Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:5])[CH2:3][OH:4].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[CH3:19][S:20]([O:4][CH2:3][C:2]([CH3:1])([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH3:5])(=[O:22])=[O:21]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(CO)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(COS(C)(=O)=O)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2-Methyl-2-phenylpropan-1-ol (51) (8.5 g, 56.6 mmol, Eq: 1.00) was stirred in dichloromethane (90.4 ml) at 0° C., triethylamine (6.87 g, 9.46 ml, 67.9 mmol, Eq: 1.2) and then methanesulfonyl chloride (7.13 g, 4.82 ml, 62.2 mmol, Eq: 1.1) were added over 3 minutes. The reaction mixture was stirred at 0° C. for 30 minutes, removed from the ice bat h and allowed to warm to room temperature and stirred for 15 hours. The reaction mixture was diluted with dichloromethane, washed with water, saturated sodium bicarbonate, and brine, and dried with magnesium sulfate. The solvent was removed on a rotary evaporator to give 2-methyl-2-phenylpropyl methanesulfonate (52) as a clear oil, (12.0 g, 93%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1.[C:26](Cl)(=[O:28])[CH3:27]>>[C:26]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]([CH3:25])[CH2:17][NH:18][S:19]([CH:22]([CH3:24])[CH3:23])(=[O:21])=[O:20])=[CH:12][CH:11]=2)=[CH:8][CH:9]=1)(=[O:28])[CH3:27]
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(CCN)cc2)cc1
Reactant: CC(=O)Cl
Product: CC(=O)NCCc1ccc(-c2ccc(C(C)CNS(=O)(=O)C(C)C)cc2)cc1

Procedure:
The title compound was prepared following the method of Example 147 and using 1 mL of a stock solution of 0.6 g (1.8 mmol) of material from Example 50 and 8 μL (0.11 mmol) acetyl chloride. NMR was consistent with the proposed compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH:8]1[CH2:12][CH2:11][N:10]([C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[C:15]([NH2:20])[N:14]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:22]OC(OC)OC.C([O-])(O)=O.[Na+]>C1(S(O)(=O)=O)C=CC=CC=1.C1(C)C=CC=CC=1>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH2:12][CH2:11][N:10]([C:13]2[N:14]=[C:15]3[NH:20][CH:22]=[N:19][C:16]3=[CH:17][CH:18]=2)[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1CCN(c2ccc(N)c(N)n2)C1
Reactant: COC(OC)OC
Agent: O=C([O-])O
Agent: O=S(=O)(O)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NC1=CN(c2ccc3nc[nH]c3n2)CC1
Yield: 95.4 %

Procedure:
The solution of [1-(5,6-diamino-pyridin-2-yl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester (2 g, 6.82 mmole), trimethylorthoformate (3.83 g, 25.9 mmole), benzenesulfonic acid (43 mg, 0.27 mmole) and toluene (100 ml) was heated to reflux overnight. The reaction solution was basified with NaHCO3 and concentrated to afford crude [1-(3H-imidazo[4,5-b]pyridine-5-yl)-pyrrolin-3-yl]-carbamic acid tert-butyl ester (1.96 g, 94%) as a dark green solid. MS(ESI) m/z 304 [M+1].
Reaction SMILES: [Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])[OH:4].ClCCl.C1(N=C=NC2CCCCC2)CCCCC1.CN(C1C=CC=CN=1)C.[C:44](O)(=[O:46])[CH3:45]>CN(C)C=O>[C:44]([O:4][CH:3]([CH2:2][Cl:1])[C:5]1[CH:10]=[C:9]([S:11](=[O:14])(=[O:13])[NH2:12])[CH:8]=[CH:7][C:6]=1[O:15][CH3:16])(=[O:46])[CH3:45]
Reactant: COc1ccc(S(N)(=O)=O)cc1C(O)CCl
Reactant: CC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1ccc(S(N)(=O)=O)cc1C(CCl)OC(C)=O

Procedure:
2.64 g (9.9 mmol) of α-chloromethyl-2-methoxy-5-sulphamoylbenzenemethanol and 100 ml of dichloromethane are introduced into a 250-ml round-bottomed flask. 10 ml of dimethylformamide are then added with stirring, followed by 852 μl of acetic acid, 2.56 g of dicyclohexylcarbodiimide and 121 mg of dimethylaminopyridine. The mixture is allowed to react for 1 hour at room temperature, and is then filtered and rinsed with 50 ml of 5% sodium hydrogen carbonate solution and then with 50 ml of water. The rinsing liquors are extracted with 2 times 20 ml of acetic acid, and the organic phases are then combined, dried and concentrated. On chromatographing the residue on a silica column with a 25:75 mixture of ethyl acetate and cyclohexane, 1.9 g of product are obtained.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:23]=[C:6]2[CH:7]=[C:8]([NH:11][C:12]([C:14]3[N:18]([CH3:19])[N:17]=[CH:16][C:15]=3[C:20](O)=[O:21])=[O:13])[CH:9]=[CH:10][N:5]2[N:4]=1.[NH:25]1[CH2:28][CH2:27][CH2:26]1.CCCP(=O)=O.C(N(C(C)C)CC)(C)C>O1CCCC1>[N:25]1([C:20]([C:15]2[CH:16]=[N:17][N:18]([CH3:19])[C:14]=2[C:12]([NH:11][C:8]2[CH:9]=[CH:10][N:5]3[N:4]=[C:3]([N:2]([CH3:1])[CH3:24])[N:23]=[C:6]3[CH:7]=2)=[O:13])=[O:21])[CH2:28][CH2:27][CH2:26]1
Reactant: CN(C)c1nc2cc(NC(=O)c3c(C(=O)O)cnn3C)ccn2n1
Reactant: C1CNC1
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CN(C)c1nc2cc(NC(=O)c3c(C(=O)N4CCC4)cnn3C)ccn2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 71 %

Procedure:
A mixture of 5-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-ylcarbamoyl)-1-methyl-1H-pyrazole-4-carboxylic acid (150 mg, 455 μmol), azetidine (123 l, 1.82 mmol), propylphosphonic anhydride (50% in ethyl acetate, 671 μl, 1.14 mmol) and diisopropylethylamine (398 μl, 2.28 mmol) in tetrahydrofurane (8 ml) is stirred for 18 hours at room temperature under nitrogen atmosphere. The solvent is evaporated and the residue triturated with sat. aqueous sodium hydrogencarbonate solution. The precipitated solid is collected by filtration, washed with water and dried affording 4-(azetidine-1-carbonyl)-N-(2-(dimethylamino)-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-1-methyl-1H-pyrazole-5-carboxamide (119 mg, 70.9%) as an off-white solid. Mp.: 240-1° C. MS: m/z=369.1 (M+H+).
Reaction SMILES: BrCCBr.C=C.Cl[Si](C)(C)C.Br[C:13]1[S:14][CH:15]=[CH:16][N:17]=1.Br[C:19]1[CH:20]=[C:21]2[C:25](=[CH:26][CH:27]=1)[CH:24]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])[CH2:23][CH2:22]2>O1CCCC1.[Zn].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>[Si:29]([O:28][CH:24]1[C:25]2[C:21](=[CH:20][C:19]([C:13]3[S:14][CH:15]=[CH:16][N:17]=3)=[CH:27][CH:26]=2)[CH2:22][CH2:23]1)([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: Brc1nccs1
Reactant: CC(C)(C)[Si](C)(C)OC1CCc2cc(Br)ccc21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=C
Agent: C[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: BrCCBr
Product: CC(C)(C)[Si](C)(C)OC1CCc2cc(-c3nccs3)ccc21
Reaction time: 24 h
Yield: 79 %

Procedure:
To a stirred suspension of zinc (899 mg, 13.75 mmol) in tetrahydrofuran (1.60 mL) was added 1,2-dibromoethane (0.118 mL, 1.37 mmol). The suspension was heated with a heat gun until no evolution of ethylene gas. Chlorotrimethylsilane (0.0698 mL, 0.55 mmol) and a solution of 2-bromothiazole (0.413 mL, 4.58 mmol) in tetrahydrofuran were added. After 15 min [(5-bromo-2,3-dihydro-1H-inden-1-yl)oxy](tert-butyl)dimethylsilane (1.0 g, 3.055 mmol) and tetrakis(triphenylphosphine)palladium(0) (70.6 mg, 0.0611 mmol) dissolved in tetrahydrofuran (8.00 mL) were added. The mixture was stirred for 24 h at reflux and quenched with 15 mL of brine. The organic layer was separated and the aqueous phase was extracted with methylene chloride (25 mL×3). The combined extracts were washed with brine, dried over anhydrous Na2SO4, and evaporated under reduced pressure. Chromatography on silica gel with 2.5% EtOAc/hexane afforded the desired coupling product (800 mg, 79%).
Reaction SMILES: C1(O[C:8]([N:14]2[CH2:18][CH2:17][CH:16]([CH2:19][C:20]([N:22]3[CH2:27][CH2:26][CH:25]([CH:28]4[C:34]5=[N:35][CH:36]=[C:37]([Br:39])[CH:38]=[C:33]5[CH2:32][CH2:31][C:30]5[CH:40]=[C:41]([Cl:45])[CH:42]=[C:43]([Cl:44])[C:29]4=5)[CH2:24][CH2:23]3)=[O:21])[CH2:15]2)=[N:9][S:10]([CH3:13])(=[O:12])=[O:11])C=CC=CC=1.[NH4+:46].[OH-]>CC(O)C>[Br:39][C:37]1[CH:38]=[C:33]2[CH2:32][CH2:31][C:30]3[CH:40]=[C:41]([Cl:45])[CH:42]=[C:43]([Cl:44])[C:29]=3[CH:28]([CH:25]3[CH2:24][CH2:23][N:22]([C:20](=[O:21])[CH2:19][CH:16]4[CH2:17][CH2:18][N:14]([C:8](=[NH:46])[NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:15]4)[CH2:27][CH2:26]3)[C:34]2=[N:35][CH:36]=1
Reactant: CS(=O)(=O)N=C(Oc1ccccc1)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: CS(=O)(=O)NC(=N)N1CCC(CC(=O)N2CCC(C3c4ncc(Br)cc4CCc4cc(Cl)cc(Cl)c43)CC2)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The product of Example 26 is dissolved in 2-propanol and concentrated NH4OH is added. The mixture is stirred at 25° C. for 24 h and then evaporated to dryness. The residue is triturated with Et2O (2×250 ml) and the ether discarded. The resulting product is chromatographed on a silica gel column to give the title compound.
Reaction SMILES: [CH2:1]([O:5][C:6](Cl)=[O:7])[CH:2]([CH3:4])[CH3:3].C[O:10][C:11]([C:13]1[CH:14]=[C:15]([CH3:39])[C:16]2[O:22][C:21]3[C:23]([Cl:35])=[CH:24][C:25]([NH:27][CH2:28][CH2:29][N:30]4[CH2:34][CH2:33][CH2:32][CH2:31]4)=[CH:26][C:20]=3[CH2:19][S:18](=[O:37])(=[O:36])[C:17]=2[CH:38]=1)=[O:12].C(N(CC)CC)C.O>C(Cl)Cl>[Cl:35][C:23]1[C:21]2[O:22][C:16]3[C:15]([CH3:39])=[CH:14][C:13]([C:11]([OH:12])=[O:10])=[CH:38][C:17]=3[S:18](=[O:37])(=[O:36])[CH2:19][C:20]=2[CH:26]=[C:25]([N:27]([C:6]([O:5][CH2:1][CH:2]([CH3:4])[CH3:3])=[O:7])[CH2:28][CH2:29][N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)[CH:24]=1
Reactant: CC(C)COC(=O)Cl
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCCC3)cc(Cl)c1O2
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(N(CCN3CCCC3)C(=O)OCC(C)C)cc1CS2(=O)=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Isobutylchloroformate (0.17 mL, 1.33 mmol) was added to a solution of Example 72k (0.40 g, 0.88 mmol) in dry CH2Cl2 (15 mL). Triethylamine (0.23 ml, 1.67 mmol) was added and the reaction mixture was stirred at 0° C. for 1 h. It was brought to room temperature, treated with water and extracted with chloroform. The organic layer was washed with water, brine, dried, concentrated and crystallised using ethyl acetate to obtain the title compound as a white solid. Yield: 0.280 g, (58%). 1H NMR (DMSO-d6): δ 0.80 (d, 6H, 2CH3), 1.70-1.80 (m, 5H, 2CH2, CH), 2.50-2.89 (m, 1H, 4CH2, CH3), 3.90 (d, 2H, CH2), 5.19 (s, 2H, CH2), 7.55 (s, 1H, Ar), 7.75 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 1H, Ar). MS: m/e (EI+) 565 (M+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH2:9].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:20][O:21][CH:22]([O:36][CH3:37])[C:23]1[C:28](F)=[C:27]([N+:30]([O-:32])=[O:31])[C:26]([O:33][CH3:34])=[CH:25][C:24]=1[F:35]>C1COCC1>[CH3:37][O:36][CH:22]([O:21][CH3:20])[C:23]1[C:24]([F:35])=[CH:25][C:26]([O:33][CH3:34])=[C:27]([N+:30]([O-:32])=[O:31])[C:28]=1[NH:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[F:1]
Reactant: COc1cc(F)c(C(OC)OC)c(F)c1[N+](=O)[O-]
Reactant: Nc1ccc(I)cc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(F)c(C(OC)OC)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.7 %

Procedure:
To a cold (−78° C.) solution of 2-fluoro-4-iodo-phenyl amine (2.97 g, 12.5 mmol) in THF (20 mL) was added LHMDS (24 mL, 1.0 M solution in hexanes 24 mmol) dropwise maintaining the temperature below −65° C. After stirring for 30 minutes a solution of 2-dimethoxymethyl-1,3-difluoro-5-methoxy-4-nitro-benzene (3.0 g, 11.4 mmol) in THF (20 mL) was added dropwise, the resultant mixture stirred cold (−78° C.) for 1 hour then allowed to warm to room temperature and stirred for 18 hours. The reaction was quenched by the addition of aqueous ammonium chloride and extracted twice with diethyl ether. The combined organic extracts were washed with water, dried (Na2SO4), filtered and concentrated in vacuo to give an orange solid. The crude orange solid was triturated in diethyl ether to give the title compound as a yellow solid (4.2 g, 77%). 1H NMR (CDCl3) 7.36 (1 H, dd, J=10.09, 1.93 Hz), 7.28-7.17 (2 H, m), 6.59 (1 H, t, J=8.62 Hz), 6.44 (1H, d, J=11.47 Hz), 5.49 (1 H, s), 3.88 (3 H, s), 3.39 (6 H, s).
Reaction SMILES: [C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)(=O)C([Cl:21])=O>CCOCC.CN(C=O)C>[C:1]1([C:7]2([CH2:12][CH2:13][CH2:14][C:15]([Cl:21])=[O:17])[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCCC1(c2ccccc2)OCCO1
Solvent: CCOCC
Solvent: CN(C)C=O
Product: O=C(Cl)CCCC1(c2ccccc2)OCCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
Step AAH (2): To a solution of 4-(2-phenyl-1,3-dioxolan-2-yl)butanoic acid (490 mg, 2.07 mmol) in anhydrous Et2O (10 mL) was added oxalyl dichloride (526 mg, 4.15 mmol). Anhydrous DMF (2 drops) was added and the resulting mixture stirred at rt for 1 h. The crude reaction was concentrated in vacuo. The residue was diluted with toluene (10 mL) and reconcentrated to afford 4-(2-phenyl-1,3-dioxolan-2-yl)butanoyl chloride (2.07 mmol).
Reaction SMILES: [C:1]1([C@@H:7]([OH:11])[CH2:8][CH2:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1N2CCN(CC2)C1.[C:20]1([CH3:30])[CH:25]=[CH:24][C:23]([S:26](Cl)(=[O:28])=[O:27])=[CH:22][CH:21]=1>C(Cl)Cl>[OH:11][C@H:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][CH2:9][O:10][S:26]([C:23]1[CH:24]=[CH:25][C:20]([CH3:30])=[CH:21][CH:22]=1)(=[O:28])=[O:27]
Reactant: OCC[C@H](O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: C1CN2CCN1CC2
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC[C@H](O)c2ccccc2)cc1
Reaction time: 1 h

Procedure:
To a solution of (S)-1-phenyl-propane-1,3-diol (0.5 g, 3.3 mmol) and triethylenediamine (368 mg, 3.3 mmol) in DCM (40 mL) cooled to 0° C. was added dropwise p-toluenesulfonyl chloride (1.96 g, 0.0103 mol) in DCM (20 mL). The reaction mixture was stirred for 1 h and then filtered through a pad of silica. The silica was washed with DCM and the filtrate was concentrated to give the title compound as a crude oil (0.485 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][NH:20][C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:26])[F:25].[H-].[Na+].Br[CH2:31][CH3:32]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][N:20]([CH2:31][CH3:32])[C:19](=[O:23])[CH:18]=3)=[CH:11][CH:10]=2)=[CH:4][C:3]=1[C:24]([F:27])([F:25])[F:26]
Reactant: O=c1cc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc[nH]1
Reactant: CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc(OCc2ccc(Oc3ccc(Cl)c(C(F)(F)F)c3)cc2)cc1=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 69.5 %

Procedure:
To a solution of 4-{[(4-{[4-chloro-3-(trifluoromethyl)phenyl]oxy}phenyl)methyl]oxy}-2(1H)-pyridinone (80 mg, 0.202 mmol) in N,N-dimethylformamide (1 mL) was added Sodium hydride (80 mg, 2.00 mmol). After stirring at rt for 10 min, bromoethane (100 μL, 1.34 mmol) was added. The reaction mixture was warmed to 80° C. and stirred for 1 h, then cooled to rt, quenched by addition of methanol, concentrated. Purification via Biotage-Qs system afforded the title product (59.5 mg) as a white solid. LC-MS (ESI): m/z 424 [M+H]+; 3.76 min (ret time).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20]Cl)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[OH:22][N:23]1[C:27](=[O:28])[C:26]2=[CH:29][CH:30]=[CH:31][CH:32]=[C:25]2[C:24]1=[O:33].C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:22][N:23]3[C:27](=[O:28])[C:26]4[C:25](=[CH:32][CH:31]=[CH:30][CH:29]=4)[C:24]3=[O:33])[N:14]([CH2:15][C:16]([OH:18])([CH3:19])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CC(C)(O)Cn1c(CCl)nc2c(N)nc3ccccc3c21
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(O)Cn1c(CON2C(=O)c3ccccc3C2=O)nc2c(N)nc3ccccc3c21
Temperature: 25 °C
Reaction time: 3 h
Yield: 20.4 %

Procedure:
A solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (1.00 g, 3.28 mmol) in DMF (3.0 mL) was added to a solution of N-hydroxyphthalimide (642 mg, 3.94 mmol) and triethylamine (0.915 mL, 6.56 mmol) in DMF (3.0 mL). The flask containing the solution of 1-[4-amino-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol was rinsed with DMF (3.0 mL), which was added to the reaction solution. The solution was stirred at room temperature for 3 hours and a solid formed. The solid was isolated by filtration, washed with dichloromethane, and dried. The off-white solid was dissolved in hot DMF (20 mL). Acetonitrile (50 mL) was added to the solution, which was then placed in a freezer. Crystals formed and were isolated by filtration, washed with acetonitrile, and dried to provide 288 mg of 2-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-1H-isoindole-1,3(2H)-dione as orange crystals, mp 270-272° C.
Reaction SMILES: O=C1NCCN(C(OC(C)(C)C)=O)C1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:29]1[CH2:34][CH2:33][NH:32][CH2:31][C:30]1=[O:35].Br[CH:37]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(Cl)Cl.CN(C)C=O>[CH:37]([N:32]1[CH2:33][CH2:34][NH:29][C:30](=[O:35])[CH2:31]1)([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1
Reactant: O=C1CNCCN1
Reactant: BrC(c1ccccc1)c1ccccc1
Agent: CC(C)(C)OC(=O)N1CCNC(=O)C1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Product: O=C1CN(C(c2ccccc2)c2ccccc2)CCN1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 3-oxopiperazine-1-carboxylate (0.6 g, 3 mmol) in methylene chloride (10 mL) was treated with trifluoroacetic acid (3 mL) at room temperature for 1 hour. The reaction mixture was concentrated and the obtained trifluoroacetic salt of 2-piperazinone was used without purification. To a piperazin-2-one 2,2,2-trifluoroacetate (0.4 g, 1.87 mmol) solution in N,N-dimethylformamide (3 mL) was added bromodiphenylmethane (0.45 g, 1.87 mmol), potassium carbonate (0.78 g, 5.7 mmol) and catalytic amount of potassium iodide and the reaction mixture was stirred at ambient temperature overnight. Then it was evaporated, partitioned in H2O/methylene chloride. The organic layer was dried over MgSO4, evaporated in vacuo and chromatographed on silica gel eluting with 30% ethyl acetate/hexane and then with 10% methanol/dichloromethane/1% ammonium hydroxide to yield the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.80 (s, 1H), 7.46 (m, 4H), 7.31 (m, 4H), 7.21 (m, 2H), 4.37 (s, 1H), 3.17 (m, 2H), 2.79 (s, 2H); MS/DCI 267 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:28])[C:5]1[CH:10]=[C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)[CH:8]=[CH:7][C:6]=1[F:27])C.Cl.Cl[CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1>>[F:27][C:6]1[CH:7]=[CH:8][C:9]([CH2:11][N:12]2[CH2:17][CH2:16][CH:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH2:31][C:32]4[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=4)[CH:19]=3)[CH2:14][CH2:13]2)=[CH:10][C:5]=1[C:4]([OH:3])=[O:28]
Reactant: CCOC(=O)c1cc(CN2CCC(c3c[nH]c4ccccc34)CC2)ccc1F
Reactant: ClCc1cccnc1
Agent: Cl
Product: O=C(O)c1cc(CN2CCC(c3cn(Cc4cccnc4)c4ccccc34)CC2)ccc1F

Procedure:
This compound was prepared following the procedure described in example 1 (part E) starting with 0.063 g (0.17 mmol) of 2-fluoro-5-[4-(1H-indol-3-yl)-piperidin-1-ylmethyl]-benzoic acid ethyl ester and 0.035 mg (0.21 mmol) of 3-chloromethyl-pyridine hydrochloride. After the described purification, 0.053 g (71% of yield) of the expected acid was obtained.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([N+:15]([O-])=O)[CH:12]=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H][H]>CO.[Pd]>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[C:13]([NH2:15])[CH:12]=[CH:11][C:10]=1[C:18]([O:20][CH3:21])=[O:19])(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [H][H]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1S(=O)(=O)NC(C)(C)C
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C

Procedure:
25.08 g (0.079 mol) of N-tert-butyl-2-methoxycarbonyl-5-nitrobenzenesulfonamide are dissolved in 1000 ml of MeOH. 0.50 g of Pd-C (10%) is added and the mixture is shaken under a hydrogen atmosphere (1 atm) until the uptake of hydrogen has finished. The catalyst is separated off and the solvent is removed by distillation. The residue is induced to crystallize by stirring with a little ethyl acetate. The resulting N-tert-butyl-5-amino-2-methoxycarbonylbenzenesulfonamide (18.3 g; 80.9% of theory) melts at 193° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30]C)=[O:29])[CH2:20]3)=[CH:13][CH:12]=1.CO.[Li+].[OH-].Cl>C1COCC1.O>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[S:35])[NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])[CH2:20]3)=[CH:15][CH:16]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)[C@@H](C(=O)O)N1Cc2cc(-c3ccc(NC(=S)Nc4ccccc4F)cc3)ccc2C1=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
The compound of example 256 (0.224 g, 0.000456 mol) was taken in THF (4 mL) and MeOH (1 mL) and to this reaction mixture, 1 N LiOH (0.095 g, 0.0022 mol) was added and stirred at room temperature for 2-3 h. After completion of the reaction, the solvent was evaporated and the residue obtained was dissolved in water and acidified with 1 N HCl to obtain the title compound, which was filtered and dried.
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[C:7]([CH2:28][O:29][CH3:30])=[N:8][N:9]3[C:14]([C:15]4[C:20]([O:21][CH3:22])=[CH:19][C:18]([CH2:23][O:24][CH3:25])=[CH:17][C:16]=4[O:26][CH3:27])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:3][CH2:2]1.[O:31]1[CH2:36][CH2:35][CH:34]([CH:37]=O)[CH2:33][CH2:32]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)(=O)C.O>[CH:1]1([CH2:4][N:5]([C:6]2[C:7]([CH2:28][O:29][CH3:30])=[N:8][N:9]3[C:14]([C:15]4[C:16]([O:26][CH3:27])=[CH:17][C:18]([CH2:23][O:24][CH3:25])=[CH:19][C:20]=4[O:21][CH3:22])=[CH:13][CH:12]=[CH:11][C:10]=23)[CH2:37][CH:34]2[CH2:35][CH2:36][O:31][CH2:32][CH2:33]2)[CH2:3][CH2:2]1
Reactant: COCc1cc(OC)c(-c2cccc3c(NCC4CC4)c(COC)nn23)c(OC)c1
Reactant: O=CC1CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COCc1cc(OC)c(-c2cccc3c(N(CC4CCOCC4)CC4CC4)c(COC)nn23)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.6 %

Procedure:
To a solution of N-cyclopropylmethyl-N-[7-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-2-(methoxymethyl)pyrazolo[1,5-a]pyridin-3-yl]amine (80 mg) dissolved in tetrahydrofuran (2 mL) was added tetrahydropyran-4-carbaldehyde (44 mg) and sodium triacetoxyborohydride (82 mg), and the reaction mixture was stirred for 30 minutes at room temperature. Water and saturated aqueous sodium bicarbonate were added to the reaction mixture, extraction was performed with ethyl acetate and the organic extract was washed with brine. The organic extract was dried over anhydrous magnesium sulfate and filtered, the solvent was evaporated under reduced pressure, the residue was purified by silica gel column chromatography and the title compound (63 mg) was obtained as a yellow oil from the n-hexane:ethyl acetate (1:2) fraction.