Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][OH:29])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:39]([Si:43](Cl)([CH3:45])[CH3:44])([CH3:42])([CH3:41])[CH3:40]>CN(C1C=CN=CC=1)C.ClCCl>[CH2:1]([O:8][CH2:9][CH2:10][N:11]([C:19]1[S:20][C@H:21]2[O:27][C@H:26]([CH2:28][O:29][Si:43]([C:39]([CH3:42])([CH3:41])[CH3:40])([CH3:45])[CH3:44])[C@@H:25]([OH:30])[C@H:24]([OH:31])[C@H:22]2[N:23]=1)[C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]2S1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N(CCOCc1ccccc1)C1=N[C@@H]2[C@@H](O)[C@H](O)[C@@H](CO[Si](C)(C)C(C)(C)C)O[C@@H]2S1
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.7 %

Procedure:
A mixture of 131 (2.8 g, 6.2 mmol), DMAP (150 mg, 1.2 mmol), triethylamine (930 g, 9.2 mol) and tert-butylchlorodimethylsilane (1.1 g, 7.5 mmol) in dichloromethane (40 mL) was stirred for 12 hours at room temperature, then quenched with saturated aqueous NaHCO3 solution (30 mL). The aqueous layer was extracted with dichloromethane (2×40 mL), and the combined organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by a silica gel column, eluted with 1%-3% methanol in dichloromethane to afford 132 as a white solid (2.6 g, 75%). (ES, m/z) [M+H]+ 569.0; 1H NMR (300 MHz, CDCl3) δ 7.28-7.38 (m, 5H), 6.13 (d, J=6.3 Hz, 1H), 4.49 (s, 2H), 4.34-4.36 (m, 1H), 4.06-4.08 (m, 1H), 3.83-390 (m, 1H), 3.59-3.67 (m, 2H), 3.30-3.55 (m, 5H), 1.58 (s, 9H), 0.98 (s, 9H), 0.15 (s, 3H), 0.08 (s, 3H).
Reaction SMILES: [CH3:1][C@H:2]1[C@@:6]([CH2:8]CC)([OH:7])[CH2:5][CH2:4][NH:3]1.[Cl:11][C:12]1[C:19]([CH3:20])=[C:18](F)[CH:17]=[CH:16][C:13]=1[C:14]#[N:15].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:11][C:12]1[C:19]([CH3:20])=[C:18]([N:3]2[CH2:4][CH2:5][C@@:6]([OH:7])([CH3:8])[C@@H:2]2[CH3:1])[CH:17]=[CH:16][C:13]=1[C:14]#[N:15]
Reactant: CCC[C@]1(O)CCN[C@H]1C
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: Cc1c(N2CC[C@](C)(O)[C@@H]2C)ccc(C#N)c1Cl

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2,3-dimethylpyrrolidin-3-ol 0.5 oxalate (260 mg), 2-chloro-4-fluoro-3-methylbenzonitrile (550 mg) and lithium carbonate (240 mg), the title compound was obtained as a colorless solid (yield: 320 mg, yield: 75%).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([N:13]([CH:21]2[CH2:23][CH2:22]2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=2)[CH:7]=1.CC1(C)C(C)(C)OB([C:32]2[CH:33]=[C:34]([CH:42]=[CH:43][CH:44]=2)[CH2:35][N:36]2[CH2:41][CH2:40][O:39][CH2:38][CH2:37]2)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC>[CH:21]1([N:13]([C:4]2[C:5]3[N:6]([C:8]([CH:11]=[O:12])=[CH:9][N:10]=3)[CH:7]=[C:2]([C:43]3[CH:44]=[CH:32][CH:33]=[C:34]([CH2:35][N:36]4[CH2:41][CH2:40][O:39][CH2:38][CH2:37]4)[CH:42]=3)[N:3]=2)[C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH2:23][CH2:22]1
Reactant: CC(C)(C)OC(=O)N(c1nc(Br)cn2c(C=O)cnc12)C1CC1
Reactant: CC1(C)OB(c2cccc(CN3CCOCC3)c2)OC1(C)C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N(c1nc(-c2cccc(CN3CCOCC3)c2)cn2c(C=O)cnc12)C1CC1
Yield: 48.3 %

Procedure:
Tert-butyl 6-bromo-3-formylimidazo[1,2-a]pyrazine-8-yl(cyclopropyl)carbamate (100 mg, 0.26 mmol), 4-[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]morpholine (118 mg, 0.39 mmol), 3M Na2CO3 (1.3 mL, 2.60 mmol) and DME (3.5 mL) were combined. The solution was degassed with a stream of N2 for 10 min. Pd(PPh3)4 was added and the solution was refluxed for 2 h. The solution was partitioned between dichloromethane (25 mL) and water (25 mL). The aqueous layer was further extracted with dichloromethane (2×25 mL). The organics were washed with brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was purified via preparative TLC (5% MeOH/dichloromethane) to afford tert-butyl cyclopropyl(3-formyl-6-(3-(morpholinomethyl)phenyl)imidazo[1,2-a]pyrazin-8-yl)carbamate (60 mg, 48%). LCMS (ES): >95% pure, m/z 478 [M+1]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[C:16]([C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=[CH:19][CH:18]=2)=[C:10]2[CH2:11][CH2:12][CH2:13][CH:14]([OH:15])[N:9]2[N:8]=1.[C:27](OC(=O)C)(=[O:29])[CH3:28]>N1C=CC=CC=1>[C:27]([O:15][CH:14]1[N:9]2[N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[C:16]([C:17]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]=[CH:19][CH:18]=3)=[C:10]2[CH2:11][CH2:12][CH2:13]1)(=[O:29])[CH3:28]
Reactant: OC1CCCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OC1CCCc2c(-c3ccnc4ccccc34)c(-c3ccccn3)nn21

Procedure:
A solution of 2-pyridin-2-yl-3-quinolin-4-yl-pyrazolo[1,5-a]piperidin-7-ol (0.04 g, 0.12 mmol) and acetic anhydride (0.2 mL) in pyridine (2 mL) at room temperature is stirred for 24 h. The mixture is partitioned between ethyl acetate and water. The organic portion is washed with water and brine, dried (sodium sulfate), filtered, and concentrated in vacuo. The residue is chromatographed on SiO2 (5% methanol/dichloromethane) to yield the title compound, 0.41 g (91%), as a white solid.
Reaction SMILES: [N:1]([O-])=O.[Na+].[NH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[CH3:16])=[CH:13][C:12]([O:17][CH3:18])=[C:11]([O:19][CH3:20])[CH:10]=2>O.C(O)(=O)C>[CH3:20][O:19][C:11]1[C:12]([O:17][CH3:18])=[CH:13][C:14]2[C:15]3[CH:16]=[N:1][NH:5][C:6]=3[CH:7]=[N:8][C:9]=2[CH:10]=1
Reactant: COc1cc2ncc(N)c(C)c2cc1OC
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc2ncc3[nH]ncc3c2cc1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 68.4 %

Procedure:
Sodium nitrite (1.28 g, 18.60 mmol), dissolved in water (2.5 ml), is added to a solution of 3-amino-6,7-dimethoxy-4-methylquinoline (2.70 g, 12.39 mmol) in glacial acetic acid (90 ml). The reaction mixture is stirred at room temperature for 3 h. When the reaction is complete, the mixture is evaporated in vacuo. The residue is taken up in water, filtered and rinsed with water. The filtrate is evaporated to dryness in vacuo. The residue obtained is filtered off with suction a number of times through a little flash silica gel in a frit with cyclohexane/ethyl acetate 4:1 (parts by volume) in order to remove impurities. The filtrate is discarded. The filter cake is subsequently washed with ethyl acetate/0-10% by vol. of ethanol, and the filtrate is evaporated to dryness in vacuo, giving 7,8-dimethoxy-3H-pyrazolo[3,4-c]-quinoline (2.29 g, purity 85%, 8.48 mmol) as a solid. MS: 230.0 (M+H+), TLC (HPTLC): Rf=0.45 (ethyl acetate/ethanol 8:1, parts by volume).
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][CH:7]=[C:6]([O:10]C)[C:3]=1[C:4]#[N:5].Br[CH:13]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:14]=O>CCO.C(Cl)Cl>[OH:10][C:6]1[CH:7]=[CH:8][N:9]2[C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:14][N:1]=[C:2]2[C:3]=1[C:4]#[N:5]
Reactant: COc1ccnc(N)c1C#N
Reactant: O=CC(Br)c1ccccc1
Solvent: CCO
Solvent: ClCCl
Product: N#Cc1c(O)ccn2c(-c3ccccc3)cnc12
Temperature: 160 °C
Yield: 84 %

Procedure:
A mixture of compounds D3 (2 g, 13.41 mmol) and D4 (6.69 g, 33.5 mmol) in EtOH (10 ml) was subjected to microwave heating at 160° C. for 45 min. The reaction mixture was cooled to room temperature and then diluted with DCM, causing a solid to precipitate. The solid obtained was filtered off, washed thoroughly with DCM and dried in vacuo to yield compound D5 (2.65 g, 84%) as a pale yellow solid.
Reaction SMILES: [H-].[Na+].CN(C)C=O.[CH2:8]([O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:33]2[CH:38]=[CH:37][C:36]([OH:39])=[CH:35][CH:34]=2)=[C:23]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH2:24][CH2:25][OH:26])=[CH:18][CH:17]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH2:40]([O:47][CH2:48][CH2:49]Br)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>[Cl-].[Na+].O>[CH2:40]([O:47][CH2:48][CH2:49][O:39][C:36]1[CH:37]=[CH:38][C:33](/[C:22](/[C:19]2[CH:20]=[CH:21][C:16]([O:15][CH2:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:17][CH:18]=2)=[C:23](\[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)/[CH2:24][CH2:25][OH:26])=[CH:34][CH:35]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: BrCCOCc1ccccc1
Reactant: OCCC(=C(c1ccc(O)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: OCC/C(=C(/c1ccc(OCCOCc2ccccc2)cc1)c1ccc(OCc2ccccc2)cc1)c1ccccc1
Reaction time: 4 h

Procedure:
The reaction vessel was charged with sodium hydride (0.43 g, 0.0178 mol) and dimethyl formamide (34 ml). 4-[1-(4-Benzyloxyphenyl)-4-hydroxy-2-phenyl-but-1-enyl]phenol (5 g, 0.0118 mol) prepared by the method of U.S. Pat. No. 4,996,225 was dissolved to dimethyl formamide (6 ml), added to the mixture at room temperature and stirring was continued for half an hour. Then benzyl-(2-bromoethyl)ether (3.06 g, 0.014 mol) was added dropwise during 20 minutes to the reaction mixture and stirring was continued for additional 4 hours. The reaction mixture was poured into brine and extracted with ethyl acetate. Organic layer was washed with 2 N hydrogen chloride solution and twice with water, dried and evaporated to dryness. The product was purified by flash chromatography (toluene: methanol, 9.8:0.2). Yield 2.8 g.
Reaction SMILES: [NH2:1][N:2]1[N:11]=[C:10]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]1=[O:18].[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([CH2:28][C:29](O)=[O:30])=[N:20]1>>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([CH2:28][C:29]([NH:1][N:2]2[N:11]=[C:10]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]2=[O:18])=[O:30])=[N:20]1
Reactant: Nn1nc(N2CCOCC2)c2ccccc2c1=O
Reactant: O=C(O)Cc1noc2ccccc12
Product: O=C(Cc1noc2ccccc12)Nn1nc(N2CCOCC2)c2ccccc2c1=O

Procedure:
The product of Example 1B and 2-(1,2-benzoxazol-3-yl)acetic acid were treated using a method similar to that described in Example 111 to give the title compound. 1H NMR (500 MHz, DMSO-d6/D2O) δ 8.32 (d, J=7.9, 1H), 8.07-7.97 (m, 3H), 7.95-7.89 (m, 1H), 7.76 (d, J=8.4, 1H), 7.69 (ddd, J=8.3, 7.0, 1.1, 1H), 7.48-7.41 (m, 1H), 4.19 (s, 2H), 3.86-3.80 (m, 4H), 3.16-3.07 (m, 4H); MS (ESI+) M/Z 406 (M+H)+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][OH:7].[CH3:8][Si:9]([CH3:28])([CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[O:10][Si:11]([CH3:21])([CH3:20])[CH2:12][CH2:13][CH2:14][O:15][CH2:16][CH:17]1[CH2:19][O:18]1>C(O)C>[OH:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][CH2:19][CH:17]([OH:18])[CH2:16][O:15][CH2:14][CH2:13][CH2:12][Si:11]([CH3:20])([CH3:21])[O:10][Si:9]([CH3:28])([CH3:8])[CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25]
Reactant: NCCOCCO
Reactant: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC1CO1
Solvent: CCO
Product: C[Si](C)(C)CC[Si](C)(C)O[Si](C)(C)CCCOCC(O)CNCCOCCO
Temperature: 70 °C

Procedure:
2-(2-Amino-ethoxy)-ethanol (3.02 g) and ethanol (40 mL) were charged to a 100 mL RB flask equipped with a magnetic stirrer. The mixture was stirred and heated to 70° C. 1,1,3,3-Tetramethyl-3-(3-oxiranylmethoxy-propyl)-1-(2-trimethylsilanyl-ethyl)-disiloxane (2.0 g) mixed with ethanol (10 mL) was placed in an addition funnel and added dropwise to the flask. The mixture was stirred and maintained at 70° C. for an additional 4 hours. The reaction progress was monitored by NMR spectroscopy. Upon reaction completion, ethanol was removed under vacuum, and the mixture was vacuum distilled to remove impurities and excess raw material.
Reaction SMILES: [OH:1][CH2:2][C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4].[CH3:16]I>C(#N)C.[Ag]=O>[CH3:16][O:1][CH2:2][C@H:3]([NH:5][C:6](=[O:15])[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH3:4]
Reactant: C[C@H](CO)NC(=O)OCc1ccccc1
Reactant: CI
Agent: O=[Ag]
Solvent: CC#N
Product: COC[C@@H](C)NC(=O)OCc1ccccc1
Yield: 71.5 %

Procedure:
To a solution of benzyl [(1R)-2-hydroxy-1-methylethyl]carbamate (0.5 g, 2.38 mmol) in acetonitrile (20 mL), silver oxide (3.8 g, 13.09 mmol) is added followed by the addition of methyl iodide (1.94 mL, 23.8 mmol). The resultant mixture was stirred overnight at room temperature. The insoluble salt was filtered off and the filtrate was concentrated. The residue was flashed using silica and Ethyl acetate/hexanes system as eluent to give the desired product as clear oil (0.38 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][CH2:16][CH2:17][CH2:18][Cl:19])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][CH2:18][CH2:17][CH2:16][C:15]#[C:14][CH:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)(C)OC(=O)N1CCC(C#CCCCCl)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: ClCCCC#CC1CCNCC1
Yield: 46.6 %

Procedure:
A solution of 14.6 g (16.3 mmol) of the crude 4-(5-Chloro-pent-1-ynyl)-piperidine-1-carboxylic acid tert-butyl ester in 44 ml CH2Cl2 was treated with 44 ml of TFA at 0° C. (for 20 min). The reaction was evaporated and partitioned between aqueous 10% KHSO4/Et2O (3×). The aqueous phase was adjusted to pH>10 by adding 1N NaOH and extracted with EtOAc (3×) The organic phase was dried over Na2SO4 and evaporated to give 1.41 g (50% over two steps) of 4-(5-Chloro-pent-1-ynyl)-piperidine, MS: 186 (MH+, 1Cl).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>CN(C=O)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Product: CN(C)C=CC(=O)c1ccccc1
Yield: 85.3 %

Procedure:
To a stirred solution of 5.0 ml (42.8 mmol) acetophenone in 40 ml DMF was added 11.4 ml (85.6 mmol) N,N-dimethylformamide dimethyl acetal and the mixture heated at reflux for 16 h. The reaction mixture was then concentrated in vacuo. Trituration in hexane/ethyl acetate (4/1) afforded 6.4 g (85%) 3-(dimethylamino)acrylophenone as a crystalline solid. EI-MS m/e (%): 175 (M+, 45), 158 ([M—OH]+, 100), 98 ([M—C6H5)+, 63), 42 (72).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]=[C:19]([OH:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:23]I>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:22])[N:13]([C:15]3[N:20]([CH3:23])[C:19](=[O:21])[CH:18]=[CH:17][CH:16]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CI
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(O)n1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1cccc(=O)n1C

Procedure:
The title compound, off-white cristalline solid, MS: m/e=324.2, 326.1 (M+H), was prepared in accordance with the general method of example 3 from 6-[4-(3-chloro-phenylethynyl)-2-methyl-imidazol-1-yl]-pyridin-2-ol and methyl iodide, along with the O-alkylation product from which it was separated by flash chromatography (gradient: EtOAc to EtOAc/MeOH 95:5).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH:23]C(=O)OC(C)(C)C)[CH2:18]2)=[CH:13][C:12]=1[O:31][CH:32]([CH3:34])[CH3:33])([O-:10])=[O:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][CH2:20][C@@H:19]([NH2:23])[CH2:18]2)=[CH:13][C:12]=1[O:31][CH:32]([CH3:34])[CH3:33])([O-:10])=[O:9]
Reactant: CC(C)Oc1cc(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)ccc1[N+](=O)[O-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)Oc1cc(N2CCC[C@@H](N)C2)ccc1[N+](=O)[O-]
Reaction time: 15 h

Procedure:
6.25 ml of trifluoroacetic acid are added, at a temperature of about 20° C., to 5.32 g of 2-methylpropan-2-yl {(3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-yl}carbamate in solution in 106 ml of dichloromethane, and the mixture is left to stir for 15 h. A further 2 ml of trifluoroacetic acid are added and the stirring is continued for 1 h. The mixture is concentrated under reduced pressure, so as to obtain an oily residue which is precipitated by adding ethyl ether. The solid obtained is filtered off and then washed with ethyl ether, so as to obtain 5.42 g of (3R)-1-[4-nitro-3-(propan-2-yloxy)phenyl]piperidin-3-amine trifluoroacetate in the form of a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=[O:8])=[CH:5][C:4]=1[N:13]([CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[S:14]([CH3:17])(=[O:16])=[O:15].Cl>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([OH:9])=[O:8])=[CH:5][C:4]=1[N:13]([CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1)[S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(OC)c(N(CCN2CCOCC2)S(C)(=O)=O)c1
Agent: Cl
Solvent: C1COCCO1
Product: COc1ccc(C(=O)O)cc1N(CCN1CCOCC1)S(C)(=O)=O
Temperature: 100 °C
Yield: 91.4 %

Procedure:
To a solution of methyl 4-methoxy-3-(N-(2-morpholinoethyl)-methylsulfonamido)benzoate (0.902 g, theoric 2.314 mmol) in dioxane (23 ml), HCl 6N (4.63 ml, 27.8 mmol) was added, and the mixture was heated to 100° C. Additional HCl 6N (3.47 ml, 20.83 mmol) was added in two portion over 24 hours with stirring at the same temperature. The volatiles were removed under vacuum and the residue was dissolved in water (20 ml) and basified with NaHCO3 sat sol. (pH 7-8). The aqueous phase was washed with EtOAc and evaporated to dryness. The residue was purified by flash chromatography on silica gel column (DCM:MeOH=9:1 to 7:3) affording 4-methoxy-3-(N-(2-morpholinoethyl)methylsulfonamido)benzoic acid (0.758 g, 2.115 mmol, 91% yield over two steps, MS/ESI+ 358.9 [MH]+).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:9]=[CH:8][C:6]=2[N:7]=1.[NH3:22]>CO>[Cl:1][C:2]1[N:3]=[C:4]([NH2:22])[C:5]2[CH:11]=[C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][C:14]=3[F:20])[N:9]=[CH:8][C:6]=2[N:7]=1
Reactant: N
Reactant: Fc1ccc(Oc2cc3c(Cl)nc(Cl)nc3cn2)c(F)c1
Solvent: CO
Product: Nc1nc(Cl)nc2cnc(Oc3ccc(F)cc3F)cc12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Compound (1E) (1.75 g, 5.33 mmol) was placed in a sealed-tube, and 7 N ammonia in MeOH (Aldrich Chemical Co.) (30 mL) was added. The tube was tightly capped, and the resulting homogeneous mixture was stirred at room temperature overnight. The next morning, TLC confirmed that the reaction was complete. The mixture was transferred to a round-bottom flask and concentrated under reduced pressure at 55° C. The residue was taken up in EtOAc (700 mL) and water (250 mL). The layers were partitioned and then separated. The organic layer was washed with water (2×250 mL) and brine (1×250 mL). The organic layer was dried over magnesium sulfate, filtered, concentrated, and pumped to give the title compound (1F) as an off-white powder (1.859 g, (M−H)−=307, Mp>300° C.).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.Br[CH2:17][CH:18](F)[F:19]>>[F:19]/[CH:18]=[CH:17]/[N:13]1[CH:14]=[C:10]([C:9]#[C:8][C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)[N:11]=[C:12]1[CH3:15]
Reactant: Cc1cc(C#Cc2c[nH]c(C)n2)ccn1
Reactant: FC(F)CBr
Product: Cc1cc(C#Cc2cn(/C=C/F)c(C)n2)ccn1

Procedure:
The title compound, MS: m/e=242.3 (M+H+), was prepared in accordance with the general method of example 1 from 2-methyl-4-(2-methyl-1H-imidazol-4-ylethynyl)-pyridine and 2-bromo-1,1-difluoro ethane as a by-product.
Reaction SMILES: [CH3:1][O-:2].[Na+].[Na].[NH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:20](F)=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:24][CH2:23]3)=[CH:13][C:12]=2[F:29])[CH2:7]1>CO>[NH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:20]([O:2][CH3:1])=[C:19]3[C:14]([C:15](=[O:28])[C:16]([C:25]([OH:27])=[O:26])=[CH:17][N:18]3[CH:22]3[CH2:23][CH2:24]3)=[CH:13][C:12]=2[F:29])[CH2:7]1
Reactant: NC1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c2F)C1
Reactant: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Product: COc1c(N2CCC(N)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reaction time: 49 h

Procedure:
To a solution of sodium methoxide prepare from sodium (0.2 g) and absolute methanol (10 ml) was added 7-(3-amino 1-pyrrolidinyl)-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3quinolinecarboxylic acid (0.47 g) and the mixture in sealed tube was stirred for 49 hours at 140° to 150° C. and then concentrated. The residue was purified by silica gel column chromatography eluting with chloroform-methanol-concentrated aqueous ammonia (20:6:1) and recrystallized from a solution of dichloromethanemethanol (1:1) to give the title compound (6 mg as pale yellow prisms, mp 207.5°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[N:20]1[CH:25]=[CH:24][C:23]([CH2:26][CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:22][CH:21]=1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:31]3[CH2:32][CH2:33][N:28]([CH2:27][CH2:26][C:23]4[CH:22]=[CH:21][N:20]=[CH:25][CH:24]=4)[CH2:29][CH2:30]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: c1cc(CCN2CCNCC2)ccn1
Product: O=C(N1CCN(CCc2ccncc2)CC1)N1Cc2ccccc2Oc2ccc(Cl)cc21
Yield: 291.3 %

Procedure:
The title compound of Example 2 (0.38 g, 1.3 mmol) was combined with the product of Example 88 (0.25 g, 1.3 mmol) and the reaction was carried out by the method of Example 4. Following chromatographic separation, 1.7 g of the white solid title product was obtained.
Reaction SMILES: [C:1]([O:14]C)(=[O:13])[CH2:2][C:3]1[C:4](=[CH:9][CH:10]=[CH:11][CH:12]=1)[C:5]([O:7]C)=O.[F:16][C:17]([F:27])([F:26])[C:18]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O>>[F:16][C:17]([F:27])([F:26])[C:18]1[C:20]2[C:25]([C:12]3[CH:11]=[CH:10][CH:9]=[C:4]4[C:5](=[O:7])[O:14][C:1](=[O:13])[C:2]=1[C:3]=34)=[CH:24][CH:23]=[CH:22][CH:21]=2
Reactant: COC(=O)Cc1ccccc1C(=O)OC
Reactant: O=C(c1ccccc1)C(F)(F)F
Product: O=C1OC(=O)c2c(C(F)(F)F)c3ccccc3c3cccc1c23

Procedure:
As described in example 14, the following compounds were prepared from dimethyl homophthalate and 2,2,2-trifluoroacetophenone:
Reaction SMILES: [H-].[Na+].[OH:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][C:10]1[C:15]2[C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1.[CH3:34]I.O>O1CCCC1>[CH3:34][O:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[O:9][C:10]1[C:15]2[C:16]([O:19][CH2:20][CH:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]3)=[N:17][O:18][C:14]=2[CH:13]=[CH:12][CH:11]=1
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(COc2noc3cccc(O[C@@H]4CCC[C@H]4O)c23)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CO[C@@H]1CCC[C@H]1Oc1cccc2onc(OCC3CCN(C(=O)OC(C)(C)C)CC3)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.4 %

Procedure:
To a suspension of sodium hydride (60% oil dispersion 11 mg, 0.277 mmol) in tetrahydrofuran (5.0 mL) was added a solution of tert-butyl 4-{[(4-{[trans-2-hydroxycyclopentyl]oxy}-1,2-benzisoxazol-3-yl)oxy]methyl}piperidine-1-carboxylate (80 mg, 0.185 mmol, EXAMPLE 32, Step 1) in tetrahydrofuran (2.0 mL) at 0° C. under nitrogen. After being stirred at 0° C. for 30 min, methyliodide (14 μL, 0.222 mmol) was added to the mixture. The mixture was stirred at 0° C. for 3 h, water was added to the mixture. The mixture was extracted with ethyl acetate (30 mL×2) and washed with brine. The extracts were combined and dried over sodium sulfate and concentrated in vacuo to give an oil. The residual oil was purified by silica gel column chromatography (hexane/ethyl acetate 5:1 to 4:1) to give 78 mg (94%) of the title compound as a colorless viscous oil.