Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:40])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=5[CH:38]=[O:39])[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(N)(=O)(=O)[OH:42].Cl([O-])=O.[Na+]>C(O)(=O)C.O>[C:38]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[C:31]1[C:19]2[CH2:18][C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:40])[CH2:9][CH2:10]3)[C:27]3[C:22]([O:21][C:20]=2[CH:28]=[CH:29][CH:30]=1)=[N:23][CH:24]=[CH:25][CH:26]=3)([OH:42])=[O:39]
Reactant: NS(=O)(=O)O
Reactant: O=Cc1ccccc1-c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Agent: [Na+]
Agent: [O-][Cl+][O-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccccc1-c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28.8 %

Procedure:
To a solution of the product of step 1 (270 mg) in acetic acid (2.2 ml) and water (0.5 ml) were added amidosulfuric acid (67 mg) and sodium chlorite (68 mg) in water (0.1 ml), and the mixture was stirred at room temperature for 15 minutes. The reaction mixture was distilled off under reduced pressure into half volume. The residue was neutralized with 1N sodium hydroxide. The precipitation was filtered and washed with water to give the titled compound (80 mg).
Reaction SMILES: [N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[C:8]#[N:9])[CH:5]=[CH:4][N:3]=[CH:2]1.N>C(O)C.[Ni]>[N:1]1([C:6]2[CH:13]=[CH:12][CH:11]=[CH:10][C:7]=2[CH2:8][NH2:9])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: N#Cc1ccccc1-n1ccnc1
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCc1ccccc1-n1ccnc1

Procedure:
A solution of 2-imidazol-1-yl-benzonitrile (200 mg, 1.2 mmol) in ethanol saturated with ammonia (20 ml) was stirred in the presence of Raney nickel (50% slurry in water, washed with ethanol, catalytic amount) under a hydrogen atmosphere for 4 h. The reaction mixture was filtered over celite and concentrated to give 2-Imidazol-1-yl-benzylamine; 1H NMR (CDCl3, 400 MHz) δ7.69 (bs, 1H), 7.57 (m, 1H), 7.47 (m, 1H), 7.38 (m, 1H), 7.27 (m, 1H), 7.22 (bs, 1H), 7.16 (m, 1H) 3.73 (s, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1csc(-c2cccnc2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccnc4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 83.7 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(3-pyridyl)thiazole (316 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatograpy, and ethyl 3-[4-phenyl-1-[4-[2-(3-pyridyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (657 mg, yield: 84%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[CH3:24][N:25]([CH3:33])[C:26](=[O:32])[CH2:27][CH2:28][C:29](O)=[O:30]>>[CH3:24][N:25]([CH3:33])[C:26](=[O:32])[CH2:27][CH2:28][C:29]([O:23][C@@:9]1([C:14]#[C:15][C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11][CH2:12][C@@H:13]2[C@H:8]1[CH2:7][CH2:6][N:5]2[C:3]([O:2][CH3:1])=[O:4])=[O:30]
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Reactant: CN(C)C(=O)CCC(=O)O
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CCC(=O)N(C)C

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and N,N-dimethylsuccinamic acid to yield (3aR,4S,7aR)-methyl 4-(4-(dimethylamino)-4-oxobutanoyloxy)-4-(m-tolylethynyl)octahydro-1H-indole-1-carboxylate. MS [2M+NH4]=898; RT=1.15 min; UPLC Method I
Reaction SMILES: [C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17](B(O)O)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.Br[C:33]1[S:37][C:36]([C:38]([O:40]C)=[O:39])=[CH:35][CH:34]=1>>[C:1]12([C:11]3[CH:20]=[C:19]4[C:14]([CH:15]=[CH:16][C:17]([C:33]5[S:37][C:36]([C:38]([OH:40])=[O:39])=[CH:35][CH:34]=5)=[CH:18]4)=[CH:13][C:12]=3[O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: OB(O)c1ccc2cc(OCc3ccccc3)c(C34CC5CC(CC(C5)C3)C4)cc2c1
Reactant: COC(=O)c1ccc(Br)s1
Product: O=C(O)c1ccc(-c2ccc3cc(OCc4ccccc4)c(C45CC6CC(CC(C6)C4)C5)cc3c2)s1
Yield: 67.4 %

Procedure:
Following the procedure of Example 1(c), but reacting 1.5 g (3.6 mmol) of 7-(1-adamantyl)-6-benzyloxy-2-naphthylboronic acid with 400 mg (1.8 mmol) of methyl 5-bromo-2-thiophenecarboxylate, 600 mg (65%) of the expected compound were obtained, which compound had a melting point of 170°-1° C.
Reaction SMILES: [CH2:1]([C:4]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[NH:9][CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3].[CH2:35]([O:37][C:38]([CH2:40][C:41](O)=[O:42])=[O:39])[CH3:36]>>[CH2:1]([C:4]1[N:16]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[C:30]3[NH:34][N:33]=[N:32][N:31]=3)=[CH:20][CH:19]=2)[C:7]2[CH:8]([C:12]([O:14][CH3:15])=[O:13])[N:9]([C:41](=[O:42])[CH2:40][C:38]([O:37][CH2:35][CH3:36])=[O:39])[CH2:10][CH2:11][C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)NCC2
Reactant: CCOC(=O)CC(=O)O
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnn[nH]3)cc1)C(C(=O)OC)N(C(=O)CC(=O)OCC)CC2

Procedure:
Methyl 2-n-propyl-3-{2'-(1H-tetrazol-5-yl)-biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate and ethoxycarbonylacetic acid are treated in the same manner as in Example 8-(1) to give methyl 2-n-propyl-5-ethoxycarbonylacetyl-3-(2'-(1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]-pyridine-4-carboxylate.
Reaction SMILES: [CH:1]1([C@@H:7]2[CH2:12][NH:11][CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]1[C:30]([N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)=[C:31]([CH:34]=[CH:35][CH:36]=1)[CH:32]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(O)(=O)C.CO>[CH:1]1([C@@H:7]2[CH2:12][N:11]([CH2:32][C:31]3[CH:34]=[CH:35][CH:36]=[C:29]([F:28])[C:30]=3[N:37]3[CH2:38][CH2:39][O:40][CH2:41][CH2:42]3)[CH2:10][C:9](=[O:13])[N:8]2[C:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[S:16][C:15]=2[C:25]([OH:27])=[O:26])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=Cc1cccc(F)c1N1CCOCC1
Reactant: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CNC[C@H]1C1CCCCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: O=C(O)c1sc(-c2ccccc2)cc1N1C(=O)CN(Cc2cccc(F)c2N2CCOCC2)C[C@H]1C1CCCCC1
Temperature: 75 °C
Reaction time: 3 h
Yield: 12 %

Procedure:
A solution of 3-((R)-2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylic acid (50.0 mg, 0.13 mmol, 1.0 equiv) and 3-fluoro-2-morpholinobenzaldehyde (108.8 mg, 0.52 mmol, 4.0 equiv) in acetic acid (0.2 mL) and methanol (0.5 mL) was stirred at room temperature for 60 minutes. Then sodium triacetoxyborohydride (110.2 mg, 0.52 mmol, 4.0 equiv) was added to the mixture and the resulting mixture was stirred at 75° C. for 3 hours. The solvent was removed by Genevac and the residue was dissolved in EtOAc (6 mL). The organic phase was washed by brine (3 mL), dried over Na2SO4 and concentrated. The residue was purified by HPLC (0.1% NH4OH) to afford the product (9 mg, 12%). MS: 577.2 [M−H+].
Reaction SMILES: [OH-].[K+].[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:52])=[N:17][C:18]([CH3:51])=[C:19]([C:35]2[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][C:44]3[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=3)=[CH:37][CH:36]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[O:31][N:30]=[C:29]([CH:32]([CH3:34])[CH3:33])[N:28]=2)[CH2:23][CH2:22]1)[C:9]([O:11]C(C)C)=[O:10])([CH3:6])([CH3:5])[CH3:4].Cl>C(O)C>[C:3]([O:7][C@@H:8]([C:15]1[C:16]([CH3:52])=[N:17][C:18]([CH3:51])=[C:19]([C:35]2[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][C:44]3[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=3)=[CH:39][CH:40]=2)[C:20]=1[N:21]1[CH2:26][CH2:25][CH:24]([C:27]2[O:31][N:30]=[C:29]([CH:32]([CH3:33])[CH3:34])[N:28]=2)[CH2:23][CH2:22]1)[C:9]([OH:11])=[O:10])([CH3:6])([CH3:4])[CH3:5]
Reactant: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)OC(C)C)c(N2CCC(c3nc(C(C)C)no3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1nc(C)c([C@H](OC(C)(C)C)C(=O)O)c(N2CCC(c3nc(C(C)C)no3)CC2)c1-c1ccc(OCCc2ccc(F)cc2)cc1
Temperature: 90 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
The potassium hydroxide (20.4 mg, 0.36 mmol) was added to a solution (S)-isopropyl 2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetate (25 mg, 0.036 mmol) in ethanol (1 mL) and stirred for 3 h at 90° C. The reaction mixture was neutralized with 1N HCl solution, extracted with EtOAc, and the organic layer was washed with brine, and dried (MgSO4). The crude material was purified by prep HPLC to afford (S)-2-(tert-butoxy)-2-(5-(4-(4-fluorophenethoxy)phenyl)-4-(4-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-1-yl)-2,6-dimethylpyridin-3-yl)acetic acid 11 mg (47%) as a mixture of diastereomers. 1H NMR (500 MHz, DMSO-d6) δ 7.41-7.39 (m, 2H), 7.23-7.22 (m, 1H), 7.17-7.13 (m, 2H), 7.02-7.01 (m, 2H), 6.96-6.94/6.86-6.84/6.80-6.77 (series m, 1H), 5.73 (br. s, 1H), 4.24 (t, J=6.6 Hz, 2H), 3.67-3.65 (m, 1H), 3.07 (t, J=6.6 Hz, 2H), 3.03-2.97 (m, 1H), 2.72-2.67 (m, 2H), 2.58-2.56 (m, 1H), 2.46 (s, 3H), 2.04 (s, 3H), 1.87-1.75 (m, 4H), 1.67-1.62 (m, 1H), 1.23 (d, J=6.6 Hz, 6H), 1.12 (s, 9H). UPLC (M+H)=645.4.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[C:12]([OH:19])[CH:11]=2)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])O.[K+].Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>CN(C)C=O>[C:1]([C:5]1[CH:6]=[C:7]([CH:20]=[C:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[C:22]=1[OH:23])[C:8]1[O:9][C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[CH:14][CH:13]=[C:12]([O:19][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39])[CH:11]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1cc(-c2cc(=O)c3ccc(O)cc3o2)cc(C(C)(C)C)c1O
Reactant: CCCCCCBr
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCCCOc1ccc2c(=O)cc(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc2c1
Reaction time: 2 h

Procedure:
0.183 g (0.5 mmol) of the compound of Example 1 and 0.25 g (2.5 mmol) of potassium hydrogen carbonate are stirred for a few moments in 10 ml of dimethylformamide at 110° C. under nitrogen until they have completely dissolved. 0.7 ml (5 mmol) of [1-bromo-n-hexane] are then added and the reaction is continued under the same conditions for two hours.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38]CC2C=CC=CC=2)=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4].C(N(CC)CC)C.[C:57]([SiH:61]([CH3:63])[CH3:62])([CH3:60])([CH3:59])[CH3:58]>ClC(Cl)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([CH3:49])([CH3:48])[C@H:13]3[C@:26]([CH3:29])([CH2:27][CH:28]=2)[C@@H:25]2[C@:16]([CH3:47])([C@@:17]4([CH3:46])[C@H:22]([CH2:23][CH2:24]2)[C@H:21]2[C@H:30]([C:33]([CH3:35])=[CH2:34])[CH2:31][CH2:32][C@:20]2([C:36]([O:38][Si:61]([C:57]([CH3:60])([CH3:59])[CH3:58])([CH3:63])[CH3:62])=[O:37])[CH2:19][CH2:18]4)[CH2:15][CH2:14]3)=[CH:7][CH:6]=1)=[O:4]
Reactant: C=C(C)[C@@H]1CC[C@]2(C(=O)OCc3ccccc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Reactant: C[SiH](C)C(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC(Cl)Cl
Product: C=C(C)[C@@H]1CC[C@]2(C(=O)O[Si](C)(C)C(C)(C)C)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 60 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
To a solution of (1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-benzyl 9-(4-(methoxycarbonyl)phenyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysene-3a-carboxylate (3.82 g, 5.76 mmol) in dichloroethane (100 mL) was added triethylamine (1.285 mL, 9.22 mmol), tert-butyldimethylsilane (1.912 mL, 11.52 mmol), and palladium(II) acetate (0.647 g, 2.88 mmol). The mixture was flushed with N2 and heated to 60° C. After 2 h, the reaction was cooled to rt, filtered through a pad of celite and silica gel to remove the solids which were washed with 25% EtOAc in hexanes. The filtrate was concentrated under reduced pressure and treated with acetic acid (25 mL), THF (10 mL) and water (3 mL). After stirring for 1 h the solids formed were collected by filtration and washed with water to give the title compound (3.62 g, 5.27 mmol, 91% yield) as a white solid. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.94 (d, J=8.28 Hz, 2H), 7.21 (d, J=8.28 Hz, 2H), 5.30 (dd, J=6.15, 1.63 Hz, 1H), 4.75 (d, J=1.76 Hz, 1H), 4.62 (s, 1H), 3.92 (s, 4H), 3.08 (td, J=10.92, 4.27 Hz, 1H), 2.35-2.22 (m, 2H), 2.17-2.06 (m, 1H), 2.02-1.84 (m, 2H), 1.71 (s, 3H), 1.01 (s, 6H), 0.99 (br. s., 3H), 0.98 (s, 9H), 0.94 (s, 6H), 1.78-0.90 (m, 16H), 0.32-0.28 (m, 6H).
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5])#[N:2].[H-].[Na+].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1.O>CN(C=O)C>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)([O:8][S:23]([C:20]1[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=1)(=[O:25])=[O:24])[C:4]([F:7])([F:5])[F:6])#[N:2]
Reactant: N#CC(O)(c1ccccc1)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC(C#N)(c2ccccc2)C(F)(F)F)cc1
Reaction time: 8 h
Yield: 70.9 %

Procedure:
5.2 g (25 mmol) of 1-cyano-2,2,2-trifluoro-1-phenyl-ethanol were dissolved in 50 ml of DMF, and 0.9 g (30 mmol) of sodium hydride (80% strength dispersion in mineral oil) was added. 5.5 g (29 mmol) of toluene-4-sulfonyl chloride were added in portions to the virtually clear solution after about 1 hour. The mixture was stirred for 8 hours, allowed to stand overnight and then poured into water. The oily liquid which separated out solidified on cooling. The solid was filtered off with suction and dried. 6.3 g of 1-cyano-1-phenyl-1-(toluene-4-sulfonyloxy)-2,2,2-trifluoroethane were obtained (colorless crystals, m.p.: 70° C. [from ligroin]).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[C:12]1[CH:13]=[CH:14][C:15]([CH2:23][OH:24])=[N:16][C:17]=1[O:18][CH2:19][CH:20]([CH3:22])[CH3:21].Cl[C:26]1[N:31]=[CH:30][N:29]=[C:28]([CH:32]([CH:39]2[CH2:41][CH2:40]2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:27]=1.Cl>C1COCC1>[CH:39]1([CH:32]([C:28]2[CH:27]=[C:26]([O:24][CH2:23][C:15]3[CH:14]=[CH:13][C:12]([C:5]4[CH:6]=[C:7]([O:10][CH3:11])[CH:8]=[CH:9][C:4]=4[F:3])=[C:17]([O:18][CH2:19][CH:20]([CH3:21])[CH3:22])[N:16]=3)[N:31]=[CH:30][N:29]=2)[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH2:41][CH2:40]1
Reactant: COc1ccc(F)c(-c2ccc(CO)nc2OCC(C)C)c1
Reactant: CCOC(=O)CC(c1cc(Cl)ncn1)C1CC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1cc(OCc2ccc(-c3cc(OC)ccc3F)c(OCC(C)C)n2)ncn1)C1CC1
Temperature: 50 °C
Reaction time: 4 h
Yield: 57.7 %

Procedure:
60% Sodium hydride (34 mg) was added to a solution of (5-(2-fluoro-5-methoxyphenyl)-6-isobutoxypyridin-2-yl)methanol (200 mg) and ethyl 3-(6-chloropyrimidin-4-yl)-3-cyclopropylpropanoate (167 mg) in THF (6.0 mL) at 0° C., and the mixture was stirred at room temperature for 30 min and at 50° C. for 4 hr. 1N Hydrochloric acid was added to the reaction mixture at 0° C., and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) and silica gel column chromatography (NH, ethyl acetate/hexane) to give the title compound (198 mg) as a colorless oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:26]([O:33][C:34](=[O:39])[NH:35][CH2:36][CH2:37]Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.C1(C)C=CC=CC=1>CN(C=O)C>[C:1]([O:5][C:6](=[O:19])[NH:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:37][CH2:36][NH:35][C:34]([O:33][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:39])=[CH:16][CH:17]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCCc1ccc(O)cc1
Reactant: O=C(NCCBr)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCc1ccc(OCCNC(=O)OCc2ccccc2)cc1
Temperature: 63 °C
Reaction time: 5.5 h
Yield: 97.7 %

Procedure:
[4-(4-Hydroxyphenyl)butyl]carbamic acid tert-butyl ester (38 g, 0.143 mole), cesium carbonate (84 g, 0.257 mole), and (2-bromoethyl)carbamic acid benzyl ester 14 (59 g, 0.23 mole) were combined in DMF (200 ml). The mixture was mechanically stirred under nitrogen at 63° C. for 5.5 h, and allowed to stand at room temperature overnight. An additional amount of (2-bromoethyl)carbamic acid benzyl ester 14 (5 g, 0.019 mole) and cesium carbonate (7.1 g, 0.21 mole) were added, and the reaction was further stirred at 65° C. for 1 h. Toluene was then added, and the stirring mixture was allowed to cool to room temperature. The mixture was suction filtered through a medium sintered glass buchner funnel and washed with toluene. The solvents were removed under vacuum at 75° C. The remaining oil was washed with hexanes (2×400 mL), then dissolved in ether (500 ml) and washed with a mixture of water and brine (10:1, 4×100 mL). The remaining solution was suction filtered through a 30 g pad of silica gel and the solvent evaporated. The residue was washed with hexanes (3×400 ml), and then placed under vacuum for 2 h to afford 61.8 g of the product 15 which was used without further purification. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.54 (m, 4H), 2.56 (t, 2H), 3.20 (m, 2H), 3.50 (m, 2H), 3.98 (t, 2H), 4.75 (br s, 1H), 5.00 (br s, 1H), 5.09 (s, 2H), 6.80 (d, 2H), 7.06 (d, 2H), 7.34 (m, 5H).
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:28])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].Cl[C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41]>ClCCl.CO>[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[C:9]([C:11]1[CH:31]=[CH:30][C:14]2[N:15]([CH3:29])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:27])[NH:28][C:40]([O:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][CH3:50])=[O:41])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccn1
Reactant: CCCCCCCCOC(=O)Cl
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCCCCCCCOC(=O)NC(=N)c1ccc(NCc2nc3cc(C(=O)N(CCC(=O)OCC)c4ccccn4)ccc3n2C)cc1
Yield: 57 %

Procedure:
Prepared analogously to Example 90 from 1-methyl-2-[N-(4-amidinophenyl)aminomethyl]benzimidazol-5-yl-carboxylic acid-N-(2-pyridyl)-N-(2-ethoxycarbonylethyl)amide hydrochloride and n-octyl chloroformate. Yield: 57% of theory, C36H45N7O5 (655.8); Rf value: 0.46 (silica gel; dichloromethane/methanol=9:1); EKA mass spectrum: (M+H)+=656; (M+H+Na)++=339.7; (M+2H)++=328.7.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16](O)=[O:17])=[CH:12][CH:11]=1)=[O:8].S(Cl)([Cl:23])=O>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:20])=[C:6]([CH:19]=1)[C:7]([NH:9][C:10]1[N:15]=[CH:14][C:13]([C:16]([Cl:23])=[O:17])=[CH:12][CH:11]=1)=[O:8]
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)O)cn1
Product: Cc1ccc(F)cc1C(=O)Nc1ccc(C(=O)Cl)cn1

Procedure:
A mixture of 6.2 g of 6-[(5-fluoro-2-methyl-benzoyl)amino]pyridine-3-carboxylic acid and 23 ml of thionyl chloride is refluxed for 1 hour. An additional 12 ml of thionyl chloride is added and the mixture refluxed for 0.5 hour. The mixture is concentrated to dryness under vacuum and 30 ml of toluene added to the residue. The toluene is removed under vacuum and the process (add toluene and remove) is repeated to give 7.7 g of crude product as a solid.
Reaction SMILES: [H-].[Na+].CO.[Br:5][CH:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]([F:21])[F:20])[N:12]=[C:11]([C:22]([F:25])([F:24])[F:23])[C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:7]Br.Cl>C1COCC1>[Br:5][C:6]([C:9]1[C:14]([C:15]([O:17][CH3:18])=[O:16])=[C:13]([CH:19]([F:21])[F:20])[N:12]=[C:11]([C:22]([F:23])([F:24])[F:25])[C:10]=1[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH2:7]
Reactant: CCOC(=O)c1c(C(F)(F)F)nc(C(F)F)c(C(=O)OC)c1C(Br)CBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: C=C(Br)c1c(C(=O)OC)c(C(F)F)nc(C(F)(F)F)c1C(=O)OCC
Temperature: 5 °C
Reaction time: 2 h
Yield: 33.9 %

Procedure:
To a stirred mixture of 0.49 g (0.012 mole) of 60% sodium hydride in oil dispersion and 4 ml of anhydrous THF is added 10 ml of methanol under nitrogen. The reaction mixture is cooled with an ice bath to 5° C. then treated slowly with a solution of 3.0 g (0.0058 mole) of product of Example 128 in 2 ml of anhydrous THF, while the reaction mixture is maintained below 15° C. The mixture is stirred at 0° C. for 2 hours and poured into 180 ml of 1% hydrochloric acid then extracted three times with 50 ml of methylene chloride. The combined methylene chloride extracts are dried over magnesium sulfate and concentrated. The residue is purified by a radially-accelerated preparatory TLC using 10% ethyl acetate/cyclohexane as eluent to give 0.85 g (33%) of the desired product as a light yellow oil, nD25 1.4734.