Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O=C(C1CCC2(OCCO2)CC1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[O:19]1[C:23]2([CH2:28][CH2:27][CH2:26][CH:25]([C:29]([OH:31])=O)[CH2:24]2)[O:22][CH2:21][CH2:20]1.O1C2(CCC(C(O)=O)CC2)OCC1>>[O:31]=[C:29]([CH:25]1[CH2:26][CH2:27][CH2:28][C:23]2([O:19][CH2:20][CH2:21][O:22]2)[CH2:24]1)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)CC(=O)C1CCC2(CC1)OCCO2
Reactant: O=C(O)C1CCCC2(C1)OCCO2
Agent: O=C(O)C1CCC2(CC1)OCCO2
Product: CCOC(=O)CC(=O)C1CCCC2(C1)OCCO2

Procedure:
Ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-7-yl)propanoate was synthesized in a manner similar to the synthesis of ethyl 3-oxo-3-(1,4-dioxaspiro[4.5]decan-8-yl)propanoate, but with 1,4-dioxaspiro[4.5]decane-7-carboxylic acid substituted for 1,4-dioxaspiro[4.5]decane-8-carboxylic acid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][O:6][CH2:5][CH2:4]1.[C:9]([O:15][CH2:16][CH3:17])(=[O:14])[CH2:10][C:11]([CH3:13])=[O:12].[CH2:18]1[O:20][CH2:19]1>>[OH:6][CH2:7][CH2:8][CH:3]1[CH2:2][O:1][C:5](=[O:12])[CH2:4]1.[O:20]1[CH2:19][CH2:18][CH:10]([C:9]([O:15][CH2:16][CH3:17])=[O:14])[CH2:11][CH2:13]1
Reactant: CCOC(=O)CC(C)=O
Reactant: OCC1CCOCC1
Reactant: C1CO1
Product: CCOC(=O)C1CCOCC1
Product: O=C1CC(CCO)CO1

Procedure:
It is known that 4-hydroxymethyltetrahydropyran can be prepared in three steps: reaction of ethyl acetoacetate with ethylene oxide to form 3-(2-hydroxyethyl)gamma-butyrolactone (EP-A-246 581), rearrangement to ethyl tetrahydropyran-4-carboxylate (EP-A-284 969), and subsequent catalytic hydrogenation to form 4-hydroxymethyltetrahydropyran (DE-A-4 141 222).
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:7](=[O:9])[CH:8]=1.[C:20](Cl)(=[O:22])[CH3:21]>N1C=CC=CC=1>[C:20]([O:1][CH2:2][C:3]1[NH:4][CH:5]=[C:6]([O:10][CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[C:7](=[O:9])[CH:8]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: COc1ccc(COc2c[nH]c(CO)cc2=O)cc1
Solvent: c1ccncc1
Product: COc1ccc(COc2c[nH]c(COC(C)=O)cc2=O)cc1
Temperature: 25 °C
Yield: 51.8 %

Procedure:
A solution of 2-(hydroxymethyl)-5-({[4-(methoxy)phenyl]methyl}oxy)-4(1H)-pyridinone (26 g, 0.1 mol) in pyridine (150 mL) was cooled to 5° C. and treated with acetyl chloride (10.48 ml, 0.149 mol). The reaction mixture was stirred and allowed to warm to room temperature then heated at 60° C. for 18 hours. Pyridine was evaporated under vacuum and the residue was triturated with water (250 mL), cooled in an ice-bath for 30 minutes. The solid formed was filtered off, washed with cold water and dried in vacuo to afford the product as a solid (15.7 g, 50%); MS (+ve ion electrospray) m/z 304 (MH+).
Reaction SMILES: [CH2:1]([NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][C:24](=O)[CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[C:11](=[O:13])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[CH2:1]([NH:7][C:8]1[S:9][C:10](=[CH:14][C:15]2[CH:16]=[CH:17][C:18]([N:21]3[CH2:26][CH2:25][CH:24]([NH:28][CH2:29][C@H:30]([OH:39])[CH2:31][O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[CH2:23][CH2:22]3)=[CH:19][CH:20]=2)[C:11](=[O:13])[N:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: NC[C@H](O)COc1ccccc1
Reactant: CCCCCCNC1=NC(=O)C(=Cc2ccc(N3CCC(=O)CC3)cc2)S1
Product: CCCCCCNC1=NC(=O)C(=Cc2ccc(N3CCC(NC[C@H](O)COc4ccccc4)CC3)cc2)S1

Procedure:
The title compound was prepared from 1-[4-(2-hexylamino-4-oxo-4H-thiazol-5-ylidenemethyl)-phenyl]-piperidin-4-one(which was obtained in Intermediate 32) and (2S)-1-amino-3-phenoxy-propan-2-ol(which was obtained in Intermediate 3) according to the procedure of Example 1 as a yellowish solid; mp 182-184° C. (dec.); 1H NMR (300 MHz, DMSO-d6) δ 0.87(t, J=6.5 Hz, 3 H), 1.20-1.40 (m, 10H), 1.50-1.65 (m, 2 H), 1.80-1.95 (m, 2 H), 2.60-4.00(m, 10H), 6.85-6.95(m, 3 H), 7.02 (d, J=9.0 Hz, 2 H), 7.20-7.35 (m, 2 H), 7.40 (d, J=9.0 Hz, 2 H), 7.45 (s, 1 H), 9.62 (brs, 1 H); MS (ES) m/z: 269.1 ((M+2 H)2+, 100%), 537.1(MH+, 20%); HRMS Calcd. for C30H41N4O3S (MH+): 537.2899. Found: 537.2875.
Reaction SMILES: F[C:2]1[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)=[O:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CN1CCCC1=O.CCOC(C)=O>[NH:9]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]=[C:10]1[C:18]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:2]2[C:7]([I:8])=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:22][CH:21]=1)=[O:19]
Reactant: Fc1ncccc1I
Reactant: O=C(c1ccc(O)cc1)c1nc2ccccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Oc2ncccc2I)cc1)c1nc2ccccc2[nH]1
Temperature: 115 °C
Reaction time: 64 h

Procedure:
A solution of 2-fluoro-3-iodopyridine (3.052 g, 13.69 mmol), (1H-benzo[d]imidazol-2-yl)(4-hydroxyphenyl)methanone (4.89 g, 20.53 mmol) and cesium carbonate (7.58 g, 23.27 mmol) in N-Methyl-2-pyrrolidinone (20 mL) was degassed and heated to 115° C. After 64 h, the reaction was cooled to 23° C., diluted with EtOAc (250 mL) and washed with water (100 mL) and brine (75 mL), dried over MgSO4, concentrated in vacuo and purified by silica gel chromatography (eluant: 0.5-1.5% methanol/dichloromethane), affording the product as a yellow solid. MS (ESI, pos. ion) m/z: 404.1 (M+1).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.O.[N-:13]=[N+:14]=[N-:15].[Na+]>CC(C)=O>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:13]=[N+:14]=[N-:15])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc(O)cc1
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(O)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-hydroxybenzene sulfonyl chloride synthesized in Synthetic example 1 (3.76 g, 19.5 mmol, and 1.00 Eq) was dissolved in acetone (50 mL) and then water (50 mL) was added thereto. The obtained mixed solution was cooled to 0° C. and NaN3 (1.41 g, 21.7 mmol, and 1.11 Eq) was added to the solution slowly, followed by stirring at 0° C. for 1 hour. After the stirring, acetone was removed by the evaporator (30° C., 150 mbar) and a water layer was extracted with dichloromethane (3×30 mL). The obtained organic layer was dried with sodium sulfate and dichloromethane was removed by the evaporator. The product as oil (3.06 g, 15.4 mmol, and 79%) was dried in vacuo to obtain 4-hydroxybenzenesulfonyl azide.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=C[CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.S(Cl)([Cl:30])(=O)=O.[CH2:32]([Cl:34])Cl>>[Cl:30][C:3]1[CH:4]=[C:5]([C:8]2([C:20]3[CH:25]=[CH:24][C:23]([OH:26])=[C:32]([Cl:34])[CH:21]=3)[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH:6]=[CH:7][C:2]=1[OH:1]
Reactant: ClCCl
Reactant: Oc1ccc(C2(c3ccc(O)cc3)CCCCCCCCCCC2)cc1
Reactant: O=S(=O)(Cl)Cl
Product: Oc1ccc(C2(c3ccc(O)c(Cl)c3)CCCCCCCCCCC2)cc1Cl

Procedure:
To a slurry containing 10 grams (0.0284 mole) of 1,1-bis(4-hydroxyphenyl)cyclododecane, prepared substantially in accordance with the procedure of Example 1, and 50 milliliters of methylene chloride, there is slowly added, at a temperature of 25°-27° C. and with stirring, a solution containing 26 grams (0.19 mole) of sulfuryl chloride and 20 milliliters of methylene chloride. During the addition of this solution the slurry turns to a solution. The reaction is followed by gas chromatographic analysis of samples removed from the reaction mixture. When analysis of these samples indicates the absence of the 1,1-bis(4-hydroxyphenyl)cyclododecane the solution is stripped on a rotary evaporator under water aspirator vacuum. Analysis of the solids indicates that they contain 93.6% of 1,1-bis(3-chloro-4-hydroxyphenyl)cyclododecane; 6% of 1-(4-hydroxyphenyl), 1-(3-chloro - 4-hydroxyphenyl)cyclododecane; and 0.4% of 1-(3-chloro-4-hydroxyphenyl),1-(3,5-dichloro-4-hydroxyphenyl)cyclododecane. The solids are recrystallized from methanol to yield the pure 1,1 -bis (3-chloro-4-hydroxyphenyl)cyclododecane, which has a melting point of 167°-169° C. and a gas chromatographic retention time of 28.04 minutes relative to 13.97 minutes for p-cumyl phenol.
Reaction SMILES: N.[N:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:9][C:10]3[CH:16]=[C:15]4[NH:17][C:18](=[O:20])[CH2:19][C:14]4=[CH:13][C:11]=3[N:12]=2)=[CH:4][CH:3]=1.C(O)C.[CH3:24][C:25]([CH3:27])=O>O>[C:25](=[C:19]1[C:14]2[C:15](=[CH:16][C:10]3[NH:9][C:8]([C:5]4[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=4)=[N:12][C:11]=3[CH:13]=2)[NH:17][C:18]1=[O:20])([CH3:27])[CH3:24]
Reactant: CC(C)=O
Reactant: O=C1Cc2cc3nc(-c4ccncc4)[nH]c3cc2N1
Agent: N
Solvent: O
Solvent: CCO
Product: CC(C)=C1C(=O)Nc2cc3[nH]c(-c4ccncc4)nc3cc21
Reaction time: 4 h

Procedure:
Ammonia is passed up to saturation into a suspension of 0.4 g. (1.6 mmol) 2-(4-pyridyl)-6,7-dihydro-3H,5H-pyrrolo[2,3-f]benzimidazol-6-one in 20 ml. ethanol and 10 ml. acetone and the reaction mixture then stirred for 2 hours at 60° C. Subsequently, a further 10 ml. acetone are added thereto and stirring continued for 4 hours at 60° C., whereafter the reaction mixture is evaporated, the residue is taken up in ethanol, acidified and suction filtered from the precipitate. The residue obtained is dissolved in water and rendered neutral and the crystals obtained are filtered off with suction and recrystallised from isopropanol/ethyl acetate. Yield: 40 mg. (9% of theory); m.p.>300° C.
Reaction SMILES: [F:1][C:2]1([F:21])[C:6]([F:8])([F:7])[C:5]2[CH:9]=[CH:10][CH:11]=[C:12]([CH2:13][CH:14]3[CH2:19][CH2:18][C:17](=O)[CH2:16][CH2:15]3)[C:4]=2[O:3]1.[C:22]([NH:24][C:25]([NH2:27])=[NH:26])#[N:23]>C(OCCOCCO)C>[NH2:27][C:25]1[N:24]=[C:22]([NH2:23])[C:18]2[CH2:19][CH:14]([CH2:13][C:12]3[C:4]4[O:3][C:2]([F:21])([F:1])[C:6]([F:8])([F:7])[C:5]=4[CH:9]=[CH:10][CH:11]=3)[CH2:15][CH2:16][C:17]=2[N:26]=1
Reactant: N#CNC(=N)N
Reactant: O=C1CCC(Cc2cccc3c2OC(F)(F)C3(F)F)CC1
Solvent: CCOCCOCCO
Product: Nc1nc(N)c2c(n1)CCC(Cc1cccc3c1OC(F)(F)C3(F)F)C2

Procedure:
This compound is prepared in a manner analogous to that of Example 1, using 3.9 grams (0.013 mole) of 4-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)cyclohexanone and 1.2 grams (0.014 mole) of cyanoguanidine in 2-(2-ethoxyethoxy)ethanol, yielding 2,4-diamino-6-(2,2,3,3-tetrafluoro-2,3-dihydrobenzofuran-7-ylmethyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[CH:4]=1.[Br:11]Br.CCCCCC>C(Cl)(Cl)Cl>[Br:11][C:8]1[CH:7]=[CH:6][C:5]([O:9][CH3:10])=[CH:4][C:3]=1[CH2:2][Br:1]
Reactant: COc1cccc(CBr)c1
Reactant: BrBr
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: COc1ccc(Br)c(CBr)c1
Temperature: 25 °C
Yield: 72.1 %

Procedure:
To a solution of above-described crude 1-(bromomethyl)-3-methoxybenzene (152.5 g) in 1 L of chloroform a solution of 134 g (0.841 mol) of bromine in 200 ml of chloroform was added dropwise by vigorous stirring at room temperature. The reaction mixture was stirred overnight at ambient temperature and then evaporated to dryness. The residue was triturated with 1000 ml of n-hexane, and the precipitate was filtered off, washed with 100 ml of n-hexane, and then dried in vacuum. An additional amount of the product was obtained by evaporation of mother liquor followed by treatment of the residue with 200 ml of n-hexane. In total, this procedure gave 153 g (55% overall yield for two stages) of 1-bromo-2-(bromomethyl)-4-methoxybenzene. (average of two runs)
Reaction SMILES: C([Mg]Cl)(C)C.[Si:6]([O:13][CH2:14][C:15]([N:18]1[C:22]2[N:23]=[C:24]([Cl:27])[N:25]=[CH:26][C:21]=2[C:20](I)=[CH:19]1)([CH3:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[C:29]1([C:35](=[N:42][C:43]2[CH:44]=[N:45][CH:46]=[C:47]([CH:54]=2)[C:48](N(OC)C)=[O:49])[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[Si:6]([O:13][CH2:14][C:15]([N:18]1[C:22]2[N:23]=[C:24]([Cl:27])[N:25]=[CH:26][C:21]=2[C:20]([C:48]([C:47]2[CH:46]=[N:45][CH:44]=[C:43]([N:42]=[C:35]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:54]=2)=[O:49])=[CH:19]1)([CH3:17])[CH3:16])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CON(C)C(=O)c1cncc(N=C(c2ccccc2)c2ccccc2)c1
Reactant: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(I)c2cnc(Cl)nc21
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(CO[Si](C)(C)C(C)(C)C)n1cc(C(=O)c2cncc(N=C(c3ccccc3)c3ccccc3)c2)c2cnc(Cl)nc21
Temperature: 0 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
Isopropyl magnesium chloride (105 mL, 210 mmol, 2.0 M in THF) was added to 7-(2-{[tert-butyl(dimethyl)silyl]oxy}-1,1-dimethylethyl)-2-chloro-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (89.0 g, 190 mmol) (see Preparation 44) in THF (450 mL) at 0° C., under nitrogen. The mixture was stirred at 0° C. for 1 hour then a solution of 5-[(diphenylmethylene)amino]-N-methoxy-N-methylnicotinamide (72.6 g, 210 mmol) (see Preparation 23) in THF (200 mL) was added dropwise at 0° C. The mixture was warmed to room temperature and stirred at this temperature for 16 hours. The reaction mixture was quenched with 10% aqueous ammonium chloride (500 mL) and the organic phase was separated. The aqueous phase was extracted with ethyl acetate (2×300 mL). The combined organic extracts were washed with brine (400 mL), dried over sodium sulfate, evaporated in vacuo and the crude material was purified by column chromatography on silica gel (gradient of heptane:EtOAc 100:0 to 60:40) to afford the title compound as a colourless gum in 66% yield, 78.9 g.
Reaction SMILES: [CH3:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[OH:11]O>C(O)(=O)C>[CH3:9][C:4]1[C:3](=[O:10])[C:2]([CH3:1])=[C:7]([CH3:8])[C:6](=[O:11])[CH:5]=1
Reactant: Cc1ccc(C)c(O)c1C
Reactant: OO
Solvent: CC(=O)O
Product: CC1=CC(=O)C(C)=C(C)C1=O
Temperature: 0 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
600 mg of the catalyst prepared in Example 6 and 10 g of 2,3,6-trimethylphenol were added to 90 ml of acetic acid. While cooling the solution with ice water, 20 g of a 30% hydrogen peroxide aqueous solution was dropwise added in about 40 minutes, and the mixture was stirred overnight. After completion of the reaction, the catalyst was removed by filtration, and the acetic acid solution was concentrated under reduced pressure to about 20 ml, diluted with ether, washed with an aqueous solution of NaHCO3 and then dried. The ether was distilled off, and the residue was subjected to distillation under reduced pressure, whereby 8.7 g of trimethylbenzoquinone (boiling point: 64° C./0.7 torr) was obtained. Further, the distillation residue was treated by column chromatography (SiO2 /CH2Cl2), whereby 0.5 g of trimethylbenzoquinone was additionally obtained. The total amount was 9.2 g (84% yield).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[N:11][N:12]([C:15]3[CH:23]=[CH:22][C:18]([C:19](O)=[O:20])=[CH:17][N:16]=3)[C:13]=2[OH:14])=[C:5]([CH3:24])[CH:4]=1)#[N:2].[N:25]1([CH2:30][CH2:31][CH2:32][NH2:33])[CH:29]=[CH:28][N:27]=[CH:26]1>>[N:25]1([CH2:30][CH2:31][CH2:32][NH:33][C:19](=[O:20])[C:18]2[CH:22]=[CH:23][C:15]([N:12]3[C:13]([OH:14])=[C:9]([C:6]4[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=4[CH3:24])[CH:10]=[N:11]3)=[N:16][CH:17]=2)[CH:29]=[CH:28][N:27]=[CH:26]1
Reactant: NCCCn1ccnc1
Reactant: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)O)cn2)c1O
Product: Cc1cc(C#N)ccc1-c1cnn(-c2ccc(C(=O)NCCCn3ccnc3)cn2)c1O

Procedure:
The title compound was prepared in a manner similar to Example 74 using 6-(4-(4-cyano-2-methylphenyl)-5-hydroxy-1H-pyrazol-1-yl)nicotinic acid and 3-(1H-imidazol-1-yl)propan-1-amine. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.09-2.17 (m, 2H) 2.44 (s, 3H) 3.32 (q, J=6.40 Hz, 2H) 4.28 (t, J=6.95 Hz, 2H) 7.63-7.72 (m, 2H) 7.74 (s, 1H) 7.78 (d, J=8.08 Hz, 1H) 7.83 (t, J=1.64 Hz, 1H) 8.19 (br. s., 1H) 8.35-8.55 (m, 2H) 8.82 (t, J=5.68 Hz, 1H) 8.89-8.96 (m, 1H) 9.11 (s, 1H) 13.26-14.08 (m, 1H). MS m/z [M+H]+ 428.2
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[C:16]([C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:17]=[CH:18][C:12]=2[O:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])[CH3:3].N1C=CC=CC=1.C(Cl)(=O)C([Cl:37])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:37][C:23]([C:22]1[CH:26]=[CH:27][C:19]([C:16]2[CH:17]=[CH:18][C:12]3[O:11][CH2:10][CH2:9][N:8]([C:6]([O:5][C:2]([CH3:4])([CH3:3])[CH3:1])=[O:7])[CH2:14][C:13]=3[CH:15]=2)=[CH:20][CH:21]=1)=[O:24]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)O)cc3)cc2C1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(C(=O)Cl)cc3)cc2C1
Temperature: 25 °C
Yield: 99.2 %

Procedure:
To a cooled (0° C.) solution of 4-(4-{[(1,1-dimethylethyl)oxy]carbonyl}-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl)benzoic acid (0.95 g, 2.6 mmol), pyridine (1.3 mL, 15 mmol) and oxalyl chloride (0.44 mL, 5.1 mmol) in toluene (10 mL) was added dimethylformamide (0.01 mL, 0.1 mmol) and the resulting mixture was warmed to room temperature. After 24 h the reaction mixture was concentrated to provide 1,1-dimethylethyl 7-[4-(chlorocarbonyl)phenyl]-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (1.0 g, 100%) as a brown oil. MS (EI) for C21H22ClNO4: 388 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([NH:11][C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][NH2:14])=[N:7][C:6]=12.C(N(C(C)C)C(C)C)C.N1([C:32](N2C=CN=C2)=[O:33])C=CN=C1.O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][N:5]2[CH:10]=[CH:9][C:8]([N:11]3[C@@H:12]([CH:15]([CH3:17])[CH3:16])[CH2:13][NH:14][C:32]3=[O:33])=[N:7][C:6]=12
Reactant: CC(C)[C@@H](CN)Nc1ccn2ncc(Br)c2n1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)[C@H]1CNC(=O)N1c1ccn2ncc(Br)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of (S)—N2-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-3-methylbutane-1,2-diamine (0.75 g, 2.52 mmol) in DMF was added N-ethyl-N-isopropylpropan-2-amine (1.38 ml, 7.55 mmol) and di(1H-imidazol-1-yl)methanone (0.816 g, 5.03 mmol) and the reaction stirred overnight at ambient temperature. The reaction was poured into water and extracted into EtOAc. The combined organic layers were washed with brine, dried over magnesium sulfate and concentrated in vacuo. The crude material was purified by chromatography, eluting with 2% MeOH/dichloromethane, to yield (S)-1-(3-bromopyrazolo[1,5-a]pyrimidin-5-yl)-5-isopropylimidazolidin-2-one (0.48 g, 58%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]3)=[C:8]([CH3:28])[C:7]=2[CH:29]=1)#[N:2].Cl.[CH2:31]([O:33][C:34](=[O:38])[CH2:35][CH2:36][NH2:37])[CH3:32].O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>CN(C)C=O.C(N(CC)CC)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11]([NH:18][C:19]3[CH:27]=[CH:26][C:22]([C:23]([NH:37][CH2:36][CH2:35][C:34]([O:33][CH2:31][CH3:32])=[O:38])=[O:24])=[CH:21][CH:20]=3)[CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]3)=[C:8]([CH3:28])[C:7]=2[CH:29]=1)#[N:2]
Reactant: CCOC(=O)CCN
Reactant: Cc1c(C(Nc2ccc(C(=O)O)cc2)C2CCCCC2)oc2ccc(C#N)cc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CCNC(=O)c1ccc(NC(c2oc3ccc(C#N)cc3c2C)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.1 %

Procedure:
To a mixture of 4-{[(5-cyano-3-methyl-1-benzofuran-2-yl)(cyclohexyl)methyl]amino}benzoic acid (250 mg) synthesized above, β-alanine ethyl ester hydrochloride (148 mg), 1-hydroxybenzotriazole monohydrate (148 mg), triethylamine (269 μL) and N,N-dimethylformamide (10 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (185 mg), and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (50% ethyl acetate/hexane) to give the title object compound (195 mg, 62%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[OH:11][CH:12]1[CH2:17][CH2:16][CH2:15][NH:14][CH2:13]1.C(N(CC)CC)C>CN(C=O)C>[N+:8]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][C:2]=1[N:14]1[CH2:15][CH2:16][CH2:17][CH:12]([OH:11])[CH2:13]1)([O-:10])=[O:9]
Reactant: OC1CCCNC1
Reactant: O=[N+]([O-])c1cnccc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cnccc1N1CCCC(O)C1

Procedure:
Method 1 of Example 1 was followed using 1 equivalent each of 4-chloro-3-nitropyridine, (+/−)-3-hydroxypiperidine and triethylamine in DMF yielding (+/−)-1-(3-nitropyridin-4-yl)piperidin-3-ol, LCMS (m/z): 224.1 (MH+); LC Rt=1.06 min.
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[CH2:7][N:6]([C:16]([C:18]3[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH3:32])=[CH:20][CH:19]=3)=[O:17])[C:5]=2[CH:4]=[CH:3][CH:2]=1.[O-:34]S([O-])(=O)=O.[Mg+2].[O-][Mn](=O)(=O)=O.[K+]>C(O)(C)(C)C.O>[O:34]=[C:10]1[C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=2[CH2:7][N:6]([C:16]([C:18]2[CH:23]=[CH:22][C:21]([NH:24][C:25](=[O:33])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[CH3:32])=[CH:20][CH:19]=2)=[O:17])[C:5]2[CH:4]=[CH:3][CH:2]=[CH:1][C:11]1=2
Reactant: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3Cc3ccccc32)cc1
Reactant: O=S(=O)([O-])[O-]
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CC(C)(C)O
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2Cc3ccccc3C(=O)c3ccccc32)cc1
Temperature: 65 °C
Yield: 107.6 %

Procedure:
A mixture of 1.08 g of N-[4-[(6,11-dihydro-5H-dibenz[b,e]azepin-5-yl)carbonyl]phenyl]-2-methylbenzamide in 50 ml of t-butanol is heated, 2 ml of water is added followed by 1.18 g of MgSO4, and 2.6 g of KMnO4. An additional 0.84 g of KMnO4 in 25 ml of water is added followed by heating at 65° C. for 18 hours. The reaction mixture is filtered and the filtrate evaporated in vacuo to give 1.2 g of a residue which is purified by column chromatography on silica gel by elution with ethyl acetate and 9:1 ethyl acetate-methanol to give 160 mg of the desired product as a solid, m.p. 115°-119° C.
Reaction SMILES: Cl[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1.[CH2:10]([NH:14][CH:15]1[CH2:20][C:19]([CH3:22])([CH3:21])[N:18]([CH3:23])[C:17]([CH3:25])([CH3:24])[CH2:16]1)[CH2:11][CH2:12][CH3:13]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH2:10]([N:14]([CH:15]1[CH2:16][C:17]([CH3:25])([CH3:24])[N:18]([CH3:23])[C:19]([CH3:21])([CH3:22])[CH2:20]1)[P:2]1[O:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][O:3]1)[CH2:11][CH2:12][CH3:13]
Reactant: CCCCNC1CC(C)(C)N(C)C(C)(C)C1
Reactant: CC1(C)COP(Cl)OC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CCCCN(C1CC(C)(C)N(C)C(C)(C)C1)P1OCC(C)(C)CO1

Procedure:
18.4 g of 2-chloro-5,5-dimethyl-1,3,2-dioxaphosphorinane are added dropwise, at room temperature, with stirring, to a solution of 19.7 g (0.1 mol) of 4-butylamino-1,2,2,6,6-pentamethylpiperidine in 100 ml of triethylamine. After heating at the reflux temperature for 15 hours, the mixture is diluted with toluene and the precipitated hydrochloride is filtered off. Evaporation of the filtrate gives 2-[N-butyl(1,2,2,6,6-pentamethyl-4-piperidyl)amino]-5,5-dimethyl-1,3,2-dioxaphosphorinane as an oil which boils at 120° under 40 Pa (Compound No. 1).