Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [H-].[Na+].[Si:3]([O:10][C@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])[CH2:16]P(=O)(OC)OC)([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4].[Cl:25][C@H:26]1[C@H:30]([CH2:31][CH2:32][CH2:33][C:34]2[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=2)[C@@H:29]([CH:43]=O)[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27]1>C1COCC1>[Si:3]([O:10][C@H:11]([CH3:24])[CH2:12][CH2:13][CH2:14][C:15](=[O:23])/[CH:16]=[CH:43]/[C@H:29]1[C@H:28]([O:45][CH:46]2[CH2:51][CH2:50][CH2:49][CH2:48][O:47]2)[CH2:27][C@@H:26]([Cl:25])[C@@H:30]1[CH2:31][CH2:32][CH2:33][C:34]1[S:38][C:37]([C:39]([O:41][CH3:42])=[O:40])=[CH:36][CH:35]=1)([C:6]([CH3:7])([CH3:8])[CH3:9])([CH3:4])[CH3:5]
Reactant: COP(=O)(CC(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)OC
Reactant: COC(=O)c1ccc(CCC[C@@H]2[C@@H](C=O)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(CCC[C@@H]2[C@@H](/C=C/C(=O)CCC[C@@H](C)O[Si](C)(C)C(C)(C)C)[C@H](OC3CCCCO3)C[C@H]2Cl)s1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 60.9 %

Procedure:
To a suspension of 54 mg of sodium hydride (60% oil dispersion, 1.35 mmol) in 1 ml of THF at 0° C. was added a solution of dimethyl (6R)-6-{[tert-butyl(dimethyl)silyl]oxy}-2-oxoheptylphosphonate 5 (552 mg, 1.57 mmol) in 1 mL THF. The mixture was stirred at 0° C. for 30 min before a solution of aldehyde 7 (460 mg, 1.1 mmol) in 1 ml of THF was added dropwise. The syringe containing the aldehyde was rinsed with 2 mL of THF to complete the addition and the mixture was stirred at 25° C. for 2.5 h. The reaction was worked up with addition of saturated aqueous ammonium chloride (50 mL) and the aqueous layer was extracted with ethyl acetate (2×75 mL). The ethyl acetate layers were combined and washed with brine, dried over 30 g of anhydrous sodium sulfate, filtered and concentrated in vacuo to yield 920 mg of crude products. Flash chromatographic purification using a 24 g silica gel cartridge eluted with 10% EtOAc-hexanes yielded 430 mg (60%) of purified enone 8; 1H NMR (CDCl3): 0.05 (s, 6H), 0.88 (s, 9H), 1.12 (d, J=6.3 Hz, 3H), 1.37-1.80 (m, 14H), 2.00 (m, 1H), 2.20 (m, 1H), 2.34 (m, 1H), 2.53 (m, 1H), 2.54 (t, J=7.2 Hz, 2H), 2.83 (m, 2H), 3.45 (m, 1H), 3.80 (m, 2H), 3.86 (s, 3H), 4.02 (m, 1H), 4.17 (m, 1H), 4.57 (m, 1H), 6.15 (m, 1H), 6.77 (m, 1H), 7.62 (d, J=3.9 Hz).
Reaction SMILES: [C:1]([NH:14][C@H:15]([CH2:34][NH:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][S:17][CH2:18][C@@H:19]([C:31]([OH:33])=O)[NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].Cl.[NH2:50][C:51]1([CH2:54][OH:55])[CH2:53][CH2:52]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]([NH:14][C@H:15]([CH2:34][NH:35][C:36](=[O:48])[CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])[CH2:16][S:17][CH2:18][C@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:31]([NH:50][C:51]1([CH2:54][OH:55])[CH2:53][CH2:52]1)=[O:33])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)O)NC(=O)CCCCCCCCCCC
Reactant: NC1(CO)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCCCCCC(=O)NC[C@H](CSC[C@H](NC(=O)OCc1ccccc1)C(=O)NC1(CO)CC1)NC(=O)CCCCCCCCCCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (5R,9R)-9-dodecanamido-3,12-dioxo-1-phenyl-2-oxa-7-thia-4,11-diazatricosane-5-carboxylic acid (1 eq) in DCM (0.1 M) was added (1-aminocyclopropyl)methanol hydrochloride (1.3 eq), DIEA (2.5 eq) and HBTU (1.2 eq). The reaction was stirred at room temperature for 2 hours then concentrated and purified by flash chromatography on a COMBIFLASH® system (ISCO) using a gradient of 0-100% EtOAc/Hex, then 0-10% MeOH/DCM to afford the title compound as an off-white solid.
Reaction SMILES: [Cl-].[NH4+].C([N:6](CC)C(C)C)(C)C.[B-](F)(F)(F)F.CCOC(C(C#N)=NOC(N(C)C)=[N+](C)C)=O.[O:34]=[C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63](O)=[O:64])[N:52]=3)=[O:50])[CH:41]=2)[NH:36]1.C(=O)([O-])O.[Na+]>CN(C=O)C>[O:34]=[C:35]1[N:44]([CH2:45][CH2:46][CH3:47])[C:43](=[O:48])[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:49]([C:51]3[N:55]4[CH:56]=[CH:57][CH:58]=[CH:59][C:54]4=[C:53]([C:60]4[CH:61]=[C:62]([CH:66]=[CH:67][CH:68]=4)[C:63]([NH2:6])=[O:64])[N:52]=3)=[O:50])[CH:41]=2)[NH:36]1
Reactant: CCN(C(C)C)C(C)C
Reactant: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(=O)O)c4)c4ccccn34)cc2c1=O
Agent: CCOC(=O)C(C#N)=NOC(N(C)C)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Product: CCCn1c(=O)[nH]c2ccc(C(=O)c3nc(-c4cccc(C(N)=O)c4)c4ccccn34)cc2c1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 89.8 %

Procedure:
10.7 mg (0.2 mmol) of ammonium chloride, 5.17 mg (0.4 mmol) of N,N-diisopropylethylamine and 49.2 mg (0.2 mmol) of TOTU are added, at 0° C., under an inert atmosphere, to 46.8 mg (0.1 mmol) of 3-{3-[(2,4-dioxo-3-propyl-1,2,3,4-tetrahydroquinazolin-6-yl)carbonyl]imidazo[1,5-a]pyridin-1-yl}benzoic acid in 2 ml of DMF. The reaction medium is stirred for 12 hours at ambient temperature and then poured into 30 ml of a saturated solution of sodium hydrogen carbonate. The precipitate obtained is filtered off, washed with water, and dried under reduced pressure at 40° C. overnight. 0.042 g of a yellow solid is obtained.
Reaction SMILES: C([N:8](CC1C=CC=CC=1)[CH:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1)C1C=CC=CC=1.[NH:23]1[CH2:28][CH2:27][O:26][CH2:25][CH2:24]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[O:26]1[CH2:27][CH2:28][N:23]([C@H:12]2[CH2:13][CH2:14][C@H:9]([NH2:8])[CH2:10][CH2:11]2)[CH2:24][CH2:25]1
Reactant: C1COCCN1
Reactant: O=C1CCC(N(Cc2ccccc2)Cc2ccccc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: N[C@H]1CC[C@H](N2CCOCC2)CC1

Procedure:
3.9 g (30 mmol) 4-dibenzylaminocyclohexanone are dissolved in 100 ml dichloromethane and stirred with 3.9 g (45 mmol) morpholine and 9.5 g (45 mmol) sodium triacetoxyborohydride for 12 h at RT. Then the mixture is combined with water and potassium carbonate, the organic phase is separated off, dried and the solvent is eliminated in vacuo. The residue is purified through a silica gel column (approx 20 ml silica gel; approx 500 ml of ethyl acetate 90/methanol 10+1% conc. ammonia). The required fractions are evaporated down in vacuo.
Reaction SMILES: [F:1][C:2]1[C:3]([NH:18][CH:19]([C:24]2([CH3:29])[CH2:28]CC[CH2:25]2)[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=NC=1.[Br:30][C:31]1[N:36]=[C:35]([NH:37][C@@H:38]([C:45]([CH3:48])([CH3:47])[CH3:46])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]([F:49])=[CH:33][C:32]=1[F:50].ClC1N=C(N[C@@H](C2(C)CCCC2)CC(OCC)=O)C(F)=CC=1C#N.BrC1C(F)=CC(F)=C(F)N=1.ClC1C(C#N)=CC(F)=C(F)N=1>C(#N)C.C(O)=O>[F:1][C:2]1[C:3]([NH:18][C@@H:19]([C:24]([CH3:28])([CH3:29])[CH3:25])[CH2:20][C:21]([OH:23])=[O:22])=[N:4][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[C:14]([F:17])[CH:15]=3)[NH:10][N:9]=2)=[C:34]([F:49])[CH:33]=1.[Br:30][C:31]1[N:36]=[C:35]([NH:37][C@@H:38]([C:45]([CH3:47])([CH3:46])[CH3:48])[CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])[C:34]([F:49])=[CH:33][C:32]=1[F:50]
Reactant: CC1(C(CC(=O)O)Nc2nc(-c3n[nH]c4ncc(F)cc34)ncc2F)CCCC1
Agent: CCOC(=O)C[C@@H](Nc1nc(Br)c(F)cc1F)C(C)(C)C
Agent: CCOC(=O)C[C@@H](Nc1nc(Cl)c(C#N)cc1F)C1(C)CCCC1
Agent: Fc1cc(F)c(Br)nc1F
Solvent: CC#N
Solvent: O=CO
Product: CC(C)(C)[C@@H](CC(=O)O)Nc1nc(-c2n[nH]c3ncc(F)cc23)c(F)cc1F

Procedure:
Compound 6 was synthesized in a manner similar to compound 12, utilizing (R)-ethyl 3-((6-bromo-3,5-difluoropyridin-2-yl)amino)-4,4-dimethylpentanoate as the intermediate for the Suzuki coupling. (R)-ethyl 3-((6-bromo-3,5-difluoropyridin-2-yl)amino)-4,4-dimethyl-pentanoate was prepared in the same fashion as intermediate, 143a, utilizing 2-bromo-3,5,6-trifluoropyridine as the starting material instead of 2-chloro-5,6-difluoropyridine-3-carbonitrile: 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J=6.4 Hz, 1H), 8.06 (s, 1H), 7.06 (t, J=9.7 Hz, 1H), 4.58 (s, 2H), 2.80 (d, J=13.2 Hz, 1H), 2.29 (dd, J=13.3, 8.7 Hz, 1H), 0.98 (s, 9H).; LCMS Gradient 10-90%, 0.1% formic acid, 5 minutes, C18/ACN, Retention Time=2.92 min, (M+H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:10]([CH3:16])=[N:11][C:12](I)=[CH:13][CH:14]=2)[CH:5]=[CH:4][N:3]=1.[C:17]([NH2:20])(=[O:19])[CH3:18].C([O-])([O-])=O.[Cs+].[Cs+].CCOC(C)=O>O1CCOCC1.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].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([NH:20][C:17](=[O:19])[CH3:18])=[N:11][C:10]=2[CH3:16])[CH:5]=[CH:4][N:3]=1
Reactant: CC(N)=O
Reactant: Cc1nc(I)ccc1Oc1ccnc(Cl)c1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(Oc2ccnc(Cl)c2)c(C)n1
Temperature: 83 °C
Yield: 55.8 %

Procedure:
A solution of 3-((2-chloropyridin-4-yl)oxy)-6-iodo-2-methylpyridine (8.5 g, 24.53 mmol) in dioxane (100 mL) was sparged with argon, treated with acetamide (5.07 g, 86 mmol), Cs2CO3 (11.99 g, 36.8 mmol), X-Phos (0.585 g, 1.226 mmol) and Pd2(dba)3 (1.123 g, 1.226 mmol) and heated at 83° C. for 16 h. The mixture was cooled to RT, treated with EtOAc, solids removed via filtration through diatomaceous earth, rinsed well with EtOAc, and the filtrate washed with H2O, then brine, dried over Na2SO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(5-((2-chloropyridin-4-yl)oxy)-6-methylpyridin-2-yl)acetamide (3.8 g, 56%) as an off-white solid. MS (ESI) m/z: 278.0 (M+H+).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]([OH:22])=O)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24].O[N:27]=[C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[O:36][C:37]([F:40])([F:39])[F:38])[NH2:29].CCN(C(C)C)C(C)C>>[CH3:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]2[O:22][N:29]=[C:28]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][C:37]([F:38])([F:39])[F:40])[N:27]=2)=[CH:16][C:15]=1[N+:23]([O-:25])=[O:24]
Reactant: Cc1ccccc1-c1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: NC(=NO)c1ccccc1OC(F)(F)F
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccccc3OC(F)(F)F)no2)cc1[N+](=O)[O-]

Procedure:
Oxalyl chloride (118 μL; 1.40 mmol; 3 eq.), Intermediate 22 (120 mg; 0.47 mmol; 1 eq.), Intermediate 2 (103 mg; 0.47 mmol, 1 eq.) and DIEA (103 μL; 1.40 mmol; 3 eq.) were reacted according to general procedure 2. Purification by column chromatography (c-hexane/ethyl acetate, 90/10) afforded the title compound as a yellow oil.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH2:19])[CH:14]=2)=[CH:7][C:6]=1[O:21][CH3:22])[CH3:2].[F:24][C:25]([F:37])([F:36])[C:26]1[CH:27]=[C:28]([S:32](Cl)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=1>>[CH2:1]([O:3][C:4](=[O:23])[C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][S:32]([C:28]3[CH:29]=[CH:30][CH:31]=[C:26]([C:25]([F:24])([F:36])[F:37])[CH:27]=3)(=[O:34])=[O:33])[CH:14]=2)=[CH:7][C:6]=1[O:21][CH3:22])[CH3:2]
Reactant: CCOC(=O)c1ccc(NC(=O)c2cccc(N)c2)cc1OC
Reactant: O=S(=O)(Cl)c1cccc(C(F)(F)F)c1
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(C(F)(F)F)c3)c2)cc1OC

Procedure:
2-Methoxy-4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid, MS (ISP): m/e=493.3 (M−H), was prepared in analogy to example 1, steps A to D. Step A was performed using 4-amino-2-methoxy-benzoic acid ethyl ester and yielded 2-methoxy-4-(3-nitro-benzoylamino)-benzoic acid ethyl ester. This was reduced to 4-(3-amino-benzoylamino)-2-methoxy-benzoic acid ethyl ester in step B. This was coupled with 3-trifluoromethyl-benzenesulfonyl chloride in step C, yielding 2-methoxy-4-[3-(3-trifluoromethyl-benzenesulfonylamino)-benzoylamino]-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [C:1]([OH:11])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:12][N:13]([CH3:29])[CH:14]1[CH2:18][CH2:17][N:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15]1>>[CH3:12][N:13]([CH3:29])[CH:14]1[CH2:18][CH2:17][N:16]([C:19]2[S:20][C:21]3[CH:27]=[C:26]([NH:28][C:1](=[O:11])[CH:2]=[CH:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15]1
Reactant: O=C(O)/C=C/c1ccccc1
Reactant: CN(C)C1CCN(c2nc3ccc(N)cc3s2)C1
Product: CN(C)C1CCN(c2nc3ccc(NC(=O)C=Cc4ccccc4)cc3s2)C1
Yield: 12.8 %

Procedure:
Prepare according to Method B, using trans-cinnamic acid (96 mg, 0.648 mmol) and 2-(3-dimethylamino-pyrrolidin-1-yl)-benzothiazol-6-ylamine (162 mg, 0.618 mmol) to afford the title compound (31 mg, 13%). mass spectrum (m/e): 393.0 [M+H]. 1H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H), 8.26 (d, 1H, J=1.3 Hz), 7.63 (d, 2H, J=7.0 Hz), 7.57 (d, 1H, J=15.7 Hz), 7.48-7.37 (m, 5H), 6.84 (d, 1H, J=15.8 Hz), 3.70 (dd, 1H, J =9.5, 7.0 Hz), 3.61 (m, 1H), 3.46 (m, 1H), 3.27 (m, 1H), 2.88 (m, 1H), 2.23-2.11 (m, 7H), 1.90 (m, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][N:6]=[CH:5]2.[OH-].[K+].Br[CH2:16][CH2:17][CH2:18][C:19]([O:21]CC)=[O:20].Cl>CS(C)=O.O.C(O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])[N:6]=[CH:5]2
Reactant: CCOC(=O)CCCBr
Reactant: O=c1[nH]ncc2cc(Br)ccc12
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Solvent: O
Product: O=C(O)CCCn1ncc2cc(Br)ccc2c1=O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a slurry of 56 gm 6-bromophthalazin-1(2H)-one (0.25 mole) in 600 ml DMSO was added 110 ml 45% KOH followed by 58.5 gm ethyl 4-bromobutyrate. The temperature of the mildly exothermic reaction was moderated with a water bath (ca. 25° C.) and was stirred for 20 hours. Ethanol (750 ml) was added, then the mixture was acidified with 125 ml concentrated HCl, diluted with 2500 ml water over about 30 minutes, stirred an additional 30 minutes, filtered, washed with water and isopropanol and dried. The product weighed 63.6 gm. A tlc of the product showed product, Rf =0.43 plus a trace of starting material, Rf =0.63.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][CH:4]=1.[F:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[CH:16]=[O:17].[C-]#N.[K+]>C(O)C>[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([C:7]([CH:16]([C:15]2[CH:18]=[CH:19][CH:20]=[C:13]([F:12])[CH:14]=2)[OH:17])=[O:8])=[CH:5][CH:4]=1
Reactant: O=Cc1cccc(F)c1
Reactant: CN(C)c1ccc(C=O)cc1
Agent: [C-]#N
Agent: [K+]
Solvent: CCO
Product: CN(C)c1ccc(C(=O)C(O)c2cccc(F)c2)cc1

Procedure:
A mixture consisting of 14.9 g. of p-dimethylaminobenzaldehyde, 12.4 g. of m-fluorobenzaldehyde, 6 g. of potassium cyanide, and 100 ml. of 65% ethanol is reacted according to the procedure of Example 20, 12.8 g. of 4-dimethylamino-3'-fluorobenzoin being obtained; m.p. 147°-149° C. An 8.2 g. portion of this benzoin is converted to its methanesulfonate ester, by the procedure of Example 20, in 9.1 g. yield, m.p. 106°-109° C. A mixture of 2.6 g. of the methanesulfonate ester, 0.91 g. of hexahydro-2H-1,3-diazepin-2-thione, and 70 ml. of acetone is left at room temperature for three days, precipitating the title compound in 2.7 g. yield, m.p. 180°-182° C.
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:11]=[C:10]([F:12])[C:9]([O:13][CH3:14])=[CH:8][C:7]=2[C:15]2[C:16]3[NH:23][CH:22]=[C:21]([C:24]([OH:26])=O)[C:17]=3[N:18]=[CH:19][N:20]=2)[CH2:3][CH2:2]1.[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH2:39])[CH2:35]1)=[O:33])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([O:31][C:32]([N:34]1[CH2:38][CH2:37][C@@H:36]([NH:39][C:24]([C:21]2[C:17]3[N:18]=[CH:19][N:20]=[C:15]([C:7]4[CH:8]=[C:9]([O:13][CH3:14])[C:10]([F:12])=[CH:11][C:6]=4[O:5][CH2:4][CH:1]4[CH2:2][CH2:3]4)[C:16]=3[NH:23][CH:22]=2)=[O:26])[CH2:35]1)=[O:33])([CH3:30])([CH3:28])[CH3:29]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N)C1
Reactant: COc1cc(-c2ncnc3c(C(=O)O)c[nH]c23)c(OCC2CC2)cc1F
Product: COc1cc(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c[nH]c23)c(OCC2CC2)cc1F

Procedure:
Starting from 4-(2-cyclopropylmethoxy-4-fluoro-5-methoxy-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid (example A79) and (R)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester the title compound is obtained as colorless solid.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([C:14](=O)[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:21](P(=O)(OCC)OCC)#[N:22].[C-]#N.[Li+].O>O1CCCC1>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH:14]([C:21]#[N:22])[CH2:15][CH2:16][O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(=O)(C#N)OCC
Reactant: O=C1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Agent: [C-]#N
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#CC1CCOc2cc(S(=O)(=O)c3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 58 %

Procedure:
7-Benzenesulfonyl-chroman-4-one from Preparation 1 above (500 mg, 1.73 mmol) was dissolved in 10 mL of tetrahydrofuran (THF). Diethyl cyanophosphonate (789 uL, 5.21 mmol) and lithium cyanide (10.42 mL, 5.21 mmol) were added, and the reaction mixture was stirred for 10 minutes at room temperature. Water (150 (mL) was added, and the aqueous mixture was extracted twice with 200 mL of EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and the solvent was evaporated under reduced pressure. The residue was dissolved in 5 mL THF, and 70 mL of MeOH was added. SmI2 (52 mL, 5.21 mmol) was then added over five minutes, and the reaction mixture was stirred for 10 minutes at room temperature. The reaction was quenched by addition of 20 mL 1 N HCl, and the resulting aqueous mixture was extracted with EtOAc and 1 N Na2S2O3. The organic phase was dried over MgSO4, and solvent was removed under reduced pressure. The residue eluted through silica gel using 40% EtOAc in hexanes, and solvent was removed under reduced pressure to yield 300 mg (1 mmol, 58%) of 7-benzenesulfonyl-chroman-4-carbonitrile. MS: 300 (M+H)+.
Reaction SMILES: [C:1]([CH2:4][N:5]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6]1)([OH:3])=[O:2].[O:25]1[CH2:40][CH:26]1[CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([O:37]CC)=[O:36])[CH2:31][CH2:30]1.[OH-].[K+].Cl>O1CCOCC1.O>[OH:25][CH:26]([CH2:27][O:28][CH:29]1[CH2:34][CH2:33][CH:32]([C:35]([OH:37])=[O:36])[CH2:31][CH2:30]1)[CH2:40][N:14]1[CH2:13][CH2:12][N:11]([CH2:17][C:18]([OH:20])=[O:19])[CH2:10][CH2:9][N:8]([CH2:21][C:22]([OH:24])=[O:23])[CH2:7][CH2:6][N:5]([CH2:4][C:1]([OH:3])=[O:2])[CH2:16][CH2:15]1
Reactant: O=C(O)CN1CCNCCN(CC(=O)O)CCN(CC(=O)O)CC1
Reactant: CCOC(=O)C1CCC(OCC2CO2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)CN1CCN(CC(=O)O)CCN(CC(O)COC2CCC(C(=O)O)CC2)CCN(CC(=O)O)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
10 g (28.87 mmol) of 1,4,7-triscarboxymethyl-1,4,7,10-tetraazacyclododecane (=DO3A) and 12.99 g (51.96 mmol) of 2,3-epoxy-1-[4-(ethoxycarbonyl)-cyclohexyloxy]-propane are added in 80 ml of dioxane/60 ml of water and adjusted to pH 13 with 6N potassium hydroxide solution. It is stirred for 12 hours at room temperature. Then, it is refluxed for 2 hours. It is adjusted to pH 7 with 5N hydrochloric acid and evaporated to dryness in a vacuum. The residue is absorptively precipitated in 200 ml of ethanol/50 ml of chloroform at 60° C. The precipitated potassium chloride is filtered off and the filtrate is concentrated by evaporation in a vacuum. The residue is purified on a reversed-phase column (RP-18, washing with water, then elution with tetrahydrofuran/water=2:1). The main fractions are concentrated by evaporation in a vacuum.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](/[CH:10]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8].[H][H]>C(O)C.[Pd]>[F:1][C:2]1[CH:3]=[C:4]([CH2:10][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:5]=[C:6]([F:9])[C:7]=1[OH:8]
Reactant: [H][H]
Reactant: CCOC(=O)/C=C/c1cc(F)c(O)c(F)c1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCc1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (E)-ethyl 3-(3,5-difluoro-4-hydroxyphenyl)acrylate (10) (0.751 g, 3.29 mmol) in ethanol (20 mL) was added Pd/C (81 mg, 10% Degussa type). A balloon of hydrogen gas was added and the reaction was evacuated and back-filled with hydrogen three times. The reaction was stirred under a hydrogen balloon overnight at room temperature, filtered through a pad of celite and concentrated in vacuo to give ethyl 3-(3,5-difluoro-4-hydroxyphenyl)propanoate (11).
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=1)([O-])=O>C(O)C.[C].[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[CH:5]=1
Reactant: CCOC(=O)c1ccc([N+](=O)[O-])cc1N[C@H]1CCCC[C@@H]1N1CCCC1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)c1ccc(N)cc1N[C@H]1CCCC[C@@H]1N1CCCC1

Procedure:
Under an atmosphere of hydrogen (1 atm) and in ethanol, catalytic hydrogenation of ethyl 4-nitro-2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoate was carried out at room temperature in the presence of 10% palladium-carbon to obtain ethyl 4-amino-2-{[(1S,2S)-2-pyrrolidin-1-ylcyclohexyl]amino}benzoate.
Reaction SMILES: [BH4-].[Na+].[C:3]1([S:9][CH2:10][C:11](=[O:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>CO>[C:3]1([S:9][CH2:10][CH:11]([OH:13])[CH3:12])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(=O)CSc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(O)CSc1ccccc1
Reaction time: 2 h
Yield: 52 %

Procedure:
732 mg (19.2 mmol) of NaBH4 were added in portions, while cooling (ice bath), to a solution of 2.46 g (14.8 mmol) of 1-(phenylthio)propan-2-one in methanol (18 ml). Stirring was then carried out for a further 2 h while cooling (ice bath). The mixture was then quenched with AcOH (17 ml) and then concentrated in vacuo. The residue was taken up in an ether/water mixture and neutralized with NaHCO3. The phases were separated and the organic phase was dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by means of CC (EA/hex 15:85), yielding 1.3 g (7.7 mmol, 52%) of 1-(phenylthio)propan-2-ol.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[O:3][C:4]1[CH:13]=[CH:12][C:11]2[NH:10]C(=O)[N:8]3[N:15]=[CH:16][N:17]=[C:7]3[C:6]=2[CH:5]=1.BrC1C=CC2NC(=O)N3N=CN=C3C=2C=1>>[F:19][C:2]([F:1])([F:18])[O:3][C:4]1[CH:13]=[CH:12][C:11]([NH2:10])=[C:6]([C:7]2[NH:8][N:15]=[CH:16][N:17]=2)[CH:5]=1
Reactant: O=c1[nH]c2ccc(OC(F)(F)F)cc2c2ncnn12
Agent: O=c1[nH]c2ccc(Br)cc2c2ncnn12
Product: Nc1ccc(OC(F)(F)F)cc1-c1ncn[nH]1
Yield: 64.6 %

Procedure:
As described for example 23c) 9-trifluoromethoxy-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one (5.51 g, 20.4 mmol), instead of 9-bromo-6H-[1,2,4]triazolo[1,5-c]quinazolin-5-one, was converted to the title compound (3.22 g, 65%) which was obtained as a light brown solid. MS: m/e=245.2 [M+H]+.