Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[O:37][CH:36]=[CH:35][C:13]=3[N:14]=[C:15]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH3:34])=[N:23][N:24]4C(OC(C)(C)C)=O)=[CH:20][CH:19]=3)[N:16]=2)[CH2:7]1)(=O)C.Cl.NCC1CCN(C(OC(C)(C)C)=O)C1.C(Cl)(=O)C.ClC1N=C(Cl)C2OC=CC=2N=1.Cl>CO>[NH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][N:8]([C:11]2[C:12]3[O:37][CH:36]=[CH:35][C:13]=3[N:14]=[C:15]([NH:17][C:18]3[CH:26]=[C:25]4[C:21]([C:22]([CH3:34])=[N:23][NH:24]4)=[CH:20][CH:19]=3)[N:16]=2)[CH2:7]1
Reactant: CC(=O)NCC1CCN(c2nc(Nc3ccc4c(C)nn(C(=O)OC(C)(C)C)c4c3)nc3ccoc23)C1
Agent: CC(C)(C)OC(=O)N1CCC(CN)C1
Agent: Cl
Agent: Clc1nc(Cl)c2occc2n1
Solvent: CO
Solvent: CC(=O)Cl
Product: Cc1n[nH]c2cc(Nc3nc(N4CCC(CN)C4)c4occc4n3)ccc12
Temperature: 90 °C
Reaction time: 32 h
Yield: 61 %

Procedure:
To a solution of tert-butyl 6-(4-(3-(acetamidomethyl)pyrrolidin-1-yl)furo[3,2-d]pyrimidin-2-ylamino)-3-methyl-1H-indazole-1-carboxylate (0.57 g, 1.1 mmol, prepared using E.1 from tert-butyl 3-(aminomethyl)pyrrolidine-1-carboxylate hydrochloride [Astatech] with acetyl chloride, C, A with 2,4-dichlorofuro[3,2-d]pyrimidine [ArkPharm] and B with Example #3, Step B) in MeOH (12 mL) was added concentrated HCl (12 mL). The mixture was stirred for about 32 h at about 90° C. The mixture was cooled to rt, and a white precipitate formed that was collected by vacuum filtration and washed with water. The solid was dissolved in hot aqueous 1 M HCl and the suspension was filtered while hot. To the filtrate was added aqueous NH4OH to reach a pH˜9, and the resulting precipitate was collected to give 4-(3-(aminomethyl)pyrrolidin-1-yl)-N-(3-methyl-1H-indazol-6-yl)furo[3,2-d]pyrimidin-2-amine (0.27 g, 61%): LC/MS (Table 2, Method h) Rt=1.61 min; MS m/z: 364 (M+H)+. Syk IC50=A
Reaction SMILES: [CH3:1][C:2]([OH:4])=[O:3].[F:5][C:6]1C=[CH:12][C:11]([CH:14]2[C:27]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[C:18]=3[NH:17][S:16](=[O:29])(=[O:28])[N:15]2[CH3:30])=[CH:10][C:7]=1C=O.[C-:31]#N.[Na+]>CO.O=[Mn]=O>[CH3:31][O:3][C:2](=[O:4])[C:1]1[CH:12]=[C:11]([CH:14]2[C:27]3[CH:26]=[CH:25][C:24]4[C:19](=[N:20][CH:21]=[CH:22][CH:23]=4)[C:18]=3[NH:17][S:16](=[O:28])(=[O:29])[N:15]2[CH3:30])[CH:10]=[CH:7][C:6]=1[F:5]
Reactant: [C-]#N
Reactant: CN1C(c2ccc(F)c(C=O)c2)c2ccc3cccnc3c2NS1(=O)=O
Reactant: CC(=O)O
Agent: O=[Mn]=O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(C2c3ccc4cccnc4c3NS(=O)(=O)N2C)ccc1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 95.8 %

Procedure:
AcOH (23.1 μl, 0.4 mmol) was added dropwise to a solution of 2-fluoro-5-(2-methyl-3,3-dioxo-1,2,3,4-tetrahydro-3λ*6*-thia-2,4,5-triaza-phenanthren-1-yl)-benzaldehyde 422 (50 mg, 0.13 mmol), MnO2 (176 mg, 2.02 mmol), and sodium cyanide (66 mg, 1.35 mmol) in MeOH (10 ml). The mixture was stirred at room temperature for 3 h. The mixture was filtered and the filtrate was diluted with water (10 ml). The mixture was extracted with EtOAc (15 ml, ×2) and DCM (15 ml). The combined organic phases were concentrated in vacuo to give the title compound (50 mg, 93%) which was used in the next step without further purification.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13](B(O)O)=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:21]1[S:25][C:24]([CH3:26])=[N:23][C:22]=1[CH3:27].C([O-])([O-])=O.[Na+].[Na+].COCCOC>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.CCO.O>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:21]3[S:25][C:24]([CH3:26])=[N:23][C:22]=3[CH3:27])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(B(O)O)c(C)nc12
Reactant: Cc1nc(C)c(Br)s1
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: CCO
Solvent: O
Solvent: COCCOC
Product: CCC(CC)c1cc(C)nn2c(-c3sc(C)nc3C)c(C)nc12
Yield: 58.4 %

Procedure:
To a microwave pressure tube is added 0.340 g (1.30 mmol) of 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine-3-yl boronic acid, 0.100 g (0.521 mmol) of 5-bromo-2,4-dimethylthiazole, 0.361 g (0.313 mmol) of Pd(PPh3)4, 0.650 mL (1.30 mmol) of 2 M aqueous Na2CO3, and 2 mL 7:3:2 DME:H2O:EtOH, and the mixture is heated at 160° C. for 40 min. Reaction is checked by MS which indicates product present. The reaction mixture is partitioned between 75 mL of ethyl acetate and 75 mL of water. The layers are separated and the aqueous is extracted 3×50 mL of ethyl acetate, dried (MgSO4), and concentrated under vacuum. The crude mixture is purified by chromatography using hexanes/ethyl acetate as a solvent system. The product containing fractions are combined to obtain 0.100 g of the product, 58% yield. MS, ES+=329.2 (M+1); 1H-NMR (DMSO-d6)=6.974 (s, 1H); 3.085-3.052 (m, 1H); 2.665 (s, 3H); 2.438 (s, 3H); 2.290 (s, 3H); 2.147 (s, 3H); 1.849-1.727 (m, 4H); 0.776-0.738 (m, 6H) ppm.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]([OH:21])=O)=[CH:15]2)(=[O:8])=[O:7].[NH2:22][C:23]1[S:24][CH:25]=[CH:26][N:27]=1.C(N(C(C)C)C(C)C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(OCC)(=O)C.CN(C)C=O>[S:24]1[CH:25]=[CH:26][N:27]=[C:23]1[NH:22][C:19]([C:16]1[NH:17][C:18]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][C:10]=2[NH:9][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:7])=[O:8])=[O:21]
Reactant: O=C(O)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Reactant: Nc1nccs1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1nccs1)c1cc2cccc(NS(=O)(=O)c3cccs3)c2[nH]1
Temperature: 60 °C
Reaction time: 18 h
Yield: 78.5 %

Procedure:
A mixture of 7-[(2-thienylsulfonyl)amino]-1H-indole-2-carboxylic acid (200 mg), 2-aminothiazole (75 mg), ethyldiisopropylamine (0.16 mL), 0-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (354 mg) and N,N-dimethylformamide (8 mL) was stirred at 60° C. for 18 hr. The reaction mixture was diluted with ethyl acetate, washed with aqueous citric acid solution, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate), and the obtained crystals were washed with ethyl acetate-hexane to give the title compound (197 mg, yield 78%) as pale-yellow crystals. melting point 300-302° C. (decomposition).
Reaction SMILES: C(O)(=[S:3])C.[C:5]([C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][CH:8]=1)#[N:6].C(O)(=O)C>C(O)(C)C.O>[C:11]([C:10]1[CH:15]=[CH:16][C:7]([C:5](=[S:3])[NH2:6])=[CH:8][CH:9]=1)([O:13][CH3:14])=[O:12]
Reactant: CC(O)=S
Reactant: COC(=O)c1ccc(C#N)cc1
Solvent: O
Solvent: CC(C)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C(N)=S)cc1
Yield: 77.7 %

Procedure:
130 g (1.7 moles) of thioacetic acid, 50 g (0.3 mole) of methyl 4-cyanobenzoate and 12 ml of glacial acetic acid were stirred for 2 hours at 80° C. The mixture was allowed to cool, 200 ml of 1:1 isopropanol/water was added, the mixture was stirred for a short time and the crystals formed were filtered off under suction. 45.5 g of 4-carbomethoxybenzothiamide of melting point 188°-190° C. were obtained in this manner.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:18]=[CH:17][C:10]([CH2:11][N:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:9]([Cl:19])[CH:8]=1.[O:20]=[C:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1>C1COCC1>[Cl:19][C:9]1[CH:8]=[C:7]([C:21]2([OH:20])[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH:18]=[CH:17][C:10]=1[CH2:11][N:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CC(C(=O)O)C1
Reactant: Clc1cc(Br)ccc1CN1CCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(Cl)c2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A 2.5 M solution of n-BuLi in hexanes (60 ml, 150 mmol) was added over 15 min to a solution of intermediate 20, 1-(4-bromo-2-chlorobenzyl)pyrrolidine (41.2 g, 150 mmol) in THF (350 ml) under a flow of nitrogen at −78° C. The reaction mixture was stirred at −78° C. for 30 min. Then a −78° C. chilled solution of 3-oxocyclobutanecarboxylic acid (8.6 g, 75 mmol) in THF (100 ml) was added drop wise for 10 min at −78° C. The mixture was warmed to RT slowly and left stirring for 18 hrs and the resulting solution was used as an intermediate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([OH:22])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([O:41][C:42](=[O:67])[CH2:43][CH2:44][CH2:45][O:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]Br)[C:48]=1[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH3:40]>CC(C)=O.CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15](=[O:32])[C:16]2[CH:21]=[C:20]([O:22][CH2:58][CH2:57][CH2:56][CH2:55][CH2:54][CH2:53][C:49]3[CH:50]=[CH:51][CH:52]=[C:47]([O:46][CH2:45][CH2:44][CH2:43][C:42]([O:41][CH2:39][CH3:40])=[O:67])[C:48]=3[CH2:60][CH2:61][C:62]([O:64][CH2:65][CH3:66])=[O:63])[CH:19]=[C:18]([C:23]3[CH:31]=[CH:30][C:26]4[O:27][CH2:28][O:29][C:25]=4[CH:24]=3)[CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CC(C)(C)OC(=O)N1CCCN(C(=O)c2cc(O)cc(-c3ccc4c(c3)OCO4)c2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(C(=O)N3CCCN(C(=O)OC(C)(C)C)CC3)cc(-c3ccc4c(c3)OCO4)c2)c1CCC(=O)OCC
Temperature: 75 °C
Reaction time: 48 h

Procedure:
To a solution of 4-(3-benzo[1,3]dioxol-5-yl-5-hydroxy-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (400 mg) in a mixture of acetone and DMF (2:1, 3 mL) were added potassium carbonate (10 eq.) and 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.1 eq). The resulting mixture was stirred at 75° C. for 2 days. Then the insoluble material was filtered out and the filtrate was diluted with ethyl acetate and washed with water and brine. The organic extract was dried over anhydrous sodium sulfate, concentrated and purified on a silica gel column using ethyl acetate and hexanes to yield 4-(3-benzo[1,3]dioxol-5-yl-5-{6-[2-(2-ethoxycarbonyl-ethyl)-3-(3-ethoxycarbonyl-propoxy)-phenyl]-hexyloxy}-benzoyl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (556 mg). The total amount of material from the previous step was dissolved in EtOH (3 mL), followed by addition of 10 M NaOH solution (10 eq.). The resulting reaction mixture was stirred at room temperature for 3 h. Then it was neutralized with 3 N HCl and extracted into ethyl acetate. The organic extract was washed with water and brine and dried over anhydrous sodium sulfate. The crude material was concentrated under reduced pressure and redissolved in a mixture of TFA and dichloromethane (1:1, 2 mL) and stirred at room temperature for 2 h. The solvents were removed under reduced pressure and the crude material was purified on reverse-phase HPLC to yield the title compound.
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([SH:16])=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].C(=O)([O-])[O-].[K+].[K+].Cl[C:26]1[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=1.CN(C)C=O>C(OCC)(=O)C>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([S:16][C:26]4[C:31]([N+:32]([O-:34])=[O:33])=[CH:30][CH:29]=[CH:28][N:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(S)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(Sc4ncccc4[N+](=O)[O-])cc3CC[C@@H]12
Yield: 65.2 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-mercapto-10b-methyl-1,2,3,4,4a,-5,6,10b-octahydrobenzo[f]quinolin-3-one (100 mg, 0.38 mmol), potassium carbonate (158 mg, 1.14 mmol), 2-chloro-3-nitropyridine (73 mg, 0.46 mmol) and 1.5 mL of anhydrous dimethylformamide, fitted with a reflux condenser, and the stirred mixture was heated at 60°, under nitrogen, for 18 h. The mixture was cooled, diluted with ethyl acetate (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (90% ethyl acetate/hexanes eluent) to give 95 mg (65%) of the title compound as an amorphous foam. mp 80°-84°. FDMS: m/e=383. α[D]589 =+73.78 (c=0.49, chloroform).
Reaction SMILES: [Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][CH:7]([C:17](=O)[CH2:18][CH2:19][CH2:20][CH3:21])[C:8](=NOC)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:25])[CH:3]=1.Cl.[Cl:27][C:28]1[CH:33]=[CH:32][C:31]([N+:34]([O-:36])=[O:35])=[CH:30][C:29]=1[NH:37][NH2:38]>>[Br:1][C:2]1[CH:24]=[CH:23][C:5]([CH2:6][C:7]2[C:17]([CH2:18][CH2:19][CH2:20][CH3:21])=[N:38][N:37]([C:29]3[CH:30]=[C:31]([N+:34]([O-:36])=[O:35])[CH:32]=[CH:33][C:28]=3[Cl:27])[C:8]=2[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:4]([F:25])[CH:3]=1
Reactant: CCCCC(=O)C(Cc1ccc(Br)cc1F)C(=NOC)C(=O)OCC
Reactant: NNc1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2Cl)c(C(=O)OCC)c1Cc1ccc(Br)cc1F
Yield: 54 %

Procedure:
By the procedure of Example 1, Step G, ethyl 3-(4-bromo-2-fluorobenzyl)-2-methoxyimino-4-oxooctanoate (from Step A) was reacted with 2-chloro-5-nitrophenylhydrazine hydrochloride. The crude product was flash chromatographed twice on silica gel (first column: gradient elution with 0.5-2% MeOH in CH2Cl2 ; second column: gradient elution with 5-20% EtOAc in hexane) to give a 54% yield of the title compound as an orange oil; homogeneous by TLC in 3:1 hexane-EtOAc; mass spectrum (FAB) m/e 538, 540 (M+1)+. 400 MHz 1H NMR (CDCl3) δ0.86 (t, J=7.3 Hz, 3H), 1.02 (t, J=7.1 Hz, 3H), 1.32 (m, 2H), 1.55 (m, 2H, partially obscured by H2O peak), 2.57 (t, J=7.8 Hz, 2H), 4.10 (s, 2H, superimposed on q, J=7.2 Hz, 2H), 6.82 (dd, J≈8, 8 Hz, 1H), 7.16 (d, J≈8 Hz, 1H), 7.23 (m, 1H, partially obscured by CHCl3 peak), 7.65 (d, J=8.8 Hz, 1H), 8.25 (dd, J=8.8, 2.6 Hz, 1H), 8.33 (d, J=2.6 Hz, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16](I)[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1.[CH2:23]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28](=[O:35])[C:27]1=[O:36])[C:24]#[CH:25]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:14]2[CH:15]=[C:16]([C:25]#[C:24][CH2:23][N:26]3[C:34]4[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=4)[C:28](=[O:35])[C:27]3=[O:36])[S:17][C:13]=2[N:12]2[C:19]([CH3:22])=[N:20][N:21]=[C:11]2[CH2:10][N:9]=1
Reactant: Cc1nnc2n1-c1sc(I)cc1C(c1ccccc1Cl)=NC2
Reactant: C#CCN1C(=O)C(=O)c2ccccc21
Solvent: CCOC(C)=O
Product: Cc1nnc2n1-c1sc(C#CCN3C(=O)C(=O)c4ccccc43)cc1C(c1ccccc1Cl)=NC2

Procedure:
This compound was prepared as described in Example 37 by coupling of 4-(2-chlorophenyl)-2-iodo-9-methyl 6H-thieno[ 3,2-f][1,2,4]triazolo[4,3-a] [1,4]diazepine with 1-(2-propynyl)-1H-indole-2,3-dione [ref. A. Lindquist et al., Acta Pharm. Suecica 9, 99 (1972)]. Chromatographic isolation and crystallization from methanol/ethyl acetate gave orange crystals with m.p. 185°-190° C. with foaming at 130°-140° C. These crystals contained according to analytical and spectral data molar amounts of ethyl acetate.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[I:6][C:7]1[CH:8]=[N:9][N:10]([CH:12]2[CH2:17][CH2:16][CH:15]([NH:18][CH2:19][CH2:20][OH:21])[CH2:14][CH2:13]2)[CH:11]=1.CCN(C(C)C)C(C)C.Cl>C1COCC1>[Cl:1][CH2:2][C:3]([N:18]([CH2:19][CH2:20][OH:21])[CH:15]1[CH2:14][CH2:13][CH:12]([N:10]2[CH:11]=[C:7]([I:6])[CH:8]=[N:9]2)[CH2:17][CH2:16]1)=[O:4]
Reactant: OCCNC1CCC(n2cc(I)cn2)CC1
Reactant: O=C(Cl)CCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(CCl)N(CCO)C1CCC(n2cc(I)cn2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Chloro-acetyl chloride (0.25 mL; 3.14 mmol; 1.1 eq.) was added dropwise over 2 min to a solution of 2-[4-(4-Iodo-pyrazol-1-yl)-cyclohexylamino]-ethanol (intermediate 25; 1.0 g; 2.89 mmol; 1.0 eq.) and DIEA (2.00 ml; 11.45 mmol; 3.96 eq.) in THF (80.00 mL) at −30° C. The reaction solution was allowed to warm slowly to RT and stirred for 16 h. It was then poured into a 1 N HCl solution and extracted with DCM. Combined organic phases were washed with saturated NaHCO3 solution, dried over magnesium sulfate, filtrated and concentrated to give 2-Chloro-N-(2-hydroxy-ethyl)-N-[4-(4-iodo-pyrazol-1-yl)-cyclohexyl]-acetamide as a brown oil. This oil was redissolved in THF (30 mL; 370 mmol; 128 eq.) and sodium tert-butoxide (2M solution in THF; 30 mL; 60.0 mmol; 21 eq.) was added in one portion. The reaction solution was heated at 40° C. for 1 h then cooled to RT and poured into 1 N HCl solution. It was extracted with DCM (twice). Combined organic phases were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was triturated sequentially with EtOAc and Et2O, filtered and dried to give the title compound as a yellow solid (275 mg; 21%). 1H NMR (300 MHz, DMSO) δ 7.98 (s, 1H), 7.50 (s, 1H), 4.40-4.25 (m, 1H), 4.25-4.10 (m, 1H), 4.03 (s, 2H), 3.87-3.75 (m, 2H), 3.32-3.23 (m, 2H), 2.14-1.99 (m, 2H), 1.93-1.60 (m, 6H). MS (ESI+): 376.2.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[O:8])[CH2:3]1.[C:17]1(=O)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1.C([BH3-])#N.[Na+]>CO>[CH2:10]([O:9][C:7]([N:4]1[CH2:5][CH2:6][C@H:2]([NH:1][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:3]1)=[O:8])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: N[C@H]1CCN(C(=O)OCc2ccccc2)C1
Reactant: O=C1CCCCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: O=C(OCc1ccccc1)N1CC[C@H](NC2CCCCC2)C1
Reaction time: 3 h
Yield: 73 %

Procedure:
To a stirred solution of (3S)-3-amino-pyrrolidine-1-carboxylic acid, benzyl ester (4.40 g, 20 mmol) in methanol (120 mL) was added cyclohexanone (2.75 g, 28 mmol) followed by sodium cyanoborohydride (1.50 g, 24 mmol) at room temprerature. After 3 h, the reaction mixture was concentrated, diluted with dichloromethane (200 mL), washed with aqueous sodium bicarbonate (100 mL), 1 N sodium hydroxide (50 mL), brine (50 mL) and dried (Na2SO4). The crude was purified by flash chromatography using 5% methanol in dichloromethane to give (3S)-3-cyclohexylamino-pyrrolidine-1-carboxylic acid benzyl ester in 73% yield. 1H NMR (300 MHz, CDCl3): in δ 7.36–7.26 (m, 5H), 5.11 (s, 2H), 3.65–3.35 (m, 4H), 3.1–2.95 (m, 1H), 2.5–2.38 (m, 1H), 2.11–1.98 (m, 1H), 1.92–1.54 (m, 5H), 1.31–0.95 (m, 6H); 13C NMR (300 MHz, CDCl3): in δ 154.9, 137.1, 128.4, 127.8, 66.7, 55.0, 54.6, 53.8, 52.6, 44.7, 44.3, 34.1, 32.8, 32.0, 26.1, 25.1; MS (ESI+), 303 (M+H); Rf=1.16.
Reaction SMILES: Cl.C([O:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[N:12][C:13]2[C:18]([C:19]=1[NH:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])=[CH:17][CH:16]=[C:15]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[CH:14]=2)=O)(=O)C.[OH-].[Na+]>CO.O>[CH2:27]([O:26][C:15]1[CH:16]=[CH:17][C:18]2[C:19]3[N:20]([CH2:21][C:22]([CH3:24])([OH:25])[CH3:23])[C:7]([CH2:6][OH:5])=[N:9][C:10]=3[CH:11]=[N:12][C:13]=2[CH:14]=1)[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(=O)OCC(=O)Nc1cnc2cc(OCc3ccccc3)ccc2c1NCC(C)(C)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(O)Cn1c(CO)nc2cnc3cc(OCc4ccccc4)ccc3c21
Temperature: 55 °C
Yield: 97.8 %

Procedure:
A mixture of 2-({7-benzyloxy-4-[(2-hydroxy-2-methylpropyl)amino]quinolin-3-yl}amino)-2-oxoethyl acetate hydrochloride (54.0 g, 0.114 mol) in methanol (270 mL) was heated to 55° C., at which point a solution was obtained. A solution of sodium hydroxide (9.2 g, 0.23 mol) in water (90 mL) was then added over a period of five minutes while heating the reaction mixture at reflux. Following the addition, the addition funnel was rinsed with water (10 mL), and the reaction mixture was heated at reflux for one hour. The reaction mixture was then cooled to ˜0° C., and the solid product was isolated by filtration, washed with methanol, deionized water, and a small volume of acetone, and dried under vacuum at 50° C. to provide 42.1 g of 1-[7-benzyloxy-2-(hydroxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as an off-white solid.
Reaction SMILES: [C:1]([C@@H:4]([N:9]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH:29]=[CH2:30])=[CH:23][CH:22]=1)[S:10]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)(=[O:12])=[O:11])[CH2:5][CH:6]([CH3:8])[CH3:7])(=[O:3])[NH2:2].[NH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C1(C)C=CC=CC=1>[Cl:19][C:16]1[CH:17]=[CH:18][C:13]([S:10]([N:9]([C@H:4]([CH2:5][CH:6]([CH3:8])[CH3:7])[C:1]([NH2:2])=[O:3])[CH2:20][C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][CH2:30][N:32]3[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]3)=[CH:23][CH:22]=2)(=[O:12])=[O:11])=[CH:14][CH:15]=1
Reactant: C=CC(=O)Nc1ccc(CN([C@@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Reactant: C1CCNCC1
Solvent: Cc1ccccc1
Product: CC(C)C[C@H](C(N)=O)N(Cc1ccc(NC(=O)CCN2CCCCC2)cc1)S(=O)(=O)c1ccc(Cl)cc1
Yield: 86.9 %

Procedure:
To a solution of N-(4-{[N-((1S)-1-carbamoyl-3-methyl-butyl)-N-(4-chlorobenzenesulfonyl)amino]-methyl}-phenyl)-acrylamide (0.10 g, 0.22 mmol) in toluene (5 mL) was added piperidine (20 mg, 0.24 mmol). The mixture was heated at a gentle reflux for 1 h and then the solvent was removed in vacuo. Purification by flash chromatography (SiO2, 10% MeOH/CH2Cl2) afforded the title compound (105 mg) in 86% yield. MS (ESI), (M+H)+449.16, 1H NMR (CDCl3, 400 MHz) δ 7.69 (d, 2H, J=8.0), 7.63 (d, 2H, J=8.0), 7.38 (d, 2H, J=8.0), 7.23 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.75 (d, 1H, Jab=16), 4.38 (d, 1H, Jab=16), 3.25 (t, 1H, J=6.0), 2.65 (t, 2H, J=6.0), 2.56-2.44 (m, 6H), 1.95 (m, 1H), 1.68-1.45 (m, 8H), 0.98 (d, 3H, J=7.0), 0.94 (d, 3H, J=7.0).
Reaction SMILES: [C:1]([C:5]1[C:6]([NH2:14])=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:3])[CH3:2].[C:15](Cl)(=[O:24])[CH:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([C:5]1[C:6]([NH:14][C:15](=[O:24])/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:7][N:8]2[CH:13]=[CH:12][CH:11]=[N:10][C:9]=12)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1c(N)nn2cccnc12
Reactant: O=C(Cl)C=Cc1ccccc1
Product: CC(C)(C)c1c(NC(=O)/C=C/c2ccccc2)nn2cccnc12

Procedure:
The product from Example 105B and cinnamoyl chloride were processed using the method analogous to that described in Example 105C to afford the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.47 (s, 9H), 6.84 (d, J=14.9 Hz, 1H), 7.02 (dd, J=7.1, 4.1 Hz, 1H), 7.38-7.48 (m, 3H), 7.57-7.64 (m, 3H), 8.51 (dd, J=4.1, 1.7 Hz, 1H), 8.95 (dd, J=7.0, 1.9 Hz, 1H), 9.98 (s, 1H); MS (DCI) m/z 321 (M+H)+; EA calculated for C19H20N4O: C, 71.23; H, 6.29; N, 17.49. Found: C, 70.95; H, 6.06; N, 17.36.
Reaction SMILES: [N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[O:11][CH2:12][CH2:13][CH3:14])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([N:20]([CH2:23]C)CC)C.BrC1[S:30][C:29]([NH2:31])=[N:28][N:27]=1>C1COCC1>[N:1]1([CH2:7][C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[O:11][CH2:12][CH2:13][CH2:14][NH:31][C:29]2[S:30][C:23]([NH2:20])=[N:27][N:28]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: Nc1nnc(Br)s1
Reactant: CCCOc1cccc(CN2CCCCC2)c1
Solvent: C1CCOC1
Product: Nc1nnc(NCCCOc2cccc(CN3CCCCC3)c2)s1

Procedure:
0.57 g (2.3 mmol) of 1-Amino-[3-[3-(1-piperidinomethyl)phenoxy]-propane, 0.35 ml of triethylamine and 0.42 g (2,3 mmol) of 5-bromo-1,3,4-thiadiazole-2-amine are heated under reflux in 20 ml of THF for 3 hours. Solid triethylammonium bromide is filtered off, the filtrate is concentrated by evaporation and the residue is purified by preparative layer chromatography.