Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].Br[CH2:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#[N:20])=[CH:17][C:16]=1[O:23][CH3:24]>O1CCOCC1.[Ag-]=O.[Ag]=O>[C:19]([C:18]1[CH:21]=[CH:22][C:15]([CH2:14][C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)=[C:16]([O:23][CH3:24])[CH:17]=1)#[N:20]
Reactant: COc1cc(C#N)ccc1CBr
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Agent: O=[Ag-]
Agent: O=[Ag]
Solvent: C1COCCO1
Product: COc1cc(C#N)ccc1Cc1c[nH]c2ccc([N+](=O)[O-])cc12
Temperature: 100 °C
Reaction time: 1 h
Yield: 30.5 %

Procedure:
An efficiently stirred mixture of 5-nitroindole (3.24 g.), bromide (W) (4.57 g.) and silver (I) oxide (4.87 g.) in dry dioxane (90 ml.) was heated at 100° C. for 5 hours. Additional silver oxide (2 g.) was added, and heating continued for 1 hour. The cooled mixture was evaporated, the residue diluted with dichloromethane, filtered, washing the filter cake with dichloromethane until the washings were colorless, and the combined filtrate evaporated. The product was purified by flash chromatography on silica gel, eluting with 3:7 v/v ethyl acetate:hexane, giving a product which was crystallized from a mixture of ethyl acetate and hexane to give 3-(4-cyano-2-methoxybenzyl)-5-nitroindole (1.87 g., 30%) as a yellow powder, m.p. 204°-206° C.; partial NMR (80 MHz, DMSO-d6): 3.92(s,3H, OMe); 4.12(s,2H, ArCH2).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5].C(N(CC)CC)C.[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22](O)=[O:23].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[CH:25][C:19]=1[CH:20]=[CH:21][C:22]([NH:2][C@H:3]([C:6]([O:8][CH3:9])=[O:7])[CH2:4][OH:5])=[O:23]
Reactant: O=C(O)C=Cc1ccccc1F
Reactant: COC(=O)[C@@H](N)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CO)NC(=O)C=Cc1ccccc1F
Yield: 97.8 %

Procedure:
The same procedures as in Example 2 were carried out from methyl L-serinate hydrochloride (2.5 g), triethylamine (2.4 mL), 2-fluorocinnamic acid (2.8 g), WSC.HCl (3.2 g), and methylene chloride (100 mL), to give the captioned compound (4.2 g, 98%) as an oily product.
Reaction SMILES: [C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16](Br)=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2].[S-2:28].[Na+].[Na+]>C(O)C>[C:1]([O:4][C@H:5]([CH3:27])[CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:19](=[O:20])[C:18]2[N:17]([CH2:21][O:22][CH2:23][CH3:24])[C:16]([SH:28])=[N:15][C:14]=2[N:13]([CH3:26])[C:11]1=[O:12])(=[O:3])[CH3:2]
Reactant: CCOCn1c(Br)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Reactant: [S-2]
Agent: [Na+]
Solvent: CCO
Product: CCOCn1c(S)nc2c1c(=O)n(CCCC[C@@H](C)OC(C)=O)c(=O)n2C
Temperature: 90 °C
Reaction time: 1 h

Procedure:
To a stirring solution of (R)-1-(5-acetoxyhexyl)-8-bromo-7-ethoxymethyl-3-methylxanthine (prepared as described above for CT 12440) (1.77 g, 4.0 mmol) in ethanol (100 ml) was added sodium sulfide (4.48 g, 80 mmol). The reaction mixture was stirred at 90° C. for 1 hour. After evaporation of the solvent under reduced pressure, the crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (7:1) to provide (R)-1-(5-acetoxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine. This product was dissolved in methanol (100 ml). A solution of hydrogen chloride in ether (1.0 M, 1.0 ml) was added and stirred at room temperature for 24 hours. After evaporation of the solvent under reduced pressure. The crude product was purified by flash chromatography on silica gel eluting with ethyl acetate-methanol (4:1) to provide (R)-1-(5-hydroxyhexyl)-7-ethoxymethyl-8-mercapto-3-methylxanthine (610 mg, 51% yield) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([CH2:6][NH:7][C:8]([C:10]2[CH:11]=[N:12][C:13]3[C:18]([C:19]=2[OH:20])=[CH:17][C:16]([C:21]#[C:22][CH2:23][OH:24])=[CH:15][CH:14]=3)=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Cl.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][NH:7][C:8]([C:10]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[C:16]([C:21]#[C:22][CH2:23][OH:24])[CH:17]=3)[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[CH:11]=2)=[O:9])=[CH:25][CH:26]=1
Reactant: CN(C)CCCCl
Reactant: O=C(NCc1ccc(Cl)cc1)c1cnc2ccc(C#CCO)cc2c1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCCn1cc(C(=O)NCc2ccc(Cl)cc2)c(=O)c2cc(C#CCO)ccc21
Temperature: 90 °C

Procedure:
A solution of N-(4-chlorobenzyl)-4-hydroxy-6-(3-hydroxy-1-propynyl)-3-quinolinecarboxamide from Preparation No. 5 (0.458 g) is dissolved in DMF (10 mL), and K2CO3 (0.69 g) and 3-dimethylaminopropyl chloride hydrochloride (0.42 g) are added. The reaction mixture is heated to 90° C. for 6 h. Water is added and a dark solid formed, which is isolated by decanting the liquid. Column chromatography (elution with 1-20% MeOH/CHCl3) gave 0.103 g of a solid. Crystallization by dissolving in CH2Cl2 with a few drops of MeOH and adding to a 1:1 solution of pentane/Et2O gave 0.072 g of the title compound as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:12][CH2:13][C:14]1([C:22]2[CH:23]=[CH:24][C:25]([C:28]([OH:31])([CH3:30])[CH3:29])=[N:26][CH:27]=2)[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1>>[Cl:1][C:2]1[C:10]([Cl:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:12][CH2:13][C:14]1([C:22]2[CH:27]=[N:26][C:25]([C:28]([OH:31])([CH3:29])[CH3:30])=[CH:24][CH:23]=2)[CH2:19][CH2:18][C:17]([F:21])([F:20])[CH2:16][CH2:15]1)=[O:6]
Reactant: CC(C)(O)c1ccc(C2(CN)CCC(F)(F)CC2)cn1
Reactant: O=C(O)c1cccc(Cl)c1Cl
Product: CC(C)(O)c1ccc(C2(CNC(=O)c3cccc(Cl)c3Cl)CCC(F)(F)CC2)cn1

Procedure:
From 2,3-dichlorobenzoic acid and 2-[5-(1-aminomethyl-4,4-difluoro-cyclohexyl)-pyridin-2-yl]-propan-2-ol. LCMS (MH+): m/z=457.1, tR (minutes, Method F)=1.97
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].Br[CH2:13][CH2:14][CH2:15][CH2:16][Cl:17].[H-].[Na+]>CN(C=O)C>[Cl:17][CH2:16][CH2:15][CH2:14][CH2:13][C:2]1([C:7]([O:9][CH2:10][CH3:11])=[O:8])[S:3][CH2:4][CH2:5][CH2:6][S:1]1
Reactant: ClCCCCBr
Reactant: CCOC(=O)C1SCCCS1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(CCCCCl)SCCCS1
Temperature: 25 °C
Reaction time: 16 h
Yield: 74.8 %

Procedure:
Step AS (1): To a solution of ethyl 1,3-dithiane-2-carboxylate (500 mg, 2.60 mmol) and 1-bromo-4-chlorobutane (1337 mg, 7.80 mmol) in DMF (10 mL) was added 60% NaH (dispersion in mineral oil, 125 mg, 3.12 mmol). The mixture was stirred at rt for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (2×100 mL). The combined organic layers were washed with water (3×100 mL) and concentrated in vacuo. The residue was purified using silica gel column chromatography (10% EtOAc/hexanes) to give ethyl 2-(4-chlorobutyl)-1,3-dithiane-2-carboxylate (550 mg, 75% yield). LC-MS (M+H)+ 283.0.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[CH:8]=[C:9]([O:13][CH2:14][O:15][CH3:16])[CH:10]=[CH:11][CH:12]=2)[O:6][CH2:5][CH2:4][O:3]1.C([Li])(C)(C)C.[C:22](=[O:24])=[O:23]>CCOCC>[CH3:1][C:2]1([C:7]2[CH:12]=[CH:11][C:10]([C:22]([OH:24])=[O:23])=[C:9]([O:13][CH2:14][O:15][CH3:16])[CH:8]=2)[O:6][CH2:5][CH2:4][O:3]1
Reactant: COCOc1cccc(C2(C)OCCO2)c1
Reactant: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCOCC
Product: COCOc1cc(C2(C)OCCO2)ccc1C(=O)O
Temperature: 10 °C

Procedure:
To a solution of methoxymethyl 3-(2-methyl-1,3-dioxolan-2-yl)phenyl ether (8.16 g, 36.4 mmol) in ether (200 mL) was added dropwise tert-butyl lithium (1.7 M solution, 26.8 mL, 1.25 equivalents) at −5 to −10° C. The reaction mixture was stirred 15 min before carbon dioxide gas was bubbled in for 5 min. The reaction mixture was allowed to warm slowly in the cold bath to about 10° C., then it was extracted with water. The aqueous layer was acidified with 5 N HCl and extracted with EtOAc. The organic phase was dried (MgSO4) and evaporated to afford a crude product which was triturated with hexane to afford the benzoic acid (4.54 g).
Reaction SMILES: C([C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1)=O.C(Cl)Cl.ClC1C=CC=C(C(OO)=[O:28])C=1>O>[OH:28][C:3]1[CH:16]=[CH:15][C:6]([O:7][CH:8]([CH3:14])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:5][CH:4]=1
Reactant: CCOC(=O)C(C)Oc1ccc(C=O)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: O
Solvent: ClCCl
Product: CCOC(=O)C(C)Oc1ccc(O)cc1
Yield: 52.9 %

Procedure:
A mixture of 2.2 g of (+)-ethyl 2-(4-formylphenoxy)propionate ([α]D25 =+51.3° optical purity: 93%), 10 ml of methylene chloride and 2.6 g of m-chloroperbenzoic acid, was reacted for 2 hours under reflux, and after an addition of 0.5 g of water, further refluxed for 1 hour. After cooling, the reaction mixture was washed twice with 20 g of a 5% sodium hydrogen carbonate aqueous solution, then with 10 g of a 5% sodium hydrogen sulfite aqueous solution and further with 10 g of water. Then, the reaction mixture was concentrated by distilling off methylene chloride and then subjected to distillation under reduced pressure, whereby 1.1 g of ethyl 2-(4-hydroxyphenoxy)propionate was obtained as a colorless transparent liquid. The boiling point was from 130° to 140° C./1 mmHg. [α]D25 =+40.6°, optical punity: 90%
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:29][CH3:30])[CH2:27][CH3:28])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:39][N:40]([CH3:44])[C:41](Cl)=[O:42]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:1]([O:5][C:6](=[O:31])[CH:7]([NH:16][C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][N:20]=[C:19]([N:26]([CH2:27][CH3:28])[CH2:29][CH3:30])[N:18]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][C:41](=[O:42])[N:40]([CH3:44])[CH3:39])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(O)cc2)C(=O)OC(C)(C)C)n1
Reactant: CN(C)C(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCN(CC)c1ncc([N+](=O)[O-])c(NC(Cc2ccc(OC(=O)N(C)C)cc2)C(=O)OC(C)(C)C)n1
Yield: 99.5 %

Procedure:
To a solution of 2-(2-diethylamino-5-nitropyrimidin-4-ylamino)-3-(4-hydroxy-phenyl)propionic acid t-butyl ester (31.80 g, 0.074 mol) in CH2Cl2 (600 mL) was added DMAP (9.00 g, 0.074 mol). After 5 minutes triethylamine (10.23 mL, 0.074 mol) was added dropwise. N,N-dimethylcarbamyl chloride (13.83 mL, 0.110 mol) was added dropwise, and the reaction was heated to reflux overnight. The reaction mixture was concentrated in vacuo and taken up in EtOAc (1 L). The organic phase was washed with 0.5 M citric acid (3×250 mL), sat. NaHCO3 (3×250 mL), brine (1×250 mL), dried (MgSO4), filtered, and concentrated in vacuo to yield 37.0 g (99%) the title compound as a white solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:24]=[CH:23][C:21]([NH:22][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[CH:15][CH:14]=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:20][CH:19]=1
Reactant: Nc1ccc(F)cc1
Reactant: O=c1[nH]c2nccc(Cl)c2c2ccccc12
Product: O=c1[nH]c2nccc(Nc3ccc(F)cc3)c2c2ccccc12
Yield: 70.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 188 using Compound 83 (100 mg, 0.43 mmol) and 4-fluoroaniline (96 mg, 0.87 mmol) to provide 202 (93 mg, 70% yield) as a white solid. LC-MS (M+H=306, obsd.=306).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[NH:24][C:23]5C=[CH:26][CH:27]=[C:28](CO)[C:22]=5[N:21]=4)=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:3][N:2]=1.[CH3:31][CH2:32][N:33]([CH:37]([CH3:39])C)[CH:34]([CH3:36])C.CS(Cl)(=O)=O.N1CCCC1>C1COCC1>[N:33]1([CH2:32][C:31]2[C:23]3[N:24]=[C:20]([C:19]4[C:13]5[C:14](=[N:15][CH:16]=[C:11]([C:4]6[C:5]7[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=7)[CH:1]=[N:2][CH:3]=6)[CH:12]=5)[NH:17][N:18]=4)[NH:21][C:22]=3[CH:28]=[CH:27][CH:26]=2)[CH2:34][CH2:36][CH2:39][CH2:37]1
Reactant: OCc1cccc2[nH]c(-c3n[nH]c4ncc(-c5cncc6ccccc56)cc34)nc12
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: C1CCNC1
Solvent: C1CCOC1
Product: c1ccc2c(-c3cnc4[nH]nc(-c5nc6c(CN7CCCC7)cccc6[nH]5)c4c3)cncc2c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.5 %

Procedure:
A suspension of Compound 3 (30 mg, 0.08 mmol) and DIPEA (28 μl, 0.36 mmol) in dry THF (1 mL) was cooled to 0° C. Methanesulfonyl chloride (18 μl, 0.23 mmol) was added dropwise and the mixture was stirred at 0° C. for 3 hours. Pyrrolidine (32 μl 0.39 mmol) was added and the suspension was gradually warmed to room temperature and stirred for 2 hours. The reaction was quenched with water (0.1 mL) and the solvent was removed in vacuo. The crude product was purified by silica gel chromatography to give Compound 7 (13 mg, 38%) as a yellow powder. 1H NMR (300 MHz MeOD) δ 9.36 (s, 1H), 9.10 (d, 1H, J=2.1 Hz), 8.78 (d, 1H, J=2.1 Hz), 8.55 (s, 1H), 8.27 (d, 1H, J=7.8 Hz), 7.95 (m, 1H), 7.83 (m, 2H), 7.72 (dd, 1H, J=1.8, 7.2 Hz), 7.39 (m, 2H), 4.75 (s, 2H), 3.38 (b, 4H), 2.01 (b, 4H); MS (ESI) m/z: 446 (M+H+).
Reaction SMILES: [N:1]1[N:2]([C:6]2[CH:11]=[CH:10][C:9]([CH2:12]O)=[CH:8][CH:7]=2)[N:3]=[CH:4][CH:5]=1.S(Cl)([Cl:16])=O.C([O-])(O)=O.[Na+]>C(Cl)Cl>[Cl:16][CH2:12][C:9]1[CH:10]=[CH:11][C:6]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)=[CH:7][CH:8]=1
Reactant: OCc1ccc(-n2nccn2)cc1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: ClCc1ccc(-n2nccn2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 50.58 g (289 mmol) of (4-[1,2,3]triazol-2-yl-phenyl)-methanol in 2000 ml of CH2Cl2, 31.59 ml (433 mmol) of thionyl chloride is added dropwise at 0-5° C. and the reaction mixture is allowed to warm to r.t. After stirring for 16 h, the reaction mixture is basified with sat. NaHCO3 at 0-5° C. and extracted with CH2Cl2. The combined extracts are washed with brine, dried over MgSO4 and concentrated under reduced pressure to provide the title compound.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].N1C=CC=CC=1.[NH:11]([C:18]1[N:23]=[C:22]([C:24]2[N:28]([CH:29]([CH3:31])[CH3:30])[C:27]([CH:32]=O)=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>CCO>[NH:11]([C:18]1[N:23]=[C:22]([C:24]2[N:28]([CH:29]([CH3:30])[CH3:31])[C:27]([CH:32]=[N:4][O:2][CH3:3])=[N:26][CH:25]=2)[CH:21]=[CH:20][N:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CON
Reactant: CC(C)n1c(-c2ccnc(Nc3ccccc3)n2)cnc1C=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=Cc1ncc(-c2ccnc(Nc3ccccc3)n2)n1C(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 90.6 %

Procedure:
Methoxylamine hydrochloride (340 mg, 4.07 mmol) and pyridine (322 mg, 4.07 mmol) was added to a solution of 2-anilino-4-(2-formyl-1-isopropylimidazol-5-yl)pyrimidine (Example 10; 250 mg, 0.814 mmol) in EtOH (10 ml) and the mixture was stirred at ambient temperature for 18 hours. The volatiles were removed by evaporation and the residue triturated with water. The solid product was collected by filtration and dried at 50° C. under vacuum to give the title compound (248 mg, 91%) as a white crystalline solid. NMR (CDCl3): 1.54 (d, 6H), 4.07 (s, 3H), 5.65-5.80 (sept, 1H), 6.95 (d, 1H), 7.15 (m, 2H), 7.34 (t, 2H), 7.50 (s 1H), 7.57 (d, 2H), 8.28 (s, 1H), 8.41 (d, 1 H); m/z 337.
Reaction SMILES: [CH:1]([CH:3]=O)=O.[NH2:5][CH2:6][CH2:7][NH:8][CH2:9][CH2:10][CH2:11][NH:12][CH2:13][CH2:14][NH2:15]>O>[NH:15]1[C:1]2=[C:3]3[N:8]([CH2:7][CH2:6][NH:5]2)[CH2:9][CH2:10][CH2:11][N:12]3[CH2:13][CH2:14]1
Reactant: O=CC=O
Reactant: NCCNCCCNCCN
Solvent: O
Product: C1CN2CCNC3=C2N(C1)CCN3
Temperature: 25 °C
Reaction time: 10 h

Procedure:
9.04 g (62.4 mmol) of a 40% by weight aqueous glyoxal solution are slowly added dropwise to a solution of 10.00 g (62.4 mmol) of N,N′-bis(2-aminoethyl)-1,3-pro-panediamine in 30 ml of water at 0° C. The mixture is maintained at this temperature for 1 hour and then stirred at ambient temperature for 10 hours. After evaporation of the water, compound 12 is isolated quantitatively in the form of a pale yellow solid and is used for the following stage without subsequent purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[CH:4][N:3]=1.C1C(=O)N([I:16])C(=O)C1>C(O)(=O)C>[I:16][C:7]1[C:2](=[O:1])[NH:3][CH:4]=[N:5][C:6]=1[CH3:8]
Reactant: Cc1cc(O)ncn1
Reactant: O=C1CCC(=O)N1I
Solvent: CC(=O)O
Product: Cc1nc[nH]c(=O)c1I

Procedure:
To a stiffed solution of 70 g (0.64 mol) 4-hydroxy-6-methyl pyrimidine in acetic acid is added 127 g (0.56 mol) NIS portion wise at RT within 15 min The reaction is stiffed for to 30 h at RT until all starting material is consumed. The reaction mixture is diluted with water and the solid product is filtered off and washed with sodium thiosulfate solution to remove excess iodine. After drying, the desired product is obtained as a pale brown solid (90 g; 60%) which is used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16](OC)=[O:17])[N:13]=2)=[N:6][CH:7]=1.O.[NH2:28][NH2:29]>CCO>[Br:1][C:2]1[CH:3]=[C:4]([O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][CH2:15][C:16]([NH:28][NH2:29])=[O:17])[N:13]=2)=[N:6][CH:7]=1
Reactant: COC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)CCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Temperature: 75 °C
Yield: 83.1 %

Procedure:
To a mixture of methyl 3-(2-(5-bromo-3-phenoxypyridin-2-ylamino)thiazol-4-yl)propanoate (1.00 g, 2.303 mmol) (Example 315) in 15 mL EtOH was added hydrazine monohydrate (8.835 mL, 11.51 mmol) and the mixture heated at 75° C. for 4 hours. The reaction was cooled to ambient temperature and quenched with water and the solids were filtered to give the title compound (0.831 g, 83.10% yield) as off white solids there were used without further purification.
Reaction SMILES: [O:1]([C:8]1[O:12][C:11]([C:13]([OH:15])=O)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O:18][C:19](=[O:29])[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([NH2:28])[CH:23]=1)C.CCN(C(C)C)C(C)C>CN(C=O)C>[O:1]([C:8]1[O:12][C:11]([C:13]([NH:28][C:24]2[CH:23]=[C:22]([CH:21]=[CH:20][C:19]([OH:29])=[O:18])[CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)o1
Reactant: CCOC(=O)C=Cc1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)C=Cc1cccc(NC(=O)c2ccc(Oc3ccccc3)o2)c1

Procedure:
5-phenoxy-2-furoic acid (3) (213 mg, 1.05 mmol) was coupled to aniline (2) (200 mg, 1.05 mmol) using Method B, except that DIPEA (270 mg, 2.09 mmol) and DMF (2 mL) were used to give the title compound. Yield: 178 mg, 96%; LC/MS tr 1.65 min; HPLC Purity: 95%; MS (ES+) m/z 378 (M+H)
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:20])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5](=[O:10])[N:6]([CH3:9])[C:7]=1[NH2:8].[F:21][C:22]([F:35])([F:34])[O:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31](O)=[O:32])[CH:27]=[CH:28][CH:29]=1.CCN=C=NCCCN(C)C>C(O)C.O>[NH2:8][C:7]1[N:6]([CH3:9])[C:5](=[O:10])[N:4]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:3](=[O:20])[C:2]=1[NH:1][C:31](=[O:32])[CH2:30][C:26]1[CH:27]=[CH:28][CH:29]=[C:24]([O:23][C:22]([F:34])([F:21])[F:35])[CH:25]=1
Reactant: COc1ccc(Cn2c(=O)c(N)c(N)n(C)c2=O)cc1
Reactant: O=C(O)Cc1cccc(OC(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Solvent: CCO
Solvent: O
Product: COc1ccc(Cn2c(=O)c(NC(=O)Cc3cccc(OC(F)(F)F)c3)c(N)n(C)c2=O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.8 %

Procedure:
To a solution of 5,6-diamino-3-(4-methoxybenzyl)-1-methylpyrimidine-2,4(1H,3H)-dione (50 mg, 0.181 mmol, intermediate 59) in ethanol (3 ml) was added 2-(3-(trifluoromethoxy)phenyl)acetic acid (40 mg, 0.181 mmol) and EDCI (52 mg, 0.271 mmol) The mixture was stirred at room temperature for 2 h. The reaction was diluted with water, filtered and the solids were rinsed with water. The solid residue was dissolved in ethyl acetate, dried over sodium sulfate, filtered and concentrated to give N-(6-amino-3-(4-methoxybenzyl)-1-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)-2-(3-(trifluoromethoxy)phenyl)acetamide (70 mg, 80.1%) as light gray solid. LCMS retention time 1.239 min; LCMS MH+ 479.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[C:43](Cl)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1.C(=O)([O-])O.[Na+]>C(Cl)Cl>[C:43]([NH:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:16][CH2:15][N:14]([C:17]([O:19][C:20]([CH3:23])([CH3:21])[CH3:22])=[O:18])[CH2:13][CH:12]2[O:24][CH2:25][C:26]2[CH:35]=[CH:34][C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=2)=[CH:7][CH:6]=1)(=[O:50])[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCN)cc2)C(OCc2ccc3ccccc3c2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCNC(=O)c3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19.2 %

Procedure:
A solution of 192.4 mg of crude tert-butyl (3RS,4RS)-4-[4-(2-amino-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in 3 ml of methylene chloride was treated at 0° C. with 51.7 ml of triethylamine and 64.9 mg (0.462 mmol, 2.0 eq.) of benzoyl chloride and the mixture was stirred at 0° C. for 0.75 hr and at room temperature for 3 hours. The reaction mixture was poured into an ice/water mixture, made basic with saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The organic phases were washed once with water and once with saturated sodium chloride solution, dried over magnesium sulphate, evaporated under reduced pressure and dried in a high vacuum. The colourless oil was separated on silica gel using a 95:5 mixture of methylene chloride and acetone as the eluent. There were obtained 44.9 mg (33% of theory) of tert-butyl (3RS,4RS)-4-[4-(2-benzoylamino-ethoxy)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate in the form of a light yellow oil; MS: 581 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH2:18])=[N:2]1.C(N(CC)CC)C.[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31](Cl)=[O:32])=[CH:29][CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>C1COCC1>[F:26][C:27]1[CH:35]=[CH:34][C:30]([C:31]([NH:18][C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2/[CH:11]=[CH:10]/[C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][N:2]=2)=[O:32])=[CH:29][CH:28]=1
Reactant: O=C(Cl)c1ccc(F)cc1
Reactant: Nc1ccccc1/C=C/c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccccc1/C=C/c1n[nH]c2ccccc12)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.3 %

Procedure:
(E)-2-[2-(1H-indazol-3-yl)vinyl]phenylamine (60 mg, 0.26 mmol) obtained in Example 2 was dissolved in THF (1.5 mL) and the solution was added with triethylamine (71 μL, mmol) and p-fluorobenzoylchloride (45 μL, 0.38 mmol), followed by stirring at room temperature for 30 minutes. Further, the reaction mixture was added with potassium carbonate and stirred for a while. Then, the solid precipitated by adding water to the mixture was collected by filtration and the solid was triturated in ethanol to obtain Compound 3 (57 mg, 62%).