followed by the addition of 2-chloroacrylonitrile (870 mg, 10 mmol). The resulting orange-yellow solution was refluxed for 1 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo and the residue was purified by reverse-phase Combiflash to afford 196a (300 mg, 27%) as a light brown solid. MS-ESI: [M+H]+ 136
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH:9]=[N:10]O)=[CH:4][CH:3]=1.C(C1N=[C:17]([C:27]2[C:28]([O:34][CH3:35])=[N:29][CH:30]=[CH:31][C:32]=2[I:33])[N:18]([OH:26])C=1C1C=CC=CC=1)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:18]([OH:26])[C:17]([C:27]3[C:28]([O:34][CH3:35])=[N:29][CH:30]=[CH:31][C:32]=3[I:33])=[N:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCc1nc(-c2c(I)ccnc2OC)n(O)c1-c1ccccc1
Reactant: O=C(C=NO)c1ccc(Br)cc1
Product: COc1nccc(I)c1-c1ncc(-c2ccc(Br)cc2)n1O
Yield: 18 %

Procedure:
(4-Bromo-phenyl)-oxo-acetaldehyde oxime (0.242 g, 1.06 mmol) was reacted as described for the synthesis of 4-ethyl-2-(4-iodo-2-methoxy-pyridin-3-yl)-5-phenyl-imidazol-1-ol and gave the title material (0.090 g, 18%). LCMS (+ESI, M+H+) m/z 472, 474.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[N:10]=[C:9]([O:11]CC2C=CC=CC=2)[C:8]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=2)=[CH:7][N:6]=1.C1(C)C=CC=CC=1>CO>[CH3:1][O:2][C:5]1[NH:6][CH:7]=[C:8]([CH2:19][C:20]2[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=2)[C:9](=[O:11])[N:10]=1
Reactant: Cc1ccc(Cc2cnc(Cl)nc2OCc2ccccc2)cn1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1nc(=O)c(Cc2ccc(C)nc2)c[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
A solution of 13.25 ml (0.0581 m) of 25% sodium methoxide in methanol was added dropwise to a mixture of 20 g (0.063 m) of 2-chloro-4-benzyloxy-5-[(6-methyl-3-pyridinyl)-methyl]-pyrimidine prepared as in Example 3 and 250 ml of toluene. The mixture is allowed to stir overnight at room temperature then washed with water and evaporated. The residual oil which was 2-methoxy-4-benzyloxy-5-[(6-methyl-3-pyridinyl)-methyl]-pyrimidine was dissolved in ethanol and hydrogenated over 0.6 g of 10% palladium on charcoal. After hydrogen absorption, the reaction mixture was filtered, concentrated to an oil which was taken up in methylene dichloride. Ether was added to give 8.4 g (59%) of 2-methoxy-5-[(6-methyl-3-pyridinyl)-methyl]-4-(1H)-pyrimidinone, m.p. 145°-147°.
Reaction SMILES: [CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([OH:14])=O)[CH:7]=2)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.ClC(OC)=O.[N:32]1([CH2:37][C:38]2[CH:44]=[CH:43][C:41]([NH2:42])=[CH:40][CH:39]=2)[CH:36]=[CH:35][N:34]=[CH:33]1>C(Cl)Cl>[CH:1]1([CH2:4][N:5]([CH2:15][CH2:16][CH3:17])[C:6]2[N:11]=[CH:10][N:9]=[C:8]([C:12]([NH:42][C:41]3[CH:40]=[CH:39][C:38]([CH2:37][N:32]4[CH:36]=[CH:35][N:34]=[CH:33]4)=[CH:44][CH:43]=3)=[O:14])[CH:7]=2)[CH2:2][CH2:3]1
Reactant: CCCN(CC1CC1)c1cc(C(=O)O)ncn1
Reactant: Nc1ccc(Cn2ccnc2)cc1
Agent: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCN(CC1CC1)c1cc(C(=O)Nc2ccc(Cn3ccnc3)cc2)ncn1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
A cooled (0° C.) solution of 6-(cyclopropylmethyl(propyl)amino)pyrimidine-4-carboxylic acid (Intermediate 21, 112 mg; 0.45 mmol) in DCM was treated with diisopropylethylamine (78.4 mL; 0.52 mmol) and methyl chloroformate (36.2 mL; 0.47 mmol). After stirring at 0° C. for 15 minutes, 4-(1H-imidazol-1-ylmethyl)aniline (Maybridge, 117 mg; 0.67 mmol) was added and the mixture stirred for 72 hours. The solvent was evaporated and the compound purified by preparative HPLC to give the title compound as a white solid.
Reaction SMILES: [C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([N:14]=[C:15]=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>C(Cl)(Cl)Cl>[C:1]([C:5]1[S:6][C:7]2[CH:13]=[C:12]([NH:14][C:15]([N:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[S:16])[C:11]([N:17]3[CH2:22][CH2:21][CH:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:10][C:8]=2[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: C1CNCCN1
Reactant: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2N=C=S)CC1
Solvent: ClC(Cl)Cl
Product: CC1CCN(c2cc3nc(C(C)(C)C)sc3cc2NC(=S)N2CCNCC2)CC1
Reaction time: 3 h
Yield: 69.6 %

Procedure:
A solution of 3.45 g of 2-tert-butyl-6-isothiocyanato-5-(4-methylpiperidin-1-yl)benzothiazole, described in Example 1, and 8.6 g of anhydrous piperazine in 30 ml of chloroform is stirred for 3 hours, washed with water, dried over anhydrous sodium sulphate and evaporated to get a sticky residue which is triturated with isopropanol and filtered to obtain 3 g of 2-tert-butyl-5-(4-methyl-piperidin-1-yl)-6-[(piperazin-1-yl)thiocarbonylamino]benzothiazole, melting at 278°-281°.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH:11]([OH:18])[C:12]([N+:15]([O-])=O)([CH3:14])[CH3:13])=[CH:7][CH:6]=1>C(O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][CH2:3][CH2:4][C:5]1[CH:20]=[CH:19][C:8]([O:9][CH2:10][CH:11]([OH:18])[C:12]([NH2:15])([CH3:14])[CH3:13])=[CH:7][CH:6]=1
Reactant: COCCc1ccc(OCC(O)C(C)(C)[N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Solvent: CC(=O)O
Product: COCCc1ccc(OCC(O)C(C)(C)N)cc1

Procedure:
19 g of 1-[4-(2-methoxyethyl)-phenoxy]-3-nitro-3-methyl-butan-2-ol are hydrogenated at 60° C. and under a pressure of 6 bar in a mixture of 250 ml of ethanol and 50 ml of glacial acetic acid in the presence of 4 g of palladium-on-charcoal (10% Pd). After the mixture has been filtered and the solvent has been evaporated off, the residue is rendered alkaline with 2N NaOH and the mixture is extracted with CH2Cl2. The organic phase is washed with water and dried with Na2SO4 to give, after evaporation, 15 g of the amine, which is converted into the hydrochloride with ethanol hydrochloric acid. Melting point: 120°-122° C. (ethyl acetate).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[CH2:6][NH:7]C(=O)OC(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:6][NH2:7])[CH:15]=[CH:16][C:17]=1[O:18][CH2:19][C:20]1[CH:21]=[N:22][C:23]([CH3:26])=[CH:24][CH:25]=1
Reactant: COc1cc(CNC(=O)OC(C)(C)C)ccc1OCc1ccc(C)nc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(CN)ccc1OCc1ccc(C)nc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.7 %

Procedure:
To a stirred solution of tert-butyl 3-methoxy-4-((6-methylpyridin-3-yl)methoxy)benzylcarbamate (29.74 g, 82.97 mmol) in dichloromethane (100 mL) was added trifluoroacetic acid (50 mL, 649.0 mmol). The resulting brown solution was allowed to stir at room temperature. After 2 h, the reaction mixture was concentrated to dryness, and the residue was dissolved in water (250 mL). The acidic solution was extracted with diethyl ether (2×125 mL; organic phases discarded). The aqueous phase was then made basic with concentrated ammonium hydroxide. The basic aqueous phase was then extracted with dichloromethane (3×100 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated to provide 19.22 g (90%) of (3-methoxy-4-((6-methylpyridin-3-yl)methoxy)phenyl)methanamine as brown solid.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]3[CH2:11][CH:10]([C:12]#[N:13])[C:8]3=[CH:9][C:2]1=2.[NH4+].[OH-]>C(O)C.[Ni]>[O:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]3[CH2:11][CH:10]([CH2:12][NH2:13])[C:8]3=[CH:9][C:2]1=2
Reactant: N#CC1Cc2cc3ccoc3cc21
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: NCC1Cc2cc3ccoc3cc21
Reaction time: 72 h

Procedure:
7 g (41.3 mmoles) of 5,6-dihydrocyclobuta[4,5]benzo[1,2-b]furan-6-carbonitrile are dissolved in 490 mL of ethanol. 70 mL of 28% NH4OH solution and 1 g of Raney nickel are added. Hydrogenation is carried out under a pressure of 5 bar, at 25° C., for 3 days. Filtration over Celite and evaporation of the filtrate to dryness are carried out. The expected product is obtained in the form of a yellow oil.