Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:27])[NH:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)=[CH:14][C:13]=1[N+:28]([O-])=O)([CH3:4])([CH3:3])[CH3:2]>CO.C1COCC1>[C:1]([O:5][C:6](=[O:31])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:27])[NH:19][C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][N:21]=2)=[CH:14][C:13]=1[NH2:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCCNc1ccc(C(=O)Nc2cc(Cl)ccn2)cc1[N+](=O)[O-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCNc1ccc(C(=O)Nc2cc(Cl)ccn2)cc1N

Procedure:
Prepared analogously to example 1b by hydrogenation of {3-[4-(4-chloro-pyridin-2-ylcarbamoyl)-2-nitro-phenylamino]-propyl}-carbamic acid tert.-butyl ester using Pt/charcoal 5% in methanol and THF.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:21])[C:10]2[CH:15]=[CH:14][N:13]=[C:12]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[CH:11]=2)=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][C:25]([C:28](O)=[O:29])=[CH:24][CH:23]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[CH3:74][O:75][C:76]1[CH:82]=[CH:81][C:79]([NH2:80])=[CH:78][CH:77]=1>CN(C=O)C>[CH3:74][O:75][C:76]1[CH:82]=[CH:81][C:79]([NH:80][C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:3]3[C:2]([CH3:1])=[CH:7][CH:6]=[C:5]([NH:8][C:9](=[O:21])[C:10]4[CH:15]=[CH:14][N:13]=[C:12]([N:16]5[CH2:20][CH2:19][CH2:18][CH2:17]5)[CH:11]=4)[CH:4]=3)=[CH:27][CH:26]=2)=[O:29])=[CH:78][CH:77]=1
Reactant: Cc1ccc(NC(=O)c2ccnc(N3CCCC3)c2)cc1-c1ccc(C(=O)O)cc1
Reactant: COc1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(NC(=O)c2ccc(-c3cc(NC(=O)c4ccnc(N5CCCC5)c4)ccc3C)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 31.6 %

Procedure:
2′-Methyl-5′-[(2-pyrrolidin-1-ylisonicotinoyl)amino]-1,1′-biphenyl-4-carboxylic acid (40 mg, 0.1 mmol), HATU (38 mg, 0.1 mmol), HOBT (13 mg, 0.1 mmol), DIPEA (52 μl), and 4-methoxyaniline (15 mg, 0.12 mmol) were mixed in DMF (1 ml) and stirred at room temperature for 18 h. The solvent was evaporated under vacuum and the residue partitioned between DCM (5 ml) and aqueous sodium carbonate (1M, 5 ml). The organic phase was applied to a silica gel flash column and eluted with DCM/ethanol/ammonia (400:8:1 then 300:8:1), which, after evaporation of the solvents under vacuum, gave N-{4′[(4-methoxyanilino)carbonyl]-6-methyl-1,1′-biphenyl-3-yl}-2-pyrrolidin-1-ylisonicotinamide (16 mg, 30%).
Reaction SMILES: [CH2:1]([S:8][CH:9]([CH:38]=O)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClCCCl.[NH:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O>[CH2:1]([S:8][CH:9]([CH2:38][N:44]1[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1)[CH2:10][NH:11][C:12]([C:14]1[NH:15][C:16]2[C:21]([CH:22]=1)=[CH:20][C:19]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:18][C:17]=2[N:28]([CH3:37])[S:29]([C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)(=[O:31])=[O:30])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(C=O)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: O
Product: CN(c1cc(OC(F)(F)F)cc2cc(C(=O)NCC(CN3CCOCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
To a mixture of N-[2-(benzylthio)-3-oxopropyl]-7-[methyl(2-thienylsulfonyl)amino]-5-(trifluoromethoxy)-1H-indole-2-carboxamide (560 mg) and 1,2-dichloroethane (15 mL) was added morpholine (170 mg) at room temperature, and the reaction mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (590 mg) was added at room temperature, and the mixture was further stirred at room temperature for 15 hr. Morpholine (170 mg) was added to the reaction mixture at room temperature, and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (590 mg) was added at room temperature, and the mixture was further stirred at room temperature for 3 hr. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The obtained residue was subjected to basic silica gel column chromatography, and eluted with hexane-ethyl acetate (4:1-2:1, volume ratio) to give the title compound (400 mg, yield 63%) as colorless crystals.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH:3]=[CH2:4].[O:6]1[CH:11]=[CH:10][CH2:9][CH2:8][CH2:7]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>ClCCl>[CH2:1]([O:5][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][O:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: C=CCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 4 h
Yield: 89 %

Procedure:
In a 1000 ml rb flask were placed 3-buten-1-ol (7.21 g, 100.00 mmol), 3,4-dihydro-2H-pyran (12.62 g, 150.00 mmol) and pyridinium p-toluenesulfonate (2.51 g, 10.00 mmol) in 350 ml of anhydrous dichloromethane. The reaction mixture was stirred at room temperature for 4 h. Then the reaction mixture was concentrated and the residue was purified by column with Hexane/Ethyl acetate=100/5 to provide 13.90 g of the desired product as an oil (89.0%). 1H-NMR (DMSO-d6) δ 5.851-5.742 (m, 1H), 5.103-5.011 (d, 1H), 4.997-4.985 (d, 1H), 4.555-4.537 (t, 1H), 3.745-3.611 (m, 2H), 3.433-3.347 (m, 2H), 2.290-2.236 (m, 2H), 1.698-1.675 (m, 2H), 1.611-1.566 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH3:15])=[CH:5]/[O:6][CH3:7].CC(N=NC(C#N)(C)C)(C#N)C.[Br:29]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:16])/[C:4](/[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1[CH2:15][Br:29])=[CH:5]/[O:6][CH3:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: CO/C=C(/C(=O)OC)c1ccc(Cl)cc1C
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: CO/C=C(/C(=O)OC)c1ccc(Cl)cc1CBr
Temperature: 25 °C

Procedure:
9.7 g (40 mmol) of the compound obtained in Step 2 was dissolved in 200 ml of carbon tetrachloride, and 0.7 g (4 mmol) of AIBN and 7.9 g (44 mmol) of N-bromosuccinimide were added thereto. The mixture was refluxed for 5 hours, and cooled to room temperature. The reaction mixture was washed with 50 ml of water twice and 50 ml portions of a brine solution, dried over anhydrous MgSO4, and distilled under a reduced pressure to obtain (E)-methyl-2-(2-bromomethyl-4-chlorophenyl)-3-methoxyacrylate containing a small amount of the starting material as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:5]([OH:7])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.[NH:47]([C:49](=[O:72])[CH2:50][CH2:51][C@@H:52]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:70])([CH3:69])[CH3:68])[CH2:53][C:54]1[CH:55]=[N:56][C:57]([C:60]([F:63])([F:62])[F:61])=[CH:58][CH:59]=1)[NH2:48]>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C:5]([NH:48][NH:47][C:49](=[O:72])[CH2:50][CH2:51][C@@H:52]([NH:64][C:65](=[O:71])[O:66][C:67]([CH3:68])([CH3:69])[CH3:70])[CH2:53][C:54]2[CH:55]=[N:56][C:57]([C:60]([F:61])([F:62])[F:63])=[CH:58][CH:59]=2)=[O:7])[CH:8]=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12]
Reactant: CC(C)(C)OC(=O)N[C@H](CCC(=O)NN)Cc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1ccc([N+](=O)[O-])c(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@H](CCC(=O)NNC(=O)c1ccc([N+](=O)[O-])c(F)c1)Cc1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 262.3 %

Procedure:
A mixture of 3-fluoro-4-nitrobenzoic acid (130 mg, 701 μmol) (commercially available from 3B Scientific Corporation Product List (Order Number 3B3-068221)), HATU (267 mg, 701 μmol), and N,N-diisopropylethylamine (132 μL, 760 μmol) in DMF (4 mL) was stirred at room temperature for 1 hour. This mixture was added dropwise to a mixture of tert-butyl ((1R)-4-hydrazino-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (220 mg, 585 μmol), prepared as shown in Scheme 24, and N,N-diisopropylethylamine (132 μL, 760 μmol) in DMF (3 mL) and the resulting mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure and the remaining residue partitioned between saturated aqueous NaHCO3 (20 mL) and DCM (20 mL). The layers were separated and the aqueous layer was extracted with DCM (3×20 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting colorless solid was dissolved in MeOH/DCM, absorbed onto silica gel and purified by flash chromatography (silica gel, 2% to 8% MeOH/DCM) to provide tert-butyl ((1R)-4-(2-((3-fluoro-4-nitrophenyl)carbonyl)hydrazino)-4-oxo-1-((6-(trifluoromethyl)-3-pyridinyl)methyl)butyl)carbamate (834 mg, 77%) as a light yellow solid. LCMS (API-ES) m/z: 566.0 (M+Na+).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][C:4]=1[CH2:14][OH:15]>O1CCCC1.[O-2].[O-2].[Mn+4]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[N:12][N:11]=[N:10]2)=[CH:5][C:4]=1[CH:14]=[O:15]
Reactant: COc1ccc(-n2cnnn2)cc1CO
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1ccc(-n2cnnn2)cc1C=O
Reaction time: 0.5 h
Yield: 83.3 %

Procedure:
Active manganese dioxide (77 mg) was added to a stirred solution of 2methoxy-5-(tetrazol-1-yl) phenylmethanol (40 mg) in tetrahydrofuran (1 ml). After 30 min the mixture was heated in an oil-bath at 70°. After a further 30 min, active manganese dioxide (67 mg) was added. After a further 1 h the mixture was allowed to cool and then filtered. The filtrate was evaporated to give the title compound as a yellow solid (33 mg); nmr, δ(d6 -DMSO), 4.4 (s,3H), 7.53 (d,1H, J=ca 10 Hz), 8.12-8.23 (m, 2H), 10.12 (s,1H), 10.40 (s,1H).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(CC)CC.[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[N:27]([CH2:28][CH2:29][O:30][C:31]4[CH:38]=[CH:37][C:36]([S:39](Cl)(=[O:41])=[O:40])=[CH:35][C:32]=43)[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]>C(Cl)Cl>[CH:17]([N:20]1[C:24]([C:25]2[N:34]=[C:33]3[C:32]4[CH:35]=[C:36]([S:39]([N:7]5[CH2:8][CH2:9][N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6]5)(=[O:41])=[O:40])[CH:37]=[CH:38][C:31]=4[O:30][CH2:29][CH2:28][N:27]3[CH:26]=2)=[N:23][CH:22]=[N:21]1)([CH3:19])[CH3:18]
Reactant: CC(C)N1CCNCC1
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)(=O)Cl)ccc1OCC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)N1CCN(S(=O)(=O)c2ccc3c(c2)-c2nc(-c4ncnn4C(C)C)cn2CCO3)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.9 %

Procedure:
To a solution of 1-isopropylpiperazine (50 mg, 0.39 mmol) and NEt3 (90 μL, 0.65 mmol) in DCM (8 mL) at 0° C. was added a suspension of 2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene-9-sulfonyl chloride from Example 121 (0.13 mmol) in DCM (8 mL) and the resulting mixture warmed to RT after 10 min then stirred for 2 h. The reaction mixture was diluted with DCM, washed with a saturated aqueous NaHCO3 solution then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, gradient 2-7% 2M NH3/MeOH in DCM) affording 128 (41 mg, 65%) as a white solid. LCMS: RT 2.90 min [M+H]+ 486.3. 1H NMR (DMSO, 400 MHz): δ 8.79 (1H, d, J=2.41 Hz), 8.00 (1H, s), 7.94 (1H, d, J=0.61 Hz), 7.63 (1H, dd, J=8.62, 2.43 Hz), 7.28 (1H, d, J=8.62 Hz), 5.76-5.69 (1H, m), 4.64-4.62 (4H, m), 2.94-2.87 (4H, m), 2.62-2.61 (1H, m), 2.54-2.43 (4H, m), 1.49 (6H, d, J=6.62 Hz), 0.89 (6H, d, J=6.53 Hz)
Reaction SMILES: C([O:4][C@H:5]1[C@H:10]([O:11]C(=O)C)[C@@H:9]([CH2:15][O:16][C:17]2[CH:18]=[CH:19][C:20]3[C:32](=[O:33])[C:31]4[C:30]5[C:25](=[CH:26][C:27]([Br:34])=[CH:28][CH:29]=5)[NH:24][C:23]=4[C:22]([CH3:36])([CH3:35])[C:21]=3[CH:37]=2)[O:8][C@H:7]([O:38][CH3:39])[C@@H:6]1[O:40]C(=O)C)(=O)C.N>CO>[Br:34][C:27]1[CH:26]=[C:25]2[C:30]([C:31]3[C:32](=[O:33])[C:20]4[CH:19]=[CH:18][C:17]([O:16][CH2:15][C@@H:9]5[C@@H:10]([OH:11])[C@H:5]([OH:4])[C@@H:6]([OH:40])[C@@H:7]([O:38][CH3:39])[O:8]5)=[CH:37][C:21]=4[C:22]([CH3:36])([CH3:35])[C:23]=3[NH:24]2)=[CH:29][CH:28]=1
Reactant: CO[C@H]1O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Agent: N
Solvent: CO
Product: CO[C@H]1O[C@H](COc2ccc3c(c2)C(C)(C)c2[nH]c4cc(Br)ccc4c2C3=O)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 21 h
Yield: 93.5 %

Procedure:
Under nitrogen atmosphere, to acetic acid (2S,3R,4S,5R,6R)-4,5-diacetoxy-6-(3-bromo-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-8-yloxymethyl)-2-methoxy-tetrahydro-pyran-3-yl ester (Compound T12-1, 34.0 mg, 51.63 μmol), methanol solution (2.50 mL, 2 M) of ammonia was added, and the mixture was stirred at room temperature for 21 hr. The reaction solution was concentrated under reduced pressure, and the resulting resides were washed with diethyl ether to obtain the target compound (25.7 mg, 94%).
Reaction SMILES: [CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[C:9]2[CH:14]=[CH:13][C:12]([CH2:15][N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)=[CH:11][CH:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:27][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI>C1COCC1>[CH:1]1([N:7]([CH3:26])[C:8](=[O:25])[C:9]2[CH:10]=[CH:11][C:12]([CH:15]([N:16]3[C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH3:27])=[CH:13][CH:14]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CN(C(=O)c1ccc(Cn2cnc3ccccc32)cc1)C1CCCCC1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CC(c1ccc(C(=O)N(C)C2CCCCC2)cc1)n1cnc2ccccc21
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 11 %

Procedure:
To a stirred solution of N-cyclohexyl-N-methyl 4-(1H-benzimidazylmethyl)benzamide (347 mg, 1 mmol) in dry THF (20 ml) at -78 ° C. was added sodium bis(trimethylsilyl)amide (1.1 ml of 1M solution in THF) under argon. The mixture was left to stir at -78° C. for 40 minutes, a solution of methyl iodide (170 mg, 1.2 mmol) in dry THF (2 ml) was added and the mixture left to warm to ambient temperature overnight. The reaction mixture was partitioned between ethyl acetate and brine, the organic layer dried (Na2SO4), concentrated to give a crude product which was purified by column chromatography (flash silica gel, 4% methanol in DCM) to yield N-cyclohexyl-N-methyl 4-(1-(1H-benzimidazyl)ethyl)benzamide (40 mg, 11%) as a white crystalline solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:24]2[CH2:29][CH2:28][N:27]([C:30]([O:32][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:31])[CH2:26][CH:25]=2)O1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:33]([O:32][C:30]([N:27]1[CH2:26][CH:25]=[C:24]([C:2]2[CH:7]=[CH:6][N:5]3[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][N:10]=[C:4]3[CH:3]=2)[CH2:29][CH2:28]1)=[O:31])([CH3:36])([CH3:34])[CH3:35]
Reactant: CCOC(=O)c1cnc2cc(Br)ccn12
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2cc(C3=CCN(C(=O)OC(C)(C)C)CC3)ccn12
Temperature: 160 °C

Procedure:
To a solution of 5-ethyl 7-bromoimidazo[1,2-a]pyridine-3-carboxylate (24g) (300 mg, 1.11 mmol) in DMF (9 mL) was added tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (414 mg, 1.34 mmol), K2CO3 (1.8M, 1.85 mL, 3.33 mmol) and Pd(PPh3)4(87 mg, 0.11 mmol). The reaction was evacuated and backfilled with nitrogen twice then heated at 160° C. for 10 minutes via microwave. After the reaction mixture was filtered through a pad of Celite, the mixture was diluted with a saturated solution of NH4Cl and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated to give crude ethyl 7-(1-(tert-butoxycarbonyl)-1,2,3,6-tetrahydropyridin-4-yl)imidazo[1,2-a]pyridine-3-carboxylate (89) (MS (m/z) 372.1 (M+1)+.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][O:6][C:7]1[C:8]([Cl:20])=[N:9][C:10]([Cl:19])=[N:11][C:12]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)C.[Li+].[OH-]>C1COCC1.O>[Cl:19][C:10]1[N:9]=[C:8]([Cl:20])[C:7]([O:6][CH2:5][C:4]([OH:21])=[O:3])=[C:12]([N:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)[N:11]=1
Reactant: CCOC(=O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1c(Cl)nc(Cl)nc1N1CCOCC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 96.6 %

Procedure:
To a solution of (2,4-dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid ethyl ester (581 mg, 1.73 mmol) in THF (10 mL) and water (2.5 mL) was added LiOH (951 μL, 1.90 mmol, 2M aqueous solution) and the resulting mixture stirred at RT for 2.5 hours. The reaction mixture was quenched with 1M HCl and extracted with ethyl acetate. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo affording (2,4-Dichloro-6-morpholin-4-yl-pyrimidin-5-yloxy)-acetic acid as a white solid (515 mg, 97%). 1H NMR (400 MHz, CDCl3): δ 4.59 (2H, s), 3.93-3.87 (4H, m), 3.81-3.75 (4H, m).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH2:21]C)=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.Cl.N[C@@H](CC)[C@@H:33](C1C=CC=C(OC)C=1)[OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([O:34][CH3:33])[CH:25]=4)[C@@H:19]([NH2:23])[CH2:20][CH3:21])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1
Reactant: CC[C@H](N)[C@H](O)c1cccc(OC)c1
Reactant: CCC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1ccccc1
Agent: Cl
Product: CC[C@H](N)[C@H](Oc1ccc2c(cnn2-c2ccc(F)cc2)c1)c1cccc(OC)c1

Procedure:
was synthesised in the same way as (91a) from (1R,2S)-2-amino-1-(3-methoxyphenyl)butan-1-ol hydrochloride (97b, 50 mg, 0.22 mmol).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:3]([CH3:6])([OH:5])[CH3:4].[Cl:14][C:15]([Cl:20])([Cl:19])[C:16](Cl)=[O:17]>N1C=CC=CC=1>[CH2:7]([C@H:2]([NH:1][C:16](=[O:17])[C:15]([Cl:20])([Cl:19])[Cl:14])[C:3]([OH:5])([CH3:4])[CH3:6])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(O)[C@@H](N)Cc1ccccc1
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Solvent: c1ccncc1
Product: CC(C)(O)[C@H](Cc1ccccc1)NC(=O)C(Cl)(Cl)Cl
Reaction time: 0.17 h
Yield: 87.7 %

Procedure:
To a solution of (8) (2.573 g, 14.37 mmol) in pyridine (50 ml) at 0° C. was added trichloroacetyl chloride (1.93 ml, 17.25 mmol). After stirring at this temperature for 10 minutes, the reaction mixture was stirred overnight at room temperature. The reaction was quenched by the addition of saturated aqueous sodium chloride solution, after which the product was extracted with dichloromethane and the combined organic extracts were washed with hydrochloric acid (1M). Concentration in vacuo and purification by flash column chromatography using 30% ethyl acetate/40-60 petroleum ether as eluant furnished the title compound (9) (4.093 g, 88%) as a solid; mp 88° C.; νmax (CDCl3) 1713 cm-1 ; [α]D24 (c 0.8 in CHCl3)=-26.8; (Found: C, 48.32; H, 4.61; N, 4.13. C13H16Cl3NO2 requires C, 48.16; H, 4.97; N, 4.32%); δH (300 MHz; CDCl3) 1.32 (3H, S, C(CH3)2), 1.40 (3H, s, C(CH3)2), 1.91 (1H, s, OH), 2.75 (1H, dd, J=10.9 and 14.2, CH2Ph), 3.20 (1H, dd, J=4.04 and 14.2, CH2Ph), 4.04-4.13 (1H, m, CHCH2), 6.80 (1H, d, J=9.3, NH); δC (125 MHz; CDCl3) 27.18 (CH3), 27.74 (CH3), 35.43 (CH2), 60.25 (CH), 72.92 (C), 93.00 (CC13), 126.89 (CH), 128.78 (CH), 129.33 (CH), 137.66 (C), 162.07 (CO); m/z (CI+, NH3) 324 (M+).
Reaction SMILES: [C:1]([C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:15])=[O:14])#[N:2].C[Si]([N:25]=[N+:26]=[N-:27])(C)C.C([Sn](=O)CCCC)CCC.O1CCCC1>C(OCC)(=O)C>[N:2]1[NH:25][N:26]=[N:27][C:1]=1[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][C:6]=2[NH:12][S:13]([C:16]1[S:17][CH:18]=[CH:19][CH:20]=1)(=[O:14])=[O:15]
Reactant: N#Cc1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1cccc2cc(-c3nn[nH]n3)[nH]c12)c1cccs1
Yield: 23 %

Procedure:
A mixture of N-(2-cyano-1H-indol-7-yl)thiophene-2-sulfonamide (0.40 g), trimethylsilylazide (0.35 mL), dibutyltin oxide (33 mg) and tetrahydrofuran (15 mL) was heated under reflux overnight. To the reaction mixture was added ethyl acetate, the mixture was ice-cooled, and the resulting crystals were filtrated, washed with cold ethyl acetate, and dried to give the title compound (0.09 g, yield 23%) as pale-yellow crystals. The crystals were recrystallized from ethyl acetate-hexane. melting point 274-275° C. (decomposition).
Reaction SMILES: Br[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[N:5][C:4]=2[CH:3]=1.[CH3:26][C:27]1[C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29](C(OC(C)(C)C)=O)[N:28]=1.C(=O)([O-])[O-].[Na+].[Na+].COCCOC>O>[CH3:26][C:27]1[NH:28][N:29]=[CH:30][C:31]=1[C:2]1[S:10][C:9]2[C:8](=[O:11])[NH:7][C:6]([C@@H:12]3[C@@H:17]4[CH2:18][C@@H:14]([CH2:15][CH2:16]4)[N:13]3[C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])=[N:5][C:4]=2[CH:3]=1
Reactant: Cc1nn(C(=O)OC(C)(C)C)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@@H](C2)[C@H]1c1nc2cc(Br)sc2c(=O)[nH]1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1[nH]ncc1-c1cc2nc([C@@H]3[C@H]4CC[C@H](C4)N3C(=O)OC(C)(C)C)[nH]c(=O)c2s1
Temperature: 100 °C
Reaction time: 3 h
Yield: 66.8 %

Procedure:
tert-Butyl (1R,3S,4S)-3-(6-bromo-4-oxo-3,4-dihydrothieno[3,2-d]pyrimidin-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate (1.03 g) and tert-butyl 3-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole-1-carboxylate (1.49 g), sodium carbonate (768 mg), 1,2-dimethoxyethane (8.0 mL) and water (4.0 mL) were placed in a flask, and the atmosphere in the flask was purged with argon. [1,1′-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride-dichloromethane complex (1:1) (197 mg) was added, and the atmosphere in the flask was purged again with argon. The reaction system was stirred at 100° C. for 3 hr, and the mixture was extracted with ethyl acetate and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the extract was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (690 mg) as a pale-yellow solid.
Reaction SMILES: [CH2:1]([NH:3][CH:4]1[CH2:8][CH2:7][NH:6][CH2:5]1)[CH3:2].F[C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1>>[CH2:1]([NH:3][CH:4]1[CH2:8][CH2:7][N:6]([C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=2)[CH2:5]1)[CH3:2]
Reactant: CCNC1CCNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: CCNC1CCN(c2ccc([N+](=O)[O-])cc2)C1

Procedure:
The compound was prepared from 3-ethylamino-pyrolidine (TCI-US) and 4-fluoro-nitrobenzene (Aldrich) following the procedure used in Example 1. MS (m+H)+: 236.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C(OC([N:23]1[C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26]OS1(=O)=O)=O)(C)(C)C>>[NH2:23][C:28]([CH3:30])([CH3:29])[CH2:27][CH2:26][N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: COC(=O)COc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)CCOS1(=O)=O
Product: COC(=O)COc1ccc2c(ccn2CCC(C)(C)N)c1

Procedure:
Prepared analogously to Component V by alkylation of methyl (1H-indol-5-yloxy)-acetate with N-tert-butoxycarbonyl-4,4-dimethyl-[1,2,3]oxathiazinane-2,2-dioxide and subsequent cleaving of the acid protecting group.