Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3]1.[CH3:8]N(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[NH4+].[Cl-].[C:32]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:44][C:45](C)([SH:49])[C:46](O)=[O:47])=[CH:39][CH:38]=2)#[CH:33]>CC#N.CCN(CC)CC>[C:32]([C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][C:40]([O:44][CH:45]([S:49][CH3:8])[C:46]([NH:1][C:2]1([CH2:6][OH:7])[CH2:5][CH2:4][CH2:3]1)=[O:47])=[CH:39][CH:38]=2)#[CH:33]
Reactant: NC1(CO)CCC1
Reactant: C#Cc1cnc2ccc(OC(C)(S)C(=O)O)cc2c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: C#Cc1cnc2ccc(OC(SC)C(=O)NC3(CO)CCC3)cc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture containing (1-amino-cyclobutyl)-methanol (preparation described in JP 08134044) (860 mg), aza-HOBT (600 mg), TBTU (1.41 g) and Et3N (1 ml) in CH3CN (30 ml), (3-ethynyl-quinolin-6-yloxy)-methyl sulfanyl-acetic acid dissolved in Et3N (1 ml) and CH3CN (30 ml) was added over 1 hr, at room temperature, under nitrogen atmosphere. The resulting brown suspension was stirred overnight at room temperature then poured into aq NH4Cl solution and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over sodium sulphate anhydrous, filtered and concentrated under reduced pressure. The crude residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate, 1/3) to give 2-(3-ethynyl-quinolin-6-yloxy)-N-(1-hydroxymethyl-cyclobutyl)-2-methylsulfanyl-acetamide (1.09 g) as slightly yellow solid.
Reaction SMILES: [C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:15]=2)[N:10](COCC[Si](C)(C)C)[CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.CO.[OH-].[NH4+]>ClCCl>[C:1]([NH:5][C:6]([C:8]1[C:16]2[C:11](=[N:12][CH:13]=[C:14]([NH:17][C:18]3[CH:19]=[N:20][C:21]([CH3:24])=[CH:22][CH:23]=3)[N:15]=2)[NH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Nc2cnc3c(n2)c(C(=O)NC(C)(C)C)cn3COCC[Si](C)(C)C)cn1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(Nc2cnc3[nH]cc(C(=O)NC(C)(C)C)c3n2)cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84.3 %

Procedure:
To a solution of N-tert-butyl-2-(6-methylpyridin-3-ylamino)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (55 mg, 121 mol) in dichloromethane (1.9 mL) was added trifluoroacetic acid (276 mg, 186 μL, 2.42 mmol) and the mixture stirred at room temperature for 16 h. The reaction mixture was concentrated in vacuo and the residue obtained then dissolved in dichloromethane (2 mL), methanol (1 mL) and ammonium hydroxide (0.25 mL) and the mixture stirred at room temperature for 1 h. The mixture was concentrated and triturated with water, then filtered to obtain a solid which was washed with ether and dried to give N-tert-butyl-2-(6-methylpyridin-3-ylamino)-5H-pyrrolo[2,3-b]pyrazine-7-carboxamide (33 mg, 102 mol, 84%) as a brown solid. 1H NMR (400 MHz, DMSO-d) δ ppm: 12.23 (s, 1H), 9.41 (s, 1H), 8.60 (d, J=2.3, 1 H), 7.91 (m, 3H), 7.59 (s, 1H), 7.06 (d, J=8.5, 1 H), 2.31 (s, 3H), 1.32 (s, 9H); MS (EI/CI) m/z: 325.1 [M+H].
Reaction SMILES: Br[C:2]1[C:14](=[O:15])[N:13]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)[C:5]2[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=2[CH:3]=1.[OH:21][CH2:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][CH:28]=1.CO.C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.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>[CH:16]1([N:13]2[C:5]3[N:6]=[C:7]([NH:11][CH3:12])[N:8]=[C:9]([CH3:10])[C:4]=3[CH:3]=[C:2]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([CH2:22][OH:21])[CH:28]=3)[C:14]2=[O:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: OCc1cccc(B(O)O)c1
Reactant: CNc1nc(C)c2cc(Br)c(=O)n(C3CCCC3)c2n1
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: Cc1ccccc1
Solvent: CO
Product: CNc1nc(C)c2cc(-c3cccc(CO)c3)c(=O)n(C3CCCC3)c2n1
Yield: 81.2 %

Procedure:
6-Bromo-8-cyclopentyl-4-methyl-2-methylamino-8H-pyrido[2,3-d]pyrimidin-7-one (5.00 g, 14.83 mmol), 3-(hydroxymethyl)phenylboronic acid (3.38 g, 22.24 mmol) and Pd(PPh3)4 (0.685 g, 0.593 mmol) were suspended in Toluene (20 mL), MeOH (10 mL) and sat. NaHCO3 (10 mL) and then heated to 100° C. overnight. The reaction was deemed complete by MS and TLC. The organic layer was injected directly onto a column, eluting with CH2Cl2 then 4% MeOH in CH2Cl2. The fractions containing the desired material, as deemed by MS, were combined and evaporated in vacuo to give a greenish beige solid. This was triturated with MeCN and filtered to give crop one, 4.7 g. A second crop was obtained of 0.25 g. A third crop was obtained of 0.10 g. The three crops were deemed to be of sufficient purity based on NMR's and were combined and washed again with MeCN to give a solid (4.39 g, 81.24%).
Reaction SMILES: ClC1N2N=C(C3C=CC=CC=3Cl)C(C3C=CC(Cl)=CC=3)=CC2=NN=1.C(NC1(C(N)=O)CNC1)C.[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:43]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)=[CH:44][C:45]2[N:46]([C:48]([N:51]3[CH2:55]C[C:53]([NH:59][CH2:60][CH3:61])([C:56]([NH2:58])=[O:57])[CH2:52]3)=[N:49][N:50]=2)[N:47]=1>>[Cl:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:42]1[C:43]([C:62]2[CH:67]=[CH:66][C:65]([Cl:68])=[CH:64][CH:63]=2)=[CH:44][C:45]2[N:46]([C:48]([N:51]3[CH2:52][C:53]([NH:59][CH2:60][CH3:61])([C:56]([NH2:58])=[O:57])[CH2:55]3)=[N:49][N:50]=2)[N:47]=1
Reactant: CCNC1(C(N)=O)CCN(c2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)C1
Agent: CCNC1(C(N)=O)CNC1
Agent: Clc1ccc(-c2cc3nnc(Cl)n3nc2-c2ccccc2Cl)cc1
Product: CCNC1(C(N)=O)CN(c2nnc3cc(-c4ccc(Cl)cc4)c(-c4ccccc4Cl)nn23)C1
Yield: 32 %

Procedure:
The title compound (70 mg, 32%) as a yellow powder was prepared from 3-chloro-6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazine (168 mg, 0.45 mmol) and 3-(ethylamino)azetidine-3-carboxamide (291 mg, 1.35 mmol) in a manner analogous to that in which 1-(6-(2-chlorophenyl)-7-(4-chlorophenyl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)-3-(ethylamino)pyrrolidine-3-carboxamide was prepared. HPLC/MS (method A): retention time=2.76 min, (M+H)+=482.2. 1H NMR (DMSO-d6, 400 MHz): δ 8.19 (s, 1H), 7.59-7.64 (m, 1H), 7.39-7.48 (m, 3H), 7.28-7.37 (m, 3H), 7.17-7.25 (m, 3H), 4.44 (d, J=8.07 Hz, 2H), 4.08 (d, J=8.07 Hz, 2H), 2.84 (bs, 1H), 2.41 (m, 2H), 1.02 (t, J=7.09 Hz, 3H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]2[CH2:21][CH2:20][C:19](=O)[C:5]=2[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[C:7]=1[C:8]([OH:10])=[O:9])C.O=[C:24]1[C:28]2[NH:29][C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:31][C:27]=2[CH2:26][CH2:25]1.[CH3:37][Mg]Br>>[CH3:1][CH:24]1[C:28]2[NH:29][C:30]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[CH:31][C:27]=2[CH2:26][CH2:25]1.[CH3:37][C:19]1[C:5]2[N:6]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[C:7]([C:8]([O:10][CH2:24][CH3:25])=[O:9])=[CH:3][C:4]=2[CH2:21][CH:20]=1
Reactant: CCc1c2c(n(COCC[Si](C)(C)C)c1C(=O)O)C(=O)CC2
Reactant: CCOC(=O)c1cc2c([nH]1)C(=O)CC2
Reactant: C[Mg]Br
Product: CCOC(=O)c1cc2c([nH]1)C(C)CC2
Product: CCOC(=O)c1cc2c(n1COCC[Si](C)(C)C)C(C)=CC2

Procedure:
The title compound was synthesized from SEM-protected ethyl 6-oxo-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate (ethyl 6-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4,5,6-tetrahydrocyclopenta[b]pyrrole-2-carboxylate) (0.5 g, 2.79 mmol) and methylmagnesium bromide (4.85 mL, 6.8 mmol, 1.4 M in toluene, 2.2 equiv) according to General Procedure 3 to give ethyl 6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate. The ethyl 6-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate was then deprotected according to General Procedure 10.3 to provide ethyl 6-methyl-1,4-dihydrocyclopenta[b]pyrrole-2-carboxylate, which was subjected to hydrogenation according to General Procedure 6. The crude product was purified by preparative HPLC using the Chromeleon purification system. A 0.1% formic acid/1% acetonitrile mixture in water (aqueous phase) and methanol (no modifier added—organic phase) using a 50 mm Dynamax HPLC C-18 column at 28 mL/min (initial gradient of 60% methanol and increasing to 100% over 7 minutes) afforded the title compound (20.8 mg, 47%). LCMS m/e 216 (M+Na). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.24 (d, J=6.83 Hz, 3H), 1.35 (t, J=7.11 Hz, 3H), 1.90-2.02 (m, 1H), 2.50-2.70 (m, 3H), 3.08-3.20 (m, J=6.92, 6.92, 6.92, 6.92, 6.77 Hz, 1H), 4.30 (qd, J=7.12, 1.39 Hz, 2H), 6.65 (d, J=1.64 Hz, 1H), 8.72 (br. s, 1H).
Reaction SMILES: C(N(CC)CC)C.[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:29])[F:28])=[CH:24][N:25]=[C:20]2[C@H:19]([NH2:31])[CH2:18][CH2:17]1.Cl[C:33](OC1C=CC([N+]([O-])=O)=CC=1)=[O:34].[C:45]1(=[O:56])[C:49]2([CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)[CH2:48][C:47](=[O:55])[NH:46]1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.ClCCl>[F:8][C:9]1[C:14]([F:15])=[CH:13][CH:12]=[CH:11][C:10]=1[C@H:16]1[CH2:22][N:21]2[C:23]([CH2:26][C:27]([F:30])([F:28])[F:29])=[CH:24][N:25]=[C:20]2[C@H:19]([NH:31][C:33]([N:52]2[CH2:51][CH2:50][C:49]3([C:45](=[O:56])[NH:46][C:47](=[O:55])[CH2:48]3)[CH2:54][CH2:53]2)=[O:34])[CH2:18][CH2:17]1
Reactant: N[C@@H]1CC[C@@H](c2cccc(F)c2F)Cn2c(CC(F)(F)F)cnc21
Reactant: O=C1CC2(CCNCC2)C(=O)N1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C1CC2(CCN(C(=O)N[C@@H]3CC[C@@H](c4cccc(F)c4F)Cn4c(CC(F)(F)F)cnc43)CC2)C(=O)N1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.8 %

Procedure:
Triethylamine (0.28 mL, 1.97 mmol) was added to a solution of the hydrochloride salt of (6S,9R)-6-(2,3-difluorophenyl)-3-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-amine (275 mg, 0.66 mmol) and 4-nitrophenyl chloroformate (139 mg, 0.69 mmol) in tetrahydrofuran (2.5 mL) at 0° C. After 15 min, a solution of the acetate salt of 2,8-diazaspiro[4.5]decane-1,3-dione (WO 2004/076455) (180 mg, 0.79 mmol) in dichloromethane (2.5 mL) and triethylamine (0.28 mL, 1.97 mmol) were added and the mixture was allowed to warm to ambient temperature. After 2 h, saturated aqueous sodium carbonate was added and the mixture was extracted with ethyl acetate (3×). The organic layer was washed with saturated aqueous sodium bicarbonate (3×), saturated brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane→90% dichloromethane/methanol) gave the title compound (213 mg). MS 540.2005 (M+1).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([OH:14])=O)=[CH:9][C:4]=2[O:3][CH2:2]1.[Cl:15]CCl>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([CH:10]=[CH:11][C:12]([Cl:15])=[O:14])=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: ClCCl
Reactant: O=C(O)C=Cc1ccc2c(c1)OCO2
Solvent: CN(C)C=O
Product: O=C(Cl)C=Cc1ccc2c(c1)OCO2
Temperature: 40 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
(Method G2) To a suspension of 3-benzo[1,3]dioxol-5-yl-acrylic acid (1a) (0.38 g, 1.98 mmol) in dichloromethane (8.0 ml) oxalyl chloride (0.62 ml, 7.08 mmol) and one drop of dimethylformamide were added. The reaction mixture was stirred at 40° C. for one hour and concentrated under reduced pressure to give crude title compound (0.41 g, 98%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]=[O:19])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:20][Li].[Cl-].[NH4+]>O1CCCC1.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[C:10]([CH:18]([OH:19])[CH3:20])[CH:11]=[C:12]3[C:17]=2[N:16]=[CH:15][CH:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1
Reactant: [Li]C
Reactant: O=Cc1cc(-c2cccc(Cl)c2)c2ncccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(O)c1cc(-c2cccc(Cl)c2)c2ncccc2c1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
8-(3-Chlorophenyl)-6-quinolincarbaldehyde (0.8 g) was dissolved in 20 mL of tetrahydrofuran and cooled to -78° C. Methyllithium (4.5 mL, 1.4M) in diethyl ether was added dropwise to the solution over 5 minutes, stirred for 20 minutes, poured into 50 mL of saturated ammonium chloride, and stirred for 5 minutes. The solution was extracted with ethyl acetate (2×75 mL). The extracts were combined and dried over MgSO4, and concentrated. The residue was chromatographed on silica gel (30:70 ethyl acetate:hexanes) to obtain 0.72 g of 8-(3-chlorophenyl)-6-(1-hydroxyethyl)quinoline as a yellow oil.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[N:9][OH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22](=[CH2:25])[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C.[Cl-].[Na+]>O.C(Cl)Cl>[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]2([O:10][N:9]=[C:8]([CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[CH2:25]2)[CH2:21][CH2:20]1)=[O:18])([CH3:14])([CH3:13])[CH3:15]
Reactant: C=C1CCN(C(=O)OC(C)(C)C)CC1
Reactant: ON=C(Cl)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CC(Cc1ccccc1)=NO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Compound W (3.33 g, 20 mmol), dissolved in abs. DCM (15 ml), was added dropwise at 0° C. within 10 min to a solution of compound B (2.81 g, 14.3 mmol in abs. DCM (22 ml)). A solution of triethylamine (11.2 ml, 80 mmol) in abs. DCM (10 ml) was added to this mixture at 0° C. within 10 min. As the reaction was highly exothermic, cooling was carried out with a mixture of ice and sodium chloride. The reaction mixture was stirred for 16 h at RT. For working up the mixture, DCM (15 ml) and water (45 ml) were added and the mixture was stirred for 15 min. After separation of the phases, the aqueous phase was extracted with DCM (2×45 ml). The phases were separated. The organic phase was washed successively with 10% citric acid solution (2×30 ml) and sat. NaCl solution (30 ml). The organic phase was dried and concentrated (5.3 g, brown oil). The residue was separated by chromatography [silica gel 60 (180 g); cyclohexane/EtOAc 7:1 (1,200 ml); 5:1 (900 ml)]. The desired product X was obtained in a yield of 681 mg (11%).
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].[C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])(=[O:11])[CH3:10].[C:23](Cl)(=[O:32])[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]>C1COCC1>[CH2:24]([C:23](=[O:32])[CH2:10][C:9]([O:12][C:13]([CH3:22])([CH2:15][CH2:16][CH2:17][CH:18]([CH3:21])[CH:19]=[CH2:20])[CH3:14])=[O:11])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:1]
Reactant: C=CC(C)CCCC(C)(C)OC(C)=O
Reactant: CC(C)[N-]C(C)C
Reactant: CCCCCCCCC(=O)Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC(C)CCCC(C)(C)OC(=O)CC(=O)CCCCCCCCC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
Lithium diisopropylamide (75.7 mL of a 2.0M solution, 0.151 mol) is placed into a 500 mL three-necked round-bottomed flask fitted with a magnetic stirrer, internal thermometer, argon inlet, and addition funnel. The flask is cooled to -78° C. 2,6-Dimethyl-7-octen-2-yl acetate (14.14 g, 0.071 mol) is dissolved in THF (20 mL) and the resulting solution added to the flask over 45 min. Once addition is complete, the mixture is stirred for an additional 15 min. before being treated with a solution of nonanoyl chloride (12.38 g, 0.067 mol) over 30 min. The mixture is warmed to -20° C. and stirred at that temperature for 18 h. After warming to 0° C., the mixture is quenched with 20% HCl (55 mL). The mixture is poured into a separatory funnel containing ether (150 mL) and water (250 mL). The aqueous layer is extracted with ether (150 mL). The combined organic layers are washed with saturated NaHCO3 solution (2×100 mL), water (2×150 mL) and brine (150 mL), dried over MgSO4 and filtered. The solvent is removed by rotary evaporation to give an orange/red oil. The oil is purified by column chromatography (elution with 2% ethyl acetate/petroleum ether) to yield a colorless oil having 1H and 13C NMR spectra consistent with the desired product.
Reaction SMILES: [O:1]1[CH:6]2[CH:2]1[CH2:3][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:5]2.[ClH:15]>O1CCOCC1.O>[OH:1][CH:2]1[CH:6]([Cl:15])[CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]([Cl:14])([Cl:13])[Cl:12])=[O:8])[CH2:3]1
Reactant: O=C(OCC(Cl)(Cl)Cl)N1CC2OC2C1
Reactant: Cl
Solvent: C1COCCO1
Solvent: O
Product: O=C(OCC(Cl)(Cl)Cl)N1CC(O)C(Cl)C1
Reaction time: 15 h

Procedure:
4.0 g of 3,4-epoxy-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine are dissolved in 15 ml of dioxane, and the solution is treated with 50 ml of 6 N hydrochloric acid. The slightly exothermic reaction is kept at room temperature by means of a water bath, and the reaction mixture is stirred for 15 hours, then diluted with water and extracted 3 times with 100 ml of methylene chloride. The organic phase is washed with 0.1 N sodium hydroxide solution and then with aqueous sodium chloride solution, dried over sodium sulphate and then evaporated to dryness, first under a water pump vacuum and then under a high vacuum, 3-hydroxy-4-chloro-1-(β,β,β-trichloroethoxycarbonyl)-pyrrolidine being obtained as a slightly yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:13]=[C:12]([OH:14])[C:11]3[CH2:15][CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1.C(C1C=CN(C2C=C(O[CH:38]3[CH2:55][CH:54]4[CH:40]([C:41](=[O:67])[N:42]([CH3:66])[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH:48][CH:49]5[C:51]([C:57]([NH:59][S:60]([N:63]([CH3:65])[CH3:64])(=[O:62])=[O:61])=[O:58])([NH:52][C:53]4=[O:56])[CH2:50]5)[CH2:39]3)C3C(=C(C)C(OC)=CC=3)N=2)N=1)(C)C>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C:8]2[N:13]=[C:12]([O:14][CH:38]3[CH2:55][CH:54]4[CH:40]([C:41](=[O:67])[N:42]([CH3:66])[CH2:43][CH2:44][CH2:45][CH2:46][CH:47]=[CH:48][CH:49]5[C:51]([C:57]([NH:59][S:60]([N:63]([CH3:64])[CH3:65])(=[O:61])=[O:62])=[O:58])([NH:52][C:53]4=[O:56])[CH2:50]5)[CH2:39]3)[C:11]3[CH2:15][CH2:16][CH2:17][C:10]=3[N:9]=2)[CH:7]=1
Reactant: Oc1nc(-c2cc(Br)ccc2F)nc2c1CCC2
Reactant: COc1ccc2c(OC3CC4C(=O)NC5(C(=O)NS(=O)(=O)N(C)C)CC5C=CCCCCN(C)C(=O)C4C3)cc(-n3ccc(C(C)C)n3)nc2c1C
Product: CN1CCCCC=CC2CC2(C(=O)NS(=O)(=O)N(C)C)NC(=O)C2CC(Oc3nc(-c4cc(Br)ccc4F)nc4c3CCC4)CC2C1=O

Procedure:
The title compound was prepared from 2-(5-bromo-2-fluorophenyl)-4-hydroxy-6,7-dihydro-5H-cyclopentapyrimidine and intermediate 24 following the procedure (Steps 13-16) reported for the preparation of N-[17-[2-(3-isopropylpyrazol-1-yl)-7-methoxy-8-methylquinolin-4-yloxy]-13-methyl-2,14-dioxo-3,13-diazatricyclo-[13.3.0.04,6]octadec-7-ene-4-carbonyl](dimethylamino)sulfonamide (29): m/z=748 (M+H)+. 1H NMR (CDCl3): 1.13-1.51 (m, 4H), 1.54-1.95 (m, 4H), 2.08-2.45 (m, 5H), 2.50-2.65 (m, 2H), 2.80-3.15 (m, 14H), 3.22-3.40 (m, 2H), 4.60 (t, J=12.4 Hz, 1H), 5.05 (t, J=9.9 Hz, 1H), 5.60-5.75 (m, 2H), 6.24 (s, 1H), 7.05 (t, J=9.5 Hz, 1H), 7.48-7.55 (m, 1H), 8.10-8.18 (m, 1H), 10.6 (br s, 1H).
Reaction SMILES: C[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CC1(O)CCC1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20](=[O:28])[O:21]C1C=CC=CN=1>[NH4+].[Cl-]>[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[O:19][C:20](=[O:21])[O:28][C:3]1([CH3:2])[CH2:4][CH2:5][CH2:6]1
Reactant: O=C(Oc1ccccn1)Oc1ccccn1
Reactant: CCCCCC
Agent: CC1(O)CCC1
Agent: [Cl-]
Agent: [NH4+]
Product: CC1(OC(=O)Oc2ccccn2)CCC1
Reaction time: 0.08 h

Procedure:
To a slurry of KH (400 mg, 35% in oil, 3.5 mmol) was added 5 mL of hexane. It was stirred for 5 min, and then the hexane was removed. This process was repeated three times. THF (5 mL) was added to this prewashed KH, and then 1-methylcyclobutanol (200 mg, 2.3 mmol) was added at 0° C. The mixture was stirred (0° C. to rt) for 1 h, and then carbonic acid dipyridin-2-yl ester (753 mg, 3.5 mmol) was added. The mixture was stirred at rt for 4 h, and the reaction was diluted with sat. aq. NH4Cl. The mixture was then extracted with EtOAc, and the solvent was removed in vacuo to obtain 200 mg of the crude carbonic acid 1-methyl-cyclobutyl ester pyridin-2-yl ester as an orange solid. It was used directly in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH2:11]O)=[CH:8][C:7]=2[CH:13]=1.P(Br)(Br)[Br:15]>C1(C)C=CC=CC=1>[Br:15][CH2:11][C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:13][C:7]=2[CH:8]=1
Reactant: BrP(Br)Br
Reactant: COc1ccc2oc(CO)cc2c1
Solvent: Cc1ccccc1
Product: COc1ccc2oc(CBr)cc2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 75.4 %

Procedure:
Compound 25 (40 mg, 0.22 mmol) was dissolved in toluene (5 mL) and the solution was cooled to 0° C. PBr3 (21 μL, 0.22 mmol) was added dropwise over 10 min. The reaction mixture was then brought up to room temperature and stirred for 1 h. The solvent was evaporated off in-vacuo. The residue was adsorbed on silica gel and purified by flash chromatography, eluting with hexane/EtOAc (4:1) to give 26 (40 mg, 74%) as an oil. 1H NMR (500 MHz, CDCl3): δ: 7.39 (1H, d, J=8.90 Hz, H-7), 7.01 (1H, d, J=2.55, H-4), 6.94 (1H, dd, J=6.35 & 2.60, H-6), 6.72 (1H, s, H-3), 4.61 (2H, s, 2-CH2), 3.86 (3H, s, OCH3).
Reaction SMILES: CC(C)=O.[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([OH:24])=[C:17]([CH:23]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:37][C:38]([F:41])([F:40])[F:39])(=O)=O>O.C(OCC)C>[CH2:5]([O:12][C:13]1[CH:14]=[CH:15][C:16]([O:24][CH2:37][C:38]([F:41])([F:40])[F:39])=[C:17]([CH:23]=1)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: CCOC(=O)c1cc(OCc2ccccc2)ccc1O
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CC(C)=O
Product: CCOC(=O)c1cc(OCc2ccccc2)ccc1OCC(F)(F)F

Procedure:
To a refluxing mixture of 100 ml of acetone, 10.3 g (0.0379 mole) of ethyl 5-benzyloxy-2-hydroxybenzoate and 10.5 g (0.0757 mole) of potassium carbonate is added dropwise over about 1 hour 13.2 g (0.0568 mole) 2,2,2-trifluoroethyl trifluoromethanesulfonate. The mixture is heated at reflux for another 16 hours then evaporated to provide a residue which is dissolved in water and diethyl ether. The layers are separated and the ether is washed with water, then saturated sodium chloride solution and dried over magnesium sulfate. The magnesium sulfate is removed by filtration and the diethyl ether is removed by evaporation to provide the product, ethyl 5-benzyloxy-2-(2,2,2-trifluoroethoxy)benzoate. The infrared spectrum of this material is consistent with the assigned structure.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:24][O:25]N)[N:18]([CH2:19][C:20]([CH3:23])([OH:22])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1.C(#[N:29])C>CN(C=O)C>[NH2:5][C:6]1[C:15]2[N:16]=[C:17]([CH2:24][O:25][N:2]([CH3:1])[C:3]([NH2:29])=[O:4])[N:18]([CH2:19][C:20]([OH:22])([CH3:23])[CH3:21])[C:14]=2[C:13]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[N:7]=1
Reactant: CC(C)(O)Cn1c(CON)nc2c(N)nc3ccccc3c21
Reactant: CC#N
Reactant: CN=C=O
Solvent: CN(C)C=O
Product: CN(OCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)O)C(N)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl isocyanate (0.148 mL, 2.39 mmol) was added to a stirred solution of 1-{4-amino-2-[(aminooxy)methyl]-1H-imidazo[4,5-c]quinolin-1-yl}-2-methylpropan-2-ol (prepared as described in Example 100, 600 mg, 1.99 mmol) in DMF (5 mL). A solid formed immediately. The mixture was stirred for 2 hours at room temperature, then was heated to form a solution to which acetonitrile (10 mL) was added. Crystals formed that were isolated by filtration and purified by chromatography using a HORIZON HPFC (silica gel, gradient elution with 5-20% 2 M NH3 in methanol/chloroform). The appropriate fractions were combined and concentrated to a solid that was dried in a vacuum oven overnight to afford N-{[4-amino-1-(2-hydroxy-2-methylpropyl)-1H-imidazo[4,5-c]quinolin-2-yl]methoxy}-N-methylurea as white crystals, mp 206-207° C.