Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[Ca+2].[Cl-].O.[N+:5]([C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:15][N:14]=1)([O-])=O>C(O)C.[Zn]>[NH2:5][C:8]1[CH:9]=[C:10]([CH:32]=[CH:33][CH:34]=1)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:30])([CH3:31])[CH3:29])=[O:26])[CH2:21][CH2:20]2)=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3cccc([N+](=O)[O-])c3)nc2)CC1
Agent: [Ca+2]
Agent: [Cl-]
Agent: [Zn]
Solvent: O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COc3cccc(N)c3)nc2)CC1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
A suspension of zinc powder (553 mg, 8.46 mmol) and calcium chloride (16 mg, 0.144 mmol) in ethanol (2.6 mL)-water (0.6 mL) was warmed to 90° C. followed by the addition of a solution of tert-butyl 4-[2-(3-nitrophenoxymethyl)pyridin-5-yl]piperidine-1-carboxylate (Example 30) (97 mg, 0.23 mmol) in ethanol (2 mL). The mixture was stirred at 90° C. for 1.5 hours, allowed to cool to room temperature and filtered through Celite pad. The filtrate was extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol=100/1→100/2) to give the title compound (84 mg, yield 94%).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.FC(F)(F)C1C=C(C(F)(F)F)C=CC=1CN1C2C(=CC(C=C3S[C:53]([N:55]4[CH2:60][CH2:59][NH:58][C@@H:57]([C:61](NC)=[O:62])[CH2:56]4)=NC3=O)=CC=2)C=N1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:58]4[CH2:59][CH2:60][N:55]([CH3:53])[CH2:56][C@@H:57]4[CH2:61][OH:62])=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CNC(=O)[C@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)CCN1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Product: CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(C(F)(F)F)cc4C(F)(F)F)c3)S2)[C@@H](CO)C1

Procedure:
5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2-[(2R)-2-(hydroxymethyl)-4-methylpiperazin-1-yl]-1,3-thiazol-4(5H)-one was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and (2R) (4-Methyl-piperazin-2-yl)-methanol following General Procedure C.
Reaction SMILES: O.[NH2:2][C@@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6].[CH:11](=O)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[BH4-].[Na+]>[OH-].[Na+]>[CH2:11]([NH:2][C@@H:3]([C:8]([OH:10])=[O:9])[CH2:4][C:5](=[O:7])[NH2:6])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)C[C@@H](N)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: NC(=O)C[C@@H](NCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 27 %

Procedure:
1.5 g (10 mmol) of D-asparagine hydrate in 5 ml of 2N sodium hydroxide solution were treated with 1.01 ml (10 mmol) of benzaldehyde and the reaction mixture was stirred homogeneously at room temperature for 20 minutes. Subsequently, 114 mg (3 mmol) of sodium borohydride were added portionwise, the mixture was stirred at room temperature for 30 minutes, a further 114 mg of sodium borohydride were added and, finally, the mixture was stirred at room temperature for a further 30 minutes. Thereafter, the aqueous phase was washed with methylene chloride and then adjusted to pH 6-7 with 1N hydrochloric acid, upon which crystallization occurred. The separated crystals were filtered off, washed with water and ether and finally dried in a high vacuum, to obtain 0.6 g (27%) of N-benzyl-3-carbamoyl-D-alanine as a white powder. MS 223 (M+H)+.
Reaction SMILES: Cl.[CH3:2][N:3]([CH2:5][CH:6]1[CH2:19][S:18][C:9]2[N:10]([CH3:17])[C:11]3[C:16]([C:8]=2[C:7]1=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH3:4].N1CC[CH2:23][CH2:22]1>O>[N:3]1([CH2:5][CH:6]2[CH2:19][S:18][C:9]3[N:10]([CH3:17])[C:11]4[C:16]([C:8]=3[C:7]2=[O:20])=[CH:15][CH:14]=[CH:13][CH:12]=4)[CH2:2][CH2:23][CH2:22][CH2:4]1
Reactant: CN(C)CC1CSc2c(c3ccccc3n2C)C1=O
Reactant: C1CCNC1
Agent: Cl
Solvent: O
Product: Cn1c2c(c3ccccc31)C(=O)C(CN1CCCC1)CS2

Procedure:
A mixture of 2.50 g (0.008 mol) of 3-[(dimethylamino)methyl]-4-oxo-9-methyl-2,3,4,9-tetrahydrothiopyrano[2,3-b]indole hydrochloride obtained in Example 1, stage E and 1.78 g (0.025 mol) of pyrrolidine in 40 ml of water is heated to reflux for 10 hours. After the mixture is cooled, the precipitate formed is drained, washed with water, dried and dissolved in 40 ml of tetrahydrofuran and the solution is treated with an ethereal solution of hydrochloric acid. The precipitate formed is drained, washed with ether and recrystallized in ethanol.
Reaction SMILES: [NH2:1][CH2:2][C@:3]([C:6]1[CH:11]=[C:10]([Br:12])[CH:9]=[CH:8][C:7]=1[F:13])([OH:5])[CH3:4].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])([O-:16])=[O:15].[OH-].[Na+]>C1COCC1.CC(OC)(C)C>[Br:12][C:10]1[CH:9]=[CH:8][C:7]([F:13])=[C:6]([C@@:3]([OH:5])([CH3:4])[CH2:2][NH:1][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])[CH:11]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: C[C@@](O)(CN)c1cc(Br)ccc1F
Agent: [Na+]
Agent: [OH-]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Product: C[C@@](O)(CNS(=O)(=O)c1ccccc1[N+](=O)[O-])c1cc(Br)ccc1F
Temperature: 20 °C
Reaction time: 2 h

Procedure:
To a solution of (S)-1-amino-2-(5-bromo-2-fluoro-phenyl)-propan-2-ol (34.7 g, 140 mmol) in THF (400 ml) was added 2-nitro-benzenesulfonyl chloride (34.9 g, 154 mmol) at 0-5° C. and afterwards 1N aqueous NaOH over a period of 0.5 h. The reaction mixture was stirred for 2 h at 20° C. The reaction mixture was diluted with TBME and washed with water and NaH2PO4 solution and brine, dried over MgSO4, filtered and concentrated to provide the title compound after crystallization from TBME-hexane as beige crystals: TLC (toluene-EtOAc 3:1): Rf=0.51; UPLC RtH5=1.118 min; ESIMS: 450, 452 [(M+NHa)+]; 1H NMR (360 MHz, CDCl3): δ 7.98 (m, 1H), 7.81 (m, 1H), 7.65 (m, 2H), 7.59 (dd, 1H), 7.24 (m, 1H), 6.79 (dd, 1H), 5.60 (t, 1H), 4.16 (br s, 1H), 3.55 (dd, 1H), 3.44 (dd, 1H), 2.51 (s, 1H), 1.51 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([NH:8][C@:9]([CH2:14][CH2:15][C:16]#[N:17])([C:11]([OH:13])=[O:12])[CH3:10])=O)=[CH:4][CH:3]=1.C(OC(=O)C)(=O)C>C1C=CC=CC=1>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]2[O:12][C:11](=[O:13])[C:9]([CH2:14][CH2:15][C:16]#[N:17])([CH3:10])[N:8]=2)=[CH:4][CH:3]=1
Reactant: C[C@](CCC#N)(NC(=O)c1ccc(Cl)cc1)C(=O)O
Solvent: CC(=O)OC(C)=O
Solvent: c1ccccc1
Product: CC1(CCC#N)N=C(c2ccc(Cl)cc2)OC1=O
Yield: 80.1 %

Procedure:
2.8 g of N-(p-chlorobenzoyl)-2-(2-cyanoethyl)alanine and 2.0 g of acetic anhydride were dissolved in 30 ml of benzene and the solution was refluxed for one hour. The solvent was then distilled off and the resulting residue was recrystallized from di-isopropyl ether, to afford 2.1 g of the desired product as a colourless powder melting at 97°-98° C.
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][C:13]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:12]2.[I:22]N1C(=O)CCC1=O>ClCCl>[I:22][C:12]1[C:11]2[C:15](=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:21])[CH:8]=[CH:9][CH:10]=2)[NH:14][C:13]=1[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: O=C1CCC(=O)N1I
Reactant: CCOC(=O)c1cc2cccc(-c3ccccc3C)c2[nH]1
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2c(-c3ccccc3C)cccc2c1I
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of EXAMPLE 564A (944 mg, 3.38 mmol) in dichloromethane (10 mL) was added 1-iodopyrrolidine-2,5-dione (798 mg, 3.55 9 mmol). The reaction mixture was stirred at room temperature for 3 hours and directly loaded on a flash column, eluting with hexane first and then with 0-50% hexane in dichloromethane. The title compound was obtained as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[CH:9]=1)[CH:5]=[O:6].[BH4-].[Na+].O>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[C:8]([O:10][Si:11]([C:14]([CH3:15])([CH3:16])[CH3:17])([CH3:13])[CH3:12])[CH:9]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cc(Br)cc(CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Bromo-5-(tert-butyl-dimethyl-silanyloxy)-benzaldehyde (7 g, 22.2 mmol) was dissolved in THF and sodium borohydride (0.92 g; 24.4 mmol) was added. The reaction mixture was stirred at room temperature for 2 h and water was added, and the reaction mixture was partly evaporated to strip off THF. Ethyl acetate was added and the phases separated. The organic phase was washed with water, dried, and evaporated to dryness. Yield: 6.4 g; HPLC-MS: m/z: 317.0 (M+); Rt: 2.37 min.
Reaction SMILES: [OH:1][C@H:2]([C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[CH:3]=[CH2:4].C12BC(CCC1)CCC2.[OH-:30].[Na+].OO>O1CCCC1.O>[OH:30][CH2:4][CH2:3][C@H:2]([OH:1])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][CH:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1
Reactant: [OH-]
Reactant: C=C[C@H](O)[C@H](CC1CCCCC1)NC(=O)OC(C)(C)C
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CCO
Temperature: 50 °C
Yield: 100.4 %

Procedure:
The resultant compound from Example 121 (327.6 mg, 1.16 mmol) in tetrahydrofuran (THF, 2 ml) at 0° C. was treated with 9-borabicyclo(3.3.1)nonane (4.6 ml, 2.2 mmol in THF). After 3 h at room temperature water (0.1 ml) then NaOH (280 mg, 7.0 mmol) in water (1 ml) then 30% H2O2 (0.70 ml, 6.9 mmol) were added and the mixture was heated at 50° C. for 90 min. The mixture was concentrated, dissolved in ethyl acetate, washed with brine, dried over Na2SO4, evaporated and chromatographed on silica gel with 2% methanol in chloroform to give 351.1 mg (100%) of the desired compound as an oil. DCI-MS: (M+H)=302.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClCCCN1CC[S:31]CC1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3([C:22]#[N:23])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:12][CH:11]=2)[CH2:5][CH2:4][S:31][CH2:3][CH2:2]1
Reactant: ClCCCN1CCSCC1
Reactant: N#CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(c2ccc(OCCCN3CCSCC3)cc2)CCOCC1
Yield: 28.5 %

Procedure:
4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]tetrahydro-2H-pyran-4-carbonitrile (750 mg, 3.69 mmol), 4-(3-chloro-propyl)-thiomorpholine (1.06 g, 5.91 mmol), DMF (15 ml) and K2CO3 (2.05 g, 14.83 mmol) were reacted together according to general procedure E. Purification by chromatography on silica, eluant DCM:MeOH:NH3 (96:3:1) provided the title compound (365 mg, 29%) as an off white solid. 1H NMR (400 MHz, CDCl3), δ 7.37 (d, 2H), 6.93 (d, 2H), 4.12-4.04 (m, 2H), 4.01 (t, 2H), 3.89 (td, 2H), 2.77-2.64 (m, 8H), 2.54 (t, 2H), 2.16-1.99 (m, 4H), 1.95 (p, 2H).
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([NH:16][C:17]([C@@H:19]3[CH:24]4[CH2:25][CH2:26][N:21]([CH2:22][CH2:23]4)[CH2:20]3)=[O:18])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:27]1([S:33]([Cl:36])(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>N1C=CC=CC=1>[ClH:36].[C:27]1([S:33]([NH:3][C:4]2[CH:9]=[CH:8][C:7]([C:10]3[CH:11]=[CH:12][C:13]([NH:16][C:17]([C@@H:19]4[CH:24]5[CH2:23][CH2:22][N:21]([CH2:26][CH2:25]5)[CH2:20]4)=[O:18])=[CH:14][CH:15]=3)=[CH:6][CH:5]=2)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: Nc1ccc(-c2ccc(NC(=O)[C@H]3CN4CCC3CC4)cc2)cc1
Reactant: O=S(=O)(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(-c2ccc(NS(=O)(=O)c3ccccc3)cc2)cc1)[C@H]1CN2CCC1CC2

Procedure:
A solution of 80 mg (0.20 mmol) of ((3R)-N-(4′-aminobiphenyl-4-yl)quinuclidine-3-carboxamide dihydrochloride (Example 7A) and 71.7 mg (0.41 mmol) of phenylsulfonyl chloride in 1.0 ml of pyridine is stirred at room temperature for 18 h. The reaction mixture is concentrated in vacuo and the residue is purified by preparative HPLC. The product fractions are concentrated, mixed with 3 ml of 1 N hydrochloric acid, again concentrated and dried under high vacuum. 52 mg (51.5% of theory) of the title compound are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:23])[S:3]([CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([C:15]2[CH2:20][CH2:19][C:18]([CH3:22])([CH3:21])[CH2:17][CH:16]=2)[CH:9]=1)(=[O:5])=[O:4].C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.[K+].[C:49]([C:51]1[N:52]=[C:53]([C:64]([O-])=[O:65])[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=1)#[N:50].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:22][C:18]1([CH3:21])[CH2:19][CH2:20][C:15]([C:10]2[CH:9]=[C:8]([CH2:7][CH2:6][S:3](=[O:4])(=[O:5])[N:2]([CH3:1])[CH3:23])[CH:13]=[CH:12][C:11]=2[NH:14][C:64]([C:53]2[N:54]([CH2:56][O:57][CH2:58][CH2:59][Si:60]([CH3:63])([CH3:62])[CH3:61])[CH:55]=[C:51]([C:49]#[N:50])[N:52]=2)=[O:65])=[CH:16][CH2:17]1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)[O-]
Reactant: CN(C)S(=O)(=O)CCc1ccc(N)c(C2=CCC(C)(C)CC2)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)S(=O)(=O)CCc1ccc(NC(=O)c2nc(C#N)cn2COCC[Si](C)(C)C)c(C2=CCC(C)(C)CC2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
A solution of 215 mg (0.638 mmol) of 2-[4-amino-3-(4,4-dimethyl-cyclohex-1-enyl)-phenyl]-ethanesulfonic acid dimethylamide (as prepared in the previous step) in CH2Cl2 (10 mL) was treated with 446 mg (0.957 mmol) of PyBroP, 214 mg (0.701 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylate potassium salt (as prepared in Example 1, step (d)) and 333 μL (1.91 mmol) of DIEA and stirred at RT for 18 h. The mixture was diluted with CH2Cl2 (20 mL) and washed with water (1×20 mL). The aqueous layer was extracted with CH2Cl2 (1×20 mL). The combined organic layers were dried (MgSO4) and concentrated in vacuo. Silica gel chromatography of the residue on a 50-g Varian MegaBond Elut SPE column with 25% EtOAc-hexane afforded 355 mg (95%) of the title compound as a white solid: Mass spectrum (ESI, m/z): Calcd. for C29H43N5O4SSi, 586.3 (M+H). found 585.9.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:24])[CH:10]([NH:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11](=O)[CH2:12][CH3:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.II.C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:8][C:9]([C:10]1[N:15]=[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:23][C:11]=1[CH2:12][CH3:13])=[O:24])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(=O)C(NC(=O)c1ccccc1)C(=O)OCc1ccccc1
Agent: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1oc(-c2ccccc2)nc1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 83.9 %

Procedure:
A mixture of 2-benzoylamino-4-methyl-3-oxo-butanoic acid benzyl ester (1.26 g, 3.88 mmol), triphenylphosphine (2.64 g, 10.09 mmol), and iodine (1.04 g, 8.225 mmol) in tetrahydrofuran (60 mL) was cooled to −78° C., followed by addition of triethylamine (2.18 mL, 15.52 mmol). The resulting solution was stirred at −78° C. for about 10 min, and then was warmed up to room temperature for about 1 hr. The solvent was removed and the residue was triturated with dichloromethane and filtered. The filtrate was evaporated and the residue dissolved in 70 mL of ethyl acetate, washed with 0.5 M citric acid (2×50 mL), saturated sodium bicarbonate (2×50 mL), and brine, dried over magnesium sulfate, filtered and then concentrated in vacuo. Flash chromatography (Merck silica gel 60, 230-400 mesh, 0-10% ethyl acetate in hexane) gave 5-ethyl-2-phenyl-oxazole-4-carboxylic acid benzyl ester (1 g) as a light yellow solid. LCMS calcd for C19H17NO3 (m/e) 321, obsd 322 (M+H).
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:36](O)=[O:37])=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH:26]=1>>[Cl:20][C:21]1[CH:22]=[CH:23][C:24]2[N:25]([C:27]([C:36]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:37])=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:29]=2)[CH:26]=1
Reactant: O=C(O)c1c(-c2ccccc2)nc2ccc(Cl)cn12
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1c(-c2ccccc2)nc2ccc(Cl)cn12

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 6-Chloro-2-phenyl-imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:23])[F:22])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[CH2:32]([S:35](Cl)(=[O:37])=[O:36])[CH2:33][CH3:34]>C(Cl)Cl>[CH2:32]([S:35]([N:4]1[CH2:3][CH2:2][N:1]([CH2:7][C:8]2[N:12]([C:13]3[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[C:15]([C:21]([F:24])([F:22])[F:23])[CH:14]=3)[N:11]=[N:10][N:9]=2)[CH2:6][CH2:5]1)(=[O:37])=[O:36])[CH2:33][CH3:34]
Reactant: N#Cc1ccc(-n2nnnc2CN2CCNCC2)cc1C(F)(F)F
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCN(Cc2nnnn2-c2ccc(C#N)c(C(F)(F)F)c2)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 93.2 %

Procedure:
4-[5-(1-piperazinylmethyl)-1H-tetrazol-1-yl]-2-(trifluoromethyl)benzonitrile (Example 101, 50 mg, 0.15 mmol) was dissolved in DCM and treated with triethylamine (41 μL, 0.29 mmol) followed by 1-propanesulfonyl chloride (20 μL, 0.18 mmol). The mixture was stirred at ambient temperature under argon for 2.5 hours. The reaction mixture was partitioned between water and DCM (5 mL each) and the layers were separated using a hydrophobic frit. The aqueous layer was extracted with further DCM (2×5 mL). The combined DCM extracts were concentrated in vacuo to give the title compound as a pale cream solid (62 mg).
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.Cl[C:24]1[N:29]=[CH:28][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:26][N:25]=1>O1CCOCC1>[C:10]([O:9][C:7]([N:1]1[CH2:6][CH2:5][N:4]([C:24]2[N:25]=[CH:26][C:27]([C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:28][N:29]=2)[CH2:3][CH2:2]1)=[O:8])([CH3:13])([CH3:12])[CH3:11]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCOC(=O)c1cnc(Cl)nc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl piperazine-1-carboxylate (10.0 g, 53.7 mmol) and diisopropylethylamine (23.4 mL, 134.25 mmol) in dioxane (80 mL) was added ethyl 2-chloropyrimidine-5-carboxylate (10 g, 53.7 mmol), and the reaction mixture was stirred at RT for 3 h. LCMS showed the reaction was completed. The reaction was concentrated to afford the title compound (17 g, crude), which was directly used in the next step without the further purification. MS (ES+) C16H24N4O4 requires: 336. found: 237, 281 [M−56+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([CH2:24]Cl)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:27][C:28]1[CH:35]=[C:32]([CH:33]=O)[C:31]([OH:36])=[CH:30][CH:29]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][N:15]2[CH2:20][CH2:19][N:18]([S:21]([C:24]3[O:36][C:31]4[CH:30]=[CH:29][C:28]([Cl:27])=[CH:35][C:32]=4[CH:33]=3)(=[O:23])=[O:22])[CH2:17][C:16]2=[O:26])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)CCl)CC2=O)CC1
Reactant: O=Cc1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCC(CN2CCN(S(=O)(=O)c3cc4cc(Cl)ccc4o3)CC2=O)CC1
Temperature: 100 °C
Reaction time: 48 h
Yield: 9.1 %

Procedure:
A mixture of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(chloromethanesulfonyl)-2-piperazinone (2.47 g), 5-chlorosalicylaldehyde (917 mg), potassium carbonate (810 mg) and DMF (30 ml) was stirred at 100° C. for 2 days, and the reaction solution was concentrated. To the residue was added water, and the mixture was extracted with ethyl acetate, washed with water and brine, dried and concentrated. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=1:4) to give colorless solid of 1-[1-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-4-(5-chlorobenzofuran-2-sulfonyl)-2-piperazinone (272 mg).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][N:31]1[C:35]2[CH:36]=[CH:37][C:38](B3OC(C)(C)C(C)(C)O3)=[CH:39][C:34]=2[N:33]=[N:32]1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]4[N:31]([CH3:30])[N:32]=[N:33][C:34]=4[CH:39]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cn1nnc2cc(B3OC(C)(C)C(C)(C)O3)ccc21
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)nnn4C)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
To a vial flushed with argon was added (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (100 mg, 0.202 mmol), 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d][1,2,3]triazole (62 mg, 0.24 mmol), Pd(PPh3)4 (23 mg, 20 μmol), and K2CO3 (83 mg, 0.6 mmol). De-gassed dioxane (2 mL) and water (0.5 mL) were then added, and the reaction was heated to 100° C. for 1 h. After cooling to 23° C., the reaction was filtered over a plug of Celite, concentrated, and purified by column chromatography (gradient 0 to 35% EtOAc in hexanes) to give the product. 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.31 (dd, J=8.7, 1.4 Hz, 1H), 7.90 (s, 1H), 7.66-7.44 (m, 5H), 5.17 (s, 1H), 4.33 (s, 3H), 4.26-4.16 (m, 2H), 2.61 (s, 3H), 1.30-1.22 (m, 3H), 0.98 (s, 9H).