Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=[O:34])[CH:5]([O:31][CH2:32][CH3:33])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:30])C.[Li+].[OH-]>>[CH2:32]([O:31][CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[N:16]=[C:17]([C:21]3[CH:26]=[CH:25][C:24]([CH:27]([CH3:29])[CH3:28])=[CH:23][CH:22]=3)[O:18][C:19]=2[CH3:20])=[CH:9][C:8]=1[CH3:30])[C:4]([OH:34])=[O:3])[CH3:33]
Reactant: CCOC(=O)C(Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1C)OCC
Agent: [Li+]
Agent: [OH-]
Product: CCOC(Cc1ccc(OCc2nc(-c3ccc(C(C)C)cc3)oc2C)cc1C)C(=O)O

Procedure:
In analogy to the procedure described in example 1 g], [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid ethyl ester was treated with LiOH to obtain [rac]-2-ethoxy-3-{4-[2-(4-isopropyl-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid as colorless liquid, which can be separated into its antipodes by methods known in the art, such as separation of the antipodes via diastereomeric salts by crystallization with optically pure amines such as e.g. (R) or (S)-1-phenyl-ethylamine, (R) or (S)-1-naphthalen-1-yl-ethylamine, brucine, quinine and quinidine or by separation of the antipodes by specific chromatographic methods using either a chiral adsorbens or a chiral eluent to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[C:9](=O)[CH2:10][O:11][C:7]=2[CH:6]=[C:5]([O:13][CH3:14])[CH:4]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:24])=CC=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[C:9](=[S:24])[CH2:10][O:11][C:7]=2[CH:6]=[C:5]([O:13][CH3:14])[CH:4]=1
Reactant: COc1cc(OC)c2c(c1)OCC2=O
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COc1cc(OC)c2c(c1)OCC2=S
Temperature: 25 °C
Reaction time: 18 h

Procedure:
This reaction was performed under nitrogen and anhydrous conditions. 4,6-Dimethoxy-3-benzofuranone (1.5 g, 6.6 mmol) was dissolved in dry toluene (25 ml), and Lawesson's reagent (1.6 g, 4 mmol) was added. The mixture was refluxed with stirring for 18 hours. The mixture was cooled to room temperature and purified by chromatography with 1:1 ether:petroleum ether. Concentration of the fractions yielded yellow/orange crystals. The crystals were washed with the eluent and clean yellow crystals were produced. 1H NMR showed at least two compounds, probably the thioketone and the thiol. Yield: 400 mg (27%). NMR: δ (ppm): 3.86, 3.88, 3.94, 3.96 (OMe, 2 from thioketone and 2 from thiol), δ (ppm): 4.04 (—OCH2C(S)—), δ (ppm): 6.40 6.52 (aromatic).
Reaction SMILES: [CH3:1][C:2]1[N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[N:4][C:3]=1[CH:15]=O.[N:17]1[C:26]2[CH:25]([NH:27][CH2:28][CH2:29][CH2:30][CH2:31][N:32]3[C:40](=[O:41])[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[C:33]3=[O:42])[CH2:24][CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][CH:18]=1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH3:15][C:3]1[N:4]=[CH:5][N:6]([CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:12])([CH3:13])[CH3:14])[C:2]=1[CH2:1][N:27]([CH:25]1[C:26]2[N:17]=[CH:18][CH:19]=[CH:20][C:21]=2[CH2:22][CH2:23][CH2:24]1)[CH2:28][CH2:29][CH2:30][CH2:31][N:32]1[C:33](=[O:42])[C:34]2[C:39](=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:40]1=[O:41]
Reactant: O=C1c2ccccc2C(=O)N1CCCCNC1CCCc2cccnc21
Reactant: Cc1c(C=O)ncn1COCC[Si](C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: Cc1ncn(COCC[Si](C)(C)C)c1CN(CCCCN1C(=O)c2ccccc2C1=O)C1CCCc2cccnc21

Procedure:
Using General Procedure B: Reaction of 5-Methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-4-carbaldehyde from above with 2-[4-(5,6,7,8-Tetrahydro-quinolin-8-ylamino)-butyl]-isoindole-1,3-dione and NaBH(OAc)3 gave 2-{4-[[5-Methyl-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-ylmethyl]-(5,6,7,8-tetrahydro-quinolin-8-yl)-amino]-butyl}-isoindole-1,3-dione as a white foam. 1H NMR (CDCl3) 6-0.04 (s, 9H), 0.87 (t, 2H, J=8.1 Hz), 1.38-1.53 (m, 2H), 1.54-1.71 (m, 3H), 1.90-2.11 (m, 3H), 2.22 (s, 3H), 2.50-2.86 (m, 4H), 3.43 (t, 2H, J=8.3 Hz), 3.52-3.65 (m, 3H), 3.75 (d, 1H, J=13.1 Hz), 4.03-4.13 (m, 1H), 5.15 (s, 2H), 7.00 (dd, 1H, J=7.6, 4.7 Hz), 7.30 (d, 1H, J=6.2 Hz), 7.40 (s, 1H), 7.66-7.72 (m, 2H), 7.77-7.85 (m, 2H), 8.45 (dd, 1H, J=4.4, 1.5 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:14]=1[NH:13][CH:12]=[CH:11]2.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]3)=[N:21][O:22][C:18]=2[CH:17]=1.C([O-])([O-])=O.[K+].[K+].[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41]>C(OCC)(=O)C.O.C(#N)C>[C:37]([OH:44])(=[O:43])/[CH:38]=[CH:39]/[C:40]([OH:42])=[O:41].[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:14]=4[NH:13][CH:12]=[CH:11]5)[CH2:27][CH2:28]3)=[N:21][O:22][C:18]=2[CH:17]=1.[F:15][C:16]1[CH:30]=[CH:29][C:19]2[C:20]([CH:23]3[CH2:24][CH2:25][N:26]([CH2:2][CH2:3][CH2:4][O:5][C:6]4[CH:7]=[CH:8][CH:9]=[C:10]5[C:14]=4[NH:13][CH:12]=[CH:11]5)[CH2:27][CH2:28]3)=[N:21][O:22][C:18]=2[CH:17]=1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Reactant: ClCCCOc1cccc2cc[nH]c12
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: Fc1ccc2c(C3CCN(CCCOc4cccc5cc[nH]c45)CC3)noc2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 54.7 %

Procedure:
A stirred mixture of 7-(3-chloropropoxy)-1H-indole (3.5 g, 17 mmol), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (3.5 g, 17 mmol), K2CO3 (2.3 g) and acetonitrile (60 ml) was refluxed for 11 hour The reaction was poured into water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate was washed with water, dried (MgSO4), and the solvent was concentrated to afford a dark oil. The oil was flash chromatographed on silica gel. Upon concentration of the appropriate fractions, 3.0 g of a white, foamy substance was obtained. The substance was dissolved in ethyl acetate (75 ml) and fumaric acid (0.97 g, 83 mmol) was added. The mixture was briefly heated to reflux, and then stirred at ambient temperature for 1.5 hours. The resultant insoluble white fumarate salt was collected and afforded 4.2 g of product. Recrystallization of the salt from dimethylformamide yielded 3.1 g (36%) of 6-fluoro-3-[1-[3-1(1H-indol-7-yl)oxy]propyl]-4-piperidinyl]-1,2-benzisoxazole hemifumarate as a white solid, m.p.=213-215° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[Cl:11][CH2:12][CH2:13][O:14][C:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])=[O:16]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[C:15]([O:14][CH2:13][CH2:12][Cl:11])=[O:16])(=[O:24])=[O:25])=[O:28])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1C(=O)OCCCl
Reactant: COc1nc(C)nc(N)n1
Solvent: ClCCl
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)OCCCl)n1
Temperature: 25 °C
Yield: 80.1 %

Procedure:
To 0.7 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 10 ml anhydrous methylene chloride solvent was added 1.45 g 2-(β-chloroethoxycarbonyl)benzenesulfonyl isocyanate with stirring at ambient temperature. The mixture was thereafter stirred for sixteen hours. The solvent was evaporated under reduced pressure and the residue triturated with hexane and filtered to yield 1.72 g of compound which melted at 167°-170° C. The solid showed infrared absorption peaks at 1700 and 1705 cm-1, consistent for N-[(4-methoxy-6-methyl-1,3,5-triazin-2yl)aminocarbonyl]-2-(2-chloroethoxycarbonyl)benzenesulfonamide.
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][C:7]3[C:12]([C:13]=2[C:15]([OH:17])=[O:16])=[CH:11][CH:10]=[CH:9][CH:8]=3)[CH:4]=[CH:3][CH:2]=1.Cl>S(Cl)(Cl)=O>[CH:11]1[C:12]2[C:7](=[N:6][C:5]3[C:14]([C:13]=2[C:15]([O:17][C:1]2[CH:14]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:16])=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(O)c1c2ccccc2nc2ccccc12
Agent: Cl
Solvent: O=S(Cl)Cl
Product: O=C(Oc1ccccc1)c1c2ccccc2nc2ccccc12

Procedure:
Acridine-9-carboxylic acid (5 g) is suspended in thionyl chloride (75 ml). The mixture is stirred under reflux for four hours. The excess of thionyl chloride is removed by distillation. The residue is suspended in pyridine (75 ml) and the mixture stirred at room temperature for ten minutes. Phenol (4.5 g) is added to the suspension. The resulting reaction mixture is stirred at room temperature for sixteen hours. The resulting solution is poured into one normal hydrochloric acid (200 ml). The precipitate that forms (6.5 g) is isolated by filtration, and recrystallized from benzene/cyclohexane. m.p. 192° C.; IR (KBr): 1750, 1177 cm-1. MS: 299, 206, 178, 152, 151. 1H-NMR: δ7.5-8.5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([NH:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)=[CH:21][CH:20]=1)([CH3:18])[CH3:17]>>[CH:16]([C:19]1[CH:24]=[CH:23][C:22]([N:25]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:29][CH:28]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:21][CH:20]=1)([CH3:18])[CH3:17]
Reactant: CC(C)c1ccc(NCc2ccc(N3CCCC3)cc2)cc1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N3CCCC3)cc1)c1ccc(C(C)C)cc1)CCC2
Yield: 32.9 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.39 g) and (4-isopropylphenyl) [(4-pyrrolidinophenyl)methyl]amine (0.56 g) as starting materials, N-(4-isopropylphenyl)-7-methoxy-N-[(4-pyrrolidinophenyl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.3 g) was obtained.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Li+].CC([N-]C(C)C)C.[Br:27][C:28]1[S:29][CH:30]=[C:31]([Br:33])[N:32]=1.[C:34](=[O:36])=[O:35].[OH-].[Na+]>C1COCC1.O>[Br:27][C:28]1[S:29][C:30]([C:34]([OH:36])=[O:35])=[C:31]([Br:33])[N:32]=1
Reactant: O=C=O
Reactant: Brc1csc(Br)n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Solvent: CC(C)NC(C)C
Product: O=C(O)c1sc(Br)nc1Br
Temperature: -75 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
To a 500 mL 3-neck round bottom flask equipped with dropping funnel and internal temperature monitor was added THF (200 mL) and N,N-diisopropylamine (14.7 mL, 105 mmol) under atmosphere of argon. After cooling at −75° C., 2.50 M of n-Butyllithium in hexane (41.1 mL, 103 mmol) was added dropwise into the solution over 30 min. The internal temperature was kept below −70° C. and the resulting solution was stirred for 15 min at −75° C. To this LDA solution was added a solution of 2,4-dibromothiazole (25.0 g, 99.8 mmol) in THF (60 mL) via dropping funnel over 40 min and the internal temperature was kept below −70° C., then this solution was stirred for 20 min at −75° C. To this solution was added crushed dry ice at −75° C. and the mixture was stirred for 15 min. At that time, 10 mL water was added dropwise. The cooling bath was removed and the mixture was brought to rt over 1 h with a water bath. The solvent was evaporated under reduced pressure to give a solid residue. The residue was suspended in 100 mL water, basified with 1.00 M of sodium hydroxide in water (110 mL) and extracted with 100 mL ether. The ether layer was washed with 0.5 N NaOH (2×30 mL). The combined aqueous solution was acidified with conc. HCl to ˜pH 2, extracted with ether (5×100 mL, adjusting the pH to ˜2 each time after separation). The combined ether solutions were washed with brine, dried over Na2SO4, filtered, evaporated to give a solid product (28.04 g, 98%). LCMS: (FA) ES+ 288, ES− 286.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:16]=[CH:15][C:14]2[C@H:13]([NH:17]C(OC(C)(C)C)=O)[CH2:12][CH2:11][CH2:10][C:9]=2[CH:8]=1)(=O)=O.[F:25][C:26]([F:30])([F:29])[CH2:27][NH2:28].C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(OCC)(=O)C>[F:25][C:26]([F:30])([F:29])[CH2:27][NH:28][CH2:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C@H:13]([NH2:17])[CH2:12][CH2:11][CH2:10]2
Reactant: NCC(F)(F)F
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCc2cc(COS(C)(=O)=O)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCc2cc(CNCC(F)(F)F)ccc21
Temperature: 100 °C

Procedure:
A mixture of (R)-(5-(tert-butoxycarbonylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)methyl methanesulfonate (400 mg, 1.13 mmol, 1.0 eq.), 2,2,2-trifluoroethanamine (360 μl, 4.52 mmol, 4.0 eq.) and K2CO3 (470 mg, 3.39 mmol, 3.0 eq.) in THF (10 ml) was heated at 100° C. in sealed tube for 16 h. After completion of the reaction (monitored by TLC), the mixture was diluted with ethyl acetate (50 ml), washed with water (20 ml) and brine (20 ml), and dried over Na2SO4. The solvent was evaporated under reduced pressure to give the crude product which was purified by column chromatography (silica gel; 20% ethyl acetate/hexanes) to yield the title compound as an off-white solid. Yield: 37% (150 mg, 0.412 mmol) 2. (R)-6-((2,2,2-Trifluoroethylamino)methyl)-1,2,3,4-tetrahydronaphthalen-1-amine TFA (1 ml) was added to a solution of (R)-tert-butyl 6-((2,2,2-trifluoroethylamino)-methyl)-1,2,3,4-tetrahydronaphthalen-1-ylcarbamate (230 mg, 0.64 mmol, 1.0 eq.) in DCM (4 ml) at 0° C. and the resulting reaction mixture was stirred at RT for 2 h. The solvent was evaporated under reduced pressure and the residue was azeotroped with toluene to yield the desired product which was used in the next step.
Reaction SMILES: [C:1](=[O:13])([O:10][CH2:11][CH3:12])[O:2][CH2:3][CH2:4][N:5]([C:7](Cl)=[O:8])[CH3:6].C(=O)(OCCN(C([N:25]1[C:33]2[C:28](=[N:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=2)[N:27]=[C:26]1[S:36]([CH2:38][C:39]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[CH:41][N:40]=1)=[O:37])=O)C)OCC>CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[C:1](=[O:13])([O:2][CH2:3][CH2:4][N:5]([C:7]([N:27]1[C:28]2=[N:29][C:30]([O:34][CH3:35])=[CH:31][CH:32]=[C:33]2[N:25]=[C:26]1[S:36]([CH2:38][C:39]1[C:44]([CH3:45])=[C:43]([O:46][CH3:47])[C:42]([CH3:48])=[CH:41][N:40]=1)=[O:37])=[O:8])[CH3:6])[O:10][CH2:11][CH3:12]
Reactant: CCOC(=O)OCCN(C)C(=O)Cl
Reactant: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2nc(OC)ccc21
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)OCCN(C)C(=O)n1c(S(=O)Cc2ncc(C)c(OC)c2C)nc2ccc(OC)nc21
Temperature: 50 °C
Reaction time: 18 h

Procedure:
To a solution of (+)-enantiomer (0.10 g) in tetrahydrofuran (5 mL), which was obtained by optically resolving 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridine synthesized by a method described in JP-A 63-146882 with preparative HPLC, were added 2-[(chlorocarbonyl)(methyl)amino]ethyl ethyl carbonate (0.081 g) obtained in Reference Synthetic Example 34, triethylamine (0.080 mL) and 4-dimethylaminopyridine (0.007 g), and stirred at 50° C. for 18 hrs. The reaction solution was concentrated under reduced pressure, and to the residue was added water (30 mL), and extracted with ethyl acetate (50 mL). The ethyl acetate layer was washed with saturated brine (30 mL), and dried over anhydrous sodium sulfate. After concentrating under reduced pressure, the residue was purified with basic silica gel column chromatography (eluted with ethyl acetate:hexane=2:1) to give a mixture of 2:1 of title compound and (+)-ethyl 2-[[[5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]sulfinyl]-1H-imidazo[4,5-b]pyridin-1-yl]carbonyl](methyl)amino]ethyl carbonate as colorless oil (0.115 g).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:7](I)=[CH:6][C:3]=1[C:4]#[N:5].[Cl-].[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:17][Zn+].NC1C=CC(CC2C=CC=CC=2)=CC=1C#N>>[NH2:1][C:2]1[CH:9]=[CH:8][C:7]([CH2:17][C:16]2[CH:19]=[CH:20][C:21]([O:22][CH3:23])=[C:14]([O:13][CH3:12])[CH:15]=2)=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: COc1ccc(C[Zn+])cc1OC
Reactant: N#Cc1cc(I)ccc1N
Agent: N#Cc1cc(Cc2ccccc2)ccc1N
Agent: [Cl-]
Product: COc1ccc(Cc2ccc(N)c(C#N)c2)cc1OC

Procedure:
From 9 (488 mg, 2 mmol) and 3,4-dimethoxybenzylzinc chloride (0.5 M in THF, 10 mL, 5.0 mmol) by the same method as 10a; yellow oil (247 mg, 46%): 1H NMR (CDCl3) δ 3.79 (s, 2H, CH2), 3.83 (s, 3H, OMe), 3.86 (s, 3H, OMe), 4.21 (br s, NH2), 6.65-6.82 (m, 4H, H-3, H-2′, H-5′, and H-6′), 7.15 (d, J=8.4 Hz, 1H, H-4),7.17 (s, 1H, H-6).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7](I)=[CH:6][CH:5]=1.[CH2:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]#[CH:14]>N1CCCCC1.[Cu]I>[C:18]([O:17][C:16]([NH:15][CH2:12][C:13]#[C:14][C:7]1[CH:8]=[CH:9][C:4]([C:3]([O:2][CH3:1])=[O:11])=[CH:5][CH:6]=1)=[O:22])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1ccc(I)cc1
Reactant: C#CCNC(=O)OC(C)(C)C
Agent: [Cu]I
Solvent: C1CCNCC1
Product: COC(=O)c1ccc(C#CCNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Methyl-4-iodobenzoate (1.5 g, 5.7 mmol) and t-butyl prop-2-ynylcarbamate (0.89 g, 5.7 mmol, reference example 82) are dissolved in piperidine (12 mL) and this solution purged with nitrogen. Copper(I) iodide (22 mg, 0.11 mmol) and dichlorobis(triphenylphosphine) palladium (40 mg, 0.057 mmol) is added and the mixture is stirred at R.T. After 2 hours, the solvent is removed in vacuo and the residue added to CH2Cl2 and washed with 1N HCl, water and brine, then dried over magnesium sulfate. The solvent is removed in vacuo and the residue purified by flash chromatography, eluting with 20% ethyl acetate/hexane to provide the title compound as a white solid (1.1 g, 67% yield): 1H NMR (300 MHz, CDCl3) d 7.98 (d, 2H), 7.48 (d, 2H), 4.79 (bs, 1H), 4.17 (d, 2H), 3.91 (s, 3H), 1.48 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([N+:12]([O-])=O)[CH:11]=1)[C:7]#[N:8])([O-])=O>CCO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([NH2:12])[CH:11]=1)[C:7]#[N:8]
Reactant: N#Cc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cc(N)cc(N)c1

Procedure:
20% Pd(OH)2 (0.13 g) was added to a stirred suspension of 3,5-dinitrobenzonitrile (0.50 g, 2.59 mmol, 1 eq, Aldrich) in 10 ml EtOH. A H2 balloon was added. After stirring over the weekend the mixture was filtered through Celite. The filter cake was rinsed with EtOH (×3). The organics were removed in vacuo. The residue was stirred in CHCl3 and the resulting mixture was filtered (×3). The CHCl3 fractions were combined, and the solvent was removed in vacuo to yield crude 3,5-diaminobenzonitrile.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-])=O)[CH:9]=2)[NH:4][C:3]=1[C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15].[ClH:23]>C(O)C.C(OCC)(=O)C.[Pd]>[ClH:23].[NH2:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][C:3]([C:14]([N:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)=[O:15])=[C:2]2[CH3:1]
Reactant: Cc1c(C(=O)N2CCN(C)CC2)[nH]c2ccc([N+](=O)[O-])cc12
Agent: [Pd]
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: Cc1c(C(=O)N2CCN(C)CC2)[nH]c2ccc(N)cc12
Temperature: 25 °C

Procedure:
A mixture of 0.245 g I.15 ((3-methyl-5-nitro-1H-indol-2-yl)-(4-methyl-piperazin-1-yl)-methanone), 25 mg Pd/C 10% in 25 ml ethanol and 20 ml ethyl acetate was stirred at ambient temperature under a hydrogen atmosphere. The reaction mixture was treated with 1N aqueous hydrochloric acid and stirring was continued under a hydrogen pressure of 50 psi for 16 h. The reaction mixture was filtered through a pad of Celite. The Celite pad was washed with ethanol and the solvent was evaporated to give a brown solid.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25](SC)=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:36][NH2:37]>>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:29][C:28]4[C:23](=[N:24][C:25]([NH:37][CH3:36])=[N:26][CH:27]=4)[N:22]([CH3:32])[C:21]3=[O:33])[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CN
Reactant: CSc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc1C)C2
Product: CNc1ncc2c(n1)N(C)C(=O)N(c1cc(NC(=O)Nc3cc(C(C)(C)C)no3)c(F)cc1C)C2
Yield: 171.8 %

Procedure:
Using a procedure analogous to Example A2, 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylthio)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.58 g, 1.2 mmol) and methylamine (1 ml, 3 mmol, 3.0M in THF) were combined to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(1-methyl-7-(methylamino)-2-oxo-1,2-dihydropyrimido[4,5-d]pyrimidin-3(4H)-yl)phenyl)urea (0.995 g, 95% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.31 (brs, 1H), 8.73 (s, 1H), 8.00 (d, J=9 Hz, 1H), 7.94 (brs, 1H), 7.23 (d, J=12 Hz, 1H), 7.02 (m, 1H), 6.04 (s, 1H), 4.55 (d, J=14 Hz, 1H), 4.35 (d, J=14 Hz, 1H), 3.24 (brs, 3H), 2.79 (d, J=5 Hz, 3H), 2.08 (s, 3H), 1.22 (s, 9H); MS (ESI) m/z: 483.3 (M+H+).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C:12]([F:15])([F:14])[C:11](=[O:16])[N:10]([CH3:17])[C:9]3[CH:18]=[N:19][C:20]([NH:22][C:23]4[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=4[O:32][CH3:33])=[N:21][C:8]2=3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.[CH3:65][C:66]([O:69][C:70]([N:72]1[CH2:77][CH2:76][CH:75]([NH2:78])[CH2:74][CH2:73]1)=[O:71])([CH3:68])[CH3:67]>ClCCl.CN(C)C=O>[C:66]([O:69][C:70]([N:72]1[CH2:77][CH2:76][CH:75]([NH:78][C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:23]([NH:22][C:20]3[N:19]=[CH:18][C:9]4[N:10]([CH3:17])[C:11](=[O:16])[C:12]([F:14])([F:15])[CH2:13][N:7]([CH:1]5[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]5)[C:8]=4[N:21]=3)=[C:24]([O:32][CH3:33])[CH:25]=2)[CH2:74][CH2:73]1)=[O:71])([CH3:68])([CH3:65])[CH3:67]
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.25 h
Yield: 63.6 %

Procedure:
A mixture of 0.10 g (0.22 mmole) of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-246), 0.089 g (0.88 mmole) of triethylamine, 0.125 g (0.33 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 5 mL of dimethylformamide was stirred for 15 minutes and then 0.066 g (0.33 mmole) of 4-amino-1-piperidinecarboxylic acid 1,1-dimethylethyl ester was added. The mixture was stirred for 3 hours, then taken up in 50 mL of dichloromethane and washed twice with 100 mL of water and then 100 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexane-ethyl acetate (gradient 50:50-0:100) to give 0.090 g of 4-[4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoylamino]-piperidine-1-carboxylic acid tert-butyl ester (I-250).