Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(CC)CC.CS(Cl)(=O)=O.[N-:13]=[N+:14]=[N-:15].[Na+].C([Si](C1SCCCS1)(C1C=CC=CC=1)C1C=CC=CC=1)CC=C.[C:40]1([Si:46]([C:73]2C=C[CH:76]=[CH:75][CH:74]=2)([CH2:61]CC(=O)NCC2C=CC=CC=2)[CH:47](NC(=O)C2C=CC=CC=2)[CH2:48][CH:49]([CH3:51])[CH3:50])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.[SiH3]O[SiH2]O[SiH3].Cl[SiH2]Cl>C(Cl)Cl.CCCCCC.CCOC(C)=O>[N:13]([CH:47]([Si:46]([CH2:73][CH2:74][CH:75]=[CH2:76])([CH3:61])[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[CH2:48][CH:49]([CH3:51])[CH3:50])=[N+:14]=[N-:15]
Reactant: CC(C)CC(NC(=O)c1ccccc1)[Si](CCC(=O)NCc1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: C=CCC[Si](c1ccccc1)(c1ccccc1)C1SCCCS1
Agent: CS(=O)(=O)Cl
Agent: Cl[SiH2]Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCCCCC
Product: C=CCC[Si](C)(c1ccccc1)C(CC(C)C)N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 46 (3.4 g, 13 mmol) in CH2Cl2 (150 mL) and Et3N (9 mL, 65 mmol) at 0° C. was added dropwise over 5 min methanesulfonyl chloride (7.4 g, 65 mmol), and the mixture was allowed to warm to rt over 1 h. After stirring overnight under argon, the mixture was cooled to 0° C. and quenched with water (50 mL). The organic layer was isolated and the aqueous layer extracted twice with 50-mL portions of CH2Cl2. The combined organic extracts were concentrated in vacuo at rt. The crude mesylate was dissolved in DMF (150 mL), and to this solution was added sodium azide (4.2 g, 64.8 mmol). After stirring overnight at rt, the mixture was partitioned between water (200 mL) and EtOAc (200 mL). The organic layer was isolated and the aqueous layer extracted twice with 50-mL portions of EtOAc. The combined organic extracts were washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated. Flash chromatography over silica gel (1/19 EtOAc:hexane) gave a colorless oil of pure 47 as a mixture of diastereomers (3.11 g 84%): R=0.80 (1/9 EtOAc:hexane); 1H NMR (300 MHz, CDCl3) δ 7.53–7.47 (m, 2H), 7.38–7.32 (m, 3H), 5.91–5.78 (m, 1H), 5.0–4.86 (m, 2H), 3.03 and 2.99 (two triplets due to diastereomers, J=2.7 Hz, 1H), 2.08 (q, J=7.8 Hz, 2H), 1.82–1.70 (m, 1H), 1.58–1.47 (m, 1H), 1.19–1.10 (m 1H), 1.06–0.94 (m, 2H), 0.89–0.83 (m, 6H), 0.38 and 0.36 (two singlets due to diastereomers, 3H); 13C NMR (75 MHz, CDCl3) δ 140.8, 134.2, 134.1, 129.6, 128.0, 113.3, 50.4, 50.3, 38.6, 38.5, 27.5, 25.8, 23.3, 20.7, 11.4, 11.0, −6.8, −7.3; IR (neat) 3067 (w), 2956 (s), 2914 (m), 2865 (m), 2099 (s), 1640 (m), 1469 (w), 1427 (m), 1259 (s), 1113 (m), 999 (w), 909 (m), 795 (m), 738 (m), 699 (m) cm−1; MS (FAB) m/e (rel. intensity) 288 (MH+, 19), 262 (10), 261 (32), 260 (100), 259 (29), 258 (39), 253 (14), 245 (20), 244 (64), 233 (15), 217 (11), 216 (16), 207 (19), 204 (54); HRMS (FAB) calcd for C16H26N3Si: 288.1896, found: 288.1895.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([O:24][Si](C(C)C)(C(C)C)C(C)C)[C:19]=3[O:35][CH3:36])=[O:17])[CH2:12][CH2:11]2)=[CH:4][CH:3]=1.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([OH:24])[C:19]=3[O:35][CH3:36])=[O:17])[CH2:14][CH2:15]2)=[CH:4][CH:3]=1
Reactant: COc1c(O[Si](C(C)C)(C(C)C)C(C)C)cccc1C(=O)C1CCN(CCc2ccc(F)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: COc1c(O)cccc1C(=O)C1CCN(CCc2ccc(F)cc2)CC1
Reaction time: 5 h
Yield: 83 %

Procedure:
Add to a solution of {1-[2-(4-fluoro-phenyl)-ethyl]-piperidin-4-yl}-(2-methoxy-3-triisopropylsilanyloxy-phenyl)-methanone, Example 2C (1.80 g, 3.50 mmol) in dry THF (5 mL) at ca. 20° C. under nitrogen, 1.0 M tetrabutylammonium fluoride in THF (4.55 mL, 4.55 mmol). After stirring 5 h, dilute the reaction with brine (100 mL) and extract with CH2Cl2 (3 ×75 mL). Dry the extracts (Na2SO4) and concentrate under vacuum. Purify the crude product by column chromatography over silica gel eluting initially with 50:50 ethyl acetate/hexane then 5:95 methanol/ethyl acetate giving the product as an oil (Rf˜0.2 in ethyl acetate), which solidifies after standing. Triturate the solid with hexanes and recrystallize from hot ether (˜30 mL) by cooling and concentrating under a nitrogen stream to ˜10 mL. Collect the resulting slightly orange crystals to obtain 1.04 g (83 %) of the title compound, mp 100-101° C.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:2]1.[H-].[Na+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CO>CN(C=O)C>[CH2:21]([N:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[C:3]([C:10]2[C:18]3[C:13](=[CH:14][N:15]=[CH:16][CH:17]=3)[NH:12][CH:11]=2)=[CH:2]1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: c1cnc2[nH]cc(-c3c[nH]c4cnccc34)c2c1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: c1ccc(Cn2cc(-c3c[nH]c4cnccc34)c3cccnc32)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 mg (0.16 mmol) of 3-(1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine (“A18”) are added to a suspension, kept under argon, of 20 mg (0.5 mmol) of sodium hydride (60% in paraffin) in 1 ml of DMF. After stirring at room temperature for one hour, 25 μl (0.26 mmol) of benzyl bromide are added, and the mixture is stirred at room temperature for 19 hours. Methanol is added to the reaction mixture, which is subsequently evaporated, and the residue is chromatographed on a silica-gel column with dichloromethane/methanol as eluent: 3-(1-benzyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-1H-pyrrolo[2,3-c]pyridine as colourless solid;
Reaction SMILES: C(OC([N:6]1[C:34]2[C:29](=[CH:30][CH:31]=[C:32]([Cl:35])[CH:33]=2)[C:8]2([CH:13]([C:14]3[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=3)[CH2:12][C:11](=[O:21])[NH:10][CH:9]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=2)[C:7]1=[O:36])=O)C.[OH-].[Na+]>>[Cl:35][C:32]1[CH:33]=[C:34]2[NH:6][C:7](=[O:36])[C:8]3([CH:13]([C:14]4[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[CH:15]=4)[CH2:12][C:11](=[O:21])[NH:10][CH:9]3[C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[CH:23]=3)[C:29]2=[CH:30][CH:31]=1
Reactant: CCOC(=O)N1C(=O)C2(c3ccc(Cl)cc31)C(c1cccc(Cl)c1)CC(=O)NC2c1cccc(F)c1
Agent: [Na+]
Agent: [OH-]
Product: O=C1CC(c2cccc(Cl)c2)C2(C(=O)Nc3cc(Cl)ccc32)C(c2cccc(F)c2)N1
Yield: 49.9 %

Procedure:
In a manner similar to the method described in example 4d, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)-2,3-dihydro-2,6′-dioxospiro[indole-3,3′-piperidine]-1-carboxylic acid ethyl ester (0.35 g, 0.66 mmol) was reacted with NaOH (48 mg, 1.19 mmol) to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-2′-(3-fluorophenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid (Yield 0.15 g, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:7])=[CH:4][CH:3]=1.[H-].[Na+].CN(C)C=O.[CH3:26][O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35]Br>CCOCC>[CH3:26][O:27][C:28](=[O:37])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][N:8]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)[C:6](=[O:7])[C:5]1[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: COC(=O)CCCCCCCBr
Reactant: COc1ccc(NC(=O)c2ccc(Cl)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: COC(=O)CCCCCCCN(C(=O)c1ccc(Cl)cc1)c1ccc(OC)cc1

Procedure:
As described in example 1(a), the reaction is carried out with 130.7 g (0.5 mol) of 4-chloro-N-(4-methoxyphenyl)-benzamide, 24.5 g (1 mol) sodium hydride, 700 cc. of dimethylformamide and 118.5 g (0.5 mol) of 8-bromocaprylic acid methyl ester. Reaction time and reaction temperature: 5 hours at 80° C., thereafter 12 hours at 100° C. The reaction mixtures are further processed as described in example 1(a). The crude product is dissolved in 300 cc. of ether. After standing for a prolonged period, the unreacted 4-chloro-N-(4-methoxyphenyl)-benzamide separates by crystallisation and is filtered off. The solvent is partly distilled off and the resulting oily crude product (181 g) is separated. 125 g are used in the next step without further purification, the remainder (56 g) is purified chromatographically on silicic acid using chloroform as eluant.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH2:5].[CH:10](O)=[O:11]>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[Cl:9])[NH:5][CH:10]=[O:11]
Reactant: O=CO
Reactant: Nc1ccc(Cl)c(Cl)c1
Solvent: O
Product: O=CNc1ccc(Cl)c(Cl)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 99 %

Procedure:
3,4-Dichloroaniline (1000.0 g, 6.172 mol) and formic acid (585 g, 12.7 mol) were charged, and the mixture was stirred at 90° C. for 1 hr. Water (1.5 L) was dropwise added with heating, and then the mixture was gradually cooled to allow precipitation of the crystals. The mixture was stirred at room temperature for 30 min., and the crystals were collected by filtration. The crystals were washed with water (1.2 L) and dried in vacuo at 40° C. for 8 hrs. to give the title compound (1160.8 g, yield 99.0%) as pale-brown crystals.
Reaction SMILES: [O:1]([C:8]1[CH:14]=[CH:13][C:11]([NH2:12])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:22][CH2:23][C:24](Cl)=[O:25]>ClCCl>[Cl:22][CH2:23][C:24]([NH:12][C:11]1[CH:10]=[CH:9][C:8]([O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:14][CH:13]=1)=[O:25]
Reactant: Nc1ccc(Oc2ccccc2)cc1
Reactant: O=C(Cl)CCl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccc(Oc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
To a solution of 4-phenoxyaniline (1.85 g, 10 mmoles) and triethylamine (2.07 ml, 15 mmoles) in 25 ml dry dichloromethane, is added stepwise a solution of chloroacetyl chloride (1.18 g, 10.5 mmoles) in 10 ml dry dichloromethane. The resulting reaction mixture is stirred for 1 hour at room temperature. Afterwards said reaction mixture is washed with 2×30 ml HCl (2 N) 1×30 ml water, dried with sodium sulfate and the solvent evaporated. 2.48 g. (Yield 95%) of 2-chloro-N-(4-phenoxyphenyl)acetamide were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][NH:7][C:8]2=[O:13].I[C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>[Cu](I)I.O1CCOCC1>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH2:5][CH2:6][N:7]([C:15]1[CH:16]=[N:17][CH:18]=[CH:19][C:20]=1[CH3:21])[C:8]2=[O:13]
Reactant: COc1cccc2c1CCNC2=O
Reactant: Cc1ccncc1I
Agent: I[Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1cccc2c1CCN(c1cnccc1C)C2=O
Yield: 3.7 %

Procedure:
Using analogous reaction conditions as described in Example 1, 5-methoxy-3,4-dihydro-2H-isoquinolin-1-one (I-13d: 0.09 g, 0.5 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.133 g, 0.0006 mol), 1,4-dioxane (30 mL), copper iodide (0.0096 g, 0.05 mmol), trans-N,N′-dimethyl-cyclohexyl-1,2-diamine (0.021 g, 0.13 mmol) and potassium phosphate (0.269 g, 0.0012 mmol) to afford the crude product. Purification by column chromatography on silica gel (1% methanol in DCM), followed by preparative TLC afforded 5 mg of the product (38.46% yield).
Reaction SMILES: [CH3:1][CH:2]([CH:14]1[C:22]2([CH3:23])[CH:17]([CH:18]([OH:24])[CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15]1)[CH2:3][CH:4]1[O:9][C:8]([CH3:11])([CH3:10])[O:7][C:6]([CH3:13])([CH3:12])[CH2:5]1.C([O-])(=O)C.[Na+].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1C1C=CC=C[NH+]=1.[Cr](Cl)([O-])(=O)=O.O>C(Cl)Cl>[CH3:1][CH:2]([CH:14]1[C:22]2([CH3:23])[CH:17]([C:18](=[O:24])[CH2:19][CH2:20][CH2:21]2)[CH2:16][CH2:15]1)[CH2:3][CH:4]1[O:9][C:8]([CH3:10])([CH3:11])[O:7][C:6]([CH3:13])([CH3:12])[CH2:5]1
Reactant: CC(CC1CC(C)(C)OC(C)(C)O1)C1CCC2C(O)CCCC12C
Agent: O=[Cr](=O)([O-])Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(CC1CC(C)(C)OC(C)(C)O1)C1CCC2C(=O)CCCC21C
Temperature: 25 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A solution of 0.101 g of 1R-[1alpha(R*,S*),3a beta, 4beta, 7a alpha]-octahydro-1-[1-methyl-2-(2,2,4,4-tetramethyl-1,3-dioxan-6-yl)ethyl]-7a-methyl-1H-inden-4-ol in 6 mL of dry methylene chloride was treated with 0.170 g of anhydrous sodium acetate and 0.345 g of 2,2'-bipyridinium chlorochromate and the mixture stirred at room temperature for 2 hours. After this time, additional 0.150 g of 2,2'-bipyridinium chlorochromate was added and the stirring continued for 1 more hour. Water was then added to the reaction mixture which was extracted with 3×50 mL of ether. The combined organic phases were washed with water, dried and evaporated. The crude residue obtained was purified by chromatography on silica, eluting with hexane/ethyl acetate (2:1) to give 0.090 g (90% yield) of pure 1R-[1alpha(R*,S*),3a beta, 4beta, 7a alpha]-octahydro-1-[1-methyl-2-(2,2,4,4-tetramethyl- 1,3-dioxan-6-yl)ethyl]-7a-methyl-1H-inden-4-one.
Reaction SMILES: [CH3:1][O:2][NH:3][CH:4]([CH3:24])[CH2:5][CH2:6][CH2:7][N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=[C:9]1[CH2:21][CH2:22][CH3:23].[C:25]1([N:31]=[C:32]=[O:33])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O1CCCC1>[CH2:21]([C:9]1[N:8]([CH2:7][CH2:6][CH2:5][CH:4]([N:3]([O:2][CH3:1])[C:32]([NH:31][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:33])[CH3:24])[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[N:13]=[CH:12][C:11]=2[N:10]=1)[CH2:22][CH3:23]
Reactant: CCCc1nc2cnc3ccccc3c2n1CCCC(C)NOC
Reactant: O=C=Nc1ccccc1
Solvent: C1CCOC1
Product: CCCc1nc2cnc3ccccc3c2n1CCCC(C)N(OC)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The preparation of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo-[4,5-c]quinolin-1-yl)butyl]hydroxylamine is described in parts A-D of Example 10. Phenyl isocyanate (0.49 mL, 4.59 mmol) was added to a solution of O-methyl-N-[1-methyl-4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]hydroxylamine (1.0 g, 3.06 mmol) in tetrahydrofuran (THF) (20 mL) and stirred for 4 hours at ambient temperature. The reaction mixture was concentrated under reduced pressure to afford 1.02 g of 1-[4-(2-propyl-1H-imidazo[4,5-c]quinolin-1-yl)-1-methylbutyl]-1-methoxy-3-phenylurea which was used without any further purification.
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23]([CH:25]=O)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.C(O)C>ClCCl>[N:27]1([N:33]=[CH:25][C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: NN1CCCCC1
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCO
Solvent: ClCCl
Product: C(=NN1CCCCC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Temperature: 80 °C
Yield: 107 %

Procedure:
To a solution containing 342 mg (1.01 mmol) of 1-trityl-1H-imidazole-4-carbaldehyde and 100 mg (1.0 mmol) of piperidin-1-ylamine are added 3.5 mL of ethanol and 1.5 mL of dichloromethane. The reaction medium is heated at 80° C. for 1 hour. The solvents are evaporated off and 450 mg of a powder are obtained and used in the following step without further purification.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][C:11]=2[F:19])[CH:5]=[CH:4][N:3]=[CH:2]1>C1COCC1.[Pd]>[N:1]1([CH2:6][CH2:7][CH2:8][NH:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][C:11]=2[F:19])[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=[N+]([O-])c1ccc(NCCCn2ccnc2)c(F)c1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(NCCCn2ccnc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
To a solution of N-(3-(1H-imidazol-1-yl)propyl)-2-fluoro-4-nitroaniline (1.20 g, 4.54 mmol) in THF (20 mL) was added catalyst Pd/C (0.30 g). The reaction mixture was stirred at rt under H2 overnight. The mixture was filtered, and the filtrate was concentrated in vacuo to give the title compound as yellow oil (1.00 g, 94%).
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7]([C:9]2[O:10][C:11]([CH3:14])=[CH:12][N:13]=2)[CH:6]=[CH:5][C:4]=1[C:15]1[N:20]=[N:19][C:18]([N:21]([CH3:32])[CH:22]2[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]2)=[CH:17][CH:16]=1.[Li+].[I-]>N1C(C)=CC(C)=CC=1C.CO.CCOC(C)=O.O>[CH3:32][N:21]([CH:22]1[CH2:27][C:26]([CH3:29])([CH3:28])[NH:25][C:24]([CH3:31])([CH3:30])[CH2:23]1)[C:18]1[N:19]=[N:20][C:15]([C:4]2[CH:5]=[CH:6][C:7]([C:9]3[O:10][C:11]([CH3:14])=[CH:12][N:13]=3)=[CH:8][C:3]=2[OH:2])=[CH:16][CH:17]=1
Reactant: COc1cc(-c2ncc(C)o2)ccc1-c1ccc(N(C)C2CC(C)(C)NC(C)(C)C2)nn1
Agent: [I-]
Agent: [Li+]
Solvent: CO
Solvent: Cc1cc(C)nc(C)c1
Solvent: CCOC(C)=O
Product: Cc1cnc(-c2ccc(-c3ccc(N(C)C4CC(C)(C)NC(C)(C)C4)nn3)c(O)c2)o1
Temperature: 170 °C
Reaction time: 4 h
Yield: 48.4 %

Procedure:
To a solution of 6-(2-methoxy-4-(5-methyloxazol-2-yl)phenyl)-N-methyl-N-(2,2,6,6-tetramethylpiperidin-4-yl)pyridazin-3-amine (106 mg, 0.24 mmol) in 2,4,6 collidine (8 mL, dried over MgSO4, and filtered), was added anhydrous LiI (292 mg, 2.18 mmol). The reaction was stirred at 170° C. for 4 h, then cooled and diluted with small amounts of MeOH and EtOAc (150 mL) and H2O (30 mL). The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified via HPLC to provide 2-(6-(methyl(2,2,6,6-tetramethylpiperidin-4-yl)amino)pyridazin-3-yl)-5-(5-methyloxazol-2-yl)phenol (49 mg). LCMS Rt=0.55 min (LCMS method Q); MS (M+1)=422.3. 1H NMR (400 MHz, METHANOL-d4) δ ppm 8.12 (d, J=9.9 Hz, 1H), 7.86 (d, J=8.8 Hz, 1H), 7.53 (dd, J=6.1, 1.8 Hz, 1H), 7.51 (s, 1H), 7.30 (d, J=10.1 Hz, 1H), 6.92 (d, J=1.0 Hz, 1H), 5.03-5.14 (m, 1H), 3.01 (s, 3H), 2.43 (d, J=1.2 Hz, 3H), 1.68 (dd, J=12.6, 3.5 Hz, 2H), 1.56 (t, J=12.3 Hz, 2H), 1.37 (s, 6H), 1.21 (s, 6H).
Reaction SMILES: [C:1]([Mg]Cl)#[CH:2].[C:5]([N:12]1[CH2:16][CH2:15][C:14](=[O:17])[CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[Cl-].[NH4+]>C1COCC1>[C:5]([N:12]1[CH2:16][CH2:15][C:14]([OH:17])([C:1]#[CH:2])[CH2:13]1)([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6]
Reactant: C#C[Mg]Cl
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: C#CC1(O)CCN(C(=O)OC(C)(C)C)C1
Reaction time: 2 h

Procedure:
Ethynyl magnesium chloride (0.5 M in THF, 210 mL, 105 mmol) was diluted with THF (100 mL) and cooled in an ice-water bath. A solution of N-Boc-3-pyrrolidinone (9.21 g, 50 mmol) (Example 97A above) in THF (100 mL) was added dropwise with cooling. The mixture was stirred for 2 h and aqueous ammonium chloride solution (100 mL, 15% W/V) was then added. The mixture was then extracted with ether (2×400 mL). The ether layers were washed with saturated aqueous sodium chloride solution (200 mL), combined, dried (MgSO4), filtered and concentrated. The residue was chromatographed (Biotage Flash 40S, EtOAc - hexanes as solvent) to give rac-N-Boc-3-hydroxy-3-ethynyl-pyrrolidine as a pale yellow oil that crystallized on standing. (Yield 10.13 g, 96.4%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:12]=3[O:11][CH2:10]2)[O:19][CH2:18][CH2:17][CH2:16]4)[C:2]1=[O:22].N1C2C(=CC=CC=2)[C:25]2([CH2:35][O:34][C:33]3[CH:36]=C4C(=C[C:32]2=3)CCO4)C1=O.CC1C=CC(S(OC[C@H]2CCCO2)(=O)=O)=CC=1.BrCC1CCCCO1>>[O:34]1[CH2:35][CH2:25][CH2:32][C@@H:33]1[CH2:36][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]2([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][C:12]=3[O:11][CH2:10]2)[O:19][CH2:18][CH2:17][CH2:16]4)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCO3
Reactant: O=C1Nc2ccccc2C12COc1cc3c(cc12)CCCO3
Agent: BrCC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2CCCO2)cc1
Product: O=C1N(C[C@H]2CCCO2)c2ccccc2C12COc1cc3c(cc12)CCCO3

Procedure:
Following the procedure as described in EXAMPLE 4 and making non-critical variations using 6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one to replace 5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-2′(1′H)-one, and (R)-(tetrahydrofuran-2-yl)methyl 4-methylbenzenesulfonate to replace 2-(bromomethyl)tetrahydro-2H-pyran, 1′-[(2R)-tetrahydrofuran-2-ylmethyl]-6,7-dihydro-5H-spiro[furo[3,2-g]chromene-3,3′-indol]-2′(1′H)-one was obtained (57%) as an off-white solid: mp 151-156° C. (diethyl ether); 1H NMR (300 MHz, CDCl3) (diastereomers) δ7.32-7.26 (m, 1H), 7.16-7.02 (m, 3H), 6.40 (s, 1H), 6.38 (s, 1H), 4.89 (d, J=9.0 Hz, 1H), 4.644, 4.640 (d, J=9.0 Hz, 1H), 4.32-4.24 (m, 1H), 4.11 (dd, J=5.4, 4.8 Hz, 2H), 3.99-3.69 (m, 4H), 2.63-2.52 (m, 2H), 2.10-1.85 (m, 5H), 1.79-1.67 (m, 1H); 13C NMR (75 MHz, CDCl3) (diastereomers) δ178.3, 178.2, 160.2, 156.3, 143.0, 132.8, 132.7, 128.8, 128.7, 123.88, 123.86, 123.82, 123.76, 123.3, 121.1, 121.0, 115.24, 115.20, 109.7, 109.5, 98.9, 80.43, 80.40, 77.1, 77.0, 68.4, 68.3, 66.7, 57.8, 57.7, 44.8, 44.7, 29.4, 29.1, 25.8, 25.7, 24.8, 24.7, 22.4; MS (ES+) m/z 378.1 (M+1).
Reaction SMILES: [C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:13][CH2:12][CH:11]([CH2:14][OH:15])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[S:18](Cl)([C:21]1[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=1)(=[O:20])=[O:19].N1C=CC=CC=1.CCOCC>C(Cl)(Cl)Cl>[C:1]([SiH2:5][O:6][C:7]([CH3:17])([CH3:16])[CH:8]1[CH2:9][CH2:10][CH:11]([CH2:14][O:15][S:18]([C:21]2[CH:27]=[CH:26][C:24]([CH3:25])=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH2:12][CH2:13]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[SiH2]OC(C)(C)C1CCC(CO)CC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OCC2CCC(C(C)(C)O[SiH2]C(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.6 %

Procedure:
To a 100 mL-flask containing 83 (3.4 g, 13.2 mmol) in CHCl3 (30 μL) was added tosyl chloride (3.26 g, 17.1 mmol) and pyridine (3.2 mL, 39.6 mmol). The reaction was allowed to stir at 25° C. for 14 hours after which time the reaction was concentrated in vacuo to yield a wet white solid. To this solid was added ether (50 mL) and the solid was filtered and subsequently washed with additional ether (2×50 mL). The ether layers were pooled, concentrated in vacuo to yield a clear oil which was purified by flash chromatography, on a silica gel column, eluting with 1:4 ether/petroleum ether to yield 84 (4.5 g, 83%) as a white solid. 1H NMR (CDCl3) δ 7.78 (d, J=7.7, 2H), 7.33 (d, J=7.7 Hz, 2H), 3, 81 (d, J=6.2 Hz, 2H), 3.37 (d, J=6.2, 2H), 2.44 (s, 3H), 1.95-1.72 (m, 4H), 1.65 (m, 1H), 1.40 (m, 1H), 1.03-0.89 (m, 4H), 0.88 (s, 9H), 0.04 (s, 6H); 13C NMR (CDCl3) δ 145.1, 133.7, 130.3, 128.4, 75.8, 68.9, 40.7, 38.0, 29.1, 26.5, 22.1, 18.9, −4.9; APCI m/z (rel intensity) 413 (MH+, 100).
Reaction SMILES: C1C=CC(C2C=CC=CC=2)=CC=1.C1C=CC(OC2C=CC=CC=2)=CC=1.[CH3:26][O:27][C:28]1[N:33]=[CH:32][C:31]([NH:34][CH:35]=[C:36]([C:42](=[O:44])[CH3:43])[C:37]([O:39]CC)=O)=[CH:30][CH:29]=1>>[OH:39][C:37]1[C:32]2[C:31](=[CH:30][CH:29]=[C:28]([O:27][CH3:26])[N:33]=2)[N:34]=[CH:35][C:36]=1[C:42](=[O:44])[CH3:43]
Reactant: CCOC(=O)C(=CNc1ccc(OC)nc1)C(C)=O
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: c1ccc(-c2ccccc2)cc1
Product: COc1ccc2ncc(C(C)=O)c(O)c2n1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 98.2 %

Procedure:
To a flask containing Dowtherm™ A (500 mL) at 250° C. was added ethyl 2-[(6-methoxypyridin-3-ylamino)methylene]-3-oxobutanoate (75 g, 0.28 mol) portion wise over 3 to 5 min and the reaction mixture was stirred for an additional 30 to 60 min. The reaction mixture was removed from the heat source, cooled to room temperature and diluted with hexanes to facilitate precipitation. The solids were filtered, washed with hexanes and acetonitrile and dried under vacuum to afford the desired product (60 g, 46%) as an off-white solid: 1H NMR (500 MHz, DMSO-d6) δ 12.48 (bs, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.00 (d, J=8.9 Hz, 1H), 7.40-7.37 (m, 1H), 7.21 (d, J=8.9 Hz, 1H), 7.01-6.99 (m, 1H), 3.96 (s, 3H), 2.61 (s, 3H); ESI MS m/z 219 [M+H]+.