Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.FC(F)(F)C(O)=O.[CH2:24]([O:26][C:27](=[O:32])[C:28]([CH2:30][F:31])=[CH2:29])[CH3:25]>ClCCl>[CH2:24]([O:26][C:27]([C:28]1([CH2:30][F:31])[CH2:29][CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:32])[CH3:25]
Reactant: C=C(CF)C(=O)OCC
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(CF)CCN(Cc2ccccc2)C1
Temperature: 25 °C

Procedure:
N-(methoxymethyl)-N-(trimethylsilylmethyl)benzylamine (548 μl, 2.14 mmol) was dissolved in the dichloromethane solution of the 2-fluoromethyl-acrylic acid ethyl ester from the previous reaction and chilled to 0 C. A solution of trifluoroacetic acid (67 μl, 0.87 mmol) in dichloromethane (0.5 ml) was added slowly. The reaction mixture was allowed to warm to room temperature in two hours and directly chromatographed on silica gel. Elution with solutions of ethyl acetate in hexanes (1:5, 1:4, 1:3) obtained the title product (143 mg) as oil.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=2)N)=[CH:5][CH:4]=1.[CH3:21][C:22]([CH3:33])([CH2:27][C:28](=O)[CH2:29][S:30][CH3:31])[C:23]([O:25]C)=[O:24]>>[Cl:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:10]3[C:15](=[CH:14][C:13]([CH:16]([CH3:18])[CH3:17])=[CH:12][CH:11]=3)[C:29]([S:30][CH3:31])=[C:28]2[CH2:27][C:22]([CH3:33])([CH3:21])[C:23]([OH:25])=[O:24])=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(N)Cc2ccc(Cl)cc2)cc1
Reactant: COC(=O)C(C)(C)CC(=O)CSC
Agent: Cl
Product: CSc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(C(C)C)cc12

Procedure:
Following the procedure of Example 10, but using 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]hydrazine hydrochloride and methyl 2,2-dimethyl-5-methylthio-4-oxopentanoate as starting materials and hydrolysis at reflux, the title compound was prepared, mp 143°-144°.
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1)[CH3:2].[S:9](N)([NH2:12])(=[O:11])=[O:10]>O1CCOCC1>[CH2:1]([N:3]1[CH2:8][CH2:7][N:6]([S:9]([NH2:12])(=[O:11])=[O:10])[CH2:5][CH2:4]1)[CH3:2]
Reactant: NS(N)(=O)=O
Reactant: CCN1CCNCC1
Solvent: C1COCCO1
Product: CCN1CCN(S(N)(=O)=O)CC1

Procedure:
To a solution of 1-Ethylpiperazine (1 g) in dioxane (10 ml) was added sulfamide (0.746 g) and the reaction mixture was then heated at reflux in dioxane for 72 h. The reaction mixture was purified by loading onto SCX and eluting with (200 ml) MeOH/NH3. The eluent was then reduced in vacuo to yield 4-Ethylpiperazine-1-sulfonamide as a white solid. A mixture of 4-ethylpiperazine-1-sulfonamide (0.289 g), tris(dibenzylideneacetone)dipalladium (0) (50 mg), 2-dicyclohexylphosphino-2′,4′,6′-tri-isopropyl-1,1′-biphenyl (XPHOS) (50 mg), cesium carbonate (0.628 g) and 2-[[6-chloro-2-[[(2,3-difluorophenyl)methyl]thio]-4-pyrimidinyl]oxy]-(2R)-propanoic acid ethyl ester ((the product of example 5 step i), 0.50 g) in dioxane (10 mL) was heated at reflux in a microwave at 100 C, 300 W, open vessel with cooling for 30 min. The reaction mixture was then reduced in vacuo and the residue was partitioned between EtOAc (150 ml) and H2O (100 ml). The organics were separated and the aqueous layer was re-extracted with EtOAc (2×150 ml). Organics were combined, dried (MgSO4) and reduced in vacuo to give the subtitle compound as a yellow solid. Yield: 0.720 g
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[NH:11][C:10](=S)[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3].[C:23](OCC)(=[O:26])[NH:24][NH2:25]>>[CH3:1][N:2]([CH2:4][C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]2[C:23](=[O:26])[NH:24][N:25]=[C:10]2[C:9]2[CH:19]=[CH:20][CH:21]=[N:22][C:8]1=2)=[O:6])[CH3:3]
Reactant: CCOC(=O)NN
Reactant: CN(C)CC(=O)N1c2ccccc2NC(=S)c2cccnc21
Product: CN(C)CC(=O)N1c2ccccc2-n2c(n[nH]c2=O)-c2cccnc21

Procedure:
A mixture of 6,11-dihydro-11-[(dimethylamino)acetyl]-5H-pyrido[2,3-b][1,5]benzodiazepin-5-thione (0.12 mole) and ethyl carbazate (1.2 mole) is heated in an oil bath preheated to 195°-205° C. using a take-off condenser (45 ml. is removed). The resulting solid is mixed with methylene chloride-water and the suspension is filtered. The filtrate is separated into layers, and the organic layer is washed with water, then brine solution and dried over anhydrous magnesium sulfate. The solvent is then evaporated and the resulting residue is repeatedly crystallized from methylene chloride to give 2,9-dihydro-9-[(dimethyl-amino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]-benzodiazepin-3-one.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.Cl[CH2:17][CH2:18][CH2:19][N:20]1[C:29]2[C:28](=[O:30])[N:26]([CH3:27])[C:25](=[O:31])[N:24]([CH3:32])[C:23]=2[N:22]=[CH:21]1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH2:17][CH2:18][CH2:19][N:20]3[C:29]4[C:28](=[O:30])[N:26]([CH3:27])[C:25](=[O:31])[N:24]([CH3:32])[C:23]=4[N:22]=[CH:21]3)[CH2:10][CH2:9]2)=[O:7])=[CH:14][CH:15]=1
Reactant: O=C(c1ccc(F)cc1)C1CCNCC1
Reactant: Cn1c(=O)c2c(ncn2CCCCl)n(C)c1=O
Product: Cn1c(=O)c2c(ncn2CCCN2CCC(C(=O)c3ccc(F)cc3)CC2)n(C)c1=O
Temperature: 100 °C
Reaction time: 8 h
Yield: 43.5 %

Procedure:
10.2 g 4-(p-fluorobenzoyl)-piperidine and 16.5 g 7-(chloropropyl)-theophylline are carefully mixed in the solid state and heated to 100° C. in a round flask in an oil bath. The mixture at first results in a clear melt, subsequently begins to crystallize and then changes into a solid mass. It is allowed to cool after 10 minutes, dissolved in ethyl acetate and 2n hydrochloric acid is added, whereby a dark oil separates in the organic phase, crystallizing on standing overnight. By recrystallizaing with 100 ml carbon tetrachloride, an intially oily then crystallizing substance is obtained, 7.4 g of the product with an mp of 114° to 119° C. (yield: 43.5%)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][NH:19][CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[C:22](OC(=O)C)(=[O:24])[CH3:23].C(N(CC)CC)C>ClCCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[C:17]3[C:16]4[CH2:18][N:19]([C:22](=[O:24])[CH3:23])[CH2:20][CH2:21][C:15]=4[NH:14][C:13]=3[N:12]=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)OC(C)=O
Reactant: Fc1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CC(=O)N1CCc2[nH]c3nccc(Nc4ccc(F)cc4)c3c2C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 13.5 %

Procedure:
(4-Fluoro-phenyl)-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (45 mg, 0.16 mmol), acetic anhydride (16 μL, 0.16 mmol), and triethylamine (66 μL, 0.48 mmol) were dissolved in 1,2-dichloroethane (2 mL), and stirred for 30 min at room temperature. The reaction was quenched with H2O, and the resulting material was filtered through an Extrelut column. The Extrelut column was washed with EtOAc, and the filtrate was concentrated. The crude material was purified via Biotage eluting with a gradient of 0 to 10% MeOH in DCM. Lyophilization of the purified product provided 62 (7 mg, 13% yield) as a oily residue. LC-MS (M+H=325, obsd.=325).
Reaction SMILES: [CH2:1]1[O:5][C@@H:4]2[C@H:6]([OH:9])[CH2:7][O:8][C@@H:3]2[C@@H:2]1[OH:10].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]=[CH2:23]>CN(C=O)C.CCOC(C)=O>[CH2:23]([O:10][C@H:2]1[C@H:3]2[O:8][CH2:7][C@@H:6]([OH:9])[C@H:4]2[O:5][CH2:1]1)[CH2:22][CH2:21][CH2:20][CH:19]=[CH2:18]
Reactant: C=CCCCCBr
Reactant: O[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C=CCCCCO[C@@H]1CO[C@H]2[C@@H]1OC[C@H]2O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1,4:3,6-dianhydro-D-mannitol (4.00 g, 27.4 mmol) and Cs2CO3 (20.0 g, 60.2 mmol) in DMF (60 ml), 6-bromo-1-hexene (5.5 ml, 41.1 mmol), was added; the mixture was stirred at room temperature for 18 hrs. Then it was diluted with EtOAc and washed with a 5% solution of sodium dihydrogen phosphate (2×40 ml) and water (2×40 ml). The organic layer was dried over sodium sulfate, filtered, concentrated and purified by flash chromatography (Biotage SP1, EtOAc/n-hexane from 20 to 80%), affording the title compound.
Reaction SMILES: Cl[C:2](=[N:14][OH:15])[C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.Cl.[C:17](=[NH:22])(OCC)[CH3:18].C(N(CC)CC)C>ClCCl>[CH2:12]([O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@H:3]([C:2]2[N:22]=[C:17]([CH3:18])[O:15][N:14]=2)[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(C)=N
Reactant: CCOC(=O)[C@H]1CC[C@H](C(Cl)=NO)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@H]1CC[C@H](c2noc(C)n2)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a suspension of cis/trans-ethyl 4-(chloro(hydroxyimino)methyl)cyclohexanecarboxylate (1.85 g, 7.92 mmol) and ethyl acetimidate hydrochloride (1.96 g, 15.8 mmol) in dichloromethane (40 ml) was added triethylamine (2.2 ml, 16 mmol) at 0-5° C. The cooling bath was removed 15 minutes after completed addition, and stirring for 18 h at room temperature was followed by heating at reflux for 4 h. The reaction mixture was washed with one 50-ml portion of 1 M aqueous hydrochloric acid solution. The aqueous layer was extracted with two 50-ml portions of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo. Flash-chromatography with n-heptane/tert-butyl methyl ether as eluent gave the title compound (1.05 g, 56%) as colorless oil. MS m/e: 239 ([M+H]+)
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15]1[C@H:20]([C:21]2[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:30]4[CH:31]=[C:32]5[C:37](=[CH:38][CH:39]=4)[CH:36]=[C:35]([C:40]4[N:41]=[C:42]([C@@H:46]6[CH2:51][C@@H:50]7[C@@H:48]([CH2:49]7)[N:47]6C(OC(C)(C)C)=O)[NH:43][C:44]=4[Cl:45])[CH:34]=[CH:33]5)=[CH:29][C:23]=3[N:22]=2)[CH2:19][C@@H:18]2[C@H:16]1[CH2:17]2)=O)(C)(C)C>C(Cl)Cl>[C@@H:16]12[CH2:17][C@@H:18]1[CH2:19][C@@H:20]([C:21]1[NH:25][C:24]3[CH:26]=[CH:27][C:28]([C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[C:35]([C:40]6[NH:41][C:42]([C@@H:46]7[CH2:51][C@@H:50]8[C@@H:48]([CH2:49]8)[NH:47]7)=[N:43][C:44]=6[Cl:45])[CH:36]=5)[CH:31]=4)=[CH:29][C:23]=3[N:22]=1)[NH:15]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc(-c2ccc3cc(-c4ccc5[nH]c([C@@H]6C[C@H]7C[C@H]7N6C(=O)OC(C)(C)C)nc5c4)ccc3c2)c(Cl)[nH]1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Clc1nc([C@@H]2C[C@H]3C[C@H]3N2)[nH]c1-c1ccc2cc(-c3ccc4[nH]c([C@@H]5C[C@H]6C[C@H]6N5)nc4c3)ccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
TFA (2 mL, 26.0 mmol) was added to a solution of a TFA salt of tert-butyl (1R,3S,5R)-3-(4-(6-(2-((1R,3S,5R)-2-(tert-butoxycarbonyl)-2-azabicyclo[3.1.0]hex-3-yl)-1H-benzimidazol-5-yl)-2-naphthyl)-5-chloro-1H-imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (131 mg, 0.140 mmol) in DCM (10 mL) and the mixture was stirred for 3 h at rt. The volatiles were removed under vacuum and the residue was taken into MeOH and filtered through a Strata XC MCX cartridge. The cartridge was washed with methanol and the compound was release from the cartridge by eluting with a solution of 2M of ammonia/methanol. The ammonia/methanol filtrate was evaporated under reduced pressure to yield 2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-5-(6-(2-((1R,3S,5R)-2-azabicyclo[3.1.0]hex-3-yl)-4-chloro-1H-imidazol-5-yl)-2-naphthyl)-1H-benzimidazole (55 mg, 0.11 mmol) as tan solid. LC-MS retention time 1.375 min; m/z 507.33 (1:1) (MH+). LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Waters Sunfire C18 4.6×30 mm 5 μm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 2 min, a hold time of 1 min, and an analysis time of 3 min where Solvent A was 10% methanol/90% water/0.1% TFA and Solvent B was 10% water/90% methanol/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode. 1H NMR (500 MHz, MeOD) δ ppm 8.26 (s, 1H), 8.19 (s, 1H), 8.00-8.09 (m, 3H), 7.92 (ddd, J=12.1, 8.6, 1.8 Hz, 2H), 7.85 (dd, J=8.6, 1.5 Hz, 1H), 7.81 (d, J=8.6 Hz, 1H), 4.96 (dd, J=11.0, 7.6 Hz, 1H), 4.64 (app t, J=9.3 Hz, 1H), 3.53-3.59 (m, 1H), 3.44-3.50 (m, 1H), 2.82 (dd, J=13.0, 7.5 Hz, 1H), 2.61-2.74 (m, 3H), 2.03-2.15 (m, 2H), 1.24-1.30 (m, 1H), 1.18-1.24 (m, 1H), 0.96-1.09 (m, 2H).
Reaction SMILES: O.[OH-].[Li+].[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:19]=1)[C:13]([O:15]C)=[O:14])[CH2:7][F:8]>O.C1COCC1>[F:4][CH2:5][CH:6]([O:9][C:10]1[CH:11]=[C:12]([CH:17]=[C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:19]=1)[C:13]([OH:15])=[O:14])[CH2:7][F:8]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(OCc2ccccc2)cc(OC(CF)CF)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.3 %

Procedure:
A solution of lithium hydroxide monohydrate (2.32 g, 55.1 mmol) in water (100 mL) was added to a solution of methyl 3-{[2-fluoro-1-(fluoromethyl)ethyl]oxy}-5-[(phenylmethyl)oxy]benzoate (7.41 g, 22.0 mmol) in THF (200 mL) and the mixture allowed to stir at RT overnight. The THF was removed in vacuo and the resulting solution partitioned between water (100 mL) and ethyl acetate (250 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The aqueous layer was then adjusted to pH 7 by addition of 1M hydrochloric acid and extracted with ethyl acetate (75 mL). The ethyl acetate layer was separated, washed with brine and dried (MgSO4). The ethyl acetate layers were combined and evaporated to give the required product (6.404 g).
Reaction SMILES: [F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:11][C:5]2[NH:6][C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:31][C:32]#[N:33]>C(#N)C>[F:1][C:2]1[C:12]([N:13]2[C:21](=[O:22])[C:20]3[CH2:19][CH2:18][CH2:17][CH2:16][C:15]=3[C:14]2=[O:23])=[CH:11][C:5]2[N:6]([CH2:31][C:32]#[N:33])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: O=C1COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc2N1
Reactant: N#CCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: N#CCN1C(=O)COc2cc(F)c(N3C(=O)C4=C(CCCC4)C3=O)cc21
Temperature: 5 °C
Yield: 37.4 %

Procedure:
A suspension of 2-[7-fluoro-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (2 g) and potassium carbonate (1.05 g) in acetonitrile (30 ml) is refluxed for 30 minutes. The resulting solution is cooled to a temperature of 5° C. To the solution is added dropwise chloroacetonitrile (0.72 g), and thereafter the solution is refluxed for 3 hours. The solvent is distilled off, and the residue is admixed with water and subjected to an extraction operation with the aid of dichloromethane. The dichloromethane layer is separated off, washed with water, and dried over sodium sulfate. The solution is concentrated to precipitate a crystalline product, which is then recrystallized in a solvent consisting of acetonitrile and water. As an end product, 2-[7-fluoro-4-cyanomethyl-2H-1,4-benzoxazin-3(4H)-on-6-yl]-4,5,6,7-tetrahydro-2H-isoindole-1,3-dione (0.84 g) is obtained. mp. 216°-220° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:35])=[O:34])[CH:13]=2)[C:8]([CH3:43])=[N:7]1.C(N(CC)CC)C.[C:54](Cl)(=[O:56])[CH3:55]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:44]=[CH:45][CH:46]=1)[CH2:5][N:6]1[C:10]([CH3:11])=[C:9]([C:12]2[C:20]3[C:15](=[N:16][CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][C:24]([N:27]5[CH2:28][CH2:29][N:30]([C:54](=[O:56])[CH3:55])[CH2:31][CH2:32]5)=[CH:23][CH:22]=4)[CH:19]=3)[N:14]([S:33]([C:36]3[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=3)(=[O:34])=[O:35])[CH:13]=2)[C:8]([CH3:43])=[N:7]1
Reactant: CC(=O)Cl
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(F)c4)c3C)c3cc(-c4ccc(N5CCNCC5)cc4)cnc32)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(c2ccc(-c3cnc4c(c3)c(-c3c(C)nn(Cc5cccc(F)c5)c3C)cn4S(=O)(=O)c3ccc(C)cc3)cc2)CC1
Temperature: 25 °C
Yield: 92.2 %

Procedure:
A stirred solution of 3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-5-(4-(piperazin-1-yl)phenyl)-1-tosyl-1H-pyrrolo[2,3-b]pyridine (100 mg, 0.157 mmol), triethylamine (47.8 mg, 0.473 mmol), DCM (3 ml) was added acetyl chloride (18.5 mg, 0.236 mmol) drop wise at 0° C. Reaction mass was gradually warmed to room temperature, reaction completed in an hour. Reaction mass was diluted with DCM and washed with water, dried over sodium sulfate and concentrated to give 98 mg (92.4% yield) of the titled compound. MS: m/z=677.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[OH:12].[C:13](=O)([O-])[O-].[K+].[K+].IC>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([N+:9]([O-:11])=[O:10])[C:3]=1[O:12][CH3:13]
Reactant: Cc1cc(Br)c(O)c([N+](=O)[O-])c1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COc1c(Br)cc(C)cc1[N+](=O)[O-]
Yield: 97.9 %

Procedure:
2-Bromo-4-methyl-6-nitro-phenol 11b (22.24 g, 95.9 mmol) was dissolved in 150 mL of acetone, followed by addition of potassium carbonate (15.9 g, 115 mmol) and iodomethane (13.7 mL, 220.6 mmol). The reaction mixture was heated to reflux overnight. The reaction was monitored by TLC until the disappearance of the starting materials. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was diluted with 100 mL of ethyl acetate and filtered. The mixture was concentrated under reduced pressure to obtain the title compound 1-bromo-2-methoxy-5-methyl-3-nitro-benzene 11c (23.1 g, yield 97.9%) as an orange solid.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:35](Cl)(=[O:37])[CH3:36]>>[C:35]([N:32]1[CH2:31][CH2:30][CH:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[CH2:34][CH2:33]1)(=[O:37])[CH3:36]
Reactant: CC(=O)Cl
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCNCC4)c(C)[nH]c23)cc1F
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)NC4CCN(C(C)=O)CC4)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f44) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][C:18]([OH:20])=O)=[CH:12][CH:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:34][OH:35].C(N)C>O1CCCC1.CN(C)C=O>[OH:35][NH:34][C:18]([CH2:17][CH2:16][C:13]1[CH:14]=[CH:15][C:10]([NH:9][C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:11][CH:12]=1)=[O:20]
Reactant: NO
Reactant: O=C(O)CCc1ccc(NC(=O)c2ccccc2)cc1
Agent: CCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: O=C(CCc1ccc(NC(=O)c2ccccc2)cc1)NO
Temperature: 25 °C
Reaction time: 1 h
Yield: 72 %

Procedure:
(Method H7) To a solution of 3-(4-benzoylamino-phenyl)-propionic acid (6b) (1.04 g, 3.86 mmol) in tetrahydrofuran (30 ml) under argon atmosphere 1,1′-carbonyldiimidazole (0.814 g, 5.0 mmol) was added and the mixture was stirred at room temperature for 1 hour. In an another vessel, a solution of hydroxylamine hydrochloride (0.805 g, 11.6 mmol) in dimethylformamide (10 ml) was treated with ethyl amine (1.62 ml, 11.6 mmol), the precipitate was filtered off and both solutions were mixed together. The resultant mixture was stirred at ambient temperature for 24 hours, concentrated under reduced pressure and diluted with 3% hydrochloric acid (15 ml). The resulting precipitate was filtered, washed with water (3×20 ml), and crystallized from acetonitrile to give the title compound as a white solid (0.790 g, 72%). M.p. 189-191° C. 1H NMR (DMSO-d6, HMDSO) δ: 2.26 (t, 2H, J=7.5 Hz); 2.79 (t, 2H, J=7.5 Hz); 7.17 (d, 2H, J=8.4 Hz); 7.45-7.60 (m, 3H); 7.67 (d, 2H, J=8.4 Hz); 7.88-8.02 (m, 2H); 8.73 (s, 1H); 10.18 (s, 1H); 10.38 ppm (s, 1H). HPLC analysis on Symmetry C18 column: impurities 1.8% (column size 3.9×150 mm; mobile phase acetonitrile −0.1M phosphate buffer (pH 2.5), 28:72; sample concentration 0.25 mg/ml; detector UV 220 nm). Anal. Calcd for C16H16N2O3, %: C, 67.59; H, 5.67; N, 9.85. Found, %: C, 67.46; H, 5.61; N, 9.87.
Reaction SMILES: [C:1]([N:5]=[C:6]=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:8]([O:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH2:22][C:23]2([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[C:9]#[C:10][CH3:11].C(N(CC)CC)C>C(Cl)Cl>[CH2:32]([O:31][C:29]([C:23]1([CH2:22][S:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH2:8][C:9]#[C:10][CH3:11])=[CH:18][CH:17]=2)(=[O:21])=[O:20])[CH2:24][CH2:25][N:26]([C:6](=[O:7])[NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH2:27][CH2:28]1)=[O:30])[CH3:33]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCNCC2)cc1
Reactant: CC(C)(C)N=C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC#CCOc1ccc(S(=O)(=O)CC2(C(=O)OCC)CCN(C(=O)NC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.3 %

Procedure:
To a solution of tert-butylisocyanate (0.097 ml, 0.85 mmol) in 8.0 mL of CH2Cl2, was added 4-[[[4-(2-Butynyloxy)phenyl]sulfonyl]methyl]-4-piperidinecarboxylic acid ethyl ester (prepared from example 36, step 2) (0.337 g, 0.81 mmol) and triethylamine (0.135 ml, 0.97 mmol) and stirred at room temperature for 2 h. The reaction was diluted with CH2Cl2 and washed with H2O, brine, dried over MgSO4, filtered, and concentrated in vacuo. The residue was triturated with ether:hexanes (1:1) to provide 0.284 g (73%) of the desired product as a white solid. Electrospray Mass Spec: 479.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].C([O-])([O-])=O.[K+].[K+].[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20]Br)=[CH:18][CH:17]=1>C(#N)C.C(OCC)(=O)C>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([CH2:20][NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[I:1])=[CH:18][CH:17]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: Nc1ccccc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Clc1ccc(CNc2ccccc2I)cc1

Procedure:
To a solution of 2-iodoaniline (280 mg, 1.82 mmol) in acetonitrile (6 mL) was added K2CO3 (212 mg, 1.54 mmol) and 4-chlorobenzyl bromide (276 mg, 1.34 mmol). After refluxing overnight under a nitrogen atmosphere, the reaction mixture was diluted with ethyl acetate and filtered. The solvent was removed under reduced pressure and the crude product was used in next step.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:18])[C:15]([OH:17])=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:19][C:20]1[CH:29]=[CH:28][C:23]2[NH:24][C:25](=[O:27])[NH:26][C:22]=2[CH:21]=1>O>[CH2:1]([CH:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:18])[C:15]([NH:19][C:20]2[CH:29]=[CH:28][C:23]3[NH:24][C:25](=[O:27])[NH:26][C:22]=3[CH:21]=2)=[O:17])[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc2[nH]c(=O)[nH]c2c1
Reactant: O=C(O)C(=O)N1CCC(Cc2ccccc2)CC1
Solvent: O
Product: O=C(Nc1ccc2[nH]c(=O)[nH]c2c1)C(=O)N1CCC(Cc2ccccc2)CC1

Procedure:
The title compound is prepared from (4-benzyl-piperidin-1-yl)-oxo-acetic acid (Example 5b) and 5-amino-1,3-dihydro-benzimidazol-2-one according to the method described in Example 2. Melting Point: >260° C. (water)