Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([OH:12])[CH:3]=1.C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].Cl>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:11])[CH2:9][CH3:10])=[C:4]([O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCC(=O)c1ccc(Br)cc1O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC(=O)c1ccc(Br)cc1OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81.3 %

Procedure:
To a solution of 1-(4-bromo-2-hydroxy-phenyl)-propan-1-one (20.0 g, 87.3 mmol) in dichloromethane (100 mL) was added triethylamine (24.3 mL, 174 mmol). The resulting solution was cooled to 0° C. and methanesulfonyl chloride (8.10 mL, 105 mmol) was added dropwise. The reaction was stirred for 30 minutes, poured into 1N aqueous hydrochloric acid (100 mL) and the layers were separated. The aqueous layer was extracted with dichloromethane (50 mL), the organic layers were combined, dried over magnesium sulfate, filtered, and concentrated to an oil which crystallized upon standing. The solid was recrystallized from a 60/40 mixture of ethanol and water (40 mL) to provide methanesulfonic acid 5-bromo-2-propionyl-phenyl ester (21.8 g, 81% yield). 1H NMR (400 MHz, CDCl3) δ 1.17 (t, 3, J=7.3), 2.90 (q, 2, J=7.3), 3.24 (s, 3), 7.51-7.56 (m, 2), 7.59 (d, 1, J=1.3). 13C NMR (100 MHz, CDCl3) δ 8.04, 35.45, 38.51, 128.18, 127.08, 130.60, 130.69, 131.82, 146.15, 200.30. IR 3049, 2940, 1691, 1590, 1343, 959, 886 cm-1. Analysis calculated for C10H12BrO4S: C, 39.10; H, 3.61. Found: C, 38.90; H, 3.70.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8](CBr)=[N:7]1)[CH3:2].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][N:6]1[C:10]2=[N:11][CH:12]=[CH:13][CH:14]=[C:9]2[C:8]([N:18]=[N+:19]=[N-:20])=[N:7]1)[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)Cn1nc(CBr)c2cccnc21
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cn1nc(N=[N+]=[N-])c2cccnc21
Temperature: 80 °C

Procedure:
A mixture of (3-(bromomethyl)-pyrazolo[3,4-b]pyridine-1-yl)acetic acid ethyl ester (0.5 Mmol, 1 eq.) and sodium azide (1 Mmol, 2 eq.) in 1 mL of DMF was heated at 80° C. for 1 h. The resultant mixture was cooled to rt, diluted with 150 mL of EtOAc, washed with water (40 mL××3), brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The solvent was removed in vacuo to provide 135.2 Mg desired product: HPLC retention time=1.84 minutes (Agilent Zorbax SB-C18, 2.1×50 Mm, 5μ, 35° C.) using 1 mL/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expect=261.1, found=261.4.
Reaction SMILES: [O:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][CH2:4][CH2:3][CH2:2]1.[Br:12][CH2:13][C:14](Br)=[O:15]>>[Br:12][CH2:13][C:14]([N:5]1[C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[O:1][CH2:2][CH2:3][CH2:4]1)=[O:15]
Reactant: c1ccc2c(c1)NCCCO2
Reactant: O=C(Br)CBr
Product: O=C(CBr)N1CCCOc2ccccc21

Procedure:
2,3,4,5-tetrahydro-1,5-benzoxazepine [E. K. Orlova et al.; Kim. Geterotsikl. Soedin.,9, 1296 (1975): Chem. abstra., 84, 59411] and bromoacetyl bromide were used to produce the above compound in the same way as Reference Example 8.
Reaction SMILES: [CH3:1][C:2]1([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][O:3]1.C(=O)(O)[O-].[Na+].[C:24](OC(=O)C)(=[O:26])[CH3:25]>>[C:24]([O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([CH3:1])([C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1)[O:3][CH2:4][CH2:5]2)(=[O:26])[CH3:25]
Reactant: CC1(c2cccnc2)OCCc2cc(O)ccc21
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Product: CC(=O)Oc1ccc2c(c1)CCOC2(C)c1cccnc1
Reaction time: 1 h

Procedure:
A mixture of 1-methyl-1(3-pyridyl)-6isochromanol (5.0 g), described in Example 22, and acetic anhydride (50 ml) is heated on the steam bath for 4 hr. The mixture is poured upon ice, left at room temperature for 1 hr, rendered basic with sodium bicarbonate and then extracted with chloroform. The extracts are washed with brine, dried, evaporated, and the residue is crystallized from isopropanol to give the title compound, m.p. 113° - 115° C.
Reaction SMILES: [Cl-].[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH3+:16].[CH3:17][C:18]1[O:22][C:21]([CH:23]=O)=[CH:20][CH:19]=1>>[Cl:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[NH:13][CH2:14][CH2:15][NH:16][CH2:23][C:21]1[O:22][C:18]([CH3:17])=[CH:19][CH:20]=1
Reactant: [NH3+]CCNc1ccc2ccccc2c1Cl
Reactant: Cc1ccc(C=O)o1
Agent: [Cl-]
Product: Cc1ccc(CNCCNc2ccc3ccccc3c2Cl)o1
Yield: 57 %

Procedure:
Prepared from 2-[(1-chloronaphthalen-2-yl)amino]ethanaminium chloride and 5-methylfuran-2-carbaldehyde in 57% yield as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([OH:19])=O)[C:10](=[O:25])[CH:9]=2)[CH:7]=1.[NH2:28][C:29]1[CH:39]=[CH:38][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:31][CH:30]=1.CC(C)N=C=NC(C)C>CN(C)C=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:26]#[N:27])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:20][C:21]([F:24])([F:23])[F:22])[C:17]([NH:28][C:29]3[CH:30]=[CH:31][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])=[CH:38][CH:39]=3)=[O:19])[C:10](=[O:25])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC(F)(F)F)C(=O)O)c(=O)cc1-c1cc(Cl)ccc1C#N
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: CC(C)N=C=NC(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(NC(=O)C(CC(F)(F)F)n2cc(OC)c(-c3cc(Cl)ccc3C#N)cc2=O)cc1
Reaction time: 0.58 h

Procedure:
63.0 mg (157 μmol) of 2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-4,4,4-trifluorobutanoic acid (racemate), 26.0 mg (157 μmol) of ethyl 4-aminobenzoate, 22.3 mg (157 μmol) of Oxima and 24.0 μl (157 μmol) of DIC in 1.6 ml of dimethylformamide were reacted according to General Method 5B. The reaction product was purified by preparative HPLC [column: Chromatorex C18, 10 μm, 125×30 mm, mobile phase: acetonitrile/0.05% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)]. Yield: 25.1 mg (28% of theory)
Reaction SMILES: C([O:8][C:9]([CH:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[CH:17]=2)[CH2:12]1)=[O:10])C1C=CC=CC=1.[OH-].[K+]>O.C(O)C>[CH2:22]([O:21][C:16]1[CH:17]=[C:18]2[C:13](=[CH:14][CH:15]=1)[CH2:12][CH:11]([C:9]([OH:10])=[O:8])[CH2:20][CH2:19]2)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(OCc1ccccc1)C1CCc2cc(OCc3ccccc3)ccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1CCc2cc(OCc3ccccc3)ccc2C1
Temperature: 25 °C
Yield: 95 %

Procedure:
A solution of 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid benzyl ester (30) (1 equi.) and potassium hydroxide (3.5 equi.) in water-ethanol (1:1) (25 mL/mmole) was stirred at 80 C temperature for 2 h, cooled to room temperature, and quenched with hydrochloric acid (5%), the resulting white solid was filtered, washed with water, and dried under vacuum to give 6-benzyloxy-1,2,3,4-tetrahydro-naphthalene-2-carboxylic acid (31) as a white solid (95%).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:5](=[O:14])[CH2:6][CH2:7][CH2:8][C:9]=2[C:10]=1[C:11]([OH:13])=O.[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH2:20]>>[CH3:15][N:16]([CH3:21])[CH2:17][CH2:18][CH2:19][NH:20][C:11]([C:10]1[C:9]2[CH2:8][CH2:7][CH2:6][C:5](=[O:14])[C:4]=2[NH:3][C:2]=1[CH3:1])=[O:13]
Reactant: Cc1[nH]c2c(c1C(=O)O)CCCC2=O
Reactant: CN(C)CCCN
Product: Cc1[nH]c2c(c1C(=O)NCCCN(C)C)CCCC2=O
Yield: 82.9 %

Procedure:
Similar procedure as Example 2, 2-methyl-7-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (S4) 0.2 g (1.0 mmol) and N1,N1-dimethylpropane-1,3-diamine 0.21 g (2.1 mmol) was reacted to give 0.23 g (83%) of the titled compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:9](CC)=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1.ClC1C=C(F)C=C[C:15]=1[O:21]C>>[Cl:1][C:2]1[C:9]([O:21][CH3:15])=[CH:8][C:5]([CH:6]=[O:7])=[C:4]([F:12])[CH:3]=1
Reactant: CCc1cc(C=O)c(F)cc1Cl
Reactant: COc1ccc(F)cc1Cl
Product: COc1cc(C=O)c(F)cc1Cl

Procedure:
Following the procedure for Intermediate 390.2, 2-chloro-4-fluoro-1-methoxybenzene (1.0 g, 6.3 mmol) afforded 840 mg of Intermediate 392.1 as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.91 (s, 3H) 6.90-7.00 (m, 1H) 7.41 (dd, J=9.35, 6.32 Hz, 1H) 10.27 (s, 1H)
Reaction SMILES: [NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1.S(=O)(=O)(O)O.[CH2:21](O)[CH3:22]>>[NH2:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([O:8][CH2:21][CH3:22])=[O:7])=[C:4]([O:14][CH3:15])[CH:3]=1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cc([N+](=O)[O-])c(N)cc1OC

Procedure:
Prepared analogously to example 655a from 4-amino-2-methoxy-5-nitro-benzoic acid with conc. sulphuric acid in ethanol.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1.[NH:12]1[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]1.CCN(CC)CC>CC#N>[OH:11][C:8]1[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:12]2[CH2:22][CH2:21][CH:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:14][CH2:13]2)=[CH:6][CH:7]=1
Reactant: Oc1ccc(OCCBr)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)C1CCN(CCOc2ccc(O)cc2)CC1

Procedure:
To a stirred suspension of 4-(2-bromo-ethoxy)-phenol (600 mg, 2.77 mmol) and ethyl isonipecotate (470 μL, 3.06 mmol) in CH3CN (12 mL) was added Et3N (768 μL, 5.54 mmol). The resultant mixture was stirred at rt overnight and then concentrated to afford the title compound, which was used immediately in the next step. MS (ESI): mass calcd. for C16H23NO4, 293.16; m/z found, 294.1 [M+H]+.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:13]([OH:15])=[O:14])[CH2:10][CH2:11][OH:12])=[O:7])([CH3:4])[CH3:3].C(=O)(O)[O-].[K+].CN(C)C=O.[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(OCC)(=O)C>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][CH2:11][OH:12])[C:13]([O:15][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:14])=[O:7])([CH3:1])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H](CCO)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
N-t-Boc-L-homoserine (5.14 g, 23.45 mmol) and potassium bicarbonate (2.46 g, 24.6 mmol) was weighed out in a round bottom flask and to it was added anhydrous N,N-dimethylformamide (100 mL) and benzyl bromide (4.2 g, 24.6 mmol). The mixture was stirred at room temperature for 18 hours. The crude mixture was then diluted with ethyl acetate and washed, respectively, with brine, saturated NaHCO3 and brine, and dried over Na2SO4. The organic layer was then concentrated down on rotovap and purified on normal phase column chromatography. Yield=7.27 g (100%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([OH:13])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[Si](C=[N+]=[N-])(C)(C)[CH3:15]>C1COCC1.CO>[C:1]([C:3]1[CH:4]=[C:5]([CH2:10][C:11]([O:13][CH3:15])=[O:12])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: N#Cc1cc(CC(=O)O)ccc1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)Cc1ccc(F)c(C#N)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.9 %

Procedure:
2-(3-Cyano-4fluorophenyl)acetic acid (4.0 g, 22.3 mmol) was diluted with THF (10 mL) and methanol (2 mL), placed under nitrogen and cooled to 0° C. TMSCHN2 (16.7 mL, 33.5 mmol) was added dropwise and the reaction was stirred for 30 minutes. The reaction was quenched with water and diluted with DCM. The layers were separated and the organic layer was dried over MgSO4, filtered and concentrated. The residue was purified using a Biotage 40M cartridge eluting with hexanes ethyl acetate (9.1) to yield methyl 2(3-cyano-4-fluorophenyl)acetate (1.76 g, 9.11 mmol, 41%) as clear oil that solidified to a white solid. 1H NMR (400 MHz, CDCl3) δ 7.48-7.59 (m, 2H), 7.19 (t, J=8.2 Hz, 1H), 3.73 (s, 3H), 3.64 (s, 2H).
Reaction SMILES: [O:1]=[C:2]1[C:7]2[C:8]([C:11]([OH:13])=[O:12])=[CH:9][O:10][C:6]=2[CH2:5][CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].I[CH2:27][CH3:28]>CN(C)C=O>[CH2:27]([C:9]1[O:10][C:6]2[CH2:5][CH2:4][CH2:3][C:2](=[O:1])[C:7]=2[C:8]=1[C:11]([OH:13])=[O:12])[CH3:28]
Reactant: CCI
Reactant: O=C(O)c1coc2c1C(=O)CCC2
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1oc2c(c1C(=O)O)C(=O)CCC2
Temperature: 60 °C
Yield: 86.9 %

Procedure:
To a stirred mixture of 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (640 g, 3.55 mol), potassium carbonate (1.7 kg, 10.65 mol) and cesium carbonate (100 g, 0.32 mol) in N,N-dimethylformamide (9.0 L) is added iodoethane (1250 g, 8.01 mol). The mixture is heated at 60° C. for 2 h. After cooling to ambient temperature, the mixture is filtered, the solid is rinsed with ethyl acetate, and the filtrate concentrated in vacuo. Water (2 L) is added then extracted with ethyl acetate (2×2 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydrobenzofuran-3-carboxylic acid (642 g). A mixture of this ester (640 g, 3.07 mol) and ammonium acetate (426 g, 5.53 mol) in N,N-dimethylformamide (320 mL) is heated to 100° C. for 2 h. The reaction mixture is concentrated in vacuo, ice water (2.5 L) is added, and extracted with dichloromethane (2×3 L); the combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and concentrated in vacuo to give ethyl 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (357 g). A mixture of this ester (170 g, 0.82 mol) in ethyl alcohol (250 mL) and a solution of sodium hydroxide (165 g, 4.1 mol) in water (1 L) is heated at reflux for 1 h, then cooled in an ice water bath. Concentrated hydrochloric acid (350 mL) is added dropwise, the precipitate collected by filtration, rinsed with ice water (3×), and dried in a vacuum oven at 75° C. to afford 4-oxo-4,5,6,7-tetrahydroindole-3-carboxylate (125 g). m.p. 269-270° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH:14]1[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][NH:15]1.CCN(C(C)C)C(C)C.[C:33](Cl)(=[O:36])[O:34][CH3:35].Cl>ClCCl>[F:2][C:3]1[CH:8]=[C:7]([O:9][C:10]([F:13])([F:12])[F:11])[CH:6]=[CH:5][C:4]=1[CH:14]1[CH2:19][CH:18]([C:20]([O:22][CH3:23])=[O:21])[CH2:17][CH2:16][N:15]1[C:33]([O:34][CH3:35])=[O:36]
Reactant: COC(=O)C1CCNC(c2ccc(OC(F)(F)F)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(OC(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 102.3 %

Procedure:
Methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-4-carboxylate hydrochloride (4.97 g, 13.89 mmol) was dissolved in dichloromethane (50 mL) and DIPEA (6.05 mL, 34.73 mmol). Methyl carbonochloridate (1.313 mL, 16.67 mmol) was added and the reaction mixture was stirred at room temperature for 4 h. 0.1 M HCl was added and the aqueous layer extracted with DCM. The combined organic layers were filtered through a phase separator and evaporated. Crude dimethyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1,4-dicarboxylate (5.39 g, 102%) was obtained as a yellow oil. MS m/z 380 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]([CH2:11][C@H:12]3[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]3)[CH:9]=[N:10][C:6]=2[CH:5]=[C:4]([Cl:19])[N:3]=1.P([O-])([O-])(O)=O.[Na+].[Na+].[Br:27]N1C(C)(C)C(=O)N(Br)C1=O>C1COCC1.CCOC(C)=O>[Br:27][C:9]1[N:8]([CH2:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([CH3:18])[CH2:14][CH2:13]2)[C:7]2[C:2]([Cl:1])=[N:3][C:4]([Cl:19])=[CH:5][C:6]=2[N:10]=1
Reactant: C[C@H]1CC[C@H](Cn2cnc3cc(Cl)nc(Cl)c32)CC1
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C[C@H]1CC[C@H](Cn2c(Br)nc3cc(Cl)nc(Cl)c32)CC1
Temperature: 35 °C
Reaction time: 0.75 h

Procedure:
4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine (1 g, 3.35 mmol) was dissolved in THF (10 mL). Disodium hydrogen phosphate (1.43 g, 10.1 mmol) was added, and the reaction was warmed to 35° C. with stirring. 1,3-dibromo-5,5-dimethylhydantoin (1.15 g, 4.02 mmol) was added in 1 portion, and the reaction was continued with stirring at 35° C. After 45 minutes, the reaction was diluted with EtOAc (100 mL) and washed with aqueous NaHSO3 and brine. The organic layer was dried over Na2SO4, filtered, and concentrated. Purification of the residue on a silica gel column with 0 to 50% EtOAc/hexanes provided 2-bromo-4,6-dichloro-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][C:6]1[N:10]([CH2:11][C:12]2[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[C:14]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]4([CH2:36][CH3:37])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]4=[O:35])[CH:22]=3)[CH:13]=2)[C:9]([CH3:38])=[N:8][CH:7]=1.Br[CH2:40][CH2:41][O:42][CH2:43][CH2:44]Br>C(#N)C.C(N(CC)CC)C>[CH2:36]([C:27]1([C:23]2[CH:22]=[C:21]([CH:26]=[CH:25][CH:24]=2)[O:20][C:14]2[CH:13]=[C:12]([CH2:11][N:10]3[C:6]([CH2:5][CH2:4][N:3]4[CH2:44][CH2:43][O:42][CH2:41][CH2:40]4)=[CH:7][N:8]=[C:9]3[CH3:38])[CH:19]=[CH:18][C:15]=2[C:16]#[N:17])[CH2:33][CH2:32][CH2:31][CH2:30][N:29]([CH3:34])[C:28]1=[O:35])[CH3:37]
Reactant: CCC1(c2cccc(Oc3cc(Cn4c(CCN)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O
Reactant: BrCCOCCBr
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCC1(c2cccc(Oc3cc(Cn4c(CCN5CCOCC5)cnc4C)ccc3C#N)c2)CCCCN(C)C1=O

Procedure:
To a solution of 4-[5-(2-amino-ethyl)-2-methyl-imidazol-1-ylmethyl]-2-[3-(3-ethyl-1-methyl-2-oxo-azepan-3-yl)-phenoxy]-benzonitrile dihydrochloride (as described in Example 11) (0.25 g, 0.456 mmol) in acetonitrile (35.0 mL) and triethylamine (1.8 mL) was added 2-bromoethyl ether (0.133 mL, 1.06 mmol) and the mixture was refluxed for 48 hr. The solvents were removed in vacuo to obtain the title compound after purification by preparative HPLC.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1.[CH3:17][NH2:18].O>O1CCCC1>[CH3:17][NH:18][C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: CN
Reactant: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(C#N)c(C#N)nc1NC(C)(C)C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
2.0 g (0.008 mol) of 2-chloro-3-tert-butylamino-5,6-dicyanopyrazine was dissolved in 50 ml of tetrahydrofuran., and 1.3 g (0.017 mol) of a 40% methylamine aqueous solution was dropwise added thereto at room temperature. The mixture was stirred for 1 hour, and then the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 1.4 g of slightly yellow crystals (yield: 76.1%, melting point: at least 250° C.).
Reaction SMILES: [O:1]=[C:2]([C:25]1[O:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][N:29]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)C(=O)OC(C)(C)C)=[CH:7][CH:6]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[O:1]=[C:2]([C:25]1[O:26][C:27]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=2)=[CH:28][N:29]=1)[CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:7][CH:6]=1
Reactant: CC(C)(C)OC(=O)N(c1ccccc1)c1ccc(CCC(=O)c2ncc(-c3ccccn3)o2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCc1ccc(Nc2ccccc2)cc1)c1ncc(-c2ccccn2)o1
Temperature: 0 °C
Reaction time: 1 h
Yield: 69.1 %

Procedure:
A solution of tert-butyl 4-(3-oxo-3-(5-(pyridin-2-yl)oxazol-2-yl)propyl)phenyl-(phenyl)carbamate (S36, 26 mg, 0.055 mmol) in anhydrous CH2Cl2 (0.8 mL) was treated with TFA (0.2 mL) and was stirred for 1 h at 0° C. The reaction mixture was allowed to warm at 25° C. and was stirred for 2 h. The reaction mixture was concentrated, diluted with saturated aqueous NaHCO3 and extracted with CH2Cl2. The organic layer was dried over Na2SO4, filtered and concentrated. Column chromatography (SiO2, 1×3 cm, pretreated with 1% Et3N-hexanes, 10-25% EtOAc-hexanes gradient) afforded 11g (14 mg, 0.038 mmol, 70%) as a pale yellow solid: 1H NMR (CDCl3, 500 MHz) 8.67 (app d, 1H, J=4.0 Hz), 7.89-7.86 (m, 2H), 7.81 (td, 1H, J=7.7, 1.8 Hz), 7.33-7.31 (m, 1H), 7.25 (dd, 2H, J=8.4, 7.3 Hz), 7.18 (d, 2H, J=8.4 Hz), 7.04-7.01 (m, 4H), 6.90 (t, 1H, J=7.3 Hz), 5.68 (br s, 1H), 3.45 (t, 2H, J=7.7 Hz), 3.07 (t, 2H, J=7.7 Hz); 13C NMR (CDCl3, 150 MHz) 187.5, 157.3, 153.3, 150.1, 146.3, 143.5, 141.3, 137.1, 133.1, 129.3 (2C), 126.9, 124.1, 120.6, 120.4, 118.4, 117.3, 40.9, 29.1, 28.2; IR (film) νmax 3389, 3053, 2925, 1698, 1598, 1519, 1495, 1469, 1425, 1380, 1311, 1176, 1152, 1118, 1064, 991, 911, 784, 738, 694 cm−1; ESI-TOF m/z 369.1475 (C23H19N3O2+ requires 369.1477).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[NH:14][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25](O)=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH3:28]>CO>[CH:1]1([O:6][C:7]2[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=2[NH:14][C:15]2[C:16]3[C:23]([CH3:24])=[C:22]([C:25]([NH2:28])=[O:26])[S:21][C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1c(C(=O)O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC3)c12
Reactant: N
Solvent: CO
Product: Cc1c(C(N)=O)sc2ncnc(Nc3ccc(F)cc3OC3CCCC3)c12

Procedure:
Prepared analogously to example 1.4 from 4-(2-cyclopentoxy-4-fluoro-phenylamino)-5-methyl-thieno[2,3-d]pyrimidine-6-carboxylic acid (59 mg) and 7 M ammonia in MeOH (0.5 ml).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[C:10](N1C=CC=CC1=O)(N1C=CC=CC1=O)=[S:11]>ClCCl>[Cl:1][C:2]1[C:3]([CH3:9])=[CH:4][C:5]([N:8]=[C:10]=[S:11])=[N:6][CH:7]=1
Reactant: Cc1cc(N)ncc1Cl
Reactant: O=c1ccccn1C(=S)n1ccccc1=O
Solvent: ClCCl
Product: Cc1cc(N=C=S)ncc1Cl
Temperature: 40 °C
Reaction time: 3 h
Yield: 84.7 %

Procedure:
To 5-chloro-4-methylpyridin-2-amine (0.41 g, 2.88 mmol) in dichloromethane (25 mL) was added 1,1′-thiocarbonyldipyridin-2(1H)-one (0.70 g, 3.0 mmol). The reaction was stirred at 40° C. for 3 hours. The reaction was cooled to room temperature. The crude mixture was purified by chromatography (Biotage: 25-100% ethyl acetate/hexane) to yield 5-chloro-2-isothiocyanato-4-methylpyridine (0.45 g, 2.44 mmol, 85% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 8.45 (s, 1 H), 7.47 (s, 1 H), 2.37 (s, 3 H). LC/MS RT=2.79; [M+H]+=184.9.
Reaction SMILES: [CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11](O)=O)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].O=P(Cl)(Cl)Cl.S(N)([NH2:25])(=O)=O>S1(CCCC1)(=O)=O>[CH3:1][C:2]1[C:7]2[NH:8][CH:9]=[N:10][C:6]=2[C:5]([C:11]#[N:25])=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: Cc1c([N+](=O)[O-])cc(C(=O)O)c2nc[nH]c12
Reactant: NS(N)(=O)=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O=S1(=O)CCCC1
Product: Cc1c([N+](=O)[O-])cc(C#N)c2nc[nH]c12
Temperature: 120 °C

Procedure:
A mixture of 7-Methyl-6-nitro-1H-benzimidazole-4-carboxylic Acid (23) (16.99 g, 76.90 mmol), POCl3 (15.76 mL, 169 mmol), and sulfamide (14.767 g, 154 mmol) in sulfolane (77 mL) is heated to about 120° C. for about 3 hours. The reaction mixture is cooled to ambient temperature and added to ice water (1 L). The resultant mixture is cooled to about 0° C. filtered to provide 7-Methyl-6-nitro-1H-benzimidazole-4-carbonitrile (24), as an off white solid (12.54 g, 80% Yield).