Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2]/[CH:3]=[CH:4]/[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N+](=[CH:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Br:1][CH2:2][CH:3]1[CH:4]([C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: BrC/C=C/c1ccccc1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CBr)C1c1ccccc1
Temperature: 25 °C
Reaction time: 60 h
Yield: 7.4 %

Procedure:
To a solution of [(E)-3-bromo-1-propenyl]benzene (705 mg, 3.58 mmol) in dichloromethane (1 ml) was added rhodium (II) acetate dimer (20 mg, 0.05 mmol). To the mixture was added dropwise at room temperature over 4 h a solution of ethyl diazoacetate (0.43 ml, 0.47 g, 4.15 mmol) in dichloromethane (2.5 ml). The mixture was stirred at room temperature for 60 h. The mixture was purified by silica column (40 g) chromatography eluting with 1:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were purified further by silica column (10 g) chromatography eluting with 9:1 hexane:dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo to give the title compound as a colourless oil (75 mg, 8%).
Reaction SMILES: F[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=1.[NH:16]1[CH:20]=[N:19][CH:18]=[N:17]1.C(=O)([O-])[O-].[K+].[K+].CCOCC>CN(C)C=O>[N:16]1([C:2]2[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([C:12]([F:15])([F:14])[F:13])[CH:3]=2)[CH:20]=[N:19][CH:18]=[N:17]1
Reactant: c1nc[nH]n1
Reactant: COC(=O)c1ccc(F)cc1C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)c1ccc(-n2cncn2)cc1C(F)(F)F
Temperature: 60 °C
Reaction time: 4 h
Yield: 83.9 %

Procedure:
To a solution of methyl 4-fluoro-2-trifluoromethylbenzoate (4.95 g) in N,N-dimethylformamide was added 1,2,4-triazole (2.0 g) and potassium carbonate (4.0 g) at 20° C. and the mixture stirred for 4 hours at 60° C. The mixture was diluted (ether), washed (aqueous citric acid) and dried (magnesium sulfate). The residue was purified by chromatography to give methyl 4-(1,2,4-triazol-1-yl)-2-trifluoromethylbenzoate (5.07 g), NMR 3.98(s,3H),7.94-8.05(2H),8.15(2H),8.71 (s,1H).
Reaction SMILES: [C:1]([OH:22])(=O)[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C(N1C=CN=C1)(N1C=CN=C1)=O.[CH2:35]([CH2:37][NH2:38])[OH:36]>CN(C=O)C>[OH:36][CH2:35][CH2:37][NH:38][C:1](=[O:22])[CH2:2][CH2:3][CH2:4][C:5]#[C:6][CH2:7][C:8]#[C:9][CH2:10][C:11]#[C:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCCCCCCCC#CCC#CCC#CCCCC(=O)O
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCCCCCCCC#CCC#CCC#CCCCC(=O)NCCO
Reaction time: 2 h

Procedure:
A solution of 8 g of 5,8,11-eicosatriynoic acid and 5.62 g of carbonyldiimidazole in 40 cm3 of anhydrous DMF is brought to 80° C. for 3 hours under an inert atmosphere. 3.25 g of ethanolamine are then added at 0° C. After 2 hours, it is verified by thin layer chromatography that the starting acid is completely converted.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[CH:21]=[CH:20][C:19]([CH:22]4[CH2:24][CH2:23]4)=[CH:18][C:17]=3[CH:25]3[CH2:27][CH2:26]3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[O:28]1[CH2:32][CH2:31][NH:30][C:29]1=[O:33]>>[CH:25]1([C:17]2[CH:18]=[C:19]([CH:22]3[CH2:24][CH2:23]3)[CH:20]=[CH:21][C:16]=2[N:13]2[CH2:14][CH2:15][N:10]([C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][O:28][C:29]4=[O:33])=[N:7][CH:6]=3)=[O:9])[CH2:11][CH2:12]2)[CH2:27][CH2:26]1
Reactant: O=C(c1ccc(Br)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Reactant: O=C1NCCO1
Product: O=C(c1ccc(N2CCOC2=O)nc1)N1CCN(c2ccc(C3CC3)cc2C2CC2)CC1
Yield: 75.9 %

Procedure:
By reaction and treatment in the same manner as in Example 1 and using (6-bromopyridin-3-yl)[4-(2,4-dicyclopropylphenyl)piperazin-1-yl]methanone (500 mg) described in Preparation Example 141 and oxazolidin-2-one (148 mg), the title compound (385 mg) was obtained.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[F:55][C:56]([F:66])([F:65])[CH2:57][C:58]1[CH:63]=[CH:62][CH:61]=[CH:60][C:59]=1[OH:64].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)(Cl)Cl>[Br:1][C:62]1[CH:61]=[CH:60][C:59]([OH:64])=[C:58]([CH2:57][C:56]([F:65])([F:66])[F:55])[CH:63]=1
Reactant: [Br-]
Reactant: Oc1ccccc1CC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Oc1ccc(Br)cc1CC(F)(F)F
Temperature: 25 °C
Reaction time: 2 h
Yield: 187.3 %

Procedure:
Tetrabutylammonium tribromide (6.56 g) was dissolved in chloroform (50 ml) and added dropwise to a solution of 2-(2,2,2-trifluoroethyl)phenol (2.4 g) in chloroform (50 ml). The reaction mixture was stirred at room temperature for 2 hrs, after which time 5% sodium thiosulfate solution (100 ml) was added and the resultant stirred for 30 mins. The mixture was then partitioned between dichloromethane (100 ml) and 1N HCl (200 ml). The organics were separated and dried over magnesium sulfate. The solvent was then removed in vacuo, the crude residue was then purified by column chromatography on silica gel eluting with 90:10 hexanes:ethyl acetate to afford the title compound as a yellow oil (3.24 g). 1H NMR (CDCl3): δ 3.50 (q, J=21.48 Hz 2H), 6.70 (d, J=2.54 Hz, 1H), 7.32 (d, J=2.54 Hz, 1H), 7.45 (s, 1H).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=[N:13][OH:14])C)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17](=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28]Br)=[CH:21][CH:20]=1>>[CH3:15][O:16][C:17](=[O:30])[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][O:14][N:13]=[CH:11][C:8]2[CH:7]=[CH:6][C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])=[CH:10][CH:9]=2)=[CH:21][CH:20]=1
Reactant: COC(=O)Cc1ccc(OCCCBr)cc1
Reactant: CC(=NO)c1ccc(C(C)(C)C)cc1
Product: COC(=O)Cc1ccc(OCCCON=Cc2ccc(C(C)(C)C)cc2)cc1

Procedure:
{4-[3-(4-tert-Butyl-benzylideneaminooxy)-propoxy]-phenyl}-acetic acid methyl ester was prepared from 1-(4-tert-butyl-phenyl)-ethanone oxime and [4-(3-bromo-propoxy)-phenyl]-acetic acid methyl ester using a procedure similar to step 2 of example 1. It was used crude in the subsequent reaction. 1H NMR (300 MHz, CDCl3); δ 8.07 (s, 1H), 7.52 (d, 2H), 7.40 (d, 2H), 7.20 (d, 2H), 6.88 (d, 2H), 4.35 (t, 2H), 4.10 (t, 2H), 3.70 (s, 3H), 3.58 (s, 2H), 2.21 (m, 2H), 1.34 (s, 9H).
Reaction SMILES: Cl.C(O[C:5](=[NH:7])[CH3:6])C.[F:8][C:9]1[CH:10]=[C:11]([CH:16]=[C:17]([F:19])[CH:18]=1)[C:12]([NH:14][NH2:15])=[O:13]>>[NH:7]=[C:5]([N:14]([C:12](=[O:13])[C:11]1[CH:10]=[C:9]([F:8])[CH:18]=[C:17]([F:19])[CH:16]=1)[NH2:15])[CH3:6]
Reactant: NNC(=O)c1cc(F)cc(F)c1
Reactant: CCOC(C)=N
Agent: Cl
Product: CC(=N)N(N)C(=O)c1cc(F)cc(F)c1

Procedure:
The compound is obtained analogously to the method described for intermediate product 1a) from 4.91 g (40 mmol) ethylacetimidate hydrochloride and 3.80 g (22 mmol) 3,5 difluoro-benzoic acid hydrazide.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10](Cl)(=[O:14])[CH:11]([CH3:13])[CH3:12].[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2>C(Cl)Cl>[F:16][C:17]1[C:25]([O:26][C:27]2[C:36]3[C:31](=[CH:32][C:33]([O:39][CH2:40][CH:41]4[CH2:46][CH2:45][N:44]([C:10](=[O:14])[CH:11]([CH3:13])[CH3:12])[CH2:43][CH2:42]4)=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][N:28]=2)=[CH:24][CH:23]=[C:22]2[C:18]=1[CH:19]=[C:20]([CH3:47])[NH:21]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: CC(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(C(=O)C(C)C)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52.3 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) and isobutyryl chloride (44 mg, 0.41 mmol), in methylene chloride (0.5 ml) were added to a suspension of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the starting material in Example 11), in methylene chloride (4 ml). After a few minutes all the material had gone into solution. The mixture was stirred for 3 hours at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. Column chromatography of the residue, eluting with 2% methanol/methylene chloride gave 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-7-[(1-isobutyrylpiperidin-4-yl)methoxy]-6-methoxyquinazoline (90 mg, 52%).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][OH:28])=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][C:33]([F:35])=[N:34][C:16]1=2)[CH3:14].O[C:37]1[C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=[CH:39][CH:38]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1COCC1>[CH2:13]([N:15]1[C:21]2[N:22]=[CH:23][C:24]([CH2:26][CH2:27][O:28][C:37]3[C:46]4[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=4)[N:40]=[CH:39][CH:38]=3)=[CH:25][C:20]=2[C:19](=[O:29])[N:18]([CH3:30])[C:17]2[CH:31]=[CH:32][C:33]([F:35])=[N:34][C:16]1=2)[CH3:14]
Reactant: Oc1ccnc2ccccc12
Reactant: CCN1c2ncc(CCO)cc2C(=O)N(C)c2ccc(F)nc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCN1c2ncc(CCOc3ccnc4ccccc34)cc2C(=O)N(C)c2ccc(F)nc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 66.5 %

Procedure:
Diethyl azodicarboxylate (DEAD) (14.3 mL, 91.0 mmol) was added drop-wise to a solution of 5,11-dihydro-11-ethyl-2-fluoro-8-(2-hydroxyethyl)-5-methyl-6H-dipyrido[3,2-b:2′,3′-e][1,4]diazepin-6-one (19.2 g, 60.7 mmol), 4-hydroxyquinoline (13.2 g, 91.0 mmol) and Ph3P (23.9 g, 91.0 mmol) in THF (300 mL) at room temperature. The mixture was stirred at room temperature for 1 h then was concentrated under reduced pressure. The residue was purified by flash chromatography (EtOAc:MeOH; 95:5) to give the title compound (17.9 g, 67% yield) as a white solid: MS (ESI) m/z 444 (M)+.
Reaction SMILES: C([O:4][C:5](=[O:44])[C:6]([CH3:43])([CH3:42])[CH2:7][C:8]1[N:9]([CH2:34][C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[C:10]2[C:15]([C:16]=1[S:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[CH:14][C:13]([O:22][CH2:23][C:24]1[N:25]=[CH:26][C:27]3[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:12][CH:11]=2)C=C.CO.[Li+].[OH-].Cl>C1COCC1>[Cl:41][C:38]1[CH:37]=[CH:36][C:35]([CH2:34][N:9]2[C:10]3[C:15](=[CH:14][C:13]([O:22][CH2:23][C:24]4[N:25]=[CH:26][C:27]5[C:32]([CH:33]=4)=[CH:31][CH:30]=[CH:29][CH:28]=5)=[CH:12][CH:11]=3)[C:16]([S:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[C:8]2[CH2:7][C:6]([CH3:43])([CH3:42])[C:5]([OH:44])=[O:4])=[CH:40][CH:39]=1
Reactant: C=CCOC(=O)C(C)(C)Cc1c(SC(C)(C)C)c2cc(OCc3cc4ccccc4cn3)ccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)Sc1c(CC(C)(C)C(=O)O)n(Cc2ccc(Cl)cc2)c2ccc(OCc3cc4ccccc4cn3)cc12
Temperature: 25 °C
Yield: 77.4 %

Procedure:
The compound from Step 1 (174 mg) was dissolved in THF (5 mL), MeOH (3 mL), 1N LiOH (1.3 mL) and heated at 65° C. for 1 hr. After cooling to r.t., the mixture was acidified with 1N HCl and extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel chromatography eluting first with 1:1 EtOAc/hexane and followed by the addition of 5% HOAc to this solvent. The title compound (126 mg), was obtained as a white solid; mp 227.5°-228.5° C.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21].[CH2:24]([C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:31]2[C:41]([CH:45]=[O:46])=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1)[CH2:25][CH2:26][CH3:27]>O1CCCC1>[CH2:24]([C:28]1[N:32]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[C:31]2[C:41]([CH:45]([OH:46])[CH:19]([CH2:18][C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)[C:20]([O:22][CH3:23])=[O:21])=[CH:42][CH:43]=[CH:44][C:30]=2[N:29]=1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCc1nc2cccc(C=O)c2n1Cc1ccccc1Cl
Reactant: COC(=O)CCc1cccs1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCc1nc2cccc(C(O)C(Cc3cccs3)C(=O)OC)c2n1Cc1ccccc1Cl
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 56.1 %

Procedure:
A solution of n-butyl lithium (0.4 mL of 2.5M in hexane, 1 mmol) in dry tetrahydrofuran (5 mL) at -78° C. under argon was treated with diisopropylamine (108 mg, 1.06 mmol). This mixture was stirred 10 minutes at -78° C. and methyl 3-(2-thienyl)propanoate (156 mg, 0.92 mmol) was added in tetrahydrofuran. After being stirred an additional 30 minutes at -78° C., a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-benzimidazole-7-carboxaldehyde (200 mg, 0.61 mmol) in tetrahydrofuran (1.5 mL) was added. This mixture was stirred at -78° C. for 15 minutes and the reaction was quenched with saturated ammonium chloride. The product was extracted into ethyl acetate, washed with water, dried and concentrated product was flash chromatographed over silica gel with 5-10% of methanol in ethyl acetate to provide 0.17 g (56%) of methyl 3-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-benzimidazol-7-yl]-3-hydroxy-2-(2-thienyl)methylpropanoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][CH:20]=[CH:19][C:18]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>O1CCCC1>[CH3:15][N:13]([CH3:14])[CH2:12][CH2:11][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([NH:1][C:17]3[C:18]([N+:26]([O-:28])=[O:27])=[CH:19][CH:20]=[CH:21][C:22]=3[N+:23]([O-:25])=[O:24])[CH:3]=2)[NH:7][CH:6]=1
Reactant: O=[N+]([O-])c1cccc([N+](=O)[O-])c1Cl
Reactant: CN(C)CCc1c[nH]c2ccc(N)cc12
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(C)CCc1c[nH]c2ccc(Nc3c([N+](=O)[O-])cccc3[N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 57 %

Procedure:
5-Amino-3-(2-dimethylaminoethyl)indole and 1-chloro-2,6-dinitrobenzene were used. Triethylamine was used as base, tetrahydrofuran was used as solvent, and the reaction was stirred at room temperature for 1 hour. Chromatography afforded the title compound (57%) as a dark red solid: mp, 187.0°-188.0° C.; 13C NMR (DMSO-d6) δ139.9, 135.2, 134.0, 132.0, 131.8, 127.2, 123.8, 117.0, 115.4, 112.9, 112.0, 109.3, 59.9, 45.1, 23.0; HRMS calculated for C18H19N5O 369.1439, found 369.1428. Anal. calcd. for C18H19N5O: C, 58.53; H, 5.18; N, 18.96. Found: C, 58.45; H, 4.96; N, 18.63.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8][CH3:9])[CH:5]=[CH:4][C:3]=1[NH2:10].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.C[O:22][CH:23](OC)[C:24]1[C:25](F)=[C:26]([CH:30]=[CH:31][C:32]=1[F:33])[C:27]([OH:29])=[O:28]>C1COCC1>[F:33][C:32]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[C:25]([NH:10][C:3]2[CH:4]=[CH:5][C:6]([S:8][CH3:9])=[CH:7][C:2]=2[F:1])[C:24]=1[CH:23]=[O:22]
Reactant: COC(OC)c1c(F)ccc(C(=O)O)c1F
Reactant: CSc1ccc(N)c(F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CSc1ccc(Nc2c(C(=O)O)ccc(F)c2C=O)c(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-methylsulfanyl-phenyl amine (1.55 g, 9.9 mmol) in THF (15 mL) was added LHMDS (9.9 mL, 1.0 M solution in hexanes 9.9 mmol) dropwise so as to maintain the temperature below −65° C. After stirring for 30 minutes a solution of 3-dimethoxymethyl-2,4-difluoro-benzoic acid (700 mg, 3.0 mmol) in THF (15 mL) was added dropwise, the resultant mixture stirred cold for 3 hours then allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride and the products partitioned between ethyl acetate and water. The aqueous layer was separated and acidified to pH 1 (concentrated HCl) and then extracted twice with ethyl acetate. The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo. The resultant residue was triturated with diethyl ether to give the title compound as a yellow solid (105 mg, 10% yield). 1H NMR (CDCl3, 400 MHz) 10.26-10.23 (2 H, m), 8.04 (1 H, dd, J=8.76, 6.31 Hz), 7.03-6.96 (2H, m), 6.91 (1 H, d, J=1.96 Hz), 6.65 (1 H, dd, J=10.02, 8.77 Hz), 2.42 (3 H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7].[C:12](OC(=O)C)(=[O:14])[CH3:13]>C(O)C>[C:12]([NH:1][C:2]1[CH:3]=[C:4]([OH:11])[C:5](=[CH:9][CH:10]=1)[C:6]([OH:8])=[O:7])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1ccc(C(=O)O)c(O)c1
Solvent: CCO
Product: CC(=O)Nc1ccc(C(=O)O)c(O)c1
Temperature: 40 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
30.6 grs (0.2 mol) p-aminosalicylic acid and 100 cc ethanol were introduced into a 250 ml flask, and the mixture was heated to 40° C. 20.4 grs (0.2 mol) acetic anhydride was then added at such a rate that the temperature did not exceed 50° C. When the addition was complete, the mixture was stirred at 50° C. for 3 hours. The product was filtered. Weight: 36 grs m.p. = 235° C. Yield = 92%.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][CH:3]=1.[NH2:13][CH:14]1[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]1>C(#N)C>[Cl:12][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:13][CH:14]3[CH2:19][CH2:18][CH2:17][N:16]([CH3:20])[CH2:15]3)=[CH:3][CH:4]=[N:5]2)=[CH:10][CH:9]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: CN1CCCC(N)C1
Solvent: CC#N
Product: CN1CCCC(Nc2ccnc3cc(Cl)ccc23)C1

Procedure:
4 g from 11.29 g of 4,7-dichloroquinoline and 6.5 g of 3-amino-1-methyl-piperidine; colourless crystals from acetonitrile, m.p.: 149°-150° C.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1.[Br:13][CH2:14][CH2:15][CH2:16]Br.C([O-])([O-])=O.[K+].[K+]>CCO.O>[Br:13][CH2:14][CH2:15][CH2:16][O:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][NH:8][C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: BrCCCBr
Reactant: O=C1NCCc2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: O=C1NCCc2ccc(OCCCBr)cc21
Reaction time: 8 h
Yield: 63.3 %

Procedure:
A mixture of intermediate 19 (326 mg, 2 mmol), 1,3-dibromopropane (0.62 mL, 6 mmol) and anhydrous K2CO3 (276 mg, 2 mmol) was dissolved in 4 mL of EtOH and the solution was heated to reflux and stirred overnight. The mixture was diluted with water and extracted with EtOAc. The combined EtOAc layers were washed with water, brine, dried over anhydrous Na2SO4, concentrated in vacuo and purified by flash chromatography on silica gel column (elution with PE/EtOAc=5:1) to give 7-(3-bromopropoxy)-3,4-dihydroisoquinolin-1(2H)-one (intermediate 20) (360 mg, 63%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[OH:8].[Br:29][CH:30]=[CH:31][CH2:32][CH2:33]Br.C(=O)([O-])[O-].[K+].[K+].O>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH:12]2[C:21]3[C:20](=[O:22])[CH2:19][CH:18]([CH2:23][CH2:24][CH3:25])[CH2:17][C:16]=3[NH:15][C:14]([CH3:26])=[C:13]2[C:27]#[N:28])[CH:5]=[C:6]([O:9][CH2:10][CH3:11])[C:7]=1[O:8][CH2:33][CH:32]=[CH:31][CH2:30][Br:29]
Reactant: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(O)c(OCC)c1
Reactant: BrC=CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CCCC1CC(=O)C2=C(C1)NC(C)=C(C#N)C2c1cc(Br)c(OCC=CCBr)c(OCC)c1
Temperature: 80 °C
Reaction time: 5 h

Procedure:
A mixture of 4-(3-bromo-5-ethoxy-4-hydroxy-phenyl)-2-methyl-5-oxo-7-propyl-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile (3.04 g), 1,4-dibromobutene (11.68 g) and potassium carbonate (1.887 g) in dioxane (100 ml) was stirred at 80° C. for 5 h. The mixture was poured into water and extracted with dichloromethane. The organic layer was dried (MgSO4), filtered and concentrated in vacuo. The residue was dissolved in acetonitrile, washed with petroleum ether and heptane to remove most of the excess of dibromobutene. The acetonitrile layer was concentrated in vacuo and the residue recrystallized from dichloromethane and heptane. Yield: 3.02 g. MS-ESI: [M+H]+=579.2
Reaction SMILES: C1(S(Cl)(=O)=O)C=CC=CC=1.[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([OH:17])=[O:16].[C:24](O)([CH3:27])([CH3:26])[CH3:25]>N1C=CC=CC=1>[CH3:11][C:12]1[CH:13]=[C:14]([CH:18]=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[C:15]([O:17][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:16]
Reactant: CC(C)(C)O
Reactant: Cc1cc(C(=O)O)ccc1[N+](=O)[O-]
Agent: O=S(=O)(Cl)c1ccccc1
Solvent: c1ccncc1
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.08 h

Procedure:
Benzenesulfonyl chloride (12.8 mL, 100 mmol) was added rapidly to a solution of 3-methyl-4-nitrobenzoic acid (9.06 g, 50 mmole) in dry pyridine (25 mL) at 40° C. The reaction was mildly exothermic. The cloudy, orange solution was stirred for 5 min, then t-butanol (4.7 mL, 50 mmole, 1 eq.) was added. After 1 h, the reddish-orange mixture was poured into ice/water (200 mL), and the resulting mixture was stirred briskly for 1 h. The solid was collected by suction filtration, washed with H2O, and dissolved in toluene (200 mL). The solution was dried (MgSO4) and filtered through a pad of silica gel eluting with toluene. Concentration gave the title compound as a yellow oil which crystallized under vacuum (9.67 g, 82%). TLC Rf 0.65 (4:1 toluene:hexane); 1H NMR (250 MHz, CDCl3) δ 7.85-8.10 (m, 3H), 2.61 (s, 3H), 1.60 (s, 9H); IR (CCl4) 1724, 1531, 1372, 1308, 1295, 1164, 1120, 843 cm-1 ; MS(ES) m/e 260.0 [M+Na]+, 238.0 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:9][CH:8]=[C:7]([O:17][CH3:18])[C:5]=2[N:6]=1.[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.Cl>N1C=CC=CC=1>[CH3:18][O:17][C:7]1[C:5]2[N:6]=[C:2]([NH:1][C:19](=[O:26])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[S:3][C:4]=2[C:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:9][CH:8]=1
Reactant: COc1ccc(-c2ccccc2)c2sc(N)nc12
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: COc1ccc(-c2ccccc2)c2sc(NC(=O)c3ccccc3)nc12
Temperature: 20 °C
Reaction time: 8 h
Yield: 67.3 %

Procedure:
To a solution of 2-amino-4-methoxy-7-phenyl-benzothiazole (100 mg, 0.4 mmol) in pyridine (2 ml) was added benzoyl chloride (55 mg, 0.4 mmol) and the mixture stirred overnight at 20 ° C. To this mixture 2N HCl to pH 1 (20 ml) was added then the mixture was extracted twice with EtOAc (20 ml), washed with saturated NaHCO3 solution, dried with Na2SO4 and the solvent evaporated. The crude product was then chromatographed over SiO2 (Merck 230-400 mesh) eluting with CH2Cl2/MeOH (98:2), the product fractions were pooled and the solvent evaporated, to afford the title compound as a white solid (97 mg, 69% yield), MS: m/e=360 (M+).
Reaction SMILES: [NH2:1][C:2]12[CH2:6][C:4](C(=O)C)([CH2:5]1)[CH2:3]2.ClC1C=CC=[C:13]([C:17]([O:19]O)=[O:18])C=1>C(Cl)(Cl)Cl>[C:17]([O:19][C:4]12[CH2:3][C:2]([NH2:1])([CH2:5]1)[CH2:6]2)(=[O:18])[CH3:13]
Reactant: CC(=O)C12CC(N)(C1)C2
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: CC(=O)OC12CC(N)(C1)C2
Reaction time: 24 h

Procedure:
A solution of 1-(3-aminobicyclo[1.1.1]pentan-1-yl)ethanone (1 mmol) in 0.5 mL of chloroform is added to a stirred mixture of m-chloroperbenzoic acid (1.5 mmol) in 2 mL of chloroform at r.t. The solution is stirred in the dark for 24 h. The mixture is filtered, and the filtrate is washed with 10% sodium bicarbonate and then water. The organic layer is dried over magnesium sulfate and concentrated. The residue is purified by a flash chromatography on silica gel (EtOAc/hexanes) to give 3-aminobicyclo[1.1.1]pentan-1-yl acetate.