Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]([C:6]1[CH:19]=[CH:18][C:17]2[O:16][C:15]3[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22]Cl)=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)=[O:5].[C:25]1([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:25]1([N:31]2[CH2:36][CH2:35][N:34]([CH2:2][CH2:3][C:4]([C:6]3[CH:19]=[CH:18][C:17]4[O:16][C:15]5[C:10](=[CH:11][C:12]([C:20](=[O:24])[CH2:21][CH2:22][N:34]6[CH2:35][CH2:36][N:31]([C:25]7[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=7)[CH2:32][CH2:33]6)=[CH:13][CH:14]=5)[CH2:9][C:8]=4[CH:7]=3)=[O:5])[CH2:33][CH2:32]2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: O=C(CCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCl)ccc1O2
Product: O=C(CCN1CCN(c2ccccc2)CC1)c1ccc2c(c1)Cc1cc(C(=O)CCN3CCN(c4ccccc4)CC3)ccc1O2

Procedure:
Prepared from compound 17 and 4-phenyl-piperazine according to General Procedure C to give a solid. Mp 206-208° C. 1H NMR (CDCl3, 400 MHz) δ7.91-7.86 (m 4H), 7.29 (t, J=10 Hz, 4H), 7.14 (d, J=10 Hz, 2H), 6.96-6.91 (m, 6H), 4.16 (s, 2H), 3.51-3.46 (m, 12H), 3.38-3.10 (m, 12H). Anal. (C39H42N4O3.).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[NH:13][CH:12]=2)=[CH:4][CH:3]=1.[H-].[Na+].[CH:22]([Si:25](Cl)([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])([CH3:24])[CH3:23].C(=O)(O)[O-].[Na+]>CN(C)C=O>[Cl:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[C:5]([CH2:10][C:11]2[C:19]3[C:14](=[N:15][CH:16]=[CH:17][CH:18]=3)[N:13]([Si:25]([CH:29]([CH3:31])[CH3:30])([CH:26]([CH3:28])[CH3:27])[CH:22]([CH3:24])[CH3:23])[CH:12]=2)=[CH:4][CH:3]=1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: COc1nc(Cl)ccc1Cc1c[nH]c2ncccc12
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nc(Cl)ccc1Cc1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a clear solution of 3-(6-chloro-2-methoxypyridin-3-ylmethyl)-1H-pyrrolo[2,3-b]pyridine (28, 0.516 g, 1.88 mmol) in dimethylformamide (10 mL) was added sodium hydride (60% dispersion, 0.113 g, 2.82 mmol). After stirring at room temperature for 30 minutes, triisopropylsilyl chloride (600 μL, 2.83 mmol) was added. The reaction was stirred at room temperature for 2 hours, then poured into aqueous (1M) sodium bicarbonate and extracted with ethyl acetate. The organic layer was separated, dried (magnesium sulfate), filtered and volatiles were removed by rotary evaporation to give a crude solid. The compound was purified by silica gel column chromatography eluting with 2% ethyl acetate in hexanes. This provided 732 mg of the desired compound as a white, crystalline solid (29, 1.70 mmol, 90%). MS (ESI) [M+H+]+=430.2.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([OH:15])=O.[CH3:16][O:17][C:18]1[CH:19]=[C:20]2[C:24](=[CH:25][C:26]=1[N:27]1[CH2:32][C@H:31]([CH3:33])[N:30]([CH3:34])[C@H:29]([CH3:35])[CH2:28]1)[NH:23][CH2:22][CH2:21]2>>[F:1][C:2]1[C:7]([C:8]([F:9])([F:10])[F:11])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:12][C:13]([N:23]1[C:24]2[C:20](=[CH:19][C:18]([O:17][CH3:16])=[C:26]([N:27]3[CH2:32][C@H:31]([CH3:33])[N:30]([CH3:34])[C@H:29]([CH3:35])[CH2:28]3)[CH:25]=2)[CH2:21][CH2:22]1)=[O:15]
Reactant: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)NCC2
Reactant: O=C(O)Cc1cccc(C(F)(F)F)c1F
Product: COc1cc2c(cc1N1C[C@@H](C)N(C)[C@@H](C)C1)N(C(=O)Cc1cccc(C(F)(F)F)c1F)CC2

Procedure:
The title compound was prepared from 2-fluoro-3-trifluoromethylphenylacetic acid (155 mg, 0.70 mmole) and D3 (150 mg, 0.54 mmole) using a similar procedure to Example 8. The product was obtained as a pale yellow oil (210 mg, 81%), which was converted to its hydrochloride salt as a beige solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH:12]2[O:13][C:14](=[O:21])[CH:15]3[CH:16]([C:17]([O:19][CH3:20])=[O:18])[CH:9]1[CH2:10][CH:11]23)=[O:6].CN(C)C=O.[C:27]([O-:32])(=[O:31])[C:28]([CH3:30])=[CH2:29].[Na+].[I-].[Na+]>O>[C:27]([O:32][CH2:2][CH2:3][CH2:4][C:5]([O:7][CH:8]1[CH:12]2[O:13][C:14](=[O:21])[CH:15]3[CH:16]([C:17]([O:19][CH3:20])=[O:18])[CH:9]1[CH2:10][CH:11]23)=[O:6])(=[O:31])[C:28]([CH3:30])=[CH2:29]
Reactant: C=C(C)C(=O)[O-]
Reactant: COC(=O)C1C2CC3C(OC(=O)C31)C2OC(=O)CCCCl
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C=C(C)C(=O)OCCCC(=O)OC1C2CC3C1OC(=O)C3C2C(=O)OC
Reaction time: 8 h
Yield: 70.2 %

Procedure:
A mixture of 10.0 g of the 4-chlorobutyrate obtained in Example 1-1-1 and 30 g of dimethylformamide was added dropwise to a mixture of 4.69 g of sodium methacrylate, 0.71 g of sodium iodide and 20 g of dimethylformamide at 60-70° C. The mixture was stirred at the temperature for 8 hours. 100 ml of water was added below 30° C. This was followed by ordinary work-up and silica gel chromatography purification, obtaining 8.12 g of the target compound (yield 70%).
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=[C:6]([Cl:10])[C:7]=1[C:8]#[N:9].[CH3:24][N:25]([CH3:37])[C:26]([C:28]1[N:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)=[O:27].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.O.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>[Cl:10][C:6]1[C:7]([C:8]#[N:9])=[C:2]([C:31]2[CH:32]=[N:33][C:28]([C:26]([N:25]([CH3:37])[CH3:24])=[O:27])=[CH:29][CH:30]=2)[C:3]([O:21][CH2:22][CH3:23])=[C:4]([CH:11]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH3:12])[CH:5]=1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cn1
Reactant: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1Br
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: C1COCCO1
Solvent: O
Product: CCOc1c(C(C)NC(=O)OC(C)(C)C)cc(Cl)c(C#N)c1-c1ccc(C(=O)N(C)C)nc1
Temperature: 90 °C
Yield: 84.6 %

Procedure:
The tert-butyl [1-(3-bromo-5-chloro-4-cyano-2-ethoxyphenyl)ethyl]carbamate (0.05 g, 0.1 mmol, Example 179, peak 2) was combined with {6-[(dimethylamino)carbonyl]pyridin-3-yl}boronic acid (0.034 g, 0.17 mmol, Example 179, Step 5) in 1,4-dioxane (3.0 mL) and potassium carbonate (0.034 g, 0.25 mmol) dissolved in water (1.0 mL) in a tube. The reaction was degassed with nitrogen and the tetrakis(triphenylphosphine)palladium(0) (0.03 g, 0.02 mmol) was added and degassed again. The tube was sealed and heated in an oil bath to 90° C. After heating for 18 h the reaction was complete. This was allowed to cool to room temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried over magnesium sulfate and concentrated to give the crude as a dark oil. The product was purified by chromatography on silica gel eluting with hexane:EtOAc gradient to give tert-butyl [1-(5-chloro-4-cyano-3-{6-[(dimethylamino)carbonyl]pyridin-3-yl}-2-ethoxyphenyl)ethyl]carbamate as a viscous oil (0.04 g, 66%). LCMS calculated for C24H30ClN4O4 (M+H)+: m/z=473.2. found: 473.1.
Reaction SMILES: [Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([OH:15])=O.[C:16](N1C=CN=C1)([N:18]1C=CN=C1)=O.CN>CN(C)C=O>[Br:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:13]([NH:18][CH3:16])=[O:15]
Reactant: O=C(O)c1cnn(-c2ccccc2)c1Br
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CN
Solvent: CN(C)C=O
Product: CNC(=O)c1cnn(-c2ccccc2)c1Br
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 41.3 %

Procedure:
Three grams of 5-bromo-1-phenyl-1H-pyrazole-4-carboxylic acid and 2.6 g of carbonyldiimidazole were dissolved in 50 ml of dimethylformamide. The mixture was allowed to stir for 20 minutes and 7 ml of 40% aqueous methylamine was added to the reaction mixture. The mixture was stirred for 2 hours at room temperature and poured into ice water. The precipitated solid was collected by filtration and recrystallized from ethanol/water to afford 1.3 g of 5-bromo-1-phenyl-N-methyl-1H-pyrazole-4-carboxamide. Yield 42%. mp=157°-159° C.
Reaction SMILES: [N+:1]([C:4]1[CH:38]=[CH:37][C:7]([N:8]([C:23]2[CH:28]=[CH:27][C:26]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])=[CH:25][CH:24]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=2)=[CH:6][CH:5]=1)([O-])=O.O.NN>[Pd].C(O)C>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([N:8]([C:23]2[CH:24]=[CH:25][C:26]([C:29]([CH3:36])([CH2:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH3:30])=[CH:27][CH:28]=2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]([CH3:22])([CH2:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH3:16])=[CH:11][CH:10]=2)=[CH:37][CH:38]=1
Reactant: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc([N+](=O)[O-])cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Agent: [Pd]
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)CC(C)(C)c1ccc(N(c2ccc(N)cc2)c2ccc(C(C)(C)CC(C)(C)C)cc2)cc1
Yield: 80 %

Procedure:
Next, 13.60 mmol of 4-nitro-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline, 0.22 of 10% Pd/C, and 150 ml of ethanol were added into a bottle. Next, the mixture was heated to reflux, and 7 ml of hydrazine monohydrate was added slowly to the mixture from a dropping funnel over a period of 1 hrs under dry nitrogen. After a further 12 hrs of reflux, the mixture solution was filtered to remove Pd/C, and the filtrate was cooled to precipitate. The crude product was collected by filtration and recrystallization from ethanol to afford 4-Amino-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline as a white crystal with a yield of 80%. The 4-amino-N,N-bis(4-(2,4,4-trimethylpentan-2-yl)phenyl)aniline had a melt point of 95° C.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[CH:5][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])[O-].[K+].[K+].[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22]Cl>CN(C=O)C.O>[CH3:17][O:18][CH2:19][CH2:20][O:21][CH2:22][O:8][C:7]([C:6]1[CH:5]=[C:4]([CH3:10])[O:3][C:2]=1[CH3:1])=[O:9]
Reactant: COCCOCCl
Reactant: Cc1cc(C(=O)O)c(C)o1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCOC(=O)c1cc(C)oc1C
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.8 %

Procedure:
A 2 L round-bottomed flask equipped with a mechanical stirrer was charged with 2,5-dimethyl-3-furoic acid (81.0 g, 0.58 mol) and potassium carbonate (95.9 g, 0.69 mol) in DMF (500 mL). An ice bath was used to cool the reaction as 2-methoxyethoxymethyl chloride (72.2 g, 0.58 mol) was added portionwise. The reaction was stirred for 5 h at rt. The mixture was then diluted with water (1.5 L) and extracted with EtOAc (2×600 mL). The combined organics were washed with water (2×900 mL) and saturated sodium chloride solution (1 L), dried over MgSO4, filtered and concentrated to afford compound 803A (103 g, 82%) as a yellow oil. 1H NMR(CDCl3): δ=6.23 (s, 1H), 5.47 (s, 1H), 3.84 (m, 2H), 3.56 (m, 2H), 3.38 (s, 3H), 2.51 (s, 3H) and 2.20 ppm (s, 3H).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]2[CH:16]3[CH2:17][O:18][C:19]([CH3:23])([CH3:22])[O:20][CH2:21][CH:15]23)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[OH-:24].[K+].Cl>O>[C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([NH:14][C@@H:15]2[CH2:21][O:20][C:19]([CH3:23])([CH3:22])[O:18][CH2:17][C@H:16]2[OH:24])(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: [OH-]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)N2C3COC(C)(C)OCC32)cc1
Agent: Cl
Agent: [K+]
Solvent: O
Product: CC(=O)Nc1ccc(S(=O)(=O)N[C@@H]2COC(C)(C)OC[C@H]2O)cc1
Temperature: 25 °C

Procedure:
A mixture of 1-(4-acetylaminobenzenesulfonyl)-4,4-dimethyl-1a,2,6,6a-tetrahydro-1H,4H-[1,3]-dioxepino[5,6-b]azirine (0.33 g), potassium hydroxide (0.14 g) and water (2.6 ml) was boiled with reflux for 60 minutes. The mixture was cooled to room temperature, acidified with diluted hydrochloric acid to pH 6.5 and evaporated to dryness at reduced pressure. The chromatography of the evaporation residue on a silica gel column by elution with a mixture of ethyl acetate/methanol (9.8:0.2) yielded trans-6-(4-acetylaminobenzene-sulfonamido)-2.2-dimethyl-1,3-dioxepane-5-ol, m.p. 203°-205° C./methylene chloride- methanol (9:1), and trans-6-sulfanylamido-2,2-dimethyl-1,3-dioxepane-5-ol.
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23](OCC)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1>>[CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)=[O:24])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[CH:9][C:8]=2[N:17]=1)[CH3:2]
Reactant: C1COCCN1
Reactant: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)OCC
Product: CCOCc1nc2cnc3ccccc3c2n1CCCCCC(=O)N1CCOCC1
Temperature: 25 °C

Procedure:
A solution of ethyl 6-(2-ethoxymethyl-1H-imidazo[4,5-c]quinolin-1-yl)hexanoate (4.0 g, 11 mmol) in morpholine (7 mL) was heated at reflux for three days, allowed to cool to ambient temperature, and concentrated under reduced pressure. The residue was dissolved in dichloromethane; the resulting solution was washed sequentially with saturated aqueous sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure to provide 4.4 g of 2-(ethoxymethyl)-1-(6-morpholin-4-yl-6-oxohexyl)-1H-imidazo[4,5-c]quinoline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1([CH2:12][N:13]2[CH:17]=[N:16][CH:15]=[N:14]2)[CH2:11][O:10]1.[SH:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:10])([CH2:11][S:18][C:19]1[N:23]=[CH:22][NH:21][N:20]=1)[CH2:12][N:13]1[CH:17]=[N:16][CH:15]=[N:14]1
Reactant: Sc1nc[nH]n1
Reactant: Clc1ccc(C2(Cn3cncn3)CO2)c(Cl)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OC(CSc1nc[nH]n1)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
2-(2,4-Dichlorophenyl)-2-(1H-1,2,4-triazol-1-yl-methyl)oxirane methanesulphonte salt (5 g, 0.0137 m), 3-mercapto-1,2,4-triazole (5 g, 0.05 m), and anhydrous potassium carbonate (14 g, 0.1 m) were stirred in dry N,N-dimethylformamide (100 ml) at 80° C. for 1 hour. The solvent was then evaporated and the residue was dissolved in water and extracted with methylene chloride. The combined extracts were washed once with dilute sodium bicarbonate solution, dried (MgSO4), and evaporated to give a solid residue which was recrystallized from isopropanol/water to give the title compound, 3.7 g (74%); m.p. 180°-182° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].C([Li])CCC.[B:22](OC(C)C)([O:27]C(C)C)[O:23]C(C)C>>[CH2:9]([C:3]1[CH:4]=[CH:5][C:6]([B:22]([OH:27])[OH:23])=[C:7]([F:8])[C:2]=1[F:1])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCc1cccc(F)c1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCc1ccc(B(O)O)c(F)c1F

Procedure:
Quantities: compound from Example 25 (31 g, 0.14 mol), n-butyllithium (14 cm3, 10.0M in hexanes, 0.14 mol) and triisopropyl borate (52.7 g, 0.28 mol). The experimental procedure was as described in Example 28.
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[O:5].Cl[C:20](OCC)=[O:21]>C(O)C>[N:10]1([CH2:9][CH2:8][CH2:7][N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][CH:17]=[CH:16][CH:15]=3)[NH:1][C:20]2=[O:21])[CH:14]=[CH:13][N:12]=[CH:11]1
Reactant: CCOC(=O)Cl
Reactant: Nc1ccccc1C(=O)NCCCn1ccnc1
Solvent: CCO
Product: O=c1[nH]c2ccccc2c(=O)n1CCCn1ccnc1

Procedure:
A mixture of 4.0 g of 2-amino-N-[3-(1H-imidazol-1-yl)propyl]benzamide and 15 ml of ethyl chloroformate was heated in an oil bath at 95°-105° C. for 1.5 hours, dissolved in 50 ml of ethanol, and concentrated. The residue was mixed with 100 ml of ethanol and 3.2 g of potassium hydroxide, heated at reflux temperature for 3 hours and concentrated. The residue was dissolved in water and acidified with acetic acid to pH 6-7. The white precipitate was separated by filtration and recrystallized from ethanol. The desired product melted at 197°-200° C.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[NH:8][CH2:7][CH2:6]2.[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23](Br)[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>ClCCl>[Br:15][C:16]1[CH:26]=[CH:25][CH:24]=[C:23]([N:8]2[CH2:7][CH2:6][C:5]3[C:10](=[CH:11][CH:12]=[C:3]([N:2]([CH3:14])[CH3:1])[CH:4]=3)[C:9]2=[O:13])[C:17]=1[CH2:18][O:19][C:20](=[O:22])[CH3:21]
Reactant: CN(C)c1ccc2c(c1)CCNC2=O
Reactant: CC(=O)OCc1c(Br)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)OCc1c(Br)cccc1N1CCc2cc(N(C)C)ccc2C1=O
Temperature: 150 °C
Yield: 27.9 %

Procedure:
6-Dimethylamino-3,4-dihydro-2H-isoquinolin-1-one (150 mg, 0.789 mmol), Acetic acid 2,6-dibromo-benzyl ester (487 mg, 1.58 mmol), cuprous iodide (30 mg, 0.16 mmol) and potassium carbonate (109 mg, 0.789 mmol) were deposited in a sealed vessel. 3 mL DMSO was added. Argon was bubbled through the mixture for 2 minutes and the lid was tightly closed. This was heated at 150° C. for 24 hours. Cuprous iodide (30 mg, 0.16 mmol) was added and the mixture was heated at 150° C. for an additional 24 hours. This was diluted with dichoromethane and filtered through a pad of celite. The filtrate was partitioned between dichloromethane and 5% aq. ammonium hydroxide. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated in vacuo, and purified by flash chromatography (gradient elution 25 to 50% ethyl acetate/hexanes) to yield Acetic acid 2-bromo-6-(6-dimethylamino-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-benzyl ester (93 mg, 0.22 mmol). MS (ESI) 417.1 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[CH:11]=[N:12][N:13]([CH3:22])[C:14]=2[C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=2)=[O:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.[NH:24]1[CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(#N)C>[N:24]1([C:2]2[C:7]([C:8]([C:10]3[CH:11]=[N:12][N:13]([CH3:22])[C:14]=3[C:15]3[CH:16]=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=3)=[O:9])=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=2)[CH2:27][CH2:26][CH2:25]1
Reactant: C1CNC1
Reactant: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3Cl)cnn2C)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2c(C(=O)c3c(Cl)ncnc3N3CCC3)cnn2C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4,6-dichloropyrimidin-5-yl)[1-methyl-5-(4-methylphenyl)-1H-pyrazol-4-yl]methanone (C5) (200 mg, 0.576 mmol) in acetonitrile (6.0 mL) were added azetidine (39.0 μL, 0.576 mmol) and N,N-diisopropylethylamine (151 μL, 0.867 mmol). The reaction mixture was stirred at room temperature overnight and then concentrated in vacuo. The product was carried to Step 7 without further purification. LCMS m/z 368.4 (M+1).
Reaction SMILES: Cl.[NH:2]=[C:3]1[C:11]([CH3:13])([CH3:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]1[CH3:14].[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1>N1C=CC=CC=1>[Cl:15][C:16]1[CH:24]=[CH:23][C:19]([C:20]([N:2]=[C:3]2[C:11]([CH3:12])([CH3:13])[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH3:14])=[O:21])=[CH:18][CH:17]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CN1C(=N)C(C)(C)c2ccccc21
Agent: Cl
Solvent: c1ccncc1
Product: CN1C(=NC(=O)c2ccc(Cl)cc2)C(C)(C)c2ccccc21

Procedure:
By reacting 15 g. of the hydrochloride of 2-imino-1,3,3-trimethylindoline (m.p. 271°-273° C) in 100 ml. of pyridine with 16.30 g. of p-chlorobenzoylchloride at the room temperature for 5 hours, 15.2 g. of the title compound are obtained. B.p. 192° C/0.1 mmHg.
Reaction SMILES: Cl[CH2:2][C:3]1[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]3[S:14][C:15]4[C:16]([N:21]=3)=[N:17][CH:18]=[CH:19][CH:20]=4)=[CH:11][C:6]=2[O:5][CH:4]=1.C([O-])([O-])=O.[K+].[K+].[CH:28]12[NH:35][CH:32]([CH2:33][CH2:34]1)[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]2>CC#N.CN(C=O)C>[S:14]1[C:15]2[C:16](=[N:17][CH:18]=[CH:19][CH:20]=2)[N:21]=[C:13]1[O:12][C:10]1[CH:9]=[CH:8][C:7]2[C:3]([CH2:2][N:35]3[CH:28]4[CH2:34][CH2:33][CH:32]3[CH2:31][N:30]([C:36](=[O:38])[CH3:37])[CH2:29]4)=[CH:4][O:5][C:6]=2[CH:11]=1
Reactant: CC(=O)N1CC2CCC(C1)N2
Reactant: ClCc1coc2cc(Oc3nc4ncccc4s3)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CN(C)C=O
Product: CC(=O)N1CC2CCC(C1)N2Cc1coc2cc(Oc3nc4ncccc4s3)ccc12
Temperature: 25 °C
Reaction time: 48 h
Yield: 34.9 %

Procedure:
To a solution of 2-(3-chloromethyl-benzofuran-6-yloxy)-thiazolo[4,5-b]pyridine (120 mg, 0.31 mmol) in CH3CN/DMF (4:1, 3 mL) was added K2CO3 (169 mg, 1.2 mmol) followed by 1-(3,8-diaza-bicyclo[3.2.1]oct-3-yl)-ethanone (47 mg, 0.31 mmol) and the reaction mixture was stirred (rt, 48 h). The reaction mixture was partitioned between DCM (10 mL) and sat. NaHCO3 (5 mL). The organic layer was separated and concentrated in vacuo. The resulting residue was purified by reverse phase HPLC to provide the title compound as a colorless solid (47 mg, 35%). MS (ESI): mass calcd. for C23H22N4O3S, 434.14; m/z found, 435.0 [M+H]+. 1H NMR (400 MHz, CDCl3): 8.56 (dd, J=4.8, 1.7, 1H), 8.02 (dd, J=7.9, 1.7, 1H), 7.84 (d, J=8.5, 1H), 7.63-7.56 (m, 2H), 7.29 (dd, J=8.5, 2.1, 1H), 7.21 (dd, J=7.9, 4.8, 1H), 4.20 (dd, J=12.7, 1.5, 1H), 3.72-3.58 (m, 2H), 3.48-3.19 (m, 4H), 2.89 (d, J=12.3, 1H), 2.06 (s, J=2.8, 3H), 2.03-1.93 (m, 2H), 1.72-1.63 (m, 2H).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.S(Cl)([Cl:12])=O>>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cccnc1

Procedure:
Thionyl chloride (10 mL) was added to nicotinic acid (370 mg, 3.0 mmol) and the mixture was stirred under reflux for 6 hr. Thionyl chloride was evaporated under reduced pressure and the residues was dried in vacuum to yield nicotinoyl chloride. Methyl 2-amino-3-hydroxybenzoate (167 mg, 1.0 mmol) and pyridine (240 mg, 3.0 mmol) were added to toluene (10 mL) and the mixture was stirred at room temperature for 30 min. Then nicotinoyl chloride (420 mg, 3.0 mmol) was added. The mixture was stirred at room temperature for 30 min then at 80° C. for 2 hr. The resulting mixture was extracted with ethyl acetate (100 mL×4) and concentrated. The crude product was purified by column chromatography (silica gel, petroleum ether:ethyl acetate 20: to 5:1) to obtain methyl 2-hydroxy-3-(nicotinamido)benzoate as a solid (215 mg, yield 79%). LC-MS (ESI) m/z 273 [M+1]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][C:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[O:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:42]([OH:44])=[O:43])[CH2:38][C:39](=[O:41])[NH2:40])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:11](=[O:12])[C@H:10]([S:13][CH2:14][CH:15]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[OH:16])[C@H:9]2[C:24]2[CH:46]=[CH:45][C:27]([O:28][CH2:29][C:30]([NH:32][CH2:33][C:34]([NH:36][C@H:37]([C:42]([OH:44])=[O:43])[CH2:38][C:39](=[O:41])[NH2:40])=[O:35])=[O:31])=[CH:26][CH:25]=2)=[CH:6][CH:7]=1
Reactant: NC(=O)C[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(=O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)C[C@H](NC(=O)CNC(=O)COc1ccc([C@@H]2[C@@H](SCC(O)c3ccc(F)cc3)C(=O)N2c2ccc(F)cc2)cc1)C(=O)O
Yield: 78.6 %

Procedure:
N-{[4-((2R,3R)-1-(4-fluorophenyl)-3-{[2-(4-fluorophenyl)-2-oxoethyl]thio}-4-oxoazetidin-2-yl)phenoxy]acetyl}glycyl-L-asparagine (0.020 g, 0.031 mmol) was dissolved in methanol (2 ml). NaBH4 (0.004 g, 0.106 mmol) was added and when the reaction was complete according to LC-MS a few drops of acetic acid were added. The solvent was removed under reduced pressure and the residue was purified by preparative HPLC on a Kromasil C8-column using 35% MeCN in 0.1M ammonium acetate buffer as eluent. After freeze-drying, 0.016 g (80%) of the title product was obtained. NMR (400 MHz, CD3COOD) 2.62 (dd 1H), 2.73 (dd, 1H), 2.90-3.07 (m, 2H), 3.89-4.08 (m, 3H), 4.55 (dd, 1H), 4.60 (ABq, 2H), 4.78-4.85 (m, 1H), 4.90 (d, 0.5H), 4.92 (d, 0.5H), 6.96-7.09 (m, 6H), 7.24-7.38 (m, 6H).