Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:9]=[N:10][N:11]([C:13]2[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=2)[CH:12]=1)(=O)=O.[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][NH:27][CH3:28])=[CH:24][CH:23]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[F:21][C:22]1[CH:30]=[CH:29][C:25]([CH2:26][N:27]([CH3:28])[CH2:6][CH2:7][C:8]2[CH:9]=[N:10][N:11]([C:13]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][N:14]=3)[CH:12]=2)=[CH:24][CH:23]=1
Reactant: CNCc1ccc(F)cc1
Reactant: CS(=O)(=O)OCCc1cnn(-c2cc(C#N)ccn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CN(CCc1cnn(-c2cc(C#N)ccn2)c1)Cc1ccc(F)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 50.3 %

Procedure:
To a mixture of 2-[1-(4-cyanopyridin-2-yl)pyrazol-4-yl]ethyl methanesulfonate (476 mg, 1.6 mmol) and (4-fluoro-benzyl)-methyl-amine (444 mg, 3.2 mmol) in ACN (30 mL) at rt was added K2CO3 (4.5 g, 32 mmol) and KI (1.0 g, 6.2 mmol. The reaction mixture was heated to 80° C. and stirred overnight. Filtered, solvent removed and purified by prep-HPLC to give the title compound (270 mg, 50%). [M+H] Calc'd for C19H18FN5, 336; Found, 336.
Reaction SMILES: [CH2:1]([N:5]1[CH2:12][CH:11]2[C:13]([CH3:15])([CH3:14])[CH:7]([CH2:8][NH:9][CH2:10]2)[CH2:6]1)[CH2:2][CH2:3][CH3:4].[N+:16]([C:19]1[CH:24]=[C:23]([N+:25]([O-:27])=[O:26])[CH:22]=[CH:21][C:20]=1F)([O-:18])=[O:17]>CC(C)=O>[CH2:1]([N:5]1[CH2:6][CH:7]2[C:13]([CH3:14])([CH3:15])[CH:11]([CH2:10][N:9]([C:20]3[CH:21]=[CH:22][C:23]([N+:25]([O-:27])=[O:26])=[CH:24][C:19]=3[N+:16]([O-:18])=[O:17])[CH2:8]2)[CH2:12]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=[N+]([O-])c1ccc(F)c([N+](=O)[O-])c1
Reactant: CCCCN1CC2CNCC(C1)C2(C)C
Solvent: CC(C)=O
Product: CCCCN1CC2CN(c3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CC(C1)C2(C)C
Reaction time: 8 h
Yield: 65.4 %

Procedure:
A solution of 4.7 g 7-(n-butyl)-9,9-dimethyl-3,7-diazabicyclo [3.3.1]nonane in 10 ml acetone was added dropwise to a solution of 4.2 g 2,4-dinitrofluorobenzene in 40 ml acetone with stirring. Stirring of the reaction mixture was continued at room temperature and the mixture was left to stand overnight. Then acetone was withdrawn and aqueous citric acid solution was added to the residue and this mixture was extracted twice with ethyl acetate. For further working-up, the aqueous residue was rendered alkaline with dilute sodium hydroxide solution. This mixture was again extracted twice with ethyl acetate. The combined organic phases were dried with magnesium sulfate and reduced. The residue was recrystallised from ether/hexane. 5.5 g 7-(n-butyl)-3-(2,4-dinitrophenyl)-9,9-dimethyl-3,7-diazabicyclo-[3.3.1]nonane with a melting point of 119° C. were obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:11]=[CH:10][C:8]([NH2:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH:12]([O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH:12]([O:15][C:16]1[CH:17]=[CH:18][C:19]([CH:20]=[N:9][C:8]2[CH:10]=[CH:11][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:6][CH:7]=2)=[CH:22][CH:23]=1)([CH3:14])[CH3:13]
Reactant: CC(C)Oc1ccc(C=O)cc1
Reactant: CS(=O)(=O)c1ccc(N)cc1
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(C=Nc2ccc(S(C)(=O)=O)cc2)cc1

Procedure:
A mixture of 1.04 g (6.09 mmol) of 4-methylsulfonylaniline (obtained in reference example 1), 1.00 mL (6.09 mmol) of 4-isopropoxybenzaldehyde (obtained in reference example 3) and 25 mL of toluene was heated at reflux in a Dean-Stark for 2 days. The solvent was removed and the crude product obtained was directly used in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([NH:14][C:15](=[O:17])[CH3:16])[C:8]=2[N:7]=[C:6]1[C:18]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:19]=1[F:25].[CH3:31]I.[H-].[Na+]>C1COCC1>[F:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([F:30])[C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[C:13]([N:14]([CH3:31])[C:15](=[O:17])[CH3:16])[C:8]=2[N:7]=[C:6]1[C:18]1[C:19]([F:25])=[CH:20][CH:21]=[CH:22][C:23]=1[F:24]
Reactant: CI
Reactant: CC(=O)Nc1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)c1cccc2c1nc(-c1c(F)cccc1F)n2Cc1c(F)cccc1F
Reaction time: 8 h
Yield: 35.3 %

Procedure:
To 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)-4-acetamidobenzimidazole (Example 88) (2.44 g, 5.90 mmol) and methyl iodide (0.60 mL, 9.69 mmol) dissolved in THF (30 mL) was added excess NaH. After stirring overnight, the solution was concentrated to dryness, diluted with CH2Cl2, and washed with water, NaHSO4(10% soln) and NaCl (sat. aq). The combined washings were dried (Na2SO4), filtered, and concentrated. The crude product was purified by flash chromatography eluting with 2% methanol in CH2Cl2, yielding 1-(2,6-Difluorobenzyl)-2-(2,6-difluorophenyl)-4-(N-methylacetamido)-benzimidazole (0.89 g, 2.08 mmol, 63% yield). M.p. 155-156° C. 1H NMR (200 MHz, CD2Cl2): δ 7.55 (m, 1H, H4′), 7.48 (br d, J=7.4 Hz, 1H, H5), 7.31 (dd, J=7.4, 7.7 Hz, 1H, H6), 7.27 (m, 1H, H4″), 7.14 (dd , J=1.1, 7.7 Hz, 1H, H7), 7.09 (m, 2H, H3′,5′), 6.84 (m, 2H, H3″,5″), 5.38 (s, 2H, CH2PhF2), 3.34 (s, 3H, NCH3), 1.83 (s, 3H, NAc).
Reaction SMILES: [CH:1]1([CH:7]([C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([O:39]CC)=[O:38])=[O:33])=[CH:28][CH:27]=1>>[CH:1]1([CH:7]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([C:32]([N:34]([CH3:42])[CH2:35][CH2:36][C:37]([OH:39])=[O:38])=[O:33])=[CH:30][CH:31]=2)[C:9]2[C:10]([CH3:24])=[N:11][N:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)CCN(C)C(=O)c1ccc(N)cc1
Reactant: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(O)C1CCCCC1
Product: Cc1nn(-c2ccc(C(F)(F)F)cc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCCC1
Yield: 34.6 %

Procedure:
Using cyclohexyl{3-methyl-1-[4-(trifluoromethyl)phenyl]-1H-pyrazol-4-yl}methanol (0.36 g) synthesized in Example 27(3) and ethyl 3-{[(4-aminophenyl)carbonyl](methyl)amino}propanoate (0.40 g) synthesized in Example 2(2) and in the same manner as in Example 1(7), the title object compound (0.20 g, 35%) was obtained as a white solid.
Reaction SMILES: BrC1C=C[C:5]([N:8]=C=S)=CC=1.[NH2:11][C:12]1[CH:17]=[C:16]([CH3:18])[CH:15]=[C:14]([CH3:19])[C:13]=1[OH:20].CCN=C=NCCCN(C)C>C1COCC1>[CH3:18][C:16]1[CH:15]=[C:14]([CH3:19])[C:13]2[O:20][C:5]([NH2:8])=[N:11][C:12]=2[CH:17]=1
Reactant: Cc1cc(C)c(O)c(N)c1
Reactant: S=C=Nc1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Solvent: C1CCOC1
Product: Cc1cc(C)c2oc(N)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 177.5 %

Procedure:
A mixture of 1-bromo-4-isothiocyanatobenzene (63.92 g, 0.298 mol) and THF (1200 mL) was treated with 2-amino-4,6-dimethylphenol (41.8 g, 0.304 mol), stirred at room temperature for 3 hours, treated with EDCI (68.46 g, 0.358 mol), warmed to 40° C. for 16 hours, cooled to room temperature, and filtered. The filtrate was concentrated at 50° C. to a final volume of about 300 mL, treated with acetonitrile (800 mL), concentrated to a volume of about 200 mL, treated with acetonitrile (800 mL), and again concentrated to a volume of about 200 mL. The mixture was treated with acetonitrile (800 mL), cooled to room temperature, and filtered. The filter cake was washed with acetonitrile (100 mL) and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 85.8 g (85%) of 5,7-dimethyl-1,3-benzoxazol-2-amine. A mixture of 5,7-dimethyl-1,3-benzoxazol-2-amine (76.4 g, 0.230 mol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi-1,3,2-dioxaborolane (73.9 g, 0.292 mol), potassium acetate (71.5 g, 0.730 mol), and DMF (760 mL) was cycled three times through vacuum degassing and nitrogen purging, treated with Pd(dppf)Cl2.CH2Cl2 (19.9 g, 0.024 mol), sealed, cycled three times through vacuum degassing and N2 purging, heated to 80° C. for 5 hours, and distilled on high vacuum (0.2 mm Hg) at 40° C. to 80° C. to remove DMF. The residue was treated with CH2Cl2 (1300 mL), stirred for 10 minutes, and filtered. The filter cake was washed with CH2Cl2 (300 mL) and the filtrate was concentrated to a volume of about 800 mL. The solution was treated with SiO2 (509 g), stirred for 10 minutes, poured onto a bed of SiO2 (790 g) in a 4 L coarse glass fritted funnel. The SiO2 was washed with 16 L of 15% ethyl acetate and the solution was concentarated at 50° C. The concentrate was treated with heptane (800 mL), concentrated, treated with heptane (900 mL), stirred at 50° C. for 30 minutes, cooled to room temperature over 2 hours, and filtered. The filter cake was washed with 100 mL heptane and dried to constant weight in a vacuum oven at 45° C. over 24 hours to provide 68.3 g (77%) of the desired product. The final product was determined to be 98.2% potency (vs. analytical standard) by HPLC. Rt=6.5 min. HPLC conditions: Zorbax SB-C8 Rapid Resolution (4.6 mm×75 mm, 3.5 um); flow 1.5 mL/min; 5:95 to 95:5 acetonitrile:water (0.1% H3PO4) over 7 minutes.
Reaction SMILES: [CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH:21]([OH:23])[CH3:22])[CH:5]1[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1)[CH:2]=[CH2:3].N1C=CC=CC=1.[C:30](OC(=O)C)(=[O:32])[CH3:31]>O>[CH2:1]([N:4]([C:11]1[N:19]=[CH:18][N:17]=[C:16]2[C:12]=1[N:13]=[CH:14][N:15]2[CH2:20][CH:21]([O:23][C:30](=[O:32])[CH3:31])[CH3:22])[CH:5]1[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]1)[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCN(c1ncnc2c1ncn2CC(C)O)C1CCCCC1
Solvent: c1ccncc1
Solvent: O
Product: C=CCN(c1ncnc2c1ncn2CC(C)OC(C)=O)C1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a solution of 2.3 g. (7.5 mmole) of the compound of Example 15 in 30 ml. pyridine there is added dropwise 1.0 ml. of acetic anhydride. The reaction mixture is stirred for 16 hours at ambient temperature, poured into water, extracted with ethyl acetate, washed neutral, dried and evaporated. There is obtained 1.8 g. of the title compound (67% of theory) in the form of an oil.
Reaction SMILES: [C:1]([Cl:5])(Cl)([Cl:3])[Cl:2].[Cl-].[Al+3].[Cl-].[Cl-].[Br:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]([F:18])[CH:12]=1>>[Br:10][C:11]1[CH:12]=[C:13]([F:18])[C:14]([F:17])=[CH:15][C:16]=1[C:1]([Cl:5])([Cl:3])[Cl:2]
Reactant: Fc1ccc(Br)cc1F
Reactant: ClC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1cc(Br)c(C(Cl)(Cl)Cl)cc1F
Yield: 68 %

Procedure:
Into a 200 ml four-necked flask equipped with a stirrer, a reflux condenser, a thermometer and a dropping funnel, 97 ml (1 mol) of carbon tetrachloride and 26.7 g (0.2 mol) of aluminum chloride were charged, and 19.3 g (0.1 mol) of 1-bromo-3,4-difluorobenzene was dropwise added under reflux. Thereafter, the mixture was reacted for 30 minutes. The reaction mixture was treated in the same manner as in Example 1 to obtain 21.1 g (yield: 68.1%) of 2-bromo-4,5-difluorobenzotrichloride.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH2:7].C(N(CC)CC)C.[F:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([F:29])[C:24]=1[O:25][CH2:26][C:27]#[CH:28])[C:19](Cl)=[O:20]>C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[NH:7][C:19](=[O:20])[C:18]1[CH:22]=[C:23]([F:29])[C:24]([O:25][CH2:26][C:27]#[CH:28])=[C:16]([F:15])[CH:17]=1
Reactant: C#CCOc1c(F)cc(C(=O)Cl)cc1F
Reactant: CC1CCCC1N
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: C#CCOc1c(F)cc(C(=O)NC2CCCC2C)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 23.9 %

Procedure:
A mixture of 0.12 g of 2-methylcyclopentylamine, 0.2 ml of triethylamine and 1 ml of ethyl acetate was added dropwise under ice cooling to a mixture of 1 ml of ethyl acetate and 0.23 g of 3,5-difluoro-4-(2-propynyloxy)benzoyl chloride. The mixture obtained was stirred at room temperature for 12 hours. Then, the reaction mixture was subjected to silica gel column chromatography to obtain 0.07 g of N-(2-methylcyclopentyl)-3,5-difluoro-4-(2-propynyloxy)benzamide (hereinafter, described as the compound 54 of the present invention) represented by the formula:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([NH:12][S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2].[S:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[CH2:37]Br>>[C:1]([C:3]1[CH:4]=[C:5]([CH:29]=[CH:30][CH:31]=1)[CH2:6][N:7]1[CH2:11][CH2:10][C@H:9]([N:12]([CH2:37][C:33]2[S:32][CH:36]=[CH:35][CH:34]=2)[S:13]([C:16]2[CH:25]=[CH:24][C:23]3[C:18](=[CH:19][C:20]([O:26][CH3:27])=[CH:21][CH:22]=3)[CH:17]=2)(=[O:15])=[O:14])[C:8]1=[O:28])#[N:2]
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1
Reactant: BrCc1cccs1
Product: COc1ccc2ccc(S(=O)(=O)N(Cc3cccs3)[C@H]3CCN(Cc4cccc(C#N)c4)C3=O)cc2c1

Procedure:
The title compound is prepared as described in EXAMPLE 90, Part A using 7-methoxynaphthalene-2-sulfonic acid [1-(3-cyanobenzyl)-2-oxopyrrolidin-3-(S)-yl]amide (0.100 g, 0.23 mmol), prepared as described in EXAMPLE 43, part A, and thiophene-2-ylmethyl bromide (0.10 g, 0.56 mmol). The crude product is triturated with hexane/ether and used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([OH:9])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH2:18](O)[C:19]#[CH:20]>>[CH3:1][C:2]1([CH3:17])[C@@H:4](/[CH:5]=[CH:6]\[C:7]([O:9][CH2:20][C:19]#[CH:18])=[O:8])[C@H:3]1[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11]
Reactant: C#CCO
Reactant: CC(C)(C)OC(=O)[C@@H]1[C@H](/C=C\C(=O)O)C1(C)C
Product: C#CCOC(=O)/C=C\[C@H]1[C@@H](C(=O)OC(C)(C)C)C1(C)C
Temperature: 20 °C
Reaction time: 16 h

Procedure:
Using the procedure of Step A of Example 13, 3.6 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-carboxy-ethenyl]cyclopropane-carboxylate and 1 ml of propargyl alcohol were reacted and the mixture was stirred at 20° C. for 16 hours and was filtered. The filtrate was extracted with methylene chloride and the organic phase was washed with 0.1N hydrochloric acid, with water until the wash water was neutral, dried and evaporated to dryness under reduced pressure. The residue was taken up in a 9-1 cyclohexane-ethyl acetate mixture and the mixture was stirred at 20° C. for 90 minutes and was filtered. The filtrate was evaporated to dryness and the residue was chromatographed over silica gel. Elution with a 9-1 cyclohexane-ethyl acetate yielded 2.1 g of tert.-butyl(1R,cis)2,2-dimethyl-3-[Z-2-(propargyloxy-carbonyl)-ethenyl]cyclopropane-carboxylate.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][S:12]([C:15]2[C:20](N)=[CH:19][CH:18]=[CH:17][N:16]=2)(=[O:14])=[O:13])[CH:4]=[CH:3][CH:2]=1.N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[N:16]1[C:15]2[S:12](=[O:14])(=[O:13])[NH:11][C:9]3[C:8](=[CH:7][CH:6]=[C:5]4[C:10]=3[N:1]=[CH:2][CH:3]=[CH:4]4)[C:20]=2[CH:19]=[CH:18][CH:17]=1
Reactant: Nc1cccnc1S(=O)(=O)Nc1cccc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: O=S1(=O)Nc2c(ccc3cccnc23)-c2cccnc21
Yield: 7.1 %

Procedure:
In a similar fashion using route 16 general procedure 61, using 3-amino-pyridine-2-sulfonic acid quinolin-8-ylamide (Intermediate 303) (180 mg, 0.6 mmol), t-butyl nitrite (0.11 ml, 0.9 mmol), AcOH (1.8 ml) and THF(1.8 ml) gave the title compound (12 mg, 7%) after purification with prep HPLC (neutral conditions).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C@H:11]2[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)[CH3:3].[C:18](Cl)(=[O:22])[CH2:19][CH2:20][CH3:21].C(N(CC)CC)C>>[C:18]([O:17][C@H:14]1[CH2:15][CH2:16][C@H:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:4][N:2]([CH3:1])[CH3:3])=[CH:6][CH:7]=2)[CH2:12][CH2:13]1)(=[O:22])[CH2:19][CH2:20][CH3:21]
Reactant: CN(C)Cc1ccc([C@H]2CC[C@H](O)CC2)cc1
Reactant: CCCC(=O)Cl
Solvent: CCN(CC)CC
Product: CCCC(=O)O[C@H]1CC[C@H](c2ccc(CN(C)C)cc2)CC1

Procedure:
from trans-4-(4-dimethylaminomethylphenyl)-cyclohexanol and butyric acid chloride/triethylamine. Colourless oil.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(=O)(=O)(O)O.[CH2:18](O)[CH3:19]>>[CH2:18]([O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH3:19]
Reactant: CCO
Reactant: O=C(O)CCCc1ccccc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccccc1
Temperature: 0 °C
Yield: 97 %

Procedure:
Part A--A solution of 4-phenylbutyric acid (50.0 g, 0.3 mol) in ethanol (140 mL) with concentrated sulfuric acid (0.53 mL) was stirred at reflux over 5 hours. The cooled solution was poured into ice water and extracted with ethyl acetate. The combined organic layers were backwashed with brine, dried over anhydrous magnesium sulfate and evaporated to dryness under reduced pressure to give 4-phenylbutyric acid ethyl ester (56.07 g, 0.29 mol, 97%) as a yellow liquid. 1H NMR (CDCl3) d 7.3-7.1 (m, 5H), 4.1 (q, 2H, J=7.1Hz), 2.7 (t, 2H, J=7.7Hz), 2.3 (t, 2H, J=7.5Hz), 1.95 (quintet, 2H, J=7.5Hz), 1.25 (t, 3H, J=7.1Hz).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[H-].[Na+].Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]#[C:20][C:21]2[N:22]=[C:23]([CH3:26])[S:24][CH:25]=2)=[CH:15][N:14]=1>CN(C=O)C>[CH3:26][C:23]1[S:24][CH:25]=[C:21]([C:20]#[C:19][C:16]2[CH:17]=[CH:18][C:13]([N:1]3[C:5]4=[N:6][CH:7]=[CH:8][CH:9]=[C:4]4[CH:3]=[CH:2]3)=[N:14][CH:15]=2)[N:22]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: Cc1nc(C#Cc2ccc(Cl)nc2)cs1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1nc(C#Cc2ccc(-n3ccc4cccnc43)nc2)cs1
Temperature: 75 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 1H-pyrrolo[2,3-b]pyridine (2.0 mmol, 236 mg) in DMF (20 mL) at 60° C. was added sodium hydride (2.5 mmol, 100 mg of 60% wt dispersion in mineral oil). After 30 min, 2-chloro-5-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (0.5 mmol, 117 mg) was added and the reaction was warmed to 75° C. and stirred overnight under nitrogen. The reaction was then partitioned with EtOAc:hexanes (1:1, 100 mL) and water (50 mL). The organic layer was washed with 5% NaCl (4×50 mL), then dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2, eluting with 3% MeOH in DCM, to afford the title compound as a white solid that was dissolved in ether and precipitated as the hydrochloride salt with 1N HCl in ether. 1H-NMR (CD3OD, 500 MHz) δ 8.88 (m, 2H), 8.65 (d, 1H), 8.54 (d, 1H), 8.30 (dd, 1H), 8.05 (d, 1H), 7.94 (s, 1H), 7.83 (dd, 1H), 7.24 (d, 1H), 2.82 (s, 3H). MS (ESI) 317.4 (M+H+).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][N:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][CH:11]=1.CS[C:18](SC)=[CH:19][N+:20]([O-:22])=[O:21]>>[CH3:15][N:13]([CH2:12][C:8]1[CH:7]=[C:6]([CH:11]=[CH:10][CH:9]=1)[O:5][CH2:4][CH2:3][CH2:2][NH:1][C:18]([NH:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][N:13]([CH3:14])[CH3:15])[CH:7]=1)=[CH:19][N+:20]([O-:22])=[O:21])[CH3:14]
Reactant: CN(C)Cc1cccc(OCCCN)c1
Reactant: CSC(=C[N+](=O)[O-])SC
Product: CN(C)Cc1cccc(OCCCNC(=C[N+](=O)[O-])NCCCOc2cccc(CN(C)C)c2)c1
Yield: 61 %

Procedure:
3-(3-aminopropoxy)-N,N-dimethylbenzenemethanamine (1.09 g) and 1,1-bis(methylthio)-2-nitroethene (413 mg) were heated as an intimate mixture on a steam bath for 90 minutes. The resulting oil was washed with ether and purified by column chromatography on silica using 2% 0.88 ammonia in methanol to give the title compound as a pale yellow oil (0.74 g). Rf 0.30, silica/2% 0.88 ammonia in methanol.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[C:6]([OH:11])[CH:5]=1)([O-:3])=[O:2].[Br:12][C:13]1[CH:18]=[C:17]([Br:19])[CH:16]=[CH:15][C:14]=1[N:20]=[C:21]=[O:22]>>[OH:11][C:6]1[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:10]=[CH:9][C:7]=1[NH:8][C:21]([NH:20][C:14]1[CH:15]=[CH:16][C:17]([Br:19])=[CH:18][C:13]=1[Br:12])=[O:22]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: O=C=Nc1ccc(Br)cc1Br
Product: O=C(Nc1ccc([N+](=O)[O-])cc1O)Nc1ccc(Br)cc1Br
Yield: 39.4 %

Procedure:
The urea was prepared from 4-nitro 2-hydroxy aniline (308 mg, 2 mmol) and 2,4-dibromo phenyl isocyanate (2 mmol) by general Method B. It was purified by dilution with methylene chloride and precipitation with hexane. Filtering afforded the title compound (0.34 g, 39%). EI-MS m/z 430 (M+H)+
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:47])[CH2:24][C@@H:25]([NH:33][C:34]([O:36][CH2:37][CH2:38][O:39][Si](C(C)(C)C)(C)C)=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13])(C(C)(C)C)(C)C>CO.C[Si](Cl)(C)C>[OH:8][CH2:9][CH2:10][O:11][C:12]([NH:14][C@H:15]([C@@H:23]([OH:47])[CH2:24][C@@H:25]([NH:33][C:34]([O:36][CH2:37][CH2:38][OH:39])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:13]
Reactant: CC(C)(C)[Si](C)(C)OCCOC(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCCO[Si](C)(C)C(C)(C)C
Agent: C[Si](C)(C)Cl
Solvent: CO
Product: O=C(N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)OCCO)OCCO
Reaction time: 2 h
Yield: 578.2 %

Procedure:
In two batches, 81.4 mg (0.016 mmol) of the compound from Example 335B above was dissolved in 2 mL of methanol to which 14.9 μL of trimethylsilyl chloride was added and stirred for 2 hours. The solvent was removed and the crude product chromatographed on silica gel, eluting with 2% and 5% methanol in methylene chloride. The solvent was removed and the product dried to afford 42.6 mg of the title compound. MS M/Z (DCI/NH3): 461 (M+H), 478 (M+NH4). Proton NMR (DMSO):δ 1.46 (t, 2H), 2.53-2.77 (4H), 3.45 (m, 3H), 3.55 (d, 1H), 3.64-3.92 (6H), 4.64 (m, 2H), 6.65 (d, 1H), 6.94 (d, 1H), 7.07-7.27 (10H). Anal calc. for C24H32N2O7.H2O: C, 60.25; H, 7.11; N, 5.86; found: C, 60.38; H, 6.56; N, 5.86.
Reaction SMILES: Cl[C:2]1[C:3]2[C:4]3[C:9]([S:10][C:11]=2[N:12]=[CH:13][N:14]=1)=[CH:8][CH:7]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:5]=3.C(=O)([O-])[O-].[K+].[K+].[N:27]1([C@H:33]2[CH2:38][CH2:37][C@H:36]([NH2:39])[CH2:35][CH2:34]2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>CC#N>[O:30]1[CH2:29][CH2:28][N:27]([C@H:33]2[CH2:34][CH2:35][C@H:36]([NH:39][C:2]3[C:3]4[C:4]5[CH:5]=[C:6]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:7]=[CH:8][C:9]=5[S:10][C:11]=4[N:12]=[CH:13][N:14]=3)[CH2:37][CH2:38]2)[CH2:32][CH2:31]1
Reactant: N[C@H]1CC[C@H](N2CCOCC2)CC1
Reactant: CCOC(=O)Cc1ccc2sc3ncnc(Cl)c3c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)Cc1ccc2sc3ncnc(N[C@H]4CC[C@H](N5CCOCC5)CC4)c3c2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 2-[3-chloro-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(13),2(7),3,5,9,11-hexaen-12-yl]acetate (500 mg, 1.63 mmol, 1.00 equiv) in MeCN (100 mL) was added potassium carbonate (2.2 g, 15.92 mmol, 10.00 equiv), TEA (495 mg, 4.89 mmol, 3.00 equiv) and trans-4-(morpholin-4-yl)cyclohexan-1-amine (1.5 g, 8.14 mmol, 5.00 equiv) subsequently at room temperature under nitrogen. The resulting solution was stirred overnight at 80° C. and cooled down to r.t. The reaction was quenched with water, extracted with 3×100 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with dichloromethane/methanol (20/1) to give 300 mg (40%) of the corresponding ethyl 2-(4-(((trans)-4-morpholinocyclohexyl)amino)benzo[4,5]thieno[2,3-d]pyrimidin-6-yl)acetate as an off-white solid. LCMS: (ES, m/z) 455 (M+H+). 1H-NMR (300 MHz, CDCl3) δ 8.57 (s, 1H), 7.88-7.85 (d, 1H), 7.71 (s, 1H), 7.42-7.40 (d, 1H), 5.33-5.31 (d, 1H), 4.30-4.21 (m, 1H), 4.19-4.09 (q, 2H), 3.81 (s, 2H), 3.75 (s, 4H), 2.61 (s, 4H), 2.38 (s, 3H), 2.05 (s, 2H), 1.55-1.52 (d, 2H), 1.45-1.41 (m, 2H), 1.31-1.27 (t, 3H).