Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@H:2]1[CH2:33][C:32]([CH3:34])=[CH:31][C@@H:30]([CH2:35][CH:36]=[CH2:37])[C:28](=[O:29])[CH2:27][C@H:26]([OH:38])[C@@H:25]([CH3:39])[C@@H:24](/[C:40](/[CH3:51])=[CH:41]/[C@H:42]2[CH2:47][C@@H:46]([O:48][CH3:49])[C@H:45]([OH:50])[CH2:44][CH2:43]2)[O:23][C:21](=[O:22])[C@H:20]2[N:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[C:13](=[O:14])[C:11](=[O:12])[C@:9]2([OH:52])[O:10][C@@H:5]([C@@H:6]([O:54][CH3:55])[CH2:7][C@H:8]2[CH3:53])[C@@H:4]([O:56][CH3:57])[CH2:3]1.[C:58]1(=[O:64])[O:63][C:61](=[O:62])[CH2:60][CH2:59]1.C(OCC)(=O)C>N1C=CC=CC=1.CN(C1C=CN=CC=1)C>[CH2:35]([CH:30]1[CH:31]=[C:32]([CH3:34])[CH2:33][CH:2]([CH3:1])[CH2:3][CH:4]([O:56][CH3:57])[CH:5]2[O:10][C:9]([OH:52])([CH:8]([CH3:53])[CH2:7][CH:6]2[O:54][CH3:55])[C:11](=[O:12])[C:13](=[O:14])[N:15]2[CH:20]([CH2:19][CH2:18][CH2:17][CH2:16]2)[C:21](=[O:22])[O:23][CH:24]([C:40]([CH3:51])=[CH:41][CH:42]2[CH2:43][CH2:44][CH:45]([O:50][C:58](=[O:64])[CH2:59][CH2:60][C:61]([OH:63])=[O:62])[CH:46]([O:48][CH3:49])[CH2:47]2)[CH:25]([CH3:39])[CH:26]([OH:38])[CH2:27][C:28]1=[O:29])[CH:36]=[CH2:37]
Reactant: C=CC[C@@H]1C=C(C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Reactant: O=C1CCC(=O)O1
Agent: C=CC[C@@H]1/C=C(\C)C[C@H](C)C[C@H](OC)[C@H]2O[C@@](O)(C(=O)C(=O)N3CCCC[C@H]3C(=O)O[C@H](/C(C)=C/[C@@H]3CC[C@@H](O)[C@H](OC)C3)[C@H](C)[C@@H](O)CC1=O)[C@H](C)C[C@@H]2OC
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: C=CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OC(=O)CCC(=O)O)C(OC)C3)C(C)C(O)CC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of the FR-900506 substance (248 mg) in pyridine (7 ml) were added succinic anhydride (145 mg) and 4-(N,N-dimethylamino)pyridine (7 mg), and the resulting mixture was stirred at room temperature for 18 hours. The reaction mixture was subjected to chromatography on pressure and the residue was subjected to chromatography on silica gel (20 g) with ethyl acetate to give 17-allyl-12-[2-[4-(3-carboxypropionyloxy)-3-methoxycyclohexyl]-1-methylvinyl]-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16,-tetraone (90 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[S:11][CH2:10][C:9](=[O:12])[NH:8][C:7]=2[CH:13]=1>C1COCC1.C(Cl)(Cl)Cl>[O:12]=[C:9]1[NH:8][C:7]2[CH:13]=[C:3]([CH:2]=[O:1])[CH:4]=[CH:5][C:6]=2[S:11][CH2:10]1
Reactant: O=C1CSc2ccc(CO)cc2N1
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: O=Cc1ccc2c(c1)NC(=O)CS2
Temperature: 70 °C
Reaction time: 4 h
Yield: 57.5 %

Procedure:
To a solution of 6-hydroxymethyl-4H-benzo[1,4]thiazin-3-one (360 mg, 1.8 mmol) in THF/CHCl3 (2:1, 18 mL) was added MO2 (1.6 g, 18 mmol) and the resulting suspension was heated to 70° C. and stirred for 4 h. The suspension was filtered through diatomaceous earth and the filtrate was concentrated. The resulting solid was triturated with EtOAc/hexanes (1:1) and a minimal amount of CH3OH to provide 200 mg (56%) of the title compound as a tan solid. MS (ESI): exact mass calculated for C9H7NO2S, 193.02; m/z found, 194.1 [M+H]+. 1H NMR (500 MHz, CDCl3): 9.94 (s, 1H), 8.78 (br s, 1H), 7.54-7.49 (m, 2H), 7.37 (d, J=1.5, 1H), 3.52 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[CH3:19][N:20]1[C:24](B2OC(C)(C)C(C)(C)O2)=[CH:23][C:22]([CH3:34])=[N:21]1>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:24]3[N:20]([CH3:19])[N:21]=[C:22]([CH3:34])[CH:23]=3)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)n(C)n1
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3cc(C)nn3C)cccc2c1N
Yield: 21.4 %

Procedure:
Using method A, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (200 mg, 0.647 mmol) and 1,3-dimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (288 mg, 1.297 mmol) were reacted to afford the title compound (45 mg, 21% yield) as a white solid.
Reaction SMILES: Cl[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:11][C:12]1[CH:13]=[C:14]([CH2:18][C:19]([N:21]2[C:29]3[C:24](=[CH:25][C:26](B4OC(C)(C)C(C)(C)O4)=[CH:27][CH:28]=3)[CH2:23][CH2:22]2)=[O:20])[CH:15]=[CH:16][CH:17]=1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].F[B-](F)(F)F.C([PH+](C(C)(C)C)C(C)(C)C)(C)(C)C>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:10][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([C:26]2[CH:25]=[C:24]3[C:29](=[CH:28][CH:27]=2)[N:21]([C:19](=[O:20])[CH2:18][C:14]2[CH:15]=[CH:16][CH:17]=[C:12]([CH3:11])[CH:13]=2)[CH2:22][CH2:23]3)[C:7]=1[C:8]#[N:9]
Reactant: Cc1cccc(CC(=O)N2CCc3cc(B4OC(C)(C)C(C)(C)O4)ccc32)c1
Reactant: N#Cc1c(Cl)cncc1Cl
Agent: [Pd]
Agent: CC(C)(C)[PH+](C(C)(C)C)C(C)(C)C
Agent: F[B-](F)(F)F
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(CC(=O)N2CCc3cc(-c4cncc(Cl)c4C#N)ccc32)c1
Temperature: 120 °C
Yield: 28.4 %

Procedure:
A mixture of 3,5-dichloro-4-pyridinecarbonitrile (400 mg, 2.312 mmol), 1-[(3-methylphenyl)acetyl]-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-indole (872 mg, 2.312 mmol), Pd2(dba)3 (42.3 mg, 0.046 mmol) and K3PO4 (982 mg, 4.62 mmol) in 9 mL of dioxane and 3 mL of water in a microwave tube was degassed and backflushed with nitrogen, followed by addition of tri-(t-butyl)phosphonium tetrafluoroborate salt (26.8 mg, 0.092 mmol). The mixture was degassed and backflushed with nitrogen. The mixture was heated in a microwave reactor at 120° C. for 40 minutes. LCMS showed there was no stating material. The mixture was cooled to room temperature, and the mixture was filtered. The filtered solid was purified by silica gel column chromatography on a silica gel cartridge using gradient elution of 100% CH2Cl2 to 90:10:1 CH2Cl2/CH3OH/NH3OH. The combined product fractions were evaporated to dryness to give 3-chloro-5-{1-[(3-methylphenyl)acetyl]-2,3-dihydro-1H-indol-5-yl}-4-pyridinecarbonitrile as a pale yellow solid (255 mg, 26% yield). LCMS [M+1] 388. 1H NMR (400 MHz, DMSO-d6) δ 2.31 (s, 3H), 3.24 (t, J=8.34 Hz, 2H), 3.85 (s, 2H), 4.25 (t, J=8.46 Hz, 2H), 7.06-7.14 (m, 3H), 7.20-7.27 (m, 1H), 7.51 (d, J=8.34, 1H), 7.58 (s, 1H), 8.21 (d, J=8.34 Hz, 1H), 8.82 (s, 1H), 8.93 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@@H:9]([C:17]([OH:19])=O)[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C1C=C2[N:26]=NN(O)C2=CC=1.O.C(Cl)CCl.[NH4+].[OH-]>CN(C=O)C.CCOC(C)=O.O>[NH2:26][C:17](=[O:19])[C@H:9]([NH:8][C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: On1nnc2ccccc21
Reactant: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(=O)O
Agent: [NH4+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@H](CC1CCCCC1)C(N)=O
Reaction time: 1 h
Yield: 91.9 %

Procedure:
To a solution of N-Boc-β-cyclohexyl-D-alanine (1.00 g, 3.69 mmol) and HOBt hydrate (0.678 g, 4.43 mmol) in DMF (10 mL), EDC (0.850 g, 4.43 mmol) was added. The mixture was stirred for 60 min. Then conc. NH4OH (1.00 mL, ˜14.0 mmol) was added. It was stirred for 18 h. Water and EtOAc were added. The organic phase was separated, washed with 5% NaHCO3, dried over Na2SO4, concentrated in vacuo to give (R)-tert-butyl 1-amino-3-cyclohexyl-1-oxopropan-2-ylcarbamate as a white solid (0.917 g).
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14](OCC)=[O:15])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[CH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCc1cn(Cc2ccccc2)cn1

Procedure:
To a stirred solution of 3-3 (4.6 g, 19 mmol) in THF (50 mL) at ambient temperature was added LiAlH4 (9.4 mL, 9.4 mmol; 1M THF solution). After 1.0 h the reaction was quenched with sat. NaK tartrate solution. The mixture was poured into a EtOAc/H2O mixture. The organic portion was washed with brine, dried (MgSO4) and concentrated to give 3-4 as a yellow viscous oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]([CH3:12])[C:9]([N+:13]([O-])=O)=[C:8]2[C:3]=1[C:4]([NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=1)=[N:5][CH:6]=[N:7]2>CCO.[Pd]>[CH3:12][C:10]1[C:9]([NH2:13])=[C:8]2[C:3]([C:4]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)=[N:5][CH:6]=[N:7]2)=[CH:2][CH:11]=1
Reactant: Cc1cc(Br)c2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: Cc1ccc2c(Nc3cccc(C(F)(F)F)c3)ncnc2c1N
Reaction time: 5 h
Yield: 66.8 %

Procedure:
To a solution of 5-bromo-7-methyl-8-nitro-N-(3-(trifluoromethyl)phenyl)quinazolin-4-amine (400 mg, 0.94 mmol) in EtOH (10 mL) was added 10% Pd/C (420 mg) and the suspension was stirred under H2 (1 atm) for 5 h. Then the reaction mixture was filtered through celite and concentrated. The residue was purified by column chromatography to afford 200 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 9.73 (s, 1H), 8.59 (s, 1H), 8.38 (s, 1H), 8.26 (d, J=7.2 Hz, 1H), 7.65-7.58 (m, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.30 (d, J=8.7 Hz, 1H), 5.63 (br s, 2H), 2.80 (s, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[CH:8]([OH:10])[CH3:9].CC1(C)C(C)(C)OB([C:19]2[CH:20]=[C:21]3[C:26](=[N:27][CH:28]=2)[NH:25][CH2:24][CH2:23][CH2:22]3)O1>>[N:25]1[C:26]2[NH:27][CH2:28][CH2:19][CH2:20][C:21]=2[CH:22]=[C:23]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]=2[CH:8]([OH:10])[CH3:9])[CH:24]=1
Reactant: CC1(C)OB(c2cnc3c(c2)CCCN3)OC1(C)C
Reactant: CC(O)c1ccncc1Br
Product: CC(O)c1ccncc1-c1cnc2c(c1)CCCN2

Procedure:
1-[3-(5,6,7,8-Tetrahydro-[1,8]naphthyridin-3-yl)-pyridin-4-yl]-ethanol is synthesized according to the procedure of Suzuki Coupling Method VI using 1-(3-bromo-pyridin-4-yl)-ethanol and crude 6-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,4-tetrahydro-[1,8]naphthyridine (which is prepared according to Step 4 of Example 105).
Reaction SMILES: [C:1]([C:4]1[C:5](I)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2].[Cl:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][C:30]=1[F:31].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.O>[C:1]([C:4]1[C:5]([C:27]2[CH:28]=[CH:29][C:30]([F:31])=[C:25]([Cl:24])[CH:26]=2)=[N:6][N:7]2[C@H:12]3[CH2:13][O:14][CH2:15][C@H:11]3[N:10]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:9][C:8]=12)(=[O:3])[NH2:2]
Reactant: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(I)nn2[C@H]2COC[C@H]21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1Cc2c(C(N)=O)c(-c3ccc(F)c(Cl)c3)nn2[C@H]2COC[C@H]21
Temperature: 80 °C
Reaction time: 16 h
Yield: 72.5 %

Procedure:
To a stirred solution of Intermediate 352F (0.370 g, 0.852 mmol) and (3-chloro-4-fluorophenyl)boronic acid (0.297 g, 1.704 mmol) in dioxane (2 mL) was added a solution of K3PO4 (0.543 g, 2.56 mmol) in water (0.5 mL) and the reaction mixture was purged with nitrogen for 10 min. PdCl2(dppf)CH2Cl2 (0.052 g, 0.064 mmol) was then added and the reaction mixture was heated to 80° C. and stirred for 16 h. The reaction mixture was diluted with water and extracted with EtOAc (3×30 mL). The combined organic layers were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified by silica gel chromatography (12 g REDISEP® column, eluting with 4% MeOH in CHCl3). Fractions containing the product were combined and evaporated to afford Intermediate 352G (0.270 g, 54%) as an off-white solid. MS(ES): m/z=437 [M+H]+.
Reaction SMILES: [C:1]([C:4]12[CH2:11][CH2:10][C:7]([NH:12][CH2:13][C:14]([N:16]3[CH2:20][C@@H:19]([F:21])[CH2:18][C@H:17]3[C:22]#[N:23])=[O:15])([CH2:8][CH2:9]1)[CH2:6][CH2:5]2)([OH:3])=O.[CH3:24][C:25]([CH3:30])([CH3:29])[CH2:26][CH2:27][NH2:28]>>[F:21][C@@H:19]1[CH2:20][N:16]([C:14](=[O:15])[CH2:13][NH:12][C:7]23[CH2:8][CH2:9][C:4]([C:1]([NH:28][CH2:27][CH2:26][C:25]([CH3:30])([CH3:29])[CH3:24])=[O:3])([CH2:5][CH2:6]2)[CH2:11][CH2:10]3)[C@H:17]([C:22]#[N:23])[CH2:18]1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CNC12CCC(C(=O)O)(CC1)CC2
Reactant: CC(C)(C)CCN
Product: CC(C)(C)CCNC(=O)C12CCC(NCC(=O)N3C[C@@H](F)C[C@H]3C#N)(CC1)CC2

Procedure:
In a similar manner to Example 87, (2S,4S)-1-[[N-[4-carboxybicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (50.0 mg) and 3,3-dimethylbutylamine (45.8 μL) were used to obtain (2S,4S)-4-fluoro-1-[[N-[4-[N-(3,3-dimethylbutyl)amino]carbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]pyrrolidine-2-carbonitrile (24.6 mg).
Reaction SMILES: C([S:4][C@H:5]1[N:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:7](=[O:14])[C@@H:6]1[Cl:15])(=O)C.[N+]([O-])([O-])=O.[Ag+:20].C(N(CC)CC)C>CO>[Cl:15][C@@H:6]1[C@@H:5]([S-:4])[N:8]([CH2:9][C:10]([O:12][CH3:13])=[O:11])[C:7]1=[O:14].[Ag+:20]
Reactant: COC(=O)CN1C(=O)[C@H](Cl)[C@H]1SC(C)=O
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)CN1C(=O)[C@H](Cl)[C@H]1[S-]
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A solution of methyl [(3S,4R)-4-acetylthio-3-chloro-2-oxo-azetidin-1-yl]acetate (3.64 g, 0.0145 mol) in methanol (125 ml) was added with stirring in subdued light to a solution of silver nitrate (3.2 g, 0.0188 mol) in methanol (55 ml). Triethylamine (2.6 ml, 0.0187 mol) was then added with ice cooling, and the reaction was stirred for 1 hr at 5-10° C. followed by 40 minutes at room temperature. The mixture was filtered and the solid washed with methanol (x2) and hexane to yield the title compound, 4.19 g (92%).
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([O:9][C:10](=[O:30])[NH:11][CH:12]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([O:25][CH2:26][CH2:27][CH2:28][OH:29])[CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:2]2.[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41](O)=[O:42])=[CH:39][CH:38]=1.NCCC(OCC)OCC>>[O:31]1[CH2:35][CH2:34][O:33][CH:32]1[CH2:36][C:37]1[CH:45]=[CH:44][C:40]([C:41]([O:29][CH2:28][CH2:27][CH2:26][O:25][C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([CH:12]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[NH:11][C:10]([O:9][C@@H:3]3[CH:4]4[CH2:5][CH2:6][N:1]([CH2:8][CH2:7]4)[CH2:2]3)=[O:30])[CH:20]=2)=[O:42])=[CH:39][CH:38]=1
Reactant: O=C(O)c1ccc(CC2OCCO2)cc1
Reactant: O=C(NC(c1ccccc1)c1cccc(OCCCO)c1)O[C@H]1CN2CCC1CC2
Agent: CCOC(CCN)OCC
Product: O=C(NC(c1ccccc1)c1cccc(OCCCOC(=O)c2ccc(CC3OCCO3)cc2)c1)O[C@H]1CN2CCC1CC2

Procedure:
The title compound was prepared as described in Chiral Example 11 Step 2 with (R)-quinuclidin-3-yl((3-(3-hydroxypropoxy)phenyl)(phenyl)methyl)carbamate and 4-(1,3-dioxolan-2-ylmethyl)-benzoic acid replacing 4-((3-(phenyl((((R)-quinuclidin-3-yloxy)carbonyl)amino)methyl)phenoxy)methyl)benzoic acid and 1-amino-3,3-diethoxypropane, respectively.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[C@H:3]([NH:6][CH3:7])[CH2:4][OH:5].[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][C:11]=1[CH3:19].O>C(Cl)Cl>[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:6]([C@@H:3]([CH:2]([CH3:8])[CH3:1])[CH2:4][OH:5])[CH3:7])=[O:15])=[CH:12][C:11]=1[CH3:19]
Reactant: CN[C@H](CO)C(C)C
Reactant: Cc1cc(C(=O)Cl)ccc1F
Solvent: O
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)[C@H](CO)C(C)C)ccc1F
Reaction time: 3 h
Yield: 83.5 %

Procedure:
TEA (1.774 mL, 12.80 mmol) was added to (S)-3-methyl-2-(methylamino)butan-1-ol (Compound B2.1) (0.5 g, 4.3 mmol) in DCM (5 mL). The mixture was cooled on an ice-bath and 4-fluoro-3-methylbenzoyl chloride (1.27 mL, 8.96 mmol) in DCM (5 mL) was dropwise (over 5 min) added. The resultant mixture was stirred at rt over night. Additional TEA (0.414 mL, 2.99 mmol) and 4-fluoro-3-methylbenzoyl chloride (0.368 g, 2.13 mmol) was added and the stirring was continued for 3 h. Water (12 mL) was added to the mixture. The organic layer was dried though a phase separator and concentrated. THF (15 mL) and NaOH was added to the residue and the resulting mixture was stirred over night. The mixture was neutralized by the addition of acetic acid. The solvent was removed and DCM (50 mL) was added. The organic phase was washed with Na2CO3 (saturated, 2×30 mL) and brine (30 mL), filtered through a phase separator and concentrated under reduced pressure to give the title compound (0.91 g, 85%). The obtained crude product was used without further purification. Mixture of rotamers: (600 MHz, CD3OD) δ 0.77-0.82, 0.95, 1.02, 1.74-1.83, 1.89-1.97, 2.23-2.31, 2.83, 2.92, 3.37-3.44, 3.58-3.74, 3.79-3.86, 4.23-4.31, 7.01-7.11, 7.18-7.36. Ratio major:minor:1:0.6. Total no of protons: 19.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[CH3:12][C:13]([CH3:39])([S:35]([NH2:38])(=[O:37])=[O:36])[CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][C:25]([Br:30])=[CH:24][C:23]=3[N:22]=[CH:21][C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34].[OH-].[NH4+:41].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl.ClCCl>[CH3:39][C:13]([CH3:12])([S:35]([NH2:38])(=[O:36])=[O:37])[CH2:14][CH2:15][CH2:16][N:17]1[C:29]2[C:28]3[CH:27]=[CH:26][C:25]([Br:30])=[CH:24][C:23]=3[N:22]=[C:21]([NH2:41])[C:20]=2[N:19]=[C:18]1[CH2:31][O:32][CH2:33][CH3:34]
Reactant: [NH4+]
Reactant: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCOCc1nc2c(N)nc3cc(Br)ccc3c2n1CCCC(C)(C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-Chloroperoxybenzoic acid (0.126 g of 70% pure material, 0.73 mmol) was added in one portion to a stirred solution of dimethyl 4-(7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide (0.30 g, 0.63 mmol) in chloroform (7 mL), and the solution was stirred for two hours at ambient temperature. Ammonium hydroxide (2 mL) and p-toluenesulfonyl chloride (0.15 g, 0.76 mmol) were sequentially added, and the mixture was stirred at ambient temperature for one hour. Dichloromethane (100 mL) was added, and the mixture was washed sequentially with 2 M aqueous sodium hydroxide (2×30 mL), saturated aqueous sodium bicarbonate (2×30 mL), and brine (30 mL); dried over magnesium sulfate; filtered; and concentrated under reduced pressure. The crude product was purified by column chromatography on silica gel (eluting with ethyl acetate:ethanol in a gradient from 100:0 to 80:20) followed by recrystallization from dichloromethane:heptane. The crystals were dried for two hours under vacuum at 40° C. to provide 0.185 g of dimethyl 4-(4-amino-7-bromo-2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)butane-1-sulfonamide as a white solid, mp 193° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.CCO.O>[Fe].CC(O)=O>[NH2:1][C:4]1[CH:5]=[C:6]([C@H:10]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH3:11])[CH:7]=[CH:8][CH:9]=1
Reactant: C[C@@H](NC(=O)OCc1ccccc1)c1cccc([N+](=O)[O-])c1
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CCO
Solvent: O
Product: C[C@@H](NC(=O)OCc1ccccc1)c1cccc(N)c1
Temperature: 25 °C
Yield: 59.8 %

Procedure:
To a refluxing solution of 64A (5 g, 16.7 mmol), EtOH (100 mL), water (30 mL) and AcOH (15 mL) was added portion-wise Fe powder (5 g, 89 mmol) over 30 min. The mixture was heated for 1 h. before cooling to ambient temperature. and filtering through celite. The filtrate was concentrated in vacuo to afford 64B (2.7 g, 61%) as an oil. MS (ESI) m/z 271.2 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[CH2:3][CH2:4][CH:5]([NH:24]C(=O)OC(C)(C)C)[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([CH3:22])[C:12]=2[CH:23]=1.Cl.O1CCOCC1>C(OCC)C>[NH2:24][CH:5]([CH2:4][CH2:3][C:2]([F:32])([F:33])[F:1])[CH2:6][O:7][C:8]1[CH:9]=[CH:10][C:11]2[C:20]3[C:15](=[CH:16][N:17]=[CH:18][CH:19]=3)[C:14](=[O:21])[N:13]([CH3:22])[C:12]=2[CH:23]=1
Reactant: Cn1c(=O)c2cnccc2c2ccc(OCC(CCC(F)(F)F)NC(=O)OC(C)(C)C)cc21
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: Cn1c(=O)c2cnccc2c2ccc(OCC(N)CCC(F)(F)F)cc21
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 86.3 %

Procedure:
To a solution of tert-butyl (5,5,5-trifluoro-1-((6-methyl-5-oxo-5,6-dihydrobenzo[c][2,7]naphthyridin-8-yl)oxy)pentan-2-yl)carbamate (150 mg, 0.322 mmol) in diethyl ether (10 mL) under nitrogen atmosphere, cooled to 0° C. was added 4M HCl in 1,4-dioxane (0.098 mL, 0.392 mmol) slowly over a period of 5 min. The light yellow reaction mixture was stirred at 0° C. for 5 min then warmed to room temperature and allowed to stir for 12 h. The solvent was removed under reduced pressure. The residual yellow oil was diluted with water (3 mL) and extracted with EtOAc (2×4 mL). The aqueous layer was separated and treated with sat. Na2CO3 solution (3 mL). The resultant aqueous layer was extracted with EtOAc (3×5 mL). The combined organic layer s were separated and washed with water (2×5 mL), brine (1×5 mL) and dried over sodium sulfate. The filtrate was evaporated under reduced pressure and purified by SFC (CO2 and 0.5% DEA in Methanol) to afford 8-((2-amino-5,5,5-trifluoropentyl)oxy)-6-methylbenzo[c][2,7]naphthyridin-5(6H)-one (102.8 mg, 0.278 mmol, 86% yield) as a white solid. LC/MS (ESI) m/e 366.2 [(M+H)+, calcd for C18H19F3N3O2366.13]; LC/MS retention time (method C): tR=1.77 min; HPLC retention time (method A): tR=7.79 min; HPLC retention time (method B): tR=8.20 min. 1H NMR (400 MHz, MeOD) δ 9.48 (d, J=0.80 Hz, 1H), 8.78 (d, J=5.60 Hz, 1H), 8.44 (d, J=8.80 Hz, 1H), 8.27 (d, J=5.60 Hz, 1H), 7.17 (d, J=2.40 Hz, 1H), 7.12 (dd, J=2.40, 8.80 Hz, 1H), 4.17-4.20 (m, 1H), 4.09 (dd, J=6.00, 9.40 Hz, 1H), 3.82 (s, 3H), 3.28-3.28 (m, 1H), 2.33-2.49 (m, 2H), 1.92-1.99 (m, 1H), 1.73-1.80 (m, 1H).
Reaction SMILES: [NH2-].[Na+].[CH2:3]([NH2:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=1Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CO>O1CCCC1>[CH2:3]([NH:10][C:23]1[CH:24]=[C:19]([O:18][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:20]=[CH:21][C:22]=1[CH3:25])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: NCc1ccccc1
Reactant: Cc1ccc(OCc2ccccc2)c(Br)c1
Agent: [NH2-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccc(OCc2ccccc2)cc1NCc1ccccc1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 72.3 %

Procedure:
100.0 g (2.56 mol) of sodium amide was added to 700 g (6.53 mol) of benzylamine under an argon atmosphere, and the mixture was stirred for 10 minutes at 60° C. A solution of 222.20 g (0.801 mol) of 1-benzyloxy-2-bromo-4-methylbenzene was dissolved in 400 ml of tetrahydrofuran was added dropwise to the above mixture over 50 minutes. The mixture was stirred for 50 minutes while maintaining the temperature at 60° C. Methanol was added under cooling with ice, and the mixture was poured into ice water. The reaction mixture was extracted with ethyl acetate-water, and the organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The residue obtained by evaporating the solvent was purified by column chromatography (silica gel, 10:1 mixture of n-hexane and ethyl acetate). The crude product thus obtained was recrystallized from n-hexane to obtain 175.80 g (yield: 72.3%) of the title compound as colorless needles.