Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]([C:5]1[N:14]([CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[C:8]2[N:9]=[C:10](Cl)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[C:21]([O:25][C:26](=[O:40])[NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH2:39])=[CH:37][CH:38]=2)[CH2:29]1)([CH3:24])([CH3:23])[CH3:22]>>[C:21]([O:25][C:26](=[O:40])[NH:27][CH:28]1[CH2:32][CH2:31][N:30]([C:33]2[CH:34]=[N:35][C:36]([NH:39][C:10]3[N:11]=[CH:12][C:7]4[CH:6]=[C:5]([C:3](=[O:4])[N:2]([CH3:20])[CH3:1])[N:14]([CH:15]5[CH2:19][CH2:18][CH2:17][CH2:16]5)[C:8]=4[N:9]=3)=[CH:37][CH:38]=2)[CH2:29]1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)nc2)C1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCC(NC(=O)OC(C)(C)C)C4)cn3)nc2n1C1CCCC1
Yield: 14.7 %

Procedure:
Using Buchwald Procedure A, 2-chloro-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethyl amide (0.13 g, 0.444 mmol) and [1-(6-amino-pyridin-3-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (0.136 g, 0.488 mmol) gave {1-[6-(7-cyclopentyl-6-dimethylcarbamoyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)-pyridin-3-yl]-pyrrolidin-3-yl}-carbamic acid tert-butyl ester (35 mg, 15%) (following SiO2 chromatography, eluting with 0-3% MeOH/dichloromethane). MS (ESI) m/z 535.3 (M+H)+
Reaction SMILES: [CH3:1][N:2]([CH2:10][CH2:11][N:12]1[CH:21]=[CH:20][C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:25])[C:18]=2[N+:22]([O-])=O)[C:13]1=[O:26])[C:3](=[O:9])[O:4][C:5]([CH3:8])([CH3:7])[CH3:6].C(O)C.[Cl-].[NH4+].O>[Fe]>[NH2:22][C:18]1[C:17]([CH3:25])=[CH:16][CH:15]=[C:14]2[C:19]=1[CH:20]=[CH:21][N:12]([CH2:11][CH2:10][N:2]([CH3:1])[C:3](=[O:9])[O:4][C:5]([CH3:6])([CH3:8])[CH3:7])[C:13]2=[O:26]
Reactant: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cc1ccc2c(=O)n(CCN(C)C(=O)OC(C)(C)C)ccc2c1N
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A round bottom flask was charged with tert-butyl methyl(2-(6-methyl-5-nitro-1-oxoisoquinolin-2(1H)-yl)ethyl)carbamate (110 mg, 0.00031 mol) and ethanol (5 mL, 0.08 mol), and the solution was heated at 85° C. Ammonium chloride (300 mg, 0.006 mol) in water (2 mL, 0.09 mol) was added followed by iron (200 mg, 0.003 mol) in two portions. The reaction was stirred for 1 hour and poured onto dichloromethane (200 mL) and extracted. The solvent was removed under reduced pressure and the residue was purified by flash chromatography. to afford the desired product as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:23])=[CH:20][N:19]=3)[C:15]=2[O:16]C)[CH:6]=[CH:5][N:4]=1.[Cl-].[Li+]>CC(N(C)C)=O>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:12]=[N:13][N:14]([C:18]3[CH:33]=[CH:32][C:21]([C:22]([NH:24][CH2:25][CH:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[O:23])=[CH:20][N:19]=3)[C:15]=2[OH:16])[CH:6]=[CH:5][N:4]=1
Reactant: COc1nccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2OC)c1OC
Agent: [Cl-]
Agent: [Li+]
Solvent: CC(=O)N(C)C
Product: COc1nccc(-c2cnn(-c3ccc(C(=O)NCC4CCOCC4)cn3)c2O)c1OC
Yield: 26 %

Procedure:
Combined 6-(4-(2,3-dimethoxypyridin-4-yl)-5-methoxy-1H-pyrazol-1-yl)-N-((tetrahydro-2H-pyran-4-yl)methyl)nicotinamide (0.029 g, 0.064 mmol) and lithium chloride (0.014 g, 0.320 mmol) in DMA (0.639 mL) and heated at 50° C. for 16 hours. The reaction mixture was purified by preparative HPLC (SunFire™ C18, 5 μm, ID 30 mm×75 mm) eluting with ACN (with 0.1% ammonium hydroxide) in water (with 0.1% ammonium hydroxide) to give the title compound (7.3 mg, 26.0%). 1H NMR (400 MHz, DMSO-d6) δ 1.05-1.23 (m, 2 H) 1.49-1.58 (m, 2 H) 1.74 (ttt, J=11.1, 11.1, 7.3, 7.3, 3.7, 3.7 Hz, 1 H) 2.01 (s, 1 H) 3.08-3.13 (m, 3 H) 3.63 (s, 3 H) 3.77 (d, J=2.8 Hz, 1 H) 3.80 (s, 4 H) 7.07 (br. s., 1 H) 7.63 (d, J=5.3 Hz, 1 H) 8.04-8.09 (m, 2 H) 8.19 (dd, J=8.8, 2.3 Hz, 1 H) 8.45 (d, J=8.8 Hz, 1 H) 8.53 (t, J=5.8 Hz, 1 H) 8.78 (d, J=2.0 Hz, 1 H). MS m/z [M+H]+ 440.5.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[S:13]([OH:16])(=[O:15])=[O:14]>ClCCl>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:13]([OH:16])(=[O:15])=[O:14])=[C:7]([I:11])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cccc(I)c1
Reactant: O=S(=O)(O)Cl
Solvent: ClCCl
Product: CC(C)(C)c1ccc(S(=O)(=O)O)c(I)c1
Yield: 95.1 %

Procedure:
Synthesized as described for 1 using 1-tert-butyl-3-iodobenzene (9.65 g; 37.09 mmol), chlorosulfonic acid (3.20 mL; 48.22 mmol), and anhydrous dichloromethane (140 mL). Trituration of the crude product from hexanes yielded the title compound as a brown oil (12.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([NH:8][N:9]=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13])=[N:6][CH:7]=1.[C:18]([C:22](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:23])(OC)=[O:19]>O1CCOCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:17])[C:5]([N:8]2[C:18](=[O:19])[C:22]([CH3:23])=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=[N:9]2)=[N:6][CH:7]=1
Reactant: O=C(C=NNc1ncc(Cl)cc1F)C(F)(F)F
Reactant: COC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCCCCC
Solvent: C1COCCO1
Product: Cc1c(C(F)(F)F)cnn(-c2ncc(Cl)cc2F)c1=O
Temperature: 50 °C

Procedure:
A solution of 8.09 g 3((5-chloro-3-fluoro-pyridine-2-yl) -hydrazono)-1,1,1-trifluoro-propan-2-one and 11.5 g 1-carbomethoxyethylidene triphenylphosphine in 200 ml dioxane was stired for 30 min. at 20° C. and then heated until complete conversion at 50° C. The reaction mixture was diluted with hexane, filtered from solid triphenylphosphine oxide through silicagel and evaporated. Further purification of the residue on silicagel (ethyl acetate-hexane 3:7) led to the desired product with m.p. 91-93° C.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1)=O.P(Cl)(Cl)(Cl)(Cl)[Cl:19]>>[F:1][C:2]([F:17])([F:16])[C:3]([Cl:19])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([F:15])([F:14])[F:13])[CH:7]=1
Reactant: O=C(Nc1cccc(C(F)(F)F)c1)C(F)(F)F
Reactant: ClP(Cl)(Cl)(Cl)Cl
Product: FC(F)(F)C(Cl)=Nc1cccc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 24.4 %

Procedure:
An intimate mixture of 120.3 g of the product of Step A and 106.6 g of phosphorus pentachloride was heated at 80° C. under an inert atmosphere for 5 hours and phosphorus oxychloride was distilled at 25° C. at 40 mm Hg to obtain 31.44 g of 2,2,2-trifluoro-N-(3-trifluoromethylphenyl)-ethanimidoyl chloride with a boiling point of 75° C. at 30 mm Hg.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:26])[C:7]=1[NH:8][C:9]1[NH:10][C:11]2[C:17]3[CH2:18][C:19]([CH3:22])([CH3:21])[O:20][C:16]=3[C:15]([C:23](O)=[O:24])=[CH:14][C:12]=2[N:13]=1.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN(C=O)C.[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH2:59])=[CH:57][CH:56]=1>C1COCC1>[Cl:54][C:55]1[CH:61]=[CH:60][C:58]([NH:59][C:23]([C:15]2[C:16]3[O:20][C:19]([CH3:21])([CH3:22])[CH2:18][C:17]=3[C:11]3[NH:10][C:9]([NH:8][C:7]4[C:6]([Cl:26])=[CH:5][N:4]=[CH:3][C:2]=4[Cl:1])=[N:13][C:12]=3[CH:14]=2)=[O:24])=[CH:57][CH:56]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Reactant: Nc1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)Cc2c(c(C(=O)Nc3ccc(Cl)cc3)cc3nc(Nc4c(Cl)cncc4Cl)[nH]c23)O1
Yield: 9.8 %

Procedure:
The title compound was prepared following the procedure as described for Example-1 using 2-[(3,5-dichloropyridin-4-yl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-3, 0.080 g, 0.203 mmol), O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (0.128 g, 0.400 mmol), TEA (1.0 mL), DMF (1.0 mL), THF (5.0 mL) and 4-chloro aniline (0.052 g, 0.400 mmol) to afford 0.010 g of the desired product. 1HNMR (DMSO-d6): δ 1.57 (s, 6H), 3.07 (s, 2H), 7.14 (s, 1H), 7.40 (d, J=9.0 Hz, 2H), 7.72 (d, J=12.3 Hz, 2H), 8.45 (s, 2H), 9.72 (s, 1H), 11.00 (s, 1H), 11.45 (s, 1H); MS [M−H]−: 500.25.
Reaction SMILES: CC(S([NH:7][CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)[C:9]([F:12])([F:11])[F:10])=O)(C)C>CO>[F:12][C:9]([F:10])([F:11])[CH:8]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[N:14]=1)[NH2:7]
Reactant: Cc1cccc(C(NS(=O)C(C)(C)C)C(F)(F)F)n1
Solvent: CO
Product: Cc1cccc(C(N)C(F)(F)F)n1
Temperature: 38 °C

Procedure:
A solution of 2-methyl-N-[2,2,2-trifluoro-1-(6-methylpyridin-2-yl)ethyl]propane-2-sulfinamide (0.2 g, 0.68 mmol) in methanol (1.4 mL) was treated with (0.5 mL of a 4M solution, 2.0 mmol) and the reaction was heated to 38° C. for 16 hours. The reaction was cooled to room temperature and partitioned between water/ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase chromatography gave 2,2,2-trifluoro-1-(6-methylpyridin-2-yl)ethanamine. LC-MS EIMS: m/z 191.1 [M+H]+.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][C:5]([O:10][CH3:11])=[C:4]([F:12])[C:3]=1[C:13]1[C:22]2[N:21]=[CH:20][CH:19]=[N:18][C:17]=2[C:16]([C:23]([OH:25])=O)=[CH:15][CH:14]=1.[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH2:40])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1>>[CH3:26][N:27]1[CH2:32][CH2:31][N:30]([CH2:33][C:34]2[N:39]=[CH:38][C:37]([NH:40][C:23]([C:16]3[C:17]4[N:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]([C:3]4[C:2]([F:1])=[C:7]([O:8][CH3:9])[CH:6]=[C:5]([O:10][CH3:11])[C:4]=4[F:12])=[CH:14][CH:15]=3)=[O:25])=[CH:36][CH:35]=2)[CH2:29][CH2:28]1
Reactant: CN1CCN(Cc2ccc(N)cn2)CC1
Reactant: COc1cc(OC)c(F)c(-c2ccc(C(=O)O)c3nccnc23)c1F
Product: COc1cc(OC)c(F)c(-c2ccc(C(=O)Nc3ccc(CN4CCN(C)CC4)nc3)c3nccnc23)c1F
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 14.1 but using 8-(2,6-difluoro-3,5-dimethoxy-phenyl)-quinoxaline-5-carboxylic acid (Step 88.1), 6-(4-methyl-piperazin-1-ylmethyl)-pyridin-3-ylamine (Step 39.1), and stirring the reaction mixture for 16 h at rt. The crude product was purified by silica gel column chromatography (DCM/MeOH/NH3aq, 94:5:1) followed by trituration in Et2O. Title compound: ESI-MS: 535.1 [M+H]+; tR=3.15 min (System 1); TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([OH:16])=O)=[C:9]([O:10][CH:11]([CH3:13])[CH3:12])[C:5]=2[CH:4]=1.[NH2:19][C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25]CC)=[O:24]>>[CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]2[S:7][C:8]([C:14]([NH:19][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([OH:25])=[O:24])=[O:16])=[C:9]([O:10][CH:11]([CH3:12])[CH3:13])[C:5]=2[CH:4]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: COc1ccc2sc(C(=O)O)c(OC(C)C)c2c1
Product: COc1ccc2sc(C(=O)Nc3cccc(C(=O)O)c3)c(OC(C)C)c2c1
Yield: 84.8 %

Procedure:
Following a procedure analogous to Example 12, 5-methoxy-3-(1-methylethoxy)benzo[b]thiophene-2-carboxylic acid (7.0 g, 26 mmol) and ethyl 3-aminobenzoate (4.3 g, 26 mmol) provides 8.5 g (78%) of the intermediate ester. Saponification of the crude ester followed by recrystallization from aqueous ethanol gives 4.2 g (53%) of product; mp 197°-200° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:22])=[C:11]([CH2:13][C:14]([N:16]3[CH2:20][CH2:19][CH2:18][C@H:17]3[CH3:21])=O)[N:12]=2)=[CH:4][CH:3]=1.Cl.Cl[CH2:25][C:26]1[N:27]=[C:28]([CH3:31])[S:29][CH:30]=1>>[CH3:22][C:10]1[O:9][C:8]([C:5]2[CH:6]=[CH:7][C:2]([O:1][CH2:25][C:26]3[N:27]=[C:28]([CH3:31])[S:29][CH:30]=3)=[CH:3][CH:4]=2)=[N:12][C:11]=1[CH2:13][CH2:14][N:16]1[CH2:20][CH2:19][CH2:18][C@H:17]1[CH3:21]
Reactant: Cc1oc(-c2ccc(O)cc2)nc1CC(=O)N1CCC[C@H]1C
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: Cc1nc(COc2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)cs1

Procedure:
The title compound is prepared in a manner substantially similar to Example 58 from 2-[2-(4-Hydroxy-phenyl)-5-methyl-oxazol-4-yl]-1-(2-(R)-methyl-pyrrolidin-1-yl)-ethanone (See Example 56) and 4-(chloromethyl)-2-methylthiazole hydrochloride. MS (m/e): 398.3 (M+1)
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:34]=[CH:35][CH:36]=1)[CH2:5][N:6]([C@@H:24]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:27][CH2:26][CH2:25]1)[C:7]([C:9]1[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=1[C:21]([OH:23])=[O:22])=[O:8].[Cl:37][C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[C:42]([Cl:44])[CH:43]=1>>[Cl:37][C:38]1[CH:39]=[C:40]([C:2]2[CH:36]=[CH:35][CH:34]=[C:4]([CH2:5][N:6]([C@@H:24]3[C:33]4[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=4)[CH2:27][CH2:26][CH2:25]3)[C:7]([C:9]3[CH:14]=[C:13]([C:15]([OH:17])=[O:16])[C:12]([C:18]([OH:20])=[O:19])=[CH:11][C:10]=3[C:21]([OH:23])=[O:22])=[O:8])[CH:3]=2)[CH:41]=[C:42]([Cl:44])[CH:43]=1
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Reactant: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(Br)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O
Product: O=C(O)c1cc(C(=O)O)c(C(=O)N(Cc2cccc(-c3cc(Cl)cc(Cl)c3)c2)[C@H]2CCCc3ccccc32)cc1C(=O)O

Procedure:
The product from Example 15B (165 mg, 0.3 mmol) and 3,5-dichlorophenylboronic acid were processed as described in Example 85 to provide the title compound.
Reaction SMILES: Cl.C(O[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6])C.[CH3:18][NH:19][CH3:20]>C(O)C>[CH3:18][N:19]([CH3:20])[C:5]([C:7]1[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=1)=[NH:6]
Reactant: CNC
Reactant: CCOC(=N)c1ccc(C(=O)OCC)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C(=N)N(C)C)cc1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
1 g (3.9 mmol) of ethyl 4-ethoxycarbonimidoylbenzoate hydrochloride was stirred in a mixture of 3 ml of ethanol and 10 ml of 50% aqueous dimethylamine solution overnight. The solvent was evaporated, and 10 ml of dioxane containing 4 N hydrogen chloride and 1 ml of ethanol were added to the residue. They were stirred at room temperature for 5 days, and the solvent was evaporated. 1 N sodium hydroxide was added to the residue. After the extraction with dichloromethane, the organic layer was washed with saturated aqueous common salt solution and then dried over anhydrous magnesium sulfate. The solvent was evaporated to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.[CH3:37][O:38][CH2:39][CH2:40][CH2:41][NH2:42]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:42][CH2:41][CH2:40][CH2:39][O:38][CH3:37])=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: COCCCN
Product: COCCCNC(=O)C(c1ccccc1)N1CCCc2cc(OC)c(OC)cc2C1Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with 3-methoxypropylamine.
Reaction SMILES: S(Cl)([Cl:3])=O.[C:5]1([NH:15][CH2:16][C:17]([OH:19])=[O:18])[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1.[CH3:20]O>C(OCC)C>[ClH:3].[CH3:20][O:18][C:17](=[O:19])[CH2:16][NH:15][C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][CH:6]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CNc1cccc2ccccc12
Reactant: CO
Solvent: CCOCC
Product: COC(=O)CNc1cccc2ccccc12
Product: Cl
Reaction time: 3 h
Yield: 98 %

Procedure:
33 mL of thionyl chloride was added dropwise to a mixture of 50.3 g of 1-naphthylglycine (racemic modification) and 200 mL of methanol (dehydrated) at an inner temperature of 35° C. over 1 hour and the mixture was stirred at the same temperature for 3 hours to effect reaction. The reaction mixture was concentrated and the concentrated residue obtained was mixed with 200 mL of diethyl ether. Then, the crystals produced were isolated by filtration and washed with 50 mL of diethyl ether. The crystals isolated by filtration were dried at an inner temperature of 50° C. under reduced pressure to obtain 61.9 g of ochre 1-naphthylglycine methyl ester hydrochloride (yield: 98%).
Reaction SMILES: [N+:1]([CH2:4][C:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=1)([O-])=O.[H][H]>CO.[Pd]>[NH2:1][CH2:4][CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1
Reactant: [H][H]
Reactant: O=[N+]([O-])CC1=Cc2ccccc2CC1
Agent: [Pd]
Solvent: CO
Product: NCC1CCc2ccccc2C1

Procedure:
2-Nitromethyl-3,4-dihydronaphthalene (XXXV) (25 g) and 20% Pd/C (1.0 g) were combined in MeOH (200 ml) and shaken in a Parr hydrogenator at 3 atmospheres hydrogen pressure for 24 hours, by which time the theoretical amount of hydrogen (4 equivalents) had been absorbed. Removal of the catalyst and solvent left an oil (24 g) which was converted to its HCl salt by solution in MeOH and addition of concentrated HCl. The product, compound XXXI.HCl, was recrystallized from 2-propanol, yielding a white solid, m.p. 230° (dec.). Its elemental analysis and NMR spectrum were consistent with the structure indicated.
Reaction SMILES: CCN(C(C)C)C(C)C.[CH3:10][CH:11]([O:13][C:14]1[CH:15]=[C:16]([CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[C:17](O)=[O:18])[CH3:12].[NH2:37][C:38]1[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:12][CH:11]([O:13][C:14]1[CH:15]=[C:16]([C:17]([NH:37][C:38]2[CH:42]=[CH:41][N:40]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:39]=2)=[O:18])[CH:20]=[C:21]([O:23][C:24]2[CH:36]=[CH:35][C:27]3[C:28](=[O:34])[N:29]([CH3:33])[CH2:30][CH2:31][O:32][C:26]=3[CH:25]=2)[CH:22]=1)[CH3:10]
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Reactant: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Oc1cc(Oc2ccc3c(c2)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
DIPEA (0.26 mL, 1.5 mmol) was added to a solution of 3-[(1-methylethyl)oxy]-5-[(4-methyl-5-oxo-2,3,4,5-tetrahydro-1,4-benzoxazepin-8-yl)oxy]benzoic acid (185 mg, 0.5 mmol), 1,1-dimethylethyl 3-amino-1H-pyrazole-1-carboxylate (110 mg, 0.6 mmol) and HATU (247 mg, 0.65 mmol) in DMF (2 mL) and the mixture stirred at RT for 16 hours. The mixture was poured onto water (30 mL), extracted with ethyl acetate (3×15 mL), the combined organic extracts washed with 1N citric acid, saturated sodium hydrogen carbonate, brine, dried (MgSO4) and evaporated in vacuo. The residue was chromatographed on silica, eluting with 60% ethyl acetate in isohexane, to give the desired compound (32 mg). 1H NMR δ (CDCl3): 1.3 (d, 6H), 1.55 (s, 9H), 3.15 (s, 3H), 3.5 (t, 2H), 4.3 (t, 2H), 4.5 (m, 1H), 6.5 (s, 1H), 6.7 (m, 2H), 7.1 (d, 1H), 7.8 (d, 1H), 7.95 (d, 1H), 8.7 (s, 1H); m/z 535 (M−H)−
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:3][CH2:2]1.Cl[C:22]1[NH:23][C:24]2[CH:30]=[CH:29][CH:28]=[CH:27][C:25]=2[N:26]=1>CC(O)C>[O:1]1[CH2:2][CH2:3][CH:4]([C:7]2[C:8]([O:13][C:14]3[CH:20]=[CH:19][C:17]([NH:18][C:22]4[NH:26][C:25]5[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=5[N:23]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][N:12]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc(Oc2nccnc2C2CCOCC2)cc1
Reactant: Clc1nc2ccccc2[nH]1
Solvent: CC(C)O
Product: c1ccc2[nH]c(Nc3ccc(Oc4nccnc4C4CCOCC4)cc3)nc2c1
Temperature: 170 °C

Procedure:
A glass microwave reaction vessel was charged with 4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)aniline (0.1536 g, 0.566 mmol) and 2-chlorobenzimidazole (0.095 g, 0.623 mmol) in IPA. The reaction mixture was stirred and heated in a Biotage Initiator microwave reactor at 170° C. for 30 min. The crude product was adsorbed onto a plug of silica gel and chromatographed through a Biotage pre-packed silica gel column (40S), eluting with a gradient of 1% to 5% MeOH in DCM, to provide N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyrazin-2-yloxy)phenyl)-1H-benzo[d]imidazol-2-amine. MS (ESI, pos. ion) m/z: 388.0 (M+1). IC50 (uM) +++++.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH3:17])[C:10]=1[CH3:18])=[O:5])[CH3:2].B(Br)(Br)Br.CCO.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[CH2:1]([O:3][C:4]([CH:6]1[CH2:8][CH:7]1[C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH3:17])[C:10]=1[CH3:18])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CC1c1ccc(OC)c(C)c1C
Agent: BrB(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: CCOC(=O)C1CC1c1ccc(O)c(C)c1C
Reaction time: 2 h
Yield: 79.4 %

Procedure:
2-(4-Methoxy-2,3-dimethyl-phenyl)-cyclopropane carboxylic acid ethyl ester (0.32 g, 1.29 mmol) obtained in Step B was dissolved in DCM (5 mL), and the reactant was cooled to 0˜5° C. BBr3 solution (3.90 mL, 3.87 mmol, 1M/DCM) was added dropwise thereto, and the mixture was stirred at 0˜5° C. for 2 hours. After the termination of the reaction, EtOH and saturated sodium bicarbonate solution were added thereto in turn, and the mixture was stirred. The separated organic layer was concentrated under reduced pressure, and the residue was purified by column chromatography (eluent, EtOAc/Hex=1/5) to obtain the title compound (0.24 g, 79%).
Reaction SMILES: [CH2:1]([OH:3])[CH3:2].[OH-].C([N+](CC)(CC)CC)C.[O:14]1[CH:20]2[CH:15]1CC(CC[Si](OC)(OC)OC)[CH2:18][CH2:19]2.C1([Si](OC)(OC)[O:37]C)C=CC=CC=1>C(OCC)(=O)C.O>[C:1]([O:37][CH:19]([CH3:18])[CH2:20][O:14][CH3:15])(=[O:3])[CH3:2]
Reactant: CO[Si](CCC1CCC2OC2C1)(OC)OC
Reactant: CCO
Reactant: CO[Si](OC)(OC)c1ccccc1
Agent: CC[N+](CC)(CC)CC
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Product: COCC(C)OC(C)=O
Temperature: 40 °C
Yield: 100 %

Procedure:
In a 3000 ml glass flask, 1400 g of ethanol, 700 g of pure water, and 50 g of 25% tetraethylammonium hydroxide were placed, and stirred. To this mixture was added dropwise a mixture of 139 g of 2-(3,4-epoxycyclohexyl) ethyl trimethoxy silane and 32 g of phenyl trimethoxy silane at a liquid temperature of 40 degrees C. After that, the solution was stirred for 2 hours at 40 degrees C. After the reaction finished, the reaction was quenched by adding 35 g of acetic acid, and ethanol was removed under a reduced pressure. To thus-obtained solution was added 2000 ml of ethyl acetate, and a water layer was separated. An organic layer was washed twice with ultrapure water. To this contents was added 600 g of propylene glycol monomethyl ether acetate (PGMEA), and the contents were heated up to a liquid temperature of 40 degrees C. under a reduced pressure to remove ethyl acetate and to give a PGMEA solution of a polymer.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]1=[O:12])=[O:5])[CH3:2].CCN(C(C)C)C(C)C.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=1[OH:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCCC1=O
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1=C(O)CCCC1
Yield: 145.3 %

Procedure:
Combine 2-oxo-cyclohexanecarboxylic acid ethyl ester (10.0 g, 55.0 mmol), Hunig's base (23.0 mL, 132.0 mmol), dichloromethane (100.0 mL), and trifluoromethane sulphonic anhydride (11.1 mL, 66.0 mmol) at −78° C. and then stir at room temperarture for 18 hours under a nitrogen atmosphere. Add water, then wash with sat sodium bicarbonate solution, citric acid, then brine, and dry over sodium sulfate. Concentrate under vacuum and flash chromatograph using 10% to 40% DCM/hexanes eluent to yield the titled compound (13.6 g, 82%). TLC Rf=0.25 in 40% DCM/hexanes. 1H NMR (CDCl3): 4.26 (q, 2H, J=7.0 Hz), 2.5 (m, 2H), 2.4 (m, 2H), 1.8 (m, 2H), 1.7 (m, 2H), 1.3 (t, 3H, J=7 Hz).