Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][NH:14][CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28]>>[Br:1][C:2]1[CH:20]=[C:19]2[C:5]([C:6](=[O:22])[C:7](=[O:21])[C:8]3[S:18][CH2:17][C:11]4([CH2:16][CH2:15][N:14]([C:27](=[O:28])[C:26]5[CH:30]=[CH:31][CH:32]=[C:24]([Cl:23])[CH:25]=5)[CH2:13][CH2:12]4)[O:10][C:9]=32)=[CH:4][CH:3]=1
Reactant: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1cccc(Cl)c1
Product: O=C1C(=O)c2ccc(Br)cc2C2=C1SCC1(CCN(C(=O)c3cccc(Cl)c3)CC1)O2

Procedure:
Compound 68 was synthesized using 9-bromospiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3-chlorobenzoyl chloride and conditions outlined in procedure N. M.p.=135-140° C.; 400 MHz 1H NMR (CDCl3) δ: 7.93-7.91 (m, 1H), 7.83-7.82 (m, 1H), 7.67-7.64 (m, 1H), 7.45-7.25 (m, 4H), 4.65-4.5 (bs, 1H), 3.80-3.65 (bs, 1H), 3.55-3.35 (m, 2H), 2.98 (s, 2H), 2.30-2.05 (m, 2H), 2.00-1.67 (m, 2H); LCMS: 518 [M+H].
Reaction SMILES: [OH-].[Na+].[CH2:3]1[CH:5]([NH:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([O:24]CC)=[O:23])=[CH:18][CH:17]=3)=[CH:12][C:11]=2[C:27]2[CH:36]=[CH:35][C:34]3[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=3[CH:28]=2)[CH2:4]1>O1CCCC1>[CH2:4]1[CH:5]([NH:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([OH:24])=[O:23])=[CH:18][CH:17]=3)=[CH:12][C:11]=2[C:27]2[CH:36]=[CH:35][C:34]3[C:33]([CH3:38])([CH3:37])[CH2:32][CH2:31][C:30]([CH3:40])([CH3:39])[C:29]=3[CH:28]=2)[CH2:3]1
Reactant: CCOC(=O)c1ccc(-c2ccc(OCCNC3CC3)c(-c3ccc4c(c3)C(C)(C)CCC4(C)C)c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)CCC(C)(C)c2cc(-c3cc(-c4ccc(C(=O)O)cc4)ccc3OCCNC3CC3)ccc21
Yield: 75.2 %

Procedure:
In a manner similar to that of Example 2a, by reaction of 270 mg (6.75 mmol) of sodium hydroxide with 340 mg (0.66 mmol) of ethyl 4′-(3-cyclopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylate (Example 19b) in 30 ml of tetrahydrofuran. 240 mg of 4′-(3-cyclopropylaminoethoxy)-3′-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphth-2-yl)biphenyl-4-carboxylic acid are obtained in the form of a white solid (m.p.=233° C., yield=75%).
Reaction SMILES: [CH3:1][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([N:28](S(C4C=CC=CC=4[N+]([O-])=O)(=O)=O)[CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:49]=4[N+:57]([O-:59])=[O:58])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:3].C([O-])([O-])=O.[K+].[K+].C1(S)C=CC=CC=1>CN(C=O)C.C1COCC1>[CH3:3][CH:2]([CH2:4][CH2:5][CH2:6][C@H:7]([C@@H:9]1[C@:26]2([CH3:27])[C@H:12]([C@H:13]3[C@H:23]([CH2:24][CH2:25]2)[C@:21]2([CH3:22])[C:16]([CH2:17][C@@H:18]([NH:28][CH2:29][CH2:30][CH2:31][NH:32][C:33](=[O:62])[CH2:34][CH2:35][NH:36][C:37](=[O:61])[CH2:38][CH2:39][NH:40][C:41](=[O:60])[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][NH:47][C:48]4[CH:53]=[CH:52][C:51]([N+:54]([O-:56])=[O:55])=[CH:50][C:49]=4[N+:57]([O-:59])=[O:58])[CH2:19][CH2:20]2)=[CH:15][CH2:14]3)[CH2:11][CH2:10]1)[CH3:8])[CH3:1]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](N(CCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])S(=O)(=O)c5ccccc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](NCCCNC(=O)CCNC(=O)CCNC(=O)CCCCCNc5ccc([N+](=O)[O-])cc5[N+](=O)[O-])CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 18 h
Yield: 73.1 %

Procedure:
To a slurry of N-[3-({3-[(3-{(3β)-cholest-5-en-3-yl [(2-nitrophenyl)sulfonyl]amino}propyl)amino]-3-oxopropyl}amino)-3-oxopropyl]-6-[(2,4-dinitrophenyl)amino]hexanamide (21, 60 mg, 0.057 mmol) and K2CO3 (90 mg, 0.651 mmol) in DMF (4 mL) and THF (1 mL) was added thiophenol (80 μL, 0.874 mmol). After 18 h at 23° C., solids were removed by filtration and solvent was removed in vacuo. The crude product was purified by flash column chromatography (CH2Cl2/MeOH/TEA, 93:4:3) to afford 2 (36 mg, 72%) mp 191-193° C.; 1H NMR (400 MHz, CDCl3) δ 9.14 (d, J=2.6 Hz, 1H), 8.56 (t, J=4.9 Hz, 1H), 8.27 (dd, J=2.6 Hz, J=9.50 Hz, 1H), 7.40 (t, J=5.2 Hz, 1H), 6.93 (d, J=9.6 Hz, 1H), 6.69 (t, J=5.5 Hz, 1H), 6.60 (t, J=5.4 Hz, 1H), 5.32 (d, J=4.4 Hz, 1H), 3.54-3.50 (m, 4H), 3.42 (dt, J=6.9 Hz, J=5.6 Hz, 2H), 3.34 (dt, J=5.6 Hz, J=5.60 Hz, 2H), 2.76 (t, J=5.6 Hz, 2H), 2.39-2.34 (m, 5H), 2.21 (t, J=7.3 Hz, 2H), 2.02-1.00 (m, 37H), 0.98 (s, 3H), 0.91 (d, J=6.5 Hz, 3H), 0.87 (d, J=1.6 Hz, 3H), 0.86 (d, J=1.6 Hz, 3H), 0.67 (s, 3H); 13C NMR (125.8 MHz, CDCl3) δ 172.5, 171.8, 171.3, 148.3, 141.2, 136.0, 130.5, 130.3, 124.3, 121.1, 113.9, 58.3, 56.8, 56.2, 50.3, 45.5, 43.3, 40.1, 39.8, 39.5, 39.3, 38.0, 37.0, 36.2 (×2), 35.8, 35.6 (×2), 35.5, 35.4, 31.9 (×2), 29.7, 29.6, 28.8, 28.4, 28.2, 28.0, 26.4, 25.0, 24.3, 23.8, 22.8, 22.5, 21.0, 19.4, 18.7, 11.8; IR (film) νmax 3295, 2927, 2849, 1633, 1546, 1340 cm−1; CI m/z 864.5959 (MH+, C48H78N7O7 requires 864.5963).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]>CO.[Rh]>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:35])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:20][CH:21]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]1)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: [Rh]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Reaction time: 24 h
Yield: 89.8 %

Procedure:
A mixture of 100 mg of the resultant compound of Example 21 and 100 mg of 5% rhodium on carbon in 3 ml of methanol was shaken under 4 atmospheres of H2 for 1 day. The resulting mixture was filtered and concentrated in vacuo. Silica gel chromatography of the residue using 20% ethyl acetate in hexane provided 92 mg (90%) of the desired compound. 1H NMR (CDCl3) δ 0.75-1.90 (br envelope, 28H), 1.44 (s, 18H), 3.30 (br, 1H), 3.63 (m, 2H), 3.72 (m, 1H), 4.41 (br, 1H), 4.66 (br d, 1H). Mass spectrum: (M+H)+ =497.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH:21]=O)[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2].[CH:24]1([NH2:27])[CH2:26][CH2:25]1.[BH4-].[Na+]>CO>[C:1]([O:5][C:6](=[O:23])[N:7]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[C:16]([CH2:21][NH:27][CH:24]2[CH2:26][CH2:25]2)[CH:15]=1)[CH2:8][CH:9]([F:11])[F:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(C=O)c1)CC(F)F
Reactant: NC1CC1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N(CCc1ccc(Cl)c(CNC2CC2)c1)CC(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.2 %

Procedure:
A mixture of [2-(4-chloro-3-formyl-phenyl)-ethyl]-(2,2-difluoro-ethyl)-carbamic acid tert-butyl ester (4.30 g, 12.4 mmol) and cyclopropylamine (1.77 mL, 12.4 mmol) in MeOH (125 mL) was stirred for 2 h at rt. Cyclopropylamine (0.44 mL, 6.2 mmol) was added, and the mixture was heated to reflux for 4 h. The mixture was allowed to cool to rt. NaBH4 (935 mg, 24.7 mmol) was added in portions. The mixture was stirred for 1 h. The solvents were removed under reduced pressure, and the residue was taken in EtOAc (800 mL). The resulting mixture was washed with aq. sat. NaHCO3 and brine. The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the crude by FC (MeOH/CH2Cl2 5:95) yielded the title compound (3.53 g, 73%). LC-MS: tR=0.83 min; ES+: 389.52.
Reaction SMILES: Cl[C:2](Cl)(Cl)[C:3](=N)[O:4][CH2:5][C:6]1[CH:11]=[C:10]([F:12])[C:9]([Br:13])=[CH:8][C:7]=1[Cl:14].[C:18]12(O)[CH2:27]C3C[CH:24]([CH2:26][CH:20]([CH2:21]3)[CH2:19]1)[CH2:25]2.FC(F)(F)S(O)(=O)=O>C(Cl)Cl.C1CCCCC1>[Br:13][C:9]1[C:10]([F:12])=[CH:11][C:6]([CH2:5][O:4][C:3]23[CH2:27][CH:18]4[CH2:19][CH:20]([CH2:26][CH:24]([CH2:25]4)[CH2:2]2)[CH2:21]3)=[C:7]([Cl:14])[CH:8]=1
Reactant: OC12CC3CC(CC(C3)C1)C2
Reactant: N=C(OCc1cc(F)c(Br)cc1Cl)C(Cl)(Cl)Cl
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Solvent: C1CCCCC1
Product: Fc1cc(COC23CC4CC(CC(C4)C2)C3)c(Cl)cc1Br
Temperature: 25 °C
Reaction time: 56 h
Yield: 44 %

Procedure:
To a solution of 4-bromo-2-chloro-5-fluorobenzyl 2,2,2-trichloroacetimidate (3.95 g, 16.49 mmol) and 1-adamantanol (0.65 g, 4.26 mmol) in methylene chloride (15 mL) and cyclohexane (30 mL) was added trifluoromethanesulfonic acid (0.04 mL, 0.45 mmol) at 0° C. The reaction mixture was stirred for 56 h at ambient temperature and quenched by addition of saturated sodium bicarbonate solution (10 mL), and then diluted with methylene chloride (100 mL). The organic layer was separated and washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (5% ethyl acetate in hexanes) and recrystallization from methanol afforded 1-((4-bromo-2-chloro-5-fluorobenzyl)-oxy)adamantane as a colorless solid (0.70 g, 43%): 1H NMR (300 MHz, CDCl3) δ 7.47 (d, J=6.3 Hz, 1H), 7.37 (d, J=9.3 Hz, 1H), 4.48 (s, 2H), 2.16 (br s, 3H), 1.82-1.80 (m, 6H), 1.70-1.55 (m, 6H).
Reaction SMILES: [CH:1]1([NH:7][NH:8][C:9]([O:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:19][C:20]([CH3:25])([CH3:24])[C:21](Br)=[O:22]>>[Br:19][C:20]([CH3:25])([CH3:24])[C:21]([N:7]([CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10])=[O:22]
Reactant: O=C(NNC1CCCCC1)OCc1ccccc1
Reactant: CC(C)(Br)C(=O)Br
Product: CC(C)(Br)C(=O)N(NC(=O)OCc1ccccc1)C1CCCCC1

Procedure:
Benzyl 2-cyclohexylhydrazinecarboxylate and 2-bromoisobutyryl bromide were used for a similar reaction and treatment as Process 3 of Example 1, and benzyl 2-(2-bromoisobutyryl)-2-cyclohexylhydrazinecarboxylate was obtained as a white oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([OH:9])=O)[CH2:3]1.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:20]=[C:19]([O:21][C:22]2[CH:23]=[CH:24][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30])=[N:26][CH:27]=2)[CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl.C1COCC1>[CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([C:7]([NH:14][C:15]2[CH:20]=[C:19]([O:21][C:22]3[CH:27]=[N:26][C:25]([NH:28][C:29]([NH:31][C:32](=[O:37])[C:33]([CH3:35])([CH3:34])[CH3:36])=[O:30])=[CH:24][CH:23]=3)[CH:18]=[CH:17][N:16]=2)=[O:9])[CH2:3]1
Reactant: CC(C)(C)C(=O)NC(=O)Nc1ccc(Oc2ccnc(N)c2)cn1
Reactant: CN1CCC(C(=O)O)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCC(C(=O)Nc2cc(Oc3ccc(NC(=O)NC(=O)C(C)(C)C)nc3)ccn2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.4 %

Procedure:
A solution of 1-methyl-pyrrolidine-3-carboxylic acid (0.082 g, 0.638 mmol) in thionyl chloride (3 mL, 41.1 mmol) and DCM (3 mL) was stirred at RT for 3 h, concentrated to dryness, suspended in THF (5 mL), added to a 0° C. solution of Example C1 (0.15 g, 0.455 mmol) and DIEA (0.239 mL, 1.366 mmol) in THF (5 mL), allowed to warm to RT and stirred overnight. The mixture was treated with 10% K2CO3, extracted with DCM (4×) and the combined organics were washed with brine, dried over Na2SO4, concentrated to dryness and purified via preparative TLC (MeOH/DCM/TEA) to afford 1-methyl-N-(4-((6-(3-pivaloylureido)pyridin-3-yl)oxy)pyridin-2-yl)pyrrolidine-3-carboxamide (113 mg, 56%). 1H NMR (400 MHz, DMSO-d6): δ 11.23 (s, 1H), 10.54 (s, 1H), 10.44 (s, 1H), 8.25 (d, J=2.9 Hz, 1H), 8.19 (d, J=5.7 Hz, 1H), 8.09 (d, J=9.0 Hz, 1H), 7.74 (dd, J=9.0, 2.9 Hz, 1H), 7.64 (d, J=2.4 Hz, 1H), 6.72 (dd, J=5.7, 2.4 Hz, 1H), 3.11 (m, 1H), 2.71 (t, J=8.5 Hz, 1H), 2.45-2.32 (m, 3H), 2.21 (s, 3H), 1.96-1.84 (m, 2H), 1.21 (s, 9H); MS (ESI) m/z: 441.2 (M+H+).
Reaction SMILES: [CH3:1][C:2]12[C:9](=[O:10])[O:8][C:6](=[O:7])[C:3]1([CH3:11])[CH2:4][CH2:5]2.[Cl:12][C:13]1[CH:14]=[C:15]([CH:17]=[C:18]([Cl:20])[CH:19]=1)[NH2:16]>>[Cl:12][C:13]1[CH:14]=[C:15]([N:16]=[C:9]([C:2]2([CH3:1])[CH2:5][CH2:4][C:3]2([CH3:11])[C:6]([OH:8])=[O:7])[OH:10])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: CC12CCC1(C)C(=O)OC2=O
Product: CC1(C(=O)O)CCC1(C)C(O)=Nc1cc(Cl)cc(Cl)c1
Yield: 34 %

Procedure:
7.7 g (0.05 mol) of 1,2-dimethylcyclobutane-1,2-dicarboxylic acid anhydride with 8.1 (0.05 mol) of 3,5-dichloroaniline are heated for 8 hours at 180° C. After cooling, the crude product is recrystallised from ethyl acetate to obtain 5.1 g (34% of theory) of 1,2-dimethylcyclobutane-1,2-dicarboxylic acid-(3,5-dichlorophenyl)-imide, the properties of which are identical to those of the compound produced according to Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([O:8]C)[CH:5]=[C:4]([Br:10])[C:3]=1[OH:11].C[Si](I)(C)C>CC#N>[Br:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[C:4]([Br:10])[C:3]=1[OH:11]
Reactant: COc1cc(Br)c(O)c(Br)c1
Agent: C[Si](C)(C)I
Solvent: CC#N
Product: Oc1cc(Br)c(O)c(Br)c1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
Dissolve 2,6-dibromo-4-methoxyphenol (23.0 g, 80.6 mmol) in CH3CN (400 mL) and add trimethylsilyl iodide (TMSI) (53 mL, 371 mmol). Reflux the solution for 4 hours and add more TMSI (50 mL, 371 mmol). Heat the reaction at reflux overnight and cool to ambient temperature. Pour into ice-H2O (700 mL) and extract with EtOAc (2×300 mL). Wash the combined extracts with saturated sodium hydrosulfite (200 mL), H2O (200 mL) and brine (100 mL), dry over MgSO4, filter and concentrate. Crystallize the residue to provide the subtitled product (21.36 g, 98%) as a tan crystalline solid.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][N:4]([CH2:7][C:8]([OH:10])=O)[N:3]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:54]=[C:55]([NH2:68])[C:56]4[CH:57]=[N:58][N:59](C5CCCCO5)[C:60]=4[CH:61]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1.Cl>CN(C=O)C.CO>[NH:44]1[C:52]2[C:47](=[C:48]([C:53]3[CH:61]=[C:60]4[C:56]([CH:57]=[N:58][NH:59]4)=[C:55]([NH:68][C:8](=[O:10])[CH2:7][N:4]4[CH:5]=[CH:6][C:2]([CH3:1])=[N:3]4)[CH:54]=3)[CH:49]=[CH:50][CH:51]=2)[CH:46]=[CH:45]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2c1cnn2C1CCCCO1
Reactant: Cc1ccn(CC(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccn(CC(=O)Nc2cc(-c3cccc4[nH]ccc34)cc3[nH]ncc23)n1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
(3-Methyl-1H-pyrazol-1-yl)acetic acid (38 mg, 0.27 mmol) (from Art-Chem GmbH), HATU (126 mg, 0.33 mmol) and DIPEA (0.158 ml, 0.91 mmol) were dissolved in DMF (2 ml) and stirred under nitrogen for 30 mins. 6-(1H-Indol-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-4-amine (100 mg, 0.30 mmol) was added and the reaction was stirred for 5 h. Further (3-methyl-1H-pyrazol-1-yl)acetic acid (38 mg, 0.27 mmol), HATU (126 mg, 0.33 mmol) and DIPEA (0.158 ml, 0.91 mmol) in DMF (1 ml) was added, after stirring together for 10 mins, and the reaction was stirred for 2 days under a nitrogen atmosphere at RT. The reaction was loaded on to a PS-aminopropyl cartridge (10 g) and eluted with DCM. Appropriate fractions were combined and evaporated in vacuo. MeOH (2 ml) and 2 M HCl (aq) (45 μl, 0.09 mmol) were added and stirred for ˜30 mins at RT. The solvent was evaporated in vacuo and the residue was dissolved in MeOH:DMSO (2 ml; 1:1, v/v) and purified by Mass Directed Automated Preparative HPLC using method B. The solvent was dried under a stream of nitrogen to give title compound (31 mg).
Reaction SMILES: Cl[CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5].[NH2:19][C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26]C)=[O:25])=[CH:22][C:21]=1[F:30].C(=O)([O-])[O-].[Na+].[Na+].[I-].[Na+]>CN(C)C(=O)C.O>[F:30][C:21]1[CH:22]=[C:23]([CH:28]=[CH:29][C:20]=1[NH:19][CH:2]([C:7]1[CH:11]=[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[O:9][C:8]=1[CH3:18])[CH2:3][CH:4]([CH3:6])[CH3:5])[C:24]([OH:26])=[O:25]
Reactant: Cc1oc(-c2ccccc2)cc1C(Cl)CC(C)C
Reactant: COC(=O)c1ccc(N)c(F)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: Cc1oc(-c2ccccc2)cc1C(CC(C)C)Nc1ccc(C(=O)O)cc1F
Temperature: 80 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A mixture of 3-(1-chloro-3-methylbutyl)-2-methyl-5-phenylfuran (1.3 g), methyl 4-amino-3-fluorobenzoate (1.7 g), sodium carbonate (1.1 g) and sodium iodide (3.0 g) in N,N-dimethylacetamide (20 mL) was stirred overnight at 80° C. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was dissolved in methanol (5 mL) and tetrahydrofuran (5 mL). 2N Lithium hydroxide (6 mL) was added, and the mixture was stirred at 70° C. for 6 hr. The reaction mixture was poured into water, and the mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (10% ethyl acetate/hexane to 50% ethyl acetate/hexane) to give the title compound (0.7 g, 40%) as an amorphous compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17]Br)[C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C1N2CN3CN(C2)CN1C3.C(O)(=[O:31])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[C:11](=[C:13]([CH:17]=[O:31])[CH:14]=[CH:15][CH:16]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(-c2nc3c(CBr)cccc3o2)cc1
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O
Product: O=Cc1cccc2oc(-c3ccc(Cl)cc3)nc12

Procedure:
A mixture of 2-(4-chlorophenyl)-4-(bromomethy)benzoxazole (P0002; 2.0 g) and hexamethylenetetramine (1.27 g) in acetic acid (15 ml) and water (7.5 ml) was refluxed for 3 hours and evaporated. EtOAc and an aqueous NaHCO3 solution were added, and the organic layer was separated, dried, and evaporated. The residue (1.47 g) was purified by silica gel (25 g) column chromatography eluting with hexane-CH2Cl2-EtOAc (5:1:1) to give pale yellow crystals of 2-(4-chlorophenyl)benzoxazole-4-carbaldehyde (P0003; 0.89 g).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[NH:8][C:9](=[O:26])[C:10]1[C:15]([C:16]([F:19])([F:18])[F:17])=[CH:14][C:13]([C:20]([F:23])([F:22])[F:21])=[CH:12][C:11]=1[O:24][CH3:25].[S:27]1[CH2:32][CH2:31][C:30](=O)[CH2:29][CH2:28]1>>[CH3:25][O:24][C:11]1[CH:12]=[C:13]([C:20]([F:21])([F:22])[F:23])[CH:14]=[C:15]([C:16]([F:19])([F:18])[F:17])[C:10]=1[C:9]([NH:8][CH:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH:2]1[NH:1][CH:30]1[CH2:31][CH2:32][S:27][CH2:28][CH2:29]1)=[O:26]
Reactant: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)N[C@@H]1CCCC[C@@H]1N
Reactant: O=C1CCSCC1
Product: COc1cc(C(F)(F)F)cc(C(F)(F)F)c1C(=O)NC1CCCCC1NC1CCSCC1

Procedure:
The title compound, white foam, MS: m/e=485.3 [(M+H)+], was prepared in accordance with the general method of example 11 from cis-N-(2-amino-cyclohexyl)-2-methoxy-4,6-bis-trifluoromethyl-benzamide (intermediate H) and tetrahydro-4H-thiopyran-4-one.
Reaction SMILES: CN(C)[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[CH2:18][CH2:17][CH2:16][N:15](CC3C=CC=CC=3)[CH2:14]2)[NH:6][CH:5]=1>CO>[CH3:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[CH:13]2[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]2)[NH:6][CH:5]=1
Reactant: CN(C)Cc1c[nH]c2cccc(C3CCCN(Cc4ccccc4)C3)c12
Solvent: CO
Product: Cc1c[nH]c2cccc(C3CCCNC3)c12
Reaction time: 1 h
Yield: 94.3 %

Procedure:
A stirred mixture of 4.3 g of the product of Step A, 1.5 g of 10% palladized carbon and 300 ml of methanol was hydrogenated at 40° C. for one hour after which another 1.5 g of 10% palladized carbon were added. The hydrogenation was continued for another hour and the mixture was filtered. The filtrate was evaporated to dryness under reduced pressure at 50° C. to obtain 2.5 g of 3-methyl-4-(piperidin-3-yl)-1H-indole melting at 150° C. The said product was dissolved in 250 ml of ethyl acetate and then a solution of hydrogen chloride in ethyl acetate was added thereto at 0° to 5° C. until the mixture was acidic. The mixture was filtered and the product was washed with ethyl acetate, dried at 50° C. under reduced pressure and was crystallized from isopropanol to obtain 2.4 g of 3-methyl-4-(piperidin-3-yl)-1H-indole hydrochloride melting at 280° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]O.P(Br)(Br)[Br:12]>COCCOC.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][Br:12]
Reactant: OCc1cc(F)ccc1Br
Reactant: BrP(Br)Br
Solvent: COCCOC
Solvent: O
Product: Fc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2-bromo-5-fluorophenyl)methanol (11, 4.10 g, 20.0 mmol) in dry DME (40 mL) at 0° C. was added a solution of PBr3 (3.25 g, 12.0 mmol) in dry DME (40 mL) dropwise. The mixture was then slowly warmed up to RT and stirred at for another 3 h. The mixture was diluted with water (100 mL), and extracted with 1:1 petroleum-ether-EtOAc (100 mL×2). The combined extracts were washed with saturated NaHCO3 and brine, dried over MgSO4 and concentrated to give 1-bromo-2-(bromomethyl)-4-fluorobenzene (12).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[CH2:9][CH2:8]1.[Cl:26]N1C(=O)CCC1=O>CN(C=O)C.[Cl-].[Na+].O>[Cl:26][C:5]1[N:4]=[CH:3][C:2]([N:7]2[CH2:12][CH2:11][CH:10]([CH:13]3[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]3)[CH2:9][CH2:8]2)=[N:1][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnccn3)CC2)CC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(C2CCN(c3cnc(Cl)cn3)CC2)CC1
Reaction time: 8 h

Procedure:
The tert-butyl 1′-pyrazin-2-yl-4,4′-bipiperidine-1-carboxylate (64 mg, 0.19 mmol, prepared as described for Example 8) and N-chlorosuccinimide (27 mg, 0.20 mmol) were dissolved in DMF (0.9 ml) and the solution stirred overnight at 50 C. The slurry was diluted with 15% brine:water (40 ml) and extracted with ethyl acetate (3×25 ml). The combined organic fraction was washed with brine, dried over magnesium sulfate, filtered, and the volatiles removed in vac. The crude material was purified by chromatography on silica gel with 10% acetone:hexanes to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[CH2:10][N:11]3C(OC(C)(C)C)=O)[CH:3]=1.[H-].[Na+].Cl[C:25]1[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=1>>[C@H:9]12[CH2:14][C@H:12]([NH:11][CH2:10]1)[CH2:13][N:8]2[C:4]1[N:5]=[CH:6][N:7]=[C:2]([NH:1][C:25]2[S:26][C:27]([C:30]#[N:31])=[CH:28][N:29]=2)[CH:3]=1
Reactant: N#Cc1cnc(Cl)s1
Reactant: CC(C)(C)OC(=O)N1C[C@@H]2C[C@H]1CN2c1cc(N)ncn1
Agent: [H-]
Agent: [Na+]
Product: N#Cc1cnc(Nc2cc(N3C[C@@H]4C[C@H]3CN4)ncn2)s1

Procedure:
Tert-butyl (1S,4S)-5-(6-aminopyrimidin-4-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate 16-2 (0.324 g, 1.11 mmol), sodium hydride (0.089 g, 2.22 mmol) and 2-chloro-1,3-thiazole-5-carbonitrile 2-2 (0.161 g, 1.11 mmol) were treated as in Scheme 4 above. The product was purified on a C18 preparative column after treating the crude product with trifluoroacetic acid and then converted to a free base form after isolation via lyophilization. Hi-Res MS: calc: 300.1026 found: 300.1039. 1NMR (DMSO): 8.36 ppm (s, 1H); 8.23 ppm (s, 1H); 5.88 ppm (s, 1H); 4.90 ppm (s, 1H); 3.77 ppm (s, 1H); 3.41 ppm (s, 1H); 3.32 ppm (m, 2H); 2.93 ppm (d, 1H); 2.79 ppm (d, 1H); 1.78 ppm (m, 1H); 1.69 ppm (m, 1H).