Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[N:5]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18]O)=[CH:14][CH:13]=2)[N:4]=1.C(N(CC)CC)C.CS([Cl:33])(=O)=O>ClCCl>[Cl:33][CH2:18][C:15]1[CH:16]=[CH:17][C:12]([N:5]2[C:6]3[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=3[C:3]([C:2]([F:21])([F:20])[F:1])=[N:4]2)=[CH:13][CH:14]=1
Reactant: OCc1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: FC(F)(F)c1nn(-c2ccc(CCl)cc2)c2c1CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94.7 %

Procedure:
To a solution of {4-[3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl]phenyl}methanol (Example 30, 1.23 g, 4.16 mmol) in dichloromethane (20 ml) under an atmosphere of argon was added triethylamine (0.75 ml, 5.4 mmol) and the mixture stirred at room temperature for 10 minutes. Metanesulfonyl chloride (0.42 ml, 5.4 mmol) was added dropwise over 5 minutes and the whole mix stirred at room temperature for 18 hours. The reaction mixture was then washed twice with water followed by saturated sodium bicarbonate. The organic layer dried over sodium sulphate and the solvent removed by rotary evaporation to give the title compound as a brown oil (1.24 g, 94%)
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23](O)[CH2:24][CH3:25])=[CH:4][CH:3]=1.COCCN(S(F)(F)[F:37])CCOC>C(#N)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([F:37])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCC(F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reaction time: 15 h
Yield: 77 %

Procedure:
To a stirred suspension of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (82.1 mg, 0.200 mmol) in acetonitrile (1.0 mL) was added bis(2-methoxyethyl)aminosulfur trifluoride at room temperature. After 15 h, the reaction mixture was diluted with ethyl acetate, washed with aqueous sodium hydrogen carbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 0-30% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless solid (63.8 mg, 0.155 mmol, 77%). Analytically pure material was obtained by recrystallization from ethyl acetate/hexane.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:20])[CH:5]=[C:6]([Cl:19])[C:7]=1[S:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:10]=1.N1C=CC=CC=1.[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[S:38](Cl)(=[O:40])=[O:39]>C1COCC1>[Cl:27][C:28]1[CH:33]=[C:32]([C:34]([F:36])([F:35])[F:37])[CH:31]=[CH:30][C:29]=1[S:38]([NH:20][C:4]1[CH:3]=[C:2]([Cl:1])[C:7]([S:8][C:9]2[CH:18]=[CH:17][C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]=2)=[C:6]([Cl:19])[CH:5]=1)(=[O:40])=[O:39]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: O=S(=O)(Nc1cc(Cl)c(Sc2ccc3ccccc3c2)c(Cl)c1)c1ccc(C(F)(F)F)cc1Cl
Yield: 51.8 %

Procedure:
The title compound was prepared using the method of example 94, starting with 3,5-dichloro-4-(naphthalen-2-ylsulfanyl)-phenylamine (90)(150 mg, 0.47 mmol), pyridine (Aldrich, 0.19 mL, 2.34 mmol) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride (Maybridge, 144 mg, 0.52 mmol) in THF. 137 mg (52%) of 97 was obtained as a pale yellow solid.
Reaction SMILES: [Na].[Cl:2][C:3]1[C:11]([Cl:12])=[C:10]2[C:6]([CH2:7][CH:8]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:9]2=[O:13])=[CH:5][C:4]=1[OH:20].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>C(O)C>[Cl:2][C:3]1[C:11]([Cl:12])=[C:10]2[C:6]([CH2:7][CH:8]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:9]2=[O:13])=[CH:5][C:4]=1[O:20][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: O=C1c2c(cc(O)c(Cl)c2Cl)CC1c1ccccc1
Reactant: CCOC(=O)CBr
Agent: [Na]
Solvent: CCO
Product: CCOC(=O)COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 70 %

Procedure:
- Sodium (629 mg., 27.3 mmol) is added to 50 ml. of absolute ethanol under a nitrogen atmosphere. After the sodium dissolves, 6,7-dichloro-5-hydroxy-2-phenyl-1-indanone (7.35 g., 25.1 mmol), and 75 ml. of additional absolute ethanol are added followed by 3.1 ml. of ethyl bromoacetate (28.1 mmol). The mixture is stirred at room temperature for 1 to 2 hrs., refluxed for 5-16 hrs. and then poured into a dilute acid-ether mixture. The crude reaction product collected and crystallized from 1:1 ethanol-water with activated charcoal provides a 70% yield of ethyl (6,7-dichloro-1-oxo-2-phenyl-5-indanyloxy)acetate, m.p. 113.5°-115°.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([O:22][CH3:23])=[N:16][C:17](F)=[CH:18]3)[N:13]=2)(=[O:11])=[O:10])=[C:6]([O:24][CH3:25])[CH:5]=[CH:4][N:3]=1.C[O-].[K+].[C:29](O)(=[O:31])C>CS(C)=O.CO.ClCCl>[Cl:1][C:2]1[C:7]([NH:8][S:9]([C:12]2[N:20]=[C:19]3[N:14]([C:15]([O:22][CH3:23])=[N:16][C:17]([O:31][CH3:29])=[CH:18]3)[N:13]=2)(=[O:11])=[O:10])=[C:6]([O:24][CH3:25])[CH:5]=[CH:4][N:3]=1
Reactant: COc1ccnc(Cl)c1NS(=O)(=O)c1nc2cc(F)nc(OC)n2n1
Reactant: CC(=O)O
Agent: C[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Solvent: CO
Product: COc1cc2nc(S(=O)(=O)Nc3c(OC)ccnc3Cl)nn2c(OC)n1

Procedure:
To a solution of 0.60 g (1.5 mmol) of N-(2-chloro-4-methoxy-3-pyridinyl)-7-fluoro-5-methoxy[1,2,4]triazolo[1,5-c]pyrimidine-2-sulfonamide in 20 mL of dimethyl sulfoxide was added with stirring 0.24 g (3.4 mmol) of potassium methoxide in 2.4 mL of dry methanol. After 1 hour 5 mL of acetic acid was added and the solution taken up in 400 mL of dichloromethane. The resulting solution was washed with water (6×150 mL), dried over magnesium sulfate, filtered, and concentrated by evaporation under reduced pressure to obtain 270 mg (20 percent of theory) of the title compound as a white solid melting at 197°-199° C. with decomposition.
Reaction SMILES: [C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:33][CH2:32][CH:31]([C:34]([OH:37])([CH3:36])[CH3:35])[CH2:30][CH2:29]3)=[O:27])[CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21]2)=[O:18])=[CH:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O.C(Cl)(Cl)[Cl:57]>>[ClH:57].[ClH:57].[C:1]([C:5]1[N:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][O:15][CH3:16])[C:8]([C:17]([N:19]([C@H:20]2[CH2:25][C@@H:24]([C:26]([N:28]3[CH2:29][CH2:30][CH:31]([C:34]([OH:37])([CH3:35])[CH3:36])[CH2:32][CH2:33]3)=[O:27])[CH2:23][NH:22][CH2:21]2)[CH2:45][CH:46]([CH3:48])[CH3:47])=[O:18])=[CH:7][N:6]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: ClC(Cl)Cl
Reactant: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@H]1C[C@@H](C(=O)N2CCC(C(C)(C)O)CC2)CN(C(=O)OC(C)(C)C)C1
Solvent: O=C(O)C(F)(F)F
Product: COCCCNc1nc(C(C)(C)C)ncc1C(=O)N(CC(C)C)[C@@H]1CNC[C@H](C(=O)N2CCC(C(C)(C)O)CC2)C1
Product: Cl
Reaction time: 1 h

Procedure:
tert-Butyl (3S,5R)-3-[({2-tert-butyl-4-[(3-methoxypropyl)amino]pyrimidin-5-yl}carbonyl)(2-methylpropyl)amino]-5-{[4-(1-hydroxy-1-methylethyl)piperidin-1-yl]carbonyl}piperidine-1-carboxylate (120 mg) was dissolved in chloroform (3 ml), TFA (1 ml) was added and the mixture was stirred for 1 hr. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was dissolved in methanol (2 ml), hydrochloric acid-methanol (2 ml) was added, and the solvent was evaporated under reduced pressure to give the object compound (66 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][Br:7].[O:8]=[CH:9][C:10]1[CH:18]=[CH:17][C:15](O)=[C:12]([O:13][CH3:14])[CH:11]=1.[C:19](=O)([O-])[O-:20].[K+].[K+]>CC(C)=O>[Br:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:19]([C:15]1[CH:17]=[CH:18][C:10]([CH:9]=[O:8])=[CH:11][C:12]=1[O:13][CH3:14])=[O:20]
Reactant: O=C([O-])[O-]
Reactant: BrCCCCCBr
Reactant: COc1cc(C=O)ccc1O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1cc(C=O)ccc1C(=O)CCCCCBr
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
An excess of 1,5-dibromopentane (100 g, 3 equivalents) was added to a suspension of vanillin (43) (22 g) and potassium carbonate (30 g) in acetone (700 mL). The reaction mixture was heated at reflux for 2.5 hours and then allowed to stir at room temperature overnight, at which time TLC and LC/MS showed the reaction to be complete. The suspension was subjected to vacuum filtration and the resulting acetone solution was evaporated to dryness under reduced pressure. The residue was applied to a pad of silica gel and washed with 10% ethyl acetate in hexane (2 L) followed by 25% ethyl acetate in hexane to elute the product, removal of excess solvent by rotary evaporation under reduced pressure afforded the product 44 as an oil which crystallised on standing in freezer (35 g, 80% yield).
Reaction SMILES: [C:1]1([C:6]([OH:8])=O)[CH2:5][CH2:4][CH2:3][CH:2]=1.[CH:9]1[CH2:13][CH2:12][CH2:11][CH:10]=1>S([O-])([O-])(=O)=O.[NH4+].[NH4+]>[C:1]12[CH2:5][CH2:4][CH2:3][C:2]=1[C@@H:13]1[C@@H:9]([CH2:10][CH2:11][CH2:12]1)[C:6]2=[O:8]
Reactant: C1=CCCC1
Reactant: O=C(O)C1=CCCC1
Agent: O=S(=O)([O-])[O-]
Agent: [NH4+]
Product: O=C1C2=C(CCC2)[C@H]2CCC[C@@H]12
Temperature: 30 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 1-cyclopentene carboxylic acid (11.2 g, 100 mmol) and cyclopentene (13.6 g, 200 mmol) was added slowly to stirring polyphosphoric acid (Aldrich, 300 g) at 60° C. in a 250 mL flask. The reaction mixture was stirred at 70–80° C. for 4 hours under nitrogen. The dark brown reaction mixture was cooled to 30° C. and poured on 300 g of ice and vigorously stirred in a cooling bath. The brown mass was then neutralized with a saturated solution of ammonium sulfate (200 ml). The resulting mixture was then extracted with Et2O (5×200 mL). The combined organic layers were washed successively with water, saturated sodium bicarbonate solution and water. The washed organic extract was then dried over anhydrous MgSO4 and concentrated in vacuo. The residue was distilled at 130–135° C. at 4 mmHg to yield 3.5 g, 25%, about 90% purity. This product was chromatographed on silica gel using hexane and ethyl acetate as eluent to obtain pure cis-tricyclo [6.3.0.03,7] undec-1(8)-en-2-one. 1H-NMR (CDCl3): δ 3.2 (m, 1 H), 3.1 (m, 1 H), 2.5 (m, 2 H), 2.4 (m, 4 H), 1.9 (m, 1 H), 1.6 (m, 4 H), 1.3 (m, 1 H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:17]([CH2:20][C:21](=O)[CH3:22])([O-:19])=[O:18].[O:24]=[C:25]1[NH:30][N:29]=[C:28]([C:31]2[CH:36]=[CH:35][C:34]([NH:37][C:38](=[O:43])/[CH:39]=[C:40](\[NH2:42])/[CH3:41])=[CH:33][CH:32]=2)[CH2:27][CH2:26]1>C(O)(C)C>[O:24]=[C:25]1[NH:30][N:29]=[C:28]([C:31]2[CH:32]=[CH:33][C:34]([NH:37][C:38]([C:39]3[CH:11]([C:10]4[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=4[S:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)[C:20]([N+:17]([O-:19])=[O:18])=[C:21]([CH3:22])[NH:42][C:40]=3[CH3:41])=[O:43])=[CH:35][CH:36]=2)[CH2:27][CH2:26]1
Reactant: CC(=O)C[N+](=O)[O-]
Reactant: C/C(N)=C/C(=O)Nc1ccc(C2=NNC(=O)CC2)cc1
Reactant: O=Cc1ccccc1SCc1ccccc1
Solvent: CC(C)O
Product: CC1=C(C(=O)Nc2ccc(C3=NNC(=O)CC3)cc2)C(c2ccccc2SCc2ccccc2)C([N+](=O)[O-])=C(C)N1

Procedure:
10 mmoles of 2-benzylmercaptobenzaldehyde, 15 mmoles of nitroacetone and 10 mmoles of 3-aminocrotonic acid N-[4-(6-oxo-1,4,5,6-tetrahydropyridazin-3-yl)-phenyl]-amide in 30 ml of isopropanol are heated at 60°-70° C. for 10 hours. The reaction mixture is concentrated and the residue is taken up in chloroform and chromatographed over silica gel using chloroform to which methanol is added. The product is recrystallized from isopropanol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([NH:9][NH2:10])=[O:8])([O-:3])=[O:2].[C:14](N1C=CN=C1)(N1C=CN=C1)=[O:15].Cl.O>C1COCC1>[N+:1]([C:4]1[CH:5]=[C:6]([C:7]2[O:8][C:14](=[O:15])[NH:10][N:9]=2)[CH:11]=[CH:12][CH:13]=1)([O-:3])=[O:2]
Reactant: NNC(=O)c1cccc([N+](=O)[O-])c1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: O=c1[nH]nc(-c2cccc([N+](=O)[O-])c2)o1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
3-Nitrobenzohydrazide (2.05 g, 11.3 mmol) obtained in Step 1 was dissolved in THF (57 mL), and the mixture was stirred at room temperature for 40 minutes after adding 1,1′-carbonyldiimidazole (2.01 g, 12.4 mmol). The mixture was stirred after adding 6 mol/L hydrochloric acid (40 mL) and water (20 mL), and the precipitated solid was filtered off and dried to give 5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one as a white solid. 5-(3-Nitrophenyl)-1,3,4-oxadiazol-2(3H)-one so obtained was dissolved in DMF (52 mL), and the mixture was stirred at room temperature for 40 minutes after adding potassium carbonate (2.14 g, 15.5 mmol) and methyl iodide (0.77 mL, 12.3 mmol). The mixture was stirred after adding water, and the precipitated solid was filtered off and dried to give 3-methyl-5-(3-nitrophenyl)-1,3,4-oxadiazol-2(3H)-one (2.17 g, 87%).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH:19][C:20]1([C:23](O)=[O:24])[CH2:22][CH2:21]1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC>C1COCC1.C(Cl)Cl.C(Cl)Cl>[OH:19][C:20]1([C:23]([NH:1][CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([C:15]([O:17][CH3:18])=[O:16])=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:5][CH:4]=2)=[O:24])[CH2:22][CH2:21]1
Reactant: O=C(O)C1(O)CC1
Reactant: COC(=O)c1ccccc1-c1ccc(CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1ccccc1-c1ccc(CNC(=O)C2(O)CC2)cc1
Reaction time: 0.08 h

Procedure:
Methyl 4′-(aminomethyl)biphenyl-2-carboxylate (0.325 g, 1.35 mmol), 1-hydroxycyclo-propanecarboxylic acid (0.151 g, 1.48 mmol) and 1-hydroxybenzotriazole hydrate (0.248 g, 1.62 mmol) were suspended in a mixture of THF/DCM (13 mL of THF/6.5 mL of DCM), followed by the addition of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.336 g, 1.75 mmol). Rapidly the solution turned homogenous, but returned to a heterogeneous mixture after 5 minutes. After 3 hours the solvent mixture was exchanged for pure DCM, prior to purification by silica gel chromatography eluted with 1-5% methanol in DCM to provide the title compound.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([N:11]1[CH2:16][CH2:15][N:14](C(OC(C)(C)C)=O)[CH2:13][CH2:12]1)=[O:10].CCN(C(C)C)C(C)C.FC(F)(F)C(O)=O>CN(C=O)C>[O:10]=[C:9]([N:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)[CH2:8][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)CBr)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCOCC1)N1CCNCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Morpholine (0.22 g, 2.59 mmol), 42-1 (0.61 g, 1.99 mmol) and DIEA (0.33 g, 2.59 mmol) were dissolved in DMF (2 mL) and stirred for 18 hours at room temperature. The DMF was then removed under reduced pressure and the residue partitioned between water and methylene chloride. The methylene chloride was drawn off, dried and evaporated to a solid to afford 42-2. This recovered product was treated with neat trifluoroacetic acid and the excess trifluoroacetic acid evaporated off. The resulting residue was partitioned between methylene chloride and aqueous Na2CO3. The free base did not extract from the aqueous so the aqueous was evaporated to dryness, washed the methanol, and the solids filetred off to afford 42-2. 1H-NMR(CD3OD): 3.69(t, 4H); 3.59 (t, 2H); 3.54(t, 2H); 3.22(s, 2H); 2.83(t, 2H); 2.77(t, 2H); 2.49(t, 4H).
Reaction SMILES: BrCC(C1C=CC=CC=1)=O.[NH2:11][C:12]1[O:13][C:14]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:15](C2C=CC=CC=2)[C:16]=1[C:17]#[N:18]>>[NH2:11][C:12]1[O:13][C:14]([C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)=[CH:15][C:16]=1[C:17]#[N:18]
Reactant: N#Cc1c(N)oc(-c2ccccc2)c1-c1ccccc1
Agent: O=C(CBr)c1ccccc1
Product: N#Cc1cc(-c2ccccc2)oc1N
Yield: 38 %

Procedure:
2 was prepared in 38% yield from 2-bromo acetophenone (1), similar to 2-amino-4,5-diphenylfuran-3-carbonitrile (see Example 5 above). 1H NMR (300 MHz, CDCl3) δ 7.50-7.47 (m, 2H), 7.39-7.33 (m, 2H), 7.27-7.25 (m, 1H), 6.54 (s, 1H), 4.86 (br, 2H). LCMS (ESI) m/z 185.0 (M+H)+.
Reaction SMILES: [I:1][C:2]1[C:3]2[C:4](=[CH:8][NH:9][N:10]=2)[N:5]=[CH:6][CH:7]=1.[H-].[Na+].Cl[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=1>CN(C=O)C.O.C(#N)C.O>[I:1][C:2]1[C:3]2[C:4](=[CH:8][N:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[N:10]=2)[N:5]=[CH:6][CH:7]=1
Reactant: Ic1ccnc2c[nH]nc12
Reactant: COc1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cn2cc3nccc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 20.1 %

Procedure:
7-Iodo-2H-pyrazolo[4,3-b]pyridine (1 g, 4.08 mmol) and sodium hydride (0.196 g, 8.16 mmol) were combined in DMF (15 mL) at room temperature. The mixture was stirred at room temperature for 10 minutes and 1-(chloromethyl)-4-methoxybenzene (0.554 ml, 4.08 mmol) was added. The mixture was stirred at room temperature for 1 hour the quenched with ice water and purified by preparative HPLC using a Phenomenex Gemini Prep 5 μm C18, 75×30 mm column eluting with a gradient of 20-90% 10 mmol NH4HCO3 in 20/80 (v/v) water/acetonitrile in 10 mmol NH4HCO3 in water to give the 7-iodo-2-(4-methoxybenzyl)-2H-pyrazolo[4,3-b]pyridine (300 mg, 20.1% yield) as a white powder. MS [M+H] found 366.1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:13]1(/[CH:19]=[C:20](\B2OC(C)(C)C(C)(C)O2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.[F-].[Cs+]>C1COCC1.C1(P([Pd-4](P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)P(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:13]1(/[CH:19]=[C:20](\[C:2]2[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH3:12])(=[O:10])=[O:9])=[CH:4][CH:3]=2)/[CH2:21][OH:22])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: CC1(C)OB(/C(=C\C2CCCCC2)CO)OC1(C)C
Reactant: CNS(=O)(=O)c1ccc(Br)cc1
Agent: c1ccc([PH](c2ccccc2)(c2ccccc2)[Pd-4]([PH](c2ccccc2)(c2ccccc2)c2ccccc2)([PH](c2ccccc2)(c2ccccc2)c2ccccc2)[PH](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: CNS(=O)(=O)c1ccc(/C(=C\C2CCCCC2)CO)cc1
Yield: 82.4 %

Procedure:
Heat a suspension of 4-bromo-N-methyl-benzenesulfonamide (0.51 g, 2.0 mmol), (E)-3-cyclohexyl-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-prop-2-en-1-ol (0.81 g, 3.06 mmol), caesiumfluoride (0.93 g, 6.12 mmol) and tetrakis(triphenylphosphino)palladium(0) (230 mg, 0.2 mmol) in 12 mL THF to 60° C. for 4 h. Remove the solvent under vacuum and add ethyl acetate, wash the organic layer with water followed by saturated sodium chloride solution. Filter through a hydrophobic filter paper and remove the solvent under vacuum. Further purify the resulting residue by column chromatography, eluting with a gradient from 100:0 to 35:65 hexanes:ethyl acetate to afford the title compound (0.51 g) as a gray solid. MS (m/e): 310 (M+H).
Reaction SMILES: [NH2:1][C:2]([C@:4]1([CH2:31][O:32][CH3:33])[CH2:8][CH2:7][C@H:6]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:23])=[CH:11][CH:10]=2)[N:5]1C(OC(C)(C)C)=O)=[O:3].C([Cl:37])(C)=O>C(OCC)(=O)C.CO>[ClH:37].[F:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C@@H:6]2[NH:5][C@:4]([CH2:31][O:32][CH3:33])([C:2]([NH2:1])=[O:3])[CH2:8][CH2:7]2)=[CH:10][CH:11]=1
Reactant: CC(=O)Cl
Reactant: COC[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1C(=O)OC(C)(C)C
Solvent: CCOC(C)=O
Solvent: CO
Product: COC[C@@]1(C(N)=O)CC[C@H](c2ccc(OCc3ccccc3F)cc2)N1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.4 %

Procedure:
To a solution of 1,1-dimethylethyl (2R,5R)-2-(aminocarbonyl)-5-(4-{[(2-fluorophenyl)methyl]oxy}phenyl)-2-[(methyloxy)methyl]-1-pyrrolidinecarboxylate (D69, 400 mg, 0.87 mmol) in a mixture of ethyl acetate (9 ml) and methanol (1 ml) at 0° C. was added AcCl (400 μl, 5.60 mmol). The mixture was stirred for 2 hours at room temperature. Two further additions of AcCl (400 μl and after 2 h another 400 μl plus additional stirring for 2 h) were required, before the reaction was complete (as shown by HPLC). The mixture was evaporated and the residue was triturated with Et2O to afford the title compound as a white solid (314 mg, 91%); Rt (HPLC) 3.71 min; MS: (ES/+) m/z: 359 [MH]+ C20H23FN2O3 requires 358; 1H NMR (500 MHz, DMSO-d6) δ (ppm): 10.05-10.25 (br.s, 1H); 8.25 (s, 1H); 8.04-8.24 (br.s, 1H); 8.02 (s, 1H); 7.52-7.65 (m, 1H); 7.38-7.51 (m, 3H); 7.21-7.33 (m, 2H); 7.07-7.17 (m, 2H); 5.19 (s, 2H); 4.59-4.76 (br.s, 1H); 4.00 (d, 1H); 3.76 (d, 1H); 3.35 (s, 3H); 2.20-2.43 (m, 2H); 2.01-2.18 (m, 1H); 1.80-1.99 (m, 1H).
Reaction SMILES: [Cl-].[CH3:2][O:3][C:4](=[O:10])/[CH:5]=[CH:6]/[C:7](O)=[O:8].[Cl:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl.[CH2:23](Cl)Cl>>[CH2:2]([O:3][C:4](=[O:10])[CH:5]=[CH:6][C:7]([C:15]1[CH:16]=[CH:17][C:12]([Cl:11])=[CH:13][CH:14]=1)=[O:8])[CH3:23]
Reactant: COC(=O)/C=C/C(=O)O
Reactant: Clc1ccccc1
Reactant: ClCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: CCOC(=O)C=CC(=O)c1ccc(Cl)cc1
Temperature: 40 °C

Procedure:
Fifteen grams (92 m mol) of fumaric acid monomethyl ester chloride were added dropwise under stirring over a period of 25 minutes to a mixture of 200 ml of chlorobenzene and 18.4 gm (138 m mol) of aluminum chloride at 20° C. After heating for 45 minutes at 40° C., the mixture was cooled, poured on ice/water containing 30 ml of concentrated hydrochloric acid, and taken up in methylene chloride, and the solution was evaporated (under reduced pressure toward the end). The residue was recrystallized from petroleum ether, and 5.7 gm of pure 4-(4'-chlorophenyl)-4-oxo-but-2-enoic acid ethyl ester (melting point: 58°-60° C.) were obtained.
Reaction SMILES: [F:1][C:2]1([F:29])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:28])[CH3:27])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[CH3:30][O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1>>[F:29][C:2]1([F:1])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[N:11]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH3:30])[CH:37]=3)[C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([O:19][CH:20]2[CH2:25][CH2:24][N:23]([CH:26]([CH3:27])[CH3:28])[CH2:22][CH2:21]2)=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1
Reactant: COc1cccc(B(O)O)c1
Reactant: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Product: COc1cccc(-n2c(C(=O)N3CCC(F)(F)CC3)cc3cc(OC4CCN(C(C)C)CC4)ccc32)c1

Procedure:
In analogy to the procedure described for the synthesis of example 6, the title compound was synthesized from (4,4-difluoro-piperidin-1-yl)-[5-(1-isopropyl-piperidin-4-yloxy)-1H-indol-2-yl]-methanone (intermediate 1) and 3-methoxyphenylboronic acid. The title compound was obtained in 90% yield as yellow foam. MS (m/e): 516.2 (MH+, 100%).