Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:17][O:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][NH2:25])=[O:23].Cl.C(N=C=NCCCN(C)C)C>N1C=CC=CC=1>[CH3:17][O:18][CH2:19][CH2:20][CH2:21][C:22]([NH:24][NH:25][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:8][CH:9]=1)=[O:23]
Reactant: O=C(O)c1ccc(-c2ccccc2)nc1
Reactant: COCCCC(=O)NN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: COCCCC(=O)NNC(=O)c1ccc(-c2ccccc2)nc1
Temperature: 60 °C
Reaction time: 10 h
Yield: 65.3 %

Procedure:
6-Phenylnicotinic acid (5.90 g) was dissolved in pyridine (150 ml), followed by addition of 4-methoxybutyric acid hydrazide hydrochloride salt (5.99 g) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride salt (8.51 g), and stirred at 60° C. for 10 hours. After the reaction solution was cooled to ambient temperature, the solvent was evaporated under reduced pressure. The resulting residue was washed with water, to afford 6-phenylnicotinic acid N′-(4-methoxybutyryl)hydrazide as pale yellow solid (6.06 g, 65%). The physico-chemical values are as follows.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=1)[NH:7][N:6]=[C:5]2[CH:14]1[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)(=[O:22])=[O:21])[CH2:16][CH2:15]1.[CH3:31][S:32]([NH:35][C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1)(=[O:34])=[O:33].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[CH3:31][S:32]([NH:35][C:36]1[CH:37]=[CH:38][C:39]([C:2]2[CH:3]=[C:4]3[C:8](=[C:9]([C:11]([NH2:13])=[O:12])[CH:10]=2)[NH:7][N:6]=[C:5]3[CH:14]2[CH2:19][CH2:18][N:17]([S:20]([CH2:23][CH2:24][CH2:25][N:26]3[CH2:27][CH2:28][CH2:29][CH2:30]3)(=[O:22])=[O:21])[CH2:16][CH2:15]2)=[CH:40][CH:41]=1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Nc1ccc(B(O)O)cc1
Reactant: NC(=O)c1cc(Br)cc2c(C3CCN(S(=O)(=O)CCCN4CCCC4)CC3)n[nH]c12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CS(=O)(=O)Nc1ccc(-c2cc(C(N)=O)c3[nH]nc(C4CCN(S(=O)(=O)CCCN5CCCC5)CC4)c3c2)cc1
Yield: 53.1 %

Procedure:
Following the general procedure of Example 66, a mixture of 5-bromo-3-(1-{[3-(1-pyrrolidinyl)propyl]sulfonyl}-4-piperidinyl)-1H-indazole-7-carboxamide (Intermediate 27) (24 mg, 0.048 mmols), {4-[(methylsulfonyl)amino]phenyl}boronic acid (31 mg, 0.144 mmols), potassium carbonate (40 mg), and Pd(PPh3)4 (3 mg) in dioxane/water (3/1, 4 mL) was reacted. The reaction mixture was concentrated, redissolved in methylene chloride and filtered. The filtrate was concentrated and the residue was purified by using a Gilson semi-preparative HPLC system, eluting with 10% B to 80% B, where A=H2O (0.1% trifluoroacetic acid) and B=CH3CN (0.1% trifluoroacetic acid) pumped at 25 mL/min to give the title compound (15 mg, 53%)
Reaction SMILES: [CH3:1][C:2]1[C:10]2[S:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[CH:14]([F:16])[F:15])=[N:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl.[S:20]([C:24]1[CH:29]=[CH:28][C:27]([NH:30][NH2:31])=[CH:26][CH:25]=1)(=[O:23])(=[O:22])[NH2:21]>>[F:15][CH:14]([F:16])[C:13]1[CH:12]=[C:11]([C:8]2[S:9][C:10]3[C:2]([CH3:1])=[CH:3][CH:4]=[CH:5][C:6]=3[N:7]=2)[N:30]([C:27]2[CH:26]=[CH:25][C:24]([S:20]([NH2:21])(=[O:23])=[O:22])=[CH:29][CH:28]=2)[N:31]=1
Reactant: Cc1cccc2nc(C(=O)CC(=O)C(F)F)sc12
Reactant: NNc1ccc(S(N)(=O)=O)cc1
Agent: Cl
Product: Cc1cccc2nc(-c3cc(C(F)F)nn3-c3ccc(S(N)(=O)=O)cc3)sc12

Procedure:
The procedure of Example 9 was repeated using 1-(7-methylbenzothiazol-2-yl)-4,4-difluorobutane-1,3-dione and 4-sulfamoylphenylhydrazine hydrochloride as the starting materials to obtain 4-[3-difluoromethyl-5-(7-methylbenzothiazol-2-yl)-1H-pyrazol-1-yl]benzenesulfonamide. NMR(DMSO-d6) δ: 2.54 (3H, s), 7.23 (1H, t, J=54.1 Hz), 7.34-7.57 (5H, m), 7.75-7.78 (3H, m), 7.94 (2H, d, J=8.6 Hz); mp 264-265° C. (ethyl acetate-ethanol)
Reaction SMILES: [CH3:1][N:2]([CH:4]([CH:7]1[CH2:16][CH2:15][C:10]2([O:14][CH2:13][CH2:12][O:11]2)[CH2:9][CH2:8]1)[C:5]#N)[CH3:3].C1COCC1.[C:22]1([CH2:28]C[Mg]Cl)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[Cl-].[NH4+]>O>[O:14]1[C:10]2([CH2:15][CH2:16][CH:7]([CH:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:8][CH2:9]2)[O:11][CH2:12][CH2:13]1
Reactant: Cl[Mg]CCc1ccccc1
Reactant: CN(C)C(C#N)C1CCC2(CC1)OCCO2
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: CN(C)C(CCc1ccccc1)C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A solution of the aminonitrile 4 (21.93 g, 97 mmol) in absol. THF (180 ml) was added dropwise to a 1 M solution of phenylethylmagnesium chloride in THF (242 ml, 242 mmol) under argon and while cooling with ice, and the mixture was stirred at RT for 20 hours. The reaction mixture was worked up by adding saturated ammonium chloride solution (100 ml) and water (100 ml) while cooling with ice, and extracting the mixture with diethyl ether (3×100 ml). The organic phase was washed with water and saturated sodium chloride solution, dried and concentrated.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].S(Cl)(Cl)=O.C(=O)(O)[O-].[Na+].[CH3:19][C:20](O)([CH3:22])[CH3:21]>>[C:20]([O:8][C:7](=[O:9])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1])([CH3:22])([CH3:21])[CH3:19]
Reactant: CC(C)(C)O
Reactant: NCCCCCC(=O)O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)CCCCCN
Temperature: 25 °C
Reaction time: 1 h
Yield: 53 %

Procedure:
In a 10 L reaction flask equipped with N2 inlet, 0.383 Kg of 6-aminocaproic acid (2.92 mol) was slowly added to 3.14 Kg of stirring thionyl chloride (26.28 mol). The maximum temperature during the addition is kept at about 30° C. Upon complete addition, the reaction was allowed to stir at 20-30° C. for 1 h, then concentrated via rotary evaporation (max 40° C. bath). Excess thionyl chloride was chased-off by the addition of toluene (0.843 Kg) and the solution was re-concentrated via rotary evaporation (max 40° C. bath). To the resulting tan solid a suspension of 0.537 Kg of sodium bicarbonate (6.42 mol) was added in 2.97 Kg of t-BuOH (40.3 mol) and reaction allowed to stir at 20-30° C. for 2 h. The excess t-BuOH was removed in vacuo (max 40° C. bath) and residue diluted with 5.17 Kg of ethyl acetate and washed with four portions of 1M NaOH (0.307 Kg in 7.68 Kg water), three portions of H2O (1.92 Kg), one portion of sat. aq. NaCl (0.767 Kg in 1.92 Kg water), dried with anhydrous Na2SO4 (0.383 Kg), filtered via Buchner funnel, rinced with ethyl acetate (1.72 Kg), and concentrated in vacuo (max 50° C. bath). The tan liquid residue was distilled (bp 97-98° C./2 mmHg) to afford 0.290 Kg of t-butyl-6-aminocaproate (53% yld) as a clear colourless to light yellow oil.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:30][CH2:29][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:27][CH2:26]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1)(C(C)(C)C)(C)C.Cl.[CH3:35][OH:36]>>[CH:35]([O:8][CH2:9][CH2:10][C@@H:11]1[CH2:23][C:22]2[C:21]3[C:20]([O:24][CH:25]4[CH2:26][CH2:27][CH:28]([N:31]([CH3:33])[CH3:32])[CH2:29][CH2:30]4)=[N:19][CH:18]=[N:17][C:16]=3[S:15][C:14]=2[CH2:13][CH2:12]1)=[O:36]
Reactant: CO
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCO[Si](C)(C)C(C)(C)C)CC4)CC1
Agent: Cl
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)C[C@@H](CCOC=O)CC4)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
To a solution of 4-[[(12S)-12-[2-[(tert-butyldimethylsilyl)oxy]ethyl]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy]-N,N-dimethylcyclohexan-1-amine (110 mg, 0.22 mmol, 1.00 equiv) in methanol (5 mL) was added hydrochloric acid (12 M, 0.5 mL) at 0° C. The resulting solution was stirred for 1 h at room temperature. The solvent was removed in vacuo and the crude product (80 mg) was purified by preparative HPLC under the following conditions (SHIMADZU): Column: SunFire Prep C18, 19*150 mm, 5 μm; mobile phase: water (with 0.1% HCOOH) and CH3CN (6.0% CH3CN up to 53.0% in 16 min); flow rate: 20 mL/min; UV detection at 254/220 nm. The product-containing fractions were collected and partially evaporated under reduced pressure to remove water and CH3CN. The residue was lyophilized overnight to give the 2-[(12S)-3-[[4-(dimethylamino)cyclohexyl]oxy]-8-thia-4,6-diazatricyclo[7.4.0.0[2,7]]trideca-1(9),2(7),3,5-tetraen-12-yl]ethan-1-ol formate (46 mg, 55%) as an off-white semi-solid. MS (ES): m/z 376 (M+H)+. 1H NMR (300 MHz, CDCl3): δ 8.49 (d, 2H), 5.22 (s, 1H), 3.82 (t, 2H), 3.16 (m, 2H), 2.88 (s, 2H), 2.66 (s, 6H), 2.48 (t, 3H), 2.19 (s, 2H), 2.05 (d, 2H), 1.70 (m, 7H).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2=[C:6]([CH:37]=1)[N:7]=[C:8]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11]2.[CH2:38]([O:40][C:41]([C:43]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45][CH:44]=1)=[O:42])[CH3:39].C(=O)([O-])[O-].[K+].[K+]>C(#N)C.CCOC(C)=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>[C:32]([O:31][C:30]([NH:29][C:8]1[CH2:9][C:10]([C:12](=[O:28])[N:13]([CH2:17][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[CH2:14][CH2:15][CH3:16])=[CH:11][C:5]2[CH:4]=[CH:3][C:2]([C:46]3[CH:47]=[CH:48][C:43]([C:41]([O:40][CH2:38][CH3:39])=[O:42])=[CH:44][CH:45]=3)=[CH:37][C:6]=2[N:7]=1)=[O:36])([CH3:35])([CH3:33])[CH3:34]
Reactant: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(Br)cc2N=C(NC(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)c1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCN(CCCO[Si](C)(C)C(C)(C)C)C(=O)C1=Cc2ccc(-c3ccc(C(=O)OCC)cc3)cc2N=C(NC(=O)OC(C)(C)C)C1
Temperature: 100 °C

Procedure:
tert-butyl (1E,4E)-8-bromo-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-2-ylcarbamate, 4-(ethoxycarbonyl)phenylboronic acid (1.5 equiv), tetrakis(triphenylphosphine)palladium(0), 2M aqueous potassium carbonate (3 equiv) were combined in 2 mls of acetonitrile in a microwave reaction vial. This mixture was heated in a microwave to 100° C. for 30 minutes. The mixture was then diluted with EtOAc, washed twice with brine, dried over sodium sulfate, and concentrated under reduced pressure. Preparative thin layer chromatography (2×0.5 mm plates, 7% MeOH/DCM) afforded ethyl 4-((1E,4E)-2-(tert-butoxycarbonylamino)-4-((3-(tert-butyldimethylsilyloxy)propyl)(propyl)carbamoyl)-3H-benzo[b]azepin-8-yl)benzoate.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[S:9][C:10]2[CH:16]=[C:15]([CH:17]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)O)[CH:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[C:11]=2[N:12]=1)(C)(C)C.[SiH](CC)(CC)CC>>[F:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:17][C:15]2[CH:14]=[C:13]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([N+:32]([O-:34])=[O:33])[CH:27]=3)[C:11]3[N:12]=[C:8]([NH2:7])[S:9][C:10]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)OC(=O)Nc1nc2c(-c3cccc([N+](=O)[O-])c3)cc(C(O)c3ccc(F)cc3)cc2s1
Agent: CC[SiH](CC)CC
Product: Nc1nc2c(-c3cccc([N+](=O)[O-])c3)cc(Cc3ccc(F)cc3)cc2s1
Temperature: 25 °C
Reaction time: 2.17 h
Yield: 83.9 %

Procedure:
BA-01. A solution of compound (7) (32.5 mg, 0.066 mmol) was treated with Et3SiH (500 uL, 3 mmol, 47 eq.). The mixture was stirred at room temperature for 130 min. until starting material XM-17 was consumed. The volatile material was removed under reduced pressure. The residue was washed with sodium bicarbonate solution, extracted with EtOAc (3×15 mL), dried. Evaporation gave a residue, which was purified chromatography on silica gel using dichloromethane/hexanes (1:1, 2:1, 3:1, 4:1, 20 mL each) followed by dichloromethane as eluent to give 21 mg of product, which contained impurities. The product thus obtained was triturated with hexanes to give 7.6 mg of desired product. BA-01. 1H NMR. LCMS: 99%.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[CH3:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:8][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[CH3:5][C:6]1[O:10][C:9]([CH2:11][N:12]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[N:14]=[C:13]2[NH:21][CH:22]2[CH2:27][CH2:26][N:25]([CH2:2][C:3]#[N:4])[CH2:24][CH2:23]2)=[CH:8][CH:7]=1
Reactant: N#CCCl
Reactant: Cc1ccc(Cn2c(NC3CCNCC3)nc3ccccc32)o1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(NC3CCN(CC#N)CC3)nc3ccccc32)o1
Temperature: 45 °C
Yield: 80.4 %

Procedure:
A mixture of 2 parts of 2-chloroacetonitrile, 8 parts of 1-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-1H-benzimidazol-2-amine, 3.1 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred and heated overnight at 45° C. The reaction mixture was poured into water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized from a mixture of acetonitrile and 2,2'-oxybispropane, yielding 7.3 parts (80.4%) of 4-[[1-[(5-methyl-2-furanyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidineacetonitrile; mp. 177.3° C. (int. 36).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[C:8]([CH3:10])[C:7]([OH:11])=[C:6]([CH3:12])[CH:5]=2)[CH2:3][CH2:2]1.[H-].[Na+].[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([NH:20][CH:21]=[N:22]2)=[C:18](Cl)[N:17]=1>>[Cl:15][C:16]1[N:24]=[C:23]2[C:19]([N:20]=[CH:21][NH:22]2)=[C:18]([O:11][C:7]2[C:6]([CH3:12])=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:8]=2[CH3:10])[N:17]=1
Reactant: Cc1cc(C2CC2)cc(C)c1O
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Product: Cc1cc(C2CC2)cc(C)c1Oc1nc(Cl)nc2[nH]cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a solution of 4-cyclopropyl-2,6-dimethylphenol (263 mg, 1.62 mmol) in 1-methyl-2-pyrridone (3 mL) at 0° C. was added NaH (65 mg, 1.62 mmol). The reaction mixture was stirred at room temperature for 30 min and a solution of 2,6-dichloropurine (102 mg, 0.54 mmol) in 1-methyl-2-pyrridone (2 mL) was added to the mixture. The mixture was heated at 100° C. for 16 h and then cooled to room temperature. The reaction was poured into ice water and extracted with CHCl3 (3×20 mL). The combined organic solution was washed with H2O (20 mL) and brine (20 mL), dried with Na2SO4, and concentrated to dryness. Silica gel chromatography (MeOH:CHCl3=5:95) yielded 114 mg (67%) of 2-chloro-6-(4-cyclopropyl-2,6-dimethylphenoxy)-9H-purine.
Reaction SMILES: [O:1]=[C:2]1[NH:6][CH2:5][CH2:4][N:3]1[CH2:7][C:8]1[N:9](CC2C=CC=CC=2)[CH:10]=[C:11]([O:15]CC2C=CC=CC=2)[C:12](=[O:14])[CH:13]=1.O.[C:31]1([CH3:41])[CH:36]=[CH:35][C:34]([S:37]([OH:40])(=[O:39])=[O:38])=[CH:33][CH:32]=1.[H][H]>CN(C)C=O.[Pd]>[C:31]1([CH3:41])[CH:32]=[CH:33][C:34]([S:37]([OH:40])(=[O:38])=[O:39])=[CH:35][CH:36]=1.[OH:15][C:11]1[C:12](=[O:14])[CH:13]=[C:8]([CH2:7][N:3]2[CH2:4][CH2:5][NH:6][C:2]2=[O:1])[NH:9][CH:10]=1
Reactant: [H][H]
Reactant: O=C1NCCN1Cc1cc(=O)c(OCc2ccccc2)cn1Cc1ccccc1
Agent: [Pd]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CN(C)C=O
Product: O=C1NCCN1Cc1cc(=O)c(O)c[nH]1
Yield: 84.4 %

Procedure:
To a solution of 2-[(2-oxo-1-imidazolidinyl)methyl]-5-(phenylmethoxy)-1-(phenylmethyl)-4(1H)pyridinone (4.98 g; 12.8 mmol) in dimethylformamide (90 ml) was added p-toluenesulfonic acid monohydrate (4.86 g; 25.6 mmol) and palladium on charcoal (1.0 g), and hydrogen was bubbled through the mixture for 30 minutes. The catalyst was filtered off by suction and the filtrate evaporated in vacuo. The residue was triturated with dichloromethane and ether, and the product filtered off by suction, yielding 4.12 g of the title compound, melting point 195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][CH:18]=[CH:17][C:3]=1[O:4][C:5]1[N:10]=[C:9]([N:11]2[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)[CH:8]=[CH:7][CH:6]=1.[F:21][C:22]([F:46])([F:45])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43]Br)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]>>[F:21][C:22]([F:45])([F:46])[CH2:23][NH:24][C:25]([C:27]1([CH2:40][CH2:41][CH2:42][CH2:43][N:14]2[CH2:15][CH2:16][N:11]([C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([O:4][C:3]4[CH:17]=[CH:18][CH:19]=[CH:20][C:2]=4[Cl:1])[N:10]=3)[CH2:12][CH2:13]2)[C:39]2[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=2[C:33]2[C:28]1=[CH:29][CH:30]=[CH:31][CH:32]=2)=[O:26]
Reactant: O=C(NCC(F)(F)F)C1(CCCCBr)c2ccccc2-c2ccccc21
Reactant: Clc1ccccc1Oc1cccc(N2CCNCC2)n1
Product: O=C(NCC(F)(F)F)C1(CCCCN2CCN(c3cccc(Oc4ccccc4Cl)n3)CC2)c2ccccc2-c2ccccc21

Procedure:
Prepared analogously to Example 2 b from 1-[6-(2-chloro-phenoxy)-pyridin-2-yl]-piperazine and 9-(4-bromo-butyl)-9H-fluorene-9-carboxylic acid-(2,2,2-trifluoroethyl)-amide.
Reaction SMILES: [CH3:1][O:2][C@H:3]1[C@@H:8]([CH3:9])[CH2:7][O:6][C@@H:5](/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@@H:4]1[OH:19].[C:20]([O:24][C:25]([NH:27][CH2:28][C:29](O)=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21].C1(N=C=NC2CCCCC2)CCCCC1.O>CN(C)C1C=CN=CC=1.ClCCl>[C:20]([O:24][C:25]([NH:27][CH2:28][C:29]([O:19][C@@H:4]1[C@@H:3]([O:2][CH3:1])[C@@H:8]([CH3:9])[CH2:7][O:6][C@H:5]1/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:30])=[O:26])([CH3:23])([CH3:22])[CH3:21]
Reactant: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1O
Reactant: CC(C)(C)OC(=O)NCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCC/C=C\[C@@H]1OC[C@H](C)[C@H](OC)[C@H]1OC(=O)CNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.9 %

Procedure:
A mixture of (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran-3-ol (9.0 mg), N-(tert-butoxycarbonyl)glycine (17.5 mg), 4-dimethylamino pyridine (12.0 mg), and dicyclohexylcarbodiimide (21.0 mg) in dry dichloro- methane (0.5 ml) was stirred for 3 hours at room temperature. To the reaction mixture water was added, and the mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. Purification of the residue by preparative thin layer chromatography gave (2S,3R,4S,5S)-4-methoxy-5-methyl-2-[(Z)-1-nonenyl]tetrahydro-2H-pyran -3-yl N-(tert-butoxycarbonyl)glycinate (12.8 mg, y. 91%), EI-MS: m/z 427 (M+)
Reaction SMILES: [SH:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C[O-].[Na+].CO.Br[CH2:15][CH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>CO>[O:19]1[CH2:20][CH2:21][CH:16]([CH2:15][S:1][C:2]2[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=2)[CH2:17][CH2:18]1
Reactant: BrCC1CCOCC1
Reactant: Oc1cccc(S)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Oc1cccc(SCC2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 59.6 %

Procedure:
3-Sulfanylphenol (250 mg) was dissolved in methanol (5 mL), and a 28% sodium methoxide-methanol solution (0.5 mL) was added thereto, followed by stirring at room temperature for 10 minutes. 4-(Bromomethyl)tetrahydro-2H-pyrane (410 mg) was added to the reaction mixture, followed by stirring at room temperature for 3 hours. The solvent was evaporated under reduced pressure, and then water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried. The solvent was evaporated under reduced pressure, and the residue was washed with hexane to obtain 3-[(tetrahydro-2H-pyran-4-ylmethyl)sulfanyl]phenol (265 mg).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([OH:20])[CH:17]=[CH:18][CH:19]=1)[CH3:13].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:11][CH:12]([C:14]1[CH:15]=[C:16]([O:20][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH:17]=[CH:18][CH:19]=1)[CH3:13]
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Reactant: CC(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)c1cccc(Oc2ccc([N+](=O)[O-])cn2)c1
Temperature: 110 °C
Yield: 82.6 %

Procedure:
In a 30 mL large microwave vial, 2-chloro-5-nitropyridine (1.041 g, 6.57 mmol, 1 equiv) was dissolved in 5.5 mL of dimethylformamide. 3-(1-methylethyl)phenol (0.90 mL, 6.57 mmol, 1 equiv) and potassium carbonate (4.54 g, 32.8 mmol, 5 equiv) were added. The reaction mixture was heated under microwave irradiation for 1 hour at 110° C. (Biotage Initiator). The reaction mixture was filtered. The filtrated solid was washed with dichloromethane (30 mL). The volatiles were evaporated under vacuum. The crude compound was dissolved in dichloromethane (20 mL) and brine was added (20 mL). The compound was extracted 2 times with dichloromethane (2×20 mL) and 2 times with ethyl acetate (2×20 mL). The organic phase was dried over sodium sulphate. Evaporation afforded the title compound (1.402 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:7]=[CH:8][C:9]2[C:15]3[S:16][C:17]([C:19]([N:21]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[Cl:29])[CH3:22])=[O:20])=[CH:18][C:14]=3[CH2:13][CH2:12][O:11][C:10]=2[CH:30]=1)=[O:4].[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:21]([CH3:22])[C:19]([C:17]1[S:16][C:15]2[C:9]3[CH:8]=[CH:7][C:6]([NH:5][C:3](=[O:4])[CH2:2][N:35]4[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]4)=[CH:30][C:10]=3[O:11][CH2:12][CH2:13][C:14]=2[CH:18]=1)=[O:20]
Reactant: CN1CCNCC1
Reactant: CN(C(=O)c1cc2c(s1)-c1ccc(NC(=O)CCl)cc1OCC2)c1ccccc1Cl
Product: CN1CCN(CC(=O)Nc2ccc3c(c2)OCCc2cc(C(=O)N(C)c4ccccc4Cl)sc2-3)CC1

Procedure:
Following the procedure in Example 147 for 237, 8-(2-chloroacetamido)-N-(2-chlorophenyl)-N-methyl-4,5-dihydro-benzo[b]thieno[2,3-d]oxepine-2-carboxamide and N-methylpiperazine were reacted to give 171. MS: (ESI+) 525.3
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9](Cl)(=[O:11])=[O:10].[NH2:14][C:15]1[N:20]=[C:19]([OH:21])[C:18]([CH2:22][C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][C:24]=2[O:30][CH3:31])=[C:17]([CH3:32])[N:16]=1.CN(C=O)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:13][C:1]1[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[C:2]=1[S:9]([O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][C:18]2[C:19]([O:21][S:9]([C:2]3[C:3]([CH3:8])=[CH:4][C:5]([CH3:7])=[CH:6][C:1]=3[CH3:13])(=[O:11])=[O:10])=[N:20][C:15]([NH2:14])=[N:16][C:17]=2[CH3:32])=[C:24]([O:30][CH3:31])[CH:25]=1)(=[O:11])=[O:10]
Reactant: COc1cc(O)ccc1Cc1c(C)nc(N)nc1O
Reactant: Cc1cc(C)c(S(=O)(=O)Cl)c(C)c1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(OS(=O)(=O)c2c(C)cc(C)cc2C)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
2-Mesitylenesulfonyl chloride (5.25 g) was added to a mixture of the product from step (iii) (5 g), TEA (7 ml) and DMAP (120 mg) in DCM (100 ml) and stirred at rt for 24 h. DMF (10 ml) was added and the mixture heated under reflux for 12 h. Another portion of 2-mesitylenesulfonyl chloride (2 g) was added and heated under reflux for a further 24 h. The mixture was partitioned between DCM/water, the organics separated, washed with aq NaHCO3 soln, brine, dried and evaporated under reduced pressure. The residue was triturated with ether/isohexane and filtered to afford the subtitle compound, 9.515 g.