Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].C([O:5][N:6]=[C:7]([CH:16]1[CH2:21][CH2:20][N:19]([CH:22]=[O:23])[CH2:18][CH2:17]1)[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=1Cl)=O.CO.[Cl-].[Na+]>O1CCCC1.CN(C)C=O.O>[CH:22]([N:19]1[CH2:20][CH2:21][CH:16]([C:7]2[C:8]3[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][C:9]=3[O:5][N:6]=2)[CH2:17][CH2:18]1)=[O:23]
Reactant: O=CON=C(c1ccc(Cl)cc1Cl)C1CCN(C=O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CN(C)C=O
Product: O=CN1CCC(c2noc3cc(Cl)ccc23)CC1
Reaction time: 16 h
Yield: 80.8 %

Procedure:
To a stirred suspension of 1.25 g of sodium hydride (prepared from 2.5 g 50% oil dispersion) in 100 ml of tetrahydrofuran was added, over 20 mins, a solution of 10 g of 1-formyl-4-(2,4-dichlorobenzoyl)piperidine O-formyl oxime in 60 ml of dimethylformamide and 40 ml of tetrahydrofuran. The stirred mixture was heated to 80°-90° (oil bath temperature) for 5 hrs and after standing at 20° for 16 hrs, 10 ml of methanol and 20 ml of water were added. The reaction mixture was added to about 1.2 l of saturated sodium chloride solution. The mixture was extracted with 400 ml of ether. The extract was washed with 800 ml of water. The aqueous phase was extracted with 400 ml of ether and the combined ether extracts were distilled to yield an oil, which crystallized on standing. Recrystallization from isopropanol-ether gave 6.5 g (67.2%) of product, mp 114°- 115°.
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[C:7]([O:18][CH3:19])[CH:6]=1)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>CCOCC>[F:17][C:14]1[CH:13]=[CH:12][C:11]([C:8]2[CH:9]=[CH:10][C:5]([CH2:3][OH:2])=[CH:6][C:7]=2[O:18][CH3:19])=[CH:16][CH:15]=1
Reactant: COC(=O)c1ccc(-c2ccc(F)cc2)c(OC)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: COc1cc(CO)ccc1-c1ccc(F)cc1
Reaction time: 8 h

Procedure:
4′-Fluoro-2-methoxy-biphenyl-4-carboxylic acid methyl ester (220 mg, 0.85 mmol) is allowed to dissolve in ether and cooled. LiAlH4 (80 mg, 2.12 mmol) is then added and the suspension is then stirred overnight. After aqueous work up, the alcohol is isolated and used directly in the next step.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]1([C:19]2[CH:20]=[C:21]([CH2:25][C:26](O)=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:18]=[N:17][N:16]=[N:15]1.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl.[Cl-].[Na+].O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[N:14]1([C:19]2[CH:20]=[C:21]([CH2:25][C:26]([N:11]3[CH2:10][CH2:9][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:13][CH2:12]3)=[O:27])[CH:22]=[CH:23][CH:24]=2)[CH:18]=[N:17][N:16]=[N:15]1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1cccc(-n2cnnn2)c1
Agent: O=C([O-])O
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccc(-n3cnnn3)c2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
BOC-piperazine (502 mg, 2.69 mmol) was stirred in DCM (10 ml) and added the [3-(1H-tetrazol-1yl)phenyl]acetic acid (500 mg, 2.449 mmol) followed by HOBT (562 mg, 3.67 mmol) and EDC (939 mg, 4.90 mmol). The reaction was stirred at RT for 1 hr. The reaction was then poured into brine/NaHCO3 mixture and extracted with DCM. The organic layer was washed with 1 N HCl then dried over NaSO4, filtered and concentrated. The residue was purified by MPLC with 40 g ISCO Redi-sep column and eluted with 5% MeOH: 95% DCM solvent system to yield tert-butyl 4-{[3-(1H-tetrazol-1yl)phenyl]acetyl}piperazine-1-carboxylate. LC-MS (IE, m/z): 373 [M+1]+; 1H-NMR (500 MHz, CDCl3) δ ppm 9.025 (s, 1H), 7.67 (s, 1H), 7.64 (d, J=8.1 Hz, 1H), 7.58 (t, J=8.8 Hz, 1H), 7.44 (d, J=7.6 Hz, 1H), 3.87 (s, 2H), 3.66 (t, J=5 Hz, 2H), 3.53-3.47 (m, 4H), 1.49 (s, 9H);
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15](Br)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:25][C:26]1[CH:31]=[CH:30][C:29](B(O)O)=[CH:28][CH:27]=1.CCCCCC>C(OCC)(=O)C>[CH2:1]([O:8][N:9]=[C:10]1[C:18]2([CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:29]3[CH:30]=[CH:31][C:26]([F:25])=[CH:27][CH:28]=3)[CH:16]=2)[NH:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OB(O)c1ccc(F)cc1
Reactant: Brc1ccc2c(c1)C1(CCCCC1)C(=NOCc1ccccc1)N2
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Fc1ccc(-c2ccc3c(c2)C2(CCCCC2)C(=NOCc2ccccc2)N3)cc1
Yield: 65.4 %

Procedure:
Prepared from 5′-bromospiro{cyclohexane-1,3′-[3H]indol}-2′(1′H)-one 2′(O-benzyloxime) (1.0 g, 2.6 mmol), and 4-fluorophenyl boronic acid (0.72 g, 5.2 mmol) according to Example 45 procedure A. The product was purified by flash silica gel chromatography; (eluant: 10:0.5 hexane:ethyl acetate) to give the desired product (0.70 g, 1.7 mmol, 67%) as a viscous oil. 1H NMR (500 MHz, DMSO-d6) δ 1.42-1.77 (8H, m), 1.95-1.99 (2H, q), 5.00 (2H, s), 6.84 (1H, d, J=8.1 Hz), 7.21-7.63 (1H, m), 9.58 (1H, s); MS (ESI(−ve)) m/z 399 (M−H)−.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][NH:11][CH:12]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1.[CH2:16]1[C:19]2([CH2:22][CH2:21][CH2:20]2)[CH2:18][C:17]1=[CH:23][C:24]#[N:25].C1CCN2C(=NCCC2)CC1>CC#N>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:12]=[N:11][N:10]([C:17]3([CH2:23][C:24]#[N:25])[CH2:18][C:19]4([CH2:22][CH2:21][CH2:20]4)[CH2:16]3)[CH:9]=2)[N:5]2[CH:13]=[CH:14][N:15]=[C:4]2[CH:3]=1
Reactant: Clc1cc2nccn2c(-c2cn[nH]c2)n1
Reactant: N#CC=C1CC2(CCC2)C1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: N#CCC1(n2cc(-c3nc(Cl)cc4nccn34)cn2)CC2(CCC2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
7-Chloro-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (Preparation M, Step A; 0.380 g, 1.73 mmol), 2-(spiro[3.3]heptan-2-ylidene)acetonitrile (Example 160, Steps A-C, 0.461 g, 3.46 mmol) and DBU (0.130 mL, 0.865 mmol) were suspended in MeCN (10 mL) and stirred at ambient temperature overnight. The reaction mixture was partitioned between saturated aqueous NH4Cl and EtOAc. The organic layer was washed with brine, dried (MgSO4), filtered concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography, eluting with 2-3% (9:1 MeOH:NH4OH)/DCM to provide 2-(2-(4-(7-chloroimidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)spiro[3.3]heptan-2-yl)acetonitrile (0.493 g, 1.40 mmol, 81% yield). MS (apci) m/z=353.1 (M+H).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[CH:8][C:9]([CH3:42])=[C:10]([CH:41]=2)[C@@H:11]([C:29]2[C:38]([CH3:39])=[CH:37][C:32]([C:33]([O:35]C)=[O:34])=[CH:31][C:30]=2[CH3:40])[O:12]C(=O)[C@H](C2C=CC3C(=CC=C(OC)C=3)C=2)C)[CH:5]=[CH:4][N:3]=[CH:2]1.[OH-].[Na+]>CO>[OH:12][C@H:11]([C:29]1[C:30]([CH3:40])=[CH:31][C:32]([C:33]([OH:35])=[O:34])=[CH:37][C:38]=1[CH3:39])[C:10]1[CH:41]=[C:6]([N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH:7]=[CH:8][C:9]=1[CH3:42]
Reactant: COC(=O)c1cc(C)c([C@@H](OC(=O)[C@@H](C)c2ccc3cc(OC)ccc3c2)c2cc(-n3ccnc3)ccc2C)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2ccnc2)cc1[C@H](O)c1c(C)cc(C(=O)O)cc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
Methyl (S)-4-[5-(1-imidazolyl)-α-{(S)-2-(6-methoxy-2-naphthyl)propionyloxy}-2-methylbenzyl]-3,5-dimethylbenzoate (47 g) obtained in Example 1 was suspended in methanol (376 ml) and an aqueous solution (95 ml) containing sodium hydroxide (8 g) was added, which was followed by stirring at 60° C. for 2 hours. The reaction mixture was concentrated and to the residue were added dimethylformamide (300 ml) and water (300 ml), which was followed by neutralization with glacial acetic acid (23 ml). The precipitated crystals were collected by filtration, washed with water and acetone, and recrystallized from dimethylformamide to give 25.3 g of (S)4-[α-hydroxy-5-(1-imidazolyl)-2-methylbenzyl]-3,5-dimethylbenzoic acid, melting point 286-288° C. (decomposition), optical rotation [α]D21 -261.5° (c=1.0, dimethylformamide).
Reaction SMILES: S([O-])(O)(=O)=O.[CH3:6][N+:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH3:13])[CH:8]=1.[C:14]([OH:17])(=[O:16])[CH3:15]>>[C:14]([O-:17])(=[O:16])[CH3:15].[CH3:6][N+:7]1[CH:11]=[CH:10][N:9]([CH2:12][CH3:13])[CH:8]=1
Reactant: CC(=O)O
Agent: CCn1cc[n+](C)c1
Agent: O=S(=O)([O-])O
Product: CC(=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
226.8 g (0.72 mol) of Ba(OH)2 (octahydrate) are suspended in 600 g of water. The suspension is heated to 80° C., resulting in the barium salt melting and forming an aqueous emulsion. 149.8 g (0.72 mol) of 1-methyl-3-ethylimidazolium hydrogensulfate are added dropwise to this emulsion, with the temperature rising to 100° C. Despite the barium sulfate which precipitates, the suspension remains readily stirrable. The reaction mixture is stirred for another 2 hours at 80° C., cooled and the precipitated BaSO4 is filtered off using Celite as filter aid. After addition of 43.5 g (0.72 mol) of glacial acetic acid, the water is removed on a rotary evaporator and the oil which remains is extracted with ethyl acetate. Drying under reduced pressure gives 113.3 g (0.67 mol) of 1-methyl-3-ethylimidazolium acetate (yield: 92%). The chloride content is 4 ppm.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH:21]4[CH2:23][CH2:22]4)(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[NH2:30][C:31]1[N:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][N:32]=1>>[O:27]1[CH2:28][CH2:29][N:24]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][N:15]([S:18]([CH:21]5[CH2:23][CH2:22]5)(=[O:20])=[O:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:34]3[CH:33]=[N:32][C:31]([NH2:30])=[N:36][CH:35]=3)[N:3]=2)[CH2:25][CH2:26]1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
Reactant: O=S(=O)(C1CC1)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Product: Nc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCN(S(=O)(=O)C5CC5)CC4)cc3n2)cn1

Procedure:
2-Chloro-6-(4-cyclopropanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine was reacted with 2-aminopyrimidine-5-boronic acid pinacol ester using General Procedure A. Purification on silica yielded 122. (400 MHz, CDCl3): 0.92-0.94 (2H, m, CH2), 1.11-1.12 (2H, m, CH2), 2.21 (1H, m, CH), 2.58-2.61 (4H, m, CH2), 3.29-3.32 (4H, m, CH2), 3.80-3.82 (6H, m, CH2), 3.94-3.97 (4H, m, CH2), 5.13 (2H, b, NH2), 7.23 (1H, s, ar), 9.21 (2H, s, ar). (M+H)+ 517.35
Reaction SMILES: [BH4-].[Na+].[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:20][CH2:19][C:18](=[O:21])[C:14]2[N:15]=[CH:16][S:17][C:13]=2[C@H:12]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26]>CO>[F:3][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[C@@H:11]1[CH2:20][CH2:19][C@@H:18]([OH:21])[C:14]2[N:15]=[CH:16][S:17][C:13]=2[C@H:12]1[NH:22][C:23](=[O:29])[O:24][C:25]([CH3:27])([CH3:26])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H]1c2scnc2C(=O)CC[C@H]1c1cccc(F)c1F
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1c2scnc2[C@H](O)CC[C@H]1c1cccc(F)c1F
Reaction time: 0.5 h

Procedure:
Sodium borohydride (9.93 mg, 0.262 mmol) was added to a methanol (5 mL) solution of tert-butyl (7S,8S)-7-(2,3-difluorophenyl)-4-oxo-5,6,7,8-tetrahydro-4H-cyclohepta[d]thiazol-8-ylcarbamate (34.5 mg, 0.087 mmol) at rt. The reaction was stirred for 0.5 h. The solvent was removed under vacuum and the product was purified by prep TLC developed with ethyl acetate in hexane (50%). There were two bands collected. The less polar was the desired product (20.1 mg. 58%): LCMS: M+H=397.24; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.57 (1H, s), 7.03-7.09 (3H, m), 5.16-5.23 (1H, m), 4.94-5.00 (1H, m), 4.85-4.91 (1H, m), 4.26 (1H, s), 3.28-3.36 (1H, m), 2.19-2.36 (3H, m), 1.64-1.69 (1H, m), 1.26-1.29 (8H, m).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].[CH3:18][NH:19][CH3:20].C(O)C>CS(C)=O.O.C(OCC)(=O)C>[CH3:18][N:19]([CH3:20])[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11]
Reactant: CNC
Reactant: COc1cc(C=O)ccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: CCO
Product: COc1cc(C=O)ccc1N(C)C
Temperature: 100 °C
Reaction time: 5 h
Yield: 98 %

Procedure:
4-Fluoro-3-methoxybenzaldehyde (500 mg, 3.24 mmol) was dissolved in 6.9 mL of DMSO and 2.8 mL of water, and then potassium carbonate (0.45 g, 3.3 mmol) and dimethylamine solution in ethanol (0.88 mL, 5.5 M, 4.8 mmol) were added to the solution at room temperature, successively. After being stirred at 100° C. for 5 h, the reaction mixture was cooled to room temperature. The reaction mixture was diluted with ethyl acetate, and the solution was washed with water, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (eluting with hexane/ethyl acetate=4/1 to 2/1) to obtain the title compound as a pale yellow oil (569 mg, 98%).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:19]3=[N:20][CH:21]=[C:22]([Cl:24])[CH:23]=[C:18]3[N:17]([CH:25]([CH3:27])[CH3:26])[C:16]2=[O:28])=[CH:11][CH:10]=1)C1C=CC=CC=1>CCOC(C)=O.[Pd]>[Cl:24][C:22]1[CH:23]=[C:18]2[N:17]([CH:25]([CH3:27])[CH3:26])[C:16](=[O:28])[N:15]([C:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=3)[C:19]2=[N:20][CH:21]=1
Reactant: CC(C)n1c(=O)n(-c2ccc(OCc3ccccc3)cc2)c2ncc(Cl)cc21
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)n1c(=O)n(-c2ccc(O)cc2)c2ncc(Cl)cc21
Reaction time: 1 h
Yield: 43.2 %

Procedure:
A mixture of 3-[4-(benzyloxy)phenyl]-6-chloro-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (600 mg) and 10% Pd—C (162 mg) in EtOAc (50 mL) was hydrogenated under balloon pressure at room temperature for 1 h. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (silica gel, eluted with 0%-50% EtOAc in hexane) to give 6-chloro-3-(4-hydroxyphenyl)-1-(1-methylethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (200 mg) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:14]([CH2:33][O:34][CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[O:13][C@@H:10]1[O:11]C)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O>C(O)(=O)C>[CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@@H:14]([CH2:33][O:34][CH2:35][C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[O:13][C@@H:10]1[OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: O[C@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Yield: 53.3 %

Procedure:
The crude methyl 2,3,4,6-tetra-O-benzyl-D-glucopyranoside 10 (210 g) is dissolved in glacial acetic acid (500 mL) and the solution is heated to nearly boiling. Hot sulfuric acid solution (3N, 130 mL) is added slowly. Heat is periodically increased and more acetic acid (20 mL) is added to dissolve any precipitate. The final cloudy solution is heated at 100°-110° C. for 2 h. After cooling, crude crystalline product is isolated by filtration and washed several times with methanol to yield product 11 as white crystals (109 g, 53%): mp. 168°-170° C. (Lit. 169°-171° C.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([OH:8])[CH:3]=1.Br[C:10]1[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=1.C(=O)([O-])[O-].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>CN(C=O)C.C(OCC)(=O)C.[Cu]I>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([C:10]2[S:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[C:13]([CH3:15])[N:14]=2)[C:4](=[O:8])[CH:3]=1
Reactant: CCOC(=O)c1sc(Br)nc1C
Reactant: Oc1cc(Cl)ccn1
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc(-n2ccc(Cl)cc2=O)nc1C
Temperature: 100 °C
Reaction time: 5 h
Yield: 0.3 %

Procedure:
4-Chloro-2-hydroxypyridine (500 mg, 3.86 mmol), ethyl 2-bromo-4-methyl-1,3-thiazole-5-carboxylate (1.06 g, 4.24 mmol), potassium carbonate (1.06 g, 7.67 mmol) and copper (I) iodide (73 mg, 0.38 mmol) were suspended in DMF (4 mL). trans(±)-N,N′-Dimethylcyclohexane-1,2-diamine (82 mg, 0.58 mmol) was added, and the mixture was stirred at 100° C. for five hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=5/1→2/1) to obtain 3.2 mg of the title compound as a white solid (0.3%).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[S:6][C:7]([NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[C:8]([C:10]([OH:12])=O)[N:9]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH3:51][C:52]1[N:57]=[C:56]([NH2:58])[CH:55]=[CH:54][CH:53]=1>CN(C)C=O>[CH3:51][C:52]1[N:57]=[C:56]([NH:58][C:10]([C:8]2[N:9]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[S:6][C:7]=2[NH:13][C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)=[O:12])[CH:55]=[CH:54][CH:53]=1
Reactant: Cc1cccc(N)n1
Reactant: COCCc1nc(C(=O)O)c(Nc2cccnc2)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCc1nc(C(=O)Nc2cccc(C)n2)c(Nc2cccnc2)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 27.1 %

Procedure:
A solution of 2-(2-methoxy-ethyl)-5-(pyridin-3-ylamino)-thiazole-4-carboxylic acid (0.032 g, 0.11 mmol) in dimethylformamide (1.00 ml) was treated with DIPEA (0.042 g, 0.33 mmol), TBTU (0.053 g, 0.16 mmol) and 6-methyl-pyridin-2-yl-amine (0.018 g, 0.16 mmol). The mixture was stirred at room temperature overnight, then purified by direct injection in preparative HPLC (ZORBAX Eclipse XDB-C18, 21.2×50 mm, 5 μm, gradient acetonitrile/water+0.1% formic acid). The tide compound (0.011 g, 27%) was obtained as a white solid, MS (ISP): m/e=370.1 (M+H+).
Reaction SMILES: [C:1]([NH:9][CH2:10][C@@H:11]([C:33]([O:35]C)=[O:34])[NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:16][C:15]=1[Cl:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Li+]>O1CCCC1.CO.O>[C:1]([NH:9][CH2:10][C@@H:11]([C:33]([OH:35])=[O:34])[NH:12][C:13](=[O:32])[C:14]1[CH:19]=[CH:18][C:17]([C:20]([NH:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([OH:30])[CH:25]=2)=[O:21])=[CH:16][C:15]=1[Cl:31])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](CNC(=O)c1ccccc1)NC(=O)c1ccc(C(=O)NCc2cccc(O)c2)cc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(NCc1cccc(O)c1)c1ccc(C(=O)N[C@@H](CNC(=O)c2ccccc2)C(=O)O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.2 %

Procedure:
A solution of 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine, methyl ester (10.7 g, 21.0 mmol) in tetrahydrofuran/methanol (3:1; 80 mL) was added to a stirred solution of lithium hydroxide monhydrate (2.65 g, 63.0 mmol) in water (40 mL) at room temperature. The reaction was stirred at room temperature overnight and then concentrated to remove methanol and tetrahydrofuran. Water (150 mL) was added and the mixture was cooled to between 0 and −5° C. The mixture was acidified to pH 3 with concentrated HCl and stirred for 10 min. The mixture was extracted twice with ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and evaporated to give 3-benzoylamino-N-[2-chloro-4-[[[(3-hydroxyphenyl)methyl]amino]carbonyl]benzoyl]-L-alanine (7.1 g). The drying agent was extracted with ethyl acetate/methanol (50:3; 2×106 mL) to give a further quantity of the product (3.3 g). Overall yield: 10.4 g (quantitative).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11](O)=[O:12])[CH:10]=1)[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH:6]=[CH:5]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CS([O-])(=O)=O.[CH3:54][O:55][C:56]([C:58]1[CH:63]=[CH:62][C:61]([C:64]2([NH3+:67])[CH2:66][CH2:65]2)=[CH:60][CH:59]=1)=[O:57].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>CN(C=O)C.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH:67][C:64]3([C:61]4[CH:62]=[CH:63][C:58]([C:56]([O:55][CH3:54])=[O:57])=[CH:59][CH:60]=4)[CH2:66][CH2:65]3)=[O:12])[CH:10]=1)[N:7]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=1)[CH:6]=[CH:5]2
Reactant: COC(=O)c1ccc(C2([NH3+])CC2)cc1
Reactant: O=C(O)c1cc(F)cc2ccn(Cc3ccc(C(F)(F)F)cc3)c12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CS(=O)(=O)[O-]
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(F)cc4ccn(Cc5ccc(C(F)(F)F)cc5)c34)CC2)cc1
Reaction time: 8 h

Procedure:
5-fluoro-1-[4-(trifluoromethyl)benzyl]-1H-indole-7-carboxylic acid (218 mg, 0.65 mmol), HATU (283 mg, 0.74 mmol) and 1-[4-(methoxycarbonyl)phenyl]cyclopropanaminium methane sulfonate (374 mg, 1.3 mmol) were dissolved in DMF (4 ml), then was added Hunig's base (0.34 ml, 2.0 mmol). The reaction mixture was aged at RT overnight. The mixture was transferred to a separating funnel with EtOAc and NaHCO3 (½ sat.). The organic layer was washed with 4× brine (½ sat.), dried over MgSO4, filtered and the solvent evaporated under reduced pressure. The product was purified by flash chromatography on silica gel. 1H NMR (500 MHz, DMSO-d6): δ 9.25 (s, 1H), 7.75 (d, 2H), 7.55 (m, 4H), 7.20 (m, 3H), 6.90 (d, 2H), 6.65 (d, 1H), 5.65 (s, 2H), 3.85 (d, 3H), 1.20 (m, 2H), 0.95 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Sn](Cl)Cl.C(OCC)(=O)C.[OH-].[Na+]>CO.O>[NH2:12][C:9]1[CH:10]=[CH:11][C:2]([Br:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1Br
Agent: Cl[Sn]Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)ccc1Br
Yield: 93.8 %

Procedure:
Methyl 2-Bromo-5-nitrobenzoate (25.3 g, 97.3 mmol) was dissolved in anhydrous methanol (50 mL), and tin (II) chloride (93.3 g, 487 mmol) was added thereto, and then the reaction mixture was refluxed for 2 hours. After cooling down, ethyl acetate (500 mL) and water (100 mL) were added thereto, and the mixture was neutralized with 4N aqueous NaOH solution, and then it was filtered on celite. The filtrate was concentrated under reduced pressure, and ethyl acetate (200 mL) was added thereto, and then it was washed with saturated NaHCO3 solution (200 mL, twice), water (200 mL) and saturated brine (200 mL) successively. The organic layer was dried over anhydrous magnesium sulfate and the solvent was removed under reduced pressure to give the titled reference compound (21.0 g) as a yellow oil. (Yield 94%)
Reaction SMILES: [CH:1]([N:4]([CH:16]([CH3:18])[CH3:17])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:8]#[N:9])([CH3:3])[CH3:2].[CH:19]([N:22]([CH:34]([CH3:36])[CH3:35])[CH2:23][CH2:24]C(C1C=CC=CC=1)C#N)([CH3:21])[CH3:20]>>[CH:16]([N:4]([CH:1]([CH3:3])[CH3:2])[CH2:5][CH2:6][C:7]([CH2:24][CH2:23][N:22]([CH:34]([CH3:36])[CH3:35])[CH:19]([CH3:21])[CH3:20])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)[C:8]#[N:9])([CH3:18])[CH3:17]
Reactant: CC(C)N(CCC(C#N)c1ccccc1)C(C)C
Reactant: CC(C)N(CCC(C#N)c1ccccn1)C(C)C
Product: CC(C)N(CCC(C#N)(CCN(C(C)C)C(C)C)c1ccccn1)C(C)C

Procedure:
Substitution of an equivalent quantity of the preceding acetonitrile for α-[2-(diisopropylamino)ethyl]-α-phenylacetonitrile called for in Example 2, Method B and substantial repetition of the procedure detailed in that example, affords α,α-bis[2-(diisopropylamino)ethyl]-α-(2-pyridyl)acetonitrile, as an oil boiling at about 155°-160° C. at 0.3 mm. pressure.