Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[F:7][C:8]1[CH:13]=[CH:12][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:10][CH:9]=1.[N:33]1[CH:38]=[CH:37][CH:36]=[C:35]([CH2:39][NH2:40])[CH:34]=1>>[F:7][C:8]1[CH:9]=[CH:10][C:11]([S:14]([CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:32]=[CH:31][C:27]([C:28]([NH:40][CH2:39][C:35]4[CH:34]=[N:33][CH:38]=[CH:37][CH:36]=4)=[O:29])=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])(=[O:16])=[O:15])=[CH:12][CH:13]=1
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(F)cc1
Yield: 77.6 %

Procedure:
Reaction of oxalyl chloride (118 λL, 1.35 mmol) and benzoic acid 47 (337 mg, 0.90 mmol) with subsequent coupling to 3-pyridinylmethylamine (101 λL, 0.99 mmol) gave benzamide 48 (325 mg, 78%) as a white powder: mp (EtOAc) 218-220° C.; 1H NMR δ 9.22 (t, J=5.9 Hz, 1H, CONH), 8.57 (d, J=1.6 Hz, 1H, H-2′), 8.47 (dd, J=4.7, 1.4 Hz, 1H, H-6′), 8.00 (d, J=8.5 Hz, 2H, H-2, H-6), 7.83-7.91 (m, 4H, H-3, H-5, H-2″, H-6″), 7.74 (br d, J=7.8 Hz, 1H, H-4′), 7.47 (br t, J=8.8 Hz, 2H, H-3″, H-5″), 7.36 (dd, J=8.8, 4.7 Hz, 1H, H-5′), 4.73 (s, 2H, CH2SO2), 4.51 (d, J=5.9 Hz, 2H, CH2N), 2.19 (s, 3H, CH3); 13C NMR δ 165.5, 165.2 (d, J=252.7), 158.1, 150.0, 148.9, 148.1, 135.4, 135.2, 134.9, 134.8 (d, J=2.9 Hz), 131.6 (2, d, J=9.9 Hz), 128.8, 128.1 (2), 125.8, 125.4 (2), 123.5, 116.4 (2, J=22.8 Hz), 52.8, 40.5, 9.7; MS m/z 466.6 (MH+, 100%). Anal. calcd for C24H20FN3O4S: C, 61.92; H, 4.33; N, 9.03. Found: C, 62.18; H, 4.38; N, 9.14%.
Reaction SMILES: C[O-].[Na+].[CH2:4]=[C:5]1[CH:11]2[CH2:12][CH:8]([CH2:9][CH2:10]2)[C:7](=[O:13])[O:6]1>CS(C)=O.O>[CH:11]12[CH2:12][CH:8]([CH2:9][CH2:10]1)[C:7](=[O:13])[CH2:4][C:5]2=[O:6]
Reactant: C=C1OC(=O)C2CCC1C2
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: O=C1CC(=O)C2CCC1C2
Reaction time: 0.5 h
Yield: 88.5 %

Procedure:
4.27 g (79 mmol) of sodium methanolate in 40 ml of dimethyl sulfoxide are used as initial charge in a reaction vessel. A solution of 7.2 g (52 mmol) of 4-methylene-3-oxa-bicyclo(3.2.1]octan-2-one in 20 ml of dimethyl sulfoxide is fed into that solution in the course of 2.5 hours at a temperature of from 25 to 35° C., with stirring. After a further 0.5 hours, the reaction mixture is diluted with 200 ml of water and extracted twice with 100 ml of ethyl acetate. The combined organic phases are washed with 100 ml of water. The aqueous phases are then combined, adjusted to pH 3 using approximately 35 ml of 2N hydrochloric acid, and extracted four times using 400 ml of ethyl acetate each time. The combined organic phases are washed with water, dried over magnesium sulfate, filtered and concentrated using a rotary evaporator. The brown solid remaining is filtered over silica gel and yields 6.3 g (46 mmol) of bicyclo[3.2.1]octane-2,4-dione with a content of 93%, corresponding to a yield of 81.4%, and a melting point of 129-130° C.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[CH:7][C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:5]1)[CH3:3].[Cl:13]N1C(=O)CCC1=O>CN(C=O)C>[Cl:13][C:7]1[C:6]([C:9]([O:11][CH3:12])=[O:10])=[N:5][N:4]([CH:2]([CH3:1])[CH3:3])[CH:8]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COC(=O)c1ccn(C(C)C)n1
Solvent: CN(C)C=O
Product: COC(=O)c1nn(C(C)C)cc1Cl
Temperature: 60 °C
Yield: 67.2 %

Procedure:
A solution of methyl 1-(1-methylethyl)-1H-pyrazole-3-carboxylate (0.13 g) in DMF (3 ml) was treated with N-chlorosuccinimide (0.103 g) and heated to 60° C. for 5 h under nitrogen. The cooled mixture was partitioned between diethyl ether (20 ml) and water (20 ml), separated, the organic extracts dried over sodium sulphate and evaporated to give the title compound as a pale yellow oil (0.105 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1.C(N(CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[O:40]=[C:41]1[CH2:46][S:45][C:44]2[CH:47]=[CH:48][C:49]([C:51](O)=[O:52])=[N:50][C:43]=2[NH:42]1>CN(C=O)C>[CH3:1][N:2]([CH2:3][CH:4]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5]1)[C:51]([C:49]1[CH:48]=[CH:47][C:44]2[S:45][CH2:46][C:41](=[O:40])[NH:42][C:43]=2[N:50]=1)=[O:52]
Reactant: O=C1CSc2ccc(C(=O)O)nc2N1
Reactant: CNCC1CCN(C(=O)OC(C)(C)C)C1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CC1CCN(C(=O)OC(C)(C)C)C1)C(=O)c1ccc2c(n1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 24 h
Yield: 82.7 %

Procedure:
To a solution of 1,1-dimethylethyl 3-[(methylamino)methyl]-1-pyrrolidinecarboxylate (153 mg, 0714 mmol) in DMF (2 mL) were added triethylamine (0.1 mL, 0.714 mmol) followed by DPPA (0.154 mL, 0.714 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carboxylic acid (150 mg, 0.714 mmol). After stirring at room temperature for 24 h, the solution was partitioned between ethyl acetate and K CO solution (5% in H O). The aqueous layer was extracted several times with ethyl acetate. The organic fractions were combined, dried over MgSO, concentrated and purified with column chromatography (silica, 0-5% MeOH in DCM) to provide the title compound as an off-white solid (240 mg, 83%): LC/MS (ES) m/e 407 (M+H).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:36]([OH:38])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([Cl:35])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C.[O:72]1[CH2:77][CH2:76][CH:75]([N:78]2[CH2:83][CH2:82][NH:81][CH2:80][CH2:79]2)[CH2:74][CH2:73]1>CN(C=O)C>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([O:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[C:22]([Cl:35])[CH:21]=3)[C:36](=[O:38])[N:81]3[CH2:80][CH2:79][N:78]([CH:75]4[CH2:76][CH2:77][O:72][CH2:73][CH2:74]4)[CH2:83][CH2:82]3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:39]=[CH:40][CH:41]=[CH:42][C:4]=2[NH:3]1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(Cl)c1OCc1ccccc1
Reactant: C1CN(C2CCOCC2)CCN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCOCC3)CC2)cc(Cl)c1OCc1ccccc1
Reaction time: 2 h

Procedure:
A solution of 150 mg (0.25 mmol) (R)-2-(4-benzyloxy-3-chloro-5-methyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 89 mg (0.28 mmol) TBTU and 44 μL (0.32 mmol) triethylamine in 1.5 mL DMF was stirred for 1 h at RT. Then 47 mg (0.28 mmol) 1-(tetrahydropyran-4-yl)-piperazine were added and the reaction solution was stirred for 2 h. The reaction solution was purified by HPLC without any further working up; the fractions containing the product were combined and lyophilised.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:9](=[N:10][CH:11]=1)[N:8]=[CH:7][N:6]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=1)[C:5]2=[O:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:43])=[O:42])[C:37](B4OC(C)(C)C(C)(C)O4)=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[O:28][C:29]3[CH:39]=[C:38]([N:40]([CH3:45])[S:41]([CH3:44])(=[O:42])=[O:43])[C:37]([C:2]4[N:3]=[C:4]5[C:9](=[N:10][CH:11]=4)[N:8]=[CH:7][N:6]([C:12]4[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=4)[C:5]5=[O:19])=[CH:36][C:30]=3[C:31]=2[C:32]([NH:34][CH3:35])=[O:33])=[CH:23][CH:22]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=c1c2nc(Br)cnc2ncn1-c1cccc(F)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4ncn(-c5cccc(F)c5)c(=O)c4n3)cc12
Temperature: 120 °C
Reaction time: 5 h
Yield: 65.5 %

Procedure:
To a stirring mixture of 6-bromo-3-(3-fluorophenyl)pteridin-4(3H)-one (32 mg, 0.099 mmol), 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (50 mg, 0.099 mmol) and Na2CO3 (18 mg, 0.199 mmol) in dioxane/H2O (1 mL/0.1 mL) was added Pd(dppf)Cl2 (10 mg) under N2 protection. The mixture was stirred in a pre-heated oil-bath at 120° C. for 5 h. The mixture was cooled and extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was purified by prep-HPLC to give the pure product of 2-(4-fluorophenyl)-5-(3-(3-fluorophenyl)-4-oxo-3,4-dihydropteridin-6-yl)-N-methyl-6-(N-methylmethylsulfonamido)benzofuran-3-carboxamide (40 mg, yield: 50%). 1H-NMR (CDCl3, 400 MHz) δ 9.20 (s, 1H), 8.36 (s, 1H), 8.13 (s, 1H), 7.87˜7.92 (m, 2H), 7.63 (s, 1H), 7.43˜7.55 (m, 1H), 7.33˜7.38 (m, 1H), 7.13˜7.25 (m, 4H), 6.07 (br s, 1H), 3.30 (s, 3H), 2.94 (d, J=4.8 Hz, 3H), 2.86 (s, 3H). MS (M+H)+: 617.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[CH3:13][O:14][CH2:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=2)[C:24]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:25]=2[C:38]([OH:40])=O)=[CH:19][CH:18]=1.[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH2:55].O>C(Cl)Cl>[CH3:51][N:52]([CH3:56])[CH2:53][CH2:54][NH:55][C:38]([C:25]1[N:26]([CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])[C:27]2[C:32]([C:24]=1[CH:23]([C:20]1[CH:21]=[CH:22][C:17]([O:16][CH2:15][O:14][CH3:13])=[CH:18][CH:19]=1)[C:41]1[CH:46]=[CH:45][C:44]([O:47][CH2:48][O:49][CH3:50])=[CH:43][CH:42]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:40]
Reactant: CN(C)CCN
Reactant: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)O)n(CCN(C)C)c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: COCOc1ccc(C(c2ccc(OCOC)cc2)c2c(C(=O)NCCN(C)C)n(CCN(C)C)c3ccccc23)cc1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.48 g, 7.71 mmol) was added to a solution of 3-{bis[4-(methoxymethoxy)phenyl]methyl}-1-(2-dimethylaminoethyl)indole-2-carboxylic acid (2.0 g, 3.86 mmol) obtained in Example 48 and N,N-dimethylethylenediamine (0.64 ml, 5.78 mmol) in 30 ml of methylene chloride, followed by stirring at room temperature for 4.5 hours. Water was added to the reaction solution followed by extraction with chloroform. The resulting organic layer was washed successively with 2N hydrochloric acid, a saturated aqueous solution of sodium bicarbonate, and a saturated aqueous solution of sodium chloride, and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to give 2.48 g (quantitative) of the title compound.
Reaction SMILES: [O:1]=[C:2]1[C@@H:8]([NH:9]C(=O)OCC2C=CC=CC=2)[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][C@H:22]([C:24]([F:27])([F:26])[F:25])[CH2:23][N:3]12.I[Si](C)(C)C>C(Cl)Cl>[NH2:9][C@H:8]1[CH2:7][CH2:6][S:5][C@H:4]2[CH2:20][CH2:21][C@H:22]([C:24]([F:26])([F:25])[F:27])[CH2:23][N:3]2[C:2]1=[O:1]
Reactant: O=C(N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O)OCc1ccccc1
Agent: C[Si](C)(C)I
Solvent: ClCCl
Product: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.7 %

Procedure:
To a solution of benzyl (4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-ylcarbamate (101 mg, 0.251 mmol) in DCM (1.2 mL) stirred at rt was added iodotrimethylsilane (150 mg, 0.752 mmol) dropwise. After the addition, the resulting yellowish solution was stirred at rt under argon for 2 hr. The reaction mixture was quenched by the dropwise addition of 1 N aqueous HCl, diluted with EtOAc, and extracted with 1 N aqueous HCl (2×3 mL). The combined HCl extracts were washed with EtOAc (2×). The aqueous layer was then basified with 1 N aqueous NaOH solution to pH 9-10 and extracted with DCM (3×10 mL). The combined DCM extracts were washed with water, saturated aqueous NaCl, dried over Na2SO4, filtered and concentrated to give (4S,8S,10aS)-4-amino-8-(trifluoromethyl)hexahydro-2H-pyrido[2,1-b][1,3]thiazepin-5(7H)-one (45 mg, 0.17 mmol, 66% yield) as a white solid. Anal. Calcd. for C10H15F3N2OS m/z 268.2. found: 269.0 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 5.14 (t, J=7.2 Hz, 1H), 4.46 (dd, J=14.7, 2.6 Hz, 1H), 3.88 (dd, J=10.5, 2.8 Hz, 1H), 3.30 (dd, J=14.8, 6.6 Hz, 1H), 3.13 (ddd, J=14.2, 11.0, 2.9 Hz, 1H), 2.74 (ddd, J=14.5, 5.9, 3.1 Hz, 1H), 2.66-2.54 (m, 1H), 2.35-2.23 (m, 1H), 2.18 (ddt, J=14.0, 5.8, 2.9 Hz, 1H), 2.08-1.94 (m, 1H), 1.89-1.55 (m, 5H).
Reaction SMILES: O.NN.[CH3:4][O:5][C:6]1[N:7]=[C:8]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][C:14]1[NH:13][C:12](=[O:20])[CH:11]([C@H:21]3[CH2:26][CH2:25][C@H:24]([N:27]4C(=O)C5C(=CC=CC=5)C4=O)[CH2:23][CH2:22]3)[O:10][C:9]2=1>ClCCl.CO>[NH2:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH:11]2[O:10][C:9]3[C:8]4[C:17](=[CH:18][CH:19]=[C:6]([O:5][CH3:4])[N:7]=4)[N:16]=[CH:15][C:14]=3[NH:13][C:12]2=[O:20])[CH2:22][CH2:23]1
Reactant: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N2C(=O)c4ccccc4C2=O)CC1)C(=O)N3
Agent: NN
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: COc1ccc2ncc3c(c2n1)OC([C@H]1CC[C@H](N)CC1)C(=O)N3
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hydrazine hydrate (2M solution in methanol, 10 mL, 20.0 mmol, 7.96 eq) is added at room temperature to a stirred solution of 2-[trans-4-(6-methoxy-2-oxo-2,3-dihydro-1H-4-oxa-1,5,9-triaza-phenanthren-3-yl)-cyclohexyl]-isoindole-1,3-dione (1.15 g, 2.51 mmol, 1.0 eq) in dichloromethane (15 mL) and methanol (15 mL). After 16 hours stirring at room temperature and 2 hours stirring at 55° C., solvent is removed and the residue is purified by preparative HPLC to afford 3-(trans-4-amino-cyclohexyl)-6-methoxy-1H-4-oxa-1,5,9-triaza-phenanthren-2-one as a yellow solid (260 mg, 32% yield).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=O)[CH2:3][CH2:2]1.[NH:8]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[NH2:9].C([BH3-])#N.[Na+]>CO>[O:1]1[CH2:6][CH2:5][CH:4]([NH:9][NH:8][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:3][CH2:2]1
Reactant: O=C1CCOCC1
Reactant: CC(C)(C)OC(=O)NN
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NNC1CCOCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tetrahydro-4H-pyran-4-one (9.69 g, 97 mmol) was added to a solution of 1,1-dimethylethyl hydrazinecarboxylate (14.07 g, 106 mmol) in methanol (100 mL) and stirred at room temperature for 3 h. The solvent was removed in vacuo, and the crude residue was suspended in acetic acid (140 mL). Next added sodium cyanoborohydride (6.69 g, 106 mmol) in portions over 3 minutes. The contents were stirred at room temperature for 60 h. The solvent was removed in vacuo, and the crude residue was suspended in DCM (100 mL). The reaction mixture was adjusted to pH 7 with 6N NaOH. The layers were separated, and the aq. layer extracted with DCM. The combined organic layers were washed with saturated NaHCO3, and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo to afford the product as a solid, 18.4 g (88%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.22 (m, 2H), 1.39 (s, 9H), 1.43-1.48 (m, 1H), 1.59-1.69 (m, 2H), 2.82-2.98 (m, 1H), 3.20-3.32 (m, 2H), 3.80 (d, J=11.62 Hz, 2H), 4.36 (br. s., 1H), 8.07-8.34 (m, 1H).
Reaction SMILES: [CH3:1][CH2:2][CH:3]([OH:6])[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:11]2[N:19]([CH3:20])[CH:18]=[C:17]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[N:13]=[C:14]([CH3:16])[N:15]=1>C1COCC1>[CH2:2]([CH:3]([O:6][C:10]1[C:11]2[N:19]([CH3:20])[CH:18]=[C:17]([C:21]3[C:26]([CH3:27])=[CH:25][C:24]([CH3:28])=[CH:23][C:22]=3[CH3:29])[C:12]=2[N:13]=[C:14]([CH3:16])[N:15]=1)[CH2:4][CH3:5])[CH3:1]
Reactant: Cc1cc(C)c(-c2cn(C)c3c(Cl)nc(C)nc23)c(C)c1
Reactant: CCC(O)CC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCC(CC)Oc1nc(C)nc2c(-c3c(C)cc(C)cc3C)cn(C)c12
Reaction time: 0.08 h

Procedure:
To a solution of 3-pentanol (0.09 ml, 0.883 mmol) in dry THF was added 60% NaH in oil (20 mg, 0.500 mmol) and stirred for 5 min. A solution of 4-chloro-2,5-dimethyl-7-(2,4,6-trimethyl-phenyl)-5H-pyrrolo[3,2-d]pyrimidine (50 mg, 0.166 mmol) in dry THF was added to the reaction mixture and the resulting mixture was heated at reflux for 2 hr. The mixture was quenched with water, extracted with ethyl acetate. The organic layer was washed with brine, separated, dried and concentrated to dryness to give the title compound as a white solid. 1H NMR (CDCl3) ä 6.92(s, 3H), 5.43(m, 1H), 4.02(s, 3H), 2.56(s, 3H), 2.29(s, 3H), 2.08(s, 6H), 1.80(m, 4H), 0.99(t, 6H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1.[Na+].[I-:18].CNCCNC>O1CCOCC1.[Cu]I>[I:18][C:2]1[S:6][C:5]([CH3:7])=[C:4]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: [I-]
Reactant: COc1ccc(Cc2cc(Br)sc2C)cc1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(Cc2cc(I)sc2C)cc1
Temperature: 120 °C
Reaction time: 18 h

Procedure:
To a solution of bromide 10 (1.5 g, 5.05 mmol) in 1.4-dioxane (10 mL) were added NaI (1.5 g, 10.1 mmol), CuI (0.1 g, 0.51 mmol) and N1,N2-dimethylethane-1,2-diamine (0.11 mL, 1.01 mmol) at room temperature. The reaction mixture was evacuated and backfilled with nitrogen. The mixture was stirred 120° C. for 18 hours. The mixture was cooled to room temperature and filtered off through celite. The filtrate was extracted with EtOAc/H2O (50 mL/50 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude product 11 was dried under high vacuum and used without further purification (2.32 g, 79%).
Reaction SMILES: [C:1]([NH:11][CH2:12][CH2:13][O:14][CH2:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([OH:22])=O)=[CH:18][CH:17]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].Cl.[NH2:26][CH2:27][C@H:28]([NH:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:39])=[O:38])[C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[C:32]([O:31][C:29](=[O:30])[C@@H:28]([NH:36][S:37]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)(=[O:39])=[O:38])[CH2:27][NH:26][C:20](=[O:22])[C:19]1[CH:18]=[CH:17][C:16]([CH2:15][O:14][CH2:13][CH2:12][NH:11][C:1]([O:3][CH2:4][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2])=[CH:24][CH:23]=1)([CH3:35])([CH3:33])[CH3:34]
Reactant: O=C(NCCOCc1ccc(C(=O)O)cc1)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)[C@H](CN)NS(=O)(=O)c1ccccc1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@H](CNC(=O)c1ccc(COCCNC(=O)OCc2ccccc2)cc1)NS(=O)(=O)c1ccccc1

Procedure:
Acid 15-3 (300 mg, 0.91 mmol), amine 2-1 (325 mg, 0.91 mmol), EDC (209 mg, 1.09 mmol), HOBT (148 mg, 1.10 mmol), and NMM (300 μL, 2.7 mmol) were combined in 4.5 mL DMF. After 16 h the mixture was diluted with EtOAc, washed with water, 10% KHSO4, sat NaHCO3, and brine, dried (MgSO4), and concentrated. Flash chromatography (silica, 70% EtOAc/hexane) provided 15-4 as an off-white solid.
Reaction SMILES: CC(C)([O-])C.[K+].[Br:7][C:8]1[CH:9]=[CH:10][C:11]2[C:12]3[N:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:19]([CH2:32]Cl)=[N:18][C:13]=3[CH:14]=[N:15][C:16]=2[CH:17]=1>C1COCC1>[Br:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12]3[N:20]4[CH2:21][CH2:22][CH2:23][N:24]([C:25]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:31])[CH2:32][C:19]4=[N:18][C:13]=3[CH:14]=[N:15]2)=[CH:10][CH:9]=1
Reactant: CC(C)(C)OC(=O)NCCCn1c(CCl)nc2cnc3cc(Br)ccc3c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCCn2c(nc3cnc4cc(Br)ccc4c32)C1
Temperature: 25 °C

Procedure:
Potassium tert-butoxide (110 mL of a 1 M solution in THF) was added to a solution of tert-butyl 3-[7-bromo-2-(chloromethyl)-1H-imidazo[4,5-c]quinolin-1-yl]propylcarbamate (41.63 g, 91.74 mmol) in THF (400 mL). The reaction was stirred for ten minutes at ambient temperature and concentrated under reduced pressure to provide tert-butyl 3-bromo-11,12-dihydro-8H-[1,4]diazepino[1′,2′:1,2]imidazo[4,5-c]quinoline-9(10H)-carboxylate in a crude mixture which was used without purification in Part E.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:8][CH:7]=1>C(O)C.C(OCC)(=O)C.[Pt](=O)=O>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:18]=[CH:17][C:9]([C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)c1ccc(C#CCCO)cc1
Agent: O=[Pt]=O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(CCCCO)cc1
Yield: 92.9 %

Procedure:
A solution of 1,1-dimethylethyl 4-(4-hydroxy-1-butyn-1-yl)benzoate (0.9 g, e.g. which can be as prepared in Intermediate 22) in a mixture of ethanol (50 ml) and ethyl acetate (5 ml) was hydrogenated over platinum(IV) oxide (PtO2, 0.09 g, 10% w/w) for 18 hours at room temperature. The mixture was filtered through a bed of Celite, washing through with ethanol. The solvents were evaporated to dryness to give the title compound as a yellowy/brown oil (0.85 g). 1H NMR (400 MHz, chloroform-d) δ (delta) ppm 1.60 (14H, m), 1.70 (2H, m), 2.70 (2H, t, J=7.53 Hz & 7.78 Hz), 3.67 (2H, t, J=6.53 Hz & 6.27 Hz) 7.23 (2H, d, J=8.28 Hz), 7.91 (2H, d, J=8.03 Hz). Extra protons at about 1.5-1.6 ppm may perhaps be due to residual H2O in CDCl3. LCMS showed TRET=3.26 min with: MH+ not seen, and [MH]++18 adduct=268.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[NH3:11]>>[NH2:11][CH2:3][CH:2]([OH:1])[CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1
Reactant: N
Reactant: C1CN(CC2CO2)CCO1
Product: NCC(O)CN1CCOCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 99.3 %

Procedure:
4-Oxiranylmethyl-morpholine 53b (6.3 g, 44 mmol) was added slowly with ammonia (450 ml, 25%, 6.6 mol) while maintaining the temperature below 0° C. in an ice-water bath. Upon completion of the addition, the reaction mixture was allowed to warm up to room temperature and stirred for 18 hours. After thin lay chromatography showed the disappearance of starting materials, the reaction mixture was concentrated under reduced pressure to obtain the title compound 1-amino-3-morpholin-4-yl-propan-2-ol 53c (7 g, yield 99%) as a white solid.
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:10][C:11](=[O:37])/[CH:12]=[CH:13]/[C:14]1[CH:15]=[C:16]2[C:33](=[N:34][CH:35]=1)[NH:32][C:31](=[O:36])[C:18]1([CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]1)[CH2:17]2)[CH3:9]>ClCCl>[O:36]=[C:31]1[C:18]2([CH2:19][CH2:20][NH:21][CH2:22][CH2:23]2)[CH2:17][C:16]2[C:33](=[N:34][CH:35]=[C:14](/[CH:13]=[CH:12]/[C:11]([O:10][CH2:8][CH3:9])=[O:37])[CH:15]=2)[NH:32]1
Reactant: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCN(C(=O)OC(C)(C)C)CC1)C(=O)N2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)/C=C/c1cnc2c(c1)CC1(CCNCC1)C(=O)N2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (5 mL) was added to a suspension of (E)-tert-butyl 6-(3-ethoxy-3-oxoprop-1-enyl)-2-oxo-2,4-dihydro-1H-spiro[[1,8]naphthyridine-3,4′-piperidine]-1′-carboxylate (1.52 g, 3.66 mmol) in dichloromethane (20 mL). The reaction mixture was stirred at room temperature for 1 hour and concentrated to dryness. The resulting residue was partitioned between an aqueous solution of sodium hydroxide (1N, 60 mL) and dichloromethane (40 mL). The aqueous layer was separated and extracted with dichloromethane (2×70 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated to dryness. The title product was obtained as a pale yellow solid (904 mg, 79%).