Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]([CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:16])[C:6]([CH3:18])([CH3:17])[CH2:5]1)=[N+]=[N-].[H][H]>CCO.[Pd]>[NH2:1][CH:4]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([O:14][CH3:15])[CH:12]=2)[C:7](=[O:16])[C:6]([CH3:18])([CH3:17])[CH2:5]1
Reactant: COc1ccc2c(c1)C(N=[N+]=[N-])CC(C)(C)C2=O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc2c(c1)C(N)CC(C)(C)C2=O
Reaction time: 5 h
Yield: 91.2 %

Procedure:
To a solution of 4-azido-6-methoxy-2,2-dimethyl-3,4-dihydronaphthalen-1(2H)-one (2.50 g, 10.2 mmol) in EtOH (100 mL) at RT was added palladium on carbon (1.08 g, 10.2 mmol) in two portions. A hydrogen balloon was affixed to the reaction flask and the head space above the solvent was purged with H2. After 5 hours, the solution was filtered through a plug of celite and concentrated to provide the crude product as an oil. The residue was purified by column chromatography 100% DCM to 50% (10% MeOH/DCM/1% NH4OH) to provide the title compound as a yellow oil (2.04 g, 91% yield). MS m/z: 220.2 (M+1).
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][CH2:3][OH:4].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1.Cl>CCCCCC.CN(C=O)C>[OH:4][CH2:3][CH2:2][CH2:1][O:5][C:9]1[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1ccc(Cl)nc1
Reactant: OCCCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: OCCCOc1ccc(C(F)(F)F)cn1
Reaction time: 1 h
Yield: 43.5 %

Procedure:
A mixture of 12.6 g of 1,3-propanediol and 100 ml of N,N-dimethylformamide was stirred under a nitrogen stream, to which 3.30 g of an oily mixture containing 60% sodium hydride was added in small portions at room temperature over 30 minutes. After further stirring continued at room temperature for 1 hour, 20 ml of a DMF solution of 10.0 g of 2-chloro-5-trifluoromethylpyridine was added dropwise over 40 minutes. After further stirring continued under a nitrogen stream at room temperature overnight, 100 ml of about 2 N diluted hydrochloric acid was added over 15 minutes to stop the reaction. The reaction mixture was extracted twice with toluene at a total volume of 500 ml. The combined toluene layer was successively washed with diluted hydrochloric acid and aqueous sodium bicarbonate solution, dried with magnesium sulfate, and concentrated to obtain an oily product. The oily product was dissolved in 300 ml of hexane by heating, followed by recrystallization, which afforded 5.3 g of 2-(3-hydroxypropyloxy)-5-trifluoromethylpyridine as almost pure crystals (44% yield), m.p. 46.6° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].[CH3:11][C:12]([CH3:19])([CH3:18])[C:13](=O)[CH2:14][C:15]#[N:16]>>[C:12]([C:13]1[CH:14]=[C:15]([NH2:16])[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[F:2])[N:10]=1)([CH3:19])([CH3:18])[CH3:11]
Reactant: NNc1ccccc1F
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Product: CC(C)(C)c1cc(N)n(-c2ccccc2F)n1
Yield: 66 %

Procedure:
using the procedure in Example 161A Step 3, 2-fluorophenylhydrazine hydrochloride (1.30 g, 8.0 mmol) and 4,4-dimethyl-3-oxopentanenitrile (1.0 g, 8.0 mmol) were reacted to give 3-tert-butyl-1-(2-fluorophenyl)-1H-pyrazol-5-amine (1.23 g, 5.28 mmol, 66%). 1H NMR (300 MHz, DMSO-d6) δ 7.46-7.29 (m, 4H), 5.31 (s, 1H), 5.05 (br s, 2H), 1.20 (s, 9H); LC-MS (ESI) m/z 234 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[I:28][C:29]1[N:30]=[C:31]([CH3:34])[NH:32][CH:33]=1>C(Cl)Cl>[I:28][C:29]1[N:30]=[C:31]([CH3:34])[N:32]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:33]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: Cc1nc(I)c[nH]1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1nc(I)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
Triethylamine (13.4 mL, 96.2 mmol) followed by trityl chloride (20.1 g, 72.1 mmol) were added to an ambient temperature solution of 4-iodo-2-methyl-1H-imidazole (ca. 10 g, 48.1 mmol) in methylene chloride (90 mL). After stirring at ambient temperature for 2 days, the reaction mixture was diluted with methylene chloride and washed with water and brine, dried (sodium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-15% acetone/methylene chloride afforded the title compound.
Reaction SMILES: Cl[C:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13]([CH3:19])([CH3:18])[C:14]([O:16][CH3:17])=[O:15])=[CH:6][CH:5]=1)=[O:3].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]([C@H:31]2[C:40]3[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=3)[NH:34][C@@H:33]([CH3:41])[CH2:32]2)[C:28](=[O:30])[CH3:29])=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:17][O:16][C:14](=[O:15])[C:13]([CH3:19])([CH3:18])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([N:34]2[C:35]3[C:40](=[CH:39][CH:38]=[CH:37][CH:36]=3)[C@H:31]([N:27]([C:28](=[O:30])[CH3:29])[C:24]3[CH:23]=[CH:22][C:21]([Cl:20])=[CH:26][CH:25]=3)[CH2:32][C@@H:33]2[CH3:41])=[O:3])=[CH:5][CH:6]=1
Reactant: CC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)Nc2ccccc21
Reactant: COC(=O)C(C)(C)CCCc1ccc(C(=O)Cl)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C(C)(C)CCCc1ccc(C(=O)N2c3ccccc3[C@H](N(C(C)=O)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 50.1 %

Procedure:
To the prepared methyl 5-[4-(chlorocarbonyl)phenyl]-2,2-dimethylpentanoate (2.9 mmol, 1.0 eq.) was added a solution of N-(4-chlorophenyl)-N-((2S,4R)-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl)acetamide (754 mg, 2.4 mmol, 0.83 eq.) in methylene chloride (8 ml) followed by diisopropylethylamine (505 ul, 2.9 mmol, 1.0 eq.) and reaction mixture was stirred at room temperature for 20 h. The mixture was concentrated and the residue dissolved in ethyl acetate and washed with water, brine, and then dried over magnesium sulfate, filtered and concentrated. The crude residue was purified by silica gel chromatography (ethyl acetate/hexane: ⅓ to ½ gradient) to afford 5-(4-{(2S,4R)-4-[acetyl-(4-chloro-phenyl)-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenyl)-2,2-dimethyl-pentanoic acid methyl ester (675 mg, 50%).
Reaction SMILES: Cl.C(O[C:5](=[O:9])[CH2:6][NH:7][CH3:8])C.[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]=[C:21]=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11].C(N(CC)CC)C>C(Cl)(Cl)Cl>[C:10]([C:14]1[CH:19]=[CH:18][C:17]([N:20]2[C:5](=[O:9])[CH2:6][N:7]([CH3:8])[C:21]2=[S:22])=[CH:16][CH:15]=1)([CH3:13])([CH3:11])[CH3:12]
Reactant: CCOC(=O)CNC
Reactant: CC(C)(C)c1ccc(N=C=S)cc1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CN1CC(=O)N(c2ccc(C(C)(C)C)cc2)C1=S
Temperature: 25 °C
Yield: 75.5 %

Procedure:
A mixture of sarcosine ethyl ester hydrochloride (7.68 g), 4-t-butylphenylisothiocyanate (9.6 g), triethyl amine (10.1 g) and chloroform (250 mL) was heated at reflux for 3 hours. The mixture was cooled to ambient temperature, washed with 2N HCl (2×200 mL), then with water (200 mL). The organic phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residue was crystallized from ethanol to give the title compound (9.9 g), m.p. 156°-158° C. Anal. Calcd. for C14H18N2O S: C, 64.09; H, 6.91; N,10.68. Found: C, 63.83; H, 7.15; N, 10.53. Mass spectrum (EI, M.+) m/z 262.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:12][N:11]([CH2:13][CH2:14][OH:15])[C:10](=[O:16])[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]([F:27])([F:26])[C:19]1[CH:24]=[CH:23][C:22](F)=[CH:21][CH:20]=1.C([O-])([O-])=O.[K+].[K+]>CC(N(C)C)=O.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([O:16][C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:27])([F:26])[F:17])=[CH:20][CH:21]=3)[N:11]([CH2:13][CH2:14][OH:15])[N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=c1cc(-c2cccc(Br)c2)[nH]n1CCO
Reactant: Fc1ccc(C(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: OCCn1nc(-c2cccc(Br)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: 160 °C
Reaction time: 13 h

Procedure:
5-(3-Bromophenyl)-2-(2-hydroxyethyl)-1,2-dihydro-3H-pyrazol-3-one (21 g, 74 mmol), 4-trifluoromethyl-1-fluorobenzene (28 mL, 220 mmol), and K2CO3 (30.6 g, 220 mmol) were combined in 140 mL of dry DMA. The mixture was heated at 160° C. with stirring in a sealed vessel for 13 h. The reaction was cooled to ambient temperature and more 4-trifluoromethyl-1-fluorobenzene (5 mL, 39 mmol) was added. The mixture was heated at 160° C. with stirring in a sealed vessel for 18 h. The reaction was cooled to ambient temperature and diluted with EtOAc. The mixture was washed with water and brine, then dried over MgSO4, filtered, and the solvent was removed under reduced pressure. The dark residue was chromatographed on a 330 g silica gel column using 0-40% EtOAc:hexanes over 70 min at 100 mL/min. The product-containing fractions were combined and the solvent was removed under reduced pressure to give 2-{3-(3-bromophenyl)-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-1-yl}ethanol as an oil which solidified on standing. Calcd (M−1-1)+: 428.2. Found: 428.3
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(O)(C)C.[N+:15]([C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([CH:1]=[N:22][C:21]2[CH:23]=[CH:24][C:18]([N+:15]([O-:17])=[O:16])=[CH:19][CH:20]=2)=[CH:3][CH:4]=1
Reactant: COc1ccc(C=O)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Solvent: CC(C)O
Product: COc1ccc(C=Nc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 25 °C
Yield: 66 %

Procedure:
To 50 g (370 mmol) of anisaldehyd in 160 ml of isopropanol 51 g (370 mmol) of para-nitroanilin are added. After 2 h at 80° C. the product precipitates. The reaction mixture cooled to room temperature and filtered. The residue is washed with isopropanol. After drying 62.9 g of product 2 is obtained (yield of 66%) in form of yellow crystals: C14H13N2O3 (257.27).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]#[N:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10].[ClH:38].C(O)C.C(=O)([O-])[O-].[NH4+:46].[NH4+]>ClCCl.C(O)C>[ClH:38].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]([CH2:31][CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[C:9]([C:11]1[CH:30]=[CH:29][C:14]2[N:15]([CH3:28])[C:16]([CH2:18][NH:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[NH:46])[NH2:27])=[CH:22][CH:21]=3)=[N:17][C:13]=2[CH:12]=1)=[O:10]
Reactant: [NH4+]
Reactant: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C#N)cc1)n2C)c1ccccc1F
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)CCN(C(=O)c1ccc2c(c1)nc(CNc1ccc(C(=N)N)cc1)n2C)c1ccccc1F
Yield: 88 %

Procedure:
Prepared analogously to Example 25d from 1-methyl-2-[N-(4-cyanophenyl)-aminomethyl]-benzimidazol-5-yl-carboxylic acid-N-(2-fluorophenyl)-N-(2-ethoxycarbonylethyl)-amide and ethanolic hydrochloric acid, ethanol and ammonium carbonate. Yield: 88% of theory, C28H29FN6O3 (516.6) Rf value: 0.08 (silica gel; dichloromethane/ethanol=4:1) ##EQU57##
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17](=[O:25])[NH:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1.[C:26]1([S:32](Cl)(=[O:34])=[O:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[Cl:8][C:9]1[C:10]([N:15]2[CH:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:18][C:17]([O:25][S:32]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)(=[O:34])=[O:33])=[N:16]2)=[N:11][CH:12]=[CH:13][CH:14]=1
Reactant: CCOC(=O)C1CC(=O)NN1c1ncccc1Cl
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)C1CC(OS(=O)(=O)c2ccccc2)=NN1c1ncccc1Cl
Reaction time: 2 h
Yield: 94 %

Procedure:
Triethylamine (1.85 g, 18.5 mmol) was added dropwise over 1 h to a mixture of ethyl 2-(3-chloro-2-pyridinyl)-5-oxo-3-pyrazolidinecarboxylate (i.e. the product of Example 1, Step A) (5.0 g, 18.5 mmol) and benzenesulfonyl chloride (3.27 g, 18.5 mmol) in dichloromethane (20 mL) at 0° C. The temperature was not allowed to exceed 1° C. After stirring the reaction mixture for an additional 2 h, a further portion of benzenesulfonyl chloride (0.5 g, 1.85 mmol) was added. Then a further portion of triethylamine (0.187 g, 1.85 mmol) was added dropwise to the mixture. After stirring for 0.5 h more, the mixture was partitioned between water (100 mL) and dichloromethane (100 mL). The organic layer was dried (MgSO4) and evaporated to provide the title product as an orange solid (7.18 g, 94% yield). Product recrystallized from ethyl acetate/hexanes melted at 84-85° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)=[CH:5][C:4]=1[C:18]([OH:20])=O.Cl.[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH2:44])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]>>[Cl:22][C:23]1[CH:24]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([CH2:36][C@@H:37]([NH:44][C:18]([C:4]3[CH:5]=[C:6]([C:9]4[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=4)[CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:20])[C:38]3[O:42][N:41]=[C:40]([CH3:43])[N:39]=3)=[CH:32][CH:31]=2)[CH:26]=[CH:27][C:28]=1[F:29]
Reactant: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C(=O)O
Reactant: Cc1noc([C@H](N)Cc2ccc(-c3ccc(F)c(Cl)c3)cc2)n1
Agent: Cl
Product: COc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1C(=O)N[C@H](Cc1ccc(-c2ccc(F)c(Cl)c2)cc1)c1nc(C)no1
Yield: 69.7 %

Procedure:
4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid [2-(3′-chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethyl]-amide (0.045 g) was prepared from 4-Methoxy-4′-nitro-biphenyl-3-carboxylic acid (0.03 g, 0.11 mmol) and 2-(3′-Chloro-4′-fluoro-biphenyl-4-yl)-1-(R)-(3-methyl-[1,2,4]oxadiazol-5-yl)-ethylamine hydrochloride salt (0.04 g, 0.11 mmol) following general procedure A
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[NH:16][CH:10]([CH2:11][O:12][CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.[CH3:26][O:27][C:28]([C:30]1[C@H:31]([C:43]2[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=2[Cl:50])[N:32]=[C:33]([C:38]2[S:39][CH:40]=[CH:41][N:42]=2)[NH:34][C:35]=1[CH2:36]Br)=[O:29]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[N:16]([CH2:36][C:35]3[NH:34][C:33]([C:38]4[S:39][CH:40]=[CH:41][N:42]=4)=[N:32][C@@H:31]([C:43]4[CH:48]=[CH:47][C:46]([F:49])=[CH:45][C:44]=4[Cl:50])[C:30]=3[C:28]([O:27][CH3:26])=[O:29])[CH:14]([CH2:13][O:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)C1=C(CBr)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC2COCC(C1)N2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)C1=C(CN2C3COCC2CN(C(=O)OC(C)(C)C)C3)NC(c2nccs2)=N[C@H]1c1ccc(F)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.6 %

Procedure:
To a mixture of 3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester (171 mg, 0.75 mmol) and DIPEA (0.45 mL, 2.5 mmol) in CH2Cl2 (10 mL) was added (R)-6-bromomethyl-4-(2-chloro-4-fluoro-phenyl)-2-thiazol-2-yl-1,4-dihydro-pyrimidine-5-carboxylic acid methyl ester (222 mg, 0.5 mmol). The mixture was stirred at room temperature for 16 hours. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography to afford 9-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydro-pyrimidin-4-ylmethyl]-3-oxa-7,9-diaza-bicyclo[3.3.1]nonane-7-carboxylic acid tert-butyl ester as yellow oil (0.28 g, 94%). MS: calc'd (MH+) 592, measured (MH+) 592.
Reaction SMILES: N1([S:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)(=[O:8])=[O:7])C=CN=C1.COS(C(F)(F)F)(=O)=O.[CH2:24]1[C:26]2([CH2:31][N:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:29][CH2:28][NH:27]2)[CH2:25]1>C(Cl)Cl.CS(C)=O>[N:9]1([S:6]([N:27]2[CH2:28][CH2:29][N:30]([C:32]3[C:33]4[CH:40]=[CH:39][NH:38][C:34]=4[N:35]=[CH:36][N:37]=3)[CH2:31][C:26]32[CH2:24][CH2:25]3)(=[O:8])=[O:7])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: c1nc(N2CCNC3(CC3)C2)c2cc[nH]c2n1
Reactant: O=S(=O)(N1CCCCC1)n1ccnc1
Agent: COS(=O)(=O)C(F)(F)F
Solvent: CS(C)=O
Solvent: ClCCl
Product: O=S(=O)(N1CCCCC1)N1CCN(c2ncnc3[nH]ccc23)CC12CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 1-(imidazole-1-sulfonyl)-piperidine (intermediate 13) (0.047 mmol) in dry CH2Cl2 (1 mL) was cooled to 0° C. and added trifluoro-methanesulfonic acid methyl ester (0.047 mmol). The reaction mixture was allowed to warm up freely to rt over a period of 4 h and then concentrated in vacuo. The residual oil was redissolved in dry CH3CN (1.5 mL), added a solution of 4-(4,7-diaza-spiro[2.5]oct-7-yl)-7H-pyrrolo[2,3-d]pyrimidine (intermediate 21) (0.047 mmol) in DMSO (1 mL) and then stirred at 50° C. for 3 h. The pure compound was obtained by standard preparative HPLC purification of the reaction mixture.
Reaction SMILES: Br[C:2]1[N:3]([CH3:23])[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26].C(N(CC)CC)C>CN(C=O)C.[Cu]I>[CH3:23][N:3]1[C:4]([C:13]2[S:14][C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH2:22])[C:20]=3[N:21]=2)=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=[C:2]1[C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24]
Reactant: Cn1c(Br)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cn1c(C#C[Si](C)(C)C)nc(-c2ccccc2)c1-c1nc2c(N)ncnc2s1
Yield: 100 %

Procedure:
2-(2-Bromo-1-methyl-4-phenyl-1H-imidazol-5-yl)[1,3]thiazolo[5,4-d]pyrimidin-7-amine (Example 26) (52 mg), PdCl2dppf (10 mg), copper(I) iodide (2 mg), trimethylsilyl acetylene (0.11 mL) and triethylamine (0.2 mL) were heated in DMF (4 mL) at 80° C. for 1 hour under an inert atmosphere. The reaction mixture was concentrated in vacuo, EtOAc (20 mL)/MeOH (0.3 mL)/water (10 mL) added and the aqueous layer removed. The organic layer was dried (MgSO4), filtered, concentrated in vacuo, then purification by flash chromatography on silica eluting with 4% MeOH/DCM gave the title compound as a light brown solid (48 mg, 100%);
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[CH:9][C:10]([NH2:13])=[N:11][CH:12]=2)=[CH:5][C:4]([C:14]2[N:18]=[C:17]([CH3:19])[O:16][N:15]=2)=[N:3]1.[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+].C(Cl)Cl>C(Cl)Cl>[Cl:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:13][C:10]1[CH:9]=[CH:8][C:7]([C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:14]3[N:18]=[C:17]([CH3:19])[O:16][N:15]=3)[CH:5]=2)=[CH:12][N:11]=1)=[O:24]
Reactant: Cc1nc(-c2cc(-c3ccc(N)nc3)n(C)n2)no1
Reactant: O=C(Cl)c1ccccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2cc(-c3ccc(NC(=O)c4ccccc4Cl)nc3)n(C)n2)no1
Temperature: 25 °C
Reaction time: 3 h
Yield: 17.7 %

Procedure:
To a solution of crude 5-[1-methyl-3-(5-methyl(1,2,4-oxadiazol-3-yl))pyrazol-5-yl]-2-pyridylamine (74) (27 mg, 0.1 mmol) in 2 ml DCM was added 2-chlorobenzoyl chloride (25 μl, 2 eq) followed by addition of DIEA (70 μl). The resulting solution was stirred at r.t. for 3 h. The reaction mixture was worked up with aq. NaHCO3/DCM. DCM phase was washed with brine, concentrated to dryness. The residue was dissolved in 2 ml THF/MeOH/H2O (5:4:1) and stirred with 1N NaOH (250 μl) at r.t. for 1 h before worked up with EA/aq. NaHCO3. Silica gel flash chromatography furnished 7 mg (2-chlorophenyl)-N-{5-[1-methyl-3-(5-methyl(1,2,4-oxadiazol-3-yl))pyrazol-5-yl](2-pyridyl)}carboxamide (75) as light yellow solid. (yield: 17.7%, purity>95%).
Reaction SMILES: [C:1]([C:3]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH2:18])=[CH:14][CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2].[Cl:30][C:31]1([Cl:38])[CH2:33][C:32]1([CH3:37])[C:34](O)=[O:35].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN1CCCC1=O>[C:1]([C:3]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH2:8][CH2:7][N:6]([C:9]([NH:11][C:12]2[CH:23]=[CH:22][C:15]([CH2:16][C@@H:17]([C:19]([OH:21])=[O:20])[NH:18][C:34]([C:32]3([CH3:37])[CH2:33][C:31]3([Cl:38])[Cl:30])=[O:35])=[CH:14][CH:13]=2)=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: CC1(C(=O)O)CC1(Cl)Cl
Reactant: N#CC1(c2ccccc2)CCN(C(=O)Nc2ccc(C[C@H](N)C(=O)O)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC1(C(=O)N[C@@H](Cc2ccc(NC(=O)N3CCC(C#N)(c4ccccc4)CC3)cc2)C(=O)O)CC1(Cl)Cl
Reaction time: 3 h

Procedure:
A suspension of 4-[[(4-cyano-4-phenyl-1-piperidinyl)carbonyl]amino]-L-phenylalanine on Wang resin (0.30 g, 0.228 mmol), 2,2-dichloro-1-methylcyclopropane carboxylic acid (0.19 g, 1.14 mmol), BOP (0.50 g, 1.14 mmol) and DIPEA (0.26 mL, 1.5 mmol) in N-methylpyrrolidinone (3 mL) was agitated for 3 hr. The mixture was filtered and washed with dichloromethane and methanol. Cleavage from the resin was effected by treatment with 90% TFA in dichloromethane for 3 min. The mixture was filtered and the filtrate evaporated to give 4-[[(4-cyano-4-phenyl-1-piperidinyl)carbonyl]amino]-N-[(2,2-dichloro-1-methylcyclopropyl)carbonyl]-L-phenylalanine. FAB MS m/z 543 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=2)=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[Cl:35])=[O:29])C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)=[CH:10][C:9]=1[NH:21][C:26](=[O:25])[CH2:27][C:28]([C:30]1[S:31][CH:32]=[CH:33][C:34]=1[Cl:35])=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1N
Reactant: CCOC(=O)CC(=O)c1sccc1Cl
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccc(F)cc2)cc1NC(=O)CC(=O)c1sccc1Cl
Yield: 60.2 %

Procedure:
Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester (Example G39) (360 mg, 1.2 mmol) and 3-(3-chloro-thiophen-2-yl)-3-oxo-propionic acid ethyl ester (Example H16) (350 mg, 1.5 mmol) according to the general procedure K. Obtained as a white-yellow solid (353 mg).
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[C:12]([SH:14])[C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:9]=1[NH:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])([CH3:4])([CH3:3])[CH3:2].[S:28](Br)([C:31]1[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=1)(=[O:30])=[O:29].N1C=CC=CC=1>CCOC(C)=O>[C:23]([O:22][C:20]([NH:19][C:9]1[C:8]([NH:7][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:27])=[CH:13][C:12]([S:14][S:28]([C:31]2[CH:37]=[CH:36][C:34]([CH3:35])=[CH:33][CH:32]=2)(=[O:30])=[O:29])=[C:11]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH:10]=1)=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)Nc1cc(S)c(C(C)(C)C)cc1NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)Br)cc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)Sc2cc(NC(=O)OC(C)(C)C)c(NC(=O)OC(C)(C)C)cc2C(C)(C)C)cc1

Procedure:
The title compound was prepared according to the General Method 15 using (2-tert-butoxycarbonylamino-4-tert-butyl-5-mercapto-phenyl)-carbamic acid tert-butyl ester (prepared in Example TT-2; 16.9 g, 42.8 mmol), tosyl bromide (10.04 g, 42.76 mmol), pyridine (10 mL), and EtOAc (150 mL). The crude product was purified by flash chromatography (5%-60% EtOAc in hexanes as eluents). 1 H-NMR (CDCl3): δ1.19 (s, 9 H), 1.53 (s, 18 H), 2.42 (s, 3 H), 6.42 (br s, 1 H), 7.22 (d, 2 H), 7.28 (s, 1 H), 7.5 (m, 3 H), 7.87 (br s, 1 H).