Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.[NH2:10][C:11]1[NH:15][N:14]=[N:13][N:12]=1>O1CCCC1.C(N(CC)CC)C.C(Cl)(=O)OCC>[NH:12]1[C:11]([NH:10][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])=[N:15][N:14]=[N:13]1
Reactant: O=C(O)c1cnccn1
Reactant: Nc1nnn[nH]1
Agent: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1nnn[nH]1)c1cnccn1

Procedure:
To a suspension of 1.50 g of pyrazine-2-carboxylic acid in 50 ml of tetrahydrofuran, 1.85 ml of triethylamine and 1.27 ml of ethyl chlorocarbonate were added dropwise successively at 0° C. under stirring. After stirring for 30 minutes at 0° C., 1.35 g of 5-amino-1H-tetrazole was added to the mixture, and the reaction mixture was stirred for 28.5 hours at room temperature. The precipitate was collected by filtration, and washed with dilute hydrochloric acid affording 2.05 g as colorless crystals, which was recrystalized from dimethylsulfoxide giving colorless crystals, m.p. 291°-296 ° C. (decomp.).
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([OH:3])=[O:2].[H-].[Na+].P(=O)([O-])[O-:15].Cl.[O:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>O>[C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[CH:21][C:20]([O:19][CH2:23][CH3:22])=[O:15])=[CH:6][CH:5]=1)([OH:3])=[O:2]
Reactant: O=[PH]([O-])[O-]
Reactant: C1CCOC1
Reactant: O=Cc1ccc(C(=O)O)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)C=Cc1ccc(C(=O)O)cc1
Reaction time: 16 h

Procedure:
4-Carboxybenzaldehyde (1.0 g) was added to sodium hydride (170 mg) in 100 mL tetrahydrofuran at 0° C. In a separate flask, triethyl phosphonoacetate (1.60 mL) was added to sodium hydride (200 mg) in 100 mL tetrahydrofuran at 0° C. The phosphonate anion solution was cannulated into the slurry of the carboxylate anion and the resulting thick white slurry was stirred for 16 hours. Water (50 mL) was added followed by concentrated hydrochloric acid until the pH was 1. The precipitate was collected by filtration, dissolved in ether and dried with magnesium sulfate. Evaporation under reduced pressure gave the product (1.47 g; 100%) as a white solid.
Reaction SMILES: C([Si](C(C)C)(C(C)C)[N:5]1[C:9]2=[N:10][CH:11]=[C:12]([OH:14])[CH:13]=[C:8]2[CH:7]=[CH:6]1)(C)C.F[C:22]1[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=1[C:24]([O:26][CH3:27])=[O:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>COCCOCCOC.CCOCC>[NH:5]1[C:9]2=[N:10][CH:11]=[C:12]([O:14][C:22]3[CH:31]=[C:30]([F:32])[CH:29]=[CH:28][C:23]=3[C:24]([O:26][CH3:27])=[O:25])[CH:13]=[C:8]2[CH:7]=[CH:6]1
Reactant: COC(=O)c1ccc(F)cc1F
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1ccc2cc(O)cnc21
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOCCOC
Solvent: CCOCC
Product: COC(=O)c1ccc(F)cc1Oc1cnc2[nH]ccc2c1

Procedure:
A mixture of EXAMPLE 277G (8.5 g), methyl 2,4-difluorobenzoate (7.05 g), and K3PO4 (9.32 g) in diglyme (40 mL) at 115° C. was stirred for 24 hours. The reaction was cooled, diluted with ether (600 mL), and washed twice with water, and brine, and concentrated. The crude product was chromatographed on silica gel with 2-50% ethyl acetate/hexanes.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]1C2CC[CH:11]([CH:12]=[CH:13]2)[S:10]1.C[N+]1([O-])CC[O:21]CC1.[CH3:25][C:26]([CH3:28])=[O:27]>C(O)(C)(C)C.[Os](=O)(=O)(=O)=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][N:8]=[C:9]1[CH:28]2[CH2:13][CH2:12][CH:11]([CH:25]([OH:21])[CH:26]2[OH:27])[S:10]1
Reactant: C[N+]1([O-])CCOCC1
Reactant: CC(C)=O
Reactant: C1=CC2CCC1SC2=NOC1CCCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: CC(C)(C)O
Product: OC1C2CCC(C(=NOC3CCCCO3)S2)C1O
Reaction time: 4 h

Procedure:
A mixture of 8 g (0.033 m) of the product of Example 8, 5.3 g (0.039 m) of N-methylmorpholine N-oxide, 4 ml of 2.5% osmium tetroxide in t-butanol, and 20 ml of acetone was stirred for four hours then extracted with ethylacetate. The organic solution was washed with brine, dried, and stripped to give 12 g of crude product which was purified by dry column chromatography (silica gel, ethylacetate:hexane::1:1) to yield 5.8 g of the title compound as a white solid, M. 124°-6° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[CH3:4][O:5][C:6]1[CH:20]=[CH:19][C:9]([CH2:10][N:11]2[CH2:16][CH2:15][CH:14]([CH:17]=O)[CH2:13][CH2:12]2)=[CH:8][CH:7]=1.[C-:21]#[N:22].[K+].Cl>O.CO>[CH3:1][N:2]([CH3:3])[CH:17]([CH:14]1[CH2:15][CH2:16][N:11]([CH2:10][C:9]2[CH:19]=[CH:20][C:6]([O:5][CH3:4])=[CH:7][CH:8]=2)[CH2:12][CH2:13]1)[C:21]#[N:22]
Reactant: [C-]#N
Reactant: COc1ccc(CN2CCC(C=O)CC2)cc1
Reactant: CNC
Agent: Cl
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccc(CN2CCC(C(C#N)N(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
40% aqueous dimethylamine solution (2.66 ml, 21 mmol), 1-(4-methoxybenzyl)-piperidine-4-carbaldehyde (750 mg, 3.2 mmol) and potassium cyanide (688 mg, 10.6 mmol) were added, while cooling with ice, to a mixture of 4 N hydrochloric acid (1.2 ml) and methanol (5 ml). The reaction mixture was stirred for 5 d at room temperature, then water (50 ml) was added and extraction with ethyl acetate was carried out (3×50 ml). The combined organic phases were dried over sodium sulfate and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]([NH:13][C:14](=[O:18])OCC)=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1.[Br:23][C:24]1[CH:25]=[C:26]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH:27]=[CH:28][CH:29]=1>>[CH3:1][O:2][C:3]1[C:12]([NH:13][C:14]([N:33]2[CH2:32][CH2:31][N:30]([C:26]3[CH:27]=[CH:28][CH:29]=[C:24]([Br:23])[CH:25]=3)[CH2:35][CH2:34]2)=[O:18])=[N:11][C:10]2[C:5](=[CH:6][C:7]([O:21][CH3:22])=[C:8]([O:19][CH3:20])[CH:9]=2)[N:4]=1
Reactant: Brc1cccc(N2CCNCC2)c1
Reactant: CCOC(=O)Nc1nc2cc(OC)c(OC)cc2nc1OC
Product: COc1cc2nc(NC(=O)N3CCN(c4cccc(Br)c4)CC3)c(OC)nc2cc1OC
Yield: 63 %

Procedure:
Ethyl N-(2,6,7-trimethoxyquinoxalin-3-yl)carbamate and 1-(3-bromophenyl)piperazine were reacted by the same way with the example 190 to obtain the titled compound (yield, 63%). 1H NMR (300 MHz, CDCl3) δ 3.28-3.30 (m, 4H), 3.78 (m, 4H), 3.97 (s, 3H), 3.99 (s, 3H), 4.13 (s, 3H), 6.86 (m, 1H), 7.01 (s, 1H), 7.06-7.07 (m, 1H), 7.13-7.16 (m, 2H), 7.22-7.28 (m, 2H).
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]2[O:12][CH2:11]2)=[CH:6][CH:5]=1)#[N:2].[CH2:15]([NH:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>CO>[C:1]([CH2:3][C:4]1[CH:14]=[CH:13][C:7]([O:8][CH2:9][CH:10]([OH:12])[CH2:11][N:19]([CH2:20][CH2:21][CH2:22][CH3:23])[CH2:15][CH2:16][CH2:17][CH3:18])=[CH:6][CH:5]=1)#[N:2]
Reactant: N#CCc1ccc(OCC2CO2)cc1
Reactant: CCCCNCCCC
Solvent: CO
Product: CCCCN(CCCC)CC(O)COc1ccc(CC#N)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
30 g. of 3-(4-cyanomethylphenoxy)propylene oxide were mixed with 133.5 ml dibutylamine and 300 ml methanol and stirred at room temperature for 20 hours. The mixture was concentrated in a rotary evaporator and the residue was taken up in 225 ml of 1 N hydrochloric acid. The acidic solution was extracted with a total of 300 ml of dichloromethane. The dichloromethane phase was discarded. The aqueous phase was mixed with about 70 ml of 4 N caustic soda solution and extracted by shaking with 200 ml dichloromethane. The dichloromethane phase was dried over sodium sulfate. The desiccant was filtered off and the dichloromethane was drawn off with a rotary evaporator.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=2[N+:31]([O-])=O)[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>C(Cl)Cl.C(O)(=O)C.[Zn]>[Si:1]([O:8][C@@H:9]1[C@H:13]([CH2:14][O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[CH2:12][C@@H:11]([O:23][C:24]2[CH:29]=[CH:28][N:27]=[C:26]([NH2:30])[C:25]=2[NH2:31])[CH2:10]1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2[N+](=O)[O-])C[C@@H]1O[Si](C)(C)C(C)(C)C
Agent: [Zn]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(C)(C)[Si](C)(C)OC[C@@H]1C[C@@H](Oc2ccnc(N)c2N)C[C@@H]1O[Si](C)(C)C(C)(C)C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
To a solution of 4-{[(1R,3S,4S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclopentyl]oxy}-3-nitropyridin-2-amine (0.361 g, 0.000725 mol) in CH2Cl2 (6.00 mL) and acetic acid (3.00 mL) was added zinc (0.474 g, 0.00725 mol) and the mixture was stirred for 30 min. The suspension was filtered and the filtrate was concentrated. The residue was dissolved in 50 ml EtOAc and 3 ml Et3N then washed with water (2×10 mL). The organic layer was dried (MgSO4) and concentrated to afford the crude product (0.297 g, 88%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][NH:9]2)=[C:4]([F:18])[CH:3]=1.CCN(C(C)C)C(C)C.[C:28](Cl)(=[O:31])[O:29][CH3:30]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:13][CH:12]([C:14]([O:16][CH3:17])=[O:15])[CH2:11][CH2:10][N:9]2[C:28]([O:29][CH3:30])=[O:31])=[C:4]([F:18])[CH:3]=1
Reactant: COC(=O)Cl
Reactant: COC(=O)C1CCNC(c2ccc(Cl)cc2F)C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(Cl)cc2F)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.9 %

Procedure:
Methyl 2-(4-chloro-2-fluorophenyl)piperidine-4-carboxylate (7.45 g, 27.42 mmol) was dissolved into DCM (120 mL) then DIPEA (11.97 mL, 68.55 mmol) was added. Methyl carbonochloridate (3.02 mL, 38.39 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 3 h. The mixture was washed with 0.1 M HCl (2×100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated leaving dimethyl 2-(4-chloro-2-fluorophenyl)piperidine-1,4-dicarboxylate (7.77 g, 86%) as an orange oil. MS m/z 330 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:29]([OH:32])CO)[CH:25]=5)[C:19]=4[N:20]=3)[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.I([O-])(=O)(=O)=O.[Na+].C(OCC)(=O)C>CO.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:14][CH2:15][C:16]3[O:17][C:18]4[CH:28]=[CH:27][C:26]5[C:21](=[CH:22][CH:23]=[C:24]([CH:29]=[O:32])[CH:25]=5)[C:19]=4[N:20]=3)[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: OCC(O)c1ccc2c(ccc3oc(CCC4(c5ccc(F)cc5)CCCCC4)nc32)c1
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: O=Cc1ccc2c(ccc3oc(CCC4(c5ccc(F)cc5)CCCCC4)nc32)c1
Reaction time: 0.5 h

Procedure:
To a solution of 1-(2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)naphtho[1,2-d]oxazol-7-yl)ethane-1,2-diol (Preparation 42D, 0.051 g, 0.117 mmol) in methanol (1 mL) at 0° C. was added a solution of sodium periodate (0.038 g, 0.176 mmol) in water (1.000 mL) dropwise and the mixture was stirred for 30 mins at the same temp. Next, about 5 mL of ethyl acetate was added and the mixture was stirred for an addition 1 hr at 0-10° C. The mixture was extracted with EtOAc, washed with brine, dried over sodium sulfate, and evaporated to give the desired 2-(2-(1-(4-fluorophenyl)cyclohexyl)ethyl)naphtho[1,2-d]oxazole-7-carbaldehyde as an oil. 1H NMR (400 MHz, CDCl3) δ ppm 10.17 (1H, s), 8.51 (1H, d, J=8.58 Hz), 8.44 (1H, s), 8.09 (1H, dd, J=8.58, 1.32 Hz), 7.89 (1H, d, J=9.02 Hz), 7.68 (1H, d, J=9.02 Hz), 7.35 (2H, dd, J=9.02, 5.28 Hz), 7.02 (2H, t, J=8.69 Hz), 2.66-2.72 (2H, m), 2.15-2.22 (2H, m), 1.17-1.92 (10H, m).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:35])=[C:16]([NH:26][C:27](=[O:34])OCC(Cl)(Cl)Cl)[C:17]([CH3:25])=[C:18]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[NH2:36][CH2:37][CH2:38][OH:39]>CCCCCC.C(OCC)(=O)C>[OH:39][CH2:38][CH2:37][NH:36][C:27]([NH:26][C:16]1[C:17]([CH3:25])=[C:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:8]=[CH:9][C:4]([CH:1]([CH3:2])[CH3:3])=[CH:5][CH:6]=3)[C:14]=2[C:15]=1[CH3:35])=[O:34]
Reactant: NCCO
Reactant: Cc1c(NC(=O)OCC(Cl)(Cl)Cl)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(NC(=O)NCCO)c(C)c2c(c1-c1ccccc1)OCC2c1ccc(C(C)C)cc1
Yield: 59 %

Procedure:
Using 2,2,2-trichloroethyl (3-(4-isopropylphenyl)-4,6-dimethyl-7-phenyl-2,3-dihydro-1-benzofuran-5-yl)carbamate obtained in Example 142 and 2-aminoethanol, the title compound was synthesized in the same manner as in Example 143. Yield: 59%. Melting point: 152-155° C. (hexane-ethyl acetate).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.[CH:38]1([CH2:41][C:42](O)=[O:43])[CH2:40][CH2:39]1.C(N(CC)CC)C.C1C=C2N=NN(O)C2=CC=1.O.CCN=C=NCCCN(C)C.Cl>CN(C=O)C>[CH:38]1([CH2:41][C:42]([NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)=[O:43])[CH2:40][CH2:39]1
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of tert-butyl (6-(7-(4-amino-2-fluorophenoxy)thieno[3,2-b]pyridin-2-yl)pyridin-3-yl)methyl(2-methoxyethyl)carbamate (11, 500 mg, 0.95 mmol), cyclopropylacetic acid (115 mg, 1.149 mmol) and triethylamine (400 μL, 2.86 mmol) in DMF (10 mL) under nitrogen were added HOBT hydrate (161 mg, 1.05 mmol) and EDC hydrochloride (457 mg, 2.38 mmol) reagents, and the reaction mixture was stirred at RT overnight. More cyclopropylacetic acid (115 mg, 1.149 mmol) and EDC hydrochloride (500 mg, 2.61 mmol) were added, and the reaction mixture was stirred at RT overnight. The reaction mixture was then quenched by addition of water and extracted with AcOEt. The organic layer was successively washed with water (×2), a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified twice by Biotage (SiliaFlash 40 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20 CV and SiliaFlash 40 g; MeOH/DCM: 0/100 to 5/95 over 20 CV, then 5/95 to 10/90 over 10 CV), to afford the title compound 12 as pale yellow sticky solid. The material was used in the next step without any further purification. MS (m/z): 607.7 (M+H).
Reaction SMILES: [CH:1]1[C:13]2[CH:12]([CH2:14][O:15][C:16]([NH:18][C@H:19]([C:25]([OH:27])=[O:26])[CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])=[O:17])[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[C:28]1([CH2:34][S:35](Cl)(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[C:28]1([CH2:34][S:35]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]([C:25]([OH:27])=[O:26])[NH:18][C:16]([O:15][CH2:14][CH:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[C:5]3[C:13]2=[CH:1][CH:2]=[CH:3][CH:4]=3)=[O:17])(=[O:37])=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: NCCCC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: O=C(N[C@@H](CCCCNS(=O)(=O)Cc1ccccc1)C(=O)O)OCC1c2ccccc2-c2ccccc21
Yield: 15 %

Procedure:
Nα-(9-fluorenylmethoxycarbonyl)-L-lysine was reacted with phenylmethylsulfonyl chloride under the conditions used in example 2 giving 15% of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[N:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([NH2:31])=[CH:28][CH:29]=2)[CH:24]=[N:23]1>C(C#N)(C)=O>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:31][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([CH2:21][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][N:15]=2)[N:23]=[CH:24]3)[N:7]=1
Reactant: Clc1ncnc(Cl)n1
Reactant: Nc1ccc2c(cnn2Cc2ccccn2)c1
Agent: CC(=O)C#N
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccn3)c2)n1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mixture of the compound 2,4-dichloro-1,3,5-triazine (267 mg, 1.78 mmol) and solid K2CO3 (1.23 g, 8.42 mmol) was suspended in AcCN (20 mL) under nitrogen at 0° C. followed by addition of a solution of 1-pyridin-2-ylmethyl-1H-indazol-5-ylamine (Step 3) (400 mg, 1.78 mmol) in AcCN (3 mL) over 5 min. The mixture was stirred at 0° C. for 1 h. The reaction was quenched by pouring onto water. The organics were extracted into EtOAc (200 mL), washed with brine, dried over anh. Na2SO4, concentrated under reduced pressure then purified by column chromatography (elution with EtOAc followed by 9:1 CH2Cl2/MeOH) to give (4-chloro-[1,3,5]triazin-2-yl)-(1-pyridin-2-ylmethyl-1H-indazol-5-yl)-amine.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[CH2:13]([N+:17]([O-])=O)/[CH:14]=[N:15]\[OH:16].C(O)(=[O:22])C>>[C:4]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[N:17]=[C:13]([OH:22])[CH:14]=[N+:15]2[O-:16])=[CH:7][CH:6]=1)([O:3][CH2:1][CH3:2])=[O:12]
Reactant: CC(=O)O
Reactant: O=[N+]([O-])C/C=N\O
Reactant: CCOC(=O)c1ccc(N)cc1
Product: CCOC(=O)c1ccc(-n2nc(O)c[n+]2[O-])cc1

Procedure:
280 g of oxime-hydrazone II (R = carbethoxyphenyl), prepared from diazotised 4-aminobenzoic acid-ethyl ester and methazonic acid, is stirred in 2000 ml of acetic acid for 10 hours at 60° C. The whole is cooled and the precipitate is filtered off with suction, well washed with water and again filtered off with suction.
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[O:43]1[CH:47]=[CH:46][CH:45]=[C:44]1[C:48]1[NH:52][N:51]=[C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])[CH:49]=1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:51]2[C:50]([C:53]([O:55][CH2:56][CH3:57])=[O:54])=[CH:49][C:48]([C:44]3[O:43][CH:47]=[CH:46][CH:45]=3)=[N:52]2)=[CH:37][CH:38]=1
Reactant: CCOC(=O)c1cc(-c2ccco2)[nH]n1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: CCOC(=O)c1cc(-c2ccco2)nn1Cc1c(-c2ccc(Cl)cc2)nc2ccccn12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and ethyl 5-(furan-2-yl)-1H-pyrazole-3-carboxylate. The regioisomers were separated silica gel chromatography. Compound 30: M/e+ 447 for C24H20ClN4O3 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8 7.93 (d, J=6.2 Hz, 1H), 7.67 (d, J=7.7 Hz, 2H), 7.56 (d, J=9.1 Hz, 1H), 7.34 (d, J=7.7 Hz, 2H), 7.25 (d, J=2.9 Hz, 1H), 7.17 (m, 1H), 6.98 (s, 1H), 6.81 (t, J=6.6 Hz, 1H), 6.62 (s, 1H), 6.09 (s, 1H), 4.40 (m, 4H), 1.39 (t, J=6.9 Hz, 3H) ppm; Compound 31: M/e+ 447 for C24H20ClN4O3 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.37 (d, J=6.9 Hz, 1H), 7.90 (d, J=8.4 Hz, 2H), 7.65 (d, J=9.1 Hz, 1H), 7.42 (m, 3H), 7.24 (m, 1H), 7.09 (s, 1H), 6.84 (td, J=6.6, 1.1 Hz, 1H), 6.58 (d, J=3.3 Hz, 1H), 6.40 (dd, J=3.3, 1.8 Hz, 1H), 6.15 (s, 2H), 4.36 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.3 Hz, 3H) ppm.
Reaction SMILES: [CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([O:33]CC)=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])(=[O:44])=[O:43])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.[OH-].[Na+]>CO>[CH:1]([N:14]1[C:22]2[C:17](=[CH:18][C:19]([Cl:23])=[CH:20][CH:21]=2)[C:16]([CH2:24][CH2:25][O:26][C:27]2[CH:37]=[CH:36][C:30]([C:31]([OH:33])=[O:32])=[C:29]([F:38])[CH:28]=2)=[C:15]1[CH2:39][CH2:40][NH:41][S:42]([CH2:45][C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][C:47]=1[Cl:52])(=[O:44])=[O:43])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc(OCCc2c(CCNS(=O)(=O)Cc3ccccc3Cl)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1F
Yield: 82 %

Procedure:
Ethyl 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoate (0.06 g, 0.1 mmol), THF (0.5 mL), MeOH (0.5 mL), and 1N NaOH (0.5 mL) were stirred together overnight. Solvents were removed and the resulting residue was taken up in water. The solution was acidified with 1N HCl and extracted with ethyl acetate. The extract was dried over sodium sulfate, and evaporated. The resulting residue was triturated with a mixture of ether and hexanes to give 0.06 g of 4-{2-[1-benzhydryl-5-chloro-2-(2-{[(2-chlorobenzyl)sulfonyl]amino}ethyl)-1H-indol-3-yl]ethoxy}-2-fluorobenzoic acid as an off-white solid; mp 132-135° C.; MS (ESI) m/z 729.74 ((M−H)−); HRMS: calcd for C39H33Cl2FN2O5S, 730.1471; found (ESI+), 731.15514.
Reaction SMILES: [Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15](S(C)=O)[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[NH2:24][C@@H:25]1[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]1[OH:31].CCN(C(C)C)C(C)C.O>CC(N(C)C)=O>[Br:1][C:2]1[CH:23]=[CH:22][C:5]2[N:6]([CH2:9][C:10]3[CH:21]=[CH:20][C:13]4[N:14]=[C:15]([NH:24][C@@H:25]5[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]5[OH:31])[O:16][C:12]=4[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1
Reactant: N[C@@H]1CCCC[C@H]1O
Reactant: CS(=O)c1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: O[C@@H]1CCCC[C@H]1Nc1nc2ccc(Cn3cnc4cc(Br)ccc43)cc2o1
Temperature: 120 °C
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A mixture of 6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)-2-(methyl sulfinyl)benzo[d]oxazole (206 mg, 0.53 mmol), (1R,2R)-2-aminocyclohexanol (91 mg, 0.79 mmol) and DIEA (136 mg, 1.06 mmol) in DMA (4 mL) was stirred at 120° C. for 2 h. The reaction mixture was cooled to rt, poured into water (30 mL) and extracted with ethyl acetate (30 mL×3). The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give (1R,2R)-2-((6-((5-bromo-1H-benzo[d]imidazol-1-yl)methyl)benzo[d]oxazol-2-yl)amino)cyclohexanol as a light yellow solid (175 mg, 74.8%). 1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 1H), 7.81-7.84 (m, 2H), 7.56 (d, J=8.7 Hz, 1H), 7.33-7.36 (s, 1H), 7.12 (s, 2H), 5.48 (s, 1H), 4.68 (d, J=4.2 Hz, 1H), 3.35 (br s, 2H), 1.90 (br s, 2H), 1.62 (br s, 2H), 1.22 (br s, 4H). LCMS (ESI) m/z 442 (M+H)+.
Reaction SMILES: [CH2:1](Cl)[CH:2]=[CH2:3].[Mg].[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.S(=O)(=O)(O)O>O1CCCC1>[Cl:6][C:7]1[CH:14]=[CH:13][C:10]([CH:11]([OH:12])[CH2:3][CH:2]=[CH2:1])=[CH:9][CH:8]=1
Reactant: C=CCCl
Reactant: O=Cc1ccc(Cl)cc1
Agent: O=S(=O)(O)O
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCC(O)c1ccc(Cl)cc1
Temperature: 25 °C
Yield: 108.6 %

Procedure:
Allyl chloride (97.88 g, 1.28 mol) in dry tetrahydrofuran (500 ml) was added to a suspension of magnesium turnings (60.08 g, 2.47 mol) in dry tetrahydrofuran (50 ml) at such a rate as to maintain steady reflux. The mixture was then heated under reflux for a further hour. 4-Chlorobenzaldehyde (120 g, 854 mmol) in dry tetrahydrofuran (600 ml) was then added dropwise and the mixture refluxed for a further 2 hours. After being cooled to room temperature the mixture was poured into ice/water, carefully acidified with 1M sulphuric acid and extracted with ether. The combined extracts were washed with brine, dried and evaporated in vacuo to give crude 4-(4-chlorophenyl)but-1-en-4-ol (169.4 g approximately 92% pure) which was used without further purification.