Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1[S:8][C:7](B(O)O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[N:12]1([CH2:17][CH:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C:25]2[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=2)=[O:24])[CH2:16][CH2:15][CH2:14][CH2:13]1>>[N:12]1([CH2:17][C@@H:18]2[CH2:22][CH2:21][CH2:20][N:19]2[C:23]([C:25]2[CH:26]=[CH:27][C:28]([C:7]3[S:8][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=3)=[CH:29][CH:30]=2)=[O:24])[CH2:13][CH2:14][CH2:15][CH2:16]1
Reactant: CC(=O)c1ccc(B(O)O)s1
Reactant: O=C(c1ccc(Br)cc1)N1CCCC1CN1CCCC1
Product: CC(=O)c1ccc(-c2ccc(C(=O)N3CCC[C@H]3CN3CCCC3)cc2)s1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 5-Acetyl-2-thiophene boronic acid and 4-(2-Pyrrolidin-1-ylmethyl-pyrrolidine-1-carbonyl)-phenyl bromide to give 42 mg (37%). MS (ES+) 383.2
Reaction SMILES: [C:1]([N:3]=[C:4](OCC)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)#[N:2].[C:14]([C:16]1[CH:29]=[CH:28][C:19]2[O:20][C:21]([CH3:27])([CH3:26])[C@@H:22]([OH:25])[C@H:23]([NH2:24])[C:18]=2[CH:17]=1)#[N:15]>CN(C)C=O.C(OCC)(=O)C>[C:14]([C:16]1[CH:29]=[CH:28][C:19]2[O:20][C:21]([CH3:27])([CH3:26])[C@@H:22]([OH:25])[C@H:23]([NH:24][C:4](=[N:3][C:1]#[N:2])[C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:18]=2[CH:17]=1)#[N:15]
Reactant: CC1(C)Oc2ccc(C#N)cc2[C@@H](N)[C@@H]1O
Reactant: CCOC(=NC#N)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1(C)Oc2ccc(C#N)cc2[C@@H](NC(=NC#N)c2ccccc2)[C@@H]1O

Procedure:
1.89 g of ethyl N-cyanobenzimidate was dissolved in 5 ml of dimethylformamide, and 2.15 g of 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-amino-2H-benzo[b]pyran-3-ol was added thereto. The mixture was reacted at a temperature of from 100° to 120° C. for 2 hours. The reaction mixture was cooled, then dissolved in 100 ml of ethyl acetate, washed four times with a saturated sodium chloride aqueous solution and then dried over anhydrous sodium sulfate. Then, ethyl acetate was distilled off under reduced pressure. The residual oily substance was purified by silica gel column chromatography to obtain 1.32 g of the above identified compound in the form of crystals.
Reaction SMILES: [C:1]1([CH:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:16][C:17]1[CH:36]=[CH:35][C:20]([CH2:21][NH:22][C:23]([C:25]2[CH:30]=[CH:29][C:28]([S:31](Cl)(=[O:33])=[O:32])=[CH:27][CH:26]=2)=[O:24])=[CH:19][CH:18]=1.CCN(CC)CC.C([O-])(O)=O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][NH:22][C:23](=[O:24])[C:25]2[CH:30]=[CH:29][C:28]([S:31]([N:9]3[C:10]4[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=4)[CH:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH2:8]3)(=[O:32])=[O:33])=[CH:27][CH:26]=2)=[CH:35][CH:36]=1
Reactant: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(C2CNc3ccccc32)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1ccc(F)cc1)c1ccc(S(=O)(=O)N2CC(c3ccccc3)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.4 %

Procedure:
Add 3-phenyl-2,3-dihydro-1H-indole (Yamamoto, Y et al. Bull Chem. Soc. Jpn 44, 1971, 541-545) (0.158, 0.81 mmol), 4-(4-fluoro-benzylcarbamoyl)-benzenesulfonyl chloride (0.266 g, 0.81 mmol), Et3N (0.161 g, 0.23 mL, 1.5 mmol) and DMAP (0.011 g, 0.09 mmol) to CH2Cl2 (25 mL) and stir at ambient temperature under N2 overnight. Dilute the reaction to 150 mL with CH2Cl2 and pour into saturated NaHCO3 (50 mL). Separate the organic layer and extract with 1M HCl (2×75 mL). Wash with brine, separate dry (MgSO4) filter and evaporate the filtrate. Chromatograph the residue on the ISCO using a gradient EtOAc-hexane system (0-100%) to give 0.167 g of the title compound. Mass spectrum (m/e) (M+1) 487.1492; Found: 487.1479.
Reaction SMILES: [Si:1]([O:8][C@@H:9]1[C@H:17]2[C@@:13]([CH3:26])([C@@H:14]([C@:18]([OH:25])([CH3:24])[CH2:19][C:20](=[CH2:23])[CH2:21]O)[CH2:15][CH2:16]2)[CH2:12][CH2:11][CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:47]>CC#N>[Cl:47][CH2:21][C:20](=[CH2:23])[CH2:19][C@@:18]([C@@H:14]1[C@:13]2([CH3:26])[C@H:17]([C@@H:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])[CH2:10][CH2:11][CH2:12]2)[CH2:16][CH2:15]1)([OH:25])[CH3:24]
Reactant: C=C(CO)C[C@](C)(O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]21C
Reactant: ClC(Cl)(Cl)Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: C=C(CCl)C[C@](C)(O)[C@H]1CC[C@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCC[C@@]21C
Reaction time: 0.5 h
Yield: 87.3 %

Procedure:
A mixture of 8 (82 mg, 0.2 mmol), Ph3P (85 mg, 3.32 mmol), CCl4 (54 mg, 0.35 mmol, dried with CaCl2), and CH3CN (2 mL, dried with CaH2) was stirred for 30 min under argon. The mixture was flash chromatographed (SiO2, 2.5×5 cm. 5% EtOAc-hexanes) to give 9 (70 mg, 77%). This unstable compound was immediately used in the next step.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=O.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)CC)C.Cl.[S:29]1[CH:33]=[CH:32][CH:31]=[C:30]1[C:34]1[N:38]=[C:37]([CH:39]2[CH2:44][CH2:43][NH2+:42][CH2:41][CH2:40]2)[O:36][N:35]=1>ClCCl>[CH3:8][CH:2]([CH3:1])[CH2:3][CH2:4][C:5]([N:42]1[CH2:43][CH2:44][CH:39]([C:37]2[O:36][N:35]=[C:34]([C:30]3[S:29][CH:33]=[CH:32][CH:31]=3)[N:38]=2)[CH2:40][CH2:41]1)=[O:7]
Reactant: CC(C)CCC(=O)O
Reactant: c1csc(-c2noc(C3CC[NH2+]CC3)n2)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)CCC(=O)N1CCC(c2nc(-c3cccs3)no2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
86 mg (2 eq.) of 4-methylvaleric acid, 141 mg (2 eq.) of 1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDCI) and 207 μl (4 eq.) of triethylamine were dissolved in 2 ml of dichloromethane. 100 mg (1 eq.) of 4-(3-thiophen-2-yl[1,2,4]oxadiazol-5-yl)piperidinium hydrochloride were then added to the reaction medium, which was then stirred at room temperature for 24 hours. The reaction medium was evaporated under reduced pressure and the residue was taken up in 20 ml of ethyl acetate. The organic phase was washed with aqueous 1N sodium hydroxide solution (3×30 ml), with aqueous 1N hydrochloric acid solution (3×30 ml) and with saturated aqueous NaCl solution (30 ml) and then dried over MgSO4 and concentrated under reduced pressure to give 102 mg (83%) of the expected compound.
Reaction SMILES: O[CH2:2][CH2:3][CH:4]([CH2:8][CH2:9]COC1C(OC)=C2C(=CC=1)N=C1NC(=O)CN1C2)C(N)=O.[CH:28]1([N:33]([CH2:56][CH2:57][OH:58])[C:34](=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[C:41](Cl)=[C:42]3[C:47](=[CH:48][CH:49]=2)[N:46]=[C:45]2[NH:50][C:51](=[O:53])[CH2:52][N:44]2[CH2:43]3)[CH2:32][CH2:31][CH2:30][CH2:29]1>>[CH:29]1([CH2:30][CH2:31][CH2:32][CH2:28][N:33]([CH2:56][CH2:57][OH:58])[C:34](=[O:55])[CH2:35][CH2:36][CH2:37][CH2:38][O:39][C:40]2[CH:41]=[C:42]3[C:47](=[CH:48][CH:49]=2)[N:46]=[C:45]2[NH:50][C:51](=[O:53])[CH2:52][N:44]2[CH2:43]3)[CH2:9][CH2:8][CH2:4][CH2:3][CH2:2]1
Reactant: COc1c(OCCCC(CCO)C(N)=O)ccc2c1CN1CC(=O)NC1=N2
Reactant: O=C1CN2Cc3c(ccc(OCCCCC(=O)N(CCO)C4CCCC4)c3Cl)N=C2N1
Product: O=C1CN2Cc3cc(OCCCCC(=O)N(CCO)CCCCC4CCCCC4)ccc3N=C2N1

Procedure:
N-cyclohexyl-N-(2-hydroxyethyl-5-(2-oxo-6-methoxy-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide; N-cyclopentyl-N-(2-hydroxyethyl)-5-(2-oxo-6-chloro-1,2,3,5-tetrahydroimidazo[2,1-b]quinazolin-7-yl)oxypentanamide;
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=3)=[N:9][C@@H:8]3[CH2:26][CH2:27][S:28][CH2:29][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[OH-].[Na+:31].[ClH:32]>O1CCOCC1>[CH2:1]([O:3][C:4]1[C:13]([O:14][CH3:15])=[CH:12][C:11]2[C:10]([C:16]3[CH:17]=[CH:18][C:19]([C:20]([OH:22])=[O:21])=[CH:24][CH:25]=3)=[N:9][C@@H:8]3[CH2:26][CH2:27][S:28][CH2:29][C@@H:7]3[C:6]=2[CH:5]=1)[CH3:2].[Cl-:32].[Na+:31]
Reactant: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)OC)cc1)=N[C@@H]1CCSC[C@H]21
Reactant: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCOc1cc2c(cc1OC)C(c1ccc(C(=O)O)cc1)=N[C@@H]1CCSC[C@H]21
Product: [Cl-]
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a solution of methyl 4-[(4aR,10bR)-9-ethoxy-8-methoxy-3,4,4a,10b-tetrahydro-1H-thiopyrano[4,3-c]isoquinolin-6-yl]benzoate (5.0 g; compound C9) in dioxane (40 ml) is added a 2.0 M aqueous sodium hydroxide solution (18.3 ml) and the reaction mixture is stirred for 1.5 h at RT. Afterwards a aqueous hydrogen chloride solution (1.83 ml, 2.0 M) is added and all volatiles are removed under vacuo to give the title compound with parts of sodium chloride.
Reaction SMILES: C1(C[NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[CH2:26]([S:32](Cl)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>>[CH2:26]([S:32]([NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1)(=[O:34])=[O:33])[CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Reactant: CCCCCCS(=O)(=O)Cl
Product: CCCCCCS(=O)(=O)Nc1cccc(CCCNC(=O)OC(C)(C)C)c1

Procedure:
Sulfonation of aniline 17 by hexane-1-sulfonyl chloride following the method used in Example 6 gives tert-butyl 3-(3-(hexylsulfonamido)phenyl)propylcarbamate.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:14]([O:15][CH3:16])=[CH:13][C:6]2[CH2:7][C:8](=[O:12])[NH:9][CH2:10][CH2:11][C:5]=2[CH:4]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][N:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([CH2:36][Cl:37])[CH2:30]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]>>[ClH:37].[CH3:17][O:18][C:19]1[CH:20]=[C:21]([CH2:27][CH2:28][N:29]2[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([CH2:36][N:9]3[C:8](=[O:12])[CH2:7][C:6]4[CH:13]=[C:14]([O:15][CH3:16])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[CH2:11][CH2:10]3)[CH2:30]2)[CH:22]=[CH:23][C:24]=1[O:25][CH3:26]
Reactant: COc1cc2c(cc1OC)CC(=O)NCC2
Reactant: COc1ccc(CCN2CCCCC(CCl)C2)cc1OC
Product: COc1ccc(CCN2CCCCC(CN3CCc4cc(OC)c(OC)cc4CC3=O)C2)cc1OC
Product: Cl

Procedure:
Prepared from 7,8-dimethoxy-1,3,4,5-tetrahydro-2-oxo-3-benzazepine and N-[2-(3,4-dimethoxy-phenyl)-ethyl]-3-chloromethyl-hexahydro-azepine analogously to Example 2.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])[CH2:9][C:10](=[O:12])[CH3:11])([O-:3])=[O:2].[CH:17]([O-])([O-])OC>N1C2C(=CC=CC=2)C=CC=1.C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[C:6]([CH:14]=[CH:15][CH:16]=1)[NH:7][C:8](=[O:13])/[CH:9]=[C:10](\[O:12][CH3:17])/[CH3:11])([O-:3])=[O:2]
Reactant: COC([O-])[O-]
Reactant: CC(=O)CC(=O)Nc1cccc([N+](=O)[O-])c1
Solvent: Cc1ccccc1
Solvent: c1ccc2ncccc2c1
Product: CO/C(C)=C\C(=O)Nc1cccc([N+](=O)[O-])c1
Temperature: 130 °C
Reaction time: 16 h
Yield: 68.4 %

Procedure:
A mixture of 33 g of m-nitro-acetylacetanilide, 38.1 g of methyl orthoformate and 13 drops of 36° Be sulfuric acid was allowed to stand for 16 hours and after the addition of 40 drops of quinoline and 150 ml of toluene, the mixture was heated to 130° C. while distilling of the methanol formed as an azeotrope. The mixture was cooled and vacuum filtered and the recovered precipitate was crystallized from acetone to obtain 24 g of m-nitro-3-methoxy-crotonanilide melting at 187° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[C:5]([C:8]2[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=2)[C:4]([O:15][CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[N:3]1.[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].[OH-:39].[K+]>ClCCl.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O>[C:25]([C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:7]([S:35]([C:32]2[CH:33]=[CH:34][C:29]([C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:30][CH:31]=2)(=[O:36])=[O:39])[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([O:15][CH2:16][CH2:17][O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:5]=2[C:8]2[CH:9]=[CH:10][C:11]([CH3:14])=[CH:12][CH:13]=2)(=[O:37])=[O:36])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: [OH-]
Reactant: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N)cc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(-c2c(OCCOc3ccccc3)nn(C)c2N(S(=O)(=O)c2ccc(C(C)(C)C)cc2)S(=O)(=O)c2ccc(C(C)(C)C)cc2)cc1
Yield: 43.5 %

Procedure:
To 1-methyl-4-(4-methylphenyl)-3-(2-phenoxyethoxy)-1H-pyrazol-5-amine (Preparation 2) (105 mg) in dichloromethane (5 ml) at room temperature was added 4-tert-butylbenzenesulfonylchloride (265 mg), tetrabutylammonium hydrogen sulfate (28 mg) and potassium hydroxide (265 mg). The mixture was sonicated for 3 hrs. The reaction was diluted with water (10 ml) and extracted with ethyl acetate (10 ml). The organic fraction was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography silica (10 g) eluted with dichloromethane to yield the title compound as a white solid (101 mg).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][NH:15][C:16]2[NH:20][C:19]3[CH:21]=[CH:22][CH:23]=[C:24]([N+:25]([O-:27])=[O:26])[C:18]=3[N:17]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.O1CCOCC1.Cl>CO>[N+:25]([C:24]1[C:18]2[N:17]=[C:16]([NH:15][CH2:14][CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[NH:20][C:19]=2[CH:21]=[CH:22][CH:23]=1)([O-:27])=[O:26]
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2nc3c([N+](=O)[O-])cccc3[nH]2)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=[N+]([O-])c1cccc2[nH]c(NCC3CCNCC3)nc12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
After dissolving 4-[(4-nitro-1H-benzimidazol-2-ylamino)-methyl]-piperidine-1-carboxylic acid tert-butyl ester (13 mg) in methanol (1 ml), a 4N hydrogen chloride-1,4-dioxane solution (1 ml) was added and the mixture was stirred at 60° C. for 1 hour. The solvent was distilled off under reduced pressure, aqueous sodium hydroxide and dichloromethane were added to the obtained residue, and extraction was performed with dichloromethane. The solvent was distilled off under reduced pressure to obtain (4-nitro-1H-benzimidazol-2-yl)-piperidin-4-ylmethyl-amine. The compound was identified by LC-MS.
Reaction SMILES: C[C:2]1[CH:7]=[CH:6][CH:5]=[C:4](C)[C:3]=1[OH:9].[P:10]([Cl:14])(Cl)(Cl)=[S:11].P(Cl)(Cl)(Cl)=O>>[P:10](=[S:11])([Cl:14])([O:9][C:3]1[CH:2]=[CH:7][CH:6]=[CH:5][CH:4]=1)[O:9][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: S=P(Cl)(Cl)Cl
Reactant: Cc1cccc(C)c1O
Solvent: O=P(Cl)(Cl)Cl
Product: S=P(Cl)(Oc1ccccc1)Oc1ccccc1

Procedure:
The title compound was prepared in similar fashion as compound 6, substituting phenol for 2,6-dimethylphenol and thiophosphoryl chloride for phosphorus oxychloride. The resulting oily residue was taken to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH3:21]I>N1C=CC=CC=1>[CH3:21][NH:1][C:2]1[CH:3]=[C:4]([C:14](=[O:20])[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(N)c1
Reactant: CI
Solvent: c1ccncc1
Product: CCOC(=O)C(=O)c1ccc(C2CCCCC2)c(NC)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.01 moles of ethyl 3-amino-4-cyclohexylphenylglyoxylate in 100 ml. of pyridine is added 0.1 moles of methyl iodide. The reaction mixture is stirred overnight at room temperature, filtered and concentrated. The residue is distilled to obtain ethyl 3-methylamino-4-cyclohexylphenylglyoxylate.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([O:8][C@@H:9]2[CH:14]3[CH2:15][CH2:16][N:11]([CH2:12][CH2:13]3)[CH2:10]2)=[N:6][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][C:22](B(O)O)=[CH:23][CH:24]=2)[CH:19]=[CH:18]1.N>>[N:11]12[CH2:16][CH2:15][CH:14]([CH2:13][CH2:12]1)[C@@H:9]([O:8][C:5]1[N:4]=[CH:3][C:2]([C:22]3[CH:21]=[C:20]4[C:25](=[CH:24][CH:23]=3)[NH:17][CH:18]=[CH:19]4)=[CH:7][N:6]=1)[CH2:10]2
Reactant: OB(O)c1ccc2[nH]ccc2c1
Reactant: Brc1cnc(O[C@H]2CN3CCC2CC3)nc1
Agent: N
Product: c1cc2cc(-c3cnc(O[C@H]4CN5CCC4CC5)nc3)ccc2[nH]1

Procedure:
The product of Example 11A (283 mg, 1 mmol) was coupled with 5-indolylboronic acid (Aldrich, 193 mg, 1.2 mmol) according to the procedure of Example 3A. The title product was purified by preparative HPLC (Gilson, column, Symmetry® C-8 7 μm, 40×100 mm. Eluting Solvent, MeCN/H2O (with 0.2% v. TFA) (v. 90/10 to 10/90 over 20 min. flow rate, 75 mL/min., uv, 250 nm) as solid (40 mg, yield, 12%). 1H NMR (300 MHz, CD3OD) δ 1.50-1.63 (m, 1H), 1.67-1.93 (m, 2H), 2.04-2.17 (m, 1H), 2.24-2.31 (m, 1H), 2.75-3.05 (m, 5H), 3.38-3.48 (m, 1H), 5.14-5.21 (m, 1H), 6.53 (dd, J=3.1, 0.7 Hz, 1H), 7.30 (d, J=3.1 Hz, 1H), 7.35 (dd, J=8.5, 1.7 Hz, 1H), 7.51 (dt, J=8.5, 0.7 Hz, 1H), 7.80 (dd, J=1.7, 0.7 Hz, 1H), 8.82 (s, 2H) ppm. MS (DCI/NH3): m/z 321 (M+H)+.
Reaction SMILES: I[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([S:12]([NH2:15])(=[O:14])=[O:13])=[CH:9]2)=[CH:4][CH:3]=1.[CH3:16][CH2:17][OH:18].CN([CH:22]=[O:23])C>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.CC([O-])=O.CC([O-])=O.[Pd+2]>[S:12]([C:8]1[CH:9]=[C:10]2[C:5]([CH:4]=[CH:3][C:2]([C:22]([O:18][CH2:17][CH3:16])=[O:23])=[CH:11]2)=[CH:6][CH:7]=1)(=[O:14])(=[O:13])[NH2:15]
Reactant: CN(C)C=O
Reactant: CCO
Reactant: NS(=O)(=O)c1ccc2ccc(I)cc2c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Product: CCOC(=O)c1ccc2ccc(S(N)(=O)=O)cc2c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 34 %

Procedure:
To a solution of 7-iodonaphthalene-2-sulfonamide (Intermediate 11, 70 mg, 0.21 mmol) in DMF (2.0 mL) and EtOH (2.0 mL, 34.2 mmol) was added bis(triphenylphosphine)palladium chloride (74 mg, 0.11 mmol). After purging the solution with nitrogen, the reaction flask was evacuated and refilled with CO. The reaction mixture was heated to 70° C. for 3 h. Pd(OAc)2 (47 mg, 0.21 mmol) was then added, and the reaction flask was evacuated and refilled with CO. After stirring under CO overnight at 70° C., the reaction mixture was cooled to room temperature, taken up in a biphasic mixture of EtOAc and water, and filtered. The layers were separated and the aqueous layer was extracted with EtOAc (3×). The combined organic fractions were dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by preparative HPLC to give the title compound (20 mg, 34%) as a white solid. 1H NMR (MeOD) δ 8.82 (s, 1H), 8.63 (d, J=1.3 Hz, 1H), 8.22 (d, J=8.8 Hz, 1H), 8.17-8.12 (m, 2H), 8.02 (dd, J=8.6, 2.0 Hz, 1H), 7.52 (s, 2H), 4.40 (q, J=7.0 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H); MS(ESI−) m/z 278.3 (M−H)−.
Reaction SMILES: Br[C:2]1[N:10]2[C:5]([CH:6]=[N:7][C:8]([NH:11][C:12]3[CH:17]=[CH:16][C:15]([N:18]4[CH2:23][CH2:22][CH:21]([N:24]5[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]5)[CH2:20][CH2:19]4)=[CH:14][C:13]=3[O:31][CH3:32])=[N:9]2)=[CH:4][CH:3]=1.[CH3:33][N:34]([CH3:38])[SH:35](=[O:37])=[O:36].[CH:39]1[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=1B(O)O.C(=O)([O-])[O-].[Na+].[Na+].O>O1CCCC1.C(O)C.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>[CH3:32][O:31][C:13]1[CH:14]=[C:15]([N:18]2[CH2:19][CH2:20][CH:21]([N:24]3[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]3)[CH2:22][CH2:23]2)[CH:16]=[CH:17][C:12]=1[NH:11][C:8]1[N:7]=[CH:6][C:5]2=[CH:4][CH:3]=[C:2]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][C:40]=3[S:35]([N:34]([CH3:38])[CH3:33])(=[O:37])=[O:36])[N:10]2[N:9]=1
Reactant: CN(C)[SH](=O)=O
Reactant: OB(O)c1ccccc1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(Br)n2n1
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: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1ncc2ccc(-c3ccccc3S(=O)(=O)N(C)C)n2n1
Temperature: 80 °C
Yield: 43 %

Procedure:
A mixture of (7-Bromo-pyrrolo[2,1-f][1,2,4]triazin-2-yl)-{2-methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenyl}-amine (0.09 g, 0.0002 mol) and N,N-dimethylsulfonamide-2-benzeneboronic acid (0.060 g, 0.00026 mol), Tetrakis(triphenylphosphine)palladium(0) (0.023 g, 0.000020 mol), 1 M of Sodium carbonate in Water (0.7 mL, 0.0007 mol), Tetrahydrofuran (4 mL,) and ethanol (4 mL) under nitrogen was heated at 80° C. overnight. Purification by prep plate chromatography gave 2-(2-{2-Methoxy-4-[4-(4-methyl-piperazin-1-yl)-piperidin-1-yl]-phenylamino}-pyrrolo[2,1-f][1,2,4]triazin-7-yl)-N,N-dimethyl-benzenesulfonamide (0.052 g, 48%) as a tan solid. MP; 198-205° C.; 1H-NMR (DMSO-d6, 400 MHz) δ 8.91 (s, 1H), 8.04-8.02 (d, 1H, J=7.80 Hz), 7.81-7.79 (t, 1H, J=7.44 Hz), 7.77-7.75 (t, 1H, J=7.56 Hz), 7.65-7.63 (d, 1H, J=7.48 Hz), 7.53-7.51 (d, 1H, J=8.76 Hz), 7.46 (s, 1H), 6.91-6.86 (q, 1H, J=4.56 Hz), 6.58-6.57 (d, 1H, J=2.40 Hz), 6.16-6.13 (d, 1H, J=12.44 Hz), 3.80 (s, 3H), 3.60-3.56 (d, 2H, J=12.44 Hz), 2.35 (s, 6H), 2.17 (s, 3H), 1.83-1.80 (d, 2H, J=11.88 Hz), 1.49-1.46 (q, 2H, J=8.52 Hz) 1.23 (s, 1H).
Reaction SMILES: [H-].[Na+].[CH3:3][C@:4]12[C:10]([CH3:12])([CH3:11])[C@H:7]([CH2:8][CH2:9]1)[CH2:6][C@@H:5]2[NH:13][C:14]([C:16]1[CH:17]=[N:18][N:19]([CH3:27])[C:20]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:15].[CH3:28]I.O>CN(C)C=O>[CH3:28][N:13]([C@H:5]1[CH2:6][C@@H:7]2[C:10]([CH3:11])([CH3:12])[C@@:4]1([CH3:3])[CH2:9][CH2:8]2)[C:14]([C:16]1[CH:17]=[N:18][N:19]([CH3:27])[C:20]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:15]
Reactant: Cn1ncc(C(=O)N[C@H]2C[C@H]3CC[C@]2(C)C3(C)C)c1-c1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1cnn(C)c1-c1ccccc1)[C@H]1C[C@H]2CC[C@]1(C)C2(C)C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% dispersion in mineral oil; 15 mg, 0.375 mmol) is added to a cooled (˜0° C.) solution of 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid ((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide (of Example 91; 100 mg, 0.3 mmol) in dry dimethylformamide (10 mL) and the mixture is allowed to stir for 30 min. Methyl iodide (30 μL, 0.49 mmol) is added and the solution is stirred at room temperature until the reaction is complete, as judged by TLC. Water is added and the solution is extracted twice with ethyl acetate. The combined organic layers are washed with water and brine, dried (magnesium sulfate), filtered, evaporated, and purified by C-18 reversed phase HPLC with a gradient of 10-100% acetonitrile/water containing 0.1% TFA as a modifier to give 1-methyl-5-phenyl-1H-pyrazole-4-carboxylic acid methyl-((1R,2S,4R)-1,7,7-trimethyl-bicyclo[2.2.1]hept-2-yl)-amide.
Reaction SMILES: C1([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[S:15](Cl)(=[O:17])=[O:16])CCCCNCC1.[NH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25].[OH-].[Na+].O1[CH2:33][CH2:32][CH2:31][CH2:30]1>O>[N:19]1([C:13]2[CH:14]=[CH:9][C:10]([S:15]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([OH:26])=[O:25])(=[O:16])=[O:17])=[CH:11][CH:12]=2)[CH2:20][CH2:21][CH2:22][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: O=S(=O)(Cl)c1ccccc1C1CCCCNCC1
Reactant: C1CCOC1
Reactant: NCCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCCCNS(=O)(=O)c1ccc(N2CCCCCCC2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4.5 g of 4-azacyclooctylbenzenesulphonyl chloride are added to a solution comprising 1.82 g of 5-aminovaleric acid and 1.87 g of sodium hydroxide dissolved in 45 cm3 of water, followed by the addition of 45 cm3 of tetrahydrofuran in order to obtain a solution. The mixture is kept stirred for 2 hours at room temperature, the tetrahydrofuran is evaporated off, the reaction medium is acidified using acetic acid, the precipitate is filtered off, washed with water and dried and 3.6 g of expected product are obtained. M.p. 149°-150° C. After crystallization in an isopropanol/water mixture (1:1), the product, melting point 153°-154° C., is obtained.