Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([O-])([O-])=O.[K+].[K+].[CH:12]12[O:18][CH:13]1[CH2:14][CH2:15][CH2:16][CH2:17]2>O>[N:1]1([C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[OH:18])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: C1CCC2OC2C1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O[C@@H]1CCCC[C@H]1n1ccnc1
Temperature: 100 °C
Reaction time: 7 h
Yield: 26 %

Procedure:
A mixture of 20.18 g of imidazole, 81.95 g of K2CO3, and 20.0 mL of cyclohexene oxide in ca. 200 mL of H2O was stirred at room temperature for 19 h, at 100° C. (bath temp.) for 7 h, and then at room temperature overnight. The mixture was extracted with 3×500 mL of EtOAc and 500 mL of CH2Cl2. The organic layers were washed with 2×300 mL of H2O and 300 mL of brine. Combined organic layers were dried over MgSO4 and concentrated. The crude product was crystallized from EtOAc to yield 8.57 g (26%) of the crystalline solid.
Reaction SMILES: [OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]\[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([OH:25])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[C:30](O)(=O)C.C(=O)([O-])O.[Na+]>CO>[OH:1][CH:2]([CH2:26][CH2:27][CH2:28][OH:29])/[CH:3]=[CH:4]\[CH:5]=[C:6]1[C:10](=[O:11])[C:9]([S:12][CH3:13])=[CH:8][C:7]1([O:25][CH3:30])[CH2:14][CH2:15][CH2:16][CH2:17][O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CC(=O)O
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(=C/C=C\C(O)CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: COC1(CCCCOc2ccccc2)C=C(SC)C(=O)C1=C/C=C\C(O)CCCO
Reaction time: 24 h
Yield: 95 %

Procedure:
To a solution of 2 mg of 5-[(Z)-4,7-dihydroxy-2-heptenylidene]-2-methylthio-4-hydroxy-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 571 dissolved in 1 ml of methanol was added 0.5 μl of acetic acid, and the mixture was stirred for 24 hours. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel chromatography to give 1.9 mg (yield 95%) of 5-[(Z)-4,7-dihydroxy-2-heptenylidene]-2-methylthio-4-methoxy-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:11][CH:12]([CH3:14])[CH3:13])=[CH:6][C:5]2[O:23][CH:24]([CH3:31])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3.[NH:32]1CCC[C@H:33]1C(O)=O.[Cu]C#N>CN(C=O)C>[C:33]([C:2]1[C:7]([O:8][CH2:9][C@@H:10]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:20])([CH3:19])[CH3:21])[CH2:11][CH:12]([CH3:13])[CH3:14])=[CH:6][C:5]2[O:23][CH:24]([CH3:31])[C:25]3[C:30]([C:4]=2[CH:3]=1)=[CH:29][CH:28]=[N:27][CH:26]=3)#[N:32]
Reactant: CC(C)C[C@@H](COc1cc2c(cc1Br)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Reactant: O=C(O)[C@@H]1CCCN1
Agent: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(C)C[C@@H](COc1cc2c(cc1C#N)-c1ccncc1C(C)O2)NC(=O)OC(C)(C)C
Temperature: 120 °C
Reaction time: 12 h
Yield: 16.7 %

Procedure:
To a mixture of tert-butyl ((2S)-1-((9-bromo-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (100 mg, 0.203 mmol) (prepared as described in Example 21, Part A) and L-proline (23.43 mg, 0.203 mmol) in DMF (2 mL) was added copper(I) cyanide (36.5 mg, 0.407 mmol). Argon gas was bubbled through the stirred suspension for 5 min. The reaction mixture was stirred under argon atmosphere at 120° C. for 12 h. The mixture was then cooled to room temperature and diluted with ethyl acetate (10 mL) and filtered through celite. The filtrate was washed with water (10 mL) and brine (10 mL). The combined organic extracts were dried over sodium sulfate and concentrated under reduced pressure to afford crude material which was purified via silica gel chromatography (pet ether: ethyl acetate mobile phase) to afford tert-butyl ((2S)-1-((9-cyano-5-methyl-5H-chromeno[3,4-c]pyridin-8-yl)oxy)-4-methylpentan-2-yl)carbamate (15 mg, 0.034 mmol, 17% yield). LCMS (ESI) m/e 438.2 [(M+H)+, calcd for C25H32N3O4 438.2] LC/MS retention time (method D): tR=1.81 min.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([O:10]C)=[O:9])#[N:4]>C1COCC1.O>[C:3]([C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][N:14]=1)[C:8]([OH:10])=[O:9])#[N:4]
Reactant: COC(=O)c1ccnc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1cc(C(=O)O)ccn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.4 %

Procedure:
Lithium hydroxide (96 mg, 4.0 mmol) was added to a solution of methyl 2-cyanoisonicotinate (0.6 g, 3.7 mmol) in THF—H2O (20 mL, 7:3 v/v) at 0° C. The reaction mixture was allowed to warm up to room temperature and further stirred for 1 h. The reaction mixture was concentrated under reduced pressure and then diluted with water. The aqueous layer was washed with EtOAc. The pH of the aqueous layer was adjusted to ˜3 using 1.5N HCl and the organic product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 2-cyanoisonicotinic acid (490 mg, yield 89%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 14.11 (br s, 1H), 8.93-8.91 (dd, J=4.9 Hz, 0.8 Hz, 1H), 8.34 (d, J=0.9 Hz, 1H), 8.11-8.10 (m, 1H). MS (ESI) m/z: Calculated for C7H4N2O2: 148.03. found: 147.2 (M−H)−.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:8])[CH2:6][NH2:7])[CH3:3].C(N(C(C)C)CC)(C)C.[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:38][CH2:37]1)[N:30]=2)[CH:22]=O.[Na]>CO.CCOC(C)=O.C(Cl)(Cl)Cl>[F:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[C:27]1[S:28][C:29]2[C:34]([N:35]=1)=[CH:33][CH:32]=[C:31]([C:36]1([C:39]3[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:37][CH2:38]1)[N:30]=2)[CH2:22][NH:7][CH2:6][C:5]([O:4][CH2:2][CH3:3])=[O:8]
Reactant: CCOC(=O)CN
Reactant: O=Cc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Agent: Cl
Agent: [Na]
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: CCOC(=O)CNCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Glycine ethyl ester hydrochloride (224 mg, 1.602 mmol) was dissolved in MeOH (4.0 mL) and chloroform (4.0 mL) before diisopropylethylamine (279 μL, 1.602 mmol) was added and stirred at ambient temperature for 15 min. 3-Fluoro-4-(5-(1-phenylcyclopropyl)-thiazolo[5,4-b]pyridin-2-yl)benzaldehyde (300 mg, 0.801 mmol) and sodium triacetoxyhydroborate (340 mg, 1.602 mmol) were then added and stirred at ambient temperature for 24 h. The reaction mixture was diluted with 100 mL of EtOAc, added to a separatory funnel, partitioned with sodium bicarbonate (saturated, aqueous), washed 1 time with 50 mL of ammonium chloride (saturated, aqueous), separated, dried over sodium sulfate, and concentrated via rotovap to give ethyl 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo-[5,4-b]pyridin-2-yl)benzylamino)acetate after flash chromatography. MS (ESI) m/z: Calculated: 461.2; Observed: 461.9 (M++H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][NH2:11])=[C:5]([O:12][CH3:13])[CH:4]=1.C(N(CC)CC)C.[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](O)=[O:38])=[CH:35][CH:34]=1)[O:28][CH2:27][CH2:26][CH:25]2[C:42]([O:44][CH2:45][CH3:46])=[O:43].O.N1(O)C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C>C(Cl)Cl.CCOC(C)=O>[Cl:21][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:31]=1[O:32][C:33]1[CH:41]=[CH:40][C:36]([C:37](=[O:38])[NH:11][CH2:10][CH2:9][C:6]3[CH:7]=[CH:8][C:3]([Cl:2])=[CH:4][C:5]=3[O:12][CH3:13])=[CH:35][CH:34]=1)[O:28][CH2:27][CH2:26][CH:25]2[C:42]([O:44][CH2:45][CH3:46])=[O:43]
Reactant: COc1cc(Cl)ccc1CCN
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4OC)cc3)c(Cl)cc21
Reaction time: 0.5 h

Procedure:
To a suspension of 2-(4-chloro-2-methoxyphenyl)ethanamine hydrochloride (Preparation 8; 23.4 g, 105 mmol) in DCM (200 ml) was added triethylamine (16.8 ml, 120 mmol), and the mixture was allowed to stir for 30 minutes (solids did not go into solution). To this was added sequentially 4-(6-chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1; 37.8 g, 100 mmol, 1H-benzo[d][1,2,3]triazol-1-ol hydrate (15.4 g, 100 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (23.1 g, 120 mmol), and the reaction was allowed to stir overnight (all solids went into solution after 2 hours). The reaction was diluted with EtOAc (600 ml) and washed with 600 mL portions of 1M HCl, saturated aqueous bicarbonate, and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated. The residue was taken up in hot ethyl acetate (500 ml) and was crystallized by the addition of hexanes (1.5 L) to yield ethyl 6-chloro-7-(4-(4-chloro-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylate (51.1 g, 93.9 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:3]=1[O:4][CH2:5][C:6]([OH:8])=O.[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][CH:18]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1>CN(C)C1C=CN=CC=1.CN(C=O)C>[CH3:14][O:15][C:16](=[O:24])[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:6](=[O:8])[CH2:5][O:4][C:3]2[CH:9]=[CH:10][C:11]([Cl:13])=[CH:12][C:2]=2[Cl:1])=[CH:19][CH:18]=1
Reactant: O=C(O)COc1ccc(Cl)cc1Cl
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(NC(=O)COc2ccc(Cl)cc2Cl)cc1
Reaction time: 8 h
Yield: 95.8 %

Procedure:
The mixture of (2,4-dichloro-phenoxy)-acetic acid (110.5 mg, 0.5 mmol), 4-aminobenzoic acid methyl ester (151.2 mg, 1.0 mmol), 4-dimethylaminopyridine (122.7 mg, 1.0 mmol) and benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (pybop) (520.3 mg, 1.0 mmol) in DMF (8.0 mL) was stirred overnight and then partitioned between ethyl acetate and 10% HCl. The organic phase was washed with brine, dried (MgSO4 anh), and concentrated. The residue was purified by silica gel flash column chromatography (n-Hexane:Ethyl acetate:MeOH=6:3:1) to give 4-[2-(2,4-dichloro-phenoxy)-acetylamino]-benzoic acid methyl ester as a white solid (169.6 mg, 95.8% yield).
Reaction SMILES: [C:1]1(=[CH:7][CH:8]=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:10]1([S:16]([C:19]#[N:20])(=[O:18])=[O:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.B(OCCCC)(OCCCC)OCCCC.C(O)CCC>C1(C)C=CC=CC=1>[C:10]1([S:16]([C:19]2[C:2]3[CH2:3][CH2:4][CH2:5][CH2:6][C:1]=3[CH:7]=[CH:8][N:20]=2)(=[O:17])=[O:18])[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1
Reactant: N#CS(=O)(=O)c1ccccc1
Reactant: O=CC=C1CCCCC1
Agent: CCCCOB(OCCCC)OCCCC
Solvent: Cc1ccccc1
Solvent: CCCCO
Product: O=S(=O)(c1ccccc1)c1nccc2c1CCCC2
Temperature: 110 °C
Yield: 15.8 %

Procedure:
First, 106 mg (purity of 84%, 0.72 mmol) of cyclohexylidene acetaldehyde, 120 mg (0.72 mmol) of benzenesulfonyl cyanide, 17 mg (0.072 mmol) of tributyl borate, 11 mg (0.14 mmol) of 1-butanol, and molecular sieves 4A (310 mg) as dehydrator were introduced to a flask (5 ml volume). Toluene (1.5 ml) was added as the solvent, and the mixture was heated for 14 hours at an internal temperature of 110° C. After this solution was cooled to room temperature, the molecular sieves was filtered off and the low-boiling components, such as solvent, etc., were removed under reduced pressure to give the desired, crude product. The crude product was purified by silica gel column chromatography (eluting solvent: ethyl acetate/hexane=⅓) to give 31 mg of 1-benzenesulfonyl-5,6,7,8-tetrahydroisoquinoline with the following properties as yellow crystals (yield of 16% based on benzenesulfonyl cyanide).
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH2:13][CH3:14])=[CH:9][CH:10]=2)[N:5]([CH2:15][CH3:16])[C:4]=1[C:17]1[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:32])[NH:25][CH2:26][C:27](OCC)=[O:28])=[CH:19][CH:18]=1)#[N:2].Cl.CC(C)=[O:36]>>[CH2:13]([O:12][C:8]1[CH:7]=[C:6]2[C:11]([C:3]([C:1]([NH2:2])=[O:36])=[C:4]([C:17]3[CH:22]=[CH:21][C:20]([N:23]4[C:27](=[O:28])[CH2:26][NH:25][C:24]4=[O:32])=[CH:19][CH:18]=3)[N:5]2[CH2:15][CH3:16])=[CH:10][CH:9]=1)[CH3:14]
Reactant: CC(C)=O
Reactant: CCOC(=O)CNC(=O)Nc1ccc(-c2c(C#N)c3ccc(OCC)cc3n2CC)cc1
Agent: Cl
Product: CCOc1ccc2c(C(N)=O)c(-c3ccc(N4C(=O)CNC4=O)cc3)n(CC)c2c1
Yield: 87 %

Procedure:
A solution of ethyl {3-[4-(3-cyano-6-ethoxy-1-ethyl-1H-indol-2-yl)-phenyl]-ureido}acetate (compound 773, 325 mg, 0.748 mmol), prepared in procedure 1AV, step A, in acetone (5 mL) is treated with HCl (3 mL, 6 N), and the resulting solution is heated to reflux overnight. The reaction mixture is cooled, and the resulting precipitate is collected by filtration, washed with ether and dried under high vacuum to afford the product, 6-ethoxy-1-ethyl-2-[4-(2,5-dioxo-imidazolidin-1-yl)-phenyl]-1H-indole-3-carboxamide (264 mg, 0.650 mmol, 87%).
Reaction SMILES: [F:1][C:2]([F:62])([F:61])[C:3]1[CH:4]=[C:5]([CH:58]=[CH:59][CH:60]=1)[CH2:6][NH:7][C:8]([C:10]1[CH:15]=[CH:14][N:13]=[C:12]([C:16]2[CH:21]=[C:20]([N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[CH:19]=[CH:18][C:17]=2[NH:28][C:29]([C:31]2[CH:32]=[C:33]([CH:55]=[CH:56][CH:57]=2)[CH2:34][N:35]([CH3:54])[CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47]([O:49]C(C)(C)C)=[O:48])=[O:30])[CH:11]=1)=[O:9].FC(F)(F)C(O)=O>ClCCl>[CH3:54][N:35]([CH2:36][CH2:37][O:38][CH2:39][CH2:40][O:41][CH2:42][CH2:43][O:44][CH2:45][CH2:46][C:47]([OH:49])=[O:48])[CH2:34][C:33]1[CH:55]=[CH:56][CH:57]=[C:31]([C:29](=[O:30])[NH:28][C:17]2[CH:18]=[CH:19][C:20]([N:22]3[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]3)=[CH:21][C:16]=2[C:12]2[CH:11]=[C:10]([C:8](=[O:9])[NH:7][CH2:6][C:5]3[CH:58]=[CH:59][CH:60]=[C:3]([C:2]([F:1])([F:61])[F:62])[CH:4]=3)[CH:15]=[CH:14][N:13]=2)[CH:32]=1
Reactant: CN(CCOCCOCCOCCC(=O)OC(C)(C)C)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(CCOCCOCCOCCC(=O)O)Cc1cccc(C(=O)Nc2ccc(N3CCCCC3)cc2-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 50-mL round-bottom flask, was placed a solution of tert-butyl 3-(2-(2-(2-((3-((2-(4-((3-(trifluoromethyl)benzyl)carbamoyl)pyridin-2-yl)-4-(piperidin-1-yl)phenyl)-carbamoyl)benzyl)(methyl)amino)ethoxy)ethoxy)ethoxy)propanoate (264 mg, 0.31 mmol, 1.00 equiv) in dichloromethane (2 mL), and trifluoroacetic acid (1 mL). The resulting solution was stirred for 2 h at room temperature. The resulting mixture was concentrated under vacuum. The crude product (200 mg) was purified by reverse phase HPLC eluting with a water/CH3CN gradient containing 0.05% TFA. The product was obtained as 46 mg (13%) of as a yellow solid. 1H-NMR (300 MHz, CD3OD, ppm): δ 8.941-8.924 (d, J=5.1 Hz, 1H), 8.665-8.635 (d, J=9.0 Hz, 1H), 8.436 (s, 1H), 8.159-8.081 (m, 3H), 7.888-7.863 (m, 1H), 7.792-7.563 (m, 7H), 4.720 (s, 2H), 4.533 (s, 2H), 3.895-3.862 (m, 6H), 3.685-3.560 (m, 14H), 3.410 (s, 2H), 2.910 (s, 3H), 2.509-2.468 (m, 2H), 2.020-2.004 (s, 4H), 1.816-1.799 (s, 2H). MS (ES, m/z): 806 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[C:5]1[C:10](Cl)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22])C.Cl.[NH:25]1[CH2:28][CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C.CCOC(C)=O>[CH3:1][O:3][C:4](=[O:23])[C:5]1[C:10]([N:25]2[CH2:28][CH2:27][CH2:26]2)=[CH:9][C:8]([C:12]2[C:17]([CH2:18][CH3:19])=[CH:16][CH:15]=[CH:14][C:13]=2[CH2:20][CH3:21])=[N:7][C:6]=1[CH3:22]
Reactant: C1CNC1
Reactant: CCOC(=O)c1c(Cl)cc(-c2c(CC)cccc2CC)nc1C
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCc1cccc(CC)c1-c1cc(N2CCC2)c(C(=O)OC)c(C)n1
Temperature: 80 °C

Procedure:
A mixture of 4-chloro-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester (Example 2, step 1) (500 mg, 1.57 mmol), azetidine hydrochloride (588 mg, 6.29 mmol) and K2CO3 (1.08 g, 7.87 mmol) in DMF (5 mL) is heated at 80° C. in a sealed tube overnight. On cooling, water (20 mL) and EtOAc (20 mL) are added. The organic layer is separated and the aqueous layer is extracted with EtOAc (10 mL). The combined organic layer is washed with water, dried, and concentrated to give 4-azetidin-1-yl-6-(2,6-diethyl-phenyl)-2-methyl-nicotinic acid methyl ester as a crude product. A solution of LiAlH4 (1M in THF, 4.5 mL) is added to a solution of this crude product in THF (5 mL). The reaction mixture is stirred at room temperature overnight, diluted with ether (10 mL), and the reaction quenched with solid Na2SO4.10H2O (1.0 g). The resulting mixture is stirred for 1 hour, filtered through celite and concentrated at reduced pressure. The crude product is purified by PTLC (10% MeOH in CH2Cl2) to give the title product. 1H NMR (CDCl3) 7.20 (t, 1H), 7.10 (d, 2H), 6.09 (s, 1H), 4.66 (s, 2H), 4.17 (t, 4H), 2.58 (s, 3H), 2.38 (m, 6H), 1.08 (t, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15](O)=[O:16])[N:12]=1.S(Cl)([Cl:32])=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27]=1[O:28][CH3:29])[CH2:5][NH:6][C:7]1[C:8]2[N:20]([CH3:21])[N:19]=[C:18]([CH2:22][CH2:23][CH3:24])[C:9]=2[N:10]=[C:11]([CH2:13][CH2:14][C:15]([Cl:32])=[O:16])[N:12]=1
Reactant: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(=O)O)nc12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCc1nn(C)c2c(NCc3ccc(OC)c(Cl)c3)nc(CCC(=O)Cl)nc12

Procedure:
1 equivalent of 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionic acid and 1.2 equivalents of thionyl chloride are stirred in dichloromethane for 2 hours. The solvent is removed and 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-propionyl chloride is obtained. The product is transferred to aqueous ammonia, stirred for one hour and, after customary working up, 3-[7-(3-chloro-4-methoxybenzylamino)-1-methyl-3-propyl-1H-pyrazolo[4,3-d]-pyrimidin-5-yl]propionamide is obtained.
Reaction SMILES: S(Cl)([Cl:3])=O.[F:5][C:6]1[CH:11]=[CH:10][C:9]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20]O)=[CH:16][CH:15]=2)=[CH:8][CH:7]=1.C(=O)(O)[O-].[Na+]>ClCCl>[Cl:3][CH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH2:13][CH2:12][C:9]2[CH:10]=[CH:11][C:6]([F:5])=[CH:7][CH:8]=2)=[CH:15][CH:16]=1
Reactant: O=S(Cl)Cl
Reactant: OCc1ccc(CCc2ccc(F)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Fc1ccc(CCc2ccc(CCl)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
At 0° C., 14.96 ml of thionyl chloride in 100 ml of dichloromethane were slowly added dropwise to a solution of 31.5 g (136.7 mmol) of {4-[2-(4-fluorophenyl)ethyl]phenyl}methanol in 400 ml of dichloromethane. After the addition had ended, the reaction mixture was warmed to room temperature and stirred at this temperature for another 2 hours. The reaction mixture was then once more cooled to 0° C., and 200 ml of saturated aqueous sodium bicarbonate solution were added slowly and carefully, with vigorous stirring. Subsequently, small portions of solid sodium bicarbonate were added to the solution until the pH had been adjusted to 6. The phases were then separated, and the organic phase was dried over magnesium sulphate, filtered and concentrated to dryness. This gave 28.5 g (114.5 mmol, 84% of theory) of the title compound.
Reaction SMILES: F[C:2]1[CH:29]=[C:28]([F:30])[CH:27]=[CH:26][C:3]=1[CH2:4][N:5]1[C:9]2=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]2[C:7]([CH2:18]SC2C=CC=CC=2)=[CH:6]1.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][C:32]1=[O:37].CCN(C(C)C)C(C)C.C(=O)(O)[O-].[Na+]>CN(C=O)C>[F:30][C:28]1[CH:29]=[CH:2][C:3]([CH2:4][N:5]2[C:9]3=[CH:10][N:11]=[C:12]([C:14]([O:16][CH3:17])=[O:15])[CH:13]=[C:8]3[C:7]([CH2:18][N:34]3[CH2:35][CH2:36][NH:31][C:32](=[O:37])[CH2:33]3)=[CH:6]2)=[CH:26][CH:27]=1
Reactant: O=C1CNCCN1
Reactant: COC(=O)c1cc2c(CSc3ccccc3)cn(Cc3ccc(F)cc3F)c2cn1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc2c(CN3CCNC(=O)C3)cn(Cc3ccc(F)cc3)c2cn1
Temperature: 50 °C
Reaction time: 4 h
Yield: 95.1 %

Procedure:
A solution of methyl 3-(chloromethyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate (24 mL, 2.0M in CH2Cl2, 48.3 mmol) [prepared as described in step 2 of example 40] was evaporated in vacuo to a residue. To this residue, anhydrous DMF (150 mL) and piperazin-2-one (386.4 mmol, 38.689, 8.0 eq.) were added followed by i-Pr2NEt (18.77 g, 145.2 mmol, 25.29 mL, 3 eq.). The mixture, under nitrogen, was placed in an oil bath and the bath was warmed to 50° C. After stirring for 4 hours (50° C.) the reaction was judged to be complete by HPLC-MS analysis. The volatiles were removed in vacuo (ca. 2 torr, at 60° C.) to give a yellow residue. Saturated aqueous sodium bicarbonate (300 mL) was added. White solid precipitated out, and the mixture was sonicated for 30 min and cooled to 10° C. The solid was filtered, washed with cold water (50 mL), and dried in vacuo to afford 18.2 g (95%) of methyl 1-(4-fluorobenzyl)-3-((3-oxopiperazin-1-yl)methyl)-1H-pyrrolo[2,3-c]pyridine-5-carboxylate. LC-MS (Eclipse XDB-C8, 0.8 mL/min, gradient 80:20 to 5:95H2O (+0.1% HOAc):CH3CN—5 minutes, APCI, +mode): RT—1.41 min, m/e=397.20 (M+H+, base). 1H NMR (300 MHz, DMSO-D6) d ppm 2.55 (t, 2H) 2.92 (s, 2H) 3.11 (s, 2H) 3.74 (s, 2H) 3.84 (s, 3H) 5.56 (s, 2H) 7.16 (t, J=8.85 Hz, 2H) 7.34 (dd, J=8.19, 5.75 Hz, 2H) 7.71 (s, 1H) 7.81 (s, 1H) 8.41 (s, 1H) 8.93 (s, 1H).
Reaction SMILES: [NH2:1][C:2]([P:8]([OH:11])(=[O:10])[OH:9])([P:4]([OH:7])(=[O:6])[OH:5])[CH3:3].C=O.P(Cl)(Cl)Cl>>[P:4]([CH:2]=[N:1][C:2]([P:4]([OH:7])(=[O:5])[OH:6])([P:8]([OH:11])(=[O:9])[OH:10])[CH3:3])([OH:7])([OH:6])=[O:5]
Reactant: CC(N)(P(=O)(O)O)P(=O)(O)O
Agent: C=O
Solvent: ClP(Cl)Cl
Product: CC(N=CP(=O)(O)O)(P(=O)(O)O)P(=O)(O)O

Procedure:
103 g. of 1-amino ethane-1,1-diphosphonic acid are suspended in 100 g. of a 30% formaldehyde solution. 85 cc. of phosphorus trichloride are added thereto drop by drop while stirring. After the addition is completed, the mixture is heated to boiling until a homogeneous mixture is formed. The water is removed by evaporation in a vacuum. The resulting phosphonic acid mixture is precipitated by the addition of acetone. N-phosphono methylene-1-amino ethane-1,1-diphosphonic acid is obtained in this manner.
Reaction SMILES: C(OC(=O)[CH:5]([S:7][C:8]1[S:12][C:11]([NH:13][C:14]([N:16]([CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[CH:17]2[CH2:20][CH2:19][CH2:18]2)=[O:15])=[N:10][CH:9]=1)[CH3:6])C.C1(NC2CCC2)CCCCCC1.NC1SC=NC=1.C([O:49][C:50](=[O:53])CS)C>>[CH:17]1([N:16]([CH:21]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:14](=[O:15])[NH:13][C:11]2[S:12][C:8]([S:7][CH2:5][CH2:6][C:50]([OH:53])=[O:49])=[CH:9][N:10]=2)[CH2:20][CH2:19][CH2:18]1
Reactant: CCOC(=O)CS
Reactant: CCOC(=O)C(C)Sc1cnc(NC(=O)N(C2CCCCCC2)C2CCC2)s1
Agent: C1CCCC(NC2CCC2)CC1
Agent: Nc1cncs1
Product: O=C(O)CCSc1cnc(NC(=O)N(C2CCCCCC2)C2CCC2)s1

Procedure:
[2-(3-Cycloheptyl-3-cyclobutyl-ureido)-thiazol-5-ylsulfanyl]-propionic acid ethyl ester prepared as described in general procedure (A) using cycloheptyl-cyclobutylamine and 5-aminothiazole-2-mercaptoacetic acid ethyl ester. Hydrolysis using general procedure (F) gave the title compound