Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]1([S:13]([C:16]2[C:17]([S:28][CH3:29])=[N:18][N:19]3[C:24]([OH:25])=[CH:23][C:22]([CH2:26]Cl)=[N:21][C:20]=23)(=[O:15])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CN(C=O)C>[C:7]1([S:13]([C:16]2[C:17]([S:28][CH3:29])=[N:18][N:19]3[C:24]([OH:25])=[CH:23][C:22]([CH2:26][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[N:21][C:20]=23)(=[O:14])=[O:15])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CSc1nn2c(O)cc(CCl)nc2c1S(=O)(=O)c1ccccc1
Reactant: C1COCCN1
Solvent: CN(C)C=O
Product: CSc1nn2c(O)cc(CN3CCOCC3)nc2c1S(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 88.1 %

Procedure:
1 ml (6 mmol) of morpholine was added to a solution of 2.0 g (5.40 mmol) of 3-benzenesulphonyl-5-chloromethyl-2-methylsulphanyl-pyrazolo[1,5-a]pyrimidin-7-ol in 20 ml of DMF and stirred at RT for 4 hrs. The reaction solution was evaporated and the residue was partitioned between 0.5N NaOH and CH2Cl2. The aqueous phase was extracted three times with CH2Cl2. The combined organic phases were dried (MgSO4), filtered and evaporated. Chromatography (SiO2, CH2Cl2/MeOH 10:1) yielded 2.0 g (88%) of 3-benzenesulphonyl-2-methylsulphanyl-5-morpholin-4-ylmethyl-pyrazolo[1,5-a]pyrimidin-7-ol as a beige foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][CH:11]([C:16]([CH3:18])=[CH2:17])[C:10]21[C:26]1[C:21](=[CH:22][C:23]([Cl:27])=[CH:24][CH:25]=1)[NH:20][C:19]2=[O:28].[CH3:29][S:30](Cl)(=[O:32])=[O:31].N1C=CC=CC=1>C(#N)C>[Cl:27][C:23]1[CH:22]=[C:21]2[NH:20][C:19](=[O:28])[C:10]3([CH:9]([C:3]4[CH:4]=[C:5]([Cl:8])[CH:6]=[CH:7][C:2]=4[NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:14][C:13](=[O:15])[NH:12][CH:11]3[C:16]([CH3:18])=[CH2:17])[C:26]2=[CH:25][CH:24]=1
Reactant: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2N)C12C(=O)Nc1cc(Cl)ccc12
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC#N
Product: C=C(C)C1NC(=O)CC(c2cc(Cl)ccc2NS(C)(=O)=O)C12C(=O)Nc1cc(Cl)ccc12
Reaction time: 4 h
Yield: 16.2 %

Procedure:
To a mixture of racemic (2′R,3R,4′S)-4′-(2-amino-5-chloro-phenyl)-6-chloro-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (40 mg, 0.1 mmol), methanesulfonyl chloride (0.0092 mL, 0.15 mmol), in acetonitrile (5 mL) was added pyridine (23 mg, 0.3 mmol) at r.t. The reaction mixture was stirred for 4 h. The mixture was concentrated and partitioned between ethyl acetate and water. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over MgSO4 and concentrated. The residue was purified with Prep. HPLC to give the title compound as a white solid (Yield: 8 mg).
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([OH:20])[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C([O-])([O-])=O.[Cs+].[Cs+]>C1COCC1.C(OCC)(=O)C>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][C:22]3[C:31]4[C:26](=[CH:27][C:28]([O:34][CH2:35][CH2:36][CH2:37][Cl:38])=[C:29]([O:32][CH3:33])[CH:30]=4)[N:25]=[CH:24][N:23]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCl
Reactant: CC(C)(C)c1cc(NC(=O)Nc2cccc(O)c2)no1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1cc2c(Oc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCCl
Temperature: 50 °C
Yield: 61 %

Procedure:
To a solution of (1-(5-tert-butyl-isoxazol-3-yl)-3-(3-hydroxy-phenyl)-urea, 300 mg, 1.089 mmol) from Example 1A and (4-chloro-7-(3-chloro-propoxy)-6-methoxy-quinazoline (343.96 mg, 1.119 mmol), from the previous step in THF, was added Cs2CO3 (532.2 mg, 1.63 mmol) and the mixture was heated at 50° C. for 12 hours. Completion of the reaction was monitored by LCMS. The reaction mixture was diluted with ethyl acetate and the ethyl acetate layer was washed with water and brine successively. The organic layer was dried (Na2SO4) and concentrated to dryness. The crude compound was purified by column chromatography to afford the pure compound 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(3-chloro-propoxy)-6-methoxy-quinazolin-4-yloxy]-phenyl}-urea, (310 mg, 61%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.55 (s, 1H), 9.00 (s, 1H), 8.55 (s, 1H), 7.55 (m, 2H), 7.40 (m, 2H), 7.25 (d, 1H), 6.95 (d, 1H), 6.45 (s, 1H), 4.35 (t, 2H), 4.00 (s, 3H), 3.85 (2, 2H), 1.30 (s, 9H); LC-MS (ESI)m/z 526 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][N:6]([CH2:9][CH:10]([CH3:12])[CH3:11])[N:5]=1)([O-])=O.CO.[H][H]>C(OCC)(=O)C.[Pd]>[CH2:9]([N:6]1[CH:7]=[CH:8][C:4]([NH2:1])=[N:5]1)[CH:10]([CH3:12])[CH3:11]
Reactant: CC(C)Cn1ccc([N+](=O)[O-])n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)Cn1ccc(N)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.5 %

Procedure:
3-Nitro-1-iso-butyl-1H-pyrazole (83 mg, 0.49 mmol) was dissolved in ethyl acetate (3 mL) and methanol (3 mL) was added. Palladium, 10 wt. % on activated carbon, wet (˜50 mg) was added to the reaction. The vial was charged with hydrogen gas (via balloon) and the reaction stirred for 16 h at 25° C. The reaction was passed through a plug of celite and concentrated in vacuo to afford 1-iso-butyl-1H-pyrazol-3-ylamine (59 mg, 86%) as a golden oil: ESI-LRMS m/e calcd for C7H13N3 [M+] 139.1, found 140.3 [M+H+].
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:12])=[C:7]([CH:11]=1)[C:8]([OH:10])=[O:9].[C-:13]#[N:14].[K+]>CN(C=O)C.O>[Cl:12][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][C:13]#[N:14])=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: [C-]#N
Reactant: O=C(O)c1cc(CBr)ccc1Cl
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#CCc1ccc(Cl)c(C(=O)O)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A solution of 5-(bromomethyl)-2-chlorobenzoic acid [WO 2001044170] (1.75 g) in DMF (20 mL) was treated with a solution of potassium cyanide (0.91 g) in water (7 mL) and the resulting solution was stirred at room temperature over 3 days. The mixture was diluted with water and extracted twice with ethyl acetate. The organic phases were discarded, whilst the aqueous phase was carefully acidified with concentrated hydrochloric acid (5 mL), venting any liberated HCN through bleach solution via a stream of nitrogen. After being stirred for 20 minutes, the aqueous phase was extracted twice more with ethyl acetate. The combined organic phases were washed three times with water, once with brine, then dried over anhydrous magnesium sulphate and concentrated in vacuo to afford the crude subtitled compound as a brown solid. Yield 1.25 g.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][C@H:9]1[CH2:13][C@@H:12]([C:14]([OH:16])=O)[C@H:11]([CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH2:20][CH2:19]2)[CH2:10]1.[NH2:31][C:32]1([C:35]#[N:36])[CH2:34][CH2:33]1>>[C:35]([C:32]1([NH:31][C:14]([C@@H:12]2[CH2:13][C@H:9]([S:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[CH2:10][C@H:11]2[CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([C:24]3[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=3)[CH2:20][CH2:19]2)=[O:16])[CH2:34][CH2:33]1)#[N:36]
Reactant: O=C(O)[C@@H]1C[C@H](Sc2ccccc2Cl)C[C@H]1CN1CCC(c2ccc(F)cc2)CC1
Reactant: N#CC1(N)CC1
Product: N#CC1(NC(=O)[C@@H]2C[C@H](Sc3ccccc3Cl)C[C@H]2CN2CCC(c3ccc(F)cc3)CC2)CC1

Procedure:
The title compound was prepared in analogy to example 68 step 11 using (1R,2R,4R)-4-(2-Chloro-phenylsulfanyl)-2-[4-(4-fluoro-phenyl)-piperidin-1-ylmethyl]-cyclopentanecarboxylic acid (example 148 step 5) and 1-amino-cyclopropanecarbonitrile. Light yellow foam (52%). MS (EI): 512.3 (M+H)+.
Reaction SMILES: C([O:4][C@H:5]([C@H:8]([C@H:13]([C@@H:18]([CH2:23][O:24][C:25](=[O:27])[CH3:26])[O:19][C:20](=[O:22])[CH3:21])[O:14][C:15](=[O:17])[CH3:16])[O:9][C:10](=[O:12])[CH3:11])[CH:6]=[O:7])(=O)C.[O:28]=[CH:29][C@@H:30]([C@H]([C@H]([C@@H](CO)O)O)O)O.C([O-])(=O)C.[Na+].C(OC(=O)C)(=O)C>ClC(Cl)C>[C:25]([O:24][C@@H:23]1[O:4][C@H:5]([CH2:6][O:7][C:29](=[O:28])[CH3:30])[C@H:8]([O:9][C:10](=[O:12])[CH3:11])[C@H:13]([O:14][C:15](=[O:17])[CH3:16])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=[O:27])[CH3:26]
Reactant: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO
Reactant: CC(=O)OC[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H](C=O)OC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O

Procedure:
The synthesis of compounds 26-31 are depicted in FIGS. 19A and 19B and are set forth in the examples hereinbelow. In this figure, the synthesis of compounds 26, 27, 28, and 36 parallels that of compounds 17, 18, 19, and 20 as set forth above and illustrated in FIG. 18. In this regard, benzyl 4,6-O-benzylidene-2-O-benzoyl-3-O-chloroacetyl-β-D-thiogalactopyranoside (compound 31) has been produced without the necessity of chromatography. D-Galactose pentaacetate 26 is produced by slurring D-galactose and about an equimolar amount (e.g., about 1.1 equivalents) of sodium acetate (NaOAc) in dichloroethane (DCE), heating to reflux and adding at least 5 equivalents of acetic anhydride (AcOAc) dropwise to the refluxing solution (about 80°-85° C.) and then maintaining the reaction system at this temperature for a sufficient period of time (about 16-32 hours) to result in formation of compound 26. This procedure optimizes the yield of β-D-galactose pentaacetate 26 and controls the exotherm of heretofore known procedures.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[F:37]C1C=C2C(=CC=1F)OC(C1C=CC=CC=1)=C(I)C2=O>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][C:23]([F:37])=[C:24]([F:29])[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=c1c(I)c(-c2ccccc2)oc2cc(F)c(F)cc12
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4cc(F)c(F)cc4c3=O)cc2)CCC1
Yield: 90 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 6,7-difluoro-3-iodo-2-phenyl-chromen-4-one was reacted to give the title compound as a pale yellow oil (91 mg, 90%). LCMS (Method B): RT=5.01 min, [M+Na]+=526.
Reaction SMILES: [C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH:9]=O)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]([CH3:24])[CH2:21][CH2:22][NH2:23])=[CH:16][CH:15]=1.[BH4-].[Na+].O>CO>[C:1]([C:5]1[CH:12]=[CH:11][C:8]([CH2:9][NH:23][CH2:22][CH2:21][N:20]([C:17]2[CH:16]=[CH:15][C:14]([Cl:13])=[CH:19][CH:18]=2)[CH3:24])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN(CCN)c1ccc(Cl)cc1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CN(CCNCc1ccc(C(C)(C)C)cc1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.8 %

Procedure:
1.62 g (10 mmol) of 4-tert-butyl benzaldehyde and 1.85 g (10 mmol) of N-(4-chloro -phenyl)-N-methyl-ethane-1,2-diamine were dissolved in 20 ml methanol and the solution was stirred for 2 h at rt. 567 mg (15 mmol) of sodium borohydride were added in portions under nitrogen. The reaction mixture was stirred at rt over night. Water was added and the solvent was evaporated. The reaction mixture was extracted with diethyl ether and the organic layer was washed with saturated aqueous NaCl solution, dried over sodium sulfate, filtered and the solvent was evaporated to leave the 2.97 g (90%) product as a yellow oil. 1H NMR (DMSO-d6, 300 MHz): δ 7.34 (d, 2H), 7.24 (d, 2H), 7.13 (d, 2H), 6.64 (d, 2H), 3.77 (s, 2H), 3.42 (t, 2H), 2.91 (s, 3H), 2.83 (t, 2H), 1.30 (s, 9H).
Reaction SMILES: [CH2:1]([N:4]([CH:12]1[CH2:17][CH2:16][N:15]([C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])[CH2:14][CH2:13]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[C:2]#[CH:3].I[C:25]1[CH:30]=[N:29][CH:28]=[CH:27][N:26]=1>C(N(CC)CC)C.[Cu]I.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>[N:26]1[CH:27]=[CH:28][N:29]=[CH:30][C:25]=1[C:3]#[C:2][CH2:1][N:4]([CH:12]1[CH2:13][CH2:14][N:15]([C:18](=[O:23])[C:19]([F:20])([F:21])[F:22])[CH2:16][CH2:17]1)[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8]
Reactant: C#CCN(C(=O)OC(C)(C)C)C1CCN(C(=O)C(F)(F)F)CC1
Reactant: Ic1cnccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CC#Cc1cnccn1)C1CCN(C(=O)C(F)(F)F)CC1
Temperature: 65 °C
Reaction time: 0.5 h

Procedure:
To a solution of 0.20 g of tert-butyl (2-propyn-1-yl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate in 6.0 mL of triethylamine, 59 μL of iodopyrazine, 0.57 mg of copper (I) iodide, and 4.2 mg of dichlorobis(triphenylphosphine)palladium(II) were added under a nitrogen atmosphere, and the mixture was stirred at 60 to 70° C. for 4 hours 30 minutes. The insoluble substance was filtered off, and the solvent was distilled off under reduced pressure. The resultant residue was purified by flash silica gel column chromatography using gradient elution with hexane:ethyl acetate=60:40 to 50:50 to obtain 0.17 g of tert-butyl (3-(pyrazin-2-yl)-2-propyn-1-yl)(1-(trifluoroacetyl)piperidin-4-yl)carbamate as a colorless oily substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]#[N:22])=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].O>CN1CCCC1=O>[CH3:1][O:2][C:3]1[C:24]([O:25][CH3:26])=[CH:23][C:6]2[N:7]([C:10]3[S:11][C:12]([C:21]4[NH:29][N:28]=[N:27][N:22]=4)=[C:13]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[N:14]=3)[CH:8]=[N:9][C:5]=2[CH:4]=1
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc2ncn(-c3nc(-c4ccccc4)c(C#N)s3)c2cc1OC
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COc1cc2ncn(-c3nc(-c4ccccc4)c(-c4nnn[nH]4)s3)c2cc1OC
Temperature: 110 °C
Reaction time: 1 h
Yield: 47.3 %

Procedure:
A mixture of 2-(5,6-Dimethoxy-benzoimidazol-1-yl)-4-phenyl-thiazole-5-carbonitrile (261 mg, 0.72 mmol), sodium azide (220 mg) and ammonium chloride (250 mg) in N-methylpyrrolidone (2.5 ml) was stirred at 110° C. for 1 hr. Water was added and the mixture was extracted with methylene chloride. After removal of solvent, the residue was purified by HPLC to yield the product (138.1 mg, yield 47%). 1H-NMR (DMSO-D6) 8.78 (s, 1H); 8.21-8.29 (m, 2H); 7.86 (s, 1H); 7.36-7.50 (m, 3H); 3.90 (s, 3H); 3.88 (s, 3H). MS M/z 406 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[N:20]=[CH:19][CH:18]=[CH:17][N:16]=1)[C:10](O)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N1C=CN=C1)([N:29]1C=CN=C1)=O.N.S(=O)(=O)(O)O>C(#N)C>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][N:14]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:15]1[N:16]=[CH:17][CH:18]=[CH:19][N:20]=1)[C:10]([NH2:29])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(=O)O
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Agent: O=S(=O)(O)O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@@H](CN(c1ccccc1)c1ncccn1)C(N)=O
Reaction time: 2 h
Yield: 95.2 %

Procedure:
A suspension of (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid (11.9 g, 33.2 mmol, >99.9% ee) in acetonitrile (36 ml) is admixed at −15° C. with a solution of 1,1′-carbonyldiimidazole (8.36 g, 51.6 mmol) in acetonitrile (125 ml), and the reaction mixture is stirred for 2 h at this temperature. Ammonia (4.0 g, 222 mmol) is then introduced, and the mixture is stirred for further 1 h and then adjUsted to pH 4.5 Using 2N sulfuric acid. Acetonitrile is distilled off, and the precipitated solid is filtered off with suction and dried to give (S)-2-tert-butoxycarbonylamino-3-(phenyl-pyrimidin-2-ylamino)-propanoic acid amide (11.3 g, 95%, >99.9% ee) as a colorless solid.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:29]([C:30]([F:33])([F:32])[F:31])=[C:28]([C:34](O)=[O:35])[CH:27]=[N:26]1>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:28]3[CH:27]=[N:26][N:25]([CH3:24])[C:29]=3[C:30]([F:33])([F:31])[F:32])=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: Cn1ncc(C(=O)O)c1C(F)(F)F
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3cnn(C)c3C(F)(F)F)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1-methyl-5-trifluoromethyl-1H-pyrazole-4-carboxylic acid. LC-MS (basic): tR=0.85 min; [M+H]+=508.1.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([OH:42])=O)[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:37])=[O:36].[NH2:49][C:50]1[N:51]=[CH:52][C:53]([C:56]2[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=2)=[N:54][CH:55]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:28][C:29]1[CH:30]=[C:31]([C@@H:39]([CH2:43][CH:44]2[CH2:48][CH2:47][CH2:46][CH2:45]2)[C:40]([NH:49][C:50]2[CH:55]=[N:54][C:53]([C:56]3[S:60][C:59]([C:61]#[N:62])=[CH:58][CH:57]=3)=[CH:52][N:51]=2)=[O:42])[CH:32]=[CH:33][C:34]=1[S:35]([CH3:38])(=[O:36])=[O:37]
Reactant: N#Cc1ccc(-c2cnc(N)cn2)s1
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(-c3ccc(C#N)s3)cn2)cc1Cl
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 56 %

Procedure:
A solution of triphenylphosphine (50.0 mg, 0.191 mmol) in methylene chloride (2 mL) cooled to 0° C. was treated with N-bromosuccinimide (35.0 mg, 0.197 mmol). The reaction mixture was stirred at 0° C. for 5 min and then treated with 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 51.0 mg, 0.154 mmol). The reaction mixture was allowed to warm to 25° C. over 15 min. The reaction mixture was then treated with 5-(5-amino-pyrazin-2-yl)-thiophene-2-carbonitrile (47.0 mg, 0.232 mmol) followed by pyridine (30.0 uL, 0.371 mmol). The resulting reaction mixture was stirred at 25° C. for 2 h. The reaction mixture was then diluted with methylene chloride and washed with a dilute aqueous hydrochloric acid solution. The aqueous layer was extracted with methylene chloride. The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH, 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-N-[5-(5-cyano-thiophen-2-yl)-pyrazin-2-yl]-3-cyclopentyl-propionamide (44.4 mg, 55.9%) as a yellow foam: mp 101–107° C. (foam to gel); (ES)+-HRMS m/e calcd for C24H23ClN4O3S2 (M+H)+515.0973, found 515.0974.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:47][CH2:48][CH2:49][O:50][CH2:51][CH2:52][O:53][CH2:54][CH2:55][P:56](=[O:63])([O:60][CH2:61][CH3:62])[O:57][CH2:58][CH3:59]>C(Cl)Cl>[CH2:61]([O:60][P:56]([CH2:55][CH2:54][O:53][CH2:52][CH2:51][O:50][CH2:49][CH2:48][NH:47][C:10](=[O:12])[C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH3:13])([O:57][CH2:58][CH3:59])=[O:63])[CH3:62]
Reactant: CCOP(=O)(CCOCCOCCN)OCC
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOP(=O)(CCOCCOCCNC(=O)[C@H](C)NC(=O)OC(C)(C)C)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (1 eq) and HBTU (1.2 eq) in DCM (0.06 M) was added DIEA (3.5 eq), followed by diethyl (2-(2-(2-aminoethoxy)ethoxy)ethyl)phosphonate (1.2 eq, from example 5, step 3). The reaction was stirred at room temperature for 2 hours. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 0-5% MeOH/DCM to give the title product as a colorless viscous oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH3:14].[Br:16]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:15])[C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[C:6]([F:13])[C:5]=1[CH2:14][Br:16]
Reactant: COC(=O)c1c([N+](=O)[O-])ccc(F)c1C
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c([N+](=O)[O-])ccc(F)c1CBr
Temperature: 85 °C
Reaction time: 6 h
Yield: 54 %

Procedure:
To a suspension of 3-fluoro-2-methyl-6-nitro-benzoic acid methyl ester (6.1 g, 28.6 mmol) and N-bromosuccinimide in 70 mL of CCl4 is added 2,2′-azobisisobutyronitrile at room temperature under nitrogen atmosphere. The reaction mixture is stirred at 85° C. for 6 hours under N2, then cooled to room temperature and filtrated. The filtrate is extracted with CH2Cl2 and washed with aqueous NaHCO3 solution followed by brine, dried over Na2SO4, filtered and evaporated in vacuo. The residue is purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to afford the 2-bromomethyl-3-fluoro-6-nitro-benzoic acid methyl ester (4.48 g, 15.3 mmol, 54%) as yellow oil. 1H-NMR (400 MHz, δ, ppm) CDCl3: 4.01 (s, 3H), 4.53 (d, 2H), 7.31 (dd, 1H), 8.17 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][CH:7]=[CH:6]2.O.Cl.[NH:15]1[CH2:20][CH2:19][C:18](=O)[CH2:17][CH2:16]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[Cl:12])[NH:8][CH:7]=[C:6]2[C:18]1[CH2:19][CH2:20][NH:15][CH2:16][CH:17]=1
Reactant: COc1cc2cc[nH]c2cc1Cl
Reactant: O=C1CCNCC1
Agent: Cl
Solvent: O
Product: COc1cc2c(C3=CCNCC3)c[nH]c2cc1Cl
Yield: 83 %

Procedure:
Beginning with 2.0 gm (11.0 mMol) 5-methoxy-6-chloro-1H-indole and 3.4 gm (22.0 mMol) 4-piperidone hydrochloride monohydrate, 2.4 gm (83%) of the title compound were recovered as a yellow solid.
Reaction SMILES: [OH:1][C@H:2]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][CH:16]=2)[CH2:7][CH2:6]1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37](Cl)=[O:38])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:35]=[CH:34][C:33]([CH2:36][C:37]([O:1][C@H:2]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH2:3][CH2:4][N:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH:17][C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH:12]=3)[CH2:7][CH2:6]2)=[O:38])=[CH:32][CH:31]=1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](O)c3ccccc3)CC2)c1
Reactant: O=C(Cl)Cc1ccc(F)cc1
Product: CC(C)C(=O)Nc1cccc(C2CCN(CC[C@H](OC(=O)Cc3ccc(F)cc3)c3ccccc3)CC2)c1

Procedure:
Prepared by Procedure Q1 and Scheme C2 (TEA) using N-(3-{1-[(3S)-3-hydroxy-3-phenylpropyl]-4-piperidinyl}phenyl)-2-methylpropanamide and (4-fluorophenyl)acetyl chloride: Anal. Calcd for C32H37FN2O3+0.07CHCl3: C, 73.4; H, 7.12; N, 5.34. Found: C, 73.4; H, 6.96; N, 5.14; ESMS m/e: 517.1 (M+H)+.