Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([CH2:15][O:16][C:17]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:11][CH:10]2[O:43][CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)=[CH:5][CH:4]=1.[CH2:55]([N:62]=[C:63]=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1>>[CH2:55]([NH:62][C:63]([O:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH:14]([CH2:15][O:16][C:17]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:13][N:12]([C:36]([O:38][C:39]([CH3:42])([CH3:40])[CH3:41])=[O:37])[CH2:11][CH:10]2[O:43][CH2:44][C:45]2[CH:54]=[CH:53][C:52]3[C:47](=[CH:48][CH:49]=[CH:50][CH:51]=3)[CH:46]=2)=[CH:5][CH:4]=1)=[O:64])[C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=1
Reactant: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: O=C=NCc1ccccc1
Product: CC(C)(C)OC(=O)N1CC(COC(c2ccccc2)(c2ccccc2)c2ccccc2)C(c2ccc(COC(=O)NCc3ccccc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 24 (m), reaction of tert-butyl (3RS,4RS,5SR)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate with benzyl isocyanate gave tert-butyl (3RS,4RS,5SR)-4-(4-benzylcarbamoyloxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-5-trityloxymethyl-piperidine-1-carboxylate, from which by cleavage of the trityl group by means of a mixture of trifluoroacetic acid and trifluoroacetic anhydride in methylene chloride analogously to Example 86 (u) there was obtained tert-butyl (3SR,4RS,5RS)-4-(4-benzylcarbamoyloxymethyl-phenyl)-3-hydroxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate. Subsequent alkylation with methyl iodide analogously to Example 1 (g) yielded tert-butyl (3SR,4RS,5RS)-4-[4-[(benzyl-methyl-carbamoyloxy)-methyl]-phenyl]-3-methoxymethyl-5-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 656 (M+NH4)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[CH:9][N:10]=2)[CH:7]=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([N:25]2[C:29](B3OC(C)(C)C(C)(C)O3)=[CH:28][CH:27]=[N:26]2)=[CH:21][CH:20]=1>>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C:8]2[N:6]3[CH:7]=[C:2]([C:29]4[N:25]([C:22]5[CH:23]=[CH:24][C:19]([Cl:18])=[CH:20][CH:21]=5)[N:26]=[CH:27][CH:28]=4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:12][CH:13]=1
Reactant: CC1(C)OB(c2ccnn2-c2ccc(Cl)cc2)OC1(C)C
Reactant: Clc1ccc(-c2cnc3ccc(Br)cn23)cc1
Product: Clc1ccc(-c2cnc3ccc(-c4ccnn4-c4ccc(Cl)cc4)cn23)cc1

Procedure:
The title compound, off-white solid (41 mg, 31%), MS (ISP) m/z=405.3 [(M+H)+], mp 172.5° C., was prepared in accordance with the general method of example 1 from 6-bromo-3-(4-chloro-phenyl)-imidazo[1,2-a]pyridine (intermediate F) (0.1 g, 0.325 mmol) and 1-(4-chloro-phenyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrazole (intermediate B) (0.12 g, 0.39 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[C:15]([O:20]C)[CH:16]=3)[CH:11]=2)[N:9]=1.Br>CC(O)=O>[Cl:26][C:22]1[CH:23]=[CH:24][CH:25]=[C:2]([Cl:1])[C:3]=1[CH2:4][C:5]1[S:6][CH:7]=[C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[CH:16]=[C:15]([OH:20])[CH:14]=[CH:13]3)[N:9]=1
Reactant: COc1ccc2cc(-c3csc(Cc4c(Cl)cccc4Cl)n3)ccc2c1
Agent: Br
Solvent: CC(=O)O
Product: Oc1ccc2cc(-c3csc(Cc4c(Cl)cccc4Cl)n3)ccc2c1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
A solution of 2-(2,6-dichlorobenzyl)-4-(6-methoxy-2-naphthyl)-1,3-thiazole (390 mg, 0.975 mmol), prepared in the previous step, in 50 mL of glacial HOAc plus 25 mL of 48% HBr was stirred under nitrogen at 120° C. for 3.5 h and then stood overnight at room temperature. The reaction was concentrated under reduced pressure. The residue was dissolved in 20% methanol-methylene chloride and neutralized with the addition of an excess of 5% NaHCO3. The aqueous layer was separated and extracted three times with 20% methanol-methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give 6-[2-(2,6-dichlorobenzyl)-1,3-thiazol-4-yl]-2-naphthol (303 mg, 80%) as a brown solid, mp 191-193° C. Elemental Analysis for C20H13Cl2NOS Calc'd: C, 62.19; H, 3.39; N, 3.63. Found: C, 61.31; H, 3.30; N, 3.42.
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]#[CH:10])[N:6]=[N:5][C:4]2=[C:11]([C:14](=[S:16])[NH2:15])[N:12]=[CH:13][N:3]12.Br[CH2:18][C:19]([C:21]1[S:22][CH:23]=[CH:24][CH:25]=1)=O>CC#N>[CH2:8]([N:7]1[C:2](=[O:1])[N:3]2[CH:13]=[N:12][C:11]([C:14]3[S:16][CH:18]=[C:19]([C:21]4[S:22][CH:23]=[CH:24][CH:25]=4)[N:15]=3)=[C:4]2[N:5]=[N:6]1)[C:9]#[CH:10]
Reactant: O=C(CBr)c1cccs1
Reactant: C#CCn1nnc2c(C(N)=S)ncn2c1=O
Solvent: CC#N
Product: C#CCn1nnc2c(-c3nc(-c4cccs4)cs3)ncn2c1=O
Yield: 73 %

Procedure:
4-Oxo-3-(prop-2-ynyl)-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carbothioamide (0.43 mmol) and 2-bromo-1-(2-thienyl)-1-ethanone (0.43 mmol) were stirred in dry MeCN (2 mL) at room temperature overnight. A precipitate formed which was filtered off and treated with basic ion exchange resin. After removal of the resin, the liquor was recombined with the original filtrate and evaporated to dryness before being purified by column chromatography eluting with 5% MeCN/DCM to give the title compound. Yield 73%. δH (DMSO-d6) 8.95 (1H, s), 8.16 (1H, s) 7.67 (1H, dd, J=3.6, 1.2), 7.58 (1H, dd, J=4.8, 1.2), 7.16 (1H, dd, J=4.8, 3.6), 5.14 (2H, d, J=2.4), 3.53 (1H, t, J=2.4).
Reaction SMILES: [CH3:1][CH:2]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[C:22](O)=[O:23])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:57][O:58][C:59](=[O:64])[C:60]([NH2:63])([CH3:62])[CH3:61]>CN(C=O)C>[CH3:57][O:58][C:59](=[O:64])[C:60]([CH3:62])([NH:63][C:22]([C:13]1[CH:14]=[CH:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:12]=1[O:11][CH:2]([CH3:1])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:23])[CH3:61]
Reactant: COC(=O)C(C)(C)N
Reactant: CC(COc1ccccc1)Oc1c(C(=O)O)ccc2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccccc2c1OC(C)COc1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of 100 mg—(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carboxylic acid in 1.5 ml abs. DMF under inert atmosphere 45 mg 1-hydroxybenzotriazole, 83 mg 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 70 μl of N,N-diisopropylethylamine were added at 0° C. After 30 minutes at 0° C. 36 mg of 2-aminoisobutyric acid methyl ester hydrochloride, followed by 70 μl of N,N-diisopropylethylamine were added. After 16 h at room temperature the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 114 mg of 2-methyl-2-{[1-(1-methyl-2-phenoxy-ethoxy)-naphthalene-2-carbonyl]-amino}-propionic acid methyl ester.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32](Cl)=[O:33])[C:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:39]1([CH2:45][CH2:46][N:47]2[CH2:52][CH2:51][O:50][CH2:49][CH2:48]2)[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:42]3[CH2:41][CH2:40][N:39]([CH2:45][CH2:46][N:47]4[CH2:48][CH2:49][O:50][CH2:51][CH2:52]4)[CH2:44][CH2:43]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:35][CH:36]([CH3:38])[CH3:37])[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)Oc1cc(C(C)(C)C)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Reactant: C1CN(CCN2CCOCC2)CCN1
Product: CC(C)Oc1cc(C(C)(C)C)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCN2CCOCC2)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-2-(4-tert-butyl-2-isopropoxy-phenyl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with 4-(2-piperazin-1-yl-ethyl)-morpholine (Aldrich) to give the title compound. HR-MS (ES, m/z) calculated for C41H54N5O3Cl2 [(M+H)+] 734.3598, observed 734.3600.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=1)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH2:18][CH2:17]1)=[O:11])=[O:6].[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH:46]=O)=[CH:44][CH:43]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO>[OH:41][C:42]1[CH:49]=[CH:48][C:45]([CH2:46][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[CH:8]=[C:9]([CH:38]=[CH:39][CH:40]=2)[C:10]([CH2:12][NH:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH:19]([O:22][C:23](=[O:37])[NH:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH2:18][CH2:17]2)=[O:11])=[O:6])=[CH:44][CH:43]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: NCCNC(=O)c1cccc(C(=O)CNCCN2CCC(OC(=O)Nc3ccccc3-c3ccccc3)CC2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Product: O=C(Nc1ccccc1-c1ccccc1)OC1CCN(CCNCC(=O)c2cccc(C(=O)NCCNCc3ccc(O)cc3)c2)CC1

Procedure:
A solution of biphenyl-2-ylcarbamic acid 1-(2-{[3-(2-aminoethylcarbamoyl)benzoyl]methylamino}ethyl)piperidin-4-yl ester (9.31 g, 17.1 mmol; prepared as described in Preparation 8) and 4-hydroxybenzaldehyde (2.30 g, 18.8 mmol, 1.1 eq) in 125 mL MeOH was stirred at room temperature for 2 hours. Na(OAc)3BH (7.26 g, 34.2 mmol, 2.0 eq) was added to the reaction at room temperature in two portions separated in one hour interval. The reaction was stirred for an additional hour before being concentrated under vacuum. The residue was taken up in 100 mL DCM and stirred with 100 mL of 1.0 N HCl for 1 hour. The aqueous phase was adjusted to pH 9 using 10.0 N NaOH. The mixture was stirred for an additional 10 minutes. The organic phase was separated, dried over Na2SO4, filtered and concentrated under vacuum. The crude material was purified using silica gel chromatography (7% MeOH in CH2Cl2 with 1% NH4OH as eluent). The title compound was obtained as an off-white solid (8.08 g, 73%). MS m/z: [M+H+] calcd for C38H43N5O5, 650.34. found, 650.2.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:42][C:43]1[CH:44]=[C:45]([CH:50]2[CH2:55][NH:54][CH2:53][CH:52]([NH:56][C:57](=[O:64])[C:58]3[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=3)[CH2:51]2)[CH:46]=[CH:47][C:48]=1[CH3:49]>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:42][C:43]1[CH:44]=[C:45]([CH:50]2[CH2:51][CH:52]([NH:56][C:57]([C:58]3[CH:59]=[CH:60][CH:61]=[CH:62][CH:63]=3)=[O:64])[CH2:53][N:54]([C:15]([C:9]3([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)=[O:17])[CH2:55]2)[CH:46]=[CH:47][C:48]=1[CH3:49]
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCOCC1
Reactant: Cc1ccc(C2CNCC(NC(=O)c3ccccc3)C2)cc1C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Product: Cc1ccc(C2CC(NC(=O)c3ccccc3)CN(C(=O)C3(NC(=O)OC(C)(C)C)CCOCC3)C2)cc1C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
75 mg (0.3 mmol) of 4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-carboxylic acid together with 110 mg (0.3 mmol) of HATU and 47 mg (0.4 mmol) of 4-dimethylaminopyridine were initially charged in 2 ml of DMF, and 60 mg (0.2 mmol) of N-[5-(3,4-dimethylphenyl)piperidin-3-yl]benzamide were added. The reaction mixture was stirred overnight at RT and then purified by preparative HPLC (Reprosil C18, water/acetonitrile gradient). Yield: 46 mg (44% of theory)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]=[CH:13][N:14]([CH3:16])[CH3:15])(=[O:11])=[O:10])=[CH:5][C:4]=1[CH2:17]Cl.[CH3:19][C:20]1([CH3:28])[CH2:25][CH:24]([CH3:26])[CH2:23][CH:22]([NH2:27])[CH2:21]1>C(Cl)Cl>[CH3:15][N:14]([CH:13]=[N:12][S:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:17][NH:27][CH:22]2[CH2:23][CH:24]([CH3:26])[CH2:25][C:20]([CH3:28])([CH3:19])[CH2:21]2)[CH:5]=1)(=[O:11])=[O:10])[CH3:16]
Reactant: COc1ccc(S(=O)(=O)N=CN(C)C)cc1CCl
Reactant: CC1CC(N)CC(C)(C)C1
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N=CN(C)C)cc1CNC1CC(C)CC(C)(C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 0.2 g of 4-methoxy-3-chloromethyl-N-dimethylaminomethylenephenylsulfon-amide, 0.37 ml of 3,3,5-trimethylcyclohexylamine and 5 ml of methylene chloride is stirred at RT for 24 hours and then concentrated in vacuo.
Reaction SMILES: [OH:1][C:2]1([C:9]2[CH:20]=[CH:19][C:12]3[N:13]([CH3:18])[C:14](=[O:17])[N:15]([CH3:16])[C:11]=3[CH:10]=2)[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:21]1[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:39])[F:38])[CH:32]=2)=[O:27])[CH2:22]1>>[CH3:18][N:13]1[C:12]2[CH:19]=[CH:20][C:9]([C:2]3([OH:1])[CH2:7][CH2:6][CH:5]([N:21]4[CH2:24][CH:23]([NH:25][C:26]([CH2:28][NH:29][C:30](=[O:41])[C:31]5[CH:36]=[CH:35][CH:34]=[C:33]([C:37]([F:40])([F:38])[F:39])[CH:32]=5)=[O:27])[CH2:22]4)[CH2:4][CH2:3]3)=[CH:10][C:11]=2[N:15]([CH3:16])[C:14]1=[O:17]
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CNC1
Reactant: Cn1c(=O)n(C)c2cc(C3(O)CCC(=O)CC3)ccc21
Product: Cn1c(=O)n(C)c2cc(C3(O)CCC(N4CC(NC(=O)CNC(=O)c5cccc(C(F)(F)F)c5)C4)CC3)ccc21

Procedure:
The title compound was prepared as a white solid by reductive amination of 5-(1-hydroxy-4-oxo-cyclohexyl)-1,3-dimethyl-1,3-dihydro-benzoimidazol-2-one (as prepared in the previous step) and N-(azetidin-3-ylcarbamoylmethyl)-3-trifluoromethyl-benzamide (as prepared in step B of Example 4) using the procedure described in Step C of Example 4.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:4]=[C:5]([C:12]([O:14]C)=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2.[OH-].[Li+]>CO.O1CCCC1>[F:17][C:2]([F:1])([F:16])[C:3]1[CH:4]=[C:5]([C:12]([OH:14])=[O:13])[CH:6]=[C:7]2[C:11]=1[NH:10][N:9]=[CH:8]2
Reactant: COC(=O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1cc(C(F)(F)F)c2[nH]ncc2c1
Temperature: 60 °C
Yield: 29.5 %

Procedure:
To a solution of methyl 7-(trifluoromethyl)-1H-indazole-5-carboxylate (62 mg, 0.25 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1 N aqueous lithium hydroxide (0.76 mL, 0.76 mmol). The reaction was heated to 60° C. for 17 hours. The reaction was concentrated and the residue was diluted with water and acidified to pH=3 with 1 N aqueous hydrochloric acid. The solution was extracted with dichloromethane (3×). The combined organics were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give the title compound (17 mg, 29%) as an off-white powder. +ESI (M+H) 231.1.
Reaction SMILES: [C:1]([C:3]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([O:13]C)=[O:12])[C:6]([CH3:15])=[N:5][C:4]=1[S:16][CH3:17])#[N:2].[OH-].[Na+]>CO>[C:1]([C:3]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([OH:13])=[O:12])[C:6]([CH3:15])=[N:5][C:4]=1[S:16][CH3:17])#[N:2]
Reactant: COC(=O)Cn1c(C)nc(SC)c(C#N)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CSc1nc(C)n(CC(=O)O)c(=O)c1C#N
Temperature: 30 °C
Yield: 69.7 %

Procedure:
To a suspension of methyl 5-cyano-1,6-dihydro-2-methyl-4-(methylthio)-6-oxo-1-pyrimidineacetate (2.3 g, 9.0 mmol) in methanol (6 mL) was added 3 N NaOH (3.3 mL, 9.9 mmol). The mixture was warmed to 30° C. for 1.5 hours, then concentrated to remove the methanol. The residue was dissolved in water (20 mL) and neutralized with 3 NHCl (3.3 mL, 9.9 mmol). The resulting precipitate was collected by filtration, and recrystallized from methanol/ether/hexane (twice) to yield pure product (1.5 g, 35%) m.p. 236°-238° C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[CH2:5][C:6]#[N:7])[CH3:2].[CH2:11]([O:13]C=O)C.[Na:16]>CCOCC>[Na:16].[CH2:1]([O:3][CH:4]([O:8][CH2:9][CH3:10])[C:5](=[CH:11][OH:13])[C:6]#[N:7])[CH3:2]
Reactant: CCOC(CC#N)OCC
Reactant: CCOC=O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(OCC)C(C#N)=CO

Procedure:
A mixture of 40.9 . of cyanacetaldehyde diethylacetal, 26.2 g. of formic acid ethyl ester and 100 ml. of absolute ether are added dropwise with stirring to a suspension of 7.4 g. of powdered sodium in 500 ml. of absolute ether. The mixture is stirred at room temperature until disappearance of the sodium (16 hours). Then, the brown precipitate formed (crude sodium salt of hydroxymethylene-cyanacetaldehyde diethylacetal) is left to settle and the supernatant solution is removed by decantation. The residue is washed by decanting twice with 200 ml. of absolute ether each time. The product is stored at 0° C. under absolute ether, since it changes on drying.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([CH:7]([OH:26])[CH:8]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:25])([F:24])[CH:21]([F:23])[F:22])[CH:14]=2)C(O)=O)=[CH:4][CH:3]=1.C([N:29]([CH2:32]C)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=[O:41])C=CC=CC=1>O1CCCC1>[Cl:1][C:2]1[S:6][C:5]([CH:7]2[O:26][C:32](=[O:41])[NH:29][CH:8]2[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][C:20]([F:24])([F:25])[CH:21]([F:22])[F:23])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: O=C(O)C(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1ccc(Cl)s1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: O=C1NC(Cc2cccc(OC(F)(F)C(F)F)c2)C(c2ccc(Cl)s2)O1

Procedure:
To a solution of (2RS,3RS)-3-(5-chloro-2-thienyl)-3-hydroxy-2-[3-(1,1,2,2 tetrafluoroethoxy)benzyl]propionic acid (8.996 g, 21.79 mmol) in tetrahydrofuran (80 ml) were added triethylamine (3.65 ml, 26.2 mmol) and diphenylphosphoryl azide (6.60 g, 24.0 mmol), and the mixture was heated under reflux overnight. The solvent of the reaction solution was evaporated under reduced pressure and the obtained crude product was purified by silica gel column chromatography (hexane/ethyl acetate=3/1-1/1) to give the objective substance.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH:13]1C(=O)OC(C)(C)[O:15][C:14]1=[O:22])[CH2:11][CH3:12].CN(C=O)C.O>CCOCC>[F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:10]([CH2:11][CH3:12])[CH2:13][C:14]([OH:22])=[O:15]
Reactant: CCC(c1cccc(OC)c1F)C1C(=O)OC(C)(C)OC1=O
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CCC(CC(=O)O)c1cccc(OC)c1F
Temperature: 90 °C
Reaction time: 8 h
Yield: 91 %

Procedure:
A 500 mL round bottom flask was charged with 5-(1-(2-fluoro-3-methoxyphenyl)propyl)-2,2-dimethyl-1,3-dioxane-4,6-dione 77.C (5.17 g, 16.7 mmol) and 10:1 DMF/water (80 mL). The pale yellow solution was stirred overnight at 90° C., cooled to room temperature, and diluted with ether. The combined organic layers were washed with water and brine, dried (MgSO4), and concentrated to afford 3-(2-fluoro-3-methoxyphenyl)pentanoic acid 77.D (3.44 g, 91.3% yield) as a yellow oil. The crude product was used without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[CH:6]=[CH:7][CH:8]=1.Cl.N1C=CC=CC=1.[OH-].[Na+]>O>[N:10]1[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=1[C:5]1[CH:4]=[C:3]([OH:2])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(-c2ccccn2)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: c1ccncc1
Product: Oc1cccc(-c2ccccn2)c1
Temperature: 190 °C
Reaction time: 8 h

Procedure:
To a 500 mL round bottom flask was added 2-(3-methoxyphenyl)pyridine (21.3 g, 115 mmol) and pyridine hydrochloride (107.5 g, 930 mmol). The reaction mixture was heated to 190° C. for 8 hours under nitrogen. The reaction mixture was cooled slightly and water was added. The mixture was stirred overnight. The pH of the solution was adjusted to 7 with 10% sodium hydroxide solution, extracted three times with dichloromethane. The organic layers were washed with 10% LiCl solution, brine, dried over magnesium sulfate, filtered, and evaporated. The residue was distilled on a Kugelrohr to remove the remaining pyridine (18 g, 91%).
Reaction SMILES: C(N(CC)CC)C.ClC(O[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[CH3:19][O:20][C:21](=[O:43])[CH2:22][NH:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]2[CH:39]=[CH:38][C:37]([C:40]#[N:41])=[CH:36][CH:35]=2)=[CH:26][CH:25]=1>C(Cl)(Cl)Cl>[CH3:19][O:20][C:21](=[O:43])[CH2:22][N:23]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:24]1[CH:25]=[CH:26][C:27]([CH2:30][CH2:31][NH:32][C:33](=[O:42])[C:34]2[CH:35]=[CH:36][C:37]([C:40]#[N:41])=[CH:38][CH:39]=2)=[CH:28][CH:29]=1
Reactant: COC(=O)CNc1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CN(Cc1ccccc1)c1ccc(CCNC(=O)c2ccc(C#N)cc2)cc1
Temperature: 50 °C

Procedure:
1.2 ml of triethylamine and 3 ml of benzyl chloroformate (50% in toluene) were added to a solution of 675 mg of N-[p-[2-(p-cyanobenzamido)ethyl]phenyl]glycine methyl ester in 15 ml of chloroform. The reaction mixture was maintained at 50° C. overnight. After working up and chromatography on silica gel with ether/petroleum ether 2:1, 500 mg of crystalline N-benzyl-N-[p-[2-(p-cyanobenzamido)ethyl]phenyl]glycine methyl ester, melting point 123°-124° C., were isolated.
Reaction SMILES: [C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH2:14])([CH3:4])([CH3:3])[CH3:2].[C:19](C1NC=CN=1)(C1NC=CN=1)=[S:20]>C(Cl)Cl>[C:1]([C:5]1[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[N:14]=[C:19]=[S:20])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1ccccc1Oc1ccccc1N
Reactant: S=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: ClCCl
Product: CC(C)(C)c1ccccc1Oc1ccccc1N=C=S
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 135a (14.48 mg, 0.0600 mmol) in anhydrous DCM (1.0 ml) was added dropwise to a cold solution of thiocarbonyl diimidazole (21.39 mg, 0.1200 mmol) in anhydrous DCM (0.50 ml). The reaction was stirred at 0° C. for 1 h and then warmed to rt with stirring for 2 h. The mixture was concentrated down to afford crude 135b which was taken directly onto the next step without purification.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:8][C:7](=S)[N:6]=[CH:5]1.[CH3:10][S:11]([O:14]C)(=[O:13])=[O:12]>C(O)C.COC(C)(C)C>[S:11]([OH:14])(=[O:13])(=[O:12])[CH3:10].[OH:1][CH2:2][CH2:3][N:4]1[CH2:8][CH2:7][N:6]=[C:5]1[S:11][CH3:10]
Reactant: OCCN1C=NC(=S)C1
Reactant: COS(C)(=O)=O
Solvent: COC(C)(C)C
Solvent: CCO
Product: CS(=O)(=O)O
Product: CSC1=NCCN1CCO
Temperature: 25 °C

Procedure:
Twenty grams of 1-(2-hydroxyethyl)-2-imidazolinethione and methyl methanesulfonate (12.75 ml) are dissolved in ethyl alcohol (90 mL) and refluxed for 2 hours. The mixture is cooled to room temperature and diluted with t-butyl methyl ether (1 liter). An oil separates which solidifies on keeping the mixture in the freezer at -20° C. for a few days. The solid is then filtered, washed with butyl methyl ether and dried to give 1-(2-hydroxyethyl)-2-methylthioimidazoline mesylate, melting point 78.9°-81.5° C.