Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Clc1ccncn1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1nc(C#Cc2cccc(Cl)c2)cn1-c1ccncn1

Procedure:
The title compound, MS: m/e=294.1/296.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 4-chloro-pyrimidine.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=1.[CH3:14][C:15]([C:18]1[CH:19]=[C:20]([S:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[S:35][CH2:36][C:37](N(C)CCC2C=CC=CN=2)=[O:38])[CH:21]=[C:22]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH:23]=1)([CH3:17])[CH3:16]>>[CH3:27][C:24]([C:22]1[CH:21]=[C:20]([S:28][C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][C@H:30]2[S:35][CH2:36][C:37]([NH:1][CH2:2][CH2:3][NH:4][C:5]2[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][N:6]=2)=[O:38])[CH:19]=[C:18]([C:15]([CH3:14])([CH3:16])[CH3:17])[CH:23]=1)([CH3:25])[CH3:26]
Reactant: NCCNc1ccc([N+](=O)[O-])cn1
Reactant: CN(CCc1ccccn1)C(=O)CS[C@@H]1CCCC[C@H]1Sc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Product: CC(C)(C)c1cc(S[C@@H]2CCCC[C@H]2SCC(=O)NCCNc2ccc([N+](=O)[O-])cn2)cc(C(C)(C)C)c1

Procedure:
Substituting 2-(2-aminoethylamino)-5-nitropyridine for the 2-(2-methylaminoethyl)pyridine of Example 16, and following the procedure described therein, gives trans-2-[[2-[[3,5-bis(1,1-dimethylethyl)phenyl]thio]cyclohexyl]thio]-N-[[(5-nitropyridin-2-yl)amino]ethyl]acetamide.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:48])([CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[N:46]=[CH:45][CH:44]=[N:43]3)=[CH:38][CH:37]=2)([OH:35])[C:31]([F:34])([F:33])[F:32])[N:8](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:9]=1>CO>[CH3:2][C:3]([CH3:48])([CH3:47])[CH2:4][C:5]1[N:6]=[C:7]([CH2:29][C:30]([C:36]2[CH:41]=[CH:40][C:39]([N:42]3[N:46]=[CH:45][CH:44]=[N:43]3)=[CH:38][CH:37]=2)([OH:35])[C:31]([F:32])([F:33])[F:34])[NH:8][CH:9]=1
Reactant: CC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)(c2ccc(-n3nccn3)cc2)C(F)(F)F)n1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(CC(O)(c2ccc(-n3nccn3)cc2)C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 0.25 mmol) was added to an ambient temperature solution of 3-[4-(2,2-dimethylpropyl)-1-trityl-1H-imidazol-2-yl]-1,1,1-trifluoro-2-[4-(2H-1,2,3-triazol-2-yl)phenyl]propan-2-ol (250 mg, 0.42 mmol) in methanol (1 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was partitioned between diethyl ether and 1 N hydrochloric acid. The aqueous phase was washed with diethyl ether, basified with 2.5 N aqueous sodium hydroxide and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (sodium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found 394
Reaction SMILES: [O:1]([C:8]1[S:9][C:10]([CH2:13][OH:14])=[CH:11][N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:15][C:16]1([CH3:28])[C@H:18]([CH:19]=[C:20]2[CH2:24][CH2:23][CH2:22][CH2:21]2)[C@H:17]1[C:25](Cl)=[O:26].N1C=CC=CC=1.Cl>C1C=CC=CC=1>[CH3:15][C:16]1([CH3:28])[C@H:18]([CH:19]=[C:20]2[CH2:21][CH2:22][CH2:23][CH2:24]2)[C@H:17]1[C:25]([O:14][CH2:13][C:10]1[S:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:12][CH:11]=1)=[O:26]
Reactant: OCc1cnc(Oc2ccccc2)s1
Reactant: CC1(C)[C@H](C=C2CCCC2)[C@H]1C(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C=C2CCCC2)[C@H]1C(=O)OCc1cnc(Oc2ccccc2)s1
Temperature: 20 °C
Reaction time: 20 h
Yield: 52.7 %

Procedure:
2.74 g of (2-phenoxy-5-thiazolyl)-methanol were added to a solution of 2 g of (1R,3R) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylic acid chloride [described in French Pat. No. 74405 published under No. 1,505,423] in 30 ml of benzene and 0.81 ml of pyridine was added dropwise thereto. The mixture was stirred at 20° C. for 20 hours and was poured into dilute aqueous hydrochloric acid. The decanted aqueous phase was extracted with ether and the combined organic phases were dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and was eluted with an 8-2 cyclohexane-ethyl acetate mixture to obtain 1.9 g of (2-phenoxy-5-thiazolyl)-methyl (1R,3R) 2,2-dimethyl-3-(cyclopentylidenemethyl)-cyclopropane-1-carboxylate meltingat 67° C.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([O:8][CH3:9])[CH:7]=1.[F:11][C:12]([F:23])([F:22])[C:13]1[CH:14]=[CH:15][C:16]([CH2:19][CH2:20][NH2:21])=[N:17][CH:18]=1>>[Cl:10][C:5]1[CH:4]=[CH:3][C:2]([NH:21][CH2:20][CH2:19][C:16]2[CH:15]=[CH:14][C:13]([C:12]([F:23])([F:11])[F:22])=[CH:18][N:17]=2)=[CH:7][C:6]=1[O:8][CH3:9]
Reactant: NCCc1ccc(C(F)(F)F)cn1
Reactant: COc1cc(Br)ccc1Cl
Product: COc1cc(NCCc2ccc(C(F)(F)F)cn2)ccc1Cl

Procedure:
In analogy to the procedure described for the synthesis example 71 (step 1), the title compound (4-chloro-3-methoxy-phenyl)-[2-(5-trifluoromethyl-pyridin-2-yl)-ethyl]-amine (MS m/e: 331.1 [M+H]+) was prepared from 5-bromo-2-chloro-anisol instead of 6-bromo-2,3-dihydro-benzofuran and 2-(5-trifluoromethyl-pyridin-2-yl)-ethylamine instead of 2-(6-trifluoromethyl-pyridin-3-yl)-ethylamine.
Reaction SMILES: [CH2:1]([N:3](CC)[CH2:4]C)C.[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH:21]=O)=[N:14]2.Cl.CNC.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[ClH:8].[Cl:8][C:9]1[CH:18]=[C:17]([Cl:19])[C:16]([OH:20])=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([CH2:21][N:3]([CH3:4])[CH3:1])=[N:14]2
Reactant: CCN(CC)CC
Reactant: O=Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CNC
Agent: Cl
Solvent: ClCCl
Solvent: ClCCCl
Product: CN(C)Cc1ccc2c(Cl)cc(Cl)c(O)c2n1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
Triethylamine (0.55 mL) was added dropwise to a stirred solution of 5,7-dichloro-8-hydroxyquinoline-2-carboxaldehyde 17 (1.0 g, 4.13 mmol) and dimethylamine hydrochloride (365 mg, 4.48 mmol) in 1,2-dichloroethane (50 mL). After 5 minutes, sodium triacetoxyborohydride (1.2 g, 5.66 mmol) was added portionwise over 5 minutes. The mixture was then allowed to stir at RT overnight. Dichloromethane (100 mL) was added, the mixture washed with saturated sodium bicarbonate (50 mL×3), dried (Na2SO4), and concentrated. The resulting residue was extracted with diethyl ether (50 mL×4), the ethereal extracts combined and concentrated. Concentrated hydrochloric acid (5 mL) was then added and the mixture concentrated in vacuo. The process was repeated twice. The residue, after washing with dichloromethane, gave 5,7-dichloro-2-dimethylaminomethyl-quinolin-8-ol hydrochloride (PBT 1033) as a pale straw-coloured solid (0.96 g, 73%). 1H NMR (DMSO-d6, 400 MHz): δ 10.80 (s, 1H), 10.40 (br, 1H), 8.60 (d, J=8.6, 1 H), 7.92 (s, 1H), 7.78 (d, J=8.6, 1 H), 4.83 (d, J=5.3, 2 H), 2.94 (s, 3H), 2.92 (s, 3H).
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([C:10]([O:12]CC)=[O:11])[N:7]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:1]([C:5]1[CH:9]=[C:8]([C:10]([OH:12])=[O:11])[N:7]([CH2:15][C:16]([N:18]([CH3:20])[CH3:19])=[O:17])[N:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cc(C(C)(C)C)nn1CC(=O)N(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1nc(C(C)(C)C)cc1C(=O)O
Temperature: 25 °C
Reaction time: 16 h
Yield: 93 %

Procedure:
To a solution of ethyl 3-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-5-carboxylate from example B17 (0.48 g, 1.7 mmol) in THF (10 mL) was added a solution of lithium hydroxide (0.21 g, 5.1 mmol) in water (5 mL) and the mixture was stirred for 16 h at RT. Solvents were removed and the residue was acidified with 3M HCl and the product was extracted with EtOAc (2×30 ml). The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated to afford 3-tert-butyl-1-(2-(dimethylamino)-2-oxoethyl)-1H-pyrazole-5-carboxylic acid (0.4, 93% yield) as a pasty mass. 1H NMR (400 MHz, DMSO-d6): δ 6.69 (s, 1H), 5.30 (s, 2H), 3.02 (s, 3H), 2.82 (s, 3H), 1.24 (m, 9H); MS (ESI) m/z: 254.0 (M+H+).
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:21][CH2:20][C:19]2[S:18][C:17]3[C:12](=[C:13]([O:22][CH:23]4[CH2:28][CH2:27][CH:26]([N:29]5[CH2:34][CH2:33][O:32][CH2:31][CH2:30]5)[CH2:25][CH2:24]4)[N:14]=[CH:15][N:16]=3)[C:11]1=2)(C(C)(C)C)(C)C.Cl>CO>[N:29]1([CH:26]2[CH2:25][CH2:24][CH:23]([O:22][C:13]3[N:14]=[CH:15][N:16]=[C:17]4[C:12]=3[C:11]3[CH:10]([CH2:9][OH:8])[CH2:21][CH2:20][C:19]=3[S:18]4)[CH2:28][CH2:27]2)[CH2:30][CH2:31][O:32][CH2:33][CH2:34]1
Reactant: CC(C)(C)[Si](C)(C)OCC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Agent: Cl
Solvent: CO
Product: OCC1CCc2sc3ncnc(OC4CCC(N5CCOCC5)CC4)c3c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a solution of 3-[[(tert-butyldimethylsilyl)oxy]methyl]-12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraene (350 mg, 0.69 mmol, 1.00 equiv) in methanol (30 mL) was added hydrochloric acid (3 M in water, 1 mL) was added at 0° C. and the resulting solution was stirred for 1 h at room temperature. The reaction was quenched with NaHCO3/brine and extracted with EtOAc ((3×80 mL). The organic layers were combined and dried over anhydrous sodium sulfate. After filtration and concentration in vacuo, the residue was purified by a silica gel column with DCM/MeOH (30:1-10:1) to provide 260 mg (96%) of (12-[[4-(morpholin-4-yl)cyclohexyl]oxy]-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(12),2(6),8,10-tetraen-3-yl)methanol as a light yellow semi-solid. MS (ES): m/z 390 [M+H]+.
Reaction SMILES: [C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:7][NH:6][CH2:5]1)#[N:2].[CH:37]1([CH2:40][C:41](O)=[O:42])[CH2:39][CH2:38]1>>[C:1]([CH2:3][C:4]1([N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[N:17][N:16]4[C:19]([C:22]5[CH:23]=[C:24]([NH:28][C:29]([NH:31][CH2:32][C:33]([F:35])([F:36])[F:34])=[O:30])[CH:25]=[CH:26][CH:27]=5)=[CH:20][N:21]=[C:15]4[CH:14]=3)[CH:10]=[N:9]2)[CH2:5][N:6]([C:41](=[O:42])[CH2:40][CH:37]2[CH2:39][CH2:38]2)[CH2:7]1)#[N:2]
Reactant: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CNC1
Reactant: O=C(O)CC1CC1
Product: N#CCC1(n2cc(-c3cnn4c(-c5cccc(NC(=O)NCC(F)(F)F)c5)cnc4c3)cn2)CN(C(=O)CC2CC2)C1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 77 starting from N-[3-(7-{1-[3-(cyanomethyl)azetidin-3-yl]-1H-pyrazol-4-yl}imidazo[1,2-b]pyridazin-3-yl)phenyl]-N′-(2,2,2-trifluoroethyl)urea and cyclopropylacetic acid. LCMS (M+H)+: m/z=578.2.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:4]=2[O:3]1.[CH:21](O)=[O:22]>N1C=CC=CC=1>[CH3:1][C:2]1([CH3:20])[N:7]=[C:6]([N:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]2=[O:14])[C:5]2[CH:15]=[C:16]([NH:19][CH:21]=[O:22])[CH:17]=[CH:18][C:4]=2[O:3]1
Reactant: CC1(C)N=C(n2ccccc2=O)c2cc(N)ccc2O1
Reactant: O=CO
Solvent: c1ccncc1
Product: CC1(C)N=C(n2ccccc2=O)c2cc(NC=O)ccc2O1

Procedure:
A solution of 1 g of 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-amino-2H-1,3-benzoxazine in 15 ml of formic acid and 1 ml of pyridine is boiled for 16 hours and evaporated. Customary work-up gives 2,2-dimethyl-4-(2-oxo-1,2-dihydro-1-pyridyl)-6-formamido-2H-1,3-benzoxazine.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)[CH:5]=[CH:4][C:3]=1[OH:17].C(=O)([O-])[O-].[K+].[K+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>CN(C=O)C>[CH2:24]([O:17][C:3]1[CH:4]=[CH:5][C:6]([CH:8]2[O:13][CH2:12][CH2:11][N:10]([CH2:14][CH2:15][CH3:16])[CH2:9]2)=[CH:7][C:2]=1[Br:1])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: BrCc1ccccc1
Reactant: CCCN1CCOC(c2ccc(O)c(Br)c2)C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCN1CCOC(c2ccc(OCc3ccccc3)c(Br)c2)C1
Temperature: 150 °C
Yield: 100 %

Procedure:
To the phenol from example 30 (117.5 mg, 0.39 mmol) in dry DMF (10 ml), under an atmosphere of nitrogen, was added potassium carbonate (75 mg, 0.54 mmol) and benzyl bromide (0.07 ml, 0.54 mmol). The reaction mixture was heated to 150° C. for 48 hours. After cooling, the reaction mixture was concentrated in vacuo and the residue partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was then re-extracted with ethyl acetate (2×20 ml). The combined organic extracts were then dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo to give the crude product as a brown oil. This was purified by column chromatography on silica eluting with dichloromethane:methanol (98:2) to give the title compound as a colourless oil (153 mg, 0.39 mmol, 100%). 1H NMR (CDCl3, 400 MHz) δ: 0.93 (t, 3H), 1.56 (q, 2H), 2.05 (t, 1H), 2.25 (t, 1H), 2.37 (t, 2H), 2.82 (d, 1H), 2.92 (d, 1H), 3.85 (t, 1H), 4.02 (d, 1H), 4.52 (d, 1H), 5.15 (s, 2H), 6.87 (d, 1H), 7.20 (d, 1H), 7.30 (d, 1H), 7.37 (t, 2H), 7.45 (d, 2H), 7.58 (s, 1H). LRMS: m/z 392 (M−H+).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]5([OH:30])[CH2:29][CH2:28]5)=[O:26])[CH2:20][CH2:19]4)[CH2:12][CH2:11]3)[C:4]=2[O:3][CH2:2]1.[H-].[Na+].[CH3:33]I>C1COCC1.O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[C:9]([N:10]3[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][C@H:18]4[CH2:23][CH2:22][C@H:21]([NH:24][C:25]([C:27]5([O:30][CH3:33])[CH2:29][CH2:28]5)=[O:26])[CH2:20][CH2:19]4)[CH2:14][CH2:15]3)[C:4]=2[O:3][CH2:2]1
Reactant: O=C(N[C@H]1CC[C@H](CCN2CCN(c3cccc4c3OCO4)CC2)CC1)C1(O)CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC1(C(=O)N[C@H]2CC[C@H](CCN3CCN(c4cccc5c4OCO5)CC3)CC2)CC1

Procedure:
To trans-1-Hydroxy-cyclopropanecarboxylic acid {4-[2-(4-benzo[1,3]dioxol-4-yl-piperazin-1-yl)-ethyl]-cyclohexyl}-amide (20 mg, 48.1 μmol, Eq: 1.00) in THF (500 μl) was added NaH (3.37 mg, 84.2 μmol, Eq: 1.75) and methyl iodide (17.1 mg, 7.52 μl, 120 μmol, Eq: 2.5). After 2 hours the reaction mixture was diluted with water (300 ul). The crude reaction mixture was concentrated in vacuo. The residue was suspended with 5 mL sat NaHCO3 and extracted with dichloromethane (2×10 mL). The organic layers were dried over MgSO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 10 g, 0% to 15% MeOH in dichloromethane) to yield the title compound as an off-white solid (12.1 mg, 58.5%), MS (ISP) m/z=430.2 [(M+H)+].
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([OH:19])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:22][CH2:23][C:24]([OH:26])=O)=[CH:5][C:4]=2[N:3]=1.ON1C2C=CC=CC=2N=N1.CN(C)CCCN=C=NCC.[S:48]1[CH2:52][CH2:51][NH:50][CH2:49]1>N1C=CC=CC=1>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][CH3:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:19])[CH3:18])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:22][CH2:23][C:24](=[O:26])[N:50]3[CH2:51][CH2:52][S:48][CH2:49]3)=[CH:5][C:4]=2[N:3]=1
Reactant: C1CSCN1
Reactant: CCc1nc2c(N)nc3cc(CCC(=O)O)ccc3c2n1CC(C)(C)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: c1ccncc1
Product: CCc1nc2c(N)nc3cc(CCC(=O)N4CCSC4)ccc3c2n1CC(C)(C)O
Reaction time: 0.25 h
Yield: 86.2 %

Procedure:
A round bottom flask, equipped with a stir bar, was charged with 3-[4-amino-2-ethyl-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-7-yl]propanoic acid (500 mg, 1.40 mmol), anhydrous pyridine (50 mL) and 1-hydroxybenzotriazole (379 mg, 2.80 mmol). After 30 minutes of stirring 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (537 mg, 2.80 mmol) was added to the reaction mixture in two portions. After 15 minutes, thiazolidine (250 mg, 2.80 mmol) was added in one portion. The pale yellow solution was stirred for 18 hours and then concentrated under reduced pressure. The resulting foam was dissolved in dichloromethane and washed with 1% aqueous sodium carbonate (2×15 mL). The combined aqueous fractions were extracted with chloroform (3×30 mL). The combined organic fractions were purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a 0-25% gradient of CMA in chloroform) followed by recrystallization from acetonitrile to provide 516 mg of 1-{4-amino-2-ethyl-7-[3-oxo-3-(1,3-thiazolidin-3-yl)propyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol as a white solid, mp 210-212° C.
Reaction SMILES: [NH2:1][C:2]([C:4]1[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]3)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=1)=[S:3].Br[CH2:34][C:35](=O)[CH2:36][CH3:37]>CCO>[CH2:36]([C:35]1[N:1]=[C:2]([C:4]2[CH:29]=[CH:28][C:7]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]3[CH:14]=[C:15]4[C:19](=[CH:20][CH:21]=3)[C@H:18]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH2:17][CH2:16]4)=[C:6]([CH2:30][CH2:31][CH3:32])[CH:5]=2)[S:3][CH:34]=1)[CH3:37]
Reactant: CCCc1cc(C(N)=S)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Reactant: CCC(=O)CBr
Solvent: CCO
Product: CCCc1cc(-c2nc(CC)cs2)ccc1OCCCOc1ccc2c(c1)CC[C@H]2CC(=O)OCC
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of ethyl ((1S)-5-{3-[4-(aminocarbonothioyl)-2-propylphenoxy]propoxy}-2,3-dihydro-1H-inden-1-yl)acetate (90 mg, 0.2 mmol) (Example 144) and 1-bromo-2-butanone (35.8 mg, 0.24 mmol) in EtOH (anhydrous, 8 mL) was heated at 70° C. for 6 h. The reaction mixture was cooled to rt, and then concentrated under reduced pressure. Purification by silica gel flash chromatography (EtOAc/hexane (v/v) 1:2) gave 42 mg (42%) of the title compound as a clear oil. LC-MS: RT=4.85 min; (M+H)+ 508.2.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[CH:5][C:4]([C:9](=[O:27])[CH2:10][C@H:11]([C:19]2[CH:26]=[CH:25][C:22]([C:23]#[N:24])=[CH:21][CH:20]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[CH3:18])=[CH:3]1.[N-:28]=[N+:29]=[N-:30].[Na+].[Cl-].[NH4+]>CN(C)C=O>[NH:28]1[C:23]([C:22]2[CH:21]=[CH:20][C:19]([C@H:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[CH3:18])[CH2:10][C:9]([C:4]3[CH:5]=[CH:6][C:7](=[O:8])[N:2]([CH3:1])[CH:3]=3)=[O:27])=[CH:26][CH:25]=2)=[N:24][N:30]=[N:29]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(C#N)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1ccccc1[C@H](CC(=O)c1ccc(=O)n(C)c1)c1ccc(-c2nnn[nH]2)cc1
Temperature: 80 °C
Reaction time: 72 h
Yield: 37.3 %

Procedure:
To a solution of (R)-4-(3-(1-methyl-6-oxo-1,6-dihydropyridin-3-yl)-3-oxo-1-o-tolyl-propyl)benzonitrile (60 mg, 168 μmol) in N,N-dimethylformamide (1 mL) was added sodium azide (54.7 mg, 842 μmol) and ammonium chloride (45.0 mg, 842 μmol). The reaction mixture was heated to 80° C. for 24 h, then another portion of sodium azide (54.7 mg, 842 μmol) and ammonium chloride (45.0 mg, 842 μmol) was added and the reaction mixture was stirred at 80° C. for another 72 h, then concentrated in vacuo. The residue was suspended in dichloro-methane/methanol 19:1, filtered, and the filtrate was purified by chromatography (SiO2, gradient dichloromethane to dichloromethane/methanol 9:1) afforded the product as a salt. This was partitioned between ethyl acetate and 1 M aq. hydrochloric acid solution. After removal of the aqueous layer, the organic layer was dried over magnesium sulfate, filtered, evaporated and precipitated with dichloromethane and heptane to produce the title compound (25 mg, 37%). White solid, MS (ESI+): m/z=: 400.2 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][C:19](=[O:22])[CH2:20][OH:21])[C:15](=[O:23])[C:14]([CH3:24])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([O:25]COC)=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4].Cl>CO>[CH2:1]([C:5]12[CH2:17][CH:16]([CH2:18][C:19](=[O:22])[CH2:20][OH:21])[C:15](=[O:23])[C:14]([CH3:24])=[C:13]1[C:12]1[C:7](=[CH:8][C:9]([OH:25])=[CH:10][CH:11]=1)[CH2:6]2)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCC12Cc3cc(OCOC)ccc3C1=C(C)C(=O)C(CC(=O)CO)C2
Agent: Cl
Solvent: CO
Product: CCCCC12Cc3cc(O)ccc3C1=C(C)C(=O)C(CC(=O)CO)C2

Procedure:
A solution of (2RS,9aSR)-9a-butyl-2-(3-hydroxy-2-oxopropyl)-7-methoxymethoxy-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one (24 mg, 0.06 mmol) in methanol (1 mL) was treated with 2N HCl (0.36 mL, 0.18 mmol) and the resulting solution was heated at reflux for 20 minutes. After cooling, the mixture was concentrated under vacuum to a residue that was dissolved in EtOAc (60 mL) and washed with 5% NaHCO3 (30 mL). The aqueous phase was back-extracted with EtOAc (30 mL). The combined organics were washed with brine, dried over MgSO4, filtered, and evaporated under vacuum. The residue was purified by PLC, using 1:1 hexanes-EtOAc as developing solvent, to afford (2RS,9aSR)-9a-butyl-7-hydroxy-2-(3-hydroxy-2-oxopropyl)-4-methyl-1,2,9,9a-tetrahydro-3H-fluoren-3-one as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:15])=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.[Br:16]Br>CC(O)=O>[Br:16][C:7]1[CH:6]=[CH:5][C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:11])([CH3:12])[CH3:13])=[C:3]([CH3:15])[C:2]=1[Cl:1]
Reactant: Cc1c(Cl)cccc1NC(=O)C(C)(C)C
Reactant: BrBr
Solvent: CC(=O)O
Product: Cc1c(NC(=O)C(C)(C)C)ccc(Br)c1Cl

Procedure:
N-(3-Chloro-2-methylphenyl)-2,2-dimethylpropanamide (0.5 g, 2.2 mmol) and bromine (1.4 g, 8.8 mmol) were combined in AcOH (25 mL) at rt for 2 h. The residue resulting from concentration was purified by flash chromatography (20-60% EtOAc-hexanes gradient) to afford the title compound: MS (ES) m/z 305 (M+1).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH2:4][C:3]1=O.[C:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([NH2:25])[CH:20]=[CH:19]3)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.Cl.ClC1C=CN=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[C:8]1([CH2:14][O:15][C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][CH:24]=2)[N:21]([NH:25][C:5]2[CH:6]=[CH:1][N:2]=[CH:3][CH:4]=2)[CH:20]=[CH:19]3)[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: Nn1ccc2cc(OCc3ccccc3)ccc21
Reactant: CN1CCCC1=O
Agent: Cl
Agent: Clc1ccncc1
Agent: O=C([O-])[O-]
Solvent: O
Product: c1ccc(COc2ccc3c(ccn3Nc3ccncc3)c2)cc1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To 250 ml of N-methyl-2-pyrrolidinone was added 5-(phenylmethoxy)-1H-indole-1-amine (29.7 g) and the solution was heated to 80° C. Then 4-chloropyridine hydrochloride (20.55 g) was added portionwise and the mixture was stirred for three hours, cooled, poured into water, basified with aqueous sodium carbonate and extracted with toluene. The organic/aqueous mixture was filtered to yield a solid (39 g), which was triturated with ether to yield a solid (27 g). Of this material, 3.0 g was eluted with 5% methanol/dichloromethane on a silica gel column via HPLC. The desired fractions were concentrated to yield a solid, 2.5 g, m.p. 143°-145° C.