Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]([CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:11][C@H:12]([OH:27])[CH2:13][N:14]1[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:15]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.CI.[C:37](=O)(O)[O-].[Na+]>O1CCCC1>[CH2:3]([N:10]([CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:11][C@H:12]([O:27][CH3:37])[CH2:13][N:14]1[CH2:15][CH2:16][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:18][CH2:19]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCN(C[C@@H](O)CN(Cc2ccccc2)Cc2ccccc2)CC1
Reactant: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@H](CN1CCN(C(=O)OC(C)(C)C)CC1)CN(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 56 %

Procedure:
Sodium hydride (333 mg, 8.30 mmol) was dissolved in 50 mL of tetrahydrofuran, added dropwise with a solution of tert-butyl 4-[(2S)-3-(dibenzylamino)-2-hydroxy-propyl]piperazine-1-carboxylate 35a (3.65 g, 8.30 mmol) in tetrahydrofuran in an ice-water bath. The reaction solution was stirred for 10 minutes and warmed up to room temperature. The reaction solution was stirred for 1 hour and cooled down to 0° C. followed by the addition of methyl iodide (1.18 g, 8.30 mmol). The reaction solution was stirred for 12 hours. The resulting solution was added with 10 mL of saturated sodium bicarbonate solution and extracted with ethyl acetate (50 mL×3). The combined organic phase was washed with saturated sodium chloride solution (50 mL), then dried over anhydrous magnesium sulfate, filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound tert-butyl 4-[(2S)-3-(dibenzylamino)-2-methoxy-propyl]piperazine-1-carboxylate 35b (2.10 g, yield: 56.0%) as a yellow oil.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[C:10](=[O:11])[N:9]2[C@@H:5]1[CH2:6][C:7](/[C:15](/[CH3:22])=[CH:16]/[C@@H:17]1[CH2:21][CH2:20][CH2:19][NH:18]1)=[C:8]2[C:12]([OH:14])=[O:13])[CH3:3].C(=O)([O-])[O-].[K+].[K+].Cl.[CH:30](=[NH:39])OCC1C=CC=CC=1>O>[CH:30]([N:18]1[CH2:19][CH2:20][CH2:21][C@H:17]1/[CH:16]=[C:15](/[C:7]1[CH2:6][C@@H:5]2[N:9]([C:10](=[O:11])[C@@H:4]2[C@H:2]([OH:1])[CH3:3])[C:8]=1[C:12]([OH:14])=[O:13])\[CH3:22])=[NH:39]
Reactant: C/C(=C\[C@@H]1CCCN1)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@H]2C1
Reactant: N=COCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: C/C(=C\[C@@H]1CCCN1C=N)C1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)O)[C@@H]2C1
Reaction time: 0.25 h
Yield: 32.5 %

Procedure:
A solution of (5R,6S)-6-[(1R)-1-hydroxyethyl]-7-oxo-3-[(E)-2-{(2S)-pyrrolidin-2-yl}-1-methylethenyl]-1-azabicyclo [3.2.0]hept-2-ene-2-carboxylic acid (0.48 g) in water (30 ml) was adjusted to pH 8.5 with aqueous potassium carbonate at 0° C. and benzyl formimidate hydrochloride (2.7 g) was added in portions while adjusting around pH 8.5 with addition of aqueous potassium carbonate. After stirring for 15 minutes at pH 8.5, the reaction mixture was washed with ethyl acetate and concentrated in vacuo. The residue was chromatographed on nonionic adsorption resin "Diaion HP-20" (50 ml) eluting successively with water and 3% aqueous acetone. The fractions containing the desired compound were collected and lyophilized to give (5S,6S)-3-[(E)-2-{(2S)-1-formimidoylpyrrolidin-2-yl}-1-methylethenyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo [3.2.0]hept- 2-ene-2-carboxylic acid (170 mg).
Reaction SMILES: CN.[ClH:3].[S:4]1(=[O:11])(=[O:10])[CH2:8][CH2:7][CH:6]([NH2:9])[CH2:5]1.S1(=O)(=O)CC=C[CH2:13]1>>[ClH:3].[CH3:13][NH:9][CH:6]1[CH2:7][CH2:8][S:4](=[O:11])(=[O:10])[CH2:5]1
Reactant: NC1CCS(=O)(=O)C1
Reactant: O=S1(=O)CC=CC1
Agent: CN
Agent: Cl
Product: CNC1CCS(=O)(=O)C1
Yield: 82.2 %

Procedure:
The procedure of Example 1 was repeated substituting 50 percent aqueous monomethylamine (174 ml.) for the ammonium hydroxide of Example 1. Sixty-four and seven-tenths grams of a white crystalline solid was obtained for a yield of 82.2 percent of theory based upon the 2,5-dihydrothiophene 1,1-dioxide. The solid sublimes over 180° C. and metls between 205° and 210° C.
Reaction SMILES: C([C:5]1N=C(N2CCC(F)(F)C2)[C:8]2[C:9](=[N:11][N:12]([CH2:14][CH3:15])N=2)[N:10]=1)(C)(C)C.[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:42][C:38]3([CH2:41][O:40][CH2:39]3)[CH2:37]2)[C:30]2[N:35]=[N:34][NH:33][C:31]=2[N:32]=1)([CH3:26])([CH3:25])[CH3:24].Cl.ClCC1N(C)C(C)=NN=1>>[C:23]([C:27]1[N:28]=[C:29]([N:36]2[CH2:37][C:38]3([CH2:39][O:40][CH2:41]3)[CH2:42]2)[C:30]2[C:31](=[N:33][N:34]([CH2:8][C:9]3[N:10]([CH3:5])[C:14]([CH3:15])=[N:12][N:11]=3)[N:35]=2)[N:32]=1)([CH3:26])([CH3:24])[CH3:25]
Reactant: CCn1nc2nc(C(C)(C)C)nc(N3CCC(F)(F)C3)c2n1
Reactant: CC(C)(C)c1nc(N2CC3(COC3)C2)c2nn[nH]c2n1
Agent: Cc1nnc(CCl)n1C
Agent: Cl
Product: Cc1nnc(Cn2nc3nc(C(C)(C)C)nc(N4CC5(COC5)C4)c3n2)n1C

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-2-ethyl-2H-[1,2,3]triazolo[4,5-d]pyrimidine (example 3, step b), the title compound was prepared from 5-tert-Butyl-7-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole hydrochloride and isolated as white solid. MS (m/e): 384.3 (MH+).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[CH2:6][O:7][C:8]1[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=1.[F:19][C:20]([F:31])([F:30])[C@H:21]1[CH2:26][CH2:25][C@H:24]([C:27](O)=[O:28])[CH2:23][CH2:22]1.COC1C=C(OC[C@H]2CCCN2C([C@H]2CC[C@H](C(F)(F)F)CC2)=O)C(C(O)=O)=NC=1>>[F:19][C:20]([F:30])([F:31])[C@H:21]1[CH2:22][CH2:23][C@H:24]([C:27]([N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[CH2:6][O:7][C:8]2[C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:10][CH:11]=[CH:12][CH:13]=2)=[O:28])[CH2:25][CH2:26]1
Reactant: CCOC(=O)c1ncccc1OC[C@H]1CCCN1
Reactant: O=C(O)[C@H]1CC[C@H](C(F)(F)F)CC1
Agent: COc1cnc(C(=O)O)c(OC[C@H]2CCCN2C(=O)[C@H]2CC[C@H](C(F)(F)F)CC2)c1
Product: CCOC(=O)c1ncccc1OC[C@H]1CCCN1C(=O)[C@H]1CC[C@H](C(F)(F)F)CC1

Procedure:
The title compound was prepared according to the procedure described in Step 5 of EXAMPLE 31 using (R)-ethyl 3-(pyrrolidin-2-ylmethoxy)picolinate bis(trifluoroactetic acid) salt (EXAMPLE 34 Step 1) and trans-4-(trifluoromethyl)cyclohexanecarboxylic acid instead of ammonium chloride and 5-methoxy-3-(((R)-1-(trans-4-(trifluoromethyl)cyclohexanecarbonyl)pyrrolidin-2-yl)m ethoxy)picolinic acid.
Reaction SMILES: Cl[C:2]1([C:9]([O:11][CH3:12])=[O:10])[C:6](=[O:7])[C:5]([Cl:8])=[CH:4][S:3]1.[CH3:13][OH:14]>>[Cl:8][C:5]1[C:6]([OH:7])=[C:2]([C:9]([O:11][CH3:12])=[O:10])[S:3][C:4]=1[O:14][CH3:13]
Reactant: COC(=O)C1(Cl)SC=C(Cl)C1=O
Reactant: CO
Product: COC(=O)c1sc(OC)c(Cl)c1O

Procedure:
2,4-Dichloro-2-methoxycarbonylthiophene-3(2H)-one (10 mmol) was stirred in anhydrous methanol at room temperature for 4 hours and the precipitate filtered, m.p. 109°-111° C. (methanol).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:10])[N:9]=1)[CH:5]=[O:6].C1(C)C=CC(S([CH2:20][N+:21]#[C-:22])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>CO>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[O:6][CH:22]=[N:21][CH:20]=2)[CH:7]=[C:8]([Cl:10])[N:9]=1
Reactant: [C-]#[N+]CS(=O)(=O)c1ccc(C)cc1
Reactant: O=Cc1cc(Cl)nc(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: Clc1cc(-c2cnco2)cc(Cl)n1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 97.7 %

Procedure:
528 mg of 2,6-dichloroisonicotinaldehyde (this compound was prepared by the method described in J. Chem. Soc., Chem. Commun., 1998, 1567-1568) was dissolved in 10 ml of methanol, and 586 mg of p-toluenesulfonyl methyl isocyanide and 415 mg of potassium carbonate ware added, and the mixture was stirred at 50° C. for 30 minutes. The reaction solution was concentrated, and then diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous solution of sodium bicarbonate and brine, and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 630 mg of the objective compound as white powder.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([OH:9])[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1.F[C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1>>[CH3:1][N:2]1[CH2:8][CH2:7][CH:6]([O:9][C:14]2[CH:23]=[CH:22][C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[C:5]2[O:10][CH:11]=[CH:12][C:4]=2[CH2:3]1
Reactant: CN1CCC(O)c2occc2C1
Reactant: Fc1ccc2ccccc2c1
Product: CN1CCC(Oc2ccc3ccccc3c2)c2occc2C1

Procedure:
The same method as in Example 1 was conducted using 5-methyl-5,6,7,8-tetrahydro-4H-furo[3,2-c]azepin-8-ol (Reference Example 21) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 2-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH3:22])[C:9]([C:15]2[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=2)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:4]([Cl:23])[CH:3]=1.C([O-])([O-])=O.[Cs+].[Cs+].[C:30]([C:32]1[CH:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][N:33]=1)#[N:31].O>O1CCOCC1>[Cl:23][C:4]1[CH:3]=[C:2]([C:35]2[CH:36]=[CH:37][C:32]([C:30]#[N:31])=[N:33][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH:8]([CH3:22])[C:9]([OH:14])([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([CH3:21])[CH:16]=1)[C:10]([F:13])([F:12])[F:11]
Reactant: CC1(C)OB(c2ccc(C#N)nc2)OC1(C)C
Reactant: Cc1cc(C(O)(C(C)c2ccc(Br)cc2Cl)C(F)(F)F)ccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cc(C(O)(C(C)c2ccc(-c3ccc(C#N)nc3)cc2Cl)C(F)(F)F)ccn1

Procedure:
A mixture of 3-(4-bromo-2-chloro-phenyl)-1,1,1-trifluoro-2-(2-methyl-pyridin-4-yl)-butan-2-ol (Example 60 step 1, 40 mg), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palldadium(II) (7 mg), Cs2CO3 (96 mg) and 2-cyanopyridine-5-boronic acid pinacol ester (CAS Reg. No. 741709-63-7, 45 mg) in dioxane (2 ml) and water (0.2 ml) was heated at 100° C. for 10 min in a sealed tube. The mixture was purified by prep. HPLC (C18-column, solvent gradient 30-98% CH3CN in 0.1% HCOOH[aq]) to give the title compound (32 mg) as a yellow solid. MS (m/e)=432.2 [M+H+].
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C(Cl)(Cl)(Cl)[Cl:14].S(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([O:11][CH3:12])=[C:6]([CH:10]=1)[C:7]([Cl:14])=[O:8]
Reactant: ClC(Cl)(Cl)Cl
Reactant: COc1ncc(Cl)cc1C(=O)O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COc1ncc(Cl)cc1C(=O)Cl

Procedure:
To a suspension of 3.76 g. (0.02 mole) of 5-chloro-2-methoxynicotinic acid in 100 ml. of carbon tetrachloride, there were added 100 ml. of thionyl chloride in one portion and the resulting mixture was then refluxed on a steam bath for a period of 90 minutes. Upon completion of this step, the clear solution so obtained was cooled and then concentrated in vacuo at room temperature to afford a residual oil. The excess thionyl chloride present was next removed in the same manner as described in Preparation A for the production of 2-methoxynicotinoyl chloride, except that only 100 ml. of benzene was employed this time (i.e., during each purification step). The yield of pure 5-chloro-2-methoxynicotinoyl chloride, obtained as the residual product, was quantitative in this particular instance.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH:15]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[CH3:16])=[CH:10][CH:9]=1)=[O:6].[OH-].[NH4+:26]>>[F:23][C:19]1[CH:18]=[C:17]([CH:15]([O:14][C:11]2[CH:12]=[CH:13][C:8]([NH:7][C:5](=[O:6])[CH2:4][C:3]([NH2:26])=[O:2])=[CH:9][CH:10]=2)[CH3:16])[CH:22]=[CH:21][CH:20]=1
Reactant: [NH4+]
Reactant: COC(=O)CC(=O)Nc1ccc(OC(C)c2cccc(F)c2)cc1
Agent: [OH-]
Product: CC(Oc1ccc(NC(=O)CC(N)=O)cc1)c1cccc(F)c1
Yield: 55 %

Procedure:
Prepared in analogy to example 3 from N-{4-[1-(3-fluoro-phenyl)-ethoxy]-phenyl}-malonamic acid methyl ester and ammonium hydroxide. Yield=55%. Colorless solid. MS: m/e=317.3 (M++H).
Reaction SMILES: [CH2:1]([N:4]([CH:10]([CH3:16])[CH:11](OC)[O:12]C)[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3].O.[Cl-].[Na+]>C(O)=O>[CH2:1]([N:4]([CH:10]([CH3:16])[CH:11]=[O:12])[C:5](=[O:9])[O:6][CH2:7][CH3:8])[CH:2]=[CH2:3]
Reactant: C=CCN(C(=O)OCC)C(C)C(OC)OC
Agent: [Cl-]
Agent: [Na+]
Solvent: O=CO
Solvent: O
Product: C=CCN(C(=O)OCC)C(C)C=O

Procedure:
182 g (0.787 mol) of ethyl N-allyl-N-(1,1-dimethoxyprop-2-yl)-carbamate in 1.5 1 of water are heated under reflux for three hours with 80 ml of formic acid. The mixture is saturated with sodium chloride, the organic phase is separated off and the aqueous phase is extracted twice with 500 ml of methylene chloride each time. The organic solutions are washed with saturated sodium hydrogen carbonate solution until neutral, dried over magnesium sulphate and concentrated, and the residue is distilled.
Reaction SMILES: Br[C:2]1([C:22]2[CH:23]=[C:24]([NH2:28])[CH:25]=[CH:26][CH:27]=2)[CH2:7][N:6]2[CH:8]=[CH:9][N:10]=[C:5]2[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[C:12]2[C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:3]1.[N:29]([C:32]1[CH:37]=[C:36]([C:38]([F:41])([F:40])[F:39])[CH:35]=[CH:34][C:33]=1[O:42][CH3:43])=[C:30]=[O:31].CN(C=O)C>ClCCl>[CH3:43][O:42][C:33]1[CH:34]=[CH:35][C:36]([C:38]([F:41])([F:40])[F:39])=[CH:37][C:32]=1[NH:29][C:30]([NH:28][C:24]1[CH:25]=[CH:26][CH:27]=[C:22]([C:2]2[N:3]=[C:4]([N:11]3[CH:15]=[CH:14][N:13]=[C:12]3[C:16]3[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=3)[C:5]3[N:6]([CH:8]=[CH:9][N:10]=3)[CH:7]=2)[CH:23]=1)=[O:31]
Reactant: Nc1cccc(C2(Br)Cn3ccnc3C(n3ccnc3-c3ccncc3)=N2)c1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc(-c2cn3ccnc3c(-n3ccnc3-c3ccncc3)n2)c1
Yield: 89.1 %

Procedure:
A solution of 3-[6-Bromo-8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenylamine (5) (400 mg), 2-isocyanato-1-methoxy-4-trifluoromethyl-benzene (246 mg), in dichloromethane (DCM) (3 ml) and DMF (0.5 ml) is stirred at room temperature for 16 hr. The mixture is concentrated in vacuo, the residue slurried with diethyl ether/methanol (20:1), and filtered to give 1-(2-Methoxy-5-trifluoromethyl-phenyl)-3-{3-[8-(2-pyridin-4-yl-imidazol-1-yl)-imidazo[1,2-a]pyrazin-6-yl]-phenyl}-urea (6) (468 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[NH:14][CH:15]=[N:16][C:10]=2[CH:9]1[C:17]1[CH:22]=[CH:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([N:33]2[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]2=[O:40])=[N:31][CH:32]=1.[H-].[Na+]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[N:14]=[CH:15][N:16]([CH2:26][C:27]3[CH:28]=[CH:29][C:30]([N:33]4[CH:38]=[C:37]([Cl:39])[CH:36]=[CH:35][C:34]4=[O:40])=[N:31][CH:32]=3)[C:10]=2[CH:9]1[C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[CH:21][CH:22]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]cnc2C1c1ccc(C#N)cc1
Reactant: O=c1ccc(Cl)cn1-c1ccc(CBr)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCc2ncn(Cc3ccc(-n4cc(Cl)ccc4=O)nc3)c2C1c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
4-(4-Cyano-phenyl)-1,4,6,7-tetrahydro-imidazo[4,5-c]pyridine-5-carboxylic acid tert-butyl ester (0.16 g, 0.50 mmol) and 5'-bromomethyl-5-chloro-[1,2']bipyridinyl-2-one (Example 10, Step 2)(0.15 g, 0.50 mmol) were dissolved in DMF (6 mL). NaH (0.02 g, 0.60 mmol) was added and stirred at RT under Ar for 1.5 h. The reaction was concentrated in vacuo and partitioned between EtOAc and satd NaHCO3 soln, washed with H2O, brine, dried (MgSO4), filtered and concentrated to give the title compound as a mixture of racemic regloisomers.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:28][O:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>CN1CCN(C)C1=O>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[O:29][CH3:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccccc1CN
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2CCCN2C(=O)OCc2ccccc2)cc1
Solvent: CN1CCN(C)C1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1CNC[C@@H]1CCCN1C(=O)OCc1ccccc1
Temperature: 93 °C
Reaction time: 7 h

Procedure:
A mixture of (2S)-2-(4-methylphenylsulfonyloxymethyl)pyrrolidine-1-carboxylic acid benzyl ester (26.2 g), 2-methoxybenzylamine (44 ml) and N,N-diisopropylethylamine (17.6 ml) in 1,3-dimethyl-2-imidazolidinone (393 ml) was stirred at 93° C. for 7 hours. The mixture was poured into ice-water and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixed solvent of dichloromethane and methanol (20:1). The fractions containing the objective compound were collected and evaporated under reduced pressure to give a syrup of (2S)-2-[(2-methoxybenzylamino)methyl]pyrrolidine-1-carboxylic acid benzyl ester (15.7 g).
Reaction SMILES: C(O[BH3-])(=O)C.[Na+].[CH:7](=O)[CH:8]([CH3:10])[CH3:9].[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:41]2[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=2)[N:20]2[CH2:23][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:27])=[O:26])[CH2:21]2)=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[Cl:12][C:13]1[CH:14]=[CH:15][C:16]([CH:19]([C:41]2[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=2)[N:20]2[CH2:21][C:22](=[CH:24][S:25]([CH2:28][C:29]3[CH:30]=[C:31]([N:35]4[CH2:40][CH2:39][N:38]([CH2:7][CH:8]([CH3:10])[CH3:9])[CH2:37][CH2:36]4)[CH:32]=[CH:33][CH:34]=3)(=[O:26])=[O:27])[CH2:23]2)=[CH:17][CH:18]=1
Reactant: O=S(=O)(C=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)Cc1cccc(N2CCNCC2)c1
Reactant: CC(C)C=O
Agent: O=C([O-])O
Agent: [BH3-]OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)CN1CCN(c2cccc(CS(=O)(=O)C=C3CN(C(c4ccc(Cl)cc4)c4ccc(Cl)cc4)C3)c2)CC1
Reaction time: 4 h
Yield: 105.2 %

Procedure:
32 mg of sodium acetoxyborohydride and then 22 mg of isobutyraldehyde are successively added, at a temperature close to 20° C., to a solution of 54.25 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]piperazine in 2 cm3 of 1,2-dichloroethane. After stirring for 4 hours at a temperature close to 20° C., 3 cm3 of dichloromethane and 2 cm3 of a saturated aqueous sodium bicarbonate solution are added to the reaction medium. After separating after settling out, the organic [lacuna] is dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure (1 kPa) at a temperature close to 40° C. 63 mg of 1-[3-({1-[bis-(4-chlorophenyl)methyl]azetidin-3-ylidene}methanesulfonylmethyl)phenyl]-4-isobutylpiperazine are thus obtained in the form of a beige lacquer [1H NMR spectrum (400 MHz, CDCl3), δ in ppm): 0.92 (d, J=7 Hz, 6H), 1.82 (mt, 1H), 2.14 (d, J=8 Hz, 2H), 2.54 (t, J=5.5 Hz, 4H), 2.75 (s, 3H), 3.18 (t, J=5.5 Hz, 4H), 3.81 (mt, 2H), 4.32 (mt, 2H), 4.49 (s, 1H), 6.78 (d, J=8 Hz, 1H), 6.89 (dd, J=8 and 2.5 Hz, 1H), 6.97 (broad s, 1H), from 7.15 to 7.30 (mt, 5H), 7.32 (d, J=8 Hz, 4H)].
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8](Cl)=[O:9].[CH2:18]([NH:22][C:23]([CH:25]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)[CH3:26])=[O:24])[CH:19]([CH3:21])[CH3:20].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:16][CH3:17])[C:13]=1[O:14][CH3:15])[CH:6]=[CH:7][C:8]([N:30]1[CH2:29][CH2:28][N:27]([CH:25]([C:23]([NH:22][CH2:18][CH:19]([CH3:21])[CH3:20])=[O:24])[CH3:26])[CH2:32][CH2:31]1)=[O:9]
Reactant: CC(C)CNC(=O)C(C)N1CCNCC1
Reactant: COc1cc(C=CC(=O)Cl)cc(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CC(=O)N2CCN(C(C)C(=O)NCC(C)C)CC2)cc(OC)c1OC
Reaction time: 1 h

Procedure:
14.40 g of 3,4,5-trimethoxycinnamoyl chloride is added to a solution of 9.20 g of 1-[1-(isobutylaminocarbonyl)ethyl]piperazine and 5.70 g of triethylamine in 200 ml of chloroform, and the resulting solution is kept standing at room temperature for 1 hour.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]2=[N:4][CH:3]=1.[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21](B2OC(C)(C)C(C)(C)O2)[CH:22]=1>>[F:16][C:17]1[CH:18]=[C:19]([C:32]2[C:33]([C:38]#[N:39])=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:20]=[C:21]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:12]([OH:15])([CH3:14])[CH3:13])=[C:10]([F:11])[C:5]3=[N:4][CH:3]=2)[CH:22]=1
Reactant: CC1(C)OB(c2cc(F)cc(-c3ccccc3C#N)c2)OC1(C)C
Reactant: CC(C)(O)c1ccn2c(Br)cnc2c1F
Product: CC(C)(O)c1ccn2c(-c3cc(F)cc(-c4ccccc4C#N)c3)cnc2c1F
Yield: 51 %

Procedure:
2-(3-Bromo-8-fluoroimidazo[1,2-α]pyridin-7-yl)propan-2-ol was coupled to 3′-fluoro-5′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)biphenyl-2-carbonitrile (prepared as described in WO 02/074773) as described in Example 1 to give 3′-fluoro-5′-[8-fluoro-7-(1-hydroxy-1-methylethyl)imidazo[1,2-α]pyridin-3-yl]biphenyl-2-carbonitrile as an off-white solid (200 mg, 51%): δH (360 MHz, CDCl3) 1.74 (6H, s), 2.13 (1H, s), 7.24 (1H, s), 7.27-7.29 (1H, m), 7.34-7.37 (1H, m), 7.51-7.58 (3H, m), 7.69-7.73 (1H, m), 7.76 (1H, s), 7.84 (1H, dd, J 8 and 1), 8.39 (1H, d, J 7); m/z (ES+) 390 [MH+].
Reaction SMILES: CC([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:15])=[N:10][CH:9]=1)(C)C(O)=O.C1(O)C=CC=CC=1.C([O:43][C:44](=[O:56])[C:45]([CH3:55])([CH3:54])[CH2:46]SC1SC(N)=NC=1)C>>[CH3:46][C:45]([CH3:55])([CH2:54][S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([C@H:27]2[CH2:32][CH2:31][C@H:30]([CH3:33])[CH2:29][CH2:28]2)[CH2:17][CH2:18][CH2:19][O:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:15])=[N:10][CH:9]=1)[C:44]([OH:56])=[O:43]
Reactant: CCOC(=O)C(C)(C)CSc1cnc(N)s1
Reactant: CC(C)(Sc1cnc(NC(=O)N(CCCOc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O
Solvent: Oc1ccccc1
Product: CC(C)(CSc1cnc(NC(=O)N(CCCOc2ccccc2)[C@H]2CC[C@H](C)CC2)s1)C(=O)O

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis 2-methyl-2-{2-[3-(trans-4-methyl-cyclohexyl)-3-(3-phenoxy-propyl)-ureido]-thiazol-5-ylsulfanyl}-propionic acid using phenol and 3-(2-amino-thiazol-5-ylsulfanyl)-2,2-dimethyl-propionic acid ethyl ester.
Reaction SMILES: [S:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[S:3].[CH:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[CH:8](=[C:7]1[S:1][C:2](=[S:3])[NH:4][C:5]1=[O:6])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=S)SC1=Cc1ccccc1
Yield: 6.4 %

Procedure:
To a solution of 10 g (75.1 mmol) of rhodanine and 7.63 ml (75.1 mmol) of benzaldehyde in 150 ml of ethanol, 0.74 ml (7.5 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 1.07 g of the desired compound (66.6% yield, pale yellow crystals).