Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC1C=CC(C2C=C3C(CN([C@@H](C(C)C)C(O)=O)C3=O)=CC=2)=CC=1)(=O)C1C=CC=CC=1.[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:61])[C:51]4[CH:56]=[CH:55][C:54]([C:57]([F:60])([F:59])[F:58])=[CH:53][CH:52]=4)=[CH:45][CH:44]=3)[CH:41]=2)[CH2:36][N:35]1[CH:62]1[CH2:67][CH2:66][CH2:65][CH:64]([C:68]([O:70]C)=[O:69])[CH2:63]1>>[O:33]=[C:34]1[C:42]2[C:37](=[CH:38][CH:39]=[C:40]([C:43]3[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:61])[C:51]4[CH:56]=[CH:55][C:54]([C:57]([F:59])([F:58])[F:60])=[CH:53][CH:52]=4)=[CH:47][CH:48]=3)[CH:41]=2)[CH2:36][N:35]1[CH:62]1[CH2:67][CH2:66][CH2:65][CH:64]([C:68]([OH:70])=[O:69])[CH2:63]1
Reactant: COC(=O)C1CCCC(N2Cc3ccc(-c4ccc(NC(=O)c5ccc(C(F)(F)F)cc5)cc4)cc3C2=O)C1
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccccc4)cc3)cc2C1=O
Product: O=C(Nc1ccc(-c2ccc3c(c2)C(=O)N(C2CCCC(C(=O)O)C2)C3)cc1)c1ccc(C(F)(F)F)cc1
Yield: 77 %

Procedure:
The compound of example 551 was prepared analogous to compound of example 98 by hydrolysis of compound of example 550.
Reaction SMILES: [OH:1][C:2]1[N:3]([CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([NH:12][CH2:13][CH2:14][OH:15])[N:5]=2.[C:24](OC(=O)C)(=[O:26])[CH3:25].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:24]([O:15][CH2:14][CH2:13][NH:12][C:6]1[N:5]=[C:4]2[C:9]([N:10]=[C:2]([OH:1])[N:3]2[CH2:16][C:17]2[CH:18]=[N:19][C:20]([CH3:23])=[CH:21][CH:22]=2)=[C:8]([NH2:11])[N:7]=1)(=[O:26])[CH3:25]
Reactant: Cc1ccc(Cn2c(O)nc3c(N)nc(NCCO)nc32)cn1
Reactant: CC(=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CC(=O)OCCNc1nc(N)c2nc(O)n(Cc3ccc(C)nc3)c2n1
Reaction time: 3 h
Yield: 12.2 %

Procedure:
To 8-hydroxy-2-(2-hydroxyethylamino)-9-{(6-methyl-3-pyridyl)methyl}adenine (100 mg, 0.32 mmol) prepared by Comparative example 10 in pyridine (1 ml) was added under ice cooling acetic anhydride (0.033 ml, 0.35 mmol), and the mixture was stirred for 3 hours. To the reaction mixture was added sodium hydrogen carbonate solution, and the mixture was extracted with chloroform. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was purified by preparative thin-layer chromatography to give the captioned compound (14 mg, 0.039 mmol, yield: 12%) as a white solid.
Reaction SMILES: C(OC([N:8]1[CH2:20][CH2:19][C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH2:21][C:22](=[O:25])[NH:23][CH3:24])[C:10]=2[CH2:9]1)=O)(C)(C)C.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:24][NH:23][C:22]([CH2:21][N:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH2:19][CH2:20][NH:8][CH2:9][C:10]1=2)=[O:25]
Reactant: CNC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)C2
Solvent: ClCCl
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)Cn1c2c(c3ccccc31)CCNC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 121 %

Procedure:
A 10 ml portion of dichloromethane solution containing 541 mg (1.58 mmol) of 2-t-butoxycarbonyl-9-methylcarbamoylmethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole was mixed with 1 ml of anisole and 1 ml of trifluoroacetic acid and stirred overnight at room temperature. The solvent was removed by evaporation under a reduced pressure, and the resulting residue was precipitated by adding acetone and diisopropyl ether, thereby obtaining 465 mg (89% in yield) of 9-methylcarbamoylmethyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole as trifluoroacetate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:21]=[C:22]([CH:24]=[C:25]([O:29][CH3:30])[C:26]=1[O:27][CH3:28])[NH2:23].Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[Cl:15][C:8]1[CH:7]=[C:6]2[C:11]([C:2]([NH:23][C:22]3[CH:24]=[C:25]([O:29][CH3:30])[C:26]([O:27][CH3:28])=[C:20]([O:19][CH3:18])[CH:21]=3)=[C:3]([C:16]#[N:17])[CH:4]=[N:5]2)=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: N#Cc1cnc2cc(Cl)c([N+](=O)[O-])cc2c1Cl
Reactant: COc1cc(N)cc(OC)c1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(Cl)c([N+](=O)[O-])cc23)cc(OC)c1OC

Procedure:
A mixture of 500 mg (1.86 mmol) of 4,7-dichloro-6-nitro-3-quinolinecarbonitrile, 342.0 mg (1.86 mmol) of 3,4,5-trimethoxyaniline and 215.5 mg (1.86 mmol) of pyridine hydrochloride in 25 mL of 2-ethoxyethanol is heated at 100–110° C. for 1.5 hours. After cooling, the mire is diluted with water and neutralized with an aqueous solution of saturated sodium carbonate. The solid is collected by filtration and is washed with water. After drying in vacuo, this yields 621.0 mg (80.5%) of the product as a deep yellow solid.
Reaction SMILES: I.[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:18])([CH3:17])[CH2:15][NH:14][CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1.CCN(C(C)C)C(C)C.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>C(Cl)Cl>[Br:2][C:3]1[CH:4]=[C:5]2[C:10]([NH:11][CH:12]3[C:16]([CH3:17])([CH3:18])[CH2:15][N:14]([S:33]([CH3:32])(=[O:35])=[O:34])[CH2:13]3)=[C:9]([C:19]([NH2:21])=[O:20])[CH:8]=[N:7][N:6]2[CH:22]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC1(C)CNCC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: I
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)CN(S(C)(=O)=O)CC1Nc1c(C(N)=O)cnn2cc(Br)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.5 %

Procedure:
A suspension of 6-bromo-4-((4,4-dimethylpyrrolidin-3-yl)amino)pyrrolo[1,2-b]pyridazine-3-carboxamide hydroiodide (97 mg, 0.25 mmol) in DCM (3 mL), was added DIPEA (0.16 mL, 0.87 mmol) and methanesulfonyl chloride (0.04 mL, 0.5 mmol). The mixture was stirred at rt overnight. The reaction was quenched with water, extracted by dichloromethane, washed with hydrochloride (0.5N), aq. sodium bicarbonate and brine. The organic layer was dried over sodium sulfate and concentrated. The residue was triturated in ether then filtered to give (+/−)-6-bromo-4-(4,4-dimethyl-1-(methylsulfonyl)pyrrolidin-3-ylamino)pyrrolo[1,2-b]pyridazine-3-carboxamide (92 mg, 86%). MS (ES+) m/z: 431.99 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16]Cl)[N:9]=[CH:8][NH:7][C:6]2=[O:18].[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.[OH-].[Na+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1)[N:9]=[CH:8][NH:7][C:6]2=[O:18]
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCCl
Reactant: C1COCCN1
Agent: [Na+]
Agent: [OH-]
Product: COc1cc2c(=O)[nH]cnc2cc1OCCCN1CCOCC1
Temperature: 50 °C
Reaction time: 2 h
Yield: 93.9 %

Procedure:
In a 5 mL volume glass vessel equipped with a stirrer and a thermometer were placed 0.5 g (1.9 mmol) of 6-methoxy-7-(3-chloropropoxy)quinazolin-4-one prepared by procedures similar to those of Reference Example V-1, 0.5 g (5.7 mmol) of morpholine, and 1.0 mL (4.0 mmol) of aqueous sodium hydroxide solution (4.0 mol/L). The resulting mixture was stirred at 50° C. for 2 hours. After the reaction was complete, the reaction mixture was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.57 g (reaction yield: 94%) of 6-methoxy-7-(3-morpholinopropoxy)-quinazolin-4-one.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]([OH:15])=O)[C:4]=2[N:3]1[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1.Cl.CN(C)CCCN=C=NCC.[CH2:41]([NH2:48])[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CC(N(C)C)=O>[O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]([NH:48][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)=[O:15])[C:4]=2[N:3]1[CH2:16][C:17]1[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=1
Reactant: NCc1ccccc1
Reactant: COc1cc(Cn2c(=O)[nH]c3cccc(CCC(=O)O)c32)cc(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CC(=O)N(C)C
Product: COc1cc(Cn2c(=O)[nH]c3cccc(CCC(=O)NCc4ccccc4)c32)cc(OC)c1OC
Temperature: 25 °C
Reaction time: 17 h

Procedure:
3-[2-Oxo-3-(3,4,5-trimethoxybenzyl)-benzimidazolyl]propionic acid (1.77 mmol, 0.69 g) (example 14) in DMA (5 ml) is charged with 1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide HCl (2.66 mmol, 0.51g). Benzylamine (2.48 mmol, 0.27 ml) is added to the suspension, and the mixture is stirred at room temperature for 17 hours. The solution is added dropwise into ice (50 g) and the colorless precipitate is filtered off and dried in vacuo. Recrystallisation from ethyl acetate yields the title product. (R1=(CH2)2—C(O)—NHR5, x=2. R5=benzyl, R2=3,4,5-trimethoxybenzyl, n=0).
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]([C:7]1[CH:8]=[C:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=2)=O.S(O)(O)(=O)=O.[CH3:33][N:34]([CH3:38])[C:35]([NH2:37])=[NH:36].[O-]CC.[Na+].C(OCC)(=O)C>C(O)C>[CH3:33][N:34]([CH3:38])[C:35]1[N:37]=[C:5]([C:7]2[CH:8]=[C:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25])[C:10]3[C:15]([CH:16]=2)=[CH:14][CH:13]=[C:12]([O:17][CH3:18])[CH:11]=3)[CH:4]=[CH:3][N:36]=1
Reactant: CN(C)C(=N)N
Reactant: COc1ccc2cc(C(=O)C=CN(C)C)cc(NC(=O)OC(C)(C)C)c2c1
Agent: CC[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1ccc2cc(-c3ccnc(N(C)C)n3)cc(NC(=O)OC(C)(C)C)c2c1
Temperature: 80 °C
Yield: 98.8 %

Procedure:
To a solution of tert-butyl (3-(3-(dimethylamino)acryloyl)-7-methoxynaphthalen-1-yl)carbamate (31) (250 mg, 0.67 mmol), and N,N-dimethylguanidine sulfate (220 mg, 0.8 mmol) in ethanol (10 ml) was added 21% wt sodium ethoxide in ethanol (218 μl, 0.67 mmol). The mixture was heated to 80° C. for 24 hours followed by addition of N,N-dimethylguanidine sulfate (110 mg, 0.4 mmol) and 21% wt sodium ethoxide in ethanol (100 μl). After a further 2 days at 80° C. the mixture was poured into ethyl acetate (150 ml) washed with water (100 ml), brine (100 ml) and dried over anhydrous magnesium sulfate. Evaporation to dryness yielded tert-butyl (3-(2-(dimethylamino)pyrimidin-4-yl)-7-methoxynaphthalen-1-yl)carbamate (140) as a pale brown foam (261 mg). 1H NMR (CDCl3) 400 MHz δ 8.41-8.36 (m, 3H), 7.88-7.87 (d, J=8.8 Hz, 1H), 7.52 (m, 2H), 7.19 (dd, J=2.4 and 9.2 Hz 1H), 7.13 (m, 1H), 7.02 (d, J=5.6 Hz, 1H) 6.65 (s, 1H), 3.97 (s, 1H), 3.31 (s, 6H), 1.57 (s, 9H), LCMS m/e 395 (M+H)
Reaction SMILES: C1C2C(COC(=O)[NH:17][C:18]([NH:20][C@@:21]3([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=4[F:36])[CH2:25][C@H:24]([O:26][CH3:27])[CH2:23][C@H:22]3[CH2:28]O)=[S:19])C3C(=CC=CC=3)C=2C=CC=1>CO>[F:36][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][C:30]=1[C@:21]12[CH2:25][C@@H:24]([O:26][CH3:27])[CH2:23][C@H:22]1[CH2:28][S:19][C:18]([NH2:17])=[N:20]2
Reactant: CO[C@@H]1C[C@@H](CO)[C@](NC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)(c2ccccc2F)C1
Solvent: CO
Product: CO[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2ccccc2F)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71 %

Procedure:
A solution of 9H-fluoren-9-ylmethyl({[(1S*,2R*,4R*)-1-(2-fluorophenyl)-2-(hydroxymethyl)-4-methoxycyclopentyl]amino}carbonothioyl)carbamate (340 mg) in methanol (20 mL)-concentrated hydrochloric acid (1 mL) was heated under reflux for three hours. The reaction solution was concentrated under reduced pressure. Acetonitrile (10 mL) and piperidine (2 mL) were added to the residue at room temperature, and the mixture was stirred at room temperature for one hour. The reaction solution was concentrated under reduced pressure. The crude product was purified by NH-silica gel column chromatography to obtain the title compound (130 mg).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][C:6]=1[CH:7]=[O:8].Cl[Mg][CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19].O1CCCC1.Cl.O>O1CCCC1>[CH3:17][C:18]([CH3:21])([CH3:20])[CH2:19][CH:7]([C:6]1[CH:5]=[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[O:3][C:2]=1[CH3:1])[OH:8]
Reactant: Cc1oc(-c2ccccc2)cc1C=O
Reactant: CC(C)(C)C[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccccc2)cc1C(O)CC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 2-methyl-5-phenylfuran-3-carbaldehyde (1.1 g) in tetrahydrofuran (20 mL) was added dropwise 1N chloro(2,2-dimethylpropyl)magnesium-tetrahydrofuran solution (9 mL) at 0° C. and, after the completion of the dropwise addition, the mixture was stirred at 0° C. for 1 hr. The reaction mixture was treated with 1N hydrochloric acid, poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column (0% ethyl acetate/hexane to 15% ethyl acetate/hexane) to give the title compound (1.1 g, 70%) as an oil.
Reaction SMILES: C([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH:14][C:15]3[O:16][C:17]([C:20]4[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=4)=[CH:18][N:19]=3)=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)C.C(OC1CC2C(NC3OC(C4C=CC(C(F)(F)F)=CC=4)=CN=3)=CC=CC=2CC=1)C>>[CH3:26][C:23]1[CH:24]=[CH:25][C:20]([C:17]2[O:16][C:15]([NH:14][C:11]3[CH:10]=[CH:9][CH:8]=[C:7]4[C:12]=3[CH2:13][C:4](=[O:3])[CH2:5][CH2:6]4)=[N:19][CH:18]=2)=[CH:21][CH:22]=1
Reactant: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C)cc4)o3)c2C1
Agent: CCOC1=CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Product: Cc1ccc(-c2cnc(Nc3cccc4c3CC(=O)CC4)o2)cc1

Procedure:
The title compound was prepared using the procedure as described in Example 1I, substituting the product of Example 9B for the product of Example 1H.
Reaction SMILES: [CH2:1]([N:5]([CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([O:29]CC)=[O:28])=[C:23]([CH3:34])[CH:22]=1)[C:6]1[C:7]([CH3:19])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.O>[CH2:1]([N:5]([CH2:20][C:21]1[CH:33]=[CH:32][C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:23]([CH3:34])[CH:22]=1)[C:6]1[C:7]([CH3:19])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCCCN(Cc1ccc(OCC(=O)O)c(C)c1)c1cccc(-c2ccc(C)cc2)c1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
Ethyl (4-{[butyl(2,4′-dimethyl-1,1′-biphenyl-3-yl)amino]methyl}-2-methylphenoxy)acetate (12.7 g, 27.6 mmol) was dissolved in THF (210 mL) and water (70 ml) was added, followed by 2M aq. NaOH (61 mL, 122 mmol). The reaction was stirred at room temperature for 1/2 hr and then evaporated to give a white slurry. The suspension was diluted with water (100 mL) and pH adjusted to pH7 with 2M aq HCl. EtOAc (200 mL) the aqueous layer was separated and extracted with EtOAc (2×100 mL). The combined organics were washed with brine (200 mL), dried (Na2SO4) and concentrated In vacuo to give the title compound as a white foam (11.1 g).
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1.[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][NH:21]2)=[CH:17][C:16]=1B1OCC(C)(C)CO1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.CCO.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:14][C:15]1[CH:23]=[C:22]2[C:18]([C:19]([C:24]([O:26][CH3:27])=[O:25])=[CH:20][NH:21]2)=[CH:17][C:16]=1[C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[C:4]([F:13])[CH:3]=1
Reactant: OCCCOc1ccc(Br)cc1F
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(B3OCC(C)(C)CO3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCO
Solvent: Cc1ccccc1
Product: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OCCCO)c(F)c3)cc12
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 72.6 %

Procedure:
To a mixture of 3-(4-bromo-2-fluorophenoxy)propan-1-ol (93 mg, 0.37 mmol), methyl 6-chloro-5-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-1H-indole-3-carboxylate (100 mg, 0.31 mmol) and potassium carbonate (128 mg, 0.93 mmol) in Toluene/EtOH (5 mL, 3:1) and water (1 ml) was added Pd(dppf)Cl2 (22 mg, 0.031 mmol). The mixture was degassed and purged with nitrogen for 5 minutes, then allowed to heat to 110° C. and stirred for 30 minutes. The reaction mixture was concentrated in vacuo to give a brown residue. The residue was purified by flash chromatography to give the title compound (85 mg, 73% yield) as a pale solid. 1H NMR (400 MHz, CD3OD) δ 8.04 (d, 2H), 7.61 (m, 2H), 7.18 (m, 2H), 4.21 (m, 2H), 3.89 (s, 3H), 3.82 (t, 2H), 2.08 (m, 2H).
Reaction SMILES: C([O:5][C:6](=[O:30])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[C:10]([CH:19]2[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[S:21](=[O:29])(=[O:28])[NH:20]2)=[CH:9]1)(C)(C)C.Br[CH:32]([CH3:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH3:18][O:17][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:7][C:6]([OH:5])=[O:30])[CH:9]=[C:10]2[CH:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[S:21](=[O:29])(=[O:28])[N:20]1[CH:32]([CH3:40])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: COc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Reactant: CC(Br)Cc1ccccc1
Product: COc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1C(C)Cc1ccccc1)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 4, step c) and (2-bromo-propyl)-benzene. MS: ESI (negative): 489 (M−H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:6].[Cl:20][C:21]1[CH:22]=[C:23]([N:28]=[C:29]=[S:30])[CH:24]=[C:25]([Cl:27])[CH:26]=1>CN(C=O)C.O>[Cl:14][C:11]1[CH:10]=[CH:9][C:8]([NH:7][C:5](=[O:6])[C:4]2[CH:15]=[CH:16][C:17]([O:18][CH3:19])=[C:2]([NH:1][C:29]([NH:28][C:23]3[CH:24]=[C:25]([Cl:27])[CH:26]=[C:21]([Cl:20])[CH:22]=3)=[S:30])[CH:3]=2)=[CH:13][CH:12]=1
Reactant: S=C=Nc1cc(Cl)cc(Cl)c1
Reactant: COc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1N
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2ccc(Cl)cc2)cc1NC(=S)Nc1cc(Cl)cc(Cl)c1
Reaction time: 8 h
Yield: 61.6 %

Procedure:
A mixture of 3-amino-N-(4-chlorophenyl)-4-methoxy-benzamide from Example 2 (1.113 g, 4.02 mmol) and 3,5-dichlorophenyl isothiocyanate (0.820 g, 4.02 mmol) in DMF (10 mL) was allowed to stand at room temperature overnight. The mixture was then diluted with 50 mL H2O and the precipitate collected by filtration and dried. Trituration in first ether then ethyl acetate followed by filtration afforded the product (1.19 g); m.p. 180-185° C.
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14]C(C)(C)C)=O)=[N:4][CH:3]=1.Cl.[CH3:20][O:21][C:22]([NH:24][C@@H:25]([CH:29]([CH3:31])[CH3:30])C(O)=O)=[O:23].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CO.C(OCC)(=O)C>[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:14])[C@@H:25]([NH:24][C:22](=[O:23])[O:21][CH3:20])[CH:29]([CH3:31])[CH3:30])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1c1ncc(Br)[nH]1
Reactant: COC(=O)N[C@H](C(=O)O)C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1ncc(Br)[nH]1)C(C)C
Temperature: 25 °C
Yield: 82.5 %

Procedure:
A solution of (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.0 g, 3.2 mmol), 4M HCl solution in dioxanes (3.95 mL, 15.8 mmol) and methanol (4 mL) was stirred at room temperature for thirty minutes. The reaction was concentrated, suspended in dichloromethane, and thoroughly concentrated. This crude amine was dissolved in dimethylformamide (6.4 mL). To this solution were added (S)-2-(methoxycarbonylamino)-3-methylbutanoic acid (582 mg, 3.3 mmol), HATU (1.3 g, 3.3 mmol) and diisopropylethylamine (1.9 mL, 11.1 mmol). The reaction was stirred at room temperature for twenty minutes, and then diluted with ethyl acetate. The organic layer was washed with water and brine, dried (Na2SO4) and concentrated. The crude material was purified by flash column chromatography to yield methyl (S)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-ylcarbamate (985 mg, 83%).
Reaction SMILES: [CH:1]([C:4]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][C:5]=1[NH2:6])([CH3:3])[CH3:2].C(=O)(O)[O-].[Na+].[Cl:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:17][CH2:18][C:19]([NH:6][C:5]1[CH:7]=[C:8]([CH3:11])[CH:9]=[CH:10][C:4]=1[CH:1]([CH3:3])[CH3:2])=[O:20]
Reactant: O=C(Cl)CCl
Reactant: Cc1ccc(C(C)C)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1ccc(C(C)C)c(NC(=O)CCl)c1
Temperature: 2.5 °C
Yield: 62.6 %

Procedure:
2-Isopropyl-5-methylaniline (286 g, 1.91 mol) and sodium bicarbonate (270 g, 3.22 mol) were charged in to a round bottomed flask with stirring under nitrogen atmosphere and cooled to 0-5° C. 2-Chloroacetyl chloride (218 g, 1.93 mol) was added drop wise at 0-5° C. over a period of 1 hour. The reaction was stirred at 0-5° C. for 1 hour. After completion of the reaction, purified water (2.86 L) was added and stirred at 25-30° C. for 15 minutes. The layers were then separated. The organic layer was washed with water (2×2.86 L) and with brine (1.43 L). The aqueous layers were combined and extracted with ethyl acetate (1.43 L). The organic layers were dried with sodium sulphate, filtered, and concentrated at 50-55° C. under vacuum (500-600 mm Hg) to ⅖ths volume. Hexanes (2.86 L) were added and the mixture was stirred at 25-30° C. for 1 hour. The solid was filtered, washed with hexanes (1.43 L), and dried at 45-50° C. under vacuum (500-600 mm Hg) to give 2-chloro-N-(2-isopropyl-5-methylphenyl)acetamide as an off-white solid (270 g, 66%): mp 97-99° C., 1H NMR (300 MHz, CDCl3) δ 8.27 (s, 1H), 7.60 (s, 1H), 7.20 (d, J=7.95 Hz, 1H), 7.04 (d, J=7.89 Hz, 1H), 4.25 (s, 2H), 2.99 (q, J=6.78 Hz, 1H), 2.34 (s, 3H), 1.26 (d, J=6.84 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 164.07, 137.28, 136.33, 132.95, 127.35, 125.62, 124.46, 43.21, 27.86, 22.98, 21.00; ESIMS m/z 226 ([M+H]+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:8]=2[CH:18]=1)N.[CH:19]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)([CH3:21])[CH3:20].Cl>C(O)(C)C>[CH:19]([N:22]1[CH2:27][CH2:26][C:25]2[NH:2][C:4]3[C:18]([C:24]=2[CH2:23]1)=[C:8]1[C:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][S:11][C:7]1=[CH:6][CH:5]=3)([CH3:21])[CH3:20]
Reactant: CC(C)N1CCC(=O)CC1
Reactant: NNc1ccc2scc(-c3ccccc3)c2c1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)N1CCc2[nH]c3ccc4scc(-c5ccccc5)c4c3c2C1

Procedure:
The compound is formed analogously to that described in Example 40, from 13.8 g of 5-hydrazino-3-phenylbenzothiophene hydrochloride and 7.5 g of 1-isopropyl-4-piperidone by boiling the starting materials in 120 ml of isopropanol containing hydrogen chloride for 4 hours. Melting point: 204° C.