Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[C:13]3[C:14]([O:18][C@H:19]4[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21][CH2:20]4)=[CH:15][CH:16]=[CH:17][C:12]=3[O:11][N:10]=2)[CH2:3][CH2:2]1.[CH:26]([C:28]1([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1)=O.C(C1(C(OC)=O)CCC1)=O>>[OH:25][C@H:22]1[CH2:23][CH2:24][C@H:19]([O:18][C:14]2[C:13]3[C:9]([O:8][CH2:7][CH:4]4[CH2:5][CH2:6][N:1]([CH2:26][C:28]5([C:34]([O:36][CH3:37])=[O:35])[CH2:33][CH2:32][O:31][CH2:30][CH2:29]5)[CH2:2][CH2:3]4)=[N:10][O:11][C:12]=3[CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21]1
Reactant: O[C@H]1CC[C@H](Oc2cccc3onc(OCC4CCNCC4)c23)CC1
Reactant: COC(=O)C1(C=O)CCOCC1
Agent: COC(=O)C1(C=O)CCC1
Product: COC(=O)C1(CN2CCC(COc3noc4cccc(O[C@H]5CC[C@H](O)CC5)c34)CC2)CCOCC1

Procedure:
The title compound was prepared according to the procedure described in Step 3 of EXAMPLE 2 using trans-4-{[3-(Piperidin-4-ylmethoxy)-1,2-benzisoxazol-4-yl]oxy}cyclohexanol (EXAMPLE 42, Step 1) and methyl 4-formyltetrahydro-2H-pyran-4-carboxylate (EXAMPLE 18, Step 1) instead of 3-(piperidin-4-ylmethoxy)-4-(2,2,2-trifluoroethoxy)-1,2-benzisoxazole and methyl 1-formylcyclobutanecarboxylate.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)[C:2]1C=CC=CC=1.BrCC#[N:21].C(=O)([O-])[O-].[K+].[K+]>CO.[Pd].C(C(C)=O)C>[C:2]([CH2:1][O:8][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:17]=1[NH:16][CH:15]=[CH:14]2)#[N:21]
Reactant: c1ccc(COc2cccc3cc[nH]c23)cc1
Reactant: N#CCBr
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CCC(C)=O
Product: N#CCOc1cccc2cc[nH]c12

Procedure:
A solution of 7-benzyloxyindole (0.5 g, 2.24 mmol) in methanol (100 ml) is hydrogenated at 60 psi (4.38 Kg/cm2) over 10% palladium on charcoal (50 mg) for 4 hours. The catalyst is filtered off and the filtrate was evaporated. A stirred solution of the residue and bromoacetonitrile (0.16 ml, 2.3 mmol) in methyl ethyl ketone (5 ml) is heated under reflux with solid anhydrous potassium carbonate (0.62 g, 4.5 mmol) for 2 hours, cooled, poured onto ice-hydrochloric acid and extracted with dichloromethane. The extract is dried and evaporated and the residue is chromatographed on silica in ethyl acetate-hexane (1:2) to give a pale solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]2[OH:32])=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:33](OCCCOC1N=CC(C2(O)CCN(C(OC(C)(C)C)=O)CC2)=CC=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[N:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:21][CH:20]2[O:32][CH2:7][C:2]2[CH:3]=[CH:33][C:34]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[CH:1]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(OCCCOCc3ccccc3)nc2)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)nc2)C(O)C1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)nc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 125 (g), by alkylating a 4:1 mixture of tert-butyl (3'RS, 4'RS)-6-(3-benzyloxy-propoxy)-3'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate and tert-butyl 6-(3-benzyloxy-propoxy)-4'-hydroxy-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate with 2-bromomethylnaphthalene and subsequent separation of the isomers there was obtained tert-butyl (3'RS,4'RS)-6-(3-benzyloxy-propoxy)-3'-(naphthalen-2-ylmethoxy)-3',4',5',6'-tetrahydro-2'H-[3,4']bipyridine-1'-carboxylate as a colourless oil; MS: 583 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[CH:18])([CH3:4])([CH3:3])[CH3:2].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([S:27]([CH3:30])(=[O:29])=[O:28])=[CH:23][C:22]=1I>>[C:1]([O:5][C:6](=[O:19])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][C:10]=1[C:17]#[C:18][C:22]1[CH:23]=[C:24]([S:27]([CH3:30])(=[O:28])=[O:29])[CH:25]=[CH:26][C:21]=1[Cl:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1cc(C#N)ccc1OCC(=O)OC(C)(C)C
Reactant: CS(=O)(=O)c1ccc(Cl)c(I)c1
Product: CC(C)(C)OC(=O)COc1ccc(C#N)cc1C#Cc1cc(S(C)(=O)=O)ccc1Cl
Yield: 74 %

Procedure:
Following the general method as outlined in Intermediate 79, starting from (4-cyano-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 46) and 1-chloro-2-iodo-4-(methylsulfonyl)benzene (Intermediate 74), the title compound was obtained as a yellow solid in 74% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [C:1]([C:3]1[N:7]([CH3:8])[C:6]([C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:10])=[N:5][CH:4]=1)#[CH:2].[N:17]([C:20]1[CH:21]=[C:22]([CH:43]=[CH:44][C:45]=1[CH3:46])[C:23]([NH:25][C:26]1[CH:31]=[C:30]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH:29]=[C:28]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:27]=1[O:41][CH3:42])=[O:24])=[N+:18]=[N-:19]>>[C:9]([C:6]1[N:7]([CH3:8])[C:3]([C:1]2[N:19]=[N:18][N:17]([C:20]3[CH:21]=[C:22]([CH:43]=[CH:44][C:45]=3[CH3:46])[C:23]([NH:25][C:26]3[CH:31]=[C:30]([C:32]([CH3:34])([CH3:35])[CH3:33])[CH:29]=[C:28]([NH:36][S:37]([CH3:40])(=[O:39])=[O:38])[C:27]=3[O:41][CH3:42])=[O:24])[CH:2]=2)=[CH:4][N:5]=1)(=[O:10])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: COc1c(NC(=O)c2ccc(C)c(N=[N+]=[N-])c2)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: C#Cc1cnc(C(=O)c2ccccc2)n1C
Product: COc1c(NC(=O)c2ccc(C)c(-n3cc(-c4cnc(C(=O)c5ccccc5)n4C)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 35 was prepared from (5-ethynyl-1-methyl-1H-imidazol-2-yl)-phenyl-methanone (Example 33) and 3-azido-N-(5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-4-methyl-benzamide in the same manner as Example 15. ESI MS m/z 642 [C33H35N7O5S+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:39])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([O:34]CC)=[O:33])=[CH:30][N:29]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=2)[CH:11]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[CH3:1][O:2][CH2:3][C@H:4]([CH3:39])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[CH:38]=[CH:37][C:31]([C:32]([OH:34])=[O:33])=[CH:30][N:29]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[CH:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=2)[CH:11]=1
Reactant: CCOC(=O)c1ccc(-c2ccc(-c3cc(Oc4ccc(S(C)(=O)=O)cc4)cc(O[C@@H](C)COC)c3)[nH]2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(-c2ccc(-c3ccc(C(=O)O)cn3)[nH]2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
Ethyl 6-(5-{3-[(1S)-2-methoxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]phenyl}-1H-pyrrol-2-yl)nicotinate (42.0 mg, 0.076 mmol) synthesized in Example (11c) was dissolved in ethanol (4 mL). An aqueous sodium hydroxide solution (5M, 2 mL) was added, and stirring was carried out at 70° C. for 2 hours. After cooling to room temperature, hydrochloric acid (2M, 5 mL) and ethyl acetate (10 mL) were added, and the solution was separated. The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, to afford the desired compound (39.6 mg, yield 99%) as a pale yellow solid.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.Cl.[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.O.[BH4-].[Na+]>C1(C)C=CC=CC=1>[ClH:23].[Cl:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:42]=[CH:41][C:38]([CH2:39][NH:1][CH:2]4[CH2:3][CH2:4][N:5]([CH2:8][C:9]5[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:16][CH3:17])[CH2:18][CH3:19])=[O:14])=[CH:11][CH:10]=5)[CH2:6][CH2:7]4)=[CH:37][CH:36]=3)=[CH:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: CCN(CC)C(=O)c1ccc(CN2CCC(N)CC2)cc1
Reactant: O=Cc1ccc(Nc2ccnc3cc(Cl)ccc23)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCN(CC)C(=O)c1ccc(CN2CCC(NCc3ccc(Nc4ccnc5cc(Cl)ccc45)cc3)CC2)cc1
Temperature: 0 °C
Reaction time: 168 h
Yield: 42.4 %

Procedure:
4-[(4-Amino-1-piperidinyl)methyl]-N,N-diethylbenzamide (3.81 g, 13.16 mmol) and 4-[(7-chloro-4-quinolinyl)amino]benzaldehyde hydrochloride (13.16 mmol, 4.20 g) are refluxed for 28 hours in 52 mL of toluene under nitrogen with azeotropic removal of water. The toluene is poured off the thick oil, which is then rinsed once with fresh toluene. The remaining traces of solvent are removed in vacuo and the resulting gum is dissolved in 55 mL of ethanol and treated with NaBH4 (14.6 mmol, 552 mg). The reaction mixture is refluxed for 50 minutes, treated with another 200 mg of NaBH4 and refluxed an additional 10 minutes. The reaction mixture is poured over 100 mL of ice, which results in the formation of an orange oil. After stirring rapidly for seven days, the water is decanted and the oil is purified by flash chromatography on silica gel (65 mm column, 5% ammonia saturated methanol in methylene chloride eluent) which affords 1.55 g (2.79 mmol, 21% yield) of the title compound as the free base. Of this, 0.95 g (1.7 mmol) are dissolved in 5 mL of methanol and treated with 1.7 mL of 1N ethereal HCl. The resulting solution is concentrated in vacuo and the residue is triturated with ether for 23 hours. The resulting yellow powder is filtered, washed with ether and dried in vacuo at 60° C. for 16.5 hours, affording 896 mg of the title compound: mp 166°-190° C. (softens slowly over this range); 1H NMR (Me2SO-d6, 400 MHz) δ9.37 (br s, 1H), 8.5 (m, 2H), 7.91 (d,J=2.2 Hz, 1H), 7.6 (m, 3H), 7.28-7.42 (m, 6H), 6.96 (d,J=5.4 Hz, 1H), 4.12 (s, 2H), 2.9-3.6 (m, 10H), 2.1 (m, 4H), 1.7-1.8 (m, 2H), 1-1.2 (m, 6H);
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[N:11]=[CH:10][NH:9][C:8]=2[C:7](=[O:13])[NH:6][C:5]1=[O:14])[CH2:2][CH3:3].[Cl:15]N1C(=O)CCC1=O>CN(C=O)C>[Cl:15][C:10]1[NH:9][C:8]2[C:7](=[O:13])[NH:6][C:5](=[O:14])[N:4]([CH2:1][CH2:2][CH3:3])[C:12]=2[N:11]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCCn1c(=O)[nH]c(=O)c2[nH]cnc21
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c(=O)c2[nH]c(Cl)nc21
Reaction time: 5 h
Yield: 43.2 %

Procedure:
3-Propyl-3,7-dihydro-1H-purine-2,6-dione (J. Med. Chem, 1993, 36 (10), 1380-6) (0.3 g, 1.5 mmol) and N-chlorosuccinimide (0.21 g, 1.5 mmol) were dissolved in DMF (5 ml) and the solution stirred for 5 h. The solution was concentrated and the solid residues washed with methanol and filtered to provide the product as a white solid (0.148 g, 42%). NMR; δH (400 MHz, d6-DMSO) 0.85 (t, 3H, J=7 Hz), 1.65 (m, 2H), 3.8 (t, 2H, J=7 Hz), 11.2 (s, 1H), one exchangeable not observed to δH 13; m/z 229[MH+]
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[NH2:15][C:16]1[CH:21]=[C:20]([CH3:22])[CH:19]=[CH:18][C:17]=1[S:23][C:24]1[CH:29]=[CH:28][C:27]([NH:30][C:31](=[O:33])[CH3:32])=[CH:26][C:25]=1[F:34]>>[F:34][C:25]1[CH:26]=[C:27]([NH:30][C:31](=[O:33])[CH3:32])[CH:28]=[CH:29][C:24]=1[S:23][C:17]1[CH:18]=[CH:19][C:20]([CH3:22])=[CH:21][C:16]=1[NH:15][C:2]1[C:3]2[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=2)[N:9]=[CH:10][CH:11]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(C)cc2N)c(F)c1
Product: CCCc1ccc2c(Nc3cc(C)ccc3Sc3ccc(NC(C)=O)cc3F)ccnc2n1
Yield: 54.3 %

Procedure:
The product from Example 2g (100 mg, 0.48 mmol) was reacted with the product from Example 39e (140 mg, 0.48 mmol) for 22 h at 120° C. following the procedure from Example 1g giving the title compound as a solid (120 mg, 54%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.99 (t, J=7.3 Hz, 3H), 1.86 (sextet, J=7.3 Hz, 2H), 2.06 (s, 3H), 2.36 (s, 3H), 3.01 (t, J=7.3 Hz, 2H), 6.28 (d, J=6.9 Hz, 1H), 7.12-7.35 (m, 5H), 7.55 (dd, J=12.1, 2.2 Hz, 1H), 7.82 (d, J=8.8 Hz, 1H), 8.42 (d, J=6.9 Hz, 1H), 9.04 (d, J=8.8 Hz, 1H); MS (ESI+) m/z 461 (M+H)+, ESI− m/z 459 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)=[CH:4][CH:3]=1.Cl[CH2:17][C:18]1[N:19]=[C:20]([C:23]2[S:24][C:25]([CH2:28][CH3:29])=[CH:26][CH:27]=2)[O:21][CH:22]=1>>[CH2:28]([C:25]1[S:24][C:23]([C:20]2[O:21][CH:22]=[C:18]([CH2:17][O:1][C:2]3[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][N:11]4[CH:15]=[CH:14][N:13]=[CH:12]4)=[CH:4][CH:3]=3)[N:19]=2)=[CH:27][CH:26]=1)[CH3:29]
Reactant: Oc1ccc(CCCn2ccnc2)cc1
Reactant: CCc1ccc(-c2nc(CCl)co2)s1
Product: CCc1ccc(-c2nc(COc3ccc(CCCn4ccnc4)cc3)co2)s1
Yield: 55 %

Procedure:
In substantially the same manner as in Working Example 72, 1-[3-(4-hydroxyphenyl)propyl]imidazole was allowed to react with 4-chloromethyl-2-(5-ethyl-2-thienyl)oxazole to give 2-(5-ethyl-2-thienyl)-4-[4-[3-(1-imidazolyl)propyl]phenoxymethyl]oxazole. The yield was 55%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 57-58° C.
Reaction SMILES: [NH2:1][C:2]1([CH3:28])[CH2:7][CH2:6][N:5]([C:8]2[NH:9][CH2:10][C:11]3[N:12]=[C:13](Cl)[N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=4)[C:16]=3[N:17]=2)[CH2:4][CH2:3]1.I.C>C(O)(=O)C>[NH2:1][C:2]1([CH3:28])[CH2:3][CH2:4][N:5]([C:8]2[N:9]=[CH:10][C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[C:21]([Cl:26])[CH:20]=4)[C:16]=3[N:17]=2)[CH2:6][CH2:7]1
Reactant: CC1(N)CCN(C2=Nc3c(nc(Cl)nc3Nc3ccc(F)c(Cl)c3)CN2)CC1
Agent: I
Solvent: CC(=O)O
Product: CC1(N)CCN(c2ncc3ncnc(Nc4ccc(F)c(Cl)c4)c3n2)CC1
Temperature: 15 °C
Reaction time: 0.5 h

Procedure:
A mixture of 80 g (0.182 mol) of (6) in 160 ml glacial acetic acid at 90° C. is added dropwise to a suspension of 11.7 g (0.378 mol) of red phosphorus in 150 ml of hydriodic acid (57%, 1.134 mol). The mixture is refluxed for 4 hours, 5 g of activated charcoal are added, the mixture is then filtered and the residue is washed with glacial acetic acid and water. The filtrate is added dropwise, with vigorous stirring, to a solution of 270 ml water, 270 ml of methanol and 270 ml of sodium hydroxide solution (50%). The mixture is stirred for a further 30 minutes at 15° C. and the solid precipitated is filtered off. This is washed twice with 500 ml of water, then suspended in 500 ml of water, filtered off and dried in vacuo at 45° C. Yield: 65.2 g (91.9%)
Reaction SMILES: Cl[C:2]1[S:3][C:4]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:5][N:6]=1.[NH4+:33].[OH-]>CCO.CCOC(C)=O>[NH2:33][C:2]1[S:3][C:4]([S:7]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[N:21]=[CH:20][C:19]([C:22]([OH:31])([C:27]([F:30])([F:29])[F:28])[C:23]([F:26])([F:25])[F:24])=[CH:18][N:17]=3)[C@@H:12]([CH3:32])[CH2:11]2)(=[O:9])=[O:8])=[CH:5][N:6]=1
Reactant: [NH4+]
Reactant: C[C@H]1CN(S(=O)(=O)c2cnc(Cl)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: C[C@H]1CN(S(=O)(=O)c2cnc(N)s2)CCN1c1ncc(C(O)(C(F)(F)F)C(F)(F)F)cn1
Temperature: 140 °C

Procedure:
A mixture of 2-(2-((2S)-4-((2-chloro-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (185 mg, 0.352 mmol) in 2 mL of EtOH and 2 mL of 30% NH4OH was heated to 140° C. for 30 min. Afterwards, the solution was diluted with EtOAc (20 mL). The solution was transferred to a reparatory funnel and washed with water (10 mL) and brine (10 mL). The combined organics were dried over MgSO4, filtered, and concentrated. The crude material was absorbed onto silica gel and purified via column chromatography (40 g silica gel, 0 to 10% MeOH in CH2Cl2) to give 2-(2-((2S)-4-((2-amino-1,3-thiazol-5-yl)sulfonyl)-2-methyl-1-piperazinyl)-5-pyrimidinyl)-1,1,1,3,3,3-hexafluoro-2-propanol (132 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([O:23]CC)=[O:22].CO.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[Cl:29])[CH2:5][N:6]1[C:14]2[C:9](=[C:10]([O:15][CH2:16][CH:17]([OH:20])[CH2:18][OH:19])[CH:11]=[CH:12][CH:13]=2)[CH:8]=[C:7]1[C:21]([OH:23])=[O:22]
Reactant: CCOC(=O)c1cc2c(OCC(O)CO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(OCC(O)CO)cccc2n1Cc1ccc(Cl)c(Cl)c1
Reaction time: 16 h
Yield: 88 %

Procedure:
Ethyl N-(3,4-dichlorobenzyl)-4-(2,3-dihydroxypropoxy)indole-2-carboxylate (85 mg) was dissolved in THF (3 ml) and methanol (1 ml) and sodium hydroxide (2M, 3.0 ml) was added and the reaction stirred for 16 hours. The reaction was then concentrated in vacuo and the residue dissolved in water. The solution was acidified by dropwise addition of acetic acid, resulting in the precipitation of a white solid which was filtered, washed with water and dried in vacuo to give the desired end product (70 mg, 81%); NMR d (CD3SOCD3) 3.40-3.53 (m, 3H), 3.98-4.10 (m, 2H), 5.80 (s, 2H), 6.59 (d, 1H), 6.88 (d, 1H), 7.09 (d, 1H), 7.20 (t, 1H), 7.30 (d, 1H), 7.36 (s, 1H), 7.51 (d, 1H); M/z (−) 408 (M−H+).
Reaction SMILES: [C:1]([OH:11])(=O)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH2:21])[CH3:20])=[CH:15][C:14]=1[N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1.CCN=C=NCCCN(C)C.Cl.CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:21][C:1](=[O:11])[CH:2]=[CH:3][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH3:20])=[CH:15][C:14]=1[N:22]1[CH2:23][CH2:24][O:25][CH2:26][CH2:27]1
Reactant: CC(N)c1ccc(F)c(N2CCOCC2)c1
Reactant: O=C(O)C=Cc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(NC(=O)C=Cc1ccccc1)c1ccc(F)c(N2CCOCC2)c1
Reaction time: 16 h

Procedure:
A mixture of cinnamic acid (23 mg), 1-(4-fluoro-3-morpholin-4-yl-phenyl)-ethylamine, Preparation 26 (34 mg), DMAP (18 mg), EDC.HCl (27 mg), and Et3N (66 mg) in CH2Cl2 (4 mL) was stirred for 16 hours. Purification by fresh chromatography over silica gel (elution with 50% ethyl acetate in hexane) gave 51 mg of the title compound as a solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7]([CH:8]=[CH:9][C:10]2[C:19]([CH3:20])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:6][C:5]([N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[N:4]1)[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[CH2:1]([N:3]1[C:7]([CH2:8][CH2:9][C:10]2[C:19]([CH3:20])=[N:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=2)=[N:6][C:5]([N:21]2[CH2:22][CH2:23][CH2:24][CH2:25]2)=[N:4]1)[CH3:2]
Reactant: CCn1nc(N2CCCC2)nc1C=Cc1nc2ccccc2nc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCn1nc(N2CCCC2)nc1CCc1nc2ccccc2nc1C
Temperature: 25 °C
Reaction time: 12 h
Yield: 31.8 %

Procedure:
2-(2-(1-ethyl-3-(pyrrolidin-1-yl)-1H-1,2,4-triazol-5-yl)vinyl)-3-methylquinoxaline (10 mg, 29.9 μmol, Eq: 1.00) was stirred in Ethyl acetate (6 ml) using 5% Pd on Ba2SO4 (3 mg, 30.8 μmol, Eq: 1.00) as catalyst in a hydrogen atmosphere. The mixture was stirred at room temperature for totally 12 h. TLC showed nearly complete conversion. The crude material was applied on silica gel an purified by column chromatography using ethyl acetate/methanol (0-5% methanol) as eluent to give 2-[2-(2-Ethyl-5-pyrrolidin-1-yl-2H-[1,2,4]triazol-3-yl)-ethyl]-3-methyl-quinoxaline (3.2 mg, 31.8%) as off-white semisolid
Reaction SMILES: [OH:1][CH2:2][C:3]1([CH3:43])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]2[CH:16]=[C:17]([C:24]([N:26]([CH:40]([CH3:42])[CH3:41])[C@@H:27]3[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:28]3)=[O:25])[C:18]([C:20]([F:23])([F:22])[F:21])=[CH:19][C:5]=2[O:4]1.[H-].[Na+].[CH3:46][O:47][CH2:48][CH2:49]Br.[Cl-].[NH4+]>CN(C)C=O>[CH:40]([N:26]([C:24]([C:17]1[C:18]([C:20]([F:23])([F:21])[F:22])=[CH:19][C:5]2[O:4][C:3]([CH2:2][O:1][CH2:49][CH2:48][O:47][CH3:46])([CH3:43])[C:8](=[O:9])[N:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][CH3:15])[C:6]=2[CH:16]=1)=[O:25])[C@@H:27]1[CH2:32][CH2:31][CH2:30][N:29]([C:33]([O:35][C:36]([CH3:37])([CH3:39])[CH3:38])=[O:34])[CH2:28]1)([CH3:41])[CH3:42]
Reactant: COCCCCN1C(=O)C(C)(CO)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COCCCCN1C(=O)C(C)(COCCOC)Oc2cc(C(F)(F)F)c(C(=O)N(C(C)C)[C@@H]3CCCN(C(=O)OC(C)(C)C)C3)cc21
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R)-3-[{[2-(hydroxymethyl)-4-(4-methoxybutyl)-2-methyl-3-oxo-7-(trifluoromethyl)-3,4-dihydro-2H-1,4-benzoxazin-6-yl]carbonyl}(isopropyl)amino]piperidine-1-carboxylate (230 mg) in N,N-dimethylformamide (3 ml) were added sodium hydride (50 mg, 55% by weight) and 2-bromoethyl methyl ether (0.11 ml), and the mixture was stirred at 80° C. for 3 hours. To the reaction solution was added a saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The mixture 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 (hexane/ethyl acetate) to give the title compound (110 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([NH2:9])=[C:4]([NH2:10])[CH:3]=1.C([O:15][C:16](=O)[CH2:17][C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]2[CH:31]=[C:30]([CH3:32])[N:29]=[C:28]([CH3:33])[CH:27]=2)[CH:21]=1)=O)(C)(C)C>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]2[NH:9][C:16](=[O:15])[CH2:17][C:18]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]4[CH:27]=[C:28]([CH3:33])[N:29]=[C:30]([CH3:32])[CH:31]=4)[CH:21]=3)=[N:10][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Solvent: Cc1ccccc1C
Product: Cc1cc(-c2cccc(C3=Nc4cc(Cl)c(Cl)cc4NC(=O)C3)c2)cc(C)n1

Procedure:
The title compound was prepared from commercially available 4,5-dichloro-1,2-phenylendiamine (109 mg, 0.61 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (200 mg, 0.61 mmol) in xylene (10 ml) under reflux conditions for 2 h according to the general procedure M. Obtained as a light brown solid (173 mg, 69%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=O)[CH:2]=1.C(N(CC)CC)C.[NH2:16][CH:17]1[CH2:22][CH2:21][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:19][CH2:18]1>[Ni].CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:16][CH:17]2[CH2:18][CH2:19][CH:20]([C:23]([O:25][CH3:26])=[O:24])[CH2:21][CH2:22]2)[CH:2]=1
Reactant: O=Cc1cccnc1
Reactant: COC(=O)C1CCC(N)CC1
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)C1CCC(NCc2cccnc2)CC1
Temperature: 50 °C
Reaction time: 6.5 h

Procedure:
6.13 g of pyridine-3-aldehyde, 5.77 g of triethylamine and 9 g of methyl 4-amino-cyclohexanecarboxylate are mixed into 250 ml of methanol. 3 g of Raney nickel are added thereto in order to hydrogenate the mixture, with stirring, for about 6.5 hours at 50° C. and 3 bar. After the catalyst has been eliminated by suction filtering the filtrate is evaporated down. The crude product is purified through silica gel with methylene chloride/methanol.