Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([CH:7](Br)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:15][CH:16]1[CH2:21][CH2:20][N:19]([CH2:22][CH2:23][CH:24]([CH3:35])[O:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[N+:32]([O-:34])=[O:33])[CH2:18][CH2:17]1.OC1CCN(CCCOC2C=CC=CC=2[N+]([O-])=O)CC1>>[C:1]1([CH:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:22][CH2:23][CH:24]([CH3:35])[O:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N+:32]([O-:34])=[O:33])[CH2:20][CH2:21]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(CCN1CCC(O)CC1)Oc1ccccc1[N+](=O)[O-]
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: O=[N+]([O-])c1ccccc1OCCCN1CCC(O)CC1
Product: CC(CCN1CCC(OC(c2ccccc2)c2ccccc2)CC1)Oc1ccccc1[N+](=O)[O-]

Procedure:
The procedure of Example 1 (a) was repeated except for using diphenylmethyl bromide and 4-hydroxy-1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine instead of diphenylmethyl bromide and 4-hydroxy-1-[3-(2-nitrophenoxy)propyl]piperidine to give oily 4-diphenylmethoxy1-[3-methyl-3-(2-nitrophenoxy)propyl]piperidine.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O=S(Cl)Cl.[CH3:16]O>>[I:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:16])=[O:5]
Reactant: CO
Reactant: O=C(O)c1cc(I)ccc1I
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(I)ccc1I

Procedure:
To a solution of 2,5-diiodobenzoic acid (1.00 g, 2.67 mmol) in anhydrous MeOH (15 mL) cooled in an ice-bath, SOCl2 (0.50 mL, 6.85 mmol) was cautiously added (exothermal reaction). After the addition, the solution was heated at reflux overnight. It was then concentrated in vacuo to give methyl 2,5-diiodobenzoate (1.04 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[O:5][C:4](=O)[CH:3]=1.Cl.[NH2:17][OH:18].NC1C=CC=CN=1>>[OH:18][N:17]1[C:6]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)=[CH:7][C:2]([CH3:1])=[CH:3][C:4]1=[O:5]
Reactant: Cc1ccc(-c2cc(C)cc(=O)o2)cc1
Reactant: NO
Agent: Cl
Agent: Nc1ccccn1
Product: Cc1ccc(-c2cc(C)cc(=O)n2O)cc1
Yield: 16.1 %

Procedure:
1 g of 4-methyl-6-(4-tolyl)-2-pyrone, 0.6 g of hydroxylamine hydrochloride and 4 g of 2-aminopyridine were heated for 1 hour to 80° C. After the usual working up, 0.173 g (16.1 %) of 1-hydroxy-4-methyl-6-(4-tolyl)-2-pyridone melting at 125° C (calc.: 6.5 % N, found: 6,6 % N) were isolated. When using pyridine instead of aminopyridine under otherwise equal reaction conditions, the yield was 0.012 g (1.1 %) only.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C([NH:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24])(OC(C)(C)C)=O>O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[NH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=[O:24]
Reactant: CC(C)(C)OC(=O)NCCCCC/C=C/C(=O)O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: NCCCCC/C=C/C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 45 mL trifluoroacetic acid and 5 mL water was chilled in an ice bath while 34 g (0.132 mole) of (9) was added with stirring. The resulting solution was allowed to warm to room temperature over 1.5 h and then evaporated under a slow nitrogen stream overnight. The residue was triturated with ether. The solid was filtered, rinsed well with ether and dried to yield 21 g of the title compound (10), mp 77°-78° C. Anal. Calcd. for C10H15NO4F3 : C, 44.28; H, 5.95; N, 5.16. Found: C, 44.07; H, 5.96; N, 5.09.
Reaction SMILES: [CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[NH:19][C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3].O.[C:34]([O:38][CH2:39][CH:40]=[CH2:41])(=[O:37])[CH:35]=[O:36].O>C1(C)C=CC=CC=1>[CH2:1]([O:4][C:5]([N:7]1[CH2:11][CH2:10][CH2:9][C@H:8]1/[CH:12]=[C:13](\[CH3:32])/[C:14](=[O:31])[CH2:15][C@H:16]1[N:19]([C:35](=[O:36])[C:34]([O:38][CH2:39][CH:40]=[CH2:41])=[O:37])[C:18](=[O:20])[C@@H:17]1[C@H:21]([O:23][Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])[CH3:22])=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCOC(=O)N1CCC[C@H]1/C=C(\C)C(=O)C[C@H]1NC(=O)[C@@H]1[C@@H](C)O[Si](C)(C)C(C)(C)C
Reactant: C=CCOC(=O)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)C(=O)N1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H]1CC(=O)/C(C)=C/[C@@H]1CCCN1C(=O)OCC=C

Procedure:
To a solution of (3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl}-3-methyl-2-oxo-3-butenyl]-3-[(1R)-1-t-butyldimethylsilyloxyethyl]-2-oxoazetidine (9.96 g) in toluene (150 ml) was added allyl glyoxylate monohydrate (3.68 g). The resulting mixture was heated to reflux with azeotropic removal of water for 4 hours. Evaporation of the solvent gave a residue of allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin2-yl}-3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]glyoxylate, which was dissolved in xylene. After evaporation of the solvent in vacuo, the residue was dissolved in dichloromethane (150 ml). To this solution were added successively 2,6-lutidine (2.75 ml) and thionyl chloride (1.95 ml) at -20° C. After stirring at -20° C. for 15 minutes, the reaction mixture was poured into a mixture of ethyl acetate (500 ml) and water (500 ml) at 5° C. After adjusting pH to around 6.5 with aqueous sodium hydrogen carbonate, the organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated. The residue was dissolved in degassed N,N-dimethylformamide (80 ml), and to the solution were added 2,6-lutidine (2.75 ml) and triphenylphosphine (1.29 g). After standing for 6 hours at ambient temperature, the reaction mixture was poured into a mixture of ethyl acetate (400 ml) and water (400 ml). The separated organic layer was washed in turn with water, cold 1N hydrochloric acid, aqueous sodium hydrogen carbonate and brine, and dried over magnesium sulfate. Evaporation of the solvent gave a residue, which was chromatographed on silica gel (200 ml) eluting with a mixture of n-hexane and ethyl acetate (9:1 - 4:6 V/V) to give allyl 2-[(3S,4R)-4-[(E)-4-{(2S)-1-allyloxycarbonylpyrrolidin-2-yl} -3-methyl-2-oxo-3-butenyl]-3-{(1R)-1-t-butyldimethylsilyloxyethyl}-2-oxoazetidin-1-yl]-2-triphenylphosphoranylideneacetate (9.78 g).
Reaction SMILES: [OH:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14].[H-].[Na+].[CH3:22]I>CN(C)C=O>[CH3:22][O:1][C:2]1([CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]1=[O:14]
Reactant: COC1=CC(=O)C(O)(CCC(C)C)c2ccccc21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC1=CC(=O)C(CCC(C)C)(OC)c2ccccc21
Reaction time: 0.5 h
Yield: 83.8 %

Procedure:
To a solution of Example 11A (40 mg, 0.154 mmol) in N,N-dimethylformamide (1 mL) at 0° C. was added 60% wt sodium hydride (24.6 mg, 0.616 mmol). The reaction solution was stirred for 0.5 h and methyliodide (0.038 mL, 0.616 mmol) was added. The solution was stirred 16 h at room temperature, quenched with saturated NH4Cl, and extracted with ethyl acetate. The organic extract was concentrated in vacuo. Column chromatography on silica (20% ethyl acetate/hexane) afforded the title compound as a white solid (35.4 mg, 84%). 1H NMR (300 MHz, DMSO-d6) δ ppm 0.55-0.65 (m, 1H), 0.68 (dd, J=6.80 Hz, 6H), 0.85-1.00 (m, 1H), 1.20-1.33 (m, 1H), 1.56-1.96 (m, 2H), 2.76-2.86 (s, 3H), 3.96-4.02 (s, 3H), 5.48-5.84 (s, 1H), 7.25-7.70 (m, 3H), 7.82 (d, J=7.72 Hz, 1H); MS m/z 274.9 (M+H)+.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:26])[N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29]>>[CH3:32][O:31][C:27](=[O:30])[CH2:28][S:29][C:2]1[S:6][C:5]([NH:7][C:8]([N:9]([CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH:10]2[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]2)=[O:26])=[N:4][CH:3]=1
Reactant: O=C(Nc1ncc(Br)s1)N(C1CCCCC1)C1CCC(C(F)(F)F)CC1
Reactant: COC(=O)CS
Product: COC(=O)CSc1cnc(NC(=O)N(C2CCCCC2)C2CCC(C(F)(F)F)CC2)s1

Procedure:
Prepared as described in general procedure (D) using 3-(5-bromo-thiazol-2-yl)-1-cyclohexyl-1-(4-trifluoromethyl-cyclohexyl)-urea (Example 204) and methyl thioglycolate.
Reaction SMILES: FC(F)(F)C([N:5]([CH2:44][CH2:45][S:46]([CH3:49])(=[O:48])=[O:47])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[S:39][CH:40]=[CH:41][CH:42]=5)[CH:30]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:8]=1)=O.O[Li].O>C1COCC1.O.CCOC(C)=O>[CH3:49][S:46]([CH2:45][CH2:44][NH:5][CH2:6][C:7]1[CH:8]=[C:9]([NH:13][C:14]2[N:19]=[C:18]([C:20]3[C:21]([C:29]4[CH:30]=[C:31]([NH:35][C:36](=[O:43])[CH2:37][C:38]5[S:39][CH:40]=[CH:41][CH:42]=5)[CH:32]=[CH:33][CH:34]=4)=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[CH:17]=[CH:16][N:15]=2)[CH:10]=[CH:11][CH:12]=1)(=[O:47])=[O:48]
Reactant: CS(=O)(=O)CCN(Cc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1)C(=O)C(F)(F)F
Agent: [Li]O
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: CS(=O)(=O)CCNCc1cccc(Nc2nccc(-c3c(-c4cccc(NC(=O)Cc5cccs5)c4)nn4ccccc34)n2)c1
Temperature: 50 °C
Yield: 62 %

Procedure:
To a solution of 2,2,2-trifluoro-N-[2-(methylsulfonyl)ethyl]-N-[(3-{[4-(2-{3-[(2-thienylacetyl)amino]phenyl}pyrazolo[1,5-a]pyridin-3-yl)-2-pyrimidinyl]amino}phenyl)methyl]acetamide (79 mg, 0.11 mmol) in THF (3 mL) was added LiOH hydrate (10 mg, 0.21 mmol) in water (0.5 mL). The solution was heated to 50° C. for 2 h, and then diluted with EtOAc, washed with 1N Na2CO3, dried over Na2SO4, and concentrated to generate the title compound in 62% yield. 1H NMR (400 MHz, d6-DMSO) δ 10.36 (s, 1H), 9.55 (s, 1H), 8.84 (d, J=6.8 Hz, 1H), 8.52 (d, J=8.9 Hz, 1H), 8.24 (d, J=5.4 Hz, 1H), 7.90 (s, 1H), 7.74-7.76 (m, 2H), 7.59 (d, J=8.1 Hz, 1H), 7.38-7.50 (m, 2H), 7.28 (d, J=7.7 Hz, 1H), 7.20 (t, J=7.8 Hz, 1H), 7.13 (t, J=6.8 Hz, 1H), 6.92-6.98 (m, 3H), 6.44-6.51 (m, 2H), 3.88 (s, 2H), 3.66 (s, 2H), 3.23 (t, J=6.3 Hz, 2H), 3.01 (s, 3H), 2.91 (t, J=6.1 Hz). ES-LC/MS m/z=638 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1.[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[Sn](C)(C)C>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([S:11][CH2:12][CH2:13][N:7]3[C@H:6]3[CH2:14][CH2:15][N:16]([C:18]([O:20][C:21]([CH3:24])([CH3:22])[CH3:23])=[O:19])[CH2:17][C@@H:5]23)[CH:10]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCS3
Reactant: C[Sn](C)(C)c1c(F)cccc1F
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3c(F)cccc3F)cc3c1N2CCS3
Yield: 76.1 %

Procedure:
The tert-butyl(6bR,10aS)-5-(2,6-difluorophenyl)-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (288 mg, 76%) was prepared via coupling of tert-butyl(6bR,10aS)-5-bromo-1,2,6b,9,10,10a-hexahydropyrido[4,3-b][1,4]thiazino[2,3,4-hi]indole-8(7H)-carboxylate (0.350 g, 0.851 mmol) with 2,6-difluorophenyltrimethyl stannane (0.707 g, 2.553 mmol) using the procedure described in Example 447 Step G.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[C:7]([C:9]2[CH:10]=[C:11]([C:15]3[CH2:21][C:20](=[O:22])[NH:19][C:18]4[CH:23]=[C:24]([C:33]([F:36])([F:35])[F:34])[C:25]([O:27][CH2:28][C:29]([F:32])([F:31])[F:30])=[CH:26][C:17]=4[N:16]=3)[CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.S(Cl)(Cl)=O.[Cl-].[NH:42]1[CH2:45][CH2:44][CH2:43]1>C(Cl)Cl.CN(C=O)C>[N:42]1([CH2:2][C:3]2[CH:8]=[C:7]([C:9]3[CH:10]=[C:11]([C:15]4[CH2:21][C:20](=[O:22])[NH:19][C:18]5[CH:23]=[C:24]([C:33]([F:36])([F:34])[F:35])[C:25]([O:27][CH2:28][C:29]([F:30])([F:31])[F:32])=[CH:26][C:17]=5[N:16]=4)[CH:12]=[CH:13][CH:14]=3)[CH:6]=[CH:5][N:4]=2)[CH2:45][CH2:44][CH2:43]1
Reactant: O=C1CC(c2cccc(-c3ccnc(CO)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1
Reactant: C1CNC1
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1CC(c2cccc(-c3ccnc(CN4CCC4)c3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from 4-[3-(2-hydroxymethyl-pyridin-4-yl)-phenyl]-7-(2,2,2-trifluoro-ethoxy)-8-trifluoromethyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Example 286) (255 mg, 0.50 mmol) by reaction with thionylchloride in CH2Cl2 and subsequent treatment of the corresponding crude chloride with azetidine in DMF according to the general procedure of example 288. Obtained as an off-white solid (153 mg, 56%).
Reaction SMILES: [ClH:1].[NH2:2][C@@H:3]([CH3:14])[C@@H:4]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([CH2:12][CH3:13])[CH:7]=1)[OH:5].[F:15][C:16]1[CH:21]=[CH:20][C:19]([N:22]2[C:30]3[C:25](=[CH:26][C:27](I)=[CH:28][CH:29]=3)[CH:24]=[N:23]2)=[CH:18][CH:17]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)CCC.[Cu]I>[ClH:1].[CH2:12]([C:8]1[CH:7]=[C:6]([C@@H:4]([O:5][C:27]2[CH:26]=[C:25]3[C:30](=[CH:29][CH:28]=2)[N:22]([C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)[N:23]=[CH:24]3)[C@@H:3]([NH2:2])[CH3:14])[CH:11]=[CH:10][CH:9]=1)[CH3:13]
Reactant: Fc1ccc(-n2ncc3cc(I)ccc32)cc1
Reactant: CCc1cccc([C@@H](O)[C@H](C)N)c1
Agent: [Cu]I
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCCC#N
Product: CCc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1

Procedure:
The subtitle compound was prepared analogous to the method described in Example 19 (step 19a). A mixture of (1R,2S)-2-amino-1-(3-ethylphenyl)propan-1-ol hydrochloride (22b, 216 mg, 1.00 mmol), 1-(4-fluorophenyl)-5-iodo-1H-indazole (406 mg, 1.20 mmol), cesium carbonate (979 mg, 3.00 mmol) and copper(I) iodide (38.1 mg, 0.20 mmol) in butyronitrile (3 mL) was heated for 19 h at +125° C. in a sealed reactiontube flushed with Argon. After final purification by HPLC the obtained material was dissolved in tert-Butyl methyl ether, and precipitated as the hydrochloride salt by adding a solution of 6-7 N HCl in 2-propanol. Yield 199 mg (46%)
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([C:16]2[CH2:20][C:19]([CH2:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=2)[CH:12]=[C:13]([CH3:15])[CH:14]=1)C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[C:32]([O:31][C:29](=[O:30])[CH2:28][C:19]1([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[O:18][N:17]=[C:16]([C:11]2[CH:12]=[C:13]([CH3:15])[CH:14]=[C:9]([OH:8])[CH:10]=2)[CH2:20]1)([CH3:34])([CH3:35])[CH3:33]
Reactant: [H][H]
Reactant: Cc1cc(OCc2ccccc2)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Cc1cc(O)cc(C2=NOC(CC(=O)OC(C)(C)C)(C(=O)OC(C)(C)C)C2)c1
Yield: 91.3 %

Procedure:
A mixture of tert-butyl 3-(3-(benzyloxy)-5-methylphenyl)-5-(2-tert-butoxy-2-oxoethyl)-4,5-dihydro-1,2-oxazole-5-carboxylate (674 mg), 10% Pd/C (containing about 55% water, 67 mg), and THF (7 mL) was stirred overnight at room temperature in a hydrogen atmosphere. The catalyst was filtered off, and then, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the title compound (500 mg).
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([N:13]1[C:17]2[CH:18]=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[C:15]2[CH:24]=[C:25]([C:28]3[CH:33]=[CH:32][C:31]([CH2:34][OH:35])=[CH:30][CH:29]=3)[CH:26]=[N:27][C:14]1=2)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C>C(Cl)Cl>[C:6]([O:10][C:11]([N:13]1[C:17]2[CH:18]=[N:19][C:20]([C:22]#[N:23])=[CH:21][C:16]=2[C:15]2[CH:24]=[C:25]([C:28]3[CH:29]=[CH:30][C:31]([CH2:34][O:35][S:2]([CH3:1])(=[O:4])=[O:3])=[CH:32][CH:33]=3)[CH:26]=[N:27][C:14]1=2)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)n1c2cnc(C#N)cc2c2cc(-c3ccc(CO)cc3)cnc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c2cnc(C#N)cc2c2cc(-c3ccc(COS(C)(=O)=O)cc3)cnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 130.3 %

Procedure:
Methanesulfonyl chloride (60 μL, 0.70 mmol) was added to a solution of 6-cyano-3-(4-hydroxymethyl-phenyl)-dipyrido[2,3-b;4′,3′-d]pyrrole-9-carboxylic acid tert-butyl ester (224 mg, 0.60 mmol) and triethylamine (110 μL, 0.80 mmol) in DCM (20 mL). The mixture was allowed to warm to ambient temperature and stirred for 2 h. The mixture was diluted with DCM (200 mL) and washed with water (100 mL). The organic phase was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to afford the title compound as yellow oil (374 mg, 99%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[CH3:24][O:25][C:26]1[CH:39]=[CH:38][C:29]([CH2:30][N:31]2[CH2:35][CH:34]([CH3:36])[NH:33][C:32]2=[O:37])=[CH:28][CH:27]=1>>[CH3:22][C:21]1[C:16]([N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:6]=[CH:7][C:2]([N:33]4[CH:34]([CH3:36])[CH2:35][N:31]([CH2:30][C:29]5[CH:38]=[CH:39][C:26]([O:25][CH3:24])=[CH:27][CH:28]=5)[C:32]4=[O:37])=[CH:3][CH:4]=3)=[O:9])[CH2:11][CH2:12]2)=[N:17][CH:18]=[C:19]([CH3:23])[CH:20]=1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(Br)cc3)CC2)c(C)c1
Reactant: COc1ccc(CN2CC(C)NC2=O)cc1
Product: COc1ccc(CN2CC(C)N(c3ccc(C(=O)N4CCN(c5ncc(C)cc5C)CC4)cc3)C2=O)cc1
Yield: 63.2 %

Procedure:
Using (4-bromophenyl)[4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl]methanone (150 mg) described in Preparation Example 165 and 1-(4-methoxybenzyl)-4-methylimidazolidin-2-one (132 mg) described in Preparation Example 52 and by the reaction and treatment in the same manner as in Example 1, the title compound (130 mg) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][CH:15]3[CH2:20][CH2:19][CH2:18][CH:17]([OH:21])[CH2:16]3)[N:12]=2)=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH2:28]Br)([O-:25])=[O:24].[OH-].[Cs+]>C(#N)C.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][O:14][C@H:15]3[CH2:20][CH2:19][CH2:18][C@@H:17]([O:21][CH2:28][C:27]4[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=4[N+:23]([O-:25])=[O:24])[CH2:16]3)[N:12]=2)=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: Cc1oc(-c2ccc(F)cc2)nc1COC1CCCC(O)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [I-]
Solvent: CC#N
Product: Cc1oc(-c2ccc(F)cc2)nc1CO[C@H]1CCC[C@@H](OCc2ccccc2[N+](=O)[O-])C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.1 g of 3-[2-(4-fluorophenyl)-5-methyloxazol-4-ylmethoxy]cyclohexanol is dissolved in 3 ml of acetonitrile, and 0.21 g of 2-nitrobenzyl bromide and 0.36 g of tetrabutylammonium iodide are added. 0.57 ml of cesium hydroxide solution (50% strength solution in water) is added dropwise, and the two-phase mixture is stirred vigorously at room temperature, for 12 hours. The reaction is checked (LCMS), showing the formation of the desired product, in addition to unreacted alcohol 3-[2-(4-fluorophenyl)-5-methyloxazol4-ylmethoxy]cyclohexanol. By addition of a further 0.2 g of 2-nitrobenzyl bromide (2 eq) at room temperature and stirring at room temperature for a further 12 hours, the reaction is terminated by addition of 2 ml of 1N hydrochloric acid and the mixture is extracted with ethyl acetate (2×10 ml). The combined organic phases are washed with saturated sodium chloride solution and dried over magnesium sulfate. Purification by HPLC gives 0.05 g of the compound 2-(4-fluorophenyl)-5-methyl4-[cis-3-(2-nitrobenzyloxy)cyclohexyloxymethyl]oxazole as a clear colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Br:11])=[C:6]([S:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[N+:23]([O-])=O)(=[O:14])=[O:13])[CH:5]=1>CN(C)C=O.[Ni]>[CH3:1][O:2][C:3](=[O:26])[C:4]1[CH:9]=[C:8]([CH3:10])[C:7]([Br:11])=[C:6]([S:12]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[C:17]=2[NH2:23])(=[O:14])=[O:13])[CH:5]=1
Reactant: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cc2cccc(Cl)c2[N+](=O)[O-])c1
Agent: [Ni]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(C)c(Br)c(S(=O)(=O)Cc2cccc(Cl)c2N)c1
Reaction time: 2 h

Procedure:
Activated Raney-Nickel was added to a solution of compound of Example 37c (1.50 g, 3.46 mmol) in dimethylformamide (100 mL). The reaction mixture was subjected to hydrogenation (25 psi pressure) for 2 h. Catalyst was filtered-off, washed with dimethylformamide and concentrated to obtain the crude product, which was then purified by column chromatography (silica gel, 30% ethyl acetate in pet. ether 60-80° C.) to obtain the title compound. Yield: 0.785 g, (56.07%). MS: m/e (ES+) 433 (M+1).
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1)=C=O.Cl>O1CCOCC1>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:15](=[O:16])[C:14]3=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=[C:13]3[C:12]2=[O:22])[CH:5]=1
Reactant: Cc1ccc(N=C=O)cc1N1C(=O)c2ccc(Cl)cc2C1=O
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(N)cc1N1C(=O)c2ccc(Cl)cc2C1=O

Procedure:
The mixture of 0.5 g of N-(4-isocyanato-o-tolyl)-4-chlorophthalimide, 25 ml of p-dioxane and 10 ml of N hydrochloric acid is refluxed for 30 minutes and evaporated. The residue is taken up in methylene chloride, the solution washed with cold 5% aqueous sodium carbonate, dried, evaporated and the residue recrystallized from ethyl acetate, to yield the N-(4-amino-o-tolyl)-4-chlorophthalimide melting at 202°-204°.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1)=O)C.[CH3:17][Mg]I>C1COCC1>[O:3]=[C:4]([C:6]1[S:10][C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)=[N:8][N:7]=1)[CH3:17]
Reactant: C[Mg]I
Reactant: CCOC(=O)c1nnc(-c2ccccn2)s1
Solvent: C1CCOC1
Product: CC(=O)c1nnc(-c2ccccn2)s1
Temperature: -40 °C
Reaction time: 2 h

Procedure:
To a mixture of 2-(5-ethoxycarbonyl-1,3,4-thiadiazol-2-yl)-pyridine (2 gm) in THF (40 ml) was added methyl magnesium iodide (15 ml, 1.4 M solution in THF) at −40° C. over a period of 15 minutes. The reaction mixture was stirred for 2 h at −40° C. It was quenched by addition of aqueous ammonium chloride solution (20 gm) and stirred at 0° C. over a period of 10 minutes. It was extracted with ethyl acetate (100 ml×2). Combined organic layers was washed with water and evaporated under vacuum to provide a title compound in 1.5 gm quantity (86%) as off white solid.
Reaction SMILES: N[C:2]1([O:8]O)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][CH:11]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13](=[O:14])[CH2:12]1.C([O-])(=O)C.[NH4+]>CO>[C:2]1(=[O:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:10][CH:11]1[CH2:17][C:16]([CH3:19])([CH3:18])[CH2:15][C:13](=[O:14])[CH2:12]1
Reactant: NC1(OO)CCCCC1
Agent: CC(=O)[O-]
Agent: CC1CC(=O)CC(C)(C)C1
Agent: [NH4+]
Solvent: CO
Product: O=C1CCCCC1

Procedure:
1-Aminocyclohexyl hydroperoxide (13.1 g), dihydroisophorone (14 g), methanol (25 cc.) and ammonium acetate (1.0 g) were mixed, store at 0°C overnight and worked up as in the previous example. Distillation gave cyclohexanone and dihydroisophorone (9.0 g), an intermediate fraction (3.2 g), b.p. below 100°C/0.7 mm,Hg., a fraction (8.1 g), b.p. 110°-114°/0.7 mm of 3,3,5'-trimethyl-1,1'-peroxy-dicyclohexylamine (peroxide equivalent, 234; perchloric acid equivalent, 245; and residue (1.5 g). The process may be carried out in the liquid or gas phase, but is preferably carried out in the gas phase as the liquid phase reaction tends to give a complex mixture of products of which only part are the desired derivatives of 1,12-dodecanedioic acid. The elevated temperature to which the 1,1'-peroxydicyclohexylamine is heated is suitably in the range 300°C to 600°C, and preferably from 400°C to 600°C. If the reaction is to be carried out in the gas phase it is preferred to use reduced pressures. Suitable pressures are of the order of 10 to 250 mm Hg.