Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:21])[CH2:4][C:5]2([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([OH:16])[C:11]=3[Br:15])[C:6]=12.C(N(CC)C(C)C)(C)C.[CH3:31][O:32][CH2:33]Cl>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[C:3](=[O:21])[CH2:4][C:5]2([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[C:10]([O:16][CH2:31][O:32][CH3:33])[C:11]=3[Br:15])[C:6]=12
Reactant: CCCCC12CCc3c(ccc(O)c3Br)C1=C(Br)C(=O)C2
Reactant: COCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCCC12CCc3c(ccc(OCOC)c3Br)C1=C(Br)C(=O)C2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 1,6-dibromo-3a-butyl-7-hydroxy-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one (189 mg, 0.46 mmol) in anhydrous DMF (2.3 mL) was placed under a N2 atmosphere and stirred at room temperature while N,N-diisopropylethylamine (0.242 mL, 1.38 mmol) and chloromethyl methyl ether (0.070 mL, 0.92 mmol) were added successively. After stirring at room temperature for 16 hours, the mixture was diluted with EtOAc and washed with 1N HCl. The organic phase was washed with 5% NaHCO3 and brine, dried over MgSO4, filtered, and concentrated under vacuum to provide crude 1,6-dibromo-3a-butyl-7-(methoxymethoxy)-3,3a,4,5-tetrahydro-2H-cyclopenta[a]naphthalen-2-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1.[H-].[Na+].I[CH3:14]>CN(C=O)C.O>[Cl:1][C:2]1[N:6]([CH3:14])[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: Clc1nc2ccccc2[nH]1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(Cl)nc2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-1H-benzimidazole (5.03 g, 33.0 mmol) in anhydrous DMF (33 mL) at 0° C. was added portion-wise 95% NaH (871 mg, 36.3 mmol). The ice bath was removed and the resulting mixture was stirred at room temperature for 1 h. Iodomethane (4.68 g, 33.0 mmol) was added and the resulting mixture was stirred at room temperature overnight. The resulting mixture was then diluted with water, and the resulting precipitate was collected by filtration and purified by recrystallization from hexane to yield 2-chloro-1-methyl-1H-benzimidazole. MS 167 (M+1)+
Reaction SMILES: C([NH:4][C@:5]1([C:22](NC(C)(C)C)=[O:23])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]2[O:17]C(C)(C)C(C)(C)[O:14]2)[CH2:8][NH:7][CH2:6]1)(=O)C.[CH3:29][N:30]1[CH:34]=[CH:33][N:32]=[C:31]1[CH:35]=O.S([O-])([O-])(=O)=[O:38].[Na+].[Na+].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[Na+].[Na+]>ClCCCl>[NH2:4][C@:5]1([C:22]([OH:23])=[O:38])[C@@H:9]([CH2:10][CH2:11][CH2:12][B:13]([OH:14])[OH:17])[CH2:8][N:7]([CH2:35][C:31]2[N:30]([CH3:29])[CH:34]=[CH:33][N:32]=2)[CH2:6]1
Reactant: CC(=O)N[C@@]1(C(=O)NC(C)(C)C)CNC[C@@H]1CCCB1OC(C)(C)C(C)(C)O1
Reactant: Cn1ccnc1C=O
Reactant: O=S(=O)([O-])[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: Cn1ccnc1CN1C[C@H](CCCB(O)O)[C@](N)(C(=O)O)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.3 %

Procedure:
A stirred solution of (3R,4S)-3-acetamido-N-tert-butyl-4-(3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propyl)pyrrolidine-3-carboxamide (Example 8, step 4) (198 mg, 0.5 mmol) and 1-methylimidazole-2-carboxaldehyde (83 mg, 0.75 mmol) in anhydrous 1,2-dichloroethane (5 mL) was treated with anhydrous sodium sulfate (1 g) and glacial acetic acid (30 mg, 0.5 mmol), stirred at room temperature for 3 h, then cooled to room temperature and treated with sodium triacetoxyborohydride (212 mg, 1.0 mmol) and stirred for 18 h. Aqueous sodium carbonate (10%, 5 mL) was added and the mixture stirred for a few minutes and extracted with ethyl acetate (30 mL, then 2×10 mL). The combined organic solution was washed with water and saturated aqueous sodium chloride (20 mL each), dried (MgSO4), and concentrated. The crude material was deprotected and isolated using the method described for example 8, step 5 to afford (3R,4S)-3-amino-4-(3-boronopropyl)-1-((1-methyl-1H-imidazol-2-yl)methyl)pyrrolidine-3-carboxylic acid (140 mg, 67%) as a pale yellow solid. NMR (D2O) δ 7.37 (s, 2 H), 4.35-4.50 (m, 2 H), 3.80 (s, 3 H), 3.40-3.60 (m, 3 H), 2.75-2.85 (m, 1 H), 2.43 (m, 1 H), 1.48 (s, 1 H), 1.15-1.30 (3 H), 0.60-0.70 (m, 2 H). MS (m+1): 311.0; MS (m−H2O+1): 293.1.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[CH2:11](Cl)Cl>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:11])=[O:7])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: ClCCl
Product: COC(=O)c1ccc(Cl)nc1
Reaction time: 8 h

Procedure:
An ethereal solution of CH2N2 (0.1 mole) is added to a suspension of 6-chloronicotinic acid (15 g) in CH2Cl2 until bubbling ceases. The reaction mixture is stirred overnight, evaporated and dried in vacuo affording the desired product as an off-white solid. M.P.=83°-85° C.
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH2:19])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:8]=1.[N:20]1[N:21]([C:25]2[CH:33]=[CH:32][CH:31]=[CH:30][C:26]=2[C:27](O)=[O:28])[N:22]=[CH:23][CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[Cl:2][C:3]1[C:4]([NH:13][C@H:14]2[CH2:18][CH2:17][CH2:16][C@@H:15]2[NH:19][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][CH:32]=[CH:33][C:25]=2[N:21]2[N:22]=[CH:23][CH:24]=[N:20]2)=[N:5][CH:6]=[C:7]([C:9]([F:11])([F:12])[F:10])[N:8]=1
Reactant: N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl
Reactant: O=C(O)c1ccccc1-n1nccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(N[C@H]1CCC[C@@H]1Nc1ncc(C(F)(F)F)nc1Cl)c1ccccc1-n1nccn1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
To a solution of (1S,2S)-1-N-[3-chloro-5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (530 mg, 1.67 mmol) in dry DMF (5.6 ml) was added 2-(2H-1,2,3-triazol-2-yl)benzoic acid (CAS number 1001401-62-2; 348 mg, 1.84 mmol), HATU (953 mg, 2.51 mmol) and triethylamine (699 μl, 5.01 mmol) and then stirred at room temperature for 17 hours. The reaction was partitioned between ethyl acetate and a saturated solution of sodium bicarbonate. The organics were washed with water, brine, dried over magnesium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (basic silica, 0-100% ethyl acetate/petrol) to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][C:5]([NH2:15])=[C:4]([F:16])[CH:3]=1.[C:17](Cl)(Cl)=[S:18]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([F:16])[C:5]([N:15]=[C:17]=[S:18])=[CH:6][C:7]=1[O:8][C:9]1[N:10]=[CH:11][CH:12]=[CH:13][N:14]=1
Reactant: S=C(Cl)Cl
Reactant: Nc1cc(Oc2ncccn2)c(Cl)cc1F
Solvent: CCOC(C)=O
Product: Fc1cc(Cl)c(Oc2ncccn2)cc1N=C=S

Procedure:
4-Chloro-2-fluoro-5-(2-pyrimidinyloxy)benzenamine (1.0 g) was dissolved in anhydrous ethyl acetate (50 ml) and thiophosgene (0.59 g) was slowly added to the stirred solution. The mixture was heated at reflux for 2 hr. Evaporation of the solvent afforded 2-(2-chloro-4-fluoro-5-isothiocyanatophenoxy)pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6]1[NH:7][CH2:8][CH2:9][N:10]=1.[Br:16][C:17]1[CH:22]=[CH:21][C:20]([N:23]=[C:24]=[O:25])=[CH:19][CH:18]=1>C(Cl)Cl>[OH2:4].[Br:16][C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24]([N:10]2[CH2:9][CH2:8][N:7]=[C:6]2[CH2:5][O:4][C:3]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:15])[C:2]=2[CH3:1])=[O:25])=[CH:19][CH:18]=1
Reactant: Cc1cccc(OCC2=NCCN2)c1C
Reactant: O=C=Nc1ccc(Br)cc1
Solvent: ClCCl
Product: Cc1cccc(OCC2=NCCN2C(=O)Nc2ccc(Br)cc2)c1C
Product: O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 2-(2,3-dimethylphenoxymethyl)-2-imidazoline (20.4 g; 1.0 mol) in methylene chloride (300 ml) was cooled to -65° C. and a solution of 4-bromophenylisocyanate (19.8 g; 1.0 mol) in methylene chloride (300 ml) added dropwise during 30 minutes. The reaction mixture was then allowed to warm to ambient temperature and left to stand for 2 hours, when a precipitate had formed. The reaction mixture was evaporated under reduced pressure and the residue recrystallised from acetone to give 1-(N-(4-bromophenyl)-carbamoyl)-2-(2,3-dimethylphenoxymethyl)-2-imidazoline monohydrate, m.p. 150°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[C:10]([NH:16][C:17]3[CH:22]=[C:21]([CH:23]=O)[CH:20]=[CH:19][C:18]=3[N+:25]([O-:27])=[O:26])[S:11][C:12]=2[C:13]([NH2:15])=[O:14])[CH:5]=[CH:6][CH:7]=1.Cl.Cl.Cl.[N:31]1([CH2:37][CH2:38][CH2:39][NH:40][CH2:41][CH2:42][CH2:43][N:44]2[CH2:49][CH2:48][O:47][CH2:46][CH2:45]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[N:31]1([CH2:37][CH2:38][CH2:39][N:40]([CH2:23][C:21]2[CH:20]=[CH:19][C:18]([N+:25]([O-:27])=[O:26])=[C:17]([NH:16][C:10]3[S:11][C:12]([C:13]([NH2:15])=[O:14])=[C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[N:9]=3)[CH:22]=2)[CH2:41][CH2:42][CH2:43][N:44]2[CH2:45][CH2:46][O:47][CH2:48][CH2:49]2)[CH2:32][CH2:33][O:34][CH2:35][CH2:36]1
Reactant: NC(=O)c1sc(Nc2cc(C=O)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reactant: C(CNCCCN1CCOCC1)CN1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)c1sc(Nc2cc(CN(CCCN3CCOCC3)CCCN3CCOCC3)ccc2[N+](=O)[O-])nc1-c1cccc(Cl)c1
Reaction time: 0.33 h
Yield: 28.2 %

Procedure:
A mixture of 0.455 g (1.13 mmole) of 4-(3-chloro-phenyl)-2-(5-formyl-2-nitro-phenylamino)-thiazole-5-carboxylic acid amide (VI.2b), 0.860 g (2.26 mmole) of bis-(3-morpholin-4-yl-propyl)-amine trihydrochloride and 50 mL of dichloromethane was stirred for 20 minutes, then 0.479 g 2.26 mmole) of sodium triacetoxy borohydride was added. The mixture was stirred for 4 days, then quenched by the addition of 50 mL of saturated sodium bicarbonate solution. The mixture was extracted three times with 50 mL of dichloromethane. The combined dichloromethane layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (90:10) to give 0.210 g of 2-(5-{[bis-(3-morpholin-4-yl-propyl)-amino]-methyl}-2-nitro-phenylamino)-4-(3-chloro-phenyl)-thiazole-5-carboxylic acid amide (VI.49a).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[O:9][C:10](=[O:15])[O:11][C:12]\1([CH3:14])[CH3:13])(=[O:3])[CH3:2].[C:16](OCC)(=O)C.COC1C=CC(O)=CC=1>>[C:1]([O:4][CH2:5][CH2:6]/[CH:7]=[C:8]1\[O:9][C:10](=[O:15])[O:11][C:12]\1([CH3:14])[CH3:13])(=[O:3])[CH:2]=[CH2:16]
Reactant: CCOC(C)=O
Reactant: CC(=O)OCC/C=C1\OC(=O)OC1(C)C
Agent: COc1ccc(O)cc1
Product: C=CC(=O)OCC/C=C1\OC(=O)OC1(C)C
Temperature: 40 °C
Reaction time: 24 h

Procedure:
280 g (1.31 mol) of (3Z)-3-(5,5-dimethyl-2-oxo-1,3-dioxolan-4-ylidene)propyl acetate (exo-VC-OAc), 1307 g (13.1 mol) of ethyl acetate, 0.28 g of 4-methoxyphenol (MeHQ) and 84 g (30% by weight) of Novozym® 435 from Novozymes were combined. The mixture was stirred at 40° C. for 24 h. The mixture was filtered and washed through with acetone, and the solvent was removed at 40° C. on a rotary evaporator. This gave 276.7 g of the product of the title compound with a purity of 92.4% (GC analysis).
Reaction SMILES: [NH:1]1[C:5]([CH:6]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8][N:7]2[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])=[N:4][N:3]=[N:2]1.IC.[C:29]([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH3:29][N:3]1[N:2]=[N:1][C:5]([CH:6]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8][N:7]2[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[N:4]1.[CH3:29][N:4]1[C:5]([CH:6]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9][CH2:8][N:7]2[C:17]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:18])=[N:1][N:2]=[N:3]1
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn[nH]2)C1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnn(C)n2)C1
Product: CCOC(=O)C1CCN(C(=O)OCc2ccccc2)C(c2nnnn2C)C1
Temperature: 25 °C
Reaction time: 3 h
Yield: 32 %
Yield: 51 %

Procedure:
1-Benzyl 4-ethyl 2-(1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (3.45 g, 9.60 mmol) was dissolved in acetone (20 mL) and iodomethane (2.99 mL, 48.00 mmol) and K2CO3 (3.98 g, 28.80 mmol) were added. The mixture was stirred at room temperature for 3 h. The reaction mixture was partitioned between water and EtOAc. The aqueous layer was extracted twice with EtOAc and the combined organic phase was washed with water and evaporated. The crude product was purified on a 100 g Biotage column with heptane/EtOAc 88/12-0/100 over 12 column volumes (CV). 1-Benzyl 4-ethyl 2-(2-methyl-2H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (1.84 g, 51%) and 1-benzyl 4-ethyl 2-(1-methyl-1H-tetrazol-5-yl)piperidine-1,4-dicarboxylate (1.14 g, 32%) were isolated. 2-Methyl-isomer: 1H NMR (400 MHz, cdcl3) δ 1.15 (t, 3H), 1.75-1.87 (m, 1H), 2.02-2.11 (m, 1H), 2.27-2.37 (m, 1H), 2.66-2.78 (m, 2H), 3.55-3.65 (m, 1H), 3.75-3.86 (m, 1H), 3.90-3.99 (m, 1H), 4.01-4.09 (m, 1H), 4.25 (s, 3H), 5.13 (q, 2H), 5.55-5.62 (m, 1H), 7.25-7.38 (m, 5H). MS m/z 374 (M+H)+. 3-Methyl-isomer: MS m/z 374 (M+H)+
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:12]=[C:13]([CH:31]=[CH2:32])[C:14]2[O:18][C:17]([C:19]3[CH:24]=[CH:23][C:22]([O:25]C(=O)C)=[C:21]([F:29])[CH:20]=3)=[N:16][C:15]=2[CH:30]=1)(=O)C.O1CCOCC1.Cl>O>[F:29][C:21]1[CH:20]=[C:19]([C:17]2[O:18][C:14]3[C:13]([CH:31]=[CH2:32])=[CH:12][C:11]([OH:10])=[CH:30][C:15]=3[N:16]=2)[CH:24]=[CH:23][C:22]=1[OH:25]
Reactant: C=Cc1cc(OC(C)=O)cc2nc(-c3ccc(OC(C)=O)c(F)c3)oc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1cc(O)cc2nc(-c3ccc(O)c(F)c3)oc12
Temperature: 90 °C
Reaction time: 1 h
Yield: 46 %

Procedure:
Potassium carbonate (55 mg) was added into a solution of 2-[4-(acetyloxy)-3-fluorophenyl]-7-vinyl-1,3-benzoxazol-5-yl acetate (0.14 g, 0.39 mmol) and 1,4-dioxane (3 mL). The mixture was stirred at 90° C. for 1 h, poured into water, acidified with HCl (2N) and extracted with EtOAc. The organic extracts were dried over MgSO4. Evaporation and crystallization from EtOAc/hexanes, gave a white solid. (0.06 g, 46% yield, m.p. 250–252° C.); MS m/e 272 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:19]1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].CI>O1CCCC1>[CH3:19][N:10]1[C:11]2[C:7](=[CH:6][CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[CH:12]=2)[CH:8]=[C:9]1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: C1COCCOCCOCCOCCOCCO1
Reactant: O=[N+]([O-])c1ccc2cc(-c3ccccc3)[nH]c2c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: Cn1c(-c2ccccc2)cc2ccc([N+](=O)[O-])cc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99.1 %

Procedure:
To a solution of 6-nitro-2-phenyl-1H-indole (106 mg, 0.44 mmol) and 18-Crown-6 (130 mg, 0.49 mmol) in anhydrous tetrahydrofuran (2 mL) at room temperature was added potassium tert-butoxide (55 mg, 0.49 mmol) followed by methyl iodide (31 μL, 0.49 mmol). The solution was stirred at room temperature for 30 min. Tetrahydrofuran was removed in vacuo. Ethyl acetate was added, and the organic layer was washed with water and then brine. The combined organic layers were dried over anhydrous MgSO4 and evaporated to afford 110 mg (98%) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]2=[NH:16])[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1.O=[C:18]([CH3:22])[C:19](=[S:21])[NH2:20]>CO>[Br:1][C:2]1[CH:15]=[C:14]2[C:5]([CH2:6][C:7]3([C:13]42[NH:20][C:19](=[S:21])[C:18]([CH3:22])=[N:16]4)[CH2:12][CH2:11][O:10][CH2:9][CH2:8]3)=[CH:4][CH:3]=1
Reactant: CC(=O)C(N)=S
Reactant: N=C1c2cc(Br)ccc2CC12CCOCC2
Solvent: CO
Product: CC1=NC2(NC1=S)c1cc(Br)ccc1CC21CCOCC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 125.5 %

Procedure:
6-Bromo-2′,3′,5′,6′-tetrahydrospiro[indene-2,4′-pyran]-1(3 H)-imine (Example 25 Step 2, 235 mg, 0.84 mmol) and 2-oxopropanethioamide (Intermediate 2, 173 mg, 1.68 mmol) were taken up in anhydrous MeOH (5 mL) and the resulting mixture was stirred at 60° C. under a nitrogen atmosphere for 3 h. When cooled to r.t. the mixture was concentrated and purified on a silica gel column eluted with 0-50% EtOAc in heptane to give 385 mg (95% yield) of the title compound; 1H NMR (500 MHz, DMSO-d6) δ ppm 12.40 (br. s, 1 H), 7.53 (dd, 1 H), 7.36 (d, 1 H), 7.03 (d, 1 H), 3.71 (td, 2 H), 3.44 (m, 2 H), 3.15 (m, 2 H), 2.29 (s, 3 H), 1.64 (s, 1 H), 1.55 (s, 1 H), 1.27 (m, 2 H); MS (ES+) m/z 365 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[C:15]([Cl:17])[CH:16]=1)[C:5]#[N:6].[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:17][C:15]1[CH:16]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[C:29]2[C:24]([O:23][CH3:22])=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[N:13][C:14]=1[O:18][CH:19]([CH3:21])[CH3:20]
Reactant: COc1ncccc1B(O)O
Reactant: CC(C)Oc1ncc(Oc2ccc(C#N)cc2Br)cc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a solution of 3-bromo-4-[(5-chloro-6-isopropoxypyridin-3-yl)oxy]benzonitrile (Preparation 25, 638 mg, 1.74 mmol) and 2-methoxy-3-pyridylboronic acid (265 mg, 1.74 mmol) in dioxan (10.5 mL) was added a 1 M aqueous solution of sodium carbonate (5.2 mL, 5.21 mmol). The reaction was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol). The reaction mixture was heated to 100° C. and stirred for 16 hours and then concentrated in vacuo The residue was partitioned between water (30 mL) and EtOAc (25 mL). The aqueous phase was separated and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by silica gel column chromatography, eluting with 9:1 heptane/EtOAc. Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (534 mg, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:13]([CH2:14][OH:15])=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[N:10]1.[Br:19][C:20]1[CH:25]=[CH:24][C:23](O)=[CH:22][C:21]=1[CH3:27].C(P(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[Br:19][C:20]1[CH:25]=[CH:24][C:23]([O:15][CH2:14][C:13]2[N:9]([C:3]3[C:4]([Cl:8])=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])[N:10]=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])=[CH:22][C:21]=1[CH3:27]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(C)c1nnn(-c2c(Cl)cccc2Cl)c1CO
Agent: CCCCP(CCCC)CCCC
Solvent: Cc1ccccc1
Product: Cc1cc(OCc2c(C(C)C)nnn2-c2c(Cl)cccc2Cl)ccc1Br
Temperature: 0 °C
Reaction time: 6 h
Yield: 67.8 %

Procedure:
To a solution of [3-(2,6-dichloro-phenyl)-5-isopropyl-3H-[1,2,3]triazol-4-yl]-methanol (300 mg, 1.05 mmol) in toluene (4 mL) are added 4-bromo-3-methyl-phenol (196 mg, 1.05 mmol) and tri-n-butylphosphine (394 μL, 1.58 mmol). The reaction mixture is cooled to 0° C. To the reaction mixture is added 1,1′-(Azocarbonyl)-dipiperidine (399 mg, 1.58 mmol) and the reaction mixture is warmed to room temperature. After 6 h, the reaction mixture is concentrated and the residue is chromatographed eluting with 10% to 20% EtOAc/hexanes to yield the title compound (324 mg, 68%). LC-ES/MS m/e 455.7 (M+1).
Reaction SMILES: C(N(CC)CC)C.[CH2:8]([C:10]1([CH2:16][CH2:17][N:18]2[CH2:23][CH2:22][CH:21]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[CH2:20][CH2:19]2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)[CH3:9].[O:32]1[CH:36]=[CH:35][CH:34]=[C:33]1[C:37](Cl)=[O:38].[Cl-].[NH4+]>C(Cl)Cl.C(Cl)(Cl)Cl>[CH2:8]([C:10]1([CH2:16][CH2:17][N:18]2[CH2:19][CH2:20][CH:21]([N:24]([C:25]3[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][N:26]=3)[C:37]([C:33]3[O:32][CH:36]=[CH:35][CH:34]=3)=[O:38])[CH2:22][CH2:23]2)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]1)[CH3:9]
Reactant: O=C(Cl)c1ccco1
Reactant: CCC1(CCN2CCC(Nc3ccc(C)cn3)CC2)CCCCC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCC1(CCN2CCC(N(C(=O)c3ccco3)c3ccc(C)cn3)CC2)CCCCC1
Reaction time: 2 h
Yield: 90.2 %

Procedure:
Triethylamine (1.33 mL, 9.55 mmol) was added to a solution of 1-[2-(1-ethylcyclohexyl)ethyl]-4-(5-methylpyridin-2-yl)aminopiperidine (1.31 g, 3.98 mmol) in methylene chloride (13 mL). After adding 2-furoyl chloride (0.47 mL, 4.78 mmol) while cooling on ice, the mixture was stirred for 2 hours. A 25% aqueous ammonium chloride solution was added to the reaction mixture, extraction was performed with chloroform, and the organic layer was washed with saturated aqueous sodium chloride. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (80 g NH silica Chromatorex DM2035, hexane:ethyl acetate=2:1) to obtain the title compound as a light yellow solid (1.52 g, 3.59 mmol) (90% yield).
Reaction SMILES: [OH2:1].Cl.[NH2:3]O.[OH-].[Na+].[CH3:7][CH:8]([N:13]=[N:14][C:15]([C:18]#[N:19])([CH3:17])[CH3:16])[CH2:9][CH:10]([CH3:12])[CH3:11]>CO>[CH3:7][CH:8]([N:13]=[N:14][C:15]([CH3:16])([CH3:17])[C:18](=[N:3][OH:1])[NH2:19])[CH2:9][CH:10]([CH3:11])[CH3:12]
Reactant: O
Reactant: NO
Reactant: CC(C)CC(C)N=NC(C)(C)C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(C)CC(C)N=NC(C)(C)C(N)=NO
Reaction time: 2 h

Procedure:
To 10 ml of water and 6.45 grams (0.0926 moles) of hydroxylamine hydrochloride in a 250 ml 3-neck round bottom flask equipped with a magnetic stirrer, air-cooled condenser, thermometer, and immersed in an ice bath was slowly added 7.42 grams (0.0926 moles) of 50% sodium hydroxide, followed by 100 ml of methanol. To this stirred mixture was added 16.4 grams (.0906 moles) of 2-(1,3-dimethyl-butylazo)-2-cyanopropane (from Example 4-a-4). The ice bath was removed and the flask stoppered and the reaction mixture stirred for 11/2 hours and allowed to stand over the weekend at room temperature. The insolubles were filtered off and the methanol filtrate was poured into 150 ml water and the product extracted with 100 ml of pentane. The pentane solution was washed twice with 100 ml portions of water, dried over anhydrous sodium sulfate, filtered and the pentane evaporated under reduced pressure on a rotating evaporator. The product was a yellow liquid and weighed 8.8 grams (46% crude yield). The infrared spectrum of the product was in agreement with the structure of 2-(1,3-dimethylbutylazo)- 2-methylpropionamidoxime (strong broad NH and OH bands at 3150-3450 cm-1, a strong imino band at 1750 cm-1 and the absence of the cyano band of the starting material at 2225 cm-1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=O)=[CH:4][CH:3]=1.[C:17]1(=O)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:17]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:10]2[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C1CCCCCC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(Br)cc1
Product: Oc1ccc(C(=C2CCCCCC2)c2ccc(Br)cc2)cc1
Yield: 78.2 %

Procedure:
The general McMurry coupling protocol, described for 14 was followed. Reaction of (4-bromophenyl)(4-hydroxyphenyl)methanone (2.77 g, 10 mmol), and cycloheptanone (3.6 mL, 30 mmol) afforded 2.795 g (78%) of the title compound 200 as an off-white solid. 1H NMR (300 MHz, CDCl3): δ 7.41 (d, J=8.1 Hz, 2H), 7.04 (d, J=6.3 Hz, 2H), 7.01 (d, J=6.3 Hz, 2H), 6.76 (d, J=8.4 Hz, 2H), 4.74 (s, 1H), 2.32 (m, 4H), 1.59 (s, 8H).