Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]2[S:24][C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:39]#[N:40])[C:22]=3[NH:25][C:26]3[CH:31]=[CH:30][C:29]([O:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)=[CH:28][CH:27]=3)[CH:17]=2)=[CH:12][CH:11]=1)=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O.C(O)(=O)C>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[S:24][C:23]4[C:18](=[N:19][CH:20]=[C:21]([C:39]#[N:40])[C:22]=4[NH:25][C:26]4[CH:31]=[CH:30][C:29]([O:32][C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=5)=[CH:28][CH:27]=4)[CH:17]=3)=[CH:14][CH:15]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: N#Cc1cnc2cc(-c3ccc(C=O)cc3)sc2c1Nc1ccc(Oc2ccccc2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(-c3cc4ncc(C#N)c(Nc5ccc(Oc6ccccc6)cc5)c4s3)cc2)CC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.7 %

Procedure:
1-Methylpiperazine (65 μL, 0.59 mmol) is added to a suspension of 2-(4-formylphenyl)-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile (200 mg, 0.45 mmol) in 4 mL of dichloromethane and 1 mL of N,N-dimethylformamide. The reaction mixture is cooled to 0° C. and sodium triacetoxyborohydride (474 mg, 2.24 mmol) is added. After stirring at 0° C. for 10 minutes, 3 drops of acetic acid are added and the reaction mixture is allowed to warm to room temperature and stirred for 4 hours. The reaction is quenched by the addition of water and then partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer is washed with water, dried over sodium sulfate, filtered and concentrated in vacuo. The residue is purified by flash column chromatography eluting with 5% methanol in dichloromethane to provide 138 mg of 2-[4-(4-methylpiperazin-1-ylmethyl)phenyl]-7-[(4-phenoxyphenyl)amino]thieno[3,2-b]pyridine-6-carbonitrile as white crystals, mp 199-201° C.; 1H NMR (DMSO-d6) δ 2.17 (s, 3H), 2.37 (br s, 8H), 3.50 (s, 2H), 7.05-7.18 (m, 5H), 7.35-7.44 (m, 6H), 7.66 (d, J=8 Hz, 2H), 7.86 (s, 1H), 8.59 (s, 1H), 9.58 (s, 1H); MS 532.3 (M+H)+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:36][C:37]1[N:38]=[C:39]([CH3:42])[S:40][CH:41]=1.CN(C)C=O>C(OCC)(=O)C>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:36][C:37]2[N:38]=[C:39]([CH3:42])[S:40][CH:41]=2)[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Cc1nc(CCl)cs1
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCc1nc(C)n(Cc2csc(C)n2)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 58.8 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1.22 g), potassium carbonate (0.94 g), 4-(chloromethyl)-2-methyl-1,3-thiazole hydrochloride (0.63 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a pale-yellow solid (0.94 g, 55%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:7](Cl)(=[O:10])[CH:8]=[CH2:9].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[C:7]([C:4]1[CH:5]=[CH:6][N:1]=[CH:2][CH:3]=1)(=[O:10])[CH:8]=[CH2:9]
Reactant: c1ccncc1
Reactant: C=CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: C=CC(=O)c1ccncc1

Procedure:
Pyridine (0.5 mL), acryloyl chloride (120 mg), and aluminium chloride (150 mg) were reacted in dichloromethane (1 mL) at from 0° C. to room temperature for 2 hours. The resultant was treated in the same manner as described in Example 1 to obtain the title compound (37.9 mg).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][CH2:12][C:13]2[CH:14]=[C:15]([C:19]3[CH:20]=[C:21]([C:29]([CH3:33])([CH3:32])[C:30]#[N:31])[CH:22]=[C:23]4[C:28]=3[N:27]=[CH:26][CH:25]=[CH:24]4)[CH:16]=[CH:17][CH:18]=2)=[CH:7][CH:6]=1)(=O)=O.C1CCN2C(=NCCC2)CC1.[CH2:45]([N:47]=[C:48]=[O:49])[CH3:46]>C1COCC1.C([O-])(O)=O.[Na+]>[C:30]([C:29]([CH3:33])([CH3:32])[C:21]1[CH:22]=[C:23]2[C:28](=[C:19]([C:15]3[CH:14]=[C:13]([CH:18]=[CH:17][CH:16]=3)[CH2:12][N:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2][CH3:1])=[CH:6][CH:7]=3)[C:48]([NH:47][CH2:45][CH3:46])=[O:49])[CH:20]=1)[N:27]=[CH:26][CH:25]=[CH:24]2)#[N:31]
Reactant: CC(C)(C#N)c1cc(-c2cccc(CNc3ccc(S(C)(=O)=O)cc3)c2)c2ncccc2c1
Reactant: CCN=C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: CCNC(=O)N(Cc1cccc(-c2cc(C(C)(C)C#N)cc3cccnc23)c1)c1ccc(SC)cc1
Temperature: 60 °C
Reaction time: 12 h

Procedure:
To solution of 2-(8-{3-[(4-methanesulfonyl-phenylamino)-methyl]-phenyl}-quinolin-6-yl)-2-methyl-propionitrile from EXAMPLE 36 (Step 1) (1.0 eq) in 2 mL of THF (0.17M) was added DBU (1.1 eq) and ethyl-isocyanate (8.3 eq). The resulting mixture was stirred at 60° C. for 12 h, poured in saturated aqueous NaHCO3 and extracted with EtOAc (2×). The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated. Flash chromatography (CH2Cl2:EtOAc; 4:1) afforded a contaminated sample of the desired compound as a oil. It was used as such in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[NH:7][CH:6]=1)=[O:4].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:1][O:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[N:7]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:6]=1)=[O:4]
Reactant: COC(=O)c1c[nH]c2ccc(Cl)cc12
Reactant: BrCc1ccccc1
Product: COC(=O)c1cn(Cc2ccccc2)c2ccc(Cl)cc12

Procedure:
Prepare by a method similar to Example 48 using 5-chloro-1H-indole-3-carboxylic acid methyl ester and benzyl bromide.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH3:24][N:25]1[C:29](=[O:30])[CH2:28][NH:27][C:26]1=[O:31]>>[CH3:1][C:2]1[C:3]([N:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([N:27]4[CH2:28][C:29](=[O:30])[N:25]([CH3:24])[C:26]4=[O:31])=[CH:19][CH:18]=3)=[O:16])[CH2:11][CH2:10]2)=[N:4][CH:5]=[C:6]([CH3:8])[CH:7]=1
Reactant: CN1C(=O)CNC1=O
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(I)cc3)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CC(=O)N(C)C4=O)cc3)CC2)c(C)c1
Yield: 30.6 %

Procedure:
Using [4-(3,5-dimethylpyridin-2-yl)piperazin-1-yl](4-iodophenyl)methanone (169 mg) described in Preparation Example 113 and 3-methylimidazolidine-2,4-dione (46 mg) described in Preparation Example 214 and by the reaction and treatment in the same manner as in Example 536, the title compound (50 mg) was obtained.
Reaction SMILES: [CH3:1][CH:2]([CH3:12])[CH2:3][CH2:4][C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)=O.[CH3:13][N:14]([CH3:16])[NH2:15]>CCO>[CH3:13][N:14]([CH3:16])[N:15]=[C:5]([C:7]1[O:8][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:3][CH:2]([CH3:12])[CH3:1]
Reactant: CN(C)N
Reactant: CC(C)CCC(=O)c1ccco1
Solvent: CCO
Product: CC(C)CCC(=NN(C)C)c1ccco1

Procedure:
A solution of 2-(4-methylvaleryl)furan (1 mmol) and N,N-dimethylhydrazine (1.5 mmol) in EtOH was heated at reflux for 24 h. Evaporation and distilation give 2-(4-methylvaleryl)furan dimethylhydrazone as a brown oil.
Reaction SMILES: C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[CH3:34][O:35][CH2:36][CH2:37][N:38]1[CH:42]=[CH:41][C:40]([C:43]2[CH:47]=[CH:46][S:45][CH:44]=2)=[C:39]1[C:48](=[O:52])[C:49]([OH:51])=O.[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]=[C:56]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][C:70]([NH2:73])=[CH:69][CH:68]=3)[CH2:63][CH2:62]2)[CH:55]=1>ClCCl>[CH3:53][C:54]1[CH:59]=[C:58]([CH3:60])[N:57]=[C:56]([N:61]2[CH2:66][CH2:65][N:64]([C:67]3[CH:72]=[CH:71][C:70]([NH:73][C:49](=[O:51])[C:48]([C:39]4[N:38]([CH2:37][CH2:36][O:35][CH3:34])[CH:42]=[CH:41][C:40]=4[C:43]4[CH:47]=[CH:46][S:45][CH:44]=4)=[O:52])=[CH:69][CH:68]=3)[CH2:63][CH2:62]2)[CH:55]=1
Reactant: COCCn1ccc(-c2ccsc2)c1C(=O)C(=O)O
Reactant: Cc1cc(C)nc(N2CCN(c3ccc(N)cc3)CC2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCCn1ccc(-c2ccsc2)c1C(=O)C(=O)Nc1ccc(N2CCN(c3cc(C)cc(C)n3)CC2)cc1
Temperature: 90 °C
Reaction time: 1 h
Yield: 26.3 %

Procedure:
Diisopropylethylamine (0.40 mL, 2.17 mmol), (2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate) (0.28 mg, 0.72 mmol) was added to a solution of [1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-oxo-acetic acid (200 mg, 0.72 mmol) in dry dichloromethane at room temperature and the reaction mixture stirred for 1 h. 4-[4-(4,6-Dimethyl-pyridin-2-yl)-piperazin-1-yl]-phenylamine (160 mg, 0.56 mmol) was added and the mixture was then heated in a sealed tube at 90° C. for 18 h. The reaction mixture was cooled to room temperature, washed with water and brine. The organic layer was dried over anhydrous sodium sulfate and evaporated under reduced pressure to give crude compound which was purified by preparative HPLC to afford N-{4-[4-(4,6-dimethyl-pyridin-2-yl)piperazin-1-yl]-phenyl}-2-[1-(2-methoxy-ethyl)-3-thiophen-3-yl-1H-pyrrol-2-yl]-2-oxo-acetamide (80 mg, 20%) as a solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:21]=O)[C:5]([N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[N:6][CH:7]=1.C[O-].[Na+].O>C(=O)(OC)OC.CO>[Br:1][C:2]1[CH:7]=[N:6][C:5]2[N:8]([CH2:17][CH:18]([CH3:20])[CH3:19])[CH2:9][CH2:10][CH2:11][C:12]([C:13]([O:15][CH3:16])=[O:14])=[CH:21][C:4]=2[CH:3]=1
Reactant: COC(=O)CCCCN(CC(C)C)c1ncc(Br)cc1C=O
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: COC(=O)OC
Product: COC(=O)C1=Cc2cc(Br)cnc2N(CC(C)C)CCC1
Temperature: 65 °C
Yield: 92.7 %

Procedure:
To a solution of methyl 5-[(5-bromo-3-formylpyridin-2-yl)(isobutyl)amino]pentanoate (840 mg) in dimethyl carbonate (20 ml) was added a 28% sodium methoxide solution in methanol (874 mg), and the mixture was heated at 65° C. for 3 hours under a nitrogen atmosphere. The mixture was returned to room temperature, water was added, and then the resulting mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to obtain the residue, and then the obtained residue was washed with hexane-ethyl acetate to give methyl 3-bromo-10-isobutyl-7,8,9,10-tetrahydropyrido[2,3-b]azocine-6-carboxylate (741 mg) as yellow crystals.
Reaction SMILES: [C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][Si](C(C)C)(C(C)C)C(C)C)[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1.[F-].[Cs+].Br[CH2:29][CH2:30][O:31][CH2:32][CH3:33]>C(C#N)(C)=O.C(Cl)Cl>[C:1]1([C:6]2[NH:7][C:8]3[C:13]([CH:14]=2)=[C:12]([O:15][CH2:29][CH2:30][O:31][CH2:32][CH3:33])[CH:11]=[CH:10][CH:9]=3)[CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: CCOCCBr
Reactant: CC(C)[Si](Oc1cccc2[nH]c(C3=CCCC3)cc12)(C(C)C)C(C)C
Agent: CC(=O)C#N
Agent: [Cs+]
Agent: [F-]
Solvent: ClCCl
Product: CCOCCOc1cccc2[nH]c(C3=CCCC3)cc12
Temperature: 60 °C
Yield: 73.7 %

Procedure:
To 500 mg (1.41 mmol) of 2-cyclopent-1-enyl-4-triisopropylsilyloxy-1H-indole (14d step 1) in 5 mL AcCN was added 255 mg (1.68 mmol, 1.2 eq) of CsF and 479 μL (4.23 mmol, 3 eq) 2-bromoethylethyl ether. The reaction was heated at 60° C. overnight then cooled to rt, diluted with CH2Cl2 and filtered through celite and concentrated. The residue was partitioned between ether and H2O, the ether layer was then washed with aqueous NaCl solution, dried (MgSO4), and concentrated under vacuum to yield 282 mg (74%) of 2-cyclopent-1-enyl-4-(2-ethoxy-ethoxy)-1H-indole.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:15]([O:17][CH2:18][CH3:19])=[O:16].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O>C(Cl)Cl>[O:1]=[CH:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCOC(=O)C(CCCCCCCCCCCCO)C(=O)OCC
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CCOC(=O)C(CCCCCCCCCCCC=O)C(=O)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 73.1 %

Procedure:
Diethyl 2-(12-hydroxydodecyl)malonate (3.91 g, 11.35 mmol) was dissolved in dry DCM (60 ml), then PCC (3.67 g, 17.025 mmol) was added portion-wise to it at 0° C. The reaction was allowed to warm to room temperature and stirring was continued for another 3 h. The reaction mixture was concentrated under reduced pressure and purified by silica gel column (8% EtOAc in Hexane) to give diethyl 2-(12-oxododecyl)malonate (2.84 g, 73%) as a colorless liquid.
Reaction SMILES: [C:1]([CH:6]1[CH2:11][CH2:10][CH:9]([CH:12]=O)[CH2:8][CH2:7]1)([CH2:4][CH3:5])([CH3:3])[CH3:2].[C:14]([C:19](=P(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[CH3:20])([O:16][CH2:17][CH3:18])=[O:15].C(O)(=O)C1C=CC=CC=1>C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14](=[O:15])[C:19]([CH3:20])=[CH:12][CH:9]1[CH2:8][CH2:7][CH:6]([C:1]([CH2:4][CH3:5])([CH3:2])[CH3:3])[CH2:11][CH2:10]1)[CH3:18]
Reactant: CCC(C)(C)C1CCC(C=O)CC1
Reactant: CCOC(=O)C(C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C(O)c1ccccc1
Solvent: Cc1ccccc1
Product: CCOC(=O)C(C)=CC1CCC(C(C)(C)CC)CC1

Procedure:
A mixture of 46.3 g of 4-tert.amyl-cyclohexane-1-carboxaldehyde, 92.3 g of (α-carbethoxy-ethylidene)-triphenyl-phosphorane and 7.6 g of benzoic acid in 250 ml of toluene is heated at reflux for 3.5 hours under nirogen gasification and the toluene is evaporated. The oily-crystalline residue is dissolved in 1600 ml of methanol/water (4:1) and exhaustively extracted with hexane. The combined hexane extracts are washed with sodium carbonate solution and water, dried over sodium sulphate and evaporated. By distillation there is obtained pure 3-(4-tert.amyl-cyclohexyl)-2-methyl-acrylic acid ethyl ester of boiling point 113°-115° C./0.03 Torr.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([N:10]2[C:16](=[O:17])[C:15]3[CH:18]=[CH:19][C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])=[CH:21][C:14]=3[NH:13][CH2:12][CH2:11]2)[C:3]=1[CH:4]=[O:5].[CH3:26][N:27]1[CH:32]=[C:31](B2OC(C)(C)C(C)(C)O2)[CH:30]=[C:29]([NH:42][C:43]2[CH:48]=[CH:47][C:46]([C:49]([N:51]3[CH2:56][CH2:55][O:54][CH2:53][CH2:52]3)=[O:50])=[CH:45][N:44]=2)[C:28]1=[O:57].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C(O)CCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[C:22]([C:20]1[CH:19]=[CH:18][C:15]2[C:16](=[O:17])[N:10]([C:6]3[CH:7]=[CH:8][CH:9]=[C:2]([C:31]4[CH:30]=[C:29]([NH:42][C:43]5[CH:48]=[CH:47][C:46]([C:49]([N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)=[O:50])=[CH:45][N:44]=5)[C:28](=[O:57])[N:27]([CH3:26])[CH:32]=4)[C:3]=3[CH:4]=[O:5])[CH2:11][CH2:12][NH:13][C:14]=2[CH:21]=1)([CH3:24])([CH3:23])[CH3:25]
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Reactant: CC(C)(C)c1ccc2c(c1)NCCN(c1cccc(Br)c1C=O)C2=O
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCCCO
Product: Cn1cc(-c2cccc(N3CCNc4cc(C(C)(C)C)ccc4C3=O)c2C=O)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
2-Bromo-6-(8-tert-butyl-5-oxo-1,2,3,5-tetrahydrobenzo[e][1,4]diazepin-4-yl)-benzaldehyde (0.100 g, 0.23 mmol),1-Methyl-3-[5-(morpholine-4-carbonyl)-pyridin-2-ylamino]-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyridin-2-one (0.091 g, 1.0 eq), xantphos (12 mg, 0.09 eq), and potassium phosphate (0.096 g, 2 eq) were taken up in n-butanol (3 mL) and water (0.5 mL) and a stream of argon was bubbled through the mixture for 1 minute. Pd(dba)2 (0.008 g, 0.06 eq) was added and argon was bubbled through for an additional minute. The reaction was heated under argon and stirred at 100° C. for 3 hours. The reaction was cooled, solvent was removed under vacuum, and placed directly on a silica gel column, eluted with 100% ethyl acetate, then 4% MeOH in CH2Cl2 to give the title compound as a brown solid, 76 mg as a 60:40 mixture (the title compound as the major component) with an impurity and used without further purification.
Reaction SMILES: C([NH:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)(OC(C)(C)C)=O.[ClH:18]>O1CCOCC1>[ClH:18].[NH2:8][CH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1
Reactant: CC(C)(C)OC(=O)NC1CCc2ccccc21
Agent: Cl
Solvent: C1COCCO1
Product: NC1CCc2ccccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
6-(N-Me, N-Et Carbamyloxy) N-Boc aminoindan (7.8 g. 23.3 mmol) was dissolved in dioxane (80 ml), and a 20% solution of gas. HCl in dioxane (80 ml) was added. After 2 hr stirring at RT the solvent was evaporated in-vacuo and the residue was treated with dry ether (200 ml) and the mixture stirred at RT for 4 hrs and filtered, to give 6.15 g (0.7 mmol, 97%) of 6-(N-Me, N-Et carbamyloxy) aminoindan hydrochloride.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[I:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]2)[CH:11]=1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[Cl:1][CH2:2][C:3]([N:18]([CH2:19][CH2:20][OH:21])[CH:15]1[CH2:14][CH2:13][CH:12]([N:10]2[CH:11]=[C:7]([I:6])[CH:8]=[N:9]2)[CH2:17][CH2:16]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: OCCNC1CCC(n2cc(I)cn2)CC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCl)N(CCO)C1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloro-acetyl chloride (0.25 mL; 3.14 mmol; 1.1 eq.) was added dropwise over 2 min to a solution of 2-[4-(4-Iodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 1.0 g; 2.89 mmol; 1.0 eq.) and DIEA (2.00 ml; 11.45 mmol; 3.96 eq.) in THF (80.00 mL) at −30° C. The reaction solution was allowed to warm slowly to RT and stirred for 16 h. It was then poured into a 1 N HCl solution and extracted with DCM. Combined organic phases were washed with saturated NaHCO3 solution, dried over magnesium sulfate, filtrated and concentrated to give 2-Chloro-N-(2-hydroxy-ethyl)-N-[4-(4-iodo-pyrazol-1-yl)-cyclohexyl]-acetamide as a brown oil. This oil was redissolved in THF (30 mL; 370 mmol; 128 eq.) and sodium tert-butoxide (2M solution in THF; 30 mL; 60.0 mmol; 21 eq.) was added in one portion. The reaction solution was heated at 40° C. for 1 h then cooled to RT and poured into 1 N HCl solution. It was extracted with DCM (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated sequentially with EtOAc and Et2O, filtered and dried to give the title compound as a yellow solid (275 mg; 21%). 1H NMR (300 MHz, DMSO) δ 7.98 (s, 1H), 7.50 (s, 1H), 4.40-4.25 (m, 1H), 4.25-4.10 (m, 1H), 4.03 (s, 2H), 3.87-3.75 (m, 2H), 3.32-3.23 (m, 2H), 2.14-1.99 (m, 2H), 1.93-1.60 (m, 6H). MS (ESI+): 376.2.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[N:7]1[C:11]2[CH:12]=[CH:13][C:14]([C:16](=[N:19]O)CC)=[CH:15][C:10]=2[N:9]=[CH:8]1.[CH2:21]1COC[CH2:22]1>[Ni]>[CH2:21]([C:15]1[C:10]2[N:9]=[CH:8][N:7]([CH:2]3[CH2:3][CH2:4][CH2:5][CH2:6][O:1]3)[C:11]=2[CH:12]=[CH:13][C:14]=1[CH2:16][NH2:19])[CH3:22]
Reactant: C1CCOC1
Reactant: CCC(=NO)c1ccc2c(c1)ncn2C1CCCCO1
Agent: [Ni]
Product: CCc1c(CN)ccc2c1ncn2C1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 35 %

Procedure:
To a solution of 1-(1-(tetrahydro-2H-pyran-2-yl)-1H-benzo[d]imidazol-5-yl)propan-1-one oxime (30 mg, 0.11 mmol) in THF (3 mL), Raney-Ni (50 mg) was added. The mixture was stirred at RT overnight. Removal of solvent followed by reverse-phase chromatography gave (4-ethyl-1-tetrahydropyran-2-yl-benzimidazol-5-yl)methanamine (10 mg, 35% yield) as a colorless oil.
Reaction SMILES: C(OC([N:6]1[CH2:30][C@:29]2([C:31](=[O:33])[CH3:32])[C@@H:8]([CH2:9][C@H:10]3[C@H:23]4[C@@:14]([F:27])([C@:15]5([CH3:26])[C:20]([C@@H:21]([F:24])[CH2:22]4)=[CH:19][C:18](=[O:25])[CH:17]=[CH:16]5)[C@@H:13]([OH:28])[CH2:12][C@@:11]32[CH3:34])[CH2:7]1)=O)=C.[ClH:35].O1CCOCC1>C(Cl)Cl>[ClH:35].[C:31]([C@:29]12[C@@:11]3([CH3:34])[CH2:12][C@H:13]([OH:28])[C@@:14]4([F:27])[C@H:23]([C@@H:10]3[CH2:9][C@H:8]1[CH2:7][NH:6][CH2:30]2)[CH2:22][C@H:21]([F:24])[C:20]1[C@:15]4([CH3:26])[CH:16]=[CH:17][C:18](=[O:25])[CH:19]=1)(=[O:33])[CH3:32]
Reactant: C=COC(=O)N1C[C@@H]2C[C@H]3[C@@H]4C[C@H](F)C5=CC(=O)C=C[C@]5(C)[C@@]4(F)[C@@H](O)C[C@]3(C)[C@]2(C(C)=O)C1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 45 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
A solution of compound 176 (495 mg, 1.041 mmol) and HCl 4M in dioxane (5205 μl, 20.82 mmol) in DCM (20 ml) is stirred at RT for 30 minutes. The solvent is evaporated and the crude is dried in vacuo for 16 hours. The crude is dissolved in MeOH (30 ml) and stirred at 45° C. for 30 minutes. The solvent is evaporated and the crude is triturated with AcOEt/Et2O (1/1 mixture) to afford the title compound (457 mg, 99%).
Reaction SMILES: [C:1]([C:4]1[S:5][C:6](C(OC)=O)=[CH:7][C:8]=1[OH:9])(=[O:3])[CH3:2].[OH-].[Na+]>[Cu].N1C2C(=CC=CC=2)C=CC=1>[C:1]([C:4]1[S:5][CH:6]=[CH:7][C:8]=1[OH:9])(=[O:3])[CH3:2]
Reactant: COC(=O)c1cc(O)c(C(C)=O)s1
Agent: [Cu]
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccc2ncccc2c1
Product: CC(=O)c1sccc1O
Yield: 58 %

Procedure:
The above-obtained methyl 2-acetyl-3-hydroxythiophene-5-carboxylate was hydrolyzed with an aqueous solution of sodium hydroxide, the hydrolyzate was heated with copper-quinoline to be decarboxylated, thereby the objective 2-acetyl-3-hydroxythiophene was obtained (yield: 58%).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:15]=[CH:14][C:13](O)=[CH:12][CH:11]=1)(=O)[C:2]1[CH:7]=CC=CC=1.C(OC1C=CC(O)=C(C)C=1)(=O)C.CC1C(O)=C(C)C(C)=C(C=1)O>>[O:9]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=2[CH2:7][CH2:2][CH2:1]1
Reactant: O=C(Oc1ccc(O)cc1)c1ccccc1
Agent: CC(=O)Oc1ccc(O)c(C)c1
Agent: Cc1cc(O)c(C)c(C)c1O
Product: c1ccc2c(c1)CCCO2

Procedure:
The same reaction and isolation procedures as Synthesis Example 22 were followed except that 4.28 g of 4-benzoyloxyphenol or 3.32 g of 4-acetoxy-2-methylphenol was used in lieu of 3.04 g of trimethylhydroquinone to give the corresponding 3,4-dihydro-2H-benzopyran derivatives. The yield and FD mass spectrum of each product are given in Table 4.