Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[Li].O.[Br:4][C:5]1[CH:6]=[C:7]([C:20]([O:22]C)=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1>C1COCC1>[Br:4][C:5]1[CH:6]=[C:7]([C:20]([OH:22])=[O:21])[N:8]([CH2:10][C:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[O:12])[CH:9]=1
Reactant: COC(=O)c1cc(Br)cn1CC(=O)c1ccc(Cl)cc1
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: O=C(Cn1cc(Br)cc1C(=O)O)c1ccc(Cl)cc1
Temperature: 40 °C
Reaction time: 3 h
Yield: 74.8 %

Procedure:
LiOH H2O (0.2 M, 6.8 mL, 1.36 mmol) was added portionwise to a solution of crude methyl 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylate (210 mg, 0.39 mmol) in THF (0.5 mL), and the mixture stirred at 40° C. for 3 h, after which time the TLC analysis showed consumption of starting material ester. The reaction mixture was diluted with aqueous NaOH solution (1M) (50 mL) and the mixture washed with CH2Cl2 (100 mL). The aqueous layer was acidified to pH 2 with aqueous HCl solution (1M) and was extracted with CH2Cl2 containing 30% of propan-2-ol (2×150 mL). The organic layers were combined, dried (MgSO4) and concentrated in vacuo to give 4-bromo-1-[2-(4-chlorophenyl)-2-oxoethyl]-1H-pyrrole-2-carboxylic acid (100 mg, yield 75%). This crude material was used in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[N:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:15][CH:14]=3)[CH:11]([C:23]3[CH:24]=[CH:25][C:26]([NH:48]CC4C=CC(OC)=CC=4OC)=[C:27]([NH:29][C:30]([C@@H:32]4[CH2:36][CH2:35][CH2:34][N:33]4[C:37](=[O:47])[C@@H:38]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH:39]([CH3:41])[CH3:40])=[O:31])[CH:28]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:48][C:26]1[CH:25]=[CH:24][C:23]([CH:11]2[CH2:10][CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=3)[N:12]2[C:13]2[CH:14]=[CH:15][C:16]([C:19]([CH3:21])([CH3:22])[CH3:20])=[CH:17][CH:18]=2)=[CH:28][C:27]=1[NH:29][C:30]([C@@H:32]1[CH2:36][CH2:35][CH2:34][N:33]1[C:37](=[O:47])[C@@H:38]([NH:42][C:43](=[O:46])[O:44][CH3:45])[CH:39]([CH3:41])[CH3:40])=[O:31]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1NCc1ccc(OC)cc1OC)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1C(=O)Nc1cc(C2CCC(c3ccc(Br)cc3)N2c2ccc(C(C)(C)C)cc2)ccc1N)C(C)C
Reaction time: 0.17 h

Procedure:
The product from example 191G (0.65 g, 0.748 mmole) was dissolved in CH2Cl2 (10 mL) then added concentrated trifluoroacetic acid (2 mL, 26 mmole)) and the reaction mixture was stirred 10 minutes. The solvent was removed in vacuo and the residue was re-evaporated twice from CH2Cl2 and once from toluene. The residue was dissolved in EtOAc (100 mL) washed with 10% NaHCO3, dried over anhydrous Na2SO4(s), filtered and solvent removed in vacuo leaving a brown foamy material as the title compound as a mixture of isomers (0.5 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:49]([OH:51])=[O:50])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:45](=[O:48])[CH:46]=[O:47])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[CH:33]=[CH:32][C:31]([O:34][C:35](=[O:43])[NH:36]C(=O)C(Cl)(Cl)Cl)=[CH:30][CH:29]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:44])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].CO.Cl>O>[C:1]([O:5][C:6]([NH:8][CH:9]([C:49]([OH:51])=[O:50])[CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([N:19]([C:45](=[O:48])[CH:46]=[O:47])[CH:20]2[CH2:23][N:22]([CH:24]([C:28]3[CH:29]=[CH:30][C:31]([O:34][C:35](=[O:43])[NH2:36])=[CH:32][CH:33]=3)[C:25]([OH:27])=[O:26])[C:21]2=[O:44])=[CH:15][CH:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3ccc(OC(=O)NC(=O)C(Cl)(Cl)Cl)cc3)C2=O)cc1)C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCOc1ccc(N(C(=O)C=O)C2CN(C(C(=O)O)c3ccc(OC(N)=O)cc3)C2=O)cc1)C(=O)O
Temperature: 25 °C
Reaction time: 7 h

Procedure:
2-[3-{4-(3-tert-Butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-[4-{N-(2,2,2-trichloroacetyl)carbamoyloxy}phenyl]acetic acid (550 mg.) was suspended in water (5 ml.), and to the suspension there were added sodium bicarbonate (250 mg.) and methanol (1 ml.). The mixture was stirred at ambient temperature for 7 hours. The reaction mixture was adjusted to pH 2 with dilute hydrochloric acid and the precipitating material was collected by filtration. The material was washed with water and then dried to give 2-[3-{4-(3-tert-butoxycarbonylamino-3-carboxypropoxy)phenylglyoxyloylamino}-2-oxo-1-azetidinyl]-2-(4-carbamoyloxyphenyl)acetic acid.
Reaction SMILES: CCN(C(C)C)C(C)C.[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21](F)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1.[CH3:39][NH:40][CH2:41][CH2:42][N:43]1[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]1>CC(N(C)C)=O>[Cl:10][C:11]1[C:12]([C:30]2[CH:31]=[N:32][N:33]3[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=23)=[N:13][C:14]([NH:17][C:18]2[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[C:21]([N:40]([CH3:39])[CH2:41][CH2:42][N:43]3[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]3)=[CH:20][C:19]=2[O:28][CH3:29])=[N:15][CH:16]=1
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Reactant: CNCCN1CCN(C)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)N(C)C
Product: COc1cc(N(C)CCN2CCN(C)CC2)c([N+](=O)[O-])cc1Nc1ncc(Cl)c(-c2cnn3ccccc23)n1
Temperature: 140 °C
Yield: 67.4 %

Procedure:
DIPEA (0.105 mL, 0.60 mmol) was added to a mixture of 5-chloro-N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-pyrazolo[1,5-a]pyridin-3-ylpyrimidin-2-amine (Intermediate 20, 0.207 g, 0.5 mmol) and N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (Intermediate 109, 0.079 g, 0.50 mmol) in DMA (5 mL). The mixture was heated in a microwave at 140° C. for 3 h. An additional portion of N-methyl-2-(4-methylpiperazin-1-yl)ethanamine (8 mg, 0.05 mmol) was added and the mixture was heated in a microwave at 140° C. for a further 1 h before being cooled to r.t. The mixture was then concentrated in vacuo and the residue was dissolved in CH3OH. Purification by ion exchange chromatography, using an SCX column and eluting with 1M methanolic ammonia provided crude material after concentration of appropriate fractions in vacuo. Further purification by FCC, eluting with 2-8% CH3OH in CH2Cl2 gave the title compound (0.186 g, 67%) as an orange foam; 1H NMR: (CDCl3) 2.26 (3H, s), 2.32-2.45 (4H, m), 2.45-2.57 (4H, m), 2.61 (2H, t), 2.89 (3H, s), 3.29 (2H, t), 3.98 (3H, s), 6.65 (1H, s), 6.93-7.00 (1H, m), 7.38 (1H, ddd), 7.44 (1H, s), 8.40 (1H, s), 8.49 (1H, d), 8.55 (1H, d), 8.91 (2H, d); m/z: ES+ MH+ 552.59.
Reaction SMILES: [C:1]1([C:7]2[CH:12]=[C:11]([CH:13]([CH2:16][OH:17])[CH2:14][OH:15])[CH:10]=[CH:9][C:8]=2[NH:18][C:19]([C:21]2[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:35])([CH3:34])[CH3:33])[CH:23]=[C:24]([C:26]#[N:27])[N:25]=2)=[O:20])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CCN(CC)CC.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>C(Cl)Cl>[C:26]([C:24]1[N:25]=[C:21]([C:19]([NH:18][C:8]2[CH:9]=[CH:10][C:11]([CH:13]([CH2:14][O:15][S:44]([CH3:43])(=[O:46])=[O:45])[CH2:16][O:17][S:44]([CH3:43])(=[O:46])=[O:45])=[CH:12][C:7]=2[C:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=2)=[O:20])[N:22]([CH2:28][O:29][CH2:30][CH2:31][Si:32]([CH3:34])([CH3:33])[CH3:35])[CH:23]=1)#[N:27]
Reactant: CS(=O)(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(CO)CO)cc1C1=CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1ccc(C(COS(C)(=O)=O)COS(C)(=O)=O)cc1C1=CCCCC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 70 %

Procedure:
A solution of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid [2-cyclohex-1-enyl-4-(2-hydroxy-1-hydroxymethyl-ethyl)-phenyl]-amide (0.600 g, 1.21 mmol, as prepared in the previous step) in CH2Cl2 (25 mL) was cooled to 0° C. and was treated with Et3N (421 μL, 3.02 mmol) and methanesulfonyl chloride (190 μL, 2.42 mmol). The mixture was stirred at 0° C. for 2 h, diluted with CH2Cl2, and washed with water. The organic layer was dried over MgSO4 and concentrated in vacuo. Silica gel chromatography of the residue with 25-50% EtOAc-hexane afforded the title compound (0.551 g, 70%) as a white solid. Mass spectrum (APCI, m/z): Calcd. for C28H40N4O8S2Si, 653.2 (M+H). found 652.8.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6]([NH:8][C@H:9]([C:18]([OH:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][C:14](Br)=[CH:13][CH:12]=1)=[O:7])([CH3:4])[CH3:3].[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>COCCOC.CCOC(C)=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>[C:2]([O:5][C:6]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]([Cl:21])[CH:27]=2)=[CH:13][CH:12]=1)[C:18]([OH:20])=[O:19])=[O:7])([CH3:4])([CH3:3])[CH3:1]
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(Br)cc1)C(=O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)O
Temperature: 85 °C
Reaction time: 2 h
Yield: 83 %

Procedure:
To a solution of Boc-L-4-bromophenylalanine (15.0 g, 43.6 mmol), 3-chlorophenylboronic acid (8.52 g, 54.5 mmol), and tetrakis(triphenylphosphine)palladium(0) (1.51 g, 1.31 mmol) in 1,2-dimethoxyethane (180 mL) was added 2M solution of aqueous NaCO3 (33 mL). The reaction mixture was heated to 85° C. After stirred for 2 hours, the reaction mixture was cooled to room temperature and diluted with EtOAc. The mixture was washed with 1M HCl and brine. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by silica gel column chromatography (eluent: 10% MeOH in dichloromethane) to give (S)-2-tert-butoxycarbonylamino-3-(3′-chloro-biphenyl-4-yl)-propionic acid (13.6 g). 1H NMR (400 MHz, CDCl3) δ 1.43 (s, 9H), 3.08-3.17 (m, 1H), 3.21-3.31 (m, 1H), 4.65 (bs, 1H), 5.01 (bs, 1H), 7.23-7.32 (m, 3H), 7.45-7.50 (m, 2H), 7.52-7.60 (m, 1H), 7.63-7.70 (m, 2H); MS: m/z (MW) 376.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[CH2:9][CH2:8][CH2:7]2)([O-])=O>C(O)C.O1CCCC1.[Pd]>[N:17]1([CH2:16][CH2:15][CH2:14][N:10]2[C:11]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:13][CH:12]=3)[CH2:7][CH2:8][CH2:9]2)[CH2:21][CH2:20][CH2:19][CH2:18]1
Reactant: O=[N+]([O-])c1ccc2c(c1)CCCN2CCCN1CCCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCO
Product: Nc1ccc2c(c1)CCCN2CCCN1CCCC1
Reaction time: 2 h
Yield: 98.4 %

Procedure:
To a stirred solution of 6-nitro-1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinoline (270 mg, 0.933 mmol) in ethanol (5 ml) and tetrahydrofuran (5.00 ml) was added palladium on activated carbon, 10 wt. % (99 mg, 0.093 mmol). The resulting suspension was stirred under an atmosphere of hydrogen (balloon pressure) and monitored by TLC. After 2 h, the reaction mixture was filtered through a pad of celite, which was then washed with methanol. The filtrate was then concentrated, giving the desired 1-(3-(pyrrolidin-1-yl)propyl)-1,2,3,4-tetrahydroquinolin-6-amine (238 mg, 0.918 mmol, 98% yield) as a dark oil.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH:9]([CH3:14])[CH2:8][N:7]([CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:6]=2[N:20]=1.[NH2:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=1.C(O)C>Cl.O>[CH:15]1([N:7]2[CH2:8][CH:9]([CH3:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)=[N:20][C:6]2=3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CC1CN(C2CCCC2)c2nc(Cl)ncc2N(C)C1=O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: CC1CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3)ncc2N(C)C1=O
Yield: 156.8 %

Procedure:
A mixture of 0.03 g (0.0001 mole) of (rac)-2-chloro-9-cyclopentyl-5,7-dimethyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one, 0.014 g (0.0001 mole) of 4-aminobenzoic acid, 0.3 mL of ethanol, 0.8 mL of water, and 1 drop of hydrochloric acid was heated to 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.062 g of (rac)-4-(9-cyclopentyl-5,7-dimethyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-benzoic acid (I-5) as an off-white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C([O-])([O-])=O.[K+].[K+].[F:26][C:27]([F:37])([F:36])[O:28][C:29]1[CH:34]=[CH:33][C:32]([OH:35])=[CH:31][CH:30]=1.CCOC(C)=O>CC(N(C)C)=O>[Br:1][C:2]1[C:7]([N:8]([CH3:19])[S:9]([C:12]2[CH:17]=[CH:16][C:15]([O:35][C:32]3[CH:33]=[CH:34][C:29]([O:28][C:27]([F:26])([F:36])[F:37])=[CH:30][CH:31]=3)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1ccc(OC(F)(F)F)cc1
Reactant: CN(c1cccnc1Br)S(=O)(=O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: CN(c1cccnc1Br)S(=O)(=O)c1ccc(Oc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 130 °C

Procedure:
To a solution of N-(2-bromo-pyridin-3-yl)-4-fluoro-N-methyl-benzenesulfonamide (0.1 g, 0.28 mmol) from Step B in dimethylacetamide (2 ml) was added K2CO3 (0.08 g, 1.0 mmol) and 4-trifluoromethoxyphenol (0.051 g, 0.28 mmol). The mixture was microwaved/heated at 130° C. (PMAX 130 on CEM Reactor) for 15 minutes. The reaction mixture was diluted EtOAc and washed with saturated NaCl and water. The organic phase was dried over sodiumsulfate and concentrated. The crude was purified through chromatography (20-50% EtOAc in hexanes) MS 502.6 (M+H)+
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:17][CH:18]([CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=[O:24])[C:19]([OH:21])=[O:20]>CS(C)=O>[C:12]([C:11]1[C:2]([NH:17][CH:18]([CH:22]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:23]([OH:25])=[O:24])[C:19]([OH:21])=[O:20])=[N:3][C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([Cl:15])=[CH:6][C:5]=2[Cl:16])([OH:14])=[O:13]
Reactant: NC(C(=O)O)C(C(=O)O)c1ccccc1
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1NC(C(=O)O)C(C(=O)O)c1ccccc1

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with 2-amino-3-phenyl-succinic acid [J. Med. Chem. 1973, 16, 1277-1280.] in DMSO to provide the title compound in good yield.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8](=[O:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11]([Mg]Br)[CH3:12]>C(OCC)C>[OH:10][C:8]([C:4]1[CH:3]=[C:2]([OH:1])[CH:7]=[CH:6][CH:5]=1)([CH2:11][CH3:12])[CH3:9]
Reactant: CC[Mg]Br
Reactant: CC(=O)c1cccc(O)c1
Solvent: CCOCC
Product: CCC(C)(O)c1cccc(O)c1

Procedure:
By using 3′-hydroxyacetophenone (200 mg) and a 3 M solution of ethylmagnesium bromide in diethyl ether (1.5 ml) as starting materials, the title compound (124.9 mg) was obtained in the same manner as that of Reference Example 69.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][O:8][C:9]1[C:14](B(O)O)=[CH:13][CH:12]=[CH:11][N:10]=1.[C:18]([O:22][C:23](=[O:34])[NH:24][C@@H:25]([C:27]1[CH:32]=[CH:31][C:30](Br)=[CH:29][CH:28]=1)[CH3:26])([CH3:21])([CH3:20])[CH3:19]>COCCOC.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>[C:18]([O:22][C:23](=[O:34])[NH:24][C@@H:25]([C:27]1[CH:28]=[CH:29][C:30]([C:14]2[C:9]([O:8][CH3:7])=[N:10][CH:11]=[CH:12][CH:13]=2)=[CH:31][CH:32]=1)[CH3:26])([CH3:19])([CH3:20])[CH3:21]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(Br)cc1
Reactant: COc1ncccc1B(O)O
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
Product: COc1ncccc1-c1ccc([C@@H](C)NC(=O)OC(C)(C)C)cc1
Temperature: 95 °C
Yield: 79.2 %

Procedure:
2M Aqueous sodium carbonate solution (3.25 ml, 6.50 mmol) was added to a mixture of 2-methoxypyridine-3-boronic acid (994 mg, 6.50 mmol), (R)-[1-(4-bromo-phenyl)-ethyl]-carbamic acid tert-butyl ester (650 mg, 2.16 mmol) and tetrakis(triphenylphosphine)palladium (0) (125 mg, 0.108 mmol) in 1,2 dimethoxyethane (27 ml). The mixture was heated at 95° C. for 16 h under nitrogen atmosphere. The solvent was evaporated and the residue partitioned between ethyl acetate and water. The organic phase was washed twice with brine, dried over anhydrous magnesium sulfate and the solvent evaporated. The resulting gum was chromatographed over silica gel eluting with heptane/dichloromethane and the solvent evaporated to give (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}-carbamic acid tert-butyl ester (593 mg, 1.71 mmol, 83.5%) as a crystalline solid. Trifluoroacetic acid (6.45 ml, 86.8 mmol) was added dropwise to a solution of (R)-{1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethyl}carbamic acid tert-butyl ester (645 mg, 1.97 mmol) in dichloromethane (6.45 ml) under a nitrogen atmosphere at 0° C. After stirring for 1 h at 0° C. the solvent was evaporated. Methanol (20 ml) was added and the mixture added to a Strata™ 5 g/20 ml SCX column. The intermediate amine was eluted with 2M ammonia in methanol. The solvent was evaporated to give (R)-1-[4-(2-methoxy-pyridin-3-yl)-phenyl]-ethylamine as a gum (425 mg, 1.86 mmol, 94.6%). The title compound was then prepared in a similar manner to (R)-2,5-dimethyl-furan-3-sulfonic acid [1-(5′-fluoro-2′-methoxy-biphenyl-4-yl)-ethyl]-amide (Example 10) using 4-bromo-3-thiophenesulfonyl chloride and 1-[4-(2-Methoxy-pyridin-3-yl)-phenyl]-ethylamine. Title compound: 1H NMR (400 MHz, CDCl3): δ 8.17 (d, 1H), 7.56 (d, 1H), 7.41, 7.20 (a/b, 4H), 7.38 (m, 1H), 6.99-6.92 (m, 2H), 5.27 (d, 1H), 4.60 (m, 1H), 3.97 (s, 3H), 1.54 (d, 3H) ppm; MS (ESI) m/z: 453 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:8])[CH2:6][OH:7].[Br:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12](Br)[N:11]=1>CN(C)C=O>[CH3:3][O:4][C:5](=[O:8])[CH2:6][O:7][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([Br:9])[N:11]=1
Reactant: Brc1cccc(Br)n1
Reactant: COC(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc(Br)n1
Yield: 80.2 %

Procedure:
A suspension of 178 mg of sodium hydride (80% dispersion in mineral oil) in 4 ml of dimethylformamide is mixed under argon atmosphere, stirring and ice cooling with a solution of 361 mg of glycolic acid methyl ester in 2 ml of dimethylformamide and stirred for 3 hours at room temperature. Then, a solution of 948 mg of 2,6-dibromopyridine in 2 ml of dimethylformamide is added under ice cooling and the mixture is stirred for 48 hours at room temperature. The reaction mixture is poured on ice and extracted with ethyl acetate. The organic phase is washed 4 times with saturated common salt solution, dried on sodium sulfate and concentrated by evaporation. 790 mg of 2-(6-bromo-2-pyridyloxy)-acetic acid methyl ester is obtained as oily crude product.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[C:15]1[CH:16]=[C:17]([N:22]2CC[NH:25][CH2:24][CH2:23]2)[CH:18]=[CH:19][C:20]=1[CH3:21]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:21][C:20]3[CH:19]=[C:18]4[C:17](=[CH:16][CH:15]=3)[NH:22][CH2:23][CH2:24][NH:25]4)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(N2CCNCC2)cc1C
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: Fc1ccc(N2CCN(Cc3ccc4c(c3)NCCN4)CC2)cc1

Procedure:
Example 6 was prepared according to Example 2 except that in Step A 1-(4-fluorophenyl)piperazine is substituted for 1-(3,4-dimethylphenyl)piperazine; mp 126°-127° C.
Reaction SMILES: [O:1]=[C:2]1[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]=2[CH:4]([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][C:23]=2[S:30]([CH3:33])(=[O:32])=[O:31])[NH:3]1.[H-].[Na+].[CH3:36][S:37](Cl)(=[O:39])=[O:38].O>O1CCCC1>[CH3:33][S:30]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:22]=1[CH:4]1[N:3]([S:37]([CH3:36])(=[O:39])=[O:38])[C:2](=[O:1])[N:7]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([C:14]([F:15])([F:17])[F:16])[CH:9]=2)[C:6]2[CH2:18][CH2:19][C:20](=[O:21])[C:5]1=2)[C:26]#[N:27])(=[O:31])=[O:32]
Reactant: CS(=O)(=O)c1cc(C#N)ccc1C1NC(=O)N(c2ccnc(C(F)(F)F)c2)C2=C1C(=O)CC2
Reactant: CS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CS(=O)(=O)c1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2ccnc(C(F)(F)F)c2)C(=O)N1S(C)(=O)=O
Temperature: 50 °C
Reaction time: 0.5 h

Procedure:
4-(2,5-dioxo-1-(2-(trifluoromethyl)pyridin-4-yl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]-pyrimidin-4-yl)-3-(methylsulfonyl)benzonitrile (example 15.6, 150 mg, 0.32 mmol) is added to a suspension of sodium hydride (60% in mineral oil, 35 mg, 0.88 mmol) in tetrahydrofuran (8.0 mL). After 10 min methanesulfonyl chloride (49 μL, 0.63 mmol) is added and the mixture is heated at 50° C. for 1.5 h. The mixture is cooled at room temperature and treated with water (1 mL). The mixture is stirred at room temperature for 30 min and purified by reversed phase HPLC (first purification: Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA; second purification: Waters Xbridge™-C18, gradient of acetonitrile in water, 0.1% NH3). Yield: 20 mg; ESI mass spectrum [M+H]+=555; Retention time HPLC: 0.90 min (Z011_S03).
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][C:10](=[O:14])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C([Li])CCC.B(F)(F)F.[CH2:24]([CH:26]1[O:28][CH2:27]1)[Cl:25]>C1COCC1>[Cl:25][CH2:24][CH:26]([OH:28])[CH2:27][N:11]1[CH2:12][CH2:13][N:8]([C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])[CH2:9][C:10]1=[O:14]
Reactant: ClCC1CO1
Reactant: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: FB(F)F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC(O)CCl)C(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 44.9 %

Procedure:
In a 50 0 ml round bottom flask with magnetic stirrer 4-Boc-piperazinone (5.08 g, 25.4 mmol) was dissolved in THF (100 mL) and cooled to −78° C. Butyllithium (1.6M in hexanes) (15.9 mL, 25.4 mmol) was added then and the mixture agitated for 30 minutes at −78° C. Boron trifluoride ethereate (3.19 mL, 25.4 mmol) was added slowly and then epichlorohydrin (1.99 mL, 25.4 mmol). The mixture was agitated for 1 hour at −78° C. and then allowed to warm up and agitated overnight. Reaction was quenched with saturated ammonium chloride, extracted three times with ethyl acetate, extracts washed with brine and evaporated. Purified by column chromatography on silica gel, eluting with 3% MeOH/CH2Cl2 to give the title compound (3.34 g, 45% yield).
Reaction SMILES: C[C:2]1[C:11]2[C:6](=[C:7]([C:13]#[C:14]CO)[CH:8]=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([CH2:17][CH2:18][CH3:19])[C:3]=1C.[OH-].[Na+].C1(C)C=CC=CC=1>C(OCC)C>[F:12][C:10]1[CH:9]=[CH:8][C:7]([C:13]#[CH:14])=[C:6]2[C:11]=1[CH:2]=[CH:3][C:4]([CH2:17][CH2:18][CH3:19])=[N:5]2
Reactant: CCCc1nc2c(C#CCO)ccc(F)c2c(C)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C#Cc1ccc(F)c2ccc(CCC)nc12
Temperature: 120 °C
Yield: 97.7 %

Procedure:
Dimethylhydroxymethyl-5-fluoro-2-propyl-8-quinolylacetylene (326 mg, 1.20 mmol) and NaOH (KISHIDA CHEMICAL CO., Ltd., 0.7 mm granular, 98 mass % article, 88.6 mg (2.22 mmol)) were placed in a 300 mL two-neck flask equipped with a reflux condenser and the air inside the flask was replaced with Ar. 3 mL of toluene was added thereto and the mixture was refluxed at 120° C. for 30 minutes. Diethyl ether was added to the reaction mixture and the mixture was washed with a saturated aqueous ammonium chloride solution and dried over magnesium sulfate, followed by distilling off of the solvent under reduced pressure by an evaporator. The crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/10) using silica gel to give 250 mg of the desired compound as a yellow solid (yield: 97.5%).