Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([C:26](OCC)=O)[CH2:22][CH2:21]1)=[CH:15][C:14]([O:31][CH3:32])=[CH:13][CH:12]=2.O.[OH-].[Na+]>O1CCCC1>[Cl:7][C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[CH2:18][CH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]1)=[CH:15][C:14]([O:31][CH3:32])=[CH:13][CH:12]=2
Reactant: CCOC(=O)N1CCC(CCc2c(Cl)cnc3ccc(OC)cc23)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc2ncc(Cl)c(CCC3CCN(C)CC3)c2c1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
0.38 g of lithium aluminum hydride are introduced progressively and portionwise into 20 ml of dry tetrahydrofuran, under an atmosphere of nitrogen. The suspension obtained is cooled to 0° C., then a solution of 1.6 g of 3-chloro-6-methoxy-4-[2-(1-ethoxycarbonyl-4-piperidyl)-ethyl]-quinoline in tetrahydrofuran is added drop by drop. The reaction medium is maintained for 3 hours in an ice bath, then 0.45 ml of water, 0.33 ml of a 5 N aqueous solution of sodium hydroxide and 15 ml of water are added, very slowly and in the order given. The insoluble mineral products formed are separated by filtration and washed twice with 30 ml of methylene chloride. The filtrate and the washings are collected, dried over magnesium sulfate, then concentrated by evaporation. The residue obtained is fixed on a column of silica and eluted with a 90/10 mixture of chloroform and diethylamine. 0.9 g of 3-chloro-6-methoxy-4-[2-(1-methyl-4-piperidyl)-ethyl]-quinoline are thus obtained, the hydrochloride of which is amorphous.
Reaction SMILES: [OH:1][CH:2]1[C:7]([O:26][CH3:27])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[CH3:28]I>>[CH3:28][O:1][CH:2]1[C:7]([O:26][CH3:27])([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][C:16]3[CH:25]=[CH:24][C:23]4[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=4)[CH:17]=3)[CH:9]=2)[CH2:6][CH2:5][O:4][CH2:3]1
Reactant: COC1(c2cccc(OCc3ccc4ccccc4c3)c2)CCOCC1O
Reactant: CI
Product: COC1COCCC1(OC)c1cccc(OCc2ccc3ccccc3c2)c1
Yield: 90 %

Procedure:
Using the procedure described in Example 1, (3RS,4SR)-3-hydroxy-4-methoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran [Example 7, Compound No. 3] was reacted with methyl iodide to give (3RS,4SR)-3,4-dimethoxy-4-[3-(naphth-2-ylmethoxy)phenyl]tetrahydropyran (90%), m.p. 131°-133° C.
Reaction SMILES: [C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]([NH2:18])[CH3:17])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:20]1[N:28]=[CH:27][N:26]=[C:25]2[C:21]=1[N:22]=[CH:23][N:24]2C1CCCCO1.CCN(C(C)C)C(C)C.Cl.O1CCOCC1>C(O)CCC>[C:1]1([N:7]2[C:11]3[CH:12]=[N:13][CH:14]=[CH:15][C:10]=3[N:9]=[C:8]2[CH:16]([NH:18][C:20]2[N:28]=[CH:27][N:26]=[C:25]3[C:21]=2[N:22]=[CH:23][NH:24]3)[CH3:17])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(N)c1nc2ccncc2n1-c1ccccc1
Reactant: Clc1ncnc2c1ncn2C1CCCCO1
Agent: Cl
Solvent: CCCCO
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1ncnc2[nH]cnc12)c1nc2ccncc2n1-c1ccccc1
Temperature: 90 °C
Reaction time: 16 h
Yield: 14.7 %

Procedure:
A mixture of 1-(3-phenyl-3H-imidazo[4,5-c]pyridin-2-yl)ethylamine (254 mg, 1.07 mmol), 6-chloro-9-(tetrahydropyran-2-yl)-9H-purine (0.35 g, 1.49 mmol) and DIPEA (0.34 mL, 1.92 mmol) in 1-butanol (3 mL) was stirred at 90° C. in a sealed tube for 16 h. The resulting mixture was concentrated in vacuo and residue was purified by chromatography (SiO2 0-10% (2M ammonia in methanol) in DCM). The product was dissolved in methanol and treated with HCl/dioxane (4M, 1.3 mL, 5.35 mmol) and stirred for 20 minutes. The mixture was loaded onto an Isolute® SCX-2 cartridge, washed with MeOH and the product eluted with 2M NH3/MeOH then concentrated in vacuo. The resulting residue was purified by chromatography (SiO2, 0-15% (2M ammonia in methanol) in DCM) to give a waxy solid which was triturated with EtOAc/diethyl ether to give 237 as a brown solid (0.056 g, 15%). LCMS (method K): Rt 1.98 min, [M+H]+ 357. 1H NMR (DMSO-d6): δ 13.10-12.60 (1H, bs), 8.43 (1H, s), 8.37 (1H, d, J=5.53 Hz), 8.13 (1H, s), 8.07 (1H, s), 7.70-7.68 (3H, m), 7.61-7.50 (3H, m), 5.49 (1H, m), 1.59 (3H, d, J=6.87 Hz)
Reaction SMILES: Br[CH2:2][C:3]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:4]=1[C:5]([O:7]CC)=O.Cl.[F:16][C:17]([F:31])([CH3:30])[CH2:18][O:19][C:20]1[C:21]([CH3:29])=[CH:22][C:23]([CH:26]([NH2:28])[CH3:27])=[N:24][CH:25]=1>>[Cl:14][C:13]1[C:3]2[CH2:2][N:28]([CH:26]([C:23]3[CH:22]=[C:21]([CH3:29])[C:20]([O:19][CH2:18][C:17]([F:31])([F:16])[CH3:30])=[CH:25][N:24]=3)[CH3:27])[C:5](=[O:7])[C:4]=2[CH:10]=[CH:11][N:12]=1
Reactant: CCOC(=O)c1ccnc(Cl)c1CBr
Reactant: Cc1cc(C(C)N)ncc1OCC(C)(F)F
Agent: Cl
Product: Cc1cc(C(C)N2Cc3c(ccnc3Cl)C2=O)ncc1OCC(C)(F)F
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (585 mg, yellow oil) from ethyl 3-(bromomethyl)-2-chloroisonicotinate (522 mg, 1.88 mmol, Step-1 of Intermediate-1) and 1-(5-(2,2-difluoropropoxy)-4-methylpyridin-2-yl)ethanamine hydrochloride (500 mg, 1.88 mmol, Amine-76, single enantiomer) in a similar manner to Intermediate-2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH:5]2C(OC)=O.Cl.[OH-].[Na+]>CO>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2
Reactant: COC(=O)C1C(=O)Nc2ccc(F)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C1Cc2cc(F)ccc2N1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 80 %

Procedure:
In a flask made of glass equipped with a stirrer, a thermometer, a dropping funnel and a reflux condenser and having an inner volume of 500 ml were charged 26.5 g (0.10 mol) of crude crystal of 5-fluoro-3-methoxycarbonyloxindole synthesized according to Example 17 with a purity of 80% (analytical value by high performance liquid chromatography), 66.9 g of methanol and 52.0 ml (0.31 mol) of 6 mol/l hydrochloric acid, and the mixture was reacted at 70 to 80° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, 55.0 ml (0.44 mol) of 8 mol/l aqueous sodium hydroxide solution was added to the mixture, and the resulting mixture was stirred at 40° C. for 30 minutes. Then, 8.3 ml (0.10 mol) of 12 mol/l hydrochloric acid was added to the resulting mixture. After removing methanol under reduced pressure, the reaction mixture was cooled to 0 to 5° C., then a solid was precipitated so that it was collected by filtration. The resulting solid was recrystallized from isopropyl alcohol/water to obtain 12.6 g (isolation yield: 80%) of 5-fluorooxindole as white crystals with a purity of 99% (areal percentage by high performance liquid chromatography).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([O:20]C)=O)[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1.[NH3:22]>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:10][C:11]3[C:12](=[C:14]([C:18]([NH2:22])=[O:20])[CH:15]=[CH:16][CH:17]=3)[N:13]=2)=[CH:5][CH:4]=1
Reactant: COC(=O)c1cccc2oc(-c3ccc(OC)cc3)nc12
Reactant: N
Product: COc1ccc(-c2nc3c(C(N)=O)cccc3o2)cc1

Procedure:
Methyl 2-(4-methoxyphenyl)benzoxazole-4-carboxylate was dissolved in liquid ammonia (30 ml) and sealed in an autoclave. The reaction mixture was left at 55° C., 20 bar for >20 hours. Once the reaction was complete the ammonia was removed and the resulting solid recrystallised from boiling ethyl acetate and petrol.
Reaction SMILES: FC1C=CC(NC(=O)NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=CC=2)=CC=1.[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:56]=[CH:55][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:66]=[CH:65][C:64]([C:67]([F:70])([F:69])[F:68])=[CH:63][CH:62]=4)=[O:59])=[CH:53][CH:52]=3)=[CH:47][CH:48]=2)[C:43]1=[O:71])[C:38]([O:40]C)=[O:39]>>[CH3:35][CH:36]([CH3:72])[C@H:37]([N:42]1[CH2:50][C:49]2[C:44](=[CH:45][C:46]([C:51]3[CH:52]=[CH:53][C:54]([NH:57][C:58]([NH:60][C:61]4[CH:62]=[CH:63][C:64]([C:67]([F:70])([F:68])[F:69])=[CH:65][CH:66]=4)=[O:59])=[CH:55][CH:56]=3)=[CH:47][CH:48]=2)[C:43]1=[O:71])[C:38]([OH:40])=[O:39]
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)Nc4ccc(C(F)(F)F)cc4)cc3)cc2C1=O
Yield: 97 %

Procedure:
The compound of example 36 was prepared analogous to compound of example 8 by hydrolysis of compound of example 35.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[C:5]([F:8])=[N:6][CH:7]=1.Cl[C:13]1[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[N:14]=1.CC(N)CC1C=CC=CC=1.OP(O)(O)=O.C([O-])(=O)C.[K+]>CCO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:13]2[N:18]=[C:17]([CH3:19])[N:16]=[C:15]([N:20]([CH2:21][C:22]3[CH:23]=[CH:24][C:25]([O:28][CH3:29])=[CH:26][CH:27]=3)[CH2:30][C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)[N:14]=2)[C:5]([F:8])=[N:6][CH:7]=1
Reactant: OB(O)c1cc(Cl)cnc1F
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Agent: CC(=O)[O-]
Agent: CC(N)Cc1ccccc1
Agent: O=P(O)(O)O
Solvent: O
Solvent: CCO
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(Cl)cnc3F)n2)cc1
Temperature: 100 °C
Yield: 77.1 %

Procedure:
A mixture of 5-chloro-2-fluoropyridin-3-ylboronic acid (454 mg, 2.59 mmol) (Combi-Blocks Inc.), 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (950 mg, 2.468 mmol), Amphos 2 (87 mg, 0.123 mmol) and potassium acetate (744 mg, 7.58 mmol) (Aldrich) in EtOH (15 mL) and water (1.5 mL) was purged with argon and heated in a microwave reactor at 100° C. for 30 min. The reaction mixture was concentrated to remove the EtOH and partitioned between water (20 mL) and EtOAc (20 mL). The aqueous phase was further extracted with EtOAc (20 mL). The combined organic phases were washed with saturated aqueous sodium chloride (40 mL). The organic phase was dried over sodium sulfate, filtered and concentrated. The crude product was purified on the ISCO (40 g column, eluent: 30-80% EtOAc in hexanes) to give 4-(5-chloro-2-fluoropyridin-3-yl)-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (913 mg, 1.902 mmol, 77% yield) as a pale yellow sticky solid. The material was used in the next step without further purification. m/z (ESI, +ve ion) 480.1 (M+H)+. 1H NMR (400 MHz, CDCl3) δ 8.53 (1H, dd, J=7.9, 2.6 Hz); 8.25 (1H, dd, J=2.6, 1.3 Hz); 7.21 (4H, d, J=8.6 Hz); 6.80-6.90 (4H, m); 4.82 (2H, s); 4.80 (2H, s); 3.81 (3H, s); 3.80 (3H, s); 2.54 (3H, s).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])=[N:5]2.C(N(CC)CC)C.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:32]=[CH:31][C:30]([N:33]=[C:34]=[O:35])=[CH:29][CH:28]=1>O1CCCC1>[N:1]1[CH:2]=[CH:3][N:4]2[C:9]=1[CH:8]=[CH:7][C:6]([O:10][C:11]1[CH:12]=[C:13]([NH:14][C:34]([NH:33][C:30]3[CH:29]=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:32][CH:31]=3)=[O:35])[CH:15]=[CH:16][CH:17]=1)=[N:5]2
Reactant: Nc1cccc(Oc2ccc3nccn3n2)c1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(C(F)(F)F)cc1)Nc1cccc(Oc2ccc3nccn3n2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 49.8 %

Procedure:
To a solution of 3-(imidazo[1,2-b]pyridazin-6-yloxy)aniline (113 mg, 0.50 mmol) and triethylamine (0.040 mL, 0.29 mmol) in tetrahydrofuran (10 mL) was added 4-(trifluoromethyl)phenyl isocyanate (0.100 mL, 0.70 mmol), and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was precipitated from methanol to give the title compound (103 mg, 50%) as a white powder.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:40])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([OH:28])=O)[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:37]=[CH:36][C:35]([C:38]#[N:39])=[CH:34][CH:33]=2)[CH:7]=1.Cl.[CH3:42][NH2:43]>C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:40])=[C:6]([N:8]2[C:15](=[O:16])[C:14]3[N:13]=[C:12]([C:17]4[CH:18]=[C:19]([CH2:25][C:26]([NH:43][CH3:42])=[O:28])[CH:20]=[N:21][C:22]=4[O:23][CH3:24])[N:11]([CH:29]([CH3:31])[CH3:30])[C:10]=3[CH:9]2[C:32]2[CH:33]=[CH:34][C:35]([C:38]#[N:39])=[CH:36][CH:37]=2)[CH:7]=1
Reactant: COc1ncc(CC(=O)O)cc1-c1nc2c(n1C(C)C)C(c1ccc(C#N)cc1)N(c1cc(Cl)ccc1C)C2=O
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=O)Cc1cnc(OC)c(-c2nc3c(n2C(C)C)C(c2ccc(C#N)cc2)N(c2cc(Cl)ccc2C)C3=O)c1

Procedure:
The title compound was prepared in analogy to the procedure described for example 147 but using the product from example 146 and methylamine hydrochloride. tR: 0.97 min (LC-MS 2); ESI-MS: 569.3/571.3 [M+H]+ (LC-MS 2); Rf=0.15 (CH2Cl2/MeOH, 20:1).
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2)CCCCC1.C(=O)([O-])[O-].[K+].[K+].Cl.Cl.[CH3:34][C:35]1[N:40]=[C:39]([N:41]2[CH2:46][CH2:45][CH:44]([NH2:47])[CH2:43][CH2:42]2)[CH:38]=[CH:37][N:36]=1.Cl[C:49]1[N:54]=[C:53]([C:55]([OH:58])([CH3:57])[CH3:56])[CH:52]=[C:51]([C:59]2[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:67])[F:66])=[CH:61][CH:60]=2)[N:50]=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:34][C:35]1[N:40]=[C:39]([N:41]2[CH2:46][CH2:45][CH:44]([NH:47][C:49]3[N:54]=[C:53]([C:55]([OH:58])([CH3:57])[CH3:56])[CH:52]=[C:51]([C:59]4[CH:64]=[CH:63][C:62]([C:65]([F:68])([F:66])[F:67])=[CH:61][CH:60]=4)[N:50]=3)[CH2:43][CH2:42]2)[CH:38]=[CH:37][N:36]=1
Reactant: CC(C)(O)c1cc(-c2ccc(C(F)(F)F)cc2)nc(Cl)n1
Reactant: Cc1nccc(N2CCC(N)CC2)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Cc1nccc(N2CCC(Nc3nc(-c4ccc(C(F)(F)F)cc4)cc(C(C)(C)O)n3)CC2)n1
Temperature: 20 °C
Reaction time: 0.17 h

Procedure:
A mixture of palladium (II) acetate (2.7 mg, 0.012 mmol) and 2-(dicyclohexylphosphino)-biphenyl (8.4 mg, 0.024 mmol) in dioxane (1 mL) was stirred under argon at 20° C. for 10 minutes. The resulting catalyst solution was added to a suspension of potassium carbonate (692 mg, 5.0 mmol), 1-(2-methyl-pyrimidin-4-yl)-piperidin-4-ylamine dihydrochloride (80 mg, 0.3 mmol), and 2-[2-chloro-6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yl]-propan-2-ol (95 mg, 0.3 mmol) in dioxane (1.7 mL). The reaction mixture was heated to 170° C. in a microwave oven for 30 minutes. The reaction mixture was cooled, diluted with water and extracted twice with ethyl acetate. The organic layer was washed with brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel using CH2Cl2/0-10% MeOH as eluent. The title compound was obtained as a light yellow solid (9 mg, 6%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:19][C:18](=O)[NH:17][C@H:16]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:15]1=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH3:29][O:28][C:25]1[CH:24]=[CH:23][C:22]([CH2:21][C@@H:16]2[CH2:15][N:14]([CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:19][CH2:18][NH:17]2)=[CH:27][CH:26]=1
Reactant: COc1ccc(C[C@H]2NC(=O)CN(Cc3ccccc3)C2=O)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H]2CN(Cc3ccccc3)CCN2)cc1
Reaction time: 1 h
Yield: 105.2 %

Procedure:
Under nitrogen atmosphere, to a suspension of lithium aluminum hydride (0.85 g) in tetrahydrofuran (65 ml) was added (3R)-1-benzyl-3-(4-methoxybenzyl)piperazine-2,5-dione (3.65 g) portionwise under ice-bath cooling. The reaction mixture was refluxed with stirring for one hour. After cooling, it was quenched by sequential addition of water (0.85 ml), 15% aqueous sodium hydroxide (0.85 ml), and water (2.5 ml) and the whole was stirred at room temperature for 30 minutes. The resulting insoluble material was removed by filtration, and the filtrate was added to a mixture of ethyl acetate (50 ml) and brine (70 ml). The organic layer was separated, dried over magnesium sulfate, and concentrated under reduced pressure to give (2R)-2-(4-methoxybenzyl)-4-benzylpiperazine (3.51 g) as a syrup.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[CH:12]=[CH:11][C:10](I)=[CH:9][C:6]=1[CH:7]=[O:8].[Cl:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[CH:28])=[N:25][CH:26]=2)=[CH:17][CH:16]=1>>[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:22]=[CH:23][C:24]([C:27]#[C:28][C:10]3[CH:11]=[CH:12][C:5]([O:4][CH2:3][CH2:2][OH:1])=[C:6]([CH:9]=3)[CH:7]=[O:8])=[N:25][CH:26]=2)=[CH:19][CH:20]=1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Reactant: O=Cc1cc(I)ccc1OCCO
Product: O=Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCO

Procedure:
The product was prepared analogously to Example 7.1e starting from 2-(2-hydroxyethoxy)-5-iodobenzaldehyde and 5-(4-chlorophenyl)-2-ethynylpyridine. Yield: 5.53 g (86% of theoretical); C22H16ClNO3 (M=377.820); calc.: molpeak (M+H)+: 378/380 (Cl); found: molpeak (M+H)+: 378/380 (Cl); HPLC-MS: 5.79 minutes (method B).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:21]I>CN(C=O)C>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([CH2:16][C:17]([O:20][CH3:21])([CH3:19])[CH3:18])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CC(C)(O)CC1CCN(C(=O)OC(C)(C)C)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(C)(C)CC1CCN(C(=O)OC(C)(C)C)CC1
Reaction time: 0.33 h
Yield: 90.7 %

Procedure:
To a mixture of 0.06 g (2.5 mmol) of NaH in 5 mL of DMF at rt was added a solution of 0.1 g (0.39 mmol) of 1-t-butoxycarbonyl-4-(2-hydroxy-2-methyl-1-propyl)piperidine in 3 mL of DMF. After stirring for 20 min, 0.22 mL (3.5 mmol) of CH3I was added to the reaction mixture and the reaction mixture was stirred for 2 h. The reaction mixture was quenched with water and extracted with EtOAc. The combined organic fractions were washed with sat'd NaCl solution, dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by chromatography (silica, hexanes:ethyl acetate, 9:1) to give 0.096 g of the title compound.
Reaction SMILES: Cl.[F:2][C:3]([F:18])([F:17])[C:4]1[N:5]=[CH:6][C:7]([NH:10][C@H:11]2[CH2:15][CH2:14][CH2:13][C@@H:12]2[NH2:16])=[N:8][CH:9]=1.[F:19][C:20]([F:31])([F:30])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](O)=[O:24].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.O>[F:19][C:20]([F:30])([F:31])[C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([NH:16][C@H:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[NH:10][C:7]1[CH:6]=[N:5][C:4]([C:3]([F:2])([F:17])[F:18])=[CH:9][N:8]=1)=[O:24]
Reactant: N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1
Reactant: O=C(O)c1ccccc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(N[C@H]1CCC[C@@H]1Nc1cnc(C(F)(F)F)cn1)c1ccccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (1S,2S)-1-N-[5-(trifluoromethyl)pyrazin-2-yl]cyclopentane-1,2-diamine hydrochloride (Intermediate 14; 60 mg, 0.21 mmol) in DMF (3 ml) was added 2-(trifluoromethyl)benzoic acid (CAS number 433-97-6; 60 mg, 0.21 mmol), TBTU (0.082 g, 0.25 mmol) and DIPEA (0.1 g, 0.84 mmol) and the reaction was stirred at room temperature for 2 hours. The reaction was diluted with water (25 ml) and extracted with ethyl acetate (30 ml×3). The organics were washed with water (50 ml), brine (25 ml), dried over sodium sulfate and concentrated in vacuo. The resulting residue was purified by column chromatography (silica, 0-45% ethyl acetate/n-hexane) to afford the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[N:5][CH:6]=[C:7]([CH3:9])[N:8]=1.[CH2:18]([O:25][C:26](ON1C(=O)CCC1=O)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH2:18]([O:25][C:26]([N:15]1[CH2:16][CH2:17][CH:12]([CH2:11][NH:10][C:4]2[C:3]([O:2][CH3:1])=[N:8][C:7]([CH3:9])=[CH:6][N:5]=2)[CH2:13][CH2:14]1)=[O:27])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=C(OCc1ccccc1)ON1C(=O)CCC1=O
Reactant: COc1nc(C)cnc1NCC1CCNCC1
Product: COc1nc(C)cnc1NCC1CCN(C(=O)OCc2ccccc2)CC1

Procedure:
The above compound was prepared in a similar manner as described in EXAMPLE 130 from 4-[(3-methoxy-5-methyl-pyrazin-2-ylamino)-methyl]-piperidine using N-(benzyloxycarbonyloxy)succinimide (Sigma-Aldrich). M.S. (M+1): 371.
Reaction SMILES: [C:1]1([N:7]2[C:12](=[O:13])[C:11]3[S:14][CH:15]=[C:16]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[C:10]=3[N:9]=[CH:8]2)C=C[CH:4]=[CH:3][CH:2]=1.NC1C(C2C=CC=CC=2[F:35])=CSC=1C(OC)=O.C(OCC)(OCC)OCC.C(N)CCC>C(O)(=O)C>[CH2:1]([N:7]1[C:12](=[O:13])[C:11]2[S:14][CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[F:35])[C:10]=2[N:9]=[CH:8]1)[CH2:2][CH2:3][CH3:4]
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CCOC(OCC)OCC
Solvent: CC(=O)O
Solvent: CCCCN
Product: CCCCn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 93.6 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1.0 ml), n-butylamine (0.076 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 113.2 mg (0.37 mmol, 93.6% yield) of the title compound.
Reaction SMILES: [CH2:1]([C:3]1[CH:9]=[CH:8][C:6]([NH2:7])=[CH:5][CH:4]=1)[CH3:2].II>O=C(C=C(C)C)C>[CH2:1]([C:3]1[CH:4]=[C:5]2[C:6](=[CH:8][CH:9]=1)[NH:7][C:3]([CH3:9])([CH3:1])[CH:4]=[C:5]2[CH3:6])[CH3:2]
Reactant: CCc1ccc(N)cc1
Agent: II
Solvent: CC(=O)C=C(C)C
Product: CCc1ccc2c(c1)C(C)=CC(C)(C)N2

Procedure:
Skraup reaction of p-ethylaniline (1.0 g) and iodine (0.34 g) in mesityl oxide (5 ml) was performed according to the method described in example 1.
Reaction SMILES: [N+:1]([C:4]1[N:5]=[C:6]2[N:11]([CH:12]=1)[CH2:10][CH:9]([CH2:13][OH:14])[CH2:8][O:7]2)([O-:3])=[O:2].[Br:15][C:16]1[CH:17]=[CH:18][C:19](F)=[N:20][CH:21]=1.[H-].[Na+]>>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([O:14][CH2:13][CH:9]2[CH2:8][O:7][C:6]3=[N:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:12][N:11]3[CH2:10]2)=[N:20][CH:21]=1
Reactant: O=[N+]([O-])c1cn2c(n1)OCC(CO)C2
Reactant: Fc1ccc(Br)cn1
Agent: [H-]
Agent: [Na+]
Product: O=[N+]([O-])c1cn2c(n1)OCC(COc1ccc(Br)cn1)C2
Yield: 67 %

Procedure:
Alkylation of oxazine alcohol 180 with 5-bromo-2-fluoropyridine (91) (2.0 equiv.) and NaH (1.74 equiv.) as in Example 2OO for 3 h, followed by chromatography of the product on silica gel, eluting with 0-0.25% MeOH/CH2Cl2 (foreruns) and then with 0.25-0.5% MeOH/CH2Cl2, gave 6-{[(5-bromo-2-pyridinyl)oxy]methyl}-2-nitro-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine (181) (67%) as a white solid: mp (MeOH/CH2Cl2/hexane) 233-235° C.; 1H NMR [(CD3)2SO] δ 8.27 (dd, J=2.5, 0.4 Hz, 1H), 8.07 (s, 1H), 7.93 (dd, J=8.8, 2.6 Hz, 1H), 6.85 (dd, J=8.9, 0.5 Hz, 1H), 4.60 (dd, J=11.0, 2.7 Hz, 1H), 4.44 (dd, J=11.1, 7.4 Hz, 1H), 4.36 (dd, J=11.0, 6.7 Hz, 1H), 4.33 (dd, J=11.0, 6.7 Hz, 1H), 4.27 (dd, J=12.5, 5.4 Hz, 1H), 4.04 (dd. J=12.6, 7.1 Hz, 1H), 2.85 (m, 1H). Anal. (C12H11BrN4O4.) C, H, N.