Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:21]([NH2:30])([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([CH3:23])[CH3:22].C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[C:24]1([C:21]([NH:30][C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)([CH3:23])[CH3:22])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: CC(C)(N)c1ccccc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Product: CC(=O)Nc1nc2ccc(-c3ccnc(NC(C)(C)c4ccccc4)n3)cc2s1

Procedure:
A solution of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.1 g, 0.3 mmol), cumylamine (0.05 mL, 0.4 mmol), cesium carbonate (0.05 g, 0.7 mmol) in N,N-DMF was heated under microwave (CEM) at 180° C. for 20 min. The mixture was diluted with DCM and washed with water, dried over sodium sulfate, and concentrated. The residue was purified by HPLC (5-100% CH3CN in water with 0.05% TFA) to give N-(6-(2-(2-phenylpropan-2-ylamino)pyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide as an off-white solid. MS (ESI pos. ion) m/z: 404 (MH+). Calculated exact mass for C22H21N5OS: 403.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11]Cl)=[CH:4][CH:3]=1.[CH3:14][CH:15]([CH3:31])[C:16]([NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:20]=1)=[O:17]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C@@H:10]([CH3:13])[CH2:11][N:28]2[CH2:29][CH2:30][CH:25]([C:21]3[CH:20]=[C:19]([NH:18][C:16](=[O:17])[CH:15]([CH3:14])[CH3:31])[CH:24]=[CH:23][CH:22]=3)[CH2:26][CH2:27]2)=[CH:4][CH:3]=1
Reactant: C[C@@H](CCl)COc1ccc(Cl)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Product: CC(C)C(=O)Nc1cccc(C2CCN(C[C@H](C)COc3ccc(Cl)cc3)CC2)c1

Procedure:
Prepared by Procedure G and Scheme B1 using 1-chloro-4-{[(2R)-3-chloro-2-methylpropyl]oxy}benzene and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 429.2 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[C:13]1([S:19]([O-:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[Na+]>CN(C)C=O.O>[C:13]1([S:19]([CH2:2][C:3]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH:6]=[CH:5][CH:4]=2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=S([O-])c1ccccc1
Reactant: ClCc1cccc2ccccc12
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=S(=O)(Cc1cccc2ccccc12)c1ccccc1

Procedure:
A solution of 1-(chloromethyl)-naphthalene (17.6 g) in dimethyl formamide (20 ml) was added to a stirred suspension of sodium benzenesulphinate (16.4 g) in dimethyl formamide (80 ml). After 20 hours at room temperature the mixture was diluted with water and the white precipitate filtered. Recrystallisation from ethyl acetate-petroleum ether 60°-80° C. gave the title product, m.p. 89° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[NH:6][C:5]2=[O:15].N[CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20].N1C=CN=C1>C(O)CCCC>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[C:7](=[O:14])[N:6]([CH2:17][C@@H:18]([OH:21])[CH2:19][OH:20])[C:5]2=[O:15]
Reactant: NC[C@@H](O)CO
Reactant: Nc1cc2c(cc1[N+](=O)[O-])C(=O)NC2=O
Agent: c1c[nH]cn1
Solvent: CCCCCO
Product: Nc1cc2c(cc1[N+](=O)[O-])C(=O)N(C[C@@H](O)CO)C2=O
Temperature: 25 °C
Yield: 83.2 %

Procedure:
A mixture of 5-amino-6-nitroisoindoline-1,3-dione (2.27 g, 10.98 mmol), (R)-3-aminopropane-1,2-diol (1.0 g, 10.98 mmol), and imidazole (0.75 g, 10.98 mmol) in 100 mL of pentanol was heated to reflux and maintained for 8 h and allowed to cool down to rt. The precipitate was filtered and washed with heptanes and dried to give a yellow crystalline solid (2.57 g, 9.14 mmol, 83%). 1H NMR (500 MHz, DMSO-d6) δ58.38 (s, 2H), 8.31 (s, 1H), 7.45 (1, 1H), 4.90 (d, J=5.0 Hz, 1H), 4.66 (t, J=5.5 Hz, 1H), 3.82-3.74 (m, 1H), 3.55 (d, J=6.5 Hz, 2H), 3.42-3.18 (m, 2H). ESI MS: m/z 279.8 (M−1).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[NH2:18].CCN(CC)CC>CN(C=O)C>[N+:8]([C:7]1[C:2]([NH:18][C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:11])=[N:3][CH:4]=[CH:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Cc1ccccc1N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccccc1Nc1ncccc1[N+](=O)[O-]
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
A mixture of 2-chloro-3-nitropyridine (4.13 g, 26.1 mmol), o-tolylamine (3.4 mL, 31.3 mmol) and Et3N (4.4 mL, 31.3 mmol) in DMF (10 mL) was stirred at 90° C. for 1 h under a nitrogen atmosphere. Additional o-tolylamine (2 mL, 18.2 mmol) was added and stirring continued for 16 h. The mixture was partitioned between DCM and water. The aqueous phase was further extracted with DCM (×3) and the combined organic fractions washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 20-100% DCM in cyclohexane) to afford the title compound as an orange solid (3.96 g, 66%). LCMS (Method C): RT 3.60 min [M+H]+ 230.3
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:11][N:12]2[C:16]([Br:17])=[C:15]([Br:18])[N:14]=[C:13]2Br)=[CH:4][C:5]2[O:9][CH2:8][O:7][C:6]=2[CH:10]=1.C(Cl)Cl.C([Mg]Br)C.Cl.[CH2:28]([O:30]CC)C>CN(C)C=O>[Br:18][C:15]1[N:14]=[C:13]([CH:28]=[O:30])[N:12]([CH2:11][C:3]2[C:2]([Cl:1])=[CH:10][C:6]3[O:7][CH2:8][O:9][C:5]=3[CH:4]=2)[C:16]=1[Br:17]
Reactant: Clc1cc2c(cc1Cn1c(Br)nc(Br)c1Br)OCO2
Reactant: CCOCC
Agent: CC[Mg]Br
Agent: Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=Cc1nc(Br)c(Br)n1Cc1cc2c(cc1Cl)OCO2
Reaction time: 0.33 h

Procedure:
20 g of the product obtained in Stage 1 above is introduced into 200 ml of anhydrous methylene chloride to which 500 ml of anhydrous ethyl ether is added. A 3M solution of ethyl magnesium bromide in ethyl ether is added and the whole is left under agitation for 20 minutes at ambient temperature. Then an excess (15 ml) of anhydrous dimethylformamide is added. After 2 hours at ambient temperature, hydrolysis is carried out with 200 ml of 1N hydrochloric acid followed by extraction 3 times with 300 ml of ethyl acetate. The organic phase is washed with saturated sodium chloride then dried and evaporated to dryness. In this way 14.5 g of expected product is obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=3)[OH:22])[C:9]2=[O:30])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[I:37][CH:38](I)[CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:11]([C:12]3[CH:13]=[CH:14][C:15]([O:18][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][I:37])=[CH:16][CH:17]=3)[CH:10]([CH2:19][CH2:20][CH:21]([C:23]3[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=3)[OH:22])[C:9]2=[O:30])=[CH:6][CH:7]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(O)cc2)N1c1ccc(F)cc1
Reactant: CCCCCC(I)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCCCCCCI)cc2)N1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg of 1-(4-fluorophenyl)-3-[3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one are dissolved in 10 ml of absolute dimethylformamide. 80 mg of powdered potassium carbonate and 0.25 ml of diiodohexane are then added. The reaction solution is stirred at room temperature overnight. After concentration using a rotary evaporator and oil pump vacuum at 40° C., the residue is purified using an SiO2 cartridge (n-heptane; n-heptane/ethyl acetate 4:1). The product is obtained as an oil. C30H32F2INO3 (619) MS (ESI): M+−18
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC>[S:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1cccnc1
Reactant: OB(O)c1cccs1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: c1cncc(-c2cccs2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 16.3 %

Procedure:
A mixture of 3-bromopryidine (1.30 mL, 13.5 mmol) and tetrakis(triphenylphosphine) (0.468 g, 0.41 mmol) in 40 mL of dimethoxyethane is stirred under nitrogen at room temperature for 10 minutes. 2-Thiophene boronic acid (1.90 g, 14.8 mmol) and 20 mL of 1N sodium carbonate are added and the resulting mixture is refluxed overnight. The solution is cooled to room temperature and filtered through Celite. The filtrate is extracted with ether (2×30 mL). The combined organic layers are dried over MgSO4, filtered and concentrated. The crude product is purified by column chromatography eluting with a gradient of 10% EtOAc/hexanes to 20% EtOAc/hexanes to afford the title compound (0.355 g, 2.20 mmol) as a light yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1.[CH3:20]C1C(C(N)=N)=NC=CC=1>>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:5]=[C:4]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:3]=1
Reactant: Cc1cccnc1C(=N)N
Reactant: Clc1cc(-c2cccnc2)nc(-c2ccccn2)n1
Product: Cc1cccnc1-c1nc(Cl)cc(-c2cccnc2)n1

Procedure:
This compound is prepared analogously to Intermediate A by replacing pyridine-2-carboxamide (step 1) with 3-methyl-pyridine-2-carboxamidine (Intermediate C)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[N:5]=[C:4]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)[N:3]=1.[N:20]1([C:26]2[N:31]=[CH:30][C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=2)[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1>CCCCCC.C(OCC)(=O)C>[O:23]1[CH2:24][CH2:25][N:20]([C:26]2[N:31]=[CH:30][C:29]([C:2]3[N:7]=[C:6]([N:8]4[CH2:13][CH2:12][O:11][CH2:10][CH2:9]4)[N:5]=[C:4]([N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)[N:3]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:22]1
Reactant: Clc1nc(N2CCOCC2)nc(N2CCOCC2)n1
Reactant: CC1(C)OB(c2ccc(N3CCOCC3)nc2)OC1(C)C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: c1cc(N2CCOCC2)ncc1-c1nc(N2CCOCC2)nc(N2CCOCC2)n1

Procedure:
Following the general procedure A, 4,4′-(6-chloro-1,3,5-triazine-2,4-diyl)dimorpholine was coupled with 6-(morpholin-4-yl)pyridine-3-boronic acid pinacol ester acid pinacol ester with reaction time of 15 h. Chromatography (hexane/ethyl acetate 1:1) gave the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C@H:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N:42]=5)=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([C:25](=[O:30])[C:26]([F:29])([F:28])[F:27])[CH2:23][CH2:22][C:21]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][C:37]([C@H:40]([OH:47])[C:41]5[CH:46]=[CH:45][CH:44]=[CH:43][N+:42]=5[O-:57])=[CH:36][CH:35]=4)=[O:32])=[CH:20][C:19]=3[CH:48]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4ccccn4)cc2)CCN3C(=O)C(F)(F)F)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc([C@H](O)c4cccc[n+]4[O-])cc2)CCN3C(=O)C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 75.7 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(2-pyridyl)methyl]phenyl]-1-trifluoroacetyl-2,3-dihydro-1H-1-benzazepine-4-carboxamide (285 mg) in dichloromethane (10 ml) was added 3-chloroperbenzoic acid (70%, 127 mg) was added at 0° C. and the mixture was stirred at room temperature for 20 hours. To the reaction solution was added sodium thiosulfate solution, and the mixture was stirred for several minutes, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution and saturated brine, dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by column chromatography (ethanol:ethyl acetate 1:4) and recrystallized from ethanol-diisopropylether to give 7-[4-(2-butoxyethoxy)phenyl]-N-[4-[(S)-hydroxy(1-oxidopyridin-2-yl)methyl]phenyl]-2,3-dihydro-1-trifluoroacetyl-1H-1-benzazepine-4-carboxamide (Compound 80) (220.9 mg) as pale yellow crystals.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH2:11]2)=[O:7])([CH3:4])[CH3:3].C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].Br[CH2:42][C:43]1[C:44]([C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[O:57][C:58]([F:61])([F:60])[F:59])=[N:45][O:46][C:47]=1[CH:48]1[CH2:50][CH2:49]1>O1CCCC1>[CH:48]1([C:47]2[O:46][N:45]=[C:44]([C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=3[O:57][C:58]([F:61])([F:60])[F:59])[C:43]=2[CH2:42][O:16][CH:14]2[CH2:15][CH:9]3[N:8]([C:6]([O:5][C:2]([CH3:1])([CH3:3])[CH3:4])=[O:7])[CH:12]([CH2:11][CH2:10]3)[CH2:13]2)[CH2:49][CH2:50]1
Reactant: CC(C)(C)OC(=O)N1C2CCC1CC(O)C2
Reactant: FC(F)(F)Oc1ccccc1-c1noc(C2CC2)c1CBr
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C2CCC1CC(OCc1c(-c3ccccc3OC(F)(F)F)noc1C1CC1)C2

Procedure:
A 250-mL flask was purged with nitrogen and then charged with N-Boc-nortropine (2.9 g, 12.8 mmol), 18-Crown-6 (3.4 g, 12.8 mmol), and anhydrous tetrahydrofuran (80 mL). Potassium tert-butoxide (2.9 g, 25.6 mmol) was added in small portions, and the mixture was stirred vigorously under nitrogen fo(1 h. 4-(bromomethyl)-5-cyclopropyl-3-(2-(trifluoromethoxy)-phenyl)isoxazole (4.18 g, 11.6 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) and added dropwise, and the reaction mixture was stirred overnight under a positive nitrogen pressure. The solvent was removed in vacuo and the mixture diluted with water (100 mL) and ethyl acetate (100 mL). The organic layer was separated, dried with anhydrous MgSO4, and evaporated in vacuo. The crude residue was purified by silica gel chromatography using a gradient of 0-100% ethyl acetate/hexanes to yield the desired product as yellow oil. MS m/z 509.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([OH:13])=O)=[CH:5]2.[CH3:14][C:15]([OH:24])([CH3:23])[CH2:16][CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.Cl>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([N:20]1[CH2:21][CH2:22][CH:17]([CH2:16][C:15]([CH3:23])([OH:24])[CH3:14])[CH2:18][CH2:19]1)=[O:13])=[CH:5]2
Reactant: O=C(O)c1cc2cc(Cl)ccc2[nH]1
Reactant: CC(C)(O)CC1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: CC(C)(O)CC1CCN(C(=O)c2cc3cc(Cl)ccc3[nH]2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 42.3 %

Procedure:
To a solution of 370 mg of 5-chloroindole-2-carboxylic acid and 300 mg of 2-methyl-1-(piperidin-4-yl)-2-propanol in 8 mL of DMF were added 360 mg of 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride and 250 mg of 1-hydroxybenzotriazole, followed by stirring at room temperature for 1 day. 0.5M aqueous hydrochloric acid was added to the reaction liquid, followed by extraction with ethyl acetate. The organic layer was washed with 0.5 M aqueous sodium hydroxide solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography [chloroform:methanol=1:0-10:1], and then crystallized from diisopropyl ether to obtain 268 mg of 1-{1-[(5-chloro-1H-indol-2-yl)carbonyl]piperidin-4-yl}-2-methylpropan-2-ol as a white crystal.
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][C:7]([NH:10][C:11]3[C:12]4[N:13]([CH:20]=[N:21][CH:22]=4)[CH:14]=[CH:15][C:16]=3[C:17]([OH:19])=O)=[C:6]([F:23])[CH:5]=2)[CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.Cl.[NH2:55][O:56][C:57]([CH3:61])([CH3:60])[CH2:58][OH:59]>CN(C=O)C>[OH:59][CH2:58][C:57]([CH3:61])([CH3:60])[O:56][NH:55][C:17]([C:16]1[CH:15]=[CH:14][N:13]2[CH:20]=[N:21][CH:22]=[C:12]2[C:11]=1[NH:10][C:7]1[CH:8]=[CH:9][C:4]([CH:1]2[CH2:3][CH2:2]2)=[CH:5][C:6]=1[F:23])=[O:19]
Reactant: O=C(O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Reactant: CC(C)(CO)ON
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(CO)ONC(=O)c1ccn2cncc2c1Nc1ccc(C2CC2)cc1F
Temperature: 25 °C
Reaction time: 18 h
Yield: 7.9 %

Procedure:
A suspension of 8-(4-cyclopropyl-2-fluoro-phenylamino)-imidazo[1,5-a]pyridine-7-carboxylic acid (0.11 g, 0.35 mmol), EDCI (0.081 g, 0.42 mmol), HOBt (0.057 g, 0.42 mmol), DIPEA (0.085 mL, 0.88 mmol) and 2-aminooxy-2-methyl-propan-1-ol hydrochloride (0.055 g, 0.39 mmol) in DMF (1.5 mL) was stirred at room temperature for 18 hours. The reaction mixture was partitioned between DCM (5 mL) and saturated aqueous NaHCO3 (5 ml). The organic layer was washed with water (5 mL), followed by brine (5 mL), then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0% to 40%, ethyl actetate in DCM) to give a yellow solid, which was further purified by preparative HPLC (Gemini 5 micron C18 250×21.20 mm column, 0.1% formic acid, gradient acetonitrile/water, 5 to 98%, ramp time 20 minutes) to afford the title compound as a yellow solid (11 mg, 8%). LCMS (method A): RT=7.57 min, [M+H]+=399. 1H NMR (DMSO-d6): 10.37 (1H, s), 8.28 (1H, s), 7.79 (1H, dd, J=7.35, 0.95 Hz), 7.14 (1H, s), 7.02-6.93 (1H, m), 6.91 (1H, d, J=8.28 Hz), 6.82 (1H, s), 6.27 (1H, s), 1.99-1.90 (1H, m), 1.15 (6H, s), 0.99-0.92 (2H, m), 0.73-0.67 (2H, m).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][C@@H:22]([CH2:32]O)[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)[Cl:54]>ClCCl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[N:24]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:23][C@@H:22]([CH2:32][Cl:54])[C:12]2=[C:13]2[C:17]=1[NH:16][C:15]([C:18]([O:20][CH3:21])=[O:19])=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)(Cl)Cl
Reactant: COC(=O)c1cc2c3c(cc(OCc4ccccc4)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COC(=O)c1cc2c3c(cc(OCc4ccccc4)c2[nH]1)N(C(=O)OC(C)(C)C)C[C@H]3CCl
Reaction time: 2 h
Yield: 91.4 %

Procedure:
256.5 mg (0.57 mmole) of methyl (1S)-5-benzyloxy-3-t-butoxycarbonyl-1-hydroxymethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate and 297.4. mg (1.13 mmole) of triphenylphosphine were dissolved in 6 ml of anhydrous dichloromethane, 0.33 ml (3.40 mmole) of carbon tetrachloride was added to the resulting solution, and the resulting mixture was stirred under argon atmosphere in the dark for 2 hours. The solvent was evaporated from the reaction mixture to give a residue, which was then purified by silica gel column chromatography using an eluate of hexane:ethyl acetate (4:1), followed by crystallization from hexane to give 245.3 mg of methyl (1S)-5-benzyloxy-3-t-butoxycarbonyl-1-chloromethyl-1,2,3,6-tetrahydropyrrolo[3,2-e]indole-7-carboxylate. Yield, 92%. NMR (CDCl3) δ: 1.58 (9H, s), 3.56 (1H, t, J=9.8 Hz), 3.88-3.97 (2H, m), 3.93 (3H, s), 4.09 (1H, m), 4.19 (1H, m), 5.22 (2H, s), 7.08 (1H, d, J=2.0 Hz), 7.39-7.50 (5H, m), 7.81 (1H, brs), 9.03 (1H, s). [α]D25 =-29.3° (c 0.18, methanol).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[NH2:4].C(=O)(O)[O-].[Na+].[I:18]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O>[Br:1][C:2]1[CH:8]=[C:7]([I:18])[CH:6]=[C:5]([C:9]([CH3:12])([CH3:11])[CH3:10])[C:3]=1[NH2:4]
Reactant: II
Reactant: CC(C)(C)c1cccc(Br)c1N
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: O
Product: CC(C)(C)c1cc(I)cc(Br)c1N
Temperature: 25 °C
Reaction time: 16 h
Yield: 65 %

Procedure:
In a 50 mL round-bottom flask was added 2-bromo-6-tert-butylaniline [prepared by the method of Onitsuka, et. al. Organometallics, 25(5), 2006, pp 1270-1278] (1.18 g, 5.17 mmol) and sodium bicarbonate (0.782 g, 9.31 mmol) in water (5 ml). The mixture was cooled in an ice bath and iodine (1.444 g, 5.69 mmol) was added in several portions. The mixture was warmed to ambient temperature and stirred for 16 h. The mixture was treated with aqueous sodium thiosulfate, extracted by ethyl acetate, dried with sodium sulfate, filtered and evaporated. The residue was purified on silica gel eluting with 5% ethyl acetate in hexane to give an oil (1.2 g, 65%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Li+].[Br-].[CH2:14]1CCN2C(=NCCC2)CC1>C(O)C>[CH2:1]([O:2][C:3](=[O:11])[CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[CH3:14]
Reactant: COC(=O)Cc1ccccc1
Reactant: C1CCC2=NCCCN2CC1
Agent: [Br-]
Agent: [Li+]
Solvent: CCO
Product: CCOC(=O)Cc1ccccc1
Temperature: 25 °C

Procedure:
Following method A, phenylacetic acid methyl ester (4.51 g, 30 mmol) and LiBr (13.03 g, 150 mmol) were dissolved in ethanol (150 ml). DBU (2.28 g, 15 mmol) was added and the reaction mixture was agitated at room temperature for an hour. It was then hydrolysed and processed as described. Vacuum distillation yielded 4.40 g (90% of the theoretical yield) of pure phenylacetic acid ethyl ester, b.p. 65.5-66° C./l Torr.