Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[N:23]=[N:24][N:25](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:26]=3)=[CH:12][CH:11]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:55]([CH3:56])[C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[N:52]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH3:2].[OH-].[Na+]>C(O)C>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:23][N:24]=[N:25][N:26]=3)=[CH:14][CH:15]=2)[C:7]2[CH:46]=[C:47]([C:51]3[N:55]([CH3:56])[C:54]4[CH:57]=[CH:58][CH:59]=[CH:60][C:53]=4[N:52]=3)[CH:48]=[C:49]([CH3:50])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
A mixture of 830 mg (1.06 mMol) of 4'-[(2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl, 2.5 ml of 1N sodium hydroxide solution and 20 ml of ethanol is stirred for 2 hours at 80° C. The solution is then evaporated down, the residue is mixed with about 30 ml of water and made slightly acidic with glacial acetic acid. It is then extracted three times with about 20 ml of methylene chloride, the combined organic extracts are washed with 20 ml of water and concentrated by evaporation. The crude product thus obtained is purified by column chromatography (50 g silica gel; methylene chloride/ethanol=97:3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[S:15][CH:16]=[C:17]([CH2:19]Cl)[N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1.C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N:21]1([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:19][C:17]3[N:18]=[C:14]([CH:11]4[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[S:15][CH:16]=3)=[CH:28][CH:27]=2)[CH:25]=[N:24][N:23]=[N:22]1
Reactant: Oc1ccc(-n2cnnn2)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2nc(CCl)cs2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCC(c2nc(COc3ccc(-n4cnnn4)cc3)cs2)CC1

Procedure:
A mixture of 4-(4-chloromethyl-thiazol-2-yl)-piperidine-1-carboxylic acid tert-butyl ester (549 mg), 4-tetrazol-1-yl-phenol (270 mg), Cs2CO3 (890 mg) in acetonitrile was heated under reflux overnight. After cooling, the reaction mixture was filtered through a pad of celite, concentrated in vacuo. Purification by chromatography (40-100% EtOAc/Hexanes) gave the desired product as a white solid. 1H NMR (CDCl3): δ 8.01 (1H, s), 7.61 (2H, d, J=8.8 Hz), 7.25 (1H, s), 7.15 (2H, d, J=8.8 Hz), 5.22 (2H, s), 4.2 (2H, br), 3.17 (1H, m), 2.87 (2H, m), 2.11 (2H, m), 1.73 (2H, m), 1.46 (9H, s).
Reaction SMILES: I[C:2]1[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[N:3]=1.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25](Br)[N:24]=1>[Li]CCCC.[Zn+2].[Br-].[Br-]>[Br:22][C:23]1[N:24]=[C:25]([C:2]2[N:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=3)[N:3]=2)[CH:26]=[CH:27][CH:28]=1
Reactant: Brc1cccc(Br)n1
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(I)n2)cc1
Agent: [Br-]
Agent: [Li]CCCC
Agent: [Zn+2]
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)nc(-c3cccc(Br)n3)n2)cc1

Procedure:
The title compound was prepared from 2-iodo-4-trifluoromethyl-6-(4-trifluoromethyl-phenyl)-pyrimidine (example A.4) (0.900 g, 2.15 mmol), n-BuLi/ZnBr2 and commercially available 2,6-dibromopyridine (0.510 g, 2.15 mmol) according to Tetrahedron Letters 1996, 37(15), 2537 and the general procedure IVc protocol b. Obtained as a yellow oil (0.658 g, 60%, 88% purity). MS (ISP) 447.8 [(M+H)+] and 450.0 [(M+2+H)+].
Reaction SMILES: C([C@H]1COC(=O)N1[C:14](=[O:28])[C@@H:15]([O:24][CH:25]([CH3:27])[CH3:26])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([OH:23])[CH:18]=1)C1C=CC=CC=1.[OH:29]O.[OH-].[Li+].O>O1CCCC1>[OH:23][C:19]1[CH:18]=[C:17]([CH2:16][C@H:15]([O:24][CH:25]([CH3:26])[CH3:27])[C:14]([OH:28])=[O:29])[CH:22]=[CH:21][CH:20]=1
Reactant: OO
Reactant: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)O[C@@H](Cc1cccc(O)c1)C(=O)O
Reaction time: 8 h

Procedure:
1.535 g of 4 (S)-Benzyl-3-[3-(3-hydroxyphenyl)-2 (S)-isopropoxypropionyl]oxazolidin-2-one was dissolved in 40 ml of tetrahydrofuran, and 3.3 ml of 30% aqueous hydrogen peroxide and 12 ml of 1N aqueous lithium hydroxide were successively added under ice-cooling, and stirring was continued at room temperature overnight. After adding water to the reaction solution, the mixture was extracted with dichloromethane and the aqueous layer was acidified by 1N hydrochloric acid. Following extraction (×3) was conducted with ethyl acetate, the organic layer was dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressures, to give 847 mg of 3-(3-hydroxyphenyl)-2(S)-isopropoxypropanoic acid. This product was then dissolved in 10 ml of N,N-dimethylformamide, and 400 mg of potassium hydrogencarbonate and 0.32 ml of ethyl iodide were successively added thereto, and stirring was continued at room temperature for 3 days. The reaction solution was diluted with ethylacetate and washed with water. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel column chromatography, to give 567 mg of the title compound as a colorless oil in the 3:1 hexane-ethyl acetate fraction.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)[CH2:3][CH2:2]1.[C:21]([NH2:25])([CH3:24])([CH3:23])[CH3:22]>>[C:21]([NH:25][C:12]([C:10]1[CH:9]=[CH:8][C:7]([N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)=[C:6]([O:5][CH2:4][CH:1]2[CH2:2][CH2:3]2)[N:11]=1)=[O:14])([CH3:24])([CH3:23])[CH3:22]
Reactant: CC(C)(C)N
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Product: CC(C)(C)NC(=O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 69 b) and tert-butylamine (CAN 75-64-9) as starting materials. MS (EI): m/e=340.5 [M+H]+.
Reaction SMILES: CS([O-])(=O)=O.N[N:7]1[CH:11]=[N+:10]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=2)[N:9]=[CH:8]1.Cl.[PH2](=O)O.N([O-])=O.[Na+].[OH-].[NH4+]>O>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:10]2[CH:11]=[N:7][CH:8]=[N:9]2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: Nn1cn[n+](Cc2ccc(Cl)c([N+](=O)[O-])c2)c1
Agent: CS(=O)(=O)[O-]
Agent: Cl
Agent: O=N[O-]
Solvent: O
Product: O=[N+]([O-])c1cc(Cn2cncn2)ccc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 83.8 %

Procedure:
To a stirred solution of 8.75 parts of 4-amino-1-[(4-chloro-3-nitrophenyl)methyl]-1,2,4-triazolium methanesulfonate in 85 parts of a hydrochloric acid solution 1N were added 7.15 parts of phosphinic acid 50%. After cooling in ice, a solution of 3.5 parts of sodium nitrite in 15 parts of water was added. The mixture was stirred for 2 hours at room temperature. An excess of concentrated ammonium hydroxide was added and stirring was continued for 15 minutes. The product was filtered off, washed with water, 2-propanol and 2,2'-oxybispropane and crystallized from 8 parts of 2-propanol. The product was filtered off and dried, yielding 5 parts (83.8%) of 1-[(4-chloro-3-nitrophenyl)methyl]-1H-1,2,4-triazole; mp. 98.9° C. (int. 143).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[C:16]4=[C:17]([CH2:19][CH2:20][N:15]4[C:14](=[O:21])[CH2:13][CH2:12]3)[CH:18]=2)O1.Br[C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:34])=[O:33])[CH:27]=[N:28][CH:29]=1>>[O:21]=[C:14]1[CH2:13][CH2:12][C:11]2[C:16]3=[C:17]([CH2:19][CH2:20][N:15]13)[CH:18]=[C:9]([C:24]1[CH:25]=[C:26]([CH2:30][NH:31][S:32]([CH2:35][CH3:36])(=[O:33])=[O:34])[CH:27]=[N:28][CH:29]=1)[CH:10]=2
Reactant: CCS(=O)(=O)NCc1cncc(Br)c1
Reactant: CC1(C)OB(c2cc3c4c(c2)CCN4C(=O)CC3)OC1(C)C
Product: CCS(=O)(=O)NCc1cncc(-c2cc3c4c(c2)CCN4C(=O)CC3)c1

Procedure:
In analogy to the procedure described for the preparation of example 45, 8-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydro-1H-pyrrolo[3,2,1-ij]quinolin-4(2H)-one has been coupled to ethanesulfonic acid (5-bromo-pyridin-3-ylmethyl)-amide (intermediate A-11) to give the title compound as a colorless amorphous solid. MS: 372.2 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[CH:10]=[C:9]([C:11]([OH:13])=O)[NH:8][C:5]2=[CH:6][N:7]=1.[C:14]1([CH2:20][C@H:21]([NH2:33])[C:22]2([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[O:26][CH2:25][CH2:24][O:23]2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.CCN=C=NCCCN(C)C>CN(C=O)C.[Cl-].[Na+].O>[C:14]1([CH2:20][C@H:21]([NH:33][C:11]([C:9]2[NH:8][C:5]3=[CH:6][N:7]=[C:2]([Cl:1])[CH:3]=[C:4]3[CH:10]=2)=[O:13])[C:22]2([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[O:26][CH2:25][CH2:24][O:23]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: N[C@@H](Cc1ccccc1)C1(c2ccccc2)OCCO1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Agent: [Cl-]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@@H](Cc1ccccc1)C1(c2ccccc2)OCCO1)c1cc2cc(Cl)ncc2[nH]1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 88 mg, 0.403 mmol) and 2-phenyl-1-(S)-(2-phenyl-[1,3]dioxolan-2-yl)ethylamine (Preparation 95, 104 mg, 0.386 mmol) in DMF (5 mL) was added HOBt (65 mg, 0.424 mmol), DIPEA (0.155 mL, 0.890 mmol) and EDCI (90 mg, 0.469 mmol). After stirring at rt for 12 h the mixture was added to diluted brine (100 mL, water/brine: 1/1). Extraction with ethyl acetate (4×25 mL), washing of the combined extracts with diluted hydrochloric acid (1M, 30 ml), diluted aqueous sodium hydroxide solution (1M, 30 ml) and brine (50 mL) followed by drying (MgSO4) gave after concentration a residue which was purified by flash chromatography on silica gel (eluent: hexane/ethyl acetate: 50/50). The title compound was obtained as a colourless oil. δH (CDCl3): 2.73 (1H, dd), 3.10 (1H, dd), 3.84-4.22 (4H, 4m), 5.01 (1H, ddd), 6.37 (1H, d), 6.72 (1H, s), 7.05-7.62 (11H, 3m), 8.64 (1H, s), 10.48 (1H, s); m/z (ES+)=448.24 [M+H]+; RT=3.64 min.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@@H:6]1Br)(=O)C.[Br-].C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1SC(N)=[NH2+])(=[O:28])C.C(O[C@@H]1[C@@H](OC(=O)C)[C@@H](OC(=O)C)[C@@H](COC(=O)C)O[C@H]1SCC#N)(=O)C>>[O:20]=[CH:19][C@@H:8]([C@H:9]([C@H:10]([C@@H:5]([CH2:6][OH:28])[OH:4])[OH:11])[OH:15])[OH:7]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CC(=O)OC[C@H]1O[C@@H](SC(N)=[NH2+])[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: CC(=O)OC[C@H]1O[C@@H](SCC#N)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: [Br-]
Product: O=C[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO

Procedure:
The galactose coupling agent 2-imino-2-methoxyethyl-1-thio-β-D-galactopyranoside (9) was prepared starting from 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (6) in 3 steps via the intermediates 2-S-(2,3,4,6-tetra-O-acetyl-β-D-galactopyranosyl)-2-thiouronium bromide (7) and cyanomethyl 2,3,4,6-tetra-O-acetyl-1-thio-β-D-galactopyranoside (8) as shown in FIG. 5.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(N(CC)CC)C.[C:18]1([S:24](Cl)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C1C=CN=CC=1.ClCCl>[C:18]1([S:24]([N:8]2[C:5]3=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=[C:4]3[CH:10]=[CH:9]2)(=[O:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: Cc1cnc2[nH]ccc2c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 63.7 %

Procedure:
To a mixture of 5-methyl-1H-pyrrolo[2,3-b]pyridine (3.5 g, 26.5 mmol), triethylamine (8.03 g, 79.5 mmol), and 4-dimethylaminopyridine (0.32 g, 2.65 mmol) in dichloromethane (100 mL) at 0° C. was added benzenesulfonyl chloride (7.0 g, 39.8 mmol). After stirring for 48 h at room temperature, the reaction was quenched with water (50 mL) and extracted with dichloromethane (2×120 mL). The organic layer was washed with a saturated sodium bicarbonate solution (2×30 mL), water (2×30 mL), brine (50 mL), dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel from QingDao, 200-300 mesh, 33% dichloromethane/hexanes) to afford 1-benzenesulfonyl-5-methyl-1H-pyrrolo[2,3-b]pyridine (4.6 g, 64%) as white solid: LC/MS m/e calcd for C14H12N2O4S [M+H]+ 273.33, observed 272.9.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]=[C:11]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].CO>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14]2[C:15]([CH3:21])=[N:16][C:17]([NH2:20])=[CH:18][CH:19]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1nc(N)ccc1C1=CCN(C(=O)OC(C)(C)C)CC1
Agent: [Pd]
Solvent: CO
Product: Cc1nc(N)ccc1C1CCN(C(=O)OC(C)(C)C)CC1
Yield: 97 %

Procedure:
Stir a mixture of 6-amino-2-methyl-3′,6′-dihydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (2.12 g) and palladium on carbon 10% wet (330 mg) in methanol (29.30 mL) under H2 (45 psi) for 48 h. Filtered over a celite pad and remove the solvent under vacuum to afford 2.07 g of the title compound. MS (ES+): m/z=292 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH3:17][N:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]([O-:29])=O)=[CH:26][C:21]=2[N:20]=[N:19]1>>[C:6]([C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:27]([C:25]2[CH:24]=[CH:23][C:22]3[N:18]([CH3:17])[N:19]=[N:20][C:21]=3[CH:26]=2)=[O:29])=[CH:10][CH:9]=1)([C:5]1[CH:15]=[CH:16][C:2]([NH:1][C:27]([C:25]2[CH:24]=[CH:23][C:22]3[N:18]([CH3:17])[N:19]=[N:20][C:21]=3[CH:26]=2)=[O:29])=[CH:3][CH:4]=1)=[O:7]
Reactant: Nc1ccc(C(=O)c2ccc(N)cc2)cc1
Reactant: Cn1nnc2cc(C(=O)[O-])ccc21
Product: Cn1nnc2cc(C(=O)Nc3ccc(C(=O)c4ccc(NC(=O)c5ccc6c(c5)nnn6C)cc4)cc3)ccc21

Procedure:
Compound 403 was prepared according to the procedure described in Scheme IV from 4,4′-diaminobenzophenone and 1-methyl-1H-benzotriazole-5-carboxylate. [M+H]+ calcd for C29H22N8O3: 531.06; found: 531.05.
Reaction SMILES: C1(C)C=CC=CC=1.[S:8](Cl)(=[O:11])(=[O:10])[NH2:9].CC(N(C)C)=O.[OH:19][CH2:20][CH2:21][O:22][CH:23]1[C:39]2([CH3:40])[CH:26]([CH:27]3[CH:36]([CH2:37][CH2:38]2)[C:35]2[CH:34]=[C:33]([O:41][CH3:42])[C:32]([OH:43])=[CH:31][C:30]=2[CH2:29][CH2:28]3)[CH2:25][CH2:24]1>C(OCC)(=O)C.C(Cl)(Cl)Cl.CO.O>[CH3:42][O:41][C:33]1[C:32]([O:43][S:8](=[O:11])(=[O:10])[NH2:9])=[CH:31][C:30]2[CH2:29][CH2:28][CH:27]3[CH:36]([CH2:37][CH2:38][C:39]4([CH3:40])[CH:26]3[CH2:25][CH2:24][CH:23]4[O:22][CH2:21][CH2:20][O:19][S:8](=[O:11])(=[O:10])[NH2:9])[C:35]=2[CH:34]=1
Reactant: NS(=O)(=O)Cl
Reactant: COc1cc2c(cc1O)CCC1C2CCC2(C)C(OCCO)CCC12
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: CO
Product: COc1cc2c(cc1OS(N)(=O)=O)CCC1C2CCC2(C)C(OCCOS(N)(=O)=O)CCC12
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A toluene solution of sulfamoyl chloride (1 ml, 0.69 mmol) was evaporated to dryness, cooled to 0° C. and then treated with dimethylacetamide (1.5 mL) then diol 48 (45 mg). After 3 h stirring at rt the reaction was diluted in ethyl acetate (20 mL), then treated with water (10 ml), the organic layer was separated and extracted with brine (5×10 mL), dried and evaporated to give a yellow oil. Column chromatography (gradient 5-10% methanol in chloroform) was used to purify the desired bis-sulfamate 49 as a clear colourless oil (21 mg) which showed δH (CDCl3, TMS=0) 7.03 (1H, s, ArH), 6.90 (1H, s, ArH), 5.02 (4H, br, 2×NH2), 4.37-4.42 (2H, m, CH2OS), 3.87 (3H, s, OMe), 3.75-3.82 (2H, m, OCH2), 3.48 (1H, dd, J 8.6 & 7.9, OCH), 2.74-2.85 (2H, m, 6-CH2), 1.25-2.50 (H, m) and 0.79 (3H, s, 18-CH3); m/z 504.6.
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].Br[C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=[O:19].S(C)C>N1C=CC=CC=1.O.C(OCC)(=O)C>[C:7]([C:6]1[CH:5]=[C:4]([O:3][C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=[O:19])[CH:13]=[CH:12][CH:11]=1)([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cccc(O)c1
Reactant: O=Cc1cccc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)c1cccc(Oc2cccc(C=O)c2)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of NaH (washed with hexane, 564 mg) in 20 mL of pyridine at 0° C. was added methyl 3-hydroxybenzoate (1.95 g), and the solution was allowed to warm to room temperature. After 5 minutes, 3-bromobenzaldehyde (1.64 mL) was added, then CuBr.SMe2 (3.15 g). The solution was heated to reflux under a stream of nitrogen. After 24 h, the reaction was cooled to room temperature and poured into ethyl acetate and water. The organic layer was washed twice with 10% aq. HCl solution, then with sat. aq. NaHCO3 solution, then with brine. The solution was dried (Na2SO4), filtered, and concentrated in vacuo to provide the crude product. Purification by silica gel chromatography (CH2 Cl2) gave the titled compound as a yellow oil.
Reaction SMILES: C([O:3][C:4](=O)[C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([NH:16][C:17]([NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:14][C:13]([C:30](C)([CH3:32])[CH3:31])=[N:12]2)=[CH:7][CH:6]=1)C.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:3][CH2:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15]([NH:16][C:17]([NH:19][C:20]3[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=[CH:22][CH:21]=3)=[O:18])=[CH:14][C:13]([CH:30]([CH3:32])[CH3:31])=[N:12]2)=[CH:7][CH:6]=1
Reactant: CCOC(=O)c1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2cccc3ccccc23)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)c1cc(NC(=O)Nc2cccc3ccccc23)n(-c2ccc(CO)cc2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 124.9 %

Procedure:
To a stirred solution of Example 195 (500 mg, 0.83 mmol) in THF (10 mL) was added LiAlH4 powder (65 mg, 1.66 mmol) in portion at 0° C. under N2. The mixture was stirred for 2 h at RT, excess LiAlH4 was destroyed by a slow addition of ice, and the reaction mixture was acidified to pH=7 with dilute HCl. After the solvent was removed, the residue was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), and filtered. After concentration in vacuo, the crude product was purified by preparative-TLC to afford 1-[2-(4-hydroxymethyl-phenyl)-5-isopropyl-2H-pyrazol-3-yl]-3-naphthalen-1-yl-urea (415 mg, 92%). 1H NMR (DMSO-d6): 9.04 (s, 1H), 8.78 (s, 1H), 7.98 (d, J=8.0 Hz, 1H), 7.90 (d, J=7.2 Hz, 2H), 7.63 (d, J=8.4 Hz, 1H), 7.55-7.42 (m, 7H), 6.39 (s, 1H), 5.30 (t, J=5.6 Hz, 1H), 4.56 (d, J=5.6 Hz, 2H), 1.27 (s, 9H); MS (ESI) m/z: 415 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:11])([CH3:10])[C@:4]([C:13]2[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1.[O:21]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[N:22]1.[B][B][B][B][B][B][B][B][B][B]>>[NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[C:5]([CH3:10])([CH3:11])[C@:4]([C:13]2[CH:18]=[C:17]([NH:19][CH2:26][C:23]3[CH:24]=[CH:25][O:21][N:22]=3)[CH:16]=[CH:15][C:14]=2[F:20])([CH3:12])[N:3]=1
Reactant: O=Cc1ccon1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(N)ccc2F)N=C1N
Agent: [B][B][B][B][B][B][B][B][B][B]
Product: CN1C(=O)C(C)(C)[C@@](C)(c2cc(NCc3ccon3)ccc2F)N=C1N

Procedure:
The reductive amination of (S)-2-amino-6-(5-amino-2-fluoro-phenyl)-3,5,5,6-tetramethyl-5,6-dihydro-3H-pyrimidin-4-one (intermediate J) and isoxazole-3-carbaldehyde using decaborane yielded the title compound as a light yellow waxy solid. MS (ESI): m/z=360.4 [M+H]+.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1.[C:28]([OH:33])(=[O:32])[CH:29]([CH3:31])O.C1(C)C(S(O)(=O)=O)=CC=CC=1>C1(C)C=CC=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][NH:18][C:19]1[CH:20]=[CH:21][C:22]([C:23]([O:25][CH:29]([C:28]([OH:33])=[O:32])[CH3:31])=[O:24])=[CH:26][CH:27]=1
Reactant: O=C(O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1
Reactant: CC(O)C(=O)O
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: Cc1ccccc1
Product: CC(OC(=O)c1ccc(NCCCCCCCCCCCCCCCCBr)cc1)C(=O)O

Procedure:
A flask containing 10.0 g. 4-(16-bromohexadecylamino)benzoic acid, 3.3 g. lactic acid, 500 mg. toluenesulfonic acid and 500 ml. toluene is equipped with a Soxhlet extractor charged with activated 4 A Linde molecular sieves. The solution is refluxed for 24 hours, during which time the Soxhlet extractor is charged twice more with fresh sieves. The hot solution is filtered and left to cool, whereupon the product separates as off-white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][NH:7][C:8]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[S:9])=[C:4]([CH:21](O)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:3]=1>CC(C)=O.Cl>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[CH2:6][N:7]=[C:8]([NH:10][CH2:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[S:9][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:4]=2[CH:3]=1
Reactant: OC(c1ccccc1)c1cc(Cl)ccc1CNC(=S)NCCc1ccccc1
Agent: Cl
Solvent: CC(C)=O
Product: Clc1ccc2c(c1)C(c1ccccc1)SC(NCCc1ccccc1)=NC2

Procedure:
A solution of 1-(4-chloro-2-(α-hydroxybenzyl)-benzyl)-3-phenethyl-thiourea (17 g; 0.041 mole) in dry acetone (400 ml) and 85 ml saturated ethanolic hydrogen chloride was stirred at room temperature for 20 hours. The reaction mixture was filtered. The filtrate was evaporated to yield the title compound in hydrochloride form (M.Pt. 120° decomp.).
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH:26](O)[CH3:27].N(C(OC(C)C)=O)=NC(OC(C)C)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[F:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=1[CH:26]([O:1][C:2]1[C:3]2[N:4]([C:9]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:10]([CH3:12])[N:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1)[CH3:27]
Reactant: CC(O)c1c(F)cccc1F
Reactant: CCOC(=O)c1c(C)nc2c(O)cc(C)cn12
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1c(C)nc2c(OC(C)c3c(F)cccc3F)cc(C)cn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5.50 g (23.5 mmol) of ethyl 8-hydroxy-2,6-dimethylimidazo[1,2-a]pyridine-3-carboxylate Example 87A, 4.46 g (28.2 mmol) of 1-(2,6-difluorophenyl)ethanol, 5.35 ml (27.0 mmol) of diisopropyl azodicarboxylate and 7.08 g (27.0 mmol) of triphenylphosphine were dissolved in 141 ml of THF, and the mixture was stirred at RT for 2 h. 0.70 ml (3.5 mmol) of diisopropyl azodicarboxylate and 0.62 g (2.3 mmol) of triphenylphosphine were added to the reaction mixture, and the reaction solution was stirred at RT for 1 h. The precipitated solid was filtered off and dried under high vacuum. This gave 4.6 g (52.8% of theory; purity 100%) of the title compound. The filtrate was concentrated and purified twice by silica gel chromatography (cyclohexane:ethyl acetate gradient=from 8:1 to 4:1). All product-containing fractions were re-purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). This gave another 2.16 g (25% of theory) of the target compound.