Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1([F:31])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1.C(N(CC)CC)C.[CH2:39]([S:42](Cl)(=[O:44])=[O:43])[CH2:40][CH3:41]>C(Cl)Cl>[F:31][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3[C:19]4[C:14](=[N:15][CH:16]=[C:17]([C:20]5[CH:21]=[N:22][N:23]([CH:25]6[CH2:26][CH2:27][N:28]([S:42]([CH2:39][CH2:40][CH3:41])(=[O:44])=[O:43])[CH2:29][CH2:30]6)[CH:24]=5)[CH:18]=4)[NH:13][CH:12]=3)=[CH:10][C:4]=2[O:3]1
Reactant: FC1(F)Oc2ccc(-c3c[nH]c4ncc(-c5cnn(C6CCNCC6)c5)cc34)cc2O1
Reactant: CCCS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCS(=O)(=O)N1CCC(n2cc(-c3cnc4[nH]cc(-c5ccc6c(c5)OC(F)(F)O6)c4c3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 324 (50 mg, 0.1182 mmol) in DCM was added triethylamine (17.9 mg, 0.1773 mmol) and propane sulfonyl chloride 339 (16.7 mg, 0.1182 mmol) and stirred for 2 h at rt. The RM was diluted with dichloromethane and washed with water twice. The organic layer was dried over sodium sulphate and concentrated to get the crude, which was purified by flash column using 100-200 mesh silica gel. The compound was eluted at 2% Methanol in chloroform as off white coloured solid 345. 1HNMR (400 MHz, DMSO) δ: 11.95 (s, 1H), 8.55 (d, 1H), 8.39 (m, 2H), 8.03 (s, 1H), 7.88 (d, 1H), 7.78 (d, 1H), 7.58 (m, 1H), 7.44 (d, 1H), 4.35 (m, 1H), 3.69 (m, 2H), 3.03 (m, 4H), 2.14 (m, 2H), 1.97 (m, 2H), 1.70 (m, 2H), 1.00 (m, 3H) and MS ES+530.1.
Reaction SMILES: [BH4-].[Na+].[Br:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)=[O:6]>CO>[Br:3][CH2:4][CH:5]([C:7]1[CH:12]=[CH:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[OH:6]
Reactant: COc1ccc(C(=O)CBr)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: COc1ccc(C(O)CBr)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 109.4 %

Procedure:
0.826 g (21.8 mmol) of sodium borohydride was added to 2-bromo-4'-methoxy-acetophenone (10 g, 43.7 mmol) in methanol (200 ml) and the mixture was stirred for 1 hour at room temperature. The mixture was concentrated in vacuo and saturated aqueous sodium chloride was added to the residue and the product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and concentrated in vacuo to give 2-bromo-1-(4'-methoxyphenyl)ethanol (11.05 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[N:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20]1[CH:21]=[C:22]2[C:27](=[CH:28][CH:29]=1)[CH2:26][NH:25][CH2:24][CH2:23]2>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:25]3[CH2:24][CH2:23][C:22]4[C:27](=[CH:28][CH:29]=[C:20]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][N:14]=5)[CH:21]=4)[CH2:26]3)=[O:13])[CH:10]=2)[CH:7]=1
Reactant: c1ccc(-c2ccc3c(c2)CCNC3)nc1
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: O=C(c1cc2ncc(Br)cn2n1)N1CCc2cc(-c3ccccn3)ccc2C1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 6-Pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(O)=[O:2].[NH3:11]>O1CCCC1>[C:1]([CH2:4][N:5]1[C:9]([SH:10])=[N:8][N:7]=[N:6]1)(=[O:2])[NH2:11]
Reactant: N
Reactant: O=C(O)Cn1nnnc1S
Solvent: C1CCOC1
Product: NC(=O)Cn1nnnc1S
Reaction time: 2.5 h

Procedure:
1-Carboxymethyltetrazole-5-thiol and 1,1-carbonyl-diimidazole were reacted as described in Example 4. To the reaction mixture was added tetrahydrofuran saturated with dry ammonia gas. The resulting suspension was stirred for 2.5 hours and the solid which formed was collected by filtration, washed with tetrahydrofuran and dissolved in methanol. Amberlite IR-120 ion-exchange resin (50 g.) was added and the suspension was stirred for 15 minutes. The resin was then removed and washed with absolute methanol. The methanol solution was concentrated to give 1- carbamoylmethyltetrazole-5-thiol, m.p. 200° (dec.).
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:33]=2)=[CH:11][CH:12]=[CH:13][C:14]=1[CH2:15][N:16]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:19])=[O:18])(=[O:8])=[O:7])C.C(=O)([O-])O.[Na+]>CCO.Cl>[CH2:25]([N:16]([CH2:15][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]([C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH2:39][CH2:40][O:41][CH3:42])[CH:33]=2)[C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7])[S:17]([C:20]1[S:21][CH:22]=[CH:23][CH:24]=1)(=[O:18])=[O:19])[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: COCCOc1cccc(-c2cccc(CN(Cc3ccccc3)S(=O)(=O)c3cccs3)c2S(=O)(=O)N=CN(C)C)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COCCOc1cccc(-c2cccc(CN(Cc3ccccc3)S(=O)(=O)c3cccs3)c2S(N)(=O)=O)c1
Yield: 37.5 %

Procedure:
550 mg of {[benzyl(thiophene-2-sulfonyl)amino]methyl}-3′-(2-methoxy)ethoxy-biphenyl-2-sulfonic acid dimethylaminomethylenamide are refluxed for 1 h in 5 ml of EtOH and 5 ml of a saturated aqueous HCl solution. 100 ml of a 10% aqueous sodium hydrogencarbonate solution are added and the mixture is extracted 3 times with 100 ml of EA each time. It is dried over magnesium sulfate and the solvent is removed in vacuo. Chromatography on silica gel using MTB/DIP 1:1 yields 188 mg of a colorless oil.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][NH2:10])=[CH:5][CH:4]=1.[N+:13]([C:16]1[CH:25]=[CH:24][CH:23]=[C:22]2[C:17]=1[CH:18]=[CH:19][O:20][C:21]2=O)([O-:15])=[O:14]>CO>[F:12][C:2]([F:11])([F:1])[C:3]1[N:8]=[CH:7][C:6]([CH2:9][N:10]2[CH:19]=[CH:18][C:17]3[C:22](=[CH:23][CH:24]=[CH:25][C:16]=3[N+:13]([O-:15])=[O:14])[C:21]2=[O:20])=[CH:5][CH:4]=1
Reactant: NCc1ccc(C(F)(F)F)nc1
Reactant: O=c1occc2c([N+](=O)[O-])cccc12
Solvent: CO
Product: O=c1c2cccc([N+](=O)[O-])c2ccn1Cc1ccc(C(F)(F)F)nc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 60.5 %

Procedure:
C-(6-Trifluoromethyl-pyridin-3-yl)-methylamine (1.00 g, 0.00568 mol) and 5-nitro-isochromen-1-one (1.14 g, 0.00568 mol) were suspended in methanol (10 mL) and the suspension was stirred at 60° C. for 3 hours, then the reaction was microwaved at 100 watts at 100° C. for 60 minutes, and then at 120° C. for 30 min. Solid thus formed was filtered out to yield the product as a yellow solid (1.2 g). MS m/z=350.4 (M+H).
Reaction SMILES: [C:1]([O:9][CH2:10][C:11]#[C:12][CH2:13]Br)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([CH:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC#N>[C:1]([O:9][CH2:10][C:11]#[C:12][CH2:13][N:25]1[CH2:26][CH2:27][CH:22]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:23][CH2:24]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCC#CCBr)c1ccccc1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=C(OCC#CCN1CCC(Cc2ccccc2)CC1)c1ccccc1
Yield: 31.7 %

Procedure:
A mixture of 1-benzoyloxy-4-bromobut-2-yne (1.26 g, 5.00 mmol), 4-benzylpiperidine (0.964 g, 5.50 mmol) and K2CO3 (1.52 g, 11.0 mmol) in 50 mL of CH3CN was refluxed under N2 for 24 hr. The inorganic salt was removed through a short column of silica gel and was washed with EtOAc (3×30 mL). The filtrate was evaporated in vacuo to give a residue, which was purified by flash chromatography to give the product as a brown oil (0.55 g, 32%): 1H NMR (CDCl3) d 1.34 (m, 2 H), 1.50 (m, 1 H), 1.63 (m, 2 H), 2.11 (m, 2 H), 2.51 (d, J=6.9 Hz, 2 H), 2.78 (m, 2 H), 2.86 (d, J=11.1 Hz, 2 H), 3.31 (s, 2 H), 4.94 (s, 2 H), 7.12-7.52 (m, 8 H); MS (m/z) 348 (M++1, 20), 347 (M+, 100), 346 (M+−1, 60), 226 (30), 105 (100).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[CH3:12][N:13]1CCCC1=O>C(OCC)(=O)C>[Cl:11][C:4]1[N:3]=[C:2]([C:12]#[N:13])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1nc(Cl)ccc1[N+](=O)[O-]
Temperature: 180 °C

Procedure:
2,6-Dichloro-3-nitropyridine (5.18 mmol, 1 g) is mixed with 5 ml of N-methyl-2-pyrrolidinone in a microwave reactor. The reaction mixture is heated at 180° C. for 15 minutes (6 bars). The crude reaction product is dissolved in ethyl acetate, filtered and washed several times using an aqueous phase. The organic phase is collected, dried on magnesium sulfate and dry concentrated. The crude product thus obtained is purified by silica gel chromatography (heptane/AcOEt) to yield, after concentration, 0.62 g (65%) of a brown oil.
Reaction SMILES: ClCCl.C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH3:14][C:15]1[C:19]([CH:20]([OH:22])[CH3:21])=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][N:16]=1>[Cl-].[Na+].O.C(OCC)(=O)C.C(N(CC)CC)C>[CH3:14][C:15]1[C:19]([C:20](=[O:22])[CH3:21])=[C:18]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[O:17][N:16]=1
Reactant: Cc1noc(-c2ccccc2)c1C(C)O
Agent: O=C(Cl)C(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(=O)c1c(C)noc1-c1ccccc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 94 %

Procedure:
To a dichloromethane solution of oxalyl chloride was added DMSO at −78° C., the mixture was stirred at −78° C. for 15 min and followed by addition of a dichloromethane solution of compound the above Compound 26. The reaction mixture was stirred for 30 min at −78° C., then triethylamine was added, after which the reaction mixture was allowed to warm to room temperature gradually. To the reaction mixture was added ethyl acetate and brine. The organic phase was dried over magnesium sulfate, and the solvent was removed under reduced pressure. The crude product, obtained in 94% yield, was used directly for the next step without purification.
Reaction SMILES: [S:1]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]2)[CH2:2]1.NC1C(C(ON2C3C=CC=CC=3N=N2)=O)=C2N=CC(CC#N)=CN2N=1>C1COCC1>[CH3:2][C:3]1([SH:1])[CH2:4][CH2:5][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]1
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CS2
Agent: N#CCc1cnc2c(C(=O)On3nnc4ccccc43)c(N)nn2c1
Solvent: C1CCOC1
Product: CC1(S)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 1-thia-6-azaspiro[2.5]octane-6-carboxylate (430 mg, 1.875 mmol) in THF (5 mL) was added LiAlH4 (Lithium Ion (1)) (0.9375 mL of 2 M, 1.875 mmol) and the solution was stirred at room temperature for 1 h. The reaction was quenched by careful dropwise addition of water (2 ml), stirred for 10 mins before the reaction mixture was partitioned between water and EtOAc. The organic extract was washed with brine, dried (MgSO4) and concentrated to give tert-butyl 4-methyl-4-sulfanyl-piperidine-1-carboxylate as a colorless oil. (380 mg, 87%). MS (ES−) 231.0.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[S:20][CH:21]=[CH:22][N:23]=3)(=[O:17])=[O:16])=[CH:11][C:10]=2[F:24])=[C:4]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)[CH:3]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[C:33](B(O)O)[CH:32]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:24][C:10]1[CH:11]=[C:12]([S:15]([NH:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)(=[O:17])=[O:16])[CH:13]=[CH:14][C:9]=1[O:8][C:5]1[C:4]([C:25]2[N:29]([CH3:30])[N:28]=[CH:27][CH:26]=2)=[CH:3][C:2]([C:33]2[CH:32]=[N:31][CH:36]=[CH:35][CH:34]=2)=[N:7][CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: Cn1nccc1-c1cc(Cl)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1nccc1-c1cc(-c2cccnc2)ncc1Oc1ccc(S(=O)(=O)Nc2nccs2)cc1F
Yield: 49.2 %

Procedure:
10 mg (0.02 mmol) of 4-((6-chloro-4-(1-methyl-1H-pyrazol-5-yl)pyridin-3-yl)oxy)-3-fluoro-N-(thiazol-2-yl)benzenesulfonamide was dissolved in 3 mL of N,N-dimethylformamide, and 3.9 mg (0.03 mmol) of (pyridin-3-yl)boronic acid was added thereto, and then 2.4 mg (10 mol %) of Pd(PPh3)4, 6.8 mg (0.64 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (45% yield) of the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:16][CH:17]2[CH2:19][CH2:18]2)[CH3:15])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:17]1([CH2:16][N:14]([CH3:15])[C:12]2[C:11]([C:20]([F:21])([F:23])[F:22])=[CH:10][C:9]3[NH:24][C:25](=[O:37])[CH2:26][C:27]([C:29]4[CH:34]=[CH:33][N:32]=[C:31]([C:35]#[N:36])[CH:30]=4)=[N:7][C:8]=3[CH:13]=2)[CH2:18][CH2:19]1
Reactant: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(CC1CC1)c1cc2c(cc1C(F)(F)F)NC(=O)CC(c1ccnc(C#N)c1)=N2

Procedure:
The title compound was prepared from [2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-5-(cyclopropylmethyl-methyl-amino)-4-trifluoromethyl-phenyl]-carbamic acid tert.-butyl ester (Example M68) (173 mg, 0.33 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (81 mg).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=[O:5].[C:12](OCC)(=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14]>CC(O)=O>[F:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4]([OH:5])=[N:6][C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[N:1]2)=[CH:7][CH:8]=1
Reactant: NC(=O)c1ccc(F)cc1N
Reactant: CCOC(=O)C(=O)OCC
Solvent: CC(=O)O
Product: CCOC(=O)c1nc(O)c2ccc(F)cc2n1
Yield: 22 %

Procedure:
A solution of 2-amino-4-fluorobenzamide (750 mg, 4.40 mmol), diethyl oxalate (20 mL), and AcOH (8 mL) was stirred at 140° C. for 16 h. The solid was collected by filtration and dried under reduced pressure to afford ethyl 7-fluoro-4-hydroxyquinazoline-2-carboxylate as a solid (235 mg, 22%). 1H NMR (300 MHz, DMSO-d6) δ 1.36 (t, J=7.08 Hz, 2H), 4.39 (q, J=7.08 Hz, 2H), 7.52 (m, 1H), 7.67 (m, 1H), 8.25 (m, 1H), 11.97 (br s, 1H), 12.77 (br s, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:13]=[C:12]2[C:8]([C:9]([CH3:14])=[CH:10][NH:11]2)=[CH:7][CH:6]=1)=[O:4].[H-].[Na+].[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20]Cl.O>CN(C)C=O>[Cl:17][C:18]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:19]=1[CH2:20][N:11]1[C:12]2[C:8](=[CH:7][CH:6]=[C:5]([C:3]([O:2][CH3:1])=[O:4])[CH:13]=2)[C:9]([CH3:14])=[CH:10]1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: ClCc1ccc(Cl)cc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc2c(C)cn(Cc3ccc(Cl)cc3Cl)c2c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 79.1 %

Procedure:
6-(Methoxycarbonyl)-3-methylindole (0.57 g) is dissolved in N,N-dimethylformamide (10 ml), to which is added sodium hydride (60% oily, 0.145 g) With cooling with ice. Then, 2,4-dichlorobenzyl chloride (0.707 g) is added thereto, and stirred at room temperature for 1.5 hours. Water is added to the reaction mixture, which is then extracted with ethyl acetate. The organic layer is washed with a saturated saline solution, and dried with anhydrous magnesium sulfate. The drying agent is removed through filtration, and the filtrate is concentrated under reduced pressure. The resulting residue is purified through silica gel column chromatography (eluent: hexane/ethyl acetate=9/1) to obtain 1-(2,4-dichlorobenzyl)-6-(methoxycarbonyl)-3-methylindole (72) (0.83 g).
Reaction SMILES: [I:1]I.Br[C:4]1[CH:5]=[C:6]2[C:19]3[CH:9]([CH2:10][C@@H:11]4[C@@H:16]([C:17]=3[CH:18]=1)[CH2:15][C@H:14]([NH:20][C:21](=[O:27])[N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])[CH2:13][N:12]4[CH3:28])[CH2:8][N:7]2[Si](C(C)(C)C)(C)C>>[CH2:23]([N:22]([CH2:25][CH3:26])[C:21]([NH:20][C@H:14]1[CH2:15][C@H:16]2[C@@H:11]([CH2:10][CH:9]3[C:19]4[C:6](=[CH:5][CH:4]=[C:18]([I:1])[C:17]2=4)[NH:7][CH2:8]3)[N:12]([CH3:28])[CH2:13]1)=[O:27])[CH3:24]
Reactant: II
Reactant: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3cc(Br)cc4c3C(C[C@H]2N(C)C1)CN4[Si](C)(C)C(C)(C)C
Product: CCN(CC)C(=O)N[C@H]1C[C@@H]2c3c(I)ccc4c3C(CN4)C[C@H]2N(C)C1

Procedure:
With iodine and 3-(13-bromo-1-tert-butyldimethylsilyl2,3-dihydro-6-methyl-8α-ergolinyl)-1,1-diethylurea:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.N1C=CC=CC=1.[C:15]1([O:21][C:22](Cl)=[O:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)Cl>[C:15]1([O:21][C:22](=[O:23])[NH:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][N:6]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Cc1ccc(N)nc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)Oc2ccccc2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a stirring mixture of 5-methyl-pyridin-2-ylamine (1.0 g, 9.25 mmol) and pyridine (20 ml) in dry CH2Cl2 add phenylchloroformate (2.2 g, 13.9 mmol) and stir for 24 hours at room temperature. Add water and a solution of 1:1 EtOAc/hexanes and separate the organic layer. Wash the organic layer with 1N HCl three times and with brine once. Dry the organic layer over Na2SO4, filter, and evaporate in vacuo. Purify by flash column chromatography (0-10% EtOAc/CH2Cl2) to obtain (5-methyl-pyridin-2-yl)-carbamic acid phenyl ester. Mass spec.: M+1=229 (AP+).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][C:10]=2[CH2:19][CH3:20])=[C:5]([O:21][CH2:22][S:23][CH3:24])[C:4]([CH3:25])=[N:3]1.ClC1C=CC=C(C(OO)=[O:34])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[C:14]([CH2:15][CH3:16])=[CH:13][C:12]([CH2:17][CH3:18])=[CH:11][C:10]=2[CH2:19][CH3:20])=[C:5]([O:21][CH2:22][S:23]([CH3:24])=[O:34])[C:4]([CH3:25])=[N:3]1
Reactant: CCc1cc(CC)c(-c2c(OCSC)c(C)nn(C)c2=O)c(CC)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCc1cc(CC)c(-c2c(OCS(C)=O)c(C)nn(C)c2=O)c(CC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.2 %

Procedure:
To a mixture of 0.30 g of 2,6-dimethyl-5-methylthiomethoxy-4-(2,4,6-triethylphenyl)-3(2H)-pyridazinone [compound (I-2-2)] and 4 mL of dichloromethane, 77 mg of m-chloroperbenzoic acid was added, followed by stirring at room temperature for 30 minutes. To the reaction mixture, an aqueous saturated sodium thiosulfate solution (10 mL) was added, followed by extraction with chloroform (10 mL×2). The organic layers was washed with an aqueous saturated sodium bicarbonate solution (10 mL), dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (ethyl acetate) to obtain 0.16 g of 2,6-dimethyl-5-methylsulfinylmethoxy-4-(2,4,6-triethylphenyl)-3(2H)-pyridazinone [compound (I-3-1)].
Reaction SMILES: COC1C=CC(C[N:8]2[C:12]3=[N:13][CH:14]=[CH:15][C:16](Cl)=[C:11]3[C:10]([CH3:18])=[N:9]2)=CC=1.[NH2:21][C:22]1[S:23][C:24]2[CH:30]=[C:29]([OH:31])[CH:28]=[CH:27][C:25]=2[N:26]=1.BrC1C=CC=CC=1>CN(C)C1C=CN=CC=1>[CH3:18][C:10]1[C:11]2[C:12](=[N:13][CH:14]=[CH:15][C:16]=2[O:31][C:29]2[CH:28]=[CH:27][C:25]3[N:26]=[C:22]([NH2:21])[S:23][C:24]=3[CH:30]=2)[NH:8][N:9]=1
Reactant: COc1ccc(Cn2nc(C)c3c(Cl)ccnc32)cc1
Reactant: Nc1nc2ccc(O)cc2s1
Agent: CN(C)c1ccncc1
Solvent: Brc1ccccc1
Product: Cc1n[nH]c2nccc(Oc3ccc4nc(N)sc4c3)c12
Temperature: 150 °C

Procedure:
A 20 mL sealable tube was charged with 1-(4-methoxybenzyl)-4-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine (0.500 g, 1.74 mmol; prepared according to the procedure of Example 43, Step E), 2-aminobenzo[d]thiazol-6-ol (0.433 g, 2.61 mmol), N,N-dimethylpyridin-4-amine (0.0425 g, 0.348 mmol), and bromobenzene (4 mL). The reaction mixture was heated under nitrogen to 150° C. for 12 hours, then cooled to room temperature and concentrated under reduced pressure. The crude material was used directly in next step. LRMS (APCI pos) m/e 418.2 (M+1).
Reaction SMILES: FC1C=CC2OC(C(N3CCN(CC4C=CC=CC=4)CC3)=O)CC=2C=1.Cl.[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH:32]([C:39]([N:41]1[CH2:46][CH2:45][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:43][CH2:42]1)=O)[CH2:33][O:34]2>>[CH3:27][O:28][C:29]1[CH:38]=[CH:37][CH:36]=[C:35]2[C:30]=1[CH2:31][CH:32]([CH2:39][N:41]1[CH2:42][CH2:43][N:44]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:45][CH2:46]1)[CH2:33][O:34]2
Reactant: COc1cccc2c1CC(C(=O)N1CCN(Cc3ccccc3)CC1)CO2
Agent: Cl
Agent: O=C(C1Cc2cc(F)ccc2O1)N1CCN(Cc2ccccc2)CC1
Product: COc1cccc2c1CC(CN1CCN(Cc3ccccc3)CC1)CO2

Procedure:
By carrying out the preparation as in Example 1, but replacing 1-[(5-fluoro-2,3-dihydrobenzofur-2-yl)carbonyl]-4-benzylpiperazine with the hydrochloride of 1-[(5-methoxychroman-3-yl)carbonyl]-4-benzylpiperazine obtained in Stage A, the title product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:17]=[CH:16][C:6]2[NH:7][C:8]([CH:10]3[O:15][CH2:14][CH2:13][NH:12][CH2:11]3)=[N:9][C:5]=2[CH:4]=1.CCN(C(C)C)C(C)C.[Cl:27][C:28]1[CH:33]=[C:32](Cl)[N:31]=[C:30]([NH2:35])[N:29]=1>C(O)C>[Cl:27][C:28]1[CH:33]=[C:32]([N:12]2[CH2:13][CH2:14][O:15][CH:10]([C:8]3[NH:7][C:6]4[CH:16]=[CH:17][C:3]([O:2][CH3:1])=[CH:4][C:5]=4[N:9]=3)[CH2:11]2)[N:31]=[C:30]([NH2:35])[N:29]=1
Reactant: COc1ccc2[nH]c(C3CNCCO3)nc2c1
Reactant: Nc1nc(Cl)cc(Cl)n1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc2[nH]c(C3CN(c4cc(Cl)nc(N)n4)CCO3)nc2c1
Temperature: 25 °C
Yield: 38.8 %

Procedure:
To a suspension of 5-(methyloxy)-2-(2-morpholinyl)-1H-benzimidazole (500 mg, 2.143 mmol) and DIPEA (693 mg, 5.36 mmol) in ethanol (10 mL) stirred at room temperature was added solid 4,6-dichloro-2-pyrimidinamine (352 mg, 2.143 mmol). The reaction mixture was stirred at 85° C. overnight. The reaction mixture was cooled to room temperature and partitioned between EtOAc (25 mL) and water (25 mL). The solvent was evaporated in vacuo to give the crude product. The crude product was added to a silica gel column and was eluted with CH2Cl2/CH3OH to afford the title compound (300 mg). LC-MS (ES) m/z=361 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[NH2:26][C:27]1[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=1>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][N:28]=2)=[O:8])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: Nc1ccc(Cl)cn1
Reactant: O=C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)cn1)c1ccc(Cl)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 74.4 %

Procedure:
To a stirring suspension of 4-chloro-2-nitrobenzoic acid (20 g, 99 mmol) in dichloromethane (500 mL) was added a few drops of DMF, followed by oxalyl chloride (15.1 g, 119 mmol). After 1.h, the solvent was removed in vacuo and the residue was dissolved in dichloromethane (500 mL). To this stirring solution was added pyridine (24 mL, 297 mmol) followed by 2-amino-5-chloropyridine (12.7 g, 99 mmol). After stirring overnight, the solvents were removed in vacuo and the residue was stirred vigorously with ethyl acetate and water for several hours. The mixture was filtered to give a white solid, which was washed with ethyl acetate and dried in vacuo to give 23 g (74%) of the title compound. The combined ethyl acetate washings and extract were then washed twice with 1 M citric acid, once with brine, twice with saturated aq sodium bicarbonate, and again with brine. The organic phase was then dried with MgSO4, filtered and concentrated in vacuo. The solid was then suspended in diethyl ether, sonicated and filtered to give a second crop of the title compound as a white solid (5.79 g, 19%).