Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:17]=[C:18]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[C:19]3[CH:24]=[C:23]([CH2:25][N:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[S:22][C:20]=3[N:21]=2)=[CH:12][N:11]=1.[C:38](O)(=[O:42])[C@H:39]([CH3:41])[OH:40]>>[OH:40][C@@H:39]([CH3:41])[C:38]([N:29]1[CH2:28][CH2:27][N:26]([CH2:25][C:23]2[S:22][C:20]3[N:21]=[C:16]([C:13]4[CH:12]=[N:11][C:10]([NH:9][CH3:8])=[CH:15][CH:14]=4)[N:17]=[C:18]([N:32]4[CH2:33][CH2:34][O:35][CH2:36][CH2:37]4)[C:19]=3[CH:24]=2)[CH2:31][CH2:30]1)=[O:42]
Reactant: CNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCNCC4)sc3n2)cn1
Reactant: C[C@H](O)C(=O)O
Solvent: O=C(O)C(F)(F)F
Product: CNc1ccc(-c2nc(N3CCOCC3)c3cc(CN4CCN(C(=O)[C@H](C)O)CC4)sc3n2)cn1

Procedure:
The crude TFA salt of N-methyl-5-(4-morpholino-6-(piperazin-1-ylmethyl)thieno[2,3-d]pyrimidin-2-yl)pyridin-2-amine was reacted with L-Lactic acid via General Procedure B to give 46 mg of 374 after reverse phase HPLC purification. MS (Q1) 498.3 (M)+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[CH:20][CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:28]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][C:12]([C:18]3[N:26]4[C:21]([C:22]([NH2:27])=[N:23][CH:24]=[N:25]4)=[C:20]([Br:28])[CH:19]=3)=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(-c3ccc4c(N)ncnn34)cc2C1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2ccc(-c3cc(Br)c4c(N)ncnn34)cc2C1
Temperature: -20 °C
Reaction time: 2 h
Yield: 150 %

Procedure:
To a solution of 7-(4-amino-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (2.2 g, 6.1 mmol) in THF (30 mL) at −20° C. was added 1,3-dibromo-5,5-dimethyl-imidazolidine-2,4-dione (884 mg, 3 mmol) in four portions. The reaction mixture was allowed to stir at −20° C. for 2 h. The solvent was evaporated and the residue was purified by column chromatography (10-50% EtOAc/Hexane) to provide 2 g (72%) of the desired product. 1H NMR (300 MHz, DMSO-d6) δ 7.9 (s, 1 H), 7.85 (d, 2 H), 7.2 (d, 2 H), 4.5 (s, 2 H), 3.5 (t, 2 H), 2.8 (t, 2 H), 1.4 (s, 9 H); ES-MS m/z 444.08 [M+H]+, HPLC RT (min) 3.24.
Reaction SMILES: [Na].[CH:2]1([N:7]2[C:11]([NH2:12])=[C:10]([C:13]([NH2:15])=[O:14])[C:9]([CH2:16][CH3:17])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3]1.[N:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH2:24][C:25](OCC)=O)[CH:19]=1.N1C=CC=C(CC([O-])=O)C=1>C(O)C.O.C(O)(=O)C>[CH:2]1([N:7]2[C:11]3=[N:12][C:25]([CH2:24][C:20]4[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=4)=[N:15][C:13](=[O:14])[C:10]3=[C:9]([CH2:16][CH3:17])[NH:8]2)[CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CCOC(=O)Cc1cccnc1
Reactant: CCc1nn(C2CCCC2)c(N)c1C(N)=O
Agent: O=C([O-])Cc1cccnc1
Agent: [Na]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: CCc1[nH]n(C2CCCC2)c2nc(Cc3cccnc3)nc(=O)c1-2
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
Sodium (0.11 g) was dissolved in ethanol and then 1-cyclopentyl-3-ethyl-5-amino-1H-pyrazole-4-carboxamide (0.49 g, 2.21 mmol) was added, followed 10 minutes later by ethyl 3-pyridinylacetate (0.73 g) in ethanol (2 mL). The reaction mixture was refluxed overnight, additional 3-pyridinylacetate (0.35 g) was added and the reaction mixture was again refluxed overnight. The reaction mixture was cooled to room temperature, the solvent was stripped and the residue was dissolved in water and treated with acetic acid (to pH of 7). The mixture was extracted with CHCl3 (3×50 mL), the organic layers were combined, dried over MgSO4 and stripped to a pale yellow oil. The oil was crystallized by the addition of ether and the product was collected by filtration and washed with ether to afford 0.4 g of 1-cyclopentyl-3-ethyl-6-[3-pyridinylmethyl]pyrazolo[3,4-d]pyrimidin-4-one.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([N:15]2[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]2=[O:22])[CH:6]=[CH:7][C:8]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.C(N(CC)CC)C.Cl[C:31]1[N:32]=[N:33][C:34]([C:37]#[N:38])=[CH:35][CH:36]=1>C(#N)C>[C:37]([C:34]1[N:33]=[N:32][C:31]([N:12]2[CH2:11][CH2:10][N:9]([C:8]3[CH:7]=[CH:6][C:5]([N:15]4[CH2:19][C@H:18]([CH2:20][OH:21])[O:17][C:16]4=[O:22])=[CH:4][C:3]=3[F:2])[CH2:14][CH2:13]2)=[CH:36][CH:35]=1)#[N:38]
Reactant: N#Cc1ccc(Cl)nn1
Reactant: O=C1O[C@@H](CO)CN1c1ccc(N2CCNCC2)c(F)c1
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: N#Cc1ccc(N2CCN(c3ccc(N4C[C@H](CO)OC4=O)cc3F)CC2)nn1
Yield: 79.1 %

Procedure:
3-(3-Fluoro4-(piperazin-1-yl)phenyl)-5(R)-hydroxymethyloxazolidin-2-one hydrochloride (6.63 g, 20 mmol) was suspended by stirring in acetonitrile (200 ml) under nitrogen, and triethylamine (4.44 g, 44 mmol) added. The mixture was stirred for 10 minutes 3-chloro-6-cyanopyridazine (2.79 g, 20 mmol) added, and the mixture heated under reflux for 18 hours. After cooling, solid was filtered, washed with water (3×150 ml) and diethyl ether (2×150 ml) to give the title product (6.3 g).
Reaction SMILES: C(O)C.[OH:4][C@@H:5]1[CH2:25][C:24]2[C@:19]([CH3:27])([CH:20]=[CH:21][C:22](=[O:26])[CH:23]=2)[C@@H:18]2[C@@H:6]1[C@H:7]1[C@:15]([CH3:28])([CH2:16][CH2:17]2)[C@@H:10]([C@@H:11]([CH:13]=[O:14])[CH3:12])[CH2:9][CH2:8]1.[BH4-].[Na+].Cl>O>[OH:4][C@@H:5]1[CH2:25][C:24]2[C@:19]([CH3:27])([CH:20]=[CH:21][C:22](=[O:26])[CH:23]=2)[C@@H:18]2[C@@H:6]1[C@H:7]1[C@:15]([CH3:28])([CH2:16][CH2:17]2)[C@@H:10]([C@H:11]([CH3:12])[CH2:13][OH:14])[CH2:9][CH2:8]1
Reactant: C[C@H](C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C[C@H](CO)[C@H]1CC[C@H]2[C@@H]3[C@H](O)CC4=CC(=O)C=C[C@]4(C)[C@H]3CC[C@]12C
Yield: 93.4 %

Procedure:
Ethanol (200 ml) was added to 20.0 g of (7α,20S)-7-hydroxy-3-oxo-pregna-1,4-diene-20-carbaldehyde. To this solution was added 0.61 g of sodium borohydride in several portions with stirring under ice cooling. After completion of the addition, the mixture was further stirred for 1 hour under ice cooling. The reaction mixture was neutralized with 1 N hydrochloric acid, then 200 ml of water was added, and the ethanol was distilled off under reduced pressure. The precipitate was collected by filtration, washed with water, then dehydrated by adding toluene to the precipitate and removing water by azeotropic distillation, and concentrated to give 18.8 g of (7α,20S)-7,21-dihydroxy-20-methyl-pregna-1,4-dien-3-one (yield 93%).
Reaction SMILES: C([C@H](NC(=O)[C@H](C1OC(C2C=CC(C3C=CC=CC=3)=CC=2)=CC=1)CC(O)=O)CO)C1C=CC=CC=1.C([O:40][C:41](=[O:73])[CH2:42][CH:43]([C:56]1[O:60][C:59]([C:61]2[CH:66]=[CH:65][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:63][CH:62]=2)=[CH:58][CH:57]=1)[C:44]([NH:46][C@H:47]([C:52](=[O:55])[NH:53][CH3:54])[C:48]([CH3:51])([CH3:50])[CH3:49])=[O:45])(C)(C)C.FC(F)(F)C(O)=O.CC(OC)(C)C>C(Cl)Cl>[CH3:49][C:48]([CH3:51])([CH3:50])[C@H:47]([NH:46][C:44](=[O:45])[CH:43]([C:56]1[O:60][C:59]([C:61]2[CH:62]=[CH:63][C:64]([C:67]3[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=3)=[CH:65][CH:66]=2)=[CH:58][CH:57]=1)[CH2:42][C:41]([OH:73])=[O:40])[C:52](=[O:55])[NH:53][CH3:54]
Reactant: CNC(=O)[C@@H](NC(=O)C(CC(=O)OC(C)(C)C)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Agent: O=C(O)C[C@H](C(=O)N[C@H](CO)Cc1ccccc1)c1ccc(-c2ccc(-c3ccccc3)cc2)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COC(C)(C)C
Product: CNC(=O)[C@@H](NC(=O)C(CC(=O)O)c1ccc(-c2ccc(-c3ccccc3)cc2)o1)C(C)(C)C
Yield: 48 %

Procedure:
According to the procedure described in Example 15(a) for the preparation of N-(1(S)-benzyl-2-hydroxyethyl)-3(S)-(2-biphenyl-4-yl-furan-5-yl)succinamic acid, N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid t-butyl ester was deprotected with trifluoroacetic acid in CH2Cl2 after 1 hour. Trituration of crude with MTBE/hex provided in 48% yield N-[2,2-dimethyl-1(S)-(methylcarbamoyl)propyl]-3-(2-(biphenyl-4-yl)-furan-5-yl)succinamic acid as a rust-colored amorphous solid. 1H NMR (CD3CN): δ 7.75 (d, 2H, J=8.5 Hz), 7.69-7.66 (m, 4H), 7.47 (t, 2H, J=7.2 Hz), 7.37 (t, 1H, J=7.2 Hz), 6.91 (d, 1H, J=7.7 Hz), 6.77 (d, 1H, J=3.3 Hz), 6.56 (bs, 1H), 6.39 (d, 1H, J=3.3 Hz), 4.24-4.19 (m, 1H), 4.12 (d, 1H, J=9.2 Hz), 3.17-3.08 (m, 1H), 2.82 (dd, 1H, J=5.0, 17.1 Hz), 2.67 (d, 3H, J=4.8 Hz), 0.86 (s, 9H). HRFABMS: Calculated for C27H31N2O5 (M+H+) 463.2233. Found: 463.2236.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10]([C:12]1([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=3)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)=[O:11])[CH2:2]2.[Br:26][CH2:27][C:28]([NH:30][C:31]1[CH:36]=[N:35][CH:34]=[CH:33][N:32]=1)=[O:29]>C(#N)C.C(OCC)C>[Br-:26].[F:25][C:21]1[CH:20]=[C:19]([C:12]2([C:10]([O:9][C@@H:3]3[CH:4]4[CH2:5][CH2:6][N+:1]([CH2:27][C:28](=[O:29])[NH:30][C:31]5[CH:36]=[N:35][CH:34]=[CH:33][N:32]=5)([CH2:8][CH2:7]4)[CH2:2]3)=[O:11])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O[C@H]1CN2CCC1CC2)C1(c2cccc(F)c2)CCCCCC1
Reactant: O=C(CBr)Nc1cnccn1
Solvent: CCOCC
Solvent: CC#N
Product: O=C(C[N+]12CCC(CC1)[C@@H](OC(=O)C1(c3cccc(F)c3)CCCCCC1)C2)Nc1cnccn1
Product: [Br-]
Reaction time: 72 h
Yield: 62.3 %

Procedure:
1-(3-Fluoro-phenyl)-cycloheptanecarboxylic acid (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)ester (Example 12d) (0.100 g) was dissolved in acetonitrile (8 mL) and 2-bromo-N-pyrazin-2-yl-acetamide (Example 11a) (0.05 g) was added. The reaction mixture was stirred for 3 days diluted with diethyl ether (8 mL), stirred for a further 10 minutes, the resulting solid was filtered and washed with diethyl ether (3×8 mL) to afford a solid which was recrystallised from hot butanone (8 mL) to afford the titled compound as a solid (0.081 g).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)[OH:4].[Cl:19][C:20]1[CH:25]=[C:24](Cl)[N:23]=[CH:22][N:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O1CCOCC1>C(OCC)(=O)C>[Cl:19][C:20]1[CH:25]=[C:24]([O:4][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)[C:2]([F:1])([F:17])[F:18])[N:23]=[CH:22][N:21]=1
Reactant: OC(c1ccccc1-c1ccncc1)C(F)(F)F
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: FC(F)(F)C(Oc1cc(Cl)ncn1)c1ccccc1-c1ccncc1
Temperature: 110 °C
Yield: 79.1 %

Procedure:
The mixture of 2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)ethanol (100 mg, 0.40 mmol), 4,6-dichloro-pyrimidine (54 mg, 0.38 mmol), cesium carbonate (468 mg, 1.44 mmol) and 1,4-dioxane (1 ml). The mixture was heated at 110° C. overnight. The reaction mixture was cooled to room temperature. 10 ml of ethyl acetate was added, and then the mixture was filtered through Celite. The filtrate was concentrated to give 110 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-pyridin-4-yl-phenyl)-ethoxy]-pyrimidine, yield: 76%.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH:7]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:6][CH2:5]2.[F-].[K+].Cl[C:21]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][CH:24]=[CH:23][N:22]=1.Cl>CN(C=O)C.O.CCOC(C)=O>[N+:27]([C:26]1[C:21]([O:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[O:8][CH:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:6][CH2:5]3)=[N:22][CH:23]=[CH:24][CH:25]=1)([O-:29])=[O:28]
Reactant: Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: Cl
Agent: [F-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cccnc1Oc1ccc2c(c1)CCC(c1ccccc1)O2
Reaction time: 0.5 h

Procedure:
6-Hydroxyflavane (0.150 g) was dissolved in 3 ml of dry DMF under nitrogen. KF (0.117 g) was added and the solution was stirred for 30 minutes at +120° C. The solution was cooled a bit and 2-chloro-3-nitropyridine was added (0.212 g) and stirred for 7 hours at +120° C. and overnight at room temperature. The reaction mixture was taken up with EtOAc and 1M HCl and water were added and phases separated. Organic phase was washed with water and pH was adjusted to 7 with 1M NaOH. Organic phase was washed with water, brine and dried over Na2SO4. Product was purified by column chromatography (CH2Cl2:n-heptane/80:20). 1H-NMR (400 MHz; d6-DMSO): δ 8.55 (dd, 1H, J=7.9 Hz, J=1.7 Hz), 8.42 (dd, 1H, J=4.9 Hz, J=1.7 Hz), 7.51-7.29 (m, 6H), 7.02-6.92 (m, 2H), 6.88 (d, 1H, J=8.7 Hz), 5.14 (dd, 1H, J=10.0 Hz, J=2.1 Hz), 3.05-2.92 (m, 1H), 2.78-2.68 (m, 1H), 2.22-2.13 (m, 1H), 2.07-1.95 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15](=[O:17])[CH3:16])[CH:6]=[C:7]([S:9]([F:14])([F:13])([F:12])([F:11])[F:10])[CH:8]=1.C(OC)(OC)OC.C1COCC1.[Br-:30].[Br-].[Br-].C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1.C1([N+](C)(C)C)C=CC=CC=1>CO.CC1(C)C2(CS(O)(=O)=O)C(CC1CC2)=O>[Br:30][CH2:16][C:15]([C:5]1[CH:6]=[C:7]([S:9]([F:10])([F:11])([F:12])([F:13])[F:14])[CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:17]
Reactant: COc1cc(C(C)=O)cc(S(F)(F)(F)(F)F)c1
Reactant: [Br-]
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: C[N+](C)(C)c1ccccc1
Solvent: C1CCOC1
Solvent: COC(OC)OC
Solvent: CO
Product: COc1cc(C(=O)CBr)cc(S(F)(F)(F)(F)F)c1
Reaction time: 8 h
Yield: 68.5 %

Procedure:
1-[3-Methoxy-5-(pentafluorosulfanyl)phenyl]ethanone (34 mg) was dissolved in absolute methanol (3 ml). To this were added, while stirring, DL-camphorsulfonic acid (0.6 mg) and trimethyl orthoformate (40 mg). After stirring for 4 h, the mixture was left to stand overnight and then absolute THF (3 ml) and phenyltrimethylammonium tribromide (40 mg) were added while stirring. After stirring at RT for 2 h, the mixture was stirred at 50° C. for 3 h, left to stand over the weekend and, after adding further phenyltrimethylammonium tribromide (20 mg), stirred at 50° C. for another 5 h. The reaction mixture was concentrated, and the residue was taken up with acetonitrile and admixed with 5N sulfuric acid while stirring. After stirring for 2 h, the mixture was concentrated and the residue was purified by means of preparative HPLC. The product-containing fractions were combined, freed of the acetonitrile, admixed with saturated sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The combined extracts were dried over magnesium sulfate, filtered and concentrated. 15 mg of the desired compound were obtained.
Reaction SMILES: [CH2:1]([O:3][CH:4]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].C(N(CC)CC)C.[CH2:25](O)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]CC>CCCCCCC>[CH2:1]([O:3][C@@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH2:9][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[O:6])[CH3:2].[CH2:1]([O:3][C@H:4]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: CCCCCCCCCCO
Solvent: CCCCCCC
Solvent: CCN(CC)CC
Product: CCCCCCCCCCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Product: CCOC(=O)[C@@H](Cc1ccc(O)cc1)OCC
Temperature: 25 °C

Procedure:
To ethyl (2RS) (+/−) 2-ethoxy-3-(4-hydroxyphenyl)propanoate (5 mg) in solution in heptane (dried on 4 Å molecular sieves) (1 ml), triethylamine (0.4 μl) and n-decanol (8 μl), were added 4 Å molecular sieves and Rhizopus arrhizus lipase (Fluka 62305; 2.2 U/g) (20 mg). The reaction mixture was shaken at room temperature and analysed at different times. The reaction mixtures were analysed by the gradient HPLC method 2 and by the chiral HPLC method 4.
Reaction SMILES: [N:1](OCC(C)C)=[O:2].[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[NH:15][CH2:16][CH2:17][Cl:18])[CH2:9][CH:10]([CH3:12])[CH3:11].O1CCCC1.Cl>C(O)C>[CH2:8]([N:13]([C@:20]1([OH:35])[C@H:26]([OH:27])[C@@H:25]([CH2:28][OH:29])[O:24][C@:22]([CH2:30][CH:31]([CH3:33])[CH3:32])([OH:23])[C@@H:21]1[OH:34])[C:14](=[O:19])[N:15]([CH2:16][CH2:17][Cl:18])[N:1]=[O:2])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)CCN(C(=O)NCCCl)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Reactant: CC(C)CON=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCO
Product: CC(C)CCN(C(=O)N(CCCl)N=O)[C@]1(O)[C@H](O)[C@@H](CO)O[C@@](O)(CC(C)C)[C@@H]1O
Yield: 67.3 %

Procedure:
Isobutyl nitrite (3.5 ml) was dropped into a solution of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)urea (3.48 g, 8.47 mmol) in a mixture of ethanol (50 ml), tetrahydrofuran (150 ml), and 2N hydrochloric acid (30 ml) with well stirring at 0° to 5° C. Thereafter, 2.51 g of 3-isopentyl-3-(isobutyl α-D-glucopyranose-3-yl)-1-(2-chloroethyl)-1-nitrosourea was obtained by the same operations of Example 63(2); yield 67.3%, m.p. 69°-71° C., [α]D20 +45.8° (C 1.0, methanol).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH2:18][OH:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1>O=[Mn]=O.ClCCl>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]#[C:17][CH:18]=[O:19])=[CH:13][CH:14]=2)[CH:9]=[N:8]1
Reactant: OCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: O=CC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.9 %

Procedure:
A 500 mL three-necked round bottom flask was charged with 3-(1-(tetrahydro-2H-pyran-2-yl) -1H-indazol-5-yl)prop-2-yn-1-ol (11.4 g, 44.2 mmol; Intermediate 16), dichloromethane (300 mL) and MnO2 (38.4 g, 442 mmol). The resulting mixture was stirred at room temperature for 16 hours. Upon completion, the reaction mixture was filtered. The filtrate was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel (1:100-1:20 EtOAc/petroleum ether) affording the title compound (6.4 g). 1H NMR (400 MHz, DMSO-d6): δ 9.45 (s, 1H), 8.27-8.25 (m, 2H), 7.87 (d, 1H), 7.66 (dd, 1H), 5.86 (dd, 1H), 3.91-3.87 (m, 1H), 3.79-3.72 (m, 1H), 2.40-2.36 (m, 1H), 2.05-1.96 (m, 2H), 1.78-1.72 (m, 1H), 1.61-1.56 (m, 2H); LCMS: 255 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13](O)=[O:14])[CH:10]=[CH:9][N:8]2[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O.[NH2:37][NH2:38].O>C1COCC1>[C:1]([C:5]1[N:6]=[C:7]2[CH:12]=[C:11]([C:13]([NH:37][NH2:38])=[O:14])[CH:10]=[CH:9][N:8]2[C:16]=1[CH2:17][CH:18]1[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: NN
Reactant: CC(C)(C)c1nc2cc(C(=O)O)ccn2c1CC1CCCCC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)c1nc2cc(C(=O)NN)ccn2c1CC1CCCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.4 %

Procedure:
2-tert-Butyl-3-cyclohexylmethylimidazo[1,2-a]pyridine-7-carboxylic acid (500 mg, 1.59 mmol) was suspended in THF (5.0 mL), and the suspension was stirred at room temperature for 1 hour after adding carbonyldiimidazole (CDI) (280 mg, 1.73 mmol). The reaction mixture was stirred at room temperature for 1 hour after adding hydrazine monohydrate (0.240 mL, 4.80 mmol). Water was added to the reaction mixture. The precipitated solid was collected by filteration, and dried under reduced pressure to give 2-tert-butyl-3-cyclohexylmethylimidazo[1,2-a]pyridine-7-carbohydrazide (331 mg, yield 79%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@:9]1([CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[C@H:11]([CH3:12])[O:10]1.C([S:22][C@@H:23]1[CH2:28][O:27][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:25][CH2:24]1)(=O)C>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]([OH:10])([C@H:11]([S:22][C@@H:23]1[CH2:24][O:25][C@@H:26](/[CH:29]=[CH:30]/[C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[O:27][CH2:28]1)[CH3:12])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1
Reactant: C[C@@H]1O[C@@]1(Cn1cncn1)c1ccc(F)cc1F
Reactant: CC(=O)S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1
Product: C[C@@H](S[C@H]1CO[C@H](/C=C/c2ccc(C(F)(F)F)cc2)OC1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Yield: 70 %

Procedure:
Reaction and treatment were carried out in the same manner as in Example 1 using (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and trans-5-(acetylthio)-2-[(E)-2-[4-(trifluoromethyl)phenyl]vinyl]-1,3-dioxane to obtain the desired compound having a melting point of 73 to 75° C. in a yield of 70%.
Reaction SMILES: N[C:2]1[C:3]([C:8](O)=O)=[CH:4][CH:5]=[CH:6][CH:7]=1.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14](C(O)=O)[CH:13]=1.[NH2:21]C1C=CC=CC=1.C=O>>[CH:2]1[C:3]([CH2:8][C:15]2[CH:14]=[CH:13][C:12]([NH2:11])=[CH:17][CH:16]=2)=[CH:4][CH:5]=[C:6]([NH2:21])[CH:7]=1
Reactant: Nc1ccccc1
Reactant: Nc1ccccc1C(=O)O
Reactant: Nc1cccc(C(=O)O)c1
Agent: C=O
Product: Nc1ccc(Cc2ccc(N)cc2)cc1

Procedure:
An 2-anilinecarboxylic acid derivative (e.g. sodium 2-anilinecarboxylate) or an 3-anilinecarboxylic acid derivative (e.g. sodium 3-anilinecarboxylate) and aniline are treated with formalin under acidic conditions to give the corresponding 4,4′-diaminodiphenylmethane derivative. This is diazotized using sodium nitrite under acidic conditions in the presence of hydrochloric acid, followed by reaction with sodium azide, to give the desired product.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[CH3:23][N:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[CH:29]=O>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:29][C:25]4[N:24]([CH3:23])[CH:28]=[CH:27][CH:26]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: Cn1cccc1C=O
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4cccn4C)cccc3n2)o1

Procedure:
The title compound, MS: m/e=347.3 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 1-methylpyrrol-2-carbaldehyde as described in example 26.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:20]2[CH2:25][CH2:24][N:23](C(NC3C=CC=CC=3)=O)[CH2:22][CH2:21]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[NH:8][C:5]2=[N:6][CH:7]=1.Br[C:36]1C(N2CCN(CC)CC2)=C([N+]([O-])=O)C(N)=N[CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].CN(C1C=CC(C=O)=CC=1)C>CN(C=O)C>[Br:1][C:2]1[C:3]([N:20]2[CH2:21][CH2:22][N:23]([CH2:36][CH3:41])[CH2:24][CH2:25]2)=[C:4]2[N:10]=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([N:17]([CH3:18])[CH3:19])=[CH:15][CH:16]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Reactant: CCN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Agent: CN(C)c1ccc(C=O)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(N(C)C)cc4)nc23)CC1
Reaction time: 18 h
Yield: 49 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-4-(4-ethylpiperazin-1-yl)-3-nitropyridin-2-amine (100 mg, 0.30 mmol), DMF (1.5 mL), 1M Na2S2O4 (3 eq, 0.90 mmol, 0.90 mL) and 4-(N,N-dimethylamino)benzaldehyde (1.05 eq, 0.32 mmol, 47 mg). After 18 h, filtration of the precipitate gave pure product (47 mg, 49%) as an off-white solid; 1H-NMR (500 MHz, DMSO-d6) 1.22 (br s, 3H, CH2CH3), 2.55 (s, 2H, CH2CH3), 2.73 (s, 2H, piperazine NCH2), 2.89 (s, 2H, piperazine NCH2), 3.01 (s, 6H, N(CH3)2), 3.80 (br s, 4H, piperazine N(CH2)2), 6.83 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.02 (d, J=8.9 Hz, 2H, N,N-dimethylaminophenyl), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.23 (br s, 1H, imidazo[4,5-b]pyridine NH);