Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:18])[C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:33](Cl)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1.C(OCC)(=O)C>CN(C)C1C=CN=CC=1.O1CCCC1>[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2([C:33]([O:17][C:14]3[CH:13]=[CH:12][C:11]([C:10]([NH:9][O:8][CH2:1][C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[O:18])=[CH:16][CH:15]=3)=[O:34])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1
Reactant: COc1ccc(C2(C(=O)Cl)CCCCC2)cc1
Reactant: O=C(NOCc1ccccc1)c1ccc(O)cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C2(C(=O)Oc3ccc(C(=O)NOCc4ccccc4)cc3)CCCCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a solution of N-(benzyloxy)4-hydroxybenzamide (14) (0.078 g, 0.32 mmol) and 4-dimethylaminopyridine (0.047 g, 0.38 mmol) in tetrahydrofuran (2 ml) under argon atmosphere at ice bath temperature a solution of 1-(4-methoxyphenyl) cyclohexanecarbonyl chloride (21a) (0.082 g, obtained in the preceding step of the synthesis) in tetrahydrofuran (2 ml) was added. The resultant white suspension was stirred at room temperature overnight and poured into ethyl acetate (80 ml). The ethyl acetate extract was washed with water (50 ml), brine (30 ml), and dried (Na2SO4). The solvent was evaporated and the residue was dissolved in a small amount of benzene (0.5-1 ml). The precipitated solid was filtered off, the filtrate was evaporated and chromatographed on silicagel (10 g) with benzene-ethyl acetate (9:1) as eluent affording the title compound (0.077 g, 52% based on 1/1) as a white solid. 1H NMR (DMSO-d6, HMDSO) δ: 1.07-2.01 (8H, m); 2.21-2.61 (2H, m, overlapped with a signal of DMSO); 3.75 (3H, s); 4.92 (2H, s); 6.97 (2H, d, J=8.5 Hz); 7.04 (2H, d, J=8.2 Hz); 7.23-7.54 (7H, m); 7.76 (2H, d, J=8.5 Hz); 11.77 (1H, s).
Reaction SMILES: [CH3:1][N:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5](=[O:12])[N:4]([C:13]2[CH:14]=[CH:15][C:16]3[S:20][N:19]=[C:18]([CH2:21][C:22]#[N:23])[C:17]=3[CH:24]=2)[C:3]1=[O:25].[Br:26]N1C(=O)CCC1=O>ClCCCl>[Br:26][CH:21]([C:18]1[C:17]2[CH:24]=[C:13]([N:4]3[C:5](=[O:12])[CH:6]=[C:7]([C:8]([F:10])([F:11])[F:9])[N:2]([CH3:1])[C:3]3=[O:25])[CH:14]=[CH:15][C:16]=2[S:20][N:19]=1)[C:22]#[N:23]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(CC#N)c3c2)c1=O
Solvent: ClCCCl
Product: Cn1c(C(F)(F)F)cc(=O)n(-c2ccc3snc(C(Br)C#N)c3c2)c1=O
Temperature: 25 °C
Yield: 56.2 %

Procedure:
To a solution of 5-[3,6-dihydro-3-methyl-2,6-dioxo-4-(trifluoromethyl)-1(2H)-pyrimidinyl]-1,2-benzisothiazole-3-acetonitrile (0.500 g, 0.00140 mol) in 1,2-dichloroethane is added N-bromosuccinimide (0.250 g, 0.00140 mol). The resultant mixture is irradiated with a UV lamp and stirred at reflux six hours. Additional N-bromosuccinimide (0.250 g, 0.00140 mol) is added and the resultant mixture is stirred 1.5 hours at reflux under a UV lamp. The mixture is cooled to room temperature and concentrated in vacuo. The resultant residue is taken up in methylene chloride, washed with water, treated with charcoal, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo to give the title product as a red glass (0.350 g, 56.2%, mp 185-187° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[O:12][N:11]=[C:10]([C:13]([O-:15])=O)[N:9]=2)=[CH:5][CH:4]=1.Cl.[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH2:33].C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:21][C:22]1[CH:23]=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[C:25]2[CH2:31][CH2:32][NH:33][C:13]([C:10]1[N:9]=[C:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:18])=[CH:17][CH:16]=2)[O:12][N:11]=1)=[O:15]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: O=C([O-])c1noc(Cc2ccc(C(F)(F)F)cc2)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(C(F)(F)F)cc2)n1
Yield: 21.3 %

Procedure:
This compound was prepared according to method F with 5-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.104 g; 0.346 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL) and 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HART (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (4 mL). The crude mixture was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and preparative HPLC method 2 to yield 0.033 g (21%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]([F:26])([F:25])[C:7]1[C:16]([C:17](O)=[O:18])=[C:15]([OH:20])[C:14]2[C:9](=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:11]=[CH:12][CH:13]=2)[N:8]=1>C1C=CC=CC=1>[F:5][C:6]([F:26])([F:25])[C:7]1[C:16]([C:17]([Cl:3])=[O:18])=[C:15]([OH:20])[C:14]2[C:9](=[C:10]([C:21]([F:24])([F:23])[F:22])[CH:11]=[CH:12][CH:13]=2)[N:8]=1
Reactant: O=C(O)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Reactant: O=S(Cl)Cl
Solvent: c1ccccc1
Product: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O

Procedure:
9.6 ml of thionyl chloride were added with stirring to a suspension of 8.75 g of the product of Step D in 285 ml of benzene and the mixture was refluxed for 90 minutes. Then, the benzene and excess thionyl chloride was evaporated and the residue was taken up twice in anhydrous benzene to obtain 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride which was used as is for the next step.
Reaction SMILES: Br[CH2:2][C:3]1[C:15]2[C:14]3[CH:13]=[CH:12][C:11]([F:16])=[CH:10][C:9]=3[C:8]([O:17]COC)=[N:7][C:6]=2[N:5]([CH3:21])[N:4]=1.[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24]C1.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[F:16][C:11]1[CH:12]=[CH:13][C:14]2[C:15]3[C:3]([CH2:2][N:22]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[N:4][N:5]([CH3:21])[C:6]=3[NH:7][C:8](=[O:17])[C:9]=2[CH:10]=1
Reactant: COCOc1nc2c(c(CBr)nn2C)c2ccc(F)cc12
Reactant: C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: Cn1nc(CN2CCCC2)c2c3ccc(F)cc3c(=O)[nH]c21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
After the completion of the reaction, the reaction solution was allowed to cool to room temperature, and the precipitated solid was removed by filtration. The filtrate was concentrated, and the residue was filtrated using silica gel (hexane:ethyl acetate=2:1). The filtrate was concentrated to give 1-bromomethyl-7-fluoro-5-methoxymethoxy-3-methyl-3H-pyrazolo[3,4-c]isoquinoline (0.50 g) as crude crystals. The crude crystals (0.50 g) of 1-bromomethyl-7-fluoro-5-methoxymethoxy-3-methyl-3H-pyrazolo[3,4-c]isoquinoline, piperidine (0.30 g) and potassium carbonate (0.39 g) were dissolved in acetonitrile (20 mL), and the reaction solution was stirred at room temperature for 2 days. After the completion of the reaction, the reaction solution was poured into water and extracted with chloroform. The organic layer was dried over magnesium sulfate, and the solvent was evaporated. The residue was purified by silica gel chromatography (hexane:ethyl acetate=10:1) to give 7-fluoro-3-methyl-1-(pyrrolidin-1-ylmethyl)-3H-pyrazolo[3,4-c]isoquinolin-5(4H)-one (0.079 g).
Reaction SMILES: [BH4-].[Na+].[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([CH:16]2[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1>C(O)(C)C.Cl>[O:3]1[CH2:7][CH2:6][O:5][CH:4]1[CH2:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C@H:16]2[CH2:21][CH2:20][C@H:19]([OH:22])[CH2:18][CH2:17]2)[CH2:14][CH2:15]1
Reactant: O=C1CCC([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: O[C@H]1CC[C@H]([C@H]2CC[C@H](CCC3OCCO3)CC2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A suspension of 2.97 g of sodium borohydride in 300 ml if isopropanol was treated dropwise while gassing with nitrogen at -70° C. with a solution of 11 g of 4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanone in 200 ml of isopropanol. After about 1 hour the reaction mixture was left to warm to room temperature, diluted with 500 ml of 0.1 N hydrochloric acid and extracted three times with 300 ml of methylene chloride each time. The organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. Crystallization of the residue (11 g) from 500 ml of ethyl acetate/petroleum ether (vol. 3:5) gave 6.6 g of pure trans-4-[trans-4-[2-(1,3-dioxolan-2-yl)ethyl]cyclohexyl]cyclohexanol with m.p. 129.5° C.
Reaction SMILES: [O:1]1[C:5]([C:6]2[CH:11]=[CH:10][C:9]([NH:12][C:13]3[N:14]=[C:15]([N:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:24][CH2:25][OH:26])[C:16]4[CH2:22][NH:21][CH2:20][CH2:19][C:17]=4[N:18]=3)=[CH:8][CH:7]=2)=[CH:4][N:3]=[CH:2]1.Cl[C:34]([O:36][CH3:37])=[O:35]>CN(C=O)C>[OH:26][CH2:25][CH2:24][N:23]([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:15]1[C:16]2[CH2:22][N:21]([C:34]([O:36][CH3:37])=[O:35])[CH2:20][CH2:19][C:17]=2[N:18]=[C:13]([NH:12][C:9]2[CH:10]=[CH:11][C:6]([C:5]3[O:1][CH:2]=[N:3][CH:4]=3)=[CH:7][CH:8]=2)[N:14]=1
Reactant: OCCN(c1ccccc1)c1nc(Nc2ccc(-c3cnco3)cc2)nc2c1CNCC2
Reactant: COC(=O)Cl
Solvent: CN(C)C=O
Product: COC(=O)N1CCc2nc(Nc3ccc(-c4cnco4)cc3)nc(N(CCO)c3ccccc3)c2C1
Reaction time: 2 h
Yield: 30.3 %

Procedure:
2-((2-(4-(Oxazol-5-yl)phenylamino)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)(phenyl)amino)ethanol (80 mg, 0.19 mmol, Example 1) was dissolved in DMF (5 mL). Methyl chloroformate (0.014 mL, 0.19 mmol) was added and the reaction was stirred for 2 h. The solvent was evaporated, the crude dissolved in few drops of dimethylformamide and acetonitrile, filtered and purified by HPLC. The fractions containing the title compound were pulled together and freezed-dried overnight, yielding methyl 4-((2-hydroxyethyl)(phenyl)amino)-2-(4-(oxazol-5-yl)phenylamino)-7,8-dihydropyrido[4,3-d]pyrimidine-6(5H)-carboxylate (28.0 mg, 30.8%).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25](=O)[CH3:26])[CH:21]=[CH:22][CH:23]=1>C1COCC1>[Cl:17][C:18]1[CH:19]=[C:20]([CH2:24][C:25]([CH3:26])=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:21]=[CH:22][CH:23]=1
Reactant: CC(=O)Cc1cccc(Cl)c1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C(C)Cc1cccc(Cl)c1
Temperature: 23 °C
Reaction time: 0.5 h

Procedure:
At 0° C., a suspension of 60% w/w NaH/mineral oil (7.13 g, 0.176 mol) in THF (250 mL) was treated dropwise with a solution of ethyl 2-(diethoxyphosphoryl)acetate (39.5 g, 0.176 mol) in THF (72 mL) over a 30 min period. The reaction was stirred for another 30 minutes, and a solution of 1-(3-chlorophenyl)propan-2-one (19.7 g, 0.117 mol) in THF (108 mL) was added dropwise over 1 h (reaction was kept at 0° C. during addition). The reaction was allowed to warm to 23° C. overnight and quenched with saturated aqueous NH4Cl (250 mL). After 2 h, the mixture was diluted with water (250 mL) and hexane (100 mL). The organic phase was collected. The aqueous layer was extracted with EtOAc (2×150 mL). Combined organic phases were dried (MgSO4), filtered, and concentrated, giving crude ethyl 4-(3-chlorophenyl)-3-methylbut-2-enoate as a mixture of E and Z isomers. The residue was carried onward without further purification. (˜25 grams). The 1H NMR reported below is from a crude mixture containing both the E and Z isomer. 1H NMR (400 MHz, CDCl3) δ 7.24-7.22 (m, 2H), 7.16 (s, 1H), 7.06-7.04 (m, 1H); 5.67 (s, 1H); 4.18-4.13 (dd, 2H); 3.40 (s, 2H), 2.11 (s, 3H), 1.30-1.26 (t, 3H).
Reaction SMILES: [C:1]1([C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[N+]=[N-])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16]1([CH2:22][C:23]([NH:25][CH:26]2[C:38](=[O:39])[N:28]3[CH:29]([C:35]([OH:37])=[O:36])[CH:30]([CH2:33][OH:34])[CH2:31][S:32][C@H:27]23)=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(O)(=O)C>C(OCC)(=O)C.O1CCCC1>[C:16]1([CH2:22][C:23]([NH:25][CH:26]2[C:38](=[O:39])[N:28]3[CH:29]([C:35]([O:37][CH:7]([C:10]4[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=4)[C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)=[O:36])[CH:30]([CH2:33][OH:34])[CH2:31][S:32][C@H:27]23)=[O:24])[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)O)C(CO)CS[C@H]12
Reactant: [N-]=[N+]=C(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(Cc1ccccc1)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)C(CO)CS[C@H]12
Temperature: 25 °C
Yield: 24.2 %

Procedure:
A solution of diphenyldiazomethane (4 g.) in ethyl acetate was added to a stirred solution of 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylic acid (7.0 g.) in ethyl acetate (100 ml.) and tetrahydrofuran (20 ml.), and stirred at room temperature for an hour. After adding acetic acid to the resultant solution, the solution was concentrated in vacuo. The residue was subjected to column chromatography on silica gel, and then eluted with a mixed solvent of ethyl acetate and diisopropyl ether. The eluate was evaporated in vacuo to give diphenylmethyl 7-(2-phenylacetamido)-3-hydroxymethylcepham-4-carboxylate (2.5 g.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1)#[N:2].[H-].[Na+].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[CH2:12]([O:9][C:5]1[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=1)[C:1]#[N:2])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cccc(O)c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cccc(OCc2ccccc2)c1
Temperature: 90 °C

Procedure:
A stirred solution of 3-cyanophenol (20 g) in dry N,N-dimethylformamide (200 mL) is treated with sodium hydride (5.6 g; 60% dispersion in mineral oil), portionwise during 40 minutes, followed by dropwise addition of benzyl bromide (20 mL). The mixture is heated at 90° C. for 4 hours, cooled and concentrated under reduced pressure. The residue is partitioned between ethyl acetate and water and the organic layer washed with 1 N sodium hydroxide (100 mL) followed by drying over magnesium sulphate and concentration. The residue is recrystallised from methanol to give 3-benzyloxybenzonitrile (24 g), in the form of a cream solid, m.p. 38-40° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:6]=[C:7]([CH:23]=[CH:24][CH:25]=1)[O:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]1[N:17]([CH3:18])[N:16]=[C:15]([NH:19][C:20](=O)[CH3:21])[N:14]=1)[CH3:3].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1>[CH3:18][N:17]1[C:13]([NH:12][CH2:11][CH2:10][CH2:9][O:8][C:7]2[CH:23]=[CH:24][CH:25]=[C:5]([CH2:4][N:2]([CH3:1])[CH3:3])[CH:6]=2)=[N:14][C:15]([NH:19][CH2:20][CH3:21])=[N:16]1
Reactant: CC(=O)Nc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCNc1nc(NCCCOc2cccc(CN(C)C)c2)n(C)n1
Yield: 56.8 %

Procedure:
A mixture of N-[5-[[3-[3-[(dimethylamino)methyl]phenoxy]propyl]-amino]-1-methyl-1H-1,2,4-triazol-3-yl]acetamide (1.1 g), lithium aluminium hydride (0.15 g) and tetrahydrofuran (20 ml) was heated at reflux for 12 h under a nitrogen atmosphere. The mixture was quenched with water (5 ml), filtered and the filtrate distilled to give the title compound as a pale yellow oil (0.6 g) b.p. 220°/0.06 mm. TLC silica, methanol/0.88 ammonia 80:1, Rf 0.54.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C@H:14]([NH:16][CH3:17])[CH3:15])[N:11]([CH3:13])[CH:12]=2)=[CH:4][CH:3]=1.Cl[C:19]([O:21][CH3:22])=[O:20].C([O-])([O-])=O.[Na+].[Na+].C1COCC1>O.CCOC(C)=O>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C@H:14]([N:16]([CH3:17])[C:19](=[O:20])[O:21][CH3:22])[CH3:15])[N:11]([CH3:13])[CH:12]=2)=[CH:6][CH:7]=1
Reactant: CN[C@H](C)c1nc(-c2ccc(I)cc2)cn1C
Reactant: COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)N(C)[C@H](C)c1nc(-c2ccc(I)cc2)cn1C
Reaction time: 2 h
Yield: 41.3 %

Procedure:
To a 250 mL round bottom flask was added (R)-1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)-N-methylethanamine (3.1 g, 9.1 mmol), methyl chloroformate (0.84 mL, 10.9 mmol), Na2CO3 (1.15 g, 10.9 mmol), and THF (100 mL). The reaction was stirred for 2 hours, followed by the addition of EtOAc (50 mL) and water (10 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give 1.50 g (41%) of (R)-methyl 1-(4-(4-iodophenyl)-1-methyl-1H-imidazol-2-yl)ethyl(methyl)carbamate as an off-white solid (M+H (m/z)=400).
Reaction SMILES: [CH3:1][C:2]([CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14])=[CH:3][CH2:4]O.P(Br)(Br)[Br:18]>C1C=CC=CC=1>[Br:18][CH2:4][CH:3]=[C:2]([CH3:1])[CH:6]=[CH:7][CH2:8][CH:9]([CH3:16])[CH2:10][CH2:11][CH:12]=[C:13]([CH3:15])[CH3:14]
Reactant: BrP(Br)Br
Reactant: CC(C)=CCCC(C)CC=CC(C)=CCO
Solvent: c1ccccc1
Product: CC(C)=CCCC(C)CC=CC(C)=CCBr
Reaction time: 1 h

Procedure:
To a mixture of 4 g. of 3,7,11-trimethyldodeca-2,4,10-trien-1-ol, and 25 ml. of benzene at 0° is added a solution of 5 ml. of phosphorus tribromide in 18 ml. of benzene over about 15 minutes. The mixture is stirred at 0° for 1 hour. The mixture is then poured onto ice and extracted with pentane. The organic phase is washed with aqueous sodium bicarbonate, water and then brine, dried over magnesium sulfate and evaporated to yield 1-bromo-3,7,11-trimethyldodeca-2,4,10-triene.
Reaction SMILES: I[C:2]1[N:7]=[C:6]([CH2:8][CH2:9][CH3:10])[C:5]([OH:11])=[CH:4][CH:3]=1.[CH3:12][N:13](C)C=O>>[OH:11][C:5]1[CH:4]=[CH:3][C:2]([C:12]#[N:13])=[N:7][C:6]=1[CH2:8][CH2:9][CH3:10]
Reactant: CCCc1nc(I)ccc1O
Reactant: CN(C)C=O
Product: CCCc1nc(C#N)ccc1O
Yield: 100 %

Procedure:
6-Iodo-2-propylpyridin-3-ol (2.0 g, 7.60 mmol) was dissolved in N,N-dimethylformamide (30 mL). Dinitrile zinc (1.34 g, 11.4 mmol) and tetrakis triphenylphosphine palladium (878 mg, 0.760 mmol) were added at room temperature, and the resultant mixture was stirred for 20 minutes under microwave irradiation. After completion of the reaction, the reaction solution was filtered using celite and extracted with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated in vacuo. The obtained residue was purified using column chromatography (hexane/ethyl acetate) and 5-hydroxy-6-propyl picolinonitrile (1.75 g, yield >100%) was obtained as a yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:22]=[CH:21][C:9]3[C:10]4[N:11]=[C:12]([C:18]([OH:20])=O)[S:13][C:14]=4[CH2:15][CH2:16][O:17][C:8]=3[CH:7]=2)[CH:3]=[N:2]1.[NH:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([CH2:29][OH:30])[CH2:24]1>>[OH:30][CH2:29][C@@H:25]1[CH2:26][CH2:27][CH2:28][N:23]([C:18]([C:12]2[S:13][C:14]3[CH2:15][CH2:16][O:17][C:8]4[CH:7]=[C:6]([C:4]5[CH:5]=[N:1][NH:2][CH:3]=5)[CH:22]=[CH:21][C:9]=4[C:10]=3[N:11]=2)=[O:20])[CH2:24]1
Reactant: OC[C@@H]1CCCNC1
Reactant: O=C(O)c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2
Product: O=C(c1nc2c(s1)CCOc1cc(-c3cn[nH]c3)ccc1-2)N1CCC[C@@H](CO)C1

Procedure:
Following the procedure for 103, 8-(1H-Pyrazol-4-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (50.0 mg, 0.2 mmol) was reacted with (R)-piperidin-3-ylmethanol (1.2 equiv) via to give 165 (18.1 mg, M+1 411.1)
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>C(#N)C>[C:11]([NH:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5])(=[O:13])[CH3:12]
Reactant: N#Cc1ccc(Cl)cc1N
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(=O)Nc1cc(Cl)ccc1C#N

Procedure:
To 100 ml of acetonitrile were added 30 g of 2-amino-4-chlorobenzonitrile obtained in Step (2) and then 30 ml of acetic anhydride, and the mixture was refluxed by heating. After the completion of the reaction, the solvent was distilled off, then to the residue was added 500 ml of water, and the crystals thus-deposited were collected by filtration, washed with water and dried. Yield: 29 g (75.6%).
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:16][S:17]([CH2:20][CH2:21][CH2:22]CC(O)=O)(=[O:19])=[O:18])=[O:15])=O)(C)(C)C.[ClH:27].C(OCC)(=[O:30])C>CO>[ClH:27].[NH2:8][C@H:9]1[CH2:13][CH2:12][CH2:11][C@H:10]1[C:14]([NH:16][S:17]([CH2:20][CH2:21][CH2:22][OH:30])(=[O:18])=[O:19])=[O:15]
Reactant: CCOC(C)=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCC[C@H]1C(=O)NS(=O)(=O)CCCCC(=O)O
Agent: Cl
Solvent: CO
Product: N[C@H]1CCC[C@H]1C(=O)NS(=O)(=O)CCCO
Temperature: 25 °C

Procedure:
To a mixture of 3-{[({(1R,2S)-2-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]sulfonyl}propylacetic acid (1.2 g) and methanol (12 ml) was added a 4 M hydrogen chloride/ethyl acetate solution (6.0 ml) under ice-cooling, followed by stirring at room temperature over one night. The reaction mixture was concentrated under reduced pressure to obtain (1R,2S)-2-amino-N-[(3-hydroxypropyl)sulfonyl]cyclopentane carboxamide hydrochloride (1.1 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:19])([F:18])[F:17])[C:10]([O:12]CC)=[O:11])=[CH:5][CH:4]=1)[CH3:2].[OH-].[Na+]>CO.C1COCC1.O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH:9]([C@@H:15]([CH3:20])[C:16]([F:17])([F:18])[F:19])[C:10]([OH:12])=[O:11])=[CH:7][CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(c1ccc(CC)cc1)[C@@H](C)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCc1ccc(C(C(=O)O)[C@@H](C)C(F)(F)F)cc1
Temperature: 40 °C
Reaction time: 9 h

Procedure:
3.0 g of ethyl (3R)-2-(4-ethylphenyl)-4,4,4-trifluoro-3-methylbutanoate (purity about 88%, about 9.16 mmol; diastereomer mixture) were dissolved in the mixture of in each case 12.4 ml of methanol, THF and water, and 5.49 g (137.35 mmol) of sodium hydroxide were added a little at a time. The reaction mixture was stirred at 40° C. for 9 h. After cooling, the volatile solvents were substantially removed under reduced pressure and the residue was diluted with water. The mixture was acidified by addition of hydrochloric acid, and the aqueous phase was extracted three times with ethyl acetate. The combined organic phases were dried over sodium sulphate, and concentrated under reduced pressure, and the residue was dried under high vacuum. This gave 2.61 g of the title compound as a crude product which was not purified any further (diastereomer ratio about 9:1).
Reaction SMILES: O=[C:2]([CH3:11])[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O.[NH2:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1>>[CH3:11][CH:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9]2)[N:12]1[C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: CC(=O)CC1CCCCC1=O
Product: CC1CC2CCCCC2N1c1ccc(C(=O)O)cc1
Yield: 65 %

Procedure:
Following the general methods as outlined under Intermediate 7, starting from 2-(2-oxopropyl)cyclohexanone and 4-aminobenzoic acid, the title compound was isolated in 65% yield (98% purity by HPLC). MS(ESI+): 256.4; MS(ESI−): 254.4.
Reaction SMILES: [CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH:13]=[CH:14][C:15]([O:20][CH3:21])=[CH:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][OH:25])[CH3:2].[Li].[Cl-].[NH4+].O>COCC(O)C.O1CCCC1.N>[CH2:1]([C@:3]12[CH2:11][CH2:10][C@@H:9]3[C:12]4[CH2:13][CH:14]=[C:15]([O:20][CH3:21])[CH2:16][C:17]=4[CH2:18][CH2:19][C@H:8]3[C@@H:7]1[CH2:6][CH2:5][C@@H:4]2[O:22][CH2:23][CH2:24][OH:25])[CH3:2]
Reactant: CC[C@]12CC[C@@H]3c4ccc(OC)cc4CC[C@H]3[C@@H]1CC[C@@H]2OCCO
Agent: N
Agent: [Cl-]
Agent: [Li]
Solvent: COCC(C)O
Solvent: O
Solvent: C1CCOC1
Product: CC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2OCCO)CC(OC)=CC4
Reaction time: 1 h
Yield: 84.5 %

Procedure:
Dissolve dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-1,3,5(10)-triene (4.0 g) in 1-methoxy-2-propanol (60 ml), tetrahydrofuran (120 ml) and liquid ammonia (300 ml). Gradually add lithium (4.0 g) with stirring over a period of one hour. Add ammonium chloride (8.0 g) and water. Filter, wash and dry the resulting precipitate. Dissolve the product in tetrahydrofuran (300 ml) and liquid ammonia (300 ml) and treat with lithium (4.0 g). Stir for one hour. Add absolute ethanol, then water. Filter the resulting precipitate and wash it with water to obtain dl-13-ethyl-17β-(2-hydroxyethoxy)-3-methoxygona-2,5(10)-diene (3.4 g); essentially no ultraviolet absorption at the 280 mμ region, infrared absorption maxima at 2.91 μ, 5.89 μ, 6.0 μ.