Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([OH:17])=O)=[N:9]1.CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>CC1CCCO1>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([O:13][CH3:14])=[CH:11][C:10]([C:15]([Cl:26])=[O:17])=[N:9]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)nn1-c1ccccc1F
Solvent: CC1CCCO1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)nn1-c1ccccc1F
Temperature: 0 °C

Procedure:
A suspension of 1-(2-fluoro-phenyl)-5-methoxy-1H-pyrazole-3-carboxylic acid (39.1 g, 167 mmol) in 2-methyltetrahydrofuran (300 ml) was cooled to 0° C. and DMF (293 μl, 3.81 mmol) was added. Oxalyl chloride (23.1 g, 182 mmol) was added dropwise. After 16 h at room temperature ca. 100 ml of the solvent were removed by distillation. The resulting suspension of the title compound was used directly in the next step.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][OH:9])=[C:4]([Cl:10])[CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.CCOC(C)=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[O:9])=[C:4]([Cl:10])[CH:3]=1
Reactant: OCc1ccc(Br)cc1Cl
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=Cc1ccc(Br)cc1Cl
Reaction time: 0.33 h

Procedure:
To a stirring solution of (4-bromo-2-chlorophenyl)methanol (4.5 g, 20 mmol) in DCM (50 mL) was added Dess-Martin periodinane (9.3 g) at 23° C. Reaction refluxed after addition. After 20 min, TLC (1:4 EtOAc/Hex) suggests full conversion of alcohol. Suspension then washed with 5% NaHCO3 (100 mL plus 15 g dry NaHCO3). Organic dried over MgSO4, concentrated onto dry silica (15 g), then purified on silica (120 g) eluting with 0>10% EtOAc/hex. 4-bromo-2-chlorobenzaldehyde isolated as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16](Br)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([F:27])([F:26])[F:25])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29].C([Sn](CCCC)(CCCC)[C:37]1[N:38]=[CH:39][S:40][CH:41]=1)CCC.[Cl-].[Li+]>O1CCOCC1.C(OCC)(=O)C.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>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:37]4[N:38]=[CH:39][S:40][CH:41]=4)=[C:15]([C:20]([F:23])([F:22])[F:21])[CH:14]=3)=[CH:11][C:10]([C:24]([F:27])([F:26])[F:25])=[N:9]2)[CH:5]=[CH:4][C:3]=1[S:28]([NH2:31])(=[O:30])=[O:29]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(Br)c(C(F)(F)F)c2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)cc2-c2ccc(-c3cscn3)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Yield: 18 %

Procedure:
To a stirred solution of 2-fluoro-4-[5-[4-bromo-3-(trifluoromethyl)phenyl]-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide (308 mg, 0.58 mmol) in dioxane (5 ml) was added 4-(tributylstannyl)thiazole (260 mg, 0.70 mmol), tetrakis(triphenylphosphine)palladium (67 mg, 0.058 mmol), lithium chloride (61 mg, 1.45 mmol), and the mixture was heated at reflux temperature for 16 hours. The reaction mixture was cooled down to room temperature, and diluted with ethyl acetate. The whole was washed with saturated potassium fluoride aqueous solution, and the precipitate was removed by filteration through celite. The resulting solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography eluting with ethyl acetate-hexane (1:2) to give title compound (56 mg, 18% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][C:3]=1[N+:13]([O-])=O>[C].[Pd].CCO.O>[NH2:13][C:3]1[CH:4]=[C:5]([CH:8]([CH3:12])[C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C(=O)O)c1ccc(N)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: CC(C(=O)O)c1ccc(N)c(N)c1
Reaction time: 5 h

Procedure:
To the flask was added EtOH/H2O (3.5:1, 45 mL) followed by 2-(4-Amino-3-nitro-phenyl)-propionic acid (5.73 g, 27.3 mmol) and 10% palladium carbon (117 mg) at room temperature. The reaction mixture was hydrogenated and stirred for 5 hrs at 64 psi then filtered through celite bed, and washed with EtOH. The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel using CH2Cl2:MeOH (10:1) as eluant.
Reaction SMILES: [C:1](=[O:12])(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl.Cl.Cl.[NH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][C:23]#[N:24])[CH2:18][CH2:17]1.[C@H:25]1([NH:34][C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([NH2:45])[CH:41]=3)[N:36]=2)[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26]1>>[C:23]([CH2:22][N:19]1[CH2:20][CH2:21][CH:16]([NH:15][C:1]([NH:45][C:40]2[CH:41]=[C:42]3[C:37](=[CH:38][CH:39]=2)[N:36]=[C:35]([NH:34][C@H:25]2[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26]2)[CH:44]=[CH:43]3)=[O:12])[CH2:17][CH2:18]1)#[N:24]
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: N#CCN1CCC(N)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: Cl
Product: N#CCN1CCC(NC(=O)Nc2ccc3nc(N[C@@H]4CCc5ccccc54)ccc3c2)CC1

Procedure:
The title compound was prepared in accordance with the general method 4 described in example 16 from bis(trichloromethyl) carbonate, (4-amino-piperidin-1-yl)-acetonitrile dihydrochlorid and (R)—N2-indan-1-yl-quinoline-2,6-diamine; MS: m/e=441.8 (M+H+).
Reaction SMILES: C(P(CCCC)CCCC)CCC.[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([OH:28])=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1.[CH3:31][C:32]1[C:37]([CH2:38]O)=[CH:36][CH:35]=[C:34]([C:40]([F:43])([F:42])[F:41])[N:33]=1.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:14][O:15][C:16](=[O:30])[CH2:17][C:18]1[C:22]2[C:23]([Cl:29])=[CH:24][C:25]([O:28][CH2:38][C:37]3[C:32]([CH3:31])=[N:33][C:34]([C:40]([F:43])([F:41])[F:42])=[CH:35][CH:36]=3)=[C:26]([Cl:27])[C:21]=2[S:20][CH:19]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2c(Cl)c(O)cc(Cl)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2c(Cl)c(OCc3ccc(C(F)(F)F)nc3C)cc(Cl)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.4 %

Procedure:
To a mixture of tri-n-butylphosphine (0.336 mL), methyl(4,7-dichloro-6-hydroxy-1-benzothiophen-3-yl)acetate (130.7 mg), (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (94 mg) and THF (4.5 mL) was added ADDP (283 mg) at room temperature. The mixture was stirred at room temperature under nitrogen atmosphere overnight. The mixture was concentrated. To the residue was added IPE and the precipitate was filtered off. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (NH, EtOAc/hexane) to give the title compound (153 mg).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:13][C:14]([F:17])([F:16])[CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:18]1C=[N:22][C:21]2N(O)N=[N:26][C:20]=2[CH:19]=1.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:21]([C:20]1([NH:26][C:10]([C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:13][C:14]([F:17])([F:16])[CH3:15])=[O:12])[CH2:19][CH2:18]1)#[N:22]
Reactant: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CC(F)(F)C[C@H](NC(=O)OC(C)(C)C)C(=O)NC1(C#N)CC1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
1.35 g (5.33 mmol) of the product from example 16, 810 mg (6.83 mmol, 1.3 eq.) of 1-amino-1-cyclopropylnitrile hydrochloride and 943 mg (6.93 mmol, 1.3 eq.) of HOAt were dissolved or suspended in 18 ml of dichloromethane, cooled to 0° C. and then admixed with 1.33 g (6.93 mmol, 1.3 eq.) of EDCl and 1.76 ml (1.596 g, 13.86 mmol, 2.6 eq.) of NEM. The mixture was stirred at 0° C. to RT for 16 h. The reaction mixture was then diluted with 40 ml of DCM and extracted by shaking with 1 N HCl solution, saturated sodium hydrogencarbonate solution and saturated NaCl solution. The organic phase was dried over sodium sulfate and concentrated by evaporation under reduced pressure. The product was sufficiently clean for further reactions.
Reaction SMILES: [CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH2:17])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2].C(=O)(O)[O-].[Na+].Cl.C1(C(=N[O:34][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=O)C#N)C=CC=CC=1>O.O1CCCC1.C(N(CC)CC)C>[CH:1]([NH:3][C:4]1[S:5][CH:6]=[C:7]([C:9](=[N:13][O:14][CH2:15][CH2:16][NH:17][C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:34])[C:10]([OH:12])=[O:11])[N:8]=1)=[O:2]
Reactant: NCCON=C(C(=O)O)c1csc(NC=O)n1
Reactant: CC(C)(C)OC(=O)ON=C(C#N)c1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCON=C(C(=O)O)c1csc(NC=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of 2-(2-formamidothiazol-4-yl)-2-(2-aminoethoxyimino)acetic acid (syn isomer, 0.80 g.) and triethylamine (0.45 g.), in a solution of a saturated aqueous solution of sodium bicarbonate (4 ml.), tetrahydrofuran (35 ml.) and water (25 ml.) was adjusted to pH 8.5 with hydrochloric acid. 2-Phenyl-2-(tert-butoxycarbonyloxyimino)acetonitrile (0.77 g.) was added to the stirred solution and stirred at room temperature for 3 hours. After distilling off tetrahydrofuran from the resultant solution, the aqueous solution was washed with diethyl ether, and adjusted to pH 1.5 with 85% phosphoric acid. The solution was extracted with ethyl acetate (50 ml.), and the extract was washed with a saturated aqueous solution of sodium chloride (10 ml.), dried over magnesium sulfate and concentrated under reduced pressure to give 2-(2-formamidothiazol-4-yl)-2-(2-tert-butoxycarbonylaminoethoxyimino)acetic acid (syn isomer, 0.40 g.).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH:14]=O)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1.[BH3-]C#N.[Na+]>CO.COC(OC)OC>[C:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][NH:16][C:17]2[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=2)[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: Nc1cccnc1
Reactant: CC(C)(C)OC(=O)N1CCCC(C=O)C1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cccnc2)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.4 %

Procedure:
To a solution of N-Boc-piperidin-3-yl-formaldehyde 3 (0.89 g, 4.16 mmol) in 3 mL of dry methanol and 3 mL of trimethylorthoformate was added 3-aminopyridine (0.39 g, 1 eq.), and the mixture was stirred at room temperature for 1.5 hours. NaBH3CN (95%, 0.29 g, 1.05 eq.) was introduced in one portion, and the mixture was stirred at room temperature overnight. The mixture was quenched with 10 mL of aqueous potassium carbonate (sat.), then extracted with ethyl acetate (3×30 ML). The extracts were combined and washed with aqueous NaHCO3 (sat., 2×10 mL), brine (20 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was purified by flash column chromatography (silica gel, hexane/ethyl acetate) to afford N-(1-Boc-piperidin-3-ylmethyl)-N-(pyridin-3-yl) amine 17 as a white solid (0.91 g, 75%). LRMS 292.
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[NH:26][C:12]2=[N:13][CH:14]=[C:15](/[CH:17]=[CH:18]/[C:19]([O:21]C(C)(C)C)=[O:20])[CH:16]=[C:11]2[NH:10]1.[Cl:27]CCl>>[ClH:27].[O:8]=[C:9]1[NH:26][C:12]2=[N:13][CH:14]=[C:15](/[CH:17]=[CH:18]/[C:19]([OH:21])=[O:20])[CH:16]=[C:11]2[NH:10]1
Reactant: CC(C)(C)OC(=O)/C=C/c1cnc2[nH]c(=O)[nH]c2c1
Reactant: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(O)/C=C/c1cnc2[nH]c(=O)[nH]c2c1
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (2 mL) was added to a suspension of (E)-tert-butyl 3-(2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-6-yl)acrylate (400 mg, 1.54 mmol) in dichloromethane (2 mL) at room temperature. The reaction mixture was stirred for 1 hour then concentrated to dryness. The resulting residue was suspended in a solution of hydrochloric acid in dioxane 4N (2 mL). After 10 minutes stirring at room temperature, the precipitate was filtered and washed with diethyl ether to afford the title product as a pale yellow solid (381 mg, quantitative).
Reaction SMILES: [Br-].[CH3:2][C:3]1([CH3:33])[S:7][C:6]2[CH:8]=[CH:9][C:10]([CH:12]([P+](C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH3:13])=[CH:11][C:5]=2[S:4]1.[CH:34]([C:36]1[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=1)=O>>[CH3:33][C:3]1([CH3:2])[S:7][C:6]2[CH:8]=[CH:9][C:10](/[C:12](/[CH3:13])=[CH:34]/[C:36]3[CH:45]=[CH:44][C:39]([C:40]([O:42][CH3:43])=[O:41])=[CH:38][CH:37]=3)=[CH:11][C:5]=2[S:4]1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(c1ccc2c(c1)SC(C)(C)S2)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Product: COC(=O)c1ccc(/C=C(\C)c2ccc3c(c2)SC(C)(C)S3)cc1

Procedure:
28.9 g of aluminum chloride were added portionwise at 0° C. to 16.8 ml of acetyl chloride in 360 ml of methylene chloride. After an additional 30 minutes at 0° C., a solution of 35.9 g of 2,2-dimethyl-1,3-benzodithiol in 180 ml of methylene chloride was slowly added dropwise and the mixture was stirred at 0° C. for an additional 12 hours and thereafter at 20° C. for 5 hours. Thereafter, the mixture was poured on to ice, extracted with methylene chloride and the extracts were washed neutral with dilute sodium hydroxide solution and water, dried over sodium sulfate and evaporated. After recrystallization from methanol/water, there were obtained 41.8 g of 2,2-dimethyl-1,3-benzodithiol-5-yl methyl ketone, melting point 75°-76° C. Then, 41.8 g of this ketone were dissolved in 1 l of ethanol, cooled to 0° C. and 7 g of sodium borohydride were added portionwise. Thereafter, the mixture was stirred at 20° C. for 3 hours, evaporated in a vacuum to a large extent, 200 ml of water were added, the mixture was adjusted slowly to pH 4 with 1N sulfuric acid while cooling and extracted three times with ether. The extracts were washed with water, dried and evaporated, and 42.6 g of α,2,2-trimethyl-1,3-benzodithiol-5-methanol were obtained. Thereafter, 39.5 g of this alcohol were reacted with 65.9 g of triphenylphosphine hydrobromide in 500 ml of acetonitrile and worked-up as described in Example 8 and 96.3 g of [1-(2,2-dimethyl-1,3-benzodithiol-5-yl)ethyl]triphenylphosphonium bromide were obtained. Then, 17.0 g of this phosphonium salt were reacted with methyl 4-formyl-benzoate in analogy to Example 8. After working-up and recrystallization from ethyl acetate/hexane, there were obtained 4.9 g of methyl p-[(E)-2-(2,2-dimethyl-1,3-benzo-dithiol-5-yl)propenyl]benzoate in the form of colorless crystals, melting point 86°-87° C.
Reaction SMILES: [N:1]1C2C=CC=CC=2N[C:2]=1[NH:10]C(O)=O.N[C:15](N)=[S:16].[S:18]([O:23]C)([O:21]C)(=[O:20])=[O:19]>>[S:18]([OH:23])([OH:21])(=[O:20])=[O:19].[CH3:15][S:16][C:2](=[NH:1])[NH2:10]
Reactant: O=C(O)Nc1nc2ccccc2[nH]1
Reactant: NC(N)=S
Reactant: COS(=O)(=O)OC
Product: CSC(=N)N
Product: O=S(=O)(O)O

Procedure:
U.S. Pat. No. 3,010,968 describes a process for making the 2-benzimidazolecarbamic.acid esters of formula (I) by reacting thiourea with dimethyl sulfate to produce 2-methylthiopseudourea sulfate. This reaction product is then reacted with an alkyl chloroformate and a base to produce an acylated 2-methylthiopseudourea, which is then reacted further with an o-phenylenediamine in the presence of a protonic acid to produce the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[C:10]2[C:9](=O)[NH:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1.[OH-].[K+].[N:15]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1>C(#N)C.O=P(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:12])[C:10]2[C:9]([N:18]3[CH2:17][CH2:16][N:15]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:20][CH2:19]3)=[N:8][CH:7]=[N:6][C:5]=2[CH2:4][CH2:3]1
Reactant: CC1(C)CCc2nc[nH]c(=O)c21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCN(c2ncnc3c2C(C)(C)CC3)CC1
Temperature: 80 °C
Yield: 47.4 %

Procedure:
A mixture of ethyl 2,2-dimethyl-5-oxocyclopentanecarboxylate (3.426 g) and ammonium acetate (14.33 g) in EtOH (100 mL) was heated at 85° C. (bath) for 1 hour. The contents were concentrated. The residue was partitioned between water and DCM. The organic phase was separated. The aqueous solution was extracted with DCM. The combined DCM solutions were washed with water and dried (Na2SO4). Upon filtration and concentration, solid ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate (2.933 g) was yielded. The ethyl 2-amino-5,5-dimethylcyclopent-1-enecarboxylate was mixed with ammonium formate (5.054 g) and formamide (7 mL) and heated at 150° C. for 16 hours. The mixture was diluted with water and extracted with 5:1 DCM-IPA. The combined extracts were dried (Na2SO4) and concentrated to give 5,5-dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one as a viscous oil (1.185 g). 5,5-Dimethyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (1.063 g) was dissolved in acetonitrile (20 mL) with POCl3 (1.78 mL). The mixture was heated at 80° C. for 10 hours. The mixture was cooled to 0° C. 50% KOH (15.3 mL) was added dropwise. t-Butyl piperazine-1-carboxylate (3.615 g) was added. The mixture was heated at 80° C. for 24 hours. The contents were concentrated. Water was added. The mixture was extracted with DCM (2×) and dried (Na2SO4). The crude material was purified with flash chromatography to give tert-butyl 4-(5,5-dimethyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (1.021 g). 1H NMR (CDCl3, 400 MHz) δ (ppm): 8.57 (s, 1H), 3.56-3.54 (m, 4H), 3.37-3.34 (m, 4H), 2.90 (t, J=7.3 Hz, 2H), 1.89 (t, J=7.3 Hz), 3H)1.48 (s, 9H), 1.40 (s, 6H). MS: 333.2 (M+1).
Reaction SMILES: [CH2:1]([NH:5][CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4].C([Al](CC)CC)C.[CH:17]12[O:23][CH:22]1[CH2:21][CH2:20][CH2:19][CH2:18]2.[OH-].[Na+]>ClCCl.CCCCCC>[CH2:1]([N:5]([C@@H:21]1[CH2:20][CH2:19][CH2:18][CH2:17][C@H:22]1[OH:23])[CH2:6][CH2:7][CH2:8][CH3:9])[CH2:2][CH2:3][CH3:4]
Reactant: C1CCC2OC2C1
Reactant: CCCCNCCCC
Agent: CC[Al](CC)CC
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: ClCCl
Product: CCCCN(CCCC)[C@@H]1CCCC[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
A! A solution of 43 ml (0.25 mole) of dibutylamine in 770 ml of dichloromethane was added with a 0.91M solution of 280 ml (0.025 mole) of triethyl-aluminium in hexane, at 0° C. under argo, and the resultant reaction mixture was stirred for 30 minutes at room temperature, then dropwise added with 25.8 ml (0.25 mole) of 7-oxabicyclo[4.1.0]heptane, and stirred overnight. A 6M solution of 200 ml (1.2 moles) of sodium hydroxide was added very slowly, and the mixture was stirred for 2 hours at room temperature. The phases were separated, and the organic one was washed with water (2×50 ml), anhydrified over sodium sulfate and evaporated. The resultant crude was distilled under vacuum to provide 43.7 g (yield: 75%) of trans-2-(N,N-dibutylamino)-cyclohexanol (b.p.--105°-107° C./1 mmHg).
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]([CH2:13]O)[CH:10]([CH2:15][OH:16])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH2:15][O:16][CH2:13][CH:11]2[CH2:12]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCC1CN(Cc2ccccc2)CC1CO
Agent: CN(C)c1ccncc1
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: c1ccc(CN2CC3COCC3C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.6 %

Procedure:
To a solution of (1-benzylpyrrolidine-3,4-diyl)dimethanol (1.44 g) in toluene (60 mL) was added Et3N (1.72 mL), TsCl (1.75 g) and DMAP (40 mg). The reaction mixture was stirred at room temperature for 12 h under N2, washed with water once, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the residue was used for next step. To a solution of the above product in toluene (20 mL) was added Et3N (0.85 mL). The reaction mixture was heated to reflux for 4 h and cooled to room temperature. The reaction mixture was washed with water followed by brine, dried over anhydrous Na2SO4 and filtrated. The filtrate was concentrated in vacuo and the residue was chromatographed with a silica gel column (eluting agent: 20:1 (v/v) CH2Cl2/CH3OH) to afford the title compound (0.51 g, 62.30%). The compound was characterized by the following spectroscopic data: MS (ESI, pos. ion) m/z: 204.3 (M+1); 1H NMR (400 MHz, CDCl3) δ: 2.31-2.35 (m, 2H), 2.71 (m, 2H), 2.79-2.81 (m, 2H), 3.57-3.60 (m, 4H), 3.76-3.80 (m, 2H), 7.24-7.34 (m, 5H) ppm.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[N:7]([CH2:16][C:17]([OH:19])=O)[N:6]=1)=[O:4].C1C=CC2N(O)N=NC=2C=1.[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH3:42])[NH:36]1)[CH2:33][CH3:34].CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:32]([C@H:35]1[CH2:39][CH2:38][C@H:37]([CH2:40][CH2:41][CH3:42])[N:36]1[C:17](=[O:19])[CH2:16][N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([CH3:21])([CH3:1])[CH3:20])=[N:6]1)[CH2:33][CH3:34]
Reactant: COc1ccc2c(C(=O)C(C)(C)C)nn(CC(=O)O)c2c1
Reactant: CCC[C@H]1CC[C@H](CCC)N1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: CCC[C@H]1CC[C@H](CCC)N1C(=O)Cn1nc(C(=O)C(C)(C)C)c2ccc(OC)cc21
Temperature: 25 °C

Procedure:
To a solution of 28.3 mg [3-(2,2-dimethylpropanoyl)-6-methoxy-1H-indazol-1-yl]acetic acid in 1 mL DMF was added 23.0 mg HOBt, 23.3 mg trans-2,5-dipropylpyrrolidine from the Step D above, 38.3 mg EDC, and 45.2 mg DIEA in that order. The mixture was stirred at room temperature over night and purified by RP-HPLC using 70-100% MeCN gradient. The pure product fractions were pooled and lyophilized to give the title compound as white solid. LC-MS: 4.48 min. (m/Z=428.4, 450.3).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([C:13]([NH:15][CH2:16][C:17]([OH:19])=O)=[O:14])=[N:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl.[Cl:52][C:53]1[CH:65]=[CH:64][CH:63]=[CH:62][C:54]=1[O:55][CH:56]1[CH2:61][CH2:60][NH:59][CH2:58][CH2:57]1>CN(C=O)C.O>[O:19]=[C:17]([N:59]1[CH2:58][CH2:57][CH:56]([O:55][C:54]2[CH:62]=[CH:63][CH:64]=[CH:65][C:53]=2[Cl:52])[CH2:61][CH2:60]1)[CH2:16][NH:15][C:13]([C:10]1[CH:9]=[CH:8][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:12][N:11]=1)=[O:14]
Reactant: Clc1ccccc1OC1CCNCC1
Reactant: O=C(O)CNC(=O)c1ccc(-c2ccccc2)cn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: O=C(NCC(=O)N1CCC(Oc2ccccc2Cl)CC1)c1ccc(-c2ccccc2)cn1
Reaction time: 8 h
Yield: 44.9 %

Procedure:
To a stirred solution of [(5-phenyl-pyridine-2-carbonyl)-amino]-acetic acid (0.07 g, 0.00027 mol) in DMF (1.5 mL) was added DIPEA (0.105 g, 0.00082 mol), HOBt (0.044 g, 0.00033 mol) and EDCI.HCl (0.062 g, 0.00033 mol) at ambient temperature. After 2 minutes 4-(2-chlorophenoxy)piperidine hydrochloride (0.081 g, 0.000327 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water and the product was extracted with ethyl acetate. The ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 0.0545 g (44%) of 5-phenyl-pyridine-2-carboxylic acid {2-oxo-2-[4-(2-chloro-phenoxy)-piperidin-1-yl]-ethyl}-amide. LCMS: 484.18 (M+1)+, 95.40%, 1H NMR (DMSO-d6): δ 9.0 (d, 1H), 8.8 (t, 1H), 8.3 (dd, 1H), 8.1 (d, 1H), 7.8 (d, 1H), 7.6-7.4 (m, 2H), 7.3-7.2 (m, 2H), 7.0-6.9 (m, 1H), 4.8-4.7 (m, 1H), 4.3 (d, 1H), 3.8-3.6 (m, 2H), 3.5 (m, 2H), 2.0-1.9 (m, 2H), 1.8-1.6 (m, 2H).