Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[CH2:4][CH2:3]1.[CH3:13][C:14]1[N:18](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:17]=[N:16][C:15]=1[CH:38]=O.[OH-].[K+]>CO>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[C:4]([CH2:38][C:15]2[N:16]=[CH:17][NH:18][C:14]=2[CH3:13])=[CH:3]1
Reactant: CN1CCC(=O)c2ccccc21
Reactant: Cc1c(C=O)ncn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cc1[nH]cnc1Cc1cn(C)c2ccccc2c1=O
Temperature: 25 °C
Reaction time: 44 h
Yield: 14.5 %

Procedure:
A suspension of 2,3-dihydro-1-methyl-4(1H)-quinolinone (915 mg) and 5-methyl-1-(triphenylmethyl)-1H-imidazole-4-carboxaldehyde (2.0 g) in methanol (25 ml) was treated with a solution of potassium hydroxide (0.5 g) in methanol (5 ml). The suspension was stirred at room temperature for 44 h and then filtered. The collected solid was heated at reflux in a mixture of acetic acid (6 ml), water (5 ml) and THF (15 ml) for 3 h. The solution was treated cautiously with 8% aqueous sodium bicarbonate (180 ml) and extracted with dichloromethane (3×60 ml). The combined, dried organic extracts were evaporated to give a solid, which was purified by FCC eluting with System A (100:12:1.2) to give the title compound (208 mg), m.p. 110°-113°.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][S:4][C@@H:5]2[C@H:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9].CO.C(OO)(=[O:28])C>C(Cl)Cl>[CH3:1][C:2]1[CH2:3][S@:4](=[O:28])[C@@H:5]2[C@H:12]([NH:13][C:14](=[O:22])[CH2:15][C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:11](=[O:23])[N:6]2[C:7]=1[C:8]([OH:10])=[O:9]
Reactant: CC(=O)OO
Reactant: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2SC1
Solvent: ClCCl
Solvent: CO
Product: CC1=C(C(=O)O)N2C(=O)[C@@H](NC(=O)Cc3ccccc3)[C@H]2[S@@](=O)C1
Reaction time: 0.25 h

Procedure:
To a stirred suspension of polymer ester of (6R, 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid (5.00g, 4.45 mole, from example 8 in methylene chloride (35 ml.) and methanol (10 ml.) cooled to 0° was added peracetic acid (38% w/v, 1.1 ml., 5.50 m.mole) in one portion. Stirring was continued for 30 minutes at 0° and for a further 15 minutes, after removal of the cooling bath. The reaction mixture was filtered and pulled as dry as possible. The product was washed with methylene chloride (2 × 50 ml.) methanol (2 × 50 ml.), and methylene chloride (2 × 50 ml.). The product was dried to constant weight in vacuo at 30° to give the pale yellow polymer ester of (1S, 6R. 7R)-3-methyl-7-phenylacetamidoceph-3-em-4-carboxylic acid 1-oxide (5.00g, which proved to be similar (infra red, nmr., and t.l.c.) with the product obtained in example 9 above.
Reaction SMILES: C([O:5][C:6](=[O:35])[CH2:7][N:8]([S:17]([C:20]1[CH:29]=[C:28]2[C:23]([C:24]([Cl:34])=[CH:25][N:26]=[C:27]2[NH:30][C:31]([NH2:33])=[NH:32])=[CH:22][CH:21]=1)(=[O:19])=[O:18])[C@@H:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:10])(C)(C)C>CCOC(C)=O.Cl>[ClH:34].[Cl:34][C:24]1[C:23]2[C:28](=[CH:29][C:20]([S:17]([N:8]([C@@H:9]([C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH3:10])[CH2:7][C:6]([OH:35])=[O:5])(=[O:18])=[O:19])=[CH:21][CH:22]=2)[C:27]([NH:30][C:31]([NH2:33])=[NH:32])=[N:26][CH:25]=1
Reactant: C[C@H](c1ccccc1)N(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: CCOC(C)=O
Product: C[C@H](c1ccccc1)N(CC(=O)O)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 147.4 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1R)-1-phenylethyl]glycine t-butyl ester (100 mg, 0.19 mmol) was dissolved in a solution of EtOAc saturated with HCl (7.0 mL) and the mixture stirred at room temperature for 4 h. The mixture was concentrated in vacuo and the residue triturated with EtOAc to give N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-[(1R)-1-phenylethyl]glycine hydrochloride (75 mg, 0.14 mmol) as a white powder.
Reaction SMILES: [C:1]1([C:7]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[S:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:25]1([CH3:34])[CH:30]=[CH:29][C:28]([N:31]=[C:32]=[O:33])=[CH:27][CH:26]=1>O1CCCC1>[CH3:34][C:25]1[CH:30]=[CH:29][C:28]([NH:31][C:32]([N:15]2[CH2:16][CH2:17][N:12]([C:10]3[S:9][N:8]=[C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[N:11]=3)[CH2:13][CH2:14]2)=[O:33])=[CH:27][CH:26]=1
Reactant: c1ccc(-c2nsc(N3CCNCC3)n2)cc1
Reactant: Cc1ccc(N=C=O)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 1-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine (200 mg, 0.812 mmol) and triethylamine (0.113 ml, 0.812 mmol) in tetrahydrofuran (2 ml) was added 4-tolyl isocyanate (0.154 ml, 1.22 mmol), and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, and the residue was recrystallized from a mixed solvent of hexane and ethyl acetate to give 298 mg (96.8%) of the desired product as a solid.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19](I)=[N:20][N:21](C3CCCCO3)[C:15]=2[CH:14]=1.[CH2:29]([N:31]1[CH2:39][C:38]2[C:33](=[N:34][CH:35]=[C:36](B(O)O)[CH:37]=2)[C:32]1=[O:43])[CH3:30]>>[F:12][C:4]1[C:5]([O:10][CH3:11])=[CH:6][C:7]([O:8][CH3:9])=[C:2]([F:1])[C:3]=1[C:13]1[N:18]=[CH:17][C:16]2[C:19]([C:36]3[CH:37]=[C:38]4[CH2:39][N:31]([CH2:29][CH3:30])[C:32](=[O:43])[C:33]4=[N:34][CH:35]=3)=[N:20][NH:21][C:15]=2[CH:14]=1
Reactant: CCN1Cc2cc(B(O)O)cnc2C1=O
Reactant: COc1cc(OC)c(F)c(-c2cc3c(cn2)c(I)nn3C2CCCCO2)c1F
Product: CCN1Cc2cc(-c3n[nH]c4cc(-c5c(F)c(OC)cc(OC)c5F)ncc34)cnc2C1=O

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 52, Step 8 starting from 6-(2,6-difluoro-3,5-dimethoxyphenyl)-3-iodo-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[4,3-c]pyridine and (6-ethyl-7-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-3-yl)boronic acid. LCMS (M+H)+=452.1.
Reaction SMILES: C1CO[CH:17]2[CH:3]([C@@H:4]([C@@H:15]([CH2:20][CH2:21][C:22](=[O:31])[C:23]([CH3:30])([CH3:29])[CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[CH2:16]2)[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])[O:2]1.[BH4-].[Na+]>CO.O>[O:2]=[C:3]1[CH2:17][CH2:16][C@H:15]([CH2:20][CH2:21][CH:22]([OH:31])[C:23]([CH3:30])([CH3:29])[CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[C@H:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCCCCC[C@H]1C2OCCOC2C[C@@H]1CCC(=O)C(C)(C)CC=C(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COC(=O)CCCCCC[C@H]1C(=O)CC[C@@H]1CCC(O)C(C)(C)CC=C(C)C
Reaction time: 0.5 h

Procedure:
To the solution of 2.4 g of 9-ethylenedioxy-15-keto-16,16,19-trimethyl-prost-18-enoic acid, methyl ester in methanol (20 ml.) 0.4 g of sodium borohydride are gradually added while the temperature is kept under 35° C. The mixture is stirred for 30 minutes, then diluted with water (150 ml.) and extracted with ethyl acetate (3×70 ml.). The organic layer is washed with water to neutrality, dried over sodium sulphate and the solvent is removed in vacuo. The oily residue (2.2 g) is suspended in 65% acetic acid (30 ml.) and stirred at room temperature for 60 minutes. The obtained solution is diluted with water (100 ml.) and extracted with diethyl ether (3×70 ml). The organic layer is washed with aqueous saturated NaHCO3 solution to neutrality, dried over sodium sulphate and the solvent is evaporated. From the oily residue (1.8 g), by chromatography on silica (200 g) and elution with benzene/ethyl acetate (4:1), 0.48 g of 9 -keto-15β-hydroxy-16,16,19-trimethyl-prost-18-enoic acid, methyl ester, 0.40 g of 9-keto-15α-hydroxy-16,16,19-trimethyl-prost-18-enoic acid, methyl ester and 0.48 g of a mixture of 15α and 15β are obtained.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[NH:11][C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:26][CH:27]1[CH2:29][CH2:28]1>CN(C=O)C>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[C:12](=[CH:13][C:14]([F:21])=[C:15]([F:20])[CH:16]=2)[N:11]([CH2:26][CH:27]2[CH2:29][CH2:28]2)[C:10]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CC1
Reactant: O=c1[nH]c2cc(F)c(F)cc2c(=O)n1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2cc(F)c(F)cc2n(CC2CC2)c(=O)n1OCc1ccccc1
Reaction time: 0.5 h
Yield: 76.7 %

Procedure:
A solution of 3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example B, 1.22 g, 4 mmol) in 25 mL of DMF was added to a suspension of sodium hydride (0.19 g, 4.8 mmol) in 20 mL of DMF and stirred for 30 minutes. Bromomethylcyclopropane (0.6 mL, 6.0 mmol) was added, and the mixture was stirred at 25° C. for 18 hours. The reaction was quenched with 1 mL of water and concentrated to an oil. The residue was dissolved in chloroform, washed with water, brine, and dried over magnesium sulfate. The solution was concentrated to give 1.10 g of the title compound as a solid, mp 121-123° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]2[CH:7]=[C:6]([C:14](Cl)=[O:15])[CH:5]=[CH:4][C:3]1=2.[OH:18][C:19]1[CH:28]=[C:27]([C:29]#[C:30][Si](C)(C)C)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]>>[OH:18][C:19]1[CH:28]=[C:27]([C:29]#[C:30][C:14](=[O:15])[C:6]2[CH:5]=[CH:4][C:3]3[C:2]([CH3:17])([CH3:1])[CH2:11][CH2:10][C:9]([CH3:13])([CH3:12])[C:8]=3[CH:7]=2)[CH:26]=[CH:25][C:20]=1[C:21]([O:23][CH3:24])=[O:22]
Reactant: COC(=O)c1ccc(C#C[Si](C)(C)C)cc1O
Reactant: CC1(C)CCC(C)(C)c2cc(C(=O)Cl)ccc21
Product: COC(=O)c1ccc(C#CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1O

Procedure:
Following the basic procedure of Example 1(b), by reacting 2.4 g (0.01 mol) of 5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthoyl chloride with 2.5 g (0.01 mol) of methyl 2-hydroxy-4-trimethylsilylethynylbenzoate, 2.9 g (74%) of the expected ester, with a melting point of 189°-190° C., were recovered.
Reaction SMILES: [C:1]1([P:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[C:8]2[CH2:12][C:11](=[O:13])[O:10][C:9]2=[O:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH2:27]>>[C:21]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:8]([CH2:12][C:11]([OH:10])=[O:13])[C:9]([OH:14])=[O:27])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C1CC(=P(c2ccccc2)(c2ccccc2)c2ccccc2)C(=O)O1
Reactant: O
Product: O=C(O)CC(C(=O)O)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
The title compound was prepared by stirring 3-triphenylphosphoranylidene dihydro-2,5-furandione (5.0 g, 0.014 mole) for 48 hours in 100 ml water. The solid residue was isolated by filtration and air-dried to give essentially quantitative yields of a product as a white crystalline solid whose IR spectrum and elemental analysis corresponded to the structure ##STR8##
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][N:11]([CH:21]1[C:30]2[N:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH2:24][CH2:23][CH2:22]1)[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][NH2:20])=[CH:15][CH:14]=1.[CH:31](=O)[C:32]1[C:33](=[CH:35][CH:36]=[CH:37][CH:38]=1)[OH:34].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[OH:34][C:33]1[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=1[CH2:31][NH:20][CH2:19][C:16]1[CH:15]=[CH:14][C:13]([CH2:12][N:11]([CH2:10][C:2]2[NH:3][C:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=3[N:1]=2)[CH:21]2[C:30]3[N:29]=[CH:28][CH:27]=[CH:26][C:25]=3[CH2:24][CH2:23][CH2:22]2)=[CH:18][CH:17]=1
Reactant: O=Cc1ccccc1O
Reactant: NCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Oc1ccccc1CNCc1ccc(CN(Cc2nc3ccccc3[nH]2)C2CCCc3cccnc32)cc1
Yield: 53.7 %

Procedure:
Using General Procedure B: To a stirred solution of N′-(1H-benzimidazol-2-ylmethyl)-N′-(5,6,7,8-tetrahydro-8-quinolinyl)-1,4-benzenedimethanamine (147 mg, 0.37 mmol) and salicylaldehyde (0.04 mL, 0.38 mmol) in CH2Cl2 (5 mL) was added NaBH(OAc)3 (100 mg, 0.47 mmol) and the resultant mixture was stirred at room temperature for 16 hours. Purification of the crude material by radial chromatography on silica gel gel (2 mm plate, 75:1:1 CH2Cl2/MeOH/NH4OH) afforded the free amine (100 mg, 54%) as a white foam.
Reaction SMILES: [F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(Cl)(Cl)=O.[CH3:16]O>>[F:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: Cc1cccc(C(=O)O)c1F
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cccc(C)c1F
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 2-fluoro-3-methylbenzoic acid (12.4 g, 80.2 mmol) in methanol (100 mL) at 0° C. was added thionyl chloride (14 g, 120.3 mmol) dropwise. The reaction mixture was stirred at reflux until complete by TLC (1-2 h). After cooling to room temperature, the mixture was partitioned between sat. NaHCO3 and ethyl acetate. The combined organic layers were dried (Na2SO4), filtered and concentrated to give methyl 2-fluoro-3-methylbenzoate as a yellow oil (13.8 g, 100%): 1H NMR (300 MHz, CDCl3) δ 7.74 (t, J=8.1 Hz, 1H), 7.37 (t, J=7.8 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 3.90 (s, 3H), 2.31 (s, 3H).
Reaction SMILES: [I:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.Cl[C:10]1[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=1.[H-].[Na+]>>[I:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:10]2[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]([O:18][CH3:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: Nc1ccc(I)cc1
Reactant: COc1cc(OC)nc(Cl)n1
Agent: [H-]
Agent: [Na+]
Product: COc1cc(OC)nc(Nc2ccc(I)cc2)n1
Yield: 39.3 %

Procedure:
In the same manner as in Reference Example 24-(1), 4-iodoaniline (220 mg) and 2-chloro-4,6-dimethoxypyrimidine (200 mg) were reacted in the presence of sodium hydride to obtain N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (141 mg). (2) In the same manner as in Reference Example 24-(2), sodium hydride (16 mg), N-(4-iodophenyl)-4,6-dimethoxypyrimidin-2-amine (140 mg) and methyl iodide (0.024 ml) were reacted to obtain N-(4-iodophenyl)-4,6-dimethoxy-N-methylpyrimidin-2-amine (118 mg).
Reaction SMILES: Cl[C:2]1[C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[NH:7][C:6]=2[N:5]=[CH:4][N:3]=1.[C:15]([O:19][C:20](=[O:29])[NH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][NH:25][CH2:24]1)([CH3:18])([CH3:17])[CH3:16].C(N(CC)CC)C>CN(C=O)C>[C:15]([O:19][C:20](=[O:29])[NH:21][CH2:22][CH:23]1[O:28][CH2:27][CH2:26][N:25]([C:2]2[C:14]3[C:13]4[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=4)[NH:7][C:6]=3[N:5]=[CH:4][N:3]=2)[CH2:24]1)([CH3:18])([CH3:16])[CH3:17]
Reactant: Clc1ncnc2[nH]c3ccccc3c12
Reactant: CC(C)(C)OC(=O)NCC1CNCCO1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC1CN(c2ncnc3[nH]c4ccccc4c23)CCO1
Temperature: 120 °C
Yield: 24.8 %

Procedure:
A mixture of 4-chloro-9H-pyrimido[4,5-b]indole (0.045 g, 0.221 mmol), morpholin-2-ylmethyl-carbamic acid tert-butyl ester (0.055 g, 0.25 mmol) and triethylamine (0.10 mL, 0.75 mmol) in DMF (0.70 mL) was heated to 120° C. in a microwave reactor for 1 hour. The cooled solution was partitioned between water (20 mL) and ethyl acetate (20 mL). The organic extract was dried (Na2SO4), filtered and concentrated. Flash column chromatography, eluting with ethyl acetate, gave the title compound as a yellow solid (0.021 g, 0.0548 mmol, 25%). LC-MS (3) Rt 5.57 min; m/z (ESI) 384 [MH+].
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH3:12].C(=O)([O-])[O-].[NH4+].[NH4+]>>[NH2:12][C@H:2]([C:1]([OH:11])=[O:10])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [NH4+]
Product: N[C@@H](Cc1ccccc1)C(=O)O
Temperature: 30 °C

Procedure:
Cells obtained by centrifugation of the culture solution at the stationary phase were resuspended in 1 L of 4 M ammonia/ammonium carbonate (pH 10.3), and 20 g of cinnamic acid was added thereto. The reaction was conducted with stirring at 30° C. and 800 rpm. A part of the reaction solution was sampled every 1 hour, and an amount of L-phenylalanine formed in the reaction solution was determined by HPLC. While a substrate was successively added to keep a substrate concentration at 2%, the reaction was continued. Then, approximately 3.5% L-phenylalanine was accumulated in the reaction solution for approximately 3 hours.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:17]2[C:22]([C:23](=O)[NH2:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH:18]=2)[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC.O>C(Cl)Cl>[C:1]([O:5][C:6](=[O:35])[NH:7][CH2:8][CH:9]1[CH2:10][CH2:11][CH:12]([CH2:15][NH:16][C:17]2[C:22]([C:23]#[N:24])=[CH:21][N:20]=[C:19]([NH:26][CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[Cl:34])[CH:18]=2)[CH2:13][CH2:14]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC1CCC(CNc2cc(NCc3ccccc3Cl)ncc2C(N)=O)CC1
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)NCC1CCC(CNc2cc(NCc3ccccc3Cl)ncc2C#N)CC1
Reaction time: 0.33 h
Yield: 40 %

Procedure:
To a suspension of (4-{[5-carbamoyl-2-(2-chloro-benzylamino)-pyridin-4-ylamino]-methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester (31 mg, 0.062 mmol) in CH2Cl2 at ambient temperature was added Burgess reagent (40 mg, 0. 168 mmol) in portions over 3 h. The resultant mixture was stirred at 25° C. for another 1 h and then water was added. The mixture was stirred for 20 min and extracted with CH2Cl2 (2×15 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica-gel column chromatography (hexanes/EtOAc, 2:1 v/v then EtOAc) to afford (4-{[2-(2-chloro-benzylamino)-5-cyano-pyridin-4-ylamino]-methyl}-cyclohexylmethyl)-carbamic acid tert-butyl ester as a white solid (12 mg, 40%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[C:8]([N:11]([CH2:40][CH2:41][N:42]([CH3:44])[CH3:43])[C:12]1[CH:39]=[CH:38][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=[CH:21][C:20]=2[NH:30]C(=O)OC(C)(C)C)=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9]>C(Cl)Cl>[C:8]([N:11]([CH2:40][CH2:41][N:42]([CH3:43])[CH3:44])[C:12]1[CH:39]=[CH:38][C:15]([C:16]([NH:18][C:19]2[CH:24]=[C:23]([C:25]3[S:26][CH:27]=[CH:28][CH:29]=3)[CH:22]=[CH:21][C:20]=2[NH2:30])=[O:17])=[CH:14][CH:13]=1)(=[O:10])[CH3:9]
Reactant: CC(=O)N(CCN(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2NC(=O)OC(C)(C)C)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)N(CCN(C)C)c1ccc(C(=O)Nc2cc(-c3cccs3)ccc2N)cc1
Reaction time: 0.75 h

Procedure:
TFA (0.5 mL) was added to the tert-butyl [2-[(4-{acetyl[2-(dimethylamino)ethyl]amino}benzoyl)amino]-4-(2-thienyl)phenyl]carbamate (0.05 g, 0.096 mmol) in DCM (1 mL). The reaction mixture was stirred for 45 min. LC/MS shows mass for the product. The mixture was concentrated and 1H NMR was taken to show pure compound. 1H NMR (600 MHz, MeOH-d4) δ 8.20 (d, J=8.4 Hz, 2H), 8.69 (d, J=1.8 Hz, 1H), 7.65 (dd, J=2.0, 8.4 Hz, 1H), 7.57 (d, J=8.4 Hz, 2H), 7.43 (dd, J=4.3, 7.4 Hz, 2H), 7.38 (d, J=8.4 Hz, 1H), 7.11 (dd, J=3.7, 5.1 Hz, 1H), 4.13 (t, J=6.1 Hz, 2H), 3.31-3.34 (m, 2H), 3.00 (s, 6H), 1.92 (s. 3H); MS: cal'd 423 (MH+), exp 423 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([F:10])[C:7]=1[CH:8]=[O:9].Cl[C:15]1[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=1>>[NH2:21][C:17]1[N:18]=[C:19]([C:4]2[CH:3]=[C:2]([F:1])[C:7]([CH:8]=[O:9])=[C:6]([F:10])[CH:5]=2)[CH:20]=[CH:15][N:16]=1
Reactant: O=Cc1c(F)cc(B(O)O)cc1F
Reactant: Nc1nccc(Cl)n1
Product: Nc1nccc(-c2cc(F)c(C=O)c(F)c2)n1
Yield: 91.3 %

Procedure:
The title compound was prepared following the General Procedure A using: (3,5-difluoro-4-formylphenyl)boronic acid (4.93 g, 26.5 mmol) and 4-chloro-2-pyrimidinamine (3.44 g, 26.5 mmol). Flash chromatography on SiO2 (gradient: 100% CHCl3 to 10% THF/90% CHCl3) afforded the title compound (5.69 g, 75%) as an off-white solid. LC-MS (ES) m/z=236 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[NH:12][CH:13]([CH3:16])[CH2:14][OH:15])=[CH:9][CH:8]=[C:7]([Cl:17])[CH:6]=2.CC(C)([O-])C.[K+]>CN(C=O)C.O>[Cl:17][C:7]1[CH:8]=[CH:9][C:10]2[C:11]3[NH:12][CH:13]([CH3:16])[CH2:14][O:15][C:2]=3[CH:3]=[N:4][C:5]=2[CH:6]=1
Reactant: CC(CO)Nc1c(Br)cnc2cc(Cl)ccc12
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1COc2cnc3cc(Cl)ccc3c2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.6 %

Procedure:
A solution of 10 g of 3-bromo-7-chloro-N-(2-hydroxy-1-methylethyl)-4-quinolinamine in 28 ml of DMF was stirred and to it was added 4.3 g of potassium-t-butoxide. The mixture was stirred at 120°-140° C. for 2 hours and then allowed to cool to room temperature. The reaction mixture was diluted with water and the organics were extracted into dichloromethane. Washing with water, drying over anhydrous magnesium sulfate and evaporation of solvents resulted in a crude solid which was purified by HPLC using 2:1 hexane/ethyl acetate as the eluent. Recrystallization from acetone yielded 2.5 g of solid with a melting point of 215°-217° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([OH:14])=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.[ClH:15].Br[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[ClH:15].[ClH:15].[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[C:13]([O:14][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1
Reactant: Cc1csc(Nc2ncccc2O)n1
Reactant: BrCc1ccccn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1csc(Nc2ncccc2OCc2ccccn2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 142.9 %

Procedure:
A vial was charged with 2-(4-methylthiazol-2-ylamino)pyridin-3-ol (75 mg, 0.362 mmol), 2-(bromomethyl)pyridine hydrochloride (75.4 mg, 0.362 mmol), potassium carbonate (175 mg, 1.27 mmol), and DMF (3 mL), and the reaction mixture was stirred overnight at room temperature. The reaction mixture was then poured into water and extracted with ether. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified over silica gel (80% EtOAc in hexanes). The residue was dissolved in 1:1 CH2Cl2:MeOH, and 2M HCl in ether was added. The solution was then concentrated to afford N-(4-methylthiazol-2-yl)-3-(pyridin-2-ylmethoxy)pyridin-2-amine dihydrochloride (96 mg, 71.4% yield) as a tan solid. 1H NMR (d6-DMSO) δ 8.77 (d, 1H), 8.19 (t, 1H), 8.07 (d, 1H), 8.04 (d, 1H), 7.67 (m, 2H), 7.16 (dd, 1H), 6.87 (s, 1H), 5.53 (s, 2H), 2.33 (s, 3H). Mass spectrum (apci) m/z=299 (M+H-2HCl).
Reaction SMILES: O1CCCCC1OC1C[CH2:12][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:10][CH2:9]1.[NH:24]1C2C(=CC(OC3CCC(O)CC3)=CC=2)C=N1>>[NH:24]1[CH2:9][CH2:10][CH:11]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[CH:18]3)[CH2:12]1
Reactant: OC1CCC(Oc2ccc3[nH]ncc3c2)CC1
Reactant: c1cc2[nH]ncc2cc1OC1CCC(OC2CCCCO2)CC1
Product: c1cc2[nH]ncc2cc1OC1CCNC1

Procedure:
The following compound of Example 379 was synthesized by carrying out reactions according to the methods described in Example 372, (b) and Example 377 except for using the tert-butyl 4-hydroxyazepane-1-carboxylate obtained in Example 322, (c), as a reagent.