Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]2[N:23]=[C:22]([C:24]([O:26]CC)=O)[O:21][N:20]=2)=[CH:4][CH:3]=1.[NH2:29][OH:30].Cl.C([O-])([O-])=O.[K+].[K+]>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][N:11]3[C:17]=2[CH2:18][C:19]2[N:23]=[C:22]([C:24]([NH:29][OH:30])=[O:26])[O:21][N:20]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=C(NO)c1nc(Cc2c(-c3ccc(Cl)cc3)nc3ccc(F)cn23)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61.9 %

Procedure:
To a solution of ethyl 3-((2-(4-chlorophenyl)-6-fluoroimidazo[1,2-a]pyridin-3-yl)methyl)-1,2,4-oxadiazole-5-carboxylate (0.125 mmol, 50.0 mg) in EtOH (10 mL) was added NH2OH.HCl (0.75 mmol, 52.1 mg) and K2CO3 (0.375 mmol, 51.8 mg) at r.t. The reaction mixture was stirred for 30 mins at r.t., and filtered. The filtrate was concentrated under reduced pressure, to give the title product (30 mg, 60.0%), as a white solid. m/e+=388 (M+H+). 1H NMR (300 MHz, in DMSO-d6): δ 12.14 (1H, D, brd, OH), δ 9.87 (1H, D, brd, NH), δ 8.69-8.68 (1H, D, dd, J=5.2, 2.4 Hz, ArH), δ 7.81-7.79 (2H, D, d, J=8.4 Hz, ArH), δ 7.74-7.71 (1H, D, dd, J=9.6, 5.2 Hz, ArH), δ 7.55-7.53 (2H, D, d, J=8.4 Hz, ArH), δ 7.47-7.41 (1H, D, m, ArH), and δ 4.73 (2H, D, s, CH2).
Reaction SMILES: C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.[NH:14]1[CH2:17][CH:16]([O:18][C:19]2[CH:24]=[CH:23][C:22]([CH:25]3[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)=[O:32])[CH2:27][CH:26]3[O:41][CH2:42][C:43]3[CH:44]=[CH:45][C:46]4[O:51][CH2:50][C:49](=[O:52])[N:48]([CH2:53][CH2:54][CH2:55][O:56][CH3:57])[C:47]=4[CH:58]=3)=[CH:21][CH:20]=2)[CH2:15]1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:68]1[S:69][CH:70]=[CH:71][N:72]=1>[Cl-].[Na+].O.O.FC(F)(F)C([O-])=O.[Pd+2].FC(F)(F)C([O-])=O.C1(C)C=CC=CC=1>[CH3:57][O:56][CH2:55][CH2:54][CH2:53][N:48]1[C:47]2[CH:58]=[C:43]([CH2:42][O:41][CH:26]3[CH:25]([C:22]4[CH:23]=[CH:24][C:19]([O:18][CH:16]5[CH2:17][N:14]([C:68]6[S:69][CH:70]=[CH:71][N:72]=6)[CH2:15]5)=[CH:20][CH:21]=4)[CH2:30][CH2:29][N:28]([C:31]([O:33][CH2:34][C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=4)=[O:32])[CH2:27]3)[CH:44]=[CH:45][C:46]=2[O:51][CH2:50][C:49]1=[O:52]
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CNC4)cc3)cc21
Reactant: Brc1nccs1
Agent: [Pd+2]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])C(F)(F)F
Solvent: O
Solvent: Cc1ccccc1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OC4CN(c5nccs5)C4)cc3)cc21
Reaction time: 0.17 h

Procedure:
A baked-out Schlenk flask is initially charged under argon with 0.071 g of tri-tert-butylphosphine and 0.114 g of palladium trifluoroacetate. 1.3 ml of degassed toluene are added and the suspension is stirred under argon over 10 minutes. 0.700 g of benzyl 4-[4-(azetidin-3-yloxy)phenyl]-3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]piperidine-1-carboxylate (Example 257c), 0.265 g of tribasic potassium phosphate and 0.290 ml of bromothiazole are added and the reaction mixture is stirred at 80-85° C. over 16 hours. The reaction mixture is cooled, diluted with 20 ml each of brine and water and subsequently extracted with 40 ml of ethyl acetate. The organic phase is dried with sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellow resin from the residue by means of flash chromatography (SiO2 60F). Rf=0.15 (4:1 EtOAc-heptane); Rt=4.34.
Reaction SMILES: F[C:2](F)(F)[C:3]([NH:5][C:6]1[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:7]=1[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])=O.[H-].[Na+].ClCC[CH2:25][N:26]1[CH2:31][CH2:30][N:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[O:38][CH3:39])[CH2:28][CH2:27]1.O>CN(C=O)C>[CH3:39][O:38][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][C:32]=1[N:29]1[CH2:28][CH2:27][N:26]([CH2:25][CH2:2][CH2:3][NH:5][C:6]2[C:16]([CH3:17])=[CH:15][CH:14]=[CH:13][C:7]=2[C:8]([N:10]([CH3:12])[CH3:11])=[O:9])[CH2:31][CH2:30]1
Reactant: Cc1cccc(C(=O)N(C)C)c1NC(=O)C(F)(F)F
Reactant: COc1ccccc1N1CCN(CCCCl)CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccccc1N1CCN(CCCNc2c(C)cccc2C(=O)N(C)C)CC1
Temperature: 50 °C
Yield: 11.3 %

Procedure:
A mixture of 2-trifluoroacetylamino-N,N,3-trimethylbenzamide (584.2 mg, 2.13 mmol), prepared as in Example 22, and sodium hydride (110 mg, 2.7 mmol) in 10 mL of DMF was heated at 50° C. for 20 minutes and then 1-chloro-3-[4-(2-methoxyphenyl)piperazin-1-yl]propane (647 mg, 2.13 mmol) was added. The mixture was heated at 80° C. for 18 hours, then poured into water and extracted with ethyl acetate (3×50 mL). The combined extract was washed with saline, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with 6% methanol/methylene chloride to give 2-{3-[4-(2-methoxy-phenyl)piperazin-1-yl]propylamino}-N,N,3-trimethylbenzamide (100 mg, 0.24 mmol).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]#[N:54])[N:44]2[C:43]1=[O:55]>>[CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@@H:52]([C:53]#[N:54])[N:44]2[C:43]1=[O:55])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Reactant: N#C[C@@H]1CCC[C@@H]2SCC[C@H](N)C(=O)N12
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@@H](C#N)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((4S,7S,10aS)-7-cyano-5-oxooctahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)-N6-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (11 mg, 0.020 mmol) and Intermediate 36 (5.3 mg, 0.020 mmol) to give a white solid (4.7 mg, 31% yield). Anal. Calcd. for C43H51N5O5S m/z 749.7. found: 750.3 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.36-7.22 (6H, m), 7.22-7.11 (6H, m), 7.08 (2H, d, J=6.0 Hz), 6.96 (2H, d), 5.36 (1H, d, J=3.8 Hz), 5.24 (1H, d, J=4.9 Hz), 5.07-4.90 (1H, m), 4.89-4.74 (1H, m), 4.02-3.86 (1H, m), 3.79 (3H, s), 3.50-3.32 (1H, m), 3.07-2.60 (5H, m), 2.57-2.35 (2H, m), 2.15 (2H, t, J=13.2 Hz), 2.05-1.87 (3H, m), 1.85-1.62 (8H, m), 1.62-1.06 (6H, m).
Reaction SMILES: [Li+].[BH4-].C[O:4][C:5](=O)[CH2:6][C:7]1[CH:12]=[C:11]([F:13])[C:10]([C:14]#[N:15])=[CH:9][C:8]=1[F:16].O>C1COCC1>[F:13][C:11]1[CH:12]=[C:7]([CH2:6][CH2:5][OH:4])[C:8]([F:16])=[CH:9][C:10]=1[C:14]#[N:15]
Reactant: COC(=O)Cc1cc(F)c(C#N)cc1F
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(F)c(CCO)cc1F
Reaction time: 12 h

Procedure:
LiBH4 (1.45 mL, 2.9 mmol, 2 M in THF) was added to a stirred solution of methyl(4-cyano-2,5-difluorophenyl)acetate (0.47 g, 2.2 mmol) in THF (25 ml) at 0° C. The resulting solution was stirred for 12 h. Water (15 ml) was added, and the resulting solution was extracted with dichloromethane (2×50 ml). The combined organic layers were dried over MgSO4, filtered, and evaporated under reduced pressure to yield the product after purification on silica gel (eluted with 5-30% ethyl acetate-hexanes) as a clear oil. 1H NMR (500 MHz, CDCl3) δ 7.32 (dd, J=5.3, J=5.0 Hz, 1H), 7.23 (dd, J=5.8, J=5.7 Hz, 1H), 3.95 (t, J=6.2, J=6.4 Hz, 2H), 2.98 (t, J=6.4, J=6.2 Hz, 2H). LC-MS (IE, m/z): 184 [M+1]+.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([O:11][CH3:12])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:18]1[CH:23]=[N:22][CH:21]=[CH:20][N:19]=1)CCC>CN(C=O)C.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.[Cu]I>[CH3:12][O:11][C:5]1[CH:4]=[N:3][C:2]([C:18]2[CH:23]=[N:22][CH:21]=[CH:20][N:19]=2)=[C:10]2[C:6]=1[CH:7]=[CH:8][NH:9]2
Reactant: COc1cnc(Br)c2[nH]ccc12
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: COc1cnc(-c2cnccn2)c2[nH]ccc12
Temperature: 90 °C
Yield: 52.9 %

Procedure:
A mixture of 7-bromo-4-methoxy-6-azaindole (1.160 g, 5.11 mmol) and 2-(tri-n-butylstannyl)pyrazine (2.07 g, 5.62 mmol) in 25 mL of dry DMF was degassed with a stream of Ar bubbles for 10 min. To this solution was added tetrakis(triphenylphosphine)palladium (0.590 g, 0.511 mmol) and CuI (0.097 g, 0.511 mmol) and the mixture was heated in a sealed tube at 90° C. for 4 h. The cooled mixture was filtered through methanesulfonic acid SCX cartridges (7×3 g) with MeOH, to remove triphenylphosphine oxide. The filtrate was evaporated and the residue triturated with MeOH to give the title compound (0.612 g, 53%) as a light yellow solid:
Reaction SMILES: BrC1C2C(S(Cl)(=O)=O)=CC=CC=2C=NC=1.C(OC(N[C@H]1CCNC1)=O)(C)(C)C.C(OC([NH:36][CH:37]([CH:39]1[CH2:42][N:41]([S:43]([C:46]2[C:47]3[C:48]([Cl:56])=[CH:49][N:50]=[CH:51][C:52]=3[CH:53]=[CH:54][CH:55]=2)(=[O:45])=[O:44])[CH2:40]1)[CH3:38])=O)(C)(C)C>>[NH2:36][CH:37]([CH:39]1[CH2:40][N:41]([S:43]([C:46]2[C:47]3[C:48]([Cl:56])=[CH:49][N:50]=[CH:51][C:52]=3[CH:53]=[CH:54][CH:55]=2)(=[O:44])=[O:45])[CH2:42]1)[CH3:38]
Reactant: CC(NC(=O)OC(C)(C)C)C1CN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1
Agent: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: O=S(=O)(Cl)c1cccc2cncc(Br)c12
Product: CC(N)C1CN(S(=O)(=O)c2cccc3cncc(Cl)c23)C1

Procedure:
4-Chloro-5-isoquinolinesulfonyl chloride obtained in Reference Example 7 and 3-[1-(tert-butoxycarbonylamino)ethyl]azetidine obtainable from 1-(diphenylmethyl)-3-(hydroxymethyl)azetidine (Oakwood) according to the method described in WO05/080394 can be used in the method of Example 1-1, Step A instead of 4-bromo-5-isoquinolinesulfonyl chloride and (S)-3-(tert-butoxycarbonylamino)pyrrolidine, respectively, to prepare 3-[1-(tert-butoxycarbonylamino)ethyl]-1-(4-chloro-5-isoquinolinesulfonyl)azetidine, and the protective group of the obtained compound can be removed according to the method described in Example 1-1, Step B to obtain the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:18][C@H:19]1[CH2:24][O:23][CH2:22][CH2:21][NH:20]1>CC(O)C>[Cl:1][C:2]1[N:7]=[C:6]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][C@@H:19]2[CH3:18])[CH:5]=[CH:4][N:3]=1
Reactant: C[C@H]1COCCN1
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: C[C@H]1COCCN1c1ccnc(Cl)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90 %

Procedure:
To a solution of 2,4-dichloropyrimidine (5.00 g, 0.034 mol) and DIPEA (8.00 mL, 0.046 mol) in 2-propanol (60 mL) at 0° C. was added (S)-3-methylmorpholine (3.73 g, 0.037 mol) dropwise. The reaction mixture was stirred at 0° C. for 30 min and then allowed to warm to RT and stirred for a further 16 h. Solvent was removed in vacuo and the residue was then partitioned between water and EtOAc. The phases were separated and the organic layer washed with brine, dried over magnesium sulfate, filtered and the solvent removed in vacuo to yield a yellow oil (6.54 g, 91%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH:7]1([NH:11][CH2:12][CH2:13][C:14]#[N:15])[CH2:10][CH2:9][CH2:8]1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>C(OCC)C.O>[CH:7]1([NH:11][CH2:12][CH2:13][CH2:14][NH2:15])[CH2:10][CH2:9][CH2:8]1
Reactant: N#CCCNC1CCC1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: NCCCNC1CCC1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.6 %

Procedure:
To a cooled (0° C.) suspension of lithium aluminum hydride (3.056 g, 80.5 mmol) in anhydrous diethyl ether (120 mL) was added a solution of 3-(cyclobutylamino)propanenitrile (5.000 g, 40.3 mmol) in anhydrous diethyl ether (40 mL), dropwise over 45 mins. The reaction mixture was stirred at room temperature for 15 mins and at reflux for 4 hrs, cooled to room temperature and stirred for 1 hr. The mixture was cooled to 0° C. and vigorously stirred while water (3.1 mL) was added dropwise, followed by 15% aqueous sodium hydroxide (3.1 mL), and finally water (9.3 mL). The resultant slurry was warmed to room temperature, stirred for 15 mins, and anhydrous magnesium sulfate added, stirring for an additional 15 mins. Solid materials were removed by filtration, washing multiple times with warm methylene chloride, and the filtrate concentrated under reduced pressure to give the desired product as a pale yellow liquid (3.44 g, 66%). 1H NMR (CDCl3, 300 MHz) 3.14 (m, 1H), 2.69-2.62 (m, 2H), 2.53-2.45 (m, 2H), 2.13-2.10 (m, 2H), 1.56-1.48 (m, 6H), 1.33 (br s, 3H).
Reaction SMILES: Cl.[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)([CH2:6]3)[CH2:4]1)[CH2:10]2.[H][H]>C(O)(=O)C.[Pt]=O>[NH2:2][C:3]12[CH2:12][CH:7]3[CH2:8][CH:9]([CH2:11][C:5]([CH:13]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]4)([CH2:6]3)[CH2:4]1)[CH2:10]2
Reactant: NC12CC3CC(C1)CC(c1ccccc1)(C3)C2
Reactant: [H][H]
Agent: O=[Pt]
Agent: Cl
Solvent: CC(=O)O
Product: NC12CC3CC(C1)CC(C1CCCCC1)(C3)C2
Yield: 70 %

Procedure:
Dissolve 0.011 mol of 1-amino-3-phenyl adamantane (V) in 150 ml glacial acetic acid, mix with 0.3 g of platinum oxide (1% on activated carbon) and hydrate in a Parr apparatus at 35° C. at a hydrogen pressure of 3 bar. Subsequently, remove the catalyst by filtration and evaporate the filtrate to dryness. Take up the residue in methanol and precipitate the product with ether. Suck off and dry. (Yield: 70%).
Reaction SMILES: C[O:2][C:3](=[O:31])[CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][C:16]2[CH:21]=[C:20]([C:22]#[C:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:19]=[C:18]([Br:30])[CH:17]=2)=[CH:8][CH:7]=1.[Li+].[OH-].O.Cl>C1COCC1.CO>[Br:30][C:18]1[CH:17]=[C:16]([C:15]#[C:14][CH2:13][O:12][C:9]2[CH:8]=[CH:7][C:6]([O:5][CH2:4][C:3]([OH:31])=[O:2])=[CH:11][CH:10]=2)[CH:21]=[C:20]([C:22]#[C:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:19]=1
Reactant: COC(=O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccccc3)c2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)COc1ccc(OCC#Cc2cc(Br)cc(C#Cc3ccccc3)c2)cc1
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of {4-[3-(3-bromo-5-phenylethynyl-phenyl)-prop-2-ynyloxy]-phenoxy}-acetic acid methyl ester (66 mg, 0.14 mmol) in THF (1.5 ml) and methanol (0.3 ml) was added a ice-cold solution of LiOH (1 M, 2 ml). The reaction mixture was stirred at 0° C. for 45 min., after which water (10 ml) and aqueous HCl (1M, 2 ml) were added. The mixture was extracted with ethyl acetate (2×5 ml), and the combined organic phases were dried and evaporated to give the title compound in 64 mg (100%) yield.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[CH2:7])=[CH:4][CH:3]=1.[CH3:10][O:11][C:12]([CH3:14])=[CH2:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.N1C=CC=CC=1>C(OCC)C.O1CCOCC1>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][C:12]([O:11][CH3:10])([CH3:14])[CH3:13])=[CH:3][CH:4]=1)=[CH2:7]
Reactant: C=Cc1ccc(O)cc1
Reactant: C=C(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Solvent: c1ccncc1
Solvent: C1COCCO1
Product: C=Cc1ccc(OC(C)(C)OC)cc1
Temperature: 10 °C
Reaction time: 20 h

Procedure:
72.1 g (600 mmol) of 4-hydroxystyrene are dissolved in a mixture of 300 ml of diethyl ether and 150 ml of dioxane under a nitrogen atmosphere in a 1500 ml sulfonation flask. 216.3 g (3000 mmol) of 2-methoxypropene are added, and the mixture is cooled to 10° C. 1,48 g (7.8 mmol) of p-toluenesulfonic acid in 28.5 g (360 mmol) of pyridine are then added dropwise in the course of 20 minutes, and the mixture is stirred at room temperature for 20 hours. The reaction mixture is washed three times with 300 ml of 0.2N NaOH and three times with 300 ml of demineralized water. The organic phase is dried using magnesium sulfate, filtered through 1 cm of Ambefiyst A27 and evaporated in a rotary evaporator. Further drying of the resultant residue under a high vacuum leaves 99.2 g (82% of theory) of the desired product in the form of a yellow oil.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[CH3:19][C:20]1[C:25]([CH3:26])=[CH:24][CH:23]=[CH:22][C:21]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].C1COCC1>C(Cl)(Cl)Cl>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:21]4[CH:22]=[CH:23][CH:24]=[C:25]([CH3:26])[C:20]=4[CH3:19])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: Cc1cccc(B(O)O)c1C
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(-c2ccc3c(c2)CC[C@H]2N(C)C(=O)CC[C@]32C)c1C
Yield: 25.4 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine)palladium(0) (23 mg, 0.02 mmol), 2,3-dimethylphenylboronic acid (117 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution and 2 mL of THF, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with chloroform (50 mL) and washed with brine (2×50 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 55 mg (25 %) of the title compound as an amorphous solid. mp 133°-140°. FDMS: m/e=333. α[D]589 =+61.90 (c=1.05, methanol).
Reaction SMILES: [C:1]1([C@@H:7]([N:9]2[C:13](=O)[CH2:12][C@H:11]([C:15]([NH2:17])=O)[CH2:10]2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[BH4-].[Na+].S(=O)(=O)(O)O.Cl>O1CCCC1>[NH2:17][CH2:15][C@H:11]1[CH2:12][CH2:13][N:9]([C@H:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH3:8])[CH2:10]1
Reactant: C[C@@H](c1ccccc1)N1C[C@@H](C(N)=O)CC1=O
Agent: Cl
Agent: O=S(=O)(O)O
Agent: [BH4-]
Solvent: C1CCOC1
Product: C[C@@H](c1ccccc1)N1CC[C@H](CN)C1
Yield: 72 %

Procedure:
(3S)-1-((S)-1-Phenylethyl)-5-oxo-3-pyrrolidinecarboxamide (150 g) was dissolved in tetrahydrofuran (2.5 l), and sodium borohydride (138 g) was added with stirring. Conc. sulfuric acid (130 ml) was dropwise added under ice-cooling. The mixture was stirred for 1 hr at room temperature, and further at refluxing temperature for 10 hr. 6N Hydrochloric acid (300 ml) was dropwise added under ice-cooling, and the mixture was stirred at refluxing temperature for 4 hr. The solvent was evaporated under reduced pressure, a 3N sodium hydroxide solution was added to make same alkaline, and the mixture was extracted with chloroform. The extract was dried over magnesium sulfate, concentrated under reduced pressure and distilled under reduced pressure to give 95 g of (3R)-3-aminomethyl-1-((S)-1-phenylethyl)pyrrolidine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[C:21]([OH:23])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>C1COCC1.CC#N>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:10][C@H:9]1[CH2:21][O:23][CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1C[C@H](OCc2ccccc2)C[C@H]1C(=O)O
Reactant: CI
Solvent: CC#N
Solvent: C1CCOC1
Product: COC[C@@H]1C[C@@H](OCc2ccccc2)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 62.2 %

Procedure:
To a solution of (2S,4R)-4-benzyloxy-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (15.5 mmol; 5.0 g) in THF (135 mL) is added 1 M THF solution of borane THF complex (31 mmol; 31 mL) at 0° C. under nitrogen. The solution is stirred for 1 hour at room temperature, quenched by dropwise addition of 15 ml of MeOH. After concentrating, the mixture is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude product. To a solution of crude material in MeCN (20 mL) were added Ag2O (46.5 mmol; 8.9 g) and MeI (155 mmol; 21.8 g) at room temperature, heated and stirred under reflux condition for 3 hours. After filtration and concentration, the resulting mixture is diluted with dichloromethane and saturated aqueous ammonium chloride solution. The product is extracted twice with dichloromethane. The combined organic layer is washed with brine, dried over MgSO4, filtered, concentrated under reduced pressure to give the crude (2S,4R)-4-benzyloxy-2-methoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (3.1 g).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.[Cl:27][C:28]1[CH:29]=[C:30](O)[CH:31]=[CH:32][CH:33]=1>CO.C(Cl)Cl>[Cl:27][C:28]1[CH:33]=[C:32]([CH:31]=[CH:30][CH:29]=1)[O:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([N:20]4[CH2:21][CH2:22][N:23]([CH3:26])[CH2:24][CH2:25]4)=[O:19])=[CH:16][CH:17]=3)=[CH:4][C:3]1=2
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Reactant: Oc1cccc(Cl)c1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cccc(Cl)c3)CCN4)cc2)CC1
Yield: 50 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3-chlorophenol (21.8 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (50% yield). LCMS: m/z=463.12(M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.00-2.12 (m, 1H), 2.27-2.33 (m, 1H), 2.33 (s, 3H), 2.34-2.6 (m, 4H), 3.4-3.7 (m, 4H), 3.7-3.9 (m, 2H), 5.18 (bs, 1H), 5.38 (t, J=3.6 Hz, 1H), 6.91 (dd, J=1.6 and 8.3 Hz, 1H), 6.99-7.04 (m, 2H), 7.23-7.27 (m, 1H), 7.43-7.50 (m, 4H), 7.61 (d, J=2.0 Hz), 8.30 (d, J=2.2 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([C:19](O)=[O:20])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[CH3:23][NH:24][CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[CH3:23][N:24]([CH2:25][CH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)[C:19]([C:12]1[C:13]([C:15]([F:18])([F:17])[F:16])=[N:14][C:9]([NH:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)=[N:10][CH:11]=1)=[O:20]
Reactant: CNCC1CCOCC1
Reactant: O=C(O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F
Agent: Cl
Product: CN(CC1CCOCC1)C(=O)c1cnc(Nc2cccc(Cl)c2)nc1C(F)(F)F

Procedure:
In a manner similar to Reference Example 1 (c) 2-(3-chlorophenylamino)-4-trifluoromethyl-pyrimidine-5-carboxylic acid (50 mg) and N-methyl-N-(tetrahydro-pyran-4-yl methyl)amine hydrochloride (39 mg) afforded, after Biotage chromatography over silica gel, eluting with 1% MeOH/CH2Cl2, the title compound (33 mg).