Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:11][NH:12][CH3:13]>>[CH3:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([N:12]([CH3:13])[CH3:11])[CH:9]=1
Reactant: Cc1ccc(C#N)c(F)c1
Reactant: CNC
Product: Cc1ccc(C#N)c(N(C)C)c1
Temperature: 80 °C
Yield: 99 %

Procedure:
To commercially available 2-fluoro-4-methylbenzonitrile 15b (2.5 g, 18.5 mmol) was added dimethylamine (4 equiv., 4.8 ml) and the solution was heated at 80° C. overnight. The reaction was evaporated and the residue was dissolved in AcOEt and washed with water and brine. The organic phase was evaporated obtaining 2.96 g of a yellow oil. Yield=99% 1HNMR (DMSO, 200 MHz) δ 2.31 (3H, s), 2.93 (6H, s), 6.74 (1H, dd, J=8 Hz, J′=0.8 Hz), 6.85 (1H, s), 7.47 (1H, d, J=8 Hz)
Reaction SMILES: C[O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:12])[CH3:11])=[CH:6][C:5]=1[Cl:13].[OH-].[Na+].Cl>C1COCC1>[Cl:13][C:5]1[CH:6]=[C:7]([CH:10]([CH3:12])[CH3:11])[CH:8]=[CH:9][C:4]=1[C:3]([OH:14])=[O:2]
Reactant: COC(=O)c1ccc(C(C)C)cc1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)c1ccc(C(=O)O)c(Cl)c1
Temperature: 70 °C

Procedure:
To solution of 2-chloro-4-isopropyl-benzoic acid methyl ester (68 mg, 0.33 mmol) in THF (3 ml) was added 2M NaOH (3 ml). The solution was heated to 70° C. for 1 hour. The reaction was cooled back to room temperature and brought to a pH of ˜3 with 1M HCl. The aqueous solution was extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated down under reduced pressure to give 2-chloro-4-isopropyl-benzoic acid as a yellow solid. Amount obtained: 62.7 mg (96%). 1H NMR (Chloroform-d) δ: 1.28 (d, J=6.8 Hz, 6 H) 2.95 (m, J=14.0, 6.9, 6.9 Hz, 1 H) 7.22 (dd, J=8.1, 1.7 Hz, 1 H) 7.36 (d, J=1.6 Hz, 1 H) 7.99 (d, J=8.2 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[Cl:9].[Mg].II.C(OC([N:20](C(OC(C)(C)C)=O)[C@H:21]([CH2:32][CH2:33]/[CH:34]=[CH:35]/[N+:36]([O-])=O)[C:22](OCC1C=CC=CC=1)=[O:23])=O)(C)(C)C>C(OCC)C>[NH2:20][C@@H:21]1[CH2:32][CH2:33][CH:34]([C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=2[Cl:9])[CH2:35][NH:36][C:22]1=[O:23]
Reactant: Clc1cccc(Br)c1Cl
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)[C@H](CC/C=C/[N+](=O)[O-])C(=O)OCc1ccccc1
Agent: II
Agent: [Mg]
Solvent: CCOCC
Product: N[C@@H]1CCC(c2cccc(Cl)c2Cl)CNC1=O
Temperature: 25 °C
Yield: 176.3 %

Procedure:
To a slurry of 1-bromo-2,3-dichlorobenzene (1.46 g, 6.46 mmol) in diethyl ether (10 mL) was added magnesium (0.157 g, 6.46 mmol) and a crystal of iodine. This mixture was refluxed for 3 h, and then cooled to room temperature. A solution of benzyl (2R,5E)-2-[bis(tert-butoxycarbonyl)amino]-6-nitrohex-5-enoate (0.50 g, 1.08 mmol) in diethyl ether (10 mL) was cooled to 0° C., and 2.0 mL of the Grignard solution prepared above was added. After 1 and 2 h, respectively, 2.0 and 1.0 mL of the Grignard solution was added. The reaction was quenched with a saturated aqueous solution of ammonium chloride, the phases separated and the organic phase washed with saturated aqueous sodium potassium tartrate and brine. The combined organics were dried over magnesium sulfate, filtered and concentrated to give a residue that was purified by silica gel chromatography (0%→3% methanol/dichloromethane) to give the title compound (0.52 g). MS 411.0 (M+1-2Boc).
Reaction SMILES: [CH2:1]=[CH:2][CH:3]([OH:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]>C(Cl)(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]=[CH:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH:7]=[CH2:8]
Reactant: C=CCCCC(O)C=C
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: C=CCCCC(=O)C=C
Temperature: 25 °C
Reaction time: 96 h
Yield: 65.6 %

Procedure:
In 100 cc of carbon tetrachloride is dissolved 3.1 g of 1,7-octadien-3-ol, followed by addition of 10 g of active manganese dioxide. The mixture is stirred at room temperature for 4 days. The reaction mixture is filtered and the solvent is distilled off under a reduced pressure of 20-30 mm Hg. As a fraction at 30°-32° C./4 mm Hg, there is obtained 2 g of 1,7-octadien-3-one. The above fraction is identified to be 1,7-octadien-3-one by the following analyses.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([NH2:7])=[N:3]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([Br:15])=[CH:11][N:10]=1.CC([O-])(C)C.[K+].O>C1COCC1>[Br:15][C:12]1[CH:13]=[CH:14][C:9]([NH:7][C:4]2[N:5]=[N:6][N:2]([CH3:1])[N:3]=2)=[N:10][CH:11]=1
Reactant: Clc1ccc(Br)cn1
Reactant: Cn1nnc(N)n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cn1nnc(Nc2ccc(Br)cn2)n1
Yield: 1.5 %

Procedure:
2-methyl-2H-tetrazole-5-amine (7.7 g, 78 mmol), 2-chloro-5-bromopyridine (10 g, 52 mmol), and potassium tert-butylate (11.6 g, 104 mmol) were dissolved in 100 mL THF, heated under reflux and reacted for 12 h. Water was added, extracted with ethyl acetate, and the organic phase was dried, concentrated, and the solid was separated by a silica gel column (dichloromethane:methanol=100:1) to obtain 5-bromo-N-(2-methyl-2H-tetrazol-5-yl)pyridine-2-amine 200 mg, at a yield of 1.5%.
Reaction SMILES: [F:1][CH:2]([F:24])[O:3][CH2:4][C@@H:5]([O:7][C:8]1[CH:9]=[C:10]([CH:20]=[C:21]([OH:23])[CH:22]=1)[C:11]([NH:13][C:14]1[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=1)=[O:12])[CH3:6].[N:25]1([C:29]([C:31]2[CH:36]=[CH:35][C:34](Br)=[CH:33][N:32]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1.C(=O)([O-])[O-].[Cs+].[Cs+].C(OCC)(=O)C>CC(N(C)C)=O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]Br.O>[N:25]1([C:29]([C:31]2[N:32]=[CH:33][C:34]([O:23][C:21]3[CH:20]=[C:10]([CH:9]=[C:8]([O:7][C@@H:5]([CH3:6])[CH2:4][O:3][CH:2]([F:1])[F:24])[CH:22]=3)[C:11]([NH:13][C:14]3[CH:18]=[CH:17][N:16]([CH3:19])[N:15]=3)=[O:12])=[CH:35][CH:36]=2)=[O:30])[CH2:28][CH2:27][CH2:26]1
Reactant: O=C(c1ccc(Br)cn1)N1CCC1
Reactant: C[C@@H](COC(F)F)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Agent: [Cu]Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@@H](COC(F)F)Oc1cc(Oc2ccc(C(=O)N3CCC3)nc2)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 160 °C
Reaction time: 4 h
Yield: 31.8 %

Procedure:
A mixture of 3-({(1S)-2-[(difluoromethyl)oxy]-1-methylethyl}oxy)-5-hydroxy-N-(1-methyl-1H-pyrazol-3-yl)benzamide (220 mg, 0.64 mmol), 2-(azetidin-1-ylcarbonyl)-5-bromopyridine (171 mg, 0.71 mmol), cesium carbonate (419 mg, 1.29 mmol) and bromotris(triphenylphosphine)copper(I) (300 mg, 0.32 mmol) in DMA (5 mL) was stirred in a ‘Biotage initiator Microwave’ at 160° C. for 4 hours. The reaction mixture was added to ethyl acetate (50 mL) and water (50 mL), the organic layer washed with brine (50 mL), dried (MgSO4), filtered and the solvent removed in vacuo to give a brown oil. The residue was chromatographed on silica, eluting with 0-100% ethyl acetate in isohexane, to give the desired compound (102 mg).
Reaction SMILES: [C:1]1([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:6]=[CH:5][C:4]([O:7][CH2:8][C:9]2[CH:10]=[C:11]([S:15]([NH2:18])(=[O:17])=[O:16])[O:12][C:13]=2[CH3:14])=[CH:3][CH:2]=1.C(N(C(C)C)CC)(C)C.[CH3:34][O:35][CH2:36][CH2:37][C:38](O)=[O:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:34][O:35][CH2:36][CH2:37][C:38]([NH:18][S:15]([C:11]1[O:12][C:13]([CH3:14])=[C:9]([CH2:8][O:7][C:4]2[CH:3]=[CH:2][C:1]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:6][CH:5]=2)[CH:10]=1)(=[O:17])=[O:16])=[O:39]
Reactant: COCCC(=O)O
Reactant: Cc1oc(S(N)(=O)=O)cc1COc1ccc(-c2ccccc2)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCC(=O)NS(=O)(=O)c1cc(COc2ccc(-c3ccccc3)cc2)c(C)o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 67 %

Procedure:
To a stirred solution of 4-(biphenyl-4-yloxymethyl)-5-methyl-furan-2-sulphonic acid amide (45) (50 mg, 0.146 mmoles) in N,N-dimethylformamide (4.0 ml) was added diisopropylethylamine (85 μl, 0.480 mmoles) then a solution of 3-methoxypropionic acid (14 μl, 0.146 mmoles) in N,N-dimethylformamide (11.0 ml). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (61 mg, 0.160 mmoles) in N,N-dimethylformamide (1.0 ml) was added and the solution stirred at room temperature for 16 hours. The reaction mixture was concentrated in-vacuo, and the residue was purified by HPLC to give compound 65 as a white solid (42 mg). LC/MS System A: Rt=3.80 mins, m/z (ES−)=428 ((M−H) for C22H23NO6S).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]2[O:13][CH2:12][CH2:11][O:10]2)[CH:5]=[CH:6][C:7]=1[CH3:8].[B:14](OC(C)C)([O:19]C(C)C)[O:15]C(C)C>>[O:10]1[CH2:11][CH2:12][O:13][CH:9]1[C:4]1[CH:5]=[CH:6][C:7]([CH3:8])=[C:2]([B:14]([OH:19])[OH:15])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1ccc(C2OCCO2)cc1Br
Product: Cc1ccc(C2OCCO2)cc1B(O)O

Procedure:
In a manner similar to that of Example 2(k), by reacting 11.1 g (46 mmol) of 2-(3-bromo-4-methylphenyl)[1,3]dioxolane with 12.3 ml (55 mmol) of triisopropyl borate, 6 g (88%) of product are obtained in the form of an oil.
Reaction SMILES: [ClH:1].NN1C(=O)C2[C:6](=[C:7]([CH3:22])[C:8](N3CC4C(C4N)C3)=C(F)C=2)N(C2CC2)C1=O.C(OC(=O)[NH:33][CH:34]1[CH:39]2[CH:35]1C[N:37]([C:40]1[C:49]([CH3:50])=[C:48]3[C:43]([C:44](=[O:56])[N:45]([NH2:55])[C:46](=[O:54])[N:47]3[CH:51]3[CH2:53][CH2:52]3)=[CH:42][C:41]=1[F:57])[CH2:38]2)(C)(C)C>>[ClH:1].[NH2:55][N:45]1[C:44](=[O:56])[C:43]2[C:48](=[C:49]([CH3:50])[C:40]([N:37]3[CH2:38][CH:39]([CH:34]([NH2:33])[CH3:35])[C:7]([CH3:22])([CH3:8])[CH2:6]3)=[C:41]([F:57])[CH:42]=2)[N:47]([CH:51]2[CH2:53][CH2:52]2)[C:46]1=[O:54]
Reactant: Cc1c(N2CC3C(N)C3C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Reactant: Cc1c(N2CC3C(C2)C3NC(=O)OC(C)(C)C)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Agent: Cl
Product: Cc1c(N2CC(C(C)N)C(C)(C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12

Procedure:
(aaaaaa) 3-Amino-7-(6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cyclopropyl-6-fluoro-8-methyl-1H-quinazoline-2,4-dione hydrochloride (Compound 134) (mp 180–182° C., MS ES: m/z 346 (MH+)) from [3-(3-amino-1-cyclopropyl-6-fluoro-8-methyl-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-3-azabicyclo[3.1.0]hex-6-yl]carbamic acid tert-butyl ester (Example 28n) using General Method A.
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1OC1C=C(C=CC=1)C(O)=O.S(Cl)(Cl)=O.CS(N)(=O)=O.[CH3:31][S:32]([NH:35][C:36](=[O:58])[C:37]1[CH:42]=[C:41]([O:43][C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2[Cl:54])[CH:40]=[CH:39][C:38]=1[N+]([O-])=O)(=[O:34])=[O:33]>N1C=CC=CC=1>[CH3:31][S:32]([NH:35][C:36](=[O:58])[C:37]1[CH:38]=[CH:39][CH:40]=[C:41]([O:43][C:44]2[CH:49]=[C:48]([C:50]([F:53])([F:52])[F:51])[CH:47]=[CH:46][C:45]=2[Cl:54])[CH:42]=1)(=[O:33])=[O:34]
Reactant: CS(=O)(=O)NC(=O)c1cc(Oc2cc(C(F)(F)F)ccc2Cl)ccc1[N+](=O)[O-]
Agent: CS(N)(=O)=O
Agent: O=C(O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CS(=O)(=O)NC(=O)c1cccc(Oc2cc(C(F)(F)F)ccc2Cl)c1

Procedure:
The acid from (b) (0.8 g) was treated with thionyl chloride followed by methanesulphonamide and pyridine as described in paragraph (d) above for compound 32. The product was recrystallised from a mixture of ether and petroleum (b.p. 40°-60°) to give compound 31 with a melting point of 132°-133°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([O:18]C1CCCCO1)[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>C(O)C.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:25])([CH:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[N:14][CH:13]=[N:12]1
Reactant: CC(OC1CCCCO1)C(O)(Cn1cncn1)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CCO
Product: CC(O)C(O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 55 °C
Reaction time: 6 h
Yield: 74 %

Procedure:
In ethanol (500 ml) was dissolved 2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yl)oxy-1-(1H-1,2,4-triazol-1-yl)-2-butanol (51.4 g), to which was added pyridinium p-toluenesulfonate (13.2 g), and the mixture was stirred for 6 hours at 55° C. To the resultant mixture was further added pyridinium p-toluenesulfonate (2.0 g), which was stirred for 1.5 hour at 55° C. The mixture was cooled, then the solvent was distilled off under reduced pressure. To the residue was added ethyl acetate (900 ml), and the mixture was washed with water (50 ml) three times. The ethyl acetate layer was dried over anhydrous magnesium suflate, then the solvent was distilled off. To the residue were added ethyl acetate (50 ml) and ethyl ether (100 ml). Precipitating crystals were collected by filtration to afford pure (99% purity) (2RS,3RS)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol (29.0 g) as diastereomer, m.p. 154°-156° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:38])[CH:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:27])=[O:26])[CH:5]([C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1)O.CCN(CC)CC.CS([Cl:50])(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3](=[O:38])[C:4]([NH:15][C:16](=[O:37])[C:17]1[CH:22]=[C:21]([Cl:50])[C:20]([Cl:23])=[CH:19][C:18]=1[NH:24][S:25]([C:28]1[C:33]2=[N:34][S:35][N:36]=[C:32]2[CH:31]=[CH:30][CH:29]=1)(=[O:26])=[O:27])=[CH:5][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=1
Reactant: COC(=O)C(NC(=O)c1ccc(Cl)cc1NS(=O)(=O)c1cccc2nsnc12)C(O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)C(=Cc1ccc(Cl)c(Cl)c1)NC(=O)c1cc(Cl)c(Cl)cc1NS(=O)(=O)c1cccc2nsnc12
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To a solution of 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4-chloro-benzoylamino]-3-(3,4-dichloro-phenyl)-3-hydroxy-propionic acid methyl ester (42 mg, 0.068 mmol) in DCM (1.5 mL) was added Et3N (38 μL, 0.273 mmol) and the mixture was cooled to 0° C. MsCl (8 μL, 0.102 mmol) was added and the mixture was warmed to rt and stirred for 1.5 h. The mixture was heated to 50° C., treated with catalytic DMAP, and stirred overnight. The mixture was diluted with satd. aq. NaHCO3 and extracted with DCM (3×). The combined organic layers were dried (MgSO4) and concentrated to provide 2-[2-(benzo[1,2,5]thiadiazole-4-sulfonylamino)-4,5-dichloro-benzoylamino]-3-(3,4-dichloro-phenyl)-acrylic acid methyl ester. The crude product was hydrolyzed as in Example 2, Part E, to provide the title compound (25% for two steps). HPLC: RT=9.97 min. MS (ESI−): mass calcd. for C22H15Cl3N4O5S2, 618.30; m/z found, 581/583 [M−H]−. 1H NMR (400 MHz, acetone-d6): 11.82 (s, 1H), 9.37 (d, J=5.1, 1H), 8.48 (d, J=7.1, 1H), 8.34 (dd, J=8.8, 0.9, 1H), 7.96-7.86 (m, 2H), 7.82-7.75 (m, 2H), 7.64-7.55 (m, 3H), 7.11 (dd, J=8.5, 2.0, 1H).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([C:20](O)=[O:21])[C:6]2[C:7]([CH3:19])=[C:8]([CH2:15][N:16]([CH3:18])[CH3:17])[N:9]([CH:12]([CH3:14])[CH3:13])[C:10]=2[CH:11]=1.[NH2:23][CH2:24][C:25]1[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=1[CH2:31][CH2:32][CH3:33].C1C=NC2N(O)N=NC=2C=1.CN1CCOCC1.C(Cl)CCl>CN(C)C=O.ClCCl>[Cl:2][C:3]1[CH:4]=[C:5]([C:20]([NH:23][CH2:24][C:25]2[C:26](=[O:35])[NH:27][C:28]([CH3:34])=[CH:29][C:30]=2[CH2:31][CH2:32][CH3:33])=[O:21])[C:6]2[C:7]([CH3:19])=[C:8]([CH2:15][N:16]([CH3:18])[CH3:17])[N:9]([CH:12]([CH3:13])[CH3:14])[C:10]=2[CH:11]=1
Reactant: Cc1c(CN(C)C)n(C(C)C)c2cc(Cl)cc(C(=O)O)c12
Reactant: CCCc1cc(C)[nH]c(=O)c1CN
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: CCCc1cc(C)[nH]c(=O)c1CNC(=O)c1cc(Cl)cc2c1c(C)c(CN(C)C)n2C(C)C
Yield: 63.2 %

Procedure:
To 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-1H-indole-4-carboxylic acid hydrochloride salt (0.42 g, 1.216 mmol), 3-(aminomethyl)-6-methyl-4-propylpyridin-2(1H)-one (0.22 g, 1.221 mmol), HOAt (0.17 g, 1.249 mmol) was added Dichloromethane (16 mL), N,N-Dimethylformamide (4 mL) and N-methylmorpholine (135 μL, 1.228 mmol). The mixture was stirred and EDC free base (0.20 g, 1.288 mmol) was added. After stirring for 2 hr LCMS showed that the reaction was complete. The reaction was evaporated to dryness under vacuum and purified by silica gel chromatography (Analogix, SF25-60 g, 0 to 8% (5% NH4OH in MeOH) in CH2Cl2). The pure fractions were combined, evaporated to dryness then taken up in 20% EtOAc in hexanes. Scratching crystallized out the product which was filtered and washed with hexanes to give the product 6-chloro-2-((dimethylamino)methyl)-1-isopropyl-3-methyl-N-((6-methyl-2-oxo-4-propyl-1,2-dihydropyridin-3-yl)methyl)-1H-indole-4-carboxamide (362 mg, 0.769 mmol, 63.2% yield) as an off-white solid. 1H NMR (400 MHz, DMSO-d6) δ=11.49 (s, 1H), 8.24 (t, J=4.9 Hz, 1H), 7.61 (d, J=1.8 Hz, 1H), 6.83 (d, J=1.8 Hz, 1H), 5.89 (s, 1H), 4.91 (quin, J=7.0 Hz, 1H), 4.31 (d, J=5.1 Hz, 2H), 3.47 (s, 2H), 2.52 (2H under DMSO), 2.14 (s, 6H), 2.12 (s, 3H), 2.10 (s, 3H), 1.62-1.53 (m, 2H), 1.51 (d, J=7.1 Hz, 6H), 0.94 (t, J=7.3 Hz, 3H). MS(ES)+ m/e 471.3 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](I)=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[O:14]1[CH2:19][CH2:18][CH:17]([CH:20]=[O:21])[CH2:16][CH2:15]1>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:20]([CH:17]2[CH2:18][CH2:19][O:14][CH2:15][CH2:16]2)[OH:21])=[CH:4][CH:3]=1
Reactant: Brc1ccc(I)cc1
Reactant: O=CC1CCOCC1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: OC(c1ccc(Br)cc1)C1CCOCC1
Temperature: -20 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
To a solution of 1-bromo-4-iodobenzene (31.1 g, 110 mmol) in THF (300 ml) (under argon atmosphere) was added isopropylmagnesium chloride (2M in THF) (60 ml, 120 mol) during 10 min at −25° C. The solution was stirred for 1 h at −20° C. and then warmed up to 0° C. and tetrahydro-pyran-4-carbaldehyde (10.98 ml, 100 mmol) was added dropwise over 10 min at 0-7° C. The reaction mixture was quenched with 1M NH4Cl (500 ml) and extracted with EtOAc (2×). The organic phases were washed with water and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was crystallized from DCM-diisopropyl ether (1:2) to give the title compound as a white solid (24.32 g, 90 mmol, 90%): HPLC: CtRet=4.43 min; 1H-NMR (400 MHz, DMSO-d6): δ 1.07 (d, 1H), 1.21 (m, 2H), 1.62 (m, 2H), 3.15 (m, 2H), 3.78 (m, 2H), 4.23 (m, 1H), 5.26 (d, 1H), 7.35 (dd, 4H)
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[CH:16]=[C:15]3[C:10]([C:11]([NH:18][CH:19]([CH3:23])[CH2:20][O:21][CH3:22])=[C:12]([NH2:17])[CH:13]=[N:14]3)=[CH:9][C:8]=2[O:24][CH3:25])=[C:5]([CH3:26])[O:4][N:3]=1.[N:27]([CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[C:28]=S>>[CH3:1][C:2]1[C:6]([C:7]2[C:8]([O:24][CH3:25])=[CH:9][C:10]3[C:11]4[N:18]([CH:19]([CH3:23])[CH2:20][O:21][CH3:22])[C:28]([NH:27][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[N:17][C:12]=4[CH:13]=[N:14][C:15]=3[CH:16]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: COCC(C)Nc1c(N)cnc2cc(-c3c(C)noc3C)c(OC)cc12
Reactant: S=C=NCCN1CCOCC1
Product: COCC(C)n1c(NCCN2CCOCC2)nc2cnc3cc(-c4c(C)noc4C)c(OC)cc3c21
Yield: 46 %

Procedure:
From 7-(3,5-dimethylisoxazol-4-yl)-6-methoxy-N4-(1-methoxypropan-2-yl)quinoline-3,4-diamine (for a preparation see Intermediate 19) (70 mg) and 4-(2-isothiocyanatoethyl)morpholine (50 mg) to give the title compound as beige solid (45 mg, 46%). LCMS (formate) Rt 0.56 min, MH+ 495
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.Br[CH2:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([O:31][CH3:32])=[O:30])=[CH:27][CH:26]=1.ClCCl>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH3:32][O:31][C:29](=[O:30])[C:28]1[CH:33]=[CH:34][C:25]([CH2:24][N:10]2[C:11]3[C@:12]4([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]4)[C:16]=3[C:17](=[O:18])[N:9]2[C:3]2[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=2[F:1])=[CH:26][CH:27]=1
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)c1ccc(Cn2c3c(c(=O)n2-c2ccc(F)cc2F)[C@@H]2CC[C@@]3(C)C2(C)C)cc1
Yield: 48.9 %

Procedure:
A solution of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 300 mg, 0.99 mmol), tetrabutylammonium iodide (270 mg, 0.7 mmol) and methyl 4-(bromomethyl)benzoate (1.00 g, 4.37 mmol) in dimethylformamide (10 mL) was heated at 100° C. for 3 h. The reaction mixture was allowed to cool. Dichloromethane (100 mL) was added, and the solution was washed with (5×25 mL), aqueous sodium thiosulfate (25 mL), and brine (25 mL), dried (magnesium sulfate, filtered, and evaporated. The residue was purified using an ISCO 40 g column, eluting with 50-100% ethyl acetate/hexanes. Fractions containing the product were concentrated and then dried under high vacuum at 50° C. give 4-[(4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-3-oxo-2,3,4,5,6,7-hexahydro-4,7-methano-indazol-1-ylmethyl]-benzoic acid methyl ester (219 mg, 49%) as a pale yellow solid. ES(+)-MS (M+H) 453.
Reaction SMILES: Br[C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6].[Cu][C:16]#[N:17]>>[C:16]([C:2]1[C:3]([F:14])=[C:4]([CH:9]=[C:10]([F:13])[C:11]=1[F:12])[C:5]([O:7][CH3:8])=[O:6])#[N:17]
Reactant: COC(=O)c1cc(F)c(F)c(Br)c1F
Reactant: N#C[Cu]
Product: COC(=O)c1cc(F)c(F)c(C#N)c1F
Yield: 61.8 %

Procedure:
A mixture of 269 g of methyl 3-bromo-2,4,5-trifluorobenzoate, 108 g of copper(I) cyanide and 400 ml of dimethylformainide is heated under reflux for 5 hours. All volatile components are distilled off in vacuo. Fractional distillation of the resulting mixture gives 133 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[NH:17][C:5]2=[CH:6][C:7]3[C:8]([CH3:16])([CH3:15])[C:9](=[O:14])[N:10]([CH3:13])[C:11]=3[CH:12]=[C:4]2[N:3]=1.CCN(C(C)C)C(C)C.[C:27](Cl)(=[O:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCOCC1>[CH3:13][N:10]1[C:11]2[CH:12]=[C:4]3[N:3]=[C:2]([NH:1][C:27](=[O:34])[C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[NH:17][C:5]3=[CH:6][C:7]=2[C:8]([CH3:15])([CH3:16])[C:9]1=[O:14]
Reactant: CN1C(=O)C(C)(C)c2cc3[nH]c(N)nc3cc21
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Solvent: O
Product: CN1C(=O)C(C)(C)c2cc3[nH]c(NC(=O)c4ccccc4)nc3cc21
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of D1 (210 mg) and DIPEA (4 ml; 23 mmol) in 1,4-dioxane (5.5 ml) is added benzoyl chloride (158 μl) at RT. The mixture is stirred for 20 h at RT and 2 h at 80° C. After completion of the reaction water is added and the aqueous layer is extracted with EtOAc. The combined organic layer is washed with saturated NaHCO3 solution and brine, dried over MgSO4 and concentrated in vacuo. Purification by flash chromatography on silica gel eluting with CH2Cl2/MeOH (98:2) afforded the desired compound (135 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14]Br)=[O:5])[CH3:2].[CH2:24]([N:26](CC)[CH2:27][CH2:28]N)[CH3:25]>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:23])=[C:8]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[NH:9][C:10]=1[CH2:11][CH2:12][CH2:13][CH2:14][N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(CCCCBr)[nH]c(C(=O)OC(C)(C)C)c1C
Reactant: CCN(CC)CCN
Solvent: ClCCl
Product: CCOC(=O)c1c(CCCCN(CC)CC)[nH]c(C(=O)OC(C)(C)C)c1C

Procedure:
5-(4-Bromo-butyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-tert-butyl ester 4-ethyl ester 60c (220 mg, 0.57 mmol) was dissolved in 5 ml of dichloromethane under stirring, and added with N,N-diethylethylenediamine (164 μl, 1.13 mmol) to the solution and refluxed for 30 minutes in an oil bath. The reaction mixture was concentrated to evaporate solvent and refluxed for another 1 hour. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure, purified by silica gel column chromatography to obtain the title compound 5-(4-diethylamino-butyl)-3-methyl-1H-pyrrole-2,4-dicarboxylic acid 2-cert-butyl ester 4-ethyl ester 60d (187 mg, yield 78%) as a white solid.