Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([C:9]2[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=2)[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)[N:4]=1.C([O-])([O-])=O.[Cs+].[Cs+].Br[C:34]([CH3:41])([CH3:40])[C:35]([O:37][CH2:38][CH3:39])=[O:36]>CN(C=O)C.O>[CH2:38]([O:37][C:35](=[O:36])[C:34]([O:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([C:7]2[CH:6]=[C:5]([NH:16][CH2:17][CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH3:26])=[CH:23][CH:24]=3)[N:4]=[C:3]([O:2][CH3:1])[N:8]=2)[CH:10]=1)([CH3:41])[CH3:40])[CH3:39]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: COc1ccc(CCNc2cc(-c3cccc(O)c3)nc(OC)n2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)Oc1cccc(-c2cc(NCCc3ccc(OC)cc3)nc(OC)n2)c1
Temperature: 60 °C
Yield: 62 %

Procedure:
A mixture of 3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenol (400 mg, 1.14 mmol, Example 35(p)], Cs2CO3 (1.1 g, 3.41 mmol), and ethyl 2-bromo-2-methylpropionate (0.5 mL, 3.41 mmol) in N,N′-dimethylformamide (4 mL) is heated to 60° C. for 15 hours. The reaction mixture is diluted with water, and extracted with ethyl acetate. The extracts are dried over magnesium sulfate, filtered and concentrated. The residue is subjected to chromatography on silica gel eluting with 50% EtOAc in heptane to afford 2-(3-{2-methoxy-6-[2-(4-methoxy-phenyl)-ethylamino]-pyrimidin-4-yl}-phenoxy)-2-methyl-propionic acid ethyl ester [0.33 g, 62%, Example 22(a)]. LCMS: RT=2.95 minutes, MS: 466 (M+H). IC50=60 nM
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=[O:10].[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH:25]=O)=[CH:19]2.N1CCCCC1>C(O)C>[CH3:11][N:12]([CH3:27])[CH2:13][CH2:14][O:15][C:16]1[CH:17]=[C:18]2[C:22](=[CH:23][CH:24]=1)[NH:21][C:20]([CH:25]=[C:3]1[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][C:2]1=[O:10])=[CH:19]2
Reactant: O=C1Cc2ccccc2N1
Reactant: CN(C)CCOc1ccc2[nH]c(C=O)cc2c1
Solvent: C1CCNCC1
Solvent: CCO
Product: CN(C)CCOc1ccc2[nH]c(C=C3C(=O)Nc4ccccc43)cc2c1
Temperature: 100 °C
Yield: 80.9 %

Procedure:
A mixture of oxindole (28 mg, 0.216 mmol), 5-(2-dimethylamino-ethoxy)-1H-indole-2-carbaldehyde (50 mg, 0.21 mmol) and piperidine (0.1 mL) in ethanol (1 mL) was heated at 100° C. for 2 hours. The precipitate was collected by vacuum filtration, washed with ethanol and dried to give 59 mg (79%) of the title compound as an orange solid.
Reaction SMILES: [OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3](OCC)=[O:4].C[O-].[Na+].CO.[CH3:17][NH:18][CH3:19].P(=O)(O)(O)O>>[OH:1][CH:2]([CH2:8][CH2:9][CH2:10][CH3:11])[C:3]([N:18]([CH3:19])[CH3:17])=[O:4]
Reactant: CCCCC(O)C(=O)OCC
Reactant: CNC
Agent: C[O-]
Agent: O=P(O)(O)O
Agent: [Na+]
Solvent: CO
Product: CCCCC(O)C(=O)N(C)C
Yield: 81 %

Procedure:
In a three-neck flask, at 20° C. and under an inert atmosphere, are mixed ethyl 2-hydroxycaproate (24.24 g; 150 mmol) and sodium methylate in solution in methanol (25% w/w) (1.6 g; 7 mmol). To this mixture, is added dimethylamine in solution in methanol (50% w/w) (26.75 g; 297 mmol) within 30 minutes. The temperature of this mixture is brought to 40° C. and maintained for 3 hours. After the return of the temperature of this reaction mixture to 20° C., orthophosphoric acid is added until a pH of 5 is obtained. The salts formed are removed by filtration and the solvents are removed under reduced pressure. 2-hydroxy-N,N-dimethylhexanamide is then obtained with a purity of 98%, i.e. a yield of 81%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[C@H:10]([O:12][C:13]1[C:14]2[O:22][CH:21]=[C:20]([C:23]3[CH2:24][CH2:25][NH:26][CH2:27][CH:28]=3)[C:15]=2[CH:16]=[N:17][C:18]=1[NH2:19])[CH3:11].[F:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[N:36]=[C:37]=[O:38].CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:19][C:18]1[N:17]=[CH:16][C:15]2[C:20]([C:23]3[CH2:24][CH2:25][N:26]([C:37]([NH:36][C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=4[F:29])=[O:38])[CH2:27][CH:28]=3)=[CH:21][O:22][C:14]=2[C:13]=1[O:12][C@@H:10]([C:3]1[C:4]([Cl:9])=[CH:5][CH:6]=[C:7]([F:8])[C:2]=1[Cl:1])[CH3:11]
Reactant: O=C=Nc1ccccc1F
Reactant: C[C@@H](Oc1c(N)ncc2c(C3=CCNCC3)coc12)c1c(Cl)ccc(F)c1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](Oc1c(N)ncc2c(C3=CCN(C(=O)Nc4ccccc4F)CC3)coc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 7-[(R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-(1,2,3,6-tetrahydropyridin-4-yl)-furo[3,2-c]pyridin-6-ylamine (10.0 mg, 0.0237 mmol), 2-fluorophenyl isocyanate (0.00597 g, 0.0436 mmol), DIPEA (0.033 mL, 0.19 mmol) in DMF (1 mL) was stirred at rt for 3 h. Purification by HPLC afforded the title compound. 1H NMR (400 MHz, CD3OD): δ=1.89 (d, J=6.8 Hz, 3H), 2.58 (br. s., 2H), 3.69-3.80 (m, 2H), 4.25 (d, J=2.5 Hz, 2H), 6.31 (br. s., 1H), 6.51 (q, J=6.7 Hz, 1H), 7.08-7.16 (m, 3H), 7.22 (t, J=8.7 Hz, 1H), 7.40 (dd, J=9.0, 4.9 Hz, 1H), 7.45-7.52 (m, 1H), 7.68 (s, 1H), 8.22 (s, 1H). MS (ES+): m/z 559.05/561.04 (100/75) [MH+]. HPLC: tR=3.42 min (ZQ3, polar—5 min).
Reaction SMILES: S[CH2:2][C@H:3]([NH:7][C@@H:8]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)[C:9]([F:15])([F:14])[C:10]([F:13])([F:12])[F:11])[C:4](O)=[O:5].[OH-].[Na+].ClCC1C=CC=C[N:28]=1.Cl>>[F:11][C:10]([F:13])([F:12])[C:9]([F:15])([F:14])[C@@H:8]([NH:7][C@H:3]([CH3:2])[C:4]([NH2:28])=[O:5])[C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1
Reactant: ClCc1ccccn1
Reactant: O=C(O)[C@H](CS)N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: C[C@@H](N[C@@H](c1ccc(F)cc1)C(F)(F)C(F)(F)F)C(N)=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a 0.2 M stock solution of 3-mercapto-2(R)-[2,2,3,3,3-pentafluoro-1-(S)-(4-fluorophenyl)propylamino]-propionic acid in NaOH (10 mL, 2 mmol), 2-chloromethylpyridine (0.328 g, 2 mmol) and 1 N solution of NaOH (1 mL) were added. After stirring the reaction mixture for 5 h at room temperature, 1 M HCl solution was added until pH 5-6. The mixture was extracted with ethyl acetate and the combined organic extracts were washed with brine and dried over sodium sulfate and concentrated to give N-(1-cyanocyclopropyl)-3-pyridin-2-ylmethanesulfanyl)-2(R)-[3,3,3,2,2-pentafluoro-1(S)-(4-fluorophenyl)propylamino]-propionamide as a foam (0.692 g) which was converted to the title compound as described in Example 6 above.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][C:10]=2[C:23]#[N:24])=[C:6]2[O:25][CH2:26][O:27][C:5]2=[C:4](I)[CH:3]=1.[CH2:29]([O:32][CH3:33])[C:30]#[CH:31].C(NC(C)C)(C)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[C:23]([C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:9]=1[NH:8][C:7]1[C:2]([Cl:1])=[CH:3][C:4]([C:31]#[C:30][CH2:29][O:32][CH3:33])=[C:5]3[O:27][CH2:26][O:25][C:6]=13)=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=2)#[N:24]
Reactant: C#CCOC
Reactant: COc1cc2ncc(C#N)c(Nc3c(Cl)cc(I)c4c3OCO4)c2cc1OC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CC(C)NC(C)C
Solvent: CCOC(C)=O
Product: COCC#Cc1cc(Cl)c(Nc2c(C#N)cnc3cc(OC)c(OC)cc23)c2c1OCO2
Temperature: 25 °C

Procedure:
A mixture of 4-(6-chloro-4-iodo-2,3-methylenedioxyanilino)-3-cyano-6,7-dimethoxyquinoline (0.25 g), methyl 2-propynyl ether (0.09 ml), N,N-diisopropylamine (0.154 ml), bis(triphenylphosphine)palladium(II) dichloride (0.069 g), cuprous iodide (0.028 g) and ethyl acetate (10 ml) was stirred and heated to reflux for 12 hours. The reaction mixture was cooled to ambient temperature and partitioned between ethyl acetate and water. The organic layer was dried over magnesium sulphate and evaporated and the residue was purified by column chromatography on silica using increasingly polar mixtures of hexane and ethyl acetate as eluent. There was thus obtained the title compound as an oil (0.138 g); NMR Spectrum: (DMSOd6) 3.42 (s, 3H), 3.97 (s, 3H), 3.99 (s, 3H), 4.38 (s, 2H), 6.17 (s, 2H), 7.13 (s, 1H), 7.36 (s, 1H), 7.92 (s, 1H), 8.39 (s, 1H), 9.42 (br s, 1H); Mass Spectrum: M+H+ 452.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][O:7][C:8](=[O:35])[CH2:9][CH:10]([NH:20][C:21]([C@@H:23]1[CH2:27][CH2:26][CH2:25][N:24]1[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=O)[C:11]([C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)=O>C1(C)C(C)=CC=CC=1.C(OCC)(=O)C>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:11]2[N:5]=[C:21]([C@@H:23]3[CH2:27][CH2:26][CH2:25][N:24]3[C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[NH:20][C:10]=2[CH2:9][C:8]([O:7][CH3:6])=[O:35])=[CH:14][CH:15]=1
Reactant: COC(=O)CC(NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C)C(=O)c1ccc(Br)cc1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: COC(=O)Cc1[nH]c([C@@H]2CCCN2C(=O)OC(C)(C)C)nc1-c1ccc(Br)cc1
Temperature: 140 °C
Reaction time: 4 h
Yield: 46.4 %

Procedure:
Ammonium acetate (9.4 g, 157 mmol) was added to a solution of Example J7, (2S)-tert-butyl 2-(4-(methoxy)-1-(4-bromophenyl)-1,4-dioxobutan-2-ylcarbamoyl)pyrrolidine-1-carboxylate (7.6 g, 15.7 mmol) in xylene (80 mL) and stirred for 4 hours at 140° C. in a screw capped 150 mL pressure vessel. After being cooled, the reaction mixture was diluted with ethyl acetate and washed with sat NaHCO3 and brine before being concentrated by rotory evaporation under high vacuum. The crude product was taken up in CH2Cl2 and charged to a 40 (M) Biotage silica gel cartridge. Gradient elution 15-100% B over 2 L (A=CH2Cl2; B=ethyl acetate) gave Example J8, (S)-tert-butyl 2-(4-(4-bromophenyl)-5-(2-methoxy-2-oxoethyl)-1H-imidazol-2-yl)pyrrolidine-1-carboxylate 3.38 g (46%). 1H NMR (500 MHz, DMSO-d6) δ 7.54 (s, 4H), 4.83-4.73 (m, 1H), 3.81 (br. s, 1H), 3.62 (s, 3H), 3.53-3.51 (m, 1H), 3.38-3.31 (m, 2H), 2.25-2.15 (m, 1H), 1.99-1.83 (m, 3H), 1.41/1.16 (s, 9H). RT=1.6 minutes (Condition 1). LCMS: Anal. Calcd. for C21H26BrN3O4 464.11; found: 464.40 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([OH:12])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][C:21]([CH3:23])=[CH2:22]>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:3]=[C:2]([O:1][CH2:22][C:21]([CH3:23])=[CH2:20])[CH:11]=[C:10]([OH:12])[CH:9]=1
Reactant: C=C(C)CBr
Reactant: COC(=O)c1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: C=C(C)COc1cc(O)cc(C(=O)OC)c1

Procedure:
The title compound was prepared in a similar manner as described for Intermediate 1a, from methyl 3,5-dihydroxybenzoate (15.0 g, 89.2 mmol), potassium carbonate (24.7 g, 178.4 mmol) and 3-bromo-2-methyl-propene (9.0 mL, 89.2 mmol). Purification by column chromatography eluting with 15% EtOAc in hexanes gave a pale yellow solid (7.80 g, 39% yield). 1H NMR (400 MHz, CDCl3) δ 7.13-7.22 (m, 2 H) 6.66 (t, J=2.27 Hz, 1 H) 5.81 (s, 1 H) 5.06-5.16 (m, 1 H) 4.93-5.04 (m, 1 H) 4.44 (s, 2 H) 3.91 (s, 3 H) 1.68-1.94 (m, 3 H); LCMS for C12H14O4 m/z 223.10 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]([CH3:8])=[N:4][NH:5][C:6]=1[Br:7].CC(C)=O.C(=O)([O-])[O-].[K+].[K+].Br[CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22]>CCCCCC>[Br:7][C:6]1[C:2]([Br:1])=[C:3]([CH3:8])[N:4]([CH:20]([CH3:26])[C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:5]=1
Reactant: CCOC(=O)C(C)Br
Reactant: Cc1n[nH]c(Br)c1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCCCCC
Product: CCOC(=O)C(C)n1nc(Br)c(Br)c1C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
A reaction mixture consisting of a solution of 13.7 g. (0.057 mole) 4,5 -dibromo-3-methylpyrazole in 200 ml. acetone and 15.7 g. (0.114 mole) anhydrous potassium carbonate was heated at the reflux temperature with continuous stirring for 15 minutes. After cooling, 10.4 g. (0.06 mole) ethyl 2-bromopropionate was added. This reaction mixture was then heated at the reflux temperature for 2.5 hours. It was cooled and filtered. The acetone was then removed by evaporation under reduced pressure, and the residue thus obtained was dissolved in hot hexane. After chilling in a refrigerator the crystals that had formed were collected on a filter. There was thus obtained 14.5 g. (75% yield) of ethyl 3,4 -dibromo-α, 5-dimethylpyrazole-1-acetate having a melting point at 61° to 62° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[C:7]([Cl:9])[CH:8]=1)[NH2:5].C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:5][C:4]1[CH:3]=[C:2]([Cl:1])[CH:8]=[C:7]([Cl:9])[CH:6]=1)=[O:24])([O-:19])=[O:18]
Reactant: Nc1cc(Cl)cc(Cl)c1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(Cl)cc(Cl)c1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80.4 %

Procedure:
To a mixture of 3,5-dichloroaniline (8.1 g) and triethylamine (7.0 ml) in chloroform (100 ml) was added dropwise a solution of 3-nitrobenzoyl chloride (9.3 g) in chloroform (50 ml). The mixture was stirred at room temperature for 1 hour, then poured into aqueous sodium bicarbonate. The resultant precipitate was collected and washed with chloroform and water to give 3-nitro-N-(3,5-dichlorophenyl)benzamide (12.50 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][OH:26])=[CH:21][CH:20]=2)[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ccc(CCI)cc1
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=c1cc(OCc2ccccc2)ccn1CCc1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.0 g (64.6 mmol) 4-benzyloxy-1H-pyridin-2-one, 23.7 g (90.4 mmol) [4-(2-iodoethyl)-phenyl]-methanol (preparation 1b) and 63.1 g (194 mmol) cesium carbonate in 55 mL of DMF is stirred overnight at RT. The reaction mixture is heated to 70° C., filtered through a pad of celite which is washed with hot DMF. The solvent is removed almost completely. After cooling to RT, MeOH is added, the precipitate is filtered, washed with EtOAc and water and is dried in vacuo at 40° C. (fraction A). MeOH is removed in vacuo, the residue is redissolved in DMF and purified by reverse HPLC (Zorbax stable bond, C18; water (0.1% formic acid)/acetonitrile 95:5 to 10:90) to give fraction B, which is combined with fraction A.
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([N:7]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH:9]=[N:8]2)=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29](Cl)(=[O:31])=[O:30].N1C=CC=CC=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[S:29]([NH:19][C:16]1[CH:17]=[CH:18][C:13]([O:12][C:10]2[CH:9]=[N:8][N:7]([C:4]3[CH:3]=[CH:2][C:1]([CH3:20])=[CH:6][CH:5]=3)[CH:11]=2)=[CH:14][CH:15]=1)(=[O:31])=[O:30]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Cc1ccc(-n2cc(Oc3ccc(N)cc3)cn2)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: Cc1ccc(-n2cc(Oc3ccc(NS(=O)(=O)c4ccc(Cl)cc4Cl)cc3)cn2)cc1
Temperature: 27.5 °C

Procedure:
4-(1-p-Tolyl-1H-pyrazol-4-yloxy)-phenylamine (100 mg, 0754 mmol), 2,4 Dichloro-benzenesulfonyl chloride (92 mg, 0.754 mmol) was taken in chloroform and 0.2 ml of pyridine was added and the reaction mixture was stirred at 20-35° C. for 3 and half an hours. Chloroform was removed under vacuum and the product was purified though column chromatography using petroleum ether and ethyl acetate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[CH:6][C:7]=1[Cl:8].C([O-])([O-])=O.[K+].[K+].Cl[CH2:17][C:18]#[N:19].CS(C)=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[Cl:8])[O:9][CH2:17][C:18]#[N:19]
Reactant: N#CCCl
Reactant: Oc1ccc(Cl)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCOc1ccc(Cl)c(Cl)c1
Temperature: 70 °C
Yield: 90.6 %

Procedure:
A mixture of 81.5 g of 3,4-dichlorophenol, 98.0 g of anhydrous K2CO3, 40.0 g of chloroacetonitrile and 100 ml of DMSO was stirred and heated to 70° C. after an initial period of ice cooling. The reaction mixture was heated at 70°-80° C. for 3 hours and the reaction mixture was then poured into 2500 ml of ice and water which resulted in crystal formation. The crystals were removed by filtration, washed with water and then dried overnight in a vacuum oven. The resulting solids were put in approximately 1 liter of boiling cyclohexane and treated with activated charcoal and then filtered. The filtrate was cooled to 10° C. and filtered, which gave 91.5 g of 3,4-dichlorophenoxyacetonitrile, m.p. 61°-62° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].C(Cl)(Cl)Cl.[C:14](Cl)(=[O:16])[CH3:15]>C(N(CC)CC)C>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[O:9][C:14](=[O:16])[CH3:15]
Reactant: Cc1ccc(C)c(O)c1
Reactant: CC(=O)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 89.3 %

Procedure:
At 0° C., to a mixture of 2,5-dimethylphenol 20 g and chloroform 150 ml was added acetyl chloride 15 g and triethylamine 49 g. The resulting mixture was raised to room temperature and was stirred for four hours. Then, the reaction mixture was extracted with chloroform. The organic layer was washed with water and was dried over anhydrous magnesium sulfate, and was then concentrated under reduced pressure. The resulting residue was subjected to a silica gel column chromatography to give acetic acid 2,5-dimethylphenyl ester 24 g.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1)=[O:4].[F:15][C:16]([F:28])([F:27])[C:17]1[CH:18]=[CH:19][C:20]2[S:24][C:23]([SH:25])=[N:22][C:21]=2[CH:26]=1>>[N:5]1([C:3](=[O:4])[CH2:2][S:25][C:23]2[S:24][C:20]3[CH:19]=[CH:18][C:17]([C:16]([F:28])([F:27])[F:15])=[CH:26][C:21]=3[N:22]=2)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: FC(F)(F)c1ccc2sc(S)nc2c1
Reactant: O=C(CCl)N1CCCc2ccccc21
Product: O=C(CSc1nc2cc(C(F)(F)F)ccc2s1)N1CCCc2ccccc21
Yield: 80 %

Procedure:
The title compound was synthesized according to General Procedure A using compound 4 as the electrophile and 5-(trifluoromethyl)benzo[d]thiazole-2-thiol as the nucleophile to yield 23 as a white solid (80%): MS m/z: 409 (M+H)+. Anal. Calcd. For, C19H15F3N2OS2: C, 55.87; H, 3.70; N, 6.86; S, 15.70; F, 13.95. Found: C, 55.79; H, 3.71; N, 6.92; S, 15.67; F, 14.07.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:19][CH2:18][C:15]([C:20](ON3C4C=CC=CC=4N=N3)=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43][NH2:44]>>[CH2:1]([O:8][C:9]([N:11]([CH2:32][C:33]([N:35]1[CH2:39][C@@H:38]([F:40])[CH2:37][C@H:36]1[C:41]#[N:42])=[O:34])[C:12]12[CH2:13][CH2:14][C:15]([C:20]([NH:44][CH3:43])=[O:21])([CH2:16][CH2:17]1)[CH2:18][CH2:19]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Reactant: CN
Product: CNC(=O)C12CCC(N(CC(=O)N3C[C@@H](F)C[C@H]3C#N)C(=O)OCc3ccccc3)(CC1)CC2

Procedure:
In a similar manner to Example 4, (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and methylamine (2.0 mol/l THF solution, 60.0 μL) were used to obtain (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(N-methylamino)carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (28.9 mg).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:13]O.C([O-])=O.[Na+]>C(O)=O>[OH:1][C:2]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:13]
Reactant: NO
Reactant: COc1ccc(C=O)c(O)c1
Agent: Cl
Agent: O=C[O-]
Agent: [Na+]
Solvent: O=CO
Product: COc1ccc(C#N)c(O)c1
Reaction time: 0.5 h
Yield: 84 %

Procedure:
2-Hydroxy-4-methoxybenzaldehyde (55 g; 0.36 mol), hydroxylamine hydrochloride (30 g; 0.43 mol) and sodium formate (34 g; 0.5 mol) were refluxed in formic acid (200 ml; 98-100%) for 1.25 h. The solution was then rapidly chilled in an ice bath, with stirring over 30 min. The resulting precipitate was separated by filtration and washed well with water. Following drying, in a desicator under vacuum, the title compound was obtained (45 g; 0.3 mol; 84% yield) as a brick-red solid, mp 169-171° C., rf (EtOAc) 0.43.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:29]3[C:24](=[CH:25][C:26]([C:30](O)=[O:31])=[CH:27][CH:28]=3)[CH:23]=[C:22]2[CH3:33])=[CH:16][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:34]1([CH:40]([NH2:43])[CH2:41][CH3:42])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:33][C:22]1[N:21]([CH2:20][C:17]2[CH:18]=[CH:19][C:14]([C:9]3[C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:15][CH:16]=2)[C:29]2[C:24]([CH:23]=1)=[CH:25][C:26]([C:30](=[O:31])[NH:43][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:41][CH3:42])=[CH:27][CH:28]=2
Reactant: Cc1cc2cc(C(=O)O)ccc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: CCC(N)c1ccccc1
Product: CCC(NC(=O)c1ccc2c(c1)cc(C)n2Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1)c1ccccc1

Procedure:
The title compound was prepared following the same protocol as described in Step 8, Example 1, using the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2-methyl-1H-indole-5-carboxylic acid instead of the 1-((2′-(tert-Butoxycarbonyl)biphenyl-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid and the 1-phenylpropan-1-amine instead of the (S)-1-(4-bromophenyl)ethanamine.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][C:5]([O:7]CC)=[O:6].[OH-].[Na+]>C1COCC1.CCO>[F:1][C:2]([F:17])([F:18])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:4][C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)CC(Cc1ccccc1)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)CC(Cc1ccccc1)C(F)(F)F
Yield: 100.7 %

Procedure:
Ethyl ester (176) (1.08 g, 4.15 mmol) was saponified with 1 N NaOH in THF and EtOH to give 0.97 g (˜100%) of the title compound (177) as a yellow oil. 1H NMR (400 MHz, CDCl3): δ 2.41 (dd, J1=16.9 Hz, J2=5.8 Hz, 1H), 2.50-2.70 (m, 2H), 3.00-3.15 (m, 2H), 7.15-7.25 (m, 3H), 7.27-7.33 (m, 2H). LCMS (ESI): m/z 231 (M−H)−.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.N1C=CC=CC=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=2)[CH2:17][CH2:16]1
Reactant: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Reactant: BrCCCCBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: COc1cc2ncnc(N3CCc4ccc(N5CCCC5)cc43)c2cc1OC
Temperature: 110 °C
Yield: 16.6 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-6-ylamine (103 mg, 0.320 mmol; from Example 30) in DMF (4 mL) was added 1,4-dibromo-butane (42 μL, 0.352 mmol) and pyridine (34 μL, 0.64 mmol) and the mixture was heated to 110° C. for 36 hours under N2(g). The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc/Et2O (1:1) and the organic phase was washed with water and brine, dried over Na2SO4(s), filtered and concentrated in vacuo. The residue was chromatographed on silica (4% MeOH/CHCl3) to afford 20 mg of product. (M.P. 198°-205° C. (dec); GC-MS: 376 (M+); anal. RP18-HPLC RT: 5.05 min.).