Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:26]=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[C:24]([O:39][CH3:40])=[CH:23][C:4]=1[CH2:5][CH2:6][N:7]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)C(=O)OC(C)(C)C>O1CCOCC1.C(Cl)Cl>[ClH:2].[Cl:2][C:3]1[C:4]([CH2:5][CH2:6][NH:7][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=2)=[CH:23][C:24]([O:39][CH3:40])=[C:25]([NH:27][C:28]([NH:30][C:31]2[CH:36]=[N:35][C:34]([C:37]#[N:38])=[CH:33][N:32]=2)=[O:29])[CH:26]=1
Reactant: COc1cc(CCN(Cc2cccc(F)c2)C(=O)OC(C)(C)C)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1cc(CCNCc2cccc(F)c2)c(Cl)cc1NC(=O)Nc1cnc(C#N)cn1
Temperature: 10 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
A solution of HCl in 1,4-dioxane (0.5 mL) was added to a solution of tert-butyl 2-chloro-4-(3-(5-cyanopyrazin-2-yl)ureido)-5-methoxyphenethyl(3-fluorobenzyl)carbamate (0.22 g 0.4 mmol) in DCM (30 mL) at 0° C. and the mixture stirred at 10° C. for 2 hours. The solvents were removed under reduced pressure to leave a solid residue that was washed with methanol (2×5 mL) and dried under reduced pressure to give the title compound (100 mg, 51%) as an off-white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=2)[CH:7]=[CH:8][CH:9]=1)(=[O:3])[CH3:2].Cl.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.[CH2:32]=O>O1CCOCC1>[N:26]1([CH2:32][CH2:2][C:1]([C:4]2[CH:5]=[C:6]([C:10]3[CH:15]=[CH:14][N:13]=[C:12]([NH:16][C:17](=[O:24])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH:11]=3)[CH:7]=[CH:8][CH:9]=2)=[O:3])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1
Reactant: CC(=O)c1cccc(-c2ccnc(NC(=O)c3ccccc3)c2)c1
Reactant: C1COCCN1
Reactant: C=O
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CCN1CCOCC1)c1cccc(-c2ccnc(NC(=O)c3ccccc3)c2)c1

Procedure:
N-[4-(3-Acetyl-phenyl)-pyridin-2-yl]-benzamide (200 mg, 0.632 mmol), morpholine HCl salt (78 mg, 0.632 mmol, 1 eq.) and paraformaldehyde (19 mg, 0.632 mmol, 1 eq.) were mixed with dioxane (2 mL) in a microwave tube. It was irradiated at 180° C. for 15 minutes. The mixture was partitioned between DCM/water (10 mL/5 mL). The aqueous layer was washed further with DCM (2×10 mL). The combined organic layer was dried (Na2SO4) and filtered. The filtrate was concentrated and the residue was chromatographed using 20/1 DCM/MeOH to give N-{4-[3-(3-Morpholin-4-yl-propionyl)-phenyl]-pyridin-2-yl}-benzamide as a slightly yellow solid (100 mg, 38%). MS: m/z 416.3 [MH+].
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.N[C@@H:11]([C:16]([OH:18])=[O:17])[C:12]([SH:15])([CH3:14])[CH3:13].C(=O)([O-])[O-:20].[K+].[K+].Cl>CO.O>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]([NH:7][C@@H:11]([C:16]([OH:18])=[O:17])[C:12]([SH:15])([CH3:14])[CH3:13])=[O:20])=[CH:4][CH:3]=1
Reactant: O=C([O-])[O-]
Reactant: CC(C)(S)[C@@H](N)C(=O)O
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: CC(C)(S)[C@@H](NC(=O)c1ccc(Br)cc1)C(=O)O

Procedure:
36.4 g (0.2 mole) 4-bromobenzonitrile, 29.8 g (0.2 mole) D-penicillamine and 13.8 g (0.1 mole) potassium carbonate were heated in 350 ml methanol and 150 ml water for 6 hours at the boiling point. After the mixture was acidified with concentrated hydrochloric acid to pH 4, it was heated one hour to a boil. After it cooled off, 53.6 g (81% of theory) of the product were isolated as a colorless precipitate with a melting point of 176° C.
Reaction SMILES: [CH3:1][N:2]([CH3:26])[C:3]1[CH:8]=[C:7]([CH2:9][N:10]([CH3:22])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)[C:6]([OH:23])=[C:5]([O:24][CH3:25])[CH:4]=1.C(N(C(C)C)CC)(C)C.[C:36](Cl)(=[O:38])[CH3:37]>ClCCl>[C:36]([O:23][C:6]1[C:7]([CH2:9][N:10]([CH3:22])[CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=2)=[CH:8][C:3]([N:2]([CH3:1])[CH3:26])=[CH:4][C:5]=1[O:24][CH3:25])(=[O:38])[CH3:37]
Reactant: CC(=O)Cl
Reactant: COc1cc(N(C)C)cc(CN(C)CCc2ccc([N+](=O)[O-])cc2)c1O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc(N(C)C)cc(CN(C)CCc2ccc([N+](=O)[O-])cc2)c1OC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
0.1 g (0.278 mmol) of 4-(dimethylamino)-2-methoxy-6-({methyl[2-(4-nitrophenyl)ethyl]-amino}methyl)phenol (compound of Example 1) are placed in solution in 5 ml of anhydrous dichloromethane in the presence of 49 μl (0.42 mmol; 1.5 eq.) of diisopropylethylamine at 0° C. 30 μl (0.42 mmol; 1.5 eq.) of acetyl chloride are added dropwise to the solution and the medium is stirred for 1 hour at ambient temperature. Then 10 ml of dichloromethane is added to the reaction medium which is then washed with 3 times 10 ml of a saturated solution of sodium chloride. The organic phase is dried over magnesium sulphate, followed by filtering and concentrating under vacuum. The residue is purified on a silica column (eluent: AcOEt/Heptane: 2/1) in order to produce a yellow oil with a yield of 60%.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][C:15](=[O:17])[CH3:16])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].I[CH3:21]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:9][CH2:10][CH:11]([N:14]([CH3:21])[C:15](=[O:17])[CH3:16])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: CC(=O)NC1CCN(c2cccc(Br)c2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)N(C)C1CCN(c2cccc(Br)c2)CC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.3 %

Procedure:
A solution of N-[1-(3-bromophenyl)-4-piperidyl]acetamide (11.6 g, 39.2 mmol) in THF (392 mL) was added to sodium hydride (6.84 g, 55% in mineral oil, 157 mmol) portionwise at 0° C. and stirred at room temperature for 10 minutes under nitrogen. The reaction mixture was added to iodomethane (7.32 mL, 118 mmol) at 0° C. and stirred at room temperature for 6 hours. The mixture was slowly quenched with water at 0° C. and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and filtered through a Celite pad. The combined filtrate and washings were concentrated. The residue was purified by silica gel column chromatography (hexane/AcOEt=80:20→0:100) to afford desired product (12.6 g, quant.) as brown oil.
Reaction SMILES: [CH3:1][C@@:2]12[C:10](=[O:11])[CH2:9][CH2:8][C@H:7]1[C@@H:6]1[CH2:12][CH:13]=[C:14]3[CH2:19][C@@H:18]([OH:20])[CH2:17][CH2:16][C@:15]3([CH3:21])[C@H:5]1[CH2:4][CH2:3]2.[CH2:22]([O:29][C:30](Cl)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH2:22]([O:29][C:30]([O:20][C@H:18]1[CH2:17][CH2:16][C@@:15]2([CH3:21])[C:14](=[CH:13][CH2:12][C@@H:6]3[C@@H:5]2[CH2:4][CH2:3][C@@:2]2([CH3:1])[C@H:7]3[CH2:8][CH2:9][C:10]2=[O:11])[CH2:19]1)=[O:31])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Product: C[C@]12CC[C@H](OC(=O)OCc3ccccc3)CC1=CC[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Reaction time: 0.5 h

Procedure:
To a stirred solution of dehydroepiandrosterone (2.88 g, 10 mmol) in methylene chloride (100 mL) is added dropwise benzylchloroformate, over a period of 30 min. following the known procedure (F. Reber and T. Reichstein, Helv. Chim. Actn, 28, 1164, 1945). After stirring for 3 h, the mixture is washed with water and evaporated to dryness. The residue is then dissolved in acetone and precipitated in iced water. After 16 h, crystals are filtered and dried in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23]OS(C)(=O)=O)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35].[NH:42]1[CH2:46][CH2:45][CH2:44][CH2:43]1.C([O-])(O)=O.[Na+]>CC#N>[CH3:1][O:2][C:3]1[CH:39]=[C:38]([O:40][CH3:41])[CH:37]=[CH:36][C:4]=1[CH2:5][N:6]1[C:11]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[N:17]([CH3:21])[C:16]([CH2:22][CH2:23][N:42]2[CH2:46][CH2:45][CH2:44][CH2:43]2)=[CH:15]3)=[C:10]([CH2:29][CH3:30])[CH:9]=[C:8]([C:31]([O:33][CH3:34])=[O:32])[C:7]1=[O:35]
Reactant: C1CCNC1
Reactant: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCOS(C)(=O)=O)n2C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCc1cc(C(=O)OC)c(=O)n(Cc2ccc(OC)cc2OC)c1-c1ccc2c(c1)cc(CCN1CCCC1)n2C
Temperature: 80 °C
Yield: 62.8 %

Procedure:
To solution of methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(methylsulfonyloxy)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.233 g, 0.40 mmol) in CH3CN (2 mL) was added pyrrolidine (0.15 mL, 1.83 mmol). Reaction mixture was heated at 80° C. for 1.5 h until complete consumption of starting material was observed. Then NaHCO3 (aqueous saturated, 5 mL) was added to the reaction and product was extracted with DCM (3×10 mL). Combined organics were washed with NaCl (aqueous saturated, 5 mL) and dried over Na2SO4. Upon solvent removal residue was purified by column chromatography using MeOH/DCM (gradient 0-10%) to afford methyl 1-(2,4-dimethoxybenzyl)-5-ethyl-6-(1-methyl-2-(2-(pyrrolidin-1-yl)ethyl)-1H-indol-5-yl)-2-oxo-1,2-dihydropyridine-3-carboxylate (0.140 g) in 62% yield.
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][CH3:9])=[C:6]([O:10][C:11]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[S:13][CH:12]=2)[N:5]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)[N:3]=1.CO.C(N(CC)CC)C>[Pd].C(OCC)(=O)C>[CH2:8]([C:7]1[CH:2]=[N:3][C:4]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=2)=[N:5][C:6]=1[O:10][C:11]1[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[S:13][CH:12]=1)[CH3:9]
Reactant: CCc1c(Cl)nc(-c2ccc(C(F)(F)F)cc2)nc1Oc1csc(C(F)(F)F)c1
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: CCOC(C)=O
Product: CCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1Oc1csc(C(F)(F)F)c1

Procedure:
A solution of 4-Chloro-5-ethyl-2-(α,α,α-trifluoro-p-tolyl)-6-{[5-(trifluoromethyl)-3-thienyl]oxy}pyrimidine (1.06 g, 2.34 mmol) in a 1:1 mixture of methanol:ethyl acetate is treated with triethylamine (0.80 ml, 5.86 mmol) and 10% Pd-C (0.32 g, 30 wt %). The resultant mixture is placed on a PARR hydrogenator at 50 psi for 2 hours (reaction is complete by TLC). The resultant mixture is filtered. The filtrate is concentrated. The 20/80) to give the title product as a white solid, 0.69 9 (70%), mp 67-68° C. identified by 1HNMR, 13CNMR, 19FNMR, mass spectral and elemental analyses.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([O:5][C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:2]1.[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22](O)=[O:23].CCN=C=NCCCN(C)C.C(O)CCC.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[N:15]=[C:14]1[C:22]([N:1]1[CH2:2][CH:3]([O:5][C:6]2[C:11]([Cl:12])=[N:10][CH:9]=[CH:8][N:7]=2)[CH2:4]1)=[O:23]
Reactant: Clc1nccnc1OC1CNC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: CCN=C=NCCCN(C)C
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(c1nc2ccccc2[nH]1)N1CC(Oc2nccnc2Cl)C1
Reaction time: 2 h
Yield: 40 %

Procedure:
To a solution of 2-(azetidin-3-yloxy)-3-chloropyrazine (see PREPARATION P22.1; 0.38 g, 2.047 mmol), 1H-benzo[d]imidazole-2-carboxylic acid (0.37 g, 2.282 mmol), EDCI (0.392 g, 2.047 mmol), butanol (0.121 g, 0.790 mmol) and DCM (25 mL) was added DIPEA (0.62 mL, 3.56 mmol). After 2 hours, the crude reaction was adsorbed onto a plug of silica gel and chromatographed through a Redi-Sep® pre-packed silica gel column (12 g), eluting with 0% to 50% EtOAc in hexane, to provide (1H-benzo[d]imidazol-2-yl)(3-(3-chloropyrazin-2-yloxy)azetidin-1-yl)methanone (270 mg, 0.819 mmol, 40.0% yield), as a white solid. MS (ESI) m/z 330.0 (MH+). IC50 (uM) 1.375.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16](Cl)[C:11]=2[CH:10]=[CH:9]1)[CH3:2].[C:20]([O:24][C:25](=[O:40])[C@H:26]([CH2:38][SH:39])[NH:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=1)(=[O:30])=[O:29])([CH3:23])([CH3:22])[CH3:21].CCN(C(C)C)C(C)C>CN1C(=O)CCC1>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][CH2:6][CH2:7][N:8]1[C:12]2[N:13]=[C:14]([CH3:18])[N:15]=[C:16]([S:39][CH2:38][C@H:26]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][C:34]([Br:37])=[CH:33][CH:32]=3)(=[O:29])=[O:30])[C:25]([O:24][C:20]([CH3:22])([CH3:23])[CH3:21])=[O:40])[C:11]=2[CH:10]=[CH:9]1)[CH3:2]
Reactant: CC(C)(C)OC(=O)[C@H](CS)NS(=O)(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)CCCn1ccc2c(Cl)nc(C)nc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CCOC(=O)CCCn1ccc2c(SC[C@H](NS(=O)(=O)c3ccc(Br)cc3)C(=O)OC(C)(C)C)nc(C)nc21
Temperature: 100 °C

Procedure:
279 mg of 4-(4-chloro-2-methyl-pyrrolo[2,3-d]pyrimidin-7-yl)-butyric acid ethyl ester (example 2a) and 655 mg of N-(4-bromobenzenesulfonyl)-(R)-cysteine-tert-butyl ester (example 6b) were dissolved in 2 ml of NMP and 0.68 ml of DIPEA were added. The reaction mixture was heated to 100° C. for 4 h. The mixture was diluted with 60 ml of EE and extracted with 10% citric acid, saturated NaCl solution and with water. The organic phase was dried over MgSO4 and the solvent was removed in vacuo. The crude product was chromatographed on silica gel eluting with EE/toluene (1:6). Yield: 108 mg.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14](OC)=[O:15])[C:9]2=[O:18])[CH:5]=[CH:4]1.[NH3:19]>CO>[OH:1][CH2:2][CH:3]1[CH2:7][CH:6]([N:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([NH2:19])=[O:15])[C:9]2=[O:18])[CH:5]=[CH:4]1
Reactant: COC(=O)c1nccn(C2C=CC(CO)C2)c1=O
Reactant: N
Solvent: CO
Product: NC(=O)c1nccn(C2C=CC(CO)C2)c1=O
Reaction time: 13 h

Procedure:
In 1 ml of methanol was dissolved 75 mg of methyl 4-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. At room temperature, 25% aqueous solution of ammonia was added and stirred for 13 hours, and then the solvent was removed under reduced pressure. Isopropanol was added to the residue, and the solid product was collected by filtration to obtain 20 mg of 4-[4-(hydroxymethyl)-2-cyclopenten-1-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a white-colored solid product.
Reaction SMILES: [NH2:1][C:2]1[CH:32]=[C:5]2[N:6]=[C:7]([CH3:31])[C:8]([C@H:22]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:23]([OH:25])=[O:24])=[C:9]([C:10]3[C:11]([CH3:21])=[C:12]4[C:17](=[C:18]([F:20])[CH:19]=3)[O:16][CH2:15][CH2:14][CH2:13]4)[N:4]2[N:3]=1.NC1C=C2N=C(C)C(C(OC(C)(C)C)C(O)=O)=C(C3[C:43]([CH3:53])=[C:44]4[C:49](=[C:50](F)C=3)[O:48][CH2:47][CH2:46][CH2:45]4)N2N=1.C1(CCC(Cl)=O)CCCC1.CCN(C(C)C)C(C)C>C1COCC1>[C:27]([O:26][C@@H:22]([C:8]1[C:7]([CH3:31])=[N:6][C:5]2[N:4]([N:3]=[C:2]([NH:1][C:47](=[O:48])[CH2:46][CH2:45][CH:44]3[CH2:43][CH2:53][CH2:50][CH2:49]3)[CH:32]=2)[C:9]=1[C:10]1[C:11]([CH3:21])=[C:12]2[C:17](=[C:18]([F:20])[CH:19]=1)[O:16][CH2:15][CH2:14][CH2:13]2)[C:23]([OH:25])=[O:24])([CH3:28])([CH3:29])[CH3:30]
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1C(OC(C)(C)C)C(=O)O
Reactant: Cc1nc2cc(N)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Agent: O=C(Cl)CCC1CCCC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc2cc(NC(=O)CCC3CCCC3)nn2c(-c2cc(F)c3c(c2C)CCCO3)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 35 %

Procedure:
A mixture of 2S)-2-(2-amino-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetic acid (22 mg, 0.050 mmol), 3-cyclopentylpropanoyl chloride (8.79 mg, 0.055 mmol), Hunig's Base (0.026 mL, 0.15 mmol) in THF (2 mL) was stirred at rt for 16 h. It was then concentrated in vacuo and purified by prep HPLC (TFA/MeOH), the desired fractions were combined and adjusted to pH=6 using a few drops of 1N NaOH. The residue was then acidified to pH=4 using a few drops of 1N HCl. This solution was extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to obtain (10 mg, 35%) of (2S)-2-tert-butoxy-2-(2-(3-cyclopentylpropanamido)-7-(8-fluoro-5-methylchroman-6-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)acetic acid as white solid.
Reaction SMILES: [CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16]#[N:17])[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.[OH:18][CH2:19][CH2:20][N:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>>[CH:1]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[CH2:8][N:7]([C:16](=[NH:17])[O:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)[CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: N#CN1Cc2ccccc2-c2ccccc2C1
Reactant: OCCN1CCOCC1
Product: N=C(OCCN1CCOCC1)N1Cc2ccccc2-c2ccccc2C1

Procedure:
starting from 5,7-dihydro-6H-dibenz[c,e]azepine-6-carbonitrile and 4-(2-hydroxyethyl)-morpholine, there is obtained 2-morpholino-ethyl 5,7-dihydro-6H-dibenz[c,e]-azepine-6-carboximidate as a resin, mass spectrum m/e: M+ 351 (1), 238 (10), 113 (100);
Reaction SMILES: C([O:8][C:9]1[C:14]([CH2:15][N:16]2[CH2:25][CH2:24][C:23]3[C:18](=[C:19]([Cl:34])[C:20]([C:27]4[N:31]([CH3:32])[N:30]=[N:29][C:28]=4[CH3:33])=[CH:21][C:22]=3[Br:26])[C:17]2=[O:35])=[C:13]([CH3:36])[CH:12]=[C:11]([CH3:37])[N:10]=1)C1C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[Br:26][C:22]1[CH:21]=[C:20]([C:27]2[N:31]([CH3:32])[N:30]=[N:29][C:28]=2[CH3:33])[C:19]([Cl:34])=[C:18]2[C:23]=1[CH2:24][CH2:25][N:16]([CH2:15][C:14]1[C:9](=[O:8])[NH:10][C:11]([CH3:37])=[CH:12][C:13]=1[CH3:36])[C:17]2=[O:35]
Reactant: Cc1cc(C)c(CN2CCc3c(Br)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(OCc2ccccc2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc(C)c(CN2CCc3c(Br)cc(-c4c(C)nnn4C)c(Cl)c3C2=O)c(=O)[nH]1
Temperature: 25 °C
Yield: 89.2 %

Procedure:
A solution of 2-{[2-(benzyloxy)-4,6-dimethylpyridin-3-yl]methyl}-5-bromo-8-chloro-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (293i, 76 mg, 0.13 mmol) in dichloromethane (4 mL) was cooled in an ice-water bath. Trifluoroacetic acid (6 mL) was added, and the mixture stirred and allowed to warm to room temperature overnight. After removal of the volatiles under vacuum, the residue was purified by silica gel chromatography (eluting with 10:1 dichloromethane/methanol) to give 5-bromo-8-chloro-2-[(4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl]-7-(1,4-dimethyl-1H-1,2,3-triazol-5-yl)-3,4-dihydroisoquinolin-1(2H)-one (Example 293, 56.9 mg, 90% yield) as a white solid). 1H NMR (400 MHZ, Methanol-d4): δ 7.79 (s, 1H), 6.10 (s, 1H), 4.75 (s, 2H), 3.84 (s, 3H), 3.59 (t, J=6.2 Hz, 2H), 3.07 (t, J=6.2 Hz, 2H), 2.30 (s, 3H), 2.24 (s, 3H), 2.16 (s, 3H). MS: 492 [M+1].
Reaction SMILES: [OH:1][CH2:2][C:3]([CH3:8])([CH3:7])[C:4](O)=[O:5].[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][NH:17][OH:18].C1(N=C=NC2CCCCC2)CCCCC1>C(O)C.C(Cl)(Cl)Cl>[Cl:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][N:17]([OH:18])[C:4](=[O:5])[C:3]([CH3:8])([CH3:7])[CH2:2][OH:1]
Reactant: ONCc1ccccc1Cl
Reactant: CC(C)(CO)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClC(Cl)Cl
Solvent: CCO
Product: CC(C)(CO)C(=O)N(O)Cc1ccccc1Cl
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.9 %

Procedure:
To a stirred solution of 3.0 grams (0.025 mole) of 3-hydroxy-2,2-dimethylpropionic acid (Example 12, Step A) and 3.9 grams (0.025 mole) of N-(2-chlorophenyl)methyl hydroxylamine (Example 1, Step A-2) in 65 ml of ethanol was added dropwise a solution of 5.2 grams (0.025 mole) of dicyclohexylcarbodiimide in 25 ml of chloroform. Upon completion of addition the reaction mixture was stirred at ambient temperature for 60 hours. The reaction mixture was concentrated under reduced pressure to give a residual solid. The solid was recrystallized from ethanol, then from ethanol-water to give a solid; mp 229°-230°. The filtrates from the recrystallizations were combined and concentrated under high vacuum to give a residual oil. The residual oil was subjected to column chromatography. Elution was accomplished using 4:1--cyclohexane:ethyl acetate. The appropriate fraction was concentrated under reduced pressure to give a solid. The solid was recrystallized from ethyl acetatehexane to give 0.51 gram of N-[(2-chlorophenyl)methyl]-N,3-dihydroxy-2,2-dimethylpropanamide; mp 130°-132°. The solid was recrystallized a second time from ethyl acetate-cyclohexane to raise the mp to 131°-132°.
Reaction SMILES: Br[CH2:2]/[CH:3]=[CH:4]/[C:5]([OH:7])=O.[C:8]([NH:12][CH3:13])([CH3:11])([CH3:10])[CH3:9].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:25]=[C:26]([NH:31][C:32]2[C:37]([C:38]#[N:39])=[CH:36][N:35]=[C:34]3[S:40][C:41]4[CH2:42][NH:43][CH2:44][CH2:45][C:46]=4[C:33]=23)[CH:27]=[CH:28][C:29]=1[F:30].CCN=C=NCCCN(C)C>C(Cl)Cl.O>[C:8]([N:12]([CH3:13])[CH2:2]/[CH:3]=[CH:4]/[C:5]([N:43]1[CH2:44][CH2:45][C:46]2[C:33]3[C:34]([S:40][C:41]=2[CH2:42]1)=[N:35][CH:36]=[C:37]([C:38]#[N:39])[C:32]=3[NH:31][C:26]1[CH:27]=[CH:28][C:29]([F:30])=[C:24]([Cl:23])[CH:25]=1)=[O:7])([CH3:11])([CH3:10])[CH3:9]
Reactant: O=C(O)/C=C/CBr
Reactant: CNC(C)(C)C
Reactant: N#Cc1cnc2sc3c(c2c1Nc1ccc(F)c(Cl)c1)CCNC3
Agent: CCN=C=NCCCN(C)C
Solvent: O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C/C=C/C(=O)N1CCc2c(sc3ncc(C#N)c(Nc4ccc(F)c(Cl)c4)c23)C1)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.1 %

Procedure:
(2E)-4-Bromobut-2-enoic acid (100 mg, 0.61 mmol) and tert-butyl methylamine (60 mg, 0.67 mmol) were dissolved in DCM (3.0 mL). DIPEA (94 mg, 0.73 mmol) was added, and the mixture was heated overnight to 50° C. After cooling to rt, the compound of Example 55A (75 mg, 0.21 mmol), DCM (1.0 mL), EDCI (48 mg, 0.25 mmol) and DIPEA (32 mg, 0.25 mmol) were added, and the mixture was stirred at rt overnight. Subsequently, it was diluted with water, and the mixture was extracted three times with DCM. The combined organic layers were dried over sodium sulfate, and the solvent was removed in vacuo. The crude product was purified by preparative HPLC to yield 41 mg (37%) of the title compound.
Reaction SMILES: [N+](C1C=CC(N)=C(N)C=1)([O-])=O.[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([N+:24]([O-])=O)[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13].[N+](C1NC2C=CC=CC=2N=1)([O-])=O>C(O)(=O)C(C)C.CCOC(C)=O.CO.[Pd]>[CH:12]([C:15]1[NH:16][C:17]2[CH:23]=[C:22]([NH2:24])[CH:21]=[CH:20][C:18]=2[N:19]=1)([CH3:14])[CH3:13]
Reactant: CC(C)c1nc2ccc([N+](=O)[O-])cc2[nH]1
Agent: [Pd]
Agent: Nc1ccc([N+](=O)[O-])cc1N
Agent: O=[N+]([O-])c1nc2ccccc2[nH]1
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CC(C)C(=O)O
Product: CC(C)c1nc2ccc(N)cc2[nH]1
Reaction time: 12 h
Yield: 92 %

Procedure:
A solution of 4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml of isobutyric acid was stirred at reflux for 12 h. The reaction mixture was concentrated in vacuo to yield a dark brown residue, which was dissolved in 100 ml of EtOAc and washed with aqueous NaHCO3. Organic layer was dried over MgSO4 and concentrated in vacuo, yielding an oil which was characterized as 2-isopropyl-5-nitrobenzimidazole and subjected to a following reaction without further purification. The nitrobenzimidazole and 50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H2. The reaction mixture was filtered and concentrated in vacuo, yielding 0.95 g (5.4 mmol, 92%) of the desired product.