Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.ClCCl.[NH2:21][C:22]1[CH:27]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:25]=[CH:24][C:23]=1[N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1>O>[N:32]1([C:23]2[CH:24]=[CH:25][C:26]([C:28]([F:29])([F:31])[F:30])=[CH:27][C:22]=2[NH:21][C:2](=[O:9])[C:3]2[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=2)[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1
Reactant: O=C(Cl)c1ccncc1
Reactant: Nc1cc(C(F)(F)F)ccc1N1CCOCC1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cc(C(F)(F)F)ccc1N1CCOCC1)c1ccncc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 23.2 %

Procedure:
Isonicotinoyl chloride hydrochloride (320 mg, 1.80 mmol, commercially available product) and triethylamine (480 μl, 3.44 mmol) were sequentially added at 0° C. to a dichloromethane (5 ml) solution of 4-[2-amino-4-(trifluoromethyl)phenyl]morpholine (196 mg, 0.796 mmol), obtained as described in Referential Example 5-2. The resulting mixture was warmed to room temperature and stirred for 60 hours. Water was added to the mixture, and the resulting mixture was extracted three times with dichloromethane. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (30 g, hexane/ethyl acetate=2/1). Thus, N-[2-(4-morpholinyl)-5-(trifluoromethyl)phenyl]isonicotinamide (GIF-0346) (65.1 mg, 23.2%) was yielded as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[N:10]2[CH2:11][CH2:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:14][C:9]2=[CH:8][C:7]1=[O:19])=[O:5])[CH3:2].[F:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23]Br>COCCOC.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O.O>[CH2:1]([O:3][C:4]([CH:6]1[N:10]2[C:11]([CH2:23][C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[F:20])=[CH:12][C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])=[N:14][C:9]2=[CH:8][C:7]1=[O:19])=[O:5])[CH3:2]
Reactant: Fc1ccccc1CBr
Reactant: CCOC(=O)C1C(=O)C=C2N=C(C(C)(C)C)CCN21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: COCCOC
Solvent: CC(C)=O
Solvent: O
Product: CCOC(=O)C1C(=O)C=C2N=C(C(C)(C)C)C=C(Cc3ccccc3F)N21
Temperature: 25 °C
Reaction time: 48 h
Yield: 81 %

Procedure:
To 6-ethoxycarbonyl-2-(tert-butyl)-4H-pyrrolo[1,2-a]pyrimid-7-one (0.5 g, 1.9 mmol.) in DME (5 ml), tetrabutylammonium fluoride (4 ml, 4.0M in THF) was added, and a white foamy material formed. 2-Fluorobenzyl bromide (0.38 ml, 3 mmol.) was added and the mixture was stirred at room temperature for 2 days. Concentration of the reaction mixture in vacuo produced an oil, which was dissolved in acetone (20 ml) and diluted with water until the solution turned a slight cloudy. Partially concentration to remove acetone by nitrogen flow resulting precipitation. The precipitates were collected by filtration and washed with water (20 ml×2), ether (20 ml×3) and dried. The desired product (0.57 g) was obtained with excellent purity; MS: 371 (M+H)+, 325; NMR (CDCl3, δ): 8.29 (1H, s), 7.43-7.14(5H, 2m), 5.99 (1H, s) 5.18 (2H,s ), 4.35 (2H, q), 1.37(3H, s), 1.26 (9H, s).
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.ON1C(=O)CCC1=O.C1(N=C=NC2CCCCC2)CCCCC1.[NH:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45]([OH:47])=[O:46].C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:43]1[CH2:50][CH2:49][CH2:48][C@H:44]1[C:45]([OH:47])=[O:46])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)O
Temperature: 0 °C
Reaction time: 3 h
Yield: 73.5 %

Procedure:
A solution of Boc—D—Cha—OH (50.4 g, 185 mmol) in dichloromethane (360 mL) was cooled to 0° C. and N-hydroxysuccinimide (22.3 g, 194 mmol) was added. Then 1,3-dicyclohexylcarbodiimide (39.0 g, 189 mmol) was added in two portions as a solution in dichloromethane (90 mL). After stirring for 3 h at 0° C., L—Pro—OH (27.6 g, 240 mmol) and N,N-diisopropylethylamine (30.9 g, 239 mmol) were added. After stirring an additional 3 h between 0° C. and 10° C., the mixture was filtered over diatomaceous earth. The filter cake was rinsed with dichloromethane (100 mL); then the combined filtrates were concentrated in vacuo. The residual oil was partitioned between ethyl acetate (100 mL) and 0.625 M aqueous NaHCO3 (320 mL). The layers were separated, and the organic phase was washed with 0.625 M aq. NaHCO3 (80 mL). The combined bicarbonate extracts were then washed with ethyl acetate (100 mL). The aqueous phase was then stirred with ethyl acetate (300 mL) and acidified with 12 N HCl (approximately 37 mL). The layers were separated and the acidic aqueous phase was extracted with ethyl acetate (100 mL). The combined ethyl acetate extracts were concentrated in vacuo. The residue was slurried with a minimal amount of ethyl acetate, filtered, washed again with ethyl acetate and dried to give 50.1 g (73%) of white powder.
Reaction SMILES: N(CCO)CCO.N1(CCOC2C=CC(CCl)=CC=2)CCCCC1.S(Cl)(Cl)=O.[CH2:29]([O:31][C:32](=[O:48])[CH2:33][S:34]([C:37]1[CH:42]=[CH:41][C:40]([O:43][CH2:44][C:45]#[C:46][CH3:47])=[CH:39][CH:38]=1)(=[O:36])=[O:35])[CH3:30].Cl.Cl.Cl[CH2:52][CH2:53][N:54]([CH2:71][CH2:72]Cl)[CH2:55][C:56]1[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH2:64][N:65]2[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]2)=[CH:58][CH:57]=1>CC(C)=O>[CH2:29]([O:31][C:32]([C:33]1([S:34]([C:37]2[CH:38]=[CH:39][C:40]([O:43][CH2:44][C:45]#[C:46][CH3:47])=[CH:41][CH:42]=2)(=[O:35])=[O:36])[CH2:72][CH2:71][N:54]([CH2:55][C:56]2[CH:61]=[CH:60][C:59]([O:62][CH2:63][CH2:64][N:65]3[CH2:70][CH2:69][CH2:68][CH2:67][CH2:66]3)=[CH:58][CH:57]=2)[CH2:53][CH2:52]1)=[O:48])[CH3:30]
Reactant: CC#CCOc1ccc(S(=O)(=O)CC(=O)OCC)cc1
Reactant: ClCCN(CCCl)Cc1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Agent: ClCc1ccc(OCCN2CCCCC2)cc1
Solvent: OCCNCCO
Solvent: O=S(Cl)Cl
Solvent: CC(C)=O
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(OCCN4CCCCC4)cc3)CC2)cc1
Temperature: 25 °C
Yield: 48 %

Procedure:
A mixture of diethanolamine (2.1 g, 20 mmol), 4-(2-piperidin-1-yl-ethoxy)-benzyl chloride (5.9 g, 20 mmol) and KCO3 (10 g, excess) was refluxed in acetone (100 ml) for 24 hrs. At the end, reaction mixture was cooled to room temperature and filtered. It was concentrated to dryness and redissolved in touene (200 ml) and thionyl chloride (6.75 g, 50 mmol). It was heated to 80° C. for 1 hr and the separated brown solid, bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine was filtered and dried. The crude product was taken to next step with out purification. Yield: 7.0 g, (89%). 4-{[4-(2-Butynyloxy)phenyl]sulfonyl}-1-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-piperidine-4-carboxylic acid ethylester was was prepared according to the general method as outlined in example 1 (step 6), starting from ethyl{[4-(2-butynyloxy)phenyl]sulfonyl}acetate (2.9 g, 10.0 mmol) and bis-(2-chloro-ethyl)-[4-(2-piperidin-1-yl-ethoxy)-benzyl]-amine dihydrochloride (4.3 g, 10 mmol), 2.8 g of product (brown oil) was isolated. Yield 48%; MS: 583 (M+H)+
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:21][CH2:22]OC)[CH2:11][CH2:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:8][CH2:7]1)=O)C.[Cl-].C[Al+]C.[CH:29]([O:32][C:33]1[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=1)([CH3:31])[CH3:30]>CCCCCCC>[C:15]1([S:12]([N:9]2[CH2:8][CH2:7][C:6]3([C:4](=[O:3])[N:37]([C:36]4[CH:38]=[CH:39][C:33]([O:32][CH:29]([CH3:31])[CH3:30])=[CH:34][CH:35]=4)[CH2:22][CH2:21]3)[CH2:11][CH2:10]2)(=[O:13])=[O:14])[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CC(C)Oc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCN(S(=O)(=O)c2ccccc2)CC1
Agent: C[Al+]C
Agent: [Cl-]
Solvent: CCCCCCC
Product: CC(C)Oc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4)CC3)C2=O)cc1
Yield: 58.1 %

Procedure:
This material was prepared in analogy to example 1 step D) from 1-benzenesulfonyl-4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (0.2 g), dimethylaluminium chloride in heptane (0.9 molar, 0.94 ml) and 4-isopropoxy-aniline (0.1 g) to give the desired 8-benzenesulfonyl-2-(4-isopropoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (0.14 g) as a yellow solid. MS (ESI): 429.18 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]([F:15])([F:14])[F:13])=[CH:8][N:7]=1.CN([CH:22]=[O:23])C.[Li]CCCC>C1COCC1>[F:13][C:12]([F:15])([F:14])[C:9]1[CH:10]=[CH:11][C:6]([O:5][C:4]2[CH:3]=[C:2]([CH:18]=[CH:17][CH:16]=2)[CH:22]=[O:23])=[N:7][CH:8]=1
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1ccc(Oc2cccc(Br)c2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1cccc(Oc2ccc(C(F)(F)F)cn2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 23.8 %

Procedure:
To a solution of 2-(3-bromophenoxy)-5-(trifluoromethyl)pyridine (8.0 g, 25.15 mmol) in THF under inert atmosphere at −78° C. was added DMF (3.8 mL, 50.3 mmol) dropwise, followed by n-BuLi (31.4 mL, 50.3 mmol) dropwise. The reaction mixture was stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl solution and the temperature was allowed to warm to room temperature. The mixture was extracted with ethyl acetate, dried over Na2SO4, and concentrated to dryness. Purification by column chromatography (EtOAc:Hexane, 40:60) gave the pure title compound (1.6 g). 1H NMR (500 MHz, CDCl3): δ 7.1 (d, 1H, J=8.5 Hz), 7.4 (m, 1H), 7.6 (m, 1H), 7.7 (d, 1H, J=7.5 Hz), 7.9 (1H), 8.4 (s, 1H), 10.0 (s, 1H).
Reaction SMILES: Cl.[C:2](Cl)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1.C(N(CC)CC)C.[NH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]2[C:28]=1[CH:27]=[N:26][CH:25]=[C:24]2[Br:29]>C1COCC1.CCOC(C)=O>[Br:29][C:24]1[C:23]2[C:28](=[C:19]([NH:18][C:2](=[O:9])[C:3]3[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=3)[CH:20]=[CH:21][CH:22]=2)[CH:27]=[N:26][CH:25]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1cccc2c(Br)cncc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cccc2c(Br)cncc12)c1cccnc1
Reaction time: 8 h

Procedure:
Nicotinoyl chloride hydrochloride (356 mg, 2 mmol) and triethylamine (558 μl, 2 mmol) are added to a solution of 8-amino-4-bromoisoquinoline (intermediate 23.2, 446 mg, 0.90 mmol) in anhydrous THF (25 ml). The reaction mixture is stirred overnight, diluted with AcOEt (200 ml) and washed twice with 1N NaOH (100 ml) and then the organic phase is dried over Na2SO4 and evaporated under vacuum. The residue is purified on silica gel, eluting with AcOEt.
Reaction SMILES: [CH:1]1([N:4]([CH2:35][CH2:36]O)[C:5]([C:7]2[C:12]([O:13][CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:11]([OH:21])[N:10]=[C:9]([CH2:22][C:23]3([C:28]4[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][CH:29]=4)[CH2:27][CH2:26][CH2:25][CH2:24]3)[N:8]=2)=[O:6])[CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>ClCCl>[CH2:14]([O:13][C:12]1[C:11](=[O:21])[N:10]=[C:9]([CH2:22][C:23]2([C:28]3[CH:29]=[CH:30][C:31]([Cl:34])=[CH:32][CH:33]=3)[CH2:27][CH2:26][CH2:25][CH2:24]2)[N:8]2[CH2:36][CH2:35][N:4]([CH:1]3[CH2:2][CH2:3]3)[C:5](=[O:6])[C:7]=12)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=C(c1nc(CC2(c3ccc(Cl)cc3)CCCC2)nc(O)c1OCc1ccccc1)N(CCO)C1CC1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: O=C1c2c(OCc3ccccc3)c(=O)nc(CC3(c4ccc(Cl)cc4)CCCC3)n2CCN1C1CC1
Reaction time: 1 h
Yield: 151.7 %

Procedure:
5-Benzyloxy-2-[1-(4-chlorophenyl)-cyclopentylmethyl]-6-hydroxypyrimidine-4-carboxylic acid cyclopropyl-(2-hydroxyethyl)-amide (326) (90 mg, 0.17 mmol) and triphenylphosphine (90.5 mg, 0.35 mmol) were taken up in dichloromethane (3 ml) at room temperature followed by the slow addition of diisopropyl azodicarboxylate (52.34 mg, 0.26 mmol) and stirring for 1 h. Dichloromethane (15 ml) was added to the reaction mixture, which was subsequently washed with water (10 ml) and brine (10 ml). The organic part was dried and concentrated under reduced pressure. The obtained residue was purified by normal silica column using 30% ethyl acetate in hexane to get 9-benzyloxy-6-[1-(4-chlorophenyl)-cyclopentylmethyl]-2-cyclopropyl-3,4-dihydro-2H-pyrazino[1,2-c]pyrimidine-1,8-dione (327) (130 mg, 56%; 2 steps) as a sticky yellow solid.
Reaction SMILES: CN1CCOCC1.[N+:8]([C:11]1[N:12]=[C:13]([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([OH:19])=O)[NH:14][CH:15]=1)([O-:10])=[O:9].ClC1N=C(OC)N=C(OC)N=1.Cl.[CH3:38][O:39][C:40](=[O:46])[C@@H:41]1[CH2:45][CH2:44][CH2:43][NH:42]1>O1CCCC1.C(OC)(C)(C)C.CO.C(Cl)Cl>[N+:8]([C:11]1[N:12]=[C:13]([CH:16]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:17]([N:42]2[CH2:43][CH2:44][CH2:45][C@H:41]2[C:40]([O:39][CH3:38])=[O:46])=[O:19])[NH:14][CH:15]=1)([O-:10])=[O:9]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: O=C(O)C(c1ccccc1)c1nc([N+](=O)[O-])c[nH]1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)[C@@H]1CCCN1C(=O)C(c1ccccc1)c1nc([N+](=O)[O-])c[nH]1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
N-Methyl morpholine (17.79 ml, 2 eq) was added to a stirred solution of 2-(4-nitroimidazolyl)-2-phenylacetic acid (1) (20 g, 80.9 mm) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (14.45 g,80.1 mm, 1.0 eq) in 175 ml of anhydrous tetrahydrofuran at 25° C. After stirring the reaction mixture at ambient temperature for 1.5 h, 14.45g (80.9 mm, 1.0 eq) of proline methyl ester hydrochloride was added. The reaction was stirred overnight at room temperature and the solvent was evaporated under a stream of nitrogen. The residue was partitioned between 200 Ml of 1M HCl and 200 mL of deionized water. The layers were separated and the organic layer was washed with saturated sodium bicarbonate solution. A quantity of water sufficient to dissolve the resulting solids was added. The organic layer was washed with brine, dried over magnesium sulfate, filtered and the volatiles were removed under vacuum to give a brown foam. The foam was dissolved in methyl t-butyl ether, methylene chloride and methanol to effect crystallization. The resulting slurry was filtered and dried under vacuum to give 17.45 g (60%) of a cream colored product MS: 358 (M+) IR (cm−1): 1744, 1668; H1 nmr d (d6 DMSO): 1.42-1.46 (m, 3H), 1.6-1.9 (m, 1H), 2.42-2.63 (m,1H), 3.21 (s, 1.5H), 3.25 (s, 1.5H), 3.30-3.36 (m, 1H), 4.01-4.06 (m, 1H), 6.36 (s, 0.5H), 6.43 (s, 0.5h), 7.0-7.2 (m, 5H), 7.38 (s, 0.5H), 7.41 (s, 0.5H), 7.75 (s, 0.5H), 7.83 (s, 0.5H)
Reaction SMILES: N1C=CC=CC=1.[O:7]([Si:15]([CH3:18])([CH3:17])[CH3:16])S(C(F)(F)F)(=O)=O.[CH2:19]([C:21]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47][C:48]2(O)[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[C:42]([CH3:55])[CH:41]=1)([C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:34][C:33]([CH3:36])([CH3:35])[C:32]([CH3:38])([CH3:37])[O:31]2)=[C:26]([CH3:39])[CH:25]=1)[CH2:22][CH3:23])[CH3:20].C(=O)(O)[O-].[Na+]>ClCCl>[CH2:19]([C:21]([C:40]1[CH:45]=[CH:44][C:43]([C:46]#[C:47][C:48]2([O:7][Si:15]([CH3:18])([CH3:17])[CH3:16])[CH2:53][CH2:52][O:51][CH2:50][CH2:49]2)=[C:42]([CH3:55])[CH:41]=1)([C:24]1[CH:29]=[CH:28][C:27]([B:30]2[O:31][C:32]([CH3:37])([CH3:38])[C:33]([CH3:35])([CH3:36])[O:34]2)=[C:26]([CH3:39])[CH:25]=1)[CH2:22][CH3:23])[CH3:20]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCC(CC)(c1ccc(C#CC2(O[Si](C)(C)C)CCOCC2)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Reaction time: 0.5 h
Yield: 87.1 %

Procedure:
Pyridine (0.353 mL, 4.380 mmol) and trimethylsilyl triflate (0.396 mL, 2.189 mmol) were added to a solution of 4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenylethynyl)-tetrahydro-pyran-4-ol (Example 130-(3); 0.55 g, 1.095 mmol) in dichloromethane (10 mL) at 0° C., and the mixture was stirred for 30 minutes. The reaction mixture was then poured into a saturated aqueous sodium bicarbonate solution, followed by extraction with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=100:0 to 50:50) to give the target compound as a colorless oil (548 mg, 87%).
Reaction SMILES: [CH:1]1([OH:10])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.CN(C)CCN(C)C.[Li]CCCC.[Br:24]C(F)(F)C(F)(F)Br.C(OC(=O)C)(=O)C.[OH-].[K+]>O.CN(C)C1C=CN=CC=1.C(N(CC)CC)C.CCCCC>[Br:24][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:1]([OH:10])[CH2:2][CH2:3]2
Reactant: OC1CCc2ccccc21
Reactant: FC(F)(Br)C(F)(F)Br
Agent: CN(C)CCN(C)C
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: O
Solvent: CCCCC
Solvent: CCN(CC)CC
Product: OC1CCc2cccc(Br)c21
Temperature: -20 °C
Reaction time: 12 h

Procedure:
To a mixture of 100 g (746 mmol) of indan-1-ol, 250 ml (1.64 mol) of N,N,N′,N′-tetramethylethylenediamine, and 3000 ml of pentane cooled to −20° C. 655 ml (1.64 mol) of 2.5M nBuLi in hexanes was added. After that the reaction mixture was refluxed for 12 h and then cooled to −80° C. Further on, 225 ml (1.87 mol) of 1,2-dibromotetrafluoroethane was added, and the resulting mixture was allowed to warm to room temperature. This mixture was stirred for 12 h, and then 100 ml of water was added. The resulting mixture was diluted with 2000 ml of water, and the organic layer was separated. The aqueous layer was extracted with 3×400 ml of toluene. The combined organic extract was dried over Na2SO4 and evaporated to dryness. The residue was distilled using a Kugelrohr apparatus, b.p. 120-140° C./1 mbar. The resulting yellow oil was dissolved in 50 ml of triethylamine, and the obtained solution added dropwise to a stirred solution of 49.0 ml (519 mmol) of acetic anhydride and 4.21 g (34.5 mmol) of 4-(dimethylamino)pyridine in 70 ml of triethylamine. The resulting mixture was stirred for 5 min, then 1000 ml of water was added, and stirring was continued for 12 h. After that the reaction mixture was extracted with 3×200 ml of ethyl acetate. The combined organic extract was washed with aqueous Na2CO3, dried over Na2SO4, and evaporated to dryness. The residue was purified by flash chromatography on silica gel 60 (40-63 um, eluent: hexane-ethyl acetate=30:1, vol.). The resulting ester was dissolved in 1000 ml of methanol, 50.5 g (900 mmol) of KOH was added, and this mixture was refluxed for 3 h. The reaction mixture was then cooled to room temperature and poured into 4000 ml of water. Crude product was extracted with 3×300 ml of dichloromethane. The combined organic extract was dried over Na2SO4 and evaporated to dryness. Yield 41.3 g (26%) of a white crystalline solid. Anal. Calc for C9H9BrO: C, 50.73; H, 4.26. Found: C, 50.85; H, 4.48. 1H NMR (CDCl3): δ 7.34 (d, J=7.6 Hz, 1H, 6-H); 7.19 (d, J=7.4 Hz, 1H, 4-H); 7.12 (dd, J=7.6 Hz, J=7.4 Hz, 1H, 5-H); 5.33 (dd, J=2.6 Hz, J=6.9 Hz, 1H, 1-H), 3.18-3.26 (m, 1H, 3- or 3′-H), 3.09 (m, 2H, 3,3′-H); 2.73 (m, 2H, 2,2′-H).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([CH3:20])[NH:18][OH:19].[C:21](Cl)(=[O:23])[CH3:22].C(N(CC)CC)C.[OH-].[Li+]>>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[CH:17]([N:18]([OH:19])[C:21](=[O:23])[CH3:22])[CH3:20]
Reactant: CC(=O)Cl
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(C)NO)c1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCN(CC)CC
Product: CC(=O)N(O)C(C)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Yield: 44.7 %

Procedure:
2-[(2,6-Dichloro-3-methylphenyl)amino]-N-hydroxy-α-methylbenzenemethanamine (1.2 g, 3.8 mmol) is reacted with acetyl chloride (0.66 g, 8.5 mmol), triethylamine (1.2 g, 11.6 mmol), and lithium hydroxide (0.46 g, 19.3 mmol) according to the procedure of Example 48 to give N-[1-[2-[(2,6-dichloro-3-methylphenyl)amino]phenyl]ethyl]-N-hydroxyacetamide (0.6 g, 45% yield); mp 185°-187° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@@H:17]4[CH2:22][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH:34]7[CH2:39][CH2:38][N:37]([C:40](OC(C)(C)C)=O)[CH2:36][CH2:35]7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:20][CH2:19][O:18]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1.[OH-].[Na+]>C=O.C(O)=O>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[N:12]=[C:11]3[N:13]([CH2:16][C@H:17]4[O:18][CH2:19][CH2:20][N:21]([C:23]5[N:28]=[CH:27][C:26]([C:29]6[CH:30]=[N:31][N:32]([CH:34]7[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]7)[CH:33]=6)=[CH:25][N:24]=5)[CH2:22]4)[N:14]=[N:15][C:10]3=[N:9][CH:8]=2)[CH:4]=[N:3]1
Reactant: Cn1cc(-c2cnc3nnn(C[C@@H]4CN(c5ncc(-c6cnn(C7CCN(C(=O)OC(C)(C)C)CC7)c6)cn5)CCO4)c3n2)cn1
Agent: C=O
Agent: [Na+]
Agent: [OH-]
Solvent: O=CO
Product: CN1CCC(n2cc(-c3cnc(N4CCO[C@H](Cn5nnc6ncc(-c7cnn(C)c7)nc65)C4)nc3)cn2)CC1
Temperature: 90 °C
Reaction time: 18 h
Yield: 33.8 %

Procedure:
(S)-tert-butyl 4-(4-(2-(2-((6-(1-methyl-1H-pyrazol-4-yl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-1-yl)methyl)morpholino)pyrimidin-5-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate 550 mg (0.88 mmol) was dissolved in 35% formaldehyde 0.5 ml and formic acid 2.5 ml, and charged with nitrogen, followed by stirring at 90° C. for 18 hours. After the completion of the reaction, the reaction mixture was cooled in an ice bath, and then adjusted to about pH 10 with a NaOH solution, followed by extraction with EA and brine, and the organic layer was dried over MgSO4. Column chromatography (methylene chloride:methanol=10:1) gave a product 161 mg (34%).
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH:5]([O:7][C:8]2[CH:13]=[CH:12][C:11]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:24])=[CH:22][C:17]=4[N:16]=[CH:15]3)=[CH:10][CH:9]=2)[CH2:4]1.[H-].[Na+].F[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][N:37]=1>CN(C=O)C>[N:37]1[CH:38]=[CH:39][CH:40]=[CH:41][C:36]=1[O:1][CH2:2][CH:3]1[CH2:4][CH:5]([O:7][C:8]2[CH:9]=[CH:10][C:11]([N:14]3[C:18]4[CH:19]=[CH:20][C:21]([C:23]([NH:25][CH2:26][C:27]5[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=5)=[O:24])=[CH:22][C:17]=4[N:16]=[CH:15]3)=[CH:12][CH:13]=2)[CH2:6]1
Reactant: Fc1ccccn1
Reactant: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OC2CC(CO)C2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(NCc1cccnc1)c1ccc2c(c1)ncn2-c1ccc(OC2CC(COc3ccccn3)C2)cc1
Temperature: 60 °C

Procedure:
1-(4-{[3-(Hydroxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide (33 mg, 0.08 mmol) was dissolved in DMF and put under N2 atmosphere. Sodium hydride (2 mg, 0.08 mmol) was added and the reaction was heated to 60° C. 2-Fluoropyridine was then added and the reaction was then heated to 80° C. for 14 h. The reaction was cooled to rt and concentrated in vacuo. The crude solid was purified using the Waters mass-directed HPLC purification system to provide 1-(4-{[3-(2-pyridyloxymethyl)cyclobutyl]oxy}phenyl)-N-pyridin-3-ylmethyl-1H-benzimidazole-5-carboxamide as an off-white solid. MS (ES+): m/z 507 (10) [MH+].
Reaction SMILES: [C:1]1([CH2:9][NH2:10])[CH:6]=[CH:5][C:4]([CH2:7][NH2:8])=[CH:3][CH:2]=1.NCC1(CN)CCCCC1>>[C:9](#[N:10])[C:1]1[CH:6]=[CH:5][C:4]([C:7]#[N:8])=[CH:3][CH:2]=1
Reactant: NCc1ccc(CN)cc1
Agent: NCC1(CN)CCCCC1
Product: N#Cc1ccc(C#N)cc1
Reaction time: 5 h

Procedure:
5.1 g of terephthalonitrile, 1.0 g of catalyst (Ni 5136P from Harshaw/Filtrol--contains 65% nickel on a silica-alumina support), and about 85 g of ethanol/ammonia (contains about 10 wt % ammonia) were charged to a 300 cc stainless steel pressure reactor. After a nitrogen purge, the vessel was charged to a pressure of 500 to 1000 psi with hydrogen. The temperature was then increased until the reaction temperature of 150° C. had been obtained (typically 20-30 min). After the desired reaction interval, the contents were cooled and sampled. Product analysis and conversion were determined by gas chromatography. Yields of para-xylylenediamine varied between 63-81% depending on hydrogen pressure and reaction time which is preferrably from 2 to 8 hours. The remainder of the product was saturated para-xylylenediamine (1.4 bis (aminomethyl) cyclohexane. Table IV sets forth specific examples of reactions run to obtain the diamines from hydrogenation of terephthalonitrile.