Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:8]1[CH2:12][C@H:11]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[C@@H:10]([C@@H:21]([O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][N:25]=2)[CH3:22])[CH2:9]1)C1C=CC=CC=1.ClC(OC(Cl)C)=O.CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Cl:30][C:27]1[CH:28]=[CH:29][C:24]([O:23][C@H:21]([C@@H:10]2[C@@H:11]([C:13]3[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=3)[CH2:12][NH:8][CH2:9]2)[CH3:22])=[N:25][CH:26]=1
Reactant: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)c(F)c1
Agent: CC(Cl)OC(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](Oc1ccc(Cl)cn1)[C@H]1CNC[C@@H]1c1ccc(Cl)c(F)c1
Temperature: 100 °C
Yield: 96 %

Procedure:
To a solution of 2-{(S)-1-[(3R,4S)-1-benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-ethoxy}-5-chloro-pyridine 98 mg (0.22 mmol) dissolved in toluene (5 mL) were added 0.072 mL (0.66 mmol) of 1-chloroethyl chloroformate and 0.11 mL (0.66 mL) of Hunig's base. The reaction mixture was heated at 100° C. for one hour. After cooling down to RT, volatiles were removed under vacuo and the crude was dissolved in MeOH (5 mL). The reaction mixture was heated at 85° C. for 30 minutes and after cooling down to RT, volatiles were removed under vacuo and the residue was directly purified on column chromatography (SiO2, CH2Cl2/MeOH 9:1) yielded 75 mg (95%) of the title compound as a light yellow oil. ES-MS m/e: 355.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])[CH:16]=3)=[CH:10][N:4]2[N:3]=1.[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=[O:30].N1C=CC=CC=1>CC#N>[Br:25][C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29]([NH:1][C:2]1[CH:7]=[CH:6][C:5]2=[N:8][C:9]([C:11]3[CH:12]=[CH:13][C:14]([CH3:24])=[C:15]([NH:17][C:18](=[O:23])[C:19]([CH3:20])([CH3:21])[CH3:22])[CH:16]=3)=[CH:10][N:4]2[N:3]=1)=[O:30]
Reactant: Cc1ccc(-c2cn3nc(N)ccc3n2)cc1NC(=O)C(C)(C)C
Reactant: O=C(Cl)c1cccc(Br)c1
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(-c2cn3nc(NC(=O)c4cccc(Br)c4)ccc3n2)cc1NC(=O)C(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 42.8 %

Procedure:
An 8-mL vial is charged with N-[5-(6-aminoimidazo[2,1-f]pyridazin-2-yl)-2-methyl-phenyl]-2,2-dimethyl-propanamide (0.097 g, 0.3 mmol), 3-bromobenzoyl chloride (0.059 mL, 0.45 mmol), pyridine (0.073 mL), and MeCN (1.0 mL). The mixture is stirred at room temperature for 16 hours, concentrated onto celite and purified by silica gel chromatography (0-100% 1:0.1 EtOAc:MeOH in CH2Cl2) to give the title compound (0.065 g). LCMS (m/z)=506.4 and 508.4 [M+H]+, tR=2.96 min.
Reaction SMILES: [O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][N:11]([C:14]4[C:15](=[O:28])[NH:16][C:17]5[C:22]([N:23]=4)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=5)[C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1.N1C=CC=CC=1.[O:35](S(C(F)(F)F)(=O)=O)[S:36]([C:39]([F:42])([F:41])[F:40])(=O)=[O:37]>ClCCl>[O:1]1[C:5]2=[CH:6][C:7]3[CH2:8][CH2:9][CH2:10][N:11]([C:14]4[C:15]([O:28][S:36]([C:39]([F:42])([F:41])[F:40])(=[O:37])=[O:35])=[N:16][C:17]5[C:22]([N:23]=4)=[CH:21][C:20]([C:24]([O:26][CH3:27])=[O:25])=[CH:19][CH:18]=5)[C:12]=3[CH:13]=[C:4]2[O:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(OS(=O)(=O)C(F)(F)F)c(N3CCCc4cc5c(cc43)OCO5)nc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 3-[2H,5H,6H,7H,8H-[1,3]dioxolo[4,5-g]quinolin-5-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (140 mg, 0.37 mmol) in dichloromethane (80 ml) was added pyridine (175 mg, 2.21 mmol) and Tf2O (510 mg, 1.81 mmol). The reaction was stirred overnight under atmosphere of nitrogen at room temperature. Then the reaction mixture was quenched with water (200 ml), extracted with dichloromethane (3×20 ml), the organic layers were combined, dried over anhydrous magnesium sulfate, and concentrated in vacuo to afford methyl 3-(7,8-dihydro-[1,3]dioxolo[4,5-g]quinolin-5(6H)-yl)-2-(trifluoromethylsulfonyloxy)quinoxaline-6-carboxylate as a red oil (150 mg, crude), which was used directly in the next step.
Reaction SMILES: [CH2:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH2:2]1.[OH:11]OS([O-])=O.[K+]>>[O:11]1[CH:8]2[CH2:7][CH2:6][C:5]3[C:10]([CH:9]12)=[CH:1][CH:2]=[CH:3][CH:4]=3
Reactant: O=S([O-])OO
Reactant: C1=Cc2ccccc2CC1
Agent: [K+]
Product: c1ccc2c(c1)CCC1OC21

Procedure:
36.5 g of 1,2-dihydronaphthalene (280.3 mmol) are treated with Oxone® according to the method described in Step A of Example 8 to yield the expected product in the form of an oil.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([OH:9])=O)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:20]=1>>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:11]([Br:14])=[CH:10][C:6]=1[C:7]([NH:15][C:16]1[S:17][CH:18]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[N:20]=1)=[O:9])(=[O:3])[CH3:2]
Reactant: CC(C)(C)c1csc(N)n1
Reactant: CC(=O)Oc1ccc(Br)cc1C(=O)O
Product: CC(=O)Oc1ccc(Br)cc1C(=O)Nc1nc(C(C)(C)C)cs1
Yield: 59.4 %

Procedure:
Using 2-acetoxy-5-bromobenzoic acid and 2-amino-4-[(1,1-dimethyl)ethyl]thiazole as the raw materials, the same operation as the Example 24 gave the title compound.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:39]=[CH:38][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([O:21]CC)=[O:20])=[CH:14][CH:15]=3)[C:10]([CH:24]=[N:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:9]2)=[CH:5][CH:4]=1.O.[OH-].[Li+]>C1COCC1>[F:40][C:2]([F:1])([F:41])[C:3]1[CH:39]=[CH:38][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:14][CH:15]=3)[C:10]([CH:24]=[N:25][O:26][CH2:27][C:28]3[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=3)=[CH:9]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)COc1ccc2c(c1)c(C=NOCc1ccc(C(F)(F)F)cc1)cn2Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 75.1 %

Procedure:
To a solution of the product of step 4 (350 mg, 0.605 mmoles) in THF (2 mL) Water: (2 ml), lithum hydroxide monohydrate (38 mg, 0.908 mmoles), was added and the reaction mixture was stirred at 25° C. for 3 hours. The reaction mixture was poured into ice cold water, acidified by dil.HCl and extracted with ethyl acetate. The combined ethyl acetate extract was washed with water & brine, dried over sodium sulphate and evaporated under reduced pressure to yield 250 mg (77%) of product as solid.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH:12]([CH2:23][C:24]1[CH:29]=[CH:28]C=CC=1)[C:13](N[C@H](C(OC)=O)CO)=[O:14].Cl.O.[CH2:32]([O:34]CC)C>>[CH3:32][O:34][C:13](=[O:14])[CH:12]([CH2:23][CH2:24][CH:29]=[CH2:28])[NH2:3]
Reactant: CCOCC
Reactant: COC(=O)[C@H](CO)NC(=O)C(Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: O
Product: C=CCCC(N)C(=O)OC
Reaction time: 2 h

Procedure:
Dissolve N-(phenylmethylene)-2-(3-butenyl)glycine methyl ester (25g) in ethyl ether (400mL) and stir with 1N hydrochloric acid (150mL) and water (150mL). Place under an argon atmosphere and stir for 2 hours. Separate the aqueous phase and adjust to pH 9, extract into chloroform, dry and evaporate the solvent in vacuo to give the title compound as a light oil (4.5g).
Reaction SMILES: [N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[N+:2]=[N-:3].N([CH2:25][CH2:26]N)=[N+]=[N-].C(N(CC)CC)C>ClCCl>[N:1]([CH2:4][CH2:5][NH:6][C:7](=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:25][CH3:26])=[N+:2]=[N-:3]
Reactant: CCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Reactant: [N-]=[N+]=NCCN
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)NCCN=[N+]=[N-]
Yield: 84.2 %

Procedure:
As in the synthesis of N-(2-azidoethyl)tetradecanamide, (0.338 g, 1.23 mmol) was reacted with 2-azidoethanamine (0.106 g, 1.23 mmol) and triethylamine (0.249 g, 2.46 mmol) in dichloromethane (5 mL) to give N-(2-azidoethyl)palmitamide (0.336 g, 84% yield). 1H NMR (300 MHz, CDCl3) δ 6.11 (s, 1H), δ 3.41 (s, 4H), δ 2.17 (t, J=7.5 Hz, 2H), δ 1.60 (m, 2H), δ 1.23 (m, 2H), δ 0.85 (t, 6.3 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3) δ 173.9, 51.1, 39.1, 36.9, 32.1, 29.9, 29.8, 29.8, 29.7, 29.6, 29.5, 25.9, 22.9, 14.3 ppm; HRMS (ESI) calcd for C18H36N4O (M+) 324.2889. found 324.2879.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH2:15].[CH3:16][O:17][C:18]([N:20]=[C:21]=[S:22])=[O:19]>CC(C)=O>[CH3:16][O:17][C:18]([NH:20][C:21](=[S:22])[NH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][C:3]=1[NH:15][C:21]([NH:20][C:18]([O:17][CH3:16])=[O:19])=[S:22])=[O:19]
Reactant: COC(=O)N=C=S
Reactant: Nc1ccc(Sc2ccccc2)cc1N
Solvent: CC(C)=O
Product: COC(=O)NC(=S)Nc1ccc(Sc2ccccc2)cc1NC(=S)NC(=O)OC

Procedure:
1.6 G. 1,2-diamino-4-phenylthiobenzene is dissolved in 30 ml. acetone and treated with 4 g. methoxycarbonyl isothiocyanate at room temperature overnight. The mixture is concentrated under vacuum and the residue triturated with ether. Recrystallization from methanol-chloroform yields pure 1,2-bis-(3-methoxycarbonyl-2-thioureido)-4-phenylthiobenzene.
Reaction SMILES: [CH:1]#[C:2][CH2:3][CH2:4][CH2:5]C.C1(C#C)C=CC=CC=1.[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#N)=[CH:18][CH:17]=1>C(C1C=CC(C#CCCCC)=CC=1)#CCCCC.C(#N)C1C=CC=CC=1>[Cl:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[C:1][CH2:2][CH2:3][CH2:4][CH3:5])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(Cl)cc1
Reactant: C#CCCCC
Agent: CCCCC#Cc1ccc(C#CCCCC)cc1
Solvent: N#Cc1ccccc1
Solvent: C#Cc1ccccc1
Product: CCCCC#Cc1ccc(Cl)cc1
Reaction time: 20 h
Yield: 64.5 %

Procedure:
The procedure was identical to Example 2, with the exception that 1-hexyne (0.450 ml; 0.329 g; 4.00 mmol) was used as a substrate instead of phenylacetylene and 4-chlorobenzonitrile (0.275 g; 2.00 mmol) was used as a substrate instead of benzonitrile. GC analysis of the organic phase of the hydrolyzed reaction sample after 20 h at 65° C. showed the presence of 1.29 mmol (65% yield) of 1-chloro-4-(1-hexynyl)benzene, 0.10 mmol 1,4-bis(1-hexynyl)benzene and no remaining 4-chlorobenzonitrile in the reaction mixture.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].Br[CH2:10][CH:11]1[CH2:13][CH2:12]1>>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[O:8][CH2:10][CH:11]1[CH2:13][CH2:12]1
Reactant: BrCC1CC1
Reactant: Oc1ccccc1Br
Product: Brc1ccccc1OCC1CC1

Procedure:
Starting from commercially available 2-bromo-phenol and bromomethyl-cyclopropane the title compound is obtained as colorless oil.
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[C:8]([O:12][CH3:13])[C:7]([N+:14]([O-:16])=[O:15])=[CH:6][C:3]=1[CH:4]=O.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][C:25](O)=[O:26])=[CH:20][CH:19]=1.C1(OP(Cl)(Cl)=O)C=CC=CC=1.C(N(CC)CC)C>ClCCCl>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[C:25](=[O:26])[O:1][C:2]3[C:3]([CH:4]=2)=[CH:6][C:7]([N+:14]([O-:16])=[O:15])=[C:8]([O:12][CH3:13])[C:9]=3[O:10][CH3:11])=[CH:20][CH:19]=1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Reactant: COc1c([N+](=O)[O-])cc(C=O)c(O)c1OC
Agent: O=P(Cl)(Cl)Oc1ccccc1
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: COc1c([N+](=O)[O-])cc2cc(-c3ccc(Cl)cc3)c(=O)oc2c1OC

Procedure:
2-Hydroxy-3,4-dimethoxy-5-nitro-benzaldehyde (2.44 g), 4-chlorophenyl acetic acid (1.82 g), PhOPOCl2 (1.6 ml) and triethylamine (4.5 ml) in 1,2-dichloroethane (125 ml) were refluxed for 5 hours as described in example 1(a). Yield: 2.40 g.
Reaction SMILES: CC(C)([O-])C.[K+].[CH2:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[C:18]1[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]([NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[C:20]([Cl:38])[CH:19]=1>C1(C)C=CC=CC=1>[Cl:38][C:20]1[CH:19]=[C:18]([N:8]2[CH2:9][CH2:10][C:11]3[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=3)[CH2:7]2)[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[C:21]=1[NH:28][C:29](=[O:37])[CH2:30][CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: O=C(CCC1CCCC1)Nc1c(Cl)cc(Br)cc1C(F)(F)F
Reactant: c1ccc2c(c1)CCNC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=C(CCC1CCCC1)Nc1c(Cl)cc(N2CCc3ccccc3C2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 28 %

Procedure:
Bis(dibenzylidineacetone)palladium (2 mg, 0.0035 mmol) and (2′-dicyclohexyl phosphanyl-biphenyl-2-yl)-dimethylamine (3.3 mg, 0.0084 mmol) were added to dry toluene (10 mL purged with argon) and stirred for 15 minutes under argon. Potassium tert-butoxide (150 mg, 1.34 mmol), 1,2,3,4-tetrahydroisoquinoline (107 mg, 0.8 mmol), and N-(4-bromo-2-chloro-6-trifluoromethyl phenyl)-3-cyclopentyl propionamide (200 mg, 0.5 mmol) were then added, and the reaction mixture was stirred at 90° C. overnight. The reaction mixture was then cooled to room temperature, concentrated, and purified by thin layer chromatography (dichloromethane: methanol 5%) to afford the title compound as a solid.
Reaction SMILES: [CH2:1]([Mg]Cl)[CH3:2].[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:20]([CH3:27])=[N:21][C:22](Cl)=[N:23][C:24]=4[CH3:25])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([O:33][CH:34]([F:36])[F:35])[C:29]([F:32])([F:31])[F:30])=[CH:8][CH:7]=1.FC(F)(F)C(O)=O>O1CCCC1.[Cl-].[NH4+].Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:5][C:6]1[C:14]2[N:13]=[C:12]3[N:15]([C:19]4[C:24]([CH3:25])=[N:23][C:22]([CH2:1][CH3:2])=[N:21][C:20]=4[CH3:27])[CH2:16][CH2:17][CH2:18][N:11]3[C:10]=2[C:9]([CH:28]([O:33][CH:34]([F:35])[F:36])[C:29]([F:32])([F:31])[F:30])=[CH:8][CH:7]=1
Reactant: Cc1nc(Cl)nc(C)c1N1CCCn2c1nc1c(Cl)ccc(C(OC(F)F)C(F)(F)F)c12
Reactant: CC[Mg]Cl
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CCc1nc(C)c(N2CCCn3c2nc2c(Cl)ccc(C(OC(F)F)C(F)(F)F)c23)c(C)n1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
Ethylmagnesium chloride (2.0 M solution in tetrahydrofuran, 0.37 mL, 0.740 mmol) was added dropwise to a stirred suspension of 9-chloro-1-(2-chloro-4,6-dimethylpyrimidin-5-yl)-6-[1-(difluoromethoxy)-2,2,2-trifluoroethyl]-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (183 mg, 0.369 mmol) and [1,3-bis(diphenylphosphino)propane]dichloronickel (20.0 mg, 0.0369 mmol) in tetrahydrofuran (1.5 mL) at 0° C., and the mixture was stirred at room temperature for 14 hr. The mixture was diluted with aqueous ammonium chloride and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a 70-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the solid, which was purified by preparative HPLC to give a mixture containing an intermediate of the title compound as the trifluoroacetic acid salt. The mixture was washed with aqueous sodium hydrogen carbonate and extracted with ethyl acetate. The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give the solid, which was washed with ethyl acetate/n-hexane to give the title compound as a colorless amorphous (16.5 mg, 0.0337 mmol, 9%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][N:12]1[C:16](=[O:17])[CH:15]=[CH:14][C:13]1=[O:18]>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:15]1[C:16](=[O:17])[N:12]([CH3:11])[C:13](=[O:18])[CH2:14]1
Reactant: Brc1ccc2[nH]ccc2c1
Reactant: CN1C(=O)C=CC1=O
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3ccc(Br)cc23)C1=O
Yield: 74.7 %

Procedure:
To a solution of 5-bromoindole (5 g, 25.5 mmol) in glacial acetic acid (60 mL) was added N-methylmaleimide (6.1 g, 56.11 mmol) and the resulting mixture was heated to reflux for 4 days. The acetic acid was removed by distillation and the crude product was dissolved in diethyl ether (500 mL) and washed with saturated sodium bicarbonate (2×100 mL) and brine (3×100 mL). The solvent was evaporated and the residue chromatographed on silica gel using hexane/ethyl acetate (1:1) as the eluent to provide 3-(5-bromo-1H-indol-3-yl)-N-methylsuccinimide (5.85 g, 75%). Yellow solid, mp 194-195° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[CH:9]([NH:12][C:13]3[O:14][CH2:15][C:16]4[CH:22]=[C:21]([NH2:23])[CH:20]=[CH:19][C:17]=4[N:18]=3)[CH2:10][O:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.[Cl:24][CH2:25][C:26](Cl)=[O:27]>>[Cl:24][CH2:25][C:26]([NH:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:13]([NH:12][CH:9]3[C:8]4[C:3]([O:2][CH3:1])=[CH:4][CH:5]=[CH:6][C:7]=4[O:11][CH2:10]3)[O:14][CH2:15][C:16]=2[CH:22]=1)=[O:27]
Reactant: COc1cccc2c1C(NC1=Nc3ccc(N)cc3CO1)CO2
Reactant: O=C(Cl)CCl
Product: COc1cccc2c1C(NC1=Nc3ccc(NC(=O)CCl)cc3CO1)CO2
Yield: 95.1 %

Procedure:
Prepared from rac-N2-(4-methoxy-2,3-dihydro-benzofuran-3-yl)-4H-benzo[d][1,3]oxazine-2,6-diamine (Example 6) (320 mg, 1.03 mmol) and chloroacetyl chloride (85.8 ul, 1.08 mmol) according to the procedure described for Example 3 step A. Obtained the title compound as an off-white solid (380 mg, 95%), MS (ISP) m/e=388.2 [(M+H)+] and 390 [(M+2+H)+].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH2:14][N:13]3[CH:21]=[CH:22][CH:23]=[C:12]3[CH2:11]2)=[O:9])=[CH:4][C:3]=1[O:24][CH3:25].[CH2:26]([CH2:30][C:31](=O)[CH3:32])[C:27]([CH3:29])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1.ClCCl>[CH3:32][C:31]1[N:1]([C:2]2[CH:7]=[CH:6][C:5]([C:8]([N:10]3[C:16]4[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=4[CH2:14][N:13]4[CH:21]=[CH:22][CH:23]=[C:12]4[CH2:11]3)=[O:9])=[CH:4][C:3]=2[O:24][CH3:25])[C:27]([CH3:29])=[CH:26][CH:30]=1
Reactant: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1N
Reactant: CC(=O)CCC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Solvent: c1ccccc1
Product: COc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1-n1c(C)ccc1C
Temperature: 25 °C

Procedure:
A solution of (4-amino-3-methoxy-phenyl)[10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10-yl]methanone prepared in the manner of Albright et al., E.P.636625-A2 (0.675g, 2 mmol) and acetonyl acetone (0.3 mL, 2.5 mmol) in benzene (100 mL) was treated with a crystal of para-toluenesulfonic acid. The stirred solution was warmed to reflux for 46 hrs using a Dean Stark trap. The reaction was cooled to room temperature, diluted with dichloromethane (100 mL), washed with saturated aqueous sodium bicarbonate then water. The residue (oil, 0.900 g) was flash chromatography on silica gel eluting with 20% ethyl acetate in hexane to yield 0.610 g of the title compound as a white foam. Recrystallization of a sample of this material yielded yellow crystals, m.p. 141–144° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[CH:10][CH:9]=1)(=O)=O.[NH:15]1[CH:19]=[CH:18][N:17]=[CH:16]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:15]2[CH:19]=[CH:18][N:17]=[CH:16]2)=[CH:9][CH:10]=1
Reactant: Cc1ccc(CCOS(C)(=O)=O)cc1
Reactant: c1c[nH]cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1ccc(CCn2ccnc2)cc1
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of 28.9 g of 2-(4-methylphenyl)ethanol methanesulfonate, 18.6 g of 1H-imidazole, 22.7 g of potassium carbonate and 600 ml of tetrahydrofuran was stirred for 18 hours at reflux temperature. After cooling, the reaction mixture was evaporated and the residue was taken up in water and extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated and the residue was destilled (13.3 Pa; 120° C.), yielding 20.1 g (83.0%) of 1-[2-(4-methylphenyl)ethyl]-1H-imidazole (interm. 6).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[CH:10][CH:9]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:20]=1[C:29]([F:32])([F:31])[F:30]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][CH:17]=1)[CH2:5][O:6][CH2:7][C:8]1[N:13]=[C:12]([NH:14][S:25]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[C:20]([C:29]([F:32])([F:30])[F:31])[CH:21]=2)(=[O:27])=[O:26])[CH:11]=[CH:10][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(F)c(C(F)(F)F)c1
Reactant: Nc1cccc(COCc2cccc(Cl)c2)n1
Product: O=S(=O)(Nc1cccc(COCc2cccc(Cl)c2)n1)c1ccc(F)c(C(F)(F)F)c1

Procedure:
This material was prepared in analogy to example 1 from 6-(3-chloro-benzyloxymethyl)-pyridin-2-ylamine (0.08 g) and 4-fluoro-3-(trifluoromethyl)-benzenesulfonyl chloride (0.092g) as a light yellow gum (0.088 g). MS (ESI−): 472.8 ([M−H]−).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[CH:8]([O:11][C:12]([N:14]1[C:27]2[C:19](=[CH:20][C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[CH:18]([NH:28][CH2:29][C:30]2[CH:35]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:33]=[C:32]([C:40]([F:43])([F:42])[F:41])[CH:31]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9].N1C=CC=CC=1.Cl>ClCCl>[CH:8]([O:11][C:12]([N:14]1[C:27]2[C:19](=[CH:20][C:21]3[CH2:22][CH2:23][CH2:24][C:25]=3[CH:26]=2)[CH:18]([N:28]([C:1](=[O:3])[CH3:2])[CH2:29][C:30]2[CH:31]=[C:32]([C:40]([F:43])([F:41])[F:42])[CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=2)[CH2:17][CH2:16][CH2:15]1)=[O:13])([CH3:10])[CH3:9]
Reactant: CC(C)OC(=O)N1CCCC(NCc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2cc3c(cc21)CCC3
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc3c(cc21)CCC3
Temperature: 25 °C
Reaction time: 14 h
Yield: 74.2 %

Procedure:
Add 3,5-bis(trifluoromethyl)benzylamine (187 mg, 0.77 mmol) followed by titanium isopropoxide (835 mg, 2.94 mmol) to 9-Oxo-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (200 mg, 0.7 mmol) at room temperature under an atmosphere of nitrogen and stir the solution for 3 days. Add methanol (3 mL) and sodium borohydride (40 mg, 1.05 mmol) and stir the mixture under nitrogen at room temperature for 16 hours. Add sodium bicarbonate saturated solution. Filter through celite and wash the residue with AcOEt. Separate organic layer, extract aqueous with AcOEt. Wash organic layer with brine and dry the organic layers over anhydrous sodium sulfate. Filter and remove the solvent under reduced pressure. Purify the residue by silica cartridge, eluting with hexanes/ethyl acetate 9:1, to afford of (+/−)-9-(3,5-bis-trifluoromethyl-benzylamino)-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid isopropyl ester (220 mg). Add acetic anhydride (0.22 mL, 2.33 mmol) dropwise to a solution of the amine (80 mg, 0.155 mmol) and pyridine (0.18 mL, 2.33 mmol) in dichloromethane (1 mL). Stir under nitrogen at room temperature for 14 h. Add 1 M hydrochloric acid and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by silica gel cartridge, eluting with hexanes/ethyl acetate 4:1, to afford the title compound (64 mg, 74%); MS (ES+): 579 (M+H+Na).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1.[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22](Cl)(=[O:24])=[O:23]>>[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[S:22]([N:1]1[CH2:6][CH2:5][CH2:4][CH:3]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:2]1)(=[O:23])=[O:24]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: CCOC(=O)C1CCCNC1
Product: CCOC(=O)C1CCCN(S(=O)(=O)c2ccc3ccccc3c2)C1
Yield: 62 %

Procedure:
Using an analogous procedure to that described in Example 2, ethyl piperidine-3-carboxylate was reacted with 2-naphthylsulphonyl chloride to give ethyl 1-(2-naphthylsulphonyl)piperidine-3-carboxylate in 62% yield.