Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[NH:13][C:14](=O)[CH2:15][CH2:16][CH:17]1[CH2:20][CH:19]([N:21]([CH2:23][C@@H:24]2[C@@H:31]3[C@@H:27]([O:28][C:29]([CH3:33])([CH3:32])[O:30]3)[C@H:26]([N:34]3[C:38]4[N:39]=[CH:40][N:41]=[C:42]([NH:43][CH2:44][C:45]5[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][C:46]=5[O:53][CH3:54])[C:37]=4[CH:36]=[CH:35]3)[CH2:25]2)[CH3:22])[CH2:18]1>C(O)(=O)C>[CH3:54][O:53][C:46]1[CH:47]=[C:48]([O:51][CH3:52])[CH:49]=[CH:50][C:45]=1[CH2:44][NH:43][C:42]1[C:37]2[CH:36]=[CH:35][N:34]([C@H:26]3[C@H:27]4[C@H:31]([O:30][C:29]([CH3:33])([CH3:32])[O:28]4)[C@@H:24]([CH2:23][N:21]([CH3:22])[CH:19]4[CH2:18][CH:17]([CH2:16][CH2:15][C:14]5[NH:13][C:3]6[CH:4]=[CH:5][C:6]([O:8][C:9]([F:12])([F:10])[F:11])=[CH:7][C:2]=6[N:1]=5)[CH2:20]4)[CH2:25]3)[C:38]=2[N:39]=[CH:40][N:41]=1
Reactant: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCC(=O)Nc4ccc(OC(F)(F)F)cc4N)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Solvent: CC(=O)O
Product: COc1ccc(CNc2ncnc3c2ccn3[C@@H]2C[C@H](CN(C)C3CC(CCc4nc5cc(OC(F)(F)F)ccc5[nH]4)C3)[C@H]3OC(C)(C)O[C@H]32)c(OC)c1
Yield: 66.7 %

Procedure:
A solution of N-(2-amino-4-(trifluoromethoxy)phenyl)-3-(3-((((3aR,4R,6R,6aS)-6-(4-((2,4-dimethoxybenzyl)amino)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-yl)methyl)(methyl)amino)cyclobutyl)propanamide (2 g, 2 mmol) in Acetic acid (4 ml) was stirred overnight at 60° C. The volatiles removed in vacuo and remaining residue purified by flash chromatography (DCM/7N NH3 in MeOH 92:8) to give the desired compound (1 g) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]([CH2:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[CH:10]=O)=[O:4].[C:15]([C:18]1[C:19](=[O:29])[NH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:17])[CH3:16].N1CCCCC1>N1C=CC=CC=1>[OH:28][C:27]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][C:19](=[O:29])[C:18]=1[C:15](=[O:17])[CH:16]=[CH:10][C:9]1[CH:12]=[CH:13][CH:14]=[C:7]([O:6][CH2:5][C:3]([O:2][CH3:1])=[O:4])[CH:8]=1
Reactant: CC(=O)c1c(O)c2ccccc2[nH]c1=O
Reactant: COC(=O)COc1cccc(C=O)c1
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: COC(=O)COc1cccc(C=CC(=O)c2c(O)c3ccccc3[nH]c2=O)c1
Temperature: 25 °C
Yield: 67.5 %

Procedure:
To a mixture of 1.43 g of 3-[(methoxycarbonyl)methoxy]benzaldehyde, 0.50 g of 3-acetyl-4-hydroxy-2(1H)-quinolinone and 6 ml pyridine was added 0.1 ml of piperidine, and this was heated under reflux for 1 hour. After cooled to room temperature, precipitated crystals were filtered, and washed with tetrahydrofuran to obtain 0.63 g of 4-hydroxy-3-[3-[3-[(methoxycarbonyl)methoxy]phenyl]-1-oxo-2-propenyl]-2(1H)-quinolinone [Compound No. (7e)] as a yellow crystal.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][C:6]1[C:15]2[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=2[N:9]=[CH:8][CH:7]=1.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=1)[C:27]([NH:1][C:2]1[CH:19]=[CH:18][CH:17]=[C:4]([O:5][C:6]2[C:15]3[NH:14][C:13](=[O:16])[CH:12]=[N:11][C:10]=3[N:9]=[CH:8][CH:7]=2)[CH:3]=1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cccc(C(=O)Cl)c1
Reactant: Nc1cccc(Oc2ccnc3ncc(=O)[nH]c23)c1
Product: CC(C)(C)c1cccc(C(=O)Nc2cccc(Oc3ccnc4ncc(=O)[nH]c34)c2)c1
Yield: 22 %

Procedure:
Method G1 was used with 8-(3-aminophenoxy)pyrido[2,3-b]pyrazin-2(1H)-one and 3-tertbutylbenzoyl chloride to afford the title compound as a white solid (14 mg, 22%).
Reaction SMILES: [CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[CH:9][C:8](C#CC3C=CC(C(OCC)=O)=CC=3)=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1.FC(F)(F)S(OC1C2C=CC([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)=CC=2C(C)(C)CC=1)(=O)=O>>[CH3:1][C:2]1([CH3:30])[C:11]2[CH:10]=[C:9]([C:49]#[C:50][C:51]3[CH:61]=[CH:60][C:54]([C:55]([O:57][CH2:58][CH3:59])=[O:56])=[CH:53][CH:52]=3)[CH:8]=[CH:7][C:6]=2[C:5]([C:25]#[C:26][CH2:27][CH2:28][CH3:29])=[CH:4][CH2:3]1
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CC=C3OS(=O)(=O)C(F)(F)F)cc1
Reactant: CCCC#CC1=CCC(C)(C)c2ccc(C#Cc3ccc(C(=O)OCC)cc3)cc21
Product: CCCC#CC1=CCC(C)(C)c2cc(C#Cc3ccc(C(=O)OCC)cc3)ccc21

Procedure:
Employing the same general procedure as for the preparation of ethyl 4-[(7,8-dihydro-8,8-dimethyl-5-(1-pentynyl)naphth-3-yl)ethynyl]benzoate (compound 75), 200 mg (0.42 mmol) of ethyl 4-[(5-trifluoromethylsulfonyloxy-7,8-dihydro-8,8-dimethylnaphth-2-yl)ethynyl]benzoate (Compound 87) was converted into the title compound (pale yellow oil) using 286 mg (4.2 mmol) of pentyne, 60 mg (0.08 mmol) of bis(triphenylphosphine)palladium (II) chloride and 20 mg (0.11 mmol) of cuprous iodide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH:31]=O)[N:12]3[C:17]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:16]=4[N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1.CC(O)=O.[CH:37]1([NH2:40])[CH2:39][CH2:38]1.C([BH3-])#N>ClCCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]([CH2:31][NH:40][CH:37]3[CH2:39][CH2:38]3)[N:12]3[C:17]4[CH:18]=[CH:19][N:20]([S:21]([C:24]5[CH:30]=[CH:29][C:27]([CH3:28])=[CH:26][CH:25]=5)(=[O:23])=[O:22])[C:16]=4[N:15]=[CH:14][C:13]=23)=[CH:5][CH:4]=1
Reactant: NC1CC1
Reactant: COc1ccc(-c2nc(C=O)n3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Agent: [BH3-]C#N
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(-c2nc(CNC3CC3)n3c2cnc2c3ccn2S(=O)(=O)c2ccc(C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
3-(4-Methoxyphenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazine-1-carbaldehyde (0.075 g, 0.17 mmol), AcOH (0.048 mL, 0.84 mmol), and cyclopropanamine (0.026 mL, 0.37 mmol) were added in DCE (1.68 mL). The mixture was stirred at rt for 30 min. MP-Cyanoborohydride (0.23 g, 0.50 mmol, 2.15 mmol/g, Biotage™) was added in one portion. The mixture was stirred at 25° C. for 72 h. The mixture was purified directly by flash chromatography (40 g silica gel column, MeOH/DCM 0% to 10%) to give N-((3-(4-methoxyphenyl)-6-tosyl-6H-imidazo[1,5-a]pyrrolo[2,3-e]pyrazin-1-yl)methyl)cyclopropanamine (0.050 g, 61%): LC/MS (Table 2, Method c) Rt=1.49 min; MS m/z: 488 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][C:18]=1[N:24]=[C:25]=[O:26].O>C1COCC1>[Cl:1][C:2]1[CH:7]=[C:6]([S:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:25]([NH:24][C:18]3[CH:19]=[C:20]([CH3:23])[CH:21]=[CH:22][C:17]=3[F:16])=[O:26])=[CH:11][CH:10]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Nc1ccc(Sc2ccnc(Cl)c2)cc1
Reactant: Cc1ccc(F)c(N=C=O)c1
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(F)c(NC(=O)Nc2ccc(Sc3ccnc(Cl)c3)cc2)c1
Temperature: 60 °C
Reaction time: 5 h

Procedure:
To a stirred solution of 4-(2-Chloro-pyridin-4-ylsulfanyl)-phenylamine (300 mg, 1.27 mmol) in anhydrous THF (10 ml) was added 2-fluoro-5-methyl-phenylisocyanate (210 mg, 1.39 mmol). The mixture was stirred at 60° C. for 5 hours, and poured into 100 ml of water. The precipitates were filtered, washed with water (50 ml), and dried to give the crude, which was purified by silica gel chromatography eluting with 2-3% MeOH/CHCl3 to give 1-[4-(2-Chloro-pyridin-4-ylsulfanyl)-phenyl]-3-(2-fluoro-5-methyl-phenyl)-urea as white solid. Yield: 410 mg, 83%.
Reaction SMILES: [F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([CH2:23][CH:24]([OH:29])[C:25]([F:28])([F:27])[F:26])[C:15]2[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=2)[C:18]#[N:19])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C.C1COCC1.Cl>C1(C)C=CC=CC=1>[F:1][C:2]([F:30])([O:6][C:7]1[CH:8]=[C:9]([CH2:13][N:14]([C:15]2[CH:22]=[CH:21][CH:20]=[C:17]([C:18]3[NH:37][N:36]=[N:35][N:19]=3)[CH:16]=2)[CH2:23][CH:24]([OH:29])[C:25]([F:27])([F:28])[F:26])[CH:10]=[CH:11][CH:12]=1)[CH:3]([F:5])[F:4]
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: N#Cc1cccc(N(Cc2cccc(OC(F)(F)C(F)F)c2)CC(O)C(F)(F)F)c1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OC(CN(Cc1cccc(OC(F)(F)C(F)F)c1)c1cccc(-c2nnn[nH]2)c1)C(F)(F)F
Temperature: 105 °C
Reaction time: 8 h
Yield: 33.4 %

Procedure:
To a solution of 3-[[[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methyl](3,3,3-trifluoro-2-hydroxypropyl)amino]benzonitrile (76 mg, 0.17 mmol) in 2 mL of toluene was added trimethyltin azide (41 mg, 0.20 mmol). The reaction mixture was heated to 105° C. and stirred overnight. TLC showed starting material to still be present so additional trimethyltin azide (41 mg, 0.20 mmol) was added. The reaction mixture was stirred overnight at 105° C., cooled to room temperature, then THF (800 μL) and concentrated HCl (500 μL) were added. HPLC analysis showed 2 peaks after 5 hours, so additional concentrated HCl (200 μL) was added. After stirring overnight, HPLC analysis showed the reaction to be complete. The mixture was filtered through a celite plug and evaporated in vacuo. The residue was purified by reverse phase HPLC eluting with 10% to 90% acetonitrile in water to give 27.2 mg (33%) of the desired tetrazole product as an oil. HRMS calcd. for C19H16F7N5O2: 480.1270 [M+H]+, found: 480.1252. 1H NMR (CDCl3) δ3.66-3.99 (m, 2H), 4.45-4.75 (m, 3H), 5.80 (dt, 1H), 6.49-6.70 (m, 1H), 6.95 (s, 1H), 6.97-7.06 (m, 3H), 7.18-7.28 (m, 3H), 7.34 (s, 1H).
Reaction SMILES: [K].[SH:2][C:3]1[S:4][C:5]2[C:6]([N:16]=1)=[N:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2.I[CH3:18]>CN(C=O)C>[CH3:18][S:2][C:3]1[S:4][C:5]2[C:6]([N:16]=1)=[N:7][CH:8]=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=2
Reactant: CCOC(=O)c1cnc2nc(S)sc2c1
Reactant: CI
Agent: [K]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cnc2nc(SC)sc2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 79.1 %

Procedure:
To a stirred mixture of ethyl 2-mercaptothiazolo[4,5-b]pyridine-6-carboxylate potassium salt (1.7 g, 6.6 mmol) from the previous step in DMF (10 mL) at 0° C. was added iodomethane (226 μL, 3.6 mmol). After the mixture was stirred at 0° C. for 2 h, it was allowed to warm slowly to rt. The mixture was partitioned between EtOAc (100 mL) and 0.5 M aq Na2CO3 (50 mL). The organic layer was separated and washed with brine (50 mL), dried over Mg2SO4, filtered, and concentrated under reduced pressure to afford ethyl 2-(methylthio)thiazolo[4,5-b]pyridine-6-carboxylate (724 mg, 82%) as a yellow solid. The material was used in the next step without further purification. 1H NMR (300 MHz, DMSO-d6) δ 9.07 (s, 2H), 4.38 (q, J=7.0 Hz, 2H), 2.86 (s, 3H), 1.36 (t, J=7.1 Hz, 3H); LCMS (ESI) m/z 255 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17](Br)[C:16]([F:20])=[CH:15][C:14]=3[CH3:21])[CH3:2].[C:26]([Cu])#[N:27]>CN1CCCC1=O.O>[CH2:1]([O:3][C:4](=[O:25])[CH2:5][C:6]1([CH2:22][CH2:23][CH3:24])[C:11]2[NH:12][C:13]3[C:18]([C:10]=2[CH2:9][CH2:8][O:7]1)=[C:17]([C:26]#[N:27])[C:16]([F:20])=[CH:15][C:14]=3[CH3:21])[CH3:2]
Reactant: N#C[Cu]
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(Br)c21
Solvent: CN1CCCC1=O
Solvent: O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)cc(F)c(C#N)c21
Temperature: 220 °C
Yield: 93.9 %

Procedure:
5-Bromo-6-fluoro-8-methyl-1-propyl-1,3,4,9-tetrahydropyrano[3,4-b]indole-1-acetic acid ethyl ester (496 mg, 1.20 mmol) and CuCN (162 mg, 1.81 mmol) was dissolved in N-methyl-2-pyrrolidinone (6 mL) and the solution was divided into the 2 microwave reaction vessels (3.0 mL each). The reaction vessels were heated in microwave at 220° C. for 15 minutes. The reaction mixtures in 2 vessels were combined and then diluted with water (10 mL). The crude mixture was extracted with EtOAc (3×20 mL). The combined organic phase was washed with brine (50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash chromatography (silica, 25% EtOAc in hexanes) to give 404 mg (94%) of title compound as a white solid. 1H NMR (DMSO): 300 MHz δ 12.02 (bs, 1H), 11.33 (bs, 1H), 7.00 (d, J=9.00 Hz, 1H), 3.96 (m, 2H), 2.95 (d, J=10.3 Hz, 1H), 2.83 (t, J=3.9 Hz, 1H), 2.72 (d, J=10.3 Hz, 1H), 2.54 (s, 3H), 1.99 (m, 2H), 1.28 (m, 1H), 0.85 (m, 1H), 0.79 (t, J=5.41 Hz, 3H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1.C(OCC)(OCC)OCC.[CH:19]1[CH:24]=CC(C2C=CC=CC=2)=C[CH:20]=1.C1C=CC(OC2C=CC=CC=2)=CC=1>>[N:3]1[C:4]2[C:5](=[N:8][CH:20]=[CH:19][CH:24]=2)[CH:6]=[CH:7][CH:2]=1
Reactant: c1ccc(-c2ccccc2)cc1
Reactant: Nc1ccc(Cl)nc1
Solvent: CCOC(OCC)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Product: c1cnc2cccnc2c1

Procedure:
The 2-chloro-5-aminopyridine A is converted by heating in the presence of ester B and triethyl orthoformate to the condensation product C as a mixture of olefin isomers (Scheme 1). Various esters that are commercially available, known in the literature or prepared using known literature procedures are applicable to the reaction. Intermediate C is added to hot Dowtherm™ A to facilitate the ring closure and to afford the 1,5-naphthyridine D. Treatment of D with phosphorus oxychloride affords the key intermediate E (Scheme 1).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[F:12][C:13]1[C:19]([F:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Nc1cccc(F)c1F
Product: O=C(O)Cc1ccccc1Nc1cccc(F)c1F

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3-difluoroaniline to yield 2-[(2,3-difluorophenyl)amino]phenylacetic acid.
Reaction SMILES: [C:1]([C:4]1[O:5][C:6]2[CH:12]=[CH:11][CH:10]=[C:9]([O:13][CH3:14])[C:7]=2[N:8]=1)(=[O:3])[CH3:2].C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH2:26](O)[CH2:27][OH:28]>C1(C)C=CC=CC=1>[CH3:14][O:13][C:9]1[C:7]2[N:8]=[C:4]([C:1]3([CH3:2])[O:28][CH2:27][CH2:26][O:3]3)[O:5][C:6]=2[CH:12]=[CH:11][CH:10]=1
Reactant: OCCO
Reactant: COc1cccc2oc(C(C)=O)nc12
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COc1cccc2oc(C3(C)OCCO3)nc12
Temperature: 25 °C

Procedure:
2-Acetyl-4-methoxybenzoxazole (200 mg), p-toluenesulphonic acid (239 mg), ethylene glycol (0.29 ml) and toluene (10 ml) were heated to reflux under Dean-Stark conditions for 2 h. After cooling to room temperature, the toluene was evaporated, and the residue partitoned between water (20 ml) and ethyl acetate (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml). The combined organic phases were washed with water (40 ml), aqueous sodium bicarbonate (2×40 ml) and water (40 ml), dried over magnesium sulphate, evaporated in vacuo and purified by flash chromatography eluting with 30% ethyl acetate in hexane to yield the title compound as a white solid (129 mg).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([NH:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:17])[F:16])[CH:9]=2)=[O:5])[CH3:2].[CH2:28]([O:30][C:31](=[O:36])[CH2:32][C:33](Cl)=[O:34])[CH3:29]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([N:19]([C:33](=[O:34])[CH2:32][C:31]([O:30][CH2:28][CH3:29])=[O:36])[CH2:20][C:21]2[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=2)[C:8]2[C:13]([CH:14]=1)=[CH:12][CH:11]=[C:10]([C:15]([F:18])([F:16])[F:17])[CH:9]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc2ccc(C(F)(F)F)cc2n1NCc1ccc(F)cc1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: C1COCCO1
Product: CCOC(=O)CC(=O)N(Cc1ccc(F)cc1)n1c(C(=O)OCC)cc2ccc(C(F)(F)F)cc21
Temperature: 100 °C
Yield: 52 %

Procedure:
A mixture of 1-(4-fluoro-benzylamino)-6-trifluoromethyl-1H-indole-2-carboxylic acid ethyl ester (240 mg, 0.63 mmol) and chlorocarbonyl-acetic acid ethyl ester (105 mg, 0.69 mmol) in dioxane (3 mL) was heated in an 100° C. oil bath for 30 min and concentrated. Crude product was purified by silica gel chromatography (5%-50% EtOAc/DCM) to provide the title compound 162 mg. ESI (m/z): 495.24 (M+H)+.
Reaction SMILES: C[N:2]([CH3:5])C=O.[N-]=[N+]=[N-].[Na+].[CH2:10]([O:12][CH:13]([O:17][CH2:18][CH3:19])[CH2:14]CCl)[CH3:11]>C(O)C.[Pd]>[CH2:10]([O:12][CH:13]([O:17][CH2:18][CH3:19])[CH2:14][CH2:5][NH2:2])[CH3:11]
Reactant: CCOC(CCCl)OCC
Reactant: CN(C)C=O
Agent: [Pd]
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(CCN)OCC
Temperature: 60 °C
Reaction time: 96 h
Yield: 63 %

Procedure:
To 500 ml of dimethylformamide (DMF) containing NaN3 (26.0 g, 400 mmol) was added 3-chloropropionaldehyde diethyl acetal (33.3 g, 200 mmol). The solution was warmed to 60° C., and the reaction was monitored by GC (50° C., 1 min to 250° C. at 15° C./min, DB5-15 m). (Retention time (tR) of starting material 5.1 min, product 6.5 min). The reaction mixture was diluated with 1 L of ice water and extracted with ether (3×500 mL). The combined ether extracts were washed with water (2×500 mL) and then dried over MgSO4. Removal of solvent afforded a crude product, which was dissolved in 500 mL of ethanol containing Pd/C (10%, 2.03 g, 2 mmol). The suspension was degassed, saturated with H2, and stirred under an H2 balloon for four days at which time GC analysis of the product amine (tR 5.4 min) indicated a complete reaction. The solution was degassed and filtered through Celite 545, and the solvent was removed under reduced pressure. The residue was diluted with 25 mL of 12N KOH and extracted with ether (2×50 mL). The ether layer was filtered through glass wool/Na2CO3 and dried over Na2CO3. The solvent was removed under water aspirator vacuum, and the residue was distilled to yield 3-aminopropanal diethylacetal (18.6 g, 126 mmol, 63%): bp17 80°-81.5° C. bp20 68°-70° C. agreed with b.p. in Becke, F. German Patent 845,348, 1952, Chem. Abstr. 47 (1952) 542); 1H--NMR (200 MHz CDCl3) δ 1.21 (t, 6 H, CH3), 1.58 (s, 2 H, NH2), 1.78 (q, 2 H CH2), 2.81 (t, 2 H, NCH2), 3.53 and 3.66 (m, 4 H, OCH2), 4.62 (t, 1 H, CH). Anal. Calcd for C7H17NO2 : C, 57.1; H, 11.6. Found: C, 57.1; H, 11.5.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][O:21]C)[N:14]([CH2:15][C:16]([CH3:19])([OH:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:5][C:4]=2[N:3]=1.CO>C(Cl)(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:20][OH:21])[N:14]([CH2:15][C:16]([CH3:17])([OH:18])[CH3:19])[C:10]=2[C:9]2[CH:8]=[CH:7][C:6]([CH2:23][CH2:24][C:25]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[O:26])=[CH:5][C:4]=2[N:3]=1
Reactant: COCc1nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c2n1CC(C)(C)O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(C)(O)Cn1c(CO)nc2c(N)nc3cc(CCC(=O)N4CCOCC4)ccc3c21
Temperature: 25 °C
Reaction time: 18 h
Yield: 10.8 %

Procedure:
A stirring solution of 1-[4-amino-2-(methoxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol (460 mg, 1.04 mmol) in chloroform (120 mL) was sealed with a septum and purged with nitrogen gas. The solution was cooled in an ice water bath and a solution of 1.0 M boron tribromide in dichloromethane (6.6 mL) was added via syringe. The reaction was stirred for 18 hours while warming to ambient temperature. In order to complete the reaction three additional portions (3 mL, 10 mL, and 10 mL) of 1.0 M boron tribromide in dichloromethane were added at approximately 18 hour intervals. Methanol (75 mL) was added. The reaction was concentrated to a dark purple liquid and then stirred in 10% aqueous hydrochloric acid (100 mL) for three days. Solid sodium carbonate was slowly added until the pH equaled 10. The solution was concentrated to a white solid. The solid was washed with methanol (2×100 mL) and filtered. The filtrate was absorbed onto silica (2 tbsp) and then purified by chromatography using a HORIZON HPFC system (silica cartridge, eluting with a CMA:chloroform gradient; 0-20% CMA over 1400 mL, followed by 20-30% CMA over 1600 mL) to provide 48 mg of 1-[4-amino-2-(hydroxymethyl)-7-(3-morpholin-4-yl-3-oxopropyl)-1H-imidazo[4,5-c]quinolin-1-yl]-2-methylpropan-2-ol as a white crystalline solid, mp 223-225° C.
Reaction SMILES: [CH3:1][C:2]([CH3:7])([CH2:5][OH:6])[CH2:3][OH:4].[H-].[Na+].[Si:10](Cl)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11].C(=O)(O)[O-].[Na+]>O1CCCC1>[Si:10]([O:4][CH2:3][C:2]([CH3:7])([CH3:1])[CH2:5][OH:6])([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CC(C)(CO)CO
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(CO)CO[Si](C)(C)C(C)(C)C
Yield: 87.7 %

Procedure:
A solution of 10 g of 2,2-dimethyl-1,3-propanediol in 100 ml of tetrahydrofuran is added in drops to a suspension of 3.85 g of sodium hydride (60%) in 30 ml of tetrahydrofuran. It is allowed to stir for 45 more minutes, and then 14.5 g of tert-butyldimethylsilyl chloride is added. Then, it is stirred for one more hour at 25° C. Then, the reaction mixture is poured into saturated sodium bicarbonate solution. It is extracted with ethyl acetate, the organic phase is washed with saturated sodium chloride solution, dried on sodium sulfate, and concentrated by evaporation in a vacuum. The crude product is purified by column chromatography on silica gel. 18.4 g of product is obtained.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([C:18]#[C:19][C:20]([C:22]3[N:23](C(OC(C)(C)C)=O)[CH:24]=[CH:25][CH:26]=3)=O)[C:13]([F:17])=[CH:14][CH:15]=2)[CH:10]=[C:9]1[O:34]C(OC(C)(C)C)=O)=O)(C)(C)C.[NH:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1.FC(F)(F)C(O)=O>C(Cl)Cl>[F:17][C:13]1[C:12]2[C:11]3[C:16](=[CH:15][CH:14]=1)[NH:8][C:9](=[O:34])[C:10]=3[C:20]([C:22]1[NH:23][CH:24]=[CH:25][CH:26]=1)=[CH:19][C:18]=2[N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)Oc1cc2c(C#CC(=O)c3cccn3C(=O)OC(C)(C)C)c(F)ccc2n1C(=O)OC(C)(C)C
Reactant: C1COCCN1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1Nc2ccc(F)c3c(N4CCOCC4)cc(-c4ccc[nH]4)c1c23
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a flask charged with 2-tert-butoxycarbonyloxy-4-[3-(1-tert-butoxycarbonyl-1H-pyrrol-2-yl)-3-oxo-prop-1-ynyl]-5-fluoro-indole-1-carboxylic acid tert-butyl ester (from Example 4 above) (220 mg, 0.39 mmol) was added morpholine (Aldrich, 2 mL, 23 mmol) and the red solution was stirred under argon at room temperature for 10 minutes. The reaction was then quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts were successively washed with water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue obtained was re-dissolved in CH2Cl2 (2 mL) and treated with trifluoroacetic acid at 0° C. for 1 hour. The reaction was then quenched with a saturated aqueous sodium bicarbonate solution (5 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were successively washed with water (5 mL) and brine (5 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The dark-brown material was then suspended in 0.5 N NaOH (8 mL) and heated to 90° C. for 6 hours. The reaction was quenched by pouring the reaction mixture into an ice-cold saturated aqueous ammonium chloride solution (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were successively washed with water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified by preparative TLC (silica gel, 50% ethyl acetate in hexanes) to afford 6-fluoro-5-morpholin-4-yl-3-(1H-pyrrol-2-yl)-1H-benzo[cd]indol-2-one as a yellow solid. (Yield 15.1 mg, 11.6%).