Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH2:8][CH2:9][C:10]4[C@@H:15]3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20].C1(Cl)C(=O)C(Cl)=C(Cl)C(=O)C=1Cl.CCOC(C)=O.CCCCCC>C(O)C>[CH3:1][C@:2]12[CH2:18][CH2:17][C@H:16]3[C@@H:7]([CH:8]=[CH:9][C:10]4[C@@H:15]3[CH2:14][CH2:13][C:12](=[O:19])[CH:11]=4)[C@@H:6]1[CH2:5][CH2:4][C:3]2=[O:20]
Reactant: C[C@]12CC[C@H]3[C@@H](CCC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Agent: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: C[C@]12CC[C@H]3[C@@H](C=CC4=CC(=O)CC[C@@H]43)[C@@H]1CCC2=O
Yield: 46.3 %

Procedure:
A solution of dione 53 (5.0 g, 18.36 mmol) and chloranil (5.4 g, 22 mmol) in dry ethanol (500 mL) was stirred at 60-65° C. for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was triturated with dichloromethane. The solid was removed by filtration, and the filtrate was concentrated to give a brown gum. Chromatography (20% EtOAc/hexane) yielded crude dione 54 as a yellow solid (2.3 g, 46%): 1H NMR (300 MHz, CDCl3) δ0.94 (s, 3, CH3), 5.78 (s, 1), 6.25 (m, 2).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C.O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: ClCc1ccccc1
Reactant: CCOC(=O)C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCO
Product: CCOC(=O)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 30 h
Yield: 62.6 %

Procedure:
1 g (6.4 mmol) of piperidine-4-carboxylic acid ethyl ester is mixed in 10 ml of absolute ethanol with 0.75 ml (6.4 mmol) of benzyl chloride and 1.52 g (11 mmol) of potassium carbonate. The batch is stirred for 30 hours at room temperature. It is then dispersed in ethyl acetate/water. The combined organic phase is washed with water, dried, filtered and concentrated by evaporation. The residue is chromatographed on silica gel with hexane:ethyl acetate=1:1 as an eluant. 991 mg (64% of theory) of N-benzylpiperidine-4-carboxylic acid ethyl ester is obtained.
Reaction SMILES: [CH3:1]COC(C1N(C(OC(C)(C)C)=O)C2=NC=C(OC(=O)C3C=CC=CC=3)C=C2C=1)=O.[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44](Br)[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36]([N:38]1[CH2:50][C@@H:49]([CH3:51])[N:48]2[C@H:40]([CH2:41][C:42]3[C:47]2=[N:46][C:45]([C@H:52]([O:54][CH3:55])[CH3:53])=[C:44]([CH3:1])[CH:43]=3)[CH2:39]1)=[O:37])([CH3:34])([CH3:33])[CH3:32]
Reactant: CO[C@H](C)c1nc2c(cc1Br)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21
Reactant: CCOC(=O)c1cc2cc(OC(=O)c3ccccc3)cnc2n1C(=O)OC(C)(C)C
Product: CO[C@H](C)c1nc2c(cc1C)C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@@H](C)N21

Procedure:
This compound was prepared in analogy to example 14, intermediate c) from (4R,9aR)-7-bromo-6-(1-(R)-methoxy-ethyl)-4-methyl-3,4,9,9a-tetrahydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester (example 47, intermediate).
Reaction SMILES: [C:1]([Si:3]([CH3:6])([CH3:5])[CH3:4])#[CH:2].C(N(CC)CC)C.[F:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:26][C@H:25]([CH2:27][N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]3)[O:24][C:23]2=[O:34])[CH:18]=[CH:19][C:20]=1I>[Cu](I)I>[F:14][C:15]1[CH:16]=[C:17]([N:22]2[CH2:26][C@H:25]([CH2:27][N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[N:29]3)[O:24][C:23]2=[O:34])[CH:18]=[CH:19][C:20]=1[C:2]#[C:1][Si:3]([CH3:6])([CH3:5])[CH3:4]
Reactant: C#C[Si](C)(C)C
Reactant: Cc1cn(C[C@H]2CN(c3ccc(I)c(F)c3)C(=O)O2)nn1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Product: Cc1cn(C[C@H]2CN(c3ccc(C#C[Si](C)(C)C)c(F)c3)C(=O)O2)nn1
Temperature: 60 °C
Yield: 94 %

Procedure:
Ethynyl(trimethyl)silane (432 mg, 4.4 mmol), copper iodide(76 mg, 0.4 mmol), triethylamine (2.02 g, 20 mmol) and palladium tetrakis triphenylphosphine (231 mg, 0.2 mmol) were added to a solution of (5R)-3-(3-fluoro-4-iodophenyl)-5-[(4-methyl-1H-1,2,3-triazol-1-yl)methyl]-1,3-oxazolidin-2-one (WO2003072575) (Intermediate 2,1.61 g, 4.0 mmol) in a sealed reaction vessel. The reaction mixture was stirred at 60° C. over night, then cooled down to room temperature and filtered through celite. The filtrate was concentrated and purified by flash chromatography on silica gel with 30% hexanes in ethyl acetate. The product was obtained as a yellowish solid (1.4 g).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:16])([F:15])[F:14])=[CH:6][C:5]=1[NH:17]C(=O)C.O.S(=O)(=O)(O)O>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:21])[C:4]1[CH:9]=[C:8]([C:10](=[O:12])[CH3:11])[C:7]([C:13]([F:14])([F:16])[F:15])=[CH:6][C:5]=1[NH2:17]
Reactant: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1NC(C)=O
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(C(C)=O)c(C(F)(F)F)cc1N
Temperature: 25 °C
Yield: 100 %

Procedure:
A solution of 5-acetyl-2-acetylamino-4-trifluoromethyl-benzoic acid methyl ester (11.5 g, 37.8 mmol) in MeOH (120 mL)/water (24 mL) was cooled to 0° C. and concentrated sulfuric acid (15.0 mL, 271 mmol) was added dropwise. Upon completion of the addition, the mixture was heated to reflux for 45 min under nitrogen, and then allowed to cool to r.t. The mixture was diluted with EtOAc and washed once with water. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo providing 5-acetyl-2-amino-4-trifluoromethyl-benzoic acid methyl ester (9.87 g, 37.8 mmol, quantitative) as a white solid, m.p. 118-121° C., ESI-MS: m/z 262 [M+H]+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][CH:25]([NH:28][CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].[N:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[C:35]([CH:43]=O)[CH:34]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][CH:25]([N:28]([CH2:29][CH:30]([CH3:32])[CH3:31])[CH2:43][C:35]2[CH:34]=[N:33][C:42]3[C:37]([CH:36]=2)=[CH:38][CH:39]=[CH:40][CH:41]=3)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: O=Cc1cnc2ccccc2c1
Reactant: CC(C)CNC1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CN(Cc1cnc2ccccc2c1)C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 59.8 %

Procedure:
Sodium triacetoxyborohydride (1.29 g, 6.09 mmol) is added to a stirred solution of 4-isobutylamino-piperidine-1-carboxylic acid tert-butyl ester (1.09 g, 4.29 mmol), quinoline-3-carboxaldehyde (0.68 g, 4.3 mmol), acetic acid (0.25 ml, 4.37 mmol), and 1,2-dichloroethane (15 ml). The reaction is stirred for 18 h at room temperature under nitrogen. The reaction is poured into 2N NaOH (100 ml) and extracted with ethyl acetate (100 ml×3). The ethyl acetate is dried over sodium sulfate and then the sodium sulfate is filtered off. The crude product is concentrated on a rotary evaporator and purified by flash chromatography on silica gel eluting with 15% acetone/hexanes to yield (1.02 g, 60%) of 4-{isobutyl-[(quinolin-3-yl)methyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester: mass spectrum (ion spray): m/z=398.2 (M+1); 1H NMR (CDCl3): δ=8.93 (1H, d), 8.09 (1H, d), 8.02 (1H, s), 7.79 (1H, d), 7.70-7.66 (1H, m), 7.55-7.51 (1H, m), 4.16 (2H, br s), 3.79 (2H, s), 2.63-2.57 (3H, m), 2.27 (2H, d), 1.77-1.65 (3H, m), 1.52-1.48 (2H, m), 1.44 (9H, s), 0.85 (6H, d).
Reaction SMILES: [CH2:1]([C@@H:5]1[C@@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4].[Li+].[CH3:16][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1>[CH2:1]([C@:5]1([CH3:16])[C@H:8]([CH2:9][CH2:10][CH2:11][CH2:12][CH3:13])[O:7][C:6]1=[O:14])[CH2:2][CH2:3][CH3:4]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CCCCC[C@H]1OC(=O)[C@@H]1CCCC
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCCCC[C@@H]1OC(=O)[C@]1(C)CCCC
Temperature: -40 °C
Reaction time: 1.5 h
Yield: 72.9 %

Procedure:
A solution of β-lactone 3a (36.3 mg, 0.1835 mmol) in 1.9 mL THF was cooled to −78° C. and 370 μL of LiHMDS (0.367 mmol, 2.0 equiv, 1.0 M solution in THF) was added under a nitrogen atmosphere. After 1.5 h, 23 μL (0.367 mmol, 2.0 equiv) of iodomethane was added and the reaction warmed to −40° C. and stirred for an additional 45 min. The reaction mixture was concentrated in vacuo and purified by flash chromatography (0→15% Et2O: hexanes) to give β-lactone 8a (28.4 mg, 73%) as a colorless oil and as a mixture of cis/trans diastereomers (dr, 6:1). Data provided for major diastereomer: Rf(15% Et2O:hexanes) 0.64; IR (thin film) 1824 cm−1; 1H NMR (500 MHz, CDCl3) δ 4.18 (dd (major diast.), J=6.0, 8.5Hz, 1H), 1.63-1.78 (m, 2H), 1.45-1.53 (m, 2H), 1.39 (s, 3H), 1.24-1.39 (m, 10H), 0.89-0.94 (m, 6H); 13C NMR (500 MHz, CDCl3) 14.1, 14.2, 20.0, 22.1, 25.5, 25.6, 26.5, 30.3, 31.7, 35.9, 56.8, 84.5, 175.5; ESI LRMS Calcd. for C13H24O2Li [M+Li]: 219. Found: 219.
Reaction SMILES: C([O:3][P:4]([CH:10]([OH:28])[CH:11]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH2:12][NH:13]C(OC(C)(C)C)=O)([CH2:6][CH2:7][CH2:8][CH3:9])=[O:5])C>Cl>[ClH:27].[NH2:13][CH2:12][CH:11]([C:21]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][CH:22]=1)[CH:10]([P:4]([CH2:6][CH2:7][CH2:8][CH3:9])(=[O:3])[OH:5])[OH:28]
Reactant: CCCCP(=O)(OCC)C(O)C(CNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: Cl
Product: CCCCP(=O)(O)C(O)C(CN)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
A solution of 0.35 g of ethyl 3-(N-tert.-butyloxycarbonylamino)-2-(4-chlorophenyl)-1-hydroxy-propyl (n-butyl)phosphinic acid in 10 ml of 5.0M aqueous hydrochloric acid is heated to reflux for 24 hours. The reaction is cooled to room temperature and washed with 3×50 ml dichloromethane and 1×50 ml ether. After evaporation of the aqueous layer the residue is co-evaporated with water (3×50 ml) and absolute ethanol (3×50 ml) and dried in high vacuum to afford 3-amino-2-(4-chlorophenyl)-1-hydroxy-propyl (n-butyl)phosphinic acid hydrochloride.
Reaction SMILES: [CH3:1][N:2]([CH3:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:10](Cl)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C[OH:19]>[Ag]=O>[OH-:19].[CH2:10]([N+:2]([CH3:9])([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CO
Reactant: CN(C)c1ccccc1
Reactant: ClCc1ccccc1
Agent: O=[Ag]
Product: C[N+](C)(Cc1ccccc1)c1ccccc1
Product: [OH-]

Procedure:
A mixture of freshly distilled N,N-dimethyl aniline (52 ml, 0.41 mol) and benzyl chloride (47 ml, 0.41 mol) was allowed to stand for several days at room temperature. The separated crystals of benzyl dimethyl anilinium chloride were filtered and washed with anhydrous ether. The chloride salt (14.3 g, 0.054 mol) and silver oxide (13.4 g, 0.057 mol) were then stirred in anhydrous methanol (300 ml) for 2 hours and the solution filtered. The filtrate may be refrigerated for storage over a molecular sieve (type 3A).
Reaction SMILES: [CH2:1](Br)[CH2:2][CH2:3][CH2:4][CH3:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][C:24]([O:27][C:28]([F:31])([F:30])[F:29])=[CH:23][CH:22]=3)=[C:17]([F:32])[CH:16]=2)[CH2:11][CH2:10]1>C1COCC1>[CH2:1]([Si@H:9]1[CH2:14][CH2:13][C@H:12]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:22]=[CH:23][C:24]([O:27][C:28]([F:29])([F:30])[F:31])=[CH:25][CH:26]=3)=[C:17]([F:32])[CH:16]=2)[CH2:11][CH2:10]1)[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CCCCCBr
Reactant: Fc1cc(C2CC[SiH](Cl)CC2)ccc1-c1ccc(OC(F)(F)F)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: CCCCC[Si@H]1CC[C@H](c2ccc(-c3ccc(OC(F)(F)F)cc3)c(F)c2)CC1

Procedure:
3.0 g (20 mmol) of n-pentyl bromide was dripped into a mixture of 0.5 g of magnesium (21 mmol) and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.8 g (21 mmol) of 4'-(4-chloro-4-silacyclohexyl)-2'-fluoro-4-trifluoromethoxybiphenyl to obtain 4'-(trans-4-n-pentyl-4-silacyclohexyl)-2'-fluoro-4-trifluoromethoxybiphenyl. The silacyclohexane rings of this product were a mixture of trans and cis isomers. They were separated by means of chromatography to obtain 6.8 g of the trans isomer (yield 80%).
Reaction SMILES: Cl.[N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([NH:12][C:13](=[O:19])[NH:14][CH2:15][C:16]([OH:18])=O)=[CH:4][CH:3]=1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH:24]=[C:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.[CH2:34](P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH3:20][C:21]1[CH:22]=[C:23]([CH:31]=[CH:32][CH:33]=1)[CH:24]=[C:25]1[CH2:30][CH2:29][N:28]([C:16](=[O:18])[CH2:15][NH:14][C:13]([NH:12][C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[N:2]=[C:3]([CH3:34])[CH:4]=2)=[O:19])[CH2:27][CH2:26]1
Reactant: O=C(O)CNC(=O)Nc1ccnc2ccccc12
Reactant: Cc1cccc(C=C2CCNCC2)c1
Reactant: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1cccc(C=C2CCN(C(=O)CNC(=O)Nc3cc(C)nc4ccccc34)CC2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of (3-quinolin-4-yl-ureido)-acetic acid hydrochloride (281.7 mg, 1 mmol), 4-(3-methyl-benzylidene)-piperidine (187.3 mg, 1 mmol), TEA (1 mL, 7 mmol) in DMF (4 mL) and T3P (50% in EtOAc, 1 mL, 1.7 mmol) is stirred for 2 h at room temperature. The DMF is evaporated, the residue dissolved in CH2Cl2 (150 mL) and washed with 1M aqueous NaOH (50 mL) and brine (30 mL). The organic phase is dried (Na2SO4), filtered and evaporated to provide the crude title compound.
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=[C:13]([C:15]2[CH:20]=[C:19]([F:21])[CH:18]=[CH:17][C:16]=2[F:22])[CH2:12][N:11]1[C:23]([N:25]([CH3:32])[CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)=[O:24])(C(C)(C)C)(C)C.[Si]([O:46][CH2:47][CH:48]=O)(C(C)(C)C)(C)C.[BH3-]C#N.[Na+]>CO.CC(O)=O>[F:22][C:16]1[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:15]=1[C:13]1[CH2:12][N:11]([C:23]([N:25]([CH:26]2[CH2:27][CH2:28][N:29]([CH2:48][CH2:47][OH:46])[CH2:30][CH2:31]2)[CH3:32])=[O:24])[C:10]([CH2:9][OH:8])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH:14]=1
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO[Si](C)(C)C(C)(C)C)c1ccccc1)C1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN(C(=O)N1CC(c2cc(F)ccc2F)=CC1(CO)c1ccccc1)C1CCN(CCO)CC1
Reaction time: 1 h

Procedure:
To 150 mg (0.28 mmol) of amine 7-2 in MeOH was added 145 mg (0.83 mmol) of (t-butyldimethylsilyloxy) acetaldehyde and several drops of HOAc. After stirring for 1 h, 35 mg (0.55 mmol) of NaCNBH3 was added and the reaction was stirred overnight in a sealed flask. The mixture was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over MgSO4, and concentrated by rotary evaporation. The residue was dissolved in dry EtOAc, saturated with HCl(g) and stirred for 1 h. The reaction was partitioned between EtOAc and saturated NaHCO3, the layers were separated, the organic phase was washed with water, dried over MgSO4, and concentrated by rotary evaporation. The residue was purified by reverse phase HPLC, but was not of sufficient purity, so it was then purified by column chromatography on silica gel with 20:1:1 EtOH/NH4OH/H2O in EtOAc to provide 11-1 as a white solid. Data 11-1: 1HNMR (500 MHz, CDCl3) δ 7.4-7.2 (m, 5H), 7.1-6.9 (m, 3H), 6.3 (s, 1H), 5.4 (m, 1H), 4.8 (m, 1H), 4.6 (m, 1H), 4.4 (m, 1H), 4.0 (m, 1H), 3.75 (m, 1H), 3.6 (m, 2H), 3.0 (m, 2H), 2.9 (s, 3H), 2.5 (m, 2H), 2.2 (m, 2H), 1.8 (m, 3H), 1.7 (m, 1H) ppm. HRMS (ES) calc'd M+H for C26H31F2N3O3: 472.2406. Found: 472.2386.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:25]([F:35])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:25]([F:35])=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:18]=3[Cl:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)NCc1c(F)ccc(C(=O)O)c1Cl
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3ccc(F)c(CNC(=O)C(C)(C)C)c3Cl)cccc12
Yield: 5.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 2-chloro-4-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-64, 159 mg, 0.56 mmol), oxalyl chloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH2Cl2 (5 mL) to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H), 8.71-8.69 (d, J=7.2 Hz, 1H), 8.49 (s, 1H), 8.15-8.13 (d, J=7.8 Hz, 1H), 7.83 (t, 1H), 7.75-7.73 (m, 1H), 7.53-7.47 (m, 2H), 7.40-7.34 (t, J=8.7 Hz, 1H), 4.43 (d, 2H), 1.54 (s, 9H), 1.08 (s, 9H); MS [M+H]+: 486.56.
Reaction SMILES: [CH2:1]([C:8]1[C:13](I)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][O:22][C@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([C@:25]1([OH:33])[CH:30]2[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]2)[CH2:26]1)#[CH:24].C(N(CC)CC)C.N>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.CN(C)C=O>[CH2:1]([C:8]1[C:13]([C:24]#[C:23][C@:25]2([OH:33])[CH:30]3[CH2:31][CH2:32][N:27]([CH2:28][CH2:29]3)[CH2:26]2)=[CH:12][CH:11]=[C:10]([N:15]2[CH2:19][C@H:18]3[O:20][CH2:21][O:22][C@H:17]3[CH2:16]2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#C[C@@]1(O)CN2CCC1CC2
Reactant: Ic1ccc(N2C[C@@H]3OCO[C@@H]3C2)nc1Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O[C@]1(C#Cc2ccc(N3C[C@@H]4OCO[C@@H]4C3)nc2Cc2ccccc2)CN2CCC1CC2
Temperature: 75 °C
Reaction time: 4 h
Yield: 31 %

Procedure:
A mixture of 116 mg of 2-benzyl-6-(cis-3,4-methylenedioxypyrrolidine-1-yl)-3-iodopyridine, 47 mg of (3R)-3-ethynyl-3-quinuclidinol, 33 mg of tetrakis(triphenylphosphine)palladium (0), 3 mg of cuprous iodide, 0.12 ml of triethylamine and 3.0 ml of N,N-dimethylformamide was heated under stirring at 75° C. for 4 hours in a nitrogen atmosphere. The reaction solution was poured into aqueous dilute ammonia, and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to NH-silica gel (Fuji Silicia) column chromatography and eluted with hexane/ethyl acetate (1:1) and then with ethyl acetate/methanol (20:1), to give 38 mg of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[N:9]2[CH2:12][C:11](=[C:13]([C:16]3[CH:21]=[C:20]([F:22])[CH:19]=[C:18]([F:23])[CH:17]=3)[CH2:14][OH:15])[CH2:10]2)=[CH:4][CH:3]=1.Cl[C:32]([O:34][C:35]1[CH:40]=[CH:39][C:38]([N+:41]([O-:43])=[O:42])=[CH:37][CH:36]=1)=[O:33]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[C:32](=[O:33])([O:34][C:35]1[CH:36]=[CH:37][C:38]([N+:41]([O-:43])=[O:42])=[CH:39][CH:40]=1)[O:15][CH2:14][C:13](=[C:11]1[CH2:12][N:9]([CH:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[C:24]2[CH:25]=[CH:26][C:27]([Cl:30])=[CH:28][CH:29]=2)[CH2:10]1)[C:16]1[CH:17]=[C:18]([F:23])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: O=C(OCC(=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1)c1cc(F)cc(F)c1)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 320 mg (0.717 mmol) of 2-{1-[bis(4-chlorophenyl)methyl]azetidin-3-ylidene}-2-(3,5-difluorophenyl)ethanol (Example 31) and 175 mg (1.43 mmol) of 4-dimethylaminopyridine in 10 mL of methylene chloride was added 217 mg (1.076 mmol) of 4-nitrophenyl chloroformate, and the reaction mixture was stirred for 4 h at rt. The reaction mixture was concentrated and the residue was purified by silica gel chromatography with hexanes/ethyl acetate=12:1 to afford the title compound as a white solid; Mass Spectrum; m/e=613 (M+1 35Cl, 35Cl) and 615 (M+1 35Cl, 37Cl).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[CH2:20][N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)[O:5][CH:6]1[CH2:9][N:8](C(OC(C)(C)C)=O)[CH2:7]1.N1C[CH:28]([O:30]C2C=CC(CN3CCCC3)=C(F)C=2)C1.N1CCC[CH2:45]1.OC1C=CC(C=O)=C(OC)C=1C>>[NH:8]1[CH2:7][CH:6]([O:5][C:4]2[CH:17]=[CH:18][C:19]([CH2:20][N:21]3[CH2:22][CH2:23][CH2:24][CH2:25]3)=[C:2]([O:30][CH3:28])[C:3]=2[CH3:45])[CH2:9]1
Reactant: C1CCNC1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2ccc(CN3CCCC3)c(F)c2)C1
Reactant: Fc1cc(OC2CNC2)ccc1CN1CCCC1
Agent: COc1c(C=O)ccc(O)c1C
Product: COc1c(CN2CCCC2)ccc(OC2CNC2)c1C
Yield: 30 %

Procedure:
Using similar protocols as described in Examples 31A, 31B and 31C employing pyrrolidine and 52A as starting materials afforded 0.25 g (30%) of 52B as an oil. 1H NMR (500 MHz, CDCl3): δ 1.75 (s, 4H), 2.16 (s, 3H), 2.51 (s, 4H), 3.70 (s, 2H), 3.74 (s, 3H), 3.79 (m, 2H), 3.91 (m, 2H), 4.97 (m, 1H), 6.29 (d, 1H), 7.11 (d, 1H), MS (APCI+) m/z 277 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH:7]=[CH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:14]CC1C=CC=CC=1)[CH3:2].C1CC=CCC=1>[Pd].C(O)(=O)C>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C@@H:6]([C:22]1[CH:23]=[N:24][C:25]([CH3:28])=[N:26][CH:27]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH3:2]
Reactant: CCOC(=O)C[C@H](C=CCCCCCOCc1ccccc1)c1cnc(C)nc1
Agent: [Pd]
Solvent: C1=CCC=CC1
Solvent: CC(=O)O
Product: CCOC(=O)C[C@H](CCCCCCCO)c1cnc(C)nc1
Temperature: 80 °C
Yield: 43 %

Procedure:
A mixture of 11-5 (1.2 g, 4.9 mmol), 10% Pd/C (1.0 g), 1,4-cyclohexadiene (10 mL), and acetic acid (30 mL) was purged with argon, and then heated at 80° C. for 6 hours. Following cooling, filtration and concentration, the mixture was diluted with ethyl acetate, washed with 10%. K2CO3 and brine, and dried over magnesium sulfate. Evaporation of the solvents gave 0.65 g (88%) of 11-6 as a yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:6][C:7]([NH:15][C:16]([C:18]1[S:41][C:21]2[N:22](C(OCC)=O)[N:23]=[C:24]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33]Cl)=[CH:29][CH:28]=3)[C:20]=2[CH:19]=1)=[O:17])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:8]>C(O)C>[CH3:8][C:7]([NH:15][C:16]([C:18]1[S:41][C:21]2[NH:22][N:23]=[C:24]([NH:25][C:26](=[O:35])[C:27]3[CH:32]=[CH:31][C:30]([CH2:33][N:1]4[CH2:5][CH2:4][CH2:3][CH2:2]4)=[CH:29][CH:28]=3)[C:20]=2[CH:19]=1)=[O:17])([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH3:6]
Reactant: C1CCNC1
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(CCl)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Solvent: CCO
Product: CC(C)(NC(=O)c1cc2c(NC(=O)c3ccc(CN4CCCC4)cc3)n[nH]c2s1)c1ccccc1
Temperature: 79 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
Pirrolidine (1.81 mL, 21.8 mmol), was added to a suspension of ethyl 5-{[(1-methyl-1-phenylethyl)amino]carbonyl}-3-[(4-chloromethyl-benzoyl)amino]-1H-thieno[2,3-c]pyrazole-1-carboxylate (3.80 mg, 7.25 mmol) in 100 mL of dry ethanol. And the resulting mixture was stirred at 79° C. for 1 hour. Afterward the volatiles were removed by evaporation under reduced pressure and the residue was purified by chromatography over silica gel (eluant dichloromethane/methyl alcohol/aqueous ammonia 92:8:01) to give 1.2 g of the title compound.