Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[NH:2][N:3]=[N:4][C:5]=1[C:6]1[CH:14]=[CH:13][C:9]([C:10]([OH:12])=O)=[CH:8][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.Cl.C(N=C=NCCCN(C)C)C.[NH2:37][C:38]1[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=1.Cl>CN(C=O)C.C(N(CC)CC)C>[N:4]1[NH:3][N:2]=[N:1][C:5]=1[C:6]1[CH:7]=[CH:8][C:9]([C:10]([NH:37][C:38]2[CH:46]=[CH:45][C:41]([C:42]([OH:44])=[O:43])=[CH:40][CH:39]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: O=C(O)c1ccc(-c2nn[nH]n2)cc1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(O)c1ccc(NC(=O)c2ccc(-c3nn[nH]n3)cc2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(2H-tetrazol-5-yl)benzoic acid (example 412, 4 mmol) and HOAt (4.2 mmol) in DMF (6 mL) was added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (4.2 mmol) and the resulting mixture was stirred at room temperature for 1 hour. An aliquot of this HOAt-ester solution (0.45 mL) was mixed with 0.25 mL of a solution of 4-aminobenzoic acid (1.2 mmol in 1 mL DMF). (Anilines as hydrochlorides can also be utilised, a slight excess of triethylamine was added to the hydrochloride suspension in DMF prior to mixing with the HOAt-ester.) The resulting mixture was shaken for 3 days at room temperature. 1N hydrochloric acid (2 mL) was added and the mixture was shaken for 16 hours at room temperature. The solid was isolated by centrifugation (alternatively by filtration or extraction) and was washed with water (3 mL). Drying in vacuo at 40° C. for 2 days afforded the title compound.
Reaction SMILES: [CH3:1][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:20]([OH:39])[C@:21]4([OH:38])[C:29](=[O:30])[C:28]([C:31]([NH2:33])=[O:32])=[C:27]([OH:34])[C@@H:26]([N:35]([CH3:37])[CH3:36])[C@@H:22]4[CH2:23]3)[C:17](=[O:18])[C:14]=2[C:15]=1[OH:16])=[O:8])([CH3:4])[CH3:3].[ClH:43]>C(#N)C>[CH3:4][C:2]([NH:5][CH2:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([N:40]([CH3:42])[CH3:41])[C:13]2[CH2:25][C@@H:24]3[C:19](=[C:17]([OH:18])[C:14]=2[C:15]=1[OH:16])[C:20](=[O:39])[C@@:21]1([OH:38])[C@H:22]([C@H:26]([N:35]([CH3:36])[CH3:37])[C:27]([C:28]([C:31]([NH2:33])=[O:32])=[C:29]1[OH:30])=[O:34])[CH2:23]3)=[O:8])([CH3:1])[CH3:3].[ClH:43]
Reactant: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(O)=C(C(N)=O)C(=O)[C@@]3(O)C(O)=C1C2=O
Agent: Cl
Solvent: CC#N
Product: CN(C)c1cc(NC(=O)CNC(C)(C)C)c(O)c2c1C[C@H]1C[C@H]3[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]3(O)C(=O)C1=C2O
Reaction time: 4 h

Procedure:
A suspension of Tigecycline was prepared by mixing a solid Tigecycline sample and acetonitrile in amounts as shown in Table B. The mixture was than stirred for about 1 hour at room temperature before concentrated hydrochloric acid was added in amounts corresponding to Table B. After stirring for about 4 hours the solid was filtered off and dried at room temperature under vacuum to obtain crystalline form A of Tigecycline hydrochloride.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:23]=[C:22](F)[C:21]([F:25])=[CH:20][C:9]=1[C:10]([O:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1)=[O:11].[Cl:26][C:27]1[CH:28]=[C:29]([OH:34])[CH:30]=[N:31][C:32]=1[F:33]>CS(C)=O.CCOC(C)=O>[Cl:26][C:27]1[CH:28]=[C:29]([O:34][C:22]2[C:21]([F:25])=[CH:20][C:9]([C:10]([O:12][C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[O:11])=[C:8]([F:7])[CH:23]=2)[CH:30]=[N:31][C:32]=1[F:33]
Reactant: Oc1cnc(F)c(Cl)c1
Reactant: Cc1ccc(OC(=O)c2cc(F)c(F)cc2F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: Cc1ccc(OC(=O)c2cc(F)c(Oc3cnc(F)c(Cl)c3)cc2F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 55.6 %

Procedure:
Potassium carbonate (1.40 g, 10.14 mmol) was added to a solution of 4-Methylphenyl 2,4,5-trifluorobenzoate (Preparation 12, 1.80 g, 6.76 mmol), 5-chloro-6-fluoropyridin-3-ol (1.05 g, 7.10 mmol) in DMSO and the mixture was stirred at room temperature for 18 hours. The reaction mixture was diluted in EtOAc (50 mL), washed with water (2×25 mL) and the organic layer dried over sodium sulfate, filtered, and concentrated in vacuo. The remaining crude was then purified by silica gel chromatography eluting with 10 to 50% EtOAc in heptane to afford the title compound (1.48 g, 56%):
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([OH:27])=O)=[C:17]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[N:16]=2)=[CH:11][N:10]=1)=O)(C)(C)C.[CH3:34][NH:35][C:36]([CH:38]1[CH2:43][CH2:42][NH:41][CH2:40][CH2:39]1)=[O:37]>>[NH2:8][C:9]1[N:10]=[CH:11][C:12]([C:15]2[N:23]=[C:22]3[C:18]([N:19]=[CH:20][N:21]3[CH2:24][C:25]([N:41]3[CH2:42][CH2:43][CH:38]([C:36]([NH:35][CH3:34])=[O:37])[CH2:39][CH2:40]3)=[O:27])=[C:17]([N:28]3[CH2:29][CH2:30][O:31][CH2:32][CH2:33]3)[N:16]=2)=[CH:13][N:14]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(-c2nc(N3CCOCC3)c3ncn(CC(=O)O)c3n2)cn1
Reactant: CNC(=O)C1CCNCC1
Product: CNC(=O)C1CCN(C(=O)Cn2cnc3c(N4CCOCC4)nc(-c4cnc(N)nc4)nc32)CC1

Procedure:
2-(2-(2-(Tert-butoxycarbonylamino)pyrimidin-5-yl)-6-morpholino-9H-purin-9-yl)acetic acid (35 mg) was reacted with N-methylpiperidine-4-carboxamide via General Procedure F followed by Boc deprotection via General Procedure E and purified via reverse phase HPLC to give 10.3 mg 122 as a white solid. MS (Q1) 481.2 (M)+.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][NH:28][CH2:27]2)[CH3:22]>CN(C=O)C>[CH2:21]([NH:23][C:24]1[CH:25]=[C:26]2[C:30](=[CH:31][CH:32]=1)[CH2:29][N:28]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:17])[C:6]([C:18]([OH:20])=[O:19])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[CH:9][C:10]=1[F:16])[CH2:27]2)[CH3:22]
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Reactant: CCNc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Product: CCNc1ccc2c(c1)CN(c1c(F)cc3c(=O)c(C(=O)O)cn(C4CC4)c3c1F)C2
Yield: 60.4 %

Procedure:
141 mg of 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 253 mg of 5-ethylaminoisoindoline, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 2 to produce 128 mg of the target compound.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.O[N:17]1[C:25](=[O:26])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:27]>>[O:27]=[C:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:25](=[O:26])[N:17]1[O:1][CH2:2][CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Product: CC(C)(C)OC(=O)N1CCC(CON2C(=O)c3ccccc3C2=O)CC1
Yield: 80 %

Procedure:
The title compound was prepared from t-butyl 4-(hydroxymethyl)piperidine-1-carboxylate and 2-hydroxyisoindoline-1,3-dione in 80% yield using the same procedure as described in the synthesis of intermediate B. LCMS (method B): [MNa]+=383, tR=2.64 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1.[NH:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[N:16]1([CH2:2][C:3]2[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=2)[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CCOC(=O)/C=C/c1ccc(CBr)cc1
Reactant: C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1ccc(CN2CCCC2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2 g (7.43 mmol) of ethyl (E)-3-(4-bromomethylphenyl)acrylate is added to a suspension of 0.69 mL (8.2 mmol) of pyrrolidine and 2.05 g (14.86 mmol) of potassium carbonate in 40 mL of DMF and stirred for 18 hours at ambient temperature. The reaction mixture is evaporated down and the residue is extracted with water and ethyl acetate. The organic phase is dried over sodium sulfate, evaporated down, and the residue is purified by column chromatography on silica gel (eluant: dichloromethane/methanol/ammonia (90:10:1)). Yield: 0.3 g (15.6% of theory); C16H21NO2 (M=259.35); calc.: molecular ion peak (M+H)+: 260; found: molecular ion peak (M+H)+: 260; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (90:10:1)).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:8]1[C:17]2[C:12](=[CH:13][C:14]([Cl:18])=[CH:15][CH:16]=2)[N:11]=[CH:10][CH:9]=1>O>[Cl:18][C:14]1[CH:13]=[C:12]2[C:17]([C:8]([N:1]3[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]3)=[CH:9][CH:10]=[N:11]2)=[CH:16][CH:15]=1
Reactant: Clc1ccc2c(Cl)ccnc2c1
Reactant: C1CNCCN1
Solvent: O
Product: Clc1ccc2c(N3CCNCC3)ccnc2c1
Temperature: 120 °C
Reaction time: 2.5 h
Yield: 41.1 %

Procedure:
Piperazine (65.2 g) was melted by heating at 120° C., and 4,7-dichloroquinoline (15.0 g) was added thereto. The mixture was stirred at 120° C. for 2.5 hr and the reaction mixture was added to water. The mixture was extracted with chloroform and concentrated under reduced pressure to give 1-(7-chloro-4-quinolyl)piperazine (7.72 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][OH:14])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:23](OC(=O)C)(=[O:25])[CH3:24].C(=O)(O)[O-].[Na+]>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][C@H:11]([CH2:13][O:14][C:23](=[O:25])[CH3:24])[O:10][C:9]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C1O[C@@H](CO)CN1c1cccc(F)c1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OC[C@H]1CN(c2cccc(F)c2)C(=O)O1
Reaction time: 18 h
Yield: 103.4 %

Procedure:
(5R)-3-(3-Fluorophenyl)-5-hydroxymethyloxazolidin-2-one (40 g, 0.189 M, see Upjohn WO 94-13649) was suspended by stirring in dry dichloromethane (400 ml) under nitrogen. Triethylamine (21 g, 0.208 M) and 4-dimethylaminopyridine (0.6 g, 4.9 mM) were added, followed by dropwise addition of acetic anhydride (20.3 g, 0.199 M) over 30 minutes, and stirring continued at ambient temperature for 18 hours. Saturated aqueous sodium bicarbonate (250 ml) was added, the organic phase separated, washed with 2% sodium dihydrogen phosphate, dried (magnesium sulfate), filtered and evaporated to give the desired product (49.6 g) as an oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]=[C:10]([NH2:19])[C:9]=2[N:8]=[C:7]1[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].[CH3:25][S:26](Cl)(=[O:28])=[O:27]>>[NH2:19][C:10]1[C:9]2[N:8]=[C:7]([CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[N:6]([CH2:5][CH2:4][CH2:3][CH2:2][NH:1][S:26]([CH3:25])(=[O:28])=[O:27])[C:18]=2[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N:11]=1
Reactant: CS(=O)(=O)Cl
Reactant: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCN
Product: CCCCCc1nc2c(N)nc3ccccc3c2n1CCCCNS(C)(=O)=O
Yield: 34.3 %

Procedure:
Using the general method of Example 245, 1-(4-aminobutyl)-2-pentyl-1H-imidazo[4,5-c]quinolin-4-amine (1.50 g, 4.6 mmol) was reacted with methanesulfonyl chloride (0.57 mL, 7.4 mmol) to provide 636 mg of N-[4-(4-amino-2-pentyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]methanesulfonamide as an off white solid, m.p. 136.8-138.1° C. Analysis: Calculated for C20H29N5O2S: % C, 59.53; % H, 7.24; % N, 17.35;
Reaction SMILES: [NH2:1][CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4].[Cl:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=O.O>ClCCl>[Cl:7][C:8]1[CH:9]=[C:10](/[CH:11]=[N:1]/[CH2:2][Si:3]([CH3:6])([CH3:5])[CH3:4])[CH:13]=[CH:14][CH:15]=1
Reactant: C[Si](C)(C)CN
Reactant: O=Cc1cccc(Cl)c1
Solvent: ClCCl
Solvent: O
Product: C[Si](C)(C)C/N=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
To a solution of (aminomethyl)trimethylsilane (Fluka) (1.6 g, 16 mmol) in dichloromethane (100 mL) was added 3-chloro-benzaldehyde (Aldrich) (1.9 g, 14 mmol). The reaction mixture was stirred at room temperature for 3 h. Water was added. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to give [1-(3-chloro-phenyl)-meth-(E)-ylidene]-trimethylsilanylmethyl-amine as a colorless oil (3 g, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[C:23]1([CH:33]([N:35]=[C:36]=[O:37])[CH3:34])[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:36]([NH:35][CH:33]([C:23]2[C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=[CH:25][CH:24]=2)[CH3:34])=[O:37])=[CH:20][CH:21]=1
Reactant: CC(N=C=O)c1cccc2ccccc12
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=O)NC(C)c4cccc5ccccc45)cc3)c2cc1OC
Yield: 72 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenoxy)quinoline (54 mg) was dissolved in toluene (5 ml) with heat, 1-(1-naphthyl)ethyl isocyanate (0.05 ml) was added, and the admixture was refluxed with heat for 100 minutes. The resulting residue was purified by column chromatography on silica gel eluting with chloroform/acetone (10/1) to obtain 65 mg of the title compound (yield: 72%).
Reaction SMILES: [OH:1][CH:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].Br[CH:10]([CH3:14])[C:11](Br)=[O:12].C(N(CC)CC)C>CC(C)=O>[CH3:14][CH:10]1[O:4][C:3](=[O:5])[CH:2]([CH:6]([CH3:8])[CH3:7])[O:1][C:11]1=[O:12]
Reactant: CC(C)C(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CC1OC(=O)C(C(C)C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 35 %

Procedure:
5.1 g α-hydroxyisovaleric acid (43 mmol) and 4.85 mL 2-bromopropionyl bromide (45 mmol) were stirred at 75° C. under nitrogen for 12 h. 300 mL acetone and 12 mL anhydrous triethylamine (86 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 500 mL ethyl acetate:hexane mixture (1:1). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.0 (q, 1H), 4.76 (d, 1H), 2.5 (m, 1H), 1.66 (d, 3H), 1.16 (d, 3H), 1.06 (d, 3H). 13C NMR (500 MHz, CDCl3): δ 167.59, 166.16, 79.83, 72.10, 29.24, 18.51, 15.86, 15.79. ELEM. ANAL. Calcd. for C8H12O4: C, 55.81; H, 6.98. Found: C, 55.55; H, 6.99. Yield: 35%.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]2)[S:5][CH:6]=1.[C:18]([C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1)(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:18]([C:21]1[CH:26]=[C:25]([C:2]2[N:3]=[C:4]([CH2:7][N:8]3[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:10]=[N:9]3)[S:5][CH:6]=2)[CH:24]=[CH:23][CH:22]=1)(=[O:20])[CH3:19]
Reactant: CC(=O)c1cccc(B(O)O)c1
Reactant: CCOC(=O)c1cnn(Cc2nc(Br)cs2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)c1cnn(Cc2nc(-c3cccc(C(C)=O)c3)cs2)c1
Temperature: 120 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
Under an argon atmosphere, to a solution (4 mL) of the compound (250 mg, 0.79 mmol) obtained in Example 30c in 1,2-dimethoxyethane were added (3-acetylphenyl)boronic acid (156 mg, 0.95 mmol), potassium carbonate (218 mg, 1.58 mmol) and tetrakistriphenylphosphinepalladium (91 mg, 0.079 mmol), and the mixture was stirred at 120° C. for 15 min under microwave conditions. The mixture was allowed to cool to room temperature, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The obtained crude product was purified by column chromatography (hexane-hexane/ethyl acetate=1/1) to give the title compound (188 mg, 67%) as a pale-brown oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[C:15](C)=[N:14][CH:13]=[N:12]1.[CH3:17]O>[Pd]>[F:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[N:11]1[CH:15]=[N:14][C:13]([CH3:17])=[N:12]1)[NH2:8]
Reactant: Cc1ncnn1-c1ccc([N+](=O)[O-])cc1F
Reactant: CO
Agent: [Pd]
Product: Cc1ncn(-c2ccc(N)cc2F)n1
Temperature: 25 °C
Reaction time: 72 h
Yield: 93 %

Procedure:
Step Q (1): 10% Palladium on carbon (2.50 g, 23.5 mmol) was added under an atmosphere of nitrogen to a chilled (ice-water bath) solution of 1-(2-fluoro-4-nitrophenyl)-5-methyl-1H-1,2,4-triazole (15.0 g, 67.5 mmol, from preparation C, step1) dissolved in methanol (400 mL). The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 72 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The reaction vessel and it contents were chilled (ice-water bath) and an additional portion of 10% Palladium on carbon (2.50 g, 23.5 mmol) was added. The flask was repeatedly evacuated and flushed with hydrogen gas (double balloon). The resulting mixture was allowed to warm to rt and left to stir for 6 h under the hydrogen atmosphere. The vessel was subsequently purged with nitrogen gas. The crude reaction mixture was filtered through a short plug of diatomaceous earth (Celite®). The reaction vessel and the Celite® were rinsed with fresh methanol. The combined filtrates were concentrated in vacuo. The residue was dried under high vacuum overnight to afford 3-fluoro-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (12.1 g, 63.0 mmol, 93% yield) as a blackish/grey solid. LC-MS (M+H)+ 193.2. 1H NMR (500 MHz, chloroform-d) δ ppm 8.31 (d, J=2.4 Hz, 1 H), 7.47 (t, J=8.7 Hz, 1 H), 6.47-6.58 (m, 2 H), 3.97 (br. s., 2 H), 2.48 (s, 3 H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH:10]([N:20]=[N+]=[N-])[CH2:11][O:12]CC1C=CC=CC=1)[C:2]1C=CC=CC=1.[ClH:24].[H][H]>C(O)C.[Pd]>[ClH:24].[CH2:1]([O:8][C:9](=[O:23])[CH:10]([CH2:11][OH:12])[NH2:20])[CH3:2]
Reactant: [H][H]
Reactant: [N-]=[N+]=NC(COCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C(N)CO
Reaction time: 40 h
Yield: 95.5 %

Procedure:
1.56 grams (0.005 mole) of 2-azido-3-benzyloxypropionic acid benzyl ester were dissolved in 10 ml of absolute ethanol, 1.10 grams (0.03 mole) of dry hydrogen chloride led in, and the mixture treated with 0.20 grams of palladium on activated carbon (10%). This reaction mixture was hydrogenated in an autoclave for 40 hours at 25° C., and a hydrogen pressure of 20 bar. After filtration, the filtrate was concentrated on the rotary evaporator, and the residue recrystallized from ethanol/diethyl ether (volume ratio about 1:1). There were obtained 0.81 grams (96% of theory) of D,L-serine ethyl ester hydrochloride having a melting point of 102°-103.5° C. (Literature: 100°-102° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)(=O)C.CCCCCC>[CH3:8][CH:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: Nc1ccccc1
Reactant: CC=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC(Cc1ccccc1)Nc1ccccc1
Yield: 50 %

Procedure:
According to GWM, 0.011 mol (=1.00 ml) of aniline and 0.011 mol (=1.43 ml) of β-methylstyrene are reacted with one another. The product is isolated by column chromatography using ethyl acetate/n-hexane (1:10) as eluent, the product (±)-N-(1-methyl-2-phenylethyl)aniline being obtained as a slightly pink liquid.
Reaction SMILES: [P:1](Cl)([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[CH:8]=1)([S:3][CH2:4][CH3:5])=[O:2].[Br:16][C:17]1[CH:18]=[CH:19][C:20]([OH:27])=[C:21]2[C:25]=1[C:24](=[O:26])[CH2:23][CH2:22]2.C(N(CC)CC)C>C1(C)C=CC=CC=1>[P:1]([O:27][C:20]1[CH:19]=[CH:18][C:17]([Br:16])=[C:25]2[C:21]=1[CH2:22][CH2:23][C:24]2=[O:26])([O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13][CH3:14])[CH:8]=1)([S:3][CH2:4][CH3:5])=[O:2]
Reactant: O=C1CCc2c(O)ccc(Br)c21
Reactant: CCSP(=O)(Cl)Oc1cccc(SC)c1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCSP(=O)(Oc1cccc(SC)c1)Oc1ccc(Br)c2c1CCC2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
S-Ethyl O-(3-methylthiophenyl) chlorothiophosphate (0.015 mole) dissolved in dry toluene (80) is charged into a glass reaction vessel equipped with a stirrer, thermometer and gas inlet tube. The solution is cooled to about 0° C. and a solution of 7-bromo-4-hydroxyindan-1-one (0.015 mole) and triethylamine (0.0175 mole) in toluene (20 ml) is slowly added with stirring. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 8 hours. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed solution is then dried and is stripped of solvent leaving a residue. This residue is chromatographed through a 200 ml clay column using ethyl acetate and hexane mixtures as the eluant. Ten separate fractions each containing increasing percentages of ethyl acetate are collected and analyzed by IR for the product. The appropriate fractions are then combined stripped of solvent and subjected to vacuum to yield the desired product S-ethyl O-(3-methylthiophenyl) O-(7-bromoindan-1-on-4-yl) thiophosphate.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:24])C=1>ClCCl.CCOCC>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[CH:10]=2)[CH:5]=[N+:4]([O-:24])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Brc1cncc2cc3ccccc3cc12
Solvent: ClCCl
Solvent: CCOCC
Product: [O-][n+]1cc(Br)c2cc3ccccc3cc2c1
Temperature: 25 °C

Procedure:
A solution of 4-bromobenzo[g]isoquinoline (7-3) (390 mg, 1.5 mmol, 1. eq) in dichloromethane (25 ml) was treated with mCPBA (˜70%, 559 mg, 2.27 mmol, 1.5 eq) and the reaction mixture was stirred at room temperature until LCMS showed complete conversion. The reaction mixture was diluted with ether, and the precipitate was collected by filtration, washed with ether, and dried to give the title N-oxide 7-4. LRMS m/z: found 274.0, 276.0, calcd. (M+H) 274.0, 276.0
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]([OH:13])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:14]1([C:20]2[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][CH:21]=2)[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1>>[O:6]([CH2:5][CH:4]([OH:13])[CH2:3][CH2:2][N:17]1[CH2:16][CH2:15][N:14]([C:20]2[CH:21]=[CH:22][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:24][CH:25]=2)[CH2:19][CH2:18]1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: OC(CCCl)COc1ccccc1
Reactant: CC(=O)Nc1ccc(N2CCNCC2)cc1
Product: CC(=O)Nc1ccc(N2CCN(CCC(O)COc3ccccc3)CC2)cc1

Procedure:
Following the procedure of Example 25, the title compound is prepared from 4-chloro-1-phenoxy-2-butanol and N-[4-(1-piperazinyl)phenyl]acetamide.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]([C:6]([OH:8])=O)[C:4]=1[NH2:12].C(O)(=O)C.[O-:17][C:18]#[N:19].[K+].[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:5]2[C:4]=1[NH:12][C:18](=[O:17])[NH:19][C:6]2=[O:8]
Reactant: N#C[O-]
Reactant: COc1cccc(C(=O)O)c1N
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: COc1cccc2c(=O)[nH]c(=O)[nH]c12
Reaction time: 2 h

Procedure:
3-Methoxyanthranilic acid (6 g, 0.036 mol) was suspended in water (200 ml, 35°) and glacial acetic acid (2.2 ml). A freshly prepared solution of potassium cyanate (3.7 g, 0.046 mol) in water (20 ml) was added dropwise to the stirred mixture. After 2 hours, sodium hydroxide (48.5 g 1.21 mol) was added in portions keeping the temperature below 40°. A clear solution was obtained momentarily before precipitating the hydrated sodium salt. After cooling, the precipitate was filtered off, dissolved in hot water which was acidified to pH 5, causing precipitation of 8-methoxy-2,4-quinazolinedione (4.6 g, 58%) m.p. 255°-257°.