Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][C:15]1[S:19][C:18]([SH:20])=[N:17][N:16]=1>CO>[CH3:13][C:4]1[CH:3]=[C:2]([S:20][C:18]2[S:19][C:15]([CH3:14])=[N:16][N:17]=2)[C:11]2[C:6](=[C:7]([OH:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=1
Reactant: Cc1nnc(S)s1
Reactant: Cc1cc(Cl)c2cccc(O)c2n1
Solvent: CO
Product: Cc1cc(Sc2nnc(C)s2)c2cccc(O)c2n1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-2-methyl-quinolin-8-ol (10 mg, 52 μmol) and 5-methyl-[1,3,4]thiadiazole-2-thiol (6.9 mg, 52 μmol) in MeOH (0.3 mL) was heated to 80° C. for 1.5 h. The solvent was removed in vacuo to give title compound. MS (m/z): 289.9 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C@@H:12]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][N:28]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[O:15][C@H:13]1[SH:14])(=[O:10])[CH3:9].[CH3:39][CH:40]([CH2:42][CH2:43][CH2:44][C@H:45]([C@@H:47]1[C@:64]2([CH3:65])[C@H:50]([C@H:51]3[C@H:61]([CH2:62][CH2:63]2)[C@:59]2([CH3:60])[C:54]([CH2:55][C@@H:56]([O:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72]I)[CH2:57][CH2:58]2)=[CH:53][CH2:52]3)[CH2:49][CH2:48]1)[CH3:46])[CH3:41]>ClCCl>[C:8]([O:11][C@@H:12]1[C@@H:18]([O:19][C:20](=[O:22])[CH3:21])[C@@H:17]([O:23][C:24](=[O:26])[CH3:25])[C@@H:16]([CH2:27][N:28]2[C:32](=[O:33])[C:31]3=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]3[C:29]2=[O:38])[O:15][C@H:13]1[S:14][CH2:72][CH2:71][CH2:70][CH2:69][CH2:68][CH2:67][O:66][C@H:56]1[CH2:57][CH2:58][C@@:59]2([CH3:60])[C:54](=[CH:53][CH2:52][C@@H:51]3[C@@H:61]2[CH2:62][CH2:63][C@@:64]2([CH3:65])[C@H:50]3[CH2:49][CH2:48][C@@H:47]2[C@H:45]([CH3:46])[CH2:44][CH2:43][CH2:42][CH:40]([CH3:41])[CH3:39])[CH2:55]1)(=[O:10])[CH3:9]
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OCCCCCCI)CC[C@]4(C)[C@H]3CC[C@]12C
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](S)O[C@H](CN2C(=O)c3ccccc3C2=O)[C@@H]1OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)O[C@H]1[C@@H](OC(C)=O)[C@@H](CN2C(=O)c3ccccc3C2=O)O[C@@H](SCCCCCCO[C@H]2CC[C@@]3(C)C(=CC[C@H]4[C@@H]5CC[C@H]([C@H](C)CCCC(C)C)[C@@]5(C)CC[C@@H]43)C2)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 78.6 %

Procedure:
Triethylamine (0.8 ml.) is added to a solution of 2,3,4-tri-O-acetyl-6-deoxy-6-phthalimido-1-thio-β-D-galactopyranose (2.5 g.) and 6-(5-cholesten-3β-yloxy)hexyl iodide (3.3 g.) in dichloromethane (20 ml.). The solution is kept at room temperature under nitrogen overnight, and washed with water, dried, and evaporated in vacuo to a syrup (4.71 g.). This material is put on a column of silica gel and eluted with chloroform followed by 2% ethyl acetate in chloroform. The desired fractions are combined and evaporated in vacuo to give the title compound (4.0 g., 78%); Rf 0.2 (CHCl3 -EtOAc. 95:5), [α]D27 -93° C. (C 1.18, chloroform); n.m.r. (chloroform-d); δ 7.60-7.91 (4 aromatic), 1.93, 2.03, and 2.24 (3 OAc) 0.68 (CH3 -18).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:21]=[C:20]([Cl:22])[CH:19]=[CH:18][C:10]=1[CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.P(Cl)(Cl)(Cl)=O>C1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:10]([CH2:11][N:12]2[CH2:13][CH2:14][O:15][CH2:16][CH2:17]2)=[C:9]([N:8]=[C:2]2[CH2:3][CH2:4][CH2:5][CH2:6][NH:1]2)[CH:21]=1
Reactant: Nc1cc(Cl)ccc1CN1CCOCC1
Reactant: O=C1CCCCN1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Product: Clc1ccc(CN2CCOCC2)c(N=C2CCCCN2)c1

Procedure:
A mixture of 2-piperidone (6 g) in benzene (50 ml), 4-(2-amino-4-chlorobenzyl)morpholine (6.8 g) in benzene (50 ml) and phosphorus oxychloride (5.5 ml) was heated at 60°-65° C. for 5 hours to give 4-[4-chloro-2-(2-piperidinylideneamino)benzyl]morpholine (m.p. 121°-122° C.) which was recrystallised from hexane.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([OH:21])=O)[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.Cl.[NH2:30][CH2:31][C:32]([NH2:34])=[O:33].ClC(OCC(C)C)=O>O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:19]([NH:30][CH2:31][C:32]([NH2:34])=[O:33])=[O:21])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N[C@@H](Cc1c[nH]cn1)C(=O)O)OCc1ccccc1
Reactant: NCC(N)=O
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: NC(=O)CNC(=O)[C@H](Cc1c[nH]cn1)NC(=O)OCc1ccccc1
Reaction time: 2 h

Procedure:
Na -t-butyloxycarbonyl-Nim -benzyloxycarbonyl-L-histidine was dissolved in tetrahydrofuran (THF) and neutralized with one equivalent of N-methylmorpholine. It was then coupled with glycinamide hydrochloride using isobutyl chloroformate and N-methylmorpholine. After two hours at -20° C. and an additional hour at ambient temperature, the reaction was quenched with 2N aqueous potassium bicarbonate. This product was extracted into ethyl acetate, washed with 1M aqueous citric acid, and saturated sodium bicarbonate. The organic phase was dried over anhydrous sodium sulfate. Filtration and evaporation gave Na -t-butyloxycarbonyl-Nim -benzyloxycarbonyl-L-histidyl-glycine amide.
Reaction SMILES: [CH2:1]([N:3]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([C@@H:26]([CH3:42])[C:27](N2[C@H](C)[C@H](C3C=CC=CC=3)OC2=O)=[O:28])[CH:23]=[CH:22][C:21]=1[O:43][CH3:44])[C:4]([CH:6]1[CH2:8][CH2:7]1)=[O:5])[CH3:2].[OH:45]O.[OH-].[Li+].Cl>C1COCC1.O>[CH:6]1([C:4]([N:3]([CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:17])([F:19])[F:18])[CH:13]=[CH:12][C:11]=2[C:20]2[C:21]([O:43][CH3:44])=[CH:22][CH:23]=[C:24]([C@@H:26]([CH3:42])[C:27]([OH:45])=[O:28])[CH:25]=2)[CH2:1][CH3:2])=[O:5])[CH2:8][CH2:7]1
Reactant: OO
Reactant: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)N2C(=O)O[C@@H](c3ccccc3)[C@H]2C)ccc1OC)C(=O)C1CC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCN(Cc1cc(C(F)(F)F)ccc1-c1cc([C@@H](C)C(=O)O)ccc1OC)C(=O)C1CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cyclopropanecarboxylic acid ethyl-{2′-methoxy-5′-[(R)-1-methyl-2-((4R,5S)-4-methyl-2-oxo-5-phenyl-oxazolidin-3-yl)-2-oxo-ethyl]-4-trifluoromethyl-biphenyl-2-ylmethyl}-amide (0.011 g, 0.02 mmol) in THF (1 mL) and H2O (1 mL) was treated with hydrogen peroxide (30%; 0.004 mL, 0.04 mmol) and lithium hydroxide (0.002 g, 0.04 mmol), and the reaction was stirred overnight at room temperature. The mixture was acidified to pH 3-4 with 1N aqueous HCl and extracted three times with EtOAc. The combined organic layers were dried and concentrated to give the title compound. M+H is 450.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[C:17]([NH:24][C@H:25]([C:34]([OH:36])=[O:35])[CH2:26][C:27]1[CH:32]=[CH:31][C:30]([OH:33])=[CH:29][CH:28]=1)(OC(C)(C)C)=O>O>[C:34]([C@@H:25]([NH:24][C:17]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:26][C:27]1[CH:28]=[CH:29][C:30]([O:33][C:2]2[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]3[C:4](=[C:5]([Cl:16])[CH:6]=[C:7]([Cl:15])[CH:8]=3)[N:3]=2)=[CH:31][CH:32]=1)([OH:36])=[O:35]
Reactant: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1Cl
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(O)cc1)C(=O)O
Solvent: O
Product: O=C(O)c1cc2cc(Cl)cc(Cl)c2nc1N[C@@H](Cc1ccc(Oc2nc3c(Cl)cc(Cl)cc3cc2C(=O)O)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 1, 2,6,8-trichloroquinoline-3-carboxylic acid is reacted with N-Boc-L-tyrosine in H2O to provide the title compound in good yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.O.P([O-])([O-])([O-])=O.[K+].[K+].[K+].FC(F)(F)S(O[C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[CH:33]=2)[C:28]=1[CH2:39][CH:40]=[CH2:41])(=O)=O.O>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:38][O:37][C:32]1[CH:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[C:28]([CH2:39][CH:40]=[CH2:41])=[C:27]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)[CH:36]=[CH:35]2
Reactant: COc1ccc(B(O)O)cc1
Reactant: C=CCc1c(OS(=O)(=O)C(F)(F)F)ccc2cc(OC)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C=CCc1c(-c2ccc(OC)cc2)ccc2cc(OC)ccc12
Yield: 74.7 %

Procedure:
4-Methoxyphenylboronic acid (10.15 g, 66.8 mmol), tripotassium phosphate hydrate (77.6 g, 278.3 mmol) and tetrakis(triphenylphosphine)palladium(0) (1.93 g, 1.67 mmol, 3 mol %) were added to a solution of 6-methoxy-1-(2-propenyl)-2-naphthyl trifluoromethanesulfonate (19.3 g, 55.66 mmol) in dioxane (300 ml), followed by heating under reflux for 8 hours under argon atmosphere. Water was added to the reaction mixture, which was then extracted with ethyl acetate, washed with saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/9), followed by recrystallization from hexane, to give 6-methoxy-2-(4-methoxyphenyl)-1-(2-propenyl)naphthalene (12.65 g, Yield 75%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([N:10]=[CH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=2)=[C:6]([Cl:19])[CH:5]=1.O.[O-]S(C(F)(F)F)(=O)=O.[Yb+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.[CH:47](=[O:51])[CH:48]([CH3:50])[CH3:49].O>O1CCCC1>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]2[C:7](=[C:6]([Cl:19])[CH:5]=1)[NH:10][CH:11]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Br:18])[CH:13]=1)[C:48]([CH3:50])([CH3:49])[CH:47]2[OH:51])=[O:20]
Reactant: COC(=O)c1ccc(N=Cc2cccc(Br)c2)c(Cl)c1
Reactant: CC(C)C=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Yb+3]
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)c1cc(Cl)c2c(c1)C(O)C(C)(C)C(c1cccc(Br)c1)N2
Temperature: 25 °C
Reaction time: 16 h
Yield: 99.8 %

Procedure:
To a stirred mixture solution of 4-[(3-bromo-benzylidene)-amino]-3-chloro-benzoic acid methyl ester (39.8 g, 113.2 mmol) and ytterbium(III) triflate hydrate (10.5 g, 16.9 mmol) in dry tetrahydrofuran (100 mL) at 25° C. was added isobutyraldehyde (10.4 mL, 113.2 mmol) and water (2.1 mL, 113.2 mmol) dropwise. The reaction mixture was stirred at 25° C. for 16 h. Then the reaction mixture was concentrated in vacuo and the residue was extracted with ethyl acetate (2×200 mL), washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-(3-bromo-phenyl)-8-chloro-4-hydroxy-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid methyl ester (48 g, quant.) as a light yellow oil which was used for next step without further purification: LC/MS m/e calcd for C19H19BrClNO3 (M+H)+: 425.73, observed: 405.9 & 407.9.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:25])([F:24])[F:23])[CH:16]=2)(=[O:14])=[O:13])[C:5]([C:8](O)=[O:9])=[N:6][CH:7]=1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[NH:33][CH3:34].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.CCN(C(C)C)C(C)C>>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]([CH3:34])[C:8]([C:5]1[C:4]([NH:11][S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([C:22]([F:24])([F:25])[F:23])[CH:16]=2)(=[O:14])=[O:13])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=1)=[O:9]
Reactant: CNc1ccccc1F
Reactant: O=C(O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1)c1ccccc1F

Procedure:
5-Chloro-3-(4-chloro-3-(trifluoromethyl)phenylsulfonamido)picolinic acid (50 mg, 0.12 mmol), (2-fluoro-phenyl)-methyl-amine (45 mg, 0.36 mmol), BOP (69 mg, 0.36 mmol), DIEA (130 L, 0.72 mmol) were reacted according to the procedure D to provide the title compound. HPLC purification (20→90% gradient of MeCN-water) provided 5-chloro-3-(4-chloro-3-trifluoromethyl-benzenesulfonylamino)-pyridine-2-carboxylic acid (2-fluoro-phenyl)-methyl-amide: MS m/z: (M+H) 522.1.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([C:18]([OH:20])=O)[N:12]=[N:11]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH:21]1([NH2:24])[CH2:23][CH2:22]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(#N)C>[CH:21]1([NH:24][C:18]([C:13]2[N:12]=[N:11][N:10]([C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=3)[C:14]=2[CH2:15][CH2:16][CH3:17])=[O:20])[CH2:23][CH2:22]1
Reactant: NC1CC1
Reactant: CCCc1c(C(=O)O)nnn1-c1ccc([N+](=O)[O-])cc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CC#N
Product: CCCc1c(C(=O)NC2CC2)nnn1-c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82 %

Procedure:
To a solution of 1-(4-nitrophenyl)-5-propyl-1H-1,2,3-triazole-4-carboxylic acid (1.38 g) obtained in Example 1b) in acetonitrile (50 ml) were successively added cyclopropylamine (0.38 ml), HOBt (0.84 g) and WSC (1.05 g), and the reaction mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate and washed with aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (ethyl acetate/hexane=1/1) to give the title compound as a pale-yellow solid (1.29 g, 82%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH2:30])[N:15]=[C:14]([C:31]3[CH:36]=[CH:35][N:34]=[CH:33][CH:32]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1.[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C:12]2[C:17]([O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[O:25][CH3:26])=[C:16]([O:27][CH2:28][CH2:29][NH:30][S:38]([CH3:37])(=[O:40])=[O:39])[N:15]=[C:14]([C:31]3[CH:32]=[CH:33][N:34]=[CH:35][CH:36]=3)[N:13]=2)(=[O:10])=[O:9])=[N:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCN
Product: COc1ccccc1Oc1c(NS(=O)(=O)c2ccc(C)cn2)nc(-c2ccncc2)nc1OCCNS(C)(=O)=O

Procedure:
According to the procedure described in Example 4a) 107 mg 5-methyl-N-[6-(2-aminoethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide was reacted with methanesulfonylchloride to give 100 mg 5-methyl-N-[6-(2-(methanesulfonylamino)-ethoxy)-5-(o-methoxyphenoxy)-2-(4-pyridyl)-4-pyrimidinyl]-2-pyridine sulfonamide. LC-MS: tR=3.72 min, [M+1]+=587.46, [M−1]−=585.50.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9](Cl)(Cl)=[O:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:15]([OH:19])[CH2:16][CH2:17][OH:18]>C1COCC1>[N+:1]([C:4]1[CH:14]=[CH:13][C:7]([CH2:8][P:9]2(=[O:10])[O:19][CH2:15][CH2:16][CH2:17][O:18]2)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc(CP(=O)(Cl)Cl)cc1
Reactant: OCCCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude (4-Nitrobenzyl)phosphonic dichloride (Compound 230E) above was dissolved in anhydrous THF (20 mL). To this solution was added TEA (840 mg, 7.5 mmol) and 1,3-propane-diol (190 mg, 2.5 mmol) at 0° C. The resulting mixture was stirred at room temperature overnight, concentrated and the residue was purified by column chromatography to give the target product (70 mg). 1H NMR (CD3OD, 400 MHz): δ=2.85 (d, J=20.0 Hz, 2H), 3.28-3.30 (m, 2 H), 3.55-3.58 (m, 2 H), 3.75-7.78 (m, 2 H), 6.64 (d, J=8.4 Hz, 2 H), 7.07 (d, J=8.4 Hz, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1)#[N:2].[C:11]1(=[O:18])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1>P(=O)(O)(O)O>[C:1]([C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:11]2=[O:18])=[CH:5][CH:4]=1)#[N:2]
Reactant: O=C1CCCCCC1
Reactant: N#Cc1ccc(C=O)cc1
Agent: O=P(O)(O)O
Product: N#Cc1ccc(C=C2CCCCCC2=O)cc1
Temperature: 100 °C

Procedure:
A mixture of 20.0 g of 4-cyanobenzaldehyde, 30.5 g of cycloheptanone, and 200 mL of 85% phosphoric acid is heated for 1.5 h at 100° C. The mixture is cooled to room temperature, and filtered. The filtrate is poured into water (800 mL), and the precipitate is filtered, washed with water, and dried. The solid is purified by flash chromatography eluting with a mixture of ether:hexane, 1:2 to afford (4-cyanophenylmethylene)cycloheptanone.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[CH2:8][CH2:7][CH2:6][NH:5]1.C(N(C(C)C)CC)(C)C.Cl[C:19]1[N:24]([CH3:25])[C:23](=[O:26])[C:22]([C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)=[C:21]([C:34]2[CH:39]=[CH:38][N:37]=[C:36]([Cl:40])[CH:35]=2)[N:20]=1>ClCCl>[Cl:40][C:36]1[CH:35]=[C:34]([C:21]2[N:20]=[C:19]([N:5]3[CH2:6][CH2:7][CH2:8][CH:4]3[CH2:3][O:2][CH3:1])[N:24]([CH3:25])[C:23](=[O:26])[C:22]=2[C:27]2[CH:28]=[C:29]([CH3:33])[CH:30]=[CH:31][CH:32]=2)[CH:39]=[CH:38][N:37]=1
Reactant: COC[C@@H]1CCCN1
Reactant: Cc1cccc(-c2c(-c3ccnc(Cl)c3)nc(Cl)n(C)c2=O)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCC1CCCN1c1nc(-c2ccnc(Cl)c2)c(-c2cccc(C)c2)c(=O)n1C
Reaction time: 0.17 h

Procedure:
To a 100 mL RBF, was added (S)-2-methoxymethyl-pyrrolidine (0.172 g, 1.5 mmol), and 50 mL dichloromethane at 0° C. under nitrogen. 0.35 mL diisopropylethylamine (2.0 mmol) was added drop wise, and stirred for 10 min. 2-Chloro-6-(2-chloropyridin-4-yl)-3-methyl-5-m-tolyl-3H-pyrimidin-4-one (0.345 g, 1.0 mmol) was added in one portion, and stirred at 0° C. to rt for 12 h. The mixture was diluted with 100 mL dichloromethane, washed with sat. NaHCO3 and brine. After purified by flash chromatography, the title compound was obtained in 0.40 g as pale yellow solid. MS (ES+): 425 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:16])[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([CH2:14][OH:15])[CH2:3]1.CCN(CC)CC.[CH3:24][S:25](Cl)(=[O:27])=[O:26]>C(Cl)Cl>[CH3:24][S:25]([O:15][CH2:14][C@@H:4]1[CH2:3][C:2]([F:1])([F:16])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8])(=[O:27])=[O:26]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CC(F)(F)C[C@H]1COS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a CH2Cl2 (22 ml) solution of (S)-tert-butyl 4,4-difluoro-2-(hydroxymethyl)pyrrolidine-1-carboxylate (2.65 g, 11.2 mmol) and Et3N (2.3 ml, 16.8 mmol), at 0° C., methylsulfonyl chloride (0.95 ml, 12.3 mmol) was added dropwise over ˜2 minutes, ice bath was removed after 15 minutes, and stirring was continued at room temperature for another 30 minutes. Reaction went to completion as monitored by LC-MS. The reaction mixture was cooled to 0° C. and was quenched by addition of saturated aqueous solution of NaHCO3 (˜30 ml), stifling was continued at 0° C. for 5 minutes and at room temperature for 15 minutes. Two layers were separated, aqueous layer was extracted with CH2Cl2 (˜30 ml). Organic layers were combined, washed with brine (˜25 ml), dried (Na2SO4), filtered, solvent was removed in vacuo. Compound ((S)-1-(tert-butoxycarbonyl)-4,4-difluoropyrrolidin-2-yl)methyl methanesulfonate was obtained as a very light yellow oil: 3.40 g (96% crude yield).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:25][C:26]([F:41])([F:40])[C:27]1[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[N:29]([CH2:36][C:37]([OH:39])=O)[N:28]=1.CCN(C(C)C)C(C)C.[CH3:51][C:52]1[S:53][C:54]([CH:63]([NH2:71])[CH2:64][C:65]2[CH:70]=[CH:69][CH:68]=[CH:67][CH:66]=2)=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1>CN(C=O)C>[CH3:51][C:52]1[S:53][C:54]([C@@H:63]([NH:71][C:37](=[O:39])[CH2:36][N:29]2[C:30]3[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[C:27]([C:26]([F:25])([F:41])[F:40])=[N:28]2)[CH2:64][C:65]2[CH:66]=[CH:67][CH:68]=[CH:69][CH:70]=2)=[C:55]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[N:56]=1
Reactant: Cc1nc(-c2ccccc2)c(C(N)Cc2ccccc2)s1
Reactant: O=C(O)Cn1nc(C(F)(F)F)c2c1CCCC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(-c2ccccc2)c([C@H](Cc2ccccc2)NC(=O)Cn2nc(C(F)(F)F)c3c2CCCC3)s1
Reaction time: 0.17 h

Procedure:
HATU (40 mg, 0.105 mmol) was added to a solution of 2-(3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazol-1-yl)acetic acid (25.0 mg, 0.1 mmol) and DIPEA (0.02 mL, 0.12 mmol) in DMF (0.3 mL). After 10 minutes, 15B (29.4 mg, 0.1 mmol) in 0.2 mL of DMF was added to the reaction. The reaction was stirred for 2 hours. LC/MS shows desired product with a small amount of acid. Purified reaction mixture on prep reverse phase HPLC using 20-80% B over 20 min. (A=0.1% TFA/H2O; B=0.1% TFA/Acetonitrile). Combined pure fractions as determined by LC/MS and lyophilized to provide the desired product. 1H NMR (400 MHz, DMSO) δ 9.02 (d, J=7.8 Hz, 1H), 7.46-7.26 (m, 4H), 7.13 (t, J=6.1 Hz, 3H), 6.99 (d, J=7.7 Hz, 2H), 5.37 (dd, J=14.8, 7.3 Hz, 1H), 4.68 (t, J=12.7 Hz, 2H), 2.99 (ddd, J=20.2, 13.5, 7.3 Hz, 2H), 2.63 (s, 3H), 2.45-2.19 (m, 4H), 1.61 (d, J=5.5 Hz, 4H); MS (m/z) 525 [M+H]+.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O1CCCC1.[CH3:16][O:17][C:18]1[N:23]2[N:24]=[C:25]([C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])[CH:26]=[C:22]2[C:21]([C:34](=[O:37])[CH2:35][CH3:36])=[CH:20][CH:19]=1.Br[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41]>O1CCCC1>[CH3:16][O:17][C:18]1[N:23]2[N:24]=[C:25]([C:27]([F:33])([F:32])[C:28]([F:29])([F:30])[F:31])[CH:26]=[C:22]2[C:21]([C:34](=[O:37])[CH:35]([CH3:36])[CH2:39][C:40]([O:42][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:41])=[CH:20][CH:19]=1
Reactant: CCC(=O)c1ccc(OC)n2nc(C(F)(F)C(F)(F)F)cc12
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)C(C)CC(=O)OC(C)(C)C)c2cc(C(F)(F)C(F)(F)F)nn12
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
In an argon atmosphere, a 1 mol/L lithium bis(trimethylsilyl)amide/tetrahydrofuran solution (4.14 mL) was added dropwise to a solution of the compound of Example 356 (1.16 g) in tetrahydrofuran (30 mL) at 0° C. The mixture was stirred at 0° C. for 20 min. Subsequently, t-butyl bromoacetate (0.797 mL) was added at 0° C. and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate (200 mL). The extract was washed sequentially with water and saturated brine and dried over anhydrous sodium sulfate. The extract was then concentrated and purified by silica gel column chromatography (hexane:ethyl acetate=2:1 v/v) to afford the title compound as a colorless powder (940 mg).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:20][CH2:19][CH2:18][CH2:17]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[CH3:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:16]3([CH2:17][CH2:18][CH2:19][CH2:20]3)[C:15](=[O:21])[N:14]([CH:22]3[CH2:23][CH2:24][N:25]([S:35]([C:31]4[CH:32]=[CH:33][CH:34]=[C:29]([CH3:28])[CH:30]=4)(=[O:37])=[O:36])[CH2:26][CH2:27]3)[N:13]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C23CCCC3)cc1OC
Reactant: Cc1cccc(S(=O)(=O)Cl)c1
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(S(=O)(=O)c4cccc(C)c4)CC3)C(=O)C23CCCC3)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 4-(3,4-dimethoxyphenyl)-2-(piperidin-4-yl)-2,3-diazaspiro[4.4]non-3-en-1-one hydrochloride (compound B10*HCl) and 3-methylbenzenesulfonyl chloride as starting compounds. The crude product is purified by crystallization from EA and diethyl ether to yield the title compound.