Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N+:8]([O-:10])=[O:9])=[N:6][CH:7]=1.CC1(C)C(C)(C)OB([C:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH:20]=2)O1.O1CCOCC1>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.O>[C:28]([O:27][C:25]([N:22]1[CH2:21][CH:20]=[C:19]([C:2]2[CH:7]=[N:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH2:24][CH2:23]1)=[O:26])([CH3:31])([CH3:29])[CH3:30]
Reactant: CC(C)(C)OC(=O)N1CC=C(B2OC(C)(C)C(C)(C)O2)CC1
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CC=C(c2ccc([N+](=O)[O-])nc2)CC1
Temperature: 80 °C
Reaction time: 15 h
Yield: 48.7 %

Procedure:
In a 500 mL round-bottomed flask, 5-bromo-2-nitropyridine (6.56 g, 32.3 mmol, Eq: 1) and tert-butyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate (10 g, 32.3 mmol, Eq: 1.00) were combined with dioxane (160 ml) to give a light yellow solution. Cs2 CO3 (21.1 g, 64.7 mmol, Eq: 2) and water (6 ml) were added. The reaction mixture was degassed with argon before bis(triphenylphosphine)palladium(II) dichloride (2.27 g, 3.23 mmol, Eq: 0.1) was added. The reaction mixture was heated to 80° C. and stirred for 15 h. The reaction mixture was poured into 500 mL H2O and extracted with EtOAc (3×200 mL). The combined extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 10% to 40% EtOAc in hexanes) to afford a pink solid. The resulting solid was triturated with ether to afford the desired product as a solid (4.8 g). The filtrate from the trituration and mixed fractions from the first chromatography were combined and purified by flash chromatography (silica gel, 220 g, 20% to 40% EtOAc in hexanes) affording additional product (2.2 g). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.52 (s, 9 H) 2.59 (d, J=1.52 Hz, 2 H) 3.72 (t, J=5.56 Hz, 2 H) 4.19 (d, J=3.03 Hz, 2 H) 6.35 (br. s., 1 H) 7.97 (dd, J=8.46, 2.40 Hz, 1 H) 8.27 (d, J=8.34 Hz, 1 H) 8.67 (d, J=2.27 Hz, 1 H).
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[N:8]([C:9]([C:11]2[N:12]=[C:13]([CH3:23])[S:14][C:15]=2[C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[O:10])[CH2:7][C@H:6]2[C@@H:4]1[CH2:5]2.[CH3:24][C:25]1[N:26]2[C:32]([CH3:33])=[C:31]([C:34](O)=[O:35])[N:30]=[C:27]2[S:28][CH:29]=1>>[CH3:23][C:13]1[S:14][C:15]([C:16]2[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=2)=[C:11]([C:9]([N:8]2[CH2:7][C@H:6]3[C@H:4]([CH2:5]3)[C@H:3]2[CH2:2][NH:1][C:34]([C:31]2[N:30]=[C:27]3[N:26]([C:32]=2[CH3:33])[C:25]([CH3:24])=[CH:29][S:28]3)=[O:35])=[O:10])[N:12]=1
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CN)c1
Reactant: Cc1csc2nc(C(=O)O)c(C)n12
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2nc3scc(C)n3c2C)c1

Procedure:
prepared by reaction of ((1S,2S,5R)-2-Aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-(2-methyl-5-m-tolyl-thiazol-4-yl)-methanone with 3,5-Dimethyl-imidazo[2,1-b]thiazole-6-carboxylic acid. LC-MS (basic): tR=0.88 min; [M+H]+=506.0.
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([NH2:17])[CH:12]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.C(N(CC)C(C)C)(C)C.Cl[C:28]([O:30][CH3:31])=[O:29]>ClCCl>[CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:28](=[O:29])[O:30][CH3:31])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1
Reactant: Cc1nnc2ccc(-c3cccc(N)c3)nn12
Reactant: COC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)Nc1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 3 h

Procedure:
To a solution of 9.24 g of 3-methyl-6-[3-(amino)-phenyl]-1,2,4-triazolo[4,3-b]pyridazine in 1.5 liters of dichloromethane was added 7.9 ml of N,N-diisopropylethylamine followed by 3.5 ml of methyl chloroformate. This mixture was stirred for 3 hours, then the solid was collected and washed with 100 ml of dichloromethane. The solid was heated with dichloromethane-hexane and filtered, giving 8.25 g of the desired product as crystals, mp 150°-153° C. (dec.).
Reaction SMILES: [CH:1]1([NH2:6])[CH2:5][CH2:4][CH2:3][CH2:2]1.[N+](N1[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[CH:11]1)([O-])=O>>[CH:1]1([N:6]2[CH:14]=[C:13]([N+:15]([O-:17])=[O:16])[N:12]=[CH:11]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC1CCCC1
Reactant: O=[N+]([O-])c1cn([N+](=O)[O-])cn1
Product: O=[N+]([O-])c1cn(C2CCCC2)cn1
Yield: 75 %

Procedure:
This reaction was carried out using the procedure for Preparation 1 with cyclopentyl amine and 1,4-dinitroimidazole to afford 205 mg (75% yield) of 1-cyclopentyl-4-nitro-1H-imidazole; 1H NMR (400 MHz, CDCl3) δ7.77 (s, 1H), 7.45 (s, 1H), 4.49 (m, 1H), 2.25 (m, 2H), 2.0-1.7 (m, 6H); MS (AP/Cl): 182.2 (M+H)+.
Reaction SMILES: C([O-])([O-])=O.[Na+].[Na+].[C:7]([C:9]1[CH:14]=[CH:13][C:12](B(O)O)=[CH:11][C:10]=1[F:18])#[N:8].I[C:20]1[CH:21]=[N:22][C:23]([N:26]2[CH2:31][CH2:30][CH:29]([C:32]3[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=3)[CH2:28][CH2:27]2)=[N:24][CH:25]=1>O1CCOCC1.CN(C=O)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>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([C:20]2[CH:25]=[N:24][C:23]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][C:35]([C@@H:38]([NH:40][C:41](=[O:43])[CH3:42])[CH3:39])=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[N:22][CH:21]=2)=[CH:11][C:10]=1[F:18])#[N:8]
Reactant: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(I)cn3)CC2)cc1
Reactant: N#Cc1ccc(B(O)O)cc1F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](C)c1ccc(C2CCN(c3ncc(-c4ccc(C#N)c(F)c4)cn3)CC2)cc1
Temperature: 70 °C
Reaction time: 6 h

Procedure:
Under argon atmosphere 0.1 mL sat. Na2CO3-solution and 3 mg (0.004 mmol) bis(triphenylphosphine)-palladium(II) chloride are added to a mixture of 16 mg (0.10 mmol) 4-cyano-3-fluorophenylboronic acid and 45 mg (0.10 mmol) (S)—N-(1-{4-[1-(5-iodopyrimidin-2-yl)-piperidin-4-yl]-phenyl}-ethyl)-acetamide (compound 4.43) in 2 mL dioxane/1 mL MeOH. The mixture was stirred at 70° C. for 6 h. After that time, the mixture was diluted with DMF and filtered. The filtrate was purified using reversed phase HPLC (water/MeOH, 0.1% TFA) to yield the desired product.
Reaction SMILES: [CH:1](/[C:9]1[N:10]=[C:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[NH:15][C:14]3[N:22]=[CH:23][CH:24]=[CH:25][C:13]=3[N:12]2[C:26]=1[C:27]1[CH:32]=[CH:31][C:30]([C:33]2([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[CH2:36][CH2:35][CH2:34]2)=[CH:29][CH:28]=1)=[CH:2]\[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>C1COCC1.CO.[Pd]>[C:3]1([CH2:2][CH2:1][C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[NH:15][C:14]4[N:22]=[CH:23][CH:24]=[CH:25][C:13]=4[N:12]3[C:26]=2[C:27]2[CH:28]=[CH:29][C:30]([C:33]3([NH:37][C:38](=[O:44])[O:39][C:40]([CH3:42])([CH3:41])[CH3:43])[CH2:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(/C=C/c4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(CCc4ccccc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1

Procedure:
(E)-tert-butyl (1-(4-(2-styryl-9H-benzo[f]imidazo[1,2-d]pyrido[2,3-b][1,4]diazepin-3-yl)phenyl)cyclobutyl)carbamate was stirred in THF-MeOH under hydrogen in the presence of 5% Pd/C to give the title compound 1HNMR (CDCl3) 400 MHz δ: 8.10 (dd, J=7.7, 1.4 Hz, 1H), 7.99 (dd, J=4.6, 1.2 Hz, 1H), 7.34-7.27 (m, 3H), 7.24 (d, J=6.9 Hz, 1H), 7.18 (d, J=7.5 Hz, 2H), 7.14 (td, J=7.5, 1.2 Hz, 1H), 6.95 (d, J=7.5 Hz, 1H), 6.90 (d, J=7.5 Hz, 2H), 6.78 (d, J=7.5 Hz, 1H), 6.59 (dd, J=8.0, 4.6 Hz, 1H), 6.29 (s, 1H), 5.08 (s, 1H), 3.12-3.07 (m, 2H), 3.01-2.95 (m, 2H), 2.56-2.38 (m, 4H), 2.16-2.07 (m, 1H), 1.91-1.82 (m, 1H), 1.48-1.19 (m, 9H); LC/MS [M+H]: 584.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([CH3:14])[N:3]=1.[CH2:15]([OH:19])[C:16]#[C:17][CH3:18].[H-].[Na+].O>CN(C)C=O>[CH3:14][C:4]1[N:5]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:7]=[C:2]([O:19][CH2:15][C:16]#[C:17][CH3:18])[N:3]=1
Reactant: CC#CCO
Reactant: Cc1nc(Cl)cc(-c2ccccc2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC#CCOc1cc(-c2ccccc2)nc(C)n1
Temperature: 25 °C
Reaction time: 12 h
Yield: 71.3 %

Procedure:
In 10 ml of N,N-dimethylformamide were dissolved 313 mg of 4-chloro-2-methyl-6-phenylpyrimidine and 118 mg of 2-butyn-1-ol, to which 67 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 12 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The resulting residue was subjected to silica gel column chromatography to give 260 mg of 2-methyl-4-phenyl-6-(2-butynyloxy)pyrimidine (the present compound (78)).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([Cl:9])[N:3]=1.[NH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=1>>[Cl:9][C:4]1[N:5]=[C:6]([Cl:8])[N:7]=[C:2]([NH:10][CH2:11][CH2:12][C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[N:3]=1
Reactant: NCCc1ccncc1
Reactant: Clc1nc(Cl)nc(Cl)n1
Product: Clc1nc(Cl)nc(NCCc2ccncc2)n1

Procedure:
Following the general procedure A 2,4,6-trichloro-1,3,5-triazine was coupled with 4-(2-Aminoethyl)pyridine with reaction time of 2 h. Purification by column chromatography gave the title compound.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15]3[C:20]([C:21]=2[Cl:22])=[CH:19][CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:9][CH:8]=1)([CH3:3])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].Br[CH2:33][CH:34]1[CH2:36][CH2:35]1.CN(C=O)C>O>[CH:1]([O:4][C:5](=[O:25])[NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]([CH2:33][CH:34]3[CH2:36][CH2:35]3)[C:15]3[C:20]([C:21]=2[Cl:22])=[CH:19][CH:18]=[C:17]([O:23][CH3:24])[CH:16]=3)=[CH:11][CH:12]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)[nH]c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc2c(Cl)c(-c3ccc(NC(=O)OC(C)C)cc3)n(CC3CC3)c2c1
Temperature: 60 °C
Reaction time: 4 h
Yield: 32.9 %

Procedure:
A mixture of [4-(3-Chloro-6-Methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (50 mg, 0.14 mmol), Cs2CO3 (95 mg, 0.29 mmol), bromomethylcyclopropane (18 μL, 0.18 mmol), and DMF (200 μL) was stirred at 60° C. for 4 h. The reaction mixture was then stirred at room temperature for 1 h, diluted with H2O and extracted with EtOAc. The organic layer was washed with H2O and brine and then dried, concentrated and purified by silica gel chromatography (7:3 CH2Cl2/hexane) to provide [4-(3-chloro-1-cyclopropylmethyl-6-methoxy-1H-indol-2-yl)-phenyl]-carbamic acid isopropyl ester (19 mg, 33%) as a white solid.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH2:14].[C:15]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:20]=[CH:19][C:18]([C:21](Cl)=[O:22])=[CH:17][CH:16]=1.C(N(CC)CC)C>ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH2:13][NH:14][C:21]([C:18]1[CH:19]=[CH:20][C:15]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[CH:16][CH:17]=1)=[O:22]
Reactant: O=C(Cl)c1ccc(-c2ccccc2)cc1
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(-c2ccccc2)cc1
Yield: 78.6 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide was obtained following Method C starting from 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.100 g, 0.424 mmol), biphenyl-4-carbonyl chloride (0.098 g; 0.445 mmol), and triethylamine (0.131 mL; 0.934 mmol) in dichloromethane (5 mL). Flash chromatography on silica gel (eluent 10% ethyl acetate in dichloromethane) furnished 0.125 g (79%) of N-(2-(5-Chloro-1H-indol-3-yl)ethyl)biphenyl-4-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12][C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=2)=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2].ClC1C=CC=C(C(OO)=O)C=1.[OH-:42].[Ca+2].[OH-:44]>C(Cl)(Cl)Cl>[C:1]([C:4]1[CH:26]=[CH:25][C:7]([O:8][CH2:9][CH2:10][CH2:11][S:12]([C:13]2[CH:18]=[CH:17][C:16]([C:19](=[O:24])[CH2:20][CH2:21][CH2:22][OH:23])=[CH:15][CH:14]=2)(=[O:44])=[O:42])=[C:6]([CH2:27][CH2:28][CH3:29])[C:5]=1[OH:30])(=[O:3])[CH3:2]
Reactant: CCCc1c(OCCCSc2ccc(C(=O)CCCO)cc2)ccc(C(C)=O)c1O
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClC(Cl)Cl
Product: CCCc1c(OCCCS(=O)(=O)c2ccc(C(=O)CCCO)cc2)ccc(C(C)=O)c1O
Reaction time: 1 h

Procedure:
The compound of Example 46. Step B (330 mg, 0.767 mmoles) was dissolved in chloroform and cooled to 0°. m-Chloroperbenzoic acid (328 mg, 1.57 mmoles) was added and the reaction stirred for one hour. Calcium hydroxide (195 mg) was added and the reaction stirred for 90 minutes at room temperature. The mixture was filtered and the filtrate evaporated to dryness. The residue crystallized from ethyl acetatehexane to yield the title compound; m.p. 99°-100°.
Reaction SMILES: [C:1](O)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].S([O:13][CH3:14])(OC)(=O)=O>O>[CH3:2][C:1]1([CH3:4])[CH2:3][CH2:2][C:1]([CH3:4])([CH3:3])[C:14]1=[O:13]
Reactant: COS(=O)(=O)OC
Reactant: CC(C)(C)O
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CC1(C)CCC(C)(C)C1=O

Procedure:
After cooling, 100 ml of t-butanol was slowly added dropwise thereto to decompose excess sodium hydride, and then 1.0 l of water was added thereto. The reaction mixture was further heated for 2 hours under reflux to decompose excess dimethyl sulfate. After cooling, the resulting two layers were separated and the organic layer was washed with aqueous saturated sodium chloride solution, and dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, and the residue was distilled under reduced pressure, whereby 59 g of 2,2,5,5-tetramethylcyclopentanone was obtained (b.p. 55° C./20 mmHg).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11](C=O)=[CH:10][C:9]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C1C=C(Cl)C=C(C(OO)=[O:36])C=1.[OH-].[K+]>C(Cl)Cl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:12][C:11]([OH:36])=[CH:10][C:9]=1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: COCCOCOc1c(-c2ccccc2)cc(C=O)cc1-c1ccccc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Product: COCCOCOc1c(-c2ccccc2)cc(O)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.5 %

Procedure:
To a stirred solution of 2′-methoxyethoxymethoxy-[1,1′;3′,1″]terphenyl-5′-carboxaldehyde (0.836 g, 2.31 mmol) in CH2Cl2 (25 mL) at room temperature was added MCPBA (0.598 g, 3.46 mmol). The reaction mixture was refluxed for 48 h. After concentration, the residue was dissolved in EtOAc (300 mL). The organic layer was washed with sat. aq. NaHCO3 until effervescence ceased followed brine (30 mL) and then dried (Na2SO4). After concentration, the residue was dissolved in THF:MeOH (3:2, 45 mL) followed by the dropwise addition of 1 N KOH (11.6 mL, 11.6 mmol). The reaction mixture was stirred at room temperature for 1.5 h and then concentrated. The residue was diluted with H2O (30 mL) and then acidified to pH 4 with 1 N HCl followed by extraction with EtOAc (300 mL). This organic layer was washed with brine (30 mL) and then dried (MgSO4). After concentration, the residue was purified by the Biotage Flash 40 apparatus (5 to 15% acetone/hexane gradient) to afford the product (0.490 g, 61%) as a solid; 1H NMR (CDCl3) δ 2.73-2.86 (m, 2H), 2.90-2.98 (m, 2H), 3.17 (s, 3H), 4.35 (s, 2H), 4.67 (s, 1H), 6.82 (s, 2H), 7.27-7.47 (m, 6H), 7.57 (d, J=9.3 Hz, 4H);mass spectrum [(+) ESI], m/z 373 (M+Na)+.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.C([O-])(=O)C.[Na+].[I:29]Cl>C(O)(=O)C.O>[I:29][C:11]1[N:10]=[CH:9][N:8]2[C:3]([C:2]([F:1])([F:22])[F:23])=[CH:4][C:5]([C:12]3[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=3)=[N:6][C:7]=12
Reactant: ClI
Reactant: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cncc3n2)cc1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3cnc(I)c3n2)cc1
Temperature: 25 °C
Reaction time: 19 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.05 g, 3.17 mmol) in acetic acid (4 mL) was added at room temperature sodium acetate (0.29 g, 3.58 mmol) and drop wise a solution of iodine monochloride (0.53 g, 3.58 mmol) in acetic acid (4 mL). The reaction mixture was stirred at room temperature for 19 h, diluted slowly with water (100 mL), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 8-iodo-4-trifluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.45 g, 100%) as an orange solid. MS (EI) 457.0 [(M)+]; mp 141° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5]([C:22]#[N:23])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[S:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)[CH2:4][CH2:3]1.C(=O)([O-])[O-].[K+].[K+].[N:30]#CBr>C(Cl)(Cl)Cl>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:5]2([C:22]#[N:23])[CH2:6][CH2:7][N:2]([C:1]#[N:30])[CH2:3][CH2:4]2)=[CH:20][CH:19]=1
Reactant: N#CBr
Reactant: CN1CCC(C#N)(c2ccccc2Sc2ccc(Cl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: N#CN1CCC(C#N)(c2ccccc2Sc2ccc(Cl)cc2)CC1

Procedure:
A solution of 14.9 g of 1-methyl-4-cyano-4-[2-(4-chlorophenylthio)phenyl]piperidine, Example 1, in 75 ml of chloroform is added dropwise to a rapidly stirring mixture of 30.4 g of potassium carbonate and 7.6 g of cyanogen bromide in 80 ml of chloroform. After total addition, the reaction mixture is refluxed for 16 hours and then successively, filtered, washed thrice with 150 ml portions of water, washed once with 50 ml saturated sodium chloride solution and dried. The residue is dissolved in chloroform and the chloroform solution is chromatographed (silica gel F60, ether as eluant). The purified material is recrystallized from acetone to give 4-[2-(4-chlorophenylthio)phenyl]-1,4-dicyanopiperidine.
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])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.[Li+].[OH-].[ClH:21].[Cl:22][CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1>C1(C)C=CC=CC=1.C(Cl)Cl>[ClH:22].[ClH:21].[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:23][C:24]1[C:25]([NH:37][CH3:38])=[N:26][C:27]2[CH:28]=[C:29]3[O:36][CH2:35][O:34][C:30]3=[CH:31][C:32]=2[CH:33]=1
Reactant: CNc1nc2cc3c(cc2cc1CCl)OCO3
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCc1nc(O)c(Cc2cc3cc4c(cc3nc2NC)OCO4)c2cc(OC)c(OC)cc12
Temperature: 150 °C
Reaction time: 1.5 h
Yield: 9 %

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35142 (245 mg, 0.99 mmol) in toluene (10 mL) in a 20 mL microwave vial equipped with a magnetic stirrer was added a 2 N aq. LiOH solution (1.00 mL, 2.00 mmol) at RT followed by 7-(chloromethyl)-N-methyl-[1,3]dioxolo[4,5-g]quinolin-6-amine hydrochloride CCH 34158B (284 mg, 0.99 mmol) and the mixture was stirred at 150° C. for 1.5 h under microwave irradiation. After cooling to RT, the mixture was diluted with CH2Cl2:MeOH=9:1 (80 mL) and the organic solution was washed with brine (10 mL), dried over Na2SO4, filtered and concentrated at 40° C. under vacuum. Purification by column chromatography (SiO2, eluent CH2Cl2:7 N NH3 solution in MeOH=100:0 to 95:5) gave, after evaporation, 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (3 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.19 M HCl solution in MeOH (2 mL). The reaction mixture was stirred for 5 min at RT and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-(methylamino)-[1,3]dioxolo[4,5-g]quinolin-7-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 62 as a beige solid (46 mg, 9% yield).
Reaction SMILES: Cl[C:2]1[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]2[CH:16]=[CH:15][C:14]3[NH:13][C:12]4[CH:17]([CH2:20][C:21]([O:23]CC)=[O:22])[CH2:18][CH2:19][C:11]=4[C:10]=3[CH:9]=2)=[CH:4][C:3]=1[C:28]([F:31])([F:30])[F:29].[Br-].[CH:33]1([Zn+])[CH2:36][CH2:35][CH2:34]1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[CH:33]1([C:2]2[CH:27]=[CH:26][C:5]([CH2:6][O:7][C:8]3[CH:16]=[CH:15][C:14]4[NH:13][C:12]5[CH:17]([CH2:20][C:21]([OH:23])=[O:22])[CH2:18][CH2:19][C:11]=5[C:10]=4[CH:9]=3)=[CH:4][C:3]=2[C:28]([F:31])([F:29])[F:30])[CH2:36][CH2:35][CH2:34]1
Reactant: [Zn+]C1CCC1
Reactant: CCOC(=O)CC1CCc2c1[nH]c1ccc(OCc3ccc(Cl)c(C(F)(F)F)c3)cc21
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Br-]
Solvent: C1CCOC1
Product: O=C(O)CC1CCc2c1[nH]c1ccc(OCc3ccc(C4CCC4)c(C(F)(F)F)c3)cc21
Temperature: 90 °C

Procedure:
To a solution of ethyl 2-(7-(4-chloro-3-(trifluoromethyl)benzyloxy)-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate (202.8 mg, 0.449 mmol) in tetrahydrofuran (1 mL) was added 0.5 M cyclobutylzinc(II) bromide solution in tetrahydrofuran (8.98 mL, 4.49 mmol) and bis(tri-t-butylphosphine)palladium (46.8 mg, 0.090 mmol) at room temperature. The mixture was heated at 90° C. for 63 h. The mixture was then quenched with 1 N aqueous HCl solution and filtered through Celite®. The filtrate was extracted with ethyl acetate. The organic layer was washed with brine solution to remove excess HCl and concentrated under reduced pressure. The residue was purified by HPLC. The combined fractions were triturated with saturated aqueous sodium bicarbonate solution to basic solution and concentrated under reduced pressure. The residue was dissolved in ethyl acetate and acidified to pH 4. The organic layer was washed with water until the aqueous layer was neutral. The organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to provide the title compound as a pink solid (32.3 mg). LCMS m/z=444.6 [M+H]+; NMR (400 MHz, DMSO-d6) δ ppm 1.78-1.87 (m, 1H), 1.93-2.02 (m, 1H), 2.03-2.12 (m, 1H), 2.16-2.28 (m, 4H), 2.34 (dd, J=15.98, 9.03 Hz, 1H), 2.60-2.75 (m, 4H), 3.41-3.51 (m, 1H), 3.74-3.84 (m, 1H), 5.12 (s, 2H), 6.70 (dd, J=8.78, 2.46 Hz, 1H), 6.92 (d, J=2.40 Hz, 1H), 7.19 (d, J=8.84 Hz, 1H), 7.66-7.78 (m, 3H), 10.46 (s, 1H), 12.20 (bs, 1H).