Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH2:18].[CH3:19][C:20]([CH3:25])([CH3:24])[C:21](Cl)=[O:22]>ClCCl>[CH:1]1[C:10]2[C:11]3[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][C:12]=3[N:8]3[C:9]=2[C:4]([CH2:5][CH2:6][CH2:7]3)=[CH:3][C:2]=1[NH:18][C:21](=[O:22])[C:20]([CH3:25])([CH3:24])[CH3:19]
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc2c3c(c1)c1c(n3CCC2)CCCCC1
Yield: 67.8 %

Procedure:
Following the procedure of Example 1, Step 4, 5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-amine (0.12 g, 0.50 mmol), trimethylacetyl chloride (0.065 mL, 0.52 mmol) and poly-(4-vinylpyridine) (700 mg) in dichloromethane (10 mL) provided 0.11 g of N-5,6,9,10,11,12-hexahydro-4H,8H-cyclohepta[4,5]pyrrolo[3,2,1-ij]quinolin-2-yl-2,2-dimethylpropanamide. MS (ESI) m/z 325; HPLC purity major: no impurities detected at 210-370 nm window; 99.5% at 246 nm (max. abs), RT=10.7 (Xterra RP18, 3.5 u, 150×4.6 mm column, 1.2 mL/min, 85/15-5/95 (Ammon. Form. Buff. pH=3.5/ACN and MeOH) for 10 min, hold 4 min); HRMS: calcd for C21H28N2O+H+, 325.22744; found (ESI, [M+H]+), 325.2271.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][O:12]1)[N:6]=[CH:5]2.C(N(CC)CC)C.[CH2:24]([OH:28])[CH2:25][C:26]#[CH:27]>CCOC(C)=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[O:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH:11]1[N:7]1[C:8]2[C:4](=[CH:3][C:2]([C:27]#[C:26][CH2:25][CH2:24][OH:28])=[CH:10][CH:9]=2)[CH:5]=[N:6]1
Reactant: Brc1ccc2c(cnn2C2CCCCO2)c1
Reactant: C#CCCO
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: OCCC#Cc1ccc2c(cnn2C2CCCCO2)c1
Temperature: 80 °C
Reaction time: 16 h
Yield: 48.8 %

Procedure:
To a mixture of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (17.0 g, 60.7 mmol; Intermediate 1), Pd(PPh3)2Cl2 (5.80 g, 6.07 mmol), CuI (1.20 g, 6.07 mmol), and triethylamine (170 mL) was added but-3-yn-1-ol (6.80 g, 97.2 mmol) under N2 atmosphere. The resulting mixture was stirred at 80° C. for 16 hours under N2 atmosphere. Upon completion, the reaction mixture was diluted with EtOAc and washed with water (3×50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (30˜50% EtOAc in petroleum ether) affording the title compound (8.0 g). 1H NMR (400 MHz, DMSO-d6): δ 8.09 (s, 1H), 7.83 (s, 1H), 7.70 (d, 1H), 7.40 (d, 1H), 5.84 (dd, 1H), 4.90 (br, 1H), 3.91-3.87 (m, 1H), 3.77-3.70 (m, 1H), 3.60 (t, 2H), 2.56 (t, 2H), 2.48-2.33 (m, 1H), 2.04-1.94 (m, 2H), 1.76-1.69 (m, 1H), 1.60-1.55 (m, 2H); LCMS: 271 (M+H)+.
Reaction SMILES: [NH2:1][C:2]([NH:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]C)=O)=[S:3].O.[NH2:13][NH2:14]>CO>[NH:13]([C:8](=[O:10])[CH2:7][CH2:6][CH2:5][NH:4][C:2]([NH2:1])=[S:3])[NH2:14]
Reactant: NN
Reactant: COC(=O)CCCNC(N)=S
Solvent: O
Solvent: CO
Product: NNC(=O)CCCNC(N)=S
Temperature: 25 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
Methyl 4-[(aminocarbothioyl)amino]butanoate (176.24 mg; 1.00 mmol; 1.00 eq.) (prepared from methyl 3-aminobutanoate, hydrochloride salt (Fluka), following procedure D) is dissolved in MeOH (10.00 ml). Hydrazine hydrate (2.97 ml; 48.89 mmol; 48.89 eq.) is added. The reaction mixture is stirred 5 hours under reflux and overnight at RT. Solvents are evaporated. The resulting oil is dissolved in MeOH and EtOH is added. A white product precipitates. It is filtrated and washed with EtOH, affording N-(4-hydrazino-4-oxobutyl)thiourea (128.5 mg; 72.91%). HPLC, Rt: 6.50 min (purity: 86.9%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].[CH3:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][C:22]=1[CH3:23])[NH2:19].CN(C1C=CC=CN=1)C>N1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:19][C:18]2[CH:20]=[CH:21][C:22]([CH3:23])=[C:16]([CH3:15])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1ccc(N)cc1C
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Product: Cc1ccc(NS(=O)(=O)c2ccc(Cl)c([N+](=O)[O-])c2)cc1C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-3-nitro-benzenesulfonyl chloride (0.51 g) in pyridine (2 mL) were added 3,4-dimethylaniline and dimethylaminopyridine (0.024 g). The reaction mixture was stirred overnight, concentrated under reduced pressure, and diluted with CH2Cl2. The mixture was washed with water, dried over Na2SO4, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 1:3 EtOAc/Hexane) to give 4-chloro-N-(3,4-dimethyl-phenyl)-3-nitro-benzenesulfonamide.
Reaction SMILES: [CH3:1][C:2]1[CH:15]=[CH:14][N:5]2[C:6](=[O:13])[C:7]([C:10]([OH:12])=O)=[CH:8][N:9]=[C:4]2[CH:3]=1.C(N(CC)CC)C.ClC(OC)=O.[CH:28]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29]1>C(Cl)(Cl)Cl>[CH:28]1([NH:33][C:10]([C:7]2[C:6](=[O:13])[N:5]3[CH:14]=[CH:15][C:2]([CH3:1])=[CH:3][C:4]3=[N:9][CH:8]=2)=[O:12])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: Cc1ccn2c(=O)c(C(=O)O)cnc2c1
Reactant: NC1CCCC1
Agent: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: Cc1ccn2c(=O)c(C(=O)NC3CCCC3)cnc2c1
Reaction time: 0.08 h
Yield: 55.3 %

Procedure:
A mixture containing 1.22 g (0.006 mol) of 8-methyl-4-oxo-4H-pyrido[1,2-a]pyrimidine-3-carboxylic acid and 0.84 ml (0.006 mol) of triethylamine in 40 ml of chloroform is cooled below -10° C. by ice-salt. A solution of 0.46 ml (0.006 mol) of methyl chloroformate in 3 ml of chloroform is dropped to the above mixture at -15° C. during 10 minutes. After stirring for 5 minutes, 0.56 g (0.0066 mol) of cyclopentylamine dissolved in 6 ml of chloroform is dropped to the above solution. The reaction mixture is stirred at -10° C. for 1 hour, then allowed to stand overnight under cooling by ice. For working up, the reaction mixture is washed 3 times with 15 ml of 5% sodium hydrogen carbonate solution each, then 3 times with 15 ml of water each. The organic phase is dried over anhydrous sodium sulfate, filtered and evaporated to yield 0.9 g (55%) of the named compound as a crystalline substance after recrystallization from ethanol, m.p.: 220°-222° C.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:16])[CH2:5][CH:6]([NH2:15])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(N1[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]2[C:29]1=[O:38])(OCC)=O>O.C(#N)C>[C:29]1(=[O:38])[N:15]([CH:6]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=2)[CH2:5][C:4]([O:3][CH3:2])=[O:16])[C:32](=[O:33])[C:31]2=[CH:34][CH:35]=[CH:36][CH:37]=[C:30]12
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Reactant: COC(=O)CC(N)c1ccc(OC)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CC(c1ccc(OC)cc1)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.1 %

Procedure:
To a stirred solution of 3-amino-3-(4-methoxyphenyl)propionic acid methyl ester hydrochloride (1.50 g, 6.1 mmol) and sodium carbonate (90.65 g, 6.1 mmol) in 40 mL of water was added N-carboethoxyphthalimide (1.34 g, 6.1 mmol) in 12 mL of acetonitrile. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was partially concentrated and this mixture was stirred for 72 hours. The resulting slurry was filtered and the solid was washed with copious amount of water. The solid was dried in vactio (30° C., <1 mm) to afford 1.70 g (50%) of methyl 3-phthalimido-3-(4-methoxyphenyl)propionate as a white powder. mp 65-66° C.; 1H NMR (DMSO-d6, 250 MHz) δ7.83-7.91 (m, 4H), 6.88-7.3 (m, 4H), 5-80 (dd, 1H, J=7.5, 2.5), 3.72 (S, 3H), 3.54 (3, 3H), 3.2-3.6 (m, 2H); 13C NMR (DMSO-d6) δ170.7, 167.5, 158.7, 134.6, 131.0, 130.5, 128.3, 123.2, 113.9, 55.0, 51.5, 49.4, 35.4. Anal. Calcd for C19H17NO5: C, 67.25; H, 5.05; N, 4.13; Found: C, 66.96; H, 5.00; N, 4.11.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH3:15])#[N:2].Br[CH2:17]CC>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([S:9]([Cl:12])(=[O:11])=[O:10])=[CH:5][C:4]=1[O:13][CH2:14][CH2:15][CH3:17])#[N:2]
Reactant: CCOc1cc(S(=O)(=O)Cl)ccc1C#N
Reactant: CCCBr
Product: CCCOc1cc(S(=O)(=O)Cl)ccc1C#N

Procedure:
The titled compound was prepared analogously to 4-cyano-3-ethoxy-benzenesulfonyl chloride (Intermediate 127c) by replacing bromoethane with 1-bromopropane.
Reaction SMILES: C([O:3][C:4](=O)[CH:5]=[C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)[CH3:7])C.[H-].C([Al+]CC(C)C)C(C)C.Cl>ClCCl.CCCCCC>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]([CH3:7])=[CH:5][CH2:4][OH:3])=[CH:13][CH:12]=1
Reactant: CCOC(=O)C=C(C)c1ccc(Cl)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [H-]
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(=CCO)c1ccc(Cl)cc1
Yield: 37.6 %

Procedure:
The above ester (1.44 g) was dissolved in dichloromethane (13 ml) and cooled to -20°. Diisobutylaluminium hydride (12.8 ml of a 1M solution in hexane) was added dropwise. After 18 hours at 25° dilute hydrochloric acid was added carefully and the mixture worked up in the usual manner to give 3-(4-chlorophenyl)but-2-en-1-ol (0.44 g). NMR 1H: 7.18(4H,s), 5.85(1H,t), 4.25(2H,d), 3.05(1H,s), 2.05(3H,s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:23][CH3:24])[CH:6]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:10]([CH3:22])[CH:9]=1)O)[CH3:2].S(Cl)(C)(=O)=O>CN(C1C=CN=CC=1)C.ClCCl.CCOCC>[CH2:1]([O:3][C:4](=[O:25])[C:5]([O:23][CH3:24])=[CH:6][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[C:10]([CH3:22])[CH:9]=1)[CH3:2]
Reactant: CCOC(=O)C(OC)C(O)c1ccc(OCc2ccccc2)c(C)c1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)c(C)c1)OC

Procedure:
A mixture of 3-(4-Benzyloxy-3-methyl-phenyl)-3-hydroxy-2-methoxy-propionic acid ethyl ester (1 eq), Mesylchloride (1 eq) triethylamine (4 eq) and a catalytic amount of DMAP (0.1 eq) in dichloromethane was stirred at room temperature over night. The reaction mixture was diluted with ether and washed with HCl 1N. Dried and concentrated in vacuo to give a residue which was chromatographed in silica gel to yield the title compound.
Reaction SMILES: Cl.Cl.[F:3][C:4]([F:24])([F:23])[C:5]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)=[CH:13][CH:12]=1)([OH:10])[C:6]([F:9])([F:8])[F:7].[Cl:25][C:26]1[N:31]=[N:30][C:29]([S:32](Cl)(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(N(CC)CC)C>C(=O)(O)[O-].[Na+].C(Cl)Cl>[Cl:25][C:26]1[N:31]=[N:30][C:29]([S:32]([N:20]2[CH2:21][CH2:22][N:17]([C:14]3[CH:13]=[CH:12][C:11]([C:5]([OH:10])([C:6]([F:9])([F:8])[F:7])[C:4]([F:3])([F:23])[F:24])=[CH:16][CH:15]=3)[CH2:18][CH2:19]2)(=[O:34])=[O:33])=[CH:28][CH:27]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)nn1
Reactant: OC(c1ccc(N2CCNCC2)cc1)(C(F)(F)F)C(F)(F)F
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=S(=O)(c1ccc(Cl)nn1)N1CCN(c2ccc(C(O)(C(F)(F)F)C(F)(F)F)cc2)CC1
Reaction time: 24 h
Yield: 34.2 %

Procedure:
To a 20 mL vial was added 1,1,1,3,3,3-hexafluoro-2-(4-(1-piperazinyl)phenyl)-2-propanol dihydrochloride (0.35 g, 0.87 mmol, Example 91), 6-chloropyridazine-3-sulfonyl chloride (0.20 g, 0.96 mmol, Archiv der Pharmazie and Berichte der Deutschen Pharmazeutischen Gesellschaft 1966, 229, 646), CH2Cl2 (10 mL) and triethylamine (0.61 mL, 4.4 mmol). After 24 h at room temperature, an additional 100 mg of 6-chloropyridazine-3-sulfonyl chloride was added and the solution was stirred for an additional hour. The reaction was diluted with saturated aqueous sodium bicarbonate and CH2Cl2. This was stirred for 5 min and then the solution was transferred onto a phase separation cartridge (Radleys Discovery Technologies, Essex, UK) with the organic phase being collected and passed through a plug of Na2SO4. The collected solution was purified by silica gel chromatography (0 to 70% EtOAc in hexanes). The resulting oil was dissolved in EtOAc/heptanes, concentrated and dried under reduced pressure to afford 2-(4-(4-((6-chloropyridazin-3-yl)sulfonyl)piperazin-1-yl)phenyl)-1,1,1,3,3,3-hexafluoro-2-propanol (0.15 g) as a yellow solid.
Reaction SMILES: C([O:5][C:6]([CH:8]1[NH:12][CH:11]([CH2:13][C:14]([CH3:17])([CH3:16])[CH3:15])[C:10]2([C:25]3[C:20](=[CH:21][C:22]([Cl:27])=[CH:23][C:24]=3[F:26])[NH:19][C:18]2=[O:28])[CH:9]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=1[F:36])=[O:7])(C)(C)C.[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40]>ClCCl>[F:37][C:38]([F:43])([F:42])[C:39]([OH:41])=[O:40].[Cl:27][C:22]1[CH:21]=[C:20]2[NH:19][C:18](=[O:28])[C:10]3([CH:9]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[C:30]=4[F:36])[CH:8]([C:6]([OH:7])=[O:5])[NH:12][CH:11]3[CH2:13][C:14]([CH3:15])([CH3:16])[CH3:17])[C:25]2=[C:24]([F:26])[CH:23]=1
Reactant: CC(C)(C)CC1NC(C(=O)OC(C)(C)C)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)cc(F)c12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid tert-butyl ester (1.8 g, 3.4 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL). The reaction mixture was stirred at room temperature for 20 h, then concentrated. The residue was then triturated with ethyl ether hexanes, concentrated, dried in vacuo to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-4-fluoro-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid as a off white solid (1.9 g, 95%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14](O)=[O:15])=[CH:5][CH:4]=1.Cl.[NH2:22][C@H:23]([C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1)[CH3:24].CCN=C=NCCCN(C)C.Cl>>[F:19][C:2]([F:1])([F:20])[C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[CH2:13][CH:12]3[CH:10]([CH2:11]3)[CH:9]2[C:14]([NH:22][C@H:23]([C:25]2[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=2)[CH3:24])=[O:15])=[CH:5][CH:4]=1
Reactant: O=C(O)C1C2CC2CN1Cc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1ccc([C@H](C)N)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: COC(=O)c1ccc([C@H](C)NC(=O)C2C3CC3CN2Cc2ccc(C(F)(F)F)cc2)cc1
Yield: 98.7 %

Procedure:
The title compound (D153) (85 mg) was prepared according to the general procedure for amides preparation (Method A) starting from 3-(4-(trifluoromethyl)benzyl)-3-azabicyclo[3.1.0]hexane-2-carboxylic acid (D110) (55 mg) and (S)-methyl 4-(1-aminoethyl)benzoate hydrochloride (43.3 mg). (EDC.HCl: 1.05 eq; reaction time: 18 hrs; RT)
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][NH:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]>CN(C)C=O.O>[CH2:3]([O:10][N:11]([CH2:26][CH2:27][CH2:28][CH2:29][CH3:30])[C:12]([NH:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][CH2:23][CH3:24])=[CH:19][CH:20]=1)=[O:13])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCCCc1ccc(NC(=O)NOCc2ccccc2)cc1
Reactant: CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCN(OCc1ccccc1)C(=O)Nc1ccc(CCCC)cc1
Temperature: 25 °C
Yield: 62 %

Procedure:
Sodium hydride (0.14 g of 80% in mineral oil, 4.7 mmol) was added to a solution of 1-benzyloxy-3-(4-butylphenyl)urea (1.25 g, 4.2 mmol) in N,N-dimethylformamide (5 mL). The reaction mixture was heated briefly on a steam bath under a nitrogen atmosphere. The reaction mixture was allowed to cool to ambient temperature then 1-bromopentane (0.63 g, 4.2 mmol) was added. The reaction mixture was heated at 90° C. overnight. The reaction mixture was cooled to ambient temperature, diluted with water and then extracted with diethyl ether. The organic layer was washed with water, dried with magnesium sulfate and then concentrated to provide 1.47 g of crude product as a brown oil. This material was purified by flash chromatography (silica gel; 1:19 ethyl acetate:hexanes) to provide 0.96 g of 1-benzyloxy-3-(4-butylphenyl)-1-pentylurea as an oil.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl[C:14]1[S:18][C:17]([C:19](=[O:21])[CH3:20])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]>O>[N+:22]([C:15]1[CH:16]=[C:17]([C:19](=[O:21])[CH3:20])[S:18][C:14]=1[S:12][C:9]1[CH:10]=[CH:11][C:6]([N+:3]([O-:5])=[O:4])=[CH:7][CH:8]=1)([O-:24])=[O:23]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: O=[N+]([O-])c1ccc(S)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc([N+](=O)[O-])cc2)s1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 38.3 %

Procedure:
Anhydrous N,N-dimethylformide (5 mL) was degassed with nitrogen for 30 minutes then sodium hydride (60% dispersion in mineral oil, 0.11 g, 2.75 mmol) was added. 4-Nitrobenzenethiol (0.38 g, 2.43 mmol) was added in portions at ambient temperature and the resulting mixture was stirred at ambient temperature under nitrogen for 20 minutes. Then 1-(5-chloro-4-nitro-2-thienyl)ethanone (0.5 g, 2.43 mmol) was added and the reaction mixture was stirred at ambient temperature overnight under nitrogen. The reaction mixture was diluted with water (40 mL) and stirred for 30 minutes. The precipitated solid was collected by filtration and washed with water (2×4 mL). The crude solid was recrystallised from acetonitrile (12 mL) to afford the title compound as a brown solid (0.302 g, 38% yield). 1H NMR (300 MHz, CDCl3) δ: 8.38 (2H, d, J=8.85 Hz), 8.09 (1H, s), 7.89 (2H, d, J=8.85 Hz), 2.50 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:6][C:5]=1Br.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3]([C:4]1[C:5]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([OH:16])[CH2:12][CH2:11]2)=[CH:8][CH:9]=1)=[O:18]
Reactant: COC(=O)c1ccc(N2CCC(O)CC2)cc1Br
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)c1ccc(N2CCC(O)CC2)cc1-c1ccccc1
Temperature: 90 °C
Yield: 91.6 %

Procedure:
A mixture of 2-bromo-4-(4-hydroxy-piperidin-1-yl)-benzoic acid methyl ester (1.2 g, 3.82 mmol), phenylboronic acid (800 mg; 6.56 mmol), potassium phosphate, tribasic, mono-hydrate (1.3 g, 10.7 mmol), and tetrakis(triphenylphosphine)palladium (500 mg, 0.433 mmol) in 1,2-dimethoxyethane (25 mL) and water (1 mL) is heated to 90° C. under a nitrogen atmosphere for 24 h. The mixture is concentrated and partitioned between ethyl acetate and water. The solvent layers are separated and the aqueous layer is extracted with ethyl acetate (3×). The combined ethyl acetate layers are dried (MgSO4), filtered, and concentrated under reduced pressure. The residue is purified on silica (120 g) eluting with a gradient of 0% to 100% ethyl acetate in heptane to provide the desired product (1.09 g, 92%) as a gummy residue. LC-ES/MS m/z 312.0 (M+1)
Reaction SMILES: [Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([O:9]CC)=O)[N:6]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[Cl:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:9])[N:6]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)c1coc(Cl)n1
Product: O=C(Nc1ccccc1)c1coc(Cl)n1

Procedure:
Prepared from ethyl 2-chlorooxazole-4-carboxylate (45.4 mg, 0.258 mmol) and aniline (24 mg, 0.258 mmol) as described in Example 154A: 1H NMR (500 MHz, methanol-D4) δ ppm 7.13-7.18 (m, 1H), 7.32-7.38 (m, 2H), 7.65-7.71 (m, 2H), 8.53 (s, 1H). MS (APCI) m/z=223 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[C:9](/[CH:11]=[CH:12]/[C:13]3[N:18]=[C:17]([NH2:19])[CH:16]=[C:15]([CH3:20])[CH:14]=3)[NH:8][C:5]2=[N:6][CH:7]=1.C(O)(=O)C>CO.O=[Pt]=O>[NH2:19][C:17]1[CH:16]=[C:15]([CH3:20])[CH:14]=[C:13]([CH2:12][CH2:11][C:9]2[NH:8][C:5]3=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=[C:4]3[N:10]=2)[N:18]=1
Reactant: Cc1cc(N)nc(/C=C/c2nc3cc(Br)cnc3[nH]2)c1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Solvent: CO
Product: Cc1cc(N)nc(CCc2nc3cc(Br)cnc3[nH]2)c1
Reaction time: 65 h
Yield: 73.7 %

Procedure:
930 mg of 6-[(E)-2-(6-bromo-3H-imidazo[4,5-b]pyridin-2-yl)-vinyl]-4-methyl-pyridin-2-ylamine (compound A11) are suspended in 300 ml of methanol. Subsequently, 805 μl acetic acid and 96 mg of Adam's catalyst [platin(IV) oxide] are added. The suspension is vigorously stirred for 65 h. Thereafter, the solution is passed through kieselguhr, which is rinsed with methanol. The filtrate is evaporated to dryness and the remaining residue (1.20 g) purified by chromatography on silica gel (eluent: dichloromethane/methanol=20:1) to afford 690 mg of the title compound as colorless powder after lyophilization from 15.0 ml dioxane and 3.0 ml water. M.p. 216° C. ESI-MS: 332.1/334.2 (MH+, 97%/100%). TLC: Rf=0.35 (dichloromethane/methanol 10:1).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](I)[C:5]([OH:9])=[CH:4][CH:3]=1.[CH3:10][Si:11]([CH3:29])([CH3:28])[CH2:12][CH2:13][O:14][CH2:15][N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH:18]=[C:17]1B(O)O>O1CCOCC1.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]>[Cl:1][C:2]1[N:7]=[C:6]([C:17]2[N:16]([CH2:15][O:14][CH2:13][CH2:12][Si:11]([CH3:29])([CH3:28])[CH3:10])[C:20]3=[N:21][CH:22]=[CH:23][CH:24]=[C:19]3[CH:18]=2)[C:5]([OH:9])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Cl)nc1I
Reactant: C[Si](C)(C)CCOCn1c(B(O)O)cc2cccnc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: C[Si](C)(C)CCOCn1c(-c2nc(Cl)ccc2O)cc2cccnc21
Temperature: 80 °C
Reaction time: 8 h
Yield: 29.2 %

Procedure:
To a mixture of 6-chloro-2-iodopyridin-3-ol (8.39 g, 32.85 mmol), (1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)boronic acid (8.00 g, 27.38 mmol) and K3PO4.3H2O (22 mg, 82.13 mmol) in 1,4-dioxane (120 mL), Pd(dppf)Cl2 (50 mg) was added under N2 protection. After stirred overnight at 80° C., the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated in vacuo. The resulting residue was purified using column chromatography (petroleum ether:EtOAc=5:1) to provide the product of 6-chloro-2-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrrolo[2,3-b]pyridin-2-yl)pyridin-3-ol (3.01 g, yield: 29%). 1H-NMR (CDCl3, 400 MHz) δ 8.40 (dd, J=4.8 Hz, 1.6 Hz, 1H), 7.96 (dd, J=8.0 Hz, 1.6 Hz, 1H), 7.39 (d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 1H), 7.17 (dd, J=8.0 Hz, 4.8 Hz, 1H), 6.82 (s, 1H), 5.85 (s, 2H), 3.65 (t, J=8.4 Hz, 2H), 0.89 (t, J=8.4 Hz, 2H), −0.08 (s, 9H). MS (M+H)+: 376/378.
Reaction SMILES: Cl.[NH2:2][OH:3].[C:4]1([CH2:10][C:11]([CH2:13][N:14]2[C:18](=[O:19])[C:17]3=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]3[C:15]2=[O:24])=O)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>N1C=CC=CC=1.C(O)C>[N:2](=[C:11]([CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])[CH2:10][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3]
Reactant: NO
Reactant: O=C(Cc1ccccc1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: O=C1c2ccccc2C(=O)N1CC(Cc1ccccc1)=NO
Yield: 29.8 %

Procedure:
A mixture of hydroxylamine hydrochloride (9 g.) and a solution of 1-phenyl-3-phthalimidoacetone (23.4 g.) in pyridine/ethanol (80 ml.-80 ml.) was stirred at ambient temperature for 3 days. The resulting solution was concentrated, the residue washed twice with a mixture of toluene and methylene chloride and dried. The residue was purified by column chromatography on activated silica gel using cyclohexane/EtOAc 7:3 v/v as eluant to give 2-oximino-1-phenyl-3-phthalimidopropane (7.35 g.) as a mixture of syn and anti isomers.