Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH2:2].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([C:17]([S:19]C)=S)[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])[CH:7]=[N:8][CH:9]=1>C(O)C.ClCCl>[CH3:1][NH:2][C:17]([C:10]1([C:6]2[CH:7]=[N:8][CH:9]=[C:4]([Br:3])[CH:5]=2)[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=[O:16])=[S:19]
Reactant: CN
Reactant: CSC(=S)C1(c2cncc(Br)c2)CCCCC1=O
Solvent: CCO
Solvent: ClCCl
Product: CNC(=S)C1(c2cncc(Br)c2)CCCCC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A 33% w/v solution of methylamine in ethanol (5.7 ml) was added dropwise to a stirred solution of 2-(5-bromopyrid-3-yl)-2-methylthiothiocarbonylcyclohexanone (1.33 g, 3.86 mmol) in ethanol (25 ml) and dichloromethane (25 ml) at 0°-5° C. The solution was stirred at room temperature for 5 hours and concentrated in vacuo at 30°-35° C. The residue was purified by flash chromatography over silica gel eluting with ethyl acetate: hexane 4:6 to give (±)-N-methyl-2-oxo-1-(5-bromopyrid-3-yl) -cyclohexanecarbothioamide (0.57 g) m.p. 201°-3° C. NMR(CDCl3) 1.68-2.16(m,4H); 2.46-2.6(m,2H); 2.66-2.8(m,2H); 3.17-3.17-3.19 (d,3H); 7.74-7.78(dd,1H); 8.38-8.39(d,1H), 8.58-8.59(d,1H); 8.8-9.0(broad singlet). Calculated for 47.7%; H,4.6%; N,8.6%. Found C, 48.2%; H,4.7%; N,8.5%.
Reaction SMILES: CN1C=C(CN(C)C(C2N(C3C=CC(F)=CC=3)C(S)=NC=2)=O)C(C)=N1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:36]1[N:37]([C:46]2[CH:51]=[CH:50][C:49]([F:52])=[CH:48][CH:47]=2)[C:38]([C:41]([O:43]CC)=[O:42])=[CH:39][N:40]=1.[OH-].[Li+].C1COCC1>O.CO>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([F:33])[C:28]=1[C:34]#[C:35][C:36]1[N:37]([C:46]2[CH:47]=[CH:48][C:49]([F:52])=[CH:50][CH:51]=2)[C:38]([C:41]([OH:43])=[O:42])=[CH:39][N:40]=1
Reactant: CCOC(=O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1
Agent: Cc1nn(C)cc1CN(C)C(=O)c1cnc(S)n1-c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: O=C(O)c1cnc(C#Cc2c(F)cccc2Cl)n1-c1ccc(F)cc1

Procedure:
2-((2-Chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylic acid (43) was prepared in a similar manner as that described for the synthesis of compound 7 using ethyl 2-((2-chloro-6-fluorophenyl)ethynyl)-1-(4-fluorophenyl)-1H-imidazole-5-carboxylate (42) (44 mg, 0.11 mmol), lithium hydroxide (11 mg, 0.46 mmol), THF (0.1 mL), methanol (0.2 mL), and water (0.4 mL).
Reaction SMILES: [C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([OH:26])=[O:25])=[CH:20][CH:19]=2)=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].O[C:28]1[CH:44]=[CH:43][C:31]([C:32]([O:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:33])=[CH:30][CH:29]=1.C1CCC(N=C=NC2CCCCC2)CC1.CN(C1C=CC=CN=1)C>O1CCCC1>[C:1]([O:11][C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([O:26][C:28]3[CH:44]=[CH:43][C:31]([C:32]([O:34][CH:35]([CH3:42])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41])=[O:33])=[CH:30][CH:29]=3)=[O:25])=[CH:20][CH:19]=2)=[CH:16][CH:17]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: CCCCCCC(C)OC(=O)c1ccc(O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: C1CCOC1
Product: CCCCCCCCC(=O)Oc1ccc(-c2ccc(C(=O)Oc3ccc(C(=O)OC(C)CCCCCC)cc3)cc2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
In 330 ml of dehydrated tetrahydrofuran were dissolved 5.00 g of 4'-nonanoyloxybiphenyl-4-carboxylic acid and 6.76 g of 1-methylheptyl 4-hydroxybenzoate synthesized in (2) above. To the solution were added 6.18 g of DCC and 0.24 g of dimethylaminopyridine, followed by stirring for one day at room temperature.
Reaction SMILES: [CH3:1][C:2]1[C:8]([OH:9])=[CH:7][C:6]([CH3:10])=[CH:5][C:3]=1[OH:4].S(=O)(=O)(O)O.[CH3:16][C:17]([CH3:22])=[CH:18][CH:19](O)[CH3:20]>C(OC(C)C)(C)C>[OH:4][C:3]1[C:2]([CH3:1])=[C:8]2[C:7]([CH:19]([CH3:20])[CH2:18][C:17]([CH3:22])([CH3:16])[O:9]2)=[C:6]([CH3:10])[CH:5]=1
Reactant: CC(C)=CC(C)O
Reactant: Cc1cc(O)c(C)c(O)c1
Agent: O=S(=O)(O)O
Solvent: CC(C)OC(C)C
Product: Cc1cc(O)c(C)c2c1C(C)CC(C)(C)O2
Yield: 60 %

Procedure:
13.8 g. of 2,5-dimethyl resorcinol were dissolved in a mixed solution comprising 70 ml of isopropyl ether and 5 ml of concentrated sulfuric acid. Then, 10 g. of 4-methyl-3-pentene-2-ol were added dropwise to the solution at the temperature of about 60° C. for about 30 minutes. The resulting solution was cooled, and washed with water, with 1 N sodium hydroxide solution, and again with water and then dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was recrystallized from ether/n-hexane, to obtain 13.2 g. (yield: 60%) of the subject compound. Melting point: 88°-89° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[NH:8]2)=[CH:4][C:3]=1[CH3:16].[H-].[Na+].Cl[CH2:20][C:21]#[N:22].O>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[N:8]2[CH2:20][C:21]#[N:22])=[CH:4][C:3]=1[CH3:16]
Reactant: N#CCCl
Reactant: CCOC(=O)c1cc2cc(C)c(Cl)cc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc2cc(C)c(Cl)cc2n1CC#N
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
A solution of ethyl 6-chloro-5-methylindole-2-carboxylate (1.5 g, 6.3 mmol) in DMF (30 mL) was added dropwise to a stirred suspension of sodium hydride (60%, 0.39 g, 10 mmol) in DMF (20 mL) at room temperature under Ar. The reaction was then cooled to 0° C. and stirred for 45 min then chloroacetonitrile (0.81 mL, 13 mmol) was added in one portion. The reaction was heated to 75° C. and stirred for 1 h. After allowing to cool to room temperature the mixture was poured into water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined organic extracts were washed with brine (1×100 mL), dried (magnesium sulfate), filtered and the solvent removed under vacuum to leave the crude product which was used immediately.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=O)[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH3:2].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>>[CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[S:24])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1)[CH3:2]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CCN(CC)C(=O)c1cccc(F)c1
Product: CCN(CC)C(=S)c1cccc(F)c1
Yield: 142 %

Procedure:
A mixture of N,N-diethyl-3-fluorobenzamide (4.69 g, 24 mmol) (cf Mills, et al., "Directed Ortho Metalation of N,N-Diethylbenzamides. Silicon Protection of Ortho Sites and the o-Methyl Group," J. of Organic Chemistry 54: 4372-4385, 1989), Lawesson's reagent (6.47 g, 16 mmol) and xylenes (150 mL) was refluxed overnight, then was concentrated and kugelrohr distilled (105-110° C. at 0.25 torr) to yield 4.8 g N,N-diethyl-3-(fluoro)thiobenzamide as a yellow oil, a 95% yield.
Reaction SMILES: [OH-].[Na+].C([O:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[CH:10][N:9]=1)(=O)C.CC1C(C)=C(OC)C(C)=C[N+]=1[O-]>>[OH:6][CH2:7][C:8]1[C:13]([CH3:14])=[C:12]([O:15][CH3:16])[C:11]([CH3:17])=[CH:10][N:9]=1
Reactant: COc1c(C)cnc(COC(C)=O)c1C
Agent: COc1c(C)c[n+]([O-])c(C)c1C
Agent: [Na+]
Agent: [OH-]
Product: COc1c(C)cnc(CO)c1C
Yield: 92.4 %

Procedure:
30% aqueous sodium hydroxide was added over a solution of crude 2-acetoxymethyl-3,5-dimethyl-4-methoxypyridine prepared from 30.06 g (0.18 mole) of 2,3,5-trimethyl-4-methoxypyridine N-oxide, to pH 13. The mass was stirred for about 3.5 hours at 25°-28° C., with addition of 30% aqueous sodium hydroxide at the appropriate rate to hold the pH to between 11.7 and 13. Once the reaction was terminated (complete disappearance of the band located towards 1700 cm-1) the pH was adjusted to 6.5 with acetic acid, water was added and the mass was extracted with methylene chloride. The solvent was removed by vacuum distillation and finally 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine was distilled at 142°-145° C. (9 torr.) as a colourless liquid which crystallised on standing. 27.23 g were obtained. Yield 92.4%.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18]([C:21]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([CH:47]=[CH:48][CH:49]=2)[C:43]([O:45]C)=O)=[N:8]1.O.[OH-].[Li+].[CH3:53][C@@H:54]([NH2:61])[C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1.O.ON1C2C=CC=CC=2N=N1>O1CCCC1.O1CCCC1.O>[C:55]1([C@H:54]([NH:61][C:43]([C:42]2[CH:47]=[CH:48][CH:49]=[C:40]([C:9]3[C:10]4[C:15](=[CH:14][CH:13]=[C:12]([C:16]5[N:20]=[CH:19][N:18]([C:21]([C:22]6[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=6)([C:28]6[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=6)[C:34]6[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=6)[N:17]=5)[CH:11]=4)[N:7]([CH:2]4[CH2:3][CH2:4][CH2:5][CH2:6][O:1]4)[N:8]=3)[CH:41]=2)=[O:45])[CH3:53])[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1
Reactant: C[C@@H](N)c1ccccc1
Reactant: COC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: On1nnc2ccccc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@@H](NC(=O)c1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 18 h
Yield: 86.4 %

Procedure:
To a stirred solution of methyl 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}benzoate (0.400 g, 0.619 mmol) in a tetrahydrofuran/water mixture (2.50 mL/1.00 mL) was added lithium hydroxide monohydrate (0.0780 g, 1.86 mmol) and the mixture heated at 60° C. for 21 h. To this mixture was added tetrahydrofuran (2.00 mL), (R)-(+)-α-methylbenzyl amine (0.240 mL, 1.86 mmol), 1-hydroxybenzotriazole hydrate (0.251 g, 1.86 mmol) and 1-(3-dimethylaminopropyl)-3-ethyl hydrochloride (0.356 g, 1.86 mmol). This mixture was stirred for 18 h at ambient temperature. After the mixture was extracted with ethyl acetate (2×), the combined organic extracts were washed with aqueous saturated sodium bicarbonate, followed by brine, dried over anhydrous sodium sulfate, filtered and evaporated. Purification of the residue by flash chromatography with 30–60% ethyl acetate/hexanes gave the title compound (0.393 g, 86% yield). ES-MS (m/z) 493 [M+1(−Tr)]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:31][CH:32]([CH3:34])[CH3:33]>CN(C)C(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([S:8]([N:11]([CH2:31][CH:32]([CH3:34])[CH3:33])[CH2:12][C:13]2[S:14][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([S:24]([CH3:27])(=[O:26])=[O:25])[CH:19]=3)=[CH:16][CH:17]=2)(=[O:9])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CBr
Reactant: CS(=O)(=O)c1cccc(-c2ccc(CNS(=O)(=O)c3cccc(Cl)c3)s2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: CC(C)CN(Cc1ccc(-c2cccc(S(C)(=O)=O)c2)s1)S(=O)(=O)c1cccc(Cl)c1

Procedure:
In analogy to example 1, step 2, 3-chloro-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide (example 7, step 2) was reacted with sodium hydride in N,N-dimethylacetamide at 0° C. followed by reaction with 1-bromo-2-methylpropane at r.t. overnight to give 3-chloro-N-isobutyl-N-[5-(3-methanesulfonyl-phenyl)-thiophen-2-ylmethyl]-benzenesulfonamide as a colorless solid. MS: 515.3 ([M+NH4]+)
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([OH:14])[C@@H:11]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:17][CH:16]=2)[C@H:10]([O:25][CH2:26][C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:37]=[C:38]([O:46][CH3:47])[C:39]2[C:44]([CH:45]=1)=[CH:43][CH:42]=[CH:41][CH:40]=2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([O:14][CH2:35][C:36]2[CH:37]=[C:38]([O:46][CH3:47])[C:39]3[C:44](=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH:45]=2)[C@@H:11]([C:15]2[CH:16]=[CH:17][C:18]([O:21][CH2:22][CH:23]=[CH2:24])=[CH:19][CH:20]=2)[C@H:10]([O:25][CH2:26][C@H:27]2[CH2:31][O:30][C:29]([CH3:33])([CH3:32])[O:28]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: C=CCOc1ccc([C@@H]2[C@@H](O)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1
Reactant: COc1cc(CCl)cc2ccccc12
Product: C=CCOc1ccc([C@@H]2[C@@H](OCc3cc(OC)c4ccccc4c3)CN(C(=O)OC(C)(C)C)C[C@H]2OC[C@H]2COC(C)(C)O2)cc1

Procedure:
In analogy to the procedure described in example 1) (f) the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(4S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-hydroxy-piperidine-1-carboxylic acid tert-butyl ester was reacted with 3-chloromethyl-1-methoxy-naphthalene [example 1) (α)] to yield the (3S,4R,5R)-4-(4-allyloxy-phenyl)-3-[(S)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy]-5-(4-methoxy-naphthalen-2-ylmethoxy)-piperidine-1-carboxylic acid tert-butyl ester as colorless oil; MS: 634(M+H)+.
Reaction SMILES: B1(B2C3CCCC2CCC3)C2CCCC1CCC2.C12CCCC(CCC1)B12[H]B2(C3CCCC2CCC3)[H]1.[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH:43]=[CH2:44].ClCCl.[Br:49][C:50]1[CH:55]=[CH:54][CH:53]=[C:52](Br)[CH:51]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCCC1.[Pd](Cl)Cl.O.CN(C)C=O>[CH3:39][O:40][C:41](=[O:45])[CH2:42][CH2:43][CH2:44][C:52]1[CH:53]=[CH:54][CH:55]=[C:50]([Br:49])[CH:51]=1
Reactant: Brc1cccc(Br)c1
Reactant: C=CCC(=O)OC
Agent: Cl[Pd]Cl
Agent: C1CC2CCCC(C1)B2B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)CCCc1cccc(Br)c1
Reaction time: 4 h
Yield: 0 %

Procedure:
[9-Borabicyclo[3.3.1]nonane dimer] (13.4 mL, 6.68 mmol) (9-BBN dimer) was added to a solution of methyl-3-butenoate (0.71 mL, 6.68 mmol) in tetrahydrofuran (2.7 mL) at 0-5° C. under an argon atmosphere, and the mixture was stirred for 4 hours. N,N-Dimethylformamide (27 mL), palladium(II) chloride, dichloromethane (130 g, 0.16 mmol), 1,3-dibromobenzene (0.77 mL, 61.37 mmol) and potassium phosphate (powdered, 1.5 g, 6.94 mmol) were added. The mixture was treated at 50° C. overnight. Water was added and the mixture extracted with diethyl ether. The extract was washed with water, brine, and dried over sodium sulfate, and concentrated to dryness. Purification by flash chromatography, eluting with hexane/ethyl acetate) gave 4-(3-bromophenyl)butyric acid methyl ester as a clear oil (0.26 mg, 16%).
Reaction SMILES: [CH2:1]([C:9]1[CH:10]([C:12]([O:14]CC)=[O:13])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[OH-].[K+]>CCOCC>[CH2:1]([C:9]1[CH:10]([C:12]([OH:14])=[O:13])[CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCCCCC1=CC1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCOCC
Product: CCCCCCCCC1=CC1C(=O)O
Yield: 81.5 %

Procedure:
Ethyl 2-octylcycloprop-2-ene-1-carboxylate (1.12 g, 5 mmol) and 100 ml of 0.2 N potassium hydroxide were stirred at room temperature for one week. Ether was added and the phases were separated. The aqueous phase was acidified and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and stripped to give 0.8 g of 2-octylcycloprop-2-ene-1-carboxylic acid.
Reaction SMILES: [C:1]([N:4]1[C:13]2[N:12]=[CH:11][C:10]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([CH:22]=3)[C:19]([OH:21])=[O:20])=[CH:9][C:8]=2[CH2:7][CH2:6][CH2:5]1)(=[O:3])[NH2:2].[CH3:23][Si](C=[N+]=[N-])(C)C>C1(C)C=CC=CC=1.CO>[CH3:23][O:20][C:19](=[O:21])[C:18]1[CH:22]=[C:14]([C:10]2[CH:11]=[N:12][C:13]3[N:4]([C:1](=[O:3])[NH2:2])[CH2:5][CH2:6][CH2:7][C:8]=3[CH:9]=2)[CH:15]=[N:16][CH:17]=1
Reactant: NC(=O)N1CCCc2cc(-c3cncc(C(=O)O)c3)cnc21
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cncc(-c2cnc3c(c2)CCCN3C(N)=O)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 32 %

Procedure:
To the solution of 5-(8-Carbamoyl-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)-nicotinic acid (100 mg, 0.33 mmol) in 12 mL of toluene/MeOH 3:1 mixture is added 2.0 M trimethylsilyl-diazomethane (0.20 mL, 0.40 mmol) under N2 atmosphere. The reaction solution is stirred at room temperature for 16 hrs. The solvents are removed in vacuo and the residue is purified by preparative HPLC to give 33 mg of the titled product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[NH:5][C:6]1[NH:7][C:8](=[O:17])[C:9]([C:12]([O:14]CC)=[O:13])=[CH:10][N:11]=1.[OH-].[Na+].O>C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][C:4]=1[NH:5][C:6]1[NH:7][C:8](=[O:17])[C:9]([C:12]([OH:14])=[O:13])=[CH:10][N:11]=1
Reactant: CCOC(=O)c1cnc(Nc2cc(OC)ccc2OC)[nH]c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)O
Product: COc1ccc(OC)c(Nc2ncc(C(=O)O)c(=O)[nH]2)c1
Reaction time: 1 h
Yield: 67.6 %

Procedure:
Ethyl 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylate (6 g) and sodium hydroxide (2 g) are added to water (100 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the reaction mixture is acidified with acetic acid, and the resulting solid is collected by filtration and recrystallized from DMF. The precipitate is collected by filtration and added to water (50 ml), and the mixture is refluxed with stirring for 1 hour. After cooling, the resulting product is collected by filtration and dried at 80° C. under reduced pressure to give 1,6-dihydro-2-(2,5-dimethoxyanilino)-6-oxo-5-pyrimidinecarboxylic acid (3.7 g). M.p. 260°-262° C.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[O:10]2)=[CH:5][CH:4]=1.Br.C(=O)(O)[O-].[Na+]>O>[OH:2][C:3]1[CH:4]=[CH:5][C:6]([CH:9]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:11]3([CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]3)[O:10]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2OC3(CCN(C)CC3)c3ccccc32)cc1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CN1CCC2(CC1)OC(c1ccc(O)cc1)c1ccccc12

Procedure:
A solution of 3.5 g. of 1,3-dihydro-3-(4-methoxyphenyl)-1'-methylspiro[isobenzofuran-1,4'-piperidine], (Example 12), and 20 ml. of 48% hydrobromic acid is heated under reflux, cooled, diluted with water, neutralized with sodium bicarbonate, and extracted with chloroform. The chloroform solution is dried over magnesium sulfate and concentrated to an oil. Trituration with ether provides crystals, m.p. 132°dec. Recrystallization raises the melting point to 273°dec.
Reaction SMILES: [C:1]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=[C:21]([C:27]([O:29]CC)=[O:28])[C:22]([O:24]CC)=[O:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13].[OH-].[K+]>O>[C:1]([C:14]1[CH:15]=[N:16][CH:17]=[CH:18][C:19]=1[CH:20]=[C:21]([C:27]([OH:29])=[O:28])[C:22]([OH:24])=[O:23])#[C:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: CCCCCCCCCCCC#Cc1cnccc1C=C(C(=O)OCC)C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CCCCCCCCCCCC#Cc1cnccc1C=C(C(=O)O)C(=O)O
Yield: 335.3 %

Procedure:
Diethyl 2-[3-(1-tridecynyl)-4-pyridyl]methylenepropane-1,3-dioate (0.47 g, 1.1 mmole, from Example 3) was added to a solution of potassium hydroxide (0.66 g) in water (7.5 ml) and the mixture was heated to reflux for 24 hours. The resulting clear solution was then acidified at 0° C. and the precipitated product was filtered off and washed with water. Recrystallisation of the dried material from ethyl acetate gave 1.37 g (34%) of the title compound, mp 175°-177° C., νmax (mull) 2500 (broad), 1740 cm-1 ; δ(DMSO) 0.84 (3H, distorted t, terminal CH3), 1.20 (14H, m, alkylene chain), 1.42 (2H, m, CH2 (CH2)2C≡C), 1.57 (2H, m, CH2CH2C≡C), 2.50 (2H, t, CH2C≡C), 7.41 (2H, d, J 5.1 Hz, C-5H), 7.74 (1H, s, Ar CH=C), 8.56 (1H, d, J 5.1 Hz, C-6H), 8.67 (1H, d, J 0.5 Hz, C-2H), 13.73 (2H, broad exchangeable, CO2H).
Reaction SMILES: C(O[C:4](=[O:19])[C@@H:5]([NH2:18])[C@@H:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[OH:7])C.[BH4-].[K+].N[C@H:23]([CH2:36]O)[C@@H:24](C1C=CC(S(C)(=O)=O)=CC=1)O.C(N(CC)CC)C>CO.CC(C)=O.C1(C)C=CC=CC=1>[CH3:24][C:23]1([CH3:36])[NH:18][C@H:5]([CH2:4][OH:19])[C@@H:6]([C:8]2[CH:9]=[CH:10][C:11]([S:14]([CH3:17])(=[O:15])=[O:16])=[CH:12][CH:13]=2)[O:7]1
Reactant: CS(=O)(=O)c1ccc([C@@H](O)[C@H](N)CO)cc1
Reactant: CCOC(=O)[C@@H](N)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: [BH4-]
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: Cc1ccccc1
Product: CC1(C)N[C@H](CO)[C@@H](c2ccc(S(C)(=O)=O)cc2)O1
Temperature: 75 °C

Procedure:
(2S,3R)-Ethyl-2-amino-3-[4-(methylsulfonyl)phenyl]-3-hydroxy-propanoate (Compound IV) (100 g, 0.3480 moles) in methanol (450 mL) reacts with potassium borohydride (28.2 g, 0.5220 moles) over 4-8 hours at 50-60° C. to quantitatively yield (1R,2R)-2-amino-1-[4-(methylsulfonyl)phenyl]-1,3-propandiol (Compound VII: R1 is methylsulfonyl) (85.4 g, 0.3480 moles) in solution. Toluene (450 mL) and acetone (450 mL) replace methanol which distills off. Addition of triethylamine (8.8 g, 0.0870 moles) with heating at 70-80° C. for 12-18 hours yields (4R,5R)-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound VIII: R1 is methylsulfonyl and R2 and R3 are methyl). Addition of triethylamine (44.5 g, 0.4402 moles) and acetyl chloride (30.0 g, 0.3828 moles) at 20-25° C. for 2-4 hours then addition of water (500 mL) precipitates the crude product. Filtration, washing with water (200 mL) then drying yields (4R,5R)-3-acetyl-2,2-dimethyl-4-hydroxymethyl-5-[4-(methylsulfonyl)phenyl]-1,3-oxazolidine (Compound II).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30](Br)[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[F:35][C:36]1[C:37]([O:45][CH3:46])=[C:38](B(O)O)[CH:39]=[CH:40][CH:41]=1>Cl[Pd]Cl.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]>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:38]5[CH:39]=[CH:40][CH:41]=[C:36]([F:35])[C:37]=5[O:45][CH3:46])[N:29]=4)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1c(F)cccc1B(O)O
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Br)n4)cc3)cc2)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(-c5cccc(F)c5OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 1, Step 10, using 1-{4′-[4-(6-bromo-pyridin-2-ylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and 3-fluoro-2-methoxyphenylboronic acid. (1,1′-Bis(diphenylphosphino)ferrocene)-dichloropalladium(II) was used in place of tetrakis(triphenylphosphine)palladium(0).