Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[S:6]([C:9]1[S:10][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21](Br)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7].[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:34]2[C:38](B(O)O)=[CH:37][N:36]([C:42]([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=3)([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)[C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[N:35]=2)=[CH:30][CH:29]=1>>[CH3:1][N:2]([CH3:26])[CH2:3][CH2:4][N:5]([CH3:25])[S:6]([C:9]1[S:10][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([C:38]4[C:34]([C:31]5[CH:30]=[CH:29][C:28]([F:27])=[CH:33][CH:32]=5)=[N:35][N:36]([C:42]([C:49]5[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=5)([C:55]5[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=5)[C:43]5[CH:44]=[CH:45][CH:46]=[CH:47][CH:48]=5)[CH:37]=4)[CH:22]=3)[N:17]=[CH:16][N:15]=2)=[CH:12][CH:13]=1)(=[O:8])=[O:7]
Reactant: CN(C)CCN(C)S(=O)(=O)c1ccc(-c2ncnc3ccc(Br)cc23)s1
Reactant: OB(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)nc1-c1ccc(F)cc1
Product: CN(C)CCN(C)S(=O)(=O)c1ccc(-c2ncnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4-c4ccc(F)cc4)cc23)s1
Yield: 29.5 %

Procedure:
131 mg 5-(6-bromoquinazolin-4-yl)-thiophen-2-sulfonic acid (2-dimethylaminoethyl)-methyl-amide (compound in Production Example 376) and 168 mg 3-(4-fluorophenyl)-1-trityl-1H-4-pyrazolylboronic acid (compound in Production Example 25) were subjected to the same reaction as in Example 9, and the isomer was separated and purified by a column to give 66 mg of the title compound as yellow crystals.
Reaction SMILES: [SH2:1].[C:2]1([CH2:8][CH2:9][C:10]([CH:19]([CH3:21])C)([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11]#[N:12])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22](NCC)C>C1(C)C=CC=CC=1>[C:2]1([CH2:8][CH2:9][C:10]([CH2:19][C:21]#[CH:22])([C:13]2[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=2)[C:11](=[S:1])[NH2:12])[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: S
Reactant: CCNCC
Reactant: CC(C)C(C#N)(CCc1ccccc1)c1cccnc1
Solvent: Cc1ccccc1
Product: C#CCC(CCc1ccccc1)(C(N)=S)c1cccnc1

Procedure:
A slow, steady stream of hydrogen sulfide was passed into a toluene solution (75 ml) of α-(2-phenylethyl)-α-(2-propyl)-3-pyridineacetonitrile (3.5 g) in the presence of diethylamine (1 ml). More diethylamine was added at the end of 1 hour (0.5 ml) and 3 hours (0.5 ml). The resultant reaction mixture was then evaporated to dryness and the residue dissolved in methylene chloride and washed with saturated sodium bicarbonate and water. After washing, the remaining organic extract was dried over sodium sulfate and worked up to give a solid. Recrystallization with hexanes produced α-(2-phenylethyl)-α-(2-propynyl)-3-pyridinethanethioamide with a melting point of 73-74° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([OH:17])[CH:12]=2)[N:3]=1.[OH-].[K+].Br[CH:21]([CH3:23])[CH3:22]>CS(C)=O>[NH2:1][C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH:21]([CH3:23])[CH3:22])[CH:12]=2)[N:3]=1
Reactant: CC(C)Br
Reactant: Nc1cc(Cl)nc(SCc2cccc(O)c2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)Oc1cccc(CSc2nc(N)cc(Cl)n2)c1
Reaction time: 8 h

Procedure:
4-amino-6-chloro-2-(3-hydroxyphenylmethylthio)-pyrimidine (135 mg, 0.50 mmol; Cpd 108) is added to a solution of KOH (280 mg, 5 mmol) in DMSO (2.5 ml) at room temperature. 2-Bromopropane (615 mg, 5 mmol) is added and the reaction stirred overnight, then poured onto water. The aqueous solution is extracted with ethyl acetate, dried with MgSO4, filtered, and concentrated in vacuo. The sample is purified by chromatography using 1:3 ethyl acetate/hexanes, mp 71° C.
Reaction SMILES: [C:1]1(O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>C1C=CC=CC=1>[CH:1]1([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Oc1ccccc1
Reactant: [H][H]
Solvent: c1ccccc1
Product: c1ccc(C2CCCCC2)cc1

Procedure:
Referring to FIG. 1, this is a flow diagram of the hydroalkylation and dealkylation stages of an integrated process according to one example of the invention for converting benzene to phenol. In the process shown in FIG. 1, fresh benzene (line 11) and hydrogen (line 12) are introduced to a hydroalkylation reactor 13, where the benzene undergoes hydroalkylation to produce cyclohexylbenzene (CHB) and poly-cyclohexylbenzenes (PCHB). The effluent from the reactor 13, containing unreacted benzene in addition to the CHB and PCHB, is removed via line 14 and fed to a distillation system 15, which divides the effluent into a C6 fraction, a C12 fraction and a C18 fraction.
Reaction SMILES: Cl.O[C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:15][CH:14]=3)=[O:12])=[C:9]([C:28]3[CH:33]=[CH:32][C:31](O)=[CH:30][CH:29]=3)[S:8][C:7]=2[CH:35]=1.C(N([CH2:41][CH3:42])CC)C.[CH2:43]([S:49](Cl)(=[O:51])=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]>CN(C1C=CN=CC=1)C.O1CCCC1>[CH2:43]([S:49]([C:3]1[CH:4]=[CH:5][C:6]2[C:10]([C:11]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:18]=3)=[O:12])=[C:9]([C:28]3[CH:29]=[CH:30][C:31]([S:49]([CH2:43][CH2:44][CH2:45][CH2:46][CH2:41][CH3:42])(=[O:51])=[O:50])=[CH:32][CH:33]=3)[S:8][C:7]=2[CH:35]=1)(=[O:51])=[O:50])[CH2:44][CH2:45][CH2:46][CH2:47][CH3:48]
Reactant: CCN(CC)CC
Reactant: CCCCCCS(=O)(=O)Cl
Reactant: O=C(c1ccc(OCCN2CCCCC2)cc1)c1c(-c2ccc(O)cc2)sc2cc(O)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCS(=O)(=O)c1ccc(-c2sc3cc(S(=O)(=O)CCCCCC)ccc3c2C(=O)c2ccc(OCCN3CCCCC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
In dry tetrahydrofuran (250 ml) 3 g (5.9 mmol) of [6-hydroxy-2-(4-hydroxyphenyl)-benzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]-methanone hydrochloride was suspended and 10 mg of DMAP was added. Triethylamine (4 g, 40 mmol) was then added and the reaction mixture was stirred for 20 minutes at room temperature under a nitrogen blanket. n-Hexylsulfonyl chloride (3.6 g, 19.6 mmol) in 25 ml of tetrahydrofuran was slowly added to the reaction mixture. The reaction was allowed to proceed at room temperature and under nitrogen for 3 days. The reaction mixture was evaporated down in vacuo and resuspended in ethyl acetate and washed with water. The organic layer was dried by filtering it through anhydrous sodium sulfate and evaporated to a yellow oil. The oil was dissolved in chloroform and chromatographed (HPLC) on a silica gel column and eluted with a linear gradient starting with chloroform and ending with chloroform-methanol (19:1 v/v). The desired fractions were determined by thin layer chromatography, combined and evaporated down to afford 3.14 g of the title compound as a thick oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[NH:15]3)=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1.[H-].[Na+].I[CH3:25]>CN(C)C=O.C(OCC)(=O)C>[CH3:1][C:2]1([CH3:21])[O:6][CH:5]([CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([CH2:12][CH2:13][C:14](=[O:18])[N:15]3[CH3:25])=[CH:10][C:9]=2[O:19][CH3:20])[CH2:4][O:3]1
Reactant: CI
Reactant: COc1cc2c(cc1CC1COC(C)(C)O1)NC(=O)CC2
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1CC1COC(C)(C)O1)N(C)C(=O)CC2
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
300 mg of 7-((2,2-dimethyl-[1,3]dioxolan-4-yl)methyl)-6-methoxy-1,2,3,4-tetrahydroquinolin-2-one was dissolved in 6 ml of N,N-dimethylformamide. While cooling on ice, 49 mg of 60% sodium hydride was added to the reaction solution, and the obtained mixture was then stirred at room temperature for 30 minutes. Thereafter, 0.29 g of iodomethane was added to the reaction solution while cooling on ice. The obtained mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with ethyl acetate and then washed with a saturated ammonium chloride aqueous solution and a saturated sodium chloride aqueous solution. The organic layer was dried over magnesium sulfate and then concentrated under a reduced pressure. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate), so as to obtain 310 mg of the subject compound.
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([OH:21])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=[O:5])[CH2:3][CH2:2]1.[CH2:24](I)[CH3:25].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH:1]1([C:4]([N:6]2[CH2:23][CH2:22][C@@:13]34[C:14]5[CH:15]=[C:16]([O:21][CH2:24][CH3:25])[CH:17]=[CH:18][C:19]=5[CH2:20][C@@H:7]2[C@@H:8]3[CH2:9][CH2:10][O:11][CH2:12]4)=[O:5])[CH2:2][CH2:3]1
Reactant: O=C(C1CC1)N1CC[C@]23COCC[C@H]2[C@H]1Cc1ccc(O)cc13
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOc1ccc2c(c1)[C@]13CCN(C(=O)C4CC4)[C@H](C2)[C@@H]1CCOC3

Procedure:
A mixture of the product of Step (b) (XXXII) (0.005 m), ethyl iodide (0.006 m) and potassium carbonate (2 g) in 20 ml of acetonitrile is heated at reflux for 18 hours. The mixture is then filtered and the filtrate is concentrated. The residue is treated with water and extracted with ethyl acetate. The extracts are dried (Na2SO4) and concentrated to give the title product.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[N:6][CH:7]=1.C([Sn](CCCC)(CCCC)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][N:36]=1)CCC>O1CCOCC1.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>[N:36]1[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=1[C:2]1[CH:7]=[N:6][C:5]([N:8]2[CH2:20][CH2:19][C:18]3[C:17]4[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=4)[NH:11][C:10]=3[CH:9]2[C:21]2[CH:22]=[CH:23][C:24]3[O:28][CH2:27][CH2:26][C:25]=3[CH:29]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: Brc1ccc(N2CCc3c([nH]c4ccccc34)C2c2ccc3c(c2)CCO3)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: c1ccc(-c2ccc(N3CCc4c([nH]c5ccccc45)C3c3ccc4c(c3)CCO4)nc2)nc1

Procedure:
The product from step A above (0.4 g, 0.896 mmol), 2-tributylstannanyl-pyridine (0.8 g, 2.17 mmol) and Pd(PPh3)4 (0.12 g, 0.104 mmol) were stirred in 1,4-dioxane (5 mL) at 88° C. for 24 h. The reaction mixture was filtered through a plug of Celite with CH2Cl2 and then concentrated to a small volume. Preparative TLC (3:7 ethyl acetate/ heaxne; then 5% CH3OH/CH2Cl2) yielded the product as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:24]([OH:26])=O)[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:12]=3[N:13]=2)=[CH:4][CH:3]=1.CCN(C(C)C)C(C)C.[CH2:36]([N:43]1[CH2:48][CH2:47][C:46]([NH2:50])([CH3:49])[CH2:45][CH2:44]1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.O>ClC(Cl)C>[CH2:36]([N:43]1[CH2:48][CH2:47][C:46]([NH:50][C:24]([C:10]2[C:11]3[C:16]([CH3:17])=[N:15][N:14]([CH:18]4[CH2:23][CH2:22][CH2:21][CH2:20][O:19]4)[C:12]=3[N:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([OH:1])=[CH:3][CH:4]=3)[CH:9]=2)=[O:26])([CH3:49])[CH2:45][CH2:44]1)[C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1
Reactant: CC1(N)CCN(Cc2ccccc2)CC1
Reactant: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)O)c12
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Solvent: O
Product: Cc1nn(C2CCCCO2)c2nc(-c3ccc(O)cc3)cc(C(=O)NC3(C)CCN(Cc4ccccc4)CC3)c12
Temperature: 40 °C
Yield: 432469.31 %

Procedure:
To a mixture of 6-(4-hydroxy-phenyl)-3-methyl-1-(tetrahydro-pyran-2-yl)-1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid (215 mg), DIPEA (313 μL) and 1-benzyl-4-methyl-piperidin-4-ylamine (175 mg) in dichloroethane (7 mL), which was being stirred at 40° C., was added BEP (200 mg). The mixture was stirred at 40° C. for 60 min, then at r.t. overnight. Water was added and the mixture was extracted with dichloromethane. To the dichloromethane phase 30% sodium methoxide in methanol (0.4 mL) was added and stirred for 30 min. The mixture was filtered and the filtrate was washed with water, dried over magnesium sulfate and concentrated. The residue was chromatographed over silica (dichloromethane/methanol gradient) to give 1420 g (43%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][CH:17]=1.[C:25]([C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)([CH3:28])([CH3:27])[CH3:26].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:25]([C:29]1[CH:30]=[CH:31][C:32]([NH:33][C:20]([C:19]2[CH:23]=[CH:24][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:21])=[CH:34][CH:35]=1)([CH3:28])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: COc1cc2nccc(Oc3ccc(C(=O)O)cc3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: COc1cc2nccc(Oc3ccc(C(=O)Nc4ccc(C(C)(C)C)cc4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 6 h
Yield: 38.3 %

Procedure:
4-[6,7-Dimethoxy-4-quinolyl)oxybenzoic acid (54 mg) and commercially available 4-tert-butylaniline (102 mg) were dissolved in N,N-dimethylformamide (3 ml), 1-ethyl-3-(3'-dimethylaminopropyl)carbodiimide hydrochloride (106 mg) was added, and the admixture was stirred at room temperature for 6 hours, after which the reaction mixture was purified in the same manner as described in Example 51 to obtain 29 mg of the title compound (yield: 35%).
Reaction SMILES: Br[CH2:2][C:3](=O)/[C:4](=[N:10]/[O:11][C@@H:12]1[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]1[O:18][CH3:19])/[C:5]([O:7][CH2:8][CH3:9])=[O:6].[NH2:21][C:22]([NH2:24])=[S:23].CN(C)C1C=CC=CC=1>>[NH2:24][C:22]1[S:23][CH:2]=[C:3](/[C:4](=[N:10]/[O:11][C@@H:12]2[CH2:17][CH2:16][CH2:15][CH2:14][C@H:13]2[O:18][CH3:19])/[C:5]([O:7][CH2:8][CH3:9])=[O:6])[N:21]=1
Reactant: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)C(=O)CBr
Reactant: NC(N)=S
Solvent: CN(C)c1ccccc1
Product: CCOC(=O)/C(=N\O[C@@H]1CCCC[C@H]1OC)c1csc(N)n1

Procedure:
Ethyl 4-bromo-(Z)-2-(trans-2-methoxycyclohexyloxyimino)-3-oxobutyrate was treated with thiourea (0.79 g) and N,N-dimethylaniline (1.318 ml) as described in Example 4d to give the title compound as an orange gum (1.78 g) after silica gel chromatography. νmax (CH2Cl2) 3460, 3370, 3250, 3100, 1730, 1605, and 1530 cm-1 ; δH (CDCl3) inter alia 1.10-1.20 (11H, m), 3.32 (1H, m), 3.43 (3H, s), 4.00-4.50 (3H, m), 6.55 (2H, br. s), and 6.66 (1H, s). [Mass spectrum: EI M+ (327)].
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17]>F[B-](F)(F)F.[Ag+]>[CH3:13][O:14][CH2:15][CH2:16][O:17][CH2:2][C:3]1[C:7]([N+:8]([O-:10])=[O:9])=[C:6]([Cl:11])[N:5]([CH3:12])[N:4]=1
Reactant: COCCO
Reactant: Cn1nc(CBr)c([N+](=O)[O-])c1Cl
Agent: [Ag+]
Agent: F[B-](F)(F)F
Product: COCCOCc1nn(C)c(Cl)c1[N+](=O)[O-]
Yield: 65 %

Procedure:
3-Bromomethyl-5-chloro-1-methyl-4-nitropyrazole (2.42 g, 9.5 mmoles), and silver tetrafluoroborate (2.22 g, 11.4 mmoles), were stirred at reflux in 2-methoxyethanol (25 ml) for 6 hours. The black solid was filtered off and the solvent removed under reduced pressure. The oil was dissolved in ethyl acetate (100 ml) and washed with water (100 ml). The organic phase was dried over magnesium sulphate and the solvent removed under reduced pressure. The product was purified by chromatography on silica eluting with 10% ethyl acetate in dichloromethane. Fractions containing product were evaporated yielding the title compound as a white solid (1.54 g, 65%).
Reaction SMILES: [C:1]([C:3]1[CH:24]=[CH:23][C:6]2[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:21])([CH3:20])[CH3:19])=[N:8][C:9]3[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=3[C:5]=2[CH:4]=1)#[CH:2].[N:25]([Si](C)(C)C)=[N+:26]=[N-:27]>CN(C=O)C.CO.O.[Cu]I>[NH:25]1[CH:2]=[C:1]([C:3]2[CH:24]=[CH:23][C:6]3[C:7]([NH:16][CH:17]([CH3:22])[C:18]([CH3:20])([CH3:19])[CH3:21])=[N:8][C:9]4[CH:10]=[CH:11][NH:12][C:13](=[O:15])[C:14]=4[C:5]=3[CH:4]=2)[N:27]=[N:26]1
Reactant: C#Cc1ccc2c(NC(C)C(C)(C)C)nc3cc[nH]c(=O)c3c2c1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: [Cu]I
Solvent: CN(C)C=O
Solvent: CO
Solvent: O
Product: CC(Nc1nc2cc[nH]c(=O)c2c2cc(-c3c[nH]nn3)ccc12)C(C)(C)C
Temperature: 100 °C
Reaction time: 8 h

Procedure:
9-ethynyl-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one (150 mg, 0.47 mmol) was dissolved in DMF/MeOH (2.0 mL) in a sealed tube. To the solution was added CuI (5.0 mg, 0.020 mmol) and azidotrimethylsilane (270 mg, 2.4 mmol) under an argon atmosphere. The mixture was stirred at 100° C. in a sealed tube for 8 h. The resulting solution was diluted with water (5 mL) and extracted with ethyl acetate (3×5 mL). The combined organic layers were washed with brine (5 mL), dried over magnesium sulfate, filtered, and purified by preparative TLC to afford 9-(1H-1,2,3-triazol-4-yl)-6-[(1,2,2-trimethylpropyl)amino]benzo[c]-1,6-naphthyridin-1(2H)-one. 1H NMR (400 MHz, MeOD) δ 10.28 (s, 1H), 8.38 (d, J=8.4 Hz, 2H), 8.30 (d, J=6.4 Hz, 1H), 7.38 (d, J=7.2 Hz, 1H), 6.64 (d, J=7.2 Hz, 1H), 4.78 (m, 1H), 1.28 (d, J=6.8 Hz, 3H), 1.04 (s, 9H). LRMS calculated for C20H22N6O [M+H]+, 363; found 363.
Reaction SMILES: O.[OH-].[Li+].[C:4]([CH2:6][C:7]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:10][N:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][C:12]=2[F:21])[CH2:8]1)#[N:5].Cl>CO.O.C1COCC1>[C:4]([CH2:6][C:7]1([N:22]2[CH:26]=[C:25]([C:27]3[CH:32]=[CH:31][N:30]=[C:29]4[NH:33][CH:34]=[CH:35][C:28]=34)[CH:24]=[N:23]2)[CH2:10][N:9]([C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][C:12]=2[F:21])[CH2:8]1)#[N:5]
Reactant: COC(=O)c1ccc(N2CC(CC#N)(n3cc(-c4ccnc5[nH]ccc45)cn3)C2)c(F)c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: N#CCC1(n2cc(-c3ccnc4[nH]ccc34)cn2)CN(c2ccc(C(=O)O)cc2F)C1
Temperature: 35 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Lithium hydroxide monohydrate (83 mg, 2.0 mmol) was added to a mixture of methyl 4-{3-(cyanomethyl)-3-[4-(1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-3-fluorobenzoate (0.34 g, 0.79 mmol) in methanol (2.0 mL), water (1.0 mL) and THF (2.0 mL). The reaction mixture was stirred at 35° C. overnight, and adjusted to pH=5 with 1.0 N HCl aqueous solution, and concentrated under reduced pressure to remove methanol and THF. The precipitate formed was filtered, washed with water and ether, and dried in vacuum to afford the desired product (0.17 g, 52%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=4171
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([C:10]3[CH:15]=[CH:14][C:13]([C:16]4[C:21]([Cl:22])=[CH:20][CH:19]=[CH:18][N:17]=4)=[CH:12][CH:11]=3)[NH:7][C:6]=2[CH:23]=1.CN(C(C(C)C)C)C.C[Si](C)(C)CCOCCl.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1.C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C>ClCCl.C1(C)C=CC=CC=1.C(OCC)(=O)C>[Cl:22][C:21]1[C:16]([C:13]2[CH:14]=[CH:15][C:10]([C:8]3[NH:7][C:6]4[CH:23]=[C:2]([N:41]5[CH2:46][CH2:45][O:44][CH2:43][CH2:42]5)[CH:3]=[CH:4][C:5]=4[N:9]=3)=[CH:11][CH:12]=2)=[N:17][CH:18]=[CH:19][CH:20]=1
Reactant: C1COCCN1
Reactant: Clc1cccnc1-c1ccc(-c2nc3ccc(Br)cc3[nH]2)cc1
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)C(C)N(C)C
Agent: C[Si](C)(C)CCOCCl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1cccnc1-c1ccc(-c2nc3ccc(N4CCOCC4)cc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 98.1 %

Procedure:
To a solution of 162 mg (0.42 mmol) 6-bromo-2-(4-(3-chloropyridin-2-yl)phenyl)-1H-benzoimidazole in 6 mL dichloromethane were added 0.2 mL (1.15 mmol) N,N-dimethylisopropylethylamine and 0.1 mL (0.57 mmol) 2-(trimethylsilyl)ethoxymethyl chloride, followed by stirring at room temperature for 16 hours. After vacuum concentration, 26 μL (0.30 mmol) morpholine, 56.3 mg (0.013 mmol) tris(dibenzylidine acetone)dipalladium(0), 10 mg (0.038 mmol) 2-(di-t-butylphosphino)biphenyl, and 38.8 mg (0.41 mmol) sodium-t-botoxide were added to the concentrate, which was then dissolved in 2.5 mL toluene and allowed to react at 90° C. for 10 min in a microwave reactor. After being cooled to room temperature, the product was dissolved in 5 mL ethyl acetate and filtered with diatomite. The filtrate was dried over magnesium sulfate and vacuum concentrated. The concentrate was dissolved in 3 mL of a mixture of trifluoro fluoroacetic acid and methylene:chloride (1:1) and stirred for 12 hours. Neutralization with 10% NaOH, extraction with ethyl acetate, drying with magnesium sulfate and vacuum concentration were sequentially conducted in that order. The residue thus obtained was separated using column chromatography (developing solvent: hexane/ethyl acetate=1/1) to produce 115 mg of 2-[4-(3-chloropyridin-2-yl)phenyl]-6-morpholin-4-yl-1H-benzoimidazole (yield 70%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[C:6]([N+:18]([O-])=O)[CH:5]=1)[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[NH2:18][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[C:14]([O:15][CH2:16][CH3:17])=[CH:13][C:7]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9]
Reactant: [H][H]
Reactant: CCOC(=O)c1cc(OCC)c(OCC)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(OCC)c(OCC)cc1N
Yield: 99.9 %

Procedure:
According to the procedure described in Example 6A Step 3, a mixture of ethyl 4,5-diethoxy-2-nitrobenzoate (7.17 g, 25.3 mmol) and Pd/C (10%, 0.7 g) in EtOAc (150 mL) was stirred under 1 atmosphere of hydrogen at room temperature overnight, to afford ethyl 2-amino-4,5-diethoxybenzoate as a solid (6.401 g, 99%) 1H NMR (300 MHz, CDCl3) δ 7.36 (s, 1H), 6.14 (s, 1H), 5.60 (br, 2H), 4.30 (q, 2H), 4.05 (m, 4H), 1.44 (t, 3H), 1.38 (m, 6H); LC-MS (ESI) m/z 254 (M+H)+.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3]([OH:5])O.S([O-])([O-])(=O)=O.[Na+].[Na+].[F:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].Cl.Cl.[NH2:25][OH:26]>O>[F:15][C:16]1[CH:17]=[C:18]([NH:19][C:3](=[O:5])[CH:2]=[N:25][OH:26])[CH:20]=[CH:21][CH:22]=1
Reactant: Nc1cccc(F)c1
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: NO
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NO)Nc1cccc(F)c1
Temperature: 80 °C

Procedure:
A mixture of chloral hydrate (0.819 g) in water (25 ml) was treated with sodium sulfate (5.10 g), 3-fluoroaniline (0.43 ml), concentrated hydrochloric acid (0.3 ml), and hydroxylamine hydrochloride (0.938 g). The mixture was warmed to 80° C. for 2 hours then allowed to cool and then filtered. The solid was washed with water and then dried in air for 16 hours to afford N-(3-fluoro-phenyl)-2-hydroxyimino-acetamide (0.756 g) as a buff solid. LC-MS (METHOD B): RT=2.51 minutes; 181 (M+H)+. (b) 2-Hydroxyimino-N-(3-methoxy-phenyl)-acetamide
Reaction SMILES: C(O[C:4]([C:6]1([CH2:12][CH2:13]OC)[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])C.[F:16][C:17]([F:30])([F:29])[O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[S:25](Cl)(=[O:27])=[O:26].[CH2:31]([O:35][C:36]1[CH:42]=[CH:41][C:39]([NH2:40])=[CH:38][CH:37]=1)[CH2:32][CH2:33][CH3:34]>>[CH2:31]([O:35][C:36]1[CH:37]=[CH:38][C:39]([N:40]2[CH2:13][CH2:12][C:6]3([CH2:7][CH2:8][N:9]([S:25]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=4[O:18][C:17]([F:30])([F:29])[F:16])(=[O:27])=[O:26])[CH2:10][CH2:11]3)[C:4]2=[O:5])=[CH:41][CH:42]=1)[CH2:32][CH2:33][CH3:34]
Reactant: O=S(=O)(Cl)c1ccccc1OC(F)(F)F
Reactant: CCCCOc1ccc(N)cc1
Reactant: CCOC(=O)C1(CCOC)CCNCC1
Product: CCCCOc1ccc(N2CCC3(CCN(S(=O)(=O)c4ccccc4OC(F)(F)F)CC3)C2=O)cc1

Procedure:
Light brown solid. MS (ESI): 527.18 (MH+). This example was prepared in analogy to example 1 step C) to D) from 4-(2-methoxy-ethyl)-piperidine-4-carboxylic acid ethyl ester (example 1 step B)), 2-trifluoromethoxy-benzenesulfonyl chloride and 4-butoxy-aniline.