Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][N:2]1[CH2:6][CH2:5][O:4][C:3]1=[O:7].[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26]([C:29](=O)[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1>>[F:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[CH2:19][C:20]1[N:24]2[N:25]=[C:26](/[C:29](=[N:1]/[N:2]3[CH2:6][CH2:5][O:4][C:3]3=[O:7])/[CH3:30])[CH:27]=[CH:28][C:23]2=[N:22][CH:21]=1
Reactant: NN1CCOC1=O
Reactant: CC(=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Product: C/C(=N\N1CCOC1=O)c1ccc2ncc(Cc3cc4cccnc4cc3F)n2n1
Yield: 24 %

Procedure:
The title compound was prepared from 3-aminooxazolidin-2-one and 1-[3-(7-fluoro-quinolin-6-ylmethyl)-imidazo[1,2-b]pyridazin-6-yl]-ethanone in analogy to the synthesis of example 1 in 24% yield. 1H-NMR (400 MHz, CDCl3) δ ppm 8.85 (dd, 1H), 8.02 (d, 1H), 7.88 (m, 2H), 7.71 (m, 3H), 7.33 (q, 1H), 4.58 (s, 2H), 4.51 (t, 2H), 4.01 (t, 2H), 2.49 (s, 3H). LCMS (method A): [MH]+=405, tR=4.76 min.
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@H:11]([OH:26])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38](O)=[O:39].O.OC1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[Cl:34][C:35]1[CH:36]=[C:37]([CH:41]=[C:42]([Cl:44])[CH:43]=1)[C:38]([NH:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:27][C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C@H:11]([OH:26])[CH2:12][C@@H:13]1[CH2:18][CH2:17][CH2:16][CH2:15][C@H:14]1[C:19]([NH:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[O:8])[CH2:3][C:4](=[O:6])[NH2:5])=[O:39]
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1
Reactant: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)NC(=O)[C@@H]1CCCC[C@H]1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 44.9 %

Procedure:
A mixture of 60 mg (0.13 mmol) of 2(S)-[3(S)-[[L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide, 25 mg (0.13 mmol) of 3,5-dichlorobenzoic acid, 18 mg (0.13 mmol) of hydroxybenzotriazole hydrate and 27 mg (0.13 mmol) of dicyclohexylcarbodiimide in 2 ml of dimethylformamide was stirred at room temperature under nitrogen for 20 hours. The mixture was then filtered and the solid was washed with dichloromethane. The combined filtrate and washings were evaporated to dryness and the residue was partitioned between 50 ml of ethyl acetate and 10 ml of saturated aqueous sodium hydrogen carbonate solution. The separated organic phase was dried over anhydrous magnesium sulphate and evaporated. The residue was chromatographed on silica gel using 5% methanol in dichloromethane for the elution. The product was purified further by recrystallization from a mixture of 2 ml of dichloromethane and 10 ml of n-hexane to give 37 mg of 2(S)-[3(S)-[[N-(3,5-dichlorobenzoyl)-L-asparaginyl]amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-1(R)-cyclohexanecarboxamide as a white solid of melting point 220°-226° C.
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=2)=[CH:4][CH:3]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>C(O)CCC.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>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:2]2[CH:17]=[CH:16][C:5]([O:6][C:7]3[C:13]([CH3:14])=[CH:12][C:10]([NH2:11])=[C:9]([CH3:15])[CH:8]=3)=[CH:4][CH:3]=2)=[CH:22][CH:21]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: Cc1cc(Oc2ccc(Br)cc2)c(C)cc1N
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CCCCO
Product: COc1ccc(-c2ccc(Oc3cc(C)c(N)cc3C)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 79.7 %

Procedure:
Under argon, 0.50 g (1.7 mmol) of 4-(4-bromophenoxy)-2,5-dimethylaniline and 0.34 g (2.2 mmol) of 4-methoxyphenylboronic acid are dissolved in 10 ml of 1-butanol and the solution is admixed with 2.23 g (6.8 mmol) of cesium carbonate, 39.5 mg (0.03 mmol) of tetrakis(triphenylphosphine)palladium(0) and 2.5 ml of water. The reaction mixture is stirred at 80° C. for 16 h, poured into water and extracted repeatedly with ethyl acetate. The combined organic phases are dried over Na2SO4 and filtered and the solvent is removed under reduced pressure. This is followed by purification by column chromatography (0.44 g, purity 99.0%, yield 79.7%, log P (pH 2.3)=3.06).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH:26]2OCCO2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16].[O:31]1[CH2:35][C:34](=[O:36])[NH:33][C:32]1=[O:37]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:23][CH2:24][CH2:25][CH2:26][CH:35]2[O:31][C:32](=[O:37])[NH:33][C:34]2=[O:36])[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][C:11]1[N:12]=[C:13]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[O:14][C:15]=1[CH3:16]
Reactant: COc1cc(CCCC2OCCO2)ccc1OCc1nc(-c2ccccc2)oc1C
Reactant: O=C1COC(=O)N1
Product: COc1cc(CCCCC2OC(=O)NC2=O)ccc1OCc1nc(-c2ccccc2)oc1C

Procedure:
In substantially the same manner as in Working Example 18, 2-[3-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]propyl]-1,3-dioxolan was condensed with 2,4-oxazolidinedione. The condensate was subjected to catalytic hydrogenation to yield 5-[4-[3-methoxy-4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]butyl]-2,4-oxazolidinedione, which was recrystallized from dichloromethane-isopropyl ether to give colorless prisms, m.p.135-136° C.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5](=[O:52])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:44]=[CH:43][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)=[CH:41][CH:40]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][NH:26]1)=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1.[CH3:53][C:54]1[O:55][C:56]([CH3:62])=[C:57]([C:59](O)=[O:60])[N:58]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:3][O:4][C:5](=[O:52])[C@@H:6]([NH:22][C:23]([C@@H:25]1[CH2:34][C:33]2[CH:32]=[C:31]3[O:35][CH2:36][C@H:37]([C:39]4[CH:40]=[CH:41][C:42]([C:45]5[CH:50]=[CH:49][CH:48]=[C:47]([Cl:51])[CH:46]=5)=[CH:43][CH:44]=4)[O:38][C:30]3=[CH:29][C:28]=2[CH2:27][N:26]1[C:59]([C:57]1[N:58]=[C:54]([CH3:53])[O:55][C:56]=1[CH3:62])=[O:60])=[O:24])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]([CH3:20])[C:15]=2[CH3:21])=[CH:10][CH:9]=1
Reactant: Cc1nc(C(=O)O)c(C)o1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)c1nc(C)oc1C)O[C@@H](c1ccc(-c2cccc(Cl)c2)cc1)CO3
Temperature: 25 °C
Reaction time: 2 h
Yield: 52.2 %

Procedure:
(S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (0.025 g), 2,5-dimethyl-oxazole-4-carboxylic acid (0.010 g), HBTU (0.027 g) in DCM (3.0 mL), DIEA (0.019 g) was added. The reaction mixture was stirred at room temperature for 2.0 hours, poured onto a silica gel column and eluted with 1% MeOH, 1:1 hexanes-EtOAc to provide (S)-2-{[(3S,8S)-3-(3′-Chloro-biphenyl-4-yl)-7-(2,5-dimethyl-oxazole-4-carbonyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester (0.0139 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N+:14]([C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20])([O-:16])=[O:15]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:19](=[O:20])[C:18]2[CH:22]=[CH:23][CH:24]=[CH:25][C:17]=2[N+:14]([O-:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 79.5 %

Procedure:
To a mixture of 1-(tert-butoxycarbonyl)piperazine (11.18 g, 60 mmol) in CH2Cl2 (120 mL) at 0° C. was added 2-nitrobenzoyl chloride (8.0 mL, 60.6 mmol). The reaction was warmed to room temperature and stirred for 2 hours. A solution of 50% satd Na2 CO3 was added and the mixture was extracted with CH2Cl2. The organic layer was washed with satd citric acid and water, dried over MgSO4, and concentrated to a slurry. Ether was added to the mixture and it was filtered to give the desired product as a white solid (16.0 g, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:20][CH2:19][C:18]5([C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:23][O:22][CH2:21]5)[CH2:17][CH2:16]4)=[N:13][N:14]=[C:10]3[CH2:9][NH:8][CH2:7][C:6]=2[CH:30]=1.C=O.[C:33]([BH3-])#N.[Na+]>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12]([N:15]4[CH2:16][CH2:17][C:18]5([C:29]6[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=6)[CH2:23][O:22][CH2:21]5)[CH2:19][CH2:20]4)=[N:13][N:14]=[C:10]3[CH2:9][N:8]([CH3:33])[CH2:7][C:6]=2[CH:30]=1
Reactant: Clc1ccc2c(c1)CNCc1nnc(N3CCC4(CC3)COCc3ccccc34)n1-2
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN1Cc2cc(Cl)ccc2-n2c(nnc2N2CCC3(CC2)COCc2ccccc23)C1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of the crude 1′-(8-chloro-5,6-dihydro-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)-1H-spiro[isochromene-4,4′-piperidine] (0.10 g, 0.24 mmol) and paraformaldehyde (0.057 g, 1.9 mmol) in methanol (2 ml) was heated at reflux for 4 h. After cooling to room temperature sodium cyanoborohydride (0.03 g, 0.47 mmol) was added at 0° C. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. Quenching with 1 M aqueous sodium hydroxide solution (30 ml) was followed by extraction with ethyl acetate.
Reaction SMILES: [C:1]([O:4][CH:5]=[CH:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2].[CH2:12]=[CH:13][CH:14]=[CH2:15]>C1(C)C=CC=CC=1>[C:1]([O:4][C@@H:5]1[CH2:15][CH:14]=[CH:13][CH2:12][C@H:6]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])(=[O:3])[CH3:2]
Reactant: C=CC=C
Reactant: CCOC(=O)C=COC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)[C@@H]1CC=CC[C@H]1OC(C)=O
Temperature: 170 °C

Procedure:
Ethyl 3-acetoxyacrylate (1, 11.0 g, 69.6 mmol) and butadiene (30.0 ml, 0.8 mol) were dissolved in toluene (distilled from calcium hydride, 25 ml); the mixture was placed in a 500 ml autoclave at -78° C. The autoclave was sealed, and then heated for 15 hours at 170° C. The autoclave was cooled and opened, the contents centrifuged, and the gummy residue extracted with toluene (3×100 ml). The toluene was removed under vacuum, and the mixture of cis and trans 1-acetoxy-2-carboethoxycyclohex-4-ene (3 and 2) was isolated by distillation (101° C. at 2 torr).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:21])([CH3:20])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1)(=O)=O.[SH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=1>>[N:26]1[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=1[S:24][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:23]=[CH:22][C:14]2[C:15]([CH3:20])([CH3:21])[O:16][C:17](=[O:19])[NH:18][C:13]=2[CH:12]=1
Reactant: Sc1ccccn1
Reactant: CC1(C)OC(=O)Nc2cc(OCCCCOS(C)(=O)=O)ccc21
Product: CC1(C)OC(=O)Nc2cc(OCCCCSc3ccccn3)ccc21

Procedure:
Prepared analogously to Example 210 from 7-(4-methanesulfonyloxy-butoxy)-4,4-dimethyl-4H-3,1-benzoxazin-2-one and 2-mercapto-pyridine.
Reaction SMILES: C(O[C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1)C1C=CC=CC=1.[Br:21]C1C=CC(/C=C/[N+]([O-])=O)=CC=1>>[Br:21][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]2[CH2:17][C@H:16]2[N+:18]([O-:20])=[O:19])=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(OCc2ccccc2)cc1
Reactant: O=[N+]([O-])/C=C/c1ccc(Br)cc1
Product: O=[N+]([O-])[C@@H]1C[C@H]1c1ccc(Br)cc1
Yield: 27 %

Procedure:
This compound was synthesized using the same methodology described in Intermediate C, using the commercially available 1-bromo-4-[(trans)-2-nitrovinyl]benzene as starting material. 27% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:16]=[CH:15][C:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cc2ccccn2)cc1
Agent: [Pd]
Solvent: CCO
Product: Nc1ccc(Cc2ccccn2)cc1
Reaction time: 8 h
Yield: 84.5 %

Procedure:
A mixture of 2-(4-nitrobenzyl)pyridine (J. Chem. Soc., p549, 1929) (1.50 g) and 5% Pd-C (0.15 g) in ethanol (30 ml) was vigorously stirred under hydrogen atmosphere for 8 hours, and the Pd-C was filtered off. The filtrate was concentrated under reduced pressure, and the residue was separated and purified with column chromatography (ethyl acetate/hexane=1:1→2:1) to give 2-(4-aminobenzyl)-pyridine (1.09 g) as yellow oil.
Reaction SMILES: Cl.[OH:2][C@H:3]1[CH2:7][NH:6][C@H:5]([C:8]([O:10][CH3:11])=[O:9])[CH2:4]1.[C:12](#[N:15])[CH:13]=[CH2:14].[OH-].[K+]>O>[C:12]([CH2:13][CH2:14][N:6]1[CH2:7][C@H:3]([OH:2])[CH2:4][C@H:5]1[C:8]([O:10][CH3:11])=[O:9])#[N:15]
Reactant: COC(=O)[C@@H]1C[C@@H](O)CN1
Reactant: C=CC#N
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](O)CN1CCC#N
Temperature: 50 °C
Yield: 46.4 %

Procedure:
To a solution of methyl (4R)-4-hydroxy-L-prolinate hydrochloride (4.53 g, 25 mmol) in water (10 mL) was added acrylonitrile (6.63 g, 125 mmol). The mixture was stirred while heating at 50° C., and a solution of potassium hydroxide (1.403 g, 25 mmol) in water (15 mL) was added dropwise. The resulting mixture was heated to 70° C. and stirred for two hours. The cooled mixture was extracted with diethyl ether (4×25 mL). The combined ether extracts were dried with MgSO4, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel using a solvent gradient of 2-5% methanol in dichloromethane to obtain desired the title compound as colorless oil (2.3 g, 46%). 1H NMR (400 MHz, DMSO-d6) δ ppm 4.95-4.87 (m, 1H), 4.26-4.17 (m, 1H), 3.62 (s, 3H), 3.50 (t, J=7.6, 1H), 3.27-3.15 (m, 1H), 2.98-2.87 (m, 1H), 2.76-2.66 (m, 1H), 2.67-2.56 (m, 2H), 2.41-2.33 (m, 1H), 1.99 (ddd, J=12.8, 7.4, 6.4, 1H), 1.93-1.83 (m, 1H); MS (ESI) m/z 199 (M+H)+.
Reaction SMILES: [NH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)[NH2:2].C1(N=[C:20]=[O:21])C=CC=CC=1>C1(OC2C=CC=CC=2)C=CC=CC=1>[C:20]1([OH:21])[N:4]2[C:5]3[C:10]([CH:11]=[CH:12][C:3]2=[N:1][N:2]=1)=[CH:9][CH:8]=[CH:7][CH:6]=3
Reactant: NNc1ccc2ccccc2n1
Reactant: O=C=Nc1ccccc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: Oc1nnc2ccc3ccccc3n12
Reaction time: 8 h

Procedure:
2-Hydrazinoquinoline (15.9 grams; 0.1 mole) was placed in a 250-milliliter three-necked flask equipped with a condenser, along with 70 milliliters of diphenyl ether. To the flask was then added 11.9 grams (0.1 mole) of phenyl isocyanate. The reaction mixture was allowed to reflux for three hours, cooled, and allowed to stand at room temperature overnight. In the morning the precipitate, the desired s-triazolo(4,3-a)quinolin-1-ol product, was filtered off and recrystallized from water. The product so obtained melted at 133.5°-4.5°C.
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:6]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[Cl:17])=[N:7][O:8][C:9]=1[CH3:10])=[O:4].[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([CH:27]=O)=[CH:26][C:21]=2[O:20][CH2:19]1>>[O:18]1[C:22]2[CH:23]=[CH:24][C:25]([C:27]3[N:2]([CH3:1])[C:3](=[O:4])[C:5]4[C:6]([C:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=5[Cl:17])=[N:7][O:8][C:9]=4[CH:10]=3)=[CH:26][C:21]=2[O:20][CH2:19]1
Reactant: O=Cc1ccc2c(c1)OCO2
Reactant: CNC(=O)c1c(-c2ccccc2Cl)noc1C
Product: Cn1c(-c2ccc3c(c2)OCO3)cc2onc(-c3ccccc3Cl)c2c1=O

Procedure:
This compound is obtained using 3-(2-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid methylamide and benzo[1,3]dioxole-5-carbaldehyde in 35% as a beige solid. Mass spectrum: m/z (M+H)+: 380.9, 382.9
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C:10]([CH3:15])([CH3:14])[C@H:9]1[C:16]([O:18]CC1C=CC=CC=1)=[O:17])C1C=CC=CC=1>[Pd]>[CH3:14][C:10]1([CH3:15])[O:11][CH2:12][CH2:13][NH:8][C@@H:9]1[C:16]([OH:18])=[O:17]
Reactant: CC1(C)OCCN(Cc2ccccc2)[C@@H]1C(=O)OCc1ccccc1
Agent: [Pd]
Product: CC1(C)OCCN[C@@H]1C(=O)O
Yield: 69.3 %

Procedure:
(S)-benzyl 4-benzyl-2,2-dimethylmorpholine-3-carboxylate (10.4 g, 30.8 mmol) was reacted with H2 by Pd/C catalysis (10%, 1 g) according to the procedure as described in Example 34, Step C to give the title compound as a white solid (3.4 g, 70%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH2:24][CH2:25]OS(C)(=O)=O)[C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2].[NH:34]1[CH2:39][CH2:38][O:37][CH2:36][CH2:35]1>CO.[Na]>[CH2:1]([N:3]1[C:7]2[CH:8]=[CH:9][C:10]([C:12]3[CH:13]=[N:14][N:15]([CH2:24][CH2:25][N:34]4[CH2:39][CH2:38][O:37][CH2:36][CH2:35]4)[C:16]=3[C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[CH:11][C:6]=2[N:5]([CH2:31][CH3:32])[C:4]1=[O:33])[CH3:2]
Reactant: C1COCCN1
Reactant: CCn1c(=O)n(CC)c2cc(-c3cnn(CCOS(C)(=O)=O)c3-c3cccc(C)c3)ccc21
Agent: [Na]
Solvent: CO
Product: CCn1c(=O)n(CC)c2cc(-c3cnn(CCN4CCOCC4)c3-c3cccc(C)c3)ccc21
Temperature: 65 °C
Reaction time: 20 h

Procedure:
[4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-acetic acid ethyl ester is prepared according to the procedures outlined in Example 334. [4-(1,3-Diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-acetic acid ethyl ester (388 mg) is diluted with tetrahydrofuran (3 mL) and methanol (4 mL). Lithium borohydride (39 mg) is added and the mixture is stirred at 23° C. for 20 hours. The reaction mixture is diluted with saturated ammonium chloride and extracted with ethyl acetate. The organic layer is dried with sodium sulfate and concentrated. Chromatography on silica gel gave 3-Diethyl-5-[1-(2-hydroxy-ethyl)-5-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one. 3-Diethyl-5-[-(2-hydroxy-ethyl)-5-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one (86.5 mg) is diluted with pyridine, (1 mL) cooled to 0° C., and treated with methanesulfonyl chloride (0.02 mL). The reaction mixture is allowed to stir for 20 hours then is treated with water and extracted with dichloromethane. The organic layer is dried with sodium sulfate and concentrated to give Methanesulfonic acid 2-[4-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-ethyl ester. Methanesulfonic acid 2-[4-(1,3-diethyl-2-oxo-2,3-dihydro-1H-benzoimidazol-5-yl)-5-m-tolyl-pyrazol-1-yl]-ethyl ester (104 mg) is diluted with morpholine (0.15 mL) and methanol (0.9 mL). The reaction is heated to 65° C. for 5 hours then allowed to stand at 23° C. for 20 hours. The reaction mixture is diluted with saturated sodium bacarbonate and extracted with ethyl acetate. Chromatography on silica gel gave 1,3-Diethyl-5-[1-(2-morpholin-4-yl-ethyl)-5-m-tolyl-1H-pyrazol-4-yl]-1,3-dihydro-benzoimidazol-2-one.
Reaction SMILES: [ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH2:12])[CH2:3]1)[CH2:9]2.[O:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22](O)=[O:23].N>>[ClH:1].[N:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([C@H:5]3[NH:12][C:22]([C:14]3[O:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:23])[CH2:3]1)[CH2:9]2
Reactant: NC1C2CC3CC1CN(C3)C2
Reactant: O=C(O)c1cc2ccccc2o1
Agent: Cl
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cc2ccccc2o1

Procedure:
Prepared from (4r)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine hydrochloride and benzofuran-2-carboxylic acid according to methods A and C. 1H NMR (300 MHz, methanol-d4) δ ppm 2.08-2.34 (m, 5H), 2.51 (s, 2H), 3.42-3.64 (m, 4H), 3.88 (d, J=12.5 Hz, 2H), 4.33 (s, 1H), 7.29-7.38 (m, 1H), 7.44-7.52 (m, 1H), 7.57 (s, 1H), 7.61 (d, J=7.4 Hz, 1H), 7.74 (d, J=7.8 Hz, 1H). MS (DCI/NH3) m/z 297. Anal. Calculated for C18H20N2O2HCl: C, 64.96; H, 6.36; N, 8.42. Found: C, 64.51; H, 6.23; N, 8.14.
Reaction SMILES: Br[C:2]1[C:7]([Cl:8])=[CH:6][N:5]=[C:4]2[NH:9][CH:10]=[CH:11][C:3]=12.[CH:12]1([NH2:17])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[Cl:8][C:7]1[CH:6]=[N:5][C:4]2[NH:9][CH:10]=[CH:11][C:3]=2[C:2]=1[NH:17][CH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Clc1cnc2[nH]ccc2c1Br
Reactant: NC1CCCC1
Product: Clc1cnc2[nH]ccc2c1NC1CCCC1
Temperature: 110 °C

Procedure:
To 4-bromo-5-chloro-1H-pyrrolo[2,3-b]pyridine (D) was added cyclopentylamine (0.5 mL) in a sealed tube. The mixture was heated to 110° C. for 24-48 h. The mixture was concentrated. Preparative HPLC provided 5-chloro-N-cyclopentyl-1H-pyrrolo[2,3-b]pyridin-4-amine (127)(7.4 mg) as the TFA salt.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1.[CH3:27][C:28]1[N:29]=[CH:30][S:31][C:32]=1[CH2:33][CH2:34]O>>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:5]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:34][CH2:33][C:32]3[S:31][CH:30]=[N:29][C:28]=3[CH3:27])=[O:22])=[CH:16][C:15]=2[O:24][CH3:25])=[C:4]([CH3:26])[N:3]=1
Reactant: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)O)cc1OC
Reactant: Cc1ncsc1CCO
Product: CCCCNc1nc(N)nc(C)c1Cc1ccc(CC(=O)OCCc2scnc2C)cc1OC

Procedure:
The title compound was prepared using the method of example 89 step (vii), using the product of example 89 step (vi) (150 mg) and 2-(4-methylthiazol-5-yl)ethanol (60 mg) to give the title compound as a gum, 10 mg.
Reaction SMILES: O.[CH3:2][N:3]([CH3:13])[C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][N:5]=1.Br[C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:2][N:3]([CH3:13])[C:4]1[N:5]=[CH:6][C:7]([C:15]2[CH:16]=[C:17]([NH2:18])[CH:19]=[CH:20][CH:21]=2)=[CH:8][CH:9]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: Nc1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CN(C)c1ccc(-c2cccc(N)c2)cn1
Temperature: 25 °C
Yield: 54 %

Procedure:
2-(dimethylamino)-pyridine-5-boronic acid hydrate (0.145 g, 0.872 mmol) and 3-bromoaniline (0.063 mL, 0.581 mmol) were combined in DME (3 mL) in a flame-dried, round-bottom flask. Na2CO3 (2M, 0.610 mL, 1.22 mmol) and Pd(PPh3)4 (0.02 g, 0.017 mmol) were added to the stirred solution. The reaction was refluxed overnight under argon flow, and subsequently cooled to room temperature. The solvent was removed under vacuum and the resulting residue was resuspended in CH2Cl2. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The crude product was purified by flash silica column chromatography (10-100% EtOAc/hexanes). The purification was monitored by TLC. The solvent was removed under vacuum from fractions containing product, resulting in 0.067 g in 54% yield.