Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:34])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([OH:30])=O)=[CH:25][C:24]=4[CH:31]=3)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.C(N(CC)CC)C.Cl.C([O:59][C:60](=[O:64])[CH2:61][NH:62][CH3:63])C>>[CH3:34][C:2]1([CH3:1])[CH2:7][CH2:6][CH2:5][CH:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]([C:20]3[CH:21]=[CH:22][C:23]4[O:27][C:26]([C:28]([N:62]([CH2:61][C:60]([OH:64])=[O:59])[CH3:63])=[O:30])=[CH:25][C:24]=4[CH:31]=3)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=2[CH3:32])[C:3]1=[O:33]
Reactant: CCOC(=O)CNC
Reactant: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)O)cc2c1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: CCC(CC)(c1ccc(OC2CCCC(C)(C)C2=O)c(C)c1)c1ccc2oc(C(=O)N(C)CC(=O)O)cc2c1

Procedure:
A solution of 5-{1-[4-(3,3-Dimethyl-2-oxo-cyclohexyloxy)-3-methyl-phenyl]-1-ethyl-propyl}-benzofuran-2-carboxylic acid (244 mg, 0.527 mmol) (from example 73A), EDC (151 mg, 0.791 mmol), HOBT (75 mg, 0.554 mmol), triethylamine (0.3 ml, 2.1 mmol), and sarcosine ethyl ester hydrochloride (105 mg, 0.685 mmol) were reacted followed by base hydrolysis as in Example 74 to yield (48 mg, 30%) MS (ES) m/e: 532.3 (M−1)
Reaction SMILES: FC[CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:23])=[O:22])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1.[F:39][CH2:40][CH2:41]CN=[N+]=[N-]>>[F:39][CH2:40][CH2:41][CH2:3][N:4]1[CH:8]=[C:7]([CH2:9][N:10]2[C:20]3[C:15](=[CH:16][C:17]([S:21]([N:24]4[CH2:28][CH2:27][CH2:26][C@H:25]4[CH2:29][O:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][C:32]=4[F:38])(=[O:22])=[O:23])=[CH:18][CH:19]=3)[C:13](=[O:14])[C:11]2=[O:12])[N:6]=[N:5]1
Reactant: [N-]=[N+]=NCCCF
Reactant: O=C1C(=O)N(Cc2cn(CCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21
Product: O=C1C(=O)N(Cc2cn(CCCF)nn2)c2ccc(S(=O)(=O)N3CCC[C@H]3COc3ccc(F)cc3F)cc21

Procedure:
was prepared according to the procedure for compound 11, with the exception that 3-fluoropropylazide was used in place of the 2-fluoroethylazide.
Reaction SMILES: CCN=C=NCCCN(C)C.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=[C:21]([C:31](O)=[O:32])[C:20]=2[CH2:34][C:35]#[N:36])=[CH:15][CH:14]=1.C1C=CC2N(O)N=NC=2C=1.[Br:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([NH2:56])[CH3:55])=[CH:50][CH:49]=1>ClCCl>[Br:47][C:48]1[CH:53]=[CH:52][C:51]([CH:54]([NH:56][C:31]([C:21]2[C:20]([CH2:34][C:35]#[N:36])=[C:19]([C:16]3[CH:15]=[CH:14][C:13]([Cl:12])=[CH:18][CH:17]=3)[N:23]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[Cl:30])[N:22]=2)=[O:32])[CH3:55])=[CH:50][CH:49]=1
Reactant: N#CCc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: CC(N)c1ccc(Br)cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(NC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1CC#N)c1ccc(Br)cc1
Reaction time: 16 h
Yield: 88 %

Procedure:
EDAC (386 mg, 2.00 mmol) was added to a stirred solution of [B1] (500 mg, 1.34 mmol) and HOBT (236 mg, 1.75 mmol) in dichloromethane (80 ml) at room temperature under argon. After 15 minutes 1-(4-bromo-phenyl)-ethylamine (322 mg, 1.61 mmol) was added and stirring continued for 16 hours. The mixture was washed with saturated aqueous sodium bicarbonate solution (3×) then with brine, dried over magnesium sulphate, filtered and evaporated in vacuo to give the title compound [C1] (655 mg, 1.18 mmol, 88%) as a foam.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1.[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1B(O)O>>[CH3:20][O:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][C:27]=1[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][S:16]([CH3:19])(=[O:18])=[O:17])[CH:10]=2)[N:3]=1
Reactant: COc1cnccc1B(O)O
Reactant: CS(=O)(=O)Cc1cccc(Nc2ncnc(Cl)n2)c1
Product: COc1cnccc1-c1ncnc(Nc2cccc(CS(C)(=O)=O)c2)n1

Procedure:
Example 8 was prepared under similar conditions as described in the preparation of Example 1 using crude 4-chloro-N-{3-[(methylsulfonyl)methyl]phenyl}-1,3,5-triazin-2-amine and (3-methoxypyridin-4-yl)boronic acid (Combi-Blocks Inc.). The batch was purified by preparative HPLC:
Reaction SMILES: [N:1]([CH:4]1[CH2:23][N:8]2[C:9]3[C:14]([C:15]([CH2:16][C:17]([O:19]CCC)=[O:18])=[C:7]2[CH2:6][CH2:5]1)=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N+:2]=[N-:3].[C:24]([C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1)#[CH:25]>>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([C:24]2[N:3]=[N:2][N:1]([CH:4]3[CH2:23][N:8]4[C:9]5[C:14]([C:15]([CH2:16][C:17]([OH:19])=[O:18])=[C:7]4[CH2:6][CH2:5]3)=[CH:13][CH:12]=[CH:11][CH:10]=5)[CH:25]=2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: CCCOC(=O)Cc1c2n(c3ccccc13)CC(N=[N+]=[N-])CC2
Reactant: C#Cc1ccc(S(C)(=O)=O)cc1
Product: CS(=O)(=O)c1ccc(-c2cn(C3CCc4c(CC(=O)O)c5ccccc5n4C3)nn2)cc1

Procedure:
The title compound was prepared using procedures described in EXAMPLE 1 from propyl (7-azido-6,7,8,9-tetrahydropyrido[1,2-a]indol-10-yl)acetate and 1-ethynyl-4-(methylsulfonyl)benzene. MS (+ESI) m/z: 451.1.
Reaction SMILES: [C:1]1([CH:7]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19].C(N(CC)CC)C>O1CCCC1.O>[CH3:17][S:18]([O:10][CH2:9][CH2:8][CH:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1)(=[O:20])=[O:19]
Reactant: OCCC(c1ccccc1)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 78.6 %

Procedure:
To a mixed solution of 3,3-diphenyl-1-propanol (24.0 g, 113 mmol) and methanesulfonyl chloride (13.7 g, 120 mmol) in tetrahydrofuran (200 mL) was added triethylamine (17.0 mL, 120 mmol) gradually at 0° C. and the mixture was stirred at room temperature for 10 minutes. This reaction mixture was diluted with water (200 mL) and extracted with 2 portions of ethyl acetate. The combined organic solution was washed with saturated aqueous sodium chloride solution, dried over MgSO4, and filtered. The filtrate was concentrated under reduced pressure and the residue was crystallized from diisopropyl ether to provide 25.8 g of the title compound. Yield 79%.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([OH:30])=O)=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[CH3:68][N:69]([CH3:74])[CH2:70][CH2:71][CH2:72][NH2:73]>C(OCC)(=O)C.O.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH2:16][CH2:17][CH3:18])[C:8]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:73][CH2:72][CH2:71][CH2:70][N:69]([CH3:74])[CH3:68])=[O:30])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc21
Reactant: CN(C)CCCN
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCCN1C(=O)C(F)(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NCCCN(C)C)cc3OC)ncc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 29.2 %

Procedure:
To a mixture of 0.05 g (0.11 mmole) of 4-(9-cyclopentyl-5-propyl-7,7-difluoro-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-methoxy-benzoic acid (I-162), 0.06 g (0.16 mmole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium-3-oxide hexafluorophosphate and 2 mL of dimethylformamide was added 0.05 mL (0.32 mmole) of diisopropylethylamine. After stirring at room temperature for 30 minutes 0.04 mL (0.32 mmole) of 3-(dimethylamino)-propylamine was then added. The mixture was stirred at room temperature for 18 hours and then diluted with ethyl acetate and water. The aqueous phase was extracted twice with ethyl acetate. The combined organic layers were washed with water then brine, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with methanol-dichloromethane (gradient, 0:100-25:75) to give 0.018 g of 4-(9-cyclopentyl-5-propyl-7,7-difluoro-6-oxo-6,7,8,9-tetra-hydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-(3-dimethylamino-propyl)-3-methoxy-benzamide (I-166).
Reaction SMILES: Cl[C:2]1[C:7]2[CH:8]=[C:9]3[N:14]([C:6]=2[C:5]([CH3:15])=[N:4][N:3]=1)[CH:13]=[CH:12][CH:11]=[CH:10]3.[NH2:16][CH2:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH3:15][C:5]1[N:4]=[N:3][C:2]([NH:16][CH2:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)=[C:7]2[C:6]=1[N:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[CH:8]2
Reactant: NCCCN1CCCCC1
Reactant: Cc1nnc(Cl)c2cc3ccccn3c12
Product: Cc1nnc(NCCCN2CCCCC2)c2cc3ccccn3c12

Procedure:
Following the procedure of Example 1, reaction of one equivalent of 1-chloro-4-methylpyridazino[4,5-b]indolizine and 10 equivalents of 1-(3-aminopropyl)piperidine at 130° C. gave the title compound as the free base (oil, 83%) after HPLC purification. Trituration with hexane gave a yellow solid (50%), mp 130°-134° C. The free base was then converted to the dihydrochloride salt (MeOH/ethereal HCl/diethyl ether), mp. 302°-303° C.
Reaction SMILES: S(=O)(O)[O-].[Na+].[CH:6](=[O:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.[C-:16]#[N:17].[Na+].COC(C)(C)C>O>[CH3:14][O:13][C:10]1[CH:11]=[CH:12][C:7]([CH:6]([OH:15])[C:16]#[N:17])=[CH:8][CH:9]=1
Reactant: COc1ccc(C=O)cc1
Reactant: [C-]#N
Agent: O=S([O-])O
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Product: COc1ccc(C(O)C#N)cc1
Temperature: 40 °C
Reaction time: 3 h

Procedure:
Water (720 ml), sodium bisulfite (81 g, 0.775 mol, 1.2 equiv) and p-anisaldehyde (88 g, 0.646 mol, 1.0 equiv) are combined, warmed to 40° C. and stirred for 3 hrs. The slurry is cooled to 5° C., and sodium cyanide (35 g, 0.711 mol, 1.1 equiv) in 140 ml water is added. The reaction is stirred for 2 hrs. at 5° C., then warmed to room temperature, and methyl-t-butyl ether (MTBE) (400 ml) added. The layers are separated after a brief stir, and the aqueous phase re-extracted with MTBE (100 ml). The combined organic layers were dried (MgSO4), and concentrated to an oil, which was seeded to afford product: 69.5 g, 65.9%. The material can be recrystallized from toluene (3 ml per g substrate, heat to 35° C., cool to 5° C., 90% recovery).
Reaction SMILES: [H-].[Na+].[N:3]1[C:11]([NH2:12])=[C:10]2[C:6]([N:7]=[CH:8][NH:9]2)=[N:5][CH:4]=1.Br[CH2:14][CH2:15][C:16]#[N:17]>CN(C=O)C.CCOC(C)=O.Cl>[C:16]([CH2:15][CH2:14][N:7]1[CH:8]=[N:9][C:10]2[C:6]1=[N:5][CH:4]=[N:3][C:11]=2[NH2:12])#[N:17]
Reactant: Nc1ncnc2nc[nH]c12
Reactant: N#CCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: N#CCCn1cnc2c(N)ncnc21
Temperature: 80 °C
Yield: 88.9 %

Procedure:
To a suspension of 57% NaH in mineral oil (0.962 g, 22.8 mmol) in dry DMF (100 mL) was added 10 (3.40 g, 24.9 mmol) under nitrogen and the mixture was heated at 80° C. for 1.0 h. A solution of 3-bromopropionitrile (2.81 g, 21.0 mmol) in DMF (5.0 mL) was added at 25° C. and the reaction was heated at 65° C. for 17 h. It was then diluted with EtOAc (250 mL) and 5% aqueous HCl solution (150 mL). The organic layer was separated and then washed with water (4×100 mL). It was dried over MgSO4 (s) and concentrated under reduced pressure. Purification of the residue was carried out by use of column chromatography (EtOAc/hexanes=7.5:2.5) to afford compound 15 (3.510 g, 18.67 mmol) in 75% yield: mp 148-150° C.; Rf(hexanes/EtOAc=1:2) 0.38; UV (EtOH) λmax 260 (ε 13,900); 1H NMR (CD3OD) δ 2.92 (t J=5.8 Hz, 2 H, CH2CN),3.43 (t, J=5.8 Hz, 2 H, CH2N), 8.35 (s, 1 H, HC2), 8.69 (s, 1 H, HC8); MS m/z 188 (M+).
Reaction SMILES: CN(OC)[C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[NH2:11].Br[C:16]1[CH:17]=[C:18]([CH:22]2[O:26][CH2:25][CH2:24][O:23]2)[CH:19]=[CH:20][CH:21]=1.CCCCCC.C([Li])CCC>O1CCCC1.C(OC(=O)C)C.O>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=1[C:3]([C:20]1[CH:19]=[C:18]([CH:22]2[O:23][CH2:24][CH2:25][O:26]2)[CH:17]=[CH:16][CH:21]=1)=[O:12]
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: CON(C)C(=O)c1cc(Cl)ccc1N
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1ccc(Cl)cc1C(=O)c1cccc(C2OCCO2)c1
Yield: 57.5 %

Procedure:
A solution of N-methyl-N-methyloxy-2-amino-5-chlorobenzamide (2 g) and 2-(3-bromophenyl)-1,3-dioxolane (2.1 g) in tetrahydrofuran (65 ml) was cooled to −78° C. To the solution was added dropwise gradually a hexane solution of n-butyl lithium (1.6 mol/L)(11.6 ml). To the mixture were added water (300 ml) and acetic acid ethyl ester (50 ml). The organic layer was washed with water and dried over anhydrous Na2SO4, then the solvent was distilled off. The residue was purified by means of a silica gel column chromatography to give 2-[3-(2-amino-5-chlorobenzoyl)phenyl-1,3-dioxolane (1.6 g) as a colorless oily compound.
Reaction SMILES: [CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[NH:19][CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1.O=[C:26]1[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]1.ClC(Cl)C.C(O)(=O)C.[Na]>>[CH3:1][N:2]1[C:15]2[C:6]([CH:7]=[CH:8][C:9]3[N:19]([CH:26]4[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]4)[CH2:18][CH:17]=[C:11]4[NH:12][C:13](=[O:16])[C:14]=2[C:10]=34)=[C:5]([CH2:20][S:21]([CH3:24])(=[O:23])=[O:22])[CH:4]=[CH:3]1
Reactant: CN1C=CC(CS(C)(=O)=O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CN1C=CC(CS(C)(=O)=O)=c2ccc3c4c([nH]c(=O)c-4c21)=CCN3C1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 50 °C
Yield: 83.7 %

Procedure:
To a mixture of Example 6a (0.015 g, 0.044 mmol) and tert-butyl 4-oxopiperidine-1-carboxylate (0.017 g, 0.087 mmol) was added dichloroethane (1 mL) and acetic acid (0.03 mL, 0.524 mmol). The reaction mixture was heated at 50° C. for 2 hours, treated with sodium triacetoxyhydroborate (0.028 g, 0.131 mmol) and heated overnight at 50° C. Additional tert-butyl 4-oxopiperidine-1-carboxylate (0.017 g, 0.087 mmol) was added and the mixture was heated for 1 hour. Additional sodium triacetoxyhydroborate (0.028 g, 0.131 mmol) was added and the mixture was heated over a second night at 50° C. The reaction mixture was cooled to ambient temperature, partitioned between ethyl acetate and water, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (silica gel, 0-6% methanol in dichloromethane) to give 0.0194 g (84%) of the title compound. 1H NMR (500 MHz, DMSO-d6) δ 10.71 (d, J=5.49 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.13 (s, 1H), 6.79 (d, J=5.49 Hz, 1H), 4.40 (m, 2H), 4.11 (s, 3H), 3.87 (m, 2H), 3.73 (m, 1H), 3.63 (m, 1H), 3.19 (m, 1H), 2.91 (s, 3H), 2.66 (m, 2H), 1.67 (m, 1H), 1.58 (m, 1H), 1.45 (m, 2H), 1.38 (s, 9H), 1.23 (m, 1H). MS (ESI+) m/z 526.8 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1.[Cl:15][C:16]1[CH:17]=[C:18]([CH2:23][OH:24])[CH:19]=[C:20]([F:22])[CH:21]=1>>[Cl:15][C:16]1[CH:17]=[C:18]([CH:19]=[C:20]([F:22])[CH:21]=1)[CH2:23][O:24][C:2]1[CH:3]=[C:4]2[N:11]([CH3:12])[C:10]([CH3:14])([CH3:13])[CH2:9][N:5]2[C:6](=[O:8])[N:7]=1
Reactant: OCc1cc(F)cc(Cl)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)cc(Cl)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one and (3-chloro-5-fluorophenyl)methanol.
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[NH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([N:18]=[CH:19][N:20]([CH3:22])[CH3:21])=[C:13]([Cl:23])[CH:12]=1>C(O)C>[Cl:17][C:15]1[CH:16]=[C:11]([N:10]=[CH:1][C:2]2[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=2[OH:4])[CH:12]=[C:13]([Cl:23])[C:14]=1[N:18]=[CH:19][N:20]([CH3:22])[CH3:21]
Reactant: CN(C)C=Nc1c(Cl)cc(N)cc1Cl
Reactant: O=Cc1ccccc1O
Solvent: CCO
Product: CN(C)C=Nc1c(Cl)cc(N=Cc2ccccc2O)cc1Cl

Procedure:
A mixture of 3.7 g. of salicylaldehyde and 7.0 g. of N'-[4-amino-2,6-dichlorophenyl]-N,N-dimethylformamidine is heated neat at 80° C. for 18 hours. The mixture is cooled and ethanol is added to give crystals. The mixture is heated and then cooled to recrystallize the product. The product is collected, washed with cold ethanol then ether to give 9.0 g. of the product of the Example as yellow crystals, m.p. 113°-115° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[CH:4][CH:3]=1.Cl[CH2:12][C:13](Cl)=[O:14].C([O-])([O-])=O.[K+].[K+]>>[F:10][C:5]1[CH:4]=[CH:3][C:2]2[NH:1][C:13](=[O:14])[CH2:12][O:8][C:7]=2[C:6]=1[F:9]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccc(F)c(F)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C1COc2c(ccc(F)c2F)N1

Procedure:
6-Amino-2,3-diflourophenol (81KK30a) (0.113 g, 0.78 mmol), 2-chloroacetyl chloride (0.10 g, 0.89 mmol) and K2CO3 (0.226 g, 1.6 mmol) were mixed according to GP1 to give the title compound as a crude (81MF2082A) (0.12 g)
Reaction SMILES: CC(C)(OC(CN(C)C(N1CCC[C@H]1C(OCC1C=CC=CC=1)=O)=O)=O)C.FC(F)(F)C(O)=O.[C:35]1(OC)[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[C:43]([CH2:46][CH2:47][N:48]([CH3:66])[C:49]([N:51]1[CH2:65][CH2:64][CH2:63][C@H:52]1[C:53]([O:55][CH2:56][C:57]1C=CC=CC=1)=[O:54])=[O:50])([OH:45])=[O:44]>>[C:43]([CH2:46][CH2:47][N:48]([CH3:66])[C:49]([N:51]1[CH2:65][CH2:64][CH2:63][C@H:52]1[C:53]([O:55][CH2:56][CH2:57][C:35]1[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=1)=[O:54])=[O:50])([OH:45])=[O:44]
Reactant: CN(CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: COc1ccccc1
Agent: CN(CC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CN(CCC(=O)O)C(=O)N1CCC[C@H]1C(=O)OCCc1ccccc1

Procedure:
The ester product from part (c) (2.7 g., 7.17 mmole) is treated for 1.5 hours with 10 ml. of trifluoroacetic acid and 1.6 ml. of anisole. After concentrating to dryness it is triturated with ether-hexane. The crude material is crystallized from ether to yield 2 g. of 1-[[(2-carboxyethyl)methylamino]carbonyl]-L-proline, phenylmethyl ester; m.p. 102°-104°.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([S:14]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C>C(O)=O>[F:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][S:14]([CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:15])=[CH:22][CH:21]=1
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)Cc2ccc(F)cc2)CC1
Solvent: O=CO
Product: O=S(Cc1ccc(F)cc1)C1CCNCC1
Yield: 95.5 %

Procedure:
Using a similar method to that described in Example 108, step 2, 1-(tert-butoxycarbonyl)-4-(4-fluorobenzylsulfinyl)piperidine (1.524 g, 4.46 mmol) was reacted with 90% formic acid (15ml) to give 1.0276 g (95%) of the title compound as a white solid. δH (250 MHz, CDCl3) 1.47 (2H, m), 1.82 (2H, m), 2.49 (2H, m), 2.69 (1H, tt, J=4.0 and 11.8 Hz), 3.03 (2H, m), 3.88 (1H, d, J=13.0 Hz), 4.11 (1H, d, J=13.0 Hz), 7.20 (2H, t, J=8.9 Hz), 7.37 (2H, m). m/e (ES+) 242 (M+H)+.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][C:11]([C:12]([O:14]CC)=[O:13])=[C:4]2[CH2:3]1.[OH-].[Li+]>CO.O>[CH3:1][N:2]1[CH2:8][CH2:7][CH2:6][N:5]2[C:9]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:10][C:11]([C:12]([OH:14])=[O:13])=[C:4]2[CH2:3]1
Reactant: CCOC(=O)c1nc(-c2ccccc2)n2c1CN(C)CCC2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN1CCCn2c(-c3ccccc3)nc(C(=O)O)c2C1
Temperature: 50 °C
Reaction time: 2 h
Yield: 72.2 %

Procedure:
To a solution of intermediate 64B (0.87 g, 2.91 mmol) in 20 mL methanol was added lithium hydroxide (0.139 g, 5.81 mmol) in 5 mL water. The reaction mixture was stirred at 50° C. for 2 hours, filtered, concentrated and neutralized with 1N HCl. The resulting solution was lyophilized to provide intermediate 64C (0.57 g, 72%) as a white solid. LCMS (+ESI) m/z 272.1 [M+H]+
Reaction SMILES: [F:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:12](=[O:13])[CH2:11][N:10]([C:14]([NH:16][CH:17]([CH3:19])[CH3:18])=[O:15])[CH:9]([CH2:20][CH2:21][N:22]([O:24][CH3:25])[CH3:23])[CH2:8]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].C1COCC1.[C:43](OCC)(=[O:49])[C:44](OCC)=[O:45]>CN(C=O)C.CO.C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:8][CH:9]([CH2:20][CH2:21][N:22]([O:24][CH3:25])[CH3:23])[N:10]3[C:14](=[O:15])[N:16]([CH:17]([CH3:19])[CH3:18])[C:44](=[O:45])[C:43]([OH:49])=[C:11]3[C:12]2=[O:13])=[CH:26][CH:27]=1
Reactant: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)CN1C(=O)NC(C)C
Reactant: CCOC(=O)C(=O)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CON(C)CCC1CN(Cc2ccc(F)cc2)C(=O)c2c(O)c(=O)n(C(C)C)c(=O)n21
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
4-(4-Fluorobenzyl)-N-isopropyl-2-{2-[methoxy(methyl)amino]ethyl}-5-oxopiperazine-1-carboxamide (777 mg, 2.04 mmol) was azeotroped with anhydrous toluene (10 μL) and dissolved in anhydrous DMF (10 mL). The solution was cooled to 0° C. under inert atmosphere and treated with 1.0 M lithium bis(trimethylsilyl)amide in THF (2.45 mL, 2.45 mmol). After stirring for 10 min, diethyl oxalate (416 μL, 3.06 mmol) was added. The mixture was stirred at 0° C. for an additional 15 min and then allowed to warm to ambient temperature. Following addition of excess 1.0 M lithium bis(trimethylsilyl)amide in THF (7.30 mL, 7.30 mmol), the reaction was stirred at ambient temperature for 18 h. The mixture was treated with MeOH and concentrated in vacuo to give a dark oil. Purification by reverse phase chromatography [95:5 water (+0.1% TFA)/MeCN (+0.1% TFA) to 5:95 water (+0.1% TFA)/MeCN (+0.1% TFA)] afforded the title compound as tan foam. 1H NMR (400 MHz, d6-DMSO) δ 11.78 (br s, 1H), 7.44-7.41 (m, 2H), 7.24-7.19 (m, 2H), 5.04 (dt, J=6.4, 13.6 Hz, 1H), 4.84 (d, J=14.8 Hz, 1H), 4.72 (br s, 1H), 4.51 (d, J=14.4 Hz, 1H), 3.77 (dd, J=3.6, 13.2 Hz, 1H), 3.43 (d, J=13.6 Hz, 1H), 3.31 (s, 3H), 2.36 (s, 3H), 2.33-2.31 (m, 2H), 1.71-1.62 (m, 1H), 1.51-1.43 (m, 1H), 1.37 (d, J=6.8 Hz, 6H). HRMS (FT/ES) M+H: calcd for (C21H27FN4O5)+ 435.2038. found 435.2038.
Reaction SMILES: [CH3:1][SiH:2]([CH3:4])[Cl:3].C1CCC=CCCC=1.[SiH4].[CH2:14]([Cl:17])[CH:15]=[CH2:16]>>[CH2:14]([Cl:17])[CH:15]=[CH2:16].[Cl:3][Si:2]([CH2:16][CH2:15][CH2:14][Cl:17])([CH3:4])[CH3:1]
Reactant: C[SiH](C)Cl
Agent: [SiH4]
Solvent: C1=CCCC=CCC1
Solvent: C=CCCl
Product: C[Si](C)(Cl)CCCCl
Temperature: 80 °C

Procedure:
Dimethylchlorosilane as one feed stream and a mixture of 2.7×10−3 mol % of di-μ-chlorobis[(cycloocta-1c,5c-diene)iridium(I)] and 7×10−1 mol % of 1,5-cyclooctadiene in allyl chloride as a second feed stream were fed in a molar ratio of silane:allyl chloride mixture of 1:1.05 at a rate of 2.8 l/h (based on the total volume of the components introduced) via separate metering pumps into a loop reactor maintained at 80° C. under a pressure of 0.4 MPa and having a volume of 1.4 l. After working up the crude mixture by distillation using a thin film evaporator to separate off the catalyst and the excess of allyl chloride, chloro(3-chloropropyl)dimethylsilane was obtained in a yield of 95% and a purity of >99% based on the silane.