Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH2:19])[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1.[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(OCC)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]3[C:13]([CH3:20])=[C:14]([NH:19][C:28](=[O:29])[C:27]4[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=4)[C:15]([CH3:18])=[C:16]([CH3:17])[C:11]=3[O:10][C:9]=2[CH3:21])=[CH:4][CH:3]=1
Reactant: Cc1oc2c(C)c(C)c(N)c(C)c2c1-c1ccc(F)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)Nc2c(C)c(C)c3oc(C)c(-c4ccc(F)cc4)c3c2C)cc1
Yield: 75 %

Procedure:
By using 3-(4-fluorophenyl)-2,4,6,7-tetramethyl-1-benzofuran-5-amine and 4-methoxybenzoyl chloride, the title compound was synthesized according to Example 1b. Yield: 75%. Melting point: 225-227° C. (Ethyl acetate).
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:8][C:9]=1[NH2:10])=[O:4].[F:15][C:16]([F:21])([F:20])[C:17](N)=[NH:18]>C(Cl)(Cl)Cl>[C:11]([C:7]1[S:6][C:5]2[C:3]([OH:4])=[N:18][C:17]([C:16]([F:21])([F:20])[F:15])=[N:10][C:9]=2[CH:8]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: COC(=O)c1sc(C(C)(C)C)cc1N
Reactant: N=C(N)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC(C)(C)c1cc2nc(C(F)(F)F)nc(O)c2s1
Temperature: 25 °C
Yield: 83.5 %

Procedure:
3-Amino-5-tert-butyl-thiophene-2-carboxylic acid methyl ester (0.50 g, 2.34 mmol, 1 eq.) and trifluoroacetamidine (263 mg, 2.34 mmol, 1 eq.) were heated neat at 150° C. until reaction was complete by TLC. Cooled to rt then dissolved resultant solids in chloroform. Dried and stripped in vacuo to give 540 mg of white solids as product. LCMS detects (M+H)+=277.
Reaction SMILES: [N:1]1([CH2:10][C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[Cl:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Br)=[CH:30][CH:29]=1>C1COCC1>[N:1]1([CH:10]([CH2:32][C:31]2[CH:34]=[CH:35][C:28]([Cl:27])=[CH:29][CH:30]=2)[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[N:2]1
Reactant: Clc1ccc(CBr)cc1
Reactant: CON(C)C(=O)Cn1nnc2ccccc21
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CON(C)C(=O)C(Cc1ccc(Cl)cc1)n1nnc2ccccc21
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
To a solution of 2.0 g (9 mmol) of 2-(1H-1,2,3-benzotriazol-1-yl)-N-methoxy-N-methylacetamide in 15 mL anhydrous THF at −78° C., 10 mL (10 mmol) of 1M lithium bis(trimethylsilyl)amide was added dropwise. After stirring for 25 min, a solution of 2.06 g (10 mmol) of 4-chlorobenzyl bromide in 2 mL anhydrous THF was added. The resulting reaction mixture was allowed to warm to RT and stirred for 6 h. This reaction was quenched, diluted with 75 mL EtOAc and washed 3 times with 10 mL each of brine, After drying the organic phase solvent removal afforded a crude product which was purified on silica gel using 40% EtOAc in hexane as solvent to afford the desired product as a solid. 1H NMR: (CDCl3): δ 3.2 (s, 3H), 3.34 (s, 3H), 3.52 (m, 1H), 3.7 (m, 1H), 6.32 (t, 1H), 6.9-8.2 (m, 8H).
Reaction SMILES: Cl[C:2]1[C:6]([C:7]#[N:8])=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]3[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=3[F:26])=[O:17])=[CH:11][CH:10]=2)[S:4][N:3]=1.[O:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][CH2:35][NH2:36])[CH2:29][CH2:28]1.C([O-])([O-])=O.[Na+].[Na+].[Cl-].[Na+].O>CCOC(C)=O>[C:7]([C:6]1[C:2]([NH:36][CH2:35][CH2:34][CH2:33][N:30]2[CH2:31][CH2:32][O:27][CH2:28][CH2:29]2)=[N:3][S:4][C:5]=1[C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[C:23]([CH3:25])[CH:22]=[CH:21][C:20]=2[F:26])=[O:17])=[CH:11][CH:10]=1)#[N:8]
Reactant: NCCCN1CCOCC1
Reactant: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(Cl)c3C#N)cc2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(-c3snc(NCCCN4CCOCC4)c3C#N)cc2)c1
Temperature: 70 °C
Yield: 16 %

Procedure:
A mixture of 1-[4-(3-chloro-4-cyanoisothiazol-5-yl)phenyl]-3-(2-fluoro-5-methylphenyl)urea (50 mg, 0.13 mmol) and 0.2 mL 3-morpholinopropylamine was heated at 70° C. for 18 hours. Then an aqueous Na2CO3/brine mixture and EtOAc workup was done, and the resulting material chromatographed eluting with CHCl3/MeOH. The resulting solid was then triturated with a 1:1/CHCl3/hexane mixture which gave the title compound as a pale yellow solid (10 mg, 16%).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[OH:32][C:33]1[CH:34]=[C:35]([O:43][S:44]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=2[Cl:53])(=[O:46])=[O:45])[CH:36]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:38]=1.[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67]O)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:56])[CH3:55]>O1CCCC1>[C:54]([O:58][C:59]([N:61]1[CH2:66][CH2:65][CH:64]([CH2:67][O:32][C:33]2[CH:34]=[C:35]([O:43][S:44]([C:47]3[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=3[Cl:53])(=[O:46])=[O:45])[CH:36]=[C:37]([C:39]([O:41][CH3:42])=[O:40])[CH:38]=2)[CH2:63][CH2:62]1)=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reactant: COC(=O)c1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1cc(OCC2CCN(C(=O)OC(C)(C)C)CC2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 0 %

Procedure:
A solution of triphenylphosphine (0.249 g, 0.95 mol) in tetrahydrofuran (20 mL) was treated with diethyl azodicarboxylate (0.131 mL, 0.83 mol) and allowed to stir at ambient temperature for 15 min. before the addition of 2-chlorobenzenesulfonic acid 3-hydroxy-5-carbomethoxyphenyl ester (0.25 g, 0.73 mol), as prepared in the preceding step, in tetrahydrofuran (5 mL) and N-tert-butoxycarbonyl-4-piperidinemethanol (0.165 g, 0.77 mol), as prepared in step f of Example 1. The reaction mixture was allowed to stir at ambient temperature overnight. The solvent was evaporated and treated with ether/hexane to produce a crystalline material, which was separated by filtration. The filtrate was evaporated to an oil, placed on a silica gel column, and eluted with 20% ethyl acetate/hexane. The appropriate fractions were evaporated to give 0.14 g of material. 1H-NMR (CDCl3 ; 300 MHz): δ 1.25 (m, 3H), 1.47 (s, 9H), 1.78 (m, 2H), 2.74 (t, 2H), 3.77 (d, 2H), 3.88 (s, 3H), 4.12 (m, 2H), 6.90 (t, 1H), 7.38 (m, 3H), 7.62 (m, 2H), 7.97 (m, 1H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][C:10]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)(O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl>O1CCOCC1>[CH2:1]([N:8]1[CH2:9][C:10]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH3:22])=[CH:19][CH:20]=2)=[CH:11][CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C2(O)CCCN(Cc3ccccc3)C2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C2=CCCN(Cc3ccccc3)C2)cc1
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 1-benzyl-3-(4-methoxyphenyl)piperidin-3-ol (3.5 g, 11.8 mmol) in dioxane (20 mL) was added concentrated HCl (3.6 mL, 43 mmol) and the reaction mixture was stirred overnight. The solvents were evaporated under reduced pressure and the residue was diluted with sat. bicarbonate solution (200 mL) and extracted with ethyl acetate (200 mL). The organic layer was dried over Na2SO4 and evaporated under reduced pressure to give the crude product which was purified via silica gel chromatography eluting with 30% ethyl acetate in hexane to give 1-benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (1.5 g, 4.2 mmol, 35.6% yield). LCMS (Method 107): (ES-API), m/z 280.2 (M+H) RT=2.263 min; 1H NMR (300 MHz, DMSO-d6) δ 7.42-7.32 (m, 4H), 7.29-7.19 (m, 3H), 6.91-6.82 (m, 2H), 6.16-5.97 (m, 1H), 3.73 (s, 3H), 3.65 (d, J=2.6 Hz, 3H), 3.23 (d, J=1.9 Hz, 2H), 2.55 (s, 1H), 2.24 (d, J=3.8 Hz, 2H).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29](OCC)=[O:30])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[F:44][C:45]1([F:49])[CH2:48][NH:47][CH2:46]1>>[Si:1]([O:18][CH2:19][C:20]1[N:25]=[C:24]2[C:26]([C:29]([N:47]3[CH2:48][C:45]([F:49])([F:44])[CH2:46]3)=[O:30])=[N:27][O:28][C:23]2=[C:22]([Cl:34])[C:21]=1[N:35]1[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1noc2c(Cl)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc12
Reactant: FC1(F)CNC1
Agent: Cl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc3c(C(=O)N4CC(F)(F)C4)noc3c2Cl)C[C@H](C)O1

Procedure:
Starting material: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-7-chloro-6-((2R,6S)-2,6-dimethylmorpholino)isoxazolo[4,5-b]pyridine-3-carboxylate (Intermediate 211) and 3,3-difluoroazetidine-HCl.
Reaction SMILES: [NH2:1][CH2:2][C@:3]12[CH2:41][CH2:40][C@@H:39]([C:42]([CH3:44])=[CH2:43])[C@@H:4]1[C@@H:5]1[C@@:18]([CH3:21])([CH2:19][CH2:20]2)[C@@:17]2([CH3:22])[C@@H:8]([C@:9]3([CH3:38])[C@@H:14]([CH2:15][CH2:16]2)[C:13]([CH3:24])([CH3:23])[C:12]([C:25]2[CH:37]=[CH:36][C:28]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])=[CH:27][CH:26]=2)=[CH:11][CH2:10]3)[CH2:7][CH2:6]1.Cl[S:46]([C:49]1[CH:57]=[CH:56][C:52]([C:53]([OH:55])=[O:54])=[CH:51][CH:50]=1)(=[O:48])=[O:47].CCN(C(C)C)C(C)C>C(Cl)Cl.C([O-])(O)=O.[Na+]>[C:32]([O:31][C:29]([C:28]1[CH:36]=[CH:37][C:25]([C:12]2[C:13]([CH3:24])([CH3:23])[C@H:14]3[C@:9]([CH3:38])([CH2:10][CH:11]=2)[C@@H:8]2[C@:17]([CH3:22])([C@@:18]4([CH3:21])[C@H:5]([CH2:6][CH2:7]2)[C@H:4]2[C@H:39]([C:42]([CH3:44])=[CH2:43])[CH2:40][CH2:41][C@:3]2([CH2:2][NH:1][S:46]([C:49]2[CH:50]=[CH:51][C:52]([C:53]([OH:55])=[O:54])=[CH:56][CH:57]=2)(=[O:48])=[O:47])[CH2:20][CH2:19]4)[CH2:16][CH2:15]3)=[CH:26][CH:27]=1)=[O:30])([CH3:33])([CH3:34])[CH3:35]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C(C)[C@@H]1CC[C@]2(CN)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(CNS(=O)(=O)c3ccc(C(=O)O)cc3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(c6ccc(C(=O)OC(C)(C)C)cc6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of tert-butyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aminomethyl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)benzoate (25 mg, 0.042 mmol) in DCM (2 ml) was added 4-(chlorosulfonyl)benzoic acid (9.19 mg, 0.042 mmol) and DIPEA (7.28 μl, 0.042 mmol). The resulting mixture was stirred for 48 h at rt. The mixture was diluted with 7 ml of sat. NaHCO3 and was extracted with dichloromethane (3×7 ml). The combined organic layers were dried with Na2SO4. The drying agent was removed by filtration and the filtrate was concentrated under reduced pressure. The crude product was used in the next step with no additional purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.O.[OH-].[Na+].[C:12](O)(=[O:14])[CH3:13]>CC(OCC1C2C(=CC=CC=2)C(COC(C)=O)=C2C=1C=CC=C2)=O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:12](=[O:14])[CH3:13])=[N:3][CH:4]=1
Reactant: Nc1ccc(Br)cn1
Reactant: CC(=O)O
Agent: CC(=O)OCc1c2ccccc2c(COC(C)=O)c2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(=O)Nc1ccc(Br)cn1
Reaction time: 1 h
Yield: 85 %

Procedure:
A solution of 2-amino-5-bromopyridine (25.0 g, 144 mmol) in acetic acid (50 ml) and acetic (25.0 g, anhydride (250 ml) was heated at reflux for two hours. The reaction mixture was then cooled and poured into water (750 ml) with stirring. After one hour, the solution was adjusted to pH 10 with 50% sodium hydroxide and the precipitate was filtered, washed with water and dried to give 26.5 g (85%) of the title product as a white flaky solid. mp 175-176° C. 1H NMR (CDCl3): δ=8.29 (d, 1 H); 8.12 (d, 1 H); 7.96 (br, 1 H); 7.78 (d of d, 1 H); 2.19 (s, 3 H). MS (El): m/z=214, 216 (M+, Br isotopes).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15](O)=[N:16]2)=[CH:11][CH:10]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:26]2[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]2=[O:34])[CH:23]=[CH:24][CH:25]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([NH:19][C:20]3[CH:21]=[C:22]([CH:26]4[N:31]([CH3:32])[CH2:30][CH2:29][N:28]([CH3:33])[C:27]4=[O:34])[CH:23]=[CH:24][CH:25]=3)=[N:16]2)=[CH:11][CH:10]=1
Reactant: CN1CCN(C)C(c2cccc(N)c2)C1=O
Reactant: COc1ccccc1-c1ccc2cnc(O)nn12
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(C4C(=O)N(C)CCN4C)c3)nn12

Procedure:
3-{3-[7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ylamino]-phenyl}-1,4-dimethyl-piperazin-2-one was prepared from 7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-ol and 3-(3-amino-phenyl)-1,4-dimethyl-piperazin-2-one in an analogous manner to Example 1052a. Product isolated as a brown foam (61 mg, 45%). LCMS (m/e) 443 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.69 (s, 1H), 7.97-7.89 (m, 1H), 7.70 (d, 1H, J=8.1 Hz), 7.45-7.36 (m, 2H), 7.25-7.17 (m, 1H), 7.15-7.08 (m, 1H), 7.05 (d, 1H, J=8.3 Hz), 7.00 (d, 1H, J=4.6 Hz), 6.96 (d, 1H, J=7.6 Hz), 6.89 (s, 1H), 6.83 (d, 1H, J=4.6 Hz), 3.84 (s, 3H), 3.73-3.64 (m, 1H), 3.63 (s, 1H), 3.26-3.17 (m, 1H), 3.03-2.94 (m, 1H), 2.99 (s, 3H), 2.69-2.58 (m, 1H), 2.09 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][NH2:17])=[C:11]([O:18][CH3:19])[N:10]=1)([CH3:4])([CH3:3])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]([C:35](O)=[O:36])[C:25]2[C:26]([CH3:34])=[CH:27][N:28]([CH:31]([CH3:33])[CH3:32])[C:29]=2[CH:30]=1.C1C=NC2N(O)N=NC=2C=1.C(Cl)CCl>ClCCl.CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][C:9]1[CH:14]=[C:13]([CH3:15])[C:12]([CH2:16][NH:17][C:35]([C:24]2[C:25]3[C:26]([CH3:34])=[CH:27][N:28]([CH:31]([CH3:32])[CH3:33])[C:29]=3[CH:30]=[C:22]([Br:21])[CH:23]=2)=[O:36])=[C:11]([O:18][CH3:19])[N:10]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: Cc1cn(C(C)C)c2cc(Br)cc(C(=O)O)c12
Reactant: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CN
Agent: On1nnc2cccnc21
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1nc(CNC(=O)OC(C)(C)C)cc(C)c1CNC(=O)c1cc(Br)cc2c1c(C)cn2C(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 97.8 %

Procedure:
To a stirred solution of tert-butyl((5-(aminomethyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (0.55 g, 1.955 mmol), 6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid (0.63 g, 2.127 mmol), and HOAt (0.27 g, 1.984 mmol) in Dichloromethane (20 mL) and DMF (5 mL) was added EDC free base (0.34 g, 2.190 mmol). The reaction was stirred at RT for 2 hr then evaporated to dryness under vacuum. The remaining was purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 40% EtOAc in hexanes) to give the product tert-butyl((5-((6-bromo-1-isopropyl-3-methyl-1H-indole-4-carboxamido)methyl)-6-methoxy-4-methylpyridin-2-yl)methyl)carbamate (1.07 g, 1.912 mmol, 98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ=8.47 (t, J=4.8 Hz, 1H), 7.76 (d, J=1.8 Hz, 1H), 7.35 (t, 1H), 7.33 (d, J=1.0 Hz, 1H), 6.99 (d, J=1.5 Hz, 1H), 6.67 (s, 1H), 4.74 (quin, J=6.6 Hz, 1H), 4.44 (d, J=4.8 Hz, 2H), 4.08 (d, J=6.3 Hz, 2H), 3.85 (s, 3H), 2.37 (s, 3H), 2.10 (s, 3H), 1.41 (s, 9H), 1.38 (d, J=6.6 Hz, 6H). MS (ES)+m/e 559.3 [M+H]+.
Reaction SMILES: [H-].[Na+].Cl[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[OH:15]>O1CCOCC1>[CH3:19][O:18][C:13]([CH:14]([O:15][C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]=1)[CH3:16])=[O:17]
Reactant: COC(=O)C(C)O
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)C(C)Oc1ncccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 73 %

Procedure:
0.8 g of sodium hydride was added to a mixture of 3.17 g of 2-chloro-3-nitropyridine, 2.19 g of methyl lactate and 20 ml of 1,4-dioxane at 10° C. The mixture was stirred at room temperature for 1.5 hours, then, poured into ice water, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 3.3 g of 2-{1-(methoxycarbonyl)ethoxy}-3-nitropyridine.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]2)=[N:4][C:5](Cl)=[N:6][CH:7]=1.[CH3:24][C@@H:25]1[CH2:30][CH2:29][C@H:28]([NH2:31])[CH2:27][CH2:26]1>>[CH3:24][C@@H:25]1[CH2:30][CH2:29][C@H:28]([NH:31][C:5]2[N:4]=[C:3]([O:9][CH2:10][CH:11]3[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH2:12]3)[C:2]([Br:1])=[CH:7][N:6]=2)[CH2:27][CH2:26]1
Reactant: C[C@H]1CC[C@@H](N)CC1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2nc(Cl)ncc2Br)CC1
Product: CC(C)(C)OC(=O)N1CCC(COc2nc(N[C@H]3CC[C@@H](C)CC3)ncc2Br)CC1

Procedure:
Using the procedure of Example 1 Step 2 tert-butyl 4-((5-bromo-2-chloropyrimidin-4-yloxy)methyl)piperidine-1-carboxylate was reacted with cis-4-methylcyclohexanamine to provide the title compound in 50% yield. 1H NMR (CDCl3, 400 MHz) 8.05 (s, 1H), 5.10 (sb, 1H), 4.15 (m, 4H), 3.96 (m, 1H), 2.71 (m, 2H), 1.95 (m, 1H), 1.78-1.48 (m, 9H), 1.44 (s, 9H), 1.28-1.16 (m, 3H), 0.91 (d, 3H); MS (ESI) m/z: Calc: 482.2 (M+). Found. 484.2 (M++2).
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[C:5]([NH:12][C:13]1[CH:18]=[C:17]([Cl:19])[C:16]([Cl:20])=[C:15]([Cl:21])[CH:14]=1)([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]>>[C:5]([NH:12][C:13]1[CH:14]=[C:15]([Cl:21])[C:16]([Cl:20])=[C:17]([Cl:19])[C:18]=1[N+:1]([O-:4])=[O:2])([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:6]
Reactant: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)c(Cl)c1
Reactant: O=[N+]([O-])O
Product: CCOC(=O)C(=O)Nc1cc(Cl)c(Cl)c(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52 %

Procedure:
20 ml 100% nitric acid was cooled to 0° C. and 2.0 g (6.8 mmol) N-ethoxalyl-3,4,5-trichloroaniline was added. The reaction mixture was stirred at 0° C. for 10 min. and 200 ml ice-water was added. The precipitate was filtered off, washed with water and ethanol to give 1.2 g (52%) of N-ethoxalyl-2-nitro-3,4,5-trichloroaniline. M.p. 84° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:19][CH:20]=[CH:21][CH:22]=2)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[Br:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2([O:19][CH:20]=[CH:21][CH2:22]2)[CH:8]=[O:9])=[CH:16][CH:17]=1
Reactant: Brc1ccc(-c2ccco2)cc1
Reactant: CN(C)C=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Solvent: Clc1ccccc1
Product: O=CC1(c2ccc(Br)cc2)CC=CO1
Reaction time: 1 h

Procedure:
(Vilsmeir procedure) Phosphorous oxychloride POCL3 (12.5 g) and Dimethyl formamide (7 ml) were added to a mixture of 2(4-bromophenyl)furan (20.4 g) in chlorobenzene (100 ml). The mixture was stirred at 10° for one hour. A further addition of POCl3 (1.5 g) and DMF (0.7 g) was then made and the reaction stirred for a further one hour at RT. The mixture was poured onto ice, neutralised with sodium carbonate and the precipitated solid crystalised from chloroform (119). This solid was chromatographed on silica gel in chloroform to give 2(4-bromophenyl)furfural (11 g) m.p. 153.5°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:23])[CH2:19][C@H:18]4[CH:24]([CH3:26])[CH3:25])=[N:16][C:12]=3[CH:11]=[C:10]([C:35](=[N:37][OH:38])[NH2:36])[N:9]=2)[CH:5]=[N:6][CH:7]=1.[C:39](N1C=CN=C1)(N1C=CN=C1)=[O:40].N12CCCN=C1CCCCC2>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]3[N:14]([CH2:27][C@H:28]4[CH2:33][CH2:32][C@H:31]([CH3:34])[CH2:30][CH2:29]4)[C:15]([N:17]4[CH2:21][C@H:20]([O:22][CH3:23])[CH2:19][C@H:18]4[CH:24]([CH3:25])[CH3:26])=[N:16][C:12]=3[CH:11]=[C:10]([C:35]3[NH:36][C:39](=[O:40])[O:38][N:37]=3)[N:9]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CO[C@@H]1C[C@@H](C(C)C)N(c2nc3cc(-c4noc(=O)[nH]4)nc(-c4cncc(Cl)c4)c3n2C[C@H]2CC[C@H](C)CC2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(5-chloropyridin-3-yl)-N′-hydroxy-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide (79 mg, 0.146 mmol) and 1,1′-carbonyldiimidazole (26.1 mg, 0.161 mmol) dissolved in acetonitrile (1 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (0.087 mL, 0.585 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction was washed with water and extracted with dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (0-10% methanol/dichloromethane, and then 0-100% ethyl acetate/hexanes, linear gradient) to afford 3-{4-(5-chloropyridin-3-yl)-2-[(2S,4R)-4-methoxy-2-(propan-2-yl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridin-6-yl}-1,2,4-oxadiazol-5(4H)-one. MS ESI calc'd. for C29H36ClN7O3 [M+H]+ 566. found 566. 1H NMR (500 MHz, DMSO-d6) δ 12.82 (s, 1H), 8.96 (d, J=1.8, 1H), 8.78 (d, J=2.4, 1H), 8.50 (t, J=2.1, 1H), 7.82 (s, 1H), 4.39-4.34 (m, 1H), 3.98 (s, 1H), 3.85-3.81 (m, 1H), 3.77 (s, 2H), 3.53 (dd, J=5.9, 15.1, 1H), 3.20 (s, 3H), 2.31-2.27 (m, 1H), 2.09-2.00 (m, 1H), 1.80-1.72 (m, 1H), 1.37 (d, J=10.5, 2H), 1.12-1.05 (m, 1H), 1.05-0.96 (m, 1H), 0.89 (d, J=7.0, 3H), 0.87 (s, 1H), 0.76 (d, J=6.8, 3H), 0.6 (d, J=6.5, 3H), 0.61-0.55 (m, 1H), 0.54-0.48 (m, 1H), 0.48-0.44 (m, 1H), 0.40-0.34 (m, 2H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:7]=[CH:8][CH:9]=1)(=[O:3])[NH2:2].NC1C=C(C=CC=1[F:35])C(N)=O.COC1C=C(B(O)O)C=CC=1OC.O.C(O)(=O)C=O>>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([F:35])=[C:6]([NH:10][CH:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([O:23][CH3:24])[CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COc1ccc(C(Nc2cccc(C(N)=O)c2)C(=O)O)cc1OC
Reactant: NC(=O)c1ccc(F)c(N)c1
Agent: COc1ccc(B(O)O)cc1OC
Agent: O=CC(=O)O
Solvent: O
Product: COc1ccc(C(Nc2cc(C(N)=O)ccc2F)C(=O)O)cc1OC
Yield: 55 %

Procedure:
19C was prepared in a procedure similar to that of 1A using 19B, 3,4-dimethoxyphenylboronic acid and glyoxylic acid monohydrate. Yield: 55%. 1H NMR (400 MHz, Methanol-d4) δ ppm 3.78 (s, 3H) 3.81 (s, 3H) 5.15 (s, 1H) 6.90 (d, J=7.91 Hz, 1H) 7.01-7.08 (m, 2H) 7.12 (d, J=1.76 Hz, 1H) 7.13-7.17 (m, 2H), LCMS: 349 (M+1).