Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.[Br:10][CH2:11][C:12]([C:14]1[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=1)=O>>[BrH:10].[N:5]1[CH:6]=[CH:7][C:2]([C:1]2[S:8][CH:11]=[C:12]([C:14]3[CH:24]=[CH:23][C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:16][CH:15]=3)[N:9]=2)=[CH:3][CH:4]=1
Reactant: NC(=S)c1ccncc1
Reactant: CCOC(=O)c1ccc(C(=O)CBr)cc1
Product: Br
Product: CCOC(=O)c1ccc(-c2csc(-c3ccncc3)n2)cc1
Yield: 67 %

Procedure:
In the same manner as in Example 74, thioisonicotinamide was reacted with ethyl 4-bromoacetylbenzoate to obtain ethyl 4-[2-(4-pyridyl)-4-thiazolyl)benzoate hydrobromide. The product was, recrystallized from ethanol. Yield: 67%. Pale Yellow prisms. Melting point: 247 to 248° C.
Reaction SMILES: CCN(C(C)C)C(C)C.[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:12]=1[C@@H:21]([NH2:26])[CH2:22][CH2:23][CH:24]=[CH2:25].Cl[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>C(Cl)Cl>[Br:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([F:19])([F:20])[F:18])=[CH:13][C:12]=1[C@@H:21]([NH:26][C:28](=[O:29])[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: C=CCC[C@H](N)c1cc(C(F)(F)F)ccc1Br
Reactant: O=C(Cl)OCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC[C@H](NC(=O)OCc1ccccc1)c1cc(C(F)(F)F)ccc1Br
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To DIPEA (7.48 mL, 42.8 mmol) and (1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-amine (4.4 g, 14.3 mmol) in DCM (20 mL) was added benzyl chloroformate at 0° C. The reaction was stirred at room temperature for 2 hours and was quenched with water. The organic was washed with 10% aqueous KOH and the aqueous was back-extracted with ethyl acetate. The combined organics were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to yield benzyl {(1S)-1-[2-bromo-5-(trifluoromethyl)phenyl]pent-4-en-1-yl}carbamate (5.8 g, 13.1 mmol). 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 1H), 7.58 (s, 1H), 7.39 (b, 5H), 7.1 (m, 1H), 5.83 (m, 1H), 5.3 (b, 1H), 5.15 (m, 3H), 2.22 (m, 1H), 2.18 (m, 1H), 1.95 (m, 1H), 1.78 (m, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]#[N:23])[CH:5]=[CH:6][CH:7]=1.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]=[C:32]=[O:33]>>[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[NH:31][C:32]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:19])[F:20])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]#[N:23])[CH:3]=1)=[O:33]
Reactant: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(N)c1
Reactant: O=C=Nc1ccccc1Cl
Product: N#Cc1cnc2c(C(F)(F)F)cccc2c1-c1cccc(NC(=O)Nc2ccccc2Cl)c1

Procedure:
The title compound was prepared from 4-(3-aminophenyl)-8(trifluoromethyl)quinoline-3-carbonitrile and 2-chlorophenyl isocyanate according to the procedure of Example 65. MS (ES) m/z 464.8.
Reaction SMILES: [CH2:1]([N:3]([CH2:24][CH3:25])[CH2:4][CH2:5][CH2:6][CH:7]([NH:9][C:10](=[O:23])[CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH3:8])[CH3:2].O=P(Cl)(Cl)Cl.CN([CH:34]=[O:35])C>>[CH2:24]([N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][CH2:6][CH:7]([NH:9][C:10](=[O:23])[CH2:11][CH2:12][N:13]1[C:22]2[C:17](=[CH:18][C:19]([CH:34]=[O:35])=[CH:20][CH:21]=2)[CH2:16][CH2:15][CH2:14]1)[CH3:8])[CH3:25]
Reactant: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2ccccc21
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Product: CCN(CC)CCCC(C)NC(=O)CCN1CCCc2cc(C=O)ccc21

Procedure:
The procedure was carried out as described previously in step (a) of Example 5 with Compound 10 (2.64 g, 7.6 mmol), POCl3 (1.5 mL, 15.3 mmol), and DMF (27 mL). Compound 11 was obtained (1.44 g, 51%) as a viscous brown liquid and used without any further purification. The structure of Compound 11 is given below:
Reaction SMILES: C(N(CC)C(C)C)(C)C.[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.O.[Cl:19][C:20]1[N:29]=[C:28](Cl)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1>C1COCC1>[Cl:19][C:20]1[N:29]=[C:28]([NH:17][NH:16][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=1
Reactant: NNc1ccccc1
Reactant: Clc1nc(Cl)c2ccccc2n1
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Clc1nc(NNc2ccccc2)c2ccccc2n1
Reaction time: 0.5 h

Procedure:
To a stirred solution of N,N-diisopropylethylamine (10 ml, 57 mmol) in THF (150 ml), 2,4dichloroquinazoline [prepared according to the procedure described by Curd, F. H. S. et al., J. Chem. Soc., (1947), 775] (5 g, 25 mmol) and phenylhydrazine (2.7 g, 25 mmol) was added. After stirring for 30 minutes, the reaction was poured into water and extracted with dichloromethane (3×100 ml). The combined organic layers were dried over Na2SO4 and evaporated under reduced pressure. The resulting solid was triturated with ethanol and filtered to afford 2-chloro-4-phenylhydrazinoquinazoline (3.2 g ) as a yellow solid, m.p. 178° C. (dec.).
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][CH2:6][O:7][CH3:8].[OH2:9].[C:10]1([CH3:20])[CH:15]=[CH:14][C:13](S(O)(=O)=O)=C[CH:11]=1>C(N(CC)CC)C>[CH3:4][O:5][CH2:6][O:7][C:8]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[CH:20]=[O:9]
Reactant: COCOC
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COCOc1cccc(C=O)c1
Yield: 60 %

Procedure:
m-Hydroxybenzaldehyde (32 g., 0.25 moles) methylene chloride (500 ml.), dimethoxymethane (100 ml., 1.13 moles), and p-toluenesulfonic acid monohydrate (250 mg.) were refluxed overnight under nitrogen using a Soxhlet extractor containing type 3A molecular sieves (150 g.). The reaction mixture was allowed to cool treated with triethylamine (2 ml.) to neutralize the acid catalyst and washed with 1N NaOH (2 × 200 ml.), water and dried (Na2SO4). Evaporation of solvent afforded a 28 g. residue, which after distillation, b.p. 92°-105° at 0.7 - 0.8 mm. gave 24.6 g. of m-methoxymethoxybenzaldehyde, (60% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[NH:16][C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[K+].Br[CH2:35][C:36]#[N:37]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[N:16]([CH2:35][C:36]#[N:37])[C:15]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#CCBr
Reactant: CC(C)(C)OC(=O)N1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2c(=O)n(CC#N)c3ccccc32)CC1
Reaction time: 0.17 h
Yield: 67.4 %

Procedure:
A solution of 4-(2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (2.91 g, 9.16 mmol) in THF (10 mL) was added dropwise to a solution of KHMDS (2.19 g, 11.0 mmol) in THF (20 mL). The mixture was stirred for 10 min then bromoacetonitrile (3.2 mL, 46 mmol) was added. The resulting mixture was stirred for 4 h then partitioned between EtOAc (750 mL) and saturated aqueous NaHCO3 (200 mL). The EtOAc layer was washed with H2O (3×200 mL) and brine (200 mL). The combined washes were extracted with EtOAc (2×150 mL). The combined extracts were dried over Na2SO4 and concentrated. Column chromatography (silica, 20-60% EtOAc/hexanes) afforded 2.20 g (67%) of 4-(3-cyanomethyl-2-oxo-2,3-dihydro-benzoimidazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester. The purified material was dissolved in CH2Cl2 (40 mL) and diluted with TFA (25 mL). The resulting mixture was stirred for 1 h then diluted with CH2Cl2 (250 mL) and washed with 1 N NaOH (100 mL). The aqueous layer was extracted with CH2Cl2 (2×100 mL). The combined extracts were dried over Na2SO4 and concentrated to 1.59 g (95%) of the title compound which was suitable for further use without purification. TLC (silica, 5% MeOH/CH2Cl2): Rf=0.1. MS (electrospray): m/z calculated for C14H17N4O [M++H] 257.14. found 257.1. 1H NMR (CDCl3, 400 Hz): 733-7.29 (m, 1H), 7.17-7.02 (m, 3H), 4.75 (s, 2H), 4.41 (tt, J=12.2, 4.4 Hz, 1H), 3.28 (br d, J=9.8 Hz, 2H), 3.11 (br s, 1H), 2.80 (t, J=10.0 Hz, 2H), 2.37 (dq, J=12.5, 4.2 Hz, 2H), 1.83 (br d, J=11.8 Hz, 2H).
Reaction SMILES: [C:1]1([O-:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[K+].[NH2:9][C:10]1[CH:15]=[CH:14][C:13](I)=[CH:12][N:11]=1>CC(N(C)C)=O>[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:12][N:11]=1
Reactant: [O-]c1ccccc1
Reactant: Nc1ccc(I)cn1
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: Nc1ccc(Oc2ccccc2)cn1

Procedure:
3.3 G. of potassium phenolate, 5.47 g. of 2-amino 5-iodopyridine and 1.78 g. of cuprous oxide in 150 ml. of dimethylacetamide are heated at reflux under a nitrogen atmosphere for 24 hours. The solvent is removed in vacuo and the residue is extracted with chloroform. Chromatography of the methylene chloride soluble portion with silica gel and elution with ethyl acetate yields 2-amino-5-phenoxy pyridine m.p. 67°-69° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][NH:17][CH2:18][CH:19]2[CH2:21][CH2:20]2)=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[CH2:32][C:33]([NH:35][CH3:36])=[O:34]>CN(C)C=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N:17]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:32][C:33]([NH:35][CH3:36])=[O:34])=[CH:11][C:10]=1[O:22][CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNC(=O)CCl
Reactant: COc1cc(CCNCC2CC2)ccc1OCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNC(=O)CN(CCc1ccc(OCc2ccccc2)c(OC)c1)CC1CC1
Temperature: 120 °C
Yield: 85 %

Procedure:
A mixture of 0.5 g (1.6 mmol) of [2-(4-benzyloxy-3-methoxy-phenyl)-ethyl]-(cyclopropylmethyl)amine, 0.27 ml (1.92 mmol) of triethylamine, 0.207 g (1.92 mmol) of 2-chloro-N-methyl-acetamide in 4 ml of dimethylformamide was heated with microwaves to 120° C. for 2 hours. The solvent was removed under vacuum and the crude was purified by flash chromatography (ethyl acetate/hexane 0:10→9:1 gradient). 0.52 g (84% yield) of the title compound was isolated as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8].[Br:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29]Br.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>CN(C=O)C.O>[Br:18][CH2:19][CH2:20][O:21][CH2:22][CH2:23][O:24][CH2:25][CH2:26][O:27][CH2:28][CH2:29][O:1][C:2]1[C:3]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[CH:4][C:5]([N+:10]([O-:12])=[O:11])=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: COCCOc1cc([N+](=O)[O-])c(C#N)cc1O
Reactant: BrCCOCCOCCOCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: COCCOc1cc([N+](=O)[O-])c(C#N)cc1OCCOCCOCCOCCBr
Temperature: 80 °C
Yield: 25 %

Procedure:
To a solution of 5-hydroxy-4-(2-methoxyethoxy)-2-nitrobenzonitrile (0.4 g) in DMF (8 mL) was added 1-bromo-2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethane (1.0 g) and K2CO3 (0.5 g). The resulting mixture was heated at 80° C. overnight under N2 atmospheres. After reaction finished, the mixture was diluted with water (50 mL) and exacted with EA (3×50 mL). The combined organic layer was dried over Na2SO4, concentrated under reduced pressure, and purification by silica chromatography to give 0.2 g of 5-(2-(2-(2-(2-bromoethoxy)ethoxy)ethoxy)ethoxy)-4-(2-methoxyethoxy)-2-nitrobenzonitrile. 1H-NMR (400 MHz, CDCl3): δ: 7.85 (s, 1H), 7.33 (s, 1H), 4.33-4.28 (m, 4H), 3.95-3.92 (m, 2H), 3.83-3.79 (m, 4H), 3.74-3.72 (m, 2H), 3.69-3.66 (m, 6H), 3.49-3.47 (m, 2H), 3.45 (s, 3H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([OH:37])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:39][CH2:40][O:41][CH3:42].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.CCOC(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([CH:23]([CH3:25])[CH3:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:36][C:35]2[C:30](=[CH:31][CH:32]=[C:33]([O:37][CH2:39][CH2:40][O:41][CH3:42])[CH:34]=2)[CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1cc(C(=O)N2Cc3ccc(O)cc3C2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: COCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COCCOc1ccc2c(c1)CN(C(=O)c1cc(C(C)C)c(OCc3ccccc3)cc1OCc1ccccc1)C2
Temperature: 25 °C
Reaction time: 2 h
Yield: 104.2 %

Procedure:
(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-(5-hydroxy-1,3-dihydro-isoindol-2-yl)-methanone (A2 from 2,4-bis-benzyloxy-5-isopropyl-benzoic acid (Preparation B10) and 5-hydroxyisoindoline) (100 mg, 0.2 mmol), 1-chloro-2-methoxy-ethane (23.6 mg, 0.25 mmol) and K2CO3 (34.5 mg, 0.25 mmol) in DMF (4 ml) were combined and stirred for 2 hours at room temperature. A further 0.25 mmol of 1-chloro-2-methoxy-ethane and K2CO3 was added then heated at 90° C. for 16 hours. Reaction cooled to room temperature and diluted with EtOAc then filtered. The filtrate was reduced in vacuo then purified by flash column chromatography, eluting with 100% petroleum ether to 100% ethyl acetate to afford 115 mg of the title compound as a colourless gel. MS: [M+H]+ 552
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[C:9]2[CH:10]=[C:11](B3OC(C)(C)C(C)(C)O3)[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:17])=[O:16])=[CH:13][C:8]=2[O:7][C:6]=1[C:29]1[C:33]([CH3:34])=[CH:32][O:31][N:30]=1)=[O:4].Cl[C:36]1[CH:45]=[CH:44][C:43]2[CH2:42][CH2:41][N:40]3[C:46]4[CH:47]=[CH:48][CH:49]=[C:50]([F:53])[C:51]=4[CH:52]=[C:39]3[C:38]=2[N:37]=1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>O1CCOCC1.O.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:53][C:50]1[C:51]2[CH:52]=[C:39]3[C:38]4[N:37]=[C:36]([C:11]5[C:12]([N:14]([CH3:19])[S:15]([CH3:18])(=[O:16])=[O:17])=[CH:13][C:8]6[O:7][C:6]([C:29]7[C:33]([CH3:34])=[CH:32][O:31][N:30]=7)=[C:5]([C:3]([NH:2][CH3:1])=[O:4])[C:9]=6[CH:10]=5)[CH:45]=[CH:44][C:43]=4[CH2:42][CH2:41][N:40]3[C:46]=2[CH:47]=[CH:48][CH:49]=1
Reactant: Fc1cccc2c1cc1n2CCc2ccc(Cl)nc2-1
Reactant: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: CNC(=O)c1c(-c2nocc2C)oc2cc(N(C)S(C)(=O)=O)c(-c3ccc4c(n3)-c3cc5c(F)cccc5n3CC4)cc12
Temperature: 85 °C
Reaction time: 3 h
Yield: 48.6 %

Procedure:
To a mixture of N-methyl-2-(4-methylisoxazol-3-yl)-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (60 mg, 0.12 mmol), 2-chloro-11-fluoro-5,6-dihydroindolo[1,2-h][1,7]naphthyridine (50 mg, 0.18 mmol) and K3PO4.3H2O (98 mg, 0.37 mmol) in dioxane/H2O (1.5 mL/0.5 mL) was added Pd2(dba)3 (8 mg, 0.008 mmol) and X-Phos (8 mg, 0.016 mmol) under N2. The mixture was stirred at 85° C. for 3 h. It was concentrated, diluted with water, extracted with EtOAc, and dried over Na2SO4. The residue was purified by prep-TLC (DCM:MeOH=60:1) to get the product (35 mg, yield: 48%). 1H-NMR (CDCl3, 400 MHz) δ 9.12 (d, J=3.6 Hz, 1H), 8.68 (s, 1H), 8.40 (s, 1H), 7.76 (s, 1H), 7.68 (d, J=7.6 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.28˜7.26 (m, 1H), 7.21˜7.12 (m, 2H), 6.85˜6.75 (m, 1H), 4.36 (t, J=6.4 Hz, 2H), 3.46 (s, 3H), 3.33 (t, J=6.4 Hz, 2H), 3.03 (d, J=4.8 Hz, 3H), 2.60 (s, 3H), 2.40 (s, 3H). MS (M+H)+: 600.
Reaction SMILES: [CH:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:5][CH:4]=1)=[CH2:2].Br[CH:26]([C:31]1[CH:36]=[C:35]([Cl:37])[C:34]([Cl:38])=[C:33]([Cl:39])[CH:32]=1)[C:27]([F:30])([F:29])[F:28].N1C=CC=CC=1C1C=CC=CN=1>ClC1C=CC=CC=1Cl.Cl[Cu]>[F:30][C:27]([F:28])([F:29])[CH:26]([C:31]1[CH:32]=[C:33]([Cl:39])[C:34]([Cl:38])=[C:35]([Cl:37])[CH:36]=1)/[CH:2]=[CH:1]/[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:6]([CH2:13][N:14]2[C:22](=[O:23])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:15]2=[O:24])=[CH:5][CH:4]=1
Reactant: FC(F)(F)C(Br)c1cc(Cl)c(Cl)c(Cl)c1
Reactant: C=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c2ccccc12
Agent: Cl[Cu]
Agent: c1ccc(-c2ccccn2)nc1
Solvent: Clc1ccccc1Cl
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 180 °C
Reaction time: 14 h
Yield: 54.5 %

Procedure:
To a stirred solution of 2-((4-vinylnaphthalen-1-yl)methyl)isoindoline-1,3-dione (1.5 g, 4.79 mmol) in 1,2-dichlorobenzene (15 mL) were added 1-(1-bromo-2,2,2-trifluoroethyl)-3,4,5-trichlorobenzene (3.2 g, 9.5 mmol), CuCl (24 mg, 0.24 mmol) and 2,2-bipyridyl (0.149 g, 0.95 mmol), and the resultant reaction mixture was degassed with argon for 30 min and then stirred at 180° C. for 14 h. After the reaction was deemed complete by TLC, the reaction mixture was cooled to ambient temperature and filtered, and the filtrate was concentrated under reduced pressure. Purification by flash chromatography (SiO2, 100-200 mesh; 25-30% EtOAc in petroleum ether) afforded the title compound as an off-white solid (1.5 g, 56%): mp 158-160° C.; 1H NMR (400 MHz, CDCl3) δ 8.40 (m, 1H), 7.89 (m, 2H), 7.74 (m, 2H), 7.64 (m, 2H), 7.58 (m, 2H), 7.46 (s, 2H), 7.36 (m, 2H), 6.31 (m, 1H), 5.30 (s, 2H), 4.21 (m, 1H); ESIMS m/z 572.08 ([M−H]−).
Reaction SMILES: [F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35]([NH:37][C:38](=[O:48])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[S:36])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:21](C)[C:22](=O)OC(C)(C)C)[CH:18]=3)[S:13][C:6]=12.Cl.Cl.FC1C=C(NC(NC(=O)CC2C=CC=CC=2)=S)C=CC=1OC1C=CN=C2C=C(C3C=CC(N4CCNCC4)=CC=3)SC=12>>[F:1][C:2]1[CH:33]=[C:32]([NH:34][C:35]([NH:37][C:38](=[O:48])[CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][C:41]=2[O:46][CH3:47])=[S:36])[CH:31]=[CH:30][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][NH:21][CH3:22])[CH:18]=3)[S:13][C:6]=12
Reactant: COc1ccccc1CC(=O)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4cnn(CCN(C)C(=O)OC(C)(C)C)c4)sc23)c(F)c1
Agent: Cl
Agent: O=C(Cc1ccccc1)NC(=S)Nc1ccc(Oc2ccnc3cc(-c4ccc(N5CCNCC5)cc4)sc23)c(F)c1
Product: CNCCn1cc(-c2cc3nccc(Oc4ccc(NC(=S)NC(=O)Cc5ccccc5OC)cc4F)c3s2)cn1
Yield: 66 %

Procedure:
Starting from the compound 183 and following the procedure described above for the synthesis of compound 159 (scheme 30, step 4, example 121), title compound 184 was obtained in 66% yield. 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.45(d, J=5.6 Hz, 1H), 8.33(s, 1H), 8.00(s, 1H), 7.85-7.75(m, 1H), 7.69(s, 1H), 7.39(t, J=8.4 Hz, 1 H), 7.35-7.28(m, 1H), 7.28-7.22(m, 1H), 7.22(d, J=7.6 Hz, 1H), 6.97(d, J=8.4 Hz, 1H), 6.89(t, J=7.6 Hz, 1H), 6.57(d, J=5.6 Hz, 1H), 4.19(t, J=6.4 Hz, 2H), 3.82(s, 2H), 3.77(s, 3H), 2.88(t, J=6.4 Hz, 2H), 2.28(s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:12]O.C([O-])(=O)C.[Na+]>C(O)=O>[OH:1][C:2]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]#[N:12]
Reactant: NO
Reactant: Cc1cccc(C=O)c1O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O=CO
Product: Cc1cccc(C#N)c1O

Procedure:
A solution of 2-hydroxy-3-methyl-benzaldehyde (1.13 g, 8.29 mmol), hydroxylamine hydrochloride (0.69 g, 9.9 mmol) and sodium acetate (0.8 g, 9.9 mmol) in formic acid (20 ml) is heated at reflux over night. The solvent is evaporated under reduced pressure and the residue is partitioned between water and ethyl acetate. The organic phase is dried and evaporated to dryness. Chromatography yields the title compound. (CDCl3, 400 MHz): 7.32 (m, 2H); 6.89 (t, 1H); 5.65 (s, 1H); 2.23 (s, 3H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[N:8]=[C:7]([NH:9][C:10]2[CH:11]=[C:12]([CH:25]=[CH:26][CH:27]=2)[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-])=O)=[CH:18][CH:17]=2)=[O:14])[CH:6]=[C:5]([NH2:28])[N:4]=1>[Pd].CO>[ClH:1].[NH2:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C:13](=[O:14])[C:12]2[CH:25]=[CH:26][CH:27]=[C:10]([NH:9][C:7]3[CH:6]=[C:5]([NH2:28])[N:4]=[C:3]([NH2:2])[N:8]=3)[CH:11]=2)=[CH:17][CH:18]=1
Reactant: Nc1cc(Nc2cccc(C(=O)Nc3ccc([N+](=O)[O-])cc3)c2)nc(N)n1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: Nc1ccc(NC(=O)c2cccc(Nc3cc(N)nc(N)n3)c2)cc1
Reaction time: 0.17 h
Yield: 75.9 %

Procedure:
To a suspension of compound B5 (567 mg, 1.41 mmol) in (MeOH) (30 mL) was added 10% Pd/C (20 mg) and hydrogenated under 40 Hg mm for 6 h. The reaction mixture was filtered through a pad of celite and the filtrate was evaporated to dryness. The residue was dissolved in a small volume of MeOH then 1 ml of 1.25M HCl in MeOH was added, stirred 10 min and evaporated to dryness. The residue was recrystallized from MeOH/EtOAc to give B6 (398 mg, 76%); mp (MeOH/EtOAc)>300° C., 1H NMR [(CD3)2SO] δ 10.37 (s, 1H, NH), 9.93 (s, 1H, NH), 7.92-7.80 (m, 4H, ArH & NH2), 7.68 (d, J=7.7 Hz, 1H, ArH), 7.61 (br s, 2H, NH2), 7.49-7.45 (m, 3H, ArH), 7.24 (br d, J=8.7 Hz, 2H, ArH), 5.45 (s, 1H, ArH), mass APCl+336.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]2[CH:8]3[CH2:19][CH:10]([C:11]4[CH:16]=[C:15]([F:17])[C:14]([Br:18])=[CH:13][C:12]=4[C:6]2=[N:5][C:4]=1[C:20]([NH2:22])=[O:21])[CH2:9]3.[C:23](O)(=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25]>>[Br:18][C:14]1[C:15]([F:17])=[CH:16][C:11]2[CH:10]3[CH2:9][CH:8]([CH2:19]3)[N:7]3[C:3]([CH2:2][NH:1][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])=[C:4]([C:20]([NH2:22])=[O:21])[N:5]=[C:6]3[C:12]=2[CH:13]=1
Reactant: CC(C)(C)C(=O)O
Reactant: NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2
Product: CC(C)(C)C(=O)NCc1c(C(N)=O)nc2n1C1CC(C1)c1cc(F)c(Br)cc1-2

Procedure:
3-(aminomethyl)-10-bromo-9-fluoro-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide was reacted with pivalic acid similarly to as described in Example 2 with non-critical modifications to afford crude 10-bromo-9-fluoro-3-(pivalamidomethyl)-6,7-dihydro-5H-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide which was reacted directly with 2-methyl-3-butyne-ol via General Procedure F to afford 15 mg (37%) of 3-[(2,2-dimethylpropanoylamino)methyl]-9-fluoro-10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6,7,12-tetrahydro-5,7-methanobenzo[c]imidazo[1,2-a]azepine-2-carboxamide. M+1=453.3.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:12]1[CH:13]=[N:14][CH:15]=[C:16]([S:18]([CH3:21])(=[O:20])=[O:19])[CH:17]=1)[CH2:9][CH2:10][CH3:11])(C)(C)C.[ClH:23].O1CCOCC1>ClCCl>[ClH:23].[ClH:23].[CH3:21][S:18]([C:16]1[CH:17]=[C:12]([CH:8]([NH2:7])[CH2:9][CH2:10][CH3:11])[CH:13]=[N:14][CH:15]=1)(=[O:20])=[O:19]
Reactant: CCCC(NC(=O)OC(C)(C)C)c1cncc(S(C)(=O)=O)c1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCCC(N)c1cncc(S(C)(=O)=O)c1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
A suspension of [1-(5-methanesulfonyl-pyridin-3-yl)-butyl]-carbamic acid tert-butyl ester (3.2 g, 9.6 mmol) in dichloromethane (12 mL) is treated HCl in dioxane (4.0 N, 24 mL, 96 mmol) and stirred for 30 min. The solvent is then removed in vacuo. The resultant residue is triturated with anhydrous ethyl ether (50 mL) and filtered (note: the collected solids are hygroscopic and turn into a liquid when left exposed to air.) Methanol is added and the solution is concentrated in vacuo to yield 1-(5-methanesulfonyl-pyridin-3-yl)-butylamine dihydrochloride (2.8 g, 100%) as a dark brown solid.