Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][O-:3].[Na+].CCO.Br[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1>O>[Br:15][C:12]1[CH:11]=[N:10][C:9]([O:3][CH2:2][CH3:1])=[CH:14][CH:13]=1
Reactant: CC[O-]
Reactant: Brc1ccc(Br)nc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(Br)cn1
Temperature: 80 °C

Procedure:
A solution of NaOEt in EtOH (21%; 157 mL, 422 mmol) was added to 2,5-dibromopyridine (4-1) (20 g; 84.4 mmol) and the mixture heated to 80° C. for 16 hours. After cooling, the mixture was poured into water, extracted twice with EtOAc, washed with water then brine, dried (MgSO4) and concentrated under reduced pressure to give crude product 4-2 as a solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH2:3][CH2:2]1.Cl.Cl[C:17]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][N:28]=2)=[CH:22][CH:21]=1)=[O:18]>ClCCl.CN(C)C=O.C(OCC)(=O)C>[F:35][C:33]([F:34])([F:36])[C:30]1[CH:31]=[CH:32][C:27]([O:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][C:17]([N:1]3[CH2:2][CH2:3][CH:4]([CH2:7][N:8]4[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]4)[CH2:5][CH2:6]3)=[O:18])=[CH:21][CH:22]=2)=[N:28][CH:29]=1
Reactant: OC1CCN(CC2CCNCC2)CC1
Reactant: O=C(Cl)Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Oc1ccc(Oc2ccc(C(F)(F)F)cn2)cc1)N1CCC(CN2CCC(O)CC2)CC1

Procedure:
The title product was prepared from 1-piperidin-4-ylmethyl-piperidine-4-ol (released form the correspondent hydrochloride by a standard procedure) and 4-(5-trifluoromethyl-pyridin-2-yloxy)-phenyl chloroformate, preparative HPLC (method C) (reaction performed in a mixture of dichloromethane and dimethylformamide). 1.7 M HCl in ethyl acetate was added to the pooled fractions containing the title product, and the fractions was evaporated to dryness (92%, white solid. HPLC-MS m/z=(M+1) 480.4, Rt: 2.38 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]#[C:9][CH:10]=[C:11]2[CH2:16][CH2:15][N:14](C3C=CC=CN=3)[CH2:13][CH2:12]2)[N:3]=1.[Br:23][C:24]1[CH:25]=[N:26][C:27](I)=[N:28][CH:29]=1>CN(C)C(=O)C>[Br:23][C:24]1[CH:25]=[N:26][C:27]([N:14]2[CH2:15][CH2:16][C:11](=[CH:10][C:9]#[C:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([CH3:1])[N:3]=3)[CH2:12][CH2:13]2)=[N:28][CH:29]=1
Reactant: Cc1cccc(C#CC=C2CCN(c3ccccn3)CC2)n1
Reactant: Brc1cnc(I)nc1
Solvent: CC(=O)N(C)C
Product: Cc1cccc(C#CC=C2CCN(c3ncc(Br)cn3)CC2)n1
Yield: 64.1 %

Procedure:
The title compound was prepared following the procedure described for the compound of Example 59, but substituting NMP with N,N-dimethylacetamide and substituting 2-fluoropyridine with 5-bromo-2-iodopyrimidine and reacting the mixture at r.t. Purification was carried out by automated flash liquid chromatography (Horizon™-Biotage) eluting with CHCl3-1.4 N MeOH NH3 100:0.5. White solid. Yield: 64.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[O:8][CH:7]=[C:6]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:5]2=O.O.[NH2:21][NH2:22]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]2[C:6]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][NH:22][N:21]=2)[C:9]([OH:8])=[CH:10][C:11]=1[OH:12]
Reactant: NN
Reactant: O=c1c(-c2ccccc2)coc2cc(O)c(Cl)cc12
Solvent: O
Solvent: CCO
Product: Oc1cc(O)c(-c2n[nH]cc2-c2ccccc2)cc1Cl

Procedure:
This compounds was synthesised in the same manner as described above. 6-Chloro-7-hydroxy-3-phenyl-chromen-4-one (0.4 g, 1.47 mmol), hydrazine hydrate (4 ml), ethanol (10 ml). 4-Chloro-6-(4-phenyl-1H-pyrazol-3-yl)-benzene-1,3-diol precipitated out on quenching as a pale yellow (0.37 g, 88%); Rf 0.3 Cf SM 0.7 ethyl acetate/hexane (75/25).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[C:21](Cl)(=[O:24])[CH:22]=[CH2:23]>C(OCC)C>[CH:8]1([N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[C:21](=[O:24])[CH:22]=[CH2:23])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: C=CC(=O)Cl
Reactant: C1CCC(NC2CCCCC2)CC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=CC(=O)N(C1CCCCC1)C1CCCCC1
Reaction time: 12 h

Procedure:
A solution of dicyclohexylamine (19.92 ml, 0.10 mole) and triethylamine (27.88 ml, 0.20 mole) in ethyl ether (100 ml) was cooled to 0° C. A solution of acryloyl chloride (7.93 ml, 0.1 mole) in ethyl ether (20 ml) was added and the solution was stirred for 12 hours, filtered and concentrated to obtain the product as a solid which was dried in vacuo. The structure was confirmed by NMR.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]([NH:13][S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:34](Br)[CH2:35][CH:36]([CH3:38])[CH3:37].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([N:8]1[CH2:12][C@@H:11]([N:13]([CH2:34][CH2:35][CH:36]([CH3:38])[CH3:37])[S:14]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[C@H:10]([NH:26][C:27](=[O:33])[O:28][C:29]([CH3:30])([CH3:32])[CH3:31])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CCBr
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)CCN([C@@H]1CN(Cc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
A mixture of tert-butyl [(3R,4R)-1-benzyl-4-{[(4-nitrophenyl)sulfonyl]amino}pyrrolidin-3-yl]carbamate (4.76 g, 10 mmol), isoamyl bromide (1.2 eq), and K2CO3 (2.76 g, 20 mmol) in 50 mL of DMF was stirred overnight at 50° C. The mixture was diluted with H2O, extracted with EtOAc, the combined organic extracts were dried with Na2SO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 5→20% EtOAc in hexane to give the title product.
Reaction SMILES: [Br:1][C:2]1[C:11]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[CH:10][C:9]([Cl:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:20](=O)[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.CCOC(C)=O.O>[Br:1][C:2]1[C:11]([N:12]([CH2:20][CH3:21])[CH:13]2[CH2:14][CH2:15][O:16][CH2:17][CH2:18]2)=[CH:10][C:9]([Cl:19])=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC=O
Reactant: COC(=O)c1cc(Cl)cc(NC2CCOCC2)c1Br
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1Br)C1CCOCC1
Reaction time: 22 h
Yield: 37.7 %

Procedure:
To a solution of methyl 2-bromo-5-chloro-3-(oxan-4-ylamino)benzoate (300 mg, 0.86 mmol) in 1,2-dichloroethane (3 ml) at room temperature under nitrogen was added acetaldehyde (96 μl, 1.7 mmol) followed by acetic acid (0.3 ml, 5.16 mmol). This solution was stirred for 5 minutes before the addition of sodium triacetoxyborohydride (0.55 g, 2.6 mmol) at room temperature with reaction monitoring by LCMS. After 22 h, further acetaldehyde (96 μl, 1.7 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (0.55 g, 2.6 mmol). After 3 days, the reaction mixture was diluted with 1,2-dichloroethane (5 ml). Acetaldehyde (962 μl, 17.2 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (1.82 g, 8.6 mmol). After 15 h, further acetaldehyde (960 μl, 17.2 mmol) was added to the reaction mixture and this was stirred for 10 minutes before the addition of sodium triacetoxyborohydride (1.82 g, 8.6 mmol). The reaction mixture was then stirred at room temperature for a further 22 hours before deionized water (25 ml) was added and the mixture was neutralised with solid NaHCO3. EtOAc (25 ml) was added and the phases were separated. The aqueous layer was then extracted with EtOAc (2×25 ml) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by FCC (10 g silica, Isolute cartridge, gradient of eluents; 99:1 Heptane:EtOAc to 8:2 Heptane:EtOAc) to give 122 mg (38%) of the title compound as a colourless oil. LC-MS 85%, m/z=376.3/378.2/379.9, 1H NMR (500 MHz, Chloroform-d) δ 7.31 (d, J=2.5 Hz, 1H), 7.18 (d, 12.4 Hz, 1H), 3.98 (dd, J=8.7, 5.5 Hz, 2H), 3.94 (s, 3H), 3.35 (td, J=11.6, 5.5 Hz, 2H), 3.19 (t, J=7.1 Hz, 1H), 3.12 (q, J=7.1 Hz, 2H), 1.75 (td, J=10.1, 8.8, 3.9 Hz, 4H), 0.92 (t, J=7.1 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:9]=[C:8]([F:32])[C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Li+].C1COCC1.Cl>CO.O>[F:32][C:8]1[CH:9]=[C:10]([C:12]2[N:17]=[C:16]3[N:18]([CH2:21][C:22]4[CH:23]=[C:24]5[C:29](=[CH:30][CH:31]=4)[N:28]=[CH:27][CH:26]=[CH:25]5)[N:19]=[N:20][C:15]3=[CH:14][CH:13]=2)[CH:11]=[C:2]([F:1])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: COC(=O)c1c(F)cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: O=C(O)c1c(F)cc(-c2ccc3nnn(Cc4ccc5ncccc5c4)c3n2)cc1F
Temperature: 25 °C
Reaction time: 12 h
Yield: 73.9 %

Procedure:
To a solution of Example 128 (0.70 g, 1.62 mmol) in methanol (3.8 ml), lithium hydroxide (0.635 g, 15.13 mmol) in water (3.8 ml) and THF (14.3 ml) were added and stirred at RT. After 12 h, pH was adjusted to ca. 7 using 0.5N HCl and the solid precipitated was filtered, washed with ethyl acetate and petroleum ether and dried under vacuum to afford the title compound as pale brown solid (0.50 g, 74%).
Reaction SMILES: [C:1]([N:3]=[C:4]([NH:15][C:16]12[CH2:23][CH2:22][C:19]([C:24]([NH2:26])=O)([CH2:20][CH2:21]1)[CH2:18][CH2:17]2)[C:5]([CH3:14])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])#[N:2].C(N(CC)CC)C.FC(F)(F)C(OC(=O)C(F)(F)F)=O>ClCCl>[C:1]([N:3]=[C:4]([NH:15][C:16]12[CH2:21][CH2:20][C:19]([C:24]#[N:26])([CH2:18][CH2:17]1)[CH2:22][CH2:23]2)[C:5]([CH3:14])([O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:6])#[N:2]
Reactant: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C(N)=O)(CC1)CC2
Solvent: ClCCl
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Product: CC(C)(Oc1ccccc1)C(=NC#N)NC12CCC(C#N)(CC1)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 82 (70 mg, 0.2 mmol) and triethylamine (120 mg, 1.2 mmol) in dichloromethane cooled in an ice bath was added trifluoroacetic anhydride (125 mg, 0.6 mmol) dropwise. After addition was complete, the mixture was stirred overnight at room temperature. After removal of the solvent, the residue was purified by preparative reverse phase HPLC [Waters 2767; Benetnach 10-C18 20×250 mm, 10 μm; 35-85% acetonitrile/water (0.05% trifluoroacetic acid), 30 mL/minute; detection at 214 and 254 nm] to give the titled compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.33 (t, J=7.85 Hz, 2H), 7.19 (t, J=7.4 Hz, 1H), 7.01 (s, 1H), 6.91 (d, J=7.6 Hz, 2H), 2.01˜2.08 (m, 12H), 1.69 (s, 6H); LCMS (ESI+) m/z 337.7 (M+H)+.
Reaction SMILES: [CH3:1][S:2][C:3]1[C:11]2[C:10]3[CH2:12][CH2:13][CH2:14][CH:15]([C:16]#[N:17])[C:9]=3[CH:8]=[CH:7][C:6]=2[NH:5][CH:4]=1.CO.[CH2:20](N)[CH2:21][NH2:22]>C(Cl)Cl>[NH:17]1[CH2:20][CH2:21][N:22]=[C:16]1[CH:15]1[C:9]2[CH:8]=[CH:7][C:6]3[NH:5][CH:4]=[C:3]([S:2][CH3:1])[C:11]=3[C:10]=2[CH2:12][CH2:13][CH2:14]1
Reactant: CSc1c[nH]c2ccc3c(c12)CCCC3C#N
Reactant: NCCN
Solvent: CO
Solvent: ClCCl
Product: CSc1c[nH]c2ccc3c(c12)CCCC3C1=NCCN1

Procedure:
The product from Example 123 (1.9 g) was dissolved in methylene chloride (35 ml) and methanol (1.5 ml) and reacted with ethylenediamine (3.5 ml) as in Example 35 giving the desired product (1.38 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([OH:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=[O:13])[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CC(=O)C[C@H]1C(=O)N1CCSC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 61.5 %

Procedure:
(2S, 4R)-4-Hydroxy-2-(thiazolidine-3-carbonyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (3.34 g, 0.0111 mol, Example 17A) was dissolved in DMSO and cooled to 0° C. To the cold solution, triethylamine (7.37 g, 0.0729 mol) and sulfur trioxide pyridine complex (8.44 g, 0.0530 mol) were added. The mixture was stirred at 0° C. for 2 hours, brought to room temperature and quenched with water. The mixture was extracted with ethyl acetate and washed with 1 M HCl (60 mL), saturated NaHCO3 (2×40 mL) and brine (1×30 mL). The organic layer was dried with Na2SO4, filtered, concentrated, and purified by column chromatography (ethyl acetate/hexane, 1/1) to give the titled compound 2.05 g. MS (ESI APCI) m/e 299 (M−H)+; 1H NMR (300 MHz, methanol-d4): δ ppm 5.07 (d, 1H), 4.80 (m, 1H), 4.57-4.68 (m, 2H), 4.45 (m, 1H), 3.85 (d, 2H), 3.78 (m, 2H), 3.17 (t, 1H), 3.05 (m, 2H), 2.44-2.49 (d, 1H), 1.47 (s, 9H).
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:16]1([C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[CH2:15]2.Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]([C:37]([C:39]2[CH:49]=[C:48]([CH3:50])[C:42]3[N:43]([CH3:47])[C:44](=[O:46])[O:45][C:41]=3[CH:40]=2)=[O:38])[CH:32]=1>CC(O)CCC>[CH3:47][N:43]1[C:42]2[C:48]([CH3:50])=[CH:49][C:39]([C:37]([C:33]3[CH:32]=[C:31]([NH:11][C:12]4[CH:13]=[C:14]5[C:27](=[CH:28][CH:29]=4)[CH2:26][C:16]4([C:24]6[C:19](=[N:20][CH:21]=[CH:22][CH:23]=6)[NH:18][C:17]4=[O:25])[CH2:15]5)[N:36]=[CH:35][N:34]=3)=[O:38])=[CH:40][C:41]=2[O:45][C:44]1=[O:46]
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2oc(=O)n(C)c12
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCCC(C)O
Product: Cc1cc(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)cc2oc(=O)n(C)c12
Reaction time: 4 h

Procedure:
16.0 mg (0.100 mmol) benzenesulphonic acid were added to 126 mg (0.500 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one and 152 mg (0.500 mmol) 6-(6-chloro-pyrimidin-4-carbonyl)-3,4-dimethyl-3H-benzoxazol-2-one in 5.0 mL of 2-pentanol and boiled for 4 h. The reaction mixture was evaporated down and purified by preparative HPLC. The fractions containing the product were combined, the organic solvent was eliminated i.vac. and the aqueous phase remaining was neutralised with 1M aqueous NaOH solution. The product precipitated as a solid was suction filtered, washed with water and dried i. vac.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=1)[CH:8]=[C:7]2O.O=P(Cl)(Cl)[Cl:32]>O1CCOCC1>[Cl:32][C:7]1[C:6]2[C:11](=[C:2]([Cl:1])[C:3]([O:21][CH2:22][CH2:23][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:4][CH:5]=2)[N:10]=[C:9]([C:12]2[S:13][CH:14]=[C:15]([CH:17]([CH3:19])[CH3:18])[N:16]=2)[CH:8]=1
Reactant: CC(C)c1csc(-c2cc(O)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)n1
Reactant: O=P(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: CC(C)c1csc(-c2cc(Cl)c3ccc(OCCN4CCOCC4)c(Cl)c3n2)n1
Temperature: 85 °C
Reaction time: 0.17 h

Procedure:
8-Chloro-2-(4-isopropyl-thiazol-2-yl)-7-(2-morpholin-4-yl-ethoxy)-quinolin-4-ol (5.0 g, 11.5 mmol) in dioxane (50 mL) were stirred at room temperature. POCl3 (5.4 g, 34.6 mmol) was added slowly to the reaction mixture. The reaction was heated to 85° C. with stirring for 10 mins. The reaction was cooled to room temperature and was quenched with ice water. The solution was extracted with ethyl acetate (3×100 mL). The combined organics were dried with sodium sulfate, filtered and were concentrated. Compound XX (4.6 g, 90%) was purified by silica gel chromatography.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.O>C(O)C>[CH:19]1([CH2:18][O:10][C:3]2[CH:4]=[CH:5][C:6]([CH2:8][OH:9])=[CH:7][C:2]=2[F:1])[CH2:21][CH2:20]1
Reactant: BrCC1CC1
Reactant: OCc1ccc(O)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: OCc1ccc(OCC2CC2)c(F)c1
Temperature: 70 °C
Reaction time: 4 h
Yield: 52 %

Procedure:
To a suspension of 2-fluoro-4-(hydroxymethyl)phenol (1.08 g, 7.61 mmol) and potassium carbonate (2.10 g, 15.2 mmol) in ethanol (15 mL) was added bromomethylcyclopropane (1.54 g, 11.4 mmol), and the mixture was stirred at 70° C. for 4 hr. Water was added thereto, and the mixture was extracted twice with ethyl acetate, and the extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=19:1 to hexane:ethyl acetate=3:2) to give the title compound (777 mg, yield 52%) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:10](OS(C)(=O)=O)[CH3:11])=[CH:4][CH:3]=1.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C)C=O.C(OC(C)C)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH:9]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]#[N:24])[CH:18]=2)[CH:10]([N:25]=[N+:26]=[N-:27])[CH3:11])=[CH:4][CH:3]=1
Reactant: [N-]=[N+]=[N-]
Reactant: CC(OS(C)(=O)=O)C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)OC(C)C
Product: CC(N=[N+]=[N-])C(Cc1ccc(Cl)cc1)c1cccc(C#N)c1
Temperature: 70 °C

Procedure:
To a solution of 4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-methylsulfonyloxybutane (1.1 kg, 2.9 mol) in N,N-dimethylformamide (4.1 L) was added sodium azide (378 g, 5.8 mol), and the reaction was heated at 70° C. for 7 h. After cooling to room temperature, the reaction mixture was diluted with isopropyl acetate (11 L) and was washed with sodium bicarbonate (50% saturated aqueous solution) and water (5.5 L). The organic layer was separated and treated with Darco KB (254 g) overnight. The mixture was filtered over solka floc, washed with toluene and concentrated. The residue was diluted with toluene (1 L) and was loaded onto a silica gel pad, which was eluted with 90:10 hexane/ethyl acetate to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH2:19])[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:7])[CH3:6].[F:22][C:23]1[CH:24]=[C:25]2[C:30](=[C:31]([F:33])[CH:32]=1)[CH2:29][C:28](=O)[CH2:27][CH2:26]2>>[CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]([N:8]1[CH:12]=[C:11]([NH:13][C:14](=[O:20])[CH:15]([NH:19][CH:28]2[CH2:27][CH2:26][C:25]3[C:30](=[C:31]([F:33])[CH:32]=[C:23]([F:22])[CH:24]=3)[CH2:29]2)[CH2:16][CH2:17][CH3:18])[N:10]=[CH:9]1)([CH3:6])[CH3:7]
Reactant: CCCC(N)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1
Reactant: O=C1CCc2cc(F)cc(F)c2C1
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CC(=O)OC)cn1

Procedure:
3-[4-(2-Amino-pentanoylamino)-imidazol-1-yl]-3-methyl-butyric acid methyl ester was reacted with 6,8-Difluoro-3,4-dihydro-1H-naphthalen-2-one to provide the title compound: C13 NMR (100 MHz, CDCl3) 14.1, 16.7, 19.5, 19.6, 28.2, 28.7, 29.6, 29.8, 36.5, 47.2, 51.9, 52.1, 52.7, 56.3, 60.2, 60.9, 101.1, 104.4, 110.6, 130.5, 137.7, 170.0; MS 463.3 m/z (M+1).
Reaction SMILES: [F:1][CH2:2][C:3]1([CH2:29][F:30])[O:8][CH2:7][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18][C:19]3[NH:23][C:22]4[CH:24]=[CH:25][CH:26]=[CH:27][C:21]=4[N:20]=3)[C:12]=2[CH3:28])[CH2:5][O:4]1.ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1.CO>[F:1][CH2:2][C:3]1([CH2:29][F:30])[O:4][CH2:5][CH:6]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]=[C:13]([CH2:17][S:18]([C:19]3[NH:20][C:21]4[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=4[N:23]=3)=[O:39])[C:12]=2[CH3:28])[CH2:7][O:8]1
Reactant: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CSc1nc2ccccc2[nH]1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: Cc1c(OCC2COC(CF)(CF)OC2)ccnc1CS(=O)c1nc2ccccc2[nH]1
Reaction time: 2 h
Yield: 68 %

Procedure:
To a toluene/methanol (10:1) (20 ml) solution of the 2-(((4-((2,2-bis(fluoromethyl)-1,3-dioxan-5-yl)methoxy)-3-methylpyridin-2-yl)methyl)thio)-1H-benzimidazole (305 mg, 700 μmol) obtained in the step (7d), a toluene/methanol (10:1) (5 ml) solution of 3-chloroperbenzoic acid (167 mg, 630 μmol as the content was regarded as 65%) was added dropwise at −50° C. to −60° C. for 5 minutes in a nitrogen atmosphere. The mixture was stirred for 2 hours in the same conditions. To the reaction mixture, a saturated aqueous solution of sodium hydrogen carbonate was added and the resultant mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (NH silica gel, elution solvent: ethyl acetate/methanol) to obtain the title compound (215 mg, yield: 68%) as a light yellow foam.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[CH:17]=[CH:16][NH:15][N:14]=3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.C1COCC1.[CH3:25][N:26]([CH3:30])[C:27](Cl)=[O:28].C([O-])(O)=O.[Na+]>CCOC(C)=O.C(N(CC)CC)C>[CH3:25][N:26]([CH3:30])[C:27]([N:15]1[CH:16]=[CH:17][C:13]([C:10]2[CH:9]=[CH:8][C:7]([O:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][CH:4]=3)=[CH:12][CH:11]=2)=[N:14]1)=[O:28]
Reactant: CN(C)C(=O)Cl
Reactant: Fc1ccc(Oc2ccc(-c3cc[nH]n3)cc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1ccc(-c2ccc(Oc3ccc(F)cc3)cc2)n1
Yield: 47.1 %

Procedure:
A solution of 3-[4-(4-fluorophenoxy)phenyl]-1H-pyrazole (467 mg, 1.84 mmol) in 7 mL of THF containing 0.3 mL (2.13 mmol) of triethylamine was treated with 0.3 mL (3.2 mmol) dimethylcarbamyl chloride added via syringe. No reaction was observed at room temperature. An additional 0.3 mL of dimethylcarbamyl chloride was added and the reaction was heated at reflux overnight. The reaction was then added to a saturated aqueous NaHCO3 solution and EtOAc. The aqueous layer was washed with EtOAc and the pooled organic layers were dried (Na2SO4), filtered and concentrated to dryness. Column chromatography (7/3 hexane/EtOAc) afforded 282 mg of the title compound as a yellow oil that solidified on standing, mp 59-63° C. 1H NMR (CDCl3): δ8.15 (d, 1H, J=2.7 Hz), 7.80 (d, 2H, J=8.4 Hz), 7.06-6.88 (m, 6H), 6.62 (d, 1H, J=2.7 Hz), 3.30 (br s, 6H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[O:15][C:14]([NH:17][C:18]4[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[C:20]([O:28][CH3:29])[CH:19]=4)=[N:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:30][S:31](Cl)(=[O:33])=[O:32]>N1C=CC=CC=1>[CH3:29][O:28][C:20]1[CH:19]=[C:18]([NH:17][C:14]2[O:15][C:16]3[C:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:1][S:31]([CH3:30])(=[O:33])=[O:32])=[CH:3][CH:4]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[N:13]=2)[CH:23]=[C:22]([O:24][CH3:25])[C:21]=1[O:26][CH3:27]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(Nc2nc3cccc(-c4ccc(N)cc4)c3o2)cc(OC)c1OC
Solvent: c1ccncc1
Product: COc1cc(Nc2nc3cccc(-c4ccc(NS(C)(=O)=O)cc4)c3o2)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of 0.12 g (0.307 mmol) [7-(4-amino-phenyl)-benzooxazol-2-yl]-(3,4,5-trimethoxy-phenyl)-amine (example 11) and 0.041 g (0.36 mmol) methanesulfonyl chloride in 6 ml pyridine is stirred for 1.5 h at room temperature. Then the reaction mixture is poured on water and extracted 3× with EtOAc. The combined organic layers are washed with 0.1N NaOH solution and water, dried over MgSO4, filtered and the filtrate is concentrated in vacuo. The residue is purified by crystallisation from dichloromethane/diethyl ether to afford the title compound as off-white crystals. Rt=2.22 min (Waters Symmetry C8, 2.1×50 mm, detection 210-250 nM, 5% to 100% CH3CN in H2O in 2 min+0.05% TFA, flow rate 1.0 ml/min); MS: 470 (M+1)+; m.p. 222-225° C.