Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][CH:11]([F:14])[CH:10]([NH:15]C(=O)C(F)(F)F)[CH2:9][CH2:8]1.C(OC([NH:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:42](O)=[O:43])=O)(C)(C)C>>[NH2:30][C:31]1[S:35][C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=2)=[N:33][C:32]=1[C:42]([NH:1][C:2]1[CH:3]=[N:4][N:5]([CH3:22])[C:6]=1[N:7]1[CH2:13][CH2:12][C@H:11]([F:14])[C@@H:10]([NH2:15])[CH2:9][CH2:8]1)=[O:43]
Reactant: CC(C)(C)OC(=O)Nc1sc(-c2ccccn2)nc1C(=O)O
Reactant: Cn1ncc(N)c1N1CCC(F)C(NC(=O)C(F)(F)F)CC1
Product: Cn1ncc(NC(=O)c2nc(-c3ccccn3)sc2N)c1N1CC[C@H](N)[C@@H](F)CC1
Yield: 74 %

Procedure:
Following the procedure for Example 107 starting from N-(1-(4-amino-1-methyl-1H-pyrazol-5-yl)-5-fluoroazepan-4-yl)-2,2,2-trifluoroacetamide and 5-(tert-butoxycarbonylamino)-2-(pyridin-2-yl)thiazole-4-carboxylic acid gave 298 as a pale yellow solid (418 mg, 74% over 2 steps). 1H NMR (400 MHz, CDCl3) δ 8.54 (d, J=4.9 Hz, 1H), 8.40 (s, 1H), 8.06 (d, J=8.0 Hz, 1H), 7.78-7.73 (m, 2H), 7.28-7.23 (m, 1H), 6.26 (s, 2H), 4.51 (dtd, J=48.0, 8.8, 3.8 Hz, 1H), 3.73 (s, 3H), 3.37-3.20 (m, 5H), 2.35-2.21 (m, 1H), 2.18-2.04 (m, 1H), 2.02-1.92 (m, 1H), 1.79-1.66 (m, 1H). Alkyl NH2 not seen. LCMS (ES+) m/z 431 (M+1)
Reaction SMILES: ClCCl.[OH:4][C@H:5]([CH2:18][NH:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][C:27]2=[O:32])=[CH:22][CH:21]=1)[CH2:6][N:7]1[C:15](=[O:16])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=[O:17].[O:33]1CCC[CH2:34]1>>[O:33]=[C:34]1[N:19]([C:20]2[CH:25]=[CH:24][C:23]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][C:27]3=[O:32])=[CH:22][CH:21]=2)[CH2:18][C@H:5]([CH2:6][N:7]2[C:15](=[O:16])[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]2=[O:17])[O:4]1
Reactant: O=C1c2ccccc2C(=O)N1C[C@H](O)CNc1ccc(N2CCOCC2=O)cc1
Reactant: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1C[C@H]1CN(c2ccc(N3CCOCC3=O)cc2)C(=O)O1
Temperature: 42.5 °C
Reaction time: 8 h

Procedure:
In a four neck round bottom flask, charged dichloromethane (3400 ml), 2-((2R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1H-isoindole-1,3(2H)-dione (340 g) and N,N′-dicarbonyldiimidazole (209.13 g) at 25 to 30° C. The obtained reaction mass then stirred for 8 hr. at 25 to 30° C. Reaction mass is concentrated under reduced pressure to obtain residue. Added tetrahydrofuran (1700 ml) to residue. The obtained mixture is heated to 40 to 45° C. for 30 minutes followed by cooling to room temperature. Finally obtained solid is filtered off and washed by tetrahydrofuran(170 ml)
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:24])[CH3:23])[CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1.[CH:26]1[CH:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=2)=[CH:28][CH:27]=1>C1COCC1>[C:32]1([C:29]2[CH:28]=[CH:27][CH:26]=[CH:31][CH:30]=2)[CH:33]=[CH:34][C:35]([NH:38][C:39]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:25])[CH:22]([CH3:23])[CH3:24])[CH:17]=[CH:18][CH:19]=3)[CH2:10][CH2:9]2)=[O:40])=[CH:36][CH:37]=1
Reactant: O=C=Nc1ccc(-c2ccccc2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCN)CC2)c1
Solvent: C1CCOC1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCCCNC(=O)Nc3ccc(-c4ccccc4)cc3)CC2)c1

Procedure:
Prepared by Procedure Q1 (THF) and Scheme AT using N-{3-[1-(6-aminohexyl)-4-piperidinyl]phenyl}-2-methylpropanamide and 4-biphenyl isocyanate: ESMS m/e: 541.3 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([CH3:16])([CH2:5][N:6]1[N:10]=[C:9]2[CH:11]=[CH:12][C:13]([Br:15])=[CH:14][C:8]2=[N:7]1)[C:3]#[N:4].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[S:24])=[CH:21][CH:20]=1>>[Br:15][C:13]1[CH:12]=[CH:11][C:9]2=[N:10][N:6]([CH2:5][C:2]([NH:1][C:23](=[S:24])[C:22]3[CH:21]=[CH:20][C:19]([C:18]([F:17])([F:28])[F:29])=[CH:27][CH:26]=3)([C:3]#[N:4])[CH3:16])[N:7]=[C:8]2[CH:14]=1
Reactant: FC(F)(F)c1ccc(C(=S)Cl)cc1
Reactant: CC(N)(C#N)Cn1nc2ccc(Br)cc2n1
Product: CC(C#N)(Cn1nc2ccc(Br)cc2n1)NC(=S)c1ccc(C(F)(F)F)cc1

Procedure:
Using a procedure similar to that described in Example 1, except using 2-amino-3-(5-bromo-2H-benzotriazol-2-yl)-2-methylpropionitrile, described in Example 25, and 4-trifluoromethylthiobenzoyl chloride, the title compound was isolated as a white solid (0.45 g, 87%). Rf=0.65 (1:1 EA/heptane). MS (ES): M/Z [M+H]=484. 1H NMR: (400 MHz, DMSO-d6): 1.74 (s, 3H), 5.36-5.53 (m, 2H), 7.58 (dd, J=9.1, 1.8 Hz, 1H), 7.84-7.92 (m, 4H), 7.95 (dd, J=9.1, 0.5 Hz, 1H), 8.29 (dd, J=1.7, 0.6 Hz, 1H) and 9.00 (s, 1H). 19F NMR (376 MHz, DMSO-d6): −41.93 (s, 3F).
Reaction SMILES: [C:1]([CH2:4][N:5]([S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:26])[CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])(O)=[O:2].[C:27]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])(=[O:30])[NH:28][NH2:29].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C>[C:32]([O:31][C:27]([NH:28][NH:29][C:1](=[O:2])[CH2:4][N:5]([S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[C:21]([Cl:26])[CH:22]=2)[CH:17]=1)(=[O:15])=[O:14])[CH2:6][CH:7]=[CH:8][C:9]([O:11][CH3:12])=[O:10])=[O:30])([CH3:35])([CH3:34])[CH3:33]
Reactant: COC(=O)C=CCN(CC(=O)O)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Reactant: CC(C)(C)OC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: COC(=O)C=CCN(CC(=O)NNC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2cc(Cl)ccc2c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 102.5 %

Procedure:
A solution of methyl 4-[carboxymethyl(6-chloro-naphthalene-2-sulfonyl)amino]-2-butenate (796 mg), tert-butyl carbazate (265 mg) and HOBt (367 mg) in acetonitrile (20 ml) was combined with WSC (575 mg) and stirred at room temperature for 15 hours. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate, washed with water and brine, dried, concentrated to obtain a residue, which was then crystallized from ether-hexane to obtain methyl 4-[[2-(N′-tert-butoxycarbonylhydrazino)-2-oxoethyl](6-chloro-naphthalene-2-sulfonyl)amino]-2-butenoate (1.05 g) as colorless crystals.
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13]Br)=[O:6])#[N:2].C(=O)([O-])[O-].[Cs+].[Cs+].[SH:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1>CC(C)=O>[C:1]([CH2:3][NH:4][C:5]([C@@H:7]1[CH2:12][CH2:11][CH2:10][CH2:9][C@H:8]1[CH2:13][S:21][C:22]1[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=1)=[O:6])#[N:2]
Reactant: Oc1ccc(S)cc1
Reactant: N#CCNC(=O)[C@@H]1CCCC[C@H]1CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCNC(=O)[C@@H]1CCCC[C@H]1CSc1ccc(O)cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
trans-2-Bromomethyl-cyclohexanecarboxylic acid cyanomethylamide (261 mg) and cesium carbonate (327 mg) were weighed into a 15 mL vial fitted with a stir bar and a vent cap. Acetone (3 mL) and 4-mercaptophenol (139 mg) were added. The reaction mixture was stirred at 50° C. overnight and then diluted with hot acetone (7 mL) and filtered through Celite™. The Celite™ was washed with hot acetone. The filtrate and wash were combined and the solvent was removed on a rotary evaporator. Chromatography of the crude product on a silica gel (using 3:1 dichloromethane:acetone as the eluent) provided the title compound as a beige solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>CO.[Cl-].[Na+].O>[OH:3][CH:1]([C:4]1[CH:5]=[C:6]([CH:24]=[CH:25][CH:26]=1)[O:7][C:8]1[C:13]([O:14][CH2:15][CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)=[CH:12][CH:11]=[CH:10][N:9]=1)[CH3:2]
Reactant: CC(=O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Agent: [BH4-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(O)c1cccc(Oc2ncccc2OCCCc2ccncc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
2-(3-Acetylphenoxy)-3-[3-(pyridin-4-yl)propoxy]pyridine (0.20 g, 0.3 mmol) obtained in Example 60 is dissolved in methanol (10 ml), and thereto is added sodium borohydride (0.50 g, 13 mmol), and the mixture is stirred at room temperature for 10 minutes. To the reaction solution is added a saturated brine (50 ml), and the mixture is extracted with ethyl acetate (100 ml). The organic layer is washed with a saturated brine (50 ml×2), dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent: chloroform/methanol) to give 2-[3-(1-hydroxyethyl)phenoxy]-3-[3-(pyridin-4-yl) propoxy]pyridine, which is further treated with fumaric acid to give the title compound (0.06 g), m.p. 93-97° C. (recrystallized from ethanol/diethyl ether).
Reaction SMILES: [CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12](Cl)[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3].CCOCC.[CH3:23][C:24]([CH3:28])([OH:27])[CH2:25][CH3:26]>>[CH3:1][S:2]([O:5][C:6]1[CH:7]=[CH:8][C:9]2[O:13][CH:12]([O:27][C:24]([CH3:28])([CH3:23])[CH2:25][CH3:26])[C:11]([CH3:16])([CH3:15])[C:10]=2[CH:17]=1)(=[O:4])=[O:3]
Reactant: CCC(C)(C)O
Reactant: CC1(C)c2cc(OS(C)(=O)=O)ccc2OC1Cl
Solvent: CCOCC
Product: CCC(C)(C)OC1Oc2ccc(OS(C)(=O)=O)cc2C1(C)C
Yield: 43 %

Procedure:
A solution of 2-chloro-2,3-dihydro-3,3-dimethylbenzofuran-5-yl methanesulphonate (14g, 0.05 mole) in 1,1-dimethylpropanol (50 ml) was boiled under reflux for 41/2 hours. After cooling, the solution was taken into ether (250 ml), washed with dilute aqueous sodium hydroxide solution (twice) and with water (twice) and dried over sodium sulphate. The solvent was then distilled off under reduced pressure to give 2,3-dihydro-3,3-dimethyl-2-(1,1-dimethylpropoxy)benzofuran-5-yl methanesulphonate (7g, 43% yield) as a pale yellow oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:8]1[C:16]2[C:11](=[C:12]([CH2:17][N:18]3[CH2:23][CH2:22][CH:21]([C:24]4[CH:25]=[C:26]([NH:30][C:31](=[O:35])[CH:32]([CH3:34])[CH3:33])[CH:27]=[CH:28][CH:29]=4)[CH2:20][CH2:19]3)[CH:13]=[CH:14][CH:15]=2)[CH:10]=[CH:9]1>>[CH3:34][CH:32]([CH3:33])[C:31]([NH:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([CH:21]2[CH2:22][CH2:23][N:18]([CH2:17][C:12]3[CH:13]=[CH:14][CH:15]=[C:16]4[C:11]=3[CH:10]=[CH:9][N:8]4[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[CH2:19][CH2:20]2)[CH:25]=1)=[O:35]
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4[nH]ccc34)CC2)c1
Reactant: Ic1ccccn1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3cccc4c3ccn4-c3ccccn3)CC2)c1

Procedure:
Prepared by Procedure C and Scheme Q1, with CuBr in place of Cu, using 2-iodopyridine and N-{3-[1-(1H-indol-4-ylmethyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 453.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([OH:32])[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)[C@@H:13]([CH2:33][C:34]([O:36]C)=[O:35])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.O.CO.ClCCl.CO>[F:1][C:2]1[CH:3]=[C:4]([S:8][CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C@@H:14]([CH2:17][CH2:18][CH:19]([OH:32])[C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([O:30][CH3:31])[CH:28]=4)[N:23]=[CH:22][CH:21]=3)[C@@H:13]([CH2:33][C:34]([OH:36])=[O:35])[CH2:12]2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C[C@H]1CN(CCSc2cccc(F)c2)CC[C@H]1CCC(O)c1ccnc2ccc(OC)cc12
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: COc1ccc2nccc(C(O)CC[C@@H]3CCN(CCSc4cccc(F)c4)C[C@@H]3CC(=O)O)c2c1
Temperature: 60 °C
Reaction time: 20 h
Yield: 86.9 %

Procedure:
A solution of 1.3 g of methyl (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetate in 20 cm3 of dioxane, to which 2 cm3 of 5N aqueous sodium hydroxide solution had been added, was heated with stirring for 20 hours at a temperature in the region of 60° C. The reaction mixture was evaporated under reduced pressure (5 kPa) at a temperature in the region of 40° C. and then the residue obtained was taken up in 30 cm3 of water and 5 cm3 of methanol, acidified with citric acid. The solvents were evaporated under the same conditions as above and then the residue obtained was taken up in 70 cm3 of a dichloromethane/methanol (80/20 by volume) mixture. The citric acid crystals were filtered off; the filtrate was evaporated as above and the evaporation residue was taken up in 30 cm3 of diethyl ether, filtered off, and dried in the air. 1.1 g of (3R,4R)-1-[2-(3-fluorophenylthio)ethyl]-4-[3-(R,S)-hydroxy-3-(6-methoxyquinolin-4-yl)propyl]piperidine-3-acetic acid were obtained in the form of a solid with a cream color.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:25])([CH3:24])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:34](=[O:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=[N:30]3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.O1CCCC1.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[CH:10]=[CH:11][C:12]([CH2:15][CH2:16][C@H:17]3[O:26][C@H:20]4[O:21][C:22]([CH3:24])([CH3:25])[O:23][C@H:19]4[C@H:18]3[CH2:27][CH2:28][N:29]3[C:34](=[O:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=[N:30]3)=[CH:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2ccc(/C=C/[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(-c2ccc(CC[C@H]3O[C@H]4OC(C)(C)O[C@H]4[C@H]3CCn3nnc4ccccc4c3=O)cc2)cn1

Procedure:
To the solution of the compound obtained from step b above (8.5 g) in a solvent mixture of tetrahydrofuran:methanol (60 mL:40 mL), 10% palladium on charcoal (4 g) was added at room temperature, and the reaction mixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixture was filtered through a celite pad and the residue was washed with methanol. The filtrate was concentrated to afford the title compound (8.1 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:22]([O:24][CH2:25][CH2:26][N:27]1[C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=2[N:29]=[C:28]1[N:36]1[CH2:42][CH2:41][CH2:40][N:39]([CH2:43][CH2:44][C:45]2([C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[CH2:49][CH2:48][NH:47][CH2:46]2)[CH2:38][CH2:37]1)[CH3:23]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([S:17]([CH3:20])(=[O:19])=[O:18])=[N:15][N:14]=[N:13]2)=[CH:8][C:4]=1[C:5]([N:47]1[CH2:48][CH2:49][C:45]([CH2:44][CH2:43][N:39]2[CH2:40][CH2:41][CH2:42][N:36]([C:28]3[N:27]([CH2:26][CH2:25][O:24][CH2:22][CH3:23])[C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[N:29]=3)[CH2:37][CH2:38]2)([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:46]1)=[O:7]
Reactant: COc1ccc(-n2nnnc2S(C)(=O)=O)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(-n5nnnc5S(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-(5-methylsulfonyl-1H-tetrazol-1-yl)benzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[CH:11][C:10](C3C=CC=CC=3)=[CH:9][C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:44][CH2:43][C:35]4([CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:23])([F:22])[F:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1N=C(N2CCC3(CN(C(OC(C)(C)C)=O)[C@H](C(OCC)=O)C3)CC2)C=C(O[C@H]([C:80]2[C:85](Br)=[CH:84][CH:83]=[CH:82][C:81]=2Br)C(F)(F)F)N=1>>[C:1]1([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:80]3[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=3)[C:8]=2[C@@H:19]([O:24][C:25]2[N:30]=[C:29]([NH2:31])[N:28]=[C:27]([N:32]3[CH2:44][CH2:43][C:35]4([CH2:39][NH:38][C@H:37]([C:40]([OH:42])=[O:41])[CH2:36]4)[CH2:34][CH2:33]3)[CH:26]=2)[C:20]([F:21])([F:23])[F:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4c(Br)cccc4Br)C(F)(F)F)nc(N)n3)CC2)CN1C(=O)OC(C)(C)C
Reactant: Nc1nc(O[C@H](c2cc(-c3ccccc3)ccc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1
Product: Nc1nc(O[C@H](c2c(-c3ccccc3)cccc2-c2ccccc2)C(F)(F)F)cc(N2CCC3(CC2)CN[C@H](C(=O)O)C3)n1

Procedure:
The title compound was prepared as described for (S)-8-(6-((R)-1-([1,1′:4′,1″-terphenyl]-2′-yl)-2,2,2-trifluoroethoxy)-2-aminopyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 51a) starting with (S)-2-tert-butyl 3-ethyl 8-(2-amino-6-((R)-1-(2,6-dibromophenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-2,3-dicarboxylate (product of Step 4, example 63ao).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([OH:13])=O)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C(Cl)(=O)C([Cl:17])=O>ClCCl>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([C:11]([Cl:17])=[O:13])[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)[C@H]1CC[C@@H](C(=O)O)CC1
Solvent: ClCCl
Product: CC(C)(C)[C@H]1CC[C@@H](C(=O)Cl)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.0 g (10.85 mmol) cis-4-tert-Butylcyclohexanecarboxylic acid are dissolved in 50 ml dichloromethane, 1.65 g (13.02 mmol) ethanedioyl dichloride are added and the solution is stirred at room temperature for one hour. The mixture is then stirred at reflux for two hours and, after cooling down to room temperature, evaporated to dryness in vacuo. The residue is then dissolved in toluene two times and again evaporated to dryness in vacuo. The residue is used in the next step without further purification.
Reaction SMILES: [N+:1]([C:4]1[C:5]([CH:11]=[CH2:12])=[C:6]([CH:8]=[CH:9][CH:10]=1)[NH2:7])([O-:3])=[O:2].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH2:13]([N:7]([CH2:11][C:5]1[CH:6]=[CH:8][CH:9]=[CH:10][CH:4]=1)[C:6]1[CH:8]=[CH:9][CH:10]=[C:4]([N+:1]([O-:3])=[O:2])[C:5]=1[CH:11]=[CH2:12])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: C=Cc1c(N)cccc1[N+](=O)[O-]
Product: C=Cc1c(N(Cc2ccccc2)Cc2ccccc2)cccc1[N+](=O)[O-]

Procedure:
The product from Example 44B and benzyl bromide were processed as described in Example 2A to provide the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][NH2:10])=[CH:4][CH:3]=1.[Cl:11][CH2:12][C:13](Cl)=[O:14]>C1COCC1>[Cl:11][CH2:12][C:13]([NH:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)=[O:14]
Reactant: NCCc1ccc(F)cc1
Reactant: O=C(Cl)CCl
Solvent: C1CCOC1
Product: O=C(CCl)NCCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.05 h

Procedure:
To a solution of 4-fluorophenylethylamine (1.0 equivalent) in dried THF was added Hunig's base (DIEA)(1 equivalent). The mixture was then stirred for 3 minutes at 0° C. Thereafter, a solution of chloroacetylchloride (1.0 equivalent) in THF was added via a syringe over a period of 7 minutes. The reaction mixture was then stirred at room temperature for 1 hour after which time the reaction mixture was condensed in vacuo, quenched with water, extracted with ethyl acetate (3×) and dried over Na2SO4. After concentration in vacuo, compound 1 shown above was obtained, which was carried on further without further purification. LC/MS=M+H 216.1 at 2.18 minutes.
Reaction SMILES: [CH2:1]([O:3][P:4](Cl)([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2].Cl.[NH2:18][CH:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1=[O:32].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][P:4]([NH:18][C@H:19]1[CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:20]1=[O:32])([CH2:6][CH2:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)CN1CCCCC(N)C1=O
Reactant: CCOP(=O)(Cl)CCCCc1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCCC[C@H](NP(=O)(CCCCc2ccccc2)OCC)C1=O
Reaction time: 0.33 h

Procedure:
A mixture of ethoxy(4-phenylbutyl)phosphinyl chloride [4.4 mmole; prepared as set forth in Example 1(f)], dry tetrahydrofuran (10 ml.), and 3-amino-2-oxo-hexahydro-1H-azepine-1-acetic acid, ethyl ester, monohydrochloride (1.0 g., 4.0 mmole) at 0° (ice bath) in an argon atmosphere is treated dropwise with triethylamine (1.7 ml., 3.0 eq.) in tetrahydrofuran (5 ml.) over 2 minutes. After 20 minutes, the ice bath is removed and the reaction mixture is stirred for an additional 1.5 hours. The reaction mixture is diluted with ethyl acetate and washed successively with saturated sodium bicarbonate, 5% potassium bisulfate, and brine, dried (MgSO4) and evaporated. The residue (2.1 g.) is chromatographed on silica (65 g.) eluting with ethyl acetate then acetone to give 1.0 g. of (S)-hexahydro-3-[[ethoxy(4-phenylbutyl)phosphinyl]amino]-2-oxo-1H-azepine-1-acetic acid, ethyl ester as an oil after evaporation. TLC (ethyl acetate) single spot at Rf =0.1.
Reaction SMILES: Cl.N1C=C[CH:5]=[CH:4][CH:3]=1.C(OCC)(OCC)(OCC)CC.[NH2:20][C:21]1[C:22]2[N:23]([N:38]=[N:39][N:40]=2)[C:24]([CH3:37])=[C:25]([CH3:36])[C:26]=1[NH:27][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>C1(C)C=CC=CC=1>[CH2:4]([C:5]1[N:27]([CH2:28][CH2:29][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])[C:26]2[C:25]([CH3:36])=[C:24]([CH3:37])[N:23]3[N:38]=[N:39][N:40]=[C:22]3[C:21]=2[N:20]=1)[CH3:3]
Reactant: CCOC(=O)CCCNc1c(C)c(C)n2nnnc2c1N
Reactant: c1ccncc1
Agent: CCOC(CC)(OCC)OCC
Agent: Cl
Solvent: Cc1ccccc1
Product: CCOC(=O)CCCn1c(CC)nc2c1c(C)c(C)n1nnnc21
Yield: 246.1 %

Procedure:
For Examples 42 and 43, pyridine hydrochloride (668 mg, 5.78 mmol) and triethyl orthopropionate (3.4 mL, 17 mmol) were added to a solution of ethyl 4-[(8-amino-5,6-dimethyltetraazolo[1,5-a]pyridin-7-yl)amino]butanoate (4.5 g, 15 mmol) in toluene (100 mL). The reaction and work-up procedure were as described for Examples 40 and 41. The crude product was recrystallized from ethyl acetate:hexane, isolated by filtration, washed with ethyl acetate:hexane, and dried under high vacuum to provide 4.7 g of ethyl 4-(8-ethyl-5,6-dimethyl-7H-imidazo[4,5-c]tetraazolo[1,5-a]pyridin-7-yl)butanoate as off-white crystals.
Reaction SMILES: [CH3:1][N:2]([CH3:15])[C:3]([CH:5]1[S:10][C:9]2[O:11][CH:12]=[CH:13][C:8]=2[C:7](=O)[CH2:6]1)=O>O1CCCC1>[CH3:15][N:2]([CH2:3][CH:5]1[S:10][C:9]2[O:11][CH:12]=[CH:13][C:8]=2[CH2:7][CH2:6]1)[CH3:1]
Reactant: CN(C)C(=O)C1CC(=O)c2ccoc2S1
Solvent: C1CCOC1
Product: CN(C)CC1CCc2ccoc2S1
Temperature: 25 °C

Procedure:
To a stirring, refluxing solution of N,N-dimethyl-4-oxo-5,6-dihydro-4H-furano[2,3-b]thiopyran-6-carboxamide (7.1 g, 0.0314 mol) in tetrahydrofuran (150 ml) was added dropwise borane-dimethyl sulfide complex (9.4 ml, 0.014 mol). The reaction was then stirred at reflux for 3 hr. when 6NHCl (25 ml) was added slowly and the reaction was heated at reflux for a further 1/2 hr. Most of the tetrahydrofuran was removed in vacuo and the residue was diluted with 6N HCl (50 ml) and heated again for 1/2 hr. The reaction was cooled to room temperature and water (100 ml) was added. The reaction was extracted once with ether (50 ml) and then basified with 10N NaOH (75 ml). The product was extracted with ethyl acetate (4×50 ml portions). The ethyl acetate solution was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the product.