Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.COC(C1N=NC(NCC2[C:40]([C:45]3[CH:50]=[CH:49]C=CC=3)=[N:41]OC=2C)=CC=1)=O>>[CH:45]1([CH2:40][NH:41][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:50][CH2:49]1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3ccc(F)cc3)noc2C)nn1
Reactant: COC(=O)c1ccc(NCc2c(-c3ccccc3)noc2C)nn1
Product: Cc1onc(-c2ccc(F)cc2)c1CNc1ccc(C(=O)NCC2CC2)nn1
Yield: 91 %

Procedure:
As described for example 73c, 6-{[3-(4-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (89 mg, 0.25 mmol) was converted, instead of 6-[(5-methyl-3-phenyl-isoxazol-4-ylmethyl)-amino]-pyridazine-3-carboxylic acid methyl ester, to the title compound (87 mg, 91%) which was obtained as an off white foam. MS: m/e=382.4 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23](Cl)(=[O:25])=[O:24])(=[O:16])=[O:15]>>[CH3:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:25])=[O:24])(=[O:16])=[O:15]
Reactant: CS(=O)(=O)c1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2S(C)(=O)=O)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methylsulfonylbenzenesulfonyl chloride as described in the synthetic METHOD B to give a white solid (28.4 mg) with purity >90%. MS (pos) m/z 405.4.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:23]=[CH:22][C:7]2[CH:8]=[C:9]([C:11]([NH:13][C@@H:14]3[CH:19]4[CH2:20][CH2:21][N:16]([CH2:17][CH2:18]4)[CH2:15]3)=[O:12])[S:10][C:6]=2[CH:5]=1.C(N(CC)CC)C.[C:31]([N:35]=[C:36]=[O:37])([CH3:34])([CH3:33])[CH3:32]>C1COCC1.CN(C=O)C>[ClH:1].[N:16]12[CH2:21][CH2:20][CH:19]([CH2:18][CH2:17]1)[C@@H:14]([NH:13][C:11]([C:9]1[S:10][C:6]3[CH:5]=[C:4]([NH:3][C:36]([NH:35][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:37])[CH:23]=[CH:22][C:7]=3[CH:8]=1)=[O:12])[CH2:15]2
Reactant: CC(C)(C)N=C=O
Reactant: Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)NC(=O)Nc1ccc2cc(C(=O)N[C@H]3CN4CCC3CC4)sc2c1
Reaction time: 18 h

Procedure:
A solution of 50 mg (0.13 mmol) of 6-amino-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide dihydrochloride in 2 ml of THF and 0.2 ml of DMF is mixed with 37.2 μl (0.27 mmol) of triethylamine and 26.5 mg (0.27 mmol) of tert-butyl isocyanate. After 18 h at room temperature, the product is purified by preparative HPLC. The concentrated product fraction is dissolved in a mixture of acetonitrile and 1 N hydrochloric acid (5:1), again concentrated and dried under high vacuum. 19 mg (32.6% of theory) of the title compound are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][SH:7])=[CH:4][CH:3]=1.Br[CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][S:7][CH:11]([CH3:17])[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: SCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCOC(=O)C(C)SCc1ccc(Cl)cc1

Procedure:
A mixture of 19.5 ml (0.15 mol) of 4-chlorobenzylmercaptan, 27.1 g (0.15 mol) of ethyl α-bromopropionate, 21 g of potassium carbonate and 0.1 g of potassium iodide in 100 ml of anhydrous acetone is kept under reflux for 6 hrs. It is filtered, the precipitate is washed with acetone and the filtrate is evaporated in vacuo. 200 ml of ether are added to the residue and the mixture is washed with dilute NaOH, dilute HCl and water, dried and evaporated in vacuo.
Reaction SMILES: [F:1][CH2:2][CH:3]([CH:8]([F:12])[CH:9]([F:11])[F:10])[C:4]([F:7])([F:6])[F:5].S(=O)(=O)(O)[OH:14]>O>[F:1][CH2:2][C:3]([OH:14])([CH:8]([F:12])[CH:9]([F:11])[F:10])[C:4]([F:7])([F:5])[F:6]
Reactant: O=S(=O)(O)O
Reactant: FCC(C(F)C(F)F)C(F)(F)F
Solvent: O
Product: OC(CF)(C(F)C(F)F)C(F)(F)F

Procedure:
As another example, 2-fluoromethyl-1,1,1,3,4,4-hexafluoro-2-butanol may be prepared by fluorinating commercially available 3-chloropropionic acid to form 1,1,1,3-tetrafluoropropane which may then be reacted with CHF2CF carbene to form 2-fluoromethyl-1,1,1,3,4,4-hexafluorobutane. The 2-fluoromethyl-1,1,1,3,4,4-hexafluorobutane may then be dehydrogenated and reacted with sulfuric acid and then water to form 2-fluoromethyl-1,1,1,3,4,4-hexafluoro-2-butanol.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH:5]=[C:6]([OH:8])[CH:7]=1.CCCCP(CCCC)CCCC.[CH2:36](O)[CH2:37][CH2:38][OH:39].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.CCCCCC>[CH3:1][C:2]1[CH:3]=[C:4]([O:9][S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:20])[F:21])(=[O:12])=[O:11])[CH:5]=[C:6]([CH:7]=1)[O:8][CH2:36][CH2:37][CH2:38][OH:39]
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Reactant: OCCCO
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(OCCCO)cc(OS(=O)(=O)c2ccccc2C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
To a solution of 5-methyl-3-(2-trifluoromethylphenylsulfonyloxy)phenol (665 mg, 2.0 mmol), as prepared in the preceding step, tri-N-butylphosphine (607 mg, 3.0 mmol), and 1,3-propanediol (760 mg, 10 mmol) in tetrahydrofuran (20 mL) was added 1,1′-(azodicarbonyl)dipiperidine (757 mg, 3.0 mmol). The mixture was stirred at room temperature overnight. Hexane (30 mL) was added to the mixture, and the precipitates were removed by filtration. The filtrate was evaporated in vacuo and the residue was purified by flash column chromatography (2:1 hexane/ethyl acetate) to give the title compound as a colorless oil (745 mg, 94%). 1H-NMR (300 MHz, CDCl3) δ8.13 (d, J=7.2 Hz, 1H), 7.99 (d, J=7.2 Hz, 1H), 7.80 (t, J=7.6 Hz, 1H), 7.70 (t, J=7.3 Hz, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 6.46 (s, 1H), 4.02 (t, J=6.0 Hz, 2H), 3.81 (m, 2H), 2.25 (s, 3H), 1.99 (m, 2H), 1.61 (s, 1H).
Reaction SMILES: S(O)(O)(=O)=O.[CH3:6][S:7][C:8](=[NH:10])[NH2:9].CN([CH:14]=[C:15]1[C:20](=O)[CH2:19][CH2:18][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:16]1)C.[OH-].[Na+]>O>[CH3:6][S:7][C:8]1[N:9]=[CH:14][C:15]2[CH2:16][N:17]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18][CH2:19][C:20]=2[N:10]=1
Reactant: CN(C)C=C1CN(C(=O)OC(C)(C)C)CCC1=O
Reactant: CSC(=N)N
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CSc1ncc2c(n1)CCN(C(=O)OC(C)(C)C)C2
Reaction time: 1 h
Yield: 40 %

Procedure:
S-Methylisothiourea sulfate (16.44 g, 59.06 mmol, 1.5 eq.) and tert-butyl 3-((dimethylamino)-methylene)-4-oxopiperidine-1-carboxylate (10.0 g, 39.37 mmol, 1.0 eq.) were taken up in water (40 ml); 1 M NaOH solution (50 ml) was added and stirring was carried out for 1 hour at 80° C. After monitoring by TLC, the reaction mixture was diluted with water (100 ml) and extracted with DCM (2×150 ml). The combined org. phases were washed with sat. NaCl solution (100 ml), dried over sodium sulfate, concentrated under reduced pressure and purified by column chromatography (silica gel, 25% ethyl acetate in hexane). Yield: 40% (4.5 g, 16.01 mmol)
Reaction SMILES: C([N+](CCCC)(CCCC)CCCC)CCC.[P:18]([O:22][CH2:23][C@@H:24]1[C@@H:28]([O:29][P:30]([O:33][CH2:34][C@@H:35]2[C@@H:39]([OH:40])[C@@H:38]([OH:41])[C@H:37]([N:42]3[CH:50]=[N:49][C:48]4[C:43]3=[N:44][CH:45]=[N:46][C:47]=4[NH2:51])[O:36]2)([OH:32])=[O:31])[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25]1)([OH:21])([OH:20])=[O:19].[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][C@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75](OCC#N)=[O:76])=[O:69])[C:61]1[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=1>O.C(#N)C>[CH2:60]([O:67][C:68]([NH:70][CH2:71][CH2:72][CH2:73][C@@H:74]([NH:81][C:82]([O:84][C:85]([CH3:88])([CH3:87])[CH3:86])=[O:83])[C:75]([O:40][C@H:39]1[C@@H:38]([OH:41])[C@H:37]([N:42]2[CH:50]=[N:49][C:48]3[C:43]2=[N:44][CH:45]=[N:46][C:47]=3[NH2:51])[O:36][C@H:35]1[CH2:34][O:33][P:30]([O:29][C@H:28]1[CH2:27][C@H:26]([N:52]2[CH:57]=[CH:56][C:55]([NH2:58])=[N:54][C:53]2=[O:59])[O:25][C@@H:24]1[CH2:23][O:22][P:18]([OH:21])([OH:20])=[O:19])([OH:32])=[O:31])=[O:76])=[O:69])[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1
Reactant: Nc1ccn([C@H]2C[C@H](OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](COP(=O)(O)O)O2)c(=O)n1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCNC(=O)OCc1ccccc1)C(=O)OCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CC#N
Product: CC(C)(C)OC(=O)N[C@H](CCCNC(=O)OCc1ccccc1)C(=O)O[C@H]1[C@@H](O)[C@H](n2cnc3c(N)ncnc32)O[C@H]1COP(=O)(O)O[C@H]1C[C@H](n2ccc(N)nc2=O)O[C@@H]1COP(=O)(O)O
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 28.6 %

Procedure:
A solution of ((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-3-(((((2R,3S,4R,5R)-5-(6-amino-9H-purin-9-yl)-3,4-dihydroxytetrahydrofuran-2-yl)methoxy) (hydroxy)phosphoryl)oxy)tetrahydrofuran-2-yl)methyl dihydrogenphosphate (Compound 1h) (67.9 mg, 0.107 mmol) in water (0.3 mL) and a solution of (S)-cyanomethyl 5-(((benzyloxy) carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk66) (173 mg, 0.427 mmol) in acetonitrile (0.3 mL) were added to buffer A (18 mL), and the mixture was stirred at room temperature for 1.25 hours. Following lyophilization, the resulting residue was purified by reverse-phase silica gel column chromatography (0.05% aqueous trifluoroacetic acid solution/0.05% trifluoroacetic acid-acetonitrile solution) to afford (2S)-(2R,3S,4R,5R)-2-((((((2R,3S,5R)-5-(4-amino-2-oxopyrimidin-1(2H)-yl)-2-((phosphonooxy)methyl)tetrahydrofuran-3-yl)oxy)(hydroxy)phosphoryl)oxy)methyl)-5-(6-amino-9H-purin-9-yl)-4-hydroxytetrahydrofuran-3-yl 5-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)pentanoate (Compound tk67) (30.1 mg, 29%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]#[CH:9])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:17])/[CH:14]=[CH:15]\I)[CH3:11]>>[CH2:10]([O:12][C:13](=[O:17])[CH:14]=[CH:15][C:9]#[C:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=1)[CH3:11]
Reactant: C#Cc1ccc(Br)cc1
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccc(Br)cc1

Procedure:
The general procedure was used to convert 1-Bromo-4-ethynyl-benzene and (Z)-ethyl-3-iodoacrylate to the title product in 20 hours. Purification by flash chromatography (355 mg, 20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (65% yield). 1H NMR (400 MHz, CDCl3) δ 7.48-7.46 (d, J=8.5, 2H), 7.39-7.36 (d, J=8.5, 2H), 6.33-6.30 (d, J=11.4, 1H), 6.16-6.13 (d, J=11.4, 1H), 4.27-4.22 (q, J=7.1, 2H), 1.33-1.29 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 164.64, 133.40, 131.68, 128.69, 123.61, 122.49, 121.60, 99.81, 87.38, 60.46, 14.29. Anal. Calcd. for C13H11BrO2: C, 55.94; H, 3.97; Br, 28.63; Found C, 56.05; H, 4.07; Br, 27.6.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=1[CH:17]([C:29](=O)[C:30]1[CH:34]=[CH:33][S:32][CH:31]=1)[CH2:18][C:19]1[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:16][O:15][C:13]1[CH:14]=[C:9]2[C:10]([C:17]([CH2:18][C:19]3[N:24]=[C:23]([C:25]([O:27][CH3:28])=[O:26])[CH:22]=[CH:21][CH:20]=3)=[C:29]([C:30]3[CH:34]=[CH:33][S:32][CH:31]=3)[NH:8]2)=[CH:11][CH:12]=1
Reactant: COC(=O)c1cccc(CC(C(=O)c2ccsc2)c2ccc(OC)cc2NC(=O)OC(C)(C)C)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1cccc(Cc2c(-c3ccsc3)[nH]c3cc(OC)ccc23)n1
Temperature: 30 °C
Reaction time: 8 h
Yield: 58.6 %

Procedure:
To a solution of methyl 6-[2-(2-tert-butoxycarbonylamino-4-methoxyphenyl)-3-oxo-3-thiophen-3-ylpropyl]pyridine-2-carboxylate (2.10 g) in dichloromethane (21 mL) was added dropwise trifluoroacetic acid (4.2 mL) under ice-cooling. This mixture was stirred at 30° C. overnight. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and this solution was washed with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (938 mg). 1H-NMR (CDCl3) δ ppm: 3.86 (3H, s), 4.05 (3H, s), 4.54 (2H, s), 6.76 (1H, dd, J=2.2, 8.5 Hz), 6.90 (1H, d, J=2.2 Hz), 7.19-7.24 (1H, m), 7.28-7.35 (2H, m), 7.41 (1H, dd, J=3.0, 5.0 Hz), 7.52 (1H, dd, J=1.3, 3.0 Hz), 7.62 (1H, t, J=7.8 Hz), 7.93-7.98 (1H, m), 8.07 (1H, br s).
Reaction SMILES: [C:1]([C:9]1[NH:10][CH:11]=[CH:12][C:13]=1[CH2:14][CH2:15][C:16](Br)([C:22]([O:24]CC)=[O:23])[C:17]([O:19][CH2:20][CH3:21])=[O:18])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(B([CH2:33][CH3:34])CC)C.O>C1C=CC=CC=1>[C:1]([C:9]1[N:10]2[C:15](=[CH:14][CH:13]=1)[C:16]([C:22]([O:24][CH2:33][CH3:34])=[O:23])([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH2:12][CH2:11]2)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCB(CC)CC
Reactant: CCOC(=O)C(Br)(CCc1cc[nH]c1C(=O)c1ccccc1)C(=O)OCC
Solvent: c1ccccc1
Solvent: O
Product: CCOC(=O)C1(C(=O)OCC)CCn2c(C(=O)c3ccccc3)ccc21
Reaction time: 1 h
Yield: 74.8 %

Procedure:
To a solution of 2-benzoyl-[3-bromo-3,3-di(ethoxycarbonyl)propyl]pyrrole (436 mg, 1.0 mmol) in benzene (20 mL) was added triethylborane (1.0M in hexane, 5 mL, 5 mmol). The reaction mixture was stirred in an open vessel for one hour. Additional triethylborane (1 mL, 1 mmol) was added and the reaction was allowed to stir in an open vessel for an additional hour. The reaction mixture was poured into water and extracted with diethyl ether. The combined organic layers were washed with saturated aqueous sodium chloride, dried (Na2SO4), and concentrated under reduced pressure. The residue was purified by chromatography on silica gel eluting with hexane/ethyl acetate (85:15) to provide 266 mg (75%) of diethyl 5-benzoyl-2,3-dihydro-1H-pyrrolizine-1,1-dicarboxylate.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]([C:14]2[C:15]3[CH:22]=[CH:21][N:20]([S:23]([C:26]4[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[C:16]=3[N:17]=[CH:18][N:19]=2)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64](O)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:54][C:55]1[CH:56]=[C:57]([NH:62][CH2:63][C:64]([N:1]2[CH2:6][CH2:5][CH2:4][C@@H:3]([N:7]([C:14]3[C:15]4[CH:22]=[CH:21][N:20]([S:23]([C:26]5[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=5)(=[O:25])=[O:24])[C:16]=4[N:17]=[CH:18][N:19]=3)[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:2]2)=[O:65])[CH:58]=[C:59]([Cl:61])[CH:60]=1
Reactant: CCOC(=O)CN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCNC1
Reactant: O=C(O)CNc1cc(Cl)cc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)CN(c1ncnc2c1ccn2S(=O)(=O)c1ccc(C)cc1)[C@@H]1CCCN(C(=O)CNc2cc(Cl)cc(Cl)c2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31 %

Procedure:
To a solution of (R)-ethyl 2-(piperidin-3-yl(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)acetate (0.2 g, 0.44 mmol) in DMF (2 mL) was added EDCI (0.13 g, 0.66 mmol), HOBt (89 mg, 0.7 mmol), 2-(3,5-dichlorophenylamino)acetic acid (0.1 g, 0.5 mmol) and DIEA (0.12 mL, 0.66 mmol) at 0° C. The solution was stirred at rt overnight, diluted with EtOAc and washed with water, brine, dried over Na2SO4 and concentrated in vacuo to give a residue which was purified by column chromatography (silica gel gradient methanol in chloroform) to afford (0.09 g, 31%) the titled compound. LCMS [M+1]: 659.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30]([O:32]CC)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:35][OH:36]>C(O)(C)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:20][CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C@H:12]1[C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[O:28][CH2:29][C:30](=[O:32])[NH:35][OH:36])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CCOC(=O)COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1
Solvent: CC(C)O
Product: O=C(COc1ccc(Cl)cc1[C@@H]1c2ccccc2CCN1C(=O)OCc1ccccc1)NO
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To an ice-cooled solution of (S)-1-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-3,4-dihydro-1H-isoquinoline-2-carboxylic acid benzyl ester (144 mg, 0.30 mmol, 1.0 eq.) in isopropanol (1.5 mL), hydroxylamine (50% w/w aqueous solution, 1.5 mL) was added. The ice bath was removed and the reaction mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated to half and water (5 mL) was added. The resulting suspension was filtered, washed with water and dried under hv to give the desired product as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3]I.[N+:5]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]([CH2:17][CH3:18])[CH2:15][OH:16])=[CH:10][CH:9]=1)([O-:7])=[O:6].P([O-])([O-])(O)=O.[K+].[K+].P([O-])(O)(O)=O.[K+]>CN(C)C=O>[CH3:3][O:16][CH2:15][CH:14]([C:11]1[CH:10]=[CH:9][C:8]([N+:5]([O-:7])=[O:6])=[CH:13][CH:12]=1)[CH2:17][CH3:18]
Reactant: CCC(CO)c1ccc([N+](=O)[O-])cc1
Reactant: CI
Agent: O=P([O-])(O)O
Agent: O=P([O-])([O-])O
Agent: [H-]
Solvent: CN(C)C=O
Product: CCC(COC)c1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a mixture of 2.2 g of sodium hydride (as a 50% oil dispersion) and 15.5 g of methyl iodide in 300 ml of dried dimethylformamide, there was added dropwise a solution of 7.1 g of 2-(4-nitrophenyl)butanol in 100 ml of dimethylformamide. The resulting mixture was stirred at room temperature for 20 hours and then poured into an aqueous solution containing 0.2 M potassium hydrogen phosphate/potassium dihydrogen phosphate buffer solution (pH 7). The resulting mixture was extracted several times with diethyl ether and the combined organic extracts were washed with aqueous dilute sodium thiosulfate solution, water, and aqueous saturated sodium chloride solution, and dried over magnesium sulfate. Evaporation of the solvent gave a red oil which was purified by chromatography on silica gel and elution with ethyl acetate/hexane to give 4-[1-(methoxymethyl)-propyl]nitrobenzene.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:4][CH:3]=1.S(Cl)([Cl:20])(=O)=O>C(Cl)Cl>[Cl:20][CH:10]([C:9](=[O:16])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=1)[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=S(=O)(Cl)Cl
Reactant: CCOC(=O)CC(=O)Cc1ccc(Cl)cc1
Solvent: ClCCl
Product: CCOC(=O)C(Cl)C(=O)Cc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.7 %

Procedure:
To a solution of ethyl 4-(4-chlorophenyl)-3-oxobutanoate (61.0 g, 253 mmol) in DCM (811 mL) in an ice bath was added sulfuryl chloride (34.2 g, 253 mmol) and the resulting solution was allowed to stir at room temperature overnight. The reaction was quenched with saturated sodium bicarbonate solution (200 mL) and the layers separated. The organic layer was washed with brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo to give 70.8 g of title compound. (100% yield). 1H NMR (400 MHz, CDCl3) δ: 7.33-7.30 (m, 2H), 7.17-7.14 (m, 2H), 4.85 (s, 1H), 4.26 (dq, 1H, J=7.2, 1.2 Hz), 4.02 (d, 1H, J=16.8 Hz), 3.97 (d, J=16.8 Hz, 1H), 1.29 (t, 3H, J=7.2 Hz).
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[OH:13])([O-:3])=[O:2].[Cl:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=1[C@@H:23](O)[CH3:24].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[Cl:14][C:15]1[C:20]([F:21])=[CH:19][CH:18]=[C:17]([Cl:22])[C:16]=1[C@H:23]([O:13][C:5]1[C:6]2[O:12][CH:11]=[CH:10][C:7]=2[CH:8]=[N:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH3:24]
Reactant: O=[N+]([O-])c1ncc2ccoc2c1O
Reactant: C[C@H](O)c1c(Cl)ccc(F)c1Cl
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@@H](Oc1c([N+](=O)[O-])ncc2ccoc12)c1c(Cl)ccc(F)c1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of 6-nitrofuro[3,2-c]pyridin-7-ol (Intermediate 7) (2.10 g, 11.6 mmol) and (S)-1-(2,6-dichloro-3-fluorophenyl)-ethanol (2.68 g, 12.8 mmol, prepared according to literature procedures: WO2006/021881A2) in THF (30 mL) were added PPh3 (4.31 g, 16.4 mmol) and diisopropyl azodicarboxylate (3.32 g, 16.4 mmol) at 0° C. After 10 min, the cold-bath was removed and the resulting mixture was stirred at rt overnight. LC-MS showed completion of the reaction. The reaction mixture was evaporated under vacuum to give an oil, which was purified by silica gel flash chromatography (DCM:Hexanes=2:1) to afford 4.2 g of the desired product as a light-yellow oil (yield: 97%). 1H NMR (CDCl3, 400 MHz): δ=1.94 (d, J=6.8 Hz, 3H), 6.69 (q, J=6.8 Hz, 1H), 6.93 (d, J=2.3 Hz, 1H), 7.05 (t, J=8.3 Hz, 1H), 7.27 (dd, J=8.8, 4.8 Hz, 1H), 7.78 (d, J=2.3 Hz, 1H), 8.42 (s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][O:11][CH:12]3[CH:17]([C:18]4[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[O:36][CH3:37])=[CH:20][CH:19]=4)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]4[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=4)=[O:39])[CH2:13]3)[CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].Cl[CH2:51][CH2:52][CH2:53][O:54][CH3:55]>CN1C(=O)N(C)CCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH3:37][O:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[CH2:29][O:28][CH2:27][CH2:26][CH2:25][O:24][C:21]1[CH:20]=[CH:19][C:18]([CH:17]2[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)=[O:39])[CH2:13][CH:12]2[O:11][CH2:10][C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[CH:2][N:1]3[CH2:51][CH2:52][CH2:53][O:54][CH3:55])=[CH:5][CH:6]=2)=[CH:23][CH:22]=1
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCc2ccc3cc[nH]c3c2)cc1
Reactant: COCCCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN1CCCN(C)C1=O
Product: COCCCn1ccc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(OCCCOCc4ccccc4OC)cc3)cc21
Reaction time: 0.08 h

Procedure:
The solution of 0.155 g of benzyl 3-(1H-indol-6-ylmethoxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.5 ml of DMPU is admixed with stirring at room temperature with 0.015 g of sodium hydride dispersion (60%). The mixture is stirred over 5 minutes and subsequently admixed with 0.081 ml of 1-chloro-3-methoxypropane and 0.007 g of tetrabutylammonium iodide. The reaction mixture is stirred at room temperature over 24 hours, cooled and poured onto water (20 ml). The mixture is extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed successively with water (2×20 ml) and brine (1×20 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.25 (1:1 EtOAc-heptane); Rt=27.51 (II).