Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:50])[CH2:33][O:34][C:35]1[N:39]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[N:38]=[C:37]([C:46]([F:49])([F:48])[F:47])[CH:36]=1)[CH2:24][C:25]([O:27]C(C)(C)C)=[O:26])=[O:21])[CH3:19])=[O:16].C(O)(C(F)(F)F)=O>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH2:11][CH:12]([CH3:14])[CH3:13])=[C:3]1[C:15]([N:17]([CH:51]1[CH2:52][CH2:53][CH2:54][CH2:55][CH2:56]1)[C@H:18]([C:20]([NH:22][CH:23]([C:32](=[O:50])[CH2:33][O:34][C:35]1[N:39]([C:40]2[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:38]=[C:37]([C:46]([F:49])([F:48])[F:47])[CH:36]=1)[CH2:24][C:25]([OH:27])=[O:26])=[O:21])[CH3:19])=[O:16]
Reactant: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)OC(C)(C)C)C(=O)COc2cc(C(F)(F)F)nn2-c2ccccc2)n(C)c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Cc1c(C(=O)N(C2CCCCC2)[C@@H](C)C(=O)NC(CC(=O)O)C(=O)COc2cc(C(F)(F)F)nn2-c2ccccc2)n(C)c2ccccc12
Yield: 47.9 %

Procedure:
Treatment of N-[(1-methyl-3-isobutyl-indole-2-carbonyl)cyclohexylalaninyl]-3-amino-4-oxo-5-[1-phenyl3-(trifluoromethyl)pyrazol-5-yloxy]-pentanoic acid, tert-butyl ester (55 mg, 0.071 mmol) with TFA as described in Example 80 gave the titled product (24.6 mg, 48%) as a white powder. MS C38H44F4N5O6, [M+H]+ =746, [M−H]− =722. TLC (CH2Cl2/MeOH, 90/10): Rf=0.26.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH:13][C@H:14]2[CH2:19][CH2:18][C@@H:17]([N:20]3[CH:24]=[N:23][CH:22]=[N:21]3)[CH2:16][CH2:15]2)=[C:6]2[S:12][CH:11]=[CH:10][C:7]2=[N:8][CH:9]=1)([O-])=O>[Pd].CO>[N:20]1([C@@H:17]2[CH2:18][CH2:19][C@H:14]([NH:13][C:5]3[C:4]([NH2:1])=[CH:9][N:8]=[C:7]4[CH:10]=[CH:11][S:12][C:6]=34)[CH2:15][CH2:16]2)[CH:24]=[N:23][CH:22]=[N:21]1
Reactant: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@@H](n2cncn2)CC1
Agent: [Pd]
Solvent: CO
Product: Nc1cnc2ccsc2c1N[C@H]1CC[C@@H](n2cncn2)CC1
Reaction time: 2 h

Procedure:
A mixture of 6-nitro-N-[cis-4-(1H-1,2,4-triazol-1-yl)cyclohexyl]thieno[3,2-b]pyridin-7-amine (32 mg, 0.093 mmol) and 10% palladium on carbon (4 mg) in methanol (0.9 mL) was hydrogenated under balloon pressure of H2 at room temperature for 2 h. The reaction was filtered and the resultant filtrate was concentrated to give the desired product, which was used directly in the next step. LCMS calculated for C15H19N6S (M+H)+: m/z=315.1. Found: 315.1.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([CH2:7]O)=[CH:4][C:3]=1[CH3:9].C(Br)(Br)(Br)[Br:11].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[Br:1][C:2]1[S:6][C:5]([CH2:7][Br:11])=[CH:4][C:3]=1[CH3:9]
Reactant: Cc1cc(CO)sc1Br
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(CBr)sc1Br

Procedure:
To a tetrahydrofuran solution (1.0 mL) of (5-bromo-4-methylthiophen-2-yl)methanol (33.7 mg, 0.163 mmol) synthesized in Reference Synthesis Example 100, carbon tetrabromide (59.4 mg, 0.179 mmol) and triphenylphosphine (47.0 mg, 0.179 mmol) were added and the resultant solution was stirred at room temperature for 20 hours. After completion of the reaction, the reaction solution was filtered and the obtained filtrate was concentrated under reduced pressure to obtain the title compound as a crude product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[CH2:10][CH:9]([N:12]([CH2:16][CH2:17][CH3:18])[CH2:13][CH2:14][CH3:15])[CH2:8][CH2:7]2.C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH3:34])=[O:32]>O1CCCC1.C(=O)(O)[O-].[Na+]>[CH2:13]([N:12]([CH2:16][CH2:17][CH3:18])[CH:9]1[CH2:8][CH2:7][C:6]2[C:11](=[C:2]([C:31]([O:33][CH3:34])=[O:32])[CH:3]=[CH:4][CH:5]=2)[CH2:10]1)[CH2:14][CH3:15]
Reactant: COC(=O)Cl
Reactant: CCCN(CCC)C1CCc2cccc(Br)c2C1
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCN(CCC)C1CCc2cccc(C(=O)OC)c2C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 63.3 %

Procedure:
Alternatively, to a solution of 8-bromo-2-dipropylamino-1,2,3,4-tetrahydronaphthalene (220 mg, 0.71 mMol) in tetrahydrofuran (5 mL) at -78° C. was added a solution of n-butyl lithium in hexane (1.6 M, 1 mL, 1.6 mMol), and the solution was stirred for two hours at -78° C. The solution was then cannulated into a solution of methyl chloroformate (0.5 mL, 6.5 mMol) in tetrahydrofuran (10 mL) at -78° C., and the reaction mixture was allowed to warm gradually to room temperature. The reaction mixture was diluted with saturated aqueous sodium bicarbonate and was then extracted with diethyl ether. The combined extracts were dried over sodium sulfate and evaporated in vacuo to give a greenish-yellow oil. Purification by flash chromatography (3:1 hexane:tetrahydrofuran+tr. NH4OH) gave the title compound as a colorless glass (130 mg, 63%). The hydrochloride salt was formed and recrystallized (acetone/diethyl ether) to give colorless crystals (m.p.=132° C.).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][C:10]2[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=2)[C:15]#[N:16])=[CH:5][CH:4]=1.[OH:18][C:19]1[C:24]([CH2:25][CH2:26][CH3:27])=[C:23](O)[CH:22]=[CH:21][C:20]=1[C:29](=[O:31])[CH3:30]>>[C:29]([C:20]1[CH:21]=[CH:22][C:23]([O:1][CH2:2][C:3]2[CH:4]=[CH:5][C:6]([S:9][C:10]3[CH:11]=[N:12][CH:13]=[C:14]([CH:17]=3)[C:15]#[N:16])=[CH:7][CH:8]=2)=[C:24]([CH2:25][CH2:26][CH3:27])[C:19]=1[OH:18])(=[O:31])[CH3:30]
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: N#Cc1cncc(Sc2ccc(CO)cc2)c1
Product: CCCc1c(OCc2ccc(Sc3cncc(C#N)c3)cc2)ccc(C(C)=O)c1O

Procedure:
Using the method of Preparation 160 using 5-(4-(hydroxymethyl)phenylthio) nicotinonitrile (1.20 g, 4.95 nmol) and 1-(2,4-dihydroxy-3-propylphenyl)ethanone (1.01 g, 5.20 mmol) affords the title compound. MS (APCI-neg) m/z (rel intensity): 417 (M−H, 100%).
Reaction SMILES: [CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[C:3]1[C:12]([Cl:13])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[CH3:1][N:2]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1)[C:3]1[C:12]([Cl:13])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: CN(c1ccc(O)cc1)c1nc2ccccc2nc1Cl
Reactant: CCOC(=O)C(C)Br
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2nc3ccccc3nc2Cl)cc1

Procedure:
4-[N-Methyl-N-(3-chloro-2-quinoxalinyl)amino]phenol was reacted with ethyl 2-bromopropionate, following essentially the same procedure as that described in Example 1 Part (b), to give ethyl 2-{4-[N-methyl-N-(3-chloro-2-quinoxalinyl)amino]phenoxy}propionate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8](O)[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1.[C:19]1(=[O:29])[NH:23][C:22](=[O:24])[C:21]2=[CH:25][CH:26]=[CH:27][CH:28]=[C:20]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:8]([N:23]2[C:19](=[O:29])[C:20]3[C:21](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:22]2=[O:24])[CH2:9][NH:10][C:11](=[O:17])[O:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)NC[C@H](O)c1cccc(Cl)c1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC[C@H](c1cccc(Cl)c1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.4 %

Procedure:
To a solution of (R)-tert-butyl (2-(3-chlorophenyl)-2-hydroxyethyl)carbamate (8.12 g, 29.9 mmol) in THF (100 mL) was added phthalimide (6.16 g, 41.8 mmol) and polymer-bound triphenylphosphine (3 mmol of PPh3/1 g of resin, 9.8 g). DTBAD (7.09 g, 30.8 mmol) in THF (20 mL) was added slowly at room temperature to the reaction mixture, which was then stirred at room temperature overnight. The reaction mixture was filtered through Celite and washed with EtOAc. The resulting filtrate was washed with Na2CO3 solution, water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo. The crude material was purified by flash chromatography (0-30% EtOAc/heptane) yielding (S)-tert-butyl (2-(3-chlorophenyl)-2-(1,3-dioxoisoindolin-2-yl)ethyl)carbamate (58.4%). LCMS (m/z): 301.1 (MH+-Boc), 1.06 min.
Reaction SMILES: [CH3:1][CH2:2][CH2:3][CH:4](C([O-])=O)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+]>Cl>[CH3:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1]
Reactant: CCCCCCCC(CCC)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CCCCCCCCCCC

Procedure:
9 g (40 mmol) of ethyl 1,4-diazatircylco[6.2.0.02,6 ]undecane-4-carboxylate are heated under reflux overnight with 50 ml of concentrated hydrochloric acid. The mixture is rendered alkaline with potassium carbonate and extracted ten times using 50 ml of chloroform each time, the extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [CH:1]1([C@@H:4]2[CH2:9][CH2:8][NH:7][CH2:6][C@H:5]2[NH:10][P:11](=[O:18])([O:15][CH2:16][CH3:17])[O:12][CH2:13][CH3:14])[CH2:3][CH2:2]1.[CH:19](=O)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(O)(=O)C.[BH3-]C#N.[Na+]>CO>[CH2:19]([N:7]1[CH2:8][CH2:9][C@@H:4]([CH:1]2[CH2:2][CH2:3]2)[C@H:5]([NH:10][P:11](=[O:18])([O:12][CH2:13][CH3:14])[O:15][CH2:16][CH3:17])[CH2:6]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: CCOP(=O)(N[C@@H]1CNCC[C@H]1C1CC1)OCC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCOP(=O)(N[C@@H]1CN(Cc2ccccc2)CC[C@H]1C1CC1)OCC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 99.7 %

Procedure:
A mixture of diethyl trans-4-cyclopropylpiperidin-3-ylphosphoramidate (1.24 g, 4.49 mmol), benzaldehyde (0.68 mL, 6.73 mmol) and acetic acid (0.51 mL, 8.98 mmol) in methanol (20 mL) was stirred at 0° C. for 30 minutes. NaCNBH3 (0.42 g, 6.73 mmol) was added at 0° C. The resulting solution was warmed to room temperature and stirred at room temperature for 1 hour. The solvent was removed in vacuo, and saturated sodium bicarbonate (20 mL) and ethyl acetate (30 mL) were added. The organic layer was separated, washed with brine, dried (sodium sulfate) and concentrated in vacuo to give diethyl trans-1-benzyl-4-cyclopropylpiperidin-3-ylphosphoramidate (1.64 g, 100%), which was used directly in the next step without purification.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:19](=[O:34])[CH2:20][C:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]2[CH:32]=[CH:31][N:30]=[N:29]2)[CH:23]=1)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:17][C:11]1[C:12]([N:14]([CH3:16])[CH3:15])=[CH:13][C:8]2[N:7]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N:28]4[CH:32]=[CH:31][N:30]=[N:29]4)[CH:23]=3)[CH2:20][C:19](=[O:34])[NH:18][C:9]=2[CH:10]=1
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3ccnn3)c2)cc1Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)c1cc2c(cc1Cl)NC(=O)CC(c1cccc(-n3ccnn3)c1)=N2

Procedure:
The title compound was prepared from {4-chloro-5-dimethylamino-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamic acid tert.-butyl ester (Example M2) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (87 mg).
Reaction SMILES: CN(C=O)C.C(Cl)(=O)C(Cl)=O.[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]([NH2:28])=O)[N:23]=1>C(#N)C>[Cl:12][C:13]1[CH:14]=[C:15]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:16][NH:17][C:18]1[C:19]2[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=3[S:29][C:20]=2[N:21]=[C:22]([CH2:24][CH2:25][C:26]#[N:28])[N:23]=1
Reactant: COc1ccc(CNc2nc(CCC(N)=O)nc3sc4ccccc4c23)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1ccc(CNc2nc(CCC#N)nc3sc4ccccc4c23)cc1Cl
Reaction time: 1 h

Procedure:
1 equivalent of DMF and 1 equivalent of oxalyl chloride are dissolved in acetonitrile at 0°. 1 equivalent of 3-[4-(3-chloro-4-methoxybenzylamino)-benzothieno[2,3-d]pyrimidin-2-yl]propionamide is then added. The mixture is subsequently stirred for one hour. After customary working up, 3-[4-(3-chloro-4-methoxybenzylamino)benzothieno[2,3-d]pyrimidin-2-yl]-propionitrile is obtained.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)[CH:7]=O.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:10][C:5]1[C:6]([CH2:7][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1
Reactant: COc1ccc(O)cc1C=O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1ccc(O)cc1CN1CCCC1
Yield: 87.2 %

Procedure:
5-Hydroxy-2-methoxybenzaldehyde (4.5 g, 0.03 mol) was added in portions for 30 min to a mixture of pyrrolidine (3.1 mL, 0.037 mol) and NaB(OAc)3H (7.8 g, 0.037 mol) in CH2Cl2 (50 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (50 mL) and 5N NaHSO4 (to pH 1) were added. The organic layer was separated and discarded. The aqueous one was alkalized with saturated K2CO3 to pH 6 and extracted with chloroform (2×50 mL). The combined extracts were dried with Na2SO4, and evaporated to give the title compound (5.42 g, 89%) was obtained as brown crystals. LCMS-data: (M+H)+ 208.1 and 209.1 (calculated for C12H17NO2 207.3). 1H NMR data (DMSO-d6): 8.79 (br. s, 1H ArOH), 6.81 (d, 1H, J=8.1 Hz, Ar—H), 6.74 (d, 1H, J=4.9 Hz, Ar—H); 6.64 (dd, 1H, J1=1.9, J2=8.1, Ar—H), 3.73 (s, 2H, OCH3), 3.42 (s, 2H, ArCH2), 2.33-2.45 (m, 4H, pyrrolidine (CH2)2N), 1.59-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26]Br)=[CH:19][CH:18]=3)[C:6]=2[CH:29]=1.[CH2:30]([NH:32][CH2:33][CH3:34])[CH3:31]>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[C:7]([C:16](=[O:28])[C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][CH2:26][N:32]([CH2:33][CH3:34])[CH2:30][CH3:31])=[CH:19][CH:18]=3)[C:6]=2[CH:29]=1
Reactant: O=C(c1ccc(OCCCBr)cc1)c1c(-c2ccccc2)oc2ccc(Cl)cc12
Reactant: CCNCC
Solvent: CCO
Product: CCN(CC)CCCOc1ccc(C(=O)c2c(-c3ccccc3)oc3ccc(Cl)cc23)cc1

Procedure:
5-Chloro-3-[4-(3-bromopropoxy)benzoyl]-2-phenylbenzofuran (2.0 g., 4.3 mmol.) is refluxed in 100 ml. of ethanol containing 9 ml. of diethylamine for ten hours. The reaction mixture is concentrated under reduced pressure and the residue is dissolved in ether. The ether solution is washed with aqueous sodium hydroxide and water then concentrated to give the title compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:26])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:10])=[O:9])[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([OH:25])=O)[S:22][C:3]1=2.CCN(C(C)C)C(C)C.[O:36]1[CH2:41][CH2:40][CH2:39][CH2:38][CH:37]1[O:42][NH2:43].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[CH3:1][C:2]1([CH3:26])[CH2:7][N:6]([S:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])(=[O:9])=[O:10])[CH2:5][C:4]2[CH:20]=[C:21]([C:23]([NH:43][O:42][CH:37]3[CH2:38][CH2:39][CH2:40][CH2:41][O:36]3)=[O:25])[S:22][C:3]1=2
Reactant: NOC1CCCCO1
Reactant: CC1(C)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cc(C(=O)O)sc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(S(=O)(=O)c2ccccc2[N+](=O)[O-])Cc2cc(C(=O)NOC3CCCCO3)sc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.8 %

Procedure:
A solution of 7,7-dimethyl-5-(2-nitrophenylsulfonyl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine-2-carboxylic acid (20 g, 50 mmol) was cooled to 0° C. DIPEA (32.3 g, 250 mmol) was added and the solution was stirred at 0° C. for 30 minutes. O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (5.8 g, 50 mmol) and HATU (22.8 g, 60 mmol) were then added and the reaction was allowed to warm to room temperature overnight. The reaction mixture was washed with water, brine and dried over anhydrous Na2SO4, concentrated and purified by silica gel chromatography (20-50% EtOAc/hexane) to afford product (23.5 g, 94%). LCMS (FA) ES+ 496; 1H NMR (400 MHz, DMSO) δ 11.60 (s, 1H), 8.10 (dd, J=7.7, 1.5 Hz, 1H), 8.02 (dd, J=7.7, 1.5 Hz, 1H), 7.90 (dtd, J=17.6, 7.5, 1.4 Hz, 2H), 7.41 (s, 1H), 4.92 (s, 1H), 4.33 (s, 2H), 4.00 (s, 1H), 3.50 (d, J=11.1 Hz, 1H), 3.38 (s, 2H), 1.72 (d, J=22.2 Hz, 3H), 1.53 (s, 3H), 1.27 (s, 6H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])(=[O:3])[NH2:2].[F:14][C:15]([F:27])([F:26])[C:16]1[CH:25]=[CH:24][C:19]([C:20](=O)[CH2:21]Br)=[CH:18][CH:17]=1>>[F:14][C:15]([F:26])([F:27])[C:16]1[CH:17]=[CH:18][C:19]([C:20]2[N:2]=[C:1]([C:4]3[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=3)[C:7]([O:9][CH3:10])=[O:8])[O:3][CH:21]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)c1cccc(C(N)=O)c1
Reactant: O=C(CBr)c1ccc(C(F)(F)F)cc1
Product: COC(=O)c1cccc(-c2nc(-c3ccc(C(F)(F)F)cc3)co2)c1
Yield: 30 %

Procedure:
In the same manner as in Example 1, methyl 3-carbamoylbenzoate was reacted with 4-trifluoromethylphenacyl bromide to obtain methyl 3-[4-(4-trifluoromethylphenyl)-2-oxazolyl]benzoate. The product was recrystallized from ethanol. Yield: 30%. Pale yellow prisms. Melting Point: 151 to 152° C.
Reaction SMILES: CS(Cl)(=O)=O.[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:35]([C:38]4C=CC(C)=CC=4)(=[O:37])=[O:36])[CH2:31][CH2:30]3)[N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH3:7]>>[CH2:6]([O:8][C:9]1[CH:10]=[C:11]([C:18]2[C@@H:27]3[C@@H:22]([CH2:23][CH:24]=[CH:25][CH2:26]3)[C:21](=[O:28])[N:20]([CH:29]3[CH2:34][CH2:33][N:32]([S:35]([CH3:38])(=[O:36])=[O:37])[CH2:31][CH2:30]3)[N:19]=2)[CH:12]=[CH:13][C:14]=1[O:15][CH2:16][CH3:17])[CH3:7]
Reactant: CCOc1ccc(C2=NN(C3CCN(S(=O)(=O)c4ccc(C)cc4)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC
Agent: CS(=O)(=O)Cl
Product: CCOc1ccc(C2=NN(C3CCN(S(C)(=O)=O)CC3)C(=O)[C@@H]3CC=CC[C@H]23)cc1OCC

Procedure:
Prepared from methanesulfonylchloride and starting compound A2 as described for compound 1. Crystallisation from methanol/water. M.p. 99-102° C.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1.[CH3:25][O:26][CH2:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1>O1CCOCC1.C([O-])([O-])=O.[Cs+].[Cs+].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>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:32]=[CH:33][C:28]([CH2:27][O:26][CH3:25])=[CH:29][CH:30]=4)[CH:14]=3)[O:9][CH:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(c3ccccc3)Oc3ccc(Br)cc32)N=C1N
Reactant: COCc1ccc(B(O)O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COCc1ccc(-c2ccc3c(c2)C2(CC(c4ccccc4)O3)N=C(N)N(C)C2=O)cc1
Temperature: 120 °C
Yield: 17.1 %

Procedure:
Pd(PPh3)2Cl2 (10 mg) in a 10 mL tube under Ar was treated sequentially with 2′-amino-6-bromo-1′-methyl-2-phenylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (20 mg, 0.052 mmol) in 1,4-dioxane (1 mL), Cs2CO3 (2 N, 0.3 mL) and 4-(methoxymethyl)phenylboronic acid (16.6 mg, 0.1 mmol). The mixture was heated at 120° C. in a microwave reactor for 30 minutes. The reaction mixture was concentrated in vacuo to give the residue, which was purified by preparative TLC to give pure 2′-amino-6-(4-(methoxymethyl)phenyl)-1′-methyl-2-phenylsp-iro[chroman-4,4′-imidazol]-5′(1′H)-one (3.8 mg, 15%). 1H-NMR (MeOD): 2.10 (t, 1H), 2.24 (t, 1H), 3.01 (s, 3H), 3.27 (s, 3H), 4.17 (m, 2H), 5.81 (d, 1H), 6.90 (m, 2H), 7.12 (d, 2H), 7.27 (m, 3H), 7.49 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([O:22]C)=[CH:18][C:17]=4[CH3:24])=[C:14]([CH3:25])[O:13][C:12]=23)[N:3]=1.B(Br)(Br)Br.CCOC(C)=O>C(Cl)Cl>[CH3:1][C:2]1[N:6]=[C:5]([CH3:7])[N:4]([C:8]2[C:9]([CH3:26])=[N:10][N:11]3[C:15]([C:16]4[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=4[CH3:24])=[C:14]([CH3:25])[O:13][C:12]=23)[N:3]=1
Reactant: COc1ccc(-c2c(C)oc3c(-n4nc(C)nc4C)c(C)nn23)c(C)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1nc(C)n(-c2c(C)nn3c(-c4ccc(O)cc4C)c(C)oc23)n1
Reaction time: 0.5 h

Procedure:
7-(3,5-Dimethyl-[1,2,4]triazol-1-yl)-3-(4-methoxy-2-methyl-phenyl)-2,6-dimethyl-pyrazolo[5,1-b]oxazole (Ex. 6.12) (100 mg, 0.285 mmol) is dissolved in dry DCM (5 ml). The contents are flushed with N2 and to this solution is added boron tribromide (1.423 ml, 1.423 mmol) dropwise at RT. After approximately 30 mins, the reaction is quenched by careful addition of H2O. The mixture is transferred to a separating funnel and extracted with DCM (50 ml). The organic portion is separated and washed with 1M HCl, 1M NaOH, brine, dried (MgSO4) and evaporated in vacuo to give a brown solid. Trituration with EtOAc affords the title compound as an off white solid. MS m/z 338.2 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ 7.25 (d, 1H), 6.8 (s, 1H), 6.75 (d, 1H), 2.35 (s, 3H), 2.30 (s, 6H), 2.2 (s, 3H), 2.15 (s, 3H).
Reaction SMILES: [NH:1]1[C:5]2[C:6]3[C:11]([CH2:12][C:4]=2[C:3]([C:13]2[CH:21]=[CH:20][C:16]([C:17](O)=[O:18])=[CH:15][CH:14]=2)=[N:2]1)=[CH:10][CH:9]=[CH:8][CH:7]=3.CN.[N:24]1(C2C=CN=CC=2)CCC[CH2:25]1.C(N=C=NC(C)C)(C)C>C(O)C.ClCCl>[CH3:25][NH:24][C:17](=[O:18])[C:16]1[CH:15]=[CH:14][C:13]([C:3]2[C:4]3[CH2:12][C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:5]=3[NH:1][N:2]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Reactant: c1cc(N2CCCC2)ccn1
Agent: CC(C)N=C=NC(C)C
Agent: CN
Solvent: CCO
Solvent: ClCCl
Product: CNC(=O)c1ccc(-c2n[nH]c3c2Cc2ccccc2-3)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A mixture of 4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzoic acid (0.8 g), methylamine in ethanol (0.27 ml of a 33% w/w solution), 4-pyrrolidinopyridine (0.47 g), diisopropylcarbodiimide (0.5 ml) and dichloromethane (30 ml) was stirred at ambient temperature for 20 hours. More methylamine in ethanol (0.3 ml of a 33% w/w solution), 4-pyrrolidinopyridine (0.5 g) and diisopropylcarbodiimide (1 ml) were added and the mixture was stirred for 3 hours at ambient temperature. The solvent was removed under reduced pressure at 50° C. The mixture was kept under vacuum for 2 hours and then dichloromethane (50 ml) was added. The mixture was stirred at ambient temperature for 20 hours and then allowed to stand for 72 hours. A solid was removed by filtration and purified by flash column chromatography on silica using toluene/acetic acid (10:1) and then ethyl acetate as the mobile phase to give N-methyl-4-(1,4-dihydroindeno[1,2-c]pyrazol-3-yl)benzamide, m.p. 182-188° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:21]([O-])=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:19])([CH3:18])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1.[H][H]>C1(C)C=CC=CC=1.[Pt]>[Cl:20][C:6]1[CH:5]=[C:4]([CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[C:17]2[O:16][C:15]([CH3:18])([CH3:19])[CH2:14][C:13]=2[CH:12]=[CH:11][CH:10]=1)[NH2:21]
Reactant: [H][H]
Reactant: CC1(C)Cc2cccc(Oc3c(Cl)cc([N+](=O)[O-])cc3Cl)c2O1
Agent: [Pt]
Solvent: Cc1ccccc1
Product: CC1(C)Cc2cccc(Oc3c(Cl)cc(N)cc3Cl)c2O1
Yield: 89.6 %

Procedure:
To a solution of 29.2 g of 3,5-dichloro-4-(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)-1-nitrobenzene in 500 ml of toluene was added 2.3 g of 5% platinum on carbon catalyst. This mixture was then charged into a 1 L rocking Parr reactor. The reactor was purged twice with nitrogen then twice with hydrogen, then finally filled with hydrogen to a pressure of 100 psig. The hydrogen pressure was maintained between 75 and 100 psig during the course of the reaction. After hydrogen uptake ceased, the reaction mixture was removed from the reactor. This was filtered through celite. Removal of the solvents afforded 23.95 g of off-white crystals. mp 140°-145° C. NMR (CDCl3): 1.53 (s, 6H), 3.03 (s, 2H), 3.70 (broad s, 2H), 6.2-7.0 (M, 5H, contains singlet at 6.62).