Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([N:7]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:3][CH:2]=1.C([Li])CCC.[B:26](OC(C)C)([O:31]C(C)C)[O:27]C(C)C.Cl>CCOCC.CCCCCC.C1(C)C=CC=CC=1>[B:26]([OH:31])([OH:27])[C:17]1[CH:18]=[CH:19][C:14]([N:7]([C:4]2[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:15][CH:16]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Brc1ccc(N(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: CCOCC
Solvent: CCCCCC
Product: OB(O)c1ccc(N(c2ccccc2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A dry ethyl ether 100 ml and dry toluene 100 ml solution of 4-bromotriphenylamine 16.2 g was cooled down to −78° C. under argon atmosphere, and a hexane solution 32.8 ml of 1.6M normal butyllithium was dropwise added thereto. The reaction solution was stirred for one hour while heating up to 0° C. The reaction solution was cooled down again to −78° C., and a dry ether 50 ml solution of triisopropyl borate 23.5 g was dropwise added thereto. The reaction solution was stirred at room temperature for 5 hours. 1N hydrochloric acid 100 ml was added thereto and stirred for one hour, and then the aqueous layer was removed. The organic layer was dried on magnesium sulfate, and the solvent was distilled off. The solid matter thus obtained was washed with hexane and toluene to obtain 10.2 g of triphenylamine-4-boronic acid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH2:13][O:12][C:11](=[O:14])[CH:10]=2)=[CH:5][CH:4]=1.[I:15]I>N1C=CC=CC=1.CCOCC>[I:15][C:10]1[C:11](=[O:14])[O:12][CH2:13][C:9]=1[C:6]1[CH:7]=[CH:8][C:3]([S:2][CH3:1])=[CH:4][CH:5]=1
Reactant: II
Reactant: CSc1ccc(C2=CC(=O)OC2)cc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CSc1ccc(C2=C(I)C(=O)OC2)cc1
Reaction time: 24 h

Procedure:
To a solution of 3 g of the product of Step 2 in 30 ml of pyridine is added 8.7 g of I2. The mixture is stirred for 24 h and then diluted with 200 ml of ether, washed with 100 ml of 5N HCl and 50 ml of 5N Na2 S2O3. The ether layer is dried over Na2SO4 and concentrated to give the title compound.
Reaction SMILES: [NH2:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4].[CH:7](=O)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[BH4-].[Na+].[OH-].[Na+]>CO>[C:8]1([CH2:7][NH:1][C@H:2]([CH2:5][CH3:6])[CH2:3][OH:4])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC[C@@H](N)CO
Reactant: O=Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC[C@H](CO)NCc1ccccc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 108.6 %

Procedure:
To (R)-(−)-2-amino-1-butanol (5 g, 56.1 mmol) in CH3OH (120 mL) was added benzaldehyde (6.24 mL, 61.7 mmol), and the reaction mixture was stirred under nitrogen for 15 minutes. The mixture was then cooled in an ice bath and sodium borohydride (2.33 g, 61.7 mmol) was added portionwise. The mixture was stirred in the ice bath for 1.5 hours. NaOH (6 N, 25 mL) was added and the mixture was concentrated. The resulting residue was taken up in 100 mL H2O and extracted with Et2O (2×). The organics were combined, dried over Na2SO4 and concentrated to afford the title compound (10.92 g) as a fluffy white solid. LC-MS (ES) m/z=180 [M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[C:27](=[O:28])[N:4]2[C:5]([C:11]([O:13][CH:14]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[O:12])=[C:6]([CH2:9][Cl:10])[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.[CH3:41][O:42]/[N:43]=[C:44](/[C:48]1[N:49]=[C:50]([NH:53][C:54]([C:67]2[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=2)([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[S:51][CH:52]=1)\[C:45](O)=[O:46].P(Cl)(Cl)(Cl)(Cl)Cl>CC#N.C(Cl)Cl.O>[Cl:10][CH2:9][C:6]1[CH2:7][S:8][C@@H:3]2[CH:2]([NH:1][C:45](=[O:46])/[C:44](=[N:43]\[O:42][CH3:41])/[C:48]3[N:49]=[C:50]([NH:53][C:54]([C:61]4[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=4)([C:67]4[CH:72]=[CH:71][CH:70]=[CH:69][CH:68]=4)[C:55]4[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=4)[S:51][CH:52]=3)[C:27](=[O:28])[N:4]2[C:5]=1[C:11]([O:13][CH:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:12]
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12
Reactant: CO/N=C(\C(=O)O)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: CC#N
Solvent: O
Solvent: ClCCl
Product: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CCl)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Benzhydryl 7-amino-3-chloromethyl-3-cephem-4-carboxylate prepared in Preparation No. 4 (2.29 g, 5.52 mmoles) in CH3CN (57 mL) was treated with bis(trimethylsilyl)acetamide (BSA, 4.09 mL, 16.6 mmoles) at room temperature for 50 minutes to give a clear solution. To the solution was added an acid chloride solution, which was prepared from (Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (IVa) (2.04 g, 4.60 mmoles) and PCl5 (1.15 g, 5.52 mmoles) in methylene chloride (20 mL). The mixture was stirred at room temperature for 30 minutes, poured into cold water (200 mL) and extracted with ethyl acetate (3×100 mL). The combined extracts were washed with aqueous NaCl, dried and evaporated. The residual syrup (4 g) was chromatographed on a silica gel (150 g) column by eluting with 10:1 and 3:1 mixtures of toluene and ethyl acetate successively. The fractions containing the desired compound were combined and evaporated to afford 2.61 g (68%) of VIa as an amorphous powder.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][NH:3][C:2]1=[O:6].Br[CH2:8][C:9]([NH:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=1)=[O:10].BrC[C:21]1[CH:25]=[C:24]([C:26]2SC(Cl)=[CH:29][CH:30]=2)O[N:22]=1>>[O:6]=[C:2]1[N:3]([C:26]2[CH:30]=[CH:29][C:21]([NH:22][C:5]([C:4]3[N:22]([CH2:8][C:9](=[O:10])[NH:11][C:12]4[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][N:13]=4)[C:21]4[CH:25]=[CH:24][CH:26]=[CH:30][C:29]=4[N:3]=3)=[O:1])=[CH:25][CH:24]=2)[CH2:4][CH2:5][O:1]1
Reactant: O=C1NCCO1
Reactant: Clc1ccc(-c2cc(CBr)no2)s1
Reactant: O=C(CBr)Nc1ccc(Cl)cn1
Product: O=C(Cn1c(C(=O)Nc2ccc(N3CCOC3=O)cc2)nc2ccccc21)Nc1ccc(Cl)cn1

Procedure:
The title compound was prepared analogously to example 41 with the difference that Oxazolidin-2-one and 2-Bromo-N-(5-chloro-pyridin-2-yl)-acetamide was used instead of 1H-Pyrimidine-2,4-dione (step (i)) and 3-Bromomethyl-5-(5-chloro-thiophen-2-yl)-isoxazole (step (iv)).
Reaction SMILES: C1(C2ON=C(C3C=CN=CC=3)C=2)CC1.[CH:15]1([C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[O:20][N:19]=2)[CH2:17][CH2:16]1.[H][H]>[Pt]=O.C(O)C>[NH2:19][C:18]([CH:15]1[CH2:17][CH2:16]1)=[CH:22][C:21]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)=[O:20]
Reactant: [H][H]
Reactant: c1cc(-c2cc(C3CC3)no2)ccn1
Agent: O=[Pt]
Agent: c1cc(-c2cc(C3CC3)on2)ccn1
Solvent: CCO
Product: NC(=CC(=O)c1ccncc1)C1CC1

Procedure:
A 1.0 g. sample of the mixture of 4-(5-cyclopropyl-3-isoxazolyl)pyridine and 4-(3-cyclopropyl-5-isoxazolyl)pyridine, obtained as described in Examples 2 and 3, is mixed with 0.125 g. of platinum oxide and 75 ml. of ethanol. This mixture is treated with hydrogen on a Parr apparatus at 40 psi for 2 hours at room temperature. The mixture is filtered and the filtrate concentrated to yield a solid. Recrystallization from ethyl acetate-petroleum ether (30°-60° C.) provides 3-amino-3-cyclopropyl-1-(4-pyridyl)-2-propen-1-one as white crystals, melting point 124°-125° C. The ethyl acetate petroleum ether (30°-60° C.) filtrate is concentrated to a solid which is recrystallized from aqueous ethanol to give 4-(5-cyclopropyl-3-isoxazolyl)pyridine as white crystals, melting point 78°-79.5° C., nmr spectrum δ6.85 (DMSO-d6, s, 4-isoxazolyl H).
Reaction SMILES: [OH:1][CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[S:15][C:16]([CH:19]3OC(C)(C)C(C)(C)[O:20]3)=[CH:17][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3].Cl>CC#N.O.CCOC(C)=O>[OH:1][CH:2]([C:4]1[O:5][C:6](=[O:28])[C:7]2[C:12]([C:13]=1[C:14]1[S:15][C:16]([CH:19]=[O:20])=[CH:17][CH:18]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH3:3]
Reactant: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C2OC(C)(C)C(C)(C)O2)s1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccc(C=O)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.3 %

Procedure:
3-(1-hydroxyethyl)-4-(5-(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)thiophen-2-yl)-1H-isochromen-1-one (Intermediate B29, 940 mg, 2.347 mmol) was dissolved in 20 ml of MeCN and 20 ml of HCl 1M were added. The clear yellow solution was stirred overnight at rt. The mixture was diluted with 50 ml of water and 200 ml of EtOAc were added. then stirred for 20 min. Phases were separated and the organic one was washed again with 100 ml of NaHCO3 sat. sol. Phases were separated again and the organic one was dried over sodium sulfate, filtered and concentrated to dryness to leave 5-(3-(1-hydroxyethyl)-1-oxo-1H-isochromen-4-yl)thiophene-2-carbaldehyde (700 mg, 2.331 mmol, 99% yield) as a yellow fluffy solid
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]#[N:9])[CH:3]=1.C[O-].[Na+].[CH2:13](N)[CH2:14][NH2:15]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]2[NH:15][CH2:14][CH2:13][N:9]=2)[CH:3]=1
Reactant: NCCN
Reactant: N#Cc1cc(Cl)ccn1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Clc1ccnc(C2=NCCN2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.7 %

Procedure:
To a solution of 4-chloropyridine-2-carbonitrile (20.0 g, 121 mmol, prepared as described by Sakamoto et al. Chem. Pharm. Bull. 1985, 33, 565-571) in MeOH (240 mL), was added sodium methoxide (0.655 g, 12.1 mmol). The reaction mixture was stirred at rt under an atmosphere of argon for 2 h. Ethylene diamine (40.0 mL, 597 mmol) was added to the reaction mixture was stirred at 50° C. for 20 h. The solution was allowed to cool to rt and concentrated. The residue was partitioned between water and DCM. The organic layer was separated, dried over MgSO4, filtered and concentrated to give the desired product as a light brown solid (21.9 g, >99%). LCMS: (FA) ES+ 182.09 (M+1).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[C:13]([NH2:16])[CH:14]=[CH:15][C:8]=2[CH2:7][CH2:6]1.[CH:17]1([NH:23][C:24]2[C:29]([Cl:30])=[CH:28][N:27]=[C:26](Cl)[N:25]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>>[Cl:30][C:29]1[C:24]([NH:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[N:25][C:26]([NH:16][C:13]2[CH:14]=[CH:15][C:8]3[CH2:7][CH2:6][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:11][CH2:10][C:9]=3[CH:12]=2)=[N:27][CH:28]=1
Reactant: Clc1ncc(Cl)c(NC2CCCCC2)n1
Reactant: COCCN1CCc2ccc(N)cc2CC1
Product: COCCN1CCc2ccc(Nc3ncc(Cl)c(NC4CCCCC4)n3)cc2CC1

Procedure:
5-Chloro-N(4)-cyclohexyl-N(2)-[3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-yl]-pyrimidine-2,4-diamine was prepared from 3-(2-methoxy-ethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepin-7-ylamine and cyclohexyl-(2,5-dichloro-pyrimidin-4-yl)-amine in an analogous manner to Example 308c. Product isolated as a pale yellow foam (65 mg, 37%). LCMS (m/e) 430 (M+H); 1H-NMR (CDCl3, 400 MHz) δ 8.87 (s, 1H), 7.40-7.30 (m, 2H), 7.07-7.00 (m, 1H), 6.97 (bs, 1H), 5.12 (d, 1H, J=4.9 Hz), 4.07-3.92 (m, 1H), 3.61-3.51 (m, 2H), 3.38 (s, 3H), 3.00-2.87 (m, 4H), 2.81-2.65 (m, 6H), 2.17-2.05 (m, 2H), 1.89-1.76 (m, 2H), 1.53-1.47 (m, 2H), 1.47-1.20 (m, 4H).
Reaction SMILES: C(OC([N:8]1[CH2:17][C@:16]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([F:26])[CH:20]=2)([CH3:18])[N:15]([CH2:27][C:28]([OH:30])=[O:29])[C:14](=[O:31])[C:9]21[CH2:13][CH2:12][CH2:11][CH2:10]2)=O)(C)(C)C.OS(O)(=O)=O.[CH3:37]O>>[F:25][C:23]1[CH:24]=[C:19]([C@@:16]2([CH3:18])[N:15]([CH2:27][C:28]([O:30][CH3:37])=[O:29])[C:14](=[O:31])[C:9]3([CH2:10][CH2:11][CH2:12][CH2:13]3)[NH:8][CH2:17]2)[CH:20]=[C:21]([F:26])[CH:22]=1
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1C[C@@](C)(c2cc(F)cc(F)c2)N(CC(=O)O)C(=O)C12CCCC2
Agent: O=S(=O)(O)O
Product: COC(=O)CN1C(=O)C2(CCCC2)NC[C@@]1(C)c1cc(F)cc(F)c1

Procedure:
A mixture of [(8R)-6-(tert-butoxycarbonyl)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]dec-9-yl]acetic acid (4.41 g, 10.1 mmol, described in Intermediate 21) and conc. H2SO4 (3.0 mL) in MeOH (100 mL) was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo to a volume of about 30 mL, poured into saturated aqueous NaHCO3 (150 mL), and extracted with EtOAc (2×200 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford the title compound. MS: m/z=353 (M+1).
Reaction SMILES: [CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]=[C:16]([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(O)=[O:21].[Na+].ClC1C=C(C=CC=1)C(OO)=O.[OH-].[Na+]>C(Cl)Cl.CCOCC.O>[CH2:1]([O:8][CH2:9][O:10][CH2:11][C@@H:12]([CH3:19])[CH2:13][CH2:14][CH:15]1[O:21][C:16]1([CH3:18])[CH3:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=CCC[C@H](C)COCOCc1ccccc1
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Solvent: CCOCC
Product: C[C@@H](CCC1OC1(C)C)COCOCc1ccccc1
Reaction time: 24 h
Yield: 73.6 %

Procedure:
Olefin 5 (3.2 g, 12.2 mmol) was dissolved in anhydrous CH2Cl2 (60 mL), and NaHCO3 (1.6 g, 18.4 mmol) was added. Then, 3-chloroperoxybenzoic acid (60%, 12.8 g, 36.6 mmol) was added at room temperature with stirring. The stirring was continued for 24 hours, and the mixture was diluted with ether, and shaken with water and 2M NaOH. The organic layer was washed with water and saturated NH4Cl, dried over Na2SO4, and evaporated. The residue was chromatographed on silica gel using hexane/EtOAc (9:1) as an eluent to give the oily product 6 (2.5 g, 74%).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1.[S:17]([O:22]C)([O:20][CH3:21])(=[O:19])=[O:18]>C(#N)C>[CH3:21][O:20][S:17]([O-:22])(=[O:19])=[O:18].[CH3:1][N+:2]([CH3:21])([CH3:16])[CH2:3][CH2:4][N:5]([CH3:15])[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[CH:8][CH:7]=1
Reactant: CN(C)CCN(C)c1ccc([N+](=O)[O-])cc1
Reactant: COS(=O)(=O)OC
Solvent: CC#N
Product: CN(CC[N+](C)(C)C)c1ccc([N+](=O)[O-])cc1
Product: COS(=O)(=O)[O-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
8.0 g (36 mmol) of the compound from Step 9.1 was dissolved in 50 mL of acetonitrile and to the solution was added dropwise 4.55 g (36 mmol) of dimethyl sulfate over a period of 5 minutes with agitation which caused the reaction mixture to warm up slightly while the product gradually separated in crystalline form. The mixture was allowed to agitate for an additional 3 hours at room temperature after which it was suction-filtered. The filter cake was washed with a small amount of acetonitrile and then dried at 40° C. under vacuum. This gave 11.0 g (88% of the theoretical) of yellow crystals.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3](B(O)O)=[N:2]1.Br[C:10]1[CH:19]=[C:18]2[C:13]([CH2:14][CH:15]([CH3:34])[N:16]([C:20]3[CH:25]=[C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)[N:23]=[C:22]([NH2:33])[N:21]=3)[CH2:17]2)=[CH:12][CH:11]=1.[C:35](=O)([O-])[O-].[Na+].[Na+].N#N>O1CCOCC1.O.Cl[Pd](Cl)(P(C(C)(C)C)(C(C)(C)C)C1C=CC(N(C)C)=CC=1)P(C1C=CC(N(C)C)=CC=1)(C(C)(C)C)C(C)(C)C>[CH2:32]([N:29]1[CH2:30][CH2:31][N:26]([C:24]2[CH:25]=[C:20]([N:16]3[CH:15]([CH3:34])[CH2:14][C:13]4[C:18](=[CH:19][C:10]([C:3]5[CH:4]=[CH:5][NH:1][N:2]=5)=[CH:11][CH:12]=4)[CH2:17]3)[N:21]=[C:22]([NH2:33])[N:23]=2)[CH2:27][CH2:28]1)[CH3:35]
Reactant: O=C([O-])[O-]
Reactant: OB(O)c1cc[nH]n1
Reactant: CC1Cc2ccc(Br)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: CN(C)c1ccc([PH](C(C)(C)C)(C(C)(C)C)[Pd](Cl)(Cl)[PH](c2ccc(N(C)C)cc2)(C(C)(C)C)C(C)(C)C)cc1
Agent: N#N
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN1CCN(c2cc(N3Cc4cc(-c5cc[nH]n5)ccc4CC3C)nc(N)n2)CC1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 1H-pyrazol-3-ylboronic acid (64.3 mg, 0.575 mmol, Frontier Scientific, Cat. No. P1638), 4-(7-bromo-3-methyl-3,4-dihydroisoquinolin-2(1H)-yl)-6-(4-methylpiperazin-1-yl)pyrimidin-2-amine (0.20 g, 0.48 mmol) (Peak 1, Example 49, Step 7), dichloro(bis{di-tert-butyl[4-(dimethylamino)phenyl]phosphoranyl})palladium (10.2 mg, 0.0144 mmol), and sodium carbonate (0.102 g, 0.958 mmol) in 1,4-dioxane (2.2 mL) and water (0.3 mL) was vacuumed and refilled with N2 for 3 times and then stirred at 90° C. for overnight. The mixture was purified by RP-HPLC (pH=10) to afford the desired product. LCMS (M+H)+: m/z=405.2.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([O:25]C)=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[OH-].[Li+].[CH3:30]O>>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH2:22][C:23]([OH:25])=[O:24])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:27]=2)=[N:7][C:6]([CH3:30])=[N:5]1)([CH3:3])[CH3:2]
Reactant: CO
Reactant: COC(=O)Cc1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Agent: [Li+]
Agent: [OH-]
Product: Cc1nc(-c2cn3c(n2)-c2ccc(CC(=O)O)cc2OCC3)n(C(C)C)n1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
A mixture of 98 mg (0.257 mmol) of methyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetate and 2.0 ml of 1.0 M of aqueous lithium hydroxide in 6 ml of methanol/tetrahydrofuram (1:1) mixture was stirred at 50° C. for 3 hours. The mixture was concentrated and acidified to pH 3 by careful addition of 1 N aqueous hydrogen chloride. The precipitate was collected and dried in high vacuum for 18 hours to give 2-(2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)acetic acid. Yield 58 mg. M/z 368.2, calc 367.16
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([O:10]C)=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:25][C:26]=3[CH3:27])[CH:15]=2)=[N:3]1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][N:17]=[C:16]([O:20][CH2:21][C:22]3[N:23]=[C:24]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)[O:25][C:26]=3[CH3:27])[CH:15]=2)=[N:3]1
Reactant: COC(=O)Cc1cn(C)nc1OCc1ccnc(OCc2nc(-c3ccccc3)oc2C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1oc(-c2ccccc2)nc1COc1cc(COc2nn(C)cc2CC(=O)O)ccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.9 %

Procedure:
A mixture of methyl [1-methyl-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethoxy]-1H-pyrazol-4-yl]acetate (686 mg), 1N aqueous sodium hydroxide solution (3 ml), tetrahydrofuran (6 ml) and ethanol (6 ml) was stirred at room temperature for 2 hrs. 1N Hydrochloric acid (3 ml) was added to the reaction mixture and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give [1-methyl-3-[2-(5-methyl-2-phenyl-4-oxazolylmethoxy)-4-pyridylmethoxy]-1H-pyrazol-4-yl]acetic acid (471 mg, yield 71%), which was then recrystallized from acetone-hexane. melting point: 126–127° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH2:7].CN1CCOCC1.[CH3:23][C:24]1[C:29]([CH:30]=[CH:31][C:32](O)=[O:33])=[CH:28][CH:27]=[C:26]([C:35]([F:38])([F:37])[F:36])[N:25]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>C1COCC1>[F:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:10]=1[NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:6][NH:7][C:32](=[O:33])[CH:31]=[CH:30][C:29]1[C:24]([CH3:23])=[N:25][C:26]([C:35]([F:36])([F:37])[F:38])=[CH:27][CH:28]=1
Reactant: Cc1nc(C(F)(F)F)ccc1C=CC(=O)O
Reactant: CS(=O)(=O)Nc1ccc(CN)cc1F
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(C(F)(F)F)ccc1C=CC(=O)NCc1ccc(NS(C)(=O)=O)c(F)c1
Reaction time: 0.08 h
Yield: 58.8 %

Procedure:
To a suspension of 3-fluoro-4-methansulfonylaminobenzylamine hydrochloride (67 mg, 0.26 mmol) in THF (5 mL) was added N-methylmorpholine (43 μL, 0.39 mmol). After stirring for 5 minutes, 3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylic acid (60 mg, 0.26 mmol) and 4-(4,6-dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM, 73 mg, 0.26 mmol) were added. The mixture was stirred at room temperature overnight, concentrated under reduced pressure, and diluted with EtOAc and water. The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by recrystallization from EtOAc/hexane to give N-(3-fluoro-4-methanesulfonylaminobenzyl)-3-(2-methyl-6-trifluoromethylpyridin-3-yl)acrylamide (66 mg, 58.8%) as a solid.
Reaction SMILES: FC(F)(F)C([NH:5][C:6]1[C:7]([CH:12]2[CH2:17][CH2:16][CH:15]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:14][CH2:13]2)=[N:8][CH:9]=[CH:10][CH:11]=1)=O.C(=O)([O-])[O-].[K+].[K+]>CO.O>[NH2:5][C:6]1[C:7]([CH:12]2[CH2:13][CH2:14][CH:15]([N:18]3[CH2:21][CH:20]([NH:22][C:23]([CH2:25][NH:26][C:27](=[O:38])[C:28]4[CH:33]=[CH:32][CH:31]=[C:30]([C:34]([F:37])([F:36])[F:35])[CH:29]=4)=[O:24])[CH2:19]3)[CH2:16][CH2:17]2)=[N:8][CH:9]=[CH:10][CH:11]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)NC1CN(C2CCC(c3ncccc3NC(=O)C(F)(F)F)CC2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: Nc1cccnc1C1CCC(N2CC(NC(=O)CNC(=O)c3cccc(C(F)(F)F)c3)C2)CC1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
N-[(1-{4-[3-(2,2,2-Trifluoro-acetylamino)-pyridin-2-yl]-cyclohexyl}-azetidin-3-ylcarbamoyl)-methyl]-3-trifluoromethyl-benzamide (0.042 g, 0.073 mmol, as prepared in Example 17: Step B) was dissolved in methanol (3 mL), treated with a solution of powdered potassium carbonate (1.103, 0.730 mmol) in water (3 mL), and stirred at ambient temperature for 5 d, then heated to 70° C. under reflux condenser for 18 h. After removing the methanol in vacuo, the reaction was diluted with water and extracted thrice with 3:1 EtOAc/2-PrOH. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and the filtrate concentrated in vacuo giving the title compound as a beige solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH2:12]1)=[O:10].[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.ClC1C=CC2[NH:30]C(=O)OC(=O)C=2C=1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][CH2:18][C:17]2[NH:30][CH2:19][CH2:20][N:16]=2)=[C:3]([C:9]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)=[O:10])[CH:4]=1
Reactant: O=c1[nH]c2ccc(Cl)cc2c(=O)o1
Reactant: C1CCNC1
Reactant: Nc1ccc(Cl)cc1C(=O)N1CCCC1
Product: O=C(c1cc(Cl)ccc1NCC1=NCCN1)N1CCCC1

Procedure:
{2-Amino-5-chlorophenyl}(1-pyrrolidinyl)methanone (prepared from pyrrolidine and 6-chloro-2H-3,1-benzoxazine-2,4(1H)-dione using the methods described in Example 17) and CMI were reacted using conditions described in the general procedure for CMI coupling to give {5-chloro-2-[(4,5-dihydro-1H-imidazol-2-ylmethyl)amino]phenyl}(1-pyrrolidinyl)methanone.
Reaction SMILES: [O:1]=[C:2]1[C:14]2[C:9](=[N:10][C:11](C#N)=[C:12]([C:15]#[N:16])[N:13]=2)[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.[CH3:19][OH:20]>>[CH3:19][O:20][C:11]1[N:10]=[C:9]2[C:8]3[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=3[C:2](=[O:1])[C:14]2=[N:13][C:12]=1[C:15]#[N:16]
Reactant: N#Cc1nc2c(nc1C#N)-c1ccccc1C2=O
Reactant: CO
Product: COc1nc2c(nc1C#N)C(=O)c1ccccc1-2
Temperature: 25 °C
Reaction time: 16 h
Yield: 126.5 %

Procedure:
To a suspension of 1 (1.10 g, 4.7 mmol) in MeOH (47 ml) sodium (110 mg) was added and the mixture was stirred at room temperature for 16 hours. The precipitate was filtered, washed with EtOH and dried under vacuum, yielding 3 (1.03 g, 93%) as yellow-green solid.