Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1([NH2:13])[C:10]([NH2:11])=[CH:9][CH:8]=[CH:7][CH:6]1[CH3:12])([CH3:4])([CH3:3])[CH3:2].C1(C)C(N)=CC=CC=1N.CC(=C)C>>[CH3:3][C:1](=[CH2:2])[CH3:4].[C:6]1([CH3:12])[CH:7]=[CH:8][CH:9]=[C:10]([NH2:11])[C:5]=1[NH2:13]
Reactant: CC1C=CC=C(N)C1(N)C(C)(C)C
Agent: C=C(C)C
Agent: Cc1c(N)cccc1N
Product: Cc1cccc(N)c1N
Temperature: 200 °C

Procedure:
Synthesis of the above recited ortho-tert-butyltoluenediamine (hereinafter t-butyl TDA) was carried out in a 1 gallon stainless steel pressure vessel equipped with a mechanical stirrer. The vessel was charged with a 150 gram portion of a powdered commercially available silica-alumina catalyst containing 13% alumina and 1500 grams (12.24 moles) of 2,6-toluenediamine. The autoclave was sealed and purged with nitrogen. A residual blanket of nitrogen was left in the autoclave, leaving the pressure at 16 psig. The contents of the reactor were heated to a temperature of 200° C. with constant agitation. Isobutylene was then introduced into the reactor and 870 grams or 15.5 moles were added over a 30 minute period resulting in an initial reaction of pressure of 970 psig. This provided a mole ratio of 1.26:1 isobutylene to toluenediamine. The reaction mixture was maintained at 200° C. for about 45 hours with constant agitation.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[Si](C=[N+]=[N-])(C)(C)[CH3:16]>C(Cl)(Cl)Cl.CO.CCOCC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:12])([F:13])[F:14])=[C:6]([CH:10]=1)[C:7]([O:9][CH3:16])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CCOCC
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(F)ccc1C(F)(F)F
Reaction time: 1 h

Procedure:
To a solution of 5-fluoro-2-(trifluoromethyl)benzoic acid (2.0 g, 9.62 mmol, Aldrich) in a mixture of chloroform and methanol (1:1, 40 ml) was added a 2 M solution of TMS-diazomethane in ether (approximately 8 ml) dropwise, in portions over about 1 h, allowing the solution to cool down between additions. The solution was evaporated in vacuo. To the residue was added chloroform (approximately 40 ml) and the solvent removed in vacuo to give methyl 5-fluoro-2-(trifluoromethyl)benzoate as a colourless slightly cloudy oil (2.09 g). To a stirred solution of phenol (1.06 g, 11.3 mmol, Aldrich) in DMSO (8 ml) under nitrogen was added potassium t-butoxide (1.27 g, 11.3 mmol) and the mixture stirred to dissolve. To the mixture was added methyl 5-fluoro-2-(trifluoromethyl)benzoate (2.09 g, 9.41 mmol) in DMSO (2 ml) and the mixture allowed to stand for one week. To the dark coloured mixture was added dilute aqueous sodium bicarbonate and the mixture extracted with ether four times. The combined organic extracts were dried (Na2SO4), filtered and the solvent removed in vacuo to leave a yellow oil (approximately 2 g). The residue was purified on silica 50 g using 0-100% DCM-cyclohexane. The appropriate fractions were combined and evaporated in vacuo to give methyl 5-(phenyloxy)-2-(trifluoromethyl)benzoate as a colourless oil (0.516 g).
Reaction SMILES: [CH2:1]=[O:2].Cl.[Cl:4][C:5]1[CH:6]=[C:7]2[O:13][C:12](=[O:14])[NH:11][C:8]2=[N:9][CH:10]=1>O>[OH:2][CH2:1][N:11]1[C:8]2=[N:9][CH:10]=[C:5]([Cl:4])[CH:6]=[C:7]2[O:13][C:12]1=[O:14]
Reactant: C=O
Reactant: O=c1[nH]c2ncc(Cl)cc2o1
Agent: Cl
Solvent: O
Product: O=c1oc2cc(Cl)cnc2n1CO
Reaction time: 4 h
Yield: 85 %

Procedure:
8 parts of 38% formaldehyde solution and 25 parts of 2N hydrochloric acid are added to a solution of 8.5 parts of 6-chlorooxazolo-[4,5-b]-pyridin-2-(3H)-one in 60 parts of water, and the whole is stirred for 4 hours at 50° to 60° C. After cooling with ice, filtration is performed and the residue is washed with ice water. There are obtained 8.5 parts of 3-hydroxymethyl-6-chloro-oxazolo[ 4,5-b]pyridin-2-(3H)-one (85% of theory), m.p. 137°-139° C.
Reaction SMILES: [Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[OH:12].Cl.[CH3:14]O>>[Br:1][C:2]1[C:10]([OH:11])=[CH:9][C:5]([C:6]([O:8][CH3:14])=[O:7])=[CH:4][C:3]=1[OH:12]
Reactant: O=C(O)c1cc(O)c(Br)c(O)c1
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc(O)c(Br)c(O)c1

Procedure:
In a 2.0-liter egg plant-type flask, a hydrochloric acid/methanol solution (500 mL) of 4-bromo-3,5-dihydroxybenzoic acid (50 g, 0.21 mol) was stirred with heating under reflux for 6 hours. Methanol was removed under reduced pressure to obtain a crude crystal. This was washed with hexane and chloroform to obtain the title compound as a colorless solid.
Reaction SMILES: Cl[C:2]1[N:3]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=3)=[CH:22][CH:21]=2)[CH:4]=[C:5]2[C:10]=1[N:9]1[C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:12]3[N:13]=[C:8]1[N:7]([CH3:17])[C:6]2=[O:18].ClC(Cl)(Cl)C(O)=O.[NH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[CH3:17][N:7]1[C:6](=[O:18])[C:5]2=[CH:4][N:3]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[N:27]=4)=[CH:22][CH:21]=3)[C:2]([NH:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:10]2[N:9]2[C@H:11]3[CH2:16][CH2:15][CH2:14][C@H:12]3[N:13]=[C:8]12
Reactant: Nc1ccccc1
Reactant: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Cl)c2N2C1=N[C@@H]1CCC[C@@H]12
Agent: O=C(O)C(Cl)(Cl)Cl
Solvent: ClCCl
Product: CN1C(=O)c2cn(Cc3ccc(-c4cccc(F)n4)cc3)c(Nc3ccccc3)c2N2C1=N[C@@H]1CCC[C@@H]12
Temperature: 100 °C
Yield: 14.5 %

Procedure:
Crude (6aR,9aS)-5,6a,7,8,9,9a-hexahydro-1-chloro-5-methyl-2-(4-(6-fluoropyridin-2-yl)benzyl)-cyclopent[4,5]imidazo[1,2-a]pyrrolo[4,3-e]pyrimidin-4(2H)-one (approx. 0.03 mmol) is dissolved in anhydrous CH2Cl2, and then trichloroacetic acid (5.2 mg, 0.03 mmol) is added, followed by aniline (5.8 uL, 0.06 mmol). The reaction mixture is heated in a Biotage microwave instrument at 100° C. for 2 hours. The mixture is purified by a semi-preparative HPLC to give 2.2 mg of product as solids. MS (ESI) m/z 507.2 [M+H]+.
Reaction SMILES: N([O-])=O.[Na+].[CH2:5]([O:7][C:8]([C:10]1[N:11]=[C:12](N)[S:13][CH:14]=1)=[O:9])[CH3:6].[Na+].[Br-:17].OS(O)(=O)=O.[OH-].[Na+]>O>[CH2:5]([O:7][C:8]([C:10]1[N:11]=[C:12]([Br:17])[S:13][CH:14]=1)=[O:9])[CH3:6]
Reactant: CCOC(=O)c1csc(N)n1
Reactant: [Br-]
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)c1csc(Br)n1
Temperature: 0 °C
Reaction time: 1 h
Yield: 37.5 %

Procedure:
A cold solution of sodium nitrite (228 mg, 3.31 mmol) in water (2.0 mL) was added dropwise to a mixture of 2-amino-thiazole-4-carboxylic acid ethyl ester (J. Am. Chem. Soc., 1946, 68, 266) (500 mg, 2.90 mmol), CuSO4 pentahydrate (2.100 g, 8.41 mmol), NaBr (1.134 g, 11.02 mmol), H2SO4 (3.0 mL) and water (3.0 mL) at −5° C. to 0° C. The reaction mixture was stirred at 0° C. for 20 minutes and at room temperature for 1 h. The reaction mixture was adjusted to pH 9 with 1N NaOH (105 mL) and the aqueous solution was washed with CHCl3 (4×50 mL). The organic solutions were combined, dried (MgSO4), filtered and concentrated. Purification by medium pressure chromatography (39:1 hexanes:EtOAc to 19:1 hexanes:EtOAc) provided 2-bromo-thiazole-4-carboxylic acid ethyl ester (257 mg).
Reaction SMILES: [Cl-].Cl[C:3](Cl)=[N+:4]([CH3:6])[CH3:5].[CH2:8]([N:13]1[C:21]2[N:20]=[CH:19][NH:18][C:17]=2[C:16](=[O:22])[NH:15]/[C:14]/1=[N:23]/[NH2:24])[CH2:9][CH2:10][CH2:11][CH3:12]>C(Cl)Cl>[CH3:5][N:4]([CH3:6])[C:3]1[N:15]2[C:16](=[O:22])[C:17]3[NH:18][CH:19]=[N:20][C:21]=3[N:13]([CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])[C:14]2=[N:23][N:24]=1
Reactant: CCCCCn1/c(=N\N)[nH]c(=O)c2[nH]cnc21
Reactant: C[N+](C)=C(Cl)Cl
Agent: [Cl-]
Solvent: ClCCl
Product: CCCCCn1c2nc[nH]c2c(=O)n2c(N(C)C)nnc12
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
To methylene chloride (10 mL) was added [B] N-(dichloromethylene)-N-methylmethanaminium chloride (0.21 g, 1.3 mmol). After stirring for 5 mins, (2Z)-3-pentyl-3,7-dihydro-1H-purine-2,6-dione 2-hydrazone (0.10 g, 0.42 mmol) was added, and the mixture was stirred at rt for 5 hrs. LCMS analysis showed product as a major peak was formed. 1N NaoH was carefully added to neutralize the acid, and the mixture was extracted with methylene chloride three times. The combined organic layers were dried by MgSO4, filtered and concentrated in vacuo to yield the desired product (84 mg, 69%). LCMS calculated for C13H20N7O(M+H): 290.2; found 290.1.
Reaction SMILES: Br.[NH2:2][C@H:3]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[CH3:9])=[O:6])[CH3:4].[C:19](Cl)(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>N1C=CC=CC=1>[C:19]([NH:2][C@H:3]([C:5]([NH:7][C@H:8]([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:9])=[O:6])[CH3:4])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@H](N)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Agent: Br
Solvent: c1ccncc1
Solvent: O
Product: C[C@H](NC(=O)c1ccccc1)C(=O)N[C@@H](C)C(=O)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
4.1 g (0.013 mol) of L-alanyl-L-alanine anilide hydrobromide were dissolved in 120 ml of dry pyridine and 3 ml (0.026 mol) of benzoyl chloride were added. The solution was stirred at room temperature for 3 hours and was then evaporated to yield a solid. 50 ml of water were added, the solid was filtered off, washed with 50 ml of water and then recrystallise from ethanol to yield 3.15 g (72%) of N-benzoyl-L-alanyl-L-alanine anilide of melting point 245°-248° C.; [α]D20 =+66.6° (c=1.086% in dimethylformamide).
Reaction SMILES: [O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@@H:18]([C:29]([OH:31])=O)[CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1.C(N(CC)CC)C.[CH3:43][O:44][CH:45]1[CH2:50][CH2:49][N:48]([CH:51]2[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]2)[CH2:47][CH2:46]1>>[O:1]=[C:2]1[N:8]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C@H:18]([CH2:19][C:20]3[CH:25]=[C:24]([CH3:26])[C:23]([OH:27])=[C:22]([CH3:28])[CH:21]=3)[C:29]([N:54]3[CH2:53][CH2:52][CH:51]([N:48]4[CH2:49][CH2:50][CH:45]([O:44][CH3:43])[CH2:46][CH2:47]4)[CH2:56][CH2:55]3)=[O:31])=[O:16])[CH2:11][CH2:10]2)[CH2:7][CH2:6][C:5]2[CH:32]=[CH:33][CH:34]=[CH:35][C:4]=2[NH:3]1
Reactant: COC1CCN(C2CCNCC2)CC1
Reactant: Cc1cc(C[C@@H](OC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc(C)c1O
Solvent: CCN(CC)CC
Product: COC1CCN(C2CCN(C(=O)[C@@H](Cc3cc(C)c(O)c(C)c3)OC(=O)N3CCC(N4CCc5ccccc5NC4=O)CC3)CC2)CC1

Procedure:
Prepared analogously to Example 1i from 80 mg (0.17 mmol) (R)-2-(4-hydroxy-3,5-dimethyl-phenyl)-1-carboxy-ethyl 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylate, 77 μL (0.55 mmol) triethylamine and 46 mg (0.17 mmol) 4-methoxy-[1,4′]bipiperidinyl (used as the bis-hydrochloride salt).
Reaction SMILES: Br[C:2]([Br:5])(Br)Br.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:25][Si:26]([CH3:36])([C:32]([CH3:35])([CH3:34])[CH3:33])[O:27][CH2:28][CH2:29]CO>C(Cl)Cl>[Br:5][CH2:2][CH2:29][CH2:28][O:27][Si:26]([CH3:36])([CH3:25])[C:32]([CH3:35])([CH3:34])[CH3:33]
Reactant: CC(C)(C)[Si](C)(C)OCCCO
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCCCBr
Temperature: -25 °C
Reaction time: 1.5 h
Yield: 86.7 %

Procedure:
5.44 g of tetrabromomethane and 4.30 g of triphenyl-phosphine were added to a solution of 2.5 g of the product of Step A in 27 ml of methylene chloride cooled down to −25° C. The reaction solution was stirred for 90 minutes at 0° C. and then was chromatographed on silica (eluant:ethyl acetate-cyclohexane 1-9) to obtain 2.885 g of the expected product.
Reaction SMILES: [CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([N+:18]([O-])=O)[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1.O.NN>CO.[Ni]>[CH3:1][N:2]([CH3:21])[CH:3]1[CH2:8][CH2:7][C:6]([C:9]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([NH2:18])[CH:16]=3)[NH:11][CH:10]=2)=[CH:5][CH2:4]1
Reactant: CN(C)C1CC=C(c2c[nH]c3ccc([N+](=O)[O-])cc23)CC1
Agent: [Ni]
Agent: NN
Solvent: CO
Solvent: O
Product: CN(C)C1CC=C(c2c[nH]c3ccc(N)cc23)CC1
Yield: 98.6 %

Procedure:
A solution of compound 112 (0.21 g, 0.735 mmol) in dry methanol (5 mL) was treated with Ra—Ni (0.05 g) followed by hydrazine hydrate (0.22 mL, 7.359 mmol) at room temperature. The reaction was placed in a pre-heated oil bath and refluxed for 5 min. The reaction brought to room temperature, filtered through celite bed and washed with methanol (2×10 mL). The solvent was evaporated and crude was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 1:9) to obtain compound 113 (0.185 g, quantitative) as a foam. mp 63-65° C.; 1H NMR (DMSO-d6) δ 1.40-1.52 (m, 1H), 1.97-2.02 (m, 1H), 2.08-2.57 (m, 11H), 4.47 (s, 2H), 5.99 (brs, 1H), 6.47 (dd, 1H, J=1.8, 8.4 Hz), 6.99 (d, 1H, J=0.9 Hz), 7.04 (d, 1H, J=8.7 Hz), 7.13 (d, 1H, J=2.4 Hz), 10.55 (s, 1H); ESI-MS m/z (%): 256 (MH+, 100), 211 (41).
Reaction SMILES: [OH:1][C@@H:2]([CH2:24][OH:25])[CH2:3][C:4]1[CH:5]=[C:6]([F:23])[C:7]([C:10]2[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH:11]=2)=[N:8][CH:9]=1.Cl.C(OCC)C>ClCCl.O1CCOCC1>[F:23][C:6]1[C:7]([C:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH:11]=2)=[N:8][CH:9]=[C:4]([CH2:3][C@@H:2]([OH:1])[CH2:24][OH:25])[CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CC=C(c2ncc(C[C@@H](O)CO)cc2F)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CCOCC
Product: OC[C@H](O)Cc1cnc(C2=CCNCC2)c(F)c1
Yield: 118.4 %

Procedure:
A solution of 4 (2.30 g, 6.53 mmol) in dichloromethane (10 mL) was stirred with 4 mol/L HCl in dioxane (25 mL) in a closed vessel at room temperature overnight. The resulting suspension was stirred for 1 h with ethyl ether. The solid precipitated was collected by filtration and washed several times with ethyl ether to afford 1.95 g (92%) of 5 as a pale yellow solid (HCl salt). The identity of compound 5 was confirmed by LC/MS and 5 was used directly for the next step.
Reaction SMILES: Cl.Cl[C:3]1[CH:8]=[CH:7][N:6]=[CH:5][CH:4]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+]>C(O)CC(C)C>[N:6]1[CH:7]=[CH:8][C:3]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[CH:4][CH:5]=1
Reactant: OC1CCNCC1
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)CCO
Product: OC1CCN(c2ccncc2)CC1
Reaction time: 60 h

Procedure:
A mixture of 4-chloropyridine hydrochloride (7.50 g), 4-hydroxypiperidine (5.06 g) and sodium bicarbonate (10.1 g) in isoamyl alcohol (60 m1) was heated under reflux with stirring for 60 hours and then evaporated. The residue was extracted several times with a boiling mixture of ethyl acetate/methanol (10:1) and the combined extracts were filtered and evaporated. The residue was sublimed at 120°-150° and 0.2 mm pressure to give the pure product, (7.30 g), m.p. 155°-156°.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=O)[CH2:12][CH3:13])[CH:6]=[C:7]([Br:10])[C:8]=1[OH:9].Cl.[NH2:16][OH:17].C>[OH-].[Na+].C(O)C>[NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:11](=[N:16][OH:17])[CH2:12][CH3:13])[CH:6]=[C:7]([Br:10])[C:8]=1[OH:9]
Reactant: CCC(=O)c1cc(Br)c(O)c(CN)c1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCC(=NO)c1cc(Br)c(O)c(CN)c1
Yield: 85.1 %

Procedure:
A solution of 9.0 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone and 7.0 g of hydroxylamine hydrochloride in 50 ml of 4N sodium hydroxide solution and 15 ml of ethanol is refluxed with heating for 40 minutes. To the reaction mixture is added activated charcoal and the charcoal is filtered off and then the mixture is adjusted to pH 6-7 with concentrated hydrochloric acid. After allowing to stand at room temperature, the precipitate is collected by filtration, washed with water and dried to give 8.1 g of 3'-aminomethyl-5'-bromo-4'-hydroxypropiophenone oxime, melting at 174°-175° C. with decomposition.
Reaction SMILES: [F:1][C:2]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-])=O)[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CCO.[Cl-].[Cl-].[Zn+2]>[F:1][C:2]1[C:14]2[N:13]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[NH2:21])[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccccc1-n1c2ccccc2c2cccc(F)c21
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Nc1ccccc1-n1c2ccccc2c2cccc(F)c21

Procedure:
50 g (163 mmol) of 1-fluoro-9-(2-nitrophenyl)-9H-carbazole are dissolved in 600 ml of EtOH, 67 g (489 mmol) of ZnCl2 are added at room temperature, and the mixture is heated under reflux for 6 h. The mixture is subsequently warmed to room temperature over the course of 1 h, 20% NaOH is added, and, after phase separation, the solvent is removed, and the residue is purified by chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30]C(=O)C)[C@@H:22]([O:23]C(=O)C)[C@H:17]([O:18]C(=O)C)[C@H:12]1[O:13]C(=O)C.[CH3:34][C:35]1[CH:43]=[CH:42][C:38]([C:39](Cl)=O)=[CH:37][CH:36]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH2:34][C:35]1[CH:43]=[CH:42][C:38]([CH3:39])=[CH:37][CH:36]=1)=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][OH:30])[C@@H:22]([OH:23])[C@H:17]([OH:18])[C@H:12]1[OH:13]
Reactant: Cc1ccc(C(=O)Cl)cc1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2ccc3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Product: Cc1ccc(Cc2cn([C@@H]3O[C@H](CO)[C@@H](O)[C@H](O)[C@H]3O)c3cccc(Cl)c23)cc1

Procedure:
4-Chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)indole obtained in Example 1-(3) and 4-methylbenzoyl chloride were treated in a manner similar to Example 2-(4), (5), (6) and (7) to give the titled compound as a colorless powder. APCI-Mass m/Z 418/420 (M+H). 1H-NMR (DMSO-d6) δ 2.25 (s, 3H), 3.21-3.25 (m, 1H), 3.32-3.39 (m, 1H), 3.43-3.47 (m, 2H), 3.61-3.69 (m, 2H), 4.22 (s, 2H), 4.53 (t, J=5.5 Hz, 1H), 5.01 (d, J=5.3 Hz, 1H), 5.15 (d, J=5.0 Hz, 1H), 5.20 (d, J=5.8 Hz, 1H), 5.39 (d, J=9.2 Hz, 1H), 7.06-7.12 (m, 5H), 7.21 (s, 1H), 7.53 (d, J=8.2 Hz, 1H).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:71]=[CH:70][C:67]([C:68]#[N:69])=[CH:66][CH:65]=1>>[C:68]([C:67]1[CH:70]=[CH:71][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:37])([CH3:35])[CH3:36])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)#[N:69]
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Reactant: N#Cc1ccc(N)cc1
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)CC1NC(C(=O)Nc2ccc(C#N)cc2)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (2.94 g, 5.07 mmol), was reacted with diisopropylethylamine (5.25 g, 40.6 mmol), diphenylphosphinic chloride (4.8 g, 20.3 mmol), then reacted with 4-aminobenzonitrile (Aldrich) (2.4 g, 20.3 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-cyano-phenyl)-amide as a off white foam (Yield 1 g, 34%).
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][N:21]=1)([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.[Cl:36][C:37]1[S:38][C:39]([CH:43]=[O:44])=[C:40]([Cl:42])[N:41]=1>>[Si:1]([O:18][CH2:19][C:20]1[N:21]=[C:22]([CH:43]([C:39]2[S:38][C:37]([Cl:36])=[N:41][C:40]=2[Cl:42])[OH:44])[C:23]([F:35])=[C:24]([Cl:34])[C:25]=1[N:26]1[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]1)([C:14]([CH3:17])([CH3:15])[CH3:16])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ncc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1sc(Cl)nc1Cl
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)nc(C(O)c3sc(Cl)nc3Cl)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting materials: (2R,6S)-4-(2-((tert-butyldiphenylsilyloxy)methyl)-4-chloro-5-fluoropyridin-3-yl)-2,6-dimethylmorpholine (Intermediate 45) and 2,4-dichlorothiazole-5-carbaldehyde.
Reaction SMILES: [NH:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4].[OH-].[Na+].[CH3:12][O:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.Cl>O.O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[CH:16][C:17]([S:20]([N:1]([CH2:6][C:7]([OH:9])=[O:8])[CH2:2][C:3]([OH:5])=[O:4])(=[O:22])=[O:21])=[CH:18][CH:19]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(O)CNCC(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CC(=O)O)CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
3.3 Parts of iminodiacetic acid and 3.2 parts of sodium hydroxide are dissolved in 50 parts of water. Into the resulting aqueous solution, 20 parts of tetrahydrofuran containing 5 parts of p-methoxybenzenesulfonyl chloride was dropped. The resulting mixture is suspending at first, but becomes transparent when stirred at room temperature for about 1.5 hours. The mixture is further stirred at 50° C for about 20 minutes to terminate the reaction. After completion of the reaction, the reaction liquid is freed from the tetrahydrofuran and then acidified with hydrochloric acid to precipitate crystals. The crystals are collected by filtration and then recrystallized from water to obtain 3.8 parts of N-p-methoxybenzenesulfonyl-iminodiacetic acid, m.p. 177°-178.5° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][C:13]([C:20]([OH:22])=O)=[C:12]2[OH:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:56][NH:57][CH2:58][C:59]([O:61]CC)=[O:60]>ClCCl.[OH-].[Na+]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[C:15]([Cl:19])=[N:14][C:13]([C:20]([N:57]([CH2:58][C:59]([OH:61])=[O:60])[CH3:56])=[O:22])=[C:12]2[OH:23])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CNC
Reactant: O=C(O)c1nc(Cl)c2ccc(OCc3ccccc3)cc2c1O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN(CC(=O)O)C(=O)c1nc(Cl)c2ccc(OCc3ccccc3)cc2c1O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
6-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, 0.5 ml of triethylamine, 0.400 g of HATU, and 0.165 g of ethyl N-methyl-amino-acetate hydrochloride were combined in 15 ml of dichloromethane and the reaction mixture was stirred at room temperature for 18 h to give, after silica gel chromatography, 0.232 g of an off-white solid, MS-(+)-ion: 429.0 amu. 0.208 g of this intermediate product were dissolved in 10 ml of methanolic NaOH (1.5 M) and the mixture was stirred at room temperature for 3 h. The solvent was removed with a rotary evaporator, the residue was dissolved in water, and the aqueous layer was extracted with 50 ml of ethyl acetate. The aqueous layer was acidified to pH=1 with aqueous HCl to give a solid precipitate. The solid was collected by suction filtration, washed with water, and dried in a vacuum oven (80° C.) to give 0.180 g of white solid: MS-(+)-ion: 401.0 amu.