Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][C@H:7]([CH3:9])[N:6]2[C:10]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:17][NH:16][C:15](=[O:23])[C:11]=3[C:12]([O:13][CH3:14])=[C:5]2[C:4]1=[O:24])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44]Br>CN(C=O)C>[Cl:40][C:41]1[CH:42]=[C:43]([CH:46]=[CH:47][C:48]=1[F:49])[CH2:44][N:16]1[CH:17]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:10]2[N:6]3[C@@H:7]([CH3:9])[CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:24])[C:5]3=[C:12]([O:13][CH3:14])[C:11]=2[C:15]1=[O:23]
Reactant: CCN1C[C@H](C)n2c(c(OC)c3c(=O)[nH]cc(C(=O)OC)c32)C1=O
Reactant: Fc1ccc(CBr)cc1Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CCN1C[C@H](C)n2c(c(OC)c3c(=O)n(Cc4ccc(F)c(Cl)c4)cc(C(=O)OC)c32)C1=O
Temperature: -25 °C
Reaction time: 0.42 h

Procedure:
To a cold (−25° C.) solution of methyl (6S)-8-ethyl-10-(methoxy)-6-methyl-1,9-dioxo-1,2,6,7,8,9-hexahydropyrido-[3′,4′:4,5]pyrrolo[1,2-a]-pyrazine-4-carboxylate (0.29 g, 0.87 mmol) in anhydrous DMF (15 mL) under an atmosphere of nitrogen, a solution of lithium bis(trimethylsilyl)amide in THF (1 M, 0.96 mmol) was added. The reaction mixture was stirred at −25° C. for 25 minutes and treated with 3-chloro-4-fluorobenzyl bromide (0.27 g, 1.2 mmol; passed through activated basic alumina). The reaction mixture was stirred at 0° C. for 40 minutes and concentrated under vacuum. The residue was partitioned between ethyl acetate and dilute aqueous HCl. The organic extract was washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was subjected to column chromatography on silica gel eluted with ethyl acetate-hexane gradient. Collection and concentration of appropriate fractions provided the titled product.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:8]([O:11]C)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].B(Br)(Br)Br.O>C(Cl)Cl>[Br:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COc1ccc(Br)c(C(=O)O)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(O)c1cc(O)ccc1Br
Temperature: -60 °C
Reaction time: 1 h

Procedure:
A mixture of 2-bromo-5-methoxybenzoic acid (10 g, 0.043 mol) in methylene chloride is cooled to -60° C., treated with boron tribromide (3.59 g, 0.143 mol), stirred at -60° C. for 1 hour, stirred at room temperature for 1 hour, cooled to -70° C., treated with additional boron tribromide (3.59 g, 0.143 mol), stirred at -70° C. for 1 hour, stirred at room temperature for 1 hour and poured into water. The aqueous mixture is extracted with ethyl acetate. The organic extracts are combined, washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to give the title product as a white solid which is identified by 1H and 13CNMR spectral analyses.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Br[CH2:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[C:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=2)=[CH:17][CH:16]=1>>[C:30]([O:29][C:27]([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:1]2[C:9]3[C:4](=[CH:5][C:6]([C:10]([OH:12])=[O:11])=[CH:7][CH:8]=3)[CH:3]=[CH:2]2)=[CH:16][CH:17]=1)=[O:28])([CH3:33])([CH3:32])[CH3:31]
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Reactant: O=C(O)c1ccc2[nH]ccc2c1
Product: CC(C)(C)OC(=O)c1ccccc1-c1ccc(Cn2ccc3cc(C(=O)O)ccc32)cc1

Procedure:
The title compound was prepared following the same protocol as described in Step 2, Example 38, using 1H-indole-5-carboxylic acid instead of the methyl 1H-indole-5-carboxylate, and the tert-butyl 4′-(bromomethyl)biphenyl-2-carboxylate instead of the 1-bromo-4-(bromomethyl)benzene. ESI-MS (m/z): 428 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:4][CH:3]=1.[O:15]([C:22]1[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>CN(C)C=O.O>[O:15]([C:22]1[CH:23]=[CH:24][C:25]([C:26]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:6][CH:7]=2)=[O:27])=[CH:29][CH:30]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=C(O)c1ccc(Oc2ccccc2)cc1
Reactant: CCOC(=O)CCc1ccc(N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1ccc(NC(=O)c2ccc(Oc3ccccc3)cc2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.5 %

Procedure:
To a solution of ethyl 4-aminobenzenepropanoate (0.70 g, 3.6 mmol) in N,N-dimethylformamide (25 mL) were added 4-phenoxybenzoic acid (0.85 g, 4.0 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.76 g, 4.0 mmol) and 1-hydroxybenzotriazole monohydrate (0.61 g, 4.0 mmol), and the mixture was stirred at room temperature for 16 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried and concentrated. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2:1) to give the title compound (0.96 g, yield 68%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[C:3]([O:18][CH3:19])=[CH:4][C:5]2[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH2:15]C)[C:6]=2[CH:17]=1.Cl[C:21]1[N:26]=[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)[C:24]([Cl:41])=[CH:23][N:22]=1>>[Cl:41][C:24]1[C:25]([NH:27][C:28]2[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[CH:30][C:29]=2[N:36]2[CH:40]=[CH:39][CH:38]=[N:37]2)=[N:26][C:21]([NH:1][C:2]2[C:3]([O:18][CH3:19])=[CH:4][C:5]3[CH2:11][N:10]([CH2:12][CH3:13])[CH2:9][C:8](=[O:14])[N:7]([CH3:15])[C:6]=3[CH:17]=2)=[N:22][CH:23]=1
Reactant: CCN1CC(=O)N(CC)c2cc(N)c(OC)cc2C1
Reactant: COc1ccc(Nc2nc(Cl)ncc2Cl)c(-n2cccn2)c1
Product: CCN1CC(=O)N(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(OC)cc4-n4cccn4)n3)c(OC)cc2C1

Procedure:
The title compound was prepared from 8-Amino-1,4-diethyl-7-methoxy-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one and (2,5-Dichloro-pyrimidin-4-yl)-(4-methoxy-2-pyrazol-1-yl-phenyl)-amine in an analogous manner to example 730 (0.071 g, 48%). Mp 105-107° C.; LCMS (m/e) 549 (M); 1H-NMR (DMSO, 400 MHz) δ 9.85 (s, 1H), 8.25 (s, 1H), 8.11 (s, 1H), 7.97-7.94 (d, 1H, J=9.10 Hz), 7.92 (s, 1H), 7.85 (s, 1H), 7.82 (s, 1H), 7.16 (m, 1H), 7.03 (s, 1H), 6.83-6.80 (d, 1H, J=9.34 Hz), 6.53 (s, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.48 (s, 2H), 3.00 (s, 4H), 2.57-2.50 (q, 2H, J=6.82 Hz), 1.08-1.04 (t, 3H, J=8.03 Hz).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[N:11]=[C:12]([O:19][C:20]3[C:27]([CH3:28])=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=3[CH3:29])[C:13]3[NH:18][CH:17]=[CH:16][C:14]=3[N:15]=2)=[CH:5][CH:4]=1)#[N:2].C1C(=O)N([Cl:37])C(=O)C1>C(Cl)Cl>[Cl:37][C:16]1[C:14]2[N:15]=[C:10]([NH:9][C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:11]=[C:12]([O:19][C:20]3[C:21]([CH3:29])=[CH:22][C:23]([C:24]#[N:25])=[CH:26][C:27]=3[CH3:28])[C:13]=2[NH:18][CH:17]=1
Reactant: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2cc[nH]c12
Reactant: O=C1CCC(=O)N1Cl
Solvent: ClCCl
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc2c(Cl)c[nH]c12
Yield: 68.9 %

Procedure:
To a solution of 4-(2-(4-cyanophenylamino)-5H-pyrrolo[3,2-d]pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (28.1 mg, 0.07 mmol) in CH2Cl2 (4 mL) was added NCS (9.9 mg, 0.07 mmol) and the resultant mixture was refluxed for 16 h. After completion of the reaction, the solvent was concentrated and purified by preparative TLC eluting with hexanes:ethyl acetate (2:1), to give the product as a pink solid (20 mg, 65%).
Reaction SMILES: Cl[C:2](Cl)([O:4][C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[N:21]=[C:22]([NH:25][C@H:26](C)[CH2:27]O)[S:23][CH:24]=2)=[CH:16][CH:15]=1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:21]=[C:22]([N:25]3[C@H:26]([CH3:27])[CH2:2][O:4][C:5]3=[O:11])[S:23][CH:24]=2)=[CH:18][CH:19]=1
Reactant: C[C@H](CO)Nc1nc(-c2ccc(Br)cc2)cs1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1COC(=O)N1c1nc(-c2ccc(Br)cc2)cs1
Reaction time: 3.5 h
Yield: 113 %

Procedure:
Triphosgene (2.62 g, 8.82 mmol) in 60 mL of methylene chloride was added under nitrogen dropwise over 1.75 h to a solution of (2R)-2-{[4-(4-bromophenyl)-1,3-thiazol-2-yl]amino}propan-1-ol (2.30 g, 7.33 mmol), prepared in the previous step, and N,N-diisopropylethylamine in 125 mL of methylene chloride at ice-bath temperature. After the addition the reaction was stirred at ice-bath temperature for 3.5 h. The ice bath was removed and the stirring continued for 15 h. The reaction was extracted with 2 N HCl, dried (anhydrous MgSO4), filtered and the solvent removed under reduced pressure to give 2.81 g of a yellow solid. Purification on the solid on 500 g of silica gel (230-400 mesh) using 30% methylene chloride-hexane to methylene chloride as the eluents gave the title compound (2.07 g, 83%) as a white solid, mp 197-199° C.; MS (ES) m/z 339.0 [M+H]+; Anal. Calcd for C13H11BrN2O2S: C, 46.03; H, 3.27; N, 8.26. Found: C, 45.80; H, 3.13; N, 8.16.
Reaction SMILES: [F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:16]([CH3:18])[CH3:17])[C:8]([C:10]2[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=2)=[O:9])=[CH:4][C:3]=1B1OC(C)(C)C(C)(C)O1.[CH3:30][C:31]1[N:32]=[CH:33][NH:34][CH:35]=1.C(Cl)(Cl)[Cl:37]>>[ClH:37].[ClH:37].[F:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][N:7]([CH:16]([CH3:17])[CH3:18])[C:8]([C:10]2[N:11]=[CH:12][N:13]([CH3:15])[CH:14]=2)=[O:9])=[CH:4][C:3]=1[N:34]1[CH:35]=[C:31]([CH3:30])[N:32]=[CH:33]1
Reactant: Cc1c[nH]cn1
Reactant: ClC(Cl)Cl
Reactant: CC(C)N(Cc1ccc(F)c(B2OC(C)(C)C(C)(C)O2)c1)C(=O)c1cn(C)cn1
Product: Cc1cn(-c2cc(CN(C(=O)c3cn(C)cn3)C(C)C)ccc2F)cn1
Product: Cl

Procedure:
A solution of N-[4-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl]-1-methyl-N-(propan-2-yl)-1H-imidazole-4-carboxamide (600 mg), 4-methylimidazole (205 mg) and di-μ-hydroxobis[(N,N,N′,N′-tetramethylethylenediamine)copper(II)]dichloride (231 mg) in chloroform (6.0 mL) was stirred under oxygen atmosphere at room temperature for 2 days. The reaction mixture was filtered through Celite, and the solvent was then distilled off under reduced pressure. The resulting residue was purified by column chromatography (NH silica gel cartridge, hexane:ethyl acetate=75:25-0:100), PTLC(NH silica gel, ethyl acetate) and PTLC (silica gel, chloroform:methanol=19:1). The resulting residue was dissolved in acetonitrile and 4N hydrochloric acid/ethyl acetate (0.08 mL) was added thereto, followed by concentration to afford the title compound (59 mg).
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([S:6][CH2:7][C:8](Cl)=C)=[CH:4][CH:3]=1.[CH2:13](N(CC)C1C=CC=CC=1)C>CCOCC>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[S:6][C:7]([CH3:8])=[CH:13][C:11]=2[CH:12]=1
Reactant: CCN(CC)c1ccccc1
Reactant: C=C(Cl)CSc1ccc(Br)cc1
Solvent: CCOCC
Product: Cc1cc2cc(Br)ccc2s1
Yield: 46 %

Procedure:
According to the procedure of W. K. Anderson, J. Chem. Soc., Perkin, 1, 1 (1976), a mixture of 3-(4-bromothiophenoxy)-2-chloro-1-propene (37.4 g, 0.142 mol) and N,N-diethylaniline (180 mL) was heated to 210°-215° C. for 2 days, cooled, and diluted with ether. The ethereal layer was washed with 10% HCl (3×200 mL), dried (MgSO4), and concentrated. Purification by column chromatography (eluant: hexane) gave 15.0 g (46%) of product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C@:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20](Cl)=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.ClC1C=C2C3(CCNC3)C[N:31]([C:38](NC3SC(Cl)=CN=3)=[O:39])[C:28]2=CC=1.NC1SC([F:53])=CN=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C@@:10]3([CH2:14][CH2:13][N:12]([C:38]([NH:31][CH3:28])=[O:39])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([F:53])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: Nc1ncc(F)s1
Reactant: O=C(Nc1ncc(Cl)s1)N1C[C@@]2(CCNC2)c2cc(Cl)ccc21
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Cl)ccc21
Product: CNC(=O)N1CC[C@@]2(C1)CN(C(=O)Nc1ncc(F)s1)c1ccc(Cl)cc12

Procedure:
The captioned compound was obtained in the form of a white solid by performing the same reactions and/or treatments as those in Example 373, with the exceptions that the (S)-5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide obtained as an intermediate of Example 52 was used instead of 5-chloro-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide, and that 2-amino-5-fluorothiazole was used instead of 2-amino-5-chlorothiazole hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](O)[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].P(Cl)(Cl)([Cl:14])=O>>[Cl:14][C:6]1[N:7]=[C:2]([CH3:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1nc(O)ccc1[N+](=O)[O-]
Product: Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A roundbottom flask was charged with a solution of 6-methyl-5-nitropyridin-2-ol (1.5 g, 9.74 mmol) in phosphorus oxychloride (5 ml). To the mixture was added phosphoryl pentachloride (2.0 g, 9.59 mmol). The resulting solution was allowed to react, with stirring, for three hours while the temperature was maintained at reflux. The mixture was poured into ice water and the solids that formed were collected by filtration to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH3:11])[CH:8]=[C:7]2[CH2:12][NH:13][CH3:14].CNCC1C2C=CC=CC=2N2CCCC=12.[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([OH:41])=O)=[CH:33][CH:32]=1.Cl.O=C1NC2N=CC(/C=C/C(O)=O)=CC=2CC1>>[NH2:30][C:31]1[N:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[C:39]([N:13]([CH2:12][C:7]2[C:6]3[C:10](=[C:2]([F:1])[CH:3]=[CH:4][CH:5]=3)[N:9]([CH3:11])[CH:8]=2)[CH3:14])=[O:41])=[CH:33][CH:32]=1
Reactant: CNCc1cn(C)c2c(F)cccc12
Reactant: Nc1ccc(/C=C/C(=O)O)cn1
Agent: CNCc1c2n(c3ccccc13)CCC2
Agent: Cl
Agent: O=C(O)/C=C/c1cnc2c(c1)CCC(=O)N2
Product: CN(Cc1cn(C)c2c(F)cccc12)C(=O)/C=C/c1ccc(N)nc1
Yield: 28.4 %

Procedure:
According to the procedure of Example 24, except substituting 7-fluoro-1-methyl-3-(methylaminomethyl)-1H-indole (0.2 g, 1.04 mmole) for the 2,3-dihydro-8-(methylaminomethyl)-1H-3a-azacyclopenta[α]indene, and substituting (E)-3-(6-amino-pyridin-3-yl)acrylic acid (0.17 g, 1.04 mmole) for the (E)-3-(7-oxo-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)acrylic acid hydrochloride salt, the title compound (0.1 g, 27%) was prepared as an off-white powder: MS (ES) m/e 339 (M+H)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=3)[NH2:18])=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=1.CCN(C(C)C)C(C)C.[CH3:39][C:40](=[CH2:44])[C:41](Cl)=[O:42]>C1COCC1>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]1[C:14]2[C:13]([C:15]3[CH:16]=[C:17]([NH:18][C:41](=[O:42])[C:40]([CH3:44])=[CH2:39])[CH:19]=[CH:20][CH:21]=3)=[N:12][CH:11]=[N:10][C:9]=2[N:8]([CH2:22][O:23][CH2:24][CH2:25][Si:26]([CH3:29])([CH3:28])[CH3:27])[CH:7]=1
Reactant: C=C(C)C(=O)Cl
Reactant: C[Si](C)(C)CCOCn1cc(C2CCCO2)c2c(-c3cccc(N)c3)ncnc21
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)C(=O)Nc1cccc(-c2ncnc3c2c(C2CCCO2)cn3COCC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a 0° C. solution of crude 3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)aniline (410 mg, 1.00 mmol) in THF (10 mL), was added DIPEA (258 mg, 2.00 mmol) followed by dropwise addition of 2-methylprop-2-enoyl chloride (125 mg, 1.20 mmol). The resulting solution was stirred for 4 hours at room temperature prior to being quenched by addition of water. The resulting solution was extracted with ethyl acetate (×3) and the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The reaction was purified by chromatography using silica gel, eluting with 0-100% EtOAc/petroleum ether. The product was collected and concentrated in vacuo to afford N-(3-(5-(tetrahydrofuran-2-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)phenyl)methacrylamide as a off-white solid. LRMS (ESI) calc'd for C26H35N4O3Si [M+H]+: 479, found 479.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]([NH:14]C(=O)OC(C)(C)C)[CH2:5][NH:6]C(=O)OC(C)(C)C.[ClH:22].CCOCC>CO>[ClH:22].[ClH:22].[CH3:1][O:2][CH2:3][C@@H:4]([NH2:14])[CH2:5][NH2:6]
Reactant: COC[C@H](CNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: COC[C@@H](N)CN
Temperature: 25 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
To a solution of di-tert-butyl [(2S)-3-methoxypropane-1,2-diyl]biscarbamate (895 mg, 2.94 mmol) in MeOH (30 mL), was added 2N HCl in Et2O (15 mL, 29.4 mmol). The reaction was stirred at rt for 18 h and the solvents evaporated to yield the title compound as a white solid (478 mg, 92%). LCMS: (FA) ES+ 105.0 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=O)[O:6][CH2:5][CH2:4][O:3]1.[Cl:14][C:15]1[CH:33]=[CH:32][C:18]2[O:19][C:20]3[CH:31]=[CH:30][CH:29]=[CH:28][C:21]=3[CH2:22][N:23]([C:24]([NH:26][NH2:27])=[O:25])[C:17]=2[CH:16]=1>>[CH3:1][C:2]1([CH2:7][CH2:8][CH2:9][C:10]([NH:27][NH:26][C:24]([N:23]2[CH2:22][C:21]3[CH:28]=[CH:29][CH:30]=[CH:31][C:20]=3[O:19][C:18]3[CH:32]=[CH:33][C:15]([Cl:14])=[CH:16][C:17]2=3)=[O:25])=[O:12])[O:3][CH2:4][CH2:5][O:6]1
Reactant: NNC(=O)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: COC(=O)CCCC1(C)OCCO1
Product: CC1(CCCC(=O)NNC(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)OCCO1

Procedure:
8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, 2-[4-(2-methyl-1,3-dioxolan-2-yl)-1-oxobutyl]hydrazide (26) was prepared in the manner described above in Example 18 from methyl 2-methyl-1,3-dioxolane-2-butanoate (25), prepared as described above in Example 25, and 8-chlorodibenz[b,f][1,4]oxazepine-10(11H)-carboxylic acid, hydrazide (1), prepared in the manner described above in Example 1, on a 2 mmol scale to yield 0.47 g (53%) of product.
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[C:6]([CH3:11])[N:5]=[CH:4][N:3]=1.C[O:13][C:14](=[O:42])[C:15]1[CH:20]=[CH:19][C:18]([N:21]([CH:31]2[CH2:36][CH2:35][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH2:40])[CH2:33][CH2:32]2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=2)=[CH:17][CH:16]=1>>[C:29]([C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][CH:26]=1)[CH2:22][N:21]([CH:31]1[CH2:32][CH2:33][N:34]([CH:37]([CH3:41])[CH2:38][CH2:39][NH:40][C:8]([C:7]2[C:2]([CH3:1])=[N:3][CH:4]=[N:5][C:6]=2[CH3:11])=[O:10])[CH2:35][CH2:36]1)[C:18]1[CH:17]=[CH:16][C:15]([C:14]([OH:42])=[O:13])=[CH:20][CH:19]=1)#[N:30]
Reactant: Cc1ncnc(C)c1C(=O)O
Reactant: COC(=O)c1ccc(N(Cc2cccc(C#N)c2)C2CCN(C(C)CCN)CC2)cc1
Product: Cc1ncnc(C)c1C(=O)NCCC(C)N1CCC(N(Cc2cccc(C#N)c2)c2ccc(C(=O)O)cc2)CC1

Procedure:
Using general procedure E with the primary amine (73 mg, 0.17 mmol) and 4,6-dimethylpyrimidine-5-carboxylic acid (37 mg, 0.24 mmol) followed by general procedure K with the resulting ester gave 4-[(3-cyano-benzyl)-(1-{3-[(4,6-dimethyl-pyrimidine-5-carbonyl)-amino]-1-methyl-propyl}-piperidin-4-yl)-amino]-benzoic acid as a beige solid (43.4 mg, 46% over 2 steps).
Reaction SMILES: O.[PH2:2]([O-:4])=[O:3].[Na+].[CH2:6]=[CH:7][CH2:8][CH2:9][CH2:10][CH3:11].OO>C(O)C.S(=O)(=O)(O)O>[CH2:6]([PH:2](=[O:4])[OH:3])[CH2:7][CH2:8][CH2:9][CH2:10][CH3:11]
Reactant: C=CCCCC
Reactant: O=[PH2][O-]
Agent: O=S(=O)(O)O
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCCCCC[PH](=O)O
Yield: 82.1 %

Procedure:
To a mixture of 95.2 g (0.898 mol) of sodium hypophosphite hydrate in 600 mL 95% ethanol, 23.8 mL of concentrated sulfuric acid was added. 1-hexene (25.2 g, 0.30 mol) was added to the stirred mixture followed by 1.76 g (0.0155 mol) of 30% hydrogen peroxide. The resulting mixture was refluxed for 8 hs, and then another 1.14 g (0.0101 mol) of hydrogen peroxide was added and the reaction mixture was continued to reflux for another 8 hs. The resulting mixture was cooled, filtered, and then the ethanol was removed using a rotary evaporator. To the resulting residue, 200 mL water was added and then 50% sodium hydroxide solution was added until the solution became alkaline. The mixture was extracted twice with 200 mL diethyl ether, and the aqueous phase was then acidified with concentrated sulfuric acid. The aqueous layer was extracted with 200 mL ethyl acetate, and the organic layer was washed with saturated sodium chloride and then dried over anhydrous magnesium sulfate. The organic layer was decanted and the drying agent was washed with another 50 mL ethyl acetate. The combined organic layers were evaporated on a rotary evaporator. 37.0 g n-hexylphosphinic acid (82.4% yield) was obtained.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:26])[CH2:9][N:10]([CH3:25])[S:11]([C:14]2[C:15]3[CH2:22][CH2:21][CH2:20]/[C:19](=[N:23]/[OH:24])/[C:16]=3[S:17][CH:18]=2)(=[O:13])=[O:12])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:34][Si:35]([N:38]=[C:39]=[O:40])([CH3:37])[CH3:36].C(OCC)(=O)C>C1(C)C=CC=CC=1>[CH3:34][Si:35]([NH:38][C:39]([O:24]/[N:23]=[C:19]1/[CH2:20][CH2:21][CH2:22][C:15]2[C:14]([S:11]([N:10]([CH2:9][CH:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[OH:26])[CH3:25])(=[O:13])=[O:12])=[CH:18][S:17][C:16]/1=2)=[O:40])([CH3:37])[CH3:36]
Reactant: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/O
Reactant: C[Si](C)(C)N=C=O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CN(CC(O)c1ccc(F)cc1)S(=O)(=O)c1csc2c1CCC/C2=N/OC(=O)N[Si](C)(C)C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of the compound (1.0 g) of Example 1 in toluene (10 mL) was added triethylamine (1.75 mL) and trimethylsilyl isocyanate. After stirring at room temperature for 2 hours, the solution was dilutied with ethyl acetate, and the resulting insoluble matter was extracted, the crude product that were obtained by removing the solvent by evaporation was purified by NH-silica gel column chromatography (ethyl acetate/hexane), and a pale yellow oily substance (1.0 g) was obtained.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1[CH:27]=[N:28][C:29]([C:32](O)=[O:33])=[CH:30][CH:31]=1.C1C=CC2N(O)N=NC=2C=1.O.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[F:19][C:2]([F:1])([F:18])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15]([C:32]([C:29]3[N:28]=[CH:27][C:26]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][N:20]=4)=[CH:31][CH:30]=3)=[O:33])[CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reactant: O=C(O)c1ccc(-c2ccccn2)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2ccccn2)cn1)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Yield: 79.2 %

Procedure:
To a solution of 1-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (Description 1) (64.7 mg, 0.220 mmol) in DMF (3 ml) was added 2,3′-bipyridine-6′-carboxylic acid (Description 5) (44 mg, 0.220 mmol), HOBT.H2O (33.7 mg, 0.220 mmol), HBTU (83 mg, 0.220 mmol) and DIPEA (0.115 ml, 0.659 mmol) and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum then DCM was added (5 ml) and washed with saturated NaHCO3 solution (5 ml). The product was concentrated under vacuum then dissolved in MeCN/DMSO 1:1 and purified by MDAP. The desired fractions were combined and evaporated under vacuum to give the title compound (83 mg).