Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:20])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]([C:14]2[O:15][C:16](Br)=[CH:17][CH:18]=2)=[O:13])[CH:6]=1.[F:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1>>[F:21][C:22]1[CH:27]=[C:26]([C:16]2[O:15][C:14]([C:12]([NH:11][C:7]3[CH:6]=[C:5]([CH2:4][C:3]([OH:2])=[O:20])[CH:10]=[CH:9][CH:8]=3)=[O:13])=[CH:18][CH:17]=2)[CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cc1cccc(NC(=O)c2ccc(Br)o2)c1
Reactant: OB(O)c1cccc(F)c1
Product: O=C(O)Cc1cccc(NC(=O)c2ccc(-c3cccc(F)c3)o2)c1

Procedure:
The furyl bromide (16) (100 mg, 0.30 mmol) was coupled to 3-fluoro-phenylboronic acid (42 mg, 0.30 mmol) using Method E. During this reaction, hydrolysis occurred. The residue was extracted using Work-up E1 to give the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1OS(C1C=CC(C)=CC=1)(=O)=O)(=[O:3])[CH3:2].[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][C:26]#[CH:27])[CH3:23]>CCCCCCC.CCOC(C)=O>[CH2:22]([N:24]([CH2:28][CH3:29])[CH2:25][C:26]#[C:27][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[NH:4][C:1](=[O:3])[CH3:2])[CH3:23]
Reactant: CC(=O)Nc1ccccc1OS(=O)(=O)c1ccc(C)cc1
Reactant: C#CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCN(CC)CC#Cc1ccccc1NC(C)=O

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-acetylamino-phenyl ester and diethyl-prop-2-ynyl-amine following the general procedure for the Sonogashira cross-coupling process described above. Chromatography eluent: heptane/EtOAc 8:2; yield (73 mg, 60%); 1H NMR δ (CDCl3): 8.47 (d, J=8.52 Hz, 1H), 7.93 (br s, 1H), 7.36 (dm, 1H), 7.31-7.23 (m, 1H), 7.02 (t, J=7.24 Hz, 1H), 3.54 (s, 2H), 2.62 (q, J=7.13 Hz, 4H), 2.21 (s, 3H), 1.11 (t, J=7.11 Hz, 6H); LCMS m/z: 244.
Reaction SMILES: O.O.O.O.O.O.[Cr](Cl)(Cl)(=O)=O.[N+]([C:15]1[CH:20]=[C:19](S(O)(=O)=O)[C:18]([OH:25])=[C:17](N)[CH:16]=1)([O-])=O.C(O)[CH2:28][OH:29]>>[CH:28](=[O:29])[C:19]1[C:18](=[CH:17][CH:16]=[CH:15][CH:20]=1)[OH:25]
Reactant: Nc1cc([N+](=O)[O-])cc(S(=O)(=O)O)c1O
Reactant: OCCO
Agent: O=[Cr](=O)(Cl)Cl
Solvent: O
Product: O=Cc1ccccc1O

Procedure:
30.9 parts of the monoazo dye formed from diazotised 4-nitro-2-amino-1-hydroxybenzene and 2-hydroxynaphthalene are stirred up with 26.7 parts of chromic chloride hexahydrate in 400 parts by volume of ethylene glycol at 120° to 125° C. until no further unchromed dye is detectable. To the resulting solution of the 1:1 chrome complex dye at 80° to 85° C. are thereupon added 23.4 parts of 4-nitro-2-amino-1-hydroxybenzene-6-sulfonic acid and 45.3 parts of the monoazo dye formed from diazotised dehydrothio-p-toluidine-7-sulfonic acid and salicylaldehyde, and the mixture is held at this temperature until the addition reaction has finished. The pH value of the reaction mixture is adjusted to and maintained at 7 to 7.5 during the reaction by the addition of 5N sodium hydroxide solution. After completion of the reaction, the chromium-containing dye is precipitated by the addition of a saturated sodium chloride solution, filtered off and dried. It is in the form of a dark powder which dissolves in water to give a brown colour, and which dyes wool, polyamide material and leather in brown shades having good fastness properties.
Reaction SMILES: Cl.[NH2:2][CH:3]1[C:30](=[O:31])[N:5]2[C:6]([C:14]([O:16][CH:17]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[O:15])=[C:7](/[CH:10]=[CH:11]\[CH2:12][CH3:13])[CH2:8][S:9][C@H:4]12.C([O-])(O)=O.[Na+].[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:56]/[O:57][CH3:58])/[C:44](ON2C3C=CC=CC=3N=N2)=[O:45])[N:42]=1>C(OCC)(=O)C>[NH2:37][C:38]1[S:39][CH:40]=[C:41](/[C:43](=[N:56]/[O:57][CH3:58])/[C:44]([NH:2][CH:3]2[C:30](=[O:31])[N:5]3[C:6]([C:14]([O:16][CH:17]([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[O:15])=[C:7](/[CH:10]=[CH:11]\[CH2:12][CH3:13])[CH2:8][S:9][C@H:4]23)=[O:45])[N:42]=1
Reactant: CO/N=C(\C(=O)On1nnc2ccccc21)c1csc(N)n1
Reactant: CC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(N)[C@H]2SC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC/C=C\C1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)/C(=N\OC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 90.8 %

Procedure:
A suspension of diphenylmethyl 7-amino-3-[(Z)-1-butenyl]-3-cephem-4-carboxylate hydrochloride (1.41 g, 3.1 mmoles) in ethyl acetate (20 ml) was shaken with aqueous NaHCO3 to give a clear two-layer solution. The organic layer was separated, washed with water and then an aqueous saturated NaCl solution, and dried over MgSO4. To the dried filtrate was added 1-[(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetoxy]benzotriazole (1.27 g, 4.0 mmoles), and the mixture was stirred at room temperature for 20 hours. The reaction mixture was filtered and the filtrate was washed with aqueous NaHCO3, water and a saturated NaCl solution, dried over MgSO4 and evaporated in vacuo. The residue was chromatographed on a silica gel column (40 g) with 3:1 CHCl3 -ethyl acetate to yield 1.7 g (91%) of the title compound. TLC (silica gel): Rf 0.25 (1:1 CHCl3 -ethyl acetate).
Reaction SMILES: [OH:1][C@@H:2]1[C@H:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][CH:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]([NH2:32])=O)[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:24][CH2:23][CH2:22][CH2:21]1.O=P(Cl)(Cl)Cl>C(N(CC)CC)C>[OH:1][CH:2]1[CH:6]([OH:7])[C@@H:5]([CH2:8][OH:9])[O:4][C@H:3]1[N:10]1[CH:18]=[N:17][C:16]2[C:11]1=[N:12][C:13]([N:25]1[CH:29]=[C:28]([C:30]#[N:32])[CH:27]=[N:26]1)=[N:14][C:15]=2[NH:19][CH:20]1[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: NC(=O)c1cnn(-c2nc(NC3CCCC3)c3ncn(C4O[C@H](CO)[C@@H](O)[C@H]4O)c3n2)c1
Solvent: CCN(CC)CC
Solvent: O=P(Cl)(Cl)Cl
Product: N#Cc1cnn(-c2nc(NC3CCCC3)c3ncn([C@@H]4O[C@H](CO)C(O)C4O)c3n2)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
429 mg of the 1-{9-[(4S,3R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carboxamide prepared in Example 5A was dissolved in 5 mL of dimethylformamide(DMF). To this solution was added 0.68 mL of triethylamine followed by chilled (0° C.) POCl3 (0.44 mL). The mixture was stirred and allowed to warm to room temperature. Stirring at room temperature continued 4 hours. The solvent was removed and the residue purified using TLC with a 10:1 dichloromethane:methanol solution to yield 1-{9-[(2R,5R)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-6-(cyclopentylamino)purin-2-yl}pyrazole-4-carbonitrile.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][N:5]([CH2:11][C:12]1[CH:13]=[C:14]([CH:48]=[CH:49][CH:50]=1)[C:15]([NH:17][C:18]1[S:19][C:20]2[CH2:47][CH2:46][CH2:45][CH2:44][C:21]=2[C:22]=1[C:23]([NH:25][C:26]1[CH:31]=[CH:30][C:29]([CH2:32][CH2:33][C:34]2[CH:43]=[CH:42][C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][CH:35]=2)=[CH:28][CH:27]=1)=[O:24])=[O:16])[CH:6]([CH2:9][CH3:10])[CH2:7][CH3:8].Br[CH2:52][C:53]1[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=1)[C:56]([O:58][CH3:59])=[O:57]>>[CH3:41][O:40][C:38]([C:37]1[CH:36]=[CH:35][C:34]([CH2:33][CH2:32][C:29]2[CH:30]=[CH:31][C:26]([NH:25][C:23]([C:22]3[C:21]4[CH2:44][CH2:45][CH2:46][CH2:47][C:20]=4[S:19][C:18]=3[NH:17][C:15]([C:14]3[CH:13]=[C:12]([CH:50]=[CH:49][CH:48]=3)[CH2:11][N:5]([CH:6]([CH2:7][CH3:8])[CH2:9][CH3:10])[CH2:4][CH2:3][N:2]([CH2:52][C:53]3[CH:54]=[C:55]([CH:60]=[CH:61][CH:62]=3)[C:56]([O:58][CH3:59])=[O:57])[CH3:1])=[O:16])=[O:24])=[CH:27][CH:28]=2)=[CH:43][CH:42]=1)=[O:39]
Reactant: COC(=O)c1cccc(CBr)c1
Reactant: CCC(CC)N(CCNC)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Product: CCC(CC)N(CCN(C)Cc1cccc(C(=O)OC)c1)Cc1cccc(C(=O)Nc2sc3c(c2C(=O)Nc2ccc(CCc4ccc(C(=O)OC)cc4)cc2)CCCC3)c1
Yield: 90.7 %

Procedure:
By using 200 mg of methyl 4-[2-(4-{[(2-{[3-({[2-(methylamino)ethyl](pentan-3-yl)amino}methyl)benzoyl]amino}-4,5,6,7-tetrahydro-1-benzothiophen-3-yl)carbonyl]amino}phenyl)ethyl]benzoate and 79 mg of methyl 3-(bromomethyl)benzoate, the reaction similar to Preparation Example 30 was performed, thereby obtaining 220 mg of methyl 3-{[(2-{[3-({3-[(4-{2-[4-(methoxycarbonyl)phenyl]ethyl}phenyl)carbamoyl]-4,5,6,7-tetrahydro-1-benzothiophen-2-yl}carbamoyl)benzyl](pentan-3-yl)amino}ethyl)(methyl)amino]methyl}benzoate.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:26])[F:25])[C:14]=3[NH:13][C:12](=O)[C:11]=2[CH:10]=[CH:9]1>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:20]2[C:19]3[CH:18]=[CH:17][CH:16]=[C:15]([O:21][CH2:22][C:23]([F:29])([F:28])[C:24]([F:27])([F:25])[F:26])[C:14]=3[N:13]=[C:12]([NH:13][CH2:14][CH2:15][OH:21])[C:11]=2[CH:10]=[CH:9]1
Reactant: Cc1ccccc1-n1ccc2c(=O)[nH]c3c(OCC(F)(F)C(F)(F)F)cccc3c21
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccccc1-n1ccc2c(NCCO)nc3c(OCC(F)(F)C(F)(F)F)cccc3c21
Reaction time: 2 h
Yield: 169.6 %

Procedure:
1-(2-Methylphenyl)-4-oxo-6-β,β,γ,γ,γ-pentafluoropropyloxy-4,5-dihydropyrrolo[3,2-c]quinoline(1.5 g, 3.8 mmol) was dissolved in phosphoryl chloride(15 ml), then the resultant was stirred for 2 hours. After removing the excess phosphoryl chloride by simple distillation, the residue was poured into iced water, neutralized with aqueous solution of sodium hydroxide (1N), and stirred at room temperature for 30 minutes. It was extracted with dichloromethane(20 ml) for 3 times, and the organic layer was washed with water(15 ml) for 3 times, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 1.5 g of desired compound as solid in 94% of yield.
Reaction SMILES: [NH:1]1[C:5]([NH:6][C:7]([NH:9]C(=O)C2C=CC=CC=2)=[S:8])=[N:4][CH:3]=[N:2]1.[OH-].[Na+].Cl>>[NH:1]1[C:5]([NH:6][C:7]([NH2:9])=[S:8])=[N:4][CH:3]=[N:2]1
Reactant: O=C(NC(=S)Nc1ncn[nH]1)c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: NC(=S)Nc1ncn[nH]1
Yield: 69.2 %

Procedure:
N-(1,2,4-triazol-5-yl)-N'-benzoylthiourea (26.0 g, 0.105 mole), from Example 6, was added at once to approximately 100ml of a 10% sodium hydroxide solution which had been preheated to boiling, and the resultant mixture was refluxed for 45 minutes. The solution was then cooled and acidified to approximately pH 3 with the addition of concentrated hydrochloric acid to provide a white solid precipitate. The solid was filtered, washed with water and dried for about 16 hours in a vacuum oven at approximately 100° C. The resultant off-white solid was stirred with about 150 ml of diethyl ether and filtered, and this procedure was repeated. The solid thus obtained was dried in a vacuum oven at about 50° C. to yield 10.4 g (69%) of N-(1,2,4-triazol-5-yl)thiourea as an off-white solid. The structural assignment was confirmed by nuclear magnetic resonance spectral analysis.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:8][C:9]3[C:10]([N:24]=2)=[CH:11][C:12]2[C:13]([CH3:23])([CH3:22])[C:14](=[O:21])[N:15]([CH:18]([CH3:20])[CH3:19])[C:16]=2[CH:17]=3)=[N:4][NH:5][CH:6]=1.[N:25]1([C:31](Cl)=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:18]([N:15]1[C:16]2[CH:17]=[C:9]3[NH:8][C:7]([C:3]4[C:2]([NH:1][C:31]([N:25]5[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]5)=[O:32])=[CH:6][NH:5][N:4]=4)=[N:24][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:23])[C:14]1=[O:21])([CH3:19])[CH3:20]
Reactant: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4N)[nH]c3cc21
Reactant: O=C(Cl)N1CCCCC1
Product: CC(C)N1C(=O)C(C)(C)c2cc3nc(-c4n[nH]cc4NC(=O)N4CCCCC4)[nH]c3cc21

Procedure:
Piperidine-1-carboxylic acid[3-(5-isopropyl-7,7-dimethyl-6-oxo-3,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-amide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-isopropyl-7,7-dimethyl-5,7-dihydro-3H-imidazo[4,5-f]indol-6-one (200 mg, 0.247 mmol) and piperidine-1-carbonyl chloride (40.0 mg, 0.271 mmol). 40 mg (37%) %) of the title compound were obtained.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]([OH:8])=[O:7])=[CH:2]1.[Cl:9]N1C(=O)CCC1=O>C(O)(=O)C>[Cl:9][C:5]1[S:1][CH:2]=[C:3]([C:6]([OH:8])=[O:7])[CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(O)c1ccsc1
Solvent: CC(=O)O
Product: O=C(O)c1csc(Cl)c1
Yield: 67.4 %

Procedure:
Thiophene-3-carboxylic acid (17.51 g, 136.6 mmol) and 1-chloro-pyrrolidine-2,5-dione (23.7 g) was refluxed in acetic acid (200 ml) for 4 h under argon before pouring onto water (700 ml). Repeated extraction with several small portions of DCM, followed by back extraction from the combined organics with several small portions of 2 M aqueous sodium hydroxide, gave a combined alkaline aqueous solution that was washed with DCM before acidified with conc. HCl to precipitate the crude material. This precipitate was recrystallized from water to yield 14.98 g of the title compound as a grey solid contaminated with approximately 20 mol % of a dichlorinated byproduct as judged from MS and 1H-NMR. 1H NMR (DMSO-d6) d (ppm): 8.15 (d, 1H), 7.37 (d, 1H).
Reaction SMILES: C([O:3][C:4](=O)[CH:5]([N:7]1[C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:21][NH2:22]>CCO>[Br:17][C:14]1[CH:13]=[C:12]2[C:11](=[CH:16][CH:15]=1)[O:10][CH2:9][C:8]1[N:7]2[CH:5]([CH3:6])[C:4](=[O:3])[NH:21][N:22]=1
Reactant: NN
Reactant: CCOC(=O)C(C)N1C(=S)COc2ccc(Br)cc21
Solvent: O
Solvent: CCO
Product: CC1C(=O)NN=C2COc3ccc(Br)cc3N21
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.3 %

Procedure:
To a solution of 2-(6-bromo-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (28 g, 81.4 mmol) in EtOH (100 mL) was added hydrazine hydrate (98%, 13.1 g, 162.8 mmol). The reaction mixture was stirred at ambient temperature overnight. The precipitate was collected by filtration and washed with cold EtOH (3×10 mL) to give 6-bromo-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one as a yellow solid (22.0 g, 74.3 mmol, 92%). 1H NMR (DMSO-d6, 400 MHz): δ 10.83 (s, 1H), 7.41 (d, J=2.0 Hz, 1H), 7.11 (d, J=2.0 Hz, J=8.4 Hz, 1H), 6.94 (d, J=8.4 Hz, 1H), 4.82 (q, J=6.8 Hz, 1H), 4.62 (d, J=13.2 Hz, 2H), 1.28 (d, J=6.8 Hz, 3H).
Reaction SMILES: C([O:4][C:5]1[CH:6]=[C:7](/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20]([O:23]C(=O)C)=[CH:19][CH:18]=2)[CH:8]=[C:9]([O:11]C(=O)C)[CH:10]=1)(=O)C.[OH-].[K+].Cl.C(OCC)(=O)C>CO>[C:7]1([CH:15]=[CH:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[CH:8]=[C:9]([OH:11])[CH:10]=[C:5]([OH:4])[CH:6]=1
Reactant: CC(=O)Oc1ccc(/C=C/c2cc(OC(C)=O)cc(OC(C)=O)c2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Product: Oc1ccc(C=Cc2cc(O)cc(O)c2)cc1
Yield: 92.9 %

Procedure:
50 mg (0.14 mmol) of (E)-3,4′,5-triacetoxystilbene was dissolved in 3 ml methanol and degassed with argon. 8 mg (0.14 mmol) of potassium hydroxide in 0.5 ml methanol were added dropwise under a slight argon stream and the mixture was heated for 30 minutes to 65° C. The obtained solution was neutralized with 1 N hydrochloric acid, poured into 10 ml of ethyl acetate and extracted 3× against 5 ml of brine. The organic phase was dried over MgSO4 and the solvent removed in vacuo giving 30 mg of resveratrol (0.13 mmol, 92%).
Reaction SMILES: [CH2:1]([C@@H:6]1[CH2:8][C@H:7]1[O:9][C:10]([O:12]N1C(=O)CCC1=O)=O)[CH2:2][CH2:3][C:4]#[CH:5].[NH2:20][C@@H:21]([CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27]C1)[C:22]([OH:24])=[O:23].C(N(CC)CC)C.O>C(#N)C.C(OCC)(=O)C>[CH:25]1([C@H:21]([NH:20][C:10]([O:9][C@@H:7]2[CH2:8][C@H:6]2[CH2:1][CH2:2][CH2:3][C:4]#[CH:5])=[O:12])[C:22]([OH:24])=[O:23])[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C#CCCC[C@@H]1C[C@H]1OC(=O)ON1C(=O)CCC1=O
Reactant: N[C@H](C(=O)O)C1CCCCC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: C#CCCC[C@@H]1C[C@H]1OC(=O)N[C@H](C(=O)O)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.9 %

Procedure:
To a solution of the product of Step 1 (457 mg) in acetonitrile (6 ml) was added (2S)-amino(cyclohexyl)ethanoic acid (352 mg) followed by triethylamine (0.720 ml) and water (6.00 ml). The mixture was stirred at room temperature for 18 hours. The mixture was diluted with ethyl acetate and washed with HCl 1N, water and brine. The organic layer was dried over sodium sulfate, filtered and concentrated. This provided the desired product (510 mg) as an oil. LRMS (ES+) M/Z (M+H)+ 308.2.
Reaction SMILES: Cl.Cl.[O:3]1[CH2:8][CH2:7][CH:6]([N:9]2[CH2:14][CH2:13][CH:12]([NH2:15])[CH2:11][CH2:10]2)[CH2:5][CH2:4]1.C(N(CC)C(C)C)(C)C.F[C:26]1[CH:31]=[C:30]([O:32][CH2:33][C:34]([F:37])([F:36])[F:35])[CH:29]=[CH:28][C:27]=1[N+:38]([O-:40])=[O:39]>CN(C)C=O>[N+:38]([C:27]1[CH:28]=[CH:29][C:30]([O:32][CH2:33][C:34]([F:35])([F:36])[F:37])=[CH:31][C:26]=1[NH:15][CH:12]1[CH2:13][CH2:14][N:9]([CH:6]2[CH2:5][CH2:4][O:3][CH2:8][CH2:7]2)[CH2:10][CH2:11]1)([O-:40])=[O:39]
Reactant: NC1CCN(C2CCOCC2)CC1
Reactant: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1F
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1ccc(OCC(F)(F)F)cc1NC1CCN(C2CCOCC2)CC1
Temperature: 75 °C
Reaction time: 0.17 h
Yield: 43.4 %

Procedure:
A stirred suspension of 1-(tetrahydro-2H-pyran-4-yl)-4-piperidinamine dihydrochloride (diHCl salt of D9, 350 mg, 1.4 mmol) in dimethylformamide (6 ml) at room temperature under argon was treated with N,N-diisopropylethylamine 51 mg, 4.0 mmol), then stirred for 10 minutes before adding 2-fluoro-1-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzene (D55, 280 mg, 1.2 mmol) and heating at 75° C. for 36 hrs. The solution was concentrated under vacuum and the residue treated with 10% Na2CO3 solution and extracted with ethyl acetate. The extract was washed with brine, dried (Na2SO4) and concentrated under vacuum. The residue was purified by chromatography on silica gel (20 g) eluting with 0-20% methanol/ethyl acetate to afford the title compound as a bright yellow solid (210 mg, 45%).
Reaction SMILES: [C:1]([N:11]1[CH2:18][C@@H:17]2[C@@H:13]([CH2:14][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@@H:28]([CH2:30]CS([O-])(=O)=O)[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:16]2)[CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].C1COCC1.C(O)(C)C.[OH-].[NH4+:48]>C(Cl)Cl>[C:1]([N:11]1[CH2:12][C@@H:13]2[C@@H:17]([CH2:16][N:15]([C:19]3[CH:24]=[CH:23][C:22]([N:25]4[CH2:29][C@H:28]([CH2:30][NH2:48])[O:27][C:26]4=[O:36])=[CH:21][C:20]=3[F:37])[CH2:14]2)[CH2:18]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1C[C@@H]2CN(c3ccc(N4C[C@@H](CCS(=O)(=O)[O-])OC4=O)cc3F)C[C@@H]2C1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC[C@H]1CN(c2ccc(N3C[C@H]4CN(C(=O)OCc5ccccc5)C[C@H]4C3)c(F)c2)C(=O)O1
Temperature: 95 °C

Procedure:
To a flame dried flask equipped with a nitrogen inlet is introduced (R)-[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methanol (1.75 g, 3.84 mmol) and methylene chloride (100 mL) cooled to 0° C. Triethylamine (0.80 mL, 5.76 mmol) and methanesulfonyl chloride are added, stirred at 0° C. for 2 hours, and warmed to ambient temperature for 1 hour. The reaction is washed with water (30 mL), saturated sodium bicarbonate (30 mL), and saline (30 mL), dried over sodium sulfate, and concentrated in vacuo to give the crude (R)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate. (R)-[[3-[4-[cis-3-(Carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]methanesulfonate is combined in a resealable tube with THF (5 mL), isopropanol (5 mL), and concentrated ammonium hydroxide (10 mL) and heated to 95° C. for 10 hours. The reaction is diluted with methylene chloride (50 mL) and washed with saline (30 mL), dried over sodium sulfate, concentrated in vacuo to give (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]amine. The crude (S)-[[3-[4-[cis-3-(carbobenzyloxy)-3,7-diazabicyclo[3.3.0]octan-7-yl]-3-fluorophenyl]-2-oxo-5-oxazolidinyl]methyl]amine (1.67 g, 3.67 mmol) is dissolved in methylene chloride (20 mL), cooled to 0° C. under nitrogen, pyridine (0.89 mL, 11.02 mmol) and acetic anhydride (0.43 mL, 4.59 mmol) are added, and the reaction is stirred 15 hours at ambient temperature. The reaction is diluted with methylene chloride (50 mL), washed with 1N HCl (25 mL), saturated sodium bicarbonate (25 mL), saline (25 mL), dried over sodium sulfate, concentrated in vacuo, and chromatographed on silica gel (230-400 mesh, 200 mL), eluting with chloroform/methanol (98/2). The appropriate fractions are combined (Rf =0.15, TLC, chloroform/methanol, 95/5) and concentrated in vacuo to give the title compound, mp 165-168° C.
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH:14]=[O:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1>CO.O>[CH3:3][O:4][C:5]1[C:13]2[O:12][C:11]([CH2:14][OH:15])=[CH:10][C:9]=2[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc2cc(C=O)oc12
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cccc2cc(CO)oc12
Reaction time: 3 h
Yield: 96.6 %

Procedure:
Sodium borohydride (0.462 g) was added in one portion to a stirred solution of 7-methoxybenzofuran-2-carbaldehyde (2.15 g) in methanol (50 ml) at room temperature and the reaction was stirred for 3 hours. The reaction mixture was then diluted with water (100 ml) and extracted with dichloromethane (3×30 ml). The organic extracts were combined, washed with water (30 ml), dried over magnesium sulphate, filtered and the solvent removed in vacuo to afford the title compound (2.10 g) as a pale orange liquid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9](=S)[NH:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.Cl[CH:14]([C:20]([CH3:22])=O)[C:15]([O:17][CH2:18][CH3:19])=[O:16].Cl>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:20]([CH3:22])[NH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: NNC(=S)Nc1cccc(Cl)c1
Reactant: CCOC(=O)C(Cl)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 31.3 %

Procedure:
A stirred slurry of 8 g (0.04 mole) of 4-(3-chlorophenyl)-3-thiosemicarbazide in 75 mL of absolute ethanol was treated with 6.8 g (0.04 mole) of ethyl 2-choroacetoacetate. The reactants quickly dissolved but a precipitate soon formed. After stirring at room temperature for 2 hr the reaction mixture was treated with 40 mL of 2N ethanolic hydrogen chloride and heated at reflux for 1 hr, then filtered while hot to remove the insoluble sulfur. The filtrate on cooling yielded 3.5 g of yellow solid and an additional 4.7 g was obtained when the filtrate was concentrated in vacuo. Recrystallization from benzene/ligroin gave 4.2 g of pale yellow brown product. Additional ligroin added to the filtrate gave, upon cooling at ~7-10° C. for ~16 hr, additional crystals but also some oil; this tri-phase mixture was filtered to yield 1.5 g of additional product. Both solids had identical mass spectra. They were combined and recrystallized twice from benzene/ligroin and finally from benzene by dissolving the solids and reducing the volume until crystallization began. Upon cooling, 3.93 g of beige plate-like crystals were collected, mp 159.5°-160° C.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(N(CC)CC)C>[S:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Temperature: 95 °C
Yield: 85 %

Procedure:
To a 25 mL round bottom flask containing a solution of crude indole-3-carboxaldehyde (4.5 mmol) in 10 mL of triethylamine was added 1.3 g (6.7 mmol) of tosyl chloride. The reaction mixture was heated to 95° C. for 4 h. The reaction mixture was quenched by pouring into 10 mL of ice water and filtered. The solid was washed with water (3×10 mL), triterated with ether (25 mL), and dried in vacuo to give N-tosyl-indole-3-carboxaldehyde (85-90% yield).