Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([N:7]([CH2:21][CH2:22]C2C=CC=CC=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:29]1([CH2:35]CC=O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[CH3:39][C@H]1CC[C@H](N)CC1.C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:39][CH:4]1[CH2:5][CH2:6][CH:1]([N:7]([CH2:21][CH2:22][CH2:35][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:8](=[O:20])[NH:9][C:10]2[S:11][C:12]([S:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:13][N:14]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)CSc1cnc(NC(=O)N(CCc2ccccc2)C2CCCCC2)s1
Reactant: C[C@H]1CC[C@H](N)CC1
Reactant: O=CCCc1ccccc1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: CC1CCC(N(CCCc2ccccc2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1

Procedure:
Prepared as described for the synthesis of [2-(3-cyclohexyl-3-phenethyl-ureido)-thiazol-5-ylsulfanyl]-acetic acid using 3-phenylpropionaldehyde, trans-4-methyl-cyclohexylamine and (2-amino-thiazol-5-ylsulfanyl)-acetic acid ethyl ester.
Reaction SMILES: [CH2:1]([C:4]([O:11][CH3:12])([C:8](Cl)=[O:9])[C:5](Cl)=[O:6])[CH:2]=[CH2:3].[CH:13]([N:16]([C:34]1[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=1)[C:17](=[O:33])[CH2:18][NH:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[NH:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:15])[CH3:14]>C1COCC1>[CH2:1]([C:4]1([O:11][CH3:12])[C:8](=[O:9])[N:19]([CH2:18][C:17]([N:16]([CH:13]([CH3:15])[CH3:14])[C:34]2[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=2)=[O:33])[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:26]([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:5]1=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCC(OC)(C(=O)Cl)C(=O)Cl
Reactant: COc1ccc(N(C(=O)CNc2ccccc2Nc2ccccc2)C(C)C)cc1
Solvent: C1CCOC1
Product: C=CCC1(OC)C(=O)N(CC(=O)N(c2ccc(OC)cc2)C(C)C)c2ccccc2N(c2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 58.4 %

Procedure:
To a stirring solution of 1.50 g (7.10 mmol) of 2-allyl-2-methoxy-propandioyl dichloride in 50 mL of THF at 0° C. is added dropwise over 2 min a solution of 1.85 g (4.74 mmol) of N-isopropyl-N-(4-methoxy-phenyl)-2-(2-phenylamino-phenylamino) acetamide, prepared as in Intermediate 43, in 20 mL of THF. The resulting solution is stirred at RT for 15 min then refluxed for 18 h. After cooling to RT the solvent is removed in vacuo and the crude product purified by silica gel flash column chromatography using hexane/EtOAc 3/1 as eluent to afford 1.46 g of the title compound as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ7.40-6.88 (m, 12H), 6.78 (d, 1H), 5.92 (m, 1H), 5.10 (m, 2H), 4.46 (d, 1H), 3.80 (s, 3H), 3.64 (m, 1H), 3.02 (s, 3H), 1.88 (m, 1H), 1.75 (m, 1H), 1.13 (m, 6H); low resolution MS (FAB) m/e 528 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:59]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:66]([O:92][CH3:93])=[CH:67][C:68]3[C:74](=[O:75])[N:73]4[CH:76]=[C:77](/[CH:79]=[CH:80]/[CH3:81])[CH2:78][C@H:72]4[C:71](=O)[N:70](COCC[Si](C)(C)C)[C:69]=3[CH:91]=2)=[CH:58][C:6]2[N:7](COCC[Si](C)(C)C)[C:8](=O)[C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:48])[C@@H:21]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]4[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:26]([CH3:28])[CH3:27])[CH3:22])=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1.[Li+].[B-](CC)(CC)CC>C1COCC1.O.CO>[CH3:1][O:2][C:3]1[C:59]([O:60][CH2:61][CH2:62][CH2:63][O:64][C:65]2[C:66]([O:92][CH3:93])=[CH:67][C:68]3[C:74](=[O:75])[N:73]4[CH:76]=[C:77](/[CH:79]=[CH:80]/[CH3:81])[CH2:78][C@H:72]4[CH:71]=[N:70][C:69]=3[CH:91]=2)=[CH:58][C:6]2[N:7]=[CH:8][C@@H:9]3[CH2:15][C:14](/[CH:16]=[CH:17]/[CH2:18][NH:19][C:20](=[O:48])[C@@H:21]([NH:23][C:24](=[O:47])[C@@H:25]([NH:29][C:30](=[O:46])[O:31][CH2:32][CH:33]4[C:45]5[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=5[C:39]5[C:34]4=[CH:35][CH:36]=[CH:37][CH:38]=5)[CH:26]([CH3:28])[CH3:27])[CH3:22])=[CH:13][N:10]3[C:11](=[O:12])[C:5]=2[CH:4]=1
Reactant: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC6c7ccccc7-c7ccccc76)C(C)C)C[C@H]4C(=O)N5COCC[Si](C)(C)C)cc3N(COCC[Si](C)(C)C)C(=O)[C@@H]2C1
Agent: CC[B-](CC)CC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: C/C=C/C1=CN2C(=O)c3cc(OC)c(OCCCOc4cc5c(cc4OC)C(=O)N4C=C(/C=C/CNC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)OCC6c7ccccc7-c7ccccc76)C(C)C)C[C@H]4C=N5)cc3N=C[C@@H]2C1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 36.4 %

Procedure:
SEM Fmoc amine 18c (0.212 g, 0.162 mmol, 1.0 eq.) was solubilised in THF (9.2 mL) and cooled to −78° C. under a nitrogen atmosphere. Super hydride solution (0.330 mL, 0.330 mmol, 2.04 eq.) was added drop wise over 4 minutes. After 45 minutes an aliquot was diluted with water and MeOH for LCMS After stirring for a further 10 mins, the reaction mixture was diluted with water (27 mL) and the cold bath removed. The organic layer was extracted with EtOAc (2×27 mL) and the combined organic extracts washed with brine (27 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dissolved in MeOH (11.05 mL), DCM (5.53 mL) and water (1.85 mL) and enough silica gel was added to form a thick suspension which was left stirring for 5 days. The suspension was filtered and washed with DCM/MeOH 9:1 (−200 mL) until complete elution of product. The organic layer was washed with brine (2×70 mL), dried over MgSO4, filtered and concentrated under reduced pressure. The resulting residue was purified by flash chromatography (silica gel; 40:1 v/v DCM/MeOH to 20:1 v/v DCM/MeOH) to afford the product as a yellow solid (0.060 g, 36%). LC/MS (2.802 min (ES+)), m/z: 1016.15 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5](/[CH:12]=[CH:13]/[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2.CN(C)C=O>[Pd].C(O)C>[CH3:1][N:2]1[C:10](=[O:11])[NH:9][C:8]2[C:3]1=[N:4][C:5]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[N:6][CH:7]=2
Reactant: Cn1c(=O)[nH]c2cnc(/C=C/c3ccccc3)nc21
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: Cn1c(=O)[nH]c2cnc(CCc3ccccc3)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 9-methyl-2-[(E)-2-phenylethenyl]-7,9-dihydro-8H-purine-8-one <the compound of Reference Example 3> (80 mg), N,N-dimethylformamide (2 ml) and ethanol (3 ml) was added 10% palladium on carbon (2 mg) and the mixture was stirred at room temperature under hydrogen atmosphere for 1 hour. The reaction mixture was filtered through Celite and the filtrate was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=100/0˜0/100) to give the title compound 47 mg.
Reaction SMILES: CO.[NH2:3][C:4]1[C:9]([C:10]2[O:14][N:13]=[C:12]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=3)[CH:11]=2)=[CH:8][CH:7]=[C:6]([NH2:23])[N:5]=1.[OH-].[Na+].[Cl:26][C:27]1[CH:32]=[N:31][CH:30]=[C:29](Cl)[N:28]=1>CN(C)C=O>[Cl:26][C:27]1[N:28]=[C:29]([O:22][C:19]2[CH:20]=[CH:21][C:16]([CH2:15][C:12]3[CH:11]=[C:10]([C:9]4[C:4]([NH2:3])=[N:5][C:6]([NH2:23])=[CH:7][CH:8]=4)[O:14][N:13]=3)=[CH:17][CH:18]=2)[CH:30]=[N:31][CH:32]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: Clc1cncc(Cl)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Nc1ccc(-c2cc(Cc3ccc(Oc4cncc(Cl)n4)cc3)no2)c(N)n1
Temperature: 100 °C
Reaction time: 0.17 h
Yield: 66.1 %

Procedure:
To a methanol (1.5 mL) solution of 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (50 mg, 0.18 mmol) described in Manufacturing Example 18-1-1 was added a 2 N sodium hydroxide solution (89 μL), which was concentrated under a reduced pressure. 2,6-Dichloropyrazine (28 mg, 0.19 mmol) and N,N-dimethylformamide (0.75 mL) were added to the residue, which was stirred for 10 minutes at 100° C. The reaction solution was partitioned into ethyl acetate and water. The organic layer was separated and concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:1, then ethyl acetate) to obtain the title compound (47 mg, 67%).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13](=[O:37])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][C:25](=[O:36])[C:26]2[CH:31]=[CH:30][C:29]([C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:28][CH:27]=2)=[S:23])=[CH:17][CH:16]=1)(C)(C)C.[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42]>C(Cl)Cl>[F:39][C:40]([F:45])([F:44])[C:41]([OH:43])=[O:42].[C:32]([C:29]1[CH:28]=[CH:27][C:26]([C:25]([NH:24][C:22](=[S:23])[NH:21][C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:13](=[O:37])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][NH2:7])=[CH:16][CH:17]=2)=[O:36])=[CH:31][CH:30]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)Nc1ccc(NC(=S)NC(=O)c2ccc(C(C)(C)C)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1ccc(C(=O)NC(=S)Nc2ccc(NC(=O)CCCCCN)cc2)cc1

Procedure:
Boc protected amine 32 (20 mg, 0.04 mmol) was stirred in CH2Cl2 (1 mL) and trifluoroacetic acid (166 μL) at rt for 30 min. Concentration in vacuo gave 33 as a pale yellow oil.
Reaction SMILES: Cl[C:2]([C:28](=[O:37])[C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:4].[C:38]([C:41]1[CH:42]=[C:43]([N:47]2[C:51]([SH:52])=[N:50][N:49]=[N:48]2)[CH:44]=[CH:45][CH:46]=1)([OH:40])=[O:39].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:36][O:35][C:32]1[CH:33]=[CH:34][C:29]([C:28]([C:2]([S:52][C:51]2[N:47]([C:43]3[CH:44]=[CH:45][CH:46]=[C:41]([C:38]([OH:40])=[O:39])[CH:42]=3)[N:48]=[N:49][N:50]=2)([Cl:27])[C:3]([N:5]([C:12]([O:14][CH:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[CH2:16][CH2:17][CH2:18][CH3:19])=[O:13])[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)=[O:4])=[O:37])=[CH:30][CH:31]=1
Reactant: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Cl)C(=O)c1ccc(OC)cc1)c1ccccc1
Reactant: O=C(O)c1cccc(-n2nnnc2S)c1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCCCCCCC(CCCC)OC(=O)N(C(=O)C(Cl)(Sc1nnnn1-c1cccc(C(=O)O)c1)C(=O)c1ccc(OC)cc1)c1ccccc1
Yield: 84.7 %

Procedure:
33 g of α-chloro-α-(4-methoxybenzoyl)-2-chloro-5-dodecyloxycarbonylacetanilide and 16 g of 1-(3-carboxyphenyl)-5-mercaptotetrazole were dispersed in 200 ml of chloroform and to which was added dropwise 10 ml of triethylamine at room temperature over a period of about 30 minutes. After stirring for 3 hours the chloroform solution washed with water and concentrated under reduced pressure. The residue was crystallized from methanol to obtain 37.4 g of α-(4-methoxybenzoyl)-α-[1-(3-carboxyphenyl)-5-tetrazolylthio]-2-chloro-5-dodecyloxycarbonylacetanilide. Yield: 85%. Melting Point: 155° to 162° C.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[C:16](=[O:17])[CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:25]([Mg]Br)[CH:26]=[CH2:27]>>[CH2:27]([C:16]1([OH:17])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:13][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:15]1)[CH:26]=[CH2:25]
Reactant: CC(C)(C)OC(=O)N1CC(=O)[C@@H](NC(=O)OCc2ccccc2)C1
Reactant: C=CC[Mg]Br
Product: C=CCC1(O)CN(C(=O)OC(C)(C)C)C[C@@H]1NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 1.44 g of the ketone of step B in 20 mL of anhydrous T° F. cooled at 0° C. was added a solution of 6.2 mL of 1 M allyl magnesium bromide. The color turned dark right away. After being stirred at room temperature overnight, the reaction mixture was quenched with 50/50 mL of EtOAc/water. Water phase was extracted twice with EtOAc. The combined organic phase was dried over Na2SO4 and concentrated under vacuum. Column chromatography on silica gel using 3:1˜2:1 hexane/EtOAc as eluent provided 0.85 g of the title compound. MS (M+H)+ 377.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]([C:6]([OH:8])=[O:7])[CH2:4][SH:5].Cl.[CH2:10](O)[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]>>[ClH:1].[CH2:10]([O:7][C:6](=[O:8])[C@H:3]([CH2:4][SH:5])[NH2:2])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: N[C@@H](CS)C(=O)O
Reactant: CCCCCCO
Agent: Cl
Product: CCCCCCOC(=O)[C@@H](N)CS

Procedure:
L-Cysteine hydrochloride 78.5 g was added to 150 ml of hexanol saturated with dry HCl gas. The mixture was heated under reflux overnight. The solution was evaporated to about half of the total volume, ethyl ether 150 ml was added. The solution gave crystals when it was cooled. Crystals were filtered and were recrystallized from ethyl acetate; yield 45 g; mp 89°-90° C.; IR (KBr) 1745 cm-1 ; NMR (CDCl3) δ 9.2-8.4 (b, 3, NH3⊕), 4.7 (5, 1, --CH--), 4.3 (t, 2, --OCH2 --), 3.4 (b, 2, CH2S--), 1.0-3.0 (m, 8), 1.0 (t, 3-, CH5).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1.[O:24]=[C:25]1[N:29]=[C:28]([NH:30][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])[CH2:27][S:26]1.C([O-])(=O)C.[NH2+]1CCCCC1>C(O)C>[F:23][C:2]([F:1])([F:22])[C:3]1[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH:9](/[CH:12]=[C:27]2/[C:28]([NH:30][C@@H:31]([C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:32][OH:33])=[N:29][C:25](=[O:24])[S:26]/2)[CH2:8][CH2:7]1
Reactant: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)SC1
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CCO
Product: CN(C)C(=O)[C@@H](CO)NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
To a solution of 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (5.57 g) and N2-[2-oxo-2,5-dihydro-1,3-thiazol-4-yl]-N,N-dimethyl-D-serinamide (5.70 g) in ethanol (80 mL) was added piperidinium acetate (2.39 g). The reaction mixture was stirred at 80° C. overnight, and the solvent was evaporated under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (methanol/ethyl acetate), and the obtained solid was washed with diisopropyl ether to give a solid. The obtained solid was recrystallized from ethyl acetate/heptane to give the title compound (3.45 g).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[NH2:17])=[C:14]([CH3:18])[C:13]([C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([C:8]1[N:9]([C:23]2[CH:27]=[CH:26][S:25][CH:24]=2)[C:10]2[C:15]([C:16]=1[N:17]=[C:29]=[O:31])=[C:14]([CH3:18])[C:13]([C:19]([F:21])([F:20])[F:22])=[CH:12][CH:11]=2)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1c(C(F)(F)F)ccc2c1c(N)c(C(=O)OC(C)(C)C)n2-c1ccsc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1c(C(F)(F)F)ccc2c1c(N=C=O)c(C(=O)OC(C)(C)C)n2-c1ccsc1

Procedure:
To a solution of 3-amino-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1E (1.74 g, 4.39 mmol) in anhydrous toluene (50 mL) was added triphosgene (0.44 g, 1.48 mmol) and triethylamine (0.89 g, 8.81 mmol). The reaction mixture was heated at reflux for 3 hours. Toluene (50 mL) was added and the organic layer was washed with water and brine. The organic layer was dried over sodium sulfate. The organic solvent was evaporated under reduced pressure to provide 3-isocyanato-1-thiophen-3-yl-methyl-5-trifluoromethyl-1H-indole-2-carboxylic acid tert-butyl ester 1F which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[N:20]=[C:5]2[C:6]([C:10]3[CH:15]=[CH:14][C:13]([S:16]([CH3:19])(=[O:18])=[O:17])=[CH:12][CH:11]=3)=[CH:7][CH:8]=[CH:9][N:4]2[N:3]=1.[CH3:21][N:22]1[C:26]([CH3:27])=[C:25]([NH2:28])[C:24]([CH3:29])=[N:23]1.C1(P(C2CCCCC2)C2(P(C3CCCCC3)C3CCCCC3)CC=CC=C2C2C=CC=CC=2)CCCCC1>>[CH3:19][S:16]([C:13]1[CH:14]=[CH:15][C:10]([C:6]2[C:5]3[N:4]([N:3]=[C:2]([NH:28][C:25]4[C:24]([CH3:29])=[N:23][N:22]([CH3:21])[C:26]=4[CH3:27])[N:20]=3)[CH:9]=[CH:8][CH:7]=2)=[CH:11][CH:12]=1)(=[O:18])=[O:17]
Reactant: CS(=O)(=O)c1ccc(-c2cccn3nc(Cl)nc23)cc1
Reactant: Cc1nn(C)c(C)c1N
Agent: C1=CCC(P(C2CCCCC2)C2CCCCC2)(P(C2CCCCC2)C2CCCCC2)C(c2ccccc2)=C1
Product: Cc1nn(C)c(C)c1Nc1nc2c(-c3ccc(S(C)(=O)=O)cc3)cccn2n1

Procedure:
[8-(4-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(1,3,5-trimethyl-1H-pyrazol-4-yl)-amine was prepared from 2-chloro-8-(4-methanesulfonyl-phenyl)-[1,2,4]triazolo[1.5-a]pyridine (0.200 g, 0.65 mmol) and 1,3,5-trimethyl-1H-pyrazol-4-ylamine (0.106 g, 0.845 mmol) with 2,2-bis-dicyclohexylphosphanyl-biphenyl (0.048 g, 0.088 mmol) as the ligand in a manner analogous to Example 2d. Product was isolated as an orange solid (0.157 g, 61%). MP=194-196° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 8.65 (d, J=6.56 Hz, 1H), 8.37 (d, J=7.50 Hz, 2H), 8.13 (s, 1H), 8.04 (d, J=7.52 Hz, 2H), 7.86 (d, J=7.47 Hz, 1H), 7.04 (t, J=7.26 Hz, 1H), 3.65 (s, 3H), 3.27 (s, 3H), 2.09 (s, 3H, 1.99 (s, 3H). MS=397 (MH)+.
Reaction SMILES: [CH3:1][N:2]([CH3:18])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1.[CH2:19]([Cl:37])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>>[Cl-:37].[CH2:19]([N+:2]([CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:17])[C:8]1[CH:13]=[CH:12][C:11]([N:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=1)([CH3:18])[CH3:1])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]
Reactant: CCCCCCCCCCCCCCCCCCCl
Reactant: CN(C)CCCNC(=O)c1ccc(N(C)C)cc1
Product: CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCNC(=O)c1ccc(N(C)C)cc1
Product: [Cl-]
Reaction time: 3 h

Procedure:
25.6 g of N-(3-dimethylaminopropyl)-p-dimethylaminobenzamide (0.103 mole) from Example 1 and 28.6 g of stearylchloride (0.099 mole) were melted together and kept at 130° C. for 3 hours. Product was crystallized from 250 ml of methylethylketone. Yield was 42 g (77% of theoretical yield).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:48]([O:55][CH2:56][C:57]([C:60]1[N:64]=[C:63]([CH3:65])[O:62][N:61]=1)([NH2:59])[CH3:58])[C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>CN(C=O)C>[CH:1]1([C:4]2[C:5]([O:13][CH2:14][C:15]([F:18])([F:17])[F:16])=[CH:6][C:7]([C:10]([NH:59][C:57]([C:60]3[N:64]=[C:63]([CH3:65])[O:62][N:61]=3)([CH3:58])[CH2:56][O:55][CH2:48][C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: O=C(O)c1cc(OCC(F)(F)F)c(C2CC2)cn1
Reactant: Cc1nc(C(C)(N)COCc2ccccc2)no1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc(C(C)(COCc2ccccc2)NC(=O)c2cc(OCC(F)(F)F)c(C3CC3)cn2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 73.9 %

Procedure:
To a solution of 5-Cyclopropyl-4-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (example 48c, 0.58 g, 2.22 mmol) in dry DMF (10 ml) was added triethylamine (270 mg, 371 μl, 2.66 mmol) and TBTU (713 mg, 2.22 mmol). The reaction mixture was stirred at room temperature for 30 minutes followed by addition of 1-(benzyloxy)-2-(5-methyl-1,2,4-oxadiazol-3-yl)propan-2-amine (example 112d, 577 mg, 2.33 mmole) and the reaction was then stirred at room temperature overnight. DMF was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was extracted with a 2M aqueous solution of sodium carbonate and the organic phase was collected. The organic phase was dried over sodium sulfate and evaporated down to dryness. The crude material was purified by flash chromatography on silica eluting with a heptane/ethyl acetate gradient to yield the title compound (805 mg, 74%) as a light yellow oil. MS (ESI, m/z): 491.5 (M+H+).
Reaction SMILES: [C:1]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:38]3[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=3)[C:9](=[O:37])[C:10]3[N:11]=[C:12]([CH2:22][N:23](CC4C=CC(OC)=CC=4)[S:24]([CH3:27])(=[O:26])=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1>C(O)(C(F)(F)F)=O>[C:1]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:8]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[C:9](=[O:37])[C:10]3[N:11]=[C:12]([CH2:22][NH:23][S:24]([CH3:27])(=[O:25])=[O:26])[N:13]([C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:14]=3[N:15]=2)=[CH:5][CH:6]=1.[C:1]1([C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:2]=[CH:3][C:4]([C:7]2[N:8]([C:38]3[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=3)[C:9](=[O:37])[C:10]3[N:11]=[C:12]([CH2:22][CH2:27][S:24]([NH2:23])(=[O:26])=[O:25])[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:5][CH:6]=1
Reactant: COc1ccc(CN(Cc2nc3c(=O)n(-c4ccc(Cl)cc4)c(-c4ccc(-c5ccccc5)cc4)nc3n2-c2ccccc2)S(C)(=O)=O)cc1
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)NCc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(-c4ccccc4)cc3)nc2n1-c1ccccc1
Product: NS(=O)(=O)CCc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(-c4ccccc4)cc3)nc2n1-c1ccccc1

Procedure:
A solution of N-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-N-(4-methoxy-benzyl)-methanesulfonamide (18 mg, 0.026 mmol) in TFA (1 mL) was heated at 90° C. in a sealed tube for 12 h. The reaction mixture was concentrated in vacuo and the resulting crude oil was purified by flash chromatography (silica, 5% MeOH/CH2Cl2) to give the title compound Ar-[2-biphenyl-4-yl-1-(4-chloro-phenyl)-6-oxo-9-phenyl-6,9-dihydro-1H-purin-8-ylmethyl]-methanesulfonamide as a white solid. 1H NMR (CDCl3) δ (ppm) 7.64 7.54 (m, 3H), 7.51 7.45 (m, 4H), 7.44 7.38 (m, 4H), 7.37 7.30 (m, 4H), 7.28 (s, 1H), 7.13 (d, 2H), 5.92 (br s, 1H), 4.48 (s, 2H), 2.99 (s, 3H); HPLC-MS calculated for C31H24ClN5O3S (M+H+): 582.1. Found 582.1.
Reaction SMILES: [CH2:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[CH2:4][CH2:3][N:2]1C(OC(C)(C)C)=O.[Cl:18][C:19]1[CH:24]=[CH:23][N:22]=[C:21]([CH3:25])[CH:20]=1.[CH2:26](N(C(C)C)C(C)C)C>>[ClH:18].[CH3:26][C:23]1[CH:24]=[C:19]([N:8]2[CH2:7][CH2:6][C:5]3([CH2:1][NH:2][CH2:3][CH2:4]3)[CH2:10][CH2:9]2)[CH:20]=[C:21]([CH3:25])[N:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: Cc1cc(Cl)ccn1
Product: Cc1cc(N2CCC3(CCNC3)CC2)cc(C)n1
Product: Cl
Yield: 50 %

Procedure:
Synthesis of this amine was carried out in analogy to Amine AMN-33 employing tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (1 eq.) and 4-chloro-2-methylpyridine (3 eq.) as starting materials. In step 1 the number of equivalents of N-ethyl-diisopropylamine was adjusted to 3. Step 1—yield: 50%; Step 2—yield: 68%