Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:35])[CH:5]([O:32][CH2:33][CH3:34])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:31])C.[Li+].[OH-]>>[CH2:33]([O:32][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:31])[C:4]([OH:35])=[O:3])[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3cccc(C(F)(F)F)c3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3cccc(C(F)(F)F)c3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{2-methyl-4-[5-methyl-2-(3-trifluoromethyl-phenyl)-oxazol-4-ylmethoxy]-phenyl}-propionic acid as colorless solid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[CH:3]=1.[NH:13]1[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]1.COCCCOCCCO>>[CH3:12][C:4]1[CH:3]=[C:2]([N:13]2[CH2:18][CH2:17][CH:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Cc1cc(Cl)c2ccccc2n1
Agent: COCCCOCCCO
Product: CCOC(=O)C1CCN(c2cc(C)nc3ccccc23)CC1
Temperature: 150 °C
Reaction time: 48 h
Yield: 162.9 %

Procedure:
4-Chloroquinaldine (0.888 g, 5 mmol) and ethyl piperidine-4-carboxylate (1.18 g, 7.5 mmol) were mixed together with dipropyleneglycolmonomethylether (5 ml) and stirred at 150° C. for 48 hours. The solvent was removed under reduced pressure and the residue purified by column chromatography (pre-packed silica column, gradient of dichloromethane/ethyl acetate) to give 2.43 g of a brown oil that was used directly in the next step. MS (APCI): m/z=298.9 [M+1]+.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[CH:10][C:5]=2[S:4][CH:3]=1.C1C(=O)N([I:19])C(=O)C1.C1COCC1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.C(OCC)(=O)C>[Br:1][C:2]1[C:6]2[C:7](=[O:11])[NH:8][CH:9]=[C:10]([I:19])[C:5]=2[S:4][CH:3]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=c1[nH]ccc2scc(Br)c12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cc(I)c2scc(Br)c12

Procedure:
The mixture of compound 10 (see Example 4(c)) (1.9 g, 8.3 mmol) and N-iodosuccimide (NIS, 2.2 g, 49.9 mmol) in DMF (25 ml) and THF (20 ml) was stirred for 5 hours at 40° C. The reaction mixture was poured into 10% Na2SO3 and ethyl acetate. The insoluble product was collected by filtration, washed with ethyl acetate and dried under reduced pressure to give 3-bromo-7-iodo-5H-thieno[3,2-c]pyridin-4-one (990 mg). The filtrate was collected, dried over Na2SO4, filtered and concentrated in vacuo. The generated precipitate was washed with MeOH to further yield 3-bromo-7-iodo-5H-thieno[3,2-c]pyridin-4-one (1.1 g). 1H NMR (400 MHz, DMSO-d6) ppm 11.75 (s, 1H), 7.79 (s, 1H), 7.57 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.Cl.C(=O)(O)[O-].[Na+].[CH2:23](O)[CH3:24]>>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([O:16][CH2:23][CH3:24])=[O:15])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: O=C(O)CCCCCCc1ccc(O)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOC(=O)CCCCCCc1ccc(O)cc1
Temperature: 25 °C

Procedure:
A 500 ml single-neck flask was charged with 7-(4-hydroxyphenyl)heptanoic acid (A4) (17.7 g, 79.7 mmole), 35 ml of the 25% HCl solution, and ethanol (90 ml). The flask was immersed in an oil bath and refluxed 4.5 hours. After cooling to room temperature, the contents were poured onto ice water (750 ml) and 375 ml of saturated sodium bicarbonate were added. The mixture was extracted with ether (3×225 ml), the combined organic layers dried (MgSO4), and concentrated by rotary evaporation (2-4 hours at 45° C.). The resulting oil, Ethyl 7-(4-hydroxyphenyl)heptanoate, was of sufficient purity to be used in the next step.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH2:24])[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2].C(O[CH:32]1[NH:36][C:35](=[O:37])[CH2:34][CH2:33]1)C>CN(C)C=O>[C:1]([O:4][C@@H:5]1[C@H:9]([O:10][C:11](=[O:13])[CH3:12])[C@@H:8]([CH2:14][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[N:19]1[C:28]2[N:27]=[CH:26][N:25]=[C:23]([NH:24][CH:32]3[CH2:33][CH2:34][C:35](=[O:37])[NH:36]3)[C:22]=2[N:21]=[CH:20]1)(=[O:3])[CH3:2]
Reactant: CCOC1CCC(=O)N1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(N)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(NC4CCC(=O)N4)ncnc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 90.8 %

Procedure:
Adenosine 2',3',5'-triacetate (2.0 g) and 5-ethoxy-2-pyrrolidinone (1.2 g) were stirred in N,N-dimethylformamide (10 ml) at 130° C. overnight. The reaction mixture was distilled to remove the N,N-dimethylformamide and the residue was subjected to silica gel column chromatography using chloroformacetone (5:3) as the eluent. The active fractions were pooled and concentrated under reduced pressure to give N6 -(5-oxo-2-pyrrolidinyl)adenosine 2',3',5'-triacetate as an oil (2.2 g).
Reaction SMILES: [Mn]([O-])(=O)(=O)=O.[K+].[CH2:7]([C@H:9]1[C@@H:14]([C:15]([O:17][CH3:18])=[O:16])[CH2:13][CH:12]=[CH:11][CH2:10]1)C.C[OH:20]>O>[CH3:18][O:17][C:15]([C@@H:14]1[C@H:10]([CH2:9][CH3:7])[CH2:11][C:12](=[O:20])[CH2:13]1)=[O:16]
Reactant: CC[C@@H]1CC=CC[C@@H]1C(=O)OC
Reactant: CO
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Solvent: O
Product: CC[C@@H]1CC(=O)C[C@@H]1C(=O)OC
Temperature: 25 °C
Reaction time: 4 h

Procedure:
24 g of potassium permanganate is dissolved in 15 ml of water, and 8.08 g of (1S, 6R)-6-ethyl-1-methoxycarbonylcyclohex-3-ene was added to the solution over a period of 20 minutes. The mixture was stirred for 4 hours at room temperature, and then 6 g of potassium permanganate was further added, followed by 1 hour of stirring. Methanol was added to the mixture, and the insoluble material was filtered off. Concentrated hydrochloric acid was added to the filtrate such as to adjust the pH thereof at 2, and the filtrate was extracted with a mixed solvent of ethyl acetate - tetrahydrofuran (1:1). After concentration, to the residue were added 50 ml of acetic anhydride and 2.5 g of sodium acetate, and the mixture was refluxed for 1.5 hours. The mixture was cooled down to room temperature, and a mixed solvent of hexane - ether was added thereto. The insoluble material was filtered off, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography (ether:hexane=1:2), thereby obtaining 3.99 g of titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCCC)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[NH:33]1[CH2:39][CH:38]([OH:40])[CH2:37][NH:36][CH2:35][CH2:34]1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:33]5[CH2:39][CH:38]([OH:40])[CH2:37][NH:36][CH2:35][CH2:34]5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1
Reactant: CCCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: OC1CNCCNC1
Product: O=C1N=C(N2CCNCC(O)C2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(6-hydroxy-[1,4]diazepan-1-yl)-thiazol-4-one was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazol-4-one and [1,4]diazepan-6-ol following General Procedure B.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([C:11]([C:13]2[C:14]([C:19]([N:21](C)[CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)=[O:12])[N:4]=1.ClC1C(C(C2N=C(OC)C=C(OC)N=2)=O)=C(C(Cl)=CC=1)C(O)=O.ClC1C(C(O)=O)=C(SC2N=C(OC)C=C(OC)N=2)C=CC=1>>[CH3:10][O:9][C:7]1[CH:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([CH:11]([OH:12])[C:13]2[C:14]([C:19]([NH:21][CH3:22])=[O:20])=[N:15][CH:16]=[CH:17][CH:18]=2)[N:6]=1
Reactant: COc1cc(OC)nc(C(=O)c2cccnc2C(=O)N(C)C)n1
Agent: COc1cc(OC)nc(C(=O)c2c(Cl)ccc(Cl)c2C(=O)O)n1
Agent: COc1cc(OC)nc(Sc2cccc(Cl)c2C(=O)O)n1
Product: CNC(=O)c1ncccc1C(O)c1nc(OC)cc(OC)n1

Procedure:
4, 7-dichloro-3-(4,6-dimethoxy-2-pyrimidnyl)-3-hexanoyloxyphthalide; 3-[(4,6-dimethoxy-2-pyrimidinyl)carbonyl]-N,N-dimethyl-2-pyridine carboxamide; 3,6-dichloro-2-[(4, 6-dimethoxy-2-pyrimidinyl)carbonyl]benzoic acid; 6-chloro-2-[(4,6-dimethoxy-2-pyrimidinyl)thio]benzoic acid (a.k.a. DPX-PE350 or pyrithiobac) and salts thereof.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](Cl)=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1.[CH3:32][S:33]([NH2:36])(=[O:35])=[O:34]>N1C=CC=CC=1>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]#[C:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:23]2[CH:31]=[CH:30][C:26]([C:27]([NH:36][S:33]([CH3:32])(=[O:35])=[O:34])=[O:28])=[CH:25][CH:24]=2)=[CH:5][CH:4]=1
Reactant: O=C(Cl)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1
Reactant: CS(N)(=O)=O
Agent: Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)NC(=O)c1ccc(NCCCCCCCCCCCC#Cc2ccc(Cl)cc2)cc1

Procedure:
A solution of 25.2 g. of 4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl chloride hydrochloride and 5.6 g. of methanesulfonamide in 250 ml. of pyridine is stirred under reflux for 2 hours and then concentrated in vacuo. The residue is partitioned between water and diethyl ether; the aqueous layer acidified with 1 N HCl, and the organic layer separated, dried and evaporated. Crystallization of the residual white solid from 60% aqueous acetic acid and then from methylene chloride-hexane affords N-{4-[13-(4-chlorophenyl)tridec-12-ynylamino]benzoyl}methanesulfonamide as a white solid.
Reaction SMILES: [C:1]1([N:7]2[C:19]3[CH:18]=[CH:17][C:16]([C:20]4[CH:21]=[CH:22][C:23]5[NH:24][C:25]6[C:30]([C:31]=5[CH:32]=4)=[CH:29][C:28]([C:33]4[CH:34]=[CH:35][C:36]5[N:37]([C:46]7[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=7)[C:38]7[C:43]([C:44]=5[CH:45]=4)=[CH:42][CH:41]=[CH:40][CH:39]=7)=[CH:27][CH:26]=6)=[CH:15][C:14]=3[C:13]3[C:8]2=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:53]1[CH:54]=[C:55]([C:59]2[N:64]=[C:63]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[CH:62]=[C:61]([C:71]3[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=3)[N:60]=2)[CH:56]=[CH:57][CH:58]=1.CC([O-])(C)C.[Na+].C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>CC1C=CC(C)=CC=1.CC([O-])=O.CC([O-])=O.[Pd+2]>[C:71]1([C:61]2[CH:62]=[C:63]([C:65]3[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=3)[N:64]=[C:59]([C:55]3[CH:56]=[C:57]([N:24]4[C:23]5[CH:22]=[CH:21][C:20]([C:16]6[CH:17]=[CH:18][C:19]7[N:7]([C:1]8[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=8)[C:8]8[C:13]([C:14]=7[CH:15]=6)=[CH:12][CH:11]=[CH:10][CH:9]=8)=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[C:28]([C:33]4[CH:34]=[CH:35][C:36]6[N:37]([C:46]7[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=7)[C:38]7[C:43]([C:44]=6[CH:45]=4)=[CH:42][CH:41]=[CH:40][CH:39]=7)[CH:29]=5)[CH:58]=[CH:53][CH:54]=3)[N:60]=2)[CH:76]=[CH:75][CH:74]=[CH:73][CH:72]=1
Reactant: c1ccc(-n2c3ccccc3c3cc(-c4ccc5[nH]c6ccc(-c7ccc8c(c7)c7ccccc7n8-c7ccccc7)cc6c5c4)ccc32)cc1
Reactant: Brc1cccc(-c2nc(-c3ccccc3)cc(-c3ccccc3)n2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: Cc1ccc(C)cc1
Product: c1ccc(-c2cc(-c3ccccc3)nc(-c3cccc(-n4c5ccc(-c6ccc7c(c6)c6ccccc6n7-c6ccccc6)cc5c5cc(-c6ccc7c(c6)c6ccccc6n7-c6ccccc6)ccc54)c3)n2)cc1

Procedure:
28.8 g (44.32 mmol) of 9,9″-diphenyl-9H,9′H,9″H-[3,3′;6′,3″]tercarbazole 29, 18.88 g (48.76 mmol) of 2-(3-bromophenyl)-4,6-diphenylpyrimidine 14 and 13.01 g (135.35 mmol) of NaOtBu are suspended in 820 ml of p-xylene. 201.21 mg (0.90 mmol) of Pd(OAc)2 and 2.7 ml of a 1M tri-tert-butylphosphine solution are added to this suspension. The reaction mixture is heated under reflux for 19 h. After cooling, the organic phase is separated off, washed three times with 100 ml of water and subsequently evaporated to dryness. The residue is extracted with hot toluene, recrystallised from toluene and finally sublimed in a high vacuum. The yield is 23.3 g (55%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[CH:11][N:10]=[C:9]2[Cl:13])[N:5]=[CH:4][N:3]=1.[CH:14]1([NH2:17])[CH2:16][CH2:15]1>CO>[Cl:13][C:9]1[N:8]([C:6]2[N:5]=[CH:4][N:3]=[C:2]([NH:17][CH:14]3[CH2:16][CH2:15]3)[CH:7]=2)[CH:12]=[CH:11][N:10]=1
Reactant: NC1CC1
Reactant: Clc1cc(-n2ccnc2Cl)ncn1
Solvent: CO
Product: Clc1nccn1-c1cc(NC2CC2)ncn1
Temperature: 50 °C
Reaction time: 12 h
Yield: 89.1 %

Procedure:
4-Chloro-6-(2-chloro-imidazol-1-yl)-pyrimidine (0.85 g, 4 mmol) and cyclopropylamine (1.4 mL, 20 mmol) were mixed in 10 mL methanol and stirred at 50° C. for 12 hours. After reaction was complete, the solvent was removed by rotary evaporation. The crude product was washed with water and taken to dryness to give the title compound (0.84 g, 90%); 1H NMR 400 MHz (DMSO-d6) δ 8.45 (s, 1H), 8.17 (d, 1H), 7.75 (s, 1 H), 7.08 (s, 1H), 6.80 (d, 1H), 3.34 (s, 1H), 0.78 (br, 2H), 0.52 (br, 2H); MS m/z 236.4 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([O:18]C)=[O:17])[CH:13]=[CH:12][CH:11]=1.[OH-].[Na+]>C1COCC1.C(OCC)(=O)C>[F:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([F:9])[C:3]=1[C:10]1[N:15]=[C:14]([C:16]([OH:18])=[O:17])[CH:13]=[CH:12][CH:11]=1
Reactant: COC(=O)c1cccc(-c2c(F)ccc(C)c2F)n1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Cc1ccc(F)c(-c2cccc(C(=O)O)n2)c1F
Reaction time: 2 h
Yield: 85 %

Procedure:
To a solution of methyl 6-(2,6-difluoro-3-methylphenyl)picolinate (1.0 equiv.) in THF was added sodium hydroxide (10 equiv.) and the reaction was stirred for 2 hours. The solution was diluted with ethyl acetate and washed with 1N NaOH (2×). The combined basic aqueous washes were combined and acidified with concentrated HCl. The acidic aqueous phase was extracted with ethyl acetate (2×), the combined organic layers were dried with magnesium sulfate, filtered, and concentrated in vacuo to provide 6-(2,6-difluoro-3-methylphenyl)picolinic acid as a white solid in 85% yield. LC/MS=250.0 (M+H), Rt=0.76 min.
Reaction SMILES: [SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([O:13]CC)=[O:12])=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1.Cl>[OH-].[Na+]>[SH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[C:6]2[N:5]=[C:4]([CH3:16])[CH:3]=1
Reactant: CCOC(=O)c1cnn2c(S)cc(C)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: Cc1cc(S)n2ncc(C(=O)O)c2n1

Procedure:
Ethyl 7-mercapto-5-methylpyrazolo[1,5-a]pyrimidine-3-carboxylate (J. Med. Chem. 1981, 24(5), 610-13) was heated in 1N aqueous sodium hydroxide solution until all has passed into solution. The reaction mixture was cooled and its pH was adjusted to 1 with aqueous hydrochloric acid. The resulting precipitate was filtered off, dried and recrystallized from dimethylformamide. There was obtained 7-mercapto-5-methyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid as a yellow powder having a of melting point of 161-162° (dec.).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1.C1(B(O)O)C=CC=CC=1.[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:35]=1B(O)O>>[CH3:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([O:40][CH3:41])[C:35]=1[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([CH3:20])[C:7](=[O:19])[CH2:8][N:9]=[C:10]([C:11]3[CH:12]=[C:13]([CH:16]=[CH:17][CH:18]=3)[C:14]#[N:15])[C:4]=2[CH:3]=1
Reactant: CN1C(=O)CN=C(c2cccc(C#N)c2)c2cc(Br)ccc21
Reactant: COc1cccc(OC)c1B(O)O
Agent: OB(O)c1ccccc1
Product: COc1cccc(OC)c1-c1ccc2c(c1)C(c1cccc(C#N)c1)=NCC(=O)N2C
Yield: 71 %

Procedure:
Prepared from 3-(7-bromo-1-methyl-2-oxo-2,3-dihydro-1H-benzo[e][1,4]diazepin-5-yl)-benzonitrile Intermediate 14 using the same method described for Example 1 and instead of using benzene boronic acid, we used 2,6-dimethoxyphenyl boronic acid. The title compound (148 mg) was obtained as a yellow solid, (yield=71%).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[N:11]1[CH:30]=[O:31])(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.CCOC(C)=O>[OH:8][CH2:9][CH:10]1[CH2:18][C:17]2[C:12](=[CH:13][CH:14]=[C:15]([N:19]3[CH2:23][C@H:22]([CH2:24][NH:25][C:26](=[O:28])[CH3:27])[O:21][C:20]3=[O:29])[CH:16]=2)[N:11]1[CH:30]=[O:31]
Reactant: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO[Si](C)(C)C(C)(C)C)N3C=O)C(=O)O1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=O)NC[C@H]1CN(c2ccc3c(c2)CC(CO)N3C=O)C(=O)O1
Temperature: 0 °C
Yield: 76.9 %

Procedure:
A stirred, ice cold mixture of the product from Step 10 (0.35 g, 0.78 mmol) and THF (20 ml), under nitrogen is treated, dropwise stirring 3 min, with 1 M tetrabutylammonium fluoride in THF (3.31 ml). It is kept in the ice bath for 5 min and at ambient temperature for 2 h. It is then diluted with EtOAc, washed with water and brine, dried (MgSO4) and concentrated. Chromatography of the residue over silica gel with acetone gave 0.20 g of the titled product: mp 132-136° C.; HRMS (FAB) calcd for C16H19N3O5+H 334.1403, found 334.1418; 1H NMR [300 MHz, (CD3)2SO] δ1.81 (s, 3H), 2.80, 3.01 (m, m, 1H), 3.38 (m, 5H), 3.69 (m, 1H), 4.06 (m, 1H), 4.45 (m, 1H), 4.68 (m, 1H), 4.89, 5.17 (t, t, 1H), 7.26 (m, 1H), 7.38, 7.86 (d, d, 1H), 7.48 (m, 1H), 8.24 (t, 1H), 8.44, 8.95 (s, s, 1H).
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=[O:20])=[CH:4][CH:3]=1.[I-:22].[Na+].[N+]([O-])(O)=O>C(O)(=O)C>[I:22][C:3]1[CH:4]=[C:5]([C:19]([OH:21])=[O:20])[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:16])([F:17])[F:15])[CH:9]=2)[C:2]=1[CH3:1]
Reactant: [I-]
Reactant: Cc1ccc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O=[N+]([O-])O
Product: Cc1c(I)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Temperature: 50 °C
Yield: 68 %

Procedure:
To 6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxylic acid (28.6 kg, 1 mol eq, limiting reagent) was added sodium iodide (15.1 kg, 1.05 mol eq) and acetic acid (200.2 L, 7 rel vol). 90% Nitric acid (20.1 kg, 3.0 mol eq) was added dropwise. The reaction was heated to 50° C. and stirred until an HPLC assay showed reaction to be complete. The reaction was cooled and stirred. The precipitated product was collected by filtration, washed with water (171.6 L, 6 rel vol) and dried to constant weight to yield the title compound (19.2 kg, 45.4 mol, 68%); 1H NMR (CDCl3): δ 2.36 (s, 3H); 7.42 (d, 1H, J=8.1 Hz); 7.50 (s, 1H); 7.78 (t, 1H, J=7.8 Hz); 7.85 (d, 1H, J=7.9 Hz); 8.86 (s, 1H); 13.44 (s, 1H) ppm; LCMS: m/z 424.0 (MH+).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]2[O:19]C=CC=2)[N:14]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C[OH:33].C(Cl)Cl>>[CH2:1]([O:8][C:9]([NH:11][C@H:12]1[C@@H:15]([CH2:16][CH2:17][C:18]([OH:33])=[O:19])[N:14]([CH2:23][C:24]([O:26][C:27]([CH3:30])([CH3:28])[CH3:29])=[O:25])[C:13]1=[O:31])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCc1ccco1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](NC(=O)OCc2ccccc2)[C@H]1CCC(=O)O
Temperature: 25 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A solution of (±)-t-butyl 2-[cis-3-benzyloxycarbonylamino-4-(2-(2-furyl)ethyl)-2-oxoazetidin-1-yl]acetate (100 mg) and sudan red 7B (0.2 mg) in 6 mL of methanol-methylene chloride (1:1) was cooled to -78° C. Ozone/oxygen was bubbled in to the solution up to the endpoint of sudan red. The solution was allowed to warm to ambient temperature when 0.25N NaOH (1.87 mL) and 30% hydrogen peroxide (0.25 mL) were added. The solution was stirred for 2 hrs and was then diluted with H2O. The organic solvents were removed, and the aqueous solution was washed with ethyl acetate. The aqueous solution was layered with ethyl acetate and the pH of the mixture lowered to 3.7 with dilute hydrochloric acid. The ethyl acetate layer was washed (saturated NaCl), dried (NaSO4), and concentrated. The residue was crystallized from diethyl ether to provide the title compound (44 mg, 46% yield), mp 118°-120° C. Recrystallization from ethyl acetate-hexane provided colorless crystals of the analytical sample.
Reaction SMILES: C[O:2][C:3](=[O:24])[C:4]1[CH:9]=[C:8]([C:10]2[S:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=3)[N:14]=2)[CH:7]=[CH:6][C:5]=1Br.[C:25]([C:27]1[CH:32]=[CH:31][C:30](B(O)O)=[CH:29][CH:28]=1)#[N:26]>>[C:25]([C:27]1[CH:32]=[CH:31][C:30]([C:5]2[C:4]([C:3]([OH:2])=[O:24])=[CH:9][C:8]([C:10]3[S:11][CH:12]=[C:13]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=4)[N:14]=3)=[CH:7][CH:6]=2)=[CH:29][CH:28]=1)#[N:26]
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: COC(=O)c1cc(-c2nc(-c3ccc(Cl)c(Cl)c3)cs2)ccc1Br
Product: N#Cc1ccc(-c2ccc(-c3nc(-c4ccc(Cl)c(Cl)c4)cs3)cc2C(=O)O)cc1
Yield: 22.2 %

Procedure:
Using the conditions of General Procedure B for Suzuki Coupling and Hydrolysis in Parallel Mode, 2-bromo-5-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-benzoic acid methyl ester (which may be prepared as described for Intermediate 6; 89 mg, 0.2 mmol) was reacted with 4-cyanophenylboronic acid (available from Combi-Blocks Inc.; 59 mg, 0.4 mmol). The resulting ester was hydrolyzed and the acid was purified to give 4′-cyano-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-biphenyl-2-carboxylic acid (20 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ 13.31 (br s, 1H), 8.49 (s, 1H), 8.43 (d, J=1.8 Hz, 1H), 8.34 (d, J=2.0 Hz, 1H), 8.26 (dd, J=8.0, 2.0 Hz, 1H), 8.09 (dd, J=8.4, 2.1 Hz, 1H), 7.92 (d, J=8.3 Hz, 2H), 7.77 (d, J=8.5 Hz, 1H), 7.56-7.64 (m, 3H).
Reaction SMILES: C(N(CC)C(C)C)(C)C.CS(Cl)(=O)=O.[CH3:15][O:16][CH2:17][C:18]1[S:22][C:21]2=[N:23][C:24]([C:28]([F:31])([F:30])[F:29])=[C:25]([CH2:26]O)[N:20]2[N:19]=1.[N-:32]=[N+:33]=[N-:34].[Na+]>ClCCl.CN(C=O)C.C(OCC)C.O>[N:32]([CH2:26][C:25]1[N:20]2[C:21]([S:22][C:18]([CH2:17][O:16][CH3:15])=[N:19]2)=[N:23][C:24]=1[C:28]([F:31])([F:30])[F:29])=[N+:33]=[N-:34]
Reactant: [N-]=[N+]=[N-]
Reactant: COCc1nn2c(CO)c(C(F)(F)F)nc2s1
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCc1nn2c(CN=[N+]=[N-])c(C(F)(F)F)nc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.6 %

Procedure:
N,N-Diisopropylethylamine (3.22 g, 24.88 mmol, 5 eq) and methanesulfonyl chloride (0.855 g, 7.47 mmol, 1.5 eq) are successively and slowly added at 0° C. to a solution of [2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methanol a3 (1.33 g, 4.98 mmol, 1 eq) in dichloromethane (30 ml). Sodium azide (0.485 g, 7.47 mmol, 1.5 eq) in suspension in DMF (5 ml) is added at 0° C., then warmed up to room temperature and the reaction mixture is stirred overnight. After hydrolysis (H2O) and extraction with diethylether, the combined organic layers are dried over MgSO4, filtered and evaporated under reduced pressure to afford 1.45 g of 5-(azidomethyl)-2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazole a18.