Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:4]([NH2:6])=[O:5])[CH3:3].[NH:7]([C:26]([O:28][CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)=[O:27])[C@H:8]([C:16]([O:18]CC1C=CC=CC=1)=O)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.NCC(N)=O>>[NH:7]([C:26]([O:28][CH2:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)=[O:27])[C@H:8]([C:16]([NH:1][C@H:2]([C:4]([NH2:6])=[O:5])[CH3:3])=[O:18])[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)OCc1ccccc1)OCc1ccccc1
Reactant: C[C@H](N)C(N)=O
Agent: NCC(N)=O
Product: C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(N)=O
Reaction time: 24 h

Procedure:
In all cases, the reaction of L-Ala-NH2 (6) with Z-L-Phe-OBn (1) was slower than Gly-NH2 (5) with Z-L-Phe-OBn (1). Further, after 24 hours, Z-L-Phe-Ala-NH2 (11) was obtained in moderate yield (33-57%) using WT, S166C—SCH2C6H5, —SCH2C6F5, and —SCH2(p-COOH—C6H4) as the catalysts. However, Z-L-Phe-Ala-NH2 (11) was obtained in 88% yield in the case of S166C—SCH2CH2NH3+. Unlike S166C—SCH2CH2NH3+, the use of M222C—SCH2CH2NH3+ did not improve the yield of the dipeptide product as compared to the WT-catalyzed reaction; only a low 22% yield of Z-L-Phe-Ala-NH2 (11) was obtained. This was possibly due to the steric interaction of this residue at the binding site, S1pocket, with the P1 substrate as mentioned above.
Reaction SMILES: [C:1]([C:3]1[CH:31]=[CH:30][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[OH:29])[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1)#[N:2].Cl[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)=[CH:36][CH:35]=1.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][CH:8](/[CH:21]=[CH:22]/[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:29][CH2:33][C:34]2[CH:35]=[CH:36][C:37]([C:40]3[CH:45]=[CH:44][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:42][CH:41]=3)=[CH:38][CH:39]=2)[CH2:9][CH2:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=2)=[CH:30][CH:31]=1)#[N:2]
Reactant: FC(F)(F)c1ccc(-c2ccc(CCl)cc2)cc1
Reactant: COC(=O)c1ccc(CCC(/C=C/c2ccccc2O)Cc2ccc(C#N)cc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)c1ccc(CCC(/C=C/c2ccccc2OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2)Cc2ccc(C#N)cc2)cc1
Yield: 90 %

Procedure:
A solution of 1150 mg (2.79 mmol) of methyl E-4-[3-(4-cyanobenzyl)-5-(2-hydroxyphenyl)pent-4-enyl]benzoate from Example 75A in 50 ml of dry acetonitrile is mixed with 908 mg (3.35 mmol) of 4-chloromethyl-4′-trifluoromethylbiphenyl from Example 23A and 579 mg (4.19 mmol) of anhydrous potassium-carbonate and heated to reflux for 12 hours. The mixture is then concentrated to dryness. The residue is taken up in ethyl acetate, washed with water and saturated sodium chloride solution and dried over sodium sulfate. The organic phase is concentrated. The resulting crude product is purified by flash chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 7:3). 1620 mg (2.51 mmol, 90% yield) of a solid are obtained.
Reaction SMILES: [CH3:1][CH:2]1[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:19])([F:18])[F:17])[CH3:9])=[N:4][C:3]1=[O:20].Br[C:22]1[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=1.[Li]N([Si](C)(C)C)[Si](C)(C)C>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:1][C:2]1([C:22]2[CH:29]=[CH:28][C:25]([C:26]#[N:27])=[CH:24][CH:23]=2)[S:6][C:5]([NH:7][C@H:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[C:16]([F:18])([F:17])[F:19])[CH3:9])=[N:4][C:3]1=[O:20]
Reactant: N#Cc1ccc(Br)cc1
Reactant: CC1SC(N[C@@H](C)c2ccccc2C(F)(F)F)=NC1=O
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Solvent: Cc1ccccc1
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C#N)cc2)S1)c1ccccc1C(F)(F)F
Temperature: 95 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-methyl-2-((S)-1-(2-(trifluoromethyl)phenyl)ethylamino)thiazol-4(5H)-one (0.2000 g, 0.662 mmol), 4-bromobenzonitrile (0.301 g, 1.65 mmol), Pd2(dba)3 (0.0303 g, 0.0331 mmol), (S)-2-(diphenylphosphino)-1-(2-(diphenylphosphino)-naphthalen-1-yl)naphthalene (0.0618 g, 0.0992 mmol), and LiN(TMS)2 (0.277 g, 1.65 mmol) was added toluene (8 mL) in a glove box. The mixture was gradually heated to 95° C. and stirred overnight. The reaction was quenched with NH4Cl (5 mL), and the reaction mixture was extracted three times with ethylacetate (30 mL). The organic phase was dried over Na2SO4, filtered and concentrated under vacuum. The crude was purified by chromatography on silica gel using 22% ethylacetate/hexane to remove the impurities and then 36% ethylacetate/hexane to obtain the product as a light yellow solid. MS (ESI, pos. ion) m/z: 404 (M+1), 402 (M-1). 1H NMR (CDCl3, 400 MHz): δ1.71-1.78 (m, 3H), 1.98-2.09 (m, 3H), 5.05 (q, J=8 Hz, 1H), 7.39-7.68 (m, 7H), 7.84 (d, J=8 Hz, 1H), 10.97 (s, 1H). % de (by 1H NMR): 48%.
Reaction SMILES: [F:1][C:2]1[CH:15]=[C:14]2[C:5]([NH:6][C:7]3[C:8]([C:17]([OH:19])=[O:18])=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]2=O)=[CH:4][CH:3]=1>CO.O>[F:1][C:2]1[CH:15]=[C:14]2[C:5]([N:6]=[C:7]3[C:12](=[CH:13]2)[CH:11]=[CH:10][CH:9]=[C:8]3[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc2c(=O)c3cc(F)ccc3[nH]c12
Solvent: CO
Solvent: O
Product: O=C(O)c1cccc2cc3cc(F)ccc3nc12
Yield: 95 %

Procedure:
Reduction of the known [Atwell et al., J. Med. Chem., 1987, 30, 658] 7-fluoro-9-oxoacridan-4-carboxylic acid as above gave 7-fluoroacridine-4-carboxylic acid (95%), mp (MeOH/H2O) 267-268° C. 1H NMR [(CD3)2SO] δ 7.87 (dd, J=8.4, 7.0 Hz, 1 H, H-2), 8.01 (ddd, J=9.5, 8.5, 2.3 Hz, 1 H, H-6), 8.13 (dd, J=9.3, 2.8 Hz, 1 H, H-8), 8.45 (dd, J=9.6, 5.3 Hz, 1 H, H-5), 8.54 (dd, J=8.5, 1.3 Hz, 1 H, H-1), 8.73 (dd, J=6.9, 1.4 Hz, 1 H, H-3), 9.47 (s, 1 H, H-9), 16. 53 (br s, 1 H, COOH). Anal. (C14H8FNO2) C, H, N, F.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:20])=[N:15][CH:16]=[C:17](Br)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:21]([S:23]([N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1)(=[O:25])=[O:24])[CH3:22].CCOC(C)=O>O>[NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10]([C:13]3[C:14]([NH2:20])=[N:15][CH:16]=[C:17]([N:29]4[CH2:28][CH2:27][N:26]([S:23]([CH2:21][CH3:22])(=[O:24])=[O:25])[CH2:31][CH2:30]4)[N:18]=3)=[N:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(=O)(=O)N1CCNCC1
Reactant: Nc1cccc(-c2nnc(-c3nc(Br)cnc3N)[nH]2)c1
Solvent: CCOC(C)=O
Solvent: O
Product: CCS(=O)(=O)N1CCN(c2cnc(N)c(-c3nnc(-c4cccc(N)c4)[nH]3)n2)CC1
Yield: 8.4 %

Procedure:
3-[5-(3-aminophenyl)-4H-1,2,4-triazol-3-yl]-5-bromo-pyrazin-2-amine (220 mg, 0.6623 mmol) was heated in neat 1-ethanesulfonyl piperazine (590.4 mg, 3.312 mmol) in the microwave at 190° C. for 2 hours. The reaction was treated with EtOAc and H2O, the two layers separated and the organics dried and concentrated to give a yellow oil which was purified by reverse phase preparative HPLC [Waters Sunfire C18, 10 uM, 100A column, gradient 10%-95% B (solvent A: 0.05% TFA in water, solvent B: CH3CN) over 16 minutes at 25 mL/min]. The fractions were collected, passed through a sodium bicarbonate cartridge and freeze-dried to give the title compound as a yellow solid (23.9 mg, 8% Yield). 1H NMR (400.0 MHz, DMSO) d 8.38 (s, 2H), 8.04 (s, 1H), 7.33 (s, 2H), 7.24 (s, 1H), 7.09 (s, 1H), 6.96 (s, 1H), 6.60 (s, 1H), 3.55 (s, 4H), 3.28 (s, 4H), 3.08 (d, J=5.7 Hz, 2H) and 1.20 (s, 3H) ppm; MS (ES+) 430.0
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][C:4]([OH:6])=[O:5].[CH2:10](N(CC)CC)[CH3:11]>C(O)C.Cl>[CH3:10][CH2:11][O:8][C:7](=[O:9])[C@@H:2]([CH2:3][C:4]([OH:6])=[O:5])[NH2:1]
Reactant: CCN(CC)CC
Reactant: N[C@H](CC(=O)O)C(=O)O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)[C@H](N)CC(=O)O
Reaction time: 2 h
Yield: 71 %

Procedure:
13.31 g of D-aspartic acid (0.1 mole) are dissolved in 135 ml of absolute ethanol containing 8.7 g of dry hydrogen chloride. The reaction mixture is stirred for about 2 hr. The solution is diluted by addition of 250 ml of absolute ethanol. Triethylamine is then added dropwise until the solution becomes alkaline. After standing for 16 hr at +4° C., the obtained crystals are filtered, washed successively with cold absolute ethanol and ether, then dried. The reaction yields 11.5 g of D-aspartic acid β-ethyl ester (71%).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([NH:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:26][C:27]([F:32])([F:31])[CH:28]1[O:30][CH2:29]1>>[O:1]([C:8]1[CH:9]=[C:10]([N:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH:23]([CH3:25])[CH3:24])[CH:17]=2)[CH2:29][CH:28]([OH:30])[C:27]([F:32])([F:31])[F:26])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)Oc1cccc(CNc2cccc(Oc3ccccc3)c2)c1
Reactant: FC(F)(F)C1CO1
Product: CC(C)Oc1cccc(CN(CC(O)C(F)(F)F)c2cccc(Oc3ccccc3)c2)c1
Yield: 27.8 %

Procedure:
The N-(3-phenoxyphenyl)-[[3-isopropoxyphenyl]methyl]amine (0.528 g, 1.59 mmol) product from EX-645B and 1,1,1-trifluoro-2,3-epoxypropane (0.506 g, 4.51 mmol) were heated to 90° C. in a sealed container for 2 d under an argon atmosphere. The resulting mixture was eluted from silica gel with an ethyl acetate in hexane gradient (0-10% ethyl acetate) and fractions were pooled after TLC analysis to give 197 mg (28%) of the desired 3-[(3-phenoxyphenyl)[[3-(isopro-poxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol product as clear, colorless oil. HRMS calcd. for C25H26F3NO3: 446.1943 [M+H]+, found: 446.1936. 1H NMR (C6D6) δ6.9-7.1 (m, 6H), 6.84 (tt, 1H), 6.74 (s, 1H), 6.66 (dd, 1H), 6.61 (d. 1H), 6.56 (t, 1H), 6.41 (td, 2H), 4.33 (s, 2H), 4.17 (septet, 1H), 3.91 (br s, 1H), 3.56 (dd, 1H), 3.31 (m, 1H,), 2.8 (br s, 1H). 1.06 (s, 6H). 19F NMR (C6D6) δ−78.85 (d, 3F).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][C@:5]2([C:20]3[CH:21]=[C:22]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH3:33])[CH:27]=4)[CH:23]=[CH:24][CH:25]=3)[N:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[S:8][CH2:9][C@@H:4]2[CH2:3]1.Cl[CH2:35][O:36][CH3:37].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:33][O:32][C:28]1[CH:27]=[C:26]([C:22]2[CH:23]=[CH:24][CH:25]=[C:20]([C@:5]34[CH2:19][C@H:2]([O:1][CH2:35][O:36][CH3:37])[CH2:3][C@H:4]3[CH2:9][S:8][C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[N:6]4)[CH:21]=2)[CH:31]=[CH:30][CH:29]=1
Reactant: COCCl
Reactant: COc1cccc(-c2cccc([C@]34C[C@H](O)C[C@H]3CSC(NC(=O)c3ccccc3)=N4)c2)c1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCO[C@@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2cccc(-c3cccc(OC)c3)c2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a stirred 0° C. solution of N-((4aR,6R,7aS)-6-hydroxy-7a-(3′-methoxybiphenyl-3-yl)-4,4a,5,6,7,7a-hexahydrocyclopenta[d][1,3]thiazin-2-yl)benzamide (0.087 g, 0.190 mmol) in anhydrous dichloromethane (0.6 mL) is added chloromethoxymethane (0.031 g, 0.379 mmol), followed by diisopropylethylamine (0.049 g, 0.379 mmol). The resulting mixture is stirred at 0° C. for 1 hour, and then is warmed to room temperature over 24 h. The mixture is diluted with dichloromethane, quenched by addition of saturated aqueous solution of sodium bicarbonate, and is extracted three times with dichloromethane. The combined organic layers are washed with water and brine. The organic layer is dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel chromatography eluting with a linear gradient of 0% to 60% ethyl acetate in hexanes over 26 minutes to give the title compound (0.089, 93%). ES/MS m/e: 503 (M+1).
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:9]=2)[C:4](=[O:17])[O:3]1.CC(C)([O-])C.[K+].[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30]([F:32])[CH:31]=1>CN(C)C=O>[F:25][C:26]1[CH:27]=[C:28]([N+:33]([O-:35])=[O:34])[CH:29]=[C:30]([F:32])[C:31]=1[CH:11]([N:12]1[CH:16]=[N:15][CH:14]=[N:13]1)[C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4](=[O:17])[O:3][C:2]2([CH3:18])[CH3:1]
Reactant: CC1(C)OC(=O)c2ccc(Cn3cncn3)cc21
Reactant: O=[N+]([O-])c1cc(F)cc(F)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C)OC(=O)c2ccc(C(c3c(F)cc([N+](=O)[O-])cc3F)n3cncn3)cc21
Reaction time: 5 h

Procedure:
To a solution of 3,3-dimethyl-5-[1,2,4-triazol-1-ylmethyl]-3H-isobenzofuran-1-one (4.47 g Intermediate 1) in N,N-dimethylformamide (250 ml) at 0° under nitrogen was added potassium tert-butoxide (4.53 g). After one hour 3,5-difluoronitrobenzene (3.22 g) was added and stirring continued for five hours. The reaction mixture was partitioned between water and ethyl acetate and the phases separated. The aqueous phase was extracted with ethyl acetate and the combined organic extracts were washed with water and brine, dried and then evaporated to yield a brown oil. This was purified by column chromatography on Merck 9385 silica eluting initially with dichloromethane through to a 50:1 mixture of dichloromethane:methanol to yield a brown foam. The brown foam was further purified by gradient elution HPLC (water-acetonitrile-trifluoroacetic acid) to give 5-[(2,6-difluoro-4-nitrophenyl)-1,2,4-triazol-1-ylmethyl]-3,3-dimethyl-3H-isobenzofuran-1-one as a yellow foam.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][P:11]([OH:13])[OH:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.C[Si](Cl)(C)C.[C:26]([O:30][CH3:31])(=[O:29])[CH:27]=[CH2:28]>C(Cl)(Cl)Cl>[OH:12][P:11]([CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:28][CH2:27][C:26]([O:30][CH3:31])=[O:29])=[O:13]
Reactant: OP(O)CCCCc1ccccc1
Reactant: C=CC(=O)OC
Agent: C[Si](C)(C)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COC(=O)CCP(=O)(O)CCCCc1ccccc1
Yield: 88.6 %

Procedure:
To a solution of 4-phenylbutyl phosphonous acid (1 g, 0.005 mole) in chloroform (40 ml) was added triethylamine (1.55 ml, 0.0111 mole), trimethyl silylchloride (1.41 ml, 0.0111 mole) and methyl acrylate (0.50 ml, 0.0055 mole). The reaction mixture was stirred at reflux for 18 hours. CHCl3 was removed in vacuo. The residue was diluted with ether and extracted with 5% aqueous NaHCO3 solution. Aqueous layers were acidified with concentrated HCl and extracted with ether. Organic layers were extracted with brine and dried over Na2SO4. Solvent was removed in vacuo to give 1.26 g of an oil. T-60 1H NMR appeared to characterize product from Michael addition.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(C(C)C)C(C)C)C.[N:42]1[CH:47]=[CH:46][C:45]([NH2:48])=[CH:44][CH:43]=1>ClCCl>[CH:1]1([N:6]2[CH2:12][C:11]([F:13])([F:14])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:48][C:45]5[CH:46]=[CH:47][N:42]=[CH:43][CH:44]=5)=[O:27])=[CH:24][C:23]=4[O:31][CH3:32])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: Nc1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(C(=O)Nc2ccncc2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 2 h
Yield: 17.4 %

Procedure:
A mixture of 0.050 g (0.11 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl-amino)-3-methoxy-benzoic acid (I-22), 0.048 g (0.12 mmole) of N-[(dimethylamino)-1H-1,2,3-triazolo[4,5-b]pyridine-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, 0.037 g (0.28 mmole) of ethyldiisopropyl amine, 0.016 g (0.17 mmole) of pyridine-4-ylamine and 0.5 ml of dichloromethane was stirred for 2 hours and then concentrated under reduced pressure. The residue was dissolved in 0.5 ml of methanol, and then precipitated by the addition of water. The residue was washed three times with water and then purified by chromatography on reverse phase silica gel, eluting with acetonitrile-water to give 0.01 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-N-pyridin-4-yl-benzamide (I-129).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1.[CH2:25]1OC(O)C[O:27][CH:26]1O.CC(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[CH3:1][N:2]([CH2:3][C:4]1([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][CH2:19][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:12][CH:11]=2)[CH2:9][CH2:8][O:7][CH2:6][CH2:5]1)[CH2:25][CH2:26][OH:27]
Reactant: OC1COC(O)CO1
Reactant: CNCC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CN(CCO)CC1(c2ccc(OCCCN3CCCC3)cc2)CCOCC1
Yield: 56.2 %

Procedure:
A solution of methyl-{4-[4-(3-pyrrolidin-1-ylpropoxy)phenyl]-tetrahydropyran-4-ylmethyl}amine (350 mg, 1.05 mmol), glycolaldehyde dimer (130 mg, 1.05 mmol) and AcOH (0.15 ml, 2.1 mmol) in DCM (5 ml) was stirred at room temperature for 18 hours. Saturated aqueous sodium carbonate (10 ml) and DCM (10 ml) were added and the mixture was shaken and partitioned. The aqueous phase was extracted with DCM (2×10 ml) and the combined organics dried (K2CO3), filtered and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel eluting with dichloromethane:methanol:ammonia (92:8:1) to provide the title compound as a clear colourless oil (223 mg, 0.59 mmol, 56%). 1H NMR (400 MHz, CDCl3) δ 1.70-1.90 (m, 6H), 1.96 (s, 3H), 2.00 (quintet, 2H), 2.14 (m, 2H), 2.37 (t, 2H), 2.40-2.60 (m, 6H), 2.65 (t, 2H), 3.35 (t, 2H), 3.50 (m, 2H), 3.76 (m, 2H), 4.01 (t, 2H), 6.89 (d, 2H), 7.19 (d, 2H). HRMS ESI+ m/z 377.2796 [MH]+.
Reaction SMILES: [CH2:1]([C:5]1[C:6]([CH3:13])=[C:7]([C:10]([OH:12])=[O:11])[S:8][CH:9]=1)[CH:2]([CH3:4])[CH3:3].[Li][CH2:15]CCC.IC>C1COCC1>[CH2:13]([C:6]1[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:9][S:8][C:7]=1[C:10]([OH:12])=[O:11])[CH3:15]
Reactant: [Li]CCCC
Reactant: Cc1c(CC(C)C)csc1C(=O)O
Solvent: CI
Solvent: C1CCOC1
Product: CCc1c(CC(C)C)csc1C(=O)O
Temperature: -78 °C
Reaction time: 1 h
Yield: 30.6 %

Procedure:
To a solution of 4-isobutyl-3-methyl-thiophene-2-carboxylic acid (991 mg, 5.0 mmol) in THF (30 mL), tert.-BuLi (7.3 mL, 11 mmol, 1.5 M in pentane) is slowly added at −78° C. The mixture is stirred at −78° C. for 1 h, then iodomethane (1.6 mL, 25.7 mmol) is added. The mixture is stirred and is allowed to warm to rt over a period of 15 h before the reaction is quenched with 1 N aq. HCl (50 mL) and extracted with DCM (1×100 mL, 2×50 mL). The combined organic extracts are dried (MgSO4), filtered and evaporated. The residue is purified by CC on silica gel eluting with a gradient of EA in hexane to give 3-ethyl-4-isobutyl-thiophene-2-carboxylic acid (325 mg) as a yellow solid; LC-MS: tR=0.98 min, 1H NMR (CD3OD): δ 7.22 (s, 1H), 2.94 (q, J=7.6 Hz, 2H), 2.42 (d, J=7.0 Hz, 2H), 1.86 (hept, J=7.0 Hz, 1H), 1.11 (t, J=7.6 Hz, 3H), 0.93 (d, J=7.0 Hz, 6H).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][C:8]=1[CH3:15].[CH:16](=[O:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]>O1CCCC1>[OH:26][CH:16]([C:7]1[CH:14]=[CH:13][C:10]([CH2:11][OH:12])=[CH:9][C:8]=1[CH3:15])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: Cc1cc(CO)ccc1Br
Reactant: CCCCCCCCCC=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCCCCCCC(O)c1ccc(CO)cc1C
Temperature: 0 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
n-Butyllithium (2.5 M in hexanes, 8.3 mL, 20.7 mmol) was added dropwise to a solution of 4-bromo-3-methylbenzyl alcohol (1.90 g, 9.44 mmol, from Step A) in tetrahydrofuran (25 mL) at −78° C. After 1 h, n-decanal (2.95 g, 18.89 mmol) was added and the reaction allowed to warm to 0° C. After 30 min, the reaction was quenched with water (25 mL) and diluted with ethyl acetate (25 mL). The organic layer was washed with sat'd sodium chloride (30 mL), dried over magnesium sulfate and concentrated in vacuo. Silica gel chromatography eluting with 25% ethyl acetate/hexane gave 1.69 g (6.07 mmol, 64%) of product: 1H NMR (500 MHz): δ 7.45 (d, J=8.0 Hz, 1H), 7.21 (d, J=7.8 Hz, 1H), 7.14 (s, 1H), 4.88-4.94 (m, 1H), 4.64 (s, 2H), 2.34 (s, 3H), 1.22-1.80 (m, 16H), 0.87 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:20][CH:19]=1)=O.[C:31]([O-])([O-])=O.[K+].[K+].[N+](=C(P(=O)(OC)OC)C(=O)C)=[N-]>CO.C(Cl)Cl>[C:1]([C:3]1[N:4]=[C:5]2[C:10]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)=[CH:9][CH:8]=[N:7][N:6]2[C:17]=1[C:18]1[CH:30]=[CH:29][C:21]([C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])=[CH:20][CH:19]=1)#[CH:31]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)c1ccc(-c2c(C=O)nc3c(N4CCOCC4)ccnn23)cc1
Agent: COP(=O)(OC)C(=[N+]=[N-])C(C)=O
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: C#Cc1nc2c(N3CCOCC3)ccnn2c1-c1ccc(C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a suspension of compound 5f (0.30 g, 0.73 mmol, Example 5) in MeOH (5 mL) was added K2CO3 (0.30 g, 2.2 mmol) and a solution of dimethyl (1-diazo-2-oxopropyl)phosphonate (0.18 g, 0.96 mmol) in MeOH (2 mL). The reaction mixture was stirred at rt for 2 days, and concentrated under reduced pressure. The residue obtained was dissolved in DCM (20 mL) and washed with water (20 mL). The aqueous layer was extracted with DCM (3×10 mL). The combined organic extracts were washed with brine, and dried over MgSO4. The mixture was filtered and concentrated to give a residue, which was purified by flash column chromatography on silica gel (20-60% EtOAc/heptane) to give the compound 17a as an off-white solid. Mass Spectrum (LCMS, ESI pos.): Calcd. for C23H24N4O3: 405.2 (M+H). found: 405.2.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6].[Si]([O:30][CH2:31][CH2:32][N:33]([CH3:45])[C:34](=[O:44])[C:35]1[CH:40]=[CH:39][C:38](F)=[C:37]([Cl:42])[C:36]=1F)(C(C)(C)C)(C)C.C(=O)([O-])[O-].[K+].[K+].O>C(#N)C>[Cl:42][C:37]1[C:36]2[O:30][CH2:31][CH2:32][N:33]([CH3:45])[C:34](=[O:44])[C:35]=2[CH:40]=[CH:39][C:38]=1[O:1][C:2]1[CH:3]=[C:4]([CH:14]=[C:15]([O:17][C@H:18]2[CH2:22][CH2:21][O:20][CH2:19]2)[CH:16]=1)[C:5]([NH:7][C:8]1[CH:12]=[CH:11][N:10]([CH3:13])[N:9]=1)=[O:6]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Reactant: Cn1ccc(NC(=O)c2cc(O)cc(O[C@H]3CCOC3)c2)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CN1CCOc2c(ccc(Oc3cc(O[C@H]4CCOC4)cc(C(=O)Nc4ccn(C)n4)c3)c2Cl)C1=O
Temperature: 140 °C
Yield: 31.9 %

Procedure:
A mixture of 3-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)-5-[(3S)-tetrahydrofuran-3-yloxy]benzamide (539 mg, 1.77 mmol), N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (539 mg, 1.77 mmol) and potassium carbonate (490 mg, 3.55 mmol) in acetonitrile (15 mL) was placed in a Smith Creator microwave reactor and heated to 140° C. for 6 hours. Distilled water was added to the reaction and the aqueous layer extracted with DCM (3×30 mL). The combined organic phase was washed with brine (30 mL), dried (MgSO4), filtered and evaporated to give a yellow oil. This was purified by column chromatography, eluting with 20-100% ethyl acetate in isohexane, to give the title compound (290 mg). 1H NMR δ (CDCl3): 2.09-2.15 (1H, m), 2.18-2.27 (1H, m), 3.23 (3H, s), 3.59 (2H, t), 3.76 (3H, s), 3.86-3.92 (1H, m), 3.94-4.00 (3H, m), 4.54 (2H, t), 4.95 (1H, d), 6.68 (1H, d), 6.78-6.81 (2H, m), 7.04-7.05 (1H, m), 7.16-7.17 (1H, m), 7.28 (1H, d), 7.70 (1H, d), 8.75 (1H, s); m/z 513 (M+H)+.