Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.S(Cl)([Cl:15])=O>C(Cl)Cl>[Cl:15][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([C:11]#[N:12])=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: O=S(Cl)Cl
Reactant: N#Cc1ccc2c(c1)CCC2O
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CCC2Cl
Reaction time: 3 h

Procedure:
1-Hydroxy-2,3-dihydro-1H-indene-5-carbonitrile (4.77 g, 30 mmol) was dissolved in 10 mL of methylene dichloride. While cooled on ice, thionyl chloride (6.6 ml, 90 mmol) was added dropwise within about 15 minutes. The solution was concentrated after being stirred for 3 hours. The residue was dissolved in ethyl acetate and the solution obtained was washed with cooled brine for 3 times, dried over anhydrous magnesium sulfate, and concentrated to obtain 1-chloro-2,3-dihydro-1H-indene-5-carbonitrile.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+].C(O)C>ClCCl>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(I)ccc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(I)ccc1OCCBr

Procedure:
A mixture of 2-methyl-4-iodophenol (5.00 grams), 1,2-dibromoethane (2.76 mL), sodium hydroxide (1.3 grams) and ethanol (100 mL) was stirred at reflux for 5 hours before being poured into ice. The crude solid was dissolved in dichloromethane and washed with 1N NaOH. The organic layer was evaporated in vacuo to give 2-Bromo-1-(2-methyl-4-iodophenoxy)ethane Compound 21a as a tan solid. 1H NMR (CDCl3) δ 6.54 (d,1H), 4.25 (t, 2H), 3.66 (t, 2H), 2.20 (s, 3H).
Reaction SMILES: [N+:1]([C:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=O)[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH:5]=1)([O-])=[O:2].Cl.[NH2:21][OH:22].Cl>N1C=CC=CC=1>[N:21](=[C:8]1[C:7]2[CH:16]=[CH:17][CH:18]=[CH:19][C:6]=2[CH2:5][C:4](=[N:1][OH:2])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]1=2)[OH:22]
Reactant: NO
Reactant: O=c1c2ccccc2cc([N+](=O)[O-])c2ccccc12
Agent: Cl
Solvent: c1ccncc1
Product: ON=C1Cc2ccccc2C(=NO)c2ccccc21
Temperature: 0 °C

Procedure:
A mixture of 50.00 g of the product mixture from the stannous chloride reduction of 10-nitro-5H-dibenzo[a,d]cyclohepten-5-one and 62.61 g (0.901 mol) of hydroxylamine hydrochloride in 500 ml of pyridine was refluxed for 6 hr, poured into 3000 ml of ice water and 100 ml of conc. HCl, and extracted with CH2Cl2. The extracts were washed with brine, dried, treated with activated charcoal, filtered, and concentrated in vacuo to give a solid suspended in pyridine. The solid was removed by filtration and the pyridine treated as above to give a white solid. The solids were combined giving 44.09 g of 5,10-dioximino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene as a white solid which had incorporated pyridine. The pyridine could not be removed by heating, high vacuum, or recrystallization: mp 220°-221°; NMR (DMSO-d6 /TMS) δ 11.62 (s, 1H, =NOH), 11.57 (s, 1H, =NOH), 7.50-7.00 (m, 8H, arom), and 3.97 (br s, 2H, benzylic); IR (CHCl3) 2.79, 3.34, 6.33, 6.99, 8.20, 8.34, 9.39, 9.74, 10.09, 10.79, 12.65 and 14.34μ.
Reaction SMILES: C([O:3][C:4](=O)[NH:5][CH2:6][CH2:7][C:8]1[S:9][C:10]([Br:13])=[CH:11][CH:12]=1)C.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>O=P(Cl)(Cl)Cl>[Br:13][C:10]1[S:9][C:8]2[CH2:7][CH2:6][NH:5][C:4](=[O:3])[C:12]=2[CH:11]=1
Reactant: CCOC(=O)NCCc1ccc(Br)s1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: O=P(Cl)(Cl)Cl
Product: O=C1NCCc2sc(Br)cc21
Yield: 37.4 %

Procedure:
Using analogous reaction conditions and workup as described in example 1, step 4, [2-(5-bromo-thiophen-2-yl)-ethyl]-carbamic acid ethyl ester (I-14c: 2.7 g, 9.8 mmol) in POCl3 (20 mL) was reacted with P2O5 (2.7 g, 19.64 mmol) to afford the crude product. Purification by column chromatography on silica gel (0.5% methanol in DCM) afforded 850 mg of the product (37.56% yield).
Reaction SMILES: O=[C:2]1[C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)(C2C=CC=CC=2)CCC[N:3]1[CH2:20]C(O)=O.F[C:25]1[CH:30]=[CH:29][C:28]([C:31]2([C:42]3[CH:47]=[CH:46][C:45](F)=[CH:44][CH:43]=3)[CH2:36][CH2:35][CH2:34][N:33]([CH2:37][C:38](O)=[O:39])[C:32]2=[O:41])=[CH:27][CH:26]=1.C1C2C(=CC=CC=2)CCN1.C1(C2(C3C=CC=CC=3)CCNC2)C=CC=CC=1>>[CH2:20]1[C:15]2[C:14](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:7][CH2:2][N:3]1[C:38](=[O:39])[CH2:37][N:33]1[CH2:34][CH2:35][CH2:36][C:31]([C:28]2[CH:29]=[CH:30][CH:25]=[CH:26][CH:27]=2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[C:32]1=[O:41]
Reactant: O=C(O)CN1CCCC(c2ccc(F)cc2)(c2ccc(F)cc2)C1=O
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Agent: c1ccc(C2(c3ccccc3)CCNC2)cc1
Agent: c1ccc2c(c1)CCNC2
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N1CCc2ccccc2C1

Procedure:
The title compound was prepared using the procedure described in Example 172 substituting 2-(2-oxo-3,3-diphenylpiperidin-1-yl)acetic acid from Example 68E for 2-(3,3-bis(4-fluorophenyl)-2-oxopiperidin-1-yl)acetic acid and 1,2,3,4-tetrahydroisoquinoline for 3,3-diphenylpyrrolidine. 1H NMR (300 MHz, CDCl3) δ ppm 7.44-7.00 (m, 14H), 4.69 (d, J=42.8, 2H), 4.32 (d, J=4.4, 2H), 3.86 (t, J=6.0, 1H), 3.67 (t, J=5.9, 1H), 3.52 (t, J=6.4, 2H), 2.88 (t, J=5.9, 2H), 2.72-2.56 (m, 2H), 1.92-1.76 (m, 2H); MS (DCI) m/z 425.1 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1)[NH:5][C:6](=[O:30])[C@H:7]([CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)[NH:8][C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].O.[NH2:39][NH2:40]>CN(C)C=O>[CH2:12]([O:11][C:9]([NH:8][C@H:7]([C:6]([NH:5][CH:4]([C:3]([NH:39][NH2:40])=[O:2])[CH2:31][C:32]1[N:33]=[CH:34][S:35][CH:36]=1)=[O:30])[CH2:19][C:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][CH:21]=1)=[O:10])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: NN
Reactant: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Solvent: CN(C)C=O
Solvent: O
Product: NNC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.4 %

Procedure:
2.10 g (4.06 mmole) of this ester were dissolved in 20 ml of dimethylformamide, and then 2.00 g (40.0 mmole) of hydrazine hydrate were added; the mixture was stirred overnight at room temperature. This reaction product was condensed by evaporation under reduced pressure, and then water was added to the residue. The precipitating crystals were collected by filtration, washed with hexane and diethyl ether and dried, to yield 1.90 g (90.5%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([C@@H:15]([C:16]4[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=4[F:23])[C@H:14]([C:24]([OH:26])=O)[NH:13][C:12]43[CH2:31][CH2:30][C:29]([CH3:33])([CH3:32])[CH2:28][CH2:27]4)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.Cl.[NH2:35][C@H:36]1[CH2:41][CH2:40][C@H:39]([C:42]([NH2:44])=[O:43])[CH2:38][CH2:37]1>>[C:42]([C@H:39]1[CH2:40][CH2:41][C@H:36]([NH:35][C:24]([C@@H:14]2[NH:13][C:12]3([CH2:27][CH2:28][C:29]([CH3:32])([CH3:33])[CH2:30][CH2:31]3)[C@:6]3([C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[NH:8][C:7]3=[O:11])[C@H:15]2[C:16]2[CH:21]=[CH:20][N:19]=[C:18]([Cl:22])[C:17]=2[F:23])=[O:26])[CH2:37][CH2:38]1)(=[O:43])[NH2:44]
Reactant: NC(=O)[C@H]1CC[C@H](N)CC1
Reactant: CC1(C)CCC2(CC1)N[C@@H](C(=O)O)[C@H](c1ccnc(Cl)c1F)C21C(=O)Nc2cc(Cl)ccc21
Agent: Cl
Product: CC1(C)CCC2(CC1)N[C@@H](C(=O)N[C@H]1CC[C@H](C(N)=O)CC1)[C@H](c1ccnc(Cl)c1F)[C@]21C(=O)Nc2cc(Cl)ccc21

Procedure:
The compound (200 mg, 0.41 mmol) obtained in Step 1 of Example 17 and trans-4-aminocyclohexanecarboxamide hydrochloride (WO2005/058892) (87 mg, 0.49 mmol) were used as starting materials and treated in the same way as in Step 2 of Example 12 to give 53 mg (21%) of the title compound as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19]O)[CH:7]=1)[CH3:2].P(Br)(Br)[Br:23]>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][Br:23])[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2CO)c1
Reactant: BrP(Br)Br
Solvent: C1COCCO1
Product: CCOC(=O)Cc1cccc(Oc2ccccc2CBr)c1
Reaction time: 1 h
Yield: 54.7 %

Procedure:
To [3-(2-hydroxymethyl-phenoxy)-phenyl]-acetic acid ethyl ester (0.90 g, 3.14 mmol) in 1,4-dioxane was added phosphorus tribromide (0.38 mL, 4.1 mmol), and the reaction was stirred for 1 hour at mom temperature. After work-up, 0.6 g of the desired product was obtained.
Reaction SMILES: Cl.Cl.[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@H:17]1[CH2:23][S:22][C@H:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:20][N:19]([CH2:29][C:30]([OH:32])=[O:31])[C:18]1=[O:33])[C:11]([O:13]CC)=[O:12].Cl>[OH-].[Na+]>[NH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C@H:10]([NH:16][C@H:17]1[CH2:23][S:22][C@H:21]([C:24]2[S:25][CH:26]=[CH:27][CH:28]=2)[CH2:20][N:19]([CH2:29][C:30]([OH:32])=[O:31])[C:18]1=[O:33])[C:11]([OH:13])=[O:12]
Reactant: CCOC(=O)[C@H](CCCCCCN)N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)O)C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NCCCCCC[C@H](N[C@H]1CS[C@H](c2cccs2)CN(CC(=O)O)C1=O)C(=O)O
Reaction time: 24 h
Yield: 96.8 %

Procedure:
142 mg of α-{6(R)-[7-amino-1(S)-ethoxycarbonylheptylamino]-5-oxo-2(S)-(2-thienyl)perhydro-1,4-thiazepin-4-yl}acetic acid dihydrochloride (prepared as described in Example 5) were dissolved in 1.2 ml of a 1N aqueous solution of sodium hydroxide, and the mixture was allowed to stand for 24 hours. At the end of this time, the mixture as adjusted to a pH value of 4.8 by the addition of 1N aqueous hydrochloric acid and the resulted precipitates were collected by filtration to give 112 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:13](Br)[N:12]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2].C([O-])=O.[NH4+]>CCOC(C)=O.[Pd]>[CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:29])=[C:8]2[C:14]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)=[CH:13][N:12]([C:22]3[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=3)[C:9]2=[CH:10][N:11]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1ncc2c(c1O)c(-c1ccccc1)c(Br)n2-c1ccc(F)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc2c(c(-c3ccccc3)cn2-c2ccc(F)cc2)c1O

Procedure:
A mixture of 2-bromo-1-(4-fluoro-phenyl)-4-hydroxy-3-phenyl-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester (514 mg, 1.13 mmol), 10% Pd—C (80 mg), and ammonium formate (1.42 g, 22.6 mmol) in EtOAc (15 mL) was refluxed for two days; then the catalysts were filtered off, the filtrate was concentrated, the left residue was purified on column to give the desired title product, ESI MS (m/z): 377 (M+H+).
Reaction SMILES: Br[C:2]1[CH:24]=[CH:23][C:5]2[C:6]3[N:7]([CH:11]=[C:12]([C:14]4[N:18]([CH:19]([CH3:21])[CH3:20])[N:17]=[C:16]([CH3:22])[N:15]=4)[N:13]=3)[CH2:8][CH2:9][O:10][C:4]=2[CH:3]=1.[C:25]([O:29][CH3:30])(=[O:28])[CH:26]=[CH2:27].C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.C(N(CC)CC)C>CN(C)C=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:19]([N:18]1[C:14]([C:12]2[N:13]=[C:6]3[C:5]4[CH:23]=[CH:24][C:2](/[CH:27]=[CH:26]/[C:25]([O:29][CH3:30])=[O:28])=[CH:3][C:4]=4[O:10][CH2:9][CH2:8][N:7]3[CH:11]=2)=[N:15][C:16]([CH3:22])=[N:17]1)([CH3:21])[CH3:20]
Reactant: C=CC(=O)OC
Reactant: Cc1nc(-c2cn3c(n2)-c2ccc(Br)cc2OCC3)n(C(C)C)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/c1ccc2c(c1)OCCn1cc(-c3nc(C)nn3C(C)C)nc1-2
Temperature: 100 °C

Procedure:
A mixture of 0.194 g (0.500 mmol) of 9-bromo-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine 411, 0.180 mL (2.00 mmol) of methyl acrylate, 22.4 mg (0.0999 mmol) of palladium acetate, 122 mg (0.400 mmol) of tri-o-tolylphosphine and 0.278 mL, (2.00 mmol) of triethylamine in 4.0 ml of N,N-Dimethylformamide was heated at 100° C. for 6 hours. The mixture was concentrated in vacuum and partitioned between ethyl acetate and water. The organic extracts were washed with dilute aqueous HCl, water, brine, dried over Na2SO4 and concentrated in vacuum. The residue was purified on 4 g silica column eluting with heptane-ethyl acetate gradient to give (E)-methyl 3-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acrylate. Yield 0.11 g. M/z 394.2, calc. 393.18.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][C:14]([NH:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[C:23]([NH:27][S:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=1)[OH:20])([CH3:16])[CH3:15])[CH:7]=[CH:6]2)#[N:2].C([Sn]([N:50]=[N+:51]=[N-:52])(CCCC)CCCC)CCC>C1(C)C=CC=CC=1>[CH3:16][C:14]([NH:17][CH2:18][C@@H:19]([C:21]1[CH:22]=[C:23]([NH:27][S:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:30])=[O:29])[CH:24]=[CH:25][CH:26]=1)[OH:20])([CH3:15])[CH2:13][CH2:12][N:8]1[C:9]2[C:5](=[CH:4][C:3]([C:1]3[NH:52][N:51]=[N:50][N:2]=3)=[CH:11][CH:10]=2)[CH:6]=[CH:7]1
Reactant: CC(C)(CCn1ccc2cc(C#N)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Solvent: Cc1ccccc1
Product: CC(C)(CCn1ccc2cc(-c3nnn[nH]3)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1

Procedure:
150 mg (0.30 mmol) N-(3-{(R)-2-[3-(5-cyano-indol-1-yl)-1,1-dimethyl-propylamino]-1-hydroxy-ethyl}-phenyl)-benzenesulphonamide (Example 1) are dissolved in 5 ml of toluene and combined with 98 μl (0.36 mmol) tributyltin azide. Then the reaction solution is refluxed for 18 hours. Another 164 μl (0.6 mmol) tributyltin azide are added. The mixture is refluxed for a further 36 hours. Then the solvent is eliminated in vacuo and the residue is chromatographed on silica gel (DCM/methanol/NH4OH=100:0:0→70:30:0.3).
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[F:24][C:25]1[C:30](B(O)O)=[CH:29][CH:28]=[CH:27][N:26]=1>>[F:24][C:25]1[C:30]([C:2]2[N:10]3[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]4[CH:13]=[CH:14][C:15]([N:18]5[CH2:23][CH2:22][O:21][CH2:20][CH2:19]5)=[CH:16][CH:17]=4)=[N:9]3)=[CH:4][CH:3]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: Brc1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12
Reactant: OB(O)c1cccnc1F
Product: Fc1ncccc1-c1ccc2cnc(Nc3ccc(N4CCOCC4)cc3)nn12

Procedure:
[7-(2-Fluoro-pyridin-3-yl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-(4-morpholin-4-yl-phenyl)-amine was prepared from (7-bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-(4-morpholin-4-yl-phenyl)-amine and 2-fluoro-3-pyridineboronic acid in an analogous manner to Example 1031b. Product isolated as a yellow solid (93 mg, 81%). m.p.=215-221° C.; LCMS (m/e) 391 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.94-8.85 (m, 1H), 8.75 (s, 1H), 8.24-8.17 (m, 1H), 7.49 (d, 2H, J=7.6 Hz), 7.36-7.27 (m, 1H), 7.19-7.12 (m, 1H), 6.90 (m, 2H, J=7.6 Hz), 6.85 (m, 1H, J=4.2 Hz), 6.70 (s, 1H), 3.92-3.85 (m, 4H), 3.17-3.10 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:7]([CH2:8][NH:9][C:10]2[N:14]([CH2:15][CH3:16])[N:13]=[C:12]([CH:17]3[CH2:19][CH2:18]3)[CH:11]=2)=[C:6]([O:20][CH3:21])[N:5]=[C:4]([O:22][CH3:23])[N:3]=1.[CH3:24][C:25]1(C)C(C)(C)OB(C=C)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH:17]1([C:12]2[CH:11]=[C:10]([NH:9][CH2:8][C:7]3[C:6]([O:20][CH3:21])=[N:5][C:4]([O:22][CH3:23])=[N:3][C:2]=3[CH:24]=[CH2:25])[N:14]([CH2:15][CH3:16])[N:13]=2)[CH2:19][CH2:18]1
Reactant: CCn1nc(C2CC2)cc1NCc1c(Cl)nc(OC)nc1OC
Reactant: C=CB1OC(C)(C)C(C)(C)O1
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: COCCOC
Solvent: O
Product: C=Cc1nc(OC)nc(OC)c1CNc1cc(C2CC2)nn1CC

Procedure:
To a solution of N-((4-chloro-2,6-dimethoxypyrimidin-5-yl)methyl)-3-cyclopropyl-1-ethyl-1H-pyrazol-5-amine (2.42 g, 7.16 mmol) in DME (50 mL) and water (15 mL) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (2.5 mL, 14.3 mmol), Pd(Ph3P)4 (0.828 g, 0.716 mmol) and sodium carbonate (2.47 g, 23.3 mmol). The mixture was sparged with argon for 15 min and then heated at reflux for 18 h. The mixture was then absorbed onto silica gel and dried under reduced pressure. After dry loading, the product was purified by FCC (10-75% EtOAc/heptane) to give 3-cyclopropyl-N-((2,4-dimethoxy-6-vinylpyrimidin-5-yl)methyl)-1-ethyl-1H-pyrazol-5-amine. MS (ESI+) m/z 330.1 (M+H)+.
Reaction SMILES: [C:1]([CH2:6][C:7]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:8]=1[CH:9]=[CH:10][NH:11]2)([O:3][CH2:4][CH3:5])=[O:2].Br[CH2:17][C:18](=[N:24][OH:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[OH:25][N:24]=[C:18]([CH2:17][C:9]1[C:8]2[C:12](=[CH:13][CH:14]=[CH:15][C:7]=2[CH2:6][C:1]([O:3][CH2:4][CH3:5])=[O:2])[NH:11][CH:10]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(CBr)=NO
Reactant: CCOC(=O)Cc1cccc2[nH]ccc12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CCOC(=O)Cc1cccc2[nH]cc(CC(=NO)C(=O)OCC)c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 71.6 %

Procedure:
To a solution of 4-(carboethoxymethyl)indole (830 mg, 4.12 mmol) and ethyl bromopyruvate 2-oxime (866 mg, 4.12 mmol) in methylene chloride (40 mL) was added anhydrous Na2CO3 (2.40 g, 22.66 mmol) at ambient temperature. After stirring at ambient temperature for 16 hours, the mixture was filtered and concentrated to dryness. The residue was chromatographed on silica gel eluted with 10% MeOH in CHCl3 /hexane (1:1→2:1) to give 0.98 g of the title compound. TLC Rf=0.61 (10%MeOH/CHCl3). MS(DCl) m/e 333 (M+H)+. 1H NMR (CDCl3, 300 MHz) δ1.25(t, J=7.4 Hz, 3H), 1.30(t, J=7.4 Hz,3H), 4.13(s,2H), 4.18(q, J=7.4 Hz,2H), 4.28(q, J=7.4 Hz,2H), 4.28(q, J=7.4 Hz,2H), 4.30(s,2H), 6.92(br s, 1H), 6.98(d, J=7.4 Hz, 1H), 7.12(t, J=7.4 Hz, 1H), 7.26(d,J=7.4 Hz, 1H), 8.03(br s, --OH), 8.17 (br s, --NH).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH3:10])[CH2:5]Cl.[C:11]([NH:14][CH:15]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12].[O-]CC.[Na+]>C(O)C>[C:11]([NH:14][C:15]([CH2:5][C:4]1[CH:7]=[CH:8][C:9]([CH3:10])=[C:2]([CH3:1])[CH:3]=1)([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:13])[CH3:12]
Reactant: Cc1ccc(CCl)cc1C
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(C)c(C)c1)(NC(C)=O)C(=O)OCC
Yield: 53.4 %

Procedure:
3,4-Dimethylbenzyl chloride (10.2 g) and diethyl acetamidomalonate (14.3 g) were added successively into a solution of sodium ethoxide (4.94 g) in ethanol. The mixture was stirred under reflux for 2 hours and filtered through Celite®. The filtrate was concentrated under reduced pressure to give crystals which were collected by filtration and washed with isopropyl ether to give colorless crystals of diethyl 2-acetylamino-2-(3,4-dimethylbenzyl)malonate (11.8 g).
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.Cl[Sn]Cl.O>CC(O)=O.Cl>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[NH:6][C:7]([C:9]3[CH:10]=[CH:11][C:12]([NH2:15])=[CH:13][CH:14]=3)=[N:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])c1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Agent: Cl
Agent: Cl[Sn]Cl
Solvent: O
Solvent: CC(=O)O
Product: Nc1ccc(-c2nc3cc(Cl)ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
In 500 mL round bottom flask was suspended 5-Chloro-2-(4-nitro-phenyl)-1H-benzoimidazole (4.23 g, 13.66 mmol) in AcOH (30 mL) at 0° C., and to the suspension was added dropwise SnCl2.H2O (9.4 g, 41.66 mmol), in HCl (15 mL). After the addition, the ice bath was removed and the mixture was allowed to stir at room temperature overnight (16 h). The mixture was poured onto ice, and NaOH (50% aq.) was slowly added to pH 12. Then the mixture was extracted with EtOAc (4×150 mL). The combined organic layers were washed with brine, dried over NaSO4 and filtered, the solvent was evaporated to yield the product as an orange oil. The oil was dissolved in EtOAc and washed with HCl (1.0 N, 100 mL) and the product was isolated as HCl salt (2.13 g, 67%).
Reaction SMILES: [OH-].[Na+].Cl.Cl.N[CH:6]1[CH:11]2[CH2:12][CH2:13][N:8]([CH2:9][CH2:10]2)[CH2:7]1.[NH2:14][C:15]([NH2:17])=[O:16].NC1C2CCN(CC2)C1>>[N:8]12[CH2:13][CH2:12][CH:11]([CH2:10][CH2:9]1)[CH2:6][CH:7]2[NH:14][C:15](=[O:16])[NH2:17]
Reactant: NC1CN2CCC1CC2
Reactant: NC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NC1CC2CCN1CC2
Temperature: 25 °C
Yield: 103.2 %

Procedure:
160.0 g of a 30% caustic soda aqueous solution was added to 22.0 g of 3-aminoquinuclidine dihydrochloride, followed by stirring at room temperature. The solution thus obtained was extracted with 80.0 g of benzene twice to obtain an upper solution, which was evaporated to obtain a solution. 6.9 g of urea was added to 17.6 g of the solution (the amount of 3-aminoquinuclidine: 14.4 g). The solution thus obtained was reacted at 160° C. for 8 hours, and after the reaction, a volatile component was removed to obtain 19.3 g of a 3-quinuclidinyl urea composition. 38.6 g of dipropylene glycol was added thereto and subjected to a foaming test. The composition of the solution is shown in Table 6.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][CH2:18][OH:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][CH2:6]1)=[O:4].CS(C)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][C:2]([CH3:21])([CH3:20])[C:3]([N:5]1[CH2:10][CH2:9][C:8]([CH2:17][CH:18]=[O:19])([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[O:7][CH2:6]1)=[O:4]
Reactant: CC(C)(C)C(=O)N1CCC(CCO)(c2ccccc2)OC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)(C)C(=O)N1CCC(CC=O)(c2ccccc2)OC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
To a 0° C. solution of the above 2-[3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]ethanol, dimethyl sulfoxide (10 mL, 141 mmol) and diisopropylethylamine (10.5 mL, 60 mmol) in 60 mL CH2Cl2 was added SO3.pyr (9.0 g, 57 mmol) in one portion. The reaction mixture was stirred at 0° C. for 2 h, quenched with saturated aqueous NaHCO3, extracted with CHCl3, dried (Na2SO4) and chromatographed (2:1 Hex:EtOAc) to provide [3-(2,2-dimethylpropanoyl)-6-phenyl-1,3-oxazinan-6-yl]acetaldehyde (2.84 g, 98%) as an oil. 1H NMR (400 MHz, CDCl3): δ 9.64 (t, 1H, J=2.7 Hz), 7.45-7.41 (m, 4H), 7.33 (m, 1H), 5.49 (dd, 1H, J=11.1, 1.9 Hz), 4.74 (d, 1H, J=11.5 Hz), 4.27 (m, 1H), 3.08 (m, 1H), 2.72 (ABqd, 2H, J=15.3, 2.8 Hz), 2.43 (ddd, 1H, J=14.2, 4.1, 3.0 Hz), 2.11 (ddd, 1H, J=14.2; 11.4, 4.3 Hz), 1.28 (s, 9H). ESI-MS 312 (M+Na).
Reaction SMILES: C(OC1C=CC(C(O)=O)=CC=1)CCCCC.ClCC[C@H](C)CCCOC1C=CC(O)=CC=1.[CH2:33]([O:41][C:42]1[CH:50]=[CH:49][C:45]([C:46]([OH:48])=[O:47])=[CH:44][CH:43]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40].[Cl:51][CH:52]([CH2:67][CH2:68][CH2:69][CH3:70])[CH2:53][C@H:54]([CH3:66])[CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:64]=[CH:63][C:62](O)=[CH:61][CH:60]=1>>[Cl:51][CH:52]([CH2:67][CH2:68][CH2:69][CH3:70])[CH2:53][C@H:54]([CH3:66])[CH2:55][CH2:56][CH2:57][O:58][C:59]1[CH:60]=[CH:61][C:62]([O:47][C:46](=[O:48])[C:45]2[CH:44]=[CH:43][C:42]([O:41][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])=[CH:50][CH:49]=2)=[CH:63][CH:64]=1
Reactant: CCCCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCCCC(Cl)C[C@H](C)CCCOc1ccc(O)cc1
Agent: CCCCCCOc1ccc(C(=O)O)cc1
Agent: C[C@@H](CCCl)CCCOc1ccc(O)cc1
Product: CCCCCCCCOc1ccc(C(=O)Oc2ccc(OCCC[C@@H](C)CC(Cl)CCCC)cc2)cc1

Procedure:
The procedure of Example 12 was followed except that the 4-n-hexyloxybenzoic acid and (R)-4-(6'-chloro-4'-methylhexyloxy)phenol were replaced by 4-n-octoxybenzoic acid and (R)-4-(6'-chloro-4'-methyldecyloxy)phenol ([α]D =+2.00°, C=1, CHCl3 solution, 26° C.) to thereby give the title compound.