Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:18])[N:9]2[CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[CH:4][CH:3]=1.[CH3:19][O:20][C:21]1[CH:29]=[C:28]([O:30][CH2:31][CH3:32])[CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].C(N(CC)CC)C.O>ClCCl>[F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][C:8](=[O:18])[N:9]2[CH:12]2[CH2:13][CH2:14][N:15]([C:23](=[O:24])[C:22]3[CH:26]=[CH:27][C:28]([O:30][CH2:31][CH3:32])=[CH:29][C:21]=3[O:20][CH3:19])[CH2:16][CH2:17]2)=[CH:4][CH:3]=1
Reactant: CCOc1ccc(C(=O)O)c(OC)c1
Reactant: O=C1CCc2ccc(F)cc2N1C1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CCOc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccc(F)cc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.4 %

Procedure:
7-Fluoro-1-(4-piperidinyl)-3,4-dihydrocarbostyril (2.37 g), 2-methoxy-4-ethoxybenzoic acid (2.43 g) and bis(2-oxo-oxazolydinyl)phosphinyl chloride (3.65 g) are dissolved in dichloromethane (50 ml) and thereto is added dropwise triethylamine (4 ml). The mixture is stirred at room temperature overnight and poured into water. The mixture is extracted with dichloromethane, dried with sodium carbonate and then purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1). The resultant is recrystallized from ethanol/water to give 7-fluoro-1-[1-(2-methoxy-4-ethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (2.5 g) as white powder, m.p. 159°-161° C.
Reaction SMILES: [N:1](=[C:3]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([CH2:11][CH3:12])([CH3:10])[S:4]1)[OH:2].[CH3:13][N:14]=[C:15]=[O:16]>>[CH3:13][NH:14][C:15]([O:2][N:1]=[C:3]1[N:7]=[C:6]([CH2:8][CH3:9])[C:5]([CH2:11][CH3:12])([CH3:10])[S:4]1)=[O:16]
Reactant: CN=C=O
Reactant: CCC1=NC(=NO)SC1(C)CC
Product: CCC1=NC(=NOC(=O)NC)SC1(C)CC

Procedure:
2-oxo-4,5-diethyl-5-methyl-3-thiazoline-oxime was reacted with methyl isocyanate as described in Example 4 to yield 2-oxo-4,5-diethyl-5-methyl-3-thiazoline-O-(methylcarbamoyl)-oxime, m.p. 88°-90° C. The 2-oxo-4,5-diethyl-5-methyl-3-thiazoline-oxime starting material melts at 125°-128° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][NH:11][CH3:12])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl[C:14]1[N:19]=[C:18]([NH:20][C:21]2[NH:25][N:24]=[C:23]([CH:26]3[CH2:28][CH2:27]3)[CH:22]=2)[CH:17]=[CH:16][N:15]=1.CCN(C(C)C)C(C)C>CC(O)C>[NH:1]1[C:9]2[C:4](=[C:5]([CH2:10][N:11]([CH3:12])[C:14]3[N:19]=[C:18]([NH:20][C:21]4[CH:22]=[C:23]([CH:26]5[CH2:28][CH2:27]5)[NH:24][N:25]=4)[CH:17]=[CH:16][N:15]=3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: Clc1nccc(Nc2cc(C3CC3)n[nH]2)n1
Reactant: CNCc1cccc2[nH]ccc12
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CN(Cc1cccc2[nH]ccc12)c1nccc(Nc2cc(C3CC3)[nH]n2)n1
Temperature: 120 °C

Procedure:
A tube was charged with 116 (280 mg, 1.75 mmol), 53 (412 mg, 1.75 mmol), DIPEA (678 mg, 5.25 mmol) and IPA (5 mL), sealed and heated at 120° C. for 14 h. The mixture was concentrated in vacuo and the residue was purified by preparative HPLC to afford 260 mg (41.4%) of I-40.
Reaction SMILES: [OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:32][CH2:33][CH3:34])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([O:11]CC)=[O:10])[CH3:3].O.[OH-].[Li+]>>[OH:1][CH:2]([C:4]1[N:5]=[C:6]([CH2:32][CH2:33][CH3:34])[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:8]=1[C:9]([OH:11])=[O:10])[CH3:3]
Reactant: CCCc1nc(C(C)O)c(C(=O)OCC)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Product: CCCc1nc(C(C)O)c(C(=O)O)n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Yield: 64.9 %

Procedure:
Following a procedure similar to that described in Example 36. 0.82 g of ethyl 4-(1-hydroxyethyl)-2-propyl-1-{4-[2-(tetrazol-5-yl)phenyl]phenyl}methylimidazole-5-carboxylate [prepared as described in Example 40(c)] was hydrolyzed using 0.43 g of lithium hydroxide monohydrate, to give 0.50 g of the title compound as a powder, melting at 198°-201° C.
Reaction SMILES: C1CCN2C(=NCCC2)CC1.[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]([C:17]1[CH:21]=[C:20]([CH2:22][CH3:23])[S:19][C:18]=1[NH:24][CH:25]=[CH:26][N+:27]([O-:29])=[O:28])=O>C1C=CC=CC=1.O1CCOCC1.C1C=CC=CC=1>[Cl:12][C:13]1[CH:33]=[CH:32][CH:31]=[CH:30][C:14]=1[C:15]1[C:26]([N+:27]([O-:29])=[O:28])=[CH:25][N:24]=[C:18]2[S:19][C:20]([CH2:22][CH3:23])=[CH:21][C:17]=12
Reactant: CCc1cc(C(=O)c2ccccc2Cl)c(NC=C[N+](=O)[O-])s1
Solvent: C1COCCO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccccc1
Product: CCc1cc2c(-c3ccccc3Cl)c([N+](=O)[O-])cnc2s1
Yield: 89.1 %

Procedure:
To a solution of DBU (5.1 g) in benzene (50 ml) was added dropwise a solution of 3-(2-chlorobenzoyl)-2-(2-nitroethenylamino)-5-ethylthiophene (5.1 g) in dioxane-benzene (1 : 1, 30 ml}over one hour with stirring under reflux. After refluxing for additional one hour, the mixture was washed with water and dried over MgSO4. The solvent was distilled off and to the residue was added isopropyl ether to obtain 4-(2-chlorophenyl)-2-ethyl-5-nitrothieno[2,3-b]pyridine as crystals (4.3 g, 89.0%). The crystals were recrystallized from isopropyl ether to obtain pale yellow prisms, mp: 72°-73° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:17](=O)[CH3:18])[CH:5]=[N:6][C:7]=1[N:8]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]1.[CH3:20][C:21]([S@:24]([NH2:26])=[O:25])([CH3:23])[CH3:22]>>[CH3:20][C:21]([S@:24]([NH:26][CH:17]([C:4]1[CH:5]=[N:6][C:7]([N:8]2[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[N:9]2)=[C:2]([CH3:1])[CH:3]=1)[CH3:18])=[O:25])([CH3:23])[CH3:22]
Reactant: CC(=O)c1cnc(-n2cc(C(F)(F)F)cn2)c(C)c1
Reactant: CC(C)(C)[S@](N)=O
Product: Cc1cc(C(C)N[S@](=O)C(C)(C)C)cnc1-n1cc(C(F)(F)F)cn1
Yield: 78 %

Procedure:
The title compound is prepared in 78% yield (2.16 g, yellows oil) from 1-(5-methyl-6-(4-(trifluoromethyl)-1H-pyrazol-1-yl)pyridin-3-yl)ethanone (2.00 g, 7.43 mmol, Step-4) and (R)-2-methylpropane-2-sulfinamide (1.35 g, 11.1 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]Br>[Fe]>[Br:10][C:3]1([CH3:9])[CH:4]=[CH:5][C:6]([F:8])=[CH:7][CH:2]1[F:1]
Reactant: Cc1ccc(F)cc1F
Reactant: BrBr
Agent: [Fe]
Product: CC1(Br)C=CC(F)=CC1F

Procedure:
The title compound was prepared by a modification of a published procedure. 2,4-Difluorotoluene was treated with iron chip and bromine at 60° C. overnight under an argon atmosphere in quantitative yield.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:7]([NH:9][C@@H:10]([C:23]([NH:25][C@H:26]([C:34]([N:36]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH3:37])=[O:35])[CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:24])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH:21]=[O:22])[CH:13]=1)=[O:8])[C@@H:4]([CH3:6])[OH:5].C(N(CC)CC)C.[CH3:52][C:53](OC(C)=O)=[O:54]>C(Cl)Cl>[NH:2]([C:53]([CH3:52])=[O:54])[C@H:3]([C:7]([NH:9][C@@H:10]([C:23]([NH:25][C@H:26]([C:34]([N:36]([CH2:38][C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[CH3:37])=[O:35])[CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)=[O:24])[CH2:11][C:12]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:14]([CH:21]=[O:22])[CH:13]=1)=[O:8])[C@@H:4]([CH3:6])[OH:5]
Reactant: C[C@@H](O)[C@H](N)C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@H](C(=O)N[C@H](Cc1cn(C=O)c2ccccc12)C(=O)N[C@@H](Cc1ccccc1)C(=O)N(C)Cc1ccccc1)[C@@H](C)O
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a solution of HCl.H-Thr-D-Trp(CHO)-Phe-NMeBzl (2.29 g) in methylene chloride (30 ml), were added triethylamine (747 mg) and Ac2O (377 mg) at -20° C. The reaction mixture was stirred for 45 minutes at the same temperature, and washed successively with water, diluted sodium hydrogencarbonate solution, water, 0.5N hydrochloric acid, and sodium chloride solution and dried over magnesium sulfate. After concentration, the residue was dissolved in 65% aqueous ethanol (45 ml) under heating, and the solution was left standing overnight at room temperature. The resulting needles were filtered, washed with 65% aqueous ethanol, and dried to give Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (1.92 g).
Reaction SMILES: [Li]CCCC.[Cl-].[CH3:7][O:8][CH2:9][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:29][C:30]1([CH3:37])[CH2:35][CH2:34][C:33](=O)[CH2:32][CH2:31]1>C1COCC1>[CH3:7][O:8][CH:9]=[C:33]1[CH2:34][CH2:35][C:30]([CH3:37])([CH3:29])[CH2:31][CH2:32]1
Reactant: CC1(C)CCC(=O)CC1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=C1CCC(C)(C)CC1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
n-BuLi (2.6 M in hexane, 2.3 mL, 5.94 mmol) was added dropwisely to a stirred solution of (methoxymethyl)triphenylphosphonium chloride (2.04 g, 5.94 mmol) in THF (20 mL) at −78° C. and stirred for 10 min at the same temperature and then stirred for 2.5 h at room temperature. The reaction mixture was cooled down to −78° C., a solution of 4,4-dimethylcyclohexanone (500 mg, 3.96 mmol) in THF (5 mL) was added slowly at −78° C. The reaction mixture was allowed to warm to room temperature and stirred at room temperature for overnight. The reaction mixture was quenched with sat. NaHCO3 aq. (20 mL) and extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to provide compound A12-1 (512.2 mg, crude) as pale yellow oil. The crude product was used for next step without purification.
Reaction SMILES: [OH:1][C:2]1[C:3](=[O:20])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[O:6][CH:7]=1.[OH:21][C:22]1C(=O)C=C(CNS(C2C=CC=CC=2)(=O)=O)OC=1CO>>[OH:1][C:2]1[C:3](=[O:20])[CH:4]=[C:5]([CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[CH:14]=2)(=[O:12])=[O:11])[O:6][C:7]=1[CH2:22][OH:21]
Reactant: O=c1cc(CNS(=O)(=O)c2ccccc2)oc(CO)c1O
Reactant: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)co2)c1
Product: Cc1cccc(S(=O)(=O)NCc2cc(=O)c(O)c(CO)o2)c1
Yield: 45.34 %

Procedure:
N-(5-Hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (9-04) (7.5 g, 45.34%) was synthesized as a white solid from N-(5-hydroxy-4-oxo-4H-pyran-2-ylmethyl)-3-methyl-benzenesulfonamide (8-04) (15.0 g, 50.84 mmol) following the procedure described for N-(5-hydroxy-6-hydroxymethyl-4-oxo-4H-pyran-2-ylmethyl)-benzenesulfonamide (9-01).
Reaction SMILES: [OH:1][C@H:2]1[CH2:15][C@@H:14]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[C@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11].[N+](=[CH2:42])=[N-]>C(Cl)Cl>[CH3:42][O:11][C:10](=[O:12])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][C@@H:3]1[C@@H:13](/[CH:23]=[CH:24]/[C@@H:25]([O:33][CH:34]2[CH2:39][CH2:38][CH2:37][CH2:36][O:35]2)[CH:26]([CH3:32])[CH2:27][CH:28]=[C:29]([CH3:31])[CH3:30])[C@H:14]([O:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][O:18]2)[CH2:15][C@@H:2]1[OH:1]
Reactant: C=[N+]=[N-]
Reactant: CC(C)=CCC(C)[C@@H](/C=C/[C@@H]1[C@@H](CCCCCCC(=O)O)[C@@H](O)C[C@H]1OC1CCCCO1)OC1CCCCO1
Solvent: ClCCl
Product: COC(=O)CCCCCC[C@@H]1[C@@H](/C=C/[C@@H](OC2CCCCO2)C(C)CC=C(C)C)[C@H](OC2CCCCO2)C[C@@H]1O

Procedure:
A solution of 1.55 g of (13E)-(8R,9S,11R,12R,15S,16RS)-9-hydroxy-16,19-dimethyl-11,15-bis(tetrahydropyran-2-yloxy)-13,18-prostadienoic acid in methylene chloride was treated with ethereal diazomethane solution until the evolution of nitrogen ceased and the solution assumed a permanent yellow color. After removal of excess diazomethane as well as the solvent, the residue (1.58 g) was used without further purification in the subsequent reaction stage.
Reaction SMILES: OCC[O:4][C:5]1[C:10]([NH:11][C:12]([C:14]2[C:23]3[C:22]4[N:24]=[CH:25][CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][CH:15]=2)=[O:13])=[CH:9][CH:8]=[CH:7][N:6]=1.[CH2:28]([N:30](CC)[CH2:31][CH3:32])[CH3:29].CS(Cl)(=O)=O>C(Cl)Cl>[CH2:28]([NH:30][CH2:31][CH2:32][N:6]1[CH:7]=[CH:8][CH:9]=[C:10]([NH:11][C:12]([C:14]2[C:23]3[C:22]4[N:24]=[CH:25][CH:26]=[CH:27][C:21]=4[CH2:20][CH2:19][CH2:18][C:17]=3[NH:16][CH:15]=2)=[O:13])[C:5]1=[O:4])[CH3:29]
Reactant: O=C(Nc1cccnc1OCCO)c1c[nH]c2c1-c1ncccc1CCC2
Reactant: CCN(CC)CC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CCNCCn1cccc(NC(=O)c2c[nH]c3c2-c2ncccc2CCC3)c1=O
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 54.2 %

Procedure:
To a mixture of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid [2-(2-hydroxy-ethoxy)pyridin-3-yl]amide (150 mg, 0.41 mmol) and triethylamine (125 mg, 1.2 mmol) in DCM (10 mL) at 0° C. is added methanesulfonyl chloride (94 mg, 0.82 mmol) dropwise. The mixture is stirred at 0° C. for 15 min. The solvent is removed and the residue is dissolved in acetonitrile (10 mL) and transferred to a sealed tube. Ethylamine (1 mL) is added and the mixture is heated at 60° C. for 3 h. The solvent is removed and the residue is separated by preparative TLC to give 87 mg of 3,4,5,6-tetrahydro-3,10-diazabenzo[e]azulene-1-carboxylic acid [1-(2-ethylaminoethyl)-2-oxo-1,2-dihydro-pyridin-3-yl]amide. LRMS Calcd 391.5; found M−1 390.2.
Reaction SMILES: [CH:1]1([C@H:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:14]4[CH:21]=[CH:20][N:19](COCC[Si](C)(C)C)[C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1.F[B-](F)(F)F.[Li+].[NH4+].[OH-]>CC#N.O>[CH:1]1([C@H:4]([N:8]2[CH:12]=[C:11]([C:13]3[C:14]4[CH:21]=[CH:20][NH:19][C:15]=4[N:16]=[CH:17][N:18]=3)[CH:10]=[N:9]2)[CH2:5][C:6]#[N:7])[CH2:3][CH2:2]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cnn([C@H](CC#N)C4CC4)c3)ncnc21
Agent: F[B-](F)(F)F
Agent: [Li+]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: N#CC[C@H](C1CC1)n1cc(-c2ncnc3[nH]ccc23)cn1
Temperature: 25 °C
Reaction time: 30 h
Yield: 87.4 %

Procedure:
A solution of (3R)-3-cyclopropyl-3-{4-[7-(2-trimethylsilanyl-ethoxymethyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-pyrazol-1-yl}-propionitrile ((R)-29, 102 g, 0.25 mol, 1.0 equiv) in MeCN (900 mL) and H2O (75 mL) was treated with solid lithium tetrafluoroborate (LiBF4, 186.0 g, 2.0 mol, 8.0 equiv) in portions (the reaction temperature increased from 15 to 38° on addition). The resulting reaction mixture was then heated at gentle reflux (light suspension formed) for 20 h. When LCMS showed the cleavage of the SEM group was complete, the reaction mixture was cooled to room temperature and subsequently to 12° before being adjusted to pH 9-10 with addition of an aqueous NH4OH solution (20%, 80 mL). The resulting suspension was stirred at room temperature until LCMS showed no N-hydroxymethyl intermediate (M++H=309) remained, typically within 24-36 h. During this period the pH of the reaction mixture dropped to 7-8, additional aqueous NH4OH solution (20%) was added to readjust the mixture to pH 9-10. The mixture was diluted with acetonitrile (300 mL), filtered, washing solids with acetonitrile (500 mL). The turbid filtrate was concentrated under reduced pressure to remove most of the MeCN to give a thick oil that contained some solids. The mixture was slowly diluted with H2O (500 mL) and the turbid solution was seeded. The solution was then concentrated under reduced pressure at room temperature until a thick suspension had formed. The suspension was further diluted with H2O (1 L) and the resulting suspension was stirred at room temperature for 2 h. The solids were collected by filtration, washed with H2O (2×500 mL) and suction dried on funnel for 1.5 h. 19F NMR showed a small amount of inorganic fluoride present and TLC (5% MeOH/EtOAc) showed a small amount of baseline material existed. Therefore, the crude solids were re-slurried in H2O (1 L) with mechanical stirring for 1 h before being collected by filtration and washed with H2O (500 mL). The wet cake was suction dried on the funnel for 1.5 h then dried in a vacuum oven at 45-50° C. for 16 h to give (3R)-3-cyclopropyl-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)pyrazol-1-yl]propionitrile ((R)-30, 60.8 g, 69.6 g theoretical, 87.4% yield) as a off-white solid. For (R)-30: C15H14N6 (MW, 278.31), LCMS (EI) m/e 279 (M++H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@@H:12]2[C@H:17]([NH:18][C:19](=O)[C:20]3[CH:34]=[CH:33][C:23]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=3)[CH2:16][CH2:15][O:14][CH2:13]2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].O=P(Cl)(Cl)Cl>C(#N)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]2[C:7](=[CH:8][C:9]=1[O:10][CH3:11])[C:19]([C:20]1[CH:34]=[CH:33][C:23]([C:24]([N:26]([CH:30]([CH3:32])[CH3:31])[CH:27]([CH3:29])[CH3:28])=[O:25])=[CH:22][CH:21]=1)=[N:18][C@H:17]1[C@@H:12]2[CH2:13][O:14][CH2:15][CH2:16]1)[CH3:2]
Reactant: CCOc1cc([C@H]2COCC[C@H]2NC(=O)c2ccc(C(=O)N(C(C)C)C(C)C)cc2)ccc1OC
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)N(C(C)C)C(C)C)cc1)=N[C@@H]1CCOC[C@H]21

Procedure:
5 mmol of N-[(3R,4R)-3-(3-Ethoxy-4-methoxy-phenyl)-tetrahydro-pyran-4-yl]-N′,N′-diisopropyl-terephthalamide are heated to boiling under reflux for 4 h in 25 ml of acetonitrile and 15 mmol of phosphorus oxytrichloride. After distilling off the excess of phosphorus oxytrichloride and about 20 ml of acetonitrile, the residue is partitioned between dichloromethane and saturated sodium hydrogencarbonate solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The solid residue is purified by column chromatography on SiO2 (di-isopropylether/methanol/triethyl amine 18/1/1 vol/vol/vol), the main product fraction is separated and concentrated yielding the title compound as grayish solid foam. M.p. 98-102° C. (unsharp, enamel-like shrinking starting at about 88° C.)
Reaction SMILES: [CH3:1][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([OH:15])[CH:11]=2)[CH2:6]1)[CH3:3].[ClH:16].[Cl:17][CH2:18][C:19]1[CH:28]=[CH:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[ClH:17].[ClH:16].[CH3:3][N:2]([CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:15][CH2:18][C:19]3[CH:28]=[CH:27][C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=3)[CH:11]=2)[CH2:6]1)[CH3:1]
Reactant: ClCc1ccc2ccccc2n1
Reactant: CN(C)CC1CCc2cc(O)ccc2C1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC1CCc2cc(OCc3ccc4ccccc4n3)ccc2C1
Temperature: 25 °C
Reaction time: 26 h

Procedure:
To a solution of 2-(N,N-dimethylamino)methyl-6-hydroxytetralin (153 mg, a free form of Reference Example 16) and 2-chloromethylquinoline hydrochloride (189 mg) in DMF (5 ml) was added potassium carbonate (260 mg) and the reaction mixture was stirred at room temperature for 26 hr. The reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated aqueous sodium chloride, dried, and concentrated. The residue was purified by alumina column chromatography (eluent: ethyl acetate:hexane=1:2) and then converted into its dihydrochloride, which was further recrystallized from methanol-ethyl acetate to obtain the titled compound (191 mg).
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](/C=C/C3C=CC=CC=3)=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.O[C:21]1C2C(=CC(CCC3C=CC=CC=3)=CC=2)[N:24]=[CH:23][CH:22]=1>C(O)C.[Pd]>[OH:1][C:2]1[C:11]2[C:6](=[C:7]3[C:8](=[CH:9][CH:10]=2)[N:24]=[CH:23][CH:22]=[CH:21]3)[N:5]=[CH:4][CH:3]=1
Reactant: Oc1ccnc2cc(CCc3ccccc3)ccc12
Reactant: Oc1ccnc2cc(/C=C/c3ccccc3)ccc12
Agent: [Pd]
Solvent: CCO
Product: Oc1ccnc2c1ccc1ncccc12
Yield: 99.2 %

Procedure:
Preparation 3: Preparation of 4-hydroxy-7-phenethylquinoline trans-4-Hydroxy-7-styrylquinoline (280 mg, 1.13 mmol) obtained in the Preparation 2 was dissolved in ethanol (200 ml), hydrogenated in the presence of 10% palladium on activated carbon (100 mg) and purified through silica gel column chromatography (Wako Gel™ C-200, methylene chloride : methanol=9 : 1) to obtain the titled compound (220mg, 78%).
Reaction SMILES: C(Cl)(C(Cl)=O)=O.[C:7]([OH:34])(=O)[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].[NH2:35][C@@H:36]([C@@H:49]([OH:66])[C@@H:50]([OH:65])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[CH2:37][O:38][C@@H:39]1[CH2:45][CH2:44][CH2:43][C@H:42]([OH:46])[C@H:41]([OH:47])[C@H:40]1[OH:48]>C1COCC1.CC([O-])=O.[Na+]>[OH:66][C@@H:49]([C@@H:50]([OH:65])[CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C@H:36]([NH:35][C:7](=[O:34])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[CH2:37][O:38][C@H:39]1[CH2:45][CH2:44][CH2:43][C@H:42]([OH:46])[C@H:41]([OH:47])[C@H:40]1[OH:48]
Reactant: CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@H](O)[C@H](O)[C@H](N)CO[C@@H]1CCC[C@H](O)[C@H](O)[C@H]1O
Agent: CC(=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCCCCCCCCC(=O)N[C@H](CO[C@H]1CCC[C@H](O)[C@H](O)[C@H]1O)[C@@H](O)[C@@H](O)CCCCCCCCCCCCCC
Temperature: 70 °C

Procedure:
(COCl)2 (2 mL) was added to hexacosanoic acid (139 mg, 0.39 mmol) and heated at 70° C. for 2 h, after which time the solution was cooled to rt, and the (COCl)2 removed under a stream of dry argon. The residual volatiles were removed under reduced pressure. The resulting crude acyl chloride was dissolved in THF (0.5 mL) and added with vigorous stirring to a solution of amine 72 (81 mg, 0.18 mmol) in THF/NaOAc(aq) (8M) (1:1, 2 mL). Vigorous stirring was maintained for 2 h, after which time the reaction mixture was left to stand and the layers were separated. The aqueous layer was extracted with THF (3×2.0 mL) and the organic layers were combined and concentrated under reduced pressure. The crude product was purified by column chromatography (10% MeOH in CHCl3) to give amide 73 as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=[O:11])=[C:4]([N+:18]([O-:20])=[O:19])[CH:3]=1.[CH2:21](O)[CH3:22]>>[CH2:21]([O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:7]([O:6][C:5]2[CH:16]=[CH:17][C:2]([Cl:1])=[CH:3][C:4]=2[N+:18]([O-:20])=[O:19])[CH:8]=1)[CH3:22]
Reactant: O=C(O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Reactant: CCO
Product: CCOC(=O)c1cccc(Oc2ccc(Cl)cc2[N+](=O)[O-])c1
Yield: 91 %

Procedure:
To the product from Example 168a (2.0 g, 6.8 mmol) in ethanol (50 mL) with cooling, was bubbled HCl gas for 10 h. The excess ethanol was removed under vacuum. The solid was taken up in ethyl acetate. The organic layer washed with saturated NaHCO3, water, brine, and dried over sodium sulfate, filtered and concentrated under vacuum giving the title compound (2.0 g, 91%).