Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:33])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:23]([C:26]2[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[C:14]2[CH:22]=[CH:21][C:17]([C:18]([OH:20])=O)=[CH:16][CH:15]=2)=[C:6]([NH2:8])[N:7]=1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.Cl.[NH2:60][C@H:61]([C:69]([O:71][CH2:72][CH3:73])=[O:70])[CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65].CN1CCOCC1>ClCCl.CN(C)C=O.C(O)(=O)C>[NH2:1][C:2]1[NH:3][C:4](=[O:33])[C:5]([CH2:9][CH2:10][CH2:11][CH2:12][N:13]([S:23]([C:26]2[CH:27]=[CH:28][C:29]([CH3:30])=[CH:31][CH:32]=2)(=[O:25])=[O:24])[C:14]2[CH:15]=[CH:16][C:17]([C:18]([NH:60][C@H:61]([C:69]([O:71][CH2:72][CH3:73])=[O:70])[CH2:62][CH2:63][C:64]([O:66][CH2:67][CH3:68])=[O:65])=[O:20])=[CH:21][CH:22]=2)=[C:6]([NH2:8])[N:7]=1
Reactant: CCOC(=O)CC[C@H](N)C(=O)OCC
Reactant: Cc1ccc(S(=O)(=O)N(CCCCc2c(N)nc(N)[nH]c2=O)c2ccc(C(=O)O)cc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCOC(=O)CC[C@H](NC(=O)c1ccc(N(CCCCc2c(N)nc(N)[nH]c2=O)S(=O)(=O)c2ccc(C)cc2)cc1)C(=O)OCC
Reaction time: 0.28 h

Procedure:
To a stirred mixture of 1.00 g (0.00209 mol) of 4-[[4-(2,4-diamino-1,6-dihydro-6-oxo-5-pyrimidinyl)butyl]tosylamino]benzoic acid.0.13 acetic acid in 6 mL of dry dichloromethane and 6 mL of dry dimethylformamide under nitrogen was added 0.433 g (0.00313 mol) of 1-hydroxybenzotriazole. After 17 min, to the mixture was added 0.646 g (0.00313 mol) of 1,3-dicyclohexylcarbodiimide and then 6 mL more dry dimethylformamide and 6 mL more dry dichloromethane. After 1 h 6 min, to the mixture was added a cloudy solution of 0.750 g (0.00313 mol) of diethyl glutamate hydrochloride and 0.633 g (0.00626 mol) of 4-methylmorpholine in 6 mL of dry dichloromethane and 6 mL of dry dimethylformamide. The mixture was stirred under nitrogen for 59 h 20 min, and to it was added 0.431 g (0.00209 mol) of 1,3-dicyclohexylcarbodiimide. The mixture was stirred for 17 h 15 min and was concentrated under vacuum at 33° C. to a residue to which was added 25 mL of methanol. Undissolved white solid was collected by suction filtration, and the filtrate was purified by a flash chromatography column consisting of 175 g of Silica Gel 60 with 8:1 ethyl acetate/methanol as the eluting solvent. Major fractions containing product were combined and concentrated under vacuum to an off-white solid; yield, 0.74 g (~50%): NMR (Me2SOd6) δ 1.14 (t, 3H), 1.17 (t, 3H), 1.2-1.4 (m, 4H), 1.9-2.2 (m, 4H), 2.37 (s, 3H) 2.4 (t, 2H), 3.55 (t, 2H), 4.03 (q, 2H), 4.10 (q, 2H), 4.41 (m, 1H), 5.58 (br s, 2H), 5.85 (br s, 2H), 7.15 (d, 2H), 7.3-7.5 (AA'BB', 4H), 7.81 (d, 2H), 8.75 (d, 1H), 9.68 (br s, 1H), 0.12 mol of dimethylformamide, 0.1 mol of an impurity containing a CONHCH moiety.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]=O)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2].[CH3:30][N:31]([CH:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)[CH:32]1[CH2:36][CH2:35][O:34][CH2:33]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH2:18][N:40]4[CH2:39][CH2:38][CH:37]([N:31]([CH3:30])[CH:32]5[CH2:36][CH2:35][O:34][CH2:33]5)[CH2:42][CH2:41]4)[N:14]3[CH3:17])=[C:10]([N:20]3[CH2:25][CH2:24][O:23][CH2:22][CH2:21]3)[N:9]=2)[C:6]2[CH:26]=[CH:27][CH:28]=[CH:29][C:5]=2[N:4]=1)[CH3:2]
Reactant: CN(C1CCNCC1)C1CCOC1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C=O)n(C)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(N(C)C4CCOC4)CC3)n(C)c2n1
Reaction time: 16 h

Procedure:
A mixture of 2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine-8-carbaldehyde (72 g, 0.19 mmol), methylpiperidin-4-yl(tetrahydrofuran-3-yl)amine (42 mg, 0.23 mmol) and 4 Å powdered molecular sieves (200 mg) in DCE (5 mL) was stirred at room temperature for 6.5 h before the addition of sodium triacetoxyborohydride (81 mg, 0.38 mmol). The reaction mixture was stirred for 16 h then filtered through celite, washing with DCM. The organic phase was washed with brine (x 1) and concentrated in vacuo. The organic phase was dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, MeOH:EtOAc, 0-20%). The resulting oil was loaded onto an Isolute® SCX-2 cartridge which was washed with MeOH/DCM and the product eluted with 2M NH3/MeOH affording 390 as a cream solid (55 mg, 53%). LCMS (Method G): RT 4.96 min [M+H]+ 546.3. 1H NMR (CDCl3, 400 MHz): δ 8.03-7.99 (m, 1 H); 7.77-7.73 (m, 1 H); 7.29-7.23 (m, 2 H); 4.34 (m, 4 H); 3.96 (m, 1 H); 3.91-3.69 (m, 12 H); 3.45-3.26 (m, 3 H); 2.97 (d, J=11.3 Hz, 2 H); 2.51 (m, 1 H); 2.26 (s, 3 H); 2.16 (t, J=11.3 Hz, 2 H); 2.03 (m, 1 H); 1.89 (m, 2 H); 1.76 (s, 2 H); 1.66 (m, 1 H) and 1.45 (t, J=7.5 Hz, 3 H)
Reaction SMILES: [S:1]1[C:5]2[S:6](=[O:10])(=[O:9])[CH2:7][CH2:8][C:4]=2[CH:3]=[C:2]1C(O)=O>N1C2C(=CC=CC=2)C=CC=1.C(OCC)(=O)C.[Cu]>[S:6]1(=[O:10])(=[O:9])[C:5]2[S:1][CH:2]=[CH:3][C:4]=2[CH2:8][CH2:7]1
Reactant: O=C(O)c1cc2c(s1)S(=O)(=O)CC2
Agent: [Cu]
Solvent: c1ccc2ncccc2c1
Solvent: CCOC(C)=O
Product: O=S1(=O)CCc2ccsc21
Temperature: 180 °C
Yield: 94.7 %

Procedure:
Copper dust (13.4 g. 0.20 mol) was added to a solution of 4,5-dihydrothieno[2,3-b]thiophene-2-carboxylic acid-6,6-dioxide (45 g, 0.20 mol) in quinoline (500 mL) in a reaction vessel fitted with an efficient condenser. The well stirred reaction mixture was heated to 180° C. for 1.5 hours under a nitrogen atmosphere. The dark solution was cooled to room temperature and diluted with ethyl acetate (2 L). The solution was washed with 6N HCl, water, saturated sodium bicarbonate, and saturated brine. The organic phase was dried over magnesium sulfate and treated with decolorizing carbon. Filtration and evaporation of solvent gave the title compound as a solid (33 g, 95%).
Reaction SMILES: [CH:1]1([NH:9][C:10](=S)[NH:11][NH2:12])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:14][CH:15]([C:21]([CH3:23])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].Cl>C(O)C>[ClH:14].[CH:1]1([NH:9][C:10]2[C:15]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:21]([CH3:23])[NH:12][N:11]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C(Cl)C(C)=O
Reactant: NNC(=S)NC1CCCCCCC1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(NC2CCCCCCC2)n[nH]c1C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.9 %

Procedure:
A stirred slurry of 18.7 g (0.093 mole) of 4-cyclooctyl-3-thiosemicarbazide in 150 mL of absolute ethanol under nitrogen atmosphere was treated with 16.5 g (0.1 mole) of ethyl 2-chloroacetoacetate, stirred at ambient temperature for 1.5 hr, treated with 50 mL of 2N ethanolic hydrogen chloride and heated at reflux for ~16 hr. The yellow-brown reaction mixture was filtered and concentrated in vacuo to a dark oil which solidified. Trituration of the crude product with warm acetone removed most of the color to give 17.9 g of product. Recrystallization from methyl ethyl ketone/isopropyl ether followed by recrystallization from methyl ethyl ketone gave 7.1 g of crystalline product, mp 161°-166° C. which was dried at 82° C. under reduced pressure for 3 hr (mp, 168°-171° C.).
Reaction SMILES: [N:1]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:2]=1[C:3]([O:5][C:6]2=[O:11])=[O:4].[Al+3].[Cl-].[Cl-].[Cl-].[CH:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[C:6]([C:7]1[C:2]([C:3]([OH:5])=[O:4])=[N:1][CH:10]=[CH:9][CH:8]=1)(=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2ncccc21
Reactant: c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: O=C(c1ccccc1)c1cccnc1C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
10 g (67 mmol) quinolinic acid anhydride was suspended in 50 ml benzene and 17.9 g (134 mmol) AlCl3 was added in portions while cooling on ice. After completion of the addition, it was stirred for a further 3 hours at room temperature, carefully admixed with ice and aspirated from the precipitate which was present. The crude product was purified by column chromatography on silica gel 60 using ethyl acetate/dichloromethane 1/1 as the eluent.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]#[N:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2].Cl.[CH2:14]([NH:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)[CH3:15]>>[CH2:1]([C:3]1[CH:4]=[C:5]([N:9]([CH3:12])[C:10]([N:16]([CH2:14][CH3:15])[C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)=[NH:11])[CH:6]=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCc1cccc(N(C)C#N)c1
Reactant: CCNc1cccc2ccccc12
Agent: Cl
Product: CCc1cccc(N(C)C(=N)N(CC)c2cccc3ccccc23)c1
Reaction time: 14 h
Yield: 71 %

Procedure:
In a 5 ml round bottom flask was placed N-(3-ethylphenyl)-N-methylcyanamide (626 mg, 3.91 mmol), N-ethyl-N-(1naphthyl)amine hydrochloride (859 mg, 4.15 mmol) and a stir bar. The flask was evacuated via aspirator and flushed with N2. This was immediately placed in a preheated 160° C. oil bath and allowed to stir under N2 for 14 h. The resultant brown glass was dissolved in methanol (6 ml) and diluted with hot distilled water (20 ml). This solution was basified with 0.1N NaOH (25 ml) and extracted with CHCl3 (5×20 ml) to yield a brownish green oil (920 mg). A TLC of this oil showed a mixture of reactants and product. Reactants were eluted by column chromatography with benzene. The product was eluted with benzene/EtOH 20:1 (TLC Rf =0.064, CHCl3 :EtOH, 1:1) to afford a pale greenish viscous oil, 460 mg (35.5%). IR (neat) 3484, 3394 (--NH), 1635 (--C=NH). 1H-NMR (CDCl3) δ 1.00 (t, 3H, J=7.5), 1.14 (t, 3H, J=6.6), 2.32 (q, 2H, J=7.5), 2.91 (s, 3H), 3.72 (q, 2H, J=6.6), 5.62 (s, 1H), 6.34-7.73 (m, 11H, H-aromat). 13C-NMR (CDCl3) CN3, 162.2; Ar, 145.9, 144.0, 140.3, 133.7, 130.3, 127.9, 127.5, 125.5, 125.1, 125.0, 124.5, 124.4, 122.7, 122.6, 122.4, 120.4; NCH2, 46.2; NCH3, 39.1; CH2, 27.9; CH3, 14.8; CH3, 12.5. Mass Spec. m/e calcd for C22H25N3, 331.2048, Found, 331.2046.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC1C=CC(S(O[CH2:18][C:19]2([OH:36])[C:23](=[O:24])[O:22][C@H:21]3[C:25]4[C@@:30]([CH3:33])([CH2:31][CH2:32][C:20]23[OH:35])[CH2:29][CH2:28][CH2:27][C:26]=4[CH3:34])(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[OH:36][C:19]1([CH2:18][N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[C:23](=[O:24])[O:22][C@H:21]2[C:25]3[C@@:30]([CH3:33])([CH2:31][CH2:32][C:20]12[OH:35])[CH2:29][CH2:28][CH2:27][C:26]=3[CH3:34]
Reactant: C1CCNCC1
Reactant: CC1=C2[C@@H]3OC(=O)C(O)(COS(=O)(=O)c4ccc(C)cc4)C3(O)CC[C@@]2(C)CCC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC1=C2[C@@H]3OC(=O)C(O)(CN4CCCCC4)C3(O)CC[C@@]2(C)CCC1
Reaction time: 24 h

Procedure:
Piperidine (70.59 mg, 0.829 mmol) was added to compound of example 5 (180 mg, 0.412 mmol) dissolved in ethanol (5 mL) and reaction mixture was stirred for 24 hours. Saturated sodium bicarbonate solution was added, and reaction mixture was extracted with dichloromethane (3×50 mL). Dichloromethane layer was washed with water and brine and was dried over sodium sulfate. Solvent was removed and the crude product was purified by column chromatography (silica gel, 5-10% ethyl acetate in petroleum ether) to obtain the title compound.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:16])(=[O:3])[CH3:2].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](O)=[O:23])=[CH:20][CH:19]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13](=[O:15])[CH3:14])=[CH:10][CH:11]=2)[C:6](=[C:22]([C:21]2[CH:25]=[CH:26][C:18]([Br:17])=[CH:19][CH:20]=2)[OH:23])[C:5]1=[O:16])(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CC(=O)N2C(C)=O
Reactant: O=C(O)c1ccc(Br)cc1
Product: CC(=O)c1ccc2c(c1)C(=C(O)c1ccc(Br)cc1)C(=O)N2C(C)=O

Procedure:
Prepared from 1,5-diacetyl-2-indolinone and 4-bromobenzoic acid
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8](SC)=[N:7][C:6]=2[CH:18]=1.C(OC(N[N:27]1[CH2:32][CH:31]2[CH2:33][CH:28]1[CH2:29][NH:30]2)=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([N:27]3[CH2:32][CH:31]4[CH2:33][CH:28]3[CH2:29][NH:30]4)=[N:7][C:6]=2[CH:18]=1
Reactant: CC(C)(C)OC(=O)NN1CC2CC1CN2
Reactant: CSC1=Nc2cc(Cl)ccc2Nc2ccccc21
Product: Clc1ccc2c(c1)N=C(N1CC3CC1CN3)c1ccccc1N2
Yield: 42 %

Procedure:
8-Chloro-11-methylsulfanyl-5H-dibenzo[b,e][1,4]diazepine (166JO50) (50 mg, 0.11 mmol) and N-(tert-butoxycarbonylamino)2,5-diazabicyclo[2.2.1]heptane (34 mg, 0.2 mmol) were reacted according to GP8 to give 15 mg of the title compound (166JO39-2).
Reaction SMILES: [C:1]12([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=3[O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=O)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.CC([O-])=O.[NH4+].[CH3:28][N+:29]([O-:31])=[O:30]>>[C:1]12([C:11]3[CH:12]=[C:13](/[CH:14]=[CH:28]/[N+:29]([O-:31])=[O:30])[CH:16]=[CH:17][C:18]=3[O:19][CH:20]([CH3:22])[CH3:21])[CH2:2][CH:3]3[CH2:4][CH:5]([CH2:6][CH:7]([CH2:9]3)[CH2:8]1)[CH2:10]2
Reactant: CC(C)Oc1ccc(C=O)cc1C12CC3CC(CC(C3)C1)C2
Reactant: C[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: CC(C)Oc1ccc(/C=C/[N+](=O)[O-])cc1C12CC3CC(CC(C3)C1)C2
Reaction time: 3 h
Yield: 88 %

Procedure:
To a stirred solution of 3-(1-admantyl)-4-isopropoxybenzaldehyde (0.24 g, 0.8 mmol) in CH3NO2 (5 mL) was added CH3CO2NH4 (0.125 g, 1.6 mmol) and the mixture was stirred for 3 h at reflux. The solvent was evaporated to dryness and the residue was diluted to 50 ml with EtOAc and washed with 1M HCl and H2O. The organic layer was separated, dried over MgSO4 and filtered. The filtrate was evaporated to dryness to give the title product (0.275 g; 88%) as yellow solid. 1H-NMR (CDCl3) 1.41 (d, 6H, J=6 Hz); 1.7-1.76 (m, 6H); 2.08-2.12 (m, 9H); 4.68-4.74 (m, 1H); 6.85 (d, 1H, J=8.45 Hz); 7.33-7.38 (m, 2H); 7.51 (d, 1H, J=13.53 Hz); 7.97 (d, 1H, J=13.54 Hz).
Reaction SMILES: [CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:14][CH3:15])[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:16])[CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:24])C=CC=CC=1>C(Cl)Cl>[CH:1]1([N:4]2[C:9]3[N:10]=[C:11]([S:14]([CH3:15])=[O:24])[N:12]=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]2=[O:16])[CH2:3][CH2:2]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2ccc(=O)n(C3CC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2ccc(=O)n(C3CC3)c2n1
Yield: 74.1 %

Procedure:
A solution of 8-cyclopropyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.5 g, 2.1 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (0.84 g, 3.2 mmol) in CH2Cl2 (5 mL) was stirred at room temperature for 20 hours. The white solid formed was collected by filtration and washed with hexane, then dried to give 8-cyclopropyl-2-methylsulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one (0.388 g, 74%). 1H NMR: δ(400 MHz, DMSO) 9.15 (s, 1H), 8.0 (d, J=9.5 Hz, 1H), 6.74 (d, J=9.5 Hz, 1 H), 2.92(s, 1H), 1.18˜1.14(m, 2H), 0.83˜0.79 (m, 2H).
Reaction SMILES: [C:1]1([CH2:14][C:15]#[N:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[O:3][CH:2]=1)[O:10][CH2:9][CH:8]=[CH:7]3.[H][H]>C(O)C.N.[Ni]>[C:1]1([CH2:14][CH2:15][NH2:16])[C:5]2=[C:6]3[C:11](=[CH:12][CH:13]=[C:4]2[O:3][CH:2]=1)[O:10][CH2:9][CH2:8][CH2:7]3
Reactant: [H][H]
Reactant: N#CCc1coc2ccc3c(c12)C=CCO3
Agent: [Ni]
Agent: N
Solvent: CCO
Product: NCCc1coc2ccc3c(c12)CCCO3

Procedure:
1.4 mmol of compound obtained in stage E are dissolved in 30 ml of ethanol saturated with ammonia, in the presence of 400 mg of Nickel (Raney). The reaction mixture is stirred at 50° C. under 50 atm of hydrogen during 5 hours. After cooling and filtration of the catalyst, the filtrate is concentrated, dissolved in a mixture of ether/water and extracted. The organic layer is dried over magnesium sulfate and concentrated to yield the title product.
Reaction SMILES: [NH:1]([C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9])[C@H:2]([C:5]([OH:7])=O)[CH2:3][OH:4].[C:18]1([Mg]Br)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.CCCCCC>C1COCC1.C(OCC)(=O)C>[OH:4][CH2:3][C@H:2]([NH:1][C:8](=[O:9])[O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:5](=[O:7])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(N[C@@H](CO)C(=O)O)OCc1ccccc1
Reactant: Br[Mg]c1ccccc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=C(N[C@@H](CO)C(=O)c1ccccc1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 20 %

Procedure:
To a stirred solution of Z-L-Ser-OH (6.00 g, 25.08 mmol) in 32 mL of anhydrous THF at 0° C. under nitrogen was added dropwise 1 M phenylmagnesium bromide in THF (32 mL, 200 mmol). The mixture was stirred 15 h at RT under nitrogen. A solution of 2 M HCl (100 mL) was slowly added at 0° C. and the mixture was partitioned between ethyl acetate (750 mL) and acidic water. The organic layer was washed with water (2×20 mL), 1 N aqueous sodium bicarbonate (2×20 mL), brine (2×20 mL) and dried over MgSO4. After removing ethyl acetate by evaporation at 30-35° C., the crude product (4.50 g, 60% yield) was cristallized in a mixture of ethyl acetate:hexane=25 mL:20 mL to give benzyl (S)-3-hydroxy-1-oxo-1-phenylpropan-2-ylcarbamate TTA 08010B as a white solid (1.40 g, 20% yield).
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)(=[O:3])[CH3:2].B(F)(F)F.[Br:27]Br.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[Br:27][CH2:2][C:1]([C:4]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](=[O:22])[NH:9]2)=[O:3]
Reactant: CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Reactant: BrBr
Agent: FB(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=C(CBr)c1ccc(OCc2ccccc2)c2[nH]c(=O)ccc12
Temperature: 30 °C

Procedure:
A dry 3 liter, 4-necked round bottom flask equipped with a mechanical stirrer, thermometer, addition funnel and refluxing condenser was charged with of 5-Acetyl-8-benzyloxycarbostyril (50 gms/0.17 moles) and dry dichloromethane (1 liter) under argon. To this solution was added boron trifluoride etharate (25.7 ml/0.204 moles). The reaction mass was heated to reflux. To this reaction mass was added slowly solution of bromine (8.4 ml/0.17 moles) in dichloromethane (100 ml) at reflux in 4 hours. The mixture was refluxed for additional 30 minutes. The mass was cooled to 30° C. and adjusted to pH 8-9 using 10% aqueous potassium carbonate solution (470 ml).
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]([CH3:37])[CH2:13][C:14]1[C:15]([CH:25]2[CH2:30][CH2:29][N:28]([C:31](=[O:36])[CH2:32][CH:33]([CH3:35])[CH3:34])[CH2:27][CH2:26]2)=[N:16][N:17](C2CCCCO2)[CH:18]=1)C(=O)OC(C)(C)C.O.CC#N>C(O)C.O1CCOCC1.Cl>[CH3:34][CH:33]([CH3:35])[CH2:32][C:31]([N:28]1[CH2:27][CH2:26][CH:25]([C:15]2[C:14]([CH2:13][N:12]([CH3:37])[CH2:11][CH2:10][NH:2][CH3:1])=[CH:18][NH:17][N:16]=2)[CH2:30][CH2:29]1)=[O:36]
Reactant: CC(C)CC(=O)N1CCC(c2nn(C3CCCCO3)cc2CN(C)CCN(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CNCCN(C)Cc1c[nH]nc1C1CCN(C(=O)CC(C)C)CC1
Reaction time: 0.02 h
Yield: 25.1 %

Procedure:
A solution of tert-butyl methyl(2-(methyl((3-(1-(3-methylbutanoyl)piperidin-4-yl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)amino)ethyl)carbamate (110 mg, 0.21 mmol, 1.00 equiv) in ethanol (2 mL), 1,4-dioxane (4 mL) and 12N hydrochloric acid (2 mL) was stirred at room temperature overnight. The resulting mixture was concentrated under vacuum and the residue was purified by Pre-HPLC with the following conditions (1#-Pre-HPLC-005 (Waters)): Column, XBridge Shield RP18 OBD Column, 5 μm, 19×150 mm; mobile phase, water with 10 mmol NH4HCO3 and CH3CN (18% CH3CN up to 58% in 10 min, up to 95% in 1 min, down to 18% in 2 min); Detector, UV 254/220 nm to give 17.7 mg (25%) of 3-methyl-1-(4-(4-((methyl (2-(methylamino)ethyl)amino)methyl)-1H-p yrazol-3-yl)piperidin-1-yl)butan-1-one as a colorless solid. 1H-NMR (300 MHz, D2O): δ 7.53 (s, 1H), 4.50-4.40 (m, 1H), 4.10-4.00 (m, 1H), 3.44 (s, 2H), 3.25-3.10 (m, 1H), 3.09-2.95 (m, 1H), 2.80-2.65 (m, 3H), 2.53-2.43 (m, 2H), 2.40-2.20 (m, 5H), 2.13 (s, 3H), 2.00-1.75 (m, 3H), 1.72-1.43 (m, 2H), 0.88 (d, J=6.8 Hz, 6H) ppm. LCMS (method R, ESI): RT=1.26 min, m/z=336.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=O)[C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:7]([OH:9])=[O:8].[NH4+].[Cl-]>CO.C1COCC1.[Zn]>[NH2:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:2]([Br:1])[C:3]=1[O:4][CH2:5][C@H:6]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:15])[CH3:16])=[O:12])[C:7]([OH:9])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](COc1c(Br)cccc1[N+](=O)[O-])C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H](COc1c(N)cccc1Br)C(=O)O
Temperature: 25 °C
Yield: 96.7 %

Procedure:
A mixture of (S)-3-(2-bromo-6-nitrophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (2.1 g, 5.18 mmol), zinc dust (3.39 g, 51.8 mmol) and NH4Cl (2.77 g, 51.8 mmol) in MeOH/THF 1:1 (40 mL) was stirred at RT until TLC indicated the reaction was complete. The mixture was then filtered and the filtrate concentrated. The residue was mixed with H2O/EtOAc (50 mL/50 mL) and extracted with EtOAc. The combined organic extracts were dried over MgSO4, filtered and the filtrate concentrated to afford (S)-3-(2-amino-6-bromophenoxy)-2-(tert-butoxycarbonylamino)propanoic acid (1.88 g, 97%) as an off-white foam which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:21]([NH:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[C:27]([F:32])[CH:26]=3)=[O:22])=[C:7]([CH:18]([CH3:20])[CH3:19])[N:8]2[CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)=[CH:4][CH:3]=1.Cl[CH2:34][CH2:35][N:36]=[C:37]=[O:38]>C(Cl)Cl>[F:32][C:27]1[CH:26]=[C:25]([CH:30]=[CH:29][C:28]=1[F:31])[CH2:24][NH:23][C:21]([C:6]1[C:5]2[C:9](=[CH:10][C:2]([NH:1][C:37]3[O:38][CH2:34][CH2:35][N:36]=3)=[CH:3][CH:4]=2)[N:8]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[C:7]=1[CH:18]([CH3:20])[CH3:19])=[O:22]
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(N)cc2n1Cc1ccccn1
Reactant: O=C=NCCCl
Solvent: ClCCl
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(NC3=NCCO3)cc2n1Cc1ccccn1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 6-amino-N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 182, 48 mg, 0.11 mmol) in CH2Cl2 (1 ml) was added chloroethyl isocyanate (10 μl, 0.12 mmol). The reaction was stirred at room temperature for 16 h, and the solvent was removed. To the residue was added H2O and the mixture was heated at 80° C. for 3 h, diluted with EtOAc, washed with aqueous K2CO3 and brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by chromatography on silica gel (0→100% EtOAc-hexanes) to yield the title compound.
Reaction SMILES: [NH2:1][C@@H:2]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[CH:5]=1)[CH3:3].C(N(CC)CC)C.[C:28]([C:32]1[CH:37]=[CH:36][C:35]([N:38]=[C:39]=[O:40])=[CH:34][CH:33]=1)([CH3:31])([CH3:30])[CH3:29]>C(Cl)Cl>[C:28]([C:32]1[CH:37]=[CH:36][C:35]([NH:38][C:39](=[O:40])[NH:1][C@@H:2]([C:4]2[CH:9]=[CH:8][C:7]([NH:10][S:11]([CH3:14])(=[O:13])=[O:12])=[C:6]([C:15]#[C:16][Si:17]([CH3:18])([CH3:20])[CH3:19])[CH:5]=2)[CH3:3])=[CH:34][CH:33]=1)([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)c1ccc(N=C=O)cc1
Reactant: C[C@@H](N)c1ccc(NS(C)(=O)=O)c(C#C[Si](C)(C)C)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[C@@H](NC(=O)Nc1ccc(C(C)(C)C)cc1)c1ccc(NS(C)(=O)=O)c(C#C[Si](C)(C)C)c1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 38.5 %

Procedure:
(R)—N-[4-(1-Amino-ethyl)-2-trimethylsilanylethynylphenyl]methanesulfonamide (75.0 mg, 0.242 mmol, 1 eq.) and Triethylamine (67.5 μl, 0.484 mmol, 2 eq.) were dissolved in methylene chloride. The mixture was cooled down to 0° C. 4-tert-Butylphenyl isocyanate (47.2 μl, 0.266 mmol, 1.1 eq.) was added into the reaction mixture. The reaction mixture was stirred for 40 min. A reaction solvent was removed in vacuo. The residue was purified with column chromatography (n-Hx:EA=2:1) to yield title compound (45.3 mg, 39%) as a solid.