Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:15]3[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=3[O:13][CH2:12][C:11]2=[O:22])[CH2:4][CH2:3]1.[O:23]=[C:24]1[CH2:29][O:28][C:27]2[CH:30]=[CH:31][C:32]([CH:34]=O)=[N:33][C:26]=2[NH:25]1.C([BH3-])#N.[Na+]>>[O:22]=[C:11]1[N:10]([CH2:9][CH2:8][N:5]2[CH2:6][CH2:7][CH:2]([NH:1][CH2:34][C:32]3[CH:31]=[CH:30][C:27]4[O:28][CH2:29][C:24](=[O:23])[NH:25][C:26]=4[N:33]=3)[CH2:3][CH2:4]2)[C:15]2[CH:16]=[C:17]([C:20]#[N:21])[CH:18]=[CH:19][C:14]=2[O:13][CH2:12]1
Reactant: O=Cc1ccc2c(n1)NC(=O)CO2
Reactant: N#Cc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Product: N#Cc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CO4)CC1)C(=O)CO2
Yield: 16.4 %

Procedure:
4-[2-(4-aminopiperidin-1-yl)ethyl]-3-oxo-3,4-dihydro-2H-1,4-benzoxazine-6-carbonitrile (Intermediate 58) (0.8 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine-6-carbaldehyde (WO 2004/058144) (140 mg, 0.79 mmol) and sodium cyanoborohydride (83 mg, 1.32 mmol) were reacted as described under Example 21 to give 60 mg (19%) product as a solid.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][CH2:8][N:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[C:6]=2[N:19]=1.Cl.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=1[O:31][CH3:32]>C(O)C.O>[CH:14]1([N:7]2[CH2:8][CH2:9][C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:19][C:6]2=3)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CN1C(=O)CCN(C2CCCC2)c2nc(Cl)ncc21
Reactant: COc1cc(C(=O)O)ccc1N
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CCC(=O)N2C
Temperature: 90 °C

Procedure:
2-Chloro-9-cyclopentyl-8,9-dihydro-5-methyl-5H-pyrimido[4,5-b][1,4]diazepin-6(7H)-one (150 mg, 0.536 mmol) in ethanol (2.25 ml) and water (9 ml) was treated with conc. HCl (0.088 ml) and 4-amino-3-methoxy benzoic acid (134 mg, 0.804 mmol). The mixture was stirred at 90° C. 24 hours, concentrated and the residue triturated with methanol/ether, filtered and the solid washed with ethanol then ether to give 4-(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxo-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as a buff powder (185.5 mg, 84%). NMR DMSO D6 1.51-1.79 (6H, m), 1.82-1.93 (2H, m), 2.70-2.75 (2H m), 3.18 (3H, s), 3.72-3.78 (2H, m), 3.98 (3H, s), 4.81-4.93 (1H, m), 7.57-7.64 (2H, m), 8.15-8.22 (2H, m), 9.46 (1H, br s); HPLC rt(min): 6.57.
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20]([C:24](=[O:36])[NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[CH2:19][CH2:18]3)[N:11]=[CH:10][N:9]=1)=[O:7])C>C1COCC1>[F:34][C:32]([F:33])([F:35])[C:28]1[CH:27]=[C:26]([NH:25][C:24]([N:20]2[C:21]3[C:17](=[CH:16][C:15]([O:14][C:12]4[N:11]=[CH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:13]=4)=[CH:23][CH:22]=3)[CH2:18][CH2:19]2)=[O:36])[CH:31]=[CH:30][CH:29]=1
Reactant: CCOC(=O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)c1cc(Oc2ccc3c(c2)CCN3C(=O)Nc2cccc(C(F)(F)F)c2)ncn1
Reaction time: 1 h

Procedure:
8.9 ml LiOH (1 M in H2O) are added to a solution of 2.80 g (5.9 mMol) 6-[1-(3-trifluoromethyl-phenylcarbamoyl)-2,3-dihydro-1H-indol-5-yloxy]-pyrimidine-4-carboxylic acid ethyl ester in 20 ml THF. After 1 h at rt, the mixture is concentrated under reduced pressure, the residue re-dissolved in EtOAc and 1 M HCl, the aqueous layer separeted off and extracted twice with EtOAc. The organic phases are washed twice with 1 M HCl, water and brine, dried (Na2SO4) and concentrated to the title compound: MS: [M−1]=443; HPLC: AtRet=12.9.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:20]4[N:25]=[CH:24][N:23]=[C:22]([C:26](O)=[O:27])[CH:21]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:29]=1.[CH3:30][C:31]1[CH:32]=[C:33]([NH2:40])[CH:34]=[C:35]2[C:39]=1[NH:38][N:37]=[CH:36]2.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][C:31]1[CH:32]=[C:33]([NH:40][C:26]([C:22]2[CH:21]=[C:20]([N:17]3[CH2:16][CH2:15][CH:14]([N:10]4[CH2:9][CH2:8][C:7]5[CH:29]=[C:3]([O:2][CH3:1])[CH:4]=[CH:5][C:6]=5[NH:12][C:11]4=[O:13])[CH2:19][CH2:18]3)[N:25]=[CH:24][N:23]=2)=[O:27])[CH:34]=[C:35]2[C:39]=1[NH:38][N:37]=[CH:36]2
Reactant: Cc1cc(N)cc2cn[nH]c12
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)O)ncn3)CC1)C(=O)N2
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)Nc4cc(C)c5[nH]ncc5c4)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.25 mmol) 6-[4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 37 mg (0.25 mmol) 7-methyl-1H-indazol-5-amine in 74 μL (0.53 mmol) TEA and 1.5 mL DMF were combined with 89 mg (0.28 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:13]([CH3:14])[C:12]3[CH:15]=[CH:16][C:17]([O:19][C:20]4[CH:25]=[CH:24][N:23]=[C:22]([C:26](O)=O)[CH:21]=4)=[CH:18][C:11]=3[N:10]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.[C:60]1([NH2:67])[CH:65]=[CH:64][CH:63]=[CH:62][C:61]=1[NH2:66].C([O-])(=O)C.[Na+]>C1COCC1.C(OCC)(=O)C>[NH:66]1[C:61]2[CH:62]=[CH:63][CH:64]=[CH:65][C:60]=2[N:67]=[C:26]1[C:22]1[CH:21]=[C:20]([O:19][C:17]2[CH:16]=[CH:15][C:12]3[N:13]([CH3:14])[C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[N:10][C:11]=3[CH:18]=2)[CH:25]=[CH:24][N:23]=1
Reactant: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(C(=O)O)c3)ccc21
Reactant: Nc1ccccc1N
Agent: CC(=O)[O-]
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cn1c(Nc2ccc(F)cc2)nc2cc(Oc3ccnc(-c4nc5ccccc5[nH]4)c3)ccc21
Temperature: 70 °C
Reaction time: 8 h

Procedure:
To a suspension of 4-[2-(4-Fluoro-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridine-2-carboxylic acid (1 eq) in dry THF, EDC-HCl (1.2 eq), HOAT (1.2 eq), and diisopropylethylamine (3 eq) were added. The suspension was stirred for 10 minutes whereupon phenylenediamine (1.1 eq) was added and the solution is allowed to stir overnight. The mixture was then diluted with ethyl acetate and washed with water. The aqueous layer was washed with ethyl acetate, the organic layers combined, dried over MgSO4, filtered, and concentrated. Acetic acid was added to the residue followed by sodium acetate (1.1 eq). The mixture was heated for 3 hours at 70° C., whereupon the solution is concentrated and the residue purified by reverse phase HPLC to afford the desired product. LCMS m/z 451.5 (MH+), tR=1.92 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH2:22])=[N:20][CH:21]=1.[CH2:23]([N:25]1[C:30](=[O:31])[N:29]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:28](=[O:39])[C:27]([C:40](O)=[O:41])=[N:26]1)[CH3:24]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:40]([C:27]2[C:28](=[O:39])[N:29]([C:32]3[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=3)[C:30](=[O:31])[N:25]([CH2:23][CH3:24])[N:26]=2)=[O:41])=[N:20][CH:21]=1
Reactant: CCn1nc(C(=O)O)c(=O)n(-c2ccc(F)cc2)c1=O
Reactant: COc1cc2nccc(Oc3ccc(N)nc3)c2cc1OC
Product: CCn1nc(C(=O)Nc2ccc(Oc3ccnc4cc(OC)c(OC)cc34)cn2)c(=O)n(-c2ccc(F)cc2)c1=O

Procedure:
This compound was synthesized using 5-(6,7-dimethoxyquinolin-4-yloxy)-pyridin-2-ylamine and 2-ethyl-4-(4-fluorophenyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazine-6-carboxylic acid using the procedure for example 1. mp=200-202° C.; LCMS m/z=585 (M+1); 1H NMR (CDCl3) δ: 11.13 (s, 1H), 8.52 (d, 1H, J=5 Hz), 8.48 (d, 1H, J=8.5 Hz), 8.27 (d, 1H, J=2.6 Hz), 7.60 (dd, 1H, J=2, 9 Hz), 7.52 (s, 1H), 7.43 (s, 1H), 7.28-7.26 (m, 3H), 6.47 (d, 1H, J=4.3 Hz), 4.33 (q, 2H, J=8.5 Hz), 4.05 (d, 6H), 1.51 (t, 3H, J=8 Hz).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:33])[CH:5]([NH:14][C:15](=[O:32])[CH2:16][O:17][CH2:18][CH:19]([O:30][CH3:31])C(OCC1C=CC=CC=1)=O)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[CH3:2].[C:34]([O:37]CC)(=[O:36])C>[Pd]>[CH2:1]([O:3][C:4](=[O:33])[CH:5]([NH:14][C:15](=[O:32])[CH2:16][O:17][CH2:18][CH2:19][O:30][CH2:31][C:34]([OH:37])=[O:36])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([OH:13])=[CH:11][CH:12]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)COCC(OC)C(=O)OCc1ccccc1
Reactant: CCOC(C)=O
Agent: [Pd]
Product: CCOC(=O)C(Cc1ccc(O)cc1)NC(=O)COCCOCC(=O)O
Temperature: 47.5 °C
Reaction time: 9 h

Procedure:
2-[2-(2-Benzyloxy carbonyl methoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (5 g) was dissolved in ethyl acetate (200 ml) in a pressure vessel. Palladium on carbon (5%, 50% wet, 2 g) was added and the mixture was stirred under an atmosphere of hydrogen (6 kg) for 9 hours at a temperature of 45-50° C. The catalyst was removed by filtration and distilled off ethyl acetate and the residue was washed with Diisopropyl ether and solvents residue was removed by applying high vacuum to get pure 2-[2-(2-Carboxy methoxy-ethoxy)-acetylamino]-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (2.2 g) as light yellow syrup. The product was characterized by 1H NMR which showed the presence of some impurities and hence was purified by column chromatography.
Reaction SMILES: [C:1]([NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[O:13]C(=O)C)([CH3:4])([CH3:3])[CH3:2].O.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[OH:13])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)Oc1ccccc1C(=O)NC(C)(C)C
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)NC(=O)c1ccccc1O
Yield: 80.7 %

Procedure:
The product from Step A (2.35 g, 0.010 mol) was dissolved in THF wand 10 mL of water was added to form a clear suspension. Hydrochloric acid (5%) was added until the solution reached a pH˜1. The reaction mixture was then refluxed for 24 hours. TLC indicated that about half of the starting material remained, so an additonal 10 mL of 5% hydrochloric acid was added and the reaction mixture was refluxed for 24 hours. The THF was then removed by rotoevaporation and the remaining aqueous mixture was extracted with hexanes (2×20 mL). The combined hexane layers were washed with water (2×40 mL), dried over MgSO4 and the hexane removed in vacuo to provide 1.56 g (80.8% yield) of the title compound as a white crystalline solid, m.p. 78-79.5° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8](Cl)[C:9]1[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=1.[N:17]1([C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C(N(CC)CC)C.[I-].[Na+]>C1(C)C=CC=CC=1.C(Cl)Cl.CCCCCC>[CH2:26]([O:25][C:23]([N:17]1[CH2:18][CH2:19][N:20]([CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[CH2:21][CH2:22]1)=[O:24])[CH3:27]
Reactant: Clc1ccc(C(Cl)c2ccccc2Cl)cc1
Reactant: CCOC(=O)N1CCNCC1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCN(C(c2ccc(Cl)cc2)c2ccccc2Cl)CC1
Temperature: 25 °C
Yield: 28.3 %

Procedure:
A stirred solution of 2.5 grams (0.009 mole) of (2-chlorophenyl)(4-chlorophenyl)methyl chloride, 1.6 grams (0.010 mole) of ethyl 1-piperazine-carboxylate, 1.4 mL (0.010 mole) of triethylamine, and 1.2 grams (0.008 mole) of sodium iodide in 25 mL of toluene was heated at reflux for about 18 hours. The resulting precipitate was collected by filtration. The filtrate was cooled to ambient temperature and 200 mL of aqueous saturated sodium bicarbonate solution was added to it. The mixture was extracted with two 100 mL portions of ethyl acetate. The combined ethyl acetate layers were washed with two 25 mL portions of an aqueous saturated sodium chloride solution. The organic layer was dried with sodium sulfate and concentrated under reduced pressure, yielding 3.2 grams of crude material. The crude material was subjected to column chromatography on silica gel with 50-25% hexane in methylene chloride, followed by pure methylene chloride, as eluants. The product-containing fractions were combined and concentrated under reduced pressure, yielding 1.0 gram of N-(ethoxycarbonyl)-N′-[(2-chlorophenyl)(4-chlorophenyl)methyl]piperazine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: COC([CH2:5][CH:6]([CH2:10][C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[C:7]([OH:9])=O)=O.Cl.Cl.[NH2:23][C@H:24]([C:31]([NH:33][C@@H:34]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH:35]([OH:42])[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37])=[O:32])[CH2:25][C:26]1[N:30]=[CH:29][NH:28][CH:27]=1.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>C(N(CC)CC)C>[CH3:39][O:38][C:36]([N:30]1[C:26]([CH2:25][C@@H:24]([C:31]([NH:33][C@@H:34]([CH2:43][CH:44]([CH3:46])[CH3:45])[CH:35]([OH:42])[C:36]([O:38][CH:39]([CH3:40])[CH3:41])=[O:37])=[O:32])[NH:23][C:7](=[O:9])[CH:6]([CH2:10][C:11]2[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH:14]=[CH:13][CH:12]=2)[CH3:5])=[CH:27][N:28]=[CH:29]1)=[O:37]
Reactant: COC(=O)CC(Cc1cccc2ccccc12)C(=O)O
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1c[nH]cn1)C(O)C(=O)OC(C)C
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)n1cncc1C[C@H](NC(=O)C(C)Cc1cccc2ccccc12)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C
Reaction time: 8 h
Yield: 55.6 %

Procedure:
To a solution of 28 mg of 3-methoxycarbonyl-2-(1-naphthylmethyl)propionic acid and 50 mg of isopropyl (2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate dihydrochloride were added successively 0.026 ml of diphenylphosphoryl azide and 0.046 ml of triethylamine, and the mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure, and a 5% aqueous sodium bicarbonate solution was added to the residue. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform/methanol=20/1 by volume) to obtain 20 mg of isopropyl (2RS,3S)-3-[3-(methoxycarbonyl)-2-(1-naphthylmethyl)propionyl-L-histidyl]amino-2-hydroxy-5-methylhexanoate as a white powder.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][NH:13][CH2:12]1)=O)(C)(C)C.[CH2:16]([O:23][C:24]([NH:26][C:27](=[NH:30])SC)=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.OS([O-])(=O)=O.[K+]>C1(C)C=CC=CC=1>[CH2:16]([O:23][C:24]([NH:26][C:27]([N:13]1[CH2:14][CH2:15][CH:11]([CH2:10][CH2:9][NH2:8])[CH2:12]1)=[NH:30])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)NCCC1CCNC1
Reactant: CSC(=N)NC(=O)OCc1ccccc1
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: Cc1ccccc1
Product: N=C(NC(=O)OCc1ccccc1)N1CCC(CCN)C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67529.2 %

Procedure:
2.18 g (0.0102 mmole) (3RS)-3-(N-tertbutyloxycarbonylaminoethyl) pyrrolidine and 2.81 g (0.0125 mole) N-benzyloxycarbonyl-S-methylisothiourea was dissolved in 30 ml toluene and heated to 60°-70° C. for eight hours followed by stirring at room temperature for one day. 0.3M KHSO4 -solution was added and the water layer was washed with a mixture of the toluene and ethyl acetate and left for 2 days under which time the Boc group was removed. The acidic water phase was made alkaline and extracted four times with CH2Cl2. The combined organic layer was dried (Na2SO4), filtered and evaporated to yield 2.0 g (51%) of the title compound.
Reaction SMILES: Br[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:9]1([CH3:18])[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:8][C:7]1[C:2]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[CH3:18])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Cc1cccnc1Br
Reactant: Cc1ccccc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Cc1ccccc1-c1ncccc1C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 2-bromo-3-methylpyridine (1.09 g; 6.34 mmol), o-tolylboronic acid (1.29 g; 9.50 mmol), and Pd(PPh3)4 (147 mg; 2 mol %) in DME (30 ml) is stirred for 10 minutes at room temperature. Sodium carbonate (32 ml of 1M solution in water; 32 mmol) is added to this mixture and the mixture is heated for 16 hours at 80° C. The reaction mixture is treated with water and extracted with dichloromethane. The combined extracts are washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue is purified by flash chromatography over silica gel (elution with 20% EtOAc/Hexane) to 3-methyl-2-o-tolyl-pyridine as a yellow oil. 1H NMR(300 MHz, CDCl3) δ 8.51(d, 1H), 7.58(d, 1H), 7.27-7.15(m, 5H), 2.14(s, 3H), 2.10(s, 3H).
Reaction SMILES: CC1C=[C:5]([N:7]2CCN(CC3C=CC(C(F)(F)F)=CC=3)C2=O)SC=1C(OCC)=O.[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3C=N[CH:49]=[CH:50][CH:51]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([O:37]CC)=[O:36]>>[CH3:29][C:30]1[N:31]=[C:32]([N:40]2[CH2:44][CH2:43][N:42]([CH2:45][C:46]3[CH:51]=[CH:50][CH:49]=[CH:5][N:7]=3)[C:41]2=[O:52])[S:33][C:34]=1[C:35]([OH:37])=[O:36]
Reactant: CCOC(=O)c1sc(N2CCN(Cc3cccnc3)C2=O)nc1C
Reactant: CCOC(=O)c1sc(N2CCN(Cc3ccc(C(F)(F)F)cc3)C2=O)cc1C
Product: Cc1nc(N2CCN(Cc3ccccn3)C2=O)sc1C(=O)O

Procedure:
Following the procedure as described in Example 14, making variations as required to replace ethyl 3-methyl-5-(2-oxo-3-(4-(trifluoromethyl)benzyl)imidazolidin-1-yl)thiophene-2-carboxylate with ethyl 4-methyl-2-(2-oxo-3-(pyridin-3-ylmethyl)imidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in quantitative yield: MS (ES+) m/z 319.1 (M+1).
Reaction SMILES: Cl.C(O)C.[Cl:5][C:6]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:7]=1[N+:15]([O-])=O.[OH-].[Na+]>O>[Cl:5][C:6]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:7]=1[NH2:15]
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Nc1cccc(N)c1Cl

Procedure:
A solution of 1 ml. of concentrated hydrochloric acid in 5 ml. of 5% ethanol is slowly added to a refluxing mixture of 10.1 g. of 1-chloro-2,6-dinitrobenzene, electrolytically reduced iron and 20 ml. of 50% ethanol. The mixture is heated at reflux for 2 hours. The mixture is allowed to cool slightly and the pH is adjusted to 8 with sodium hydroxide solution. The iron products are removed by filtration. The solvent is removed from the filtrate to leave a solid which is dissolved in water and extracted with methylene chloride. Removal of the solvents leaves an oily solid which upon recrystallization of from Skellysolve B gives off-white crystals of 2-chloro-1,3-diaminobenzene having a melting point of 82°-83.5° C.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:13]2[C:8](=[N:9][CH:10]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)[CH:12]=2)[C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:5]1=[O:34].C(N(C(C)C)CC)(C)C.[N:44]1([C:50](Cl)=[O:51])[CH2:49][CH2:48][O:47][CH2:46][CH2:45]1>CN(C=O)C>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][C:11]2[CH:12]=[C:13]3[C:8]([C:7]([OH:22])=[C:6]([C:23]([NH:25][CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][O:31][CH2:32][CH2:33]4)=[O:24])[C:5](=[O:34])[N:4]3[CH2:3][CH2:2][NH:1][C:50]([N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[O:51])=[N:9][CH:10]=2)=[CH:20][CH:19]=1
Reactant: NCCn1c(=O)c(C(=O)NCCN2CCOCC2)c(O)c2ncc(Cc3ccc(F)cc3)cc21
Reactant: O=C(Cl)N1CCOCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCCN1CCOCC1)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CCNC(=O)N2CCOCC2)c1=O

Procedure:
A solution of 1-(2-aminoethyl)-7-[(4-fluorophenyl)methyl]-4-hydroxy-N-[2-(4-morpholinyl)ethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxamide (0.025 g, 0.052 mmol) and diisopropyl ethylamine (0.05 mL, 0.29 mmol) in DMF (5 mL) under nitrogen was treated with 4-morpholinecarbonyl chloride (0.008 mL, 0.068 mmol) at 40° C. for 1 h then 3½ h at ambient temperature. The reaction was concentrated in vacuo and the resulting residue was triturated with Et2O:MeOH, filtered, washed with 2:1 Et2O:MeOH, and dried in vacuo to provide the title compound as an off-white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 1.3 (s, 1 H), 3.10 (s, 2 H), 3.13-3.22 (m, 8 H), 3.27-3.33 (m, 1 H), 3.42-3.50 (m, 4 H), 3.55 (d, J=10.67 Hz, 2 H), 3.63-3.73 (m, 2 H), 3.78 (d, J=4.49 Hz, 1 H), 3.93-4.05 (m, 2 H), 4.14 (s, 2 H), 4.30 (t, J=6.67 Hz, 2 H), 7.11-7.19 (m, 2 H), 7.39-7.47 (m, 2 H), 8.34 (s, 1 H), 8.57 (d, J=1.12 Hz, 1 H), 9.88 (br. s., 1 H), 10.38-10.48 (m, 1 H); ES+ MS: 583 (M+H+).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([CH:17]2[CH2:20][N:19](C(C3C=CC=CC=3)C3C=CC=CC=3)[CH2:18]2)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OC(Cl)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([CH:17]2[CH2:18][NH:19][CH2:20]2)[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CN(C(c3ccccc3)c3ccccc3)C2)CC1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C2CNC2)CC1
Reaction time: 2 h
Yield: 125 %

Procedure:
To a solution of compound 8b (3.4 g, 7.7 mmol) in CH2Cl2 was added 1-chloroethyl chloroformate (2.5 mL, 23.1 mmol) at 0° C. under a N2 atmosphere. The ice bath was removed and the reaction stirred for 2 h. The organic phase was concentrated under reduced pressure, and MeOH was added to the resultant residue. The reaction was refluxed for 2 h at which time the solvent was removed under reduced pressure. The residue was partitioned between chloroform and aqueous HCl (1N). The aqueous layer was separated, made basic with aqueous NaOH (3N), and extracted with chloroform. The organic layer was then dried (K2CO3), filtered and concentrated to afford compound 8c (2.65 g). MS m/z (M+H+) 276.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[Cl:19][C:20]1[CH:26]=[CH:25][C:23](N)=[CH:22][CH:21]=1.[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:22][CH:21]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: N#Cc1nc2ccc3ncnc(Nc4ccc(Cl)cc4)c3c2s1
Yield: 89 %

Procedure:
Prepared from VII and 4-chloroaniline. Flash chromatography eluent (DCM-EtOAc, 5:5). Yield: 89%; yellow solid; mp>260° C.; IR (KBr) νmax/cm−1 2850, 2229, 1643, 1609, 1583, 1550, 1491, 1480, 1457, 1377, 1355, 1307, 1270, 1214, 1164, 1130, 1092, 1010, 980, 831; 1H NMR (300 MHz, DMSO-d6) δ 8.51 (d, 1H, J=8.7 Hz), 8.18 (s, 1H), 7.76 (d, 1H, J=8.7 Hz), 7.38 (m, 2H), 7.04 (m, 2H); HRMS calcd for C16H9N5SCl (M+H+): 338.0267, found 338.0274.