Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:35])[CH2:3][CH2:4][N:5]([CH2:33]C)[C:6](=[O:32])[CH2:7][O:8][C@H:9]1[C:12]([CH2:15][CH3:16])([CH2:13][CH3:14])[C:11](=[O:17])[N:10]1[C:18]([NH:20][C@@H:21]([C:25]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][CH:26]=1)[CH2:22][CH2:23][CH3:24])=[O:19].C(O)(=O)[C@H](CC(O)=O)O>>[CH3:35][N:2]([CH3:1])[CH2:3][CH2:4][N:5]([CH3:33])[C:6](=[O:32])[CH2:7][O:8][C@H:9]1[C:12]([CH2:13][CH3:14])([CH2:15][CH3:16])[C:11](=[O:17])[N:10]1[C:18]([NH:20][C@@H:21]([C:25]1[CH:26]=[CH:27][C:28]([CH3:31])=[CH:29][CH:30]=1)[CH2:22][CH2:23][CH3:24])=[O:19]
Reactant: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1OCC(=O)N(CC)CCN(C)C)c1ccc(C)cc1
Agent: O=C(O)C[C@H](O)C(=O)O
Product: CCC[C@@H](NC(=O)N1C(=O)C(CC)(CC)[C@@H]1OCC(=O)N(C)CCN(C)C)c1ccc(C)cc1

Procedure:
2-(S)-[2-[[2-(Dimethylamino)ethyl]ethylamino]-2-oxoethoxy]-3,3-diethyl-N-[1-(R)-(4-methylphenyl) butyl]-4-oxo-1-azetidinecarboxamide or the L-malic acid salt thereof; or
Reaction SMILES: [CH3:1][O:2][C:3]1([CH3:38])[C:8]2=[N:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)[N:12]=[C:7]2[N:6]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([O:35]CC)=[O:34])[CH2:5][CH2:4]1.OC1(C)C2=NC(C3C=CC(C)=CC=3)=C(C3C=CC(C)=CC=3)N=C2N(CCCCCCC(OCC)=O)CC1.[OH-].[Na+].C(OCC)(=O)C.Cl>C(O)C>[CH3:1][O:2][C:3]1([CH3:38])[C:8]2[C:7](=[N:12][C:11]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=3)[N:9]=2)[N:6]([CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][C:33]([OH:35])=[O:34])[CH2:5][CH2:4]1
Reactant: CCOC(=O)CCCCCCN1CCC(C)(OC)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: CCOC(=O)CCCCCCN1CCC(C)(O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COC1(C)CCN(CCCCCCC(=O)O)c2nc(-c3ccc(C)cc3)c(-c3ccc(C)cc3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the mixture of compounds from step 1 (120 mg) in Ethanol (5 ml) was added 2M NaOH (aq) (0.478 ml, 0.956 mmol) and the suspension was stirred under an atmosphere of nitrogen at room temperature overnight. The resulting suspension was treated ethyl acetate (20 ml) followed by 2M HCl (aq) (˜3 ml) until pH 5-6 was reached. The resulting mixture was washed with water (˜20 ml). The organic layer was separated and dried over MgSO4, filtered and concentrated under reduced pressure to give a yellow oil/solid. Purification of the solid by chromatography on silica eluting with EtOAc in iso-hexane afforded the titled compound;
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([NH:8][C:9]2[C:10](Cl)=[N:11][CH:12]=[N:13][CH:14]=2)=O)=[CH:4][C:3]=1[C:18]#[N:19].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:29])=CC=1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]2[S:29][C:10]3[N:11]=[CH:12][N:13]=[CH:14][C:9]=3[N:8]=2)=[CH:4][C:3]=1[C:18]#[N:19]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: N#Cc1cc(C(=O)Nc2cncnc2Cl)ccc1Cl
Solvent: Cc1ccccc1
Product: N#Cc1cc(-c2nc3cncnc3s2)ccc1Cl
Temperature: 25 °C
Yield: 130.3 %

Procedure:
The above-obtained 4-chloro-N-(4-chloro-5-pyrimidinyl)-3-cyanobenzamide (7.98 g, 27.2 mmol) and Lawesson's reagent (8.25 g, 20.4 mmol) were suspended in toluene (150 mL). The suspension was refluxed with heating for 8 hours, and cooled to room temperature to filtrate precipitated crystals. The crystals were washed with chloroform (75×2), and air-dried to obtain 7.25 g (yield: 98%) of the subject compound as pale yellow crystals.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([N:17](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4].Cl.[Cl:43]CCl>O1CCOCC1>[ClH:43].[CH2:1]([C:5]1[N:6]([CH2:33][CH2:34][S:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[C:7]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:32]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc2c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc3c(c2n1CCSc1ccccc1)CCCC3
Reactant: ClCCl
Agent: Cl
Solvent: C1COCCO1
Product: CCCCc1nc2c(N)nc3c(c2n1CCSc1ccccc1)CCCC3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A round bottom flask was charged with a magnetic stir bar, di(tert-butyl) 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-ylimidodicarbonate (0.50 g, 0.86 mmol), a 4 M solution of hydrochloric acid in dioxane (5 mL), and dichloromethane (5 mL). The reaction was judged to be complete after stirring at ambient temperature for 2 hours. The volatiles were removed under reduced pressure to afford an off white solid. The material was recrystallized from acetonitrile to provide 2-butyl-1-[2-(phenylthio)ethyl]-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinolin-4-amine hydrochloride (0.17 g, 1.30 mmol) as fluffy white needles, m.p. 237-238° C. Analysis. Calculated for C22H28N4S.(H2O)1/4.(HCl)2: % C, 57.70; % H, 6.71; % N, 12.23. Found % C, 57.62; % H, 6.57; % N, 12.41. 1H-NMR (300 MHz, DMSO) δ 7.81 (bs, 2H), δ 7.22-7.39 (m, 5H), δ 4.64 (t, J=6.8 Hz, 2H), δ 3.40 (t, J=6.8 Hz, 2H), δ 2.75 (m, 6H), δ 1.71 (m, 6H), δ 1.34 (sextet, J=7.3 Hz, 2H), δ 0.89 (t, J=7.3 Hz, 3H) MS (CI) for C22H28N4S (H2O)1/4 (HCl)2 m/z 381 (MH+), 245, 137
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[N:33][NH2:34])[C:10]1[C:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:14][C:13]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[C:12]([Br:32])[CH:11]=1.[C:35](N1C=CN=C1)(N1C=CN=C1)=[O:36]>C1COCC1>[CH2:17]([O:16][C:15]1[CH:14]=[C:13]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[C:12]([Br:32])=[CH:11][C:10]=1[C:9]1[N:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[CH3:1])[C:35]([OH:36])=[N:34][N:33]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Cc1ccccc1NC(=NN)c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: Cc1ccccc1-n1c(O)nnc1-c1cc(Br)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.9 %

Procedure:
1.7 A solution of 30.98 g of N-(2-methylphenyl)-3-bromo-4,6-dibenzyloxybenzamide hydrazone in 200 ml of THF is slowly added at 45-50° to a solution of 11.67 g of 1,1′-carbonyldiimidazole in 1 l of THF. The mixture is stirred at room temperature for 30 minutes, the solvent is removed, and the residue is subjected to conventional work-up, giving 26 g of 5-(2,4-dibenzyloxy-5-bromophenyl)-4-(2-methylphenyl)-3-hydroxy-4H-1,2,4-triazole, Rf 2.25.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC.Br[CH2:30][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([C:44]3[C:48]([CH2:49][CH2:50][CH3:51])=[C:47]([C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[O:46][N:45]=3)[O:41][N:40]=2)=[CH:35][CH:34]=1)[OH:32].CCN(C(N1N=NN(C2C(Cl)=CC=CC=2)C1=O)=O)C1CCCCC1>CS(C)=O.CO>[OH:32][CH:31]([C:33]1[CH:38]=[CH:37][C:36]([C:39]2[N:43]=[C:42]([C:44]3[C:48]([CH2:49][CH2:50][CH3:51])=[C:47]([C:52]4[CH:53]=[CH:54][CH:55]=[CH:56][CH:57]=4)[O:46][N:45]=3)[O:41][N:40]=2)=[CH:35][CH:34]=1)[CH2:30][N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:7][C:8]([OH:10])=[O:9])[CH2:2]1
Reactant: CCCc1c(-c2nc(-c3ccc(C(O)CBr)cc3)no2)noc1-c1ccccc1
Reactant: O=C(O)CC1CCCNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: CCN(C(=O)n1nnn(-c2ccccc2Cl)c1=O)C1CCCCC1
Agent: [OH-]
Solvent: CO
Solvent: CS(C)=O
Product: CCCc1c(-c2nc(-c3ccc(C(O)CN4CCCC(CC(=O)O)C4)cc3)no2)noc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-(piperidin-3-yl)acetic acid (51 mg, 0.36 mmol) in 0.5 mL dry DMSO was added tetrabutylammonium hydroxide (0.360 mL, 360 μmol, 1M in THF) and the reaction mixture was stirred at room temperature for 15 min. 2-bromo-1-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethanol, Preparation 1C (30 mg, 0.066 mmol) was dissolved in 0.5 mL DMSO and added and the reaction mixture was agitated at 400 rpm on an INNOVA® platform shaker at 80° C. for 1.5 hours. The reaction was diluted with 250 μL of MeOH and purified by HPLC (MeOH—H2O-TFA) to give 2-(1-(2-hydroxy-2-(4-(5-(5-phenyl-4-propylisoxazol-3-yl)-1,2,4-oxadiazol-3-yl)phenyl)ethyl)piperidin-3-yl)acetic acid. MS (m+1)=517. HPLC RT=2.08 min using a Waters Masslynx instrument equipped with a 19×100 mm 5 uM C18 column and a method of 0-100% B solvent over 15 min at a flow rate of 20 mL/min. Solvent A is 5:95 acetonitrile/water; solvent B is 95:5 acetonitrile/water and both contain 0.5% TFA.
Reaction SMILES: [CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:57])[CH:24]([NH:25][C:26](=[O:56])[C:27](=[N:53][O:54][CH3:55])[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH2:58]Cl)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[I-].[Na+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N+:81]([C:84]1[CH:91]=[CH:90][C:87]([CH:88]=O)=[CH:86][CH:85]=1)([O-:83])=[O:82].C(=O)([O-])O.[Na+].NC1SC=C(C(=NOC(C(O)=O)(C)C)C(NC2C(=O)N3C(C(O)=O)=C(C=CC4C=CC([N+]([O-])=O)=CC=4[N+]([O-])=O)CS[C@H]23)=O)N=1>>[CH:1]([O:14][C:15]([C:17]1[N:22]2[C:23](=[O:57])[CH:24]([NH:25][C:26](=[O:56])[C:27](=[N:53][O:54][CH3:55])[C:28]3[N:29]=[C:30]([NH:33][C:34]([C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=4)([C:41]4[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=4)[C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[S:31][CH:32]=3)[C@H:21]2[S:20][CH2:19][C:18]=1[CH:58]=[CH:88][C:87]1[CH:90]=[CH:91][C:84]([N+:81]([O-:83])=[O:82])=[CH:85][CH:86]=1)=[O:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: CC(C)(ON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=Cc3ccc([N+](=O)[O-])cc3[N+](=O)[O-])CS[C@H]12)c1csc(N)n1)C(=O)O
Agent: O=C([O-])O
Agent: [I-]
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=Cc3ccc([N+](=O)[O-])cc3)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Yield: 54.8 %

Procedure:
7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-chloromethyl-3-cephem-4-carboxylic acid benzhydryl ester (395 mg, 0.47 mmol), sodium iodide (70 mg, 0.47 mmol), triphenylphosphine (123 mg, 0.47 mmol), 4-nitrobenzaldehyde (284 mg, 1.88 mmol) and sodium hydrogen carbonate (120 mg, 1.4 mmol) were used to conduct the procedure similar to that shown in (1) of Example 1 to obtain 242 mg (yield: 55%) of 7-[2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-(4-nitrostyryl)-3-cephem-4-carboxylic acid benzhydryl ester as yellow powder.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([O:21]C3C=CC([N+]([O-])=O)=CC=3)=O)[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].[NH:35]1[CH2:40][CH2:39][S:38][CH2:37][CH2:36]1.C(N(CC)C(C)C)(C)C.CN1CCCC1=O>C(OCC)(=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][N:17]([C:19]([N:35]3[CH2:40][CH2:39][S:38][CH2:37][CH2:36]3)=[O:21])[CH2:16][CH:15]([C:31]([O:33][CH3:34])=[O:32])[CH2:14]2)[CH:5]=[CH:6][C:7]=1[O:8][C:9]([F:11])([F:12])[F:10]
Reactant: C1CSCCN1
Reactant: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)Oc2ccc([N+](=O)[O-])cc2)C1
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: COC(=O)C1CC(c2ccc(OC(F)(F)F)c(F)c2)CN(C(=O)N2CCSCC2)C1
Temperature: 150 °C

Procedure:
2.40 g (4.93 mmol) of the compound from Example 93A, 3.56 g (34.5 mmol) of thiomorpholine and 3.0 ml (2.32 g, 17.3 mmol) of N,N-diisopropylethylamine were added to 28 ml of 1-methyl-2-pyrrolidone and heated in 2 portions in a single-mode microwave (Emrys Optimizer) at 150° C. for 1 h. For workup, the reaction solutions were combined and admixed with water. After addition of ethyl acetate and phase separation, the organic phase was washed with saturated aqueous sodium chloride solution, dried (magnesium sulphate), filtered and concentrated under reduced pressure. Yield: 1.97 g (89% of theory)
Reaction SMILES: [CH3:1][N:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:5][CH:4]([NH2:19])[C:3]1=[O:20].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][CH:23]=1>O1CCCC1>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][C:29]([NH:19][CH:4]2[N:5]=[C:6]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[N:2]([CH3:1])[C:3]2=[O:20])=[O:30])=[CH:24][CH:23]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Solvent: C1CCOC1
Product: CN1C(=O)C(NC(=O)Nc2ccc(Cl)cc2)N=C(c2ccccc2)c2ccccc21
Reaction time: 8 h

Procedure:
Equimolar amounts of 1,3-dihydro-1-methyl-3(RS)-amino-5-phenyl-2H-1,4-benzodiazepin-2-one and 4-chlorophenyl isocyanate 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.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][C@H:15]1[CH2:17][O:16]1)[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[NH:24][CH:23]=[C:22]2[CH3:28].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CN(C=O)C>[OH:16][C@H:15]([CH2:17][N:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1)[CH2:14][O:13][C:12]1[CH:11]=[C:10]2[C:5]([C:6]([O:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][CH:23]=[C:22]4[CH3:28])=[N:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[O:2][CH3:1]
Reactant: C1COCCN1
Reactant: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H]1CO1
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4[nH]cc(C)c4c3)ncnc2cc1OC[C@H](O)CN1CCOCC1
Temperature: 60 °C
Reaction time: 24 h
Yield: 92.1 %

Procedure:
A mixture of (2R)-6-methoxy-4-(3-methylindol-5-yloxy)-7-(oxiran-2-ylmethoxy)quinazoline (350 mg, 0.93 mmol), (prepared as described in Example 278), and morpholine (0.24 ml, 2.78 mmol) in DMF (5 ml) was stirred at 60° C. for 24 hours and allowed to cool to ambient temperature. The solvents were removed in vacuo and the residue purified by silica column chromatography using gradient elution (dichloromethane, 5% methanol/95% dichloromethane, methanol/dichloromethane/0.880 saturated aqueous ammonia (100/8/1)) to give (2R)-7-(2-hydroxy-3-morpholinopropoxy)-6-methoxy-4-(3-methylindol-5-yloxy)quinazoline (398 mg, 93%).
Reaction SMILES: [C]=O.I[C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]=1[C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18].CCN(C(C)C)C(C)C.C([SiH](CCCCCCCC)CCCCCCCC)CCCCCCC.CN([CH:66]=[O:67])C>CCOC(C)=O.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd](Cl)Cl>[CH:66]([C:4]1[CH:16]=[CH:15][C:7]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])=[CH:6][C:5]=1[C:17]([N:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:20]1)=[O:18])=[O:67]
Reactant: CC(C)(C)OC(=O)c1ccc(I)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CCCCCCCC[SiH](CCCCCCCC)CCCCCCCC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)c1ccc(C=O)c(C(=O)N2CCc3ccccc3C2)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
Carbon monoxide was bubbled through a solution of tert-butyl 4-iodo-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (1.36 g, 2.94 mmol) and 1,1′-bis-(diphenylphosphino)-ferrocene) palladium dichloride (0.241 g, 0.294 mmol) in DMF (20 mL) at 70° C. for 10 min. DIPEA (1.28 mL, 7.34 mmol) and trioctylsilane (2.64 mL, 5.87 mmol) were added. The reaction mixture was stirred at 70° C. under CO (balloon) overnight. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with sat. aq. sodium bicarbonate solution, 10% aq. LiCl solution, and then sat. aq. sodium bicarbonate solution again. The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography (Isco 40 g column eluting from 0-40% EtOAc/hexanes) to give the title compound (537 mg, 50%) as a yellow foam. 1H NMR (CDCl3, 1.5:1 mixture of amide rotamers) δ 10.19 (s, 0.5H), 10.14 (s, 0.5H), 8.17-8.13 (m, 1H), 8.03-7.98 (m, 2H), 7.26-7.10 (m, 4H), 5.00 (s, 1H), 4.33 (m, 1H), 4.09 (t, J=6 Hz, 1H), 3.45 (t, J=6 Hz, 1H), 3.04 (t, J=6 Hz, 1H), 2.80 (t, J=6 Hz, 1H), 1.61 (s, 9H); MS(ESI+) m/z 366.2 (M+H)+.
Reaction SMILES: [I:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][O:7][CH:8]([C:30]2[S:31][C:32]([C:35]3[CH:40]=[CH:39][C:38]([C:41]([F:44])([F:43])[F:42])=[CH:37][CH:36]=3)=[CH:33][CH:34]=2)[CH2:9][CH2:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][C:16]([CH3:25])([CH3:24])[C:17]([O:19]C(C)(C)C)=[O:18])=[C:13]([Cl:28])[C:12]=2[Cl:29])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>>[I:1][C:2]1[CH:46]=[CH:45][C:5]([CH2:6][O:7][CH:8]([C:30]2[S:31][C:32]([C:35]3[CH:36]=[CH:37][C:38]([C:41]([F:42])([F:44])[F:43])=[CH:39][CH:40]=3)=[CH:33][CH:34]=2)[CH2:9][CH2:10][C:11]2[CH:27]=[CH:26][C:14]([O:15][C:16]([CH3:25])([CH3:24])[C:17]([OH:19])=[O:18])=[C:13]([Cl:28])[C:12]=2[Cl:29])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CCC(OCc2ccc(I)cc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(Oc1ccc(CCC(OCc2ccc(I)cc2)c2ccc(-c3ccc(C(F)(F)F)cc3)s2)c(Cl)c1Cl)C(=O)O

Procedure:
2-(4-(3-(4-Iodobenzyloxy)-3-(5-(4-(trifluoromethyl)phenyl)thien-2-yl)propyl)-2,3-dichlorophenoxy)-2-methylpropanoic acid is prepared from tert-butyl 2-(4-(3-(4-iodobenzyloxy)-3-(5-(4-(trifluoromethyl) phenyl)thien-2-yl)propyl)-2,3-dichlorophenoxy)-2-methylpropanoate according to general procedure E using 10 equivalents of trifluoroacetic acid.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[SH:9][CH2:10][CH2:11][C:12]([OH:14])=[S:13]>ClCCl.[I-].[Zn+2].[I-]>[O:14]=[C:12]1[S:13][CH:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:9][CH2:10][CH2:11]1
Reactant: OC(=S)CCS
Reactant: O=Cc1ccccc1
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: O=C1CCSC(c2ccccc2)S1
Temperature: 25 °C

Procedure:
To a solution of benzaldehyde (1.06 g, 10 mm) and 3-mercaptothiopropionic acid (1.22 g, 10 mm) in dichloromethane (25 cc) was added dry zinc iodide (1 mm, 320 mg) and the mixture was refluxed for 3.5 hrs. It was cooled to room temperature, diluted with dichloromethane and successively washed with IN HCl, brine and dried with sodium sulphate. Removal of the solvent yielded the essentially pure title compound.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[C:16]3[N:17]([C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[C:26]([NH:30][CH2:31][C:32]5[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=5)[N:25]=4)=[CH:22][N:23]=3)[CH:18]=[CH:19][N:20]=2)[CH2:10][CH2:9]1)(C)(C)C>C(O)C.Cl>[CH2:31]([NH:30][C:26]1[N:25]=[C:24]([C:21]2[N:17]3[CH:18]=[CH:19][N:20]=[C:15]([NH:14][CH:11]4[CH2:12][CH2:13][CH:8]([NH2:7])[CH2:9][CH2:10]4)[C:16]3=[N:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC(C)(C)OC(=O)NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccccc5)n4)cnc23)CC1
Agent: Cl
Solvent: CCO
Product: NC1CCC(Nc2nccn3c(-c4cccc(NCc5ccccc5)n4)cnc23)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of {4-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-ylamino]-cyclohexyl}-carbamic acid tert-butyl ester (80 mg, 0.156 mmol) in ethanol (4 mL) and concentrated HCl (4 mL) was stirred at room temperature for 15 hours. The reaction mixture was then concentrated under reduced pressure. The obtained crude product was purified by preparative-HPLC to give N-[3-(6-benzylamino-pyridin-2-yl)-imidazo[1,2-a]pyrazin-8-yl]-cyclohexane-1,4-diamine; hydrochloride. (Yield 50 mg).
Reaction SMILES: N(C(OC(C)C)=O)=NC(OC(C)C)=O.[OH:15][C@H:16]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH:53]1([NH:59][C:60]2[CH:69]=[C:68]3[C:63]([C:64](=[O:77])[C:65](CO)=[CH:66][N:67]3[CH:70]3[CH2:74][CH2:73][CH2:72][CH2:71]3)=[CH:62][C:61]=2[F:78])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1>O.ClCCl>[CH:53]1([NH:59][C:60]2[CH:69]=[C:68]3[C:63]([C:64](=[O:77])[C:65]([O:15][C@@H:16]([CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:17]([O:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[O:18])=[CH:66][N:67]3[CH:70]3[CH2:71][CH2:72][CH2:73][CH2:74]3)=[CH:62][C:61]=2[F:78])[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]1
Reactant: O=C(OCc1ccccc1)[C@H](O)Cc1ccccc1
Reactant: O=c1c(CO)cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O
Product: O=C(OCc1ccccc1)[C@H](Cc1ccccc1)Oc1cn(C2CCCC2)c2cc(NC3CCCCC3)c(F)cc2c1=O
Reaction time: 0.25 h
Yield: 55.6 %

Procedure:
213 μl of diisopropyl azodicarboxylate was added to a 5.0 ml dichloromethane solution of 263 mg of benzyl (2R)-2-hydroxy-3-phenylpropanoate and 270 mg of triphenylphosphine at 0° C., followed by stirring for 15 minutes. Then, 177 mg of 7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-3-(hydroxymethyl)quinolin-4(1H)-one was added thereto, followed by stirring at room temperature for 4 hours. Water was added to the reaction mixture, followed by extraction with EtOAc and washing with aqueous saturated sodium chloride. After drying over anhydrous sodium sulfate and subsequent evaporation under a reduced pressure, the residue was purified by silica gel column chromatography to obtain 160 mg of benzyl (2S)-2-{[7-(cyclohexylamino)-1-cyclopentyl-6-fluoro-4-oxo-1,4-dihydroquinolin-3-yl]oxy}-3-phenylpropanoate.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]=[O:8])=[CH:3][CH:2]=1.[CH2:9](O)[CH2:10][OH:11].C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1C=CC=CC=1>[O:8]1[CH2:9][CH2:10][O:11][CH:7]1[C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1
Reactant: O=Cc1ccncc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccccc1
Product: c1cc(C2OCCO2)ccn1

Procedure:
A stirred solution of pyridine-4-carboxaldehyde (8.7 ml, 90 mmol), ethylene glycol (10 ml, 180 mmol) and p-toluene sulfonic acid (18.8 g, 99 mmol) in benzene (70 ml) was refluxed overnight. A Dean-Stark apparatus was used to remove water azeotropically from the reaction. After ˜15 h the mixture was cooled, then made basic with aq. NaOH (20% w/v, ˜30 ml). The benzene layer was isolated and the aqueous layer was washed with dichloromethane until no more product came out (˜5×60 ml). The combined organic phases were dried (Na2SO4) and solvent removed in vacuo to give the pure 4-(1,3 dioxolan-2-yl) pyridine [Registry No. 61379-59-7] as a pale yellow liquid that solidified under vacuum (12.57 g, 92%). 1H NMR (300 MHz, CDCl3): δ 4.06 (4H, m, O—(CH2)2—O), 5.82 (1H, s, O—CH—O), 7.39 (2H, d, J=6-Hz, H-3, H-5), 8.63 (2H, d, J=6 Hz, H-2, H-6) ppm.
Reaction SMILES: CC1(C)[O:7][CH2:6][C:5]([NH:24]C(=O)OC(C)(C)C)([CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:12][CH:11]=2)[CH2:4][O:3]1>FC(F)(F)C(O)=O.C(Cl)Cl.CO>[NH2:24][C:5]([CH2:8][NH:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:14][CH:15]=1)([CH2:6][OH:7])[CH2:4][OH:3]
Reactant: CCCCCCCCc1ccc(NCC2(NC(=O)OC(C)(C)C)COC(C)(C)OC2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: CCCCCCCCc1ccc(NCC(N)(CO)CO)cc1
Yield: 82.2 %

Procedure:
A solution of a product of Step A (0.32 g; 0.71 mmol) in 60% trifluoroacetic acid in CH2Cl2 (4 ml) was stirred for 15 min at room temperature then diluted to 6 ml with methanol (MeOH). The resulting mixture was evaporated to dryness under reduced pressure and the residue dried in vacuo for 1 h. This was purified by flash column chromatography (FCC) (SiO2; CH2Cl2 saturated with NH4OH:MeOH 95:5), to give pure title compound (0.18 g; 82%), as colourless solid. 1H-NMR (CDCl3) 0.86 (tr, 2H, J=6.96 Hz); 1.25 (m, 10H); 1.52 (m, 2H); 2.1-2.51 (broad m, 4H); 2.47 (tr, 2H, J=7.9 Hz); 3.1 (s, 2H); 3.55 (m, 4H); 4.05 (broad s, 1H); 6.6 (d, 2H, J=8.34 Hz); 6.96 (d, 2H, J=8.34 Hz).