Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([O:15][CH2:16][O:17][C:18](=[O:46])[N:19]([C:43](=[O:45])[CH3:44])[CH2:20][C@@H:21]1[O:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:40][C:39]4[C:35](=[N:36][N:37]([CH3:41])[CH:38]=4)[CH2:34]3)=[C:29]([F:42])[CH:28]=2)[CH2:22]1)=[O:14])=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[C:43]([N:19]([CH2:20][C@@H:21]1[O:25][C:24](=[O:26])[N:23]([C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:40][C:39]4[C:35](=[N:36][N:37]([CH3:41])[CH:38]=4)[CH2:34]3)=[C:29]([F:42])[CH:28]=2)[CH2:22]1)[C:18]([O:17][CH2:16][O:15][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][NH:8]1)=[O:14])=[O:46])(=[O:45])[CH3:44]
Reactant: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)N(C[C@H]1CN(c2ccc(N3Cc4cn(C)nc4C3)c(F)c2)C(=O)O1)C(=O)OCOC(=O)[C@@H]1CCCN1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 11 (1 equiv) in dichloromethane at rt under nitrogen is added TFA (5 equiv) dropwise. The reaction mixture is stirred at rt for 2 h, concentrated in vacuo, purified directly by HPLC (C-18 column, 0-100% gradient elution, MeCN:H2O with 0.1% TFA), and fractions containing product are lyophilized to give the title compound. Theoretical MS 545 (M+1)+
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:7]2[N:8]([CH3:24])[CH:9]=[C:10]([C:13]([NH:15][CH2:16][C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)=[O:14])[C:11](=[O:12])[C:6]=2[S:5][C:4]=1[CH2:25][N:26]([CH2:28][C@@H:29]([OH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH3:27].C(N(C(C)C)CC)(C)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>C(Cl)Cl>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][NH:15][C:13]([C:10]2[C:11](=[O:12])[C:6]3[S:5][C:4]([CH2:25][N:26]([CH2:28][C@@H:29]([OH:36])[C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=4)[CH3:27])=[C:3]([CH2:2][NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[C:7]=3[N:8]([CH3:24])[CH:9]=2)=[O:14])=[CH:22][CH:21]=1
Reactant: CS(=O)(=O)Cl
Reactant: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CN)C[C@@H](O)c1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(Cc1sc2c(=O)c(C(=O)NCc3ccc(Cl)cc3)cn(C)c2c1CNS(C)(=O)=O)C[C@@H](O)c1ccccn1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a cold (0° C.), stirred solution of 96 mg of 3-(aminomethyl)-N-(4-chlorobenzyl)-2-{[[(2R)-2-hydroxy-2-pyridin-2-ylethyl](methyl)amino]methyl}-4-methyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxamide and 40 μL of diisopropylethylamine in 2 mL of CH2Cl2 is added 15 μL of methanesulfonyl chloride. The solution is stirred at 0° C. for 20 min, then quenched with dil. HCl and aqueous NaHCO3 to pH 7.0. The mixture is extracted three times with CHCl3, and the combined extracts dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography of the residue on silica using 3-4% MeOH in CH2Cl2 furnishes 114 mg of the title compound as a white foam. Recrystallization from EtOAc provides white crystals.
Reaction SMILES: C1(O[C:8](=[O:18])[NH:9][C:10]2[C:11]([O:16][CH3:17])=[N:12][CH:13]=[CH:14][CH:15]=2)C=CC=CC=1.[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[CH3:17][O:16][C:11]1[C:10]([NH:9][C:8]([N:28]2[CH2:29][CH2:30][N:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:26][CH2:27]2)=[O:18])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: COc1ncccc1NC(=O)Oc1ccccc1
Product: COc1ncccc1NC(=O)N1CCN(c2ccccc2)CC1
Yield: 88 %

Procedure:
Phenyl-N-(2-methoxypyridin-3-yl)carbamate and 1-phenylpiperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:11])=[O:10])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1.[F:28][C:29]([F:40])([F:39])[C:30]1([CH2:33]OS(C)(=O)=O)[CH2:32][CH2:31]1>>[F:1][C:2]1[CH:7]=[C:6]([CH2:8][S:9]([CH3:12])(=[O:10])=[O:11])[CH:5]=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]2[CH2:21][CH:20]([CH:22]3[CH2:27][CH2:26][N:25]([CH2:33][C:30]4([C:29]([F:40])([F:39])[F:28])[CH2:32][CH2:31]4)[CH2:24][CH2:23]3)[O:19][C:16]2=[CH:17][N:18]=1
Reactant: CS(=O)(=O)OCC1(C(F)(F)F)CC1
Reactant: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCNCC2)C3)c(F)c1
Product: CS(=O)(=O)Cc1ccc(-c2cc3c(cn2)OC(C2CCN(CC4(C(F)(F)F)CC4)CC2)C3)c(F)c1

Procedure:
The title compound is prepared from 5-(2-fluoro-4-methanesulfonylmethyl-phenyl)-2-piperidin-4-yl-2,3-dihydro-furo[2,3-c]pyridine and methanesulfonic acid (1-trifluoromethyl-cyclopropyl)methyl ester following a procedure analogous to that described for Example 2. LC (method 1): tR=1.01 min; Mass spectrum (ESI+): m/z=513 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18](O)=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1.[CH2:36]([S:38]([NH2:41])(=[O:40])=[O:39])[CH3:37]>>[Cl:1][C:2]1[C:3]([CH3:35])=[C:4]([NH:8][C:9]2[N:14]3[N:15]=[CH:16][C:17]([C:18]([NH:41][S:38]([CH2:36][CH3:37])(=[O:40])=[O:39])=[O:19])=[C:13]3[N:12]=[CH:11][C:10]=2[C:21]([N:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:25][CH2:24]2)=[O:22])[CH:5]=[CH:6][CH:7]=1
Reactant: CCS(N)(=O)=O
Reactant: Cc1c(Cl)cccc1Nc1c(C(=O)N2CCC(c3ccccc3)CC2)cnc2c(C(=O)O)cnn12
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3cccc(Cl)c3C)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 50 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(3-chloro-2-methylphenylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (53 mg, 0.11 mmol) obtained in step 2 and ethanesulfonamide (58 mg,' 0.55 mmol), the title compound (32 mg, 50%) was obtained.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:13][C@@H:12]([CH3:14])[CH2:11][C@H:10]1[C:15]1[NH:16][CH:17]=[C:18]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[CH:26]=[C:25]([C:30]2[CH:35]=[CH:34][C:33]([C:36]4[N:37]=[C:38]([C@@H:41]5[CH2:45][C@H:44]([CH3:46])[CH2:43][N:42]5C(OC(C)(C)C)=O)[NH:39][CH:40]=4)=[CH:32][CH:31]=2)[CH:24]=[CH:23]3)[N:19]=1)=O)(C)(C)C>O1CCOCC1.CO>[CH3:46][C@@H:44]1[CH2:43][NH:42][C@H:41]([C:38]2[NH:39][CH:40]=[C:36]([C:33]3[CH:34]=[CH:35][C:30]([C:25]4[CH:24]=[CH:23][C:22]5[C:27](=[CH:28][CH:29]=[C:20]([C:18]6[N:19]=[C:15]([C@@H:10]7[CH2:11][C@H:12]([CH3:14])[CH2:13][NH:9]7)[NH:16][CH:17]=6)[CH:21]=5)[CH:26]=4)=[CH:31][CH:32]=3)[N:37]=2)[CH2:45]1
Reactant: C[C@H]1C[C@@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7C(=O)OC(C)(C)C)n6)ccc5c4)cc3)c[nH]2)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@@H]1CN[C@H](c2nc(-c3ccc(-c4ccc5cc(-c6c[nH]c([C@@H]7C[C@H](C)CN7)n6)ccc5c4)cc3)c[nH]2)C1
Reaction time: 2 h

Procedure:
A solution of 4N HCl in dioxane (15 mL) was added to tert-butyl (2S,4S)-2-(4-(4-(6-(2-((2S,4S)-1-(tert-butoxycarbonyl)-4-methyl-2-pyrrolidinyl)-1H-imidazol-4-yl)-2-naphthyl)phenyl)-1H-imidazol-2-yl)-4-methyl-1-pyrrolidinecarboxylate (200 mg. 0.285 mmol) in MeOH (5 mL) and stirred at ambient conditions for 2 hours, concentrated, and dried under vacuum. Tetra HCl salt (assume theoretical: 185 mg). LC-MS retention time 2.64 min; calcd. for C32H35N6: 503.29 m/z Found 503.20 [M+H]+. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a PHENOMENEX® Luna 2.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 0.8 mL/min, a gradient of 100% Solvent A/0% Solvent B to 0% Solvent A/100% Solvent B, a gradient time of 4 min, a hold time of 1 min and an analysis time of 5 min where Solvent A was 5% methanol/95% water/0.1% TFA and Solvent B was 95% methanol/5% water/0.1% TFA. MS data was determined using a MICROMASS® Platform for LC in electrospray mode.
Reaction SMILES: Cl.[CH2:2]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([OH:21])=[O:20])=[CH:16][CH:17]=2)[NH:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].Cl.[CH3:23]O>>[CH2:2]([CH:10]1[C:18]2[C:13](=[CH:14][C:15]([C:19]([O:21][CH3:23])=[O:20])=[CH:16][CH:17]=2)[NH:12][CH2:11]1)[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CO
Reactant: CCCCCCCCC1CNc2cc(C(=O)O)ccc21
Agent: Cl
Product: CCCCCCCCC1CNc2cc(C(=O)OC)ccc21

Procedure:
(RS)-3-(n-Octyl)indoline-6-carboxylic acid hydrochloride (7.5 g) in methanol (500 ml), containing hydrochloric acid (50 ml, of strength 36% w/v), was refluxed for 18 hours. The solvent was removed in vacuo and water (100 ml) was added to the residue to give a solid, which was collected, washed with water (2×200 ml) and dried. The solid was dissolved in dichloromethane and was washed with an aqueous solution of sodium bicarbonate (100 ml of strength 2% w/v) and then water (100 ml) and was dried over sodium sulphate. The solvent was removed in vacuo to give a pale yellow oil, which solidified. The solid was recrystallised from a mixture (4:1) of methanol and water to give (RS)-methyl 3-(n-octyl)indoline-6-carboxylate (4.8 g), in the form of a white solid, m.p. 57°-60° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:7]([O:10][C:11]([F:14])([F:13])[F:12])=[CH:6][C:3]=1[CH:4]=[O:5].I[C:16]1([S:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17]1>C1(C)C=CC=CC=1.C(OCC)(=O)C.C(=O)([O-])[O-].[Ag+2]>[C:20]1([S:19][C:16]2([O:1][C:2]3[CH:9]=[CH:8][C:7]([O:10][C:11]([F:12])([F:13])[F:14])=[CH:6][C:3]=3[CH:4]=[O:5])[CH2:18][CH2:17]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: IC1(Sc2ccccc2)CC1
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Agent: [Ag+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=Cc1cc(OC(F)(F)F)ccc1OC1(Sc2ccccc2)CC1
Temperature: 40 °C
Reaction time: 8 h
Yield: 22.2 %

Procedure:
Silver carbonate (1.2 g, 4.34 mmol) was added to a solution of 2-hydroxy-5-(trifluoromethoxy)benzaldehyde (0.5 g, 2.43 mmol) and (1-iodocycloprop-1-yl)phenylsulfide (Cohen T. and Matz J. R., J. Am. Chem. Soc. 1980, 102, 6902) (1.2 g, 4.34 mmol) in toluene (30 mL) and the mixture was stirred at 40° C. overnight. The mixture was cooled, diluted with ethyl acetate and filtered, washing well with ethyl acetate. The mixture was washed with aqueous sodium hydroxide, dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with hexane/Et2O (95:5), to give the title compound as a yellow oil (191 mg, 27%). 1H NMR (360 MHz, CDCl3) δ 1.51-1.56 (2H, m), 1.44-1.48 (2H, m), 7.25-7.35 (7H, m), 7.69 (1H, d, J 2.0 Hz), and 10.26 (1H, s).
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([CH:24]=[CH:25][CH:26]=3)[NH2:23])[CH2:14][CH2:13]2)[N:3]=1.[CH:27]1([C:30](Cl)=[O:31])[CH2:29][CH2:28]1>>[CH3:1][C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N:12]2[CH2:13][CH2:14][N:15]([CH2:18][CH2:19][C:20]3[CH:21]=[C:22]([NH:23][C:30]([CH:27]4[CH2:29][CH2:28]4)=[O:31])[CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:17]2)[N:3]=1
Reactant: Cc1ccc2c(N3CCN(CCc4cccc(N)c4)CC3)cccc2n1
Reactant: O=C(Cl)C1CC1
Product: Cc1ccc2c(N3CCN(CCc4cccc(NC(=O)C5CC5)c4)CC3)cccc2n1
Yield: 70 %

Procedure:
The title compound was prepared in 70% yield according to the general procedure for the preparation of the amides (Method B) starting from 3-{2-[4-(2-methyl-5quinolinyl)-1-perazinyl]ethyl}aniline (D6) and cyclopropanecarbonyl chloride.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1.[C:19]([O:23][CH3:24])(=[O:22])[CH:20]=[CH2:21].C(N(CC)CC)C>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:24][O:23][C:19](=[O:22])[CH:20]=[CH:21][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[CH2:12][CH2:11][CH2:10][CH:9]=2)=[CH:4][CH:3]=1
Reactant: C=CC(=O)OC
Reactant: Brc1ccc(C2=CCCCc3ccccc32)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(C2=CCCCc3ccccc32)cc1
Temperature: 100 °C
Yield: 91.3 %

Procedure:
To a solution of 9-(4-bromophenyl)-6,7-dihydro-5H-benzocycloheptene (2a, compound I, R3=H, X=Br, n=2) (12.38 g, 41 mmol) in DMF (30 mL) was added methyl acrylate (38.2 g, 444 mmol), triethylamine (29.0 g, 286 mmol), and bis(triphenylphosphine)palladium(II) chloride (7.0 g, 10.0 mmol). The mixture was placed in a pressure bottle and heated at 100° C. for 4 days. The solvent was removed under reduced pressure and the residue was chromatographed (silica gel, 7.5 to 15% EtOAc/hexanes) to give the ester (2b) as a white solid (11.4 g, 90%): 1H NMR (CDCl3) δ 7.69 (d, J=15.7 Hz, 1H), 7.45 (d, J=8.1 Hz, 2H), 7.24 (m, 5H), 6.98 (m, 1H), 6.52 (t, J=7.3 Hz, 1H), 6.43 (d, J=15.7 Hz, 1H), 3.81 (s, 3H), 2.65 (t, J=7.0 Hz, 2H), 2.17 (m, 2H), 1.98 (m, 2H); APcI m/z: 346 (M+H+CH3CN+, 100%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CCOC(C)=O>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH2:20])=[O:19])=[C:8]2[S:5]([NH:4][CH2:3][CH2:2][NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])(=[O:6])=[O:7]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCS(=O)(=O)NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 60 h

Procedure:
A solution of the product from Example 63 (15 mg, 0.038 mmol), triethylamine (0.017 mL, 0.11 mmol) and ethanesulfonyl chloride (0.004 mL, 0.04 mmols) were combined in a sealed tube and heated to 65° C. overnight. The solvent was removed under a stream of N2 and replaced with DMF. After adding an additional 3 equivalents of ethanesulfonyl chloride and triethylamine, the reaction was heated to 65° C. for 8 hours and stirred at room temperature for 60 hours. The mixture was diluted with EtOAc and washed with 10% Na2CO3 and brine, dried over Na2SO4, filtered and concentrated in vac o. Purification by reversed-phase preparative HPLC gave the titled compound. ESI+ MS: 453 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][OH:21])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>C(Cl)Cl>[CH2:1]([O:8][C:9]([N:11]1[CH2:19][C:18]2[C:13](=[CH:14][CH:15]=[C:16]([CH2:20][O:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:17]=2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(OCc1ccccc1)N1Cc2ccc(CO)cc2C1
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc2c(c1)CN(C(=O)OCc1ccccc1)C2
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution (5° C.) of 5-hydroxymethyl-1,3-dihydro-isoindole-2-carboxylic acid benzyl ester (11 Kg, 38.8 mol, step 7) and Et-3N (7.04 L, 50.6 mol) in DCM (55 L) was added methanesulphonyl chloride (2.97 L, 38.4 mol) so that the internal temp <10° C. After stirring for 0.5 h at 5° C. the solution was used below in step 9.
Reaction SMILES: [CH2:1]([C:3]1([CH2:15][CH3:16])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][NH:5][CH2:4]1)[CH3:2].[CH:17]([O:20][C:21]1[CH:29]=[CH:28][C:27]([S:30]([CH3:33])(=[O:32])=[O:31])=[CH:26][C:22]=1[C:23](O)=[O:24])([CH3:19])[CH3:18]>>[CH2:15]([C:3]1([CH2:1][CH3:2])[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([O:13][CH3:14])[CH:11]=2)[CH2:6][N:5]([C:23]([C:22]2[CH:26]=[C:27]([S:30]([CH3:33])(=[O:32])=[O:31])[CH:28]=[CH:29][C:21]=2[O:20][CH:17]([CH3:19])[CH3:18])=[O:24])[CH2:4]1)[CH3:16]
Reactant: CCC1(CC)CNCc2ccc(OC)cc21
Reactant: CC(C)Oc1ccc(S(C)(=O)=O)cc1C(=O)O
Product: CCC1(CC)CN(C(=O)c2cc(S(C)(=O)=O)ccc2OC(C)C)Cc2ccc(OC)cc21

Procedure:
Prepared in analogy to example 1.1 from 4,4-diethyl-6-methoxy-1,2,3,4-tetrahydro-isoquinoline and 2-isopropoxy-5-methanesulfonyl-benzoic acid (Example 2.1).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:3]=1.[CH3:17][O:18][CH2:19][CH2:20][O:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Cl:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[NH:8][C:4]1[CH:3]=[C:2]([NH:26][C:25]2[CH:24]=[CH:23][C:22]([O:21][CH2:20][CH2:19][O:18][CH3:17])=[CH:28][CH:27]=2)[N:7]=[CH:6][N:5]=1
Reactant: Fc1ccc(Nc2cc(Cl)ncn2)cc1Cl
Reactant: COCCOc1ccc(N)cc1
Product: COCCOc1ccc(Nc2cc(Nc3ccc(F)c(Cl)c3)ncn2)cc1
Yield: 49 %

Procedure:
Using an analogous reaction procedure to that described in Example 6, 6-chloro-4-(3'-chloro-4'-fluoroanilino)pyrimidine (0.258 g) was reacted with 4-(2-methoxyethoxy)aniline (0.206 g). The reaction product was chromatographed on silica and precipitated from a mixture of methylene chloride and hexane to give 4-(3'-chloro-4'-fluoroanilino)-6-[4'-(2-methoxyethoxy)anilino]pyrimidine in 49% yield, m.p. 208°-210° C.;
Reaction SMILES: Cl[S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3].C[Si](C)(C)[NH:18][C:19]1[C:24]([Cl:25])=[CH:23][CH:22]=[C:21]([CH3:26])[C:20]=1[Cl:27].CS(C)=O>CC#N>[Cl:27][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[C:24]([Cl:25])[C:19]=1[NH:18][S:2]([C:5]1[N:15]=[C:8]2[N:9]=[C:10]([CH3:14])[CH:11]=[C:12]([CH3:13])[N:7]2[N:6]=1)(=[O:4])=[O:3]
Reactant: Cc1ccc(Cl)c(N[Si](C)(C)C)c1Cl
Reactant: Cc1cc(C)n2nc(S(=O)(=O)Cl)nc2n1
Solvent: CC#N
Solvent: CS(C)=O
Product: Cc1cc(C)n2nc(S(=O)(=O)Nc3c(Cl)ccc(C)c3Cl)nc2n1
Temperature: 25 °C
Yield: 81.3 %

Procedure:
A solution consisting of 106.8 mg (0.433 mmole) of 2-chlorosulfonyl-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine, 0.5 ml of CH3CN, and 252 μl (1.30 mmole) of N-trimethylsilyl-3-methyl-2,6-dichloroaniline was stirred at room temperature and 10 μl (0.14 mmole) of dimethyl sulfoxide (DMSO) added dropwise. The solution was stirred for 2 hours during which time a precipitate formed. The CH3CN was removed under nitrogen and the residual solid treated with 1 ml of 1N HCl. The mixture was stirred for 10 min, filtered, and the precipitate washed with acetone to obtain 136 mg of N-(2,6-dichloro-3-methylphenyl)-5,7-dimethyl-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide product as an off-white solid. The solid was washed with methanol and dried to give 120 mg (0.310 mmole, 71.6 percent yield) of product as a white solid, m.p. 286.5°-288° C.
Reaction SMILES: [CH2:1]([O:6][CH:7]([CH3:12])[CH2:8][CH2:9][CH2:10][OH:11])[CH2:2][CH2:3][CH2:4][CH3:5].[S:13](Cl)([C:16]1[CH:22]=[CH:21][C:19]([CH3:20])=[CH:18][CH:17]=1)(=[O:15])=[O:14].O>N1C=CC=CC=1>[C:19]1([CH3:20])[CH:21]=[CH:22][C:16]([S:13]([O:11][CH2:10][CH2:9][CH2:8][CH:7]([O:6][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[CH3:12])(=[O:15])=[O:14])=[CH:17][CH:18]=1
Reactant: CCCCCOC(C)CCCO
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: CCCCCOC(C)CCCOS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Yield: 99.6 %

Procedure:
17 g of 4-pentyloxypentanol was dissolved in 60 ml of pyridine, and under stirring, 22.4 g of tosyl chloride was added at below 10° C. in 40 min. The mixture was raised to 25° C. and stirred for 3 hours. After the reaction, cold water was added, and the product was extracted with ether, followed by successive washing with 5% hydrochloric acid and water and drying with anhydrous MgSO4. The solvent was distilled off to obtain 31.9 g of 4-pentyloxypentyl p-toluenesulfonate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH3:19])=[O:17])=[CH:12][C:11]=1[CH2:20][OH:21].[H-].[Na+].Br[CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][C:13]([C:16]([O:18][CH2:19][CH:2]=[C:3]([CH3:10])[CH3:4])=[O:17])=[CH:12][C:11]=1[CH2:20][O:21][CH2:25][CH:26]=[C:27]([CH3:29])[CH3:28]
Reactant: CC(C)=CCBr
Reactant: COC(=O)c1ccc(-c2cc(OC)ccc2F)c(CO)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(C(=O)OCC=C(C)C)cc2COCC=C(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77 %

Procedure:
To a solution of 66.63A (0.322 mmol) in DMF (4 mL), was added NaH (0.0100 g, 0.419 mmol). The resulting mixture was stirred at room temperature for 10 minutes. 1-Bromo-3-methylbut-2-ene (0.240 g, 1.61 mmol) (commercially available from Aldrich) was added and the mixture was stirred at room temperature for 2 hours. After removing solvent, the residue was purified by flash chromatography (silica gel, 1:6 EtOAc/hexane) and gave 67.27A as a colorless oil, in 77% yield. MS ESI (pos.) m/e: 430 (M+18)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35]>>[NH2:26][C:24]1[C:25]2=[C:17]([C:12]3[CH:13]=[CH:14][C:15]4[C:10]([CH:11]=3)=[N:9][N:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:16]=4)[CH:18]=[C:19]([CH:27]3[CH2:31][CH2:30][N:29]([CH2:33][C:34]([N:36]([CH3:38])[CH3:37])=[O:35])[CH2:28]3)[N:20]2[N:21]=[CH:22][N:23]=1
Reactant: Nc1ncnn2c(C3CCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN(C)C(=O)CCl
Product: CN(C)C(=O)CN1CCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Yield: 46.4 %

Procedure:
5-(2-benzyl-2H-indazol-6-yl)-7-pyrrolidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (100 mg, 0.244 mmol) was reacted with 2-chloro-N,N-dimethylacetamide (33 mg, 0.269 mmol) following the procedure of Example 136. The product was then chromatographed using 0-6% (2N NH3 in methanol)/dichloromethane to yield 56 mg (46%) of product. 1H NMR (300 MHz, dichloromethane-d2) δ 8.04 (s, 1 H), 7.89 (s, 1 H), 7.80 (d 1 H), 7.77-7.73 (m, 2 H), 7.36 (m, 5 H), 7.23 (d, 1 H), 6.66 (s, 1 H), 5.62 (s, 2 H), 5.43 (bs, 2 H), 4.00 (m, 1 H), 3.45 (m, 1 H), 3.35 (t, 1H), 3.18 (s, 2 H) 2.75-26.60 (m, 8 H), 2.45 (m, 1 H), 2.00 (m, 1 H); ES-MS m/z 495.2 [M+H]+, HPLC RT (min) 2.13.
Reaction SMILES: [CH2:1]([CH:4]([C:9]([O:11]C)=O)[C:5]([O:7]C)=O)[C:2]#[CH:3].Cl.[C:14]([NH2:17])(=[NH:16])[CH3:15]>CO>[CH3:15][C:14]1[N:17]=[C:5]([OH:7])[C:4]([CH2:1][C:2]#[CH:3])=[C:9]([OH:11])[N:16]=1
Reactant: C#CCC(C(=O)OC)C(=O)OC
Reactant: CC(=N)N
Agent: Cl
Solvent: CO
Product: C#CCc1c(O)nc(C)nc1O
Yield: 36.9 %

Procedure:
To a 250 mL flask was added 1 (3.96 g, 20 mmol), 2 (1.85 g, 20 mmol) and 50 mL anhydrous MeOH. After 800 mg (20 mmol) Na was added to the solution, yellow precipitate was observed. The resulting mixture was refluxed overnight. The yellow precipitate was collected by filtration and then dissolved in 10 mL H2O. The pH of the resulting solution was adjusted to 6.5 by adding 2 N HCl to afford a yellow precipitate, which was collected by filtration and dried over P2O5 to afford 1.21 g (37%) of 3: TLC Rf0.11 (CHCl3/MeOH 6:1); mp>300° C.; 1H NMR (DMSO-d6) δ 2.23 (s, 3 H), 3.05 (s, 2 H), 3.32 (s, 1 H), 11.92 (s, 2 H).