Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:10])[CH2:4][C@@H:5]([CH3:9])[C:6](O)=[O:7].CN(C=O)C.C(Cl)(=O)C(Cl)=O.[CH3:22][N:23]1[CH:27]=[CH:26][C:25]([NH2:28])=[N:24]1>C1COCC1.C(N(CC)CC)C>[CH3:9][C@@H:5]([C:6]([NH:28][C:25]1[CH:26]=[CH:27][N:23]([CH3:22])[N:24]=1)=[O:7])[CH2:4][C:3]([O:2][CH3:1])=[O:10]
Reactant: Cn1ccc(N)n1
Reactant: COC(=O)C[C@@H](C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C[C@@H](C)C(=O)Nc1ccn(C)n1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2R)-4-methoxy-2-methyl-4-oxobutanoic acid (0.30 mL) and DMF (20 μL) in THF (5.0 mL) was added oxalyl chloride (0.25 mL). The reaction mixture was stirred at room temperature for 3 hr, and 1-methyl-1H-pyrazol-3-amine (200 mg) and triethylamine (0.62 mL) were added thereto. The reaction mixture was stirred at room temperature for 15 hr, and extracted with ethyl acetate. The extract was washed with saturated aqueous ammonium chloride solution and saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (345 mg).
Reaction SMILES: C(OC([C:8]([CH2:10][O:11][NH:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:38]=[CH:37][C:36]4[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=4)[N:30]=3)[CH2:24][CH2:23]2)[CH:15]=1)=[O:9])=O)(C)(C)C.FC(F)(F)C(O)=O.Cl>C(Cl)(Cl)Cl>[N:30]1[C:31]2[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:37]=[CH:38][C:29]=1[CH2:28][N:25]1[CH2:26][CH2:27][N:22]([C:16]2[CH:15]=[C:14]([CH:19]=[CH:18][C:17]=2[O:20][CH3:21])[CH2:13][NH:12][O:11][CH:10]=[C:8]=[O:9])[CH2:23][CH2:24]1
Reactant: COc1ccc(CNOCC(=O)C(=O)OC(C)(C)C)cc1N1CCN(Cc2ccc3ccccc3n2)CC1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(CNOC=C=O)cc1N1CCN(Cc2ccc3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 81.3 %

Procedure:
A mixture comprising 1.3 g of t-butyloxycarbonyl-3-[4-(2-quinolylmethyl)-piperazin-1-yl]-carbonylmethoxy-4-methoxybenzylamine, 14 ml of chloroform and 2.8 g of trifluoroacetic acid, was stirred at room temperature for one day. To the reaction solution, 50 ml of chloroform and 50 ml of 0.5N hydrochloric acid were added, and the mixture was reversely extracted. The aqueous layer was adjusted to pH 12 with an aqueous sodium hydroxide solution and extracted with chloroform. The organic layer was washed with an aqueous potassium carbonate solution and then dried over anhydrous sodium sulfate. Then, the solvent was distilled off under reduced pressure to obtain 850 mg of the above-identified compound as oily substance.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][C@H:27]1[CH2:36][C@@H:35]2[N:30]([C:31](=[O:52])/[C:32](=[CH:37]/[C:38]3[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=3)/[CH2:33][CH2:34]2)[C@H:29]([C:53]2[CH:58]=[C:57]([F:59])[C:56]([F:60])=[C:55]([F:61])[CH:54]=2)[CH2:28]1)(C(C)(C)C)(C)C.[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1>[F:59][C:57]1[CH:58]=[C:53]([C@@H:29]2[CH2:28][C@@H:27]([OH:26])[CH2:36][C@@H:35]3[N:30]2[C:31](=[O:52])/[C:32](=[CH:37]/[C:38]2[CH:43]=[CH:42][C:41]([N:44]4[CH:48]=[C:47]([CH3:49])[N:46]=[CH:45]4)=[C:40]([O:50][CH3:51])[CH:39]=2)/[CH2:33][CH2:34]3)[CH:54]=[C:55]([F:61])[C:56]=1[F:60]
Reactant: COc1cc(/C=C2\CC[C@@H]3C[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COc1cc(/C=C2\CC[C@@H]3C[C@H](O)C[C@@H](c4cc(F)c(F)c(F)c4)N3C2=O)ccc1-n1cnc(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
TBAF (1.0 M solution in THF, 144 μL) was added to a solution of (E)-(6S*,8S*,9aR*)-8-(tert-butyldimethylsilanyloxy)-6-(3,4,5-trifluorophenyl)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene]octahydroquinolizin-4-one (44.1 mg) in THF (1.0 mL), and the reaction solution was stirred at room temperature overnight. A saturated ammonium chloride solution and ethyl acetate were added to the reaction solution, and the organic layer was separated. The resulting organic layer was washed with brine, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 25.4 mg of the title compound. The property values of the compound are as follows.
Reaction SMILES: CN(C)CCCOC1C=CC(C2SC(NC3C=CC=CC=3)=NC=2)=CC=1.[S:26]1[CH:30]=[CH:29][C:28]([C:31]2[S:35][C:34]([NH:36][C:37]3[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=3)=[N:33][CH:32]=2)=[CH:27]1.Cl.Cl[CH2:46][CH2:47][N:48]1[CH2:52][CH2:51][CH2:50][CH2:49]1>C(Cl)Cl.CO>[N:48]1([CH2:47][CH2:46][O:43][C:40]2[CH:41]=[CH:42][C:37]([NH:36][C:34]3[S:35][C:31]([C:28]4[CH:29]=[CH:30][S:26][CH:27]=4)=[CH:32][N:33]=3)=[CH:38][CH:39]=2)[CH2:52][CH2:51][CH2:50][CH2:49]1
Reactant: Oc1ccc(Nc2ncc(-c3ccsc3)s2)cc1
Reactant: ClCCN1CCCC1
Agent: CN(C)CCCOc1ccc(-c2cnc(Nc3ccccc3)s2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CO
Product: c1cc(-c2cnc(Nc3ccc(OCCN4CCCC4)cc3)s2)cs1

Procedure:
The title compound is prepared as described in Example 8 for {5-[4-(3-dimethylamino-propoxy)-phenyl]-thiazol-2-yl}-phenyl-amine but starting from 4-(5-thiophen-3-yl-thiazol-2-yl-amino)-phenol (Example 12) and using 1-(2-chloroethyl)-pyrrolidine hydrochloride. Title compound: ES-MS: 372.0 [M+H]+; single peak at tR=6.07 min (System 1); Rf=0.30 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [Cl:1][C:2]1[C:11]([C:12](OCC)=[O:13])=[C:10]([CH2:17][CH3:18])[C:9]2[C:4](=[CH:5][C:6]([F:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>ClCCl>[Cl:1][C:2]1[C:11]([CH2:12][OH:13])=[C:10]([CH2:17][CH3:18])[C:9]2[C:4](=[CH:5][C:6]([F:21])=[C:7]([O:19][CH3:20])[CH:8]=2)[N:3]=1
Reactant: CCOC(=O)c1c(Cl)nc2cc(F)c(OC)cc2c1CC
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Product: CCc1c(CO)c(Cl)nc2cc(F)c(OC)cc12
Temperature: 40 °C
Yield: 63.6 %

Procedure:
A solution of ethyl 2-chloro-4-ethyl-7-fluoro-6-methoxy-3-quinolinecarboxylate (10.8 g, 35 mmol) in anhydrous dichloromethane (200 ml) is treated dropwise at ambient temperature under an inert atmosphere with diisobutylaluminium hydride (1M in dichloromethane, 65 ml, 65 mmol), then heated at 40° C. for 4 hours. After cooling down to 0° C., a 20% aqueous solution of Rochelle salt (105 ml) and dichloromethane (200 ml) are added cautiously and the reaction mixture is maintained under agitation for 1 hour, followed by decanting and washing three times with water. The organic phase is dried over magnesium sulphate and the solvent is evaporated off. The residue is purified by column chromatography (SiO2, AcOEt/Hpt: 5/95 to 50/50). 6 g of a white solid is obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([N+:13]([O-])=O)=[CH:8][C:7]=1[CH3:16]>[Pd].C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[O:20][CH3:21])[O:5][C:6]1[C:11]([CH3:12])=[CH:10][C:9]([NH2:13])=[CH:8][C:7]=1[CH3:16]
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])cc2C)cc1Br
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(Oc2c(C)cc(N)cc2C)cc1Br
Reaction time: 3 h
Yield: 94 %

Procedure:
A mixture of the title product of Step A (5.0 g) and 10% palladium on carbon (0.6 g) in ethyl acetate (100 ml) was hydrogenated at 50 psi for 3 h. The reaction was filtered through Celite and concentrated to afford the title compound of Step B as a yellow solid (4.3 g). MS (APCl+) Calc: 321; Found 322 (M+1).
Reaction SMILES: Cl[CH:2]([CH3:27])[C:3]([NH:5][C:6]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:4].[CH3:28][NH2:29]>>[CH3:28][NH:29][CH:2]([CH3:27])[C:3]([NH:5][C:6]1[C:22]([O:23][CH3:24])=[C:21]([O:25][CH3:26])[CH:20]=[CH:19][C:7]=1[CH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=[CH:11][N:10]=1)=[O:4]
Reactant: CN
Reactant: COc1ccc(Cc2nccc3ccccc23)c(NC(=O)C(C)Cl)c1OC
Product: CNC(C)C(=O)Nc1c(Cc2nccc3ccccc23)ccc(OC)c1OC

Procedure:
Following the procedure of Example 1, but reacting 1-(2-[2-chloro-propionyl] amino-3,4-dimethoxybenzyl) isoquinoline with methylamine, there is obtained 1-(2-[2-methylamino-propionyl] amino-3,4-dimethoxybenzyl)isoquinoline.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N+:15]([O-:17])=[O:16])=[CH:6][C:5]([N:18]2[C:23](=[O:24])[CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[NH:20][C:19]2=[O:29])=[C:4]([F:30])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[N+:37](C1C=C([N+]([O-])=O)C=CC=1ON)([O-])=O>CN(C)C=O>[NH2:37][N:20]1[C:21]([C:25]([F:28])([F:27])[F:26])=[CH:22][C:23](=[O:24])[N:18]([C:5]2[CH:6]=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[N+:15]([O-:17])=[O:16])[C:2]([Cl:1])=[CH:3][C:4]=2[F:30])[C:19]1=[O:29]
Reactant: O=c1cc(C(F)(F)F)[nH]c(=O)n1-c1cc(Oc2ccccc2[N+](=O)[O-])c(Cl)cc1F
Reactant: NOc1ccc([N+](=O)[O-])cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Nn1c(C(F)(F)F)cc(=O)n(-c2cc(Oc3ccccc3[N+](=O)[O-])c(Cl)cc2F)c1=O
Temperature: 25 °C
Reaction time: 20 h
Yield: 43.5 %

Procedure:
A suspension of 3-[4-chloro-2-fluoro-5-(2-nitrophenoxy)phenyl]-6-trifluoromethyl-1,2,3,4-tetrahydropyrimidine-2,4,-dione (1.0 g), potassium carbonate (0.37 g), and 2,4-dinitrophenoxyamine (0.54 g) in anhydrous N,N-dimethylformamide (20 ml) was stirred at room temperature for 20 hours. The solution was processed and the resulting oil was chromatographed on silica gel eluting with methylene chloride:hexane:ethyl acetate, 2:3:0.5. The product was crystallized from methylene chloride:hexane:ethyl acetate to give a white solid (0.45 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.S(Cl)([Cl:16])=O.CN(C)C=O>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11]([Cl:16])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CCCCc1ccccc1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCCCc1ccccc1

Procedure:
In 2.3 ml of methylene chloride was added 0.470 g of 5-phenylvaleric acid, to which were added at ambient temperature 0.287 ml of thionyl chloride and 0.020 ml of N,N-dimethylformamide. After a reaction at the same temperature as above for 4 hours, the reaction mixture was concentrated under reduced pressure, 5.0 ml of toluene was added and the resulting mixture was further concentrated under reduced pressure. Thus, 0.510 g of 5-phenylvaleric acid chloride was obtained as a light yellow oily product.
Reaction SMILES: C(C(CC)CNCC1SC(C2C=C3C(=C(C(N)=O)C=2)NC=C3C2CCN(S(CC)(=O)=O)CC2)=CC=1)C.[CH:37]([C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)=O.[CH3:47][C@H:48]([NH2:53])[C:49]([CH3:52])([CH3:51])[CH3:50].[BH3-]C#N.[Na+]>>[CH3:47][C@H:48]([NH:53][CH2:37][C:39]1[S:43][C:42]([B:44]([OH:46])[OH:45])=[CH:41][CH:40]=1)[C:49]([CH3:52])([CH3:51])[CH3:50]
Reactant: C[C@H](N)C(C)(C)C
Reactant: O=Cc1ccc(B(O)O)s1
Agent: CCC(CC)CNCc1ccc(-c2cc(C(N)=O)c3[nH]cc(C4CCN(S(=O)(=O)CC)CC4)c3c2)s1
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@H](NCc1ccc(B(O)O)s1)C(C)(C)C
Yield: 38.9 %

Procedure:
Following the general procedure of 5-(5-{[(2-ethylbutyl)amino]methyl}-2-thienyl)-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide, (5-formyl-2-thienyl)boronic acid (50 mg, 0.32 mmol), [(1S)-1,2,2-trimethylpropyl]amine (32 mg, 0.32 mmol), and NaCNBH3 (40 mg, 0.64 mmol) were reacted to give 30 mg of crude [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid. The crude [5-({[(1S)-1,2,2-trimethylpropyl]amino}methyl)-2-thienyl]boronic acid was then reacted with 5-bromo-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide (65 mg, 0.157 mmol), K2CO3 (130 mg, 0.942 mmol), and tetrakis(triphenylphosphine)palladium(0) (9 mg, 0.0079 mmol) to give 10.3 mg of the title compound (12%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].F[C:8]1[CH:15]=[CH:14][C:13]([I:16])=[CH:12][C:9]=1[CH:10]=O.Cl.Cl.[N:19]1[CH:24]=[CH:23][C:22]([NH:25][NH2:26])=[CH:21][CH:20]=1>CN1CCCC1=O>[I:16][C:13]1[CH:12]=[C:9]2[C:8](=[CH:15][CH:14]=1)[N:25]([C:22]1[CH:23]=[CH:24][N:19]=[CH:20][CH:21]=1)[N:26]=[CH:10]2
Reactant: O=Cc1cc(I)ccc1F
Reactant: NNc1ccncc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: Ic1ccc2c(cnn2-c2ccncc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.3 %

Procedure:
Cesiumcarbonate (26.84 g, 82.38 mmol) is added to a suspension of 2-fluoro-5-iodobenzaldehyde (6.87 g, 27.46 mmol) and 4-pyridylhydrazine dihydrochloride (5 g, 27.46 mmol) in 136 mL N-methylpyrrolidon. The reaction mixture is stirred overnight at r.t. After checking that the hydrazone has been formed (1H-NMR) the reaction mixture is heated for 4 h at 160° C. The reaction mixture is allowed to cool down and the darkbrown suspension is poured on 1000 mL ice water. After vigorously stirring at r.t. for 45 min, the precipitated product is sucked off via a glass microfibre filter, washed with water and dried at the evaporator at 45° C. The title compound is obtained with a yield of 92.3% (8.14 g).
Reaction SMILES: C([O:5][C:6](=[O:45])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH2:13][CH:14]([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[B:15]2[O:23]C3C(C)(C4CC(C3)C4(C)C)O2)[C:8]=1[O:43]C)(C)(C)C.B(Cl)(Cl)Cl>>[OH:23][B:15]1[CH:14]([NH:28][C:29](=[O:42])[C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)[CH2:13][C:9]2[C:8](=[C:7]([C:6]([OH:5])=[O:45])[CH:12]=[CH:11][CH:10]=2)[O:43]1
Reactant: COc1c(CC(NC(=O)c2ccc(-c3ccncc3)cc2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: O=C(NC1Cc2cccc(C(=O)O)c2OB1O)c1ccc(-c2ccncc2)cc1

Procedure:
Prepared from 2-Methoxy-3-[2-(4-pyridin-4-yl-benzoylamino)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)-ethyl]-benzoic acid tert-butyl ester and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 389.0 (MH)+.
Reaction SMILES: [CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:18][CH:17]=3)[O:11][C:10](=[O:12])[CH2:9][C:8](=[O:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:29][C:30]1[CH:35]=[C:34]([CH3:36])[N:33]2[N:37]=[C:38]([CH:40]=O)[N:39]=[C:32]2[N:31]=1>>[CH:1]1([C:6]2([CH2:14][CH2:15][C:16]3[CH:17]=[CH:18][C:19]([C:22]4[C:23]([CH3:28])=[N:24][O:25][C:26]=4[CH3:27])=[CH:20][CH:21]=3)[O:11][C:10](=[O:12])[C:9]([CH2:40][C:38]3[N:39]=[C:32]4[N:31]=[C:30]([CH3:29])[CH:35]=[C:34]([CH3:36])[N:33]4[N:37]=3)=[C:8]([OH:13])[CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1noc(C)c1-c1ccc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)cc1
Reactant: Cc1cc(C)n2nc(C=O)nc2n1
Product: Cc1cc(C)n2nc(CC3=C(O)CC(CCc4ccc(-c5c(C)noc5C)cc4)(C4CCCC4)OC3=O)nc2n1

Procedure:
The title compound was prepared by coupling 6-Cyclopentyl-6-{2-[4-(3,5-dimethyl-isoxazol-4-yl)-phenyl]-ethyl}-dihydro-pyran-2,4-dione (Example A(18)) to 5,7-Dimethyl-[1,2,4]triazolo[1,5-α]pyrimidine-2-carbaldehyde using the Me2NHBH3 method described in the synthesis of Example B(31).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1CN.Cl[C:11]1[NH:12]C2C=CC=CC=2[N:15]=1>C(Cl)Cl>[N:1]1[C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[NH:12][C:11]=1[NH2:15]
Reactant: NCc1ccccc1N
Reactant: Clc1nc2ccccc2[nH]1
Solvent: ClCCl
Product: Nc1nc2ccccc2[nH]1
Temperature: 110 °C
Yield: 75.1 %

Procedure:
A mixture of 2-aminobenzylamine (500 mg, 4.1 mmol) and 2-chlorobenzoimidazole (305 mg, 2.0 mmol) was heated at 110° C. for 18 h. The resulting solid was dissolved in CH2Cl2 (30 mL) and washed with H2O (30 mL). The organic layer was separated, dried over Na2SO4, and concentrated to provide crude benzimidazole-amine (200 mg) which was treated with CDI (500 mg, 3.0 mmol) in anhydrous DMF (15 mL). After stirring at RT for 18 h, the reaction mixture was concentrated and the viscous residue was triturated with CH2Cl2. The precipitates were filtered and recrystallized from DMSO (3 mL) and CH2Cl2 (0.5 mL) to afford the title compound as an off-white solid. MS m/z: 265 (M+H+). Anal. Calc'd for C15H12N4O: C, 68.17; H, 4.58; N, 21.20; O, 6.05; Found C, 68.35; H, 4.71; N, 21.27; O, 6.04.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[C@H:10]([CH2:11][C:12]3[C:17]2=[N:16][C:15](Br)=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(N1C[C@@H](C)N2C(=CC3C2=NC=CC=3)C1)=O)(C)(C)C.C([BH3-])#N.[Na+]>>[C:1]([O:5][C:6]([N:8]1[CH2:20][C@@H:19]([CH3:21])[N:18]2[CH:10]([CH2:11][C:12]3[C:17]2=[N:16][CH:15]=[CH:14][CH:13]=3)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H]2Cc3ccc(Br)nc3N21
Agent: C[C@@H]1CN(C(=O)OC(C)(C)C)Cc2cc3cccnc3n21
Agent: [BH3-]C#N
Agent: [Na+]
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)CC2Cc3cccnc3N21

Procedure:
This compound was prepared in analogy to Example 2 intermediate b), from (R)-4-methyl-3,4-dihydro-1H-2,4a,5-triaza-fluorene-2-carboxylic acid tert-butyl ester and sodium cyano borohydride.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][N:9]=2)=[CH:4][CH:3]=1.[CH2:16]([O:18][C:19]([C:21]1([CH2:36]I)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]>>[CH2:16]([O:18][C:19]([C:21]1([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[N:9]=[CH:10][C:11]([C:14]#[N:15])=[CH:12][N:13]=3)=[CH:6][CH:7]=2)[CH2:25][CH2:24][N:23]([C:26](=[O:35])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=2[O:33][CH3:34])[CH2:22]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)C1(CI)CCN(C(=O)c2ccccc2OC)C1
Reactant: N#Cc1cnc(-c2ccc(O)cc2)nc1
Product: CCOC(=O)C1(COc2ccc(-c3ncc(C#N)cn3)cc2)CCN(C(=O)c2ccccc2OC)C1

Procedure:
The title compound was prepared according to the method described for Preparation 29 using 2-(4-hydroxy-phenyl)-pyrimidine-5-carbonitrile and 3-iodomethyl-1-(2-methoxy-benzoyl)-pyrrolidine-3-carboxylic acid ethyl ester (Preparation 15) to afford the racemate as a white solid (53 mg, 30%)
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[C:16]([N:18]([CH2:38][CH:39]([CH3:41])[CH3:40])[C@H:19]1[CH2:24][C@@H:23]([C:25](=[O:30])N(OC)C)[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:20]1)=[O:17].[CH3:42][Mg]Br.C1COCC1.[Cl-].[NH4+]>C1COCC1>[C:25]([C@H:23]1[CH2:22][N:21]([C:31]([O:33][C:34]([CH3:36])([CH3:37])[CH3:35])=[O:32])[CH2:20][C@@H:19]([N:18]([C:16]([C:8]2[N:7]([CH2:6][CH2:5][CH2:4][CH2:3][O:2][CH3:1])[C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=3[N:9]=2)=[O:17])[CH2:38][CH:39]([CH3:40])[CH3:41])[CH2:24]1)(=[O:30])[CH3:42]
Reactant: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(=O)N(C)OC)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Reactant: C[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: COCCCCn1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C(C)=O)CN(C(=O)OC(C)(C)C)C2)nc2ccccc21
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of tert-butyl (3S,5R)-3-[{[1-(4-methoxybutyl)-1H-benzimidazol-2-yl]carbonyl}(2-methylpropyl)amino]-5-[methoxy(methyl)carbamoyl]piperidine-1-carboxylate (1.06 g) in THF (20 ml) was added 1M-methyl magnesium bromide-THF solution (9.24 ml), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (1:9-3:2) was concentrated under reduced pressure to give the object product (0.59 g).
Reaction SMILES: [OH:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[O:4][N:3]=1.[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29]O)=[O:26])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([O:24][C:25]([NH:27][CH2:28][CH2:29][O:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]([O:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[CH:11][CH:12]=2)[O:4][N:3]=1)=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)NCCO
Reactant: Oc1cc(-c2ccc(Oc3ccccc3)cc2)on1
Product: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(Oc3ccccc3)cc2)on1
Yield: 73.5 %

Procedure:
3-Hydroxy-5-(4-phenoxyphenyl)isoxazole (0.2 g) and 2-(N-tert-butoxycarbonylamino)ethanol (0.14 g) were subjected to reaction and post-treatment in a similar manner to that described in Example 9(a) to obtain the title compound (0.23 g, 74%) as a colorless powder.
Reaction SMILES: [C:1]1([C:7]2[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]([CH:18]3[CH2:27][CH2:26][C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:28]=[CH2:29])[CH:24]=4)[C:19]3=O)=O)[O:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO.O.[NH2:34][NH2:35]>O1CCOCC1>[C:1]1([C:7]2[C:11]([C:12]([F:13])([F:15])[F:14])=[C:10]([C:16]3[NH:34][N:35]=[C:19]4[C:18]=3[CH2:27][CH2:26][C:25]3[CH:24]=[C:23]([CH:28]=[CH2:29])[CH:22]=[CH:21][C:20]4=3)[O:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=Cc1ccc2c(c1)CCC(C(=O)c1onc(-c3ccccc3)c1C(F)(F)F)C2=O
Reactant: NN
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: C=Cc1ccc2c(c1)CCc1c-2n[nH]c1-c1onc(-c2ccccc2)c1C(F)(F)F
Temperature: 90 °C
Reaction time: 14 h
Yield: 74.7 %

Procedure:
To 2-(3-phenyl-4-(trifluoromethyl)isoxazole-5-carbonyl)-6-vinyl-3,4-dihydronaphthalen-1(2H)-one (Preparation 22A, 0.25 g, 0.608 mmol) in a 50 mL round bottom flask was added methanol (2 mL) followed by hydrazine hydrate (0.040 mL, 0.790 mmol) at room temperature. Dioxane (2 mL) was added and the homogenous reaction mixture was heated at 90° C. for 1 h. The reaction mixture was stirred at room temperature for 14 h, concentrated under reduced pressure, azeotroped with methanol (2×10 mL, water bath heated to ˜60° C.) and kept under high vacuum for 15 min to yield 3-phenyl-4-(trifluoromethyl)-5-(7-vinyl-4,5-dihydro-2H-benzo[g]indazol-3-yl)isoxazole (0.24 g, 0.454 mmol, 74.6% yield) as a thick oil. LC/MS M+1=408.1.
Reaction SMILES: Br[C:2]1[C:15]([F:16])=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][C@@H:8]2[CH3:13])=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[C:20]([C:26]2[N:30]([CH:31]3[CH2:36][CH2:35][O:34][CH2:33][CH2:32]3)[C:29]([CH3:37])=[N:28][CH:27]=2)=[N:21][C:22]([NH2:25])=[N:23][CH:24]=1.CC(C)([O-])C.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CN(C=O)C>[F:16][C:15]1[CH:14]=[C:5]([CH2:6][N:7]2[CH2:12][CH2:11][O:10][CH2:9][C@@H:8]2[CH3:13])[C:4]([F:17])=[CH:3][C:2]=1[NH:25][C:22]1[N:21]=[C:20]([C:26]2[N:30]([CH:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[C:29]([CH3:37])=[N:28][CH:27]=2)[C:19]([F:18])=[CH:24][N:23]=1
Reactant: C[C@H]1COCCN1Cc1cc(F)c(Br)cc1F
Reactant: Cc1ncc(-c2nc(N)ncc2F)n1C1CCOCC1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Cc1ncc(-c2nc(Nc3cc(F)c(CN4CCOC[C@@H]4C)cc3F)ncc2F)n1C1CCOCC1
Temperature: 120 °C

Procedure:
(S)-4-(4-Bromo-2,5-difluorobenzyl)-3-methylmorpholine (430 mg, 1.40 mmol), 5-fluoro-4-(2-methyl-1-(tetrahydro-2H-pyran-4-yl)-1H-imidazol-5-yl)pyrimidin-2-amine (389 mg, 1.40 mmol) and potassium tert-butoxide (158 mg, 1.40 mmol) were mixed in dioxane (7 mL) and argon was bubbled through the mixture for 5 minutes. Pd2(dba)3 (154 mg, 0.17 mmol) and X-Phos (161 mg, 0.34 mmol) were added followed by DMF (1.75 mL) and the reaction mixture was heated in a microwave reactor at 120° C. for 40 minutes.