Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19](Br)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(C1CCN(C(=O)[C@H](NC(C2C3C(=NC=C(Br)N=3)N(COCC[Si](C)(C)C)C=2)=O)C2CC2)CC1)#N.[CH3:67][NH:68][C:69](=[O:89])[C:70]1[CH:75]=[CH:74][N:73]=[C:72]([Sn](CCCC)(CCCC)CCCC)[CH:71]=1.C(C1C=CN=C([Sn](CCCC)(CCCC)CCCC)C=1)(C)(C)C>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:31])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:72]4[CH:71]=[C:70]([C:69](=[O:89])[NH:68][CH3:67])[CH:75]=[CH:74][N:73]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc(C(=O)NC)ccn1
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(Br)nc12)C(=O)N1CC(C#N)C1
Agent: CCCC[Sn](CCCC)(CCCC)c1cc(C(C)(C)C)ccn1
Agent: C[Si](C)(C)CCOCn1cc(C(=O)N[C@@H](C(=O)N2CCC(C#N)CC2)C2CC2)c2nc(Br)cnc21
Product: CNC(=O)c1ccnc(-c2cnc3[nH]cc(C(=O)N[C@H](C)C(=O)N4CC(C#N)C4)c3n2)c1

Procedure:
Prepared according to the procedure outlined in Example 111, steps 4-5 substituting 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide for 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(4-cyano-piperidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide and N-methyl-2-tributylstannanyl-isonicotinamide for 4-tert-butyl-2-(tributylstannyl)pyridine. MS: (M+H)+=433.
Reaction SMILES: CC([Mg]Cl)C.[Br:6][C:7]1[CH:12]=[CH:11][C:10](Br)=[CH:9][N:8]=1.CN(C)[CH:16]=[CH:17][CH:18]=[O:19].Cl>C1COCC1>[Br:6][C:7]1[N:8]=[CH:9][C:10]([CH:16]=[CH:17][CH:18]=[O:19])=[CH:11][CH:12]=1
Reactant: CN(C)C=CC=O
Reactant: Brc1ccc(Br)nc1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: O=CC=Cc1ccc(Br)nc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 25.9 %

Procedure:
2-Propylmagnesium chloride (2.0 M in THF, 5.00 mL 10.00 mmol) was added to a solution of 2,5-dibromopyridine (2.37 g, 10.00 mmol) in THF (5.0 mL) at RT. The resulting brown suspension was stirred for 1 h and then cooled to 0° C. 3-Dimethylaminoacrolein (95%, 1.30 mL, 12.36 mmol) was added and the mixture was warmed to RT and stirred for 2 h. 2 N HCl was added and after 5 min the mixture was cooled to 0° C. The precipitated solids were removed by filtration and partitioned between ethyl acetate (75 mL) and 10% NaOH (25 mL). The ethyl acetate layer was washed with brine (25 mL), dried (MgSO4), and concentrated. Recrystallization from ethyl acetate provided 550 mg (26%) of the title compound as shiny brown flakes. MS 211 (M+H)+.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2F)[O:7][C@H:6]1[CH2:34][O:35][C:36](=[O:38])[CH3:37])(=[O:3])[CH3:2].[H-].[Na+].[Br-].C(O[C@@H:46]1[C@@H:52](OC(=O)C)[C@@H:51](OC(=O)C)[C@@H:50]([CH2:61]OC(=O)C)O[C@@H:47]1O)(=O)C>>[C:16]([O:15][C@H:9]1[C@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:5]([O:4][C:1](=[O:3])[CH3:2])[C@H:6]([CH2:34][O:35][C:36](=[O:38])[CH3:37])[O:7][C@@H:8]1[O:19]/[C:20](/[C:29]([O:31][CH2:32][CH3:33])=[O:30])=[CH:21]\[C:22]1[CH:27]=[C:26]([C:47]2[CH:46]=[CH:52][CH:51]=[CH:50][CH:61]=2)[CH:25]=[CH:24][CH:23]=1)(=[O:18])[CH3:17]
Reactant: CC(=O)OC[C@H]1O[C@H](O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: CCOC(=O)/C(=C/c1ccccc1F)O[C@H]1O[C@@H](COC(C)=O)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)/C(=C/c1cccc(-c2ccccc2)c1)O[C@H]1O[C@@H](COC(C)=O)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Yield: 26 %

Procedure:
The title compound was prepared as described for C4 using methyl 3-(3-arylphenyl)-2-oxopropanoate B12 (100 mg, 0.373 mmol), sodium hydride (9.0 mg, 0.373 mmol) and 2,3,4,6-tetra-O-acetyl-α-D-galactose bromide (153 mg, 0.373 mmol). The compound was isolated in the form of white solid in 26% yield.
Reaction SMILES: CC[O:3][C:4]([P:6]([O:11]CC)([O:8]CC)=[O:7])=[O:5].[OH-:14].[Na+:15]>O>[OH2:3].[OH2:14].[OH2:3].[OH2:3].[OH2:3].[OH2:3].[C:4]([P:6](=[O:7])([O-:11])[O-:8])([OH:5])=[O:3].[Na+:15].[Na+:15].[Na+:15]
Reactant: CCOC(=O)P(=O)(OCC)OCC
Reactant: [OH-]
Agent: [Na+]
Solvent: O
Product: O=C(O)P(=O)([O-])[O-]

Procedure:
Using the method of Nylen, Ber., 57B, 1023 (1924), a solution of 21 parts of triethyl carboxyphosphonate in 60 parts of water containing 24 parts of 50% sodium hydroxide was refluxed for 2 hrs. The solution was allowed to cool overnight. Filtration of the reaction mixture gave 4.7 parts of the product, trisodium carboxyphosphonate hexahydrate, mp >250°; νKBr = 1560, 1530 cm-1.
Reaction SMILES: [NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([OH:12])=O)[CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)=[O:48].Cl.C(N(CC)C(C)C)(C)C>ClCCl>[NH:1]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@@H:2]([C:10]([N:45]1[CH2:59][CH2:58][CH2:57][C@H:46]1[C:47]([O:49][CH2:50][C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)=[O:48])=[O:12])[CH2:3][CH:4]1[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9]1
Reactant: O=C(OCc1ccccc1)[C@@H]1CCCN1
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Yield: 98.5 %

Procedure:
To a stirred solution of 11.64 g of Boc-D-Cha-OH in 100 mL of dichloromethane at 0° C. was added 6.36 g of HOBt and 9.72 g of DCC. After 20 minutes a solution of 10.35 g of H-Pro-OBzl.HCl in 40 mL of dichloromethane adjusted with N,N-diisopropyl ethylamine to pH 8 was added. After 16 h the reaction mixture was filtered and the filtrate was washed successively with water, 0.1 N hydrochloric acid, water, aqueous 5% sodium hydrogencarbonate and brine. All aqueous washes were extracted twice with ethyl acetate, all organic extracts combined, dried over sodium sulfate and concentrated. To the residue was added a mixture of ethyl acetate/heptanes=1/1 (v/v), the resulting suspension filtered and the filtrate purified by chromatography on silica gel (eluent: ethyl acetate/heptanes=1/1 v/v) to yield 19.34 g of Boc-D-Cha-Pro-OBzl.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.[OH-].[Na+]>O>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[CH:20]=[C:21]([O:25][CH2:26][C:27]([OH:29])=[O:28])[CH:22]=[N:23][CH:24]=2)=[O:18])[CH2:13][CH2:12]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)COc1cncc(C(=O)N2CCN(c3ccccc3C(C)(C)C)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)c1ccccc1N1CCN(C(=O)c2cncc(OCC(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 92.4 %

Procedure:
A mixture of tert-butyl [(5-{[4-(2-tert-butylphenyl)piperazin-1-yl]carbonyl}pyridin-3-yl)oxy]acetate obtained in Example 35 (500 mg) and trifluoroacetic acid (7 mL) was stirred at room temperature for 3 h. Water was added to the reaction solution, and subsequently 1 M sodium hydroxide solution was added to the mixture to pH 5-6. The resulting precipitate was collected and dried under reduced pressure to provide the title compound (405 mg, 93%) as crystals.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]Br)=[C:4]([Cl:10])[CH:3]=1.[C-:11]#[N:12].[K+]>ClC(Cl)C.O.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:11]#[N:12])=[C:4]([Cl:10])[CH:3]=1
Reactant: [C-]#N
Reactant: Clc1cc(Br)ccc1CBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: CC(Cl)Cl
Solvent: O
Product: N#CCc1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 4 h
Yield: 290.2 %

Procedure:
To a stirred solution of 4-bromo-1-bromomethyl-2-chlorobenzene (16, 62.5 g, 0.22 mol) in dichloroethane (522 mL) and water (480 mL) was added tetrabutylammonium chloride (5.05 g), followed by a solution of potassium cyanide (43.2 g, 75.8 mmol) in water (523 mL). and the solution was stirred for 4 h at room temperature. The layers were separated and the aqueous layer was extracted with dichloroethane (100 mL). The combined organic layers were washed with water (100 mL), dried over sodium sulfate filtered and evaporated. The crude product (52 g) was distilled under reduced pressure (1 mmHg), affording (4-bromo-2-chlorophenyl)-acetonitrile (45.5 g, 0.220 mol, 90%).
Reaction SMILES: [F:1][CH:2]([F:12])[O:3][C:4]1[CH:11]=[CH:10][C:7]([CH2:8][NH2:9])=[CH:6][CH:5]=1.C[O:14][C:15](=O)[C:16]1[C:21]([I:22])=[CH:20][C:19]([F:23])=[CH:18][C:17]=1[CH2:24]Br.C([O-])([O-])=O.[K+].[K+]>C1(C)C=CC=CC=1>[F:23][C:19]1[CH:18]=[C:17]2[C:16](=[C:21]([I:22])[CH:20]=1)[C:15](=[O:14])[N:9]([CH2:8][C:7]1[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:12])[F:1])=[CH:11][CH:10]=1)[CH2:24]2
Reactant: NCc1ccc(OC(F)F)cc1
Reactant: COC(=O)c1c(I)cc(F)cc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C1c2c(I)cc(F)cc2CN1Cc1ccc(OC(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 34.8 %

Procedure:
A mixture of 4-difluoromethoxy-benzyl amine (0.173 g, 1.0 mmol), 2-bromomethyl-4-fluoro-6-iodo-benzoic acid methyl ester (0.270 g, 0.73 mmol), and K2CO3 (0.207 g, 1.5 mmol) in toluene (4 mL) was heated with stirring at 100° C. for 2 h. The resulting mixture was filtered and concentrated. Silica gel column chromatography using 30% ethyl acetate in hexane afforded 5-fluoro-7-iodo-2-(4-difluoromethoxy-benzyl)-2,3-dihydro-isoindol-1-one (0.110 g, 35%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.18 (s, 2H), 4.84 (s, 2H), 6.52 (t, 1H), 7.10 (m, 3H), 7.28 (d, 2H), 7.64 (d, 1H). GC-MS: m/z 433 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:12]=[CH:13][CH2:14][N+:15]([O-:17])=[O:16])=[C:7]([CH:11]=1)[C:8](O)=[O:9].C(OC(=O)C)(=O)C.C([O-])(=O)C.[K+]>>[CH3:1][O:2][C:3]1[CH:11]=[C:7]2[C:6](=[CH:5][CH:4]=1)[N:12]=[CH:13][C:14]([N+:15]([O-:17])=[O:16])=[C:8]2[OH:9]
Reactant: COc1ccc(N=CC[N+](=O)[O-])c(C(=O)O)c1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: COc1ccc2ncc([N+](=O)[O-])c(O)c2c1

Procedure:
The title compound is prepared in analogy to Example 19b starting from 7.15 g (0.029 mol) of 5-methoxy-2-[2-nitro-ethylidenamino]-benzoic acid (Example 44e), 32 ml acetic anhydride, and 3.52 g (0.035 mol) potassium acetate. The title compound which precipitates from the solution, is filtered off, washed with acetic acid, and dried overnight at 85° C. mp: 278-281° C.; MS: 221 (M++1); HPLC: tret=10.23 min (Grad 1).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[OH:13])[C:5](OCC)=[O:6].[CH3:14][NH:15][NH2:16]>>[CH3:14][N:15]([C:5](=[O:6])[C:4]1[CH:10]=[CH:11][C:12]([OH:13])=[C:2]([OH:1])[CH:3]=1)[NH2:16]
Reactant: CNN
Reactant: CCOC(=O)c1ccc(O)c(O)c1
Product: CN(N)C(=O)c1ccc(O)c(O)c1

Procedure:
0.11 g (0.05 mol) of 3,4-dihydroxybenzoic acid, ethyl ester and 106 ml of methylhydrazine (2 mol) were refluxed for 3 days. The reaction mixture was evaporated in vacuo and the oily residue treated with ethanol and evaporated again. This was repeated once more. After retreatment with ethanol, 3,4-dihydroxybenzoic acid, 1-methylhydrazide began to crystallize. The crude product was removed by filtration and recrystallized from ethanol; yield: 3.8 g, melting point 202°-205° C.
Reaction SMILES: C([O:4][C:5]1[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])=[N:7][C:8]([Cl:11])=[CH:9][CH:10]=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].CO>O>[Cl:11][C:8]1[N:7]=[C:6]([O:12][CH2:13][C:14]([O:16][CH3:17])=[O:15])[C:5]([OH:4])=[CH:10][CH:9]=1
Reactant: COC(=O)COc1nc(Cl)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)COc1nc(Cl)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 3-acetoxy-6-chloro-2-(methoxycarbonyl)methoxypyridine, potassium carbonate and methanol is stirred for 3 hours at room temperature. The reaction solution is poured into water, and extracted with ethyl acetate. The organic layer is dried over anhydrous magnesium sulfate, and concentrated. The residue is subjected to silica gel column chromatography to obtain 6-chloro-3-hydroxy-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: C(Cl)(=O)C.C1([C@H](OC(=O)[NH:15][C@@H:16]2[C@@H:25]([O:26][CH3:27])[CH2:24][C:23]3[C:18](=[CH:19][C:20]([C:28](=[O:30])[NH2:29])=[CH:21][CH:22]=3)[C:17]2([CH2:33][CH3:34])[CH2:31][CH3:32])C)C=CC=CC=1>C(O)C>[NH2:15][C@H:16]1[C:17]([CH2:31][CH3:32])([CH2:33][CH3:34])[C:18]2[CH:19]=[C:20]([C:28]([NH2:29])=[O:30])[CH:21]=[CH:22][C:23]=2[CH2:24][C@@H:25]1[O:26][CH3:27]
Reactant: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1NC(=O)O[C@H](C)c1ccccc1
Solvent: CC(=O)Cl
Solvent: CCO
Product: CCC1(CC)c2cc(C(N)=O)ccc2C[C@H](OC)[C@H]1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
Acetyl chloride (193 mL, 2710 mmol) was added dropwise to ethanol (260 mL, 4500 mmol) at −5° C. over 40 min keeping the internal temperature below 30° C. The resulting solution was added over 5 min, at 10° C., to a mixture of ((2S,3S)-7-carbamoyl-1,1-diethyl-3-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-carbamic acid (R)-1-phenyl-ethyl ester (49.0 g, 115 mmol) and ethanol (200 mL). The reaction mixture was stirred at room temperature overnight, and concentrated to ˜100 mL by rotary evaporation. Ethyl acetate (100 mL) was added and the resulting slurry was stirred at 0° C. for 30 min and filtered. The filter cake was washed with ethyl acetate and dried to yield the hydrochloride salt of the title compound (30 g, >99% purity). The volume of the filtrate was reduced almost to dryness. Isopropyl alcohol (20 mL) was added and the resulting thick slurry was stirred for 30 min and filtered. The filter cake was washed with ethyl acetate (2×20 mL) and dried under vacuum overnight to yield additional title compound (5.5 g, >97% purity). 1H NMR (DMSO-d6): δ (ppm) 0.49 (t, 3H), 0.63 (t, 3H), 1.62 (q, 2H), 1.89 (m, 1H), 2.09 (m, 1H), 2.60 (dd, 1H), 3.22 (m, 1H), 3.41 (s, 3H), 3.50 (dd, 1H), 3.82 (q, 1H), 7.19 (d, 1H), 7.31 (br, 1H), 7.70 (d, 1H), 7.71 (s, 1H), 7.98 (br, 1H), 8.15 (br, 3H).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][C:12]([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)([CH2:14][CH2:15]OS(C)(=O)=O)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[CH2:37]([O:39][C:40]([NH:42][C:43]1([C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)[CH2:48][CH2:47][NH:46][CH2:45][CH2:44]1)=[O:41])[CH3:38].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C.C(Cl)Cl.CCOCC.O>[OH2:11].[ClH:27].[CH2:1]([N:8]1[CH2:13][C:12]([CH2:14][CH2:15][N:46]2[CH2:45][CH2:44][C:43]([NH:42][C:40]([O:39][CH2:37][CH3:38])=[O:41])([C:49]3[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=3)[CH2:48][CH2:47]2)([C:21]2[CH:26]=[CH:25][C:24]([Cl:27])=[C:23]([Cl:28])[CH:22]=2)[O:11][CH2:10][C:9]1=[O:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)NC1(c2ccccc2)CCNCC1
Reactant: CS(=O)(=O)OCCC1(c2ccc(Cl)c(Cl)c2)CN(Cc2ccccc2)C(=O)CO1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)NC1(c2ccccc2)CCN(CCC2(c3ccc(Cl)c(Cl)c3)CN(Cc3ccccc3)C(=O)CO2)CC1
Temperature: 90 °C
Reaction time: 0.5 h
Yield: 65.2 %

Procedure:
A mixture of 1.1 g of the compound obtained in step B of EXAMPLE 14, 1 g of 4-(ethoxycarbonylamino)-4-phenylpiperidine trifluoroacetate and 0.7 g of K2CO3 in 3 ml of DMF is heated at 80-100° C. for 2 hours. After cooling to RT, the reaction mixture is poured into water and stirred for 30 minutes and the precipitate formed is wrung, washed with water and dried under vacuum at 60° C. The precipitate is chromatographed on silica H using a DCM/MeOH mixture (from 100/1; v/v to 100/4.5; v/v) as the eluent. The product obtained is dissolved in DCM, a saturated solution of hydrochloric acid in ether is added until the pH is 1, and the precipitate formed is wrung to give 0.52 g of the expected product. M.p.=148-150° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:9]3[CH2:10][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12][CH2:13][CH2:14][C:8]=3[N:7]([CH3:22])[C:6]=2[N:23]=1.[F:24][C:25]([F:40])([F:39])[C:26]1[N:31]=[CH:30][C:29]([C:32]2[CH:37]=[CH:36][NH:35][C:34](=[O:38])[CH:33]=2)=[CH:28][CH:27]=1.C([O-])([O-])=O.[Cs+].[Cs+].OC1C=CC=C2C=1N=CC=C2>CS(C)=O.[Cu](I)I>[CH3:22][N:7]1[C:8]2[CH2:14][CH2:13][CH2:12][N:11]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10][C:9]=2[C:5]2[CH:4]=[CH:3][C:2]([N:35]3[CH:36]=[CH:37][C:32]([C:29]4[CH:30]=[N:31][C:26]([C:25]([F:24])([F:39])[F:40])=[CH:27][CH:28]=4)=[CH:33][C:34]3=[O:38])=[N:23][C:6]1=2
Reactant: O=c1cc(-c2ccc(C(F)(F)F)nc2)cc[nH]1
Reactant: Cn1c2c(c3ccc(Br)nc31)CN(C(=O)OC(C)(C)C)CCC2
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: Oc1cccc2cccnc12
Solvent: CS(C)=O
Product: Cn1c2c(c3ccc(-n4ccc(-c5ccc(C(F)(F)F)nc5)cc4=O)nc31)CN(C(=O)OC(C)(C)C)CCC2
Temperature: 130 °C
Reaction time: 0.5 h
Yield: 69 %

Procedure:
tert-butyl 2-bromo-10-methyl-7,8,9,10-tetrahydropyrido[3′,2′:4,5]pyrrolo[3,2-c]azepine-6(5H)-carboxylate (0.15 g, 0.40 mmol), 4-(6-(trifluoromethyl)pyridin-3-yl)pyridin-2(1H)-one (95 mg, 0.40 mmol), and Cs2CO3 (0.14 g, 0.44 mmol) were suspended in DMSO (2.3 mL), and the mixture was degassed under vacuum for 15 min. The system was flushed with Ar, and 8-hydroxyquinoline (17 mg, 0.12 mmol) and copper iodide (91 mg, 0.48 mmol) were added to the suspension. The evacuation/Ar flushing process was repeated twice more, and the reaction mixture was heated at 130° C. for 18 h under N2. The mixture was cooled, diluted with 5.0:3.5:1.5 NH4Cl (aq.)/NH4OH/H2O (30 mL), and the resulting suspension was stirred at ambient temperature for 30 min. The resulting solids were collected by filtration, dissolved in CH2Cl2 (40 mL) and washed with 5.0:3.5:1.5 NH4C1(aq.)/NH4OH/H2O (2×30 mL). The resulting organic solution was dried over Na2SO4 and filtered. Activated charcoal was added to the filtrate, the resulting suspension was filtered through a celite plug with 80:18:2 CH2Cl2/MeOH/NH4OH, and the filtrate was concentrated to dryness under reduced pressure. Flash chromatography (12 g ISCO column, (1:1 hexanes/EtOAc)/(80:18:2 CH2Cl2/MeOH/NH4OH), 100:0 for 4 column volumes, increased to 50:50 over 20 column volumes and held for 4 column volumes; increased to 0:100 over 10 column volumes) gave the title compound (149 mg, 70%) as a yellow film: 1H NMR (500 MHz, DMSO-d6) δ 9.20 (d, J=2.0 Hz, 1H), 8.50 (dd, J=8.0, 1.5 Hz, 1H), 8.07-8.02 (m, 3H), 7.39 (d, J=8.5 Hz, 1H), 7.02 (d, J=2.0 Hz, 1H), 6.84 (dd, 7.5, 2.0 Hz, 1H), 4.61 (s, 2H), 3.74 (s, 3H), 3.68 (t, J=5.5 Hz, 2H), 3.05 (t, J=5.5 Hz, 2H), 1.98-1.93 (m, 2H), 1.36-1.28 (m, 9H).
Reaction SMILES: CCO.C1COCC1.[CH3:9][O:10]/[N:11]=[C:12](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1.[OH-].[Na+]>O>[CH3:9][O:10]/[N:11]=[C:12](/[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)\[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)COc1ccc(OCc2ccc(OC/C(=N\OC)c3ccccc3)cc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: C1CCOC1
Product: CO/N=C(\COc1ccc(COc2ccc(OCC(=O)O)cc2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 49.5 %

Procedure:
To a 25 mL RB flask fitted with magnetic stirrer was charged 3 mL of ethanol and 3 mL of THF. To the stirred solvent was added ethyl {4-[(4-{[(2Z)-2-(methoxyimino)-2-phenylethyl]oxy}benzyl)oxy]phenoxy}acetate (0.13 g, 1.289 mmol) and NaOH was added followed by water (1 mL) at 0° C. Then it was stirred at RT for 5 h. After completion of the reaction (reaction monitored by TLC), reaction mixture was evaporated completely and the crude was washed with ether, and diluted with water and then neutralized with 1N HCl, then extracted with ethyl acetate, organic layer was washed with water and brine, dried over sodium sulphate. The organic layer was evaporated on rotavapor to give the product (0.06 g Yield: 49.5%). Purity: 97.98%
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:21][C:22]([C:24]2[C:25](=[O:40])[N:26]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:27]([CH2:30][C@@H:31]([OH:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.[C:41]([NH:48][CH2:49][C:50](O)=[O:51])([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[C:44]([O:43][C:41]([NH:48][CH2:49][C:50]([O:33][C@@H:31]([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22](=[O:23])[NH:21][C:4]2[CH:5]=[CH:6][C:7]([O:8][C:9]3[C:18]4[C:13](=[CH:14][C:15]([O:19][CH3:20])=[CH:16][CH:17]=4)[N:12]=[CH:11][CH:10]=3)=[C:2]([F:1])[CH:3]=2)[C:25](=[O:40])[N:26]1[C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:51])=[O:42])([CH3:47])([CH3:46])[CH3:45]
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Reactant: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)O)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Agent: CN(C)c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: COc1ccc2c(Oc3ccc(NC(=O)c4c(C)n(C[C@H](C)OC(=O)CNC(=O)OC(C)(C)C)n(-c5ccccc5)c4=O)cc3F)ccnc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 113.4 %

Procedure:
To a mixture of (S)—N-(3-fluoro-4-(7-methoxyquinolin-4-yloxy)phenyl)-1-(2-hydroxylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (1.0 g, 1.84 mmol), N-Boc-glycine (0.644 g, 3.68 mmol, ABCR) and DMAP (0.45 g, 3.68 mmol, Aladdin) in 12 mL of CH2Cl2 at 0° C. was added EDC solid (1.0582 g, 5.52 mmol, Aladdin) in portions. After stirring at 0° C. for 2 hrs, the reaction mixture was warmed up to room temperature and continued to stir overnight. The reaction mixture was diluted with CH2Cl2 (100 mL), and the result solution was washed with 0.1 N HCl (10 mL×2), followed by saturated NaHCO3 (10 mL×2) and water (20 mL), the aqueous phase was extracted with EtOAc (15 mL×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by a silica gel column chromatography (EtOAc:hexane=2:1) to give the desired compound as a yellow solid (1.46 g, 70.1%).
Reaction SMILES: O=[C:2]1[CH:6]([C:7]([O:9][CH3:10])=[O:8])[CH2:5][S:4][CH2:3]1.[ClH:11].[NH2:12]O>CO>[ClH:11].[NH2:12][C:2]1[C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][S:4][CH:3]=1
Reactant: NO
Reactant: COC(=O)C1CSCC1=O
Agent: Cl
Solvent: CO
Product: COC(=O)c1cscc1N
Yield: 57.4 %

Procedure:
3-Oxo-4-methoxycarbonyltetrahydrothiophene (28 g) was heated under reflux for 1 hour with hydroxylamine hydrochloride (11.5 g) in methanol (80 ml). The mixture was then cooled and a first crop was filtered off and washed with dry diethyl ether to afford the title compound (18.4 g, 57.6%) m.p. 203° to 205° C. On further cooling a second crop (2.7 g, 8.5%) was obtained, m.p. 201° to 202° C. The total yield was thus 66.1%.