Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[OH:10].[H-].[Na+].Cl[C:14]1[C:19]([CH3:20])=[C:18]([Cl:21])[CH:17]=[C:16]([CH3:22])[N+:15]=1[O-:23]>C1COCC1>[Cl:21][C:18]1[C:19]([CH3:20])=[C:14]([O:10][C:3]2[C:4]([CH3:9])=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[N+:15]([O-:23])=[C:16]([CH3:22])[CH:17]=1
Reactant: Cc1c(Cl)cc(C)[n+]([O-])c1Cl
Reactant: Cc1cc(C)c(O)c(C)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc(C)c(Oc2c(C)c(Cl)cc(C)[n+]2[O-])c(C)c1
Yield: 90.1 %

Procedure:
To a solution of 2,4,6-trimethylphenol (415 mg, 3.05 mmol) in dry THF (20 ml) was treated with 60% sodium hydride in oil (122 mg, 3.05 mmol) at room temperature. After all H2 was evolved, 2,4-dichloro-3,6-dimethyl-pyridine 1-oxide (585.4 mg, 3.05 mmol) was added and the resulting mixture was heated at reflux for 2 hours. The mixture was quenched with saturated ammonium chloride and extracted with ethyl acetate. The organic layer was dried and concentrated to dryness to give solid. The solid was recrystallized from pet ether to give 802 mg (90%) of the title compound as white crystals, mp 106-107° C. 1H NMR (CDCl3) δ7.04 (s, 1H), 6.78 (s, 2H), 2.41 (s, 3H), 2.36 (s, 3H), 2.22 (s, 3H), 2.06 (s, 6H) ppm.
Reaction SMILES: [Si:1]([O:18][CH2:19][C@@H:20]([N:23]1[C@H:28]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)[C@@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[CH2:26][CH:25]([O:43][CH3:44])[C:24]1=[O:45])[CH2:21][CH3:22])([C:14]([CH3:17])([CH3:16])[CH3:15])([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.[CH:46]([N-]C(C)C)([CH3:48])[CH3:47].[Li+].C(Br)C=C>C1COCC1>[CH2:48]([C@@:25]1([O:43][CH3:44])[CH2:26][C@H:27]([C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([Cl:42])[CH:37]=2)[C@@H:28]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)[N:23]([C@@H:20]([CH2:21][CH3:22])[CH2:19][O:18][Si:1]([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:24]1=[O:45])[CH:46]=[CH2:47]
Reactant: CC(C)[N-]C(C)C
Reactant: CC[C@@H](CO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)N1C(=O)C(OC)C[C@H](c2cccc(Cl)c2)[C@H]1c1ccc(Cl)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: C=CCBr
Product: C=CC[C@@]1(OC)C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N([C@@H](CC)CO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C1=O
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A solution of (5R,6S)-1-((S)-1-((tert-butyldiphenylsilyl)oxy)butan-2-yl)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methoxypiperidin-2-one (495 mg, 0.749 mmol; Example 203, Step B) in THF (7.49 mL) was sparged with argon for 5 minutes and cooled to 0° C. 1.0 M lithiumdiisopropylamide solution in THF (1.461 mL, 1.461 mmol) was added dropwise. The internal temperature did not rise above 2° C. After 30 minutes, allyl bromide (0.194 mL, 2.247 mmol) was added. The cooling bath was replaced with a room temperature water bath. After 70 minutes, the mixture was quenched with sat. aq. NH4Cl solution and extracted with ethyl acetate. The organic layer was washed with sat. aq. NaCl solution, dried over Na2SO4 and concentrated. The residue was purified by flash chromatography on silica gel (40 g column, eluent: 5 to 30% ethyl acetate/hexanes) to afford the title compound as the more polar diastereomer.
Reaction SMILES: C([Li])CCC.C(OC(=O)NC1C=CN=C(Cl)C=1C)(C)(C)C.C(OC(N1CCC(C(=O)NCOC)CC1)=O)(C)(C)C.C(OC([N:48]1[CH2:53][CH2:52][CH:51]([C:54](=O)[CH2:55][C:56]2[C:57]([Cl:70])=[N:58][CH:59]=[CH:60][C:61]=2[NH:62]C(OC(C)(C)C)=O)[CH2:50][CH2:49]1)=O)(C)(C)C.C(OC(N1C2C=CN=C(Cl)C=2CC1(C1CCN(C(OC(C)(C)C)=O)CC1)O)=O)(C)(C)C.FC(F)(F)C(O)=O>C1COCC1.C(Cl)Cl>[Cl:70][C:57]1[C:56]2[CH:55]=[C:54]([CH:51]3[CH2:52][CH2:53][NH:48][CH2:49][CH2:50]3)[NH:62][C:61]=2[CH:60]=[CH:59][N:58]=1
Reactant: CC(C)(C)OC(=O)Nc1ccnc(Cl)c1CC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: CC(C)(C)OC(=O)N1CCC(C2(O)Cc3c(ccnc3Cl)N2C(=O)OC(C)(C)C)CC1
Agent: COCNC(=O)C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cc1c(NC(=O)OC(C)(C)C)ccnc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Solvent: ClCCl
Product: Clc1nccc2[nH]c(C3CCNCC3)cc12
Temperature: -20 °C

Procedure:
n-Butyllithium (3.36 mL of 2.5M in hexanes, 8.4 mmol) was added dropwise to a stirring solution of (2-chloro-3-methylpyridin-4-yl)carbamic acid tert-butyl ester (0.971 g, 4 mmol) in THF (50 mL) at −78° C., under nitrogen. Warmed the reaction mixture to −20° C. for 15 minutes, before cooling back to −78° C. and adding a solution of 4-(methoxymethylcarbamoyl)piperidine-1-carboxylic acid tert-butyl ester (1.089 g, 4 mmol) in THF (10 mL). Warmed the reaction slowly to room temperature over 2 hours, and quenched with 1N HCl (50 mL). Extracted into ethyl acetate, washed with saturated aqueous sodium hydrogencarbonate, and dried over magnesium sulfate. Flash column chromatography gave a 1:1 mixture, by NMR, of the ring open and ring closed tautomers of the required intermediate {4-[(tert-butoxycarbonylamino-2-chloropyridin-3-yl)acetyl]piperidine-1-carboxylic acid tert-butyl ester and 2-(1-tert-butoxycarbonylpiperidin-4-yl)-4-chloro-2-hydroxy-2,3-dihydropyrrolo[3,2-c]pyridine-1-carboxylic acid tert-butyl ester}. This material (845 mg, 1.88 mmol) was dissolved in methylene chloride (40 mL) and stirred vigorously at room temperature during the dropwise addition of trifluoroacetic acid (4 mL). After 2 hours the reaction mixture was concentrated to dryness, and flash column chromatographed on silica gel with ammonium hydroxide/methylene chloride/methanol to give the pure free base product as a white powder (420 mg, 1.76 mmol). 1H NMR (d4-MeOH) δ 7.87 (d, 1H), 7.31 (d, 1H), 6.39 (s, 1H), 3.52-3.45 (m, 2H), 3.20-3.09 (m, 3H), 2.36-2.25 (m, 2H), 2.04-1.88 (m, 2H). ESI MS (M+1)+: 236, 238 (Cl).
Reaction SMILES: [CH2:1]=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:9]=[CH:10]C1C=CC(C=C)=CC=1.C1C=CC(I)=CC=1.C#C>CN(C=O)C>[CH:9]#[C:10][CH2:4][CH2:5][C:6]#[C:7][CH2:8][CH2:3][CH2:2][CH3:1]
Reactant: C=Cc1ccccc1
Reactant: C=Cc1ccc(C=C)cc1
Agent: C#C
Solvent: Ic1ccccc1
Solvent: CN(C)C=O
Product: C#CCCC#CCCCC
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
WANG iodopolystyrene (100 mg), synthesized as described in Example 1, was dissolved in a solvent mixture of DMF/distilled water/TEA (9:1:1) (5 mL) and allowed to swell for 30 minutes at room temperature. 1,5-decadiyne (100 mg) in DMF (2 mL) was added to the polymer bead suspension. Potassium carbonate (50 mg, 0.36 mm) and tetrabutylammonium bromide (50 mg, 0.16 mM) were then added and the suspension was stirred under argon atmosphere for 30 minutes. Tetrakis (triphenylphosphine) palladium (0) (25 mg, 0.02 mM) was added rapidly. The reaction mixture was heated to 80° C. and agitated at that temperature under an argon atmosphere for 16 hours and allowed to cool to room temperature. When the mixture had reached room temperature, a saturated solution of ammonium acetate (5 mL) was added and the mixture agitated at room temperature for 30 minutes, DME (5 mL) was added and the mixture was agitated for an additional 30 minutes, transferred to a fritted filter funnel and washed sequentially with distilled water, DMF, distilled water, 2 N HCl, distilled water, DMF, distilled water, methanol, DCM and methanol (50 mL of each which was allowed to equilibrate for 10 minutes between washes). The product was dried under vacuum to produce a tagged bead containing only one Raman active acetylene tag.
Reaction SMILES: Br[CH2:2][C:3]1[C:11]2[O:10][C:9]([F:13])([F:12])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.C1N2CN3CN(C2)CN1C3.Cl.[OH2:25]>>[F:12][C:9]1([F:13])[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([CH:2]=[O:25])[C:11]=2[O:10]1
Reactant: FC1(F)Oc2cccc(CBr)c2O1
Reactant: O
Agent: C1N2CN3CN1CN(C2)C3
Agent: Cl
Product: O=Cc1cccc2c1OC(F)(F)O2

Procedure:
117 g of crude 4-bromomethyl-2,2-difluoro-1,3-benzodioxole are added to 120 g of urotropin in 250 ml of water and the mixture is heated under reflux for 3 hours. 120 ml of hydrochloric acid in 150 ml of water are then added and the mixture is heated for a further 3 hours. The crude product is then driven over with steam, removed from the receiver and shaken with 100 g of sodium bisulphate in 250 ml of water. After extraction with methylene chloride, the aqueous phase is acidified with 2N sulphuric acid and the aldehyde is separated off and distilled. The yield is 53 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([N+:23]([O-])=O)=[CH:4][CH:3]=1>[Pd].C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH2:23])=[C:6]2[C:10]=1[N:9]=[C:8]1[N:11]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]21
Reactant: O=[N+]([O-])c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Pd]
Solvent: CC(=O)O
Product: Nc1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.1 %

Procedure:
A mixture of 9-chloro-1-(2,4-dichlorophenyl)-6-nitro-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole (123 mg, 0.308 mmol) and 10% palladium on carbon (12 mg) in acetic acid (5.0 mL) was stirred under hydrogen atmosphere at room temperature for 8 hr. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 50-100% ethyl acetate/n-hexane gradient mixture. The filtrate was concentrated in vacuo to give the title compound (51 mg, 0.139 mmol, 45%) as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:13]#[C:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][C:20]2[C:21]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[C:22]([CH:30]=[CH:31][CH:32]=2)[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:5]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:7]=1.O.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+]>CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:35]([CH2:34][CH2:33][C:21]1[C:20]([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][C:14]#[C:13][C:4]2[CH:3]=[C:2]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)[CH:7]=[C:6]([C:8](=[O:12])[N:9]([CH3:11])[CH3:10])[CH:5]=2)=[CH:32][CH:31]=[CH:30][C:22]=1[O:23][CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])([OH:37])=[O:36]
Reactant: CN(C)C(=O)c1cc(Br)cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)c1
Reactant: OB(O)c1cccc(F)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CN(C)C(=O)c1cc(C#CCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cccc(F)c2)c1
Temperature: 78 °C

Procedure:
To a solution of 4-[3-[7-(3-bromo-5-dimethylcarbamoyl-phenyl)-hept-6-ynyl]-2-(2-carboxy-ethyl)-phenoxy]-butyric acid (80 mg, 0.14 mmol) in EtOH (4 mL)/H2O (1 mL) were added 3-fluorophenylboronic acid (39 mg, 0.28 mmol), potassium carbonate (77 mg, 0.56 mmol) and Pd(PPh3)4 (3 mg, 0.0028 mmol). The mixture was heated at 78° C. for 5 h and then cooled to room temperature. The reaction mixture was filtered using a syringe filter 0.45 μm and the filtrate was concentrated under reduced pressure. The crude oil was then purified by preparative HPLC using acetonitrile/water gradient.
Reaction SMILES: [CH3:1][C:2]1([CH:19]([CH2:23][CH3:24])C(O)=O)[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2.C(Cl)(=O)[C:26](Cl)=[O:27].[BH4-].[BH4-].[BH4-].[BH4-].[Na+].[Na+].[Na+].[Na+].Cl>O1CCOCC1.CN(C)C=O.CO>[OH:27][CH2:26][CH2:24][CH2:23][CH2:19][C:2]1([CH3:1])[C:14]2[N:13]3[CH:15]=[CH:16][N:17]=[C:12]3[C:11](=[O:18])[NH:10][C:9]=2[C:8]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCC(C(=O)O)C1(C)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: CN(C)C=O
Product: CC1(CCCCO)c2ccccc2-c2[nH]c(=O)c3nccn3c21
Temperature: 10 °C
Reaction time: 4 h

Procedure:
A stirred suspension of 0.6 g of (10-methyl-4,5-dihydro-4-oxo-10H-imidazo[1,2-a]indeno[1,2-e]-pyrazin-10-yl)butyric acid in 20 ml of dioxane is cooled to a temperature in the region of 10° C., under an argon atmosphere, and 0.19 ml of oxalyl chloride is added. A solution of 0.5 ml of dimethylformamide in 5 ml of dioxane is then added dropwise. After the addition, the mixture is left stirring for 4 hours at a temperature in the region of 20° C. A further 0.38 ml of oxalyl chloride and 6 ml of dimethylformamide are added dropwise and stirring is continued for 1 hour. A solution of 0.38 g of sodium tetraborohydride in 10 ml of dimethylformamide is then added dropwise and the stirring is continued overnight. The reaction mixture is treated with 10 ml of methanol, acidified to pH 1 with 1N hydrochloric acid and concentrated on a rotary evaporator. The evaporation residue is purified by chromatography on a column of silica (100 g) eluting, under a pressure of 0.5 bar, first with a dichloromethane/methanol mixture (95/5 by volume) and then with a dichloromethane/methanol/28% aqueous ammonia mixture (90/10/0.5 by volume). 70 mg of 10-(4-hydroxybutyl)-10-methyl-5H,10H-imidazo[1,2-a]indeno-[1,2-e]pyrazin-4-one are obtained in the form of a white solid (1H NMR spectrum [300 MHz; (CD3)2SO-d6 ; δ in ppm]: 0.52 (mt, 2H: CH2); 1.29 (quintet, J=7.5 Hz, 2H: CH2); 1.57 (s, 3H: CH3); 2.17 and 2.36 (2 mts, 1H each: hetero-CH2); 3.14 (t, J=7.5 Hz, 1H: CH2O); 4.19 (broad s, 1H: OH); 7.38 (mt, 2H: H 7 and H 8); 7.67 and 8.24 (2 broad s, 1H each: H of the imidazole); 7.60 and 7.87 (2 broad d, J=7.5 Hz, 1H each: H 6 and H9)).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[CH:12]=[C:13]([N:23]4[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]4=[O:30])[CH:14]=[C:15]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:16]=3[O:17][CH3:18])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:31](OC(=O)C)(=[O:33])[CH3:32]>>[C:19]([C:15]1[C:16]([O:17][CH3:18])=[C:11]([C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:31](=[O:33])[CH3:32])[S:3][C:4]=3[CH:10]=2)[CH:12]=[C:13]([N:23]2[CH:28]=[CH:27][C:26](=[O:29])[NH:25][C:24]2=[O:30])[CH:14]=1)([CH3:22])([CH3:21])[CH3:20]
Reactant: COc1c(-c2ccc3nc(N)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Reactant: CC(=O)OC(C)=O
Product: COc1c(-c2ccc3nc(NC(C)=O)sc3c2)cc(-n2ccc(=O)[nH]c2=O)cc1C(C)(C)C
Temperature: 100 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
A mixture of the product from Example 53 (30 mg, 0.071 mmol) and acetic anhydride (3 mL) was stirred at 100° C. for 2 h, and then allowed to cool to room temperature. The resulting solid was collected by filtration, washed with H2O, and dried to give the title compound as an off-white solid (29 mg, 88%). 1H NMR (300 MHz, DMSO-d6) δ 12.42 (s, 1H) 11.41 (d, J=2.21 Hz, 1H) 8.12 (d, J=1.47 Hz, 1H) 7.82 (d, J=8.46 Hz, 1H) 7.78 (d, J=8.09 Hz, 1H) 7.61 (dd, J=8.46, 1.84 Hz, 1H) 7.31 (q, J=2.70 Hz, 2H) 5.64 (dd, J=8.09, 2.21 Hz, 1H) 3.24 (s, 3H) 2.22 (s, 3H) 1.41 (s, 9H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[N:10][C:11]=1[CH:12](OC)[O:13]C)[N:8]([C:17]([NH:19][C:20]1[CH:25]=[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])[C:23]([C:31]#[N:32])=[CH:22][N:21]=1)=[O:18])[CH2:7][CH2:6][CH2:5]2.[S:33]1[CH:37]=[CH:36][CH:35]=[C:34]1B1OC(C)(C)C(C)(C)O1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.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]>[C:31]([C:23]1[C:24]([NH:26][CH2:27][CH2:28][O:29][CH3:30])=[CH:25][C:20]([NH:19][C:17]([N:8]2[C:9]3[C:4](=[CH:3][C:2]([C:34]4[S:33][CH:37]=[CH:36][CH:35]=4)=[C:11]([CH:12]=[O:13])[N:10]=3)[CH2:5][CH2:6][CH2:7]2)=[O:18])=[N:21][CH:22]=1)#[N:32]
Reactant: CC1(C)OB(c2cccs2)OC1(C)C
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(Br)c(C(OC)OC)nc32)ncc1C#N
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: COCCNc1cc(NC(=O)N2CCCc3cc(-c4cccs4)c(C=O)nc32)ncc1C#N
Temperature: 120 °C
Reaction time: 0.25 h

Procedure:
A suspension of 6-bromo-N-(5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)-7-(dimethoxymethyl)-3,4-dihydro-1,8-naphthyridine-1(2H)-carboxamide (intermediate 315, 50 mg, 0.099 mmol), thiophene-2-boronic acid pinacol ester (25 mg, 0.119 mmol), PdCl2(dppf) (8 mg, 10.9 μmol) and saturated aqueous Na2CO3 (140 μl) in DME (420 μl) was sealed in a vial and purged with argon. The reaction mixture was stirred at 120° C. for 15 min in a microwave. The suspension was diluted with DCM and water, phases were separated and the aqueous layer was extracted with DCM (2×). The combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography eluting with a gradient of MeOH (2-4%) in DCM, followed by another purification eluting with a gradient of EtOAc (70-100%) in hexanes. Product fractions were combined, evaporated and dried to yield the title compound as a white solid. (UPLC-MS 3) tR 1.23 min; ESI-MS 509.2 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 8.31 (s, 1H), 7.62-7.55 (m, 2H), 7.44 (d, 1H), 7.31 (d, 1H), 7.18-7.13 (m, 1H), 5.57 (s, 1H), 5.33 (s, 1H), 4.10 (t, 2H), 3.66 (t, 2H), 3.48 (s, 11H), 2.91 (t, 2H), 2.09-2.00 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH:15](O)=O>[Pd]>[NH:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[C:2]=2[N:1]=[CH:15]1
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Reactant: O=CO
Agent: [Pd]
Product: COC(=O)c1cccc2[nH]cnc12
Temperature: 100 °C
Reaction time: 23 h

Procedure:
To a suspension of methyl 2-amino-3-nitrobenzoate (1.0 g) in formic acid (>87%) was added 5% palladium on carbon (100 mg) and the suspension was heated with stirring at 100° C. for 23 hours. After the reaction mixture was cooled to room temperature, the catalyst was filtered off on celite, and the mother liquor was concentrated in vacuo. The residual solid was washed with diethyl ether under stirring, the solid was collected by filtration to obtain the titled compound (872 mg) as a colorless powder.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl.[CH3:13]O>>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:3]=1[C:4]([O:6][CH3:13])=[O:5]
Reactant: Nc1ccc(F)cc1C(=O)O
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(F)ccc1N
Temperature: 100 °C
Yield: 42 %

Procedure:
A solution of 2-amino-5-fluorobenzoic acid (9.29 mmol, 1.440 g) in a mixture of HCl/MeOH (3N, 30 ml) was heated at 100° C. overnight. The solvent was evaporated and the crude mixture was extracted between DCM and K2CO3 saturated aqueous solution. The organic phase was evaporated and the crude mixture was purified by chromatography over SiO2 with hexane/ethyl acetate mixtures affording 0.650 g (yield 42%) of the expected product.
Reaction SMILES: [CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C:15]([F:18])([F:17])[F:16])(=[O:5])=[O:4]>C(O)(=O)C.[Fe]>[CH3:1][N:2]([CH3:19])[S:3]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][C:7]=1[C:15]([F:17])([F:16])[F:18])(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Fe]
Solvent: CC(=O)O
Product: CN(C)S(=O)(=O)c1ccc(N)cc1C(F)(F)F
Yield: 83 %

Procedure:
To a heated mixture containing 13.5 g (0.045 mole) of the amide prepared as in (b) above in 250 ml of 5% acetic acid was added portionwise and with stirring 12 g of iron powder. The mixture was refluxed for 1/2 hour. The mixture was filtered while hot and the cooled filtrate was extracted with ether. The ether extract was washed with aqueous sodium bicarbonate, dried, concentrated and recrystallized from ether-hexane (1:2) to give 10.1 g (83%) of product as a colorless solid; m.p. 140°-142° C.
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([C:7]2[CH:11]=[CH:10][O:9][CH:8]=2)[N:3]=1.FC(F)(F)C(O)=O.[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)=[O:30])=[N:20]1.C(N(CC)CC)C.O>CN(C)C=O>[O:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([NH:28][C:29]([N:31]2[CH2:36][CH2:35][N:34]([C:2]3[S:6][N:5]=[C:4]([C:7]4[CH:11]=[CH:10][O:9][CH:8]=4)[N:3]=3)[CH2:33][CH2:32]2)=[O:30])=[N:20]1
Reactant: O=C(Nc1noc2ccccc12)N1CCNCC1
Reactant: Clc1nc(-c2ccoc2)ns1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1noc2ccccc12)N1CCN(c2nc(-c3ccoc3)ns2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 20 %

Procedure:
To a solution of 5-chloro-3-(3-furyl)-1,2,4-thiadiazole (104 mg, 0.555 mmol) and N-1,2-benzisoxazol-3-ylpiperazine-1-carboxamide trifluoroacetate (200 mg, 0.555 mmol) in N,N-dimethylformamide (2 ml) was added triethylamine (0.389 ml, 2.78 mmol) at room temperature, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured to water, and the precipitated solid was separated by filtration, which was recrystallized from a mixed solvent of ethyl acetate and tetrahydrofuran to give 44.0 mg (20.0%) of the desired product.
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:8])[C:4]([F:7])([F:6])[F:5].[H-].[Na+].[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1C=CC=CC=1>[CH3:1][N:2]([Si:11]([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12])[C:3](=[O:8])[C:4]([F:7])([F:6])[F:5]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CNC(=O)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: c1ccccc1
Product: CN(C(=O)C(F)(F)F)[Si](C)(C)C(C)(C)C
Temperature: 0 °C

Procedure:
To 800 ml of dry benzene:acetonitrle (v/v, 1:1) was added 127 g (1.0 mole) of N-methyl-trifluoroacetamide. To this solution, while stirring and maintaining the temperature at 0 degrees C., was slowly added 23.5 g (0.98 mole) of sodium hydride. The solution was then stirred for 4 hours at 4 degrees C. At this time, 173.34 g (1.15 mole) of t-butyldimethylsilyl chloride was added in four equal aliquots over a period of 80 minutes. After the last addition the solution was stirred for 2 hours at 4 degrees C. The precipitate of sodium chloride was then removed from the reaction mixture by filtration under dry nitrogen and the resulting filter cake washed twice with 100 ml each of dry benzene. Washings and filtrate were combined and concentrated. The remaining yellow solution was fractionally distilled with the distillate at 158-172 degrees C. being collected. Redistillation of this fraction gave the desired product.
Reaction SMILES: I[CH2:2][CH2:3][CH2:4][N:5]1[CH:9]=[CH:8][C:7]([C:10]([O:12][CH3:13])=[O:11])=[C:6]1[CH2:14][C:15]([O:17][CH3:18])=[O:16].[H-].[Na+].CN(C)C=O>[Na+].[Cl-]>[C:7]1([C:10]([O:12][CH3:13])=[O:11])[CH:8]=[CH:9][N:5]2[CH2:4][CH2:3][CH2:2][CH:14]([C:15]([O:17][CH3:18])=[O:16])[C:6]=12
Reactant: COC(=O)Cc1c(C(=O)OC)ccn1CCCI
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccn2c1C(C(=O)OC)CCC2
Reaction time: 1 h

Procedure:
A solution of 17 g. of methyl N-(3-iodopropyl)-3-carbomethoxypyrrole-2-acetate is added portionwise over an hour to a stirred suspension of 52.7 g. (99%) NaH in 300 ml. dry dimethylformamide at 0° C. and maintained in nitrogen. The temperature is allowed to reach 20° and stirring is continued for 1 hour. The reaction mixture is diluted with saturated NaCl and extracted with benzene 4 times. The combined extracts are washed with water, dried over sodium sulfate and evaporated to dryness in vacuo. Recrystallization of the residue using benzene-hexane affords dimethyl 5,6,7,8-tetrahydropyrrolo[1,2-a]-pyridine-1,8-dicarboxylate (VII, R=H, n=1) m.p. 108° C.