Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[CH:3]=1.[CH3:9][N:10]1[CH:14]=[C:13](B2OC(C)(C)C(C)(C)O2)[CH:12]=[N:11]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Br:8][C:4]1[CH:3]=[C:2]([C:13]2[CH:12]=[N:11][N:10]([CH3:9])[CH:14]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Brc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cc(-c2cccc(Br)c2)cn1
Temperature: 90 °C
Reaction time: 1.5 h

Procedure:
1,3-Dibromobenzene (0.38 mL, 3.2 mmol), 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (595 mg, 2.86 mmol), Pd(dppf)Cl2 (260 mg, 0.320 mmol), and potassium phosphate (2.0 g, 9.5 mmol) were combined in a flask and dissolved in dioxane (16.0 mL) and water (1.6 mL). The flask was then sealed and flushed with argon. The reaction mixture was allowed to stir at 90° C. for 90 minutes. The mixture was then cooled to ambient temperature and diluted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4, and concentrated in vacuo. The residue was purified by MPLC on silica gel (50% EtOAc/hexanes) to afford the title compound.
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1)#[N:2].[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH2:27])=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[CH2:12]([NH:19][C:20]([C:22]1[S:26][C:25]([NH:27][C:7](=[O:8])[C:6]2[CH:10]=[CH:11][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)=[N:24][C:23]=1[CH3:28])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C(=O)Cl)cc1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2ccc(C#N)cc2)sc1C(=O)NCc1ccccc1
Yield: 23 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 4-cyanobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 23% yield; m.p. 256-258° C.; 1H NMR (DMSO-d6, 300 MHz) δ 8.64 (t, J=5.7 Hz, 1H), 8.19 (d, J=8.2 Hz, 2H), 7.99 (d, J=8.2 Hz, 2H), 7.49-7.18 (m, 5H), 4.37 (d, J=5.7 Hz, 2H), 2.51 (s, 3H); MS (ES+) m/z 377.2 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[C:14]([F:19])[CH:13]=2)[C:3]=1[CH3:20].[CH3:21][C:22]1([CH3:37])[C:26]2=[N:27][CH:28]=[C:29]([N:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[CH:30]=[C:25]2[NH:24][CH2:23]1.CC(C)([O-])C.[Na+]>CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].C1(C)C=CC=CC=1>[F:19][C:14]1[CH:13]=[C:12]([C:4]2[C:3]([CH3:20])=[C:2]([N:24]3[C:25]4[C:26](=[N:27][CH:28]=[C:29]([N:31]5[CH2:32][CH2:33][O:34][CH2:35][CH2:36]5)[CH:30]=4)[C:22]([CH3:37])([CH3:21])[CH2:23]3)[C:11]3[C:6](=[N:7][CH:8]=[CH:9][CH:10]=3)[N:5]=2)[CH:17]=[C:16]([F:18])[CH:15]=1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Reactant: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1Cl
Agent: Cl[Pd+]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(F)c2)nc2ncccc2c1N1CC(C)(C)c2ncc(N3CCOCC3)cc21

Procedure:
Prepared according to procedure Y using 4-chloro-2-(3,5-difluorophenyl)-3-methyl-1,8-naphthyridine (68 mg, 0.234 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (54.6 mg, 0.234 mmol), sodium tert-butoxide (45 mg, 0.468 mmol) and XPhos precatalyst (17.1 mg, 0.023 mmol) in toluene (4 mL) for 2 hours at 110° C. Purification by reverse phase HPLC (10 to 60% acetonitrile in waiter) gave 2-(3,5-difluorophenyl)-4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-3-methyl-1,8-naphthyridine. 1H NMR (400 MHz, chloroform-d) δ ppm 9.13 (1H, dd, J=4.3, 2.0 Hz), 8.17 (1H, dd, J=8.2, 2.0 Hz), 7.65 (1H, d, J=2.3 Hz), 7.45 (1H, dd, J=8.3, 4.2 Hz), 7.25-7.28 (2H, m), 6.91-6.98 (1H, m), 5.78 (1H, d, J=2.5 Hz), 3.86-3.91 (1H, m), 3.79-3.84 (1H, m), 3.71-3.78 (4H, m), 2.94-3.04 (4H, m), 2.37 (3H, s), 1.58 (3H, s), 1.53 (3H, s). Mass Spectrum (ESI) m/e=488.2 (M+1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)[CH:8]=[CH:9][C:10]=1[O:11][CH3:12])(=[O:4])=[O:3].[CH2:19](I)[CH3:20]>>[CH2:19]([N:16]1[CH2:15][CH2:14][N:13]([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:5]([S:2]([CH3:1])(=[O:3])=[O:4])[CH:6]=2)[CH2:18][CH2:17]1)[CH3:20]
Reactant: CCI
Reactant: COc1ccc(N2CCNCC2)cc1S(C)(=O)=O
Product: CCN1CCN(c2ccc(OC)c(S(C)(=O)=O)c2)CC1

Procedure:
Beginning with 1-(3-Methanesulfonyl-4-methoxy-phenyl)-piperazine and Et-I, the title compound was recovered by the procedure described in Example 2: MS m/z (rel. intensity, 70 eV)) 298 (M+, 81), 283 (45), 84 (36), 57 (bp), 56 (41).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH3:12])[CH:9]=[CH:10][CH:11]=1.[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:13]=[CH:14][CH:15]=1)[O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][Br:16]
Reactant: Cc1cccc(Oc2cccc(F)c2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1cccc(Oc2cccc(CBr)c2)c1
Temperature: 10 °C
Yield: 58.3 %

Procedure:
90 g (0.445 mol) of 3-(3-fluorophenoxy)-toluene were dissolved in 300 ml of anhydrous carbon tetrachloride and heated under reflux together with 79.3 g of N-bromosuccinimide. After reaching 70° C., 5 g of azodiisobutyronitrile were added. After about 10-20 minutes the reaction commenced, with evolution of heat, and after the exothermic reaction had subsided the mixture was heated for a further 4 hours under reflux. The reaction batch was then cooled to 10° C., the succinimide was filtered off and the carbon tetrachloride was distilled of in vacuo. The oil which remained was distilled at 143°-150° C./1 mm Hg. 72.9 g (58.2% of theory) of 3-(3-fluorophenoxy)-benzyl bromide were obtained.
Reaction SMILES: C([O:5]O)(C)(C)C.[Cl:7][C:8]1[C:13]([Cl:14])=[C:12]([S:15][CH2:16][CH3:17])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:24])([F:23])[F:22]>CCCCCCCCCC.C(Cl)(Cl)Cl>[Cl:7][C:8]1[C:13]([Cl:14])=[C:12]([S:15]([CH2:16][CH3:17])=[O:5])[CH:11]=[CH:10][C:9]=1[NH:18][C:19](=[O:27])[C@:20]([OH:26])([CH3:25])[C:21]([F:22])([F:23])[F:24]
Reactant: CC(C)(C)OO
Reactant: CCSc1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Solvent: ClC(Cl)Cl
Solvent: CCCCCCCCCC
Product: CCS(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1Cl
Reaction time: 18 h

Procedure:
t-Butyl hydrogen peroxide (2.4 ml of a 5.5M solution in decane) was added to a solution of (R)-N-[2,3-dichloro-4-ethylsulphanylphenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide Method 1) (0.23 g) and d-10-camphorsulphonic acid (0.018 g) in chloroform (10 ml) and the mixture was stirred for 18 hours. Volatile material was removed by evaporation and the residue was purified by chromatography on a silica gel Mega Bond Elut column eluting with 0-50% EtOAc/isohexane to give the title compound (0.22 g) as a white solid. NMR (CDCl3+1 drop DMSO): 1.21-1.28 (m, 3H), 1.71 (s, 3H), 2.77-2.89 (m, 1H), 3.04-3.16 (m, 1H), 7.14 (s, 1H), 7.78 (d, 1H), 8.66 (d, 1H), 9.73 (s, 1H); m/z: 376.
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=[O:12])=[CH:8][CH:7]=[CH:6][CH:5]=2.[Br:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1>>[Br:13][C:14]1[CH:19]=[C:18]([N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]([CH:11]=[O:12])=[C:2]2[Cl:1])[CH:17]=[CH:16][CH:15]=1
Reactant: OB(O)c1cccc(Br)c1
Reactant: O=Cc1c(Cl)[nH]c2ccccc12
Product: O=Cc1c(Cl)n(-c2cccc(Br)c2)c2ccccc12
Yield: 87 %

Procedure:
2-Chloro-1H-indole-3-carboxaldehyde is reacted with 3-bromophenylboronic acid as described in Step 1 of Example 29 to afford 1-(3-bromophenyl)-2-chloro-1H-indole-3-carboxaldehyde (87% yield) as a cream solid. ESI/MS 334 (M), 375 [(M+2+CH3CN) adduct]; RT=3.59 min.
Reaction SMILES: [CH:1]12[CH2:14][CH:9]([CH:10](O)[CH:11]1O)[CH2:8][C:7]1[C:2]2=[N:3][CH:4]=[CH:5][CH:6]=1.I([O-])(=O)(=O)=O.[Na+].[CH2:21]([NH2:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)C.O.ClC(Cl)C.C(OCC)(=O)C>[C:22]1([CH2:21][N:28]2[CH2:11][CH:1]3[CH2:14][CH:9]([CH2:8][C:7]4[C:2]3=[N:3][CH:4]=[CH:5][CH:6]=4)[CH2:10]2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: NCc1ccccc1
Reactant: OC1C2Cc3cccnc3C(C2)C1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Solvent: O
Product: c1ccc(CN2CC3Cc4cccnc4C(C3)C2)cc1
Reaction time: 0.25 h
Yield: 49.9 %

Procedure:
To a solution of 3-azatricyclo[7.2.1.02,7]dodeca-2,4,6-triene-10,11-diol (Preparation 24, 1.16 g, 6.07 mmol) in ethanol (40 ml) was added sodium periodate (1.35 g, 6.07 mmol) in water (20 ml) to produce a yellow slurry. After 15 min, water and ethyl acetate were added and the layers were separated, the aqueous layer washed with ethyl acetate (4×50 ml) and then dichloromethane. The combined organic extracts were dried (Na2SO4) to give an orange oil. The oil was diluted with dichloroethane (50 ml), benzylamine (0.65 g, 6.07 mmol) was added followed by sodium triacetoxyborohydride (4.12 g, 19.4 mmol). After 7 h, saturated sodium hydrogen carbonate solution (75 ml) and ethyl acetate (75 ml) were added and the reaction mixture was stirred for 20 min. The layers were separated and the aqueous layer was extracted with ethyl acetate (2×50 ml). The combined organic extracts were washed with water and brine, and then dried (Na2SO4) and concentrated in vacuo to give the crude product. Purification by flash chromatography produced the title compound as a light yellow oil (0.80 g, 50%).
Reaction SMILES: [S:1]([N:11]1[C:19]2[CH:18]=[CH:17][N:16]=[C:15]([CH:20]([NH2:22])[CH3:21])[C:14]=2[CH:13]=[CH:12]1)([C:4]1[CH:10]=[CH:9][C:7]([CH3:8])=[CH:6][CH:5]=1)(=[O:3])=[O:2].Cl[C:24]1[N:29]=[C:28]([NH:30][C:31]2[CH:35]=[C:34]([CH:36]3[CH2:38][CH2:37]3)[NH:33][N:32]=2)[CH:27]=[CH:26][N:25]=1.CCN(C(C)C)C(C)C>CC(C(O)C(C)C)C>[CH:36]1([C:34]2[NH:33][N:32]=[C:31]([NH:30][C:28]3[CH:27]=[CH:26][N:25]=[C:24]([NH:22][CH:20]([C:15]4[C:14]5[CH:13]=[CH:12][N:11]([S:1]([C:4]6[CH:5]=[CH:6][C:7]([CH3:8])=[CH:9][CH:10]=6)(=[O:3])=[O:2])[C:19]=5[CH:18]=[CH:17][N:16]=4)[CH3:21])[N:29]=3)[CH:35]=2)[CH2:38][CH2:37]1
Reactant: Clc1nccc(Nc2cc(C3CC3)[nH]n2)n1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)N)nccc32)cc1
Agent: CC(C)C(O)C(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)n2ccc3c(C(C)Nc4nccc(Nc5cc(C6CC6)[nH]n5)n4)nccc32)cc1
Temperature: 140 °C
Reaction time: 18 h
Yield: 51.6 %

Procedure:
A mixture of (±)-1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethanamine (referential example 11) (800 mg, 2.54 mmol), 2-chloro-N-(5-cyclopropyl-1H-pyrazol-3-yl)-pyrimidin-4-amine (500 mg, 2.12 mmol), and DIPEA (820 mg, 6.36 mmol) in 2,4-dimethylpentan-3-ol (10 mL) in a sealed tube under nitrogen was stirred at 140° C. for 18 h. The crude product was purified by preparative HPLC to afford 563 mg (51.7%) of (±)—N4-(5-cyclopropyl-1H-pyrazol-3-yl)-N2-(1-(1-tosyl-1H-pyrrolo[3,2-c]pyridin-4-yl)ethyl)pyrimidine-2,4-diamine as a yellow solid (563 mg, 51.7%): MS (ESI) m/z: 515.2 [M+1]+
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8](O)=[O:9])=[CH:4][CH:3]=1.O=S(Cl)[Cl:17]>CN(C=O)C>[Br:1][C:2]1[CH:14]=[CH:13][C:5]([O:6][C:7]([CH3:12])([CH3:11])[C:8]([Cl:17])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(Oc1ccc(Br)cc1)C(=O)O
Solvent: CN(C)C=O
Product: CC(C)(Oc1ccc(Br)cc1)C(=O)Cl
Yield: 78 %

Procedure:
A mixture of 2-(4-bromophenoxy)-2-methylpropanoic acid (10.0 g, 38.6 mmol). DMF (0.5 mL) and SOCl2 (40 mL) was heated for 3 h, allowed to cool and distilled to yield the sub-title compound (8.4 g, 78%).
Reaction SMILES: B(Br)(Br)Br.C[O:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13].CS(N)(=O)=O>C(Cl)Cl>[OH:6][C:7]1[CH:8]=[C:9]([CH:16]=[CH:17][CH:18]=1)[CH2:10][NH:11][S:12]([CH3:15])(=[O:14])=[O:13]
Reactant: COc1cccc(CNS(C)(=O)=O)c1
Agent: BrB(Br)Br
Agent: CS(N)(=O)=O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1cccc(O)c1
Yield: 102.6 %

Procedure:
A solution of BBr3 (1.0M in CH2Cl2, 111 mL, 111 mmol) was slowly added to a solution of N-(3-methoxy-benzyl)-methanesulfonamide (12.000 g, 55.7 mmol) in CH2Cl2(200 mL) at 0° C. The reaction methanesulfonamide (12.000 g, 55.7 mmol) in CH2Cl2(200 mL) at 0° C. The reaction cautiously added and the solution was concentrated in vacuo. Flash chromatography (1:1 hexanes:EtOAc) provided N-(3-hydroxy-benzyl)-methanesulfonamide (11.50 g). 1H NMR (400 MHz, CDCl3) δ 7.20 (m, 1H), 6.84 (m, 2H), 6.77 (m, 1H), 4.83 (bs, 1H), 4.24 (s, 2H), 2.86 (s, 3H); MS 201 (M+).
Reaction SMILES: [CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[C:10](Br)[C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1.C(O)=O.C(N(CC)CC)C>[Pd].C1(C)C=CC=CC=1>[CH:1]1([C:4]2[N:14]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]#[N:29])=[CH:18][CH:17]=3)[C:7]3=[N:8][CH:9]=[CH:10][C:11]([CH3:12])=[C:6]3[N:5]=2)[CH2:3][CH2:2]1
Reactant: Cc1c(Br)cnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: O=CO
Solvent: Cc1ccccc1
Product: Cc1ccnc2c1nc(C1CC1)n2Cc1ccc(-c2ccccc2C#N)cc1
Yield: 78 %

Procedure:
Toluene (30 ml) was added to 2.0 g (4.5 mmol) of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-6-bromo-7-methyl-3H-imidazo[4,5-b]pyridine, 1.24 g (27.0 mmol) of formic acid, 4.55 g (45.0 mmol) of triethylamine and 10% Pd-C (100 mg), followed by heating under reflux for 6 hours. After the reaction liquid was brought to room temperature and filtered to remove the catalyst, vacuum concentration was effected. Chloroform (50 ml) and water (50 ml) were added to the residue and the obtained mixture was caused liquid-liquid separation. The aqueous phase was further extracted with chloroform (30 ml) twice. The organic phases were combined, dried over anhydrous magnesium sulfate and subjected to vacuum concentration. The residue was purified by silica gel column chromatography (n-hexane/ethyl acetate) to give 1.28 g of 2-cyclopropyl-3-(2'-cyanobiphenyl-4-yl)methyl-7-methyl-3H-imidazo[4,5-b]pyridine (yield 70%).
Reaction SMILES: [CH:1]1([CH2:7]Br)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:9]([CH2:11][NH2:12])[OH:10]>CCO>[CH:1]1([CH2:7][NH:12][CH2:11][CH2:9][OH:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NCCO
Reactant: BrCC1CCCCC1
Solvent: CCO
Product: OCCNCC1CCCCC1
Temperature: 75 °C
Yield: 51.3 %

Procedure:
A mixture of cyclohexylmethylbromide (23.2 g, 131 mmol) and ethanolamine (47.9 g, 786 mmol) in EtOH (131 mL) was heated at 75° C. for 2 hours. NMR analysis of an aliquot showed the reaction was complete. The reaction was then concentrated to remove ethanol and the resulting residue was diluted with DCM. The organic layer was washed successively with water (3×100 mL) and brine (100 mL) and then dried over sodium sulfate, filtered, and concentrated to give the title intermediate as a light yellowish oil (10.57 g). (m/z): [M+H]+ calcd for C9H19NO, 158.16. found 158.2. 1H NMR (CDCl3, 300 MHz) δ (ppm): 3.59 (t, J=5.4 Hz, 2H), 2.73 (t, J=5.4 Hz, 2H), 2.42 (d, J=6.6 Hz, 2H), 1.6-1.77 (m, 6H), 1.36-1.6 (m, 1H), 1.10-1.28 (m, 2H), 0.82-0.95 (m, 2H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([NH:10][C:11]3[N:15]([CH3:16])[C:14]4[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:13]=4[N:12]=3)=[N:7][C:6]=2[CH:24]=1.[CH3:25][O:26][CH2:27][CH2:28][NH2:29].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:25][O:26][CH2:27][CH2:28][NH:29][C:21]([C:19]1[CH:18]=[CH:17][C:14]2[N:15]([CH3:16])[C:11]([NH:10][C:8]3[S:9][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:24][C:6]=4[N:7]=3)=[N:12][C:13]=2[CH:20]=1)=[O:23]
Reactant: Cn1c(Nc2nc3cc(F)ccc3s2)nc2cc(C(=O)O)ccc21
Reactant: COCCN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: COCCNC(=O)c1ccc2c(c1)nc(Nc1nc3cc(F)ccc3s1)n2C

Procedure:
2-(5-Fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (32 mg) was prepared by following General Procedure F using 2-(5-fluoro-benzothiazol-2-ylamino)-1-methyl-1H-benzimidazole-5-carboxylic acid (34 mg), 2-methoxy-ethylamine (0.1 ml), HBTU (38 mg), and DIEA (0.1 ml). LCMS: m/z 401; and 1H NMR (DMSO-d6, 400 MHz): δ 8.46 (t, 1H), 8.05 (d, 1H), 7.95 (s, 1H), 7.79-7.71 (m, 2H), 7.42 (d, 1H), 7.30 (d, 1H), 6.99 (t, 1H), 3.65 (s, 3H), 3.51-3.42 (m, 2H), 3.36 (d, 2H), and 2.73 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:16]([OH:17])[C@@H:15]([CH2:18][O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[O:14][CH:11]([O:12][CH3:13])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[C:37]([O:17][C@@H:16]1[C@@H:15]([CH2:18][O:19][S:20]([C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[CH:25][CH:24]=2)(=[O:22])=[O:21])[O:14][CH:11]([O:12][CH3:13])[CH2:10][C@H:9]1[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)(=[O:44])[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: COC1C[C@@H](OCc2ccccc2)[C@H](O)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Reactant: O=C(Cl)c1ccccc1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COC1C[C@@H](OCc2ccccc2)[C@H](OC(=O)c2ccccc2)[C@@H](COS(=O)(=O)c2ccc(C)cc2)O1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.7 %

Procedure:
The compound (16.9 g, 40.0 mmol) synthesized in Example 6 (6c) was dissolved in methylene chloride (150 mL) and triethylamine (22 mL, 0.16 mol), benzoyl chloride (14 mL, 0.12 mol) and 4-dimethylaminopyridine (489 mg, 4.00 mmol) were added thereto, followed by stirring of the mixture at room temperature for 18 hours. After water (80 mL) was added to the reaction mixture and the mixture was extracted with methylene chloride (100 mL), the organic layer was washed with saturated brine (50 mL) and dried with anhydrous sodium sulfate, followed by distilling off of the solvent under reduced pressure. The residue was purified using silica gel flash column chromatography (hexane:ethyl acetate, 4:1-3:1, V/V) to obtain the desired title compound (20.8 g, yield 99%) as a yellow oil.
Reaction SMILES: C(O[C:6]([N:8](C)[C:9]1[C:17]([O:18][CH3:19])=[C:16]2[C:12]([C:13]3[CH:30]=[C:29]([CH3:31])[CH:28]=[N:27][C:14]=3[N:15]2C(OC(C)(C)C)=O)=[C:11]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH:33]=2)[CH:10]=1)=O)(C)(C)C.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH2:41]([S:38]([C:34]1[CH:33]=[C:32]([C:11]2[CH:10]=[C:9]([NH:8][CH3:6])[C:17]([O:18][CH3:19])=[C:16]3[C:12]=2[C:13]2[CH:30]=[C:29]([CH3:31])[CH:28]=[N:27][C:14]=2[NH:15]3)[CH:37]=[CH:36][CH:35]=1)(=[O:40])=[O:39])[CH3:42]
Reactant: CCS(=O)(=O)c1cccc(-c2cc(N(C)C(=O)OC(C)(C)C)c(OC)c3c2c2cc(C)cnc2n3C(=O)OC(C)(C)C)c1
Solvent: COc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)c1cccc(-c2cc(NC)c(OC)c3[nH]c4ncc(C)cc4c23)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
The crude residue from previous step (Compound 251) was dissolved in 3 mL CH2Cl2 and to were sequentially added 0.2 mL of anisole and 1 mL of TFA. The mixture was stirred at room temperature for 2 h. Solvent was removed in vacuum and the residue was basified with saturated aqueous NaHCO3 and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and finally purified flash chromatography to furnish Compound 252 (287 mg, 70%, for 2 steps).
Reaction SMILES: [Na+].[I-].C[Si](Cl)(C)C.O[C:9]1([CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:16]2[N:12]([C:13]3[CH:20]=[CH:19][N:18]=[C:17]([S:21][CH3:22])[C:14]=3[CH:15]=2)[CH2:11][CH2:10]1>CC#N>[CH3:22][S:21][C:17]1[C:14]2[CH:15]=[C:16]3[N:12]([C:13]=2[CH:20]=[CH:19][N:18]=1)[CH2:11][CH2:10][CH:9]3[CH2:23][C:24]([O:26][CH3:27])=[O:25]
Reactant: COC(=O)CC1(O)CCn2c1cc1c(SC)nccc12
Agent: C[Si](C)(C)Cl
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)CC1CCn2c1cc1c(SC)nccc12
Reaction time: 0.5 h

Procedure:
To NaI (0.300 g) in CH3CN (3.2 mL) was added TMSCl (0.266 mL). This mixture was added to a suspension of methyl [8-hydroxy-1-(methylthio)-7,8-dihydro-6H-pyrido[3,4-b]pyrrolizin-8-yl]acetate (0.15 g, 0.515 mmol) in CH3CN (1.5 mL), in a water bath. After a period of 0.5 h, the reaction mixture was partitioned between EtOAc and NaHCO3. The organic phase was separated, washed with sodium thiosulphate, dried over MgSO4 and evaporated. The title compound was purified by flash chromatography.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:10]=[CH:11][CH:12]=1)[C:6]([NH:8][CH3:9])=O.S(Cl)(Cl)=O.[N-:17]=[N+:18]=[N-:19].[Na+].Cl[Si](C)(C)C>C1(C)C=CC=CC=1.C(#N)C.O>[CH3:9][N:8]1[C:6]([C:5]2[CH:4]=[C:3]([CH:12]=[CH:11][CH:10]=2)[CH2:2][Cl:1])=[N:19][N:18]=[N:17]1
Reactant: CNC(=O)c1cccc(CCl)c1
Reactant: [N-]=[N+]=[N-]
Agent: C[Si](C)(C)Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: O
Product: Cn1nnnc1-c1cccc(CCl)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a suspension of 3-(chloromethyl)-N-methyl-benzamide (27.2 g, 148 mmol) in toluene (100 mL) was added thionyl chloride (16.2 mL, 222 mmol) at room temperature. The resulting suspension was heated at reflux for 15 hours. The reaction mixture was cooled to room temperature and then concentrated under vacuum. The residue was azeotroped with toluene and dried under high vacuum. To a suspension of sodium azide (11.6 g, 178 mmol) in acetonitrile (140 mL) was added chlorotrimethylsilane (23.7 mL, 187 mmol) at room temperature and the suspension was stirred for 1.5 hours. The reaction mixture was cooled to −10° C. and the above crude imidoyl chloride (148 mmol) in acetonitrile (40 mL) was added over 5 minutes. The mixture was stirred for 2 hours at 0° C. and then stirred at room temperature for 15 hours. The reaction mixture was diluted with water (200 mL) and extracted with ethyl acetate (2×100 mL). The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Filtration and concentration gave a light yellow solid which was dissolved in hexanes-ethyl acetate (220 mL, 11:9 ratio) at 60-70° C. The resulting solution was stored in the refrigerator and the precipitated solids were collected by filtration and washed with hexanes. After drying in air, 3-(1-methyltetrazol-5-yl)benzyl chloride was isolated as 24.5 g (79.5%) of a white amorphous solid, mp 63-65° C.; HRMS (ES+) cald. for C9H9ClN4 [(M+H)+] 209.0589, obsd. 209.0588.