Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[NH:9][N:8]=[C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=3)[N:6]=2)[CH2:2]1.C(N(CC)CC)C.[CH3:23][NH:24][C:25]1[N:30]2[CH:31]=[CH:32][N:33]=[C:29]2[N:28]=[C:27]([C:34]2[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=2)[C:26]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>CN1C(=O)CCC1>[CH3:23][NH:24][C:25]1[N:30]2[CH:31]=[CH:32][N:33]=[C:29]2[N:28]=[C:27]([C:34]2[CH:41]=[CH:40][C:37]([CH2:38][N:1]3[CH2:4][CH:3]([C:5]4[N:6]=[C:7]([C:10]5[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=5)[NH:8][N:9]=4)[CH2:2]3)=[CH:36][CH:35]=2)[C:26]=1[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: CNc1c(-c2ccccc2)c(-c2ccc(C=O)cc2)nc2nccn12
Reactant: c1ccc(-c2n[nH]c(C3CNC3)n2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Solvent: CN1CCCC1=O
Product: CNc1c(-c2ccccc2)c(-c2ccc(CN3CC(c4n[nH]c(-c5ccccn5)n4)C3)cc2)nc2nccn12
Reaction time: 1 h
Yield: 37.3 %

Procedure:
257 mg (0.94 mmol) 2-(5-Azetidine-3-yl-[1,2,4]triazole-3-yl)-pyridine×2HCl are dissolved in 7.3 mL NMP. After addition of 0.26 mL (1.88 mmol) triethylamine the reaction mixture is stirred for one hour. 280 mg (0.85 mmol) 4-(5-Methylamino-6-phenyl-imidazo[1,2-a]pyrimidin-7-yl)-benzaldehyde and 0.12 mL (2.05 mmol) acetic acid are added. The reaction mixture is stirred for 24 hours at room temperature. 469.9 mg (2.2 mmol) NaBH(OAc)3, are added in portions and the reaction mixture is stirred at room temperature over night. The reaction mixture is treated with saturated NaHCO3. The precipitate is filtered off, washed with water, dried and purified by chromatography (silicagel, eluents: dichloromethane/methanol) yielding 163 mg (33.5%) of the desired title compound.
Reaction SMILES: [CH3:1][N:2]([C:4]([N:6]=[C:7]([NH2:9])[NH2:8])=[NH:5])[CH3:3].C(N)C(O)=O.CN(C(N=C(N)N)=N)C.Cl>>[CH3:1][N:2]([C:4]([NH:6][C:7]([NH2:9])=[NH:8])=[NH:5])[CH3:3]
Reactant: CN(C)C(=N)N=C(N)N
Agent: Cl
Agent: NCC(=O)O
Product: CN(C)C(=N)NC(=N)N

Procedure:
Below, we specify a preferred embodiment, which is not intended to limit the synthesis of the metformin glycinate salt, which was synthesized from the metformin hydrochloride salt, where free metformin was produced by releasing the hydrochloride counterion, using an ion-exchange column for this purpose; the metformin base released was dissolved in an aqueous medium and, subsequently, glycine was added at ambient temperature under constant stirring; subsequently, the resulting product is heated until a concentrated solution is produced, an organic solvent is added which does not react with the components present and wherein glycine is insoluble in order to create insolubility in the medium and favor crystallization of the saturated medium; all of this in order to precipitate the excess glycine and then separate it by filtering; the filtrate was concentrated again until precipitation of the metformin glycinate salt was achieved, this precipitate is washed and purified.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[C:11]([NH:19][C:20]2[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=2)[N:10]=1>>[CH:1]1([O:7][C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=[C:11]([NH:19][C:20]3[CH:24]=[C:23]([CH3:25])[NH:22][N:21]=3)[N:10]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OC1CCCCC1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: Cc1cc(Nc2cc3ccccc3c(OC3CCCCC3)n2)n[nH]1

Procedure:
Similar procedure as described in example 10 was used, starting from cyclohexanol and (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine to give (1-cyclohexyloxy-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine. LC-MS m/e 323(MH+).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC(OCC(C)C)=O.[NH2:18][C:19]1[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=[C:21]([N:29]([CH2:33][CH:34]=[CH2:35])[CH2:30][CH:31]=[CH2:32])[N:20]=1>CN(C)C1C=CN=CC=1.C(N(CC)CC)C.C(Cl)Cl>[CH2:33]([N:29]([CH2:30][CH:31]=[CH2:32])[C:21]1[N:20]=[C:19]([NH:18][C:1](=[O:9])[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[N:24]2[O:25][C:26](=[O:28])[N:27]=[C:23]2[N:22]=1)[CH:34]=[CH2:35]
Reactant: O=C(O)c1ccccc1
Reactant: C=CCN(CC=C)c1nc(N)n2oc(=O)nc2n1
Agent: CC(C)COC(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CCN(CC=C)c1nc(NC(=O)c2ccccc2)n2oc(=O)nc2n1

Procedure:
3.3 g. of benzoic acid are dissolved in 70 ml. of methylene chloride and 2.7 g. of triethylamine. The solution is stirred and treated at 0° C. with 3.5 g. of isobutyl chloroformate in 25 ml. of methylene chloride. The mixture is then stirred at 0° C. for 30 minutes and subsequently at room temperature for 1 hour. The solution is treated with a suspension of 5 g. of 7-amino-5-diallylamino-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-2-one in 200 ml. of methylene chloride, 12.5 ml. of triethylamine and 0.6 g. of 4-dimethylaminopyridine. The mixture obtained is stirred at room temperature for 18 hours and then washed with 100 ml. of water. The organic phase is dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained is purified by column chromatography, there being obtained N-{5-diallylamino-2-oxo-2H-[1,2,4]oxadiazolo[2,3-a]-s-triazin-7-yl}benzamide having a melting point of 182°-183° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].ClCCl.[OH:9][CH2:10][C@@H:11]1[C@@H:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:14][N:13]([C:22]([O:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)=[O:23])[CH2:12]1>C(N(CC)CC)C>[CH3:1][S:2]([O:9][CH2:10][C@@H:11]1[C@@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:14][N:13]([C:22]([O:24][C:25]2[CH:26]=[CH:27][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:29][CH:30]=2)=[O:23])[CH2:12]1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(OC(=O)N2C[C@H](CO)[C@@H](c3ccccc3)C2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC(=O)N2C[C@H](COS(C)(=O)=O)[C@@H](c3ccccc3)C2)cc1
Temperature: 25 °C

Procedure:
A 0.84 ml portion of methanesulfonyl chloride was added dropwise to a 30 ml dichloromethane solution of 3.5 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-(hydroxymethyl)-4-phenylpyrrolidine-1-carboxylate and 2.75 ml of triethylamine, and stirred at room temperature for 2Hours. Thereafter, its work-up was carried out in the standard method to obtain 4.3 g of 4-(methoxycarbonyl)phenyl (3R,4S)-3-{[(methylsulfonyl)oxy]methyl}-4-phenylpyrrolidine-1-carboxylate as a colorless amorphous substance. EP: 434.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:13]([O:17][C:18]([CH:20]=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]>C1COCC1>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]=[CH:20][C:18]([O:17][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:19])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)(C)OC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CCCCCc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C=CCCCCc1ccccc1
Reaction time: 2.5 h
Yield: 79.4 %

Procedure:
To a solution of 5-phenylpentanal (60 mmol) in anhydrous THF (100 mL) at room temperature is added (t-butoxycarbonylmethylene)triphenyl-phosphorane (27.5 g, 72 mmol). The resulting orange solution is stirred for 2.5 hours, after which TLC analysis indicated complete reaction. The reaction mixture is concentrated in vacuo to afford a crude product which is chromatographed on silica gel (hexane/EtOAc, 19:1) to afford 12.4 g of t-butyl 7-phenyl-2-heptenoate (80%) as a colorless oil. TLC [pet-ether/EtOAc, 9:1, Rf (aldehyde)=0.60, Rf (ester)=0.80]. 1H NMR (300 MHz, CDCl3) δ 1.45 (s, 9H), 1.65 (m, 4H), 2.18 (q, 2H), 2.61 (t, 2H), 5.70 (d, 1H), 6.82 (dt, 1H), 7.10-7.30 (m, 5H) ppm.
Reaction SMILES: [C:1](Cl)(=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Br.[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([F:35])=[C:31]([OH:34])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:36])[CH2:23][CH2:22]1.ClCCl.C(N(CC)CC)C>O>[Cl:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]1([CH:24]2[C:33]3[C:28](=[CH:29][C:30]([F:35])=[C:31]([O:34][C:1](=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH:32]=3)[CH2:27][CH2:26][N:25]2[CH3:36])[CH2:23][CH2:22]1
Reactant: CN1CCc2cc(F)c(O)cc2C1C1(c2ccccc2Cl)CC1
Reactant: CCCCCCCCCC(=O)Cl
Agent: Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCCCCCCCCC(=O)Oc1cc2c(cc1F)CCN(C)C2C1(c2ccccc2Cl)CC1

Procedure:
Decanoyl chloride (0.61 g) was added to a stirring suspension of (+)-1- [1-(2-chlorophenyl)cyclopropyl]-6-fluoro-7-hydroxy-2-methyl-1,2,3,4-tetrahydroisoquinoline hydrobromide (1 g, prepared in a similar manner to that described in Example 62) and dichloromethane (25 ml). Triethylamine (1.35 ml) was added and the stirring was maintained for 1.5 hours. Water was then added, and the organic layer washed with 2N aqueous sodium hydroxide solution, then water and dried over potassium carbonate. The solvent was removed in vacuo and the residual oil was purified by liquid chromatography using petroleum ether (b.p. 40°-60° C.) as impurity eluant, then 5% ether in petroleum ether (b.p. 40°-60° C.) as product eluant. The solvent was removed in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-decanoyloxy-6-fluoro-2-methyl-1,2,3,4-tetrahydroisoquinoline (0.85 g) which had a specific optical rotation αD of +10.6°.
Reaction SMILES: C[C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[C:4](CC)[C:3]=1I.[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C@H:21]2[C@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[NH:25][C:24]3=[O:32])[CH2:22]2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C@@H:21]2[C@@:23]3([C:31]4[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=4)[N:25]([C:3]4[CH:4]=[C:5]([CH:9]=[CH:10][CH:2]=4)[C:6]([OH:8])=[O:7])[C:24]3=[O:32])[CH2:22]2)=[CH:19][CH:20]=1
Reactant: O=C1Nc2ccccc2[C@@]12C[C@H]2c1ccc(Cl)cc1
Reactant: CCc1c(C(=O)[O-])ccc(C)c1I
Product: O=C(O)c1cccc(N2C(=O)[C@@]3(C[C@@H]3c3ccc(Cl)cc3)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 81 starting from methyl-ethyl-3-iodobenzoate (commercially available), (1R,2R) and (1S,2S)-2-(4-chlorophenyl)spiro [cyclopropane-1,3′-indolin]-2′-one prepared as in Scheme 1 LC/MS m/e calcd. for C23H16ClNO3 389, observed (M+H)+: 390.1. 1H NMR (400 MHz, DMSO-d6) δppm 2.31-2.42 (m, 2 H) 3.42 (t, J=8.72 Hz, 1 H) 6.88 (d, J=7.58 Hz, 1 H) 7.15 (t, J=7.20 Hz, 1 H) 7.22-7.28 (m, 1 H) 7.28-7.36 (m, 3 H) 7.36-7.41 (m, 2 H) 7.60-7.70 (m, 2 H) 7.86 (s, 1 H) 7.93-8.00 (m, 1 H) 13.24 (br. s, 1 H).
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].C(N(C(C)C)CC)(C)C.[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=O)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O.O>[CH3:5][O:4][N:3]([CH3:2])[C:28]([CH:25]1[CH2:24][CH2:23][N:22]([C:20]([O:19][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:21])[CH2:27][CH2:26]1)=[O:30]
Reactant: CNOC
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CON(C)C(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 48 h
Yield: 110.6 %

Procedure:
To a solution of N,O-dimethylhydroxylamine hydrochloride (894 mg, 9.17 mmol), 2-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronio hexafluorphosphate (HBTU) (3.48 g, 9.17 mmol) and diisopropylethylamine (DIPEA) in N,N-dimethylformamide (40 mL) was carefully added 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (2 g, 8.73 mmol) and the reaction mixture was stirred at room temperature for 2 days. The mixture was diluted with water (200 mL), extracted with ethyl acetate, washed with aqueous citric acid 5%, aqueous sodium bicarbonate 4%, water, and brine and dried over sodium sulphate. The solvent was removed under reduced pressure and the residue was purified by column chromatography on silica flash, using ethyl acetate as eluent (isocratic), to yield the title compound (2.63 g, 99%) as yellowish oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:8]([OH:11])[CH:9]=[CH2:10]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(N(CC)CC)C>[C:2]1([CH2:10][CH2:9][CH:8]=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C=CCO
Reactant: Ic1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Product: O=CCCc1ccccc1
Temperature: 100 °C
Yield: 27 %

Procedure:
0.1 g Palladium acetate, 10.2 g iodobenzene, 4.4 g allyl alcohol and 6.0 g triethylamine were heated while stirring under nitrogen to 100° C. After one hour the iodobenzene was 97% reacted and there was produced 27% 3-phenylpropanal and 13% hydratropic aldehyde.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1)C.[BH4-].[Na+]>CO>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH2:5][CH2:4][OH:3])[CH:7]=1
Reactant: CCOC(=O)Cc1cccnc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCc1cccnc1
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of pyridin-3-yl-acetic acid ethyl ester (33 g, 197.36 mmol) in methanol (400 mL) was added sodium borohydride (74.66 g, 1.9 mole). The reaction mixture was refluxed for 12 h, then cooled to rt, quenched with water (300 mL), concentrated. The residue was extracted with DCM (500 mL), dried over sodium sulfate, concentrated to afford the title product (20.76 g).
Reaction SMILES: Br[C:2]1[CH:14]=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][C:5]1[N:10]=[CH:9][CH:8]=[CH:7][N:6]=1.CC1(C)C(C)(C)OB([C:23]2[CH:24]=[CH:25][C:26]([C:29]3[CH:30]=[N:31][C:32]([NH2:35])=[N:33][CH:34]=3)=[N:27][CH:28]=2)O1>>[N:6]1[CH:7]=[CH:8][CH:9]=[N:10][C:5]=1[O:4][C:3]1[CH:11]=[CH:12][CH:13]=[CH:14][C:2]=1[C:23]1[CH:24]=[CH:25][C:26]([C:29]2[CH:34]=[N:33][C:32]([NH2:35])=[N:31][CH:30]=2)=[N:27][CH:28]=1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Reactant: Brc1ccccc1Oc1ncccn1
Product: Nc1ncc(-c2ccc(-c3ccccc3Oc3ncccn3)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 88 using 2-(2-bromophenoxy)pyrimidine and 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine. MS (ESI): mass calcd. for C19H14N6O, 342.12; m/z found, 343.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.97 (s, 2H), 8.70 (dd, J=2.3, 0.8, 1H), 8.48 (d, J=4.8, 2H), 8.06 (dd, J=8.3, 2.3, 1H), 7.85 (dd, J=8.3, 0.9, 1H), 7.58 (dd, J=7.6, 1.8, 1H), 7.56-7.50 (m, 1H), 7.48-7.41 (m, 1H), 7.30 (dd, J=8.0, 1.2, 1H), 7.10 (t, J=4.8, 1H).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[CH3:14][NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33].C(N(CC)CC)C.Cl>C(O)C>[C:4]([C:3]1[CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=[CH:10][C:2]=1[N:15]([CH3:14])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH3:33])([OH:6])=[O:5]
Reactant: CCCCCCCCCCCCCCCCCCNC
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCN(C)c1ccc([N+](=O)[O-])cc1C(=O)O

Procedure:
A mixture of 20g 2-chloro-5-nitrobenzoic acid, 28.6g methyl octadecylamine and 20 ml triethylamine was heated on a steam bath for 6 hours. The resulting solid was dissolved in aqueous ethanol, and then 6N HCl was added to give a pH of 3. The product was filtered and recrystallized from ethanol and then from acetone. m.p. = 108°-109°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([CH2:11][OH:12])=[CH:8][C:9]=1[Cl:10])=[O:4].I(O)(=O)(=O)=[O:14]>CC#N.CCOC(C)=O.C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:11]([OH:14])=[O:12])=[CH:8][C:9]=1[Cl:10])=[O:4]
Reactant: [O-][I+3]([O-])([O-])O
Reactant: COC(=O)c1sc(CO)cc1Cl
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1sc(C(=O)O)cc1Cl
Reaction time: 0.5 h
Yield: 86.5 %

Procedure:
A mixture of 3-chloro-5-hydroxymethyl-thiophene-2-carboxylic acid methyl ester (1.3 g, 6.29 mmol) and Periodic Acid (3.15 g, 13.84 mmol) in MeCN (40 ml) was stirred for 30 min. A solution of PCC (0.027 g, 0.13 mmol) in MeCN (2 ml) was added. After 5 h, the reaction mixture was diluted with EtOAc (250 ml), washed with sodium sulfite, brine, dried over sodium sulfate, filtered and evaporated. Isolate 1.20 g (86%) of yellow solid product.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[CH:12]=[CH:11][S:10][CH:9]=2)[N:3]=1.C([Sn](CCCC)(CCCC)[C:18]1[N:22]2[CH:23]=[CH:24][C:25]([C:27]([F:30])([F:29])[F:28])=[N:26][C:21]2=[N:20][CH:19]=1)CCC>>[S:10]1[CH:11]=[CH:12][C:8]([C:4]2[N:3]=[C:2]([C:18]3[N:22]4[CH:23]=[CH:24][C:25]([C:27]([F:28])([F:29])[F:30])=[N:26][C:21]4=[N:20][CH:19]=3)[CH:7]=[CH:6][CH:5]=2)=[CH:9]1
Reactant: Brc1cccc(-c2ccsc2)n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnc2nc(C(F)(F)F)ccn12
Product: FC(F)(F)c1ccn2c(-c3cccc(-c4ccsc4)n3)cnc2n1
Yield: 11.2 %

Procedure:
2-Bromo-6-(thien-3-yl)pyridine (2.20 g, 9.1 mmol) was coupled to 3-tributylstannyl-7-trifluoromethylimidazo[1,2-α]pyrimidine (9.0 mmol) by the method of Example 1. Purification by chromatography on silica gel eluting with isohexane on a gradient of ethyl acetate (10-80%) and trituration with isohexane followed by crystallisation from ethyl acetate-isohexane gave 3-[6-(thien-3-yl)pyridin-2-yl]-7-trifluoromethyl-imidazo[1,2-α]pyrimidine (350 mg) as a pale yellow solid: δH (400 MHz, CDCl3) 7.40 (1H, d, J 7), 7.48-7.50 (1H, m), 7.60 (1H, d, J 8), 7.69-7.73 (2H, m), 7.86 (1H, dd, J 8 and 8), 7.92-7.94 (1H, m), 8.54 (1H, s), 10.56 (1H, d, J 7); m/z (ES+) 347 (M++H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20]>CN(C=O)C.O>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][O:10][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[CH2:1][CH2:2][CH3:3])[CH3:23]
Reactant: CCCc1ccccc1O
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCc1ccccc1OCC(=O)OCC
Temperature: 0 °C
Yield: 103.9 %

Procedure:
2-Propylphenol (15.0 g, 110 mmol) was dissolved in DMF (70 mL), and stirred at 0° C. To the solution was added K2CO3 (30.43 g, 220.2 mmol) and ethyl 2-bromoacetate (13.43 mL, 121.1 mmol), and the reaction was stirred at room temperature for 3.5 h. The reaction was diluted with water, and the product was extracted with EtOAc twice. The organic layer was washed with water, brine, dried over Na2SO4, and concentrated in vacuo to give residue. The residue was purified using silica gel column chromatography (hexane/EtOAc=30/1) to give 4.2 (25.4 g). 1H NMR (400 MHz) (CDCl3) δ 7.18-7.08 (2H, m); 6.91 (1H, t, J=7.4 Hz); 6.71 (1H, d, J=8.1 Hz); 4.62 (2H, s); 4.25 (2H, q, J=7.1 Hz); 2.68-2.57 (2H, m); 1.70-1.60 (2H, m); 1.29 (3H, t, J=7.1 Hz); 0.95 (3H, t, J=7.4 Hz).
Reaction SMILES: [C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20](C)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].[CH3:31][N:32]([C:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][N:35]=1)[CH3:33]>>[C:1]([O:5][CH:6]([C:12]1[C:21]([CH3:22])=[C:20]([C:37]2[CH:36]=[N:35][C:34]([N:32]([CH3:33])[CH3:31])=[CH:39][CH:38]=2)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]=1[C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: CCOC(=O)C(OC(C)(C)C)c1c(C)c(C)c2ccccc2c1-c1ccc(Cl)cc1
Product: Cc1c(C(OC(C)(C)C)C(=O)O)c(-c2ccc(Cl)cc2)c2ccccc2c1-c1ccc(N(C)C)nc1

Procedure:
2-tert-Butoxy-2-(1-(4-chlorophenyl)-4-(6-(dimethylamino)pyridin-3-yl)-3-methylnaphthalen-2-yl)acetic acid (137) was prepared in a manner similar to 2-tert-butoxy-2-(1-(4-chlorophenyl)-3,4-dimethylnaphthalen-2-yl)acetic acid of Example 125, except using 2-(N,N-dimethylamino)-pyridin-5-yl-boronic acid in the Suzuki reaction, giving the title compound. 1H-NMR: (400 MHz, DMSO-d6): δ 8.02-8.00 (m, 1H); 7.78 (m, broad, 1H); 7.72-7.69 (m, 1H); 7.67-7.65 (m, 1H); 7.52-7.49 (m, 1H); 7.45-7.36 (m, 4H); 7.23 (d, J=8.0 Hz, 2H); 5.11 (s, 1H); 2.29 (d, J=1.2 Hz, 3H); 0.93 (d, J=1.2 Hz, 9H). LCMS-ESI+ (m/z): [M+H]+ calcd for C30H32ClN2O3: 503.2; Found: 503.3.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][C:12]2[N:15]=[C:16]([C:18]([NH:20][C@@H:21]3[CH2:26][CH2:25][CH2:24][CH2:23][C@@H:22]3[NH2:27])=[O:19])[S:17][C:11]=2[CH2:10]1.[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[N:34](S(C1C=CC=CC=1)(=O)=O)[C:33]([S:47](Cl)(=[O:49])=[O:48])=[CH:32]2.[OH-].[Na+].Cl>ClCCl.O1CCCC1.CO.O.C(N(CC)CC)C>[ClH:28].[Cl:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[NH:34][C:33]([S:47]([NH:27][C@@H:22]1[CH2:23][CH2:24][CH2:25][CH2:26][C@@H:21]1[NH:20][C:18]([C:16]1[S:17][C:11]3[CH2:10][N:9]([CH3:8])[CH2:14][CH2:13][C:12]=3[N:15]=1)=[O:19])(=[O:48])=[O:49])=[CH:32]2
Reactant: O=S(=O)(Cl)c1cc2cc(Cl)ccc2n1S(=O)(=O)c1ccccc1
Reactant: CN1CCc2nc(C(=O)N[C@@H]3CCCC[C@@H]3N)sc2C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1CCc2nc(C(=O)N[C@H]3CCCC[C@H]3NS(=O)(=O)c3cc4cc(Cl)ccc4[nH]3)sc2C1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
(±)-cis-N-[(5-methyl-4,5,6,7-tetrahydrothiazolo-[5,4-c]pyridin-2-yl)carbonyl]-1,2-cyclohexanediamine trifluoroacetate (400 mg) was suspended in dichloromethane (10 ml), triethylamine (0.514 ml) and 5-chloro-1-phenylsulfonylindole-2-sulfonyl chloride (Japanese Patent Application Laid-Open No. 2000-119253) (319 mg) were added, and the mixture was stirred at room temperature for 15 minutes. After water was added to the reaction mixture to conduct liquid separation, the resultant organic layer was dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale yellow foamy substance. This substance was dissolved in tetrahydrofuran (3 ml), and methanol (2 ml) and a 1N aqueous solution (1.5 ml) of sodium hydroxide were added to heat the mixture under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and dichloromethane and 1N hydrochloric acid were added to the residue to conduct liquid separation. After the resultant organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (dichloromethane:methanol=100:3) to obtain a pale yellow foamy substance. This substance was added to 1N hydrochloric acid (1 ml), and the mixture was concentrated under reduced pressure to obtain the title compound (108 mg) as a pale yellow foamy substance.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([C:18]#[C:19][CH2:20][O:21][CH3:22])=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([C:5]1[C:6]([CH2:18][CH2:19][CH2:20][O:21][CH3:22])=[N:7][C:8]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:9][C:10]=1[CH3:11])=[O:4]
Reactant: COCC#Cc1nc(N2CCOCC2)cc(C)c1C(=O)OC
Agent: [Pd]
Solvent: CO
Product: COCCCc1nc(N2CCOCC2)cc(C)c1C(=O)OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.5 %

Procedure:
To a solution of 500 mg (1.64 mmol) 2-(3-methoxyprop-1-ynyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester in MeOH (30 ml) was added 170 mg 10%-Pd/C. The reaction solution was stirred under hydrogen atmosphere (balloon) at RT for 16 h. Then the mixture was filtered through celite and the filtrate was concentrated in vacuo. Purification of the residue by CC (hexane/EtOAc 9:1) provided 480 mg (1.55 mmol, 95%) 2-(3-methoxypropyl)-4-methyl-6-morpholino-pyridine-3-carboxylic acid methylester.