Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:29]=[CH:28][C:13]3=[N:14][N:15]([C:17]4[CH:22]=[C:21]([C:23]([CH3:26])([CH3:25])[CH3:24])[CH:20]=[CH:19][C:18]=4[OH:27])[N:16]=[C:12]3[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:30]=[O:31].C([NH:36][CH2:37][CH2:38][CH2:39][CH3:40])CCC.C[O-].[Na+].Cl>>[CH2:18]([C:19]1[CH:20]=[C:21]([C:23]([CH3:24])([CH3:25])[CH3:26])[CH:22]=[C:17]([N:15]2[N:36]=[C:37]3[CH:38]=[CH:39][C:40]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:8])=[O:9])=[CH:12][C:13]3=[N:14]2)[C:30]=1[OH:31])[C:19]1[CH:20]=[C:21]([C:23]([CH3:26])([CH3:24])[CH3:25])[CH:22]=[C:17]([N:15]2[N:14]=[C:13]3[CH:28]=[CH:29][C:10]([S:7]([C:1]4[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=4)(=[O:9])=[O:8])=[CH:11][C:12]3=[N:16]2)[C:18]=1[OH:27]
Reactant: CCCCNCCCC
Reactant: CC(C)(C)c1ccc(O)c(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c1
Reactant: C=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Product: CC(C)(C)c1cc(Cc2cc(C(C)(C)C)cc(-n3nc4ccc(S(=O)(=O)c5ccccc5)cc4n3)c2O)c(O)c(-n2nc3ccc(S(=O)(=O)c4ccccc4)cc3n2)c1
Temperature: 205 °C
Reaction time: 3 h
Yield: 54.3 %

Procedure:
5-Phenylsulfonyl-2-(2-hydroxy-5-tert-butylphenyl)-2H-benzotriazole (15 g, 0.037 mol), paraformaldehyde (0.63 g, 0.019 mol) and di-n-butylamine (5.0 g, 0.386 mol) are charged to a reactor which is then sealed. The temperature is increased to 110° C. at which time sodium methoxide (0.33 g, 0.0069 mol) is added. The reaction mixture is then heated to 205° C. and held there for three hours, The reaction mass is then cooled to 110° C. and 100 mL of xylenes are added. The reaction mass is neutralized with 10% aqueous hydrochloric acid and the organic phase is twice washed with water. The xylene phase is filtered through a plug of silica gel and is then distilled. The crude Mannich product is recrystallized twice from heptane to yield 8.3 g of the title compound having a melting point of 224-234° C.
Reaction SMILES: CO.[NH2:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]([C:24]1[CH:29]=[CH:28][C:27]([C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:26][CH:25]=1)[C:7](=[O:23])[N:8]2[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C:19]#[C:20][CH3:21])[CH2:14]1.[BH4-].[Na+]>C(OCC)(=O)C>[NH2:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]([C:24]1[CH:29]=[CH:28][C:27]([CH:30]([OH:37])[C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)=[CH:26][CH:25]=1)[C:7](=[O:23])[N:8]2[C@@H:13]1[CH2:17][CH2:16][N:15]([C:18](=[O:22])[C:19]#[C:20][CH3:21])[CH2:14]1
Reactant: CC#CC(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(C(=O)c4ccccc4)cc3)c3c(N)ncnc32)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC#CC(=O)N1CC[C@@H](n2c(=O)n(-c3ccc(C(O)c4ccccc4)cc3)c3c(N)ncnc32)C1
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
A methanol (1 mL) solution of the compound (30 mg) prepared in Example 19(40) was cooled to 0° C.; sodium borohydride (2.4 mg) was added; and stirring was carried out for 30 minutes. The reaction mixture was diluted with ethyl acetate and was then washed with water and a saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate followed by concentration under reduced pressure, and the obtained residue was purified by silica gel column chromatography (ethyl acetate→ethyl acetate:methanol=10:1) to obtain the title compound (28 mg) having the physical property values indicated below.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:24])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:22])[F:21])=[CH:8][C:9]=1[C:10]([F:13])([F:12])[F:11])([O-:3])=[O:2].[H-].[Na+].[C:27]([C:31]1[CH:35]=[C:34]([C:36](O)=[O:37])[O:33][N:32]=1)([CH3:30])([CH3:29])[CH3:28].C(Cl)(=O)C(Cl)=O>C1COCC1.C(Cl)Cl.CN(C=O)C>[N+:1]([C:4]1[C:5]([NH:24][C:36]([C:34]2[O:33][N:32]=[C:31]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:35]=2)=[O:37])=[N:6][C:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[C:20]([F:23])([F:21])[F:22])=[CH:8][C:9]=1[C:10]([F:11])([F:12])[F:13])([O-:3])=[O:2]
Reactant: Nc1nc(-c2ccccc2C(F)(F)F)cc(C(F)(F)F)c1[N+](=O)[O-]
Reactant: CC(C)(C)c1cc(C(=O)O)on1
Agent: O=C(Cl)C(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CC(C)(C)c1cc(C(=O)Nc2nc(-c3ccccc3C(F)(F)F)cc(C(F)(F)F)c2[N+](=O)[O-])on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-ylamine (64.0 mg, 0.182 mmol, prepared as described in STEP D above) in THF (10 mL) was treated with NaH (21.9 mg, 0.547 mmol, 60% dispersion in oil), and the resulting mixture was allowed to stir at room temperature for 1 h. Simultaneously, a solution of 3-tert-butyl-isoxazole-5-carboxylic acid (40.1 mg, 0.237 mmol, prepared as described in Example I above) in anhydrous DCM (10 mL) was treated with oxalyl chloride (20.7 μL, 0.237 mmol) and DMF (2 drops), and the resulting mixture was stirred at room temperature for 1 h. Volatile components were removed in vacuo, and the residue was taken up in anhydrous THF (6 mL). The above-prepared acid chloride solution was added to the sodium anilide solution above, and the mixture was stirred at room temperature for 1 h. The mixture was quenched with saturated aqueous NH4CI (20 mL) and extracted twice with EtOAc (25 mL). The residue was purified on a 12-g SEPRA Si 50 SPE column (Flow rate=15 mL/min; Eluent=EtOAc-hexanes, 1:99 for 10 min, then 1:99 to 1:4 over 40 min) to yield 3-tert-butyl-isoxazole-5-carboxylic acid [3-nitro-4-trifluoromethyl-6-(2-trifluoromethyl-phenyl)-pyridin-2-yl]-amide as an off-white solid. Mass Spectrum (LCMS, APCI pos.): Calculated for C21H16N4O4F6: 503.1 (M+H). Measured: 503.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[N:30](C(OC(C)(C)C)=O)[C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23](O)=[O:24].[S:43]1[CH:47]=[CH:46][N:45]=[C:44]1[N:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.FC(F)(F)C(O)=O>C(#N)C.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:14]1[CH2:15][CH2:16][CH2:17][CH2:18]1)=[O:13])[N:8]=[CH:7][N:6]=[C:5]2[NH:19][CH:20]([C:26]1[NH:30][C:29]2[CH:38]=[CH:39][C:40]([Cl:42])=[CH:41][C:28]=2[N:27]=1)[CH2:21][CH2:22][C:23]([N:51]1[CH2:52][CH2:53][N:48]([C:44]2[S:43][CH:47]=[CH:46][N:45]=2)[CH2:49][CH2:50]1)=[O:24]
Reactant: CC(C)(C)OC(=O)n1c(C(CCC(=O)O)Nc2ncnc3cc(C(=O)N4CCCC4)c(Cl)cc23)nc2cc(Cl)ccc21
Reactant: c1csc(N2CCNCC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: CC#N
Product: O=C(CCC(Nc1ncnc2cc(C(=O)N3CCCC3)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1)N1CCN(c2nccs2)CC1

Procedure:
Prepared analogously to Example 61 from 6-chloro-4-[1-(1-tert.-butyloxycarbonyl-5-chloro-1H-benzimidazol-2-yl)-3-hydroxycarbonyl-propyl-amino]-7-(pyrrolidin-1-yl-carbonyl)-quinazoline and 1-thiazol-2-yl-piperazine with TBTU in acetonitrile/tetrahydrofuran and subsequent reaction with trifluoroacetic acid.
Reaction SMILES: [CH2:1]([CH2:6][NH2:7])[CH2:2][C:3](O)=[O:4].[P:8]([OH:11])([OH:10])[OH:9].[P:12](=O)([OH:15])([OH:14])[OH:13].P(Cl)(Cl)(Cl)=O>O.C1(C)C=CC=CC=1>[CH2:1]([CH2:6][NH2:7])[CH2:2][C:3]([P:12]([OH:15])([OH:14])=[O:13])([P:8]([OH:11])([OH:10])=[O:9])[OH:4]
Reactant: NCCCC(=O)O
Reactant: O=P(O)(O)O
Reactant: OP(O)O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Product: NCCCC(O)(P(=O)(O)O)P(=O)(O)O
Temperature: 90 °C
Yield: 68.2 %

Procedure:
A 500 ml cylindrical reactor equipped with a mechanical stirrer, a thermometer, a reflux condenser and a dropping funnel, was loaded with GABA (4.12 g, 0.04 mole), phosphorous acid (9.84 g, 0.12 mole), ortho-phosphoric acid (11.80 g, 0.12 mole), and toluene (50 ml). The suspension was heated to 90° C. and phosphorous oxychloride (11.2 ml, 0.12 mole) was added dropwise during 20 minutes. The reaction mixture was then heated to 95° C. for 20.5 hours. Water (50 ml) was added after cooling the reaction mixture to 80° C. The mixture was stirred vigorously till the solidified product dissolved completely. The toluene and the aqueous phases were separated and the aqueous phase was heated at 95° C. for 5.5 hours. The aqueous phase was cooled to 25° C. and absolute ethanol (50 ml) was added to precipitate the final product. The suspension was cooled to 5° C. for 1 hour. The white product was filtered, washed with absolute ethanol (2×20 ml) and dried at 65° C. for 5 hours to obtain 6.80 g (68%) of alendronic acid monohydtare.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19](N)=[CH:18][CH:17]=2)=[C:12]([O:23][CH3:24])[CH:11]=1.[BH3-][C:26]#[N:27].[Na+].[CH2:29]=O>CO.CC(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:21]=[CH:20][C:19]([N:27]([CH3:26])[CH3:29])=[CH:18][CH:17]=2)=[C:12]([O:23][CH3:24])[CH:11]=1
Reactant: C=O
Reactant: [BH3-]C#N
Reactant: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(N)cn1
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1cc(-c2nc3ccccc3o2)ccc1-c1ccc(N(C)C)cn1
Reaction time: 8 h

Procedure:
6-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]pyridin-3-amine (22 mg, 0.070 mmol) was dissolved in MeOH (2 mL), and AcOH (2 drops). NaCNBH3 (44 mg, 0.70 mmol) and formaldehyde (50 μL, 0.70 mmol) were added and the mixture was stirred overnight. The mixture was partitioned between CH2Cl2 and dilute brine. The aqueous layer was extracted with CH2Cl2 (3×15 mL). The combined organic layers were dried over MgSO4, filtered and concentrated. The crude mixture was adsorbed onto silica gel and purified by automated flash chromatography using an EtOAc/hexanes gradient to afford the desired 6-[4-(1,3-benzoxazol-2-yl)-2-methoxyphenyl]-N,N-dimethylpyridin-3-amine: 1H NMR (CDCl3, 300 MHz) δ 8.24–8.23 (d, 1H), 7.94 (s, 2H), 7.87 (s, 1H), 7.84–7.79 (m, 2H), 7.59 (m, 1H), 7.38–7.35 (m, 2H), 7.07–7.06 (m, 1H), 4.01 (s, 3H), 3.04 (s, 6H). MS (ESI) 346 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]=O)=[CH:8][CH:7]=[C:6]([C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:5]=2.[C:21]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)(=[O:23])[CH3:22].N1CCCCC1>CO>[C:13]([C:6]1[CH:5]=[C:4]2[C:9]([C:10](/[CH:11]=[CH:22]/[C:21]([C:24]3[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=3)=[O:23])=[C:2]([CH3:1])[NH:3]2)=[CH:8][CH:7]=1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(=O)c1ccncc1
Reactant: Cc1[nH]c2cc(C(=O)c3ccccc3)ccc2c1C=O
Solvent: CO
Solvent: C1CCNCC1
Product: Cc1[nH]c2cc(C(=O)c3ccccc3)ccc2c1/C=C/C(=O)c1ccncc1
Reaction time: 24 h
Yield: 74.7 %

Procedure:
In a dried 100 mL round bottom flask under argon, compound 29 (50 mg, 0.19 mmol) was dissolved in anhydrous methanol (3 mL). 4-Acetyl-pyridine (21 μL, 0.19 mmol) and piperidine (19 μL, 0.19 mmol) were added and the reaction was refluxed. After 24 hours, the reaction was cooled, filtered and rinsed with cold hexanes and dried under vacuum, yielding 52 mg (74%) of pure yellow solid. 1H NMR (600 MHz, d6-DMSO): δ 12.350 (s, 1H, N—H), 8.832-8.222 (d, J=6.0, 2H, pyr-2,6H), 8.255-8.241 (d, J=8.4, 1H, indole-4H), 8.125-8.099 (d, J=15.6, 1H, C═CH), 8.008-7.999 (d, J=5.4, 2H, pyr-3,5H), 7.801 (s, 1H, indole-7H), 7.766-7.754 (d, J=7.2, 2 H, phenyl-2,6H), 7.683-7.642 (m, 2H, phenyl-4H, indole-5H), 7.585-7.563 (m, 3H, C═CH, phenyl-3,5H), 2.659 (s, 3H, methyl). 13C NMR (150 MHz, d6-DMSO): δ 195.5, 188.2, 150.6, 148.5, 144.6, 138.7, 138.2, 135.4, 132.0, 130.6, 129.4, 129.2, 128.4, 123.1, 121.5, 119.9, 114.5, 114.1, 109.6, 12.3. Melting point: 267-270° C. TLC (ethyl acetate:hexanes 4:1) Rf=0.29. Elemental analysis calculated for C24H18N2O2 0.05H2O: C, 78.48; H, 4.97; N, 7.63. found: C, 78.08; H, 5.01; N, 7.50.
Reaction SMILES: [NH:1]([C:3]1[CH2:9][N:8]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:6]2[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:5]=2[N:4]=1)[NH2:2].[CH:24]([O-])([O-])OCC.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[C:10]1([C:7]2[C:6]3[CH:16]=[C:17]([C:20]([F:23])([F:22])[F:21])[CH:18]=[CH:19][C:5]=3[N:4]3[CH:24]=[N:2][N:1]=[C:3]3[CH2:9][N:8]=2)[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: NNC1=Nc2ccc(C(F)(F)F)cc2C(c2ccccc2)=NC1
Reactant: CCOC([O-])[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: FC(F)(F)c1ccc2c(c1)C(c1ccccc1)=NCc1nncn1-2
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a mixture of 3.2 parts of 2-hydrazino-5-phenyl-7-trifluoromethyl-3H-1,4-benzodiazepine, prepared in Example 4, 8.5 parts of ethyl orthoformate and 50 parts by volume of chloroform, is added dropwise 7.6 parts of p-toluenesulfonic acid at a temperature below 10° C. The mixture is stirred at room temperature for 2.5 hours. After completion of the reaction, the reaction mixture is neutralized with a saturated aqueous solution of sodium bicarbonate. The chloroform layer is separated, washed with water and dried over sodium sulfate. Evaporation of the solvent yields 6-phenyl-8-trifluoromethyl-4H-s-triazolo [4,3-a] [1,4] benzodiazepine as crystals. The crystals are dissolved in ethanol and the insoluble material is removed by filtration. The filtrate is concentrated and recrystallized from ethyl acetate to give colorless flakes. Melting point: 258° C to 260° C.
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]([NH2:7])=[S:6])[CH3:3].C(=O)(O)[O-].[Na+].[Cl:13][CH2:14][C:15](=O)[CH2:16]Cl>ClCCCl>[ClH:13].[Cl:13][CH2:14][C:15]1[N:7]=[C:5]([CH2:4][N:2]([CH3:3])[CH3:1])[S:6][CH:16]=1
Reactant: CN(C)CC(N)=S
Reactant: O=C(CCl)CCl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(C)Cc1nc(CCl)cs1
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 118 g. of dimethylaminothioacetamide, 92.4 g. of sodium bicarbonate, 140 g. of 1,3-dichloropropanone and 600 ml. of 1,2-dichloroethane was stirred at ambient temperature for 24 hours, and was then filtered. To the filtrate, at ice-bath temperature, was added 131 g. of thionyl chloride, dropwise. One hundred ml. of additional 1,2-dichloroethane was added, and the mixture was stirred for 2 hours at ambient temperature and then for 1 hour under reflux. The mixture was then chilled overnight, warmed to ambient temperature and filtered. The filter cake was washed with 200 ml. of 1,2-dichloroethane and blown dry, and the solids were dried overnight under vacuum to obtain 202.5 g. of the desired product, substantially identical to the product of Example 5.
Reaction SMILES: [Br:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]4[N:26]([C:27]5[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=5)[C:25](=[O:34])[CH:24]4[CH2:35][CH2:36][CH:37]([C:39]4[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=4)[OH:38])=[CH:19][CH:18]=3)=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:46]1[N:51]2[CH2:52][CH2:53][N:48]([CH2:49][CH2:50]2)[CH2:47]1>C1(C)C=CC=CC=1>[Br-:1].[F:33][C:30]1[CH:31]=[CH:32][C:27]([N:26]2[C:25](=[O:34])[CH:24]([CH2:35][CH2:36][CH:37]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][CH:40]=3)[OH:38])[CH:23]2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:6]4[CH:5]=[CH:4][C:3]([CH2:2][N+:48]56[CH2:53][CH2:52][N:51]([CH2:50][CH2:49]5)[CH2:46][CH2:47]6)=[CH:8][CH:7]=4)=[CH:10][CH:11]=3)=[CH:18][CH:19]=2)=[CH:28][CH:29]=1
Reactant: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(-c4ccc(CBr)cc4)cc3)cc2)N1c1ccc(F)cc1
Reactant: C1CN2CCN1CC2
Solvent: Cc1ccccc1
Product: O=C1C(CCC(O)c2ccc(F)cc2)C(c2ccc(OCc3ccc(-c4ccc(C[N+]56CCN(CC5)CC6)cc4)cc3)cc2)N1c1ccc(F)cc1
Product: [Br-]

Procedure:
Compound (21) and DABCO were dissolved in toluene and reacted analogously to Example IV, giving the product (22) as a colorless solid of molecular weight 780.76 (C44H44BrF2N3O3); MS (ESI): 700.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:27](O)=[O:28])=[N:22][CH:23]=[C:24]([Cl:26])[CH:25]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:27]([C:21]3[C:20]([Cl:19])=[CH:25][C:24]([Cl:26])=[CH:23][N:22]=3)=[O:28])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: O=C(O)c1ncc(Cl)cc1Cl
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Product: C[C@]1(c2cc(NC(=O)c3ncc(Cl)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 3,5-dichloro-pyridine-2-carboxylic acid following procedure I yielded the title compound as a colorless solid. MS (ISP): m/z=433.2 [M+H]+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:10][CH:11]([C:16]([CH3:18])=[CH2:17])[C:12]([O:14]C)=[O:13].[N-]=C=O>C1C=CC=CC=1>[C:8](=[O:9])([O-:10])[NH2:7].[C:1]1([NH:7][C:8]([O:10][CH:11]([C:16]([CH3:18])=[CH2:17])[C:12]([O-:14])=[O:13])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C=C(C)C(O)C(=O)OC
Reactant: O=C=Nc1ccccc1
Agent: [N-]=C=O
Solvent: c1ccccc1
Product: C=C(C)C(OC(=O)Nc1ccccc1)C(=O)[O-]
Product: NC(=O)[O-]

Procedure:
A benzene solution (50 ml) of phenyl isocyanate (1.19 g, 10 mmol) and methyl 2-hydroxy-3-methyl-3-butenoate (2.0 g, 10 mmol) was stirred at room temperature for 2 hours. It was confirmed by NMR and IR analysis of the reaction mixture that the isocyanate was completely consumed and a carbamate, 2-(N-phenylcarbamoyloxy)-3-methyl-3-butenoate, was produced. After the addition of triethylamine to the reaction mixture, the solution was further heated at reflux for 3 hours. The solvent was then removed under reduced pressure and methanol (10 ml) was added to the resulting residue to precipitate white crystals of the desired product. These crystals (1.51 g) were separated by filtration and identified as 3-phenyl-5-isopropylidne-1,3-oxazolidine-2,4-dione by NMR and IR analysis.
Reaction SMILES: ClC1C=CC(C(Cl)=O)=CC=1.Cl[C:12]1[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][N:13]=1.Cl[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[C:28]1[C:33]([C:34]2[NH:35][CH:36]=[CH:37][N:38]=2)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42]C2C=CC([N+]([O-])=O)=CN=2)[N:29]=1>>[Cl:27][C:25]1[CH:24]=[CH:23][C:22]([C:28]2[C:33]([C:34]3[NH:38][CH:37]=[CH:36][N:35]=3)=[CH:32][N:31]=[C:30]([NH:39][CH2:40][CH2:41][NH:42][C:12]3[N:13]=[CH:14][C:15]([C:18]#[N:19])=[CH:16][CH:17]=3)[N:29]=2)=[CH:21][CH:26]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: O=C(Cl)c1ccc(Cl)cc1
Product: N#Cc1ccc(NCCNc2ncc(-c3ncc[nH]3)c(-c3ccc(Cl)cc3)n2)nc1

Procedure:
6-[(2-{[4-(4-chlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]amino}ethyl)amino]-pyridine-3-carbonitrile was prepared from 4-chlorobenzoyl chloride and 2-chloro-5-(cyano)pyridine using the general method for [4-(2,4-dichlorophenyl)-5-imidazol-2-ylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine.
Reaction SMILES: [OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][N:12]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:5][CH:4]=1.CN>C(O)C>[OH:1][CH2:2][C:3]1[O:7][C:6]([CH2:8][S:9][CH2:10][CH2:11][NH2:12])=[CH:5][CH:4]=1
Reactant: O=C1c2ccccc2C(=O)N1CCSCc1ccc(CO)o1
Agent: CN
Solvent: CCO
Product: NCCSCc1ccc(CO)o1
Yield: 45.8 %

Procedure:
A solution of 2-[2-[[5-(hydroxymethyl)-2-furanylmethyl]thio]ethyl]-1H-isoindole-1,3(2H)-dione (5.0 g) in ethanol (50 ml) was stirred in the presence of methylamine (33% in ethanol) (15 ml) for 15 mins. The residue was subjected to column chromatography (silica/methanol-ethyl acetate 1:1, then methanol) and the appropriate eluates were evaporated. Chloroform (50 ml) was added to the oily product, the solution dried (anhyd. magnesium sulphate) and evaporated yielding the title compound as a pale yellow oil (1.35 g).
Reaction SMILES: [Br-].[N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[Zn+].[CH3:9][O:10][N:11]=[C:12]1[C:20]2[C:15](=[C:16](Br)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1>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>[CH3:9][O:10][N:11]=[C:12]1[C:20]2[C:15](=[C:16]([C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][N:2]=3)[CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: [Zn+]c1ccccn1
Reactant: CON=C1CCc2c(Br)cccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Product: CON=C1CCc2c1cccc2-c1ccccn1
Temperature: 120 °C

Procedure:
2-Pyridylzinc bromide (10 mL, 5 mmol, 0.5M in THF) was added to 4-bromoindan-1-one O-methyl-oxime (600 mg, 2.5 mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) under nitrogen atmosphere. The stirred solution was heated at 120° C. for 10 minutes on the microwave. After cooling to ambient temperature, the reaction mixture was filtered through celite, then silica gel with ethyl acetate. The filtrate was concentrated to a brown oil and chromatographed on silica gel with 20-40% ethyl acetate in hexane. Obtained 4-pyridin-2-ylindan-1-one O-methyloxime (326 mg, 55%) as a yellow oil. MS (DCI/NH3) m/z: 239.09 [M+H]+. 1H NMR (DMSO-d6) δ: 2.82 (m, 2H), 3.29 (m, 2H), 3.92 (s, 3H), 7.36 & 7.38 (pair of dd, 1H), 7.43 (t, 1H), 7.64 (dd, 1H), 7.74 (dd, 1H), 7.75 (dt, 1H), 7.91 (td, 1H), 8.68 & 8.69 (pair of dd, 1H).
Reaction SMILES: [CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([OH:12])=O)=[N:8][CH:9]=2)[CH2:3][CH2:2]1.[CH3:18][C:19]1[O:23][N:22]=[C:21]([C:24]([NH2:31])([CH3:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])[N:20]=1.Br>>[CH:1]1([C:4]2[C:5]([O:13][CH:14]([CH3:17])[CH2:15][F:16])=[CH:6][C:7]([C:10]([NH:31][C:24]([C:21]3[N:20]=[C:19]([CH3:18])[O:23][N:22]=3)([CH3:30])[CH2:25][S:26]([CH3:29])(=[O:28])=[O:27])=[O:12])=[N:8][CH:9]=2)[CH2:2][CH2:3]1
Reactant: Cc1nc(C(C)(N)CS(C)(=O)=O)no1
Reactant: CC(CF)Oc1cc(C(=O)O)ncc1C1CC1
Agent: Br
Product: Cc1nc(C(C)(CS(C)(=O)=O)NC(=O)c2cc(OC(C)CF)c(C3CC3)cn2)no1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 5-cyclopropyl-4-(1-fluoropropan-2-yloxy)picolinic acid (enantiomer B) (example 289b) and 2-(5-methyl-1,2,4-oxadiazol-3-yl)-1-methylsulfonyl-propan-2-amine;hydrobromide (enantiomer A) (example 124b) as starting materials and isolated (52.5 mg, 71%); MS (ESI, m/z): 441.4 (M+H+).
Reaction SMILES: [CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][CH:10]=1.Br[C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.CO.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>[CH3:1][C@@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][OH:27])=[CH:21][CH:20]=2)=[CH:11][CH:10]=1
Reactant: C[C@@H]1CCCN1CCc1ccc(B(O)O)cc1
Reactant: OCCc1ccc(Br)cc1
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: Cc1ccccc1
Solvent: CO
Product: C[C@@H]1CCCN1CCc1ccc(-c2ccc(CCO)cc2)cc1
Temperature: 100 °C

Procedure:
A mixture of (R)-4-(2-(2-methylpyrrolidin-1-yl)ethyl)phenylboronic acid (1.00 g, 4.29 mmol), 2-(4-bromophenyl)ethanol (0.862 g, 4.29 mmol), 2M Na2CO3 (2.145 mL, 4.29 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.149 g, 0.129 mmol) in toluene (3 mL) and MeOH (0.857 mL) was heated at 100° C. under microwave irradiation for 2.5 h. The mixture was extracted with EtOAc, toluene and DCM. The combined organics were concentrated. The residue was purified by column chromatography and recrystallized from EtOAc to give the title compound. LCMS m/z=310.5 [M+H]+.