Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][O:5][CH2:6][C:7]1[S:8][CH:9]=[CH:10][N:11]=1.[BH4-].[Na+]>CO>[S:8]1[CH:9]=[CH:10][N:11]=[C:7]1[CH2:6][O:5][CH2:4][CH2:3][OH:2]
Reactant: COC(=O)COCc1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OCCOCc1nccs1
Temperature: 25 °C
Yield: 86.9 %

Procedure:
A cooled (0° C.) sol. of (thiazol-2-ylmethoxy)acetic acid methyl ester (31.0 g, 165.6 mmol) in MeOH (830 mL) was treated portionwise with NaBH4 (31.0 g, 1.66 mol). The reaction mixture was allowed to warm to rt over 1 h. The mixture was then quenched with water, and extracted with CH2Cl2 (3×). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give the title compound as an orange oil (22.9 g, 87%) that was not further purified. LC-MS: tR=0.44 min, ES+: 160.19.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1.[CH2:14]([O:16][P:17]([O:21]CC)[O:18][CH2:19][CH3:20])[CH3:15]>>[CH2:14]([O:16][P:17]([CH2:2][C:3]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:5][N:4]=1)([O:18][CH2:19][CH3:20])=[O:21])[CH3:15]
Reactant: CCOP(OCC)OCC
Reactant: ClCc1cc(-c2ccccc2)on1
Product: CCOP(=O)(Cc1cc(-c2ccccc2)on1)OCC
Yield: 62.7 %

Procedure:
3-Chloromethyl-5-phenylisoxazole (2.07 g, 10 mmol) and triethylphosphite (1.72 ml, 10 mmol) were heated at reflux for 2 h then the mixture distilled under reduced pressure to yield the title compound (1.85 g, 6.27 mmol, 63%); b.p. 192° at 0.5 mm Hg; νmax (film) 2980, 2900, 1610, 1590, 1570, 1500, 1450, 1420, 1390, 1250, 1160, 1060-1010, 970, 760, 690 cm-1 ; δH (CDCl3) 1.30(3H,t, J 7 Hz,OCH2CH3), 3.30(2H,d,J 21 Hz,CH2 -P), 4.20(2H,m,OCH2CH3), 6.60(1H,s,CH-het), 7.2-7.9(5H,m,Ph).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([O:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8](O)=[O:9])(=[O:3])[CH3:2].S(Cl)([Cl:23])=O>C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]([I:20])=[C:7]([C:11]([I:19])=[C:12]([O:15][C:16](=[O:18])[CH3:17])[C:13]=1[I:14])[C:8]([Cl:23])=[O:9])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1c(I)c(OC(C)=O)c(I)c(C(=O)O)c1I
Reactant: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: CC(=O)Oc1c(I)c(OC(C)=O)c(I)c(C(=O)Cl)c1I
Reaction time: 5 h
Yield: 88 %

Procedure:
To a solution of 3,5-diacetoxy-2,4,6-triiodobenzoic acid (9.5 g) in ethyl acetate (80 mL) at 55° C. was added thionyl chloride (5.5 mL) and stirred 5 h. The solution was evaporated and the dry residue crystallized from ethyl acetate to yield 8.6 g (88%) 3,5-diacetoxy-2,4,6-triiodobenzoic acid chloride.
Reaction SMILES: Cl.[CH2:2]1[C:11]2[C:6](=[C:7]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.Cl.[N:18]1([C:23](N)=[NH:24])C=CC=N1.C(N(C(C)C)CC)(C)C.[OH-].[Na+]>CN(C=O)C>[C:23]([N:3]1[CH2:4][CH2:5][C:6]2[C:11](=[CH:10][CH:9]=[CH:8][C:7]=2[NH:12][S:13]([CH3:16])(=[O:15])=[O:14])[CH2:2]1)(=[NH:18])[NH2:24]
Reactant: CS(=O)(=O)Nc1cccc2c1CCNC2
Reactant: N=C(N)n1cccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)Nc1cccc2c1CCN(C(=N)N)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A suspension of N-(1,2,3,4-tetrahydro-5-isoquinolyl)methanesulfonamide hydrochloride obtainable by the method of Example 19(b) of WO 98/30560 (15 g, 69 mmol), 1H-pyrazole-1-carboxamidine hydrochloride (10.0 g, 0.57 mol) and diisopropylethylamine (16.2 g, 125 mmol) in DMF (119 ml) was stirred overnight at room temperature. After this time 2N aqueous sodium hydroxide-was added to adjust to pH 12. The resulting white suspension was stirred for three hours, filtered and the solid dried in vacuo overnight at 45° C. to give 14.5 g of the title product (95%).
Reaction SMILES: [C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:10][C@@H:9]1[CH2:28]OS(C)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[Li+].[BH4-]>C1COCC1>[C:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH:20]2[CH2:25][CH2:24][C:23]([CH3:27])([CH3:26])[CH2:22][CH2:21]2)[C:14](=[O:19])[C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:10][C@H:9]1[CH3:28])([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2]
Reactant: CC1(C)CCC(N(C(=O)C(C)(C)C)[C@H]2C[C@H](COS(C)(=O)=O)N(C(=O)OC(C)(C)C)C2)CC1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1C[C@H](N(C(=O)C(C)(C)C)C2CCC(C)(C)CC2)CN1C(=O)OC(C)(C)C
Temperature: 70 °C
Reaction time: 5 h
Yield: 54.9 %

Procedure:
To a solution of BOC-(2R,4S)-4-[(4,4-dimethylcyclohexyl)(2,2-dimethylpropanoyl)amino]-2-{[(methylsulfonyl)oxy]methyl}pyrrolidine (580 mg, 1.19 mmol) prepared in Step B in THF (5 ml) was added dropwise LiBH4 (77 mg, 3.57 mmol) at 70° C. The solution was stirred at 70° C. for 5 h, concentrated in vacuo, and extracted with EtOAC. The organic extracts were washed with a saturated NaHCO3 aqueous solution and brine, dried over MgSO4, and concentrated in vacuo. The residue was purified by column chromatography (eluent: EtOAc:Hex=1/4) to give the title compound (258 mg, 53%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:12][O:11][C:10](=[O:13])[NH:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23](Cl)=[N:22][C:21]=12.O>CN(C=O)C>[Br:16][C:17]1[CH:18]=[N:19][N:20]2[CH:25]=[CH:24][C:23]([N:9]3[C@@H:8]([C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)[CH2:12][O:11][C:10]3=[O:13])=[N:22][C:21]=12
Reactant: Clc1ccn2ncc(Br)c2n1
Reactant: O=C1N[C@@H](c2ccc(F)cc2)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1OC[C@H](c2ccc(F)cc2)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 42.2 %

Procedure:
To a solution of (S)-4-(4-fluorophenyl)oxazolidin-2-one (0.43 g, 2.4 mmol) in DMF (10 mL) was added sodium hydride (0.095 g, 2.4 mmol) and the reaction stirred at ambient temperature for 30 minutes. 3-Bromo-5-chloropyrazolo[1,5-a]pyrimidine (0.50 g, 2.2 mmol) was added and the reaction was stirred for 2 hours at ambient temperature. The reaction mixture was poured into water (100 mL) and extracted into ether (2×100 mL). The organic layer was washed with brine (2×20 mL), dried over MgSO4 and concentrated under vacuum. The crude material was purified by silica gel chromatography, eluting with 2% EtOAc/DCM to yield (S)-3-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-4-(4-fluorophenyl)oxazolidin-2-one (0.35 g, 43%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:24])=[C:19]([CH:21]=[CH:22][CH:23]=2)[NH2:20])[CH:5]=[CH:4][N:3]=1.[NH4+:25].[OH-].O1CCOCC1>O>[NH2:20][C:19]1[C:18]([F:24])=[C:17]([C:9]2[N:10]=[C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])[S:12][C:8]=2[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH2:25])[N:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: [NH4+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)c1nc(-c2cccc(N)c2F)c(-c2ccnc(N)n2)s1
Temperature: 130 °C
Yield: 83.3 %

Procedure:
In a microwave reaction vessel 3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (590 mg, 1.626 mmol) was combined with NH4OH 28-30% (15 mL, 385 mmol) and 1,4-dioxane (4 mL). The mixture was heated in the microwave for 40 min at 130° C. The crude product was then diluted with water (100 mL) followed by extraction with EtOAc (100 mL). The EtOAc layer was washed with brine then dried over Na2SO4. The organics were then filtered and concentrated to dryness. The crude material was dissolved in DCM (2 mL), injected onto the top of a silica gel column then purified using EtOAc and hexanes. Desired fractions were concentrated to dryness to yield the title compound of Step A as a beige powder (490 mg, 1.355 mmol, 83% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.06 (d, J=5.1 Hz, 1H), 6.97 (t, J=7.8 Hz, 1H), 6.86 (t, J=8.2 Hz, 1H), 6.71 (s, 2H), 6.58 (t, J=6.2 Hz, 1H), 6.15 (d, J=5.1 Hz, 1H), 5.26 (s, 2H), 1.42 (s, 9H).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=1>>[CH3:37][O:36][C:33]1[CH:34]=[CH:35][C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:27])([F:25])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])=[CH:31][CH:32]=1
Reactant: COc1ccc(Br)cc1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12f and 4-bromoanisole
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@@H:12]2[O:13][N:14]([CH3:22])[C:15]3[C:20]([Cl:21])=[CH:19][CH:18]=[CH:17][C:16]=3[C@:11]2([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:10][C@H:9]1[C:31]([OH:33])=[O:32])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>C(OCC)(=O)C.[Pd]>[Cl:21][C:20]1[C:15]2[N:14]([CH3:22])[O:13][CH:12]3[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:31]([OH:33])=[O:32])[CH2:10][C@@:11]3([O:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C:16]=2[CH:17]=[CH:18][CH:19]=1
Reactant: CN1O[C@H]2N(C(=O)OC(C)(C)C)[C@H](C(=O)O)C[C@@]2(OC(=O)OC(C)(C)C)c2cccc(Cl)c21
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CN1OC2N(C(=O)OC(C)(C)C)[C@H](C(=O)O)C[C@@]2(OC(=O)OC(C)(C)C)c2cccc(Cl)c21
Yield: 68.9 %

Procedure:
A solution of (2S,3aR,9bR)-3-(tert-butoxycarbonyl)-9b-[(tert-butoxycarbonyl)oxy]-6-chloro-5-methyl-1,2,3,3a,5,9b-hexahydropyrrolo[2,3-c][2,1]benzoxazine-2-carboxylic acid (Preparation 150, 25.4 g) in ethyl acetate (200 ml) was treated with 10% palladium on charcoal (5 g) and stirred under 50 p.s.i. of hydrogen gas for 170 hours. The reaction mixture was filtered through celite, evaporated and purified by flash column chromatography eluting with ethyl acetate:hexane (1:4) to give the product as a white foam (17.5 g).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11](Cl)(=[O:13])=[O:12].[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16]1)(=[O:13])=[O:12]
Reactant: c1ccc2[nH]ccc2c1
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Product: O=S(=O)(c1ccc2ccccc2c1)n1ccc2ccccc21
Yield: 92 %

Procedure:
The title compound was prepared from naphthalene-2-sulfonyl chloride and 1H-indole, according to Method A, described above. Yield 92%; mp 103-105° C.; 1H NMR (CDCl3) δ 8.33-8.34 (m, 1H), 7.85-7.89 (dd, J=8 Hz, 1H), 7.69-7.76 (m, 1H), 7.52-7.64 (m, 3H), 7.29-7.46 (m, 4H), 6.97-7.24 (m, 2H), 6.46-6.48 (dd, J=4 Hz, 1H); 13C NMR (CDCl3) δ 135.6, 135.5, 135.3, 132.3, 131.2, 130.1, 129.8, 128.9, 128.3, 128.2, 126.8, 125.1, 123.8, 121.9, 121.8, 113.9, 109.7; MS (AP+) m/z 308.04 (M++1).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.Cl[Si](C)(C)C.CC([Mg]Cl)C.[CH2:22]([O:24][C:25]([CH:27]1[CH2:29][CH:28]1[CH:30]=[O:31])=[O:26])[CH3:23]>C1COCC1>[CH2:22]([O:24][C:25]([CH:27]1[CH2:29][CH:28]1[CH:30]([C:2]1[N:10]2[C:5]([C:6]([NH2:11])=[N:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1)[OH:31])=[O:26])[CH3:23]
Reactant: Nc1ncnn2c(Br)ccc12
Reactant: CCOC(=O)C1CC1C=O
Agent: CC(C)[Mg]Cl
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Product: CCOC(=O)C1CC1C(O)c1ccc2c(N)ncnn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 29.3 %

Procedure:
To a stirred solution of 7-bromo-pyrrolo[2,1-f][1,2,4]triazin-4-ylamine (5.27 g, 24.7 mmol) in anhydrous THF (40 mL) was added chlorotrimethylsilane (5.9 g, 54.4 mmol) at rt. The reaction mixture was stirred at rt for 2 hours and cooled in an ice water bath. 2-propylmagnesium chloride in THF (52 mL, 104 mmol, 2.0 M) was added dropwise, and the reaction mixture was allowed stirred at rt for 2 hours. The reaction was cooled to 0° C. with an ice bath, and 2-formyl-cyclopropanecarboxylic acid ethyl ester (4.6 g, 32 mmol) was added. The reaction mixture was stirred at rt for 1 hour. The mixture was quenched with saturated, aqueous ammonium chloride (20 mL) In ice water bath. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was washed with water, brine, dried by Na2SO4, filtered and concentrated. The crude product was separated by column (30% EtOAc/70% Hexane) to give 2.0 g (30%) of product. 1H NMR (300 MHz, DMSO-d6) δ 8.80 (s, 1 H), 8.75 (bs, 2 H), 6.80 (s, 1 H), 6.60 (m, 1 H), 5.40 (s, 1 H), 5.0-4.8 (m, 1 H), 4.0 (m, 2 H), 1.9-1.8 (m, 2 H), 1.2 (t, 3 H), 1.0 (m, 2 H); ES-MS m/z 277.34 [M+H]+, HPLC RT (min) 1.51.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]=2[N:3]=1.CC(C)([O-])C.[Na+].[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29]Br)[N:24]=1>CS(C)=O>[Br:22][C:23]1[N:24]=[C:25]([CH2:29][N:8]2[CH2:7][CH:6]3[CH2:12][O:13][CH2:14][CH2:15][N:5]3[C:4]3[N:3]=[C:2]([Cl:1])[N:11]=[CH:10][C:9]2=3)[CH:26]=[CH:27][CH:28]=1
Reactant: BrCc1cccc(Br)n1
Reactant: Clc1ncc2c(n1)N1CCOCC1CN2
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: Clc1ncc2c(n1)N1CCOCC1CN2Cc1cccc(Br)n1

Procedure:
The title compound was prepared in a manner similar to PREPARATION x9 using 2-chloro-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridine (PREPARATION x2, 300 mg, 1.324 mmol) in DMSO (20 mL) followed by sodium tert-butoxide (153 mg, 1.588 mmol) and 2-bromo-6-(bromomethyl)pyridine (332 mg, 1.324 mmol). 1H NMR (400 MHz, DMSO-d6) δ 2.92-3.04 (m, 1 H), 3.12-3.24 (m, 2 H), 3.40-3.53 (m, 2 H), 3.62-3.72 (m, 1 H), 3.86-4.00 (m, 2 H), 4.19-4.28 (m, 1 H), 4.42-4.64 (m, 2 H), 7.31 (s, 4 H), 7.36-7.43 (m, 4 H), 7.56 (s, 3 H), 7.72 (d, J=7.83 Hz, 4 H). ESI-MS m/z [M+H]+ calc'd for C15H15BrClN5O, 396.01; found 396.1.
Reaction SMILES: F[C:2]1[CH:10]=[C:9]([F:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:13][C:14]1[CH:20]=[C:19]([I:21])[CH:18]=[CH:17][C:15]=1[NH2:16].[NH2-].[Li+].Cl>C(#N)C>[F:11][C:9]1[C:8]([F:12])=[CH:7][C:3]([C:4]([OH:6])=[O:5])=[C:2]([NH:16][C:15]2[CH:17]=[CH:18][C:19]([I:21])=[CH:20][C:14]=2[F:13])[CH:10]=1
Reactant: Nc1ccc(I)cc1F
Reactant: O=C(O)c1cc(F)c(F)cc1F
Agent: Cl
Agent: [Li+]
Agent: [NH2-]
Solvent: CC#N
Product: O=C(O)c1cc(F)c(F)cc1Nc1ccc(I)cc1F
Temperature: 60 °C
Yield: 43.5 %

Procedure:
2,4,5-Trifluorobenzoic acid (643 mg, 3.65 mmol) and 2-fluoro-4-iodoaniline (1.0 g, 4.22 mmol) were taken into acetonitrile (30 mL) followed by addition of lithium amide (290 mg, 12.7 mmol) and the mixture was heated to 60° C. under a nitrogen atmosphere for one hour. On cooling to room temperature the mixture was added to 1 N aqueous hydrochloric acid (100 mL) and the precipitate formed was collected by filtration and washed once with water then hexanes and dried in vacuo to give 4,5-difluoro-2-[(2-fluoro-4-iodophenyl)amino]benzoic acid (624 mg, 43% yield) as a tan solid. 1H-NMR (400 MHz, D6-DMSO): 13.65 (br s, 1H), 9.63 (s, 1H), 7.84 (tr, 1H), 7.71 (d, 1H), 7.52 (d, 1H), 7.32 (tr, 1H), 7.03-6.98 (dd, 1H).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:16]=[CH:15][C:13]([NH2:14])=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](O)=[O:30])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18].C(OC1C=CC(NC(C2C=CC=CN=2)=O)=CC=1)C1C=CC=CC=1>>[CH2:20]([O:19][C:17]([N:27]1[CH2:34][CH2:33][CH2:32][C@H:28]1[C:29](=[O:30])[NH:14][C:13]1[CH:12]=[CH:11][C:10]([O:9][CH2:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:16][CH:15]=1)=[O:18])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=C(O)[C@@H]1CCCN1C(=O)OCc1ccccc1
Reactant: Nc1ccc(OCc2ccccc2)cc1
Agent: Cl
Agent: O=C(Nc1ccc(OCc2ccccc2)cc1)c1ccccn1
Product: O=C(Nc1ccc(OCc2ccccc2)cc1)[C@@H]1CCCN1C(=O)OCc1ccccc1

Procedure:
This compound was prepared from 4-benzyloxyaniline hydrochloride (4.0 g, 17.0 mmol) and (−)-N-carbobenzyloxy-l-proline (4.44 g, 17.8 mmol), using the same method to prepare pyridine-2-carboxylic acid (4-benzyloxyphenyl)amide, to give the product as a colorless solid, 7.51 g (98%), which was used without further purification in the subsequent step. MS m/z 431 (MH+). 1H NMR(CDCl3) δ 1.83-2.61 (m, 4H), 3.44-3.65 (m, 2H), 4.40-4.55 (m, 1H), 5.03 (s, 2H), 5.22 (br s, 2H), 6.90 (d, 2H) and 7.20-7.45 (m, 12H).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=2)[N:11]([CH2:20][CH:21]2[CH2:23][CH2:22]2)[CH:10]=1)=[O:8].N[C:25]1SC(C)=CN=1>>[CH3:25][C:5]1[S:1][C:2]([NH:6][C:7]([C:9]2[C:17]3[C:12](=[CH:13][C:14]([CH2:18][OH:19])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:10]=2)=[O:8])=[N:3][CH:4]=1
Reactant: Cc1cnc(N)s1
Reactant: O=C(Nc1nccs1)c1cn(CC2CC2)c2cc(CO)ccc12
Product: Cc1cnc(NC(=O)c2cn(CC3CC3)c3cc(CO)ccc23)s1

Procedure:
The compound was prepared according to the procedure given for 1-Cyclopropylmethyl-6-hydroxymethyl-1H-indole-3-carboxylic acid thiazol-2-ylamide using 2-amino-5-methyl-thiazole.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[C@@H:19]2[CH2:20][CH2:21][C@H:15]1[C:16](=O)[NH:17][CH2:18]2)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[CH2:7]([N:14]1[CH:19]2[CH2:20][CH2:21][CH:15]1[CH2:16][NH:17][CH2:18]2)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1NC[C@H]2CC[C@@H]1N2Cc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: c1ccc(CN2C3CCC2CNC3)cc1
Temperature: 67.5 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a stirred suspension of lithium aluminium hydride in tetrahudrofuran (30 ml) at 0° C. was added a solution of (1S,5R)-8-benzyl-3,8-diazabicyclo[3.2.1]octan-2-one (prepared according to the procedure reported in US200565178 A1, 1.0 g, 4.62 mmol) in 15 ml tetrahudrofuran (15 ml) under nitrogen atmosphere. The reaction mixture was allowed to stir at 25° C. for 2 h and at 65-70° C. for 1 h. The reaction mixture was cooled to 0° C. and slowly quenched with 15% aqueous Sodium hydroxide (5 ml). The reaction mixture was diluted with ethyl acetate (50 ml) and filtered through a celite bed. The filtrate was dried over sodium sulphate and concentrated under reduced pressure to obtain the title compound (0.85 g, 91%).
Reaction SMILES: [CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[C:4]([OH:14])=[C:3]1[C:15]([NH:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][N:23]=1)=[O:16].[OH-].[K+:25]>CO>[CH3:1][N:2]1[S:11](=[O:13])(=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([O-:14])=[C:3]1[C:15]([NH:17][C:18]1[N:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:16].[K+:25]
Reactant: CN1C(C(=O)Nc2ccccn2)=C(O)c2ccccc2S1(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CN1C(C(=O)Nc2ccccn2)=C([O-])c2ccccc2S1(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 84.3 %

Procedure:
10 g of piroxicam was suspended in 83 g of methanol. To this suspension was added 1.95 g of 85% KOH at 15° to 20° C. The resulting solution was stirred for 30 minutes at the same temperature, filtered and evaporated to remove methanol. The residue was dissolved by adding 74.2 g of isopropyl alcohol and the resulting solution was stirred for one hour at 20° to 25° C. and then cooled to 0° C. to precipitate the solid product. The resulting solid was filtered, washed with 24.7 g of isopropyl alcohol and then dried in vacuum to obtain 9.4 g (Yield 84%) of piroxicam potassium.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[C:6]([F:8])[CH:7]=1.Cl.N[C@H](C([NH:19][CH:20]1[C:26](=[O:27])[N:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24]2[CH:34]=[CH:35][CH:36]=[CH:37][C:23]=2[N:22]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[C:21]1=[O:44])=O)C>>[F:8][C:6]1[CH:5]=[C:4]([CH2:9][C:10]([NH:19][C@H:20]([C:26]([C:20]2([NH2:19])[C:21](=[O:44])[N:22]([C:38]3[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=3)[C:23]3[CH:37]=[CH:36][CH:35]=[CH:34][C:24]=3[N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:26]2=[O:27])=[O:27])[CH3:21])=[O:12])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C(O)Cc1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NC1C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O
Agent: Cl
Product: C[C@H](NC(=O)Cc1cc(F)cc(F)c1)C(=O)C1(N)C(=O)N(c2ccccc2)c2ccccc2N(c2ccccc2)C1=O

Procedure:
Following General Procedure I above using 3,5difluorophenylacetic acid (Lancaster) and 3-(L-alaninyl)-amino-2,4-dioxo-1,5-bis-phenyl-2,3,4,5-tetrahydro-1H-1,5-benzodiazepine hydrochloride (Example 8-W), the title compound was prepared as a white solid (melting point=139-141° C.). Purification was by flash chromatography eluting with CH2Cl2/EtOAc (1:1). Rf=0.46 (CH2Cl2/EtOAc, 1:1).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][C:8]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)([CH3:12])[C:9](O)=[O:10]>C(OCC)C>[CH3:12][C:8]([C:13]1[CH:14]=[CH:15][C:16]([Cl:19])=[CH:17][CH:18]=1)([CH3:7])[CH2:9][OH:10]
Reactant: CC(C)(C(=O)O)c1ccc(Cl)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: CC(C)(CO)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.9 %

Procedure:
A stirring mixture of 5.4 grams (0.136 mole) of lithium aluminum hydride in 300 mL of diethyl ether is cooled in an ice-water bath, and a solution of 45.0 grams (0.226 mole) of 2-methyl-2-(4-chlorophenyl)propanoic acid in 300 mL of diethyl ether is added dropwise during a one hour period. Upon completion of addition, the reaction mixture is allowed to warm to ambient temperature where it is stirred for about 18 hours. After this time the reaction mixture is cooled in an ice-water bath, and the reaction is quenched with the careful dropwise addition of water. Upon completion of addition, the reaction mixture is made basic with the slow addition of aqueous 10% sodium hydroxide. The mixture is then made acidic with aqueous 2N hydrochloric acid. The organic layer is separated and dried with magnesium sulfate. The mixture is filtered and concentrated under reduced pressure, yielding 41.7 grams of 2-methyl-2-(4-chlorophenyl)propanol. The NMR spectrum is consistent with the proposed structure.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[Na].[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]1([C:18]([C:20]2[CH:25]=[CH:24][C:23]([I:26])=[CH:22][CH:21]=2)=[CH2:19])[CH2:17][O:16]1>CN(C=O)C>[F:7][C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:9]=1[C:15]([OH:16])([C:18]([C:20]1[CH:21]=[CH:22][C:23]([I:26])=[CH:24][CH:25]=1)=[CH2:19])[CH2:17][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C=C(c1ccc(I)cc1)C1(c2ccc(F)cc2F)CO1
Agent: [Na]
Solvent: CN(C)C=O
Product: C=C(c1ccc(I)cc1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 5 h
Yield: 59 %

Procedure:
Sodium 1,2,4-triazole (12.15 g, 133 mmol) was added to a solution of (2,4-difluorophenyl)-2-[1-(4-iodophenyl)ethenyl]oxirane [34.3 g, 89 mmol, from step (e)] in dry DMF (350 ml) under nitrogen at 70° C. The mixture was stirred for 5 hours, cooled, and the solvent removed under reduced pressure. The residue was partitioned between ether (800 ml) and water (2×500 ml). The organic solution was dried (MgSO4), filtered, and silica gel (60-200μ, 75 g) was added. The ether was removed under reduced pressure and the residual solid was applied to the top of a silica gel column (40-60μ, 300 g) and the product was eluted using hexane and increasing amounts of ethyl acetate (0-75%). The product was obtained as a white foam (23.8 g, 61%), which was characterised by 1H-N.M.R. spectroscopy.