Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH:17]([O:19]C)Cl.O>C(Cl)Cl.Cl[Ti](Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[C:8]2[O:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[C:7]=2[C:6]([CH:17]=[O:19])=[CH:5][CH:4]=1
Reactant: COc1cccc2c1oc1ccccc12
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: COc1ccc(C=O)c2c1oc1ccccc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 108.4 %

Procedure:
4-methoxy-dibenzofuran (3.07 g, 15.5 mmoles) is dissolved in DCM (50 mL) under nitrogen atmosphere. The solution is cooled to 0° C. and dichloromethyl-methyl ether (1.68 mL, 18.6 mmoles) and subsequently TiCl4 (1N solution in DCM, 18.6 mL, 18.6 mmoles) are added dropwise. The solution is stirred at 0° C. and the reaction is completed after 1 hour. The reaction mixture is poured into cold water and extracted with DCM. The combined organic layers are washed again with water and brine, dried over sodium sulphate and evaporated to dryness to give 3.54 g of crude compound. The reaction is repeated on additional 2.04 g of starting material to yield additional 2.51 g of crude compound. The two crude mixtures are combined and purified together by flash chromatography on SiO2 (eluent: gradient AcOEt/hexane from 10/90 to 20/80) to give 3.8 g of the desired compound.
Reaction SMILES: [C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([NH:12][CH:13]([CH2:18][OH:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:11][C:6]=2[S:5][C:4]=1[NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])#[N:2].C(N(C(C)C)CC)(C)C.[CH:37]1([C:43](Cl)=[O:44])[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]1>ClCCl>[C:1]([C:3]1[C:7]2[CH2:8][CH2:9][CH:10]([N:12]([CH:13]([CH2:18][OH:19])[C:14]([CH3:17])([CH3:16])[CH3:15])[C:43]([CH:37]3[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[O:44])[CH2:11][C:6]=2[S:5][C:4]=1[NH:20][C:21](=[O:27])[CH:22]([CH2:25][CH3:26])[CH2:23][CH3:24])#[N:2]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(NC(CO)C(C)(C)C)C2
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)C(=O)Nc1sc2c(c1C#N)CCC(N(C(=O)C1CCCCC1)C(CO)C(C)(C)C)C2
Reaction time: 16 h

Procedure:
To a solution of the intermediate isolated in Step A in 5.0 mL of dichloromethane was added 0.175 mL (1.00 mmol) of di-isopropylethylamine and 0.041 mL (0.280 mmol) of cyclohexanecarbonyl chloride. After stirring 16 h at ambient temperate, the reaction mixture was concentrated in vacuo, and purified by preparative reversed phase HPLC, affording the title compound as a white solid.
Reaction SMILES: CS(C)=O.[Cl-].[CH2:6]([N:13]([CH3:30])[C:14]([CH2:16][CH2:17][C:18]([N:20]1[CH2:24][CH2:23][CH2:22][C@H:21]1[CH:25]([OH:29])[C:26]([OH:28])=[O:27])=[O:19])=[O:15])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[CH2:31](N(CC)CC)[CH3:32]>C(Cl)Cl.O>[CH2:31]([O:27][C:26](=[O:28])[C:25]([C@@H:21]1[CH2:22][CH2:23][CH2:24][N:20]1[C:18](=[O:19])[CH2:17][CH2:16][C:14](=[O:15])[N:13]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[CH3:30])=[O:29])[CH3:32]
Reactant: CCN(CC)CC
Reactant: CN(Cc1ccccc1)C(=O)CCC(=O)N1CCC[C@H]1C(O)C(=O)O
Agent: [Cl-]
Solvent: O
Solvent: ClCCl
Solvent: CS(C)=O
Product: CCOC(=O)C(=O)[C@@H]1CCCN1C(=O)CCC(=O)N(C)Cc1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
DMSO (443 μl) was added dropwise to a solution of oxyalyl chloride (260 μl) in methylene chloride (10 ml) cooled to -78° C. The solution was stirred for 15 mins at the same temperature. A solution of (2RS)-2-[(2S)-1-[3-(N-benzyl-N-methylcarbamoyl]propanoyl]pyrrolidin-2-yl]-2-hydroxyacetic acid theyl ester (700 mg) in methylene chloride (6 ml) was added dropwise to the solution at the same temperature. The mixture was stirred for 20 mins. Triethylamine (1.42 ml) was added dropwise to the solution. The solution was stirred for 10 mins at the same temperature, and for 30 mins. at 0° C. Water was added to the reaction solution. The mixture was extracted with EtOAc. The extract was washed, dried and evaporated. The residue was purified by column chromatography on silica gel (hexane-EtOAc) to give the title compound (627 mg) having the following physical data:
Reaction SMILES: [H-].[Na+].[C:3]1([OH:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[C:14]([C:21]3[NH:29][C:28]4[CH:27]([CH3:30])[CH2:26][NH:25][C:24](=[O:31])[C:23]=4[CH:22]=3)[CH:15]=[CH:16][CH:17]=2)[N:12]=1.C(O)(C(F)(F)F)=O>CN(C=O)C.CS(C)=O>[CH3:30][CH:27]1[CH2:26][NH:25][C:24](=[O:31])[C:23]2[CH:22]=[C:21]([C:14]3[CH:15]=[CH:16][CH:17]=[C:18]4[C:13]=3[N:12]=[C:11]([O:9][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[CH:20]=[CH:19]4)[NH:29][C:28]1=2
Reactant: CC1CNC(=O)c2cc(-c3cccc4ccc(Cl)nc34)[nH]c21
Reactant: Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: CC1CNC(=O)c2cc(-c3cccc4ccc(Oc5ccccc5)nc34)[nH]c21
Temperature: 80 °C
Reaction time: 0.17 h
Yield: 63.3 %

Procedure:
To a slurry of NaH (60% in mineral oil; 0.036 g, 0.898 mmol) in 0.5 mL DMF was added phenol (0.085 g, 0.898 mmol). After 10 min, 2-(2-chloroquinolin-8-yl)-7-methyl-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (Example 27; 0.040 g, 0.128 mmol) was added and the reaction was heated to 80° C. for 2 h. The reaction was cooled, treated with DMSO and TFA (0.069 ml, 0.898 mmol), filtered, and purified by rpHPLC (Phenomenex Gemini 150×30 mm C18 column, 15-100% ACN/H2O with 0.1% TFA); product-containing fraction was treated with saturated aq. NaHCO3 and DCM. The organic layer was separated, and the aq. layer was extracted 3×DCM. The combined organic layers were then dried over Na2SO4, filtered, and concentrated in vacuo to give rac-7-methyl-2-(2-phenoxyquinolin-8-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (0.030 g, 0.081 mmol, 63% yield) as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 11.10 (1H, br. s), 8.50 (1H, d, J=9.0 Hz), 8.13 (1H, dt, J=7.5, 0.7 Hz), 7.80 (1H, dt, J=7.9, 0.7 Hz), 7.55-7.65 (2H, m), 7.49 (1H, t, J=7.7 Hz), 7.33-7.45 (4H, m), 6.83-6.99 (2H, m), 3.44 (1H, ddt, J=12.3, 5.6, 0.6, 0.6 Hz), 2.92-3.06 (1H, m), 2.55-2.60 (1H, m), 0.90 (3H, d, J=6.8 Hz). m/z (ESI, +ve) 370.1 (M+H)+.
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]([N+:43]([O-])=O)[C:39]([NH2:42])=[N:40][CH:41]=1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[NH:67]1[CH2:72][CH2:71][CH:70]([O:73][C:74]2[CH:81]=[CH:80][C:77]([CH:78]=O)=[CH:76][CH:75]=2)[CH2:69][CH2:68]1>C(O)C.CN(C=O)C>[Br:35][C:36]1[C:37]([N:46]2[CH2:51][CH2:50][N:49]([CH2:52][C:53]3[CH:54]=[N:55][CH:56]=[CH:57][CH:58]=3)[CH2:48][CH2:47]2)=[C:38]2[N:43]=[C:78]([C:77]3[CH:76]=[CH:75][C:74]([O:73][CH:70]4[CH2:71][CH2:72][NH:67][CH2:68][CH2:69]4)=[CH:81][CH:80]=3)[NH:42][C:39]2=[N:40][CH:41]=1
Reactant: O=Cc1ccc(OC2CCNCC2)cc1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccnc3)CC2)c1[N+](=O)[O-]
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: Brc1cnc2[nH]c(-c3ccc(OC4CCNCC4)cc3)nc2c1N1CCN(Cc2cccnc2)CC1
Reaction time: 6 h
Yield: 24 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 5-bromo-3-nitro-4-(4-(pyridin-3-ylmethyl)piperazin-1-yl)pyridin-2-amine (30 mg, 0.076 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.23 mmol, 0.23 mL) and 4-(piperidin-4-yloxy)benzaldehyde (1.2 eq, 0.091 mmol, 22 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 85:15) gave the product (10 mg, 24%) as a colourless solid; δH (500 MHz, DMSO-d6) 1.77-1.81 (m, 2H, 2× piperidine CHAHB), 2.09-2.11 (m, 2H, 2× piperidine CHAHB), 2.62 (s, br, 4H, piperazine N(CH2)2), 3.00-3.07 (m, 2H, 2× piperidine CHAHB), 3.20-3.24 (m, 2H, 2× piperidine CHAHB), 3.62 (s, 2H, NCH2), 3.66 (s, br, 4H, piperazine N(CH2)2), 4.70-4.76 (m, 1H, piperidine CH), 7.15 (d, J=8.9 Hz, 2H, phenyl H-3 & H-5), 7.39 (dd, J=7.6, 4.7 Hz, 1H, pyridine H-5), 7.78 (d, br, J=7.8 Hz, pyridine H-4), 8.13 (d, J=8.7 Hz, 2H, phenyl H-2 & H-6), 8.21 (s, 1H, imidazo[4,5-b]pyridine H-5), 8.49 (dd, J=4.7, 1.4 Hz, 1H, pyridine H-6), 8.56 (s, br, 1H, pyridine H-2), 13.42 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN1CCOCC1.Cl.[CH3:21][O:22][NH:23][CH3:24].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.Cl>C(#N)C>[Br:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([N:23]([O:22][CH3:21])[CH3:24])=[O:6]
Reactant: COc1cccc(C(=O)O)c1Br
Reactant: CNOC
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: Cl
Agent: [Cl-]
Solvent: CC#N
Solvent: CN1CCOCC1
Product: COc1cccc(C(=O)N(C)OC)c1Br
Temperature: 25 °C
Reaction time: 17 h

Procedure:
2-Bromo-3 methoxy benzoic acid (14.2 g, 61.5 mmol) was dissolved in acetonitrile (250 mL), added with 4-methylmorpholine (13.5 mL, 123 mmol), N-methoxy methanamine hydrochloride (7.19 g, 73.8 mmol) and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium chloride (20.4 g, 73.8 mmol), and stirred for 17 hours at room temperature. 1 N aqueous hydrochloric acid solution was added to the reaction solution, which was then extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate, 85:15-25:75, V/V) to give the title compound as a colorless oily substance (16.8 g, quantitative).
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[O:7][C:6](=[O:8])[N:5]([C:9]2[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][N:10]=2)[CH2:4]1.O[C:17]1[CH:21]=[CH:20][O:19][N:18]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[O:19]1[CH:20]=[CH:21][C:17]([O:1][CH2:2][C@@H:3]2[O:7][C:6](=[O:8])[N:5]([C:9]3[CH:14]=[C:13]([Br:15])[CH:12]=[CH:11][N:10]=3)[CH2:4]2)=[N:18]1
Reactant: O=C1O[C@@H](CO)CN1c1cc(Br)ccn1
Reactant: Oc1ccon1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1O[C@@H](COc2ccon2)CN1c1cc(Br)ccn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.9 %

Procedure:
To a stirred solution of 5(R)-hydroxymethyl-3-(4-bromo-pyrid-2-yl)oxazolidin-2-one (EP 694543; 3.75 g, 13.7 mmol), 3-hydroxyisoxazole (1.28 g, 15.1 mmol) and triphenylphosphine(4.31 g, 16.4 mmol) in anhydrous THF (83 ml), was added dropwise diisopropyl azodicarboxylate(3.20 g, 3.11 ml, 15.8 mmol) and stirred at room temperature for 5h. The solvent was then removed by rotary evaporation and purification by MPLC (Merck 9385 silica, eluting with CH2Cl2) and trituration with diethyl ether gave the title compound as a white solid (2.93 g, 63%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[NH2:23][C@H:24]1[CH2:29][C:28]2[C:30]([N:34]3[CH2:39][CH2:38][N:37]([CH3:40])[CH2:36][CH2:35]3)=[CH:31][CH:32]=[CH:33][C:27]=2[O:26][CH2:25]1>CN(C)C=O>[CH3:40][N:37]1[CH2:38][CH2:39][N:34]([C:30]2[C:28]3[CH2:29][C@H:24]([NH:23][C:7]([C:6]4[CH:5]=[N:4][CH:3]=[C:2]([CH3:1])[CH:10]=4)=[O:9])[CH2:25][O:26][C:27]=3[CH:33]=[CH:32][CH:31]=2)[CH2:35][CH2:36]1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: CN1CCN(c2cccc3c2C[C@H](N)CO3)CC1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1cncc(C(=O)N[C@@H]2COc3cccc(N4CCN(C)CC4)c3C2)c1
Temperature: 25 °C
Reaction time: 28 h
Yield: 34.5 %

Procedure:
A solution of 5-methylnicotinic acid (141 mg, 1.03 mmol) and 1,1′-carbonyldiimidazole (183 mg, 1.13 mmol) in anhydrous N,N-dimethylformamide (5 mL) was stirred at 75° C. for 55 min. The mixture was allowed to cool, and a solution of (S)-3-amino-5-(4-methylpiperazin-1-yl)-3,4-dihydro-2H-1-benzopyran (232 mg, 0.94 mmol) in N,N-dimethylformamide (5 mL) was added. The reaction mixture was stirred at room temperature for 28 h. The solvent was removed in vacuo, and the residue was purified by column chromatography on silica (eluent: chloroform/ethanol; 87:13+0.5% NH3). The product was contaminated with a large amount of imidazole which could be removed by the following procedure: The mixture was dissolved in diethyl ether (100 mL), washed with water (2×20 mL) and treated with brine (10 mL). The ethereal layer was dried (MgSO4), and the solvent was removed in vacuo to give 119 mg (35% yield) of the title compound as a white solid: mp sinters >68° C.; [α]21D−82° (c 1.0, chloroform); EIMS (70 eV) m/z (relative intensity) 366 (21, M+).
Reaction SMILES: Br[C:2]1[CH:14]=[C:13]2[C:5]([C:6]3[CH:7]=[CH:8][C:9]([N:35]([C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[CH:10][C:11]=3[C:12]2([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])=[CH:4][CH:3]=1.C([Li])CCC.CN([CH:56]=[O:57])C.Cl>C1COCC1.CO>[C:36]1([N:35]([C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)[C:9]2[CH:10]=[C:11]3[C:6]([C:5]4[CH:4]=[CH:3][C:2]([CH:56]=[O:57])=[CH:14][C:13]=4[C:12]3([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])=[CH:7][CH:8]=2)[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(Br)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: CO
Solvent: C1CCOC1
Product: CCCCCCCCCCC1(CCCCCCCCCC)c2cc(C=O)ccc2-c2ccc(N(c3ccccc3)c3ccccc3)cc21
Reaction time: 0.5 h
Yield: 88 %

Procedure:
To a solution of (7-bromo-9,9-didecylfluoren-2-yl)diphenylamine (34.6 g, 0.05 mol) in THF (200 mL), cooled to less than −50° C., a solution of n-butyllithium in hexanes (1.6M, 45 mL, 0.072 mol) was added over 15 minutes. After 30 minutes, a solution of DMF (7.5 mL, 0.097 mol) in THF (40 mL) was added, and after 1 hour, the temperature was allowed to rise to 0° C. The mixture was cooled in an ice bath, and treated with dilute hydrochloric acid (7.5 mL conc. HCl mixed with 60 mL water). After dilution with toluene (200 mL), the organic phase was washed with water, aqueous sodium bicarbonate, and saturated sodium chloride solution, dried and concentrated. The residue was chromatographed over 500 g of silica gel. Elution with 20% toluene-heptane and after removal of solvent, the product, which was initially obtained as a glassy solid, on standing with methanol (150 mL), crystallized into yellow solids, 28.2 g, (88% yield), m.p. 77-78.5° C. Anal. Calcd. for C46H59NO: C, 86.06%; H, 9.26%; N, 2.18%. Found: C, 85.81%; H, 9.49%; N, 2.10%. 1H NMR (270 MHz; CDCl3, ppm): 0.61-0.65 (broad), 0.83, 0.85, 0.88 (triplet), 1.05-1.29 (complex, broad), 1.80-2.00 (complex multiplet), decyl protons, 20H; 7.02, 7.03, 7.04, 7.05, 7.06, 7.07, 7.12,, 7.15, 7.24, 7.26, 7.29, 7.59, 7.62, 7.69, 7.72, 7.80, 7.82, 7.83 (complex multiplets, aromatic protons, 16H); 10.02 (singlet, CHO proton, 1H). 13C-NMR (CDCl3, noise-decoupled, ppm): 14.11, 22.66, 23.84, 29.11, 29.29, 29.55, 29.92,31.88, 40.03, 55.15 (sp3 carbons); 118.21, 119.11, 121.70, 122.82, 123.11, 123.31, 124.38, 129.30, 130.83, 134.02, 134.51, 147.49, 147.64, 148.85, 151.30, 153.69 (sp2 carbons); 192.19 (sp2 carbon of CHO moiety).
Reaction SMILES: [I-].C[S+](C)(C)=O.[H-].[Na+].[CH3:9][N:10]1[C:14]([O:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH2:24]/[CH:25]=[CH:26]/[C:27]([F:30])([F:29])[F:28])[N:17]=2)=[CH:13][C:12]([C:31]([F:34])([F:33])[F:32])=[N:11]1.O>CS(C)=O>[CH3:9][N:10]1[C:14]([O:15][C:16]2[CH:21]=[C:20]([CH3:22])[CH:19]=[C:18]([O:23][CH:24]=[CH:25][CH2:26][C:27]([F:30])([F:28])[F:29])[N:17]=2)=[CH:13][C:12]([C:31]([F:34])([F:32])[F:33])=[N:11]1
Reactant: Cc1cc(OC/C=C/C(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Agent: C[S+](C)(C)=O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(OC=CCC(F)(F)F)nc(Oc2cc(C(F)(F)F)nn2C)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 3.1 %

Procedure:
To a solution of trimethylsulfoxonium iodide (4.5 g, 20.5 mmol) in DMSO (50 ml) is added NaH (60% in oil, 0.82 g, 20.5 mmol) and the resulting mixture is stirred for 1 h at ambient temperature. To the resulting solution is added dropwise a solution of (E)-2-(1-methyl-3-trifluoromethylpyrazol-5-yloxy)-4-methyl-6-(4,4,4-trifluorobut-2-enyloxy)pyridine (example 1,7.1 g, 18.6 mmol) at 10° C. After 3 h of stirring at ambient temperature, the dark mixture is hydrolyzed with water (200 ml) and extracted 3 times with diethylether (50 ml). The organic fractions are washed with water, dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. Purification by flash chromatography (silica gel: pentane/ethyl acetate 9/1 v/v) yields the title compound (0.22 g, 3.1% yield) of m.p. 56° C.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32]>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:14][CH2:15][CH:16]([C:19]4[C:27]5[O:26][CH2:25][CH2:24][C:23]=5[CH:22]=[CH:21][CH:20]=4)[CH2:17][CH2:18]3)=[O:12])=[CH:7][N:8]2[CH2:29][CH2:30][N:31]([CH3:33])[CH3:32])=[CH:4][CH:3]=1
Reactant: CN(C)CCCl
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC(c2cccc3c2OCC3)CC1
Product: CN(C)CCn1cc(C(=O)N2CCC(c3cccc4c3OCC4)CC2)c2ccc(Cl)cc21

Procedure:
Analogous to general procedure II, the alkylation of (6-chloro-1H-indol-3-yl)-[4-(2,3-dihydro-benzofuran-7-yl)-piperidin-1-yl]-methanone (prepared herein) with (commercially available) (2-chloro-ethyl)-dimethyl-amine gave the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br>CO>[Br:12][C:8]1[C:9]([CH3:11])=[CH:10][C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1ccc(C(=O)O)c(O)c1
Reactant: BrBr
Solvent: CO
Product: Cc1cc(O)c(C(=O)O)cc1Br
Temperature: -20 °C
Reaction time: 1 h
Yield: 66.6 %

Procedure:
After dissolving 2-hydroxy-4-methylbenzoic acid (24.54 g, 161.29 mmol) in methanol (300 ml), the solution was cooled to −20° C. A solution of bromine (26.03 g) in methanol (50 ml) was added dropwise over 1 hour. The reaction mixture was stirred at room temperature for 1 hour and then concentrated. The residue was heated to dissolution in methanol (100 ml) and water (40 ml) was added. The precipitated crystals were filtered off and washed with 50% methanol-water. The precipitated crystals in the filtrate were also filtered off and washed with 50% methanol-water. The crystals were combined and dried to yield the title compound (24.8 g) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@H:11]2[CH2:17][O:16][C@@H:13]([CH:14]=[O:15])[C@@H:12]2[OH:18])=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][S:10][C@@H:11]2[C@@H:12]([OH:18])[C@H:13]([CH2:14][OH:15])[O:16][CH2:17]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(CS[C@H]2CO[C@@H](C=O)[C@@H]2O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CS[C@H]2CO[C@@H](CO)[C@@H]2O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.9 %

Procedure:
To a room temperature solution, under argon, of 10.9 g of product from Example 322 in 115 ml of absolute ethyl alcohol is added 1.57 g of sodium borohydride. The reaction is stirred at room temperature for 1 hour. Water is added dropwise with stirring and the mixture is concentrated in vacuo. The residue is extracted with methylene chloride, washed with water, dried and concentrated in vacuo to give after chromatography (Silica gel: 50-75% ethyl acetate/hexane) 7.68 g of the desired product.
Reaction SMILES: C(N(CC)CC)C.[O:8]1[CH:12]=[CH:11][CH:10]=[C:9]1[CH2:13][OH:14].[Br:15][CH:16]([CH3:20])[C:17](Br)=[O:18]>C(Cl)(Cl)Cl>[Br:15][CH:16]([CH3:20])[C:17]([O:14][CH2:13][C:9]1[O:8][CH:12]=[CH:11][CH:10]=1)=[O:18]
Reactant: CC(Br)C(=O)Br
Reactant: OCc1ccco1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC(Br)C(=O)OCc1ccco1
Temperature: 25 °C
Reaction time: 24 h
Yield: 67 %

Procedure:
Triethylamine (5.26 g, 0.052 mol) is added to an ice-cooled solution of 2 furylmethanol (5.10 g, 0.052 mol) in 70 ml of chloroform. This is followed by the gradual addition of 2-bromopropionyl bromide (9.93 g, 0.046 mol) in 10 ml of chloroform. The reaction mixture is stirred at RT for 24 h. To workup, the reaction mixture is washed with water (1 times 80 ml), 10% sulfuric acid (1 times 80 ml) and with saturated NaHCO3 solution (2 times 50 ml). The organic phase is dried over magnesium sulfate, concentrated and dried in a high vacuum. The yield is 67%.
Reaction SMILES: C([O:9][C@H:10]1[C@@H:14]([O:15]C(=O)C2C=CC=CC=2)[C@H:13]([CH2:24][O:25]C(=O)C2C=CC=CC=2)[O:12][C@@H:11]1[N:34]1[CH:41]=[C:40]([F:42])[C:38](=[O:39])[NH:37][C:35]1=[O:36])(=O)C1C=CC=CC=1>N.CO>[C@H:11]1([N:34]2[CH:41]=[C:40]([F:42])[C:38](=[O:39])[NH:37][C:35]2=[O:36])[O:12][C@@H:13]([CH2:24][OH:25])[C@H:14]([OH:15])[C@@H:10]1[OH:9]
Reactant: O=C(OC[C@@H]1O[C@H](n2cc(F)c(=O)[nH]c2=O)[C@@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)c1ccccc1
Agent: N
Solvent: CO
Product: O=c1[nH]c(=O)n([C@H]2O[C@@H](CO)[C@H](O)[C@@H]2O)cc1F
Yield: 96.8 %

Procedure:
Compound 5 (0.75 g, 1.30 mmol) in NH3 /MeOH (100 ml) was stirred at room temperature overnight and worked up as in Example 1, Step C to give pure 6 (0.33 g, 96%) as white crystals: m.p. 147°-148° C.
Reaction SMILES: N#N.Cl[CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:13][CH3:14])([CH3:12])[CH3:11])[N:9]=1.[N+:15]([C:18]1[CH:22]=[N:21][NH:20][N:19]=1)([O-:17])=[O:16].CCN(C(C)C)C(C)C>CN(C=O)C.CC(=O)OCC.O>[CH3:14][O:13][C:10]([C:8]1[N:9]=[C:5]([CH2:4][N:20]2[N:19]=[C:18]([N+:15]([O-:17])=[O:16])[CH:22]=[N:21]2)[O:6][CH:7]=1)([CH3:12])[CH3:11]
Reactant: O=[N+]([O-])c1cn[nH]n1
Reactant: COC(C)(C)c1coc(CCl)n1
Agent: N#N
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COC(C)(C)c1coc(Cn2ncc([N+](=O)[O-])n2)n1
Temperature: 50 °C
Reaction time: 8 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 2-(chloromethyl)-4-(2-methoxypropan-2-yl)oxazole (134 mg, 0.71 mmol) in DMF (2.0 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (T. E. Eagles et al. Organic preparations and procedures 2 (2), 117-119, 1970; P. N. Neuman J. Heterocycl. Chem. 8, 51-56, 1971) (1.01 g of a 8% solution in DMF, 0.71 mmol) in DMF (2.0 mL) pre-treated for 30 min with DIPEA (0.24 mL, 1.41 mmol) and the reaction mixture was stirred overnight at 50° C. Water (16 mL), followed by EA (16 mL) was added. The layers were separated and the org. layer was washed with water (3×6 mL), dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (1:1 hept-EA) gave the title compound as a yellow oil: TLC: rf (1:1 hept-EA)=0.33. LC-MS-conditions 06: tR=0.69 min, [M+H]+=268.13.
Reaction SMILES: N.[Na].[CH2:3]([C@:6]1([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:12])[O:10][C@H](C2C=CC=CC=2)[C@H](C2C=CC=CC=2)[N:7]1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH:4]=[CH2:5].[Cl-].[NH4+]>C1COCC1.C(O)C>[C:28]([O:27][C:25]([NH:7][C@:6]([CH2:32][CH:33]([CH3:35])[CH3:34])([CH2:3][CH:4]=[CH2:5])[C:11]([OH:12])=[O:10])=[O:26])([CH3:31])([CH3:30])[CH3:29]
Reactant: C=CC[C@]1(CC(C)C)C(=O)O[C@H](c2ccccc2)[C@H](c2ccccc2)N1C(=O)OC(C)(C)C
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: C1CCOC1
Product: C=CC[C@@](CC(C)C)(NC(=O)OC(C)(C)C)C(=O)O
Reaction time: 0.33 h

Procedure:
60 ml of ammonia were condensed at −78° C. Then 624 mg of sodium were added in 2 portions at an interval of 10 min. The mixture was stirred for 20 min. At −60° C., a solution of tert-butyl (3R,5S,6R)-3-allyl-3-isobutyl-2-oxo-5,6-diphenylmorpholine-4-carboxylate 1.22 g and 1.6 ml of ethanol in 20 ml of THF was added dropwise thereto. The mixture was stirred at −45° C. for 1.5 h, and the reaction was stopped by adding solid ammonium chloride until the blue color disappeared. The ammonia is then allowed to evaporate off, and 50 ml of water are added to the residue. The THF is removed in vacuo. The aqueous is adjusted to pH 2 with 1 N HCl and extracted 3 times with 60 ml of ethyl acetate each time. The combined organic phases are dried with MgSO4. The solvents are removed in vacuo and the residue is purified by chromatography on silica gel.