Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:24]3[CH2:27][CH:26]([NH:28]C(=O)OC(C)(C)C)[CH2:25]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:1]([C:5]1[N:9]([CH2:10][CH:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:8]2[CH:17]=[CH:18][C:19]([S:21]([N:24]3[CH2:25][CH:26]([NH2:28])[CH2:27]3)(=[O:23])=[O:22])=[CH:20][C:7]=2[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CN(S(=O)(=O)c2ccc3c(c2)nc(C(C)(C)C)n3CC2CCOCC2)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)c1nc2cc(S(=O)(=O)N3CC(N)C3)ccc2n1CC1CCOCC1
Yield: 85.9 %

Procedure:
tert-butyl (1-{[2-tert-butyl-1-(tetrahydro-2H-pyran-4-ylmethyl)-1H-benzimidazol-5-yl]sulfonyl}azetidin-3-yl)carbamate (0.84 g, 1.66 mmol) (see following step B for preparation) in CH2Cl2 (10 mL) was treated with TFA (5 mL) for 1 h at room temperature. Upon evaporation, the residue was dissolved in H2O (20 mL), neutralized with 2 N NaOH to pH=10, and extracted with CH2Cl2 (5×30 mL). The combined organic phases were washed with NaCl (10 mL) and dried over Na2SO4. After concentration, 0.58 g (86%) of a white solid was obtained as the title compound. 1H NMR (400 MHz, METHANOL-D4) δ 1.45-1.62 (m, 4 H), 1.63 (s, 9 H), 2.28-2.44 (m, 1 H), 3.30-3.39 (m, 2 H), 3.82-3.89 (m, 3 H), 3.89-3.97 (m, 2 H), 3.99-4.10 (m, 2 H), 4.48 (d, J=7.62 Hz, 2 H), 7.85 (dd, J=8.69, 1.66 Hz, 1 H), 7.98 (d, J=8.79 Hz, 1 H), 8.15 (d, J=1.76 Hz, 1 H); MS (ESI) (M+H)+=407.0; Anal. Calcd for C20H30N4O3S+2.10 TFA+0.20 CH3OH+0.20H2O (656.01): C, 44.67; H, 5.12; N, 8.54. Found: C, 44.68; H, 5.15; N, 8.56.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][N:30]=1)[C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([NH:23][CH2:24][CH:25]3[CH2:27][CH2:26]3)=[O:22])=[CH:17][CH:16]=2)[C:11]([CH3:14])=[CH:12][CH:13]=1)=[O:6].[CH3:31][O:32][CH2:33][CH:34]1[CH2:38][CH2:37][CH2:36][NH:35]1>CS(C)=O>[CH:25]1([CH2:24][NH:23][C:21]([C:18]2[CH:19]=[CH:20][C:15]([C:10]3[C:11]([CH3:14])=[CH:12][CH:13]=[C:8]([NH:7][C:5](=[O:6])[C:4]4[CH:28]=[CH:29][N:30]=[C:2]([N:35]5[CH2:36][CH2:37][CH2:38][CH:34]5[CH2:33][O:32][CH3:31])[CH:3]=4)[CH:9]=3)=[CH:16][CH:17]=2)=[O:22])[CH2:27][CH2:26]1
Reactant: Cc1ccc(NC(=O)c2ccnc(Cl)c2)cc1-c1ccc(C(=O)NCC2CC2)cc1
Reactant: COCC1CCCN1
Solvent: CS(C)=O
Product: COCC1CCCN1c1cc(C(=O)Nc2ccc(C)c(-c3ccc(C(=O)NCC4CC4)cc3)c2)ccn1

Procedure:
A solution of 2-chloro-N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)isonicotinamide (50 mg, 0.12 mmol) and 2-(methoxymethyl)pyrrolidine (1 ml) in DMSO (1 ml) was heated at 140° C. for 24 h in a sealed tube. The reaction was concentrated under vacuum, the residue chromatographed on an SPE (C18) eluting with a water/acetonitrile gradient, to give, after evaporation of the solvents under vacuum N-(4′-{[(cyclopropylmethyl)amino]carbonyl}-6-methyl-1,1′-biphenyl-3-yl)-2-(2-methoxymethylpyrrolidin-1-yl)isonicotinamide (16 mg). NMR; δH [2H6]—DMSO 10.29,(1H, s), 8.62,(1H, t), 8.21,(1H, d), 7.93,(2H, d), 7.70,(1H, dd), 7.65,(1H, d), 7.44,(2H, d), 7.30,(1H, d), 7.00,(1H, d), 6.89,(1H, s), 4.23,(1H, b), 3.52-3.47,(2H, m), 3.26,(5H, m), 3.16,(2H, t), 2.20,(3H, s), 2.07-1.90,(4H, m), 1.04,(1H, m), 0.43,(2H, m), 0.24,(2H, m). LCMS: retention time 2.78 min, MH+499.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:11]=[C:10]([O:12][CH3:13])[CH:9]=[C:8]([O:14][CH3:15])[N:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C.O>[CH3:13][O:12][C:10]1[CH:9]=[C:8]([O:14][CH3:15])[N:7]=[C:6]([C:4]([OH:5])=[O:3])[N:11]=1
Reactant: CCOC(=O)c1nc(OC)cc(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1cc(OC)nc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
17.1 g of 2-ethoxycarbonyl-4,6-dimethoxypyrimidine are dissolved in 300 ml of ethanol, and 3.4 g of sodium hydroxide in 50 ml of water are added. This solution is stirred for 4 hours at room temperature and refluxed for 1 hour. The mixture is cooled, and most of the ethanol is removed on a rotary evaporator. The residue is taken up in water and extracted using dichloromethane. The aqueous-alkaline phase is acidified to a pH of 2-3 using 6 N hydrochloric acid, and any precipitated product is filtered off with suction. This gives 9.6 g of 4,6-dimethoxypyrimidine-2-carboxylic acid of melting point 155°-157° C.
Reaction SMILES: [NH2:1]/[C:2](/[CH3:27])=[CH:3]\[C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[C:9]([Cl:26])[CH:8]=1)=[O:5].[C:28](OCC)(OCC)(OCC)[CH3:29]>>[Cl:26][C:9]1[CH:8]=[C:7]([N:6]2[C:4](=[O:5])[CH:3]=[C:2]([CH3:27])[N:1]=[C:28]2[CH3:29])[CH:12]=[CH:11][C:10]=1[N:13]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCOC(C)(OCC)OCC
Reactant: CCCCCCN(CCCCCC)c1ccc(NC(=O)/C=C(/C)N)cc1Cl
Product: CCCCCCN(CCCCCC)c1ccc(-n2c(C)nc(C)cc2=O)cc1Cl
Temperature: 150 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of (Z)-3-amino-N-(3-chloro-4-(dihexylamino)phenyl)but-2-enamide (3.94 g, 10 mmol) and triethyl orthoacetate (80 mL) was stirred at 150° C. overnight. The mixture was then cooled to rt and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=2:1) to give the title compound as pale yellow oil (1.36 g, 33%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:17]2[C@@H:12]([C:13]3[C:21]([OH:22])=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:24]1[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CN1CCCC1=O>C(OCC)(=O)C>[C:1]([O:5][C:6]([N:8]1[C@@H:17]2[C@@H:12]([C:13]3[C:21]([O:22][C:24]4[N:25]=[N:26][C:27]([CH3:30])=[CH:28][CH:29]=4)=[CH:20][CH:19]=[CH:18][C:14]=3[CH2:15][CH2:16]2)[CH2:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]2c3c(O)cccc3CC[C@@H]21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Oc2cccc3c2[C@H]2CCCN(C(=O)OC(C)(C)C)[C@H]2CC3)nn1
Temperature: 150 °C
Reaction time: 1.5 h

Procedure:
A mixture of cis-10-hydroxy-2,3,4a,5,6,10b-hexahydro-1H-benzo[f]quinoline-4-carboxylic acid tert-butyl ester (0.40 g), 3-chloro-6-methyl-pyridazine (0.13 g), cesium carbonate (0.35 g), and N-methylpyrrolidinone (5 mL) is stirred at 150° C. for 1.5 h. After cooling to room temperature, the mixture is diluted with ethyl acetate and washed with water and brine and dried (Na2SO4). The solvent is evaporated and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 3:1→1:2) to give the title compound. Yield: 0.14 g (impure); LC (method 1): tR=4.19 min; Mass spectrum (ESI+): m/z=396 [M+H]+.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH3:29]>>[CH2:28]([N:27]([CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1)[CH2:26][CH2:25][O:24][CH3:23])[CH3:29]
Reactant: CCNCCOC
Reactant: Fc1ccc(-c2nsc3cc(OCCCCBr)ccc23)cc1
Product: CCN(CCCCOc1ccc2c(-c3ccc(F)cc3)nsc2c1)CCOC

Procedure:
In analogy to example 3.1, 6-(4-Bromo-butoxy)-3-(4-fluoro-phenyl)-benzo[d]isothiazole and N-(2-Methoxyethyl)ethylamine were converted to yield Ethyl-{4-[3-(4-fluoro-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl}-(2-methoxy-ethyl)-amine which was transferred into its salt by treatment with formic acid, MS: 403 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][OH:9].[Na].[H-].[Na+].Cl[C:15]1[C:20]([C:21]#[N:22])=[CH:19][CH:18]=[CH:17][N:16]=1>C1(C)C=CC=CC=1>[C:21]([C:20]1[C:15]([O:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][N:2]([CH3:10])[CH3:1])=[N:16][CH:17]=[CH:18][CH:19]=1)#[N:22]
Reactant: N#Cc1cccnc1Cl
Reactant: CN(C)CCCCCCO
Agent: [H-]
Agent: [Na+]
Agent: [Na]
Solvent: Cc1ccccc1
Product: CN(C)CCCCCCOc1ncccc1C#N

Procedure:
6-Dimethylaminohexanol is converted into its sodium salt with sodium hydride in toluene, followed by reaction of the sodium salt with 2-chloro-3-cyanopyridine to give 3-cyano-2-(6-dimethylaminohexyloxy)pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][C:12](=[O:18])[NH:13]3)[CH:6]=[CH:7][CH:8]=1.[CH2:19]([N:21]([CH2:35][CH3:36])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=O)[NH:29][CH:28]=1)=[O:26])[CH3:20]>C(O)C.N1CCCCC1>[CH2:35]([N:21]([CH2:19][CH3:20])[CH2:22][CH2:23][NH:24][C:25]([C:27]1[C:31]([CH3:32])=[C:30]([CH:33]=[C:11]2[C:10]3[C:14](=[CH:15][CH:16]=[CH:17][C:9]=3[C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[NH:13][C:12]2=[O:18])[NH:29][CH:28]=1)=[O:26])[CH3:36]
Reactant: COc1cccc(-c2cccc3c2CC(=O)N3)c1
Reactant: CCN(CC)CCNC(=O)c1c[nH]c(C=O)c1C
Solvent: C1CCNCC1
Solvent: CCO
Product: CCN(CC)CCNC(=O)c1c[nH]c(C=C2C(=O)Nc3cccc(-c4cccc(OC)c4)c32)c1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 57.1 %

Procedure:
To a solution of 4-(3-methoxy-phenyl)-1,3-dihydro-indol-2-one (59.8 mg, 0.25 mmol) and 5-formyl-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (65.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. The solvent was evaporated and the solid was washed by ether for three times to provide pure product 5-[4-(3-methoxy-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-4-methyl-1H-pyrrole-3-carboxylic acid (2-diethylamino-ethyl)-amide (67.5 mg, 57%).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:26]=[CH:25][C:8]2[N:9]([CH2:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[C:10]([CH2:12][C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[OH-].[Na+].Cl>CO.C1COCC1>[CH:19]1([CH2:18][N:9]2[C:8]3[CH:25]=[CH:26][C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]=3[N:11]=[C:10]2[CH2:12][C:13]2[S:14][CH:15]=[CH:16][CH:17]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COC(=O)c1ccc2c(c1)nc(Cc1cccs1)n2CC1CCCCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2c(c1)nc(Cc1cccs1)n2CC1CCCCC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 84.8 %

Procedure:
To 13.60 g of 1-Cyclohexylmethyl-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid methyl ester in 25 ml of methanol and 100 ml of THF were added 37 ml of 2 M aqueous sodium hydroxide solution. The reaction stirred at rt for 6 h. The reaction mixture was adjusted to pH 4 by the addition of 2M aqueous hydrochloric acid and was extracted with ethyl acetate three times. The combined organic phases were dried over sodium sulphate and concentrated in vacuo. The residue was purified by chromatography (silica, heptane/ethyl acetate) to yield 11.1 g (85%) of 1-Cyclohexylmethyl-2-thiophen-2-ylmethyl-1H-benzoimidazole-5-carboxylic acid.
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[C:21]([N:25]=[C:26]=[O:27])([CH3:24])([CH3:23])[CH3:22]>O1CCCC1>[CH3:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:26]([NH:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:27])[C:3]1=[O:20]
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Reactant: CC(C)(C)N=C=O
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)NC(C)(C)C)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 3(R,S)-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and t-butylisocyanate were mixed in 8 ml of dry tetrahydrofuran at room temperature. The reaction mixture was allowed to stand for 8 hours and was then filtered. The collected solids were washed with tetrahydrofuran and dried in vacuo over P2O5 to give the analytical product: m.p. 281°-282° C.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.[C:13]([C:16]([CH3:18])=O)([CH3:15])=O>C(O)(C)C>[ClH:1].[CH:4]([O:3][CH2:15][C:13]1[N:9]=[C:8]([C:7]2[CH:11]=[CH:12][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH:10][C:16]=1[CH3:18])([CH3:12])[CH3:5]
Reactant: COc1ccc(C(=N)N)cc1
Reactant: CC(=O)C(C)=O
Agent: Cl
Solvent: CC(C)O
Product: COc1ccc(-c2nc(COC(C)C)c(C)[nH]2)cc1
Yield: 161.9 %

Procedure:
To a solution of 38.4 g (0.206 mole) of p-methoxy-benzamidine hydrochloride in 1 liter of refluxing isopropyl alcohol is added 25 g (0.25 mole) of biacetyl. The mixture is stirred and refluxed for 72 hours. The solvent is removed to dryness under reduced pressure and the solid residue taken up in fresh hot isopropyl alcohol. Ether is added and, on chilling, pale yellow crystals form which are collected to give about 49.5 g (81% yield) of 4-isopropoxymethyl-2-(p-methoxyphenyl)-5-methylimidazole hydrochloride as very pale yellow crystals, m.p. 149°-150° C (dec.). Recrystallization twice from isopropyl alcohol-ether with charcoaling gives the product as white crystals, m.p. 149°-150° C (dec.).
Reaction SMILES: [OH:1][CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)=[CH:5][CH:4]=1.Cl.[CH:28](Cl)(Cl)Cl>>[CH3:28][O:1][CH:2]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:9]2[NH:13][C:12]3[CH:14]=[CH:15][C:16]([C:18]([NH2:20])=[O:19])=[CH:17][C:11]=3[N:10]=2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C(O)c4ccccc4)cc3)nc2c1
Reactant: ClC(Cl)Cl
Agent: Cl
Product: COC(c1ccccc1)c1ccc(-c2nc3cc(C(N)=O)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
To a solution of 2-[4-(hydroxy-phenyl-methyl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide (Example 19, 8.7 mg, 0.02 mmol) in chloroform (1.0 mL) was added concentrated HCl (0.1 mL). The reaction mixture was stirred at RT for 2 h. Organics were removed under reduced pressure, and purification using preparative TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2) afforded 4.2 mg (47%) of the title compound. HPLC (Method A): Rt=6.97. MS (ESI+): mass calculated for C22H19N3O2, 357.1; m/z found, 358.2 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.18 (br s, 1H), 8.08 (d, J=8.2 Hz, 2H), 7.82 (br d, J=8.0 Hz, 1H), 7.64 (br s, 1H), 7.56 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.35 (t, J=7.5 Hz, 2H), 7.28-7.25 (m, 1H), 5.39 (s, 1H), 3.40 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[OH:14])[CH3:4].[Cl:16][CH2:17][CH2:18]OS(C1C=CC=CC=1)(=O)=O>CN(C)C=O>[CH2:3]([O:5][C:6](=[O:15])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[O:14][CH2:18][CH2:17][Cl:16])[CH3:4]
Reactant: O=S(=O)(OCCCl)c1ccccc1
Reactant: CCOC(=O)Cc1ccccc1O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccccc1OCCCl
Temperature: 100 °C
Yield: 53.6 %

Procedure:
50% Sodium hydride in mineral oil (8.11 g, 169 mmol) was added portionwise to a solution of 2-hydroxy-phenyl-acetic acid ethyl ester (30.4 g, 169 mmol) in dimethylformamide (100 ml). After the initial effervescence had ended the reaction was heated to 100° C. for 10 minutes and was cooled to room temperature. A solution of benzene sulfonic acid 2-chloro-ethyl ester (37.2 g, 169 mmol) in dimethylformamide (5 ml) was then added and the reaction was heated to 100° C. for one hour, and allowed to cool to room temperature over 18 hours. The reaction mixture was partitioned between diethylether (300 ml) and water (300 ml) and the organic phase was removed and washed with water (100 ml), dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by thermal distillation to give [2-(2-chloro-ethoxy)-phenyl]-acetic acid ethyl ester (22.0 g) as a pale yellow oil. Bp 170° C. to 180° C. νmax (thin film) 1735 cm−1 (C═O, ester); no O—H stretch. Anal. Found C, 59.35; H, 6.29. C12H15CIO3 requires C, 59.38; H, 6.23%.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][C:7]1[NH:8][CH:9]=[CH:10][N:11]=1.[C:12](N1C=CN=C1)([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13].CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:8]1[CH:9]=[CH:10][N:11]=[C:7]1[NH:6][C:12]([N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)=[O:13]
Reactant: Nc1ncc[nH]1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: O=S(=O)(O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1ncc[nH]1)n1ccnc1

Procedure:
To a stirred suspension of 2-aminoimidazole sulfate (667 mg, 5.05 mmol) in CH2Cl2 (25 mL) was added 1,1′-carbonyldiimidazole followed by DIPEA (2.70 mL, 15.50 mmol). The resultant mixture was stirred at room temperature overnight then concentrated under reduced pressure and provided 1.53 g of imidazole-1-carboxylic acid (1H-imidazol-2-yl)-amide as a brown solid.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH3:19])=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[CH:7][CH:8]=1.[C-:20]#[N:21].[Na+].O>CS(C)=O>[CH3:19][C:4]1[C:3]([CH2:2][C:20]#[N:21])=[CH:8][CH:7]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=1
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1nc(-c2ccc(C(F)(F)F)cc2)ccc1CC#N
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
27.2 g of 3-chloromethyl-2-methyl-6-(4-trifluoromethyl-phenyl)-pyridine (95.2 mmol) were dissolved in 100 ml of dimethyl sulfoxide; 5.9 g of sodium cyanide (120 mmol) were added and the mixture was stirred at room temperature for 18 hours. Then, the reaction mixture was poured into a mixture of ice and water and was subsequently extracted with 3 portions of 400 ml of tert-butyl methyl ether. The combined organic phases were washed with water, then with brine and dried with anhydrous sodium sulfate. After evaporation of the solvent, 25.2 g (95.8% of theory) of [2-methyl-6-(4-trifluoromethyl-phenyl)-pyridin-3-yl]-acetonitrile were obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](O)=[O:24])[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[CH:34]1([NH2:37])[CH2:36][CH2:35]1.CCN=C=NCCCN(C)C.Cl.ON1C2C=CC=CC=2N=N1>>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[C:21]([C:23](=[O:24])[NH:37][CH:34]4[CH2:36][CH2:35]4)[N:22]=3)[CH2:14][C@H:13]2[O:31][CH2:32][CH3:33])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: NC1CC1
Reactant: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCOC(=O)c1sc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCC)C2)nc1C(=O)NC1CC1
Yield: 76.7 %

Procedure:
The same operation as in Example (247a) was performed using cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-(ethoxycarbonyl)-1,3-thiazole-4-carboxylic acid obtained in Example (50a) (300 mg, 0.60 mmol), cyclopropylamine (0.08 mL, 1.20 mmol), WSC hydrochloride (345 mg, 1.80 mmol) and 1-hydroxybenzotriazole (81 mg, 0.60 mmol), to obtain 248 mg of the title compound as a white solid (77%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]([CH3:43])([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH2:16][CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][C:29](=[O:32])[N:28]4[CH2:33][CH:34]=[C:35]([C:37]5[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=5)[N:36]=[C:27]34)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH:11]=1)[CH3:9])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]([C:10]1[CH:11]=[C:12]([CH2:16][CH:17]([NH:19][C:20]2[N:25]=[C:24]([N:26]3[CH2:31][CH2:30][C:29](=[O:32])[N:28]4[CH2:33][CH:34]=[C:35]([C:37]5[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=5)[N:36]=[C:27]34)[CH:23]=[CH:22][N:21]=2)[CH3:18])[CH:13]=[CH:14][CH:15]=1)([CH3:9])[CH3:43]
Reactant: CC(Cc1cccc(C(C)(C)NC(=O)OC(C)(C)C)c1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(Cc1cccc(C(C)(C)N)c1)Nc1nccc(N2CCC(=O)N3CC=C(c4ccccc4)N=C32)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of [1-methyl-1-(3-{2-[4-(4-oxo-8-phenyl-3,4-dihydro-2H, 6H-pyrimido[1,2-a]pyrimidin-1-yl)-pyrimidin-2-ylamino]-propyl}-phenyl)-ethyl]-carbamic acid tert-butyl ester (0.25 g, 0.42 mmol) and trifluoroacetic acid (1 mL) in dichloromethane (2 mL) was stirred at room temperature for 30 min. The mixture was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate and was purified by chromatography on silica gel using 0-8% 2 M NH3 MeOH/CH2Cl2. M+1=496. 1NMR (CDCl3) d (3H, 1.23 ppm), s (6H, 1.47 ppm), m (2H, 2.21 ppm), m (1H, 2.82 ppm), m (1H, 2.98 ppm), s (1H, 3.48 ppm), m (4H, 4.12 ppm), m (1H, 4.35 ppm), d (1H, 4.95 ppm), s (1H, 6.60 ppm), d (1H, 7.09 ppm), d (1H, 7.21 ppm), m (2H, 7.36 ppm), m (3H, 7.44 ppm), dd (2H, 7.91 ppm), d (1H, 8.16 ppm).
Reaction SMILES: [NH2:1][CH:2](/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[C:3]([OH:5])=[O:4].Cl.[CH2:14](O)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:14]([O:4][C:3](=[O:5])[CH:2]([NH2:1])/[CH:6]=[CH:7]/[CH2:8][P:9]([OH:12])([OH:11])=[O:10])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: NC(/C=C/CP(=O)(O)O)C(=O)O
Reactant: CCCCCCCCO
Agent: Cl
Product: CCCCCCCCOC(=O)C(N)/C=C/CP(=O)(O)O

Procedure:
2.0 g of E-2-amino-5-phosphono-3-pentenoic acid are suspended in 30 ml of n-octanol and the suspension is saturated with hydrogen chloride gas for 4 hours at 70°. The mixture is concentrated in vacuo at 70° to half its volume, 50 ml of diethyl ether and 15 ml of propylene oxide are added and the whole is filtered. Recrystallisation from water/acetone 1:1 yields E-2-amino-5-phosphono-3-pentenoic acid octyl ester, m.p. 161°-162°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](O)=[O:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15].[CH3:31][Li]>C(OCC)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[N:11]=[C:12]([N:16]([C:20]2[CH:25]=[C:24]([C:26](=[O:27])[CH3:31])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])[CH2:17][CH2:18][CH3:19])[S:13][C:14]=1[CH3:15]
Reactant: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(=O)O)ccc1OC
Reactant: [Li]C
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CCCN(c1nc(-c2ccc(OC)cc2Cl)c(C)s1)c1cc(C(C)=O)ccc1OC
Reaction time: 2 h

Procedure:
At 0° C., under an inert atmosphere, 2 g of 4-(2-chloro-4-methoxyphenyl)-5-methyl-2-[N-(5-carboxy-2-methoxyphenyl)-N-propylamino]thiazole are dissolved in 30 ml of diethyl ether. Methyllithium (3 equivalents) is slowly added to the ethereal solution. When the addition is complete, the reaction mixture is brought to room temperature. After 2 hours, it is diluted with ethyl acetate and then hydrolyzed. The organic phase is washed with water and then dried over sodium sulphate. After evaporation, the residue is purified on a silica gel. The expected product is obtained in the form of a powder; m.p.=50° C.
Reaction SMILES: [ClH:1].N([C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20][NH:19][C:17]3=2)[N:12]=[C:11]([CH3:22])[CH:10]=1)C1C=CC=CC=1.[CH2:23]([C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH2:24][CH2:25][CH3:26]>C(O)C>[ClH:1].[CH2:23]([C:27]1[CH:28]=[CH:29][C:30]([NH:31][N:19]2[C:17]3=[C:18]4[C:13](=[CH:14][CH:15]=[C:16]3[N:21]=[CH:20]2)[N:12]=[C:11]([CH3:22])[CH:10]=[CH:9]4)=[CH:32][CH:33]=1)[CH2:24][CH2:25][CH3:26]
Reactant: CCCCc1ccc(N)cc1
Reactant: Cc1cc(Nc2ccccc2)c2c(ccc3nc[nH]c32)n1
Agent: Cl
Solvent: CCO
Product: CCCCc1ccc(Nn2cnc3ccc4nc(C)ccc4c32)cc1

Procedure:
A mixture of the compound of Example I, C. (21.7 g., 0.1 mole) and p-n-butylaniline (14.9 g., 0.1 mole) in ethanol (200 ml.) was stirred and refluxed overnight. The reaction solution was concentrated to dryness by rotary evaporator and the residue was collected and dried at 100°C to yield 36.5 g. (99.7%) yellow crystals, m.p. 296°-303°C. A small sample (5.0 g.) was recrystallized from nitromethane (750 ml.) and dried to yield 1.9 g. yellow crystals, m.p. 287°-302°C. A repeated recrystallization gave m.p. 303°-306°C.