Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:36])[CH2:3][CH2:4][NH:5][C:6](=[O:35])[CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]3[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:17]=3[C:16]=2[C:15]2[CH:14]=[C:13]([O:33]C)[CH:12]=[CH:11][C:10]1=2.N>O>[CH3:36][N:2]([CH3:1])[CH2:3][CH2:4][NH:5][C:6](=[O:35])[CH2:7][CH2:8][N:9]1[C:21]2[CH:20]=[C:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:18]3[C:28](=[O:32])[NH:29][C:30](=[O:31])[C:17]=3[C:16]=2[C:15]2[CH:14]=[C:13]([OH:33])[CH:12]=[CH:11][C:10]1=2
Reactant: COc1ccc2c(c1)c1c3c(c(-c4ccccc4)cc1n2CCC(=O)NCCN(C)C)C(=O)NC3=O
Agent: N
Solvent: O
Product: CN(C)CCNC(=O)CCn1c2ccc(O)cc2c2c3c(c(-c4ccccc4)cc21)C(=O)NC3=O

Procedure:
Reaction of methyl ether (247) (70 mg, 0.14 mmol) prepared as described in example 207 according to the procedure described in example 81, except that the reaction mixture was diluted with water, basified by the addition of concentrated ammonia and extracted with ethyl acetate. The organic layer was dried, the drying agent was removed and the solution was concentrated to dryness. Chromatography on silica eluting with ethyl acetate/methanol/triethylamine (1:0:0 to 3:1:trace). Crystallization from ethyl acetate/hexane then gave amide (254) (35 mg, 53%) as an orange powder, mp 176–180° C. 1H NMR δ [(CD3)2SO] 11.06 (br s, 1H), 9.35 (br s, 1H), 8.39 (d, J=2.5 Hz, 1H), 7.77 (s, 1H), 7.74 (t, J=5.6 Hz, 1H), 7.66 (m, 2H), 7.53 (d, J=8.8 Hz, 1H), 7.48 (m, 3H), 7.12 (dd, J=8.8, 2.5 Hz, 1H), 4.69 (t, J=6.4 Hz, 2H), 2.94 (m, 2H), 2.58 (t, J=6.4 Hz, 2H), 1.91 (s, 6H), 1.87 (m, 2H). Found: C, 66.87; H, 5.83; N, 11.47. C27H26N4O4.3/4H2O requires: C, 67.00; H, 5.73; N, 11.57.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][NH:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])[CH3:2].[H-].[Na+].[CH3:20]I.[NH4+].[Cl-]>CN(C=O)C>[CH2:1]([O:3][CH:4]([O:15][CH2:16][CH3:17])[CH2:5][N:6]([CH3:20])[C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11])[CH3:2]
Reactant: CI
Reactant: CCOC(CNc1cccc(C#N)c1)OCC
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CCOC(CN(C)c1cccc(C#N)c1)OCC
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 72.9 %

Procedure:
To a stirred solution of 3-(2,2-diethoxyethylamino)benzonitrile (0.84 g, 3.59 mmol) in anhydrous DMF (5 mL) at 0° C. was added NaH (0.10 g, 4.30 mmol) portionwise. After 20 min, MeI (0.61 g, 4.30 mmol) was added, and the mixture was stirred at room temperature for 6 h. The reaction mixture was cooled to 0° C., and to it, aqueous NH4Cl (10 mL) solution was added dropwise. The aqueous mixture was extracted with CHCl3 (2×30 mL), and the organic phase was dried over anhydrous Na2SO4, filtered, and evaporated to dryness under reduced pressure. The residue was purified by MPLC on silica gel using a mixture of EtOAc and hexane as eluent to give 3-((2,2-diethoxyethyl)(methyl)amino)benzonitrile (0.65 g, 73%) as a viscous liquid. 1H NMR (400 MHz, CDCl3): δ 7.28-7.24 (m, 1H), 6.96-6.93 (m, 3H), 4.60 (t, 1H, J=5.2 Hz), 3.76-3.69 (m, 2H), 3.55-3.47 (m, 2H), 3.46 (d, 2H, J=5.2 Hz), 3.02 (s, 3H), 1.20 (t, 6H, J=7.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])/[C:4](/[CH3:10])=[CH:5]\[C:6]([O:8][CH3:9])=[O:7].[Br:12]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.N(C(C)(C)C#N)=NC(C)(C)C#N>[CH3:1][O:2][C:3](=[O:11])/[C:4](/[CH2:10][Br:12])=[CH:5]/[C:6]([O:8][CH3:9])=[O:7]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)/C=C(/C)C(=O)OC
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)/C=C(\CBr)C(=O)OC
Temperature: 25 °C
Reaction time: 36 h
Yield: 85.5 %

Procedure:
To a solution of (Z)-2-methyl-2-butenedioic acid dimethyl ester (15.3 g) in carbon tetrachloride (300 ml) were added N-bromosuccinimide (25.8 g) and 2,2′-azobis(isobutyronitrile) (319 mg), and the mixture was stirred for 36 hours at reflux. After cooling the mixture to room temperature, the insoluble substance was filtered off, and the filtrate was concentrated. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=1/0 to 18/1) to give the titled compound (19.6 g).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])O)O)O)[OH:4].[NH4+].[OH-]>>[CH3:2][CH2:3][CH2:5][CH2:7][CH2:2][CH:3]1[O:4][C:11](=[O:12])[CH2:9][CH2:7][CH2:5]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: [NH4+]
Agent: [OH-]
Product: CCCCCC1CCCC(=O)O1
Reaction time: 40 h

Procedure:
A 15 1 bioreactor containing 10 1 of medium was seeded with 2×800 ml of an inoculum of Clostridium tyrobutyricum I-776. Strict anaerobic and sterile conditions were maintained. The pH was kept at 6.5, the temperature at 35° C., the stirring speed at 300/min; the initial concentration of glucose was 90 g/l. When the glucose was exhausted (48 h), the cells were gathered for centrifugation over 30 min at 4° C., for example at 10000 ×g. The humid mass of the cells was gathered and put into a 2 1 reactor under strictly sterile and anaerobic conditions. The volume was adjusted to a total of 1 1 with a buffer solution of pH 7. The medium contained about 90 g/l of dry matter. NH4OH was added to maintain a pH of 7, and a glucose solution of 500 g/l was also added, to adjust the glucose concentration to about 20 g/l. 2-Decen-5-olide was added semicontinuously. After 40 h, δ-decalactone was obtained in a concentration of 7 g/l, which corresponds to a conversion of 72%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([CH2:15][C:16]([F:19])([F:18])[F:17])[CH:7]=[C:6]([C:20]([O:22]CC)=[O:21])[C:5]2=[O:25]>C(O)(=O)C.O.S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([O:13][CH3:14])[C:11]=1[F:12])[N:8]([CH2:15][C:16]([F:19])([F:17])[F:18])[CH:7]=[C:6]([C:20]([OH:22])=[O:21])[C:5]2=[O:25]
Reactant: CCOC(=O)c1cn(CC(F)(F)F)c2c(OC)c(F)c(F)cc2c1=O
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: COc1c(F)c(F)cc2c(=O)c(C(=O)O)cn(CC(F)(F)F)c12

Procedure:
800 mg (2.19 mmol) of the compound of Example 23A are provided in a mixture of 25 ml of acetic acid-water-sulfuric acid 12:8:1 and stirred over night under reflux. For the work-up the solvent is removed to a large extent on a rotary evaporator, the residue is adjusted carefully to pH 3 while cooling with ice with a saturated sodium hydrogen carbonate solution, the suspension is diluted with water, the precipitate is collected by suction filtration and after drying the filter residue under high vacuum, 575 mg of the title compound are obtained.
Reaction SMILES: Cl[C:2](=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6].[Br:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][CH:20]=1)[C:17]([CH3:22])([CH3:21])[C:16](=[O:23])[CH:15]=[C:14]2[OH:24]>ClCCCl.C(Cl)Cl>[C:2]([O:24][C:14]1[C:13]2[C:18](=[CH:19][CH:20]=[C:11]([Br:10])[CH:12]=2)[C:17]([CH3:22])([CH3:21])[C:16](=[O:23])[CH:15]=1)(=[O:9])[CH2:3][CH2:4][C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)CCC(=O)Cl
Reactant: CC1(C)C(=O)C=C(O)c2cc(Br)ccc21
Solvent: ClCCCl
Solvent: ClCCl
Product: COC(=O)CCC(=O)OC1=CC(=O)C(C)(C)c2ccc(Br)cc21
Yield: 85 %

Procedure:
Methyl 4-chloro-4-oxobutyrate (0.107 mL, 0.873 mmol) was added to a solution of 6-bromo-4-hydroxy-1,1-dimethylnaphthalen-2(1H)-one (0.212 g, 0.794 mmol), TEA (0.121 mL, 0.873 mmol) in 1,2-dichloroethane (3 mL). The mixture was diluted with DCM, washed with water, washed with NaHCO3, and dried over MgSO4. The crude product was purified by flash chromatography using EtOAc/hexane to afford 7-bromo-4,4-dimethyl-3-oxo-3,4-dihydronaphthalen-1-yl methyl succinate in 85% yield. 1H-NMR (300 MHz, CDCl3) δ ppm 7.74 (1H, d, J=2.0 Hz), 7.59 (1H, dd, J=8.4, 2.1 Hz), 7.36 (1H, d, J=8.5 Hz), 6.20 (1H, s), 3.73 (3H, s), 3.01 (2H, t, J=6.0 Hz), 2.80 (2H, t, J=6.0 Hz), 1.48 (6H, s). MS m/z: 381.
Reaction SMILES: CO[C:3]([C:5]1[NH:6][S:7](=[O:21])(=[O:20])[C:8]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]=[CH:12][C:9]=2[C:10]=1[OH:11])=[O:4].[Cl:22][C:23]1[CH:24]=[C:25]([CH:27]=[CH:28][CH:29]=1)[NH2:26]>C1(C)C(C)=CC=CC=1>[Cl:22][C:23]1[CH:24]=[C:25]([NH:26][C:3]([C:5]2[NH:6][S:7](=[O:20])(=[O:21])[C:8]3[C:19]4[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=4)[CH:13]=[CH:12][C:9]=3[C:10]=2[OH:11])=[O:4])[CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1
Reactant: Nc1cccc(Cl)c1
Solvent: Cc1ccccc1C
Product: O=C(Nc1cccc(Cl)c1)C1=C(O)c2ccc3ccccc3c2S(=O)(=O)N1

Procedure:
A mixture consisting of 1 gm (3.3 millimols) of 4-hydroxy-2H-naphtho[2,1-e]-1,2-thiazine-3-carboxylic acid methyl ester-1,1-dioxide, 0.5 gm (4 millimols) of 3-chloroaniline and 200 ml of anhydrous xylene was refluxed for 25 hours in a Soxhlet apparatus equippedwith a 4-A-molecular sieve. Upon cooling, the desired product crystallized out. Yield: 0.9 gm (68% of theory); m.p. 262° C (decomp.).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:10][CH2:11][C:12]([OH:14])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.S(O)(O)(=O)=O.[CH3:42][N:43]1[C:47]([NH2:48])=[C:46]([NH2:49])[CH:45]=[N:44]1.C(N(CC)C(C)C)(C)C>ClCCl.O1CCCC1.[Cl-].[Na+].O>[NH2:48][C:47]1[N:43]([CH3:42])[N:44]=[CH:45][C:46]=1[NH:49][C:12](=[O:14])[CH2:11][CH2:10][N:8]([CH3:9])[C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(CCC(=O)O)C(=O)OC(C)(C)C
Reactant: Cn1ncc(N)c1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCC(=O)Nc1cnn(C)c1N)C(=O)OC(C)(C)C
Reaction time: 1 h
Yield: 49.3 %

Procedure:
To a suspension of 3-[N-(tert-butoxycarbonyl)-N-methylamino]propanoic acid (3.33 g) in dichloromethane (33 ml) and tetrahydrofuran (33 ml) were added HOBT (3.33 g) and WSC HCl (6.29 g), and the mixture was stirred for 1 hour. To the solution were added 1-methyl-1H-pyrazole-4,5-diamine sulfate (3.45 g) and N,N-diisopropylethylamine (11.4 ml). The reaction mixture was stirred at room temperature overnight. To the resulting solution was added brine and extracted with tetrahydrofuran/ethyl acetate=1/1. The extract was dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give tert-butyl N-{3-[(5-amino-1-methyl-1H-pyrazol-4-yl)amino]-3-oxopropyl}-N-methylcarbamate as an oil (2.4 g). This product was used in the next step without further purification.
Reaction SMILES: [CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2].[CH3:26][NH:27][C:28]1[N:33]=[C:32](Br)[CH:31]=[CH:30][CH:29]=1.[F-].[Cs+].O>COCCOCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(OCC)(=O)C>[CH2:1]([O:3]/[C:4](=[CH:10]\[C:11]1[CH:12]=[CH:13][C:14]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]([NH:27][CH3:26])[N:33]=2)=[CH:15][CH:16]=1)/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH3:2]
Reactant: CNc1cccc(Br)n1
Reactant: CCOC(=O)/C(=C/c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: COCCOCCOC
Solvent: O
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)n2)cc1)OCC
Temperature: 80 °C
Yield: 76.6 %

Procedure:
1.0 g (2.9 mmol) of ethyl (Z)-2-ethoxy-3-[4-(4,4,5,5-tetramethyl[1.3]dioxaborolan-2-yl)phenyl]acrylate, 0.4 g (2.4 mmol) of 6-methylamino-2-bromopyridine and 1.1 g (7.2 mmol) of caesium fluoride are dissolved in 60 mL of diethylene glycol dimethyl ether. After bubbling nitrogen through the reaction mixture for 20 minutes, 0.1 g (0.15 mmol) of dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium is added. The reaction mixture is heated at 80° C. for 18 hours with vigorous stirring. After cooling, the reaction is worked up by addition of 60 mL of water and extraction with ethyl acetate. The organic phases are combined, washed with saturated aqueous sodium chloride solution and then dried over magnesium sulfate. After filtration, the solvents are evaporated off. The crude product obtained is purified by chromatography on a column of silica eluted with a 90/10 heptane/ethyl acetate mixture to give 0.6 g (76%) of ethyl (Z)-2-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]acrylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:13](Cl)=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1)[C:8]([C@@H:20]([N:22]1[C:30](=[O:31])[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[C:23]1=[O:32])[CH3:21])=[CH:7]2.O1CCO[CH2:35][CH2:34]1.C([Al](CC)CC)C.Cl>[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[C:13]([CH2:34][CH3:35])=[N:14][CH:15]=[C:16]([F:18])[CH:17]=1)[C:8]([C@@H:20]([N:22]1[C:23](=[O:32])[C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]1=[O:31])[CH3:21])=[CH:7]2
Reactant: C[C@@H](c1cc2cccc(Cl)c2nc1-c1cc(F)cnc1Cl)N1C(=O)c2ccccc2C1=O
Reactant: C1COCCO1
Agent: [Pd]
Agent: CC[Al](CC)CC
Agent: Cl
Product: CCc1ncc(F)cc1-c1nc2c(Cl)cccc2cc1[C@H](C)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C

Procedure:
A mixture of 2-((S)-1-(8-chloro-2-(2-chloro-5-fluoropyridin-3-yl)quinolin-3-yl)-ethyl)isoindoline-1,3-dione (192.7 mg, 413 μmol), dioxan (15 mL, 175989 μmol)-, triethylaluminum (236 mg, 2066 μmol) and tetrakis(triphenylphosphine)-palladium (96 mg, 83 μmol) was refluxed for 4 hs under N2, cooled to room temperature. The reaction mixture was acidified with HCl (2N) and the solvent was evaporated. The residue was diluted with water, basified with NaOH (20%), and the mixture was extracted with EtOAc. The combined extracts were washed with water, brine, dried and concentrated. Purification of the residue by flash chromatography over silica gel, gradient elution, 0-100% EtOAc in hexane, gave 2-((S)-1-(8-chloro-2-(2-ethyl-5-fluoropyridin-3-yl)quinolin-3-yl)ethyl)isoindol-ine-1,3-dione, Mass Spectrum (ESI) m/e=460.1 (M+1). And 2-((S)-1-(8-chloro-2-(5-fluoropyridin-3-yl)quinolin-3-yl)ethyl)isoindoline-1,3-dione, Mass Spectrum (ESI) m/e=432.1(M+1).
Reaction SMILES: CCN=C=NCCCN(C)C.FC1C=C(NC([C:23]2[CH:24]=[C:25](C(O)=O)[CH:26]=[C:27]3[C:32]=2[O:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]3=[O:39])C)C=C(F)C=1.N1CC[C@H](O)C1.OP=O>C(Cl)Cl>[O:36]1[CH2:37][CH2:38][N:33]([C:30]2[O:31][C:32]3[C:27]([C:28](=[O:39])[CH:29]=2)=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:34][CH2:35]1
Reactant: CC(Nc1cc(F)cc(F)c1)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Agent: CCN=C=NCCCN(C)C
Agent: O=PO
Agent: O[C@H]1CCNC1
Solvent: ClCCl
Product: O=c1cc(N2CCOCC2)oc2ccccc12
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 95 %

Procedure:
EDCI (102 mg, 0.53 mmol) was added in one portion to 8-(1-(3,5-difluorophenylamino) ethyl)-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 0.35 mmol, enantiomer 2 ([α]D20°-102°, described as a starting material in Example 7.0a), (S)-pyrrolidin-3-ol (0.043 mL, 0.53 mmol) and HOPO (47.1 mg, 0.42 mmol) dissolved in DCM (2 mL) in a screwcap vial. The resulting solution was stirred at RT for 5 min then 50° C. for 30 min. More EDCI (˜50 mg) was added to complete the reaction. The solution was washed with a 10% aq. citric acid solution, water, brine and dried over magnesium sulfate. The solvent was evaporated and the crude product purified by flash chromatography on silica gel (40 g) eluting with 0 to 10% MeOH in DCM. The solvent was evaporated to dryness to afford 8-(1-(3,5-difluorophenylamino)ethyl)-6-(S)-3-hydroxypyrrolidine-1-carbonyl)-2-morpholino-4H-chromen-4-one (95%) as a off-white foam. Mass Spectrum: M+H+ 500. NMR Spectrum (CDCl3): 1.60 (d, 3H), 1.89-2.11 (m, 1H), 2.54 (bs, 0.5H), 2.81 (bs, 0.5H), 3.29-3.43 (m, 2H), 3.51 (bs, 4H), 3.64-3.78 (m, 2H), 3.79-3.91 (m, 5H), 4.42 (bs, 0.5H), 4.54 (bs, 0.5H), 4.59 (bs, 0.5H), 4.70 (bs, 0.5H), 4.87-4.95 (m, 1H), 5.54 (bs, 1H), 5.89-6.01 (m, 2H), 6.09 (dd, 1H), 7.85 (s, 0.5H), 7.87 (s, 0.5H), 8.18 (bs, 0.5H), 8.25 (bs, 0.5H).
Reaction SMILES: I[Si](C)(C)C.[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[N:25](C(OC(C)(C)C)=O)[N:24]=[C:23]2/[CH:36]=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])(=[O:18])=[O:17])(=[O:9])=[O:8].N>C(Cl)(Cl)Cl>[CH3:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[S:16]([NH:19][C:20]1[CH:21]=[C:22]2[C:26](=[CH:27][CH:28]=1)[NH:25][N:24]=[C:23]2/[CH:36]=[CH:37]/[C:38]([O:40][CH3:41])=[O:39])(=[O:17])=[O:18])(=[O:9])=[O:8]
Reactant: COC(=O)/C=C/c1nn(C(=O)OC(C)(C)C)c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Agent: C[Si](C)(C)I
Agent: N
Solvent: ClC(Cl)Cl
Product: COC(=O)/C=C/c1n[nH]c2ccc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)cc12
Temperature: 20 °C
Reaction time: 16 h
Yield: 15.6 %

Procedure:
Methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]acrylate can be obtained in the following way: 40 μl of iodotrimethylsilane are added dropwise to a solution, maintained under an atmosphere of argon, of 150 mg of methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1-tert-butoxycarbonylindazol-3-yl]acrylate in 10 ml of chloroform, and the mixture is stirred at a temperature in the region of 20° C. for 16 hours. 5 ml of an aqueous solution containing 5% of aqueous ammonia are then added and the medium is extracted with dichloromethane. The pooled organic extracts are washed with distilled water, dried over magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The white foam thus isolated is recrystallized from 8 ml of acetonitrile. 19 mg of methyl (E)-3-[5(2-methylsulfonylbenzenesulfonylamino)-1H-indazol-3-yl]-acrylate are thus obtained in the form of a white solid melting at 253° C. (analysis C18H17N3O6S2 % calculated C, 49.65; H, 3.93; N, 9.65; O, 22.04; S, 14.73. % found C, 49.14; H, 3.92; N, 9.47; S, 14.23).
Reaction SMILES: COC1C=C2C(CCC(NC)C2)=CC=1.BrCCCC[N:20]1[C:24](=[O:25])[C:23]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:22]2[C:21]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[C:24]1(=[O:25])[NH:20][C:21](=[O:30])[C:22]2=[CH:29][CH:28]=[CH:27][CH:26]=[C:23]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Agent: CNC1CCc2ccc(OC)cc2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccccc21
Temperature: 60 °C
Reaction time: 18 h
Yield: 151 %

Procedure:
A mixture of 7-methoxy-2-(R,S)-methylamino-1,2,3,4-tetrahydronaphthalene (3.02 g, 15.9 mmol), N-(4-bromobutyl)phthalimide (4.82 g, 17.1 mmol), anhydrous potassium carbonate (4.80 g, 34.7 mmol) and dry dimethylformamide (75 ml) was heated at 60° C. for 2 h, then left at room temperature for 18 h. Excess solvent was evaporated in vacuo, and the residue was partitioned between water (200 ml) and dichloromethane (3×100 ml). The organic phase was dried (Na2SO4) then evaporated in vacuo to give an oil. Chromatography on silica with 0-5% methanol-dichloromethane elution gave the intermediate phthalimide (3.8 g) as an oil which solidified. The latter was dissolved in ethanol (20 ml) and treated with hydrazine hydrate (2 ml; excess). Stirring at room temperature was carried out for 18 h, followed by reflux for 1 h. The mixture was cooled to 0° C., then filtered. The filtrate was evaporated in vacuo and the residue dissolved in dichloromethane (50 ml). Anhydrous sodium sulfate was added, and the mixture was filtered through kieselguhr. The filtrate was evaporated in vacuo to give the title compound (1.90 g, 46%).
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:21]=[CH:20][C:9]([O:10][C:11]3[N:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13]([OH:15])=O)=[CH:8][CH:7]=2)=[N:4][N:3]=[N:2]1.S(=O)(=O)(O)O>>[NH:4]1[C:5]([C:6]2[CH:7]=[CH:8][C:9]3[O:10][C:11]4=[N:19][CH:18]=[CH:17][CH:16]=[C:12]4[C:13](=[O:15])[C:20]=3[CH:21]=2)=[N:1][N:2]=[N:3]1
Reactant: O=C(O)c1cccnc1Oc1ccc(-c2nnn[nH]2)cc1
Agent: O=S(=O)(O)O
Product: O=c1c2cc(-c3nnn[nH]3)ccc2oc2ncccc12
Temperature: 180 °C
Yield: 64.1 %

Procedure:
A mixture of 0.5 g of 2-[4-(5-1H-tetrazolyl)phenoxy]nicotinic acid and 5 ml of concentrated sulfuric acid is heated at 180° C for 2.5 hours, and then poured into ice water. The crystalline precipitate is filtered off, washed with water and with methanol and recrystallized from dimethylformamide to give 0.3 g of 7-(5-1H-tetrazolyl)-5-oxo-5H-[1]benzopyrano[2,3-b]pyridine melting at above 300° C.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[CH:4][N:3]=1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>CS(C)=O.C(OCC)(=O)C>[CH3:18][C:17]1[O:16][N:15]=[C:14]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]=1[C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([N:25]3[CH2:30][CH2:29][O:28][CH2:27][CH2:26]3)=[N:3][CH:4]=2)=[N:12][N:11]=1
Reactant: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(Cl)nc2)o1
Reactant: C1COCCN1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1onc(-c2ccccc2)c1-c1nnc(-c2ccc(N3CCOCC3)nc2)o1
Temperature: 160 °C
Yield: 70511.3 %

Procedure:
To a solution of 2-chloro-5-[5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazol-2-yl]-pyridine (200 mg, 0.59 mmol) in DMSO (2 mL) was added morpholine (257 mg, 2.95 mmol) and the reaction mixture was heated for 1 h at 160° C. After cooling to ambient temperature it was diluted with ethyl acetate (20 mL) and washed with aqueous sodium carbonate (saturated) and water. Drying over sodium sulfate and purification by chromatography (SiO2, heptane:ethyl acetate=80:20 to 70:30) afforded the title compound (162 g, 70%) as a white solid. MS: m/e=390.3 [M+H]+.
Reaction SMILES: [Li][C:2](C)(C)C.[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=O)[CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1.O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1.CCCCCC>[I:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[CH2:2])[CH:14]([CH3:16])[CH3:15])=[CH:9][CH:8]=1
Reactant: [Li]C(C)(C)C
Reactant: CC(C)C(=O)c1ccc(I)cc1
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C=C(c1ccc(I)cc1)C(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 7.07 g (20 mmol) of methyltriphenylphosphonium bromide in 50 mL of dry THF at 0° C. were added t-BuLi of (14.7 ml, 1.5 M in hexane) and the solution turned brown. After 1 hour of stirring at 0° C., the crude 1-(4-Iodo-phenyl)-2-methyl-propan-1-one from the last step in 20 mL of THF were added dropwise and the solution was stirred for 14 hours at room temperature. After cooling to ca. 20° C., 52 mL of water were added and the solution was extracted with dichloromethane (3×50 mL). The organic layer was dried over MgSO4 and the solvent was removed to give the crude title compound as white solid. The product was used for the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](=[O:11])[N:8]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:7]([C@@H:18]([NH:20][C:21]1[C:22]3[C:29]([C:30](O)=[O:31])=[CH:28][NH:27][C:23]=3[N:24]=[CH:25][N:26]=1)[CH3:19])=[N:6]2.[CH2:33]([NH2:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC>CN(C=O)C>[CH2:33]([NH:40][C:30]([C:29]1[C:22]2[C:21]([NH:20][C@H:18]([C:7]3[N:8]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)[C:9](=[O:11])[C:10]4=[C:2]([CH3:1])[CH:3]=[CH:4][N:5]4[N:6]=3)[CH3:19])=[N:26][CH:25]=[N:24][C:23]=2[NH:27][CH:28]=1)=[O:31])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)O)c34)n(-c3ccccc3)c(=O)c12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4[nH]cc(C(=O)NCc5ccccc5)c34)n(-c3ccccc3)c(=O)c12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 46.8 %

Procedure:
(S)-4-((1-(5-Methyl-4-oxo-3-phenyl-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl)ethyl)amino)-7H-pyrrolo[2,3-d]pyrimidine-5-carboxylic acid (30 mg, 0.07 mmol), benzylamine (20 mg, 0.19 mmol) and diisopropylethylamine (50 μl, 0.29 mmol) were dissolved in DMF (1.5 ml) and stirred for 30 min. The reaction flask was then sealed and T3P® (50% in DMF, 50 μl) was added dropwise and the reaction mixture was stirred overnight at room temperature. The mixture was poured into ice-water and extracted with ethyl acetate. The resulting organic solution was washed with water and brine, dried over magnesium sulphate, filtered and the solvents were removed under reduced pressure. The product was purified by flash chromatography (0% to 5% DCM/MeOH) to give 17 mg (46% yield) of the title compound as a white solid.