Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=[C:4]([N:17]2C(C)=CC=C2C)[CH:3]=1.Cl.NO.[OH-].[K+]>C(O)C.O>[NH2:17][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([CH2:8][CH2:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:5]=1
Reactant: Cc1cc(CCCc2ccccc2)nc(-n2c(C)ccc2C)c1
Agent: Cl
Agent: NO
Agent: [K+]
Solvent: CCO
Solvent: O
Product: Cc1cc(N)nc(CCCc2ccccc2)c1

Procedure:
By analogy to Example 56, Step B, 4-methyl-2-(2,5-dimethylpyrrol-1-yl)-6-(3-phenylpropyl)pyridine was treated with 4.6 equivalents of hydroxylamine hydrochloride and 2.8 equivalents of potassium hydroxide in refluxing ethanol/water to yield 2-amino-4-methyl-6-(3-phenylpropyl)pyridine as a yellow oil which spontaneously crystallized.
Reaction SMILES: [OH-].[Na+].Cl.[NH2:4]O.[C:6]([CH2:14][C:15]([O:17]CC)=O)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl>O.C(O)C>[C:7]1([C:6]2[O:13][N:4]=[C:15]([OH:17])[CH:14]=2)[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Oc1cc(-c2ccccc2)on1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
40 g of sodium hydroxide was dissolved in 200 ml of water and 300 ml of ethanol. 69.5 g of hydroxylamine hydrochloride was added to the solution. A mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water was added to the solution so that the pH thereof was adjusted to 10.0. 192 g of ethyl benzoylacetate and a mixed solution of 2N sodium hydroxide and a 3:2 mixture of ethanol and water were added dropwise to the solution at the same time under cooling with ice in such a manner that the pH thereof was 10±0.3. After the dropwise addition was finished, the solution was stirred at room temperature for 3 hours. The reaction mixture was then poured into a mixture of 500 g of conc. hydrochloric acid and 500 g of ice. 2.5 l of ethanol was added to the reaction mixture. The reaction mixture was heated under reflux for 3 hours. 2 l of water was added to cool the solution. The resulting crystals were filtered off, washed with water, and dried. (Yield: 98 g (61%); m.p.: 150°-151° C.)
Reaction SMILES: I[C:2]1[N:6]2[CH:7]=[C:8]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]2=[N:4][CH:3]=1.[CH3:25][Si:26]([C:29]#[CH:30])([CH3:28])[CH3:27].CCN(CC)CC.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[F:14][C:11]([F:12])([F:13])[C:10]1[C:5]2[N:6]([C:2]([C:30]#[C:29][Si:26]([CH3:28])([CH3:27])[CH3:25])=[CH:3][N:4]=2)[CH:7]=[C:8]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:9]=1
Reactant: C#C[Si](C)(C)C
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)c3ncc(I)n3c2)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1cnc2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)cn12
Temperature: 23 °C
Reaction time: 0.17 h

Procedure:
A mixture of 3-iodo-8-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-imidazo[1,2-a]pyridine (8.36 g, 18 mmol), trimethylsilylacetylene (5.1 mL, 37 mmol), Et3N (7.66 mL, 55 mmol), PdCl2(PPh3)2 (64 mg, 0.5 mol %) and PPh3 (48 mg, 1 mol %) in THF (40 mL) was stirred for 10 min at 23° C. while being purged with Argon. Then CuI (10 mg, 0.3 mol %) was added.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[N+:9]([O-])=O.C(OCC)(=O)C.CCCCCC>C(O)C.[Pd]>[NH2:9][C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccncc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1ccncc1N
Yield: 100 %

Procedure:
To a mixture of 4-Methoxy-3-nitropyridine (5.0 g, 32.44 mmole) in ethanol (100 mL) was added 10% palladium on carbon catalyst (200 mg). The resulting mixture was allowed to shake under a hydrogen atmosphere (50 psi) for 6 h. at room temperature. TLC (50% ethyl acetate/hexane) indicated complete consumption of starting material. Filtration through celite to remove the catalyst and concentration gave 3- Amino-4 methoxypyridine (4.0 g, 32.44 mmol, 100% yield) as dark red oil.
Reaction SMILES: [C:1]([C:4]1[N:8]2[CH2:9][CH2:10][N:11]([CH3:25])[C:12]3([CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]3)[C:7]2=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[ClH:26].O1CCOCC1>C(Cl)Cl>[ClH:26].[ClH:26].[CH3:25][N:11]1[C:12]2([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)[C:7]2=[CH:6][CH:5]=[C:4]([C:1](=[O:3])[CH3:2])[N:8]2[CH2:9][CH2:10]1
Reactant: CC(=O)c1ccc2n1CCN(C)C21CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(=O)c1ccc2n1CCN(C)C21CCNCC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To tert-butyl 6-acetyl-2-methyl-Spiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-1′-carboxylate (300 mg, 0.86 mmol) and methylene chloride (1.7 mL) was added hydrogen chloride in dioxane (1.60 mL of 4 M, 6.40 mmol) The reaction was stirred at room temperature for 0.5 hours. The solvent was evaporated under reduced pressure to yield 1-(2-methylspiro[3,4-dihydropyrrolo[1,2-a]pyrazine-1,4′-piperidine]-6-yl)ethanone dihydrochloride as a light green solid in quantitative yield. ESI-MS m/z calc. 247.2, found 248.2 (M+1)+; Retention time: 0.17 minutes (3 minute run).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21](O)=[O:22])=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][O:35][C:36](=[O:50])[CH2:37][CH2:38][CH2:39][NH:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47](=[O:49])[NH2:48].CCN(C(C)C)C(C)C>ClCCl.CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:34][O:35][C:36](=[O:50])[CH2:37][CH2:38][CH2:39][N:40]([C:21](=[O:22])[C:20]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:18]([O:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:28]2[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=2)[CH:19]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[C:47](=[O:49])[NH2:48]
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Reactant: COC(=O)CCCNc1ccccc1C(N)=O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.2 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (0.090 ml) and DMF (0.01 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (0.060 g) in anhydrous dichloromethane (1 ml). The reaction was stirred at room temperature for 2 h then 4-(2-carbamoyl phenylamino)-butyric acid methyl ester (0.037 g), DMAP (0.002 g) and DIPEA (0.078 ml) were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate solution, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:cyclohexane (9:1 v/v), neat ethyl acetate and dichloromethane:methanol (9:1) to give the title compound as a colourless gum (0.031 g).
Reaction SMILES: [CH2:1]([O:19][CH:20]1[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23][CH:22]([CH2:64][OH:65])[CH2:21]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].N1C=CC=CC=1.[C:72]1([CH3:82])[CH:77]=[CH:76][C:75]([S:78](Cl)(=[O:80])=[O:79])=[CH:74][CH:73]=1>C(Cl)(Cl)Cl.CN(C1C=CN=CC=1)C>[S:78]([C:75]1[CH:76]=[CH:77][C:72]([CH3:82])=[CH:73][CH:74]=1)([O:65][CH2:64][CH:22]1[CH2:21][CH:20]([O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH:25]([O:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])[CH:24]([O:45][CH2:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH2:23]1)(=[O:80])=[O:79]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCCCCCCCCCCCCCCCCCOC1CC(CO)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCCOC1CC(COS(=O)(=O)c2ccc(C)cc2)CC(OCCCCCCCCCCCCCCCCCC)C1OCCCCCCCCCCCCCCCCCC
Reaction time: 120 h
Yield: 96.1 %

Procedure:
3,4,5-Tris(octadecyloxy)cyclohexylmethyl alcohol (68.5 g, 74.5 mmol) was dissolved in chloroform (700 ml), pyridine (26.9 ml, 0.33 mol), DMAP (903 mg, 7.39 mmol) and p-toluenesulfonyl chloride (44.9 g, 0.236 mol) were added, and the mixture was stirred for 5 days. The solvent was evaporated, and the residue was precipitated with acetonitrile (700 ml) and washed with acetonitrile (700 ml) to give 3,4,5-tris(octadecyloxy)cyclohexylmethyl tosylate (76.9 g, 71.6 mmol, 96%).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C@H:3]1[CH2:16][O:17][CH3:18].[F:19][C:20]([F:35])([F:34])[C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[C:24]([NH:26][CH2:27][C:28](O)=[O:29])=[O:25].C(N(C(C)C)CC)(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(#N)C.C(OCC)(=O)C>[CH3:18][O:17][CH2:16][C@H:3]1[C@@H:2]([NH:1][C:28](=[O:29])[CH2:27][NH:26][C:24](=[O:25])[C:23]2[CH:31]=[CH:32][CH:33]=[C:21]([C:20]([F:19])([F:35])[F:34])[CH:22]=2)[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4]1
Reactant: O=C(O)CNC(=O)c1cccc(C(F)(F)F)c1
Reactant: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 2.75 h
Yield: 60.4 %

Procedure:
A solution of tert-butyl (1R,3R,4S)-4-amino-3-(methoxymethyl)cyclohexylcarbamate (45 mg, assumed 0.163 mmol) in acetonitrile (1.5 mL) was treated sequentially with 2-(3-(trifluoromethyl)benzamido)acetic acid (43 mg, 0.174 mmol, see PCT WO 0250019), diisopropylethylamine (61 μL, 0.348 mmol) and TBTU (62 mg, 0.192 mmol). The mixture was stirred at rt for 2.75 h, then was diluted with ethyl acetate, washed sequentially with 1.0 M aqueous HCl, saturated aqueous NaHCO3, water and brine, dried over Na2SO4 and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel, eluting with 1:3 v/v hexane-ethyl acetate, to provide tert-butyl (1R,3R,4S)-3-(methoxymethyl)-4-(2-(3-(trifluoromethyl)benzamido)acetamido)cyclohexylcarbamate as a white solid (48 mg). MS found: (M+H)+=488.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:24])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([CH2:22][OH:23])[N:21]=2)[CH2:7]1.S([O-])([O-])(=O)=O.[Mg+2]>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[Cl:28])[CH2:5][N:6]1[CH2:11][CH2:10][O:9][C@@H:8]([CH2:12][NH:13][C:14](=[O:24])[CH2:15][S:16][C:17]2[S:18][CH:19]=[C:20]([CH:22]=[O:23])[N:21]=2)[CH2:7]1
Reactant: O=C(CSc1nc(CO)cs1)NC[C@H]1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: [Mn+4]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: ClC(Cl)Cl
Product: O=Cc1csc(SCC(=O)NC[C@H]2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
The resultant product (1.53 g) of (70-1) was dissolved in chloroform (10 mL), magnesium sulfate (500 mg) was added, manganese dioxide (1.35 g) was further added, and the mixture was stirred overnight at room temperature. Magnesium sulfate (500 mg) and manganese dioxide (1.35 g) were further added and the mixture was stirred at room temperature for 7 hrs. The reaction mixture was filtered through celite, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography using a mixed solvent of chloroform and methanol as an eluent. The solvent was evaporated from the eluent to give the title compound (643 mg) as a colorless oil.
Reaction SMILES: [C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:27])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[NH:23][CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:3][CH:2]=1.[CH:46]1(B(O)O)[CH2:48][CH2:47]1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Cl>CN(C1C=CN=CC=1)C.CC([O-])=O.CC([O-])=O.[Cu+2].C1(C)C=CC=CC=1>[C:1]1([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[C:12]3[CH:13]=[C:14]([F:27])[C:15]([C:18]4[CH:19]=[C:20]5[C:24](=[CH:25][CH:26]=4)[N:23]([CH:46]4[CH2:48][CH2:47]4)[CH:22]=[CH:21]5)=[C:16]([F:17])[C:11]=3[N:10]=[C:9]2[O:28][CH:29]2[CH2:34][CH2:33][CH:32]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:31][CH2:30]2)=[CH:5][CH:6]=1
Reactant: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5[nH]ccc5c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Reactant: OB(O)C1CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CN(C)c1ccncc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCC(Oc2nc3c(F)c(-c4ccc5c(ccn5C5CC5)c4)c(F)cc3n2Cc2ccc(-c3ccccc3)cc2)CC1
Temperature: 95 °C

Procedure:
A 10 mL flask was charged with ethyl 4-{[1-(biphenyl-4-ylmethyl)-4,6-difluoro-5-(1H-indol-5-yl)-1H-benzimidazol-2-yl]oxy}cyclohexanecarboxylate (0.080 g, 0.132 mmol), DMAP (0.048 g, 0.396 mmol), cyclopropylboronic acid (0.023 g, 0.264 mmol), and Cu(OAc)2 (4.8 mg, 0.026 mmol) under a nitrogen atmosphere. Toluene (1.3 mL) was added and the resulting suspension was treated with a 0.6 M solution of NaHMDS in toluene (0.220 mL, 0.132 mmol) dropwise via syringe. Dry air was purged into the reaction vessel, and the reaction was heated at 95° C. overnight. The dark reaction mixture was then cooled to ambient temperature and treated with 20 mL of 1 N HCl. The aqueous layer was separated and extracted with EtOAc (2×25 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated. Purification of the resulting crude residue by preparative TLC (25% EtOAc/hexanes) furnished the title compound as a pale yellow residue. LCMS: calculated for C40H37F2N3O3 645.74, observed rule 646.2 (M+H)+ (Rt 3.03/4 min).
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:12]([O:13][CH2:14][CH3:15])=[CH:11][C:10]([CH:16]=[O:17])=[CH:9][C:8]=1[CH:18]1[CH2:20][CH2:19]1)(=O)=O.[F:23][C:24]1[CH:25]=[C:26](B(O)O)[CH:27]=[CH:28][C:29]=1[F:30].[F-].[Cs+].COCCOC>O>[CH:18]1([C:8]2[CH:9]=[C:10]([CH:16]=[O:17])[CH:11]=[C:12]([O:13][CH2:14][CH3:15])[C:7]=2[C:27]2[CH:26]=[CH:25][C:24]([F:23])=[C:29]([F:30])[CH:28]=2)[CH2:19][CH2:20]1
Reactant: CCOc1cc(C=O)cc(C2CC2)c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(F)c(F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: O
Product: CCOc1cc(C=O)cc(C2CC2)c1-c1ccc(F)c(F)c1
Yield: 58.6 %

Procedure:
(1,1′-Bis(diphenylphosphino)ferrocene)dichloropalladium(II) (1.30 g) was added to a mixture of 2-cyclopropyl-6-ethoxy-4-formylphenyl trifluoromethanesulfonate (3.00 g), (3,4-difluorophenyl)boronic acid (5.60 g), cesium fluoride (5.39 g), and DME (15 mL), and the resultant mixture was stirred at 100° C. for 15 hours in an argon atmosphere. Water was added to the reaction mixture, and the mixture was filtered through celite. The filtrate was subjected to extraction with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (1.57 g).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39]([CH:46]=O)=[CH:38]1)(=[O:36])=[O:35].N1CCCCC1>CO>[Cl:26][C:27]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:28]=1[S:34]([N:37]1[C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[C:39](/[CH:46]=[C:7]2\[O:8][C:4]3[C:3]([CH2:12][N:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=3[C:6]\2=[O:9])=[CH:38]1)(=[O:36])=[O:35]
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: O=Cc1cn(S(=O)(=O)c2ccc(Cl)cc2Cl)c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2cn(S(=O)(=O)c4ccc(Cl)cc4Cl)c4ccccc24)C3=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 1-(2,4-dichlorophenylsulfonyl)-1H-indole-3-carboxaldehyde (0.102 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol (2 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-[(2-{[1-(2,4-dichlorophenylsulfonyl)-1H-indol-3-yl]methylene}-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.147 g, 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18](O)=[O:19].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C>C1COCC1>[Br:15][C:16]1[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:17]=1[C:18]([NH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)=[CH:9][CH:10]=1)=[O:19]
Reactant: Nc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: Cc1ccc(C(=O)O)c(Br)c1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCCl
Product: Cc1ccc(C(=O)Nc2ccc(-c3ccc(Cl)cc3)cc2)c(Br)c1
Temperature: 25 °C

Procedure:
4′-chloro-[1,1′-biphenyl]-4-amine (159 mg, 0.78 mmol), 2-bromo-4-methylbenzoic acid (140 mg, 0.65 mmol), EDC (125 mg, 0.65 mmol), HOBt (100 mg, 0.65 mmol), and diisopropylethyl amine (0.22 mL, 1.30 mmol) were dissolved in THF (2.6 mL) and stirred at room temperature. After 3 h the resulting mixture directly purified via column chromatography to yield the title compound.
Reaction SMILES: Cl.[O:2]1[CH2:7][CH2:6][CH:5]([NH:8][NH2:9])[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:27])[CH3:26])=[C:19]([C:28](=O)/[CH:29]=[CH:30]/N(C)C)[CH:18]=1.O.C(OCC)(=O)C>C(O)C>[Br:16][C:17]1[C:22]([CH3:23])=[CH:21][C:20]([NH:24][C:25](=[O:27])[CH3:26])=[C:19]([C:28]2[N:8]([CH:5]3[CH2:6][CH2:7][O:2][CH2:3][CH2:4]3)[N:9]=[CH:30][CH:29]=2)[CH:18]=1
Reactant: NNC1CCOCC1
Reactant: CC(=O)Nc1cc(C)c(Br)cc1C(=O)/C=C/N(C)C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=O)Nc1cc(C)c(Br)cc1-c1ccnn1C1CCOCC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
To a solution of 3.37 g of tetrahydro-2H-pyran-4-ylhydrazine hydrochloride in 120 mL of ethanol was added 3.82 g of powdery potassium carbonate, followed by stirring at room temperature for 30 minutes. To a mixture was added 6 g of N-{4-bromo-2-[(2E)-3-(dimethylamino)prop-2-enoyl]-5-methylphenyl}acetamide, followed by stirring at 80° C. for 16 hours and cooling to room temperature. The mixture was poured into a mixture of water/ethyl acetate, and the aqueous layer was separated. The organic layer 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 (n-hexane/ethyl acetate) to obtain 3.96 g of N-{4-bromo-5-methyl-2-[1-(tetrahydro-2H-pyran-4-yl)-1H-pyrazol-5-yl]phenyl}acetamide.
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:14][C:15]([O:18][C:19]([N:21]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:22]([C:30]1[C:35]([F:36])=[C:34](Cl)[N:33]=[C:32]([Cl:38])[N:31]=1)[C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])=[O:20])([CH3:17])[CH3:16]>CN(C=O)C.C(OCC)C>[CH3:17][C:15]([O:18][C:19]([N:21]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[N:22]([C:30]1[C:35]([F:36])=[C:34]([NH:4][CH:1]([CH3:3])[CH3:2])[N:33]=[C:32]([Cl:38])[N:31]=1)[C:23]([O:25][C:26]([CH3:27])([CH3:28])[CH3:29])=[O:24])=[O:20])([CH3:14])[CH3:16]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)c1nc(Cl)nc(Cl)c1F
Reactant: CC(C)N
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOCC
Product: CC(C)Nc1nc(Cl)nc(N(C(=O)OC(C)(C)C)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1F
Yield: 94.9 %

Procedure:
To a vigorously stirred solution of isopropyl amine (83 μL, 1.21 mmol) in DMF (6 mL) at 0° C. was added DIPEA (0.24 mL, 1.33 mmol) followed immediately by tris(1,1-dimethylethyl)2-(2,6-dichloro-5-fluoro-4-pyrimidinyl)-1,1,2-hydrazinetricarboxylate (600 mg, 1.21 mmol). When the reaction was complete as determined by LCMS, the reaction mixture was diluted with diethyl ether (˜40 mL) and washed with water (3×40 mL). The combined three aqueous layers were back-extracted once with diethyl ether, and then the combined organics were dried (Na2SO4) and concentrated in vacuo. This crude product was purified by flash chromatography (Combiflash, 5-60% ethyl acetate/hexanes, 1% triethylamine) to provide tris(1,1-dimethylethyl)2-{2-chloro-5-fluoro-6-[(1-methylethyl)amino]-4-pyrimidinyl}-1,1,2-hydrazinetricarboxylate (597 mg, 95%). LCMS: (M+H)+: 520.2.
Reaction SMILES: [Li+].[OH-].C[O:4][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:17][C:18](=[O:26])[C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[C:9]=2[CH:8]=1)=[O:6]>CO.O>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[C:18]([NH:17][C@H:10]1[C:9]2[CH:8]=[C:7]([C:5]([OH:6])=[O:4])[CH:16]=[CH:15][C:14]=2[CH2:13][CH2:12][CH2:11]1)=[O:26]
Reactant: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1ccc2c(c1)[C@H](NC(=O)c1ccccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 81.4 %

Procedure:
LiOH (4 equiv.) was added to a suspension of (8R)-8-[(2-chloro-benzoyl)amino]-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid methyl ester (B-06) in methanol and water and the reaction mixture was stirred at 25° C. for 2.5 hours. (According to TLC control: educt still present) The reaction mixture was topped up with 2 equiv. of LiOH and stirred at 25° C. overnight. Methanol was distilled off and the aqueous residue was diluted with ether and dist. water. The phases were separated and the aqueous phase was acidified with 1N HCl. Finally, the aqueous phase was extracted 4× with ethyl acetate (spot test) and the extract was dried over sodium sulfate and concentrated. Yield:81.4%.