Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:10]3[CH:11]=[CH:12][N:13]=[CH:14][C:15]=3[CH:16]=[CH:17][CH:18]=2)[CH:5]=[N:6][CH:7]=1.[C:19](=[NH:32])([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.CC(C)([O-])C.[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:26]1([C:19]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N:32][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([NH:8][C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][N:13]=[CH:14]4)[CH:3]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: Brc1cncc(Nc2cccc3cnccc23)c1
Reactant: N=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: c1ccc(C(=Nc2cncc(Nc3cccc4cnccc34)c2)c2ccccc2)cc1
Yield: 64.6 %

Procedure:
A mixture of Example 23C (175 mg, 0.58 mmol), benzophenone imine (150 mg, 0.83 mmol), Pd2(dba)3 (54 mg, 0.06 mmol), BINAP (55 mg, 0.09 mmol), and sodium tert-butoxide (80 mg, 0.82 mmol) in 3 mL toluene was heated to 75-80° C. for 4 hours and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (150 mg, 64%).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8](=[O:14])[N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:6]=2[CH:5]=[CH:4][CH:3]=1.[CH3:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[C:26](I)[C:25]([C:29]([F:32])([F:31])[F:30])=[CH:24][N:23]=2)[C:18]([CH3:33])=[N:17]1>>[CH3:15][N:16]1[CH:20]=[C:19]([NH:21][C:22]2[CH:27]=[C:26]([NH:1][C:2]3[C:7]4[C:8](=[O:14])[N:9]([CH3:13])[CH2:10][CH2:11][O:12][C:6]=4[CH:5]=[CH:4][CH:3]=3)[C:25]([C:29]([F:31])([F:30])[F:32])=[CH:24][N:23]=2)[C:18]([CH3:33])=[N:17]1
Reactant: Cc1nn(C)cc1Nc1cc(I)c(C(F)(F)F)cn1
Reactant: CN1CCOc2cccc(N)c2C1=O
Product: Cc1nn(C)cc1Nc1cc(Nc2cccc3c2C(=O)N(C)CCO3)c(C(F)(F)F)cn1
Yield: 54.6 %

Procedure:
6-Amino-4-methyl-2,3-dihydro-1,4-benzoxazepin-5-one (151 mg, 0.79 mmol, see Example 3.22) and N-(1,3-dimethylpyrazol-4-yl)-4-iodo-5-(trifluoromethyl)pyridin-2-amine (150 mg, 0.39 mmol) were reacted using the procedure in Example 5.02. The reaction mixture was purified by preparative HPLC using a Waters X-Bridge reverse-phase column (C-18, 5 microns silica, 19 mm diameter, 100 mm length, flow rate of 40 ml/minute) and decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent, followed by flash chromatography on silica gel eluting with 0 to 5% MeOH in EtOAc/DCM (1:1). The solvent was evaporated to dryness and triturated in a mixture of 30% tBuOMe in pentane to give the title compounds as a light white foam (95 mg, 54%). 1H NMR spectrum (500 MHz, CDCl3): 2.15 (s, 3H), 3.21 (s, 3H), 3.50 (t, 2H), 3.81 (s, 3H), 4.35 (t, 2H), 6.19 (s, 1H), 6.30 (s, 1H), 6.70 (dd, 1H), 7.19 (dd, 1H), 7.23 (dd, 1H), 7.38 (s, 1H), 8.20 (s, 1H), 9.21 (s, 1H); Mass spectrum: ESI+ MH+ 447.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[Cl:17])=[C:6]([CH3:18])[N:5]=[C:4]([N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[N:3]=1.[K].[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH2:39])(=[O:38])=[O:37])=[CH:32][CH:31]=1)([CH3:29])([CH3:28])[CH3:27]>CS(C)=O>[C:26]([C:30]1[CH:35]=[CH:34][C:33]([S:36]([NH:39][C:2]2[C:7]([O:8][C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[Cl:17])=[C:6]([CH3:18])[N:5]=[C:4]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)[N:3]=2)(=[O:37])=[O:38])=[CH:32][CH:31]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1ccc(S(N)(=O)=O)cc1
Reactant: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2Cl)c1
Agent: [K]
Solvent: CS(C)=O
Product: COc1ccc(Cl)c(Oc2c(C)nc(N3CCOCC3)nc2NS(=O)(=O)c2ccc(C(C)(C)C)cc2)c1
Yield: 93 %

Procedure:
10.7 g of 4-[4-chloro-5-(2-chloro-5-methoxy-phenoxy)-6-methyl-pyrimidin-2-yl]-morpholine and 21.6g of p-t-butyl-benzene sulphonamide potassium in 150 ml of dry dimethyl sulphoxide were heated to 120° C. under argon for 16 hours. Thereafter, the dimethylsulphoxide was distilled off, the residue was partitioned between ethyl acetate and 1N hydrochloric acid and the organic phase was washed neutral. The organic phase was dried, the solvent was evaporated and the residue was recrystallized from dichloromethane-ethanol. There were obtained 14.7 g 4-tert-butyl-N-[5-(2-chloro-5-methoxy-phenoxy)-6-methyl-2-(morpholin-4-yl)-pyrimidin-4-yl]-benzenesulphonamide, m.p 154° C., MS: M=546.
Reaction SMILES: [CH2:1]=[C:2]1[O:6][C:4](=[O:5])[CH2:3]1.[CH3:7][O:8][CH:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:11]>>[C:4]([O:11][CH2:10][CH:9]([O:8][CH3:7])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])[CH2:3][C:2]([CH3:1])=[O:6]
Reactant: COC(CO)c1ccccc1
Reactant: C=C1CC(=O)O1
Product: COC(COC(=O)CC(C)=O)c1ccccc1

Procedure:
In a similar manner, diketene was reacted with (±)-2-methoxy-2-phenylethanol to obtain 2-methoxy-2-phenylethyl acetoacetate, BP 115°-120° C./0.2 mm.
Reaction SMILES: [CH3:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[CH:5][N:4]([C:10]([C:13]2[NH:17][CH:16]=[N:15][N:14]=2)([CH3:12])[CH3:11])[N:3]=1.Br[CH:19]([CH3:21])[CH3:20].C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.O>[CH:19]([C:13]1([C:10]([N:4]2[CH:5]=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([CH3:1])=[N:3]2)([CH3:12])[CH3:11])[N:17]=[CH:16][NH:15][NH:14]1)([CH3:21])[CH3:20]
Reactant: CC(C)Br
Reactant: Cc1nn(C(C)(C)c2nnc[nH]2)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: Cc1nn(C(C)(C)C2(C(C)C)N=CNN2)cc1[N+](=O)[O-]
Temperature: 50 °C
Reaction time: 8 h
Yield: 68.8 %

Procedure:
To a solution of 3-(2-(3-methyl-4-nitro-1H-pyrazol-1-yl)propan-2-yl)-4H-1,2,4-triazole (1.3 g, 5.5 mmol) in CH3CN (30 mL) was added 2-bromopropane (813 mg, 6.60 mmol) and Cs2CO3 (1.79 g, 5.50 mmol). The mixture was stirred at 50° C. overnight. After cooling down, the mixture was diluted with water and extracted with ethyl acetate. The organic layer was concentrated to afford the title compound (1.06 g, 70%). LC-MS (ESI): m/z=279 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)[N:3]=1.[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH2:24]>>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:26])=[C:23]([CH:25]=1)[NH:24][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)[N:3]=1
Reactant: COCc1cc(Cl)nc(-c2csc(C)n2)n1
Reactant: COc1ccc(C)c(N)c1
Product: COCc1cc(Nc2cc(OC)ccc2C)nc(-c2csc(C)n2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine (50 mg, 0.196 mmol) and 5-methoxy-2-methylaniline (27 mg, 0.196 mmol) similar to Example 13 and isolated as a tan oil (42 mg, 60%). 1H NMR (CDCl3): 8.12 (s, 1H), 7.19 (d, J=8.4 Hz, 1H), 6.99 (d, J=2.4 Hz, 1H), 6.89 (s, 1H), 6.75 (dd, J=3.0, 8.7 Hz, 1H), 6.56 (s, 1H), 4.50 (s, 2H), 3.80 (s, 3H), 3.44 (s, 3H), 2.83 (s, 3H), 2.21 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](=O)[C:2]1=O.[NH2:12][NH:13][C:14]([NH2:16])=[S:15].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>O>[NH:16]1[C:2]2[NH:1][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[N:12]=[N:13][C:14]1=[S:15]
Reactant: O=C1Nc2ccccc2C1=O
Reactant: NNC(N)=S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: S=c1nnc2c([nH]1)[nH]c1ccccc12
Temperature: 25 °C

Procedure:
To a solution of indole-2,3-dione 14b (74 mmol, 1 equiv.) in water (600 mL) is added thiosemicarbazide 14a (81.4 mmol, 1.1 equiv.) and potassium carbonate (11 mmol, 1.5 equiv.) as disclosed in Gladych, J. M. Z.; Hornby, R.; Hunt, J. H.; Jack, D.; Boyle, J. J.; Ferlauto, R. J.; Haff, R. F.; Kornendy, C. G; Standfield, F. J.; Stewart, R. C. J. Med. Chem. 1972, 15, 277-281 and references cited therein. The solution is stirred and refluxed for 7 hours. The red-orange solution is allowed to cool to room temperature overnight. The solution is acidified with acetic acid, and a yellow precipitate forms. The precipitate is filtered and washed with water, and dried under vacuum for 15 hours to yield 1,9-Dihydro-1,3,4,9-tetraaza-fluorene-2-thione 14c as a yellow powder.
Reaction SMILES: [NH4+].[N:2]([C@H:5]1[CH2:10][C@H:9]([OH:11])[C@@H:8]([CH2:12][O:13][P:14]([OH:17])([OH:16])=[O:15])[O:7][CH2:6]1)=[N+:3]=[N-:4].[N:18]([C@H]1[C@H](O)[C@H](O)[C@@H](CO)[O:23]C1)=[N+]=[N-]>>[NH4+:2].[NH4+:18].[N:2]([C@H:5]1[C@H:10]([OH:23])[C@H:9]([OH:11])[C@@H:8]([CH2:12][O:13][P:14]([OH:17])([OH:16])=[O:15])[O:7][CH2:6]1)=[N+:3]=[N-:4]
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](COP(=O)(O)O)[C@@H](O)C1
Reactant: [N-]=[N+]=N[C@@H]1CO[C@H](CO)[C@@H](O)[C@H]1O
Agent: [NH4+]
Product: [N-]=[N+]=N[C@@H]1CO[C@H](COP(=O)(O)O)[C@@H](O)[C@H]1O

Procedure:
Phosphate 12 is prepared similarly to phosphate 5 starting from azide 11 (0.503 g, 2.66 mmol). Coarse purification by column chromatography and silica gel (0.35% ammonia (20% aqueous solution in i-PrOH) pale yellow oil 12 (0.353 g, 46%). Rf 0.4 (i-PrOH/25%-NH4OHaq/H2O 6/4/1). This product is used without further purification.
Reaction SMILES: [C:1]([S:4][CH2:5][C@H:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7](O)=[O:8])(=[O:3])[CH3:2].S(Cl)([Cl:19])=O>>[C:1]([S:4][CH2:5][CH:6]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:7]([Cl:19])=[O:8])(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)SC[C@H](Cc1ccccc1)C(=O)O
Product: CC(=O)SCC(Cc1ccccc1)C(=O)Cl

Procedure:
2.0 g (8.40 mmol) of (R)-2-acetylthiomethyl-3-phenylpropanoic acid (Ia R) (Example 1, stage e) are placed in a round-bottomed flask. The flask is cooled by an ice-water bath and 1.2 g (10.08 mmol) of thionyl chloride are added dropwise. The mixture is stirred overnight to room temperature.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[N:13]=[C:12]1[CH:20]([O:24][CH3:25])[C:21](O)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH2:28]([O:35][C:36](=[O:48])[NH:37][C:38]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][NH2:47])=[CH:42][CH:41]=1)=[NH:39])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([O:35][C:36](=[O:48])/[N:37]=[C:38](\[NH2:39])/[C:40]1[CH:41]=[CH:42][C:43]([CH2:46][NH:47][C:21](=[O:22])[CH:20]([C:12]2[N:11]([CH2:10][CH2:9][O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]=2)[O:24][CH3:25])=[CH:44][CH:45]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: N=C(NC(=O)OCc1ccccc1)c1ccc(CN)cc1
Reactant: COC(C(=O)O)c1nc2ccccc2n1CCOCc1ccccc1
Agent: Cl
Product: COC(C(=O)NCc1ccc(/C(N)=N/C(=O)OCc2ccccc2)cc1)c1nc2ccccc2n1CCOCc1ccccc1

Procedure:
According to general procedure C, (RS)-[1-(2-benzyloxy-ethyl)-1H-benzoimidazol-2-yl]-methoxy-acetic acid was reacted with [(4-aminomethyl-phenyl)-imino-methyl]-carbamic acid benzyl ester dihydrochloride (CAS 172348-75-3) to give (RS)-[1-amino-1-[4-({2-[1-(2-benzyloxy-ethyl)-1H-benzoimidazol-2-yl]-2-methoxy-acetylamino}-methyl)-phenyl]-meth-(Z)-ylidene]-carbamic acid benzyl ester. Off-white gum.
Reaction SMILES: [OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:3]1.S(OC)(O[CH3:22])(=O)=O>CC(O)=O.O=[Pt]=O.[Pd]>[OH:1][CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][N:13]2[CH3:22])[CH2:3]1
Reactant: COS(=O)(=O)OC
Reactant: OC1Cc2ccccc2C(c2ccccn2)C1
Agent: O=[Pt]=O
Agent: [Pd]
Solvent: CC(=O)O
Product: CN1CCCCC1C1CC(O)Cc2ccccc21

Procedure:
The 2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)-pyridine thus obtained is quaternized with dimethyl sulfate on the steam bath neat. After several hours, the salt is dissolved in HOAc and reduced over a mixture of PtO2 and Pd/C to yield 2-(3-hydroxy-1,2,3,4-tetrahydronaphthalenyl)-1-methyl piperidine.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>CO>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[N:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C:13]1=[O:18])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(N2CCCCC2=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C(=O)O)ccc1N1CCCCC1=O

Procedure:
Prepared analogously to Example 2d from methyl 3-methyl-4-(piperidin-2-on-1-yl)benzoate and 1-molar sodium hydroxide solution in methanol.
Reaction SMILES: [C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=C(O)C(O)=O)([CH3:4])([CH3:3])[CH3:2].CC(C)=[O:18]>O=[Mn]=O>[C:1]([C:5]1[O:9][CH:8]=[N:7][C:6]=1[CH:10]=[O:18])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)c1ocnc1C=C(O)C(=O)O
Reactant: CC(C)=O
Agent: O=[Mn]=O
Product: CC(C)(C)c1ocnc1C=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of oxazole alcohol 3 (9.9 g, 64 mmol) in acetone (200 mL, Aldrich, Cat. No. 179124) was added MnO2 (27.7 g, 319 mmol, 5 equiv., Wako Pure Chemical, Osaka, Japan, Cat. No. 138-09675), and the mixture was stirred at room temperature overnight. After celite filtration to remove MnO2, the solvent was removed by evaporation, and the residual pale brown oil was dissolved in CHCl3 and applied to silica-gel column chromatography (prepared with CHCl3), then eluted with CHCl3:MeOH (100:1 to 50:1), to give an pale yellow oil of aldehyde 4 (5.54 g, 57% (38% in two steps)). Rf 0.65 (CHCl3:MeOH=10:0.5), 1H NMR (300 MHz CDCl3) δ 10.10 (s, 1H), 7.77 (s, 1H), 1.47 (s, 9H); HRMS (EI): m/z 153.0794 (M+) (Calcd for C8H11NO2: 153.0790).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].C(Cl)(=O)[C:14](Cl)=[O:15]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([N:6]=[C:14]=[O:15])=[O:5]
Reactant: NC(=O)c1cc(F)c(F)cc1Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: O=C=NC(=O)c1cc(F)c(F)cc1Cl

Procedure:
2-Chloro-4,5-difluorobenzamide was dissolved in dichloromethane, admixed with 1.5 eq. of oxalyl chloride and heated to reflux for 16 hours. The reaction mixture was concentrated under high vacuum and reacted in stage b without further purification.
Reaction SMILES: [N:1]1([C:6]([C:8]2[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][C:9]=2[CH3:17])=[O:7])[CH2:5][CH:4]=[CH:3][CH2:2]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)CC)(C)C.[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH2:59])[CH3:58])=[N:56][C:52]=2[CH:51]=1.ClCl>O1CCCC1.ClCCl.C(O)C>[Cl:49][C:50]1[CH:61]=[CH:60][C:53]2[NH:54][C:55]([C@@H:57]([NH:59][C:12](=[O:14])[C:11]3[CH:15]=[CH:16][C:8]([C:6]([N:1]4[CH2:2][CH:3]=[CH:4][CH2:5]4)=[O:7])=[C:9]([CH3:17])[CH:10]=3)[CH3:58])=[N:56][C:52]=2[CH:51]=1
Reactant: C[C@H](N)c1nc2cc(Cl)ccc2[nH]1
Reactant: Cc1cc(C(=O)O)ccc1C(=O)N1CC=CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: ClCl
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)N[C@@H](C)c2nc3cc(Cl)ccc3[nH]2)ccc1C(=O)N1CC=CC1
Yield: 96 %

Procedure:
Prepared analogously to Example 1g from 4-(2,5-dihydropyrrol-1-ylcarbonyl)-3-methylbenzoic acid, TBTU, diisopropylethylamine, and (1S)-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine in tetrahydrofuran. Yield: 96%; Rf value: 0.50 (silica gel: dichloromethane/ethanol=9:1); C22H21ClN4O2 (408.887); mass spectrum: (M+H)+=409/411 (chlorine isotope).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]([Cl:13])[C:3]=1[O:4][CH2:5][CH2:6]Cl.[CH2:14]([NH2:17])[CH2:15][CH3:16]>O>[CH2:14]([NH:17][CH2:6][CH2:5][O:4][C:3]1[C:2]([Cl:1])=[CH:11][C:10]([Cl:12])=[CH:9][C:8]=1[Cl:13])[CH2:15][CH3:16]
Reactant: CCCN
Reactant: ClCCOc1c(Cl)cc(Cl)cc1Cl
Solvent: O
Product: CCCNCCOc1c(Cl)cc(Cl)cc1Cl

Procedure:
N-n-propyl-N-2-(2,4,6-trichlorophenoxy)-ethylamine is prepared by selectively chlorinating 2-phenoxy ethanol by reacting it with chlorine either in the presence of hydrogen chloride at a temperature of from -10° C. to 50° C. or in the presence of urea at a temperature of from 20° C. to 55° C. in a water/carbon tetrachloride solvent mixture to form 2-(2,4,6-trichlorophenoxy)ethanol; reacting the 2-(2,4,6-trichlorophenoxy)ethanol with thionyl chloride in the presence of a catalytic amount of tetraalkyl ammonium chloride, optionally in the presence of a solvent to form 2-(2,4,6-trichlorophenoxy)ethyl chloride; and reacting the 2-(2,4,6-trichlorophenoxy) ethyl chloride with n-propylamine at a temperature of from 20° C. to 150° C., optionally in the presence of water to form N-n-propyl-N-2-(2,4,6-trichlorophenoxy) ethyl amine.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br>C(#N)C>[CH2:4]([CH:3]([C:11]1[CH:12]=[C:13]([OH:17])[CH:14]=[CH:15][CH:16]=1)[CH2:2][N:1]1[CH2:29][CH2:28][CH2:27][CH2:26]1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NCC(Cc1ccccc1)c1cccc(O)c1
Reactant: BrCCCCBr
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Oc1cccc(C(Cc2ccccc2)CN2CCCC2)c1

Procedure:
To 3-(1-amino-3-phenylpropan-2-yl)phenol (0.6 g, 2.6 mmol) dissolved in 40 ml acetonitrile was added triethylamine (0.81 ml, 5.8 mmol) followed by 1,4-dibromobutane (0.37 ml, 3.2 mmol). The mixture was heated to reflux for 3 h then poured on ice-water and extracted twice with dichloromethane. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered and the solvent evaporated to obtain a yellow oil. m=665 mg (90%)
Reaction SMILES: [C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22](Br)=[C:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][CH:6]1[O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2].C1(P([CH:54]2[CH2:59][CH2:58]CCC2)C2CCCCC2)CCCCC1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C1(B(O)O)CC1>C1(C)C=CC=CC=1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:1]([O:4][C@H:5]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@H:8]([C:19]2[CH:24]=[CH:23][C:22]([CH:58]3[CH2:59][CH2:54]3)=[C:21]([CH2:26][C:27]3[CH:36]=[CH:35][C:30]4[O:31][CH2:32][CH2:33][O:34][C:29]=4[CH:28]=3)[CH:20]=2)[O:7][CH:6]1[O:37][C:38](=[O:40])[CH3:39])(=[O:3])[CH3:2]
Reactant: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Reactant: CC(=O)OC1O[C@@H](c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(=O)OC1O[C@@H](c2ccc(C3CC3)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 181.2 %

Procedure:
Step-IX: To a stirred solution of acetic acid (3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-yl ester (2.75 g, 4.4 mmol) in toluene (25 ml) was added tricyclohexylphosphine (495 mg, 1.8 mmol), a solution of potassium phosphate tribasic (3.75 g, 1.8 mmol) in water (5 ml), cyclopropylboronic acid (1.14 g, 13.2 mmol). The reaction mixture was degassed for 45 min then added palladium (II) acetate (148 mg, 0.7 mmol). Reaction mixture was stirred at 90° C. for overnight. Reaction mixture was cooled to room temperature and was filtered through celite bed, washed with ethyl acetate (25 ml). Organic layer was washed with water (25 ml) followed by brine (25 ml), dried over sodium sulfate, concentrated and purified by column chromatography to give 1.9 g of acetic acid (3S,4R,5S,6S)-3,4,5-triacetoxy-6-[4-cyclopropyl-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-tetrahydro-pyran-2-yl ester. MS (ES) m/z 600.3 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH:27]C(=O)OC(C)(C)C)[CH2:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[N:22][CH:21]=[CH:20]4)[CH:14]=[N:13]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C@H:9]([NH2:27])[CH2:10][CH2:11][N:12]2[CH:16]=[C:15]([C:17]3[CH:18]=[C:19]4[C:24](=[CH:25][CH:26]=3)[CH:23]=[N:22][CH:21]=[CH:20]4)[CH:14]=[N:13]2)=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@H](CCn1cc(-c2ccc3cnccc3c2)cn1)Cc1ccc(Cl)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H](CCn1cc(-c2ccc3cnccc3c2)cn1)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
A mixture of tert-butyl(S)-1-(4-chlorophenyl)-4-(4-(isoquinolin-6-yl)-1H-pyrazol-1-yl)butan-2-ylcarbamate (320 mg, 0.67 mmol) and TFA (5.00 mL, 64 mmol) in DCM (5 mL) was stirred at room temperature for 2 hours. After concentration by vacuum distillation, the residue was purified by reverse-phase HPLC (Phenomenex Synergi 4m Max RP 80 A column, 150×21 mm, 20 mL/min, 10-95% CH3CN/H2O, 0.1% TFA, 10.5 minute gradient) to give the product as an off-white solid (165 mg, 65%). HRMS (TOF) Calcd for C22H22ClN4+: 377.1535, found: 377.1531.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.C([Li])CCC.[B:17](OC)([O:20]C)[O:18]C.Cl.[OH-].[Na+]>C1COCC1>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[CH:4]=[C:3]1[B:17]([OH:20])[OH:18]
Reactant: Cc1ccc2c(ccn2C)c1
Reactant: COB(OC)OC
Agent: Cl
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)cc(B(O)O)n2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 11.9 %

Procedure:
To a 0° C. solution of 1,5-dimethyl-1H-indole (1.10 g, 7.58 mmol) and THF (15 mL) is added 1.6M n-Bu—Li (5.7 mL, 9.09 mmol) the solution is warmed to ambient temperature and stirred for 1 h. The solution is cooled to 0° C. and B(OMe)3 (1.01 mL, 9.09 mmol) is added. The solution is warmed to ambient temperature and stirred overnight. 1M HCl (20 mL) is added and the pH adjusted to 7 with 1M NaOH. The aqueous phase is extracted with EtOAc (2×30 mL). The combined organic layers are washed with brine, dried over MgSO4, filtered and concentrated. The solids are triturated with hexane, and recrystallized from toluene/hexane to furnish the title compound (0.17 g, 0.90 mmol, 12%). 1H NMR (CDCl3), δ 2.38 (s, 3H), 4.08 (s, 3H), 6.91 (s, 1H), 6.99 (d, J=8.9 Hz, 1H), 7.29-7.38 (m, 2H) ppm. LC/MS (m/z): calcd. for C10H12BNO2 (M+H)+: 190.1. found: 146.1.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1)(=[O:13])=[O:12].Cl[C:21]1[C:26]([C:27]#[N:28])=[CH:25][CH:24]=[CH:23][N:22]=1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([CH:14]1[CH2:19][CH2:18][N:17]([C:21]2[N:22]=[CH:23][CH:24]=[CH:25][C:26]=2[C:27]#[N:28])[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: N#Cc1cccnc1Cl
Reactant: O=S(=O)(c1ccc2ccccc2c1)C1CCNCC1
Product: N#Cc1cccnc1N1CCC(S(=O)(=O)c2ccc3ccccc3c2)CC1
Yield: 78.4 %

Procedure:
Using the procedure from Example 7A, Step 7E, 4-(2-naphthylsulfonyl)piperidine (Example 11, Step 3, 130 mg, 0.51 mmol) was reacted with 2-chloro-3-cyanopyridine (139 mg, 1.0 mmol) to afford the title compound (151 mg), a white solid, in 78% yield.