Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[CH:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.[N+](C1C=CC([O:30][C:31](=O)[NH:32][C:33]2[CH:38]=[CH:37][C:36]([N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)=[CH:35][CH:34]=2)=CC=1)([O-])=O>C(Cl)Cl.CO.N.C(Cl)Cl>[N:39]1([C:36]2[CH:35]=[CH:34][C:33]([NH:32][C:31]([N:18]3[CH2:19][CH2:20][CH:15]([C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH2:16][CH2:17]3)=[O:30])=[CH:38][CH:37]=2)[CH2:40][CH2:41][O:42][CH2:43][CH2:44]1
Reactant: O=C(Nc1ccc(N2CCOCC2)cc1)Oc1ccc([N+](=O)[O-])cc1
Reactant: COc1cc2ncnc(C3CCNCC3)c2cc1OC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: COc1cc2ncnc(C3CCN(C(=O)Nc4ccc(N5CCOCC5)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 85.8 %

Procedure:
A mixture of 6,7-dimethoxy-4-piperidin-4-yl-quinazoline (111.4 mg, 408 μmol), prepared as described in Example 1d, but with purification by silica flash chromatography (9:1 DCM/MeOH saturated with NH3), (4-morpholin-4-yl-phenyl)-carbamic acid 4-nitro-phenyl ester (147 mg, 429 μmol), prepared as described in the previous step, and DCM (700 μL) was treated with TEA (63 μL, 449 μmol) in one portion at rt. The homogeneous amber solution was stirred at rt for 3.5 h, diluted with DCM (1.3 mL), and washed with 2 M K2CO3 (2 mL). The aqueous layer was extracted with DCM (2×2 mL), the organic layers were combined, dried (Na2SO4), and concentrated, and the residue was purified with silica flash chromatography (1:1 DCM/acetone) to afford the title compound (167.1 mg, 86%). 1H-NMR (300 MHz, CDCl3): δ 9.08 (s, 1H), 7.34 (s, 1H), 7.31-7.24 (m, 3H), 6.88 (m, 2H), 6.31 (br s, 1H), 4.32-4.22 (m, 2H), 4.07 (s, 3H), 4.06 (s, 3H), 3.86 (m, 4H), 3.59 (m, 1H), 3.23-3.07 (m, 6H), 2.24-2.07 (m, 2H), 2.05-1.93 (m, 2H). LC/MS (ESI): calcd mass 477.2, found 478.3 (MH+). Select fractions of this material were combined (112.5 mg) and submitted for combustion analysis: Anal. Calcd for C26H31N5O4: C, 65.39; H, 6.54; N, 14.67. Found: C, 65.26; H, 6.58; N, 14.51.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]=[C:10]=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:12][NH:13][S:14]([CH2:17][Cl:18])(=[O:16])=[O:15].C(N(CC)CC)C>C(OCC)C>[CH3:12][N:13]([S:14]([CH2:17][Cl:18])(=[O:16])=[O:15])[C:10]([NH:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:11]
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Reactant: CNS(=O)(=O)CCl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CN(C(=O)Nc1ccc(Cl)c(Cl)c1)S(=O)(=O)CCl
Temperature: 20 °C
Yield: 64.1 %

Procedure:
A solution of 19 g of 3,4-dichlorophenyl isocyanate in 150 ml of ethyl ether was added to a solution of 14.4 g of N-methyl-N-chloromethylsulfonyl-amine in 150 ml of ethyl ether and after the addition of 0.1 ml of triethylamine, the mixture was stirred for a hour at 20° C. The crystals formed were recovered by vacuum filtration, were washed, dried and dissolved in chloroform. The insolubles were removed by filtration and the filtrate was concentrated to dryness. The product was crystallized from methyl ethyl ketone to obtain 21.3 g of N-methyl-N-chloromethylsulfonyl-N'-(3,4-dichlorophenyl)-urea melting at 119° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([OH:50])=[O:49])([CH3:4])([CH3:3])[CH3:2].[B-](F)(F)(F)F.CN(C(O[N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[N+](C)C)C.CCN(C(C)C)C(C)C>C(#N)C>[C:1]([O:5][C:6](=[O:61])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](=[O:60])[NH:26][C@H:27]([C:53]([O:55][C:56]([CH3:59])([CH3:58])[CH3:57])=[O:54])[CH2:28][CH2:29][C:30](=[O:52])[NH:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][C:39](=[O:51])[NH:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][C:48]([O:50][N:75]1[C:80](=[O:81])[CH2:79][CH2:78][C:76]1=[O:77])=[O:49])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)O)C(=O)OC(C)(C)C
Reactant: CN(C)C(ON1C(=O)CCC1=O)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CC(C)(C)OC(=O)CCCCCCCCCCCCCCCCCCC(=O)N[C@@H](CCC(=O)NCCOCCOCC(=O)NCCOCCOCC(=O)ON1C(=O)CCC1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
To a solution of 19-{(S)-1-tert-Butoxycarbonyl-3-[2-(2-{[2-(2-carboxymethoxyethoxy)ethyl-carbamoyl]methoxy}ethoxy)ethylcarbamoyl]propylcarbamoyl}nonadecanoic acid tert-butyl ester (3.1 g) in acetonitrile (50 ml) was added TSTU (1.39 g) and DIPEA (0.91 ml). The mixture was stirred at room temperature over night and then concentrated in vacuo. To the residue was added aqueous 0.1 N HCl (100 ml) and ethyl acetate (200 ml). The layers were separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were washed with water and brine, dried (magnesium sulphate) and concentrated in vacuo to give an oil. Yield 99% (3.4 g).
Reaction SMILES: [Na].Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2)[CH:6]=[C:5]([Cl:14])[N:4]=1.[CH3:15][OH:16]>>[Cl:14][C:5]1[N:4]=[C:3]([O:16][CH3:15])[C:12]2[C:7]([CH:6]=1)=[CH:8][C:9]([F:13])=[CH:10][CH:11]=2
Reactant: CO
Reactant: Fc1ccc2c(Cl)nc(Cl)cc2c1
Agent: [Na]
Product: COc1nc(Cl)cc2cc(F)ccc12
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
To a solution of 125 mg (3.00 mmol) sodium in 40 mL MeOH was added 668 mg (3.00 mmol) 1,3-dichloro-6-fluoro-isoquinoline. The reaction mixture was stirred at 70° C. for 30 min. The solvent was removed by distillation and the residue diluted with ice water. The precipitate was filtered off, washed with water and dried.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:15](=[O:16])[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:17]=1.[C:18]([Mg]Cl)([CH3:21])([CH3:20])[CH3:19].[Cl-].[NH4+].ClC1C=CC2C(C(C)(C)C)(O)C3=NC=CC=C3CCC=2C=1>C1COCC1>[CH3:19][C:18]([C:13]1[CH:14]=[C:9]2[CH2:8][CH2:7][C:6]3[CH:17]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[C:15](=[O:16])[C:10]2=[N:11][CH:12]=1)([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Mg]Cl
Reactant: O=C1c2ccc(Cl)cc2CCc2cccnc21
Agent: CC(C)(C)C1(O)c2ccc(Cl)cc2CCc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)c1cnc2c(c1)CCc1cc(Cl)ccc1C2=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 20.05 grams (82.28 mmol) of 8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one in 400 ml of dry THF at -72° C. and under an atmosphere of nitrogen was added dropwise over 40 minutes 66.0 ml of 2.7M t-butyl magnesium chloride in THF. The reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was then poured into 10% aqueous ammonium chloride and extracted four times with CH2Cl2. The combined organic portions were dried over MgSO4, filtered, and concentrated in vacuo to give the title tom pound, along with 8-chloro-11-(1,1-dimethyl-1-ethyl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ol. These compounds were separated via flash chromatography to give the title compound, which was recrystallized from isopropyl ether to give 4.37 grams (18%) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=2)[N:7]=1.[CH3:14][N:15]1[CH:19]=[C:18](B2OC(C)(C)C(C)(C)O2)[CH:17]=[N:16]1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[CH3:14][N:15]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]3[N:6]([C:8]([C@@H:11]([OH:13])[CH3:12])=[N:9][N:10]=3)[N:7]=2)[CH:17]=[N:16]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: C[C@H](O)c1nnc2ccc(Cl)nn12
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: O
Solvent: C1COCCO1
Product: C[C@H](O)c1nnc2ccc(-c3cnn(C)c3)nn12

Procedure:
A mixture of (S)-1-(6-chloro[1,2,4]triazolo[4,3-b]pyridazin-3-yl)ethanol (30.0 mg, 0.151 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (62.8 mg, 0.302 mmol), Pd(PPh3)4 (20 mg, 0.02 mmol), potassium carbonate (62.6 mg, 0.453 mmol) and 4:1 dioxane:water (5 mL) was heated to 85° C. for 1 h. The organic solvent was removed in vacuo, and the material was transferred to a separatory funnel and extracted with DCM. The organic layer was dry-loaded onto silica gel, and the material was purified via column chromatography, eluting with 10% MeOH/DCM. The fractions containing the pure product were concentrated in vacuo to afford the title compound as a white solid. MS (ES+): m/z 245.08 (100) [MH+]. HPLC: tR=2.00 min (ZQ3, polar—5 min).
Reaction SMILES: Br[CH2:2][C:3](=O)[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[C:11]([NH:18][C:19]([NH2:21])=[NH:20])([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].O>CN(C=O)C>[NH2:21][C:19]1[N:18]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:2]=[C:3]([CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])[N:20]=1
Reactant: CCCCCCC(=O)CBr
Reactant: CC(C)(C)OC(=O)NC(=N)N
Solvent: CN(C)C=O
Solvent: O
Product: CCCCCCc1cn(C(=O)OC(C)(C)C)c(N)n1
Reaction time: 48 h
Yield: 57.3 %

Procedure:
1-bromooctan-2-one (1.00 g, 4.83 mmol) was placed in a 50 mL round bottomed flask with a stir bar and dissolved in 10 mL of DMF. Boc guanidine (2.31 g, 14.89 mmol) was then added to the reaction mixture and it was allowed to stir for 48 hours. Water was then added to the reaction mixture and it was placed in a separatory funnel. The mixture was then extracted twice with ethyl acetate, washed twice with water, washed twice with brine, concentrated de vacuo and then purified via column chromatography (5% methanol/95% dichloromethane) to provide tert-butyl 2-amino-4-hexyl-1H-imidazole-1-carboxylate as a hygroscopic light yellow solid (0.74 g, 57% yield). 1H NMR (300 MHz, CDCl3) δ 6.69 (s, 2H), δ 6.34 (s, 1H), δ 2.20 (t, J=7.5 Hz, 2H), δ 1.44 (bs, 11H), 1.17 (s, 6H), δ 0.76 (s, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.1, 149.6, 139.3, 105.7, 84.1, 31.8, 29.2, 28.4, 28.3, 28.0, 22.7, 14.2 ppm; IR νmax (cm−1) 3421, 2109, 1644, 1442, 1204, 1142; HRMS (ESI) calcd for C14H25N3O2 (M+) 267.1946, found 267.1940. Then, tert-butyl 2-amino-4-hexyl-1H-imidazole-1-carboxylate was dissolved in a 1:4 mixture of trifluoroacetic acid/dichloromethane and allowed to stir for five hours and then concentrated de vacuo. The sample was then dissolved with a dilute HCl/methanol (5 drops HCl/50 mL of methanol) and then concentrated in vacuo to provide 4-(5phenylpentyl)-1H)-imidazol-2-amine hydrochloride as a hygroscopic light yellow solid (0.57 g, 57% overall yield). 1H NMR (300 MHz, CD3OD) δ 6.34 (bs, 3H), δ 2.41 (t, J=7.5 Hz, 2H), δ1.56 (m, 2H), δ 1.28 (bs, 6H), δ 0.82 (t, J=6.6 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 151.4, 131.9, 111.9, 35.3, 32.4, 31.9, 28.3, 26.3, 17.1 ppm; IR νmax (cm−1) 3411, 2099, 1638; HRMS (ESI) calcd for C9H17N3 (M+) 167.1422, found 167.1416.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:14]([CH2:20][CH2:21][CH2:22][CH3:23])=[N:13][C:7]=3[C:8]([NH2:12])=[N:9][C:10]=2[CH:11]=1.[CH2:24]([O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1B(O)O)[CH2:25][CH3:26]>>[CH2:20]([C:14]1[N:15]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:6]2[C:5]3[CH:4]=[CH:3][C:2]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=4[O:27][CH2:24][CH2:25][CH3:26])=[CH:11][C:10]=3[N:9]=[C:8]([NH2:12])[C:7]=2[N:13]=1)[CH2:21][CH2:22][CH3:23]
Reactant: CCCOc1ccccc1B(O)O
Reactant: CCCCc1nc2c(N)nc3cc(Br)ccc3c2n1CC(C)C
Product: CCCCc1nc2c(N)nc3cc(-c4ccccc4OCCC)ccc3c2n1CC(C)C

Procedure:
7-Bromo-2-butyl-1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine and 2-propoxybenzeneboronic acid were coupled according to the general procedure described in Part J of Example 1. The product was recrystallized from isopropanol, collected by filtration, dissolved in CH2Cl2, and then precipitated with hexanes to afford 2-butyl-1-isobutyl-7-(2-propoxyphenyl)-1H-imidazo[4,5-c]quinolin-4-amine as a white powder, m.p. 174.5-176.0° C.
Reaction SMILES: [N:1](=[C:3]1[S:7][CH2:6][CH2:5][S:4]1)[OH:2].[CH3:8][N:9]([S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:10](F)=[O:11].C(N(CC)CC)C>O1CCOCC1>[CH3:8][N:9]([S:13][S:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:10]([O:2][N:1]=[C:3]1[S:7][CH2:6][CH2:5][S:4]1)=[O:11]
Reactant: ON=C1SCCS1
Reactant: CN(SSC(C)(C)C)C(=O)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CN(SSC(C)(C)C)C(=O)ON=C1SCCS1

Procedure:
2-[[O-[N-Methyl-N-(tert-butylthiosulfenyl)carbamoyl]oximino]]-1,3-dithiolane was prepared according to the procedure described in Example I, by reacting 2.9 g (0.0214 m) of 2-oximino-1,3-dithiolane, 4.23 g (0.0214 m) of N-methyl-N-(tert-butylthiosulfenyl)carbamoyl fluoride and 2.17 g (0.0214 m) of triethylamine in 50 ml of dioxane. 2-[[O-[N-Methyl-N-tert-butylthiosulfenyl)carbamoyl]oximino]]-1,3-dithiolane crystallized from methylene chloride isopropyl ether to yield 4.0 g of a white solid. It was then recrystallized from ethyl acetate to yield a solid, m.p. 112°-114° C.
Reaction SMILES: [CH:1]([N:4](C(C)C)[CH2:5]C)(C)C.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:20])=[C:15]([CH:19]=1)[C:16](O)=[O:17].CNC.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([Br:20])=[C:15]([CH:19]=1)[C:16]([N:4]([CH3:5])[CH3:1])=[O:17]
Reactant: CCN(C(C)C)C(C)C
Reactant: Nc1ccc(Br)c(C(=O)O)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(N)ccc1Br
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Diisopropyl ethylamine (21 ml, 121 mmol) was dissolved in a solution of 5-amino-2-bromo benzoic acid (5 g, 23 mmol), dimethylamine (5 g, 115 mmol) and BOP (51 g, 121 mmol) in 100 ml DMF. And the reaction mixture was stirred at room temperature 30 minutes. Three times of water was added into the reaction solution. The reaction mixture was extracted by ethyl acetate. The organic layer was evaporated to give a crude product, which was purified using column chromatography to give the product. (3.1 g, 54%)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.CCN(CC)CC.FC(F)(F)S(O[CH2:45][C:46]([F:49])([F:48])[F:47])(=O)=O>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH:26]4[CH2:31][CH2:30][N:29]([CH2:45][C:46]([F:49])([F:48])[F:47])[CH2:28][CH2:27]4)[CH:24]=3)=[CH:7][N:8]2[S:11]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)(=[O:12])=[O:13])=[CH:4][CH:3]=1
Reactant: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCNCC3)c2)c2ccc(F)cc21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: O=S(=O)(c1ccccc1)n1cc(-c2cnn(CC3CCN(CC(F)(F)F)CC3)c2)c2ccc(F)cc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 83.9 %

Procedure:
A mixture of 6-fluoro-1-(phenylsulfonyl)-3-(1-(piperidin-4-ylmethyl)-1H-pyrazol-4-yl)-1H-indole (Intermediate 21; 277 mg; 0.63 mmol), Et3N (0.40 mL; 2.87 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (147 mg; 0.63 mmol) in toluene (40 mL) was stirred at 80° C. overnight. The reaction mixture was concentrated and purified by reverse phase flash chromatography to afford 275 mg (84%) of the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].[F:27][C:28]1[CH:29]=[C:30]([N:35]2[CH:39]=[CH:38][C:37]([NH2:40])=[N:36]2)[CH:31]=[CH:32][C:33]=1[F:34].N1C2C(=NC=CC=2)N(O)N=1.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:40][C:37]3[CH:38]=[CH:39][N:35]([C:30]4[CH:31]=[CH:32][C:33]([F:34])=[C:28]([F:27])[CH:29]=4)[N:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: Nc1ccn(-c2ccc(F)c(F)c2)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)Nc4ccn(-c5ccc(F)c(F)c5)n4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 60 h
Yield: 92.3 %

Procedure:
To a solution of 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (0.050 g, 0.13 mmol), 1-(3,4-difluorophenyl)-1H-pyrazol-3-amine (0.028 g, 0.15 mmol), and 3H-[1,2,3]triazolo[4,5-b]pyridin-3-ol (0.018 g, 0.13 mmol) in DMF (0.7 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.028 g, 0.15 mmol), and the reaction was allowed to stir at ambient temperature for 60 hours. The reaction was diluted with EtOAc and washed with 10% citric acid, saturated sodium bicarbonate, and saturated sodium chloride. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with a linear gradient of 5-70% EtOAc/hexanes to yield the desired product (0.067 g, 0.12 mmol, 91% yield).
Reaction SMILES: [I-:1].[Na+].C(Cl)(=O)C.Cl[C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:9]=12>C(#N)C>[I:1][C:8]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[N:11]=[C:10]2[S:20][C:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=3[C:9]=12
Reactant: CCOC(=O)c1c(C)nc2sc3c(c2c1Cl)CCCC3
Reactant: [I-]
Agent: [Na+]
Solvent: CC(=O)Cl
Solvent: CC#N
Product: CCOC(=O)c1c(C)nc2sc3c(c2c1I)CCCC3
Temperature: 25 °C
Reaction time: 30 h
Yield: 78.1 %

Procedure:
Sodium iodide (994.0 g, 6.63 Mol) was added over 5 minutes to a stirred solution of acetyl chloride (177 mL, 2.48 Mol) and ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate (Preparation 4, 257 g, 0.83 Mol) in acetonitrile (2.0 L) at room temperature. The resulting mixture was heated to reflux and stirred for 30 hours. The mixture was allowed to cool to room temperature and stood for 72 hours. The solids were collected by filtration and washed with cold acetonitrile (500 mL). The solids were partitioned between dichloromethane (1.5 L) and water (0.75 L). The aqueous layer was basified to pH 9 by addition of 2 M sodium hydroxide solution and the two layers were separated. The organic layer was washed with 2 M sodium thiosulphate solution (800 mL), brine (800 mL), dried (Na2SO4), filtered and concentrated under reduced pressure to give the title compound (260.0 g, 78%) as a beige solid. This material was determined by 1H NMR spectroscopy to be a 13:1 mixture of ethyl (4-iodo-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate and ethyl (4-chloro-2-methyl-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridine-3-yl)carboxylate respectively.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:11](N)=O)[CH3:10])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].F[B-](F)(F)F.C([O+](CC)CC)C.[F:26][C:27]1[CH:28]=[CH:29][C:30]([N+:40]([O-])=O)=[C:31]([NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH:32]=1>C(Cl)Cl>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:10]1[N:33]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[C:31]2[CH:32]=[C:27]([F:26])[CH:28]=[CH:29][C:30]=2[N:40]=1)[CH3:11])([CH3:7])([CH3:6])[CH3:5]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(N)=O
Reactant: O=[N+]([O-])c1ccc(F)cc1Nc1ccccn1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: C[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 0.1 %

Procedure:
(Prep 2) To a suspension of (S)-Boc-alaninamide (79.4 g, 0.42 mol) in DCM (750 mL) was added triethyloxonium tetrafluoroborate (69.5 g, 0.37 mol) and the reaction mixture stirred at RT for 2 h, during which the solids dissolved. The reaction mixture was concentrated in vacuo and the residue dissolved in ethanol (750 mL). (5-Fluoro-2-nitrophenyl)pyridin-2-yl-amine (57.1 g, 0.28 mol) was added and the reaction heated at 70° C. for 1 h. The reaction mixture was concentrated in vacuo, the residue dissolved in water and the product extracted with EtOAc (3×150 mL). The combined organic extracts were washed with brine, dried (MgSO4) and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, eluting with 0-100% EtOAc in cyclohexane) to yield the title compound as a white foam (60.3 mg, 60%).
Reaction SMILES: S(Cl)([Cl:3])=O.CN(C)C=O.[Cl:10][C:11]1[CH:12]=[C:13]([NH:17][C:18](=[O:25])[O:19][CH2:20][C:21]#CCO)[CH:14]=[CH:15][CH:16]=1>C(Cl)CCl>[CH:15]1[CH:16]=[C:11]([Cl:10])[CH:12]=[C:13]([NH:17][C:18]([O:19][C:20]#[C:21][Cl:3])=[O:25])[CH:14]=1
Reactant: O=C(Nc1cccc(Cl)c1)OCC#CCO
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Nc1cccc(Cl)c1)OC#CCl

Procedure:
In another preparation on the same scale, the thionyl chloride and dimethylformamide in 25 ml of EDC were stirred at 65° while a warm solution of 4-hydroxy-2-butynyl N-(3-chlorophenyl)carbamate in 75 ml of EDC was added dropwise over 60 minutes. Barban (6.5 g) was obtained by evaporation of the solvent after 17 hours at 65° and analyzed by HPLC: barban 97.6% (w/w); biscarbanate -- 2.2% (w/w); bisurea -- 1.6% (w/w).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=[C:4]([Cl:16])[N:3]=1.[I-:17].[Na+].I>C(Cl)(Cl)Cl>[Cl:16][C:4]1[N:3]=[C:2]([I:17])[N:7]=[C:6]([N:8]2[CH2:14][CH:13]3[O:15][CH:10]([CH2:11][CH2:12]3)[CH2:9]2)[CH:5]=1
Reactant: Clc1cc(N2CC3CCC(C2)O3)nc(Cl)n1
Reactant: [I-]
Agent: I
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Clc1cc(N2CC3CCC(C2)O3)nc(I)n1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
In a 20 mL scintillation vial was placed 3-(2,6-dichloropyrimidin-4-yl)-8-oxa-3-azabicyclo[3.2.1]octane (9, 780 mg, 3 mmol) in chloroform (2 ml) to give a very light yellow solution. Sodium iodide (749 mg, 5 mmol) was added to give a suspension. The mixture was cooled to 0° C. and an aqueous solution (57% w/w) of hydrogen iodide (0.356 ml, 2.70 mmol) was added, resulting in a thick yellow precipitate. The mixture was stirred at room temperature for 16 hours. LCMS indicated only a trace of product being formed. Additional aqueous. HI (356 μL) was added and the mixture was stirred at room temperature for 64 hours. Additional aqueous HI was added (712 μL) and the suspension was stirred for an additional 7 hours. LCMS showed the presence of the desired product as the main peak along with a dehalogenated impurity and starting material. The mixture was diluted with water and solid K2CO3 was added to pH˜8. The aqueous phase was extracted with dichloromethane. The organic phase was washed with aqueous sodium thiosulfate to decolorize, dried over MgSO4, filtered and concentrated. The crude product was added to a silica gel column and was eluted with ethyl acetate in hexanes (15-40%). Collected fractions were concentrated to give 588 mg (1.7 mmol, 56%) of a white solid, which was a mixture of the desired product containing approximately 20% starting material. The mixture was carried on to the next step.