Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([C:11]2[N:16]=[C:15]([NH:17][CH3:18])[N:14]=[C:13]([N:19]3[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]([C:26]([NH:28][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[O:27])[CH2:20]3)[CH:12]=2)=[CH:5][C:4]=1F)#[N:2].[NH2:37][NH2:38]>C(O)C>[NH2:2][C:1]1[C:3]2[C:4](=[CH:5][C:6]([C:11]3[N:16]=[C:15]([NH:17][CH3:18])[N:14]=[C:13]([N:19]4[C@H:24]([CH3:25])[CH2:23][CH2:22][C@H:21]([C:26]([NH:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[O:27])[CH2:20]4)[CH:12]=3)=[CH:7][C:8]=2[O:9][CH3:10])[NH:38][N:37]=1
Reactant: NN
Reactant: CNc1nc(-c2cc(F)c(C#N)c(OC)c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Solvent: CCO
Product: CNc1nc(-c2cc(OC)c3c(N)n[nH]c3c2)cc(N2C[C@@H](C(=O)NCc3ccccc3)CC[C@H]2C)n1
Temperature: 100 °C

Procedure:
Dissolved (3S,6R)-1-[6-[4-cyano-3-fluoro-5-(methyloxy)phenyl]-2-(methylamino)-4-pyrimidinyl]-6-methyl-N-(phenylmethyl)-3-piperidinecarboxamide (96 mg, 0.196 mmol) with Ethanol (2 mL) in a 5 mL sealable vial then added hydrazine (0.185 mL, 5.89 mmol). The reaction was capped and heat overnight at 100° C. The reaction was concentrated then dissolved in 1 mL of DMSO and purified on HPLC (HPLC condition: open-access Gilson using Unipoint software with a Varian Polaris 5u C18(2) 100A, 50×30.00 mm 5 micron. 10-minute run (35 ml/min, 28% ACN/H2O, 0.1% TFA to 53% ACN/H2O, 0.1% TFA) with UV detection at 254 nm). Product fractions were pooled and the volume was reduced by reduce pressure until most of the MeCN was removed then the aqueous saturated NaHCO3 (10 mL) added. The mixture was then extracted with EtOAc (3×10 mL). The organic was pooled, washed with saturated. NaCl, dried over MgSO4, filtered, and concentrated. Then transferred in to 40 mL vial then water was added then freeze-dried to isolate 36 mg of off white solid. LC-MS (ES) m/z=501 [M+H]+. 1H NMR (400 MHz, DMSO-d6) d ppm 1.17 (d, J=7.07 Hz, 3H) 1.67 (d, J=3.54 Hz, 2H) 1.75 (dd, J=12.88, 3.03 Hz, 1H) 1.80-1.93 (m, 1H) 2.31-2.42 (m, 1H) 2.83 (d, J=4.55 Hz, 3H) 2.98 (br. s., 1H) 3.94 (s, 3H) 4.31 (dd, J=9.73, 5.94 Hz, 2H) 4.78 (br. s., 1H) 5.03 (br. s., 2H) 6.56 (br. s., 2H) 6.94 (br. s., 1H) 7.28 (d, J=7.07 Hz, 2H) 7.31-7.37 (m, 2H) 7.51 (br. s., 1H) 8.50 (t, J=5.94 Hz, 1H)
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:18]/[OH:19])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH2:16][CH3:17])(=[O:15])=[O:14])=[O:9])[N:6]=1.Br[CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23].O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:18]/[O:19][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])/[C:8]([O:10][CH2:11][CH2:12][S:13]([CH2:16][CH3:17])(=[O:14])=[O:15])=[O:9])[N:6]=1
Reactant: CCS(=O)(=O)CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: CCS(=O)(=O)CCOC(=O)/C(=N\OCC(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 40 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
In 180 ml of acetone was suspended 6 g (0.019 mole) of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-hydroxyiminoacetate as obtained in Example 9 followed by a serial addition of 5.7 g (0.0292 mole) of t-butyl bromoacetate, 0.9 ml of water and 10.8 g of anhydrous potassium carbonate. The mixture was stirred at 40° C. for 2 hours and the insoluble matter was filtered off. To the filtrate was added 200 ml of water and 200 ml of ethyl acetate was added to extract the reaction product. The aqueous layer was further extracted with ethyl acetate. The organic layers were combined, washed with water and concentrated to dryness under reduced pressure to give 6.0 g of ethylsulfonylethyl 2-(2-aminothiazol-4-yl)-(Z)-2-(t-butoxycarbonylmethoxyimino)acetate as white crystals. (Yield, 73.0%)
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][C:8]1[CH:16]=[CH:15][C:14]2[N:13]([C:17](C)([CH3:26])[C:18](=[O:25])[C:19]3[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=3)[C:12]3[CH2:28][CH2:29][N:30]([CH:32]=O)[CH2:31][C:11]=3[C:10]=2[CH:9]=1.[CH2:34]1COCC1>>[CH3:34][O:25]/[C:18](/[C:19]1[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=1)=[C:17](\[N:13]1[C:14]2[CH:15]=[CH:16][C:8]([CH3:7])=[CH:9][C:10]=2[C:11]2[CH2:31][N:30]([CH3:32])[CH2:29][CH2:28][C:12]1=2)/[CH3:26]
Reactant: C1CCOC1
Reactant: Cc1ccc2c(c1)c1c(n2C(C)(C)C(=O)c2ccncc2)CCN(C=O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CO/C(=C(/C)n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Reaction time: 0.17 h

Procedure:
LAH (87 mg, 52.63 mmol) was taken in dry THF (10 mL) under inert atmosphere stirred for 10 min, 8-methyl-5-(2-methyl-1-oxo-1-(pyridin-4-yl)propan-2-yl)-3,4-dihydro-1H-pyrido[4,3-b]indole-2(5H)-carbaldehyde (0.33 g, 0.914 mmol) was added portionwise and stirred at RT for 1 h. The reaction was monitored by TLC. LAH was quenched with sat. sodium sulfate (aqueous) at 0° C., filtered the reaction mass. The filtrate was extracted with EtOAc, dried over anhydrous sodium sulfate and evaporated to dryness to afford 0.24 g of the title compound as a yellow sticky solid. 1H NMR (CDCl3, free base) δ (ppm): 8.36 (d, 2H), 7.20 (s, 1H), 7.10 (d, 1H), 7.0 (d, 1H), 6.78 (d, 2H), 3.78 (s, 2H), 3.60 (s, 3H), 2.82 (m, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.50 (s, 3H), 2.42 (s, 3H), 2.30 (m, 1H), 2.19 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([O:33]C)=[O:32])[C:6]=2[CH:35]=1.[OH-].[Na+].O.Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([C:12](=[O:29])[C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:28])[C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[CH3:27])=[N:15][CH:14]=3)[CH2:10][CH2:9][CH2:8][CH:7]([CH2:30][C:31]([OH:33])=[O:32])[C:6]=2[CH:35]=1
Reactant: COC(=O)CC1CCCN(C(=O)c2ccc(NC(=O)c3ccccc3C)nc2)c2ccc(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1ccccc1C(=O)Nc1ccc(C(=O)N2CCCC(CC(=O)O)c3cc(Cl)ccc32)cn1
Temperature: 25 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
To a suspension of 7-chloro-5-methoxycarbonylmethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.6 g) in ethanol (20 ml) is added 5N aqueous sodium hydroxide solution (4 ml), and the mixture is stirred at room temperature for 4 hours. Water is added to the reaction solution, and the mixture is made weak acidic with diluted hydrochloric acid, and extracted with dichloromethane. The extract is washed with water, dried over magnesium sulfate, and evaporated under reduced pressure to remove the solvent. The residue is crystallized from diethyl ether, and further recrystallized from diethyl ether to give 7-chloro-5-carboxymethyl-1-[6-(2-methylbenzoylamino)nicotinoyl]-2,3,4,5-tetrahydro-1H-benzazepine (1.5 g) as white powder.
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH2:7][CH:6](Br)[C:5]1=[O:10])(=[O:3])[NH2:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:30]([C:34]1[CH:35]=[C:36]([CH:39]=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[C:41]=1[OH:42])[CH:37]=O)([CH3:33])([CH3:32])[CH3:31].C(N(CC)CC)C>C1COCC1.C(O)C>[C:1]([N:4]1[CH2:8][CH2:7][C:6](=[CH:37][C:36]2[CH:35]=[C:34]([C:30]([CH3:31])([CH3:33])[CH3:32])[C:41]([OH:42])=[C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])[CH:39]=2)[C:5]1=[O:10])(=[O:3])[NH2:2]
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Reactant: NC(=O)N1CCC(Br)C1=O
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C=C2CCN(C(N)=O)C2=O)cc(C(C)(C)C)c1O
Temperature: 70 °C
Yield: 60.9 %

Procedure:
A solution of 2.0 g of N-carbamoyl-3-bromopyrrolidin-2-one (9.7 mmole) and 2.78 g of triphenylphosphine (10.6 mmole) in 30 ml of THF was stirred under heating at 70° C. for 20 hours. The reaction mixture was cooled down to room temperature, then the precipitated crystals were collected. The obtained Wittig salt (1.34 g, 2.86 mmole), 3,5-di-tert-butyl-4-hydroxybenzaldehyde (670 mg, 2.86 mmole), and triethylamine (580 mg, 5.73 mmole) were dissolved into 60 ml of ethanol, and the mixture was stirred under heating at 70° C. for 2 hours. The reaction mixture was evaporated, then the residue was dissolved into ethyl acetate, which was washed with water and saturated brine, dried over magnesium sulfate, and evaporated. The residue was separated by using silica gel chromatography (toluene:ethyl acetate=3:1) and recrystallized from dichloromethane-n-hexane, whereby 600 mg of the objective compound was obtained in 17.1% yield. The physical constants are described on Table 1.
Reaction SMILES: [C:1]([C:5]1[C:6]([OH:19])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2].[P:20]([O:23][C:24]1[C:25](=[CH:27][CH:28]=[CH:29][CH:30]=1)[OH:26])(Cl)[OH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:20]([OH:23])([OH:19])[OH:21].[C:1]([C:5]1[C:6]([C:27]2[CH:28]=[CH:29][CH:30]=[C:24]([OH:23])[C:25]=2[OH:26])=[CH:7][C:8]2[C:13]([CH:14]=1)=[CH:12][C:11]([C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][CH:9]=2)([CH3:4])([CH3:3])[CH3:2]
Reactant: Oc1ccccc1OP(O)Cl
Reactant: CC(C)(C)c1ccc2cc(O)c(C(C)(C)C)cc2c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc2cc(-c3cccc(O)c3O)c(C(C)(C)C)cc2c1
Product: OP(O)O
Temperature: 6 °C

Procedure:
6.0 weight parts of 3,6-di-t-butyl-2-naphthol was dissolved in 86.7 weight parts of dry toluene and the solution cooled to about 6° C. Under nitrogen, 4.08 weight parts of catechol phosphorochloridite was added to the solution. Then 2.37 weight parts of triethyl amine was added slowly to the cooled solution with stirring. This solution was stirred for about 16 hours at room temperature. The reaction mixture was filtered, washed twice with water, dried with MgSO4, and rotoevaporated to remove all traces of toluene. A gray oil was obtained. A product yield of 57 weight percent was obtained. The expected structure was confirmed by infra red and nuclear magnetic resonance spectra, and the molecular weight by the field desorption/mass spectrum.
Reaction SMILES: [Li+].[Br-:2].Cl[CH2:4][C:5](=[CH2:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].C1COCC1>[Br:2][CH2:4][C:5](=[CH2:15])[CH2:6][O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=C(CCl)COCc1ccccc1
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(CBr)COCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.2 %

Procedure:
LiBr (2.7 g, 31.6 mmol) was flame dried under vacuum and then cooled to room temperature. TBABr (255 mg, 0.79 mmol), (2-chloromethyl-allyloxymethyl)-benzene (3.1 g, 15.8 mmol) and THF (5 mL) were then added and the suspension was stirred at 60° C. for 2 h. The mixture was filtered through Celite and the solvent was removed in vacuo to give the title compound (3.4 g) as a colourless oil which was used in the next step without further purification. 1H NMR (CDCl3): 7.47-7.30 (5H, m), 5.47-5.33 (1H, m), 5.30 (1H, q), 4.56 (2H, s), 4.19 (2H, s), 4.08 (2H, s).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[N:5]=[N:4][CH:3]=1.C(N(CC)CC)C.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>O1CCCC1.C(Cl)(Cl)Cl>[Cl:8][C:7]1[C:2]([NH:1][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][N:4]=[N:5][C:6]=1[Cl:9]
Reactant: Nc1cnnc(Cl)c1Cl
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: O=C(Nc1cnnc(Cl)c1Cl)Oc1ccccc1
Temperature: 0 °C
Reaction time: 72 h
Yield: 26.4 %

Procedure:
A stirred suspension of 2.0 grams (0.012 mole) of 4-amino-5,6-dichloropyridazine in 75 ml of tetrahydrofuran is cooled to 0° C. and 1.5 grams (0.015 mole) of triethylamine is added in one portion. A solution of 2.3 grams (0.015 mole) of phenyl chloroformate in tetrahydrofuran is added dropwise during a 30 minute period. Upon completion of addition the reaction mixture is allowed to warm to ambient temperature where it is stirred for three days. The reaction mixture is taken up in 500 ml of chloroform and filtered to collect 0.98 gram of phenyl N-(5,6-dichloro-4-pyridazinyl)carbamate. The filtrate is concentrated under reduced pressure to a residue. The residue is subjected to column chromatography on silica gel to yield an additional 0.9 gram of phenyl N-(5,6-dichloro-4-pyridazinyl)carbamate.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.O>[N:15]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])=[N+:16]=[N-:17]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCCCCCC(=O)O
Temperature: 80 °C
Reaction time: 5 h

Procedure:
To 11-bromoundecanoic acid (1.73 g) dissolved in N,N-dimethylformamide (DMF) was added sodium azide (1.5 g), and the mixture was heated to a temperature of 80° C. and stirred for 5 hours. The reaction mixture was then diluted with cooling water and extracted with ethyl acetate to give 11-azidoundecanoic acid. To the mixed solution of 11-azidoundecanoic acid (1 g) and para-nitrophenol (612 mg) in DMF was added N,N'-dicyclohexylcarbodiimide (920 mg), and the mixture was stirred for 12 hours. The reaction mixture was filtered and concentrated to give the active ester of 11-azidoundecanoic acid. To the active ester (284 mg) dissolved in DMF were further added 6-(4'-N-glycylspicaminyl-amino)purine hydrochloride (300 mg) and triethylamine (1.1 ml), and the mixture was stirred for 12 hours. The solvent was removed by distillation, and the residue was subjected to chromatography on a silica gel column with eluent systems of chloroform-methanol (from 7:1 to 5:1) to give SPK410 in the yield of 171 mg.
Reaction SMILES: I[CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:29]C)[N:19]2[CH2:22][CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[C:15]([NH2:31])[N:14]=1)[CH2:9][CH2:10][CH3:11].CCN(C(C)C)C(C)C.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CS(C)=O>[NH2:31][C:15]1[N:14]=[C:13]([O:12][CH2:8][CH2:9][CH2:10][CH3:11])[N:21]=[C:20]2[C:16]=1[NH:17][C:18](=[O:29])[N:19]2[CH2:22][CH:23]1[CH2:24][CH2:25][N:26]([CH:2]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]2)[CH2:27][CH2:28]1
Reactant: IC1CCCCC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CC3CCNCC3)c2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CS(C)=O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CC3CCN(C4CCCCC4)CC3)c2n1
Temperature: 50 °C
Reaction time: 18 h
Yield: 4.7 %

Procedure:
Iodocyclohexane (0.1 mmol) was weighed into a tube and an aliquot (0.4 ml, 0.12 mmol) of a solution of 2-(butyloxy)-8-(methyloxy)-9-(4-piperidinylmethyl)-9H-purin-6-amine (0.402 g mg, 1.2 mmol) suspended in DMF (4.8 ml) was added to each tube. DIPEA (40 μl, 0.229 mmol) and potassium carbonate (46 mg) was added to each tube, the tube was heated at 50° C. for 18 hours. An additional portion of iodocyclohexane (15 μl) and DIPEA (40 μl) was added and heating continued for a further 18 hours. DMSO (250 uL) was added and the solution and the mixture purified by Mass Directed AutoPrep (Method A). The solvent was evaporated in vacuo using the Genevac. The residue was redissolved in 4M HCl/dioxane (0.2 ml), capped and stood at room temperature for 18 hours. The solvent was dried under a stream of nitrogen in the Radleys blowdown apparatus. The sample was dissolved in 1:1 DMSO:MeOH and purified by MDAP (Method C) and the solvent was evaporated in vacuo using the Genevac. The material was redissolved in methanol (0.5 ml), and applied to top of 0.1 g aminopropyl SPE (preconditioned with methanol, 1.5 ml). The cartridge was eluted with methanol (1.5 ml), the solvent was removed to give the title compound (1.9 mg).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([NH2:10])[CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:24])=[O:23])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14](O)=[O:15].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(OCC)(=O)C>[Cl:11][C:12]1[C:20]([NH:21][S:22]([CH2:25][CH2:26][CH3:27])(=[O:23])=[O:24])=[CH:19][CH:18]=[C:17]([F:28])[C:13]=1[C:14]([NH:10][C:8]1[CH:9]=[C:4]2[CH:3]=[CH:2][NH:1][C:5]2=[N:6][CH:7]=1)=[O:15]
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)O)c1Cl
Reactant: Nc1cnc2[nH]ccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)Nc2cnc3[nH]ccc3c2)c1Cl
Reaction time: 24 h
Yield: 25.5 %

Procedure:
1H-Pyrrolo[2,3-b]pyridin-5-amine (20 mg, 0.150 mmol) in N,N-dimethylformamide (1.5 mL) was sequentially treated with 2-chloro-6-fluoro-3-(propylsulfonamido)benzoic acid (48.9 mg, 0.165 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (31.7 mg, 0.165 mmol), and 1-hydroxybenzotriazole (22.3 mg, 0.165 mmol) at ambient temperature. After 24 hours, the reaction mixture was diluted with ethyl acetate and washed with water (4×), sodium bicarbonate (2×), and brine (1×), dried over sodium sulfate and concentrated. The crude product was triturated with dichloromethane to provide 2-chloro-6-fluoro-3-(propylsulfonamido)-N-(1H-pyrrolo[2,3-b]pyridin-5-yl)benzamide (61.7 mg, 0.0382 mmol, 25.4% yield) as a solid. 1H NMR (400 MHz, CD3OD) δ 8.40-8.35 (d, 2H), 7.73-7.67 (q, 1H), 7.45-7.42 (d, 1H), 7.31-7.25 (t, 1H), 6.53-6.50 (d, 1H), 3.15-3.08 (t, 2H), 1.93-1.82 (m, 2H), 1.08-1.02 (t, 3H); MS (APCI-neg) m/z=409.1 (M-H).
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]>CO.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(N)c1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 91 %

Procedure:
To a suspension of methyl 2-amino-3-nitrobenzoate (15 g, 76.5 mmol) in methanol (800 mL) was added 10% palladium on carbon (50% wet; 6.5 g), and the mixture was stirred at room temperature for 20 hours under hydrogen atmosphere. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. The residual solid was crystallized from diisopropyl ether-hexane to give 11.57 g (69.6 mmol, 91.0%) of the title compound as a dark yellow needle.
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:22])[F:21])(=[O:12])=[O:11])[CH2:7][NH:6]1)=[O:4].[C:24](OC(C)(C)C)(=[O:29])[CH2:25][C:26]([CH3:28])=[O:27]>>[CH3:1][O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][C:14]=2[C:20]([F:23])([F:21])[F:22])(=[O:11])=[O:12])[CH2:7][N:6]1[C:24](=[O:29])[CH2:25][C:26](=[O:27])[CH3:28])=[O:4]
Reactant: CC(=O)CC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1
Product: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccc(Br)cc2C(F)(F)F)CN1C(=O)CC(C)=O

Procedure:
In analogy to the procedure described in example 192f, (2S,4R)-4-(4-bromo-2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester (example 18) was reacted with tert-butyl acetoacetate to give the title compound as brown oil.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1.S(Cl)(Cl)=O.[C:16]1([NH:22][NH2:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>N1C=CC=CC=1>[C:16]1([NH:22][NH:23][C:7](=[O:9])[C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:11][CH:10]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CSc1ccc(C(=O)O)cc1
Reactant: NNc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: c1ccncc1
Product: CSc1ccc(C(=O)NNc2ccccc2)cc1
Temperature: 31 °C
Reaction time: 72 h
Yield: 69 %

Procedure:
A mixture consisting of 21.88 g. (0.130 mole) p-(methylthio)benzoic acid and 25 ml. thionyl chloride was heated at the reflux temperature until evolution of gas ceased and a clear solution was obtained. After removing the excess thionyl chloride on a rotary evaporator and then under substantially complete vacuum, the solid residue that remained was dissolved in 35 ml. dioxane. The dioxane solution was mixed with a solution consisting of 14.06 g. (0.130 mole) phenylhydrazine in 100 ml. pyridine initially at 5° to 10°C. Inadvertently, about one-third of the acid chloride was added rapidly and the mixture was heated to 31°C. by the exothermic reaction. The reaction mixture was set aside at 25°C. with continuous stirring for three days. It was then poured into 1.5 l. water in order to precipitate the desired p-(methylthio)benzoic acid 2-phenylhydrazide. The precipitate was collected on a filter, washed with water, washed with 1N hydrochloride acid, and finally washed with water. The washed filter cake was then recrystallized from 3A alcohol to give 23.2 g. (69% yield) of p-(methylthio)benzoic acid 2-phenylhydrazide having a melting point at 165.5° to 167.5°C. Recrystallization from 250 ml. ethyl acetate gave the compound melting at 167° to 168°C. (shrinks at 162°C.) Two further recrystallizations from ethyl acetate gave the compound melting at 167° to 168.5°C. with shrinkage at 161.5°C.
Reaction SMILES: [CH2:1]([N:5]([CH2:33][CH2:34][CH2:35][CH3:36])[C:6]([C:8]1[N:9]=[C:10]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[O:24])[NH:11][CH:12]=1)=[O:7])[CH2:2][CH2:3][CH3:4].Br[CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][Si:44]([C:57]([CH3:60])([CH3:59])[CH3:58])([C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>>[Si:44]([O:43][CH2:42][CH2:41][O:40][CH2:39][CH2:38][N:11]1[CH:12]=[C:8]([C:6](=[O:7])[N:5]([CH2:1][CH2:2][CH2:3][CH3:4])[CH2:33][CH2:34][CH2:35][CH3:36])[N:9]=[C:10]1[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[C:23]([O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)=[O:24])([C:57]([CH3:59])([CH3:60])[CH3:58])([C:51]1[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=1)[C:45]1[CH:46]=[CH:47][CH:48]=[CH:49][CH:50]=1
Reactant: CCCCN(CCCC)C(=O)c1c[nH]c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Reactant: CC(C)(C)[Si](OCCOCCBr)(c1ccccc1)c1ccccc1
Product: CCCCN(CCCC)C(=O)c1cn(CCOCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)c(-c2ccc(C(=O)OC)cc2C(=O)OCc2ccccc2)n1
Yield: 85.6 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 274A, 3-benzyl 1-methyl 4-(4-(dibutylcarbamoyl)-1H-imidazol-2-yl)isophthalate (200 mg, 0.40 mmol) and (2-(2-bromoethoxy)ethoxy)(tert-butyl)diphenylsilane (165 mg, 0.40 mmol) were converted to the title compound (280 mg, 84%). 1H NMR (CDCl3) δ 8.66 (d, J=2.0 Hz, 1H), 8.16 (dd, J=8.0, 2.0 Hz, 1H), 7.62-7.57 (m, 4H), 7.57 (s, 1H), 7.52 (d, J=8.0 Hz, 1H), 7.42-7.32 (m, 9H), 7.24-7.22 (m, 2H), 5.12 (s, 2H), 3.96 (s, 3H), 3.94-3.85 (m, 2H), 3.69-3.63 (m, 4H), 3.46-3.43 (m, 4H), 3.67 (t, J=5.2 Hz, 2H), 1.65-1.55 (m, 4H), 1.40-1.15 (m, 4H), 1.01 (s, 9H), 1.00-0.85 (m, 6H); MS(ESI+) m/z 819.4 (M+H)+.
Reaction SMILES: [CH:1]1([N:7]2[C:11](=[O:12])[C:10]([N+:13]([O-])=O)=[C:9]([CH3:16])[N:8]2[CH3:17])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>CO.C1COCC1.CC(OC)(C)C.[Pd]>[NH2:13][C:10]1[C:11](=[O:12])[N:7]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]2)[N:8]([CH3:17])[C:9]=1[CH3:16]
Reactant: Cc1c([N+](=O)[O-])c(=O)n(C2CCCCC2)n1C
Agent: [Pd]
Solvent: COC(C)(C)C
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(N)c(=O)n(C2CCCCC2)n1C
Temperature: 25 °C
Reaction time: 57.5 h

Procedure:
To 2-cyclohexyl-1,5-dimethyl-4-nitro-1H-pyrazol-3(2H)-one (415 g, 1.73 mol) in MeOH (4500 ml) and THF (4500 ml) was added 10% Pd/C (70 g) and the reaction mixture was hydrogenated at 0.1 bar and RT for 57.5 h. The resulting mixture was filtered through a pressure strainer and washed with methanol (1×1 L) and THF (2×1 L). The filtrate was concentrated under reduced pressure to give a dark red oil. The oil was dissolved immediately in TBME (4 L), concentrated under reduced pressure to ca. 2 L and seeded (100 mg). The suspension was stirred for 2 h at RT and cooled in an ice bath for 1 hr. The solid was collected by filtration and washed with ice cold TBME in portionwise until the filtrate was colourless and dried under vacuum to give the title compound;