Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([O:11]C2CCCCO2)[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)=[O:32])=[O:28].C(O)(=O)C.C1COCC1>O>[F:1][C:2]([F:44])([CH2:40][CH2:41][CH2:42][CH3:43])[C:3](=[O:39])[CH2:4][CH2:5][C@H:6]1[C@H:10]([OH:11])[CH2:9][C:8](=[O:18])[C@@H:7]1[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([O:29][CH2:30][C:31]([C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1)=[O:32])=[O:28]
Reactant: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CCCCC(F)(F)C(=O)CC[C@H]1[C@H](O)CC(=O)[C@@H]1C/C=C\CCCCCC(=O)OCC(=O)c1ccccc1
Reaction time: 8 h

Procedure:
The compound (56) (0.514 g) was dissolved in a mixed solvent (30 ml) consisting of acetic acid, THF and water (4:2:1) and the solution was kept overnight at the room temperature. The resultant mixture was worked up with the conventional procedure and the obtained crude product was subjected to silicagel column chromatography to give the titled compound (46). Yield: 0.272 g (61%).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C@@H:9]([C:12]([OH:14])=[O:13])[CH2:10][OH:11]>C(O)(=O)C>[C:1]([NH:8][C@H:9]([CH2:10][OH:11])[C:12]([OH:14])=[O:13])(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: N[C@H](CO)C(=O)O
Solvent: CC(=O)O
Product: CC(=O)N[C@H](CO)C(=O)O
Temperature: 30 °C

Procedure:
Acetic anhydride (10.79 ml) was added to a suspension of D-serine (10 grams) in acetic acid (150 ml) and stirred at 25-35° C. After completion of the reaction, acetic acid was removed by distillation followed by co-distillation with tetrahydrofuran. Isopropyl alcohol (30 ml) and methyltertiarybutylether (60 ml) was added to the obtained residue and stirred for 30 minutes. The obtained solid was filtered off and then solvent from the filtrate was distilled off completely under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:20])=[CH:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)=[CH:8][C:7]=2[N:20]=[C:21]1[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cncc(-c2ccc(NC(C)(C)C)c(N)c2)c1
Reactant: N#Cc1cccc(C=O)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C#N)c2)n3C(C)(C)C)c1
Yield: 64.8 %

Procedure:
N1-tert-Butyl-4-(5-methoxy-pyridin-3-yl)-benzene-1,2-diamine (0.630 g, 2.32 mmol) is dissolved in DMF (5 mL) and water (1 mL). To this solution is added 3-formyl-benzonitrile (0.315 g, 2.40 mmol), followed by Oxone (1.54 g, 2.50 mmol). This reaction mixture is sonicated at room temperature for 1 hour. The solvent is removed in vacuum. The residue is partitioned between EtOAc (3×10 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer is washed with brine, dried over sodium sulfate and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexane) to give 3-[1-tert-butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-benzonitrile (0.575 g, 65%) as a white solid.
Reaction SMILES: Cl.[CH2:2]([NH:4][CH2:5][C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:3].Cl[C:22]1[N:27]=[N:26][C:25]([C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1.C([O-])(O)=O.[Na+].O>CN1CCCC1=O.C(OCC)(=O)C>[CH2:14]([O:13][C:7]1[CH:8]=[CH:9][C:10]([Br:12])=[CH:11][C:6]=1[CH2:5][N:4]([C:22]1[N:27]=[N:26][C:25]([C:28]([NH2:30])=[O:29])=[CH:24][CH:23]=1)[CH2:2][CH3:3])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: NC(=O)c1ccc(Cl)nn1
Reactant: CCNCc1cc(Br)ccc1OCc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCN(Cc1cc(Br)ccc1OCc1ccccc1)c1ccc(C(N)=O)nn1
Temperature: 115 °C
Reaction time: 2 h
Yield: 84.7 %

Procedure:
A mixture of N-ethyl-N-(2-benzyloxy-5-bromobenzyl)amine hydrochloride salt (87 g), 6-chloropyridazine-3-carboxamide (35 g) and NaHCO3 (41 g) in 1-methyl-2-pyrrolidinone was heated at 115° C. for 24 hours, cooled to 20° C. and added to water (1100 ml) with vigorous stirring, maintaining the temperature below 30° C. with external cooling. Ethyl acetate (725 ml) was added and the mixture stirred at 20° C. for 2 hours. The precipitate was filtered, dried, washed with 40-60 petroleum ether and dried under vacuum at 65° C. to give 6-[N-(2-benzyloxy-5-bromobenzyl)-N-ethylamino]pyridazine-3-carboxamide (83 g, 84.7% yield), mpt. 171-172° C.
Reaction SMILES: [CH3:1][N:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=1)[CH:3]=O.[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[N:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:18]=2[CH3:24])=[CH:14][C:13]=1[C:27]([F:30])([F:29])[F:28].[OH-].[Na+].Cl[CH2:34]Cl>>[Cl:11][C:12]1[CH:26]=[CH:25][C:15]([O:16][C:17]2[N:22]=[CH:21][C:20]([N:23]=[CH:1][N:2]([CH2:3][CH3:34])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][N:6]=3)=[CH:19][C:18]=2[CH3:24])=[CH:14][C:13]=1[C:27]([F:30])([F:28])[F:29]
Reactant: Cc1cc(N)cnc1Oc1ccc(Cl)c(C(F)(F)F)c1
Reactant: CN(C=O)c1ccccn1
Reactant: ClCCl
Agent: [Na+]
Agent: [OH-]
Product: CCN(C=Nc1cnc(Oc2ccc(Cl)c(C(F)(F)F)c2)c(C)c1)c1ccccn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a 25 ml single-necked round-bottomed flask, N-methyl-N-pyridin-2-yl-formamide (0.5 ml) is solubilized in dry dichloromethane (4 ml) at ambient temperature (colourless solution). Under stirring phosphorous oxide chloride (0.4 ml) is added dropwise by syringe. Stirring at ambient temperature is continued for 1 hour. To this solution, 6-(4-Chloro-3-trifluoromethyl-phenoxy)-5-methyl-pyridin-3-ylamine (0.6 g) dissolved in 1.0 ml of dry dichloromethane is added dropwise by syringe, giving a yellow solution. Stirring is continued at an ambient temperature for 1 hour. The mixture is then poured into ice/water (pH=2, water phase). 2 M aqueous NaOH is then added to get a pH of about 11 and stirring is continued for 10 minutes. The mixture is then extracted with dichloromethane (2×50 ml). The combined organic phases are then dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this gum by flash chromatography over silica gel with hexane/ethyl acetate 1:1 (v:v) gives 0.33 g of the compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)#[N:31]>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:35]3[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[N:33][CH:34]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: CC(C)N1CCC(Oc2ccc3c(c2)cc(C(=O)N2CCC(F)(F)CC2)n3-c2ccc(C#N)nc2)CC1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 2-cyanopyridine-5-boronic acid pinacol ester. The title compound was obtained in 51% yield as yellow foam. MS (m/e): 508.4 (MH+, 100%).
Reaction SMILES: C[N:2]([CH3:13])[CH:3]=[C:4]([C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)[CH:5]=O.[C:14](#[N:18])[CH2:15]C#N.[CH3:19][O-:20].[Na+]>CO>[CH3:19][O:20][C:13]1[N:2]=[CH:3][C:4]([C:7]2[CH:8]=[CH:9][N:10]=[CH:11][CH:12]=2)=[CH:5][C:15]=1[C:14]#[N:18]
Reactant: CN(C)C=C(C=O)c1ccncc1
Reactant: N#CCC#N
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1ncc(-c2ccncc2)cc1C#N

Procedure:
A recently published abstract ["Current Abstracts of Chemistry", Vol. 74, Issue 814, Item 285573, 1979] of a Polish publication [Nantkanomirski and Kaczmarek, Polish J. Pharmacol. Pharmacy 30(5), 707-12 (1978)] shows, inter alia, the reaction of 3-dimethylamino-2-(4-pyridinyl)acrolein [same as β-(dimethylamino)-α-(4-pyridinyl)acrolein] with malononitrile in the presence of sodium methoxide in methanol to produce 2-methoxy-5-(4-pyridinyl)nicotinonitrile.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([OH:16])=O)[C:9]2=[O:17])=[CH:4][CH:3]=1.[CH:18]1[CH:19]=[CH:20][C:21]2N(O)N=N[C:22]=2[CH:23]=1.CCN=C=NCCCN(C)C.Cl.[CH3:40][O:41][C:42]1[CH:43]=[C:44]2[C:49](=[CH:50][C:51]=1[O:52][CH3:53])[N:48]=[CH:47][CH:46]=[C:45]2[O:54][C:55]1[CH:60]=[CH:59][C:58]([NH2:61])=[CH:57][C:56]=1[F:62]>CN(C=O)C>[CH2:53]([O:52][C:51]1[CH:50]=[C:49]2[C:44]([C:45]([O:54][C:55]3[CH:60]=[CH:59][C:58]([NH:61][C:14]([C:10]4[C:9](=[O:17])[N:8]([C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)[CH:13]=[CH:12][CH:11]=4)=[O:16])=[CH:57][C:56]=3[F:62])=[CH:46][CH:47]=[N:48]2)=[CH:43][C:42]=1[O:41][CH3:40])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3F)c2cc1OC
Reactant: O=C(O)c1cccn(-c2ccc(F)cc2)c1=O
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc(NC(=O)c4cccn(-c5ccc(F)cc5)c4=O)cc3F)ccnc2cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.1 %

Procedure:
To a mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid (74 mg, 0.32 mmol), HOBt (16 mg) and EDCI.HCl (65 mg, 0.34 mmol) in DMF (3 mL) was added a solution of 4-(6,7-dimethoxyquinolin-4-yloxy)-3-fluorobenzenamine (120 mg, 0.31 mmol) in DMF (3 mL) at rt, and the reaction mixture was stirred overnight at rt. It was directly purified by preparative HPLC to afford the product (46 mg, 20%) as a white TFA salt solid. 1H NMR (DMF-d7) δ 12.22 (s, 1H), 8.71 (d, 1H, J=6.0 Hz), 8.59 (d, 1H, J=7.2 Hz), 8.14-7.31 (m, 15H), 6.84 (d, 1H, J=5.5 Hz), 6.72 (t, 1H, J=7.2 Hz), 5.35 (s, 2H), 4.02 (s, 3H); MS(ESI+) m/z 606.3 (M+H)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=O)[CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8].Cl.[NH2:20][O:21][CH2:22][CH2:23][O:24][C:25]1[CH:38]=[CH:37][C:28]([CH2:29][CH:30]2[S:34][C:33](=[O:35])[NH:32][C:31]2=[O:36])=[CH:27][CH:26]=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[S:7]([C:10]1[CH:15]=[CH:14][C:13]([C:16](=[N:20][O:21][CH2:22][CH2:23][O:24][C:25]2[CH:26]=[CH:27][C:28]([CH2:29][CH:30]3[S:34][C:33](=[O:35])[NH:32][C:31]3=[O:36])=[CH:37][CH:38]=2)[CH3:17])=[CH:12][CH:11]=1)(=[O:9])=[O:8]
Reactant: NOCCOc1ccc(CC2SC(=O)NC2=O)cc1
Reactant: CC(=O)c1ccc(S(=O)(=O)c2ccccn2)cc1
Agent: Cl
Product: CC(=NOCCOc1ccc(CC2SC(=O)NC2=O)cc1)c1ccc(S(=O)(=O)c2ccccn2)cc1
Yield: 61.3 %

Procedure:
Following a procedure similar to that described in Example 40(f), 150 mg of 4'-(2-pyridylsulfonyl)acetophenone were reacted with 183 mg of 5-[4-(2-aminooxyethoxy) benzyl]thiazolidine-2,4-dione hydrochloride [prepared as described in Example 40(e)]. The reaction mixture was then concentrated by evaporation under reduced pressure, and the resulting residue was extracted with ethyl acetate. The extract was washed with water and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel, using a 2:98 by volume mixture of methanol and methylene chloride as the eluent, to give 185 mg of the title compound as a gum.
Reaction SMILES: [CH2:1]([N:8]([CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:24]([CH2:45][CH3:46])[C@@H:25]3[C@@H:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=4)[CH2:29][CH2:28][N:27]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:26]3)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:48])([CH3:47])[C:12]1=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:57](=O)([O-])[O-].[K+].[K+].CI.[Cl-].[NH4+]>C(#N)C>[CH2:1]([N:8]([CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[CH2:9][CH2:10][N:11]1[C:16]2[CH:17]=[C:18]([C:22]([N:24]([CH2:45][CH3:46])[C@@H:25]3[C@@H:30]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37][CH3:57])[CH:32]=4)[CH2:29][CH2:28][N:27]([C:38]([O:40][C:41]([CH3:44])([CH3:42])[CH3:43])=[O:39])[CH2:26]3)=[O:23])[C:19]([F:21])=[CH:20][C:15]=2[O:14][C:13]([CH3:47])([CH3:48])[C:12]1=[O:49])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(C(=O)c1cc2c(cc1F)OC(C)(C)C(=O)N2CCN(Cc1ccccc1)Cc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(O)c1
Reactant: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Agent: [NH4+]
Solvent: CI
Solvent: CC#N
Product: CCN(C(=O)c1cc2c(cc1F)OC(C)(C)C(=O)N2CCN(Cc1ccccc1)Cc1ccccc1)[C@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1c1cccc(OC)c1
Yield: 81.7 %

Procedure:
tert-Butyl (rac.)-(3R,4R)-3-[({4-[2-(dibenzylamino)ethyl]-7-fluoro-2,2-dimethyl-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-6-yl}carbonyl)(ethyl)amino]-4-(3-hydroxyphenyl)piperidine-1-carboxylate (82.5 mg) was dissolved in acetonitrile (2 ml), and thereto were added potassium carbonate (29.8 mg) and methyl iodide (13.4 μl), and the mixture was refluxed for 3 hours. The reaction solution was cooled, and thereto was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (the developing solvent: hexane/ethyl acetate=2/1) to give the title compound (68.6 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8](F)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-:15].[K+].[CH3:17]O>>[F:1][C:2]1[CH:10]=[C:9]([N+:11]([O-:13])=[O:12])[C:8]([O:15][CH3:17])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: [OH-]
Reactant: O=C(O)c1cc(F)c([N+](=O)[O-])cc1F
Reactant: CO
Agent: [K+]
Product: COc1cc(C(=O)O)c(F)cc1[N+](=O)[O-]
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 2,5-difluoro-4-nitrobenzoic acid (55 g, 291 mmol) in methanol (800 mL) at 80° C. was added a methanolic solution of potassium hydroxide (48.9 g, 873 mmol in 175 mL MeOH, pre-heated at 80° C. to dissolve) dropwise in a period of 2 h using an addition funnel. The reaction mixture was continuously stirred for 1 h after addition was completed. It was then concentrated, acidified with HCl to pH=1-2. The reaction mixture was then vigorously stirred overnight. Fine powder was filtered, washed with more water and dried to give the product as light yellow powder (55.4 g, 90%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.95 (s, 3H) 7.66 (d, J=4 Hz, 1H) 8.01 (d, J=8 Hz, 1H). [M+H] calc'd for C8H6FNO5, 216. found 216.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]=[CH:10][NH:11][C:6]2=[CH:5][C:4]=1[O:12][CH3:13].Cl[C:15]1([C:21]([O:23][CH3:24])=[O:22])[C:19](=[O:20])[CH:18]=[CH:17][S:16]1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[N:8]=[C:7]2[N:9]([C:17]3[S:16][C:15]([C:21]([O:23][CH3:24])=[O:22])=[C:19]([OH:20])[CH:18]=3)[CH:10]=[N:11][C:6]2=[CH:5][C:4]=1[O:12][CH3:13]
Reactant: COC(=O)C1(Cl)SC=CC1=O
Reactant: COc1cc2[nH]cnc2nc1OC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1sc(-n2cnc3cc(OC)c(OC)nc32)cc1O

Procedure:
In a similar manner as described for example C6, 1.50 g of the above-synthesized 5,6-dimethoxy-1H-imidazo[4,5-b]pyridine and 0.81 g of methyl 2-chloro-3-oxo-2,3-dihydrothiophene-2-carboxylate in 40 ml chloroform yield the title compounds as an isomeric mixture which was used for the next step without further purification (example B4).
Reaction SMILES: [OH:1][CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2.[Si:23](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24].N1C=CC=CC=1>CN(C)C=O>[O:1]([CH2:2][C@@:3]12[C@@H:20]3[C@H:11]([C@H:12]4[C@@:16]([CH2:18][CH2:19]3)([CH3:17])[C:15](=[O:21])[CH2:14][CH2:13]4)[CH2:10][CH2:9][C:8]1=[CH:7][C:6](=[O:22])[CH2:5][CH2:4]2)[Si:23]([C:26]([CH3:29])([CH3:28])[CH3:27])([CH3:25])[CH3:24]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@]43CO)[C@@H]1CCC2=O
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: CC(C)(C)[Si](C)(C)OC[C@]12CCC(=O)C=C1CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.25 h

Procedure:
19-Hydroxy-4-androstene-3,17-dione, t-butyldimethylsilylchloride and pyridine are mixed in dry dimethylformamide and heated on a steam bath overnight. The reaction mixture is poured onto water and stirred well for 15 minutes. The resulting solid is filtered and dissolved in methylenechloride, dried over magnesium sulfate and the solvent removed. The residue is crystallized from an acetone-hexane solution to yield 19-t-butyldimethylsiloxy-4-androstene-3,17-dione.
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:5]=1.[Li][CH2:18]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH3:18][C:12]1[Se:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:15])[F:16])=[CH:9][CH:8]=2)=[CH:14][CH:13]=1
Reactant: [Li]CCCC
Reactant: FC(F)(F)Oc1ccc(-c2ccc[se]2)cc1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CI
Solvent: CCOCC
Product: Cc1ccc(-c2ccc(OC(F)(F)F)cc2)[se]1
Temperature: -70 °C
Reaction time: 24 h

Procedure:
8.6 g (29.5 mmol) of 2-(4-trifluoromethoxyphenyl)selenophene are initially introduced in 50 ml of diethyl ether, and 25.0 ml (39.8 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −70° C. 7.4 ml (0.12 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 24 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed successively with water, 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1). The further purification is carried out by recrystallisation from n-heptane. 2-Methyl-5-(4-trifluoromethoxyphenyl)selenophene is obtained as a colourless solid (m.p. 122° C.).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH2:5][F:6])[C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:15]([O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:16]>C1CCCCC1.C(OCC)(=O)C>[C:3]([C:2]([NH:1][C:15](=[O:16])[O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:7])[CH2:5][F:6])#[N:4]
Reactant: CC(N)(C#N)CF
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: CC(C#N)(CF)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1.34 g (11.83 mmol, about 90%) of rac-2-amino-3-fluoro-2-methylpropanonitrile from Example 53A in 29 ml of THF/water (9/1) were admixed with 5.07 g (36.67 mmol) of potassium carbonate. At 0° C., 1.69 ml (11.83 mmol) of benzyl chloroformate were slowly added dropwise and the reaction mixture was stirred at RT overnight. The solvent was decanted off and the aqueous phase was twice extracted by shaking with THF and then decanting off the THF. The combined organic phases were dried over sodium sulphate, filtered and concentrated. The residue was separated by means of silica gel chromatography (eluent:cyclohexane/ethyl acetate gradient) and the product fractions were concentrated by evaporation on a rotary evaporator. 1.89 g of the target compound were obtained (66% of theory, 97% purity).
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:37])[CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:36])[CH2:21][CH2:22][NH:23][C:24]([C:26]3[NH:27][C:28]4[C:33]([CH:34]=3)=[CH:32][C:31]([Cl:35])=[CH:30][CH:29]=4)=[O:25])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1>C1COCC1.CO.O>[Cl:35][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[NH:27][C:26]([C:24]([NH:23][CH2:22][CH2:21][C:20]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([C@H:10]3[CH2:11][CH2:12][C@H:7]([CH2:6][C:5]([OH:37])=[O:4])[CH2:8][CH2:9]3)=[CH:14][CH:15]=1)=[O:36])=[O:25])=[CH:34]2
Reactant: COC(=O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C[C@H]1CC[C@H](c2ccc(NC(=O)CCNC(=O)c3cc4cc(Cl)ccc4[nH]3)cc2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
NaOH (56.5 mg, 1.4 mmol) was added to trans-[4-(4-{3-[(5-chloro-1H-indole-2-carbonyl)amino]propionylamino}phenyl)cyclohexyl]acetic acid methyl ester (70 mg, 0.14 mmol) dissolved in THF/MeOH/water (20 mL, 3:2:1). The reaction mixture was stirred at 25° C. for 5 hours, concentrated under vacuum, and the residue was acidified with 1M HCl up to pH 2 and extracted with ethyl acetate. The extract was washed with brine and dried with anhydrous sodium sulfate and concentrated under vacuum. The residue was stirred with acetonitrile and filtered. The filtrate was eluted with a gradient of methanol/DCM (5-10%) on a silica gel by a column chromatography and purified to obtain the desired compound (64 mg, 94%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5](OCCCCCCC)=[C:6]([CH:38]=1)[C:7]([NH:9][C@@H:10]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2OC2C=CC(C(F)(F)F)=CC=2)=[CH:17][CH:16]=1)[C:11]([OH:13])=[O:12])=[O:8].[Cl:47][C:48]1[CH:49]=[C:50](B(O)O)[CH:51]=[CH:52][C:53]=1[F:54]>>[C:18]1([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:17]=[CH:16][C:15]([CH2:14][C@H:10]([NH:9][C:7]([C:6]2[CH:38]=[CH:2][C:3]([C:50]3[CH:51]=[CH:52][C:53]([F:54])=[C:48]([Cl:47])[CH:49]=3)=[CH:4][CH:5]=2)=[O:8])[C:11]([OH:13])=[O:12])=[CH:20][CH:19]=1
Reactant: CCCCCCCOc1ccc(Br)cc1C(=O)N[C@@H](Cc1ccc(-c2ccccc2Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: O=C(N[C@@H](Cc1ccc(-c2ccccc2)cc1)C(=O)O)c1ccc(-c2ccc(F)c(Cl)c2)cc1
Yield: 81.6 %

Procedure:
3-Biphenyl-4-yl-(2S)-[(5-bromo-benzoyl-amino)-propionic acid (100 mg, 0.23 mmol) was reacted with 3-chloro-4-fluoro-phenyl boronic acid (0.123 mg, 0.69 mmol) by following general procedure D to afford title compound (89 mg, 80%) as a white solid. 1H NMR (400 MHz, CD3COCD3): 4.05 (dd, 2H), 5.00 (m, 1H), 7.32 (m, 1H), 7.44 (m, 4H), 7.62 (m, 4H), 7.71 (m, 1H), 7.74 (m, 2H), 7.84 (m, 1H), 7.96 (m, 3H). LC/MS (m/z): 474 (M+1)+.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6](=[O:17])[N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[CH:8]=1.Br[C:19](=[C:26]=O)[CH2:20][CH2:21][CH2:22][O:23][CH2:24][CH3:25].CN(C)C=[O:31]>>[CH2:24]([O:23][C:22]([CH2:21][CH2:20][CH2:19][CH2:26][N:5]1[C:4]([CH3:3])=[CH:8][N:7]([N:9]=[CH:10][C:11]2[CH:12]=[N:13][CH:14]=[CH:15][CH:16]=2)[C:6]1=[O:17])=[O:31])[CH3:25]
Reactant: CN(C)C=O
Reactant: CCOCCCC(Br)=C=O
Reactant: Cc1cn(N=Cc2cccnc2)c(=O)[nH]1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)CCCCn1c(C)cn(N=Cc2cccnc2)c1=O
Reaction time: 0.5 h

Procedure:
0.72 g of sodium hydride are added to a suspension of 4.1 g of 2,3-dihydro-4-methyl-2-oxo-1-pyrid-3-ylmethyleneamino-1H-imidazole in 80 ml of N,N-dimethylformamide. The mixture is heated to 50°, treated with a solution of 5.22 g of 1-bromo-4-ethoxy-carbonyl-butane in 20 ml of N,N-dimethylformamide, and stirred for 30 minutes. The N,N-dimethylformamide is then removed on a rotary evaporator. The residue is treated with ethyl acetate, during which process sodium bromide precipitates. The mixture is filtered over Celite, and the filtrate is evaporated. The residue is treated with hexane, during which process crystals precipitate. The crystals are filtered off with suction and dried yielding the title compound melting at 74°-76°.