Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[CH:22]=[CH:21][C:5]([O:6][CH2:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1.[C:23]([O:27][CH2:28][CH3:29])(=[O:26])[C:24]#[CH:25]>CN(C)C=O.[Cu]=O>[O:14]([C:10]1[N:9]=[C:8]([CH2:7][O:6][C:5]2[CH:21]=[CH:22][C:2]([CH:25]=[CH:24][C:23]([O:27][CH2:28][CH3:29])=[O:26])=[CH:3][CH:4]=2)[CH:13]=[CH:12][CH:11]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: C#CC(=O)OCC
Reactant: Ic1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Agent: O=[Cu]
Solvent: CN(C)C=O
Product: CCOC(=O)C=Cc1ccc(OCc2cccc(Oc3ccccc3)n2)cc1
Temperature: 110 °C
Reaction time: 15 h

Procedure:
To a solution of 2-((4-iodophenoxy)methyl)-6-phenoxypyridine (160 mg) in dimethylformamide (2 ml), 0.116 ml of ethyl propiolate and 69 mg of copper (II) oxide were added, and the reaction solution was stirred at 110° C. for 15 hours. The reaction solution was cooled and then Celite-filtered, and the filtrate was distilled off under reduced pressure. The residue obtained was purified by silica gel column chromatography (eluent: hexane/ethyl acetate (0:100-20:80-33/67)) to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]2[NH:10][CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:18][C:19]1[O:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=1>CN(C)C=O.O>[Cl:1][C:2]1[C:3]2[N:10]([CH2:18][C:19]3[O:23][C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:21][CH:20]=3)[CH:9]=[CH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: Clc1ncnc2cc[nH]c12
Reactant: CCOC(=O)c1ccc(CCl)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(Cn2ccc3ncnc(Cl)c32)o1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.9 %

Procedure:
To a suspension of 4-chloro-5H-pyrrolo[3,2-d]pyrimidine (500 mg) in N,N-dimethylformamide (6.5 mL) was added potassium carbonate (541 mg) under ice-cooling, and the mixture was stirred for 15 min. while warming to room temperature. Ethyl 5-(chloromethyl)-2-furoate (737 mg) was added to the reaction mixture, and the mixture was stirred at room temperature for 16 hrs. The reaction mixture was diluted with water (20 mL), and extracted with a mixed solvent (40 mL×3) of ethyl acetate/tetrahydrofuran (1/1). The organic layer washed with saturated brine (20 mL×3) and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (silica gel, eluent:hexane/ethyl acetate=80/20→10/90). The object fraction was concentrated under reduced pressure and dried to give the title compound (825 mg) as a pale-yellow solid.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31]>CN(C=O)C>[N:3]1[CH:8]=[CH:7][C:6]([N:9]([C:17]2[CH:18]=[CH:19][C:20]([O:23][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])=[CH:21][CH:22]=2)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N(c1ccncc1)c1ccc(O)cc1
Reactant: CCOC(=O)CCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc(N(C(=O)OC(C)(C)C)c2ccncc2)cc1
Reaction time: 0.08 h

Procedure:
Sodium hydride (50% w/w dispersion in mineral oil, 55 mg) was added under argon to a stirred solution of the product from step iii) above (300 mg)in dry DMF (5 ml). After five minutes, ethyl 6-bromohexanoate (0.20 ml) was added and the mixture stirred for 16 hours. The DMF was evaporated in vacuo and the residue partitioned between dichloromethane and water. The aqueous phase was extracted with further dichloromethane. The combined organic extracts were washed with water then dried, and evaporated. The residue was purified by chromatography on alumina, eluting with dichloromethane and the 1% v/v methanol/dichloromethane. Evaporation of the appropriate fractions gave ethyl 6-[4-[N-(4-pyridyl)-N-tertiary-butyloxycarbonylamino]phenoxy]hexanoate, 260 mg, as a yellow gum: NMR (CDCl3) δ8.40(2H,dd), 7.16(2H,dd), 7.07(2H,m), 6.90(2H,m), 4.13(2H,q), 3.98(2H,t), 2.34(2H,t), 1.78(4H,m), 1.57(2H,m), 1.44(9H,s), 1.26(3H;t); m/e 429 (M+H)+.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14]([OH:16])=O)[N:11]=C(C(O)=O)[CH:9]=1)=[N+:2]=[N-:3].[C:20](Cl)(=O)[C:21]([Cl:23])=[O:22].C(Cl)(Cl)[Cl:27]>CN(C=O)C>[N:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[C:12]([C:14]([Cl:27])=[O:16])[N:11]=[C:20]([C:21]([Cl:23])=[O:22])[CH:9]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCOc1cc(C(=O)O)nc(C(=O)O)c1
Reactant: ClC(Cl)Cl
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCOc1cc(C(=O)Cl)nc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
4-(3-azidopropoxy)-pyridine-2,6-dicarboxylic acid 43 (1.33 g, 5.0 mmol) was suspended in chloroform (80 mL) and DMF (0.4 mL). Oxalyl chloride (2.7 mL, 3.9 g, 30.7 mmol) was added dropwise to the above stirred suspension. The resulting reaction mixture was stirred at room temperature for 2 days. The solvent was evaporated and the residue was dried under high vacuum for 24 hours. The 4-(3-azidopropoxy)-pyridine-2,6-dicarbonyldichloride obtained was used for the next coupling reaction directly without further purification.
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[NH:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:20]1.CCN(C(C)C)C(C)C>CCCCO>[Br:1][C:2]1[C:3]([N:19]2[CH2:23][CH2:22][C@@H:21]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:29])([CH3:28])[CH3:30])[CH2:20]2)=[C:4]2[C:10]([NH:11][C:12](=[O:17])[C@H:13]([O:15][CH3:16])[CH3:14])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CO[C@H](C)C(=O)Nc1c[nH]c2ncc(Br)c(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)c12
Temperature: 135 °C
Yield: 61.1 %

Procedure:
(R)—N-(5-Bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-methoxypropanamide (0.6 g, 1.9 mmol), (R)-tert-butyl pyrrolidin-3-ylcarbamate (1.1 g, 5.7 mmol), and DIEA (0.99 mL, 5.7 mmol, d 0.742) were place in n-BuOH (4 mL) and heated at 135° C. for 12 hours. The reaction was cooled to room temperature, concentrated, and purified by silica gel chromatography (500:15 DCM:MeOH) to give tert-butyl (R)-1-(5-bromo-3-((R)-2-methoxypropanamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)pyrrolidin-3-ylcarbamate (0.56 g, 61% yield).
Reaction SMILES: [Cl:1][C:2]1(O)[N:19]=[CH:18][N:17]=[C:16]2[C:3]1=[N:4][CH2:5][N:6]2[C@@H:7]1[O:15][C@H:12]([CH2:13][OH:14])[C@@H:10]([OH:11])[C@H:8]1[OH:9].[CH2:21]([O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38](OC)OC)=[CH:34][CH:33]=1)[CH:22]=[CH2:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(N(CC)CC)C>CN(C=O)C>[CH2:21]([O:24][C:25](=[O:43])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:31][C:32]1[CH:37]=[CH:36][C:35]([CH:38]2[O:11][CH:10]3[CH:12]([CH2:13][OH:14])[O:15][CH:7]([N:6]4[CH:5]=[N:4][C:3]5[C:16]4=[N:17][CH:18]=[N:19][C:2]=5[Cl:1])[CH:8]3[O:9]2)=[CH:34][CH:33]=1)[CH:22]=[CH2:23]
Reactant: OC[C@H]1O[C@@H](N2CN=C3C2=NC=NC3(O)Cl)[C@H](O)[C@@H]1O
Reactant: C=CCOC(=O)CCCCCOc1ccc(C(OC)OC)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCOC(=O)CCCCCOc1ccc(C2OC3C(CO)OC(n4cnc5c(Cl)ncnc54)C3O2)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
A mixture of 6-chloroinosine (4, 32.5 g, 113 mmol) and the acetal linker 3 (47.5 g, 147 mmol) was dissolved in DMF (230 mL). p-Toluenesulfonic acid monohydrate (1.1 g, 5.7 mmol) was added, and the solution was placed on a Buechi R-134 rotavapor and agitated under reduced pressure (70 mbar) at 50° C. for 15 h. The solvent was removed in vacuo, the resulting residue was dissolved in EtOAc (1 L) and neutralized with triethyl amine (0.8 mL, 5.7 mmol). The solution was then washed with saturated aqueous NaCl (3×1 L), H2O (1 L), dried (MgSO4), filtered and concentrated. The resulting residue was taken up in EtOAc and triturated with hexanes, upon which the product precipitated as a white powder (5, 59.3 g, 109 mmol, 96%, mixture of two diastereomers): M.p.: 103-105° C.; 1H-NMR (400 MHz, CDCl3) δ=8.78 (s, 1H), 8.77 (s, 1H′), 8.41 (s, 1H), 8.33 (s, 1H′), 7.47 (d, J=8.6 ,2H), 7.37 (d, J=8.6, 2H′), 6.95 (d, J=8.5, 2H), 6.89 (d, J=8.5, 2H′), 6.24 (s, 1H), 6.19 (m, 1H, 1H′), 6.02 (s, 1H′), 5.91 (m, 1H, 1H′), 5.37-5.18 (m, 4H, 4H′), 4.77 (m, 1H, 1H′), 4.72 (s, 1H, 1H′), 4.58 (m, 2H, 2H′), 4.04-3.85 (m, 4H, 4H′), 2.37 (m, 2H, 2H′), 1.81 (m, 2H, 2H′), 1.71 (m, 2H, 2H′), 1.52 (m, 2H, 2H′); 13C -NMR (400 MHz, CDCl3) δ=173.4, 173.4, 160.5, 160.4, 152.0, 151.8, 150.8, 150.7, 132.8, 132.6, 132.3, 132.3, 132.1, 132.1, 128.2 (2C), 128.0 (2C), 127.5, 127.5, 118.3, 118.3, 114.8, 114.8, 114.6 (2C), 114.6 (2C), 108.0, 104.9, 93.5, 91.6, 86.4, 86.4, 84.3, 83.8, 83.3, 80.5, 67.9, 67.8, 65.1, 65.1, 63.2, 62.9, 34.2, 34.2, 28.9, 28.9, 25.7, 25.7, 24.7, 24.7; IR (film) ν=3233, 3109, 3073, 2934, 1727, 1595, 1396, 1245, 1194, 1167, 1101, 1073, 984, 832; HRMS (MALDI-FTMS) m/z 567.1627(567.1617 calculated for C26H29N4O7ClNa (M+Na)+).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16]Cl.C(N(CC)C(C)C)(C)C.[I-].[K+]>CN(C=O)C>[N:1]1([C:2]2[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: Nc1ccc(CCO)cc1
Reactant: ClCCOCCCl
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: OCCc1ccc(N2CCOCC2)cc1
Yield: 58 %

Procedure:
4-Aminobenzeneethanol (20.2 g), 2-chloroethyl ether (21.1 g), N,N-diisopropylethylamine (38.1 g) and potassium iodide (48.8 g) in DMF were heated to 80° under nitrogen for 60 h. The solvent was evaporated and the residue (~143 g) was purified by FCC eluting with ER-CX (1:1→1:0) to give the title compound as a pink-white solid (17.7 g) m.p. 57°.
Reaction SMILES: N1([C@]23CC[C@@H](C(C)=C)[C@@H]2[C@@H]2[C@@](C)(CC3)[C@@]3(C)[C@@H]([C@]4(C)[C@@H](CC3)C(C)(C)C(=O)CC4)CC2)CC1.[CH3:34][S:35]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)(=[O:37])=[O:36].[N:44]1([C@:47]23[CH2:83][CH2:82][C@@H:81]([C:84]([CH3:86])=[CH2:85])[C@@H:48]2[C@@H:49]2[C@@:62]([CH3:65])([CH2:63][CH2:64]3)[C@@:61]3([CH3:66])[C@@H:52]([C@:53]4([CH3:80])[C@@H:58]([CH2:59][CH2:60]3)[C:57]([CH3:68])([CH3:67])[C:56]([C:69]3[CH2:74][CH:73]5[CH:71]([CH:72]5[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:70]=3)=[CH:55][CH2:54]4)[CH2:51][CH2:50]2)[CH2:46][CH2:45]1>>[CH3:65][C@:62]12[C@@:61]3([CH3:66])[C@@H:52]([C@:53]4([CH3:80])[C@@H:58]([CH2:59][CH2:60]3)[C:57]([CH3:67])([CH3:68])[C:56]([C:69]3[CH2:74][CH:73]5[CH:71]([CH:72]5[C:75]([O:77][CH2:78][CH3:79])=[O:76])[CH:70]=3)=[CH:55][CH2:54]4)[CH2:51][CH2:50][C@@H:49]1[C@H:48]1[C@H:81]([C:84]([CH3:86])=[CH2:85])[CH2:82][CH2:83][C@:47]1([NH:44][CH2:45][CH2:46][N:41]1[CH2:42][CH2:43][CH:38]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:39][CH2:40]1)[CH2:64][CH2:63]2
Reactant: CS(=O)(=O)C1CCNCC1
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Agent: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CCC(=O)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCC(S(C)(=O)=O)CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CC7C(C6)C7C(=O)OCC)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Yield: 33.2 %

Procedure:
The title compound was prepared following the method describe on step 1 for the preparation of (1R,3aS,5aR,5bR,7aR,11aR,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)octadecahydro-1H-cyclopenta[a]chrysen-9(5bH)-one using 4-(methylsulfonyl)piperidine and ethyl 3-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)bicyclo[3.1.0]hex-2-ene-6-carboxylate as the reactants. The product was obtained as a mixture of diastereomers in 33.2% yield. MS: m/e 749.6 (M+H)+, 2.794 min (method 8). 1H NMR (400 MHz, CHLOROFORM-d) δ 5.84-5.75 (m, 1H), 5.49-5.38 (m, 1H), 4.69 (br. s., 1H), 4.59 (br. s., 1H), 4.19-4.04 (m, 2H), 3.12 (dd, J=15.6, 12.8 Hz, 1H), 2.98-2.74 (m, 7H), 2.68-2.51 (m, 5H), 2.45 (d, J=7.5 Hz, 4H), 2.22-2.10 (m, 3H), 2.09-1.74 (m, 8H), 1.69 (s, 3H), 1.65-1.30 (m, 12H), 1.26 (m, 6H), 1.06 (br. s., 5.5H), 1.02 (s, 3H), 0.98-0.92 (m, 4.5H), 0.85-0.78 (m, 3H).
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH2:11])[CH2:9][NH2:10]>C(O)C.O=[Pt]=O>[CH:1]1([NH:10][CH2:9][CH2:8][NH2:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C1CCCCC1
Reactant: NCCN
Agent: O=[Pt]=O
Solvent: CCO
Product: NCCNC1CCCCC1
Reaction time: 1 h

Procedure:
Cyclohexanone (50 g) and ethylene diamine (60 g) were mixed in ethanol (50 ml) at room temperature and allowed to stand for one hour. Meanwhile Adams catalyst (1 g) in ethanol (20 ml) was pre-reduced on a Parr apparatus at 60 p.s.i. under hydrogen for one hour. The imine solution was added to the hydrogenation flask and reduced at 60 p.s.i. for 18 hours. The catalyst was removed by filtration and the ethanol removed under vacuum. N-Cyclohexyl ethylene diamine was obtained on distillation of the crude product collecting the fraction boiling between 110°-120° C. at 20 ram.
Reaction SMILES: [CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([O:10]CC(Cl)(Cl)Cl)=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([O:27][CH:28]=[O:29])[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[C@H:4]2[S:3]1.C(O)(=O)C>[Zn].CN(C)C=O>[CH3:1][CH:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[N:5]2[C:16](=[O:31])[CH:17]([NH:18][C:19](=[O:30])[CH:20]([O:27][CH:28]=[O:29])[C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C@H:4]2[S:3]1
Reactant: CC1C=C(C(=O)OCC(Cl)(Cl)Cl)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2S1
Agent: [Zn]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC1C=C(C(=O)O)N2C(=O)C(NC(=O)C(OC=O)c3ccccc3)[C@H]2S1
Reaction time: 1 h
Yield: 85.4 %

Procedure:
2,2,2-Trichloroethyl 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylate (1.58 g), zinc powder (1.5 g) and glacial acetic acid (1.5 ml) were added to anhydrous dimethylformamide (15 ml), and the mixture was stirred for 1 hour under ice-cooling. After the reaction, zinc powder was filtered off, and the filtrate was poured into a mixture of 5% hydrochloric acid (30 ml) and ethyl acetate (30 ml) and then extracted. The aqueous layer was further extracted twice with ethyl acetate (30 ml). The ethyl acetate layer was combined, and the combined solution was washed with 5% hydrochloric acid and water, and then dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was pulverized by adding isopropyl ether, followed by filtration, and dried to give amorphous 2-methyl-7-(2-formyloxy-2-phenylacetamido)-3-cephem-4-carboxylic acid (1.0 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH2:6][C:5]2=[O:12].[CH2:13]=O.[BH3-][C:16]#[N:17].[Na+].Cl>CCO>[CH3:13][N:17]([CH3:16])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH2:6][C:5]2=[O:12]
Reactant: C=O
Reactant: Nc1ccc2c(c1)C(=O)CC=N2
Reactant: [BH3-]C#N
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CN(C)c1ccc2c(c1)C(=O)CC=N2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59.9 %

Procedure:
To a solution of 6-amino-4-quinolone (O1) (112 mg, 0.71 mmol) and aqueous formaldehyde (40% w/v, 1.6 mL, 21.2 mmol) in EtOH (10 mL) were sequentially added NaBH3CN (335 mg, 5.67 mmol) and 1N HCl (2.8 mL, 2.8 mmol), and the resulting bright yellow suspension was stirred at room temperature for 15 minutes. After this time, solvent was removed under reduced pressure, and the residue then dried by two MeOH azeotrope cycles. The residue was resuspended in MeOH and filtered through Celite, and solvent was removed under reduced pressure. The residue was crystallized from MeOH:EtOAc to give 6-dimethylamino-4-quinolone (O2) (80 mg, 60%) as an amorphous tan solid; 1H NMR [(CD3)2SO] δ 2.93 [s, 6H, ArN(CH3)2], 5.90 [d, J=7.00 Hz, 1H, ArH], 7.13 [br s, ArOH], 7.24 [m, 2H, ArH], 7.45 [dd, J=7.41, 2.29 Hz, 1H, ArH], 7.74 [d, J=7.00 Hz, 1H, ArH]. LCMS (APCl+): 189 (100%). Rf=0.48 (10% MeOH:CH2Cl2).
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:16][C:17]([O:19]CC)=O.[Cl:22]N1C(=O)CCC1=O.Cl>O1CCOCC1>[O:19]=[C:17]1[CH2:16][C:3]2[C:2](=[C:7]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[F:15])[CH:6]=[C:5]([Cl:22])[CH:4]=2)[NH:1]1
Reactant: CCOC(=O)Cc1cccc(Oc2ccccc2F)c1N
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: C1COCCO1
Product: O=C1Cc2cc(Cl)cc(Oc3ccccc3F)c2N1
Temperature: 80 °C
Yield: 51.5 %

Procedure:
To a solution of ethyl 2-[2-amino-3-(2-fluorophenoxy)phenyl]acetate (8.5 g.) in dioxane (100 ml.) was added N-chlorosuccinimide (4.3 g.), and the mixture was stirred for an hour at 80° C. To the reaction mixture was added conc. hydrochloric acid (0.1 ml.), and the mixture was stirred for 10 minutes at ambient temperature. Dioxane was distilled off from the resulting mixture under reduced pressure. To the residue was added water and the mixture was extracted with ethyl acetate (200 ml.) twice. The extract was washed with a saturated aqueous solution of sodium chloride (100 ml.) twice, dried over magnesium sulfate and then evaporated under reduced pressure. The residue was washed with a mixture of diethyl ether and n-hexane (1:10) and recrystallized from ethanol to give crystals of 2-oxo-5-chloro-7-(2-fluorophenoxy)indoline (4.2 g.), mp 204° to 207° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:8](=[O:10])[CH3:9])[CH:7]=1.[CH3:12][C:13]1([CH3:21])[CH2:18][CH:17]([CH:19]=O)[CH2:16][CH2:15][O:14]1.N1CCCC1>CO>[Br:1][C:2]1[CH:7]=[C:6]2[C:5](=[CH:4][CH:3]=1)[O:11][CH:19]([CH:17]1[CH2:16][CH2:15][O:14][C:13]([CH3:21])([CH3:12])[CH2:18]1)[CH2:9][C:8]2=[O:10]
Reactant: CC1(C)CC(C=O)CCO1
Reactant: CC(=O)c1cc(Br)ccc1O
Solvent: CO
Solvent: C1CCNC1
Product: CC1(C)CC(C2CC(=O)c3cc(Br)ccc3O2)CCO1
Yield: 76.2 %

Procedure:
A solution of 1-(5-bromo-2-hydroxyphenyl)ethanone (13.5 g, 62.78 mmol), 2,2-dimethyltetrahydro-2H-pyran-4-carbaldehyde (9.40 g, 62.78 mmol) and pyrrolidine (5.22 mL, 62.78 mmol) in MeOH (125 mL) was heated to reflux for 3 h. The mixture was allowed to reach r.t. and then concentrated. The residue was dissolved in EtOAc (100 mL) and washed with 1M NaOH (60 mL), 1M HCl (60 mL), and brine (60 mL) successively. The organic phase was concentrated and the residue was purified by flash chromatography with a gradient of 10% EtOAc in heptane to 40% EtOAc in heptane to give the title compound (16.22 g, 76% yield): 1H NMR (500 MHz, DMSO-d6) δ ppm 1.15 (m, 6H), 1.26 (m, 2H), 1.52 (m, 1H), 1.76 (m, 1H), 2.12 (ddd, 1H), 2.65 (m, 1H), 2.83 (m, 1H), 3.57 (m, 1H), 3.66 (m, 1H), 4.32 (ddd, 1H), 7.05 (dd, 1H), 7.70 (dd, 1H), 7.78 (d, 1H); MS (ES−) m/z 337 [M−H].
Reaction SMILES: C[O:2][C:3]([CH:5]1[C:13]2[C:8](=[CH:9][C:10]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=3)=[O:16])=[C:11]([OH:14])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4]>CCOCC>[C:20]1([CH3:23])[CH:21]=[CH:22][C:17]([C:15]([C:10]2[CH:9]=[C:8]3[C:13](=[CH:12][C:11]=2[OH:14])[CH:5]([C:3]([OH:4])=[O:2])[CH2:6][CH2:7]3)=[O:16])=[CH:18][CH:19]=1
Reactant: COC(=O)C1CCc2cc(C(=O)c3ccc(C)cc3)c(O)cc21
Solvent: CCOCC
Product: Cc1ccc(C(=O)c2cc3c(cc2O)C(C(=O)O)CC3)cc1

Procedure:
Analogously to the method described in Example 2, 8.5 g of 5-(p-toluoyl)-6-hydroxy-indane-1-carboxylic acid methyl ester give 5-(p-toluoyl)-6-hydroxy-indane-1-carboxylic acid in the form of yellow crystals of melting point 186°-8° C. (from ether).
Reaction SMILES: [NH2:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:17]([CH3:28])[C:18]([CH2:21][N:22]5[CH2:26][CH2:25][CH2:24][C:23]5=[O:27])=[CH:19][N:20]=4)[S:15][C:8]=23)=[C:4]([F:31])[CH:3]=1.ClC(Cl)(O[C:36](=[O:42])OC(Cl)(Cl)Cl)Cl.[CH:44]1([NH2:47])[CH2:46][CH2:45]1>C1COCC1>[CH:44]1([NH:47][C:36]([NH:1][C:2]2[CH:30]=[CH:29][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:17]([CH3:28])[C:18]([CH2:21][N:22]6[CH2:26][CH2:25][CH2:24][C:23]6=[O:27])=[CH:19][N:20]=5)[S:15][C:8]=34)=[C:4]([F:31])[CH:3]=2)=[O:42])[CH2:46][CH2:45]1
Reactant: NC1CC1
Reactant: Cn1c(CN2CCCC2=O)cnc1-c1cc2nccc(Oc3ccc(N)cc3F)c2s1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: Cn1c(CN2CCCC2=O)cnc1-c1cc2nccc(Oc3ccc(NC(=O)NC4CC4)cc3F)c2s1
Temperature: 25 °C
Yield: 51.3 %

Procedure:
To a solution of 136 (77 mg, 0.176 mmol) in THF (10 mL) was added TEA (0.074 mL, 0.528 mmol) and triphosgene (52.2 mg, 1.451 mmol) in THF (5 mL) and the mixture was stirred at RT for an hour. Cyclopropylamine (10.5 mg, 0.176 mmol) was added and the reaction mixture was stirred at RT overnight. The reaction mixture was then concentrated and partitioned between with DCM and saturated NaHCO3 solution. The organic phase was collected, dried over anhydrous Na2SO4, filtered and concentrated. Purification of the residue by column chromatography (10% MeOH in EtOAc) afforded title compound 137 (47 mg, 51% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.69 (s, 1H), 8.50 (d, J=5.48 Hz, 1H), 7.89 (s, 1H), 7.70 (m, 1H), 7.35 (t, J=8.99 Hz, 1H), 7.17 (m, 1H), 7.05 (s, 1H), 6.65 (d, J=5.48 Hz, 1H), 6.55 (m, 1H), 4.46 (s, 2H), 3.82 (s, 3H), 3.22 (t, J=6.84 Hz, 2H), 2.52 (m, 1H), 2.27 (t, J=7.82 Hz, 2H), 1.90 (m, 2H), 0.63 (m, 2H), 0.40 (m, 2H). MS (m/z)=521.638 (M+H)
Reaction SMILES: [C:1]([OH:12])(=O)[CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10].[C:13]([O-])(=[O:23])[CH2:14]CCC=CCCCC.C=CCCCC>Cl[Ru](=CC1C=CC=CC=1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)Cl>[C:13]([O:12][CH2:1][CH2:2][CH2:3][CH2:4][CH:5]=[CH:6][CH2:7][CH2:8][CH2:9][CH3:10])(=[O:23])[CH3:14]
Reactant: CCCCC=CCCCC(=O)O
Reactant: CCCCC=CCCCC(=O)[O-]
Agent: Cl[Ru](Cl)(=Cc1ccccc1)([P](C1CCCCC1)(C1CCCCC1)C1CCCCC1)[P](C1CCCCC1)(C1CCCCC1)C1CCCCC1
Solvent: C=CCCCC
Product: CCCCC=CCCCCOC(C)=O

Procedure:
For example, 5-hexenoic acid or an ester of 5-hexenoic acid (e.g. methyl 5-hexenoate, ethyl 5-hexenoate, etc.) could be used instead of 1-hexene, but the synthesis would entail a reduction of a carboxylic acid or an ester to an alcohol followed by acetylation. These syntheses are respectively shown in FIGS. 6 and 7. With reference to FIGS. 6 an 7, the 5-hexenoic acid or 5-hexenoate is reacted with 5-decene to form 5-decenoic acid or 5-decenoate, respectively, in the presence of Grubbs' catalyst and under vacuum. The resulting 5-decenoic acid or 5-decenoate are then reacted with 1-hexene, reduced, and acetylated to form 5-decenyl acetate. In addition, synthesizing 5-decenoic acid would have advantages because the salt of 5-decenoic acid could be recrystallized to increase the trans-isomer to greater than 90 percent trans-5-decenoic acid, which is then reduced and acetylated to greater than 90 percent trans-5-decenyl acetate.