Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[CH2:16][CH2:15][C:14]2[N:13]([CH2:17][C:18]([C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)([OH:20])[CH3:19])[C:12]3[N:11]=[CH:10][C:9]([Cl:27])=[CH:8][C:7]=3[C:6]=2[CH2:5]1)C=C.CN1C(=O)CC(=O)N(C)C1=O>C(Cl)Cl.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:27][C:9]1[CH:10]=[N:11][C:12]2[N:13]([CH2:17][C:18]([C:21]3[CH:22]=[CH:23][N:24]=[CH:25][CH:26]=3)([OH:20])[CH3:19])[C:14]3[CH2:15][CH2:16][NH:4][CH2:5][C:6]=3[C:7]=2[CH:8]=1
Reactant: C=CCN1CCc2c(c3cc(Cl)cnc3n2CC(C)(O)c2ccncc2)C1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CN1C(=O)CC(=O)N(C)C1=O
Solvent: ClCCl
Product: CC(O)(Cn1c2c(c3cc(Cl)cnc31)CNCC2)c1ccncc1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 42.9 %

Procedure:
1-(6-Allyl-3-chloro-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-2-pyridin-4-yl-propan-2-ol (260 mg, 0.680 mmol) was dissolved in DCM (7 mL) and N2 was purged into the reaction mixture. 1,3-Dimethyl barbituric acid (318 mg, 2.04 mmol) and Pd(PPh3)4 (15 mg, 0.013 mmol) was added and the mixture stirred for 45 min at RT. After consumption of starting material, the reaction mixture was diluted with saturated potassium carbonate and extracted with DCM (3×50 mL). The combined organic layer was dried over anhydrous sodium sulfate and concentrated, and the crude product was purified by reverse phase chromatography to obtain 100 mg of 1-(3-chloro-5,6,7,8-tetrahydro-1,6,9-triaza-fluoren-9-yl)-2-pyridin-4-yl-propan-2-ol. 1H NMR (CDCl3, freebase) δ (ppm): 8.51 (d, 2H), 8.14 (s, 1H), 7.67 (s, 1H), 7.33 (d, 2H), 4.39 (d, 1H), 4.36 (d, 1H), 3.93 q (d, 2H), 3.16 (m, 2H), 2.62 (m, 1H), 2.40 (m, 1H), 1.57 (s, 3H). Separation by chiral HPLC provided enantiomers 12a and 12b. Optical rotations: Compound 12a, (+)121.78 (c 0.53, Chloroform, 97.32% HPLC purity); Compound 12b, (−)118.34 (c 0.54, Chloroform, 99.01% HPLC purity).
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([OH:13])=O)=[O:8])(=[O:3])[CH3:2].C(N(CC)CC)C.ClC(OCC)=O.[CH3:31][N:32]([CH3:36])[CH2:33][CH2:34][NH2:35].N1C(=O)CC(=O)NC1=O>C(Cl)Cl.CO>[C:1]([S:4][CH2:5][CH:6]([CH2:14][CH:15]([CH3:17])[CH3:16])[C:7]([NH:9][CH2:10][C:11]([NH:35][CH2:34][CH2:33][N:32]([CH3:36])[CH3:31])=[O:13])=[O:8])(=[O:3])[CH3:2]
Reactant: CN(C)CCN
Reactant: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)O
Agent: CCOC(=O)Cl
Agent: O=C1CC(=O)NC(=O)N1
Solvent: CO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)SCC(CC(C)C)C(=O)NCC(=O)NCCN(C)C
Temperature: -10 °C
Reaction time: 0.5 h

Procedure:
A 2.61 g (0.01 mole) sample of (±)-N-[2-(acetylmercaptomethyl)-4-methyl-1-oxopentyl]glycine is slurried in 50 ml of CH2Cl2. Triethylamine (1.08 g, 0.01 mole) is added to give a solution which is cooled to -10° C. and treated with 1.08 g (0.01 mole) of ethyl chloroformate. After 1/2 hour, a solution of N,N-dimethylethylenediamine (0.88 g, 0.01 mole) in 10 ml of CH2Cl2 is added, and stirring from -5° C. to +25° C. continued for 2 hours. The mixture is evaporated and triturated with ethyl acetate. The triethylamine hydrochloride is filtered and the filtrates evaporated to an oil, 3.6 g. A 2.95 g sample of oil is dissolved with 1 equivalent of barbituric acid in methanol, filtered and evaporated to a foam. Addition of acetonitrile gives a white solid which is washed (briefly) with absolute ethanol and then acetonitrile. Recrystallization from 100 ml of acetonitrile gives a white powder, 1.3 g of (±)-N2 -[2-[(acetylthio)methyl]-4-methyl-1-oxopentyl]-N-[2-(dimethylamino)ethyl]glycinamide, barbituric acid (1:1) salt (34%), m.p. 151°-154°, which analyzes correctly for a salt with 1.0 mole of barbituric acid and 0.5 mole of water.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=1)=[O:3].[CH2:13]([CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.Cl.[CH2:27]=O>C(O)C.CCOC(C)=O>[CH2:13]([CH:20]1[CH2:25][CH2:24][N:23]([CH2:27][CH2:1][C:2]([C:4]2[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=2)=[O:3])[CH2:22][CH2:21]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: C=O
Reactant: CC(=O)c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(CCN1CCC(Cc2ccccc2)CC1)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Yield: 20.3 %

Procedure:
To a solution of 3-nitroacetophenone (109) (0.60 g, 3.63 mmol) and 4-benzylpiperidine (103) (0.64 g, 3.63 mmol) in absolute ethanol (5 mL) was added concentrated hydrochloric acid (0.30 mL, 3.60 mmol). The mixture was heated under reflux and paraformaldehyde (0.32 g, 10.96 mmol) was added in four portions over a period of 40 minutes. The resulting mixture was heated under reflux overnight before it was allowed to cool to room temperature and diluted with EtOAc (100 mL). Following sequential washings with 1 N NaOH (2×100 mL), water (100 mL), and brine (100 mL), the organic solution was dried (Na2SO4) and concentrated. The residue was purified via flash silica gel chromatography to provide 110 (0.26 g, 20%) as a dark syrup.
Reaction SMILES: [CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12](N)=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[N+]([O-])([O-])=[O:23].[Na+].O>C(O)(=O)C>[CH:1]([C:4]1[CH:17]=[C:16]2[C:7]([O:8][C:9]3[CH:10]=[C:11]([C:20]#[N:21])[C:12]([OH:23])=[N:13][C:14]=3[C:15]2=[O:18])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])[O-]
Reactant: CC(C)c1ccc2oc3cc(C#N)c(N)nc3c(=O)c2c1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)c1ccc2oc3cc(C#N)c(O)nc3c(=O)c2c1
Temperature: 70 °C

Procedure:
To a solution of 0.5 g of 7-isopropyl-2-amino-3-cyano-1-azaxanthone in 80 ml of acetic acid was added gradually 1.0 g of sodium nitrate at 70° C. After one hour period, 3 ml of water was added to the mixture which was heated at 70° C. for a further one hour. The solvent was distilled off under reduced pressure and then, to the residue, water was added. The yellow precipitate was collected by filtration, rinsed with water and recrystallized from ethanol to give 7-isopropyl-2-hydroxy-3-cyano-1-azaxanthone as yellow crystals, m.p. > 300° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12](OS(C(F)(F)F)(=O)=O)=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:51][CH2:50][N:49]([C:52](=[O:54])[CH3:53])[CH2:48][CH2:47]3)=[CH:42][N:41]=2)[C:26]2[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:27]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2].O.C(OCC)(=O)C.[CH3:64][N:65](C)C=O>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[C-]#N.[Zn+2].[C-]#N>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([C:64]#[N:65])=[CH:13][CH:14]=2)[C@@H:9]([NH:24][CH:25]([C:40]2[N:45]=[CH:44][C:43]([N:46]3[CH2:47][CH2:48][N:49]([C:52](=[O:54])[CH3:53])[CH2:50][CH2:51]3)=[CH:42][N:41]=2)[C:26]2[CH:27]=[C:28]([C:36]([F:39])([F:38])[F:37])[CH:29]=[C:30]([C:32]([F:33])([F:34])[F:35])[CH:31]=2)[CH2:8][C@H:7]1[CH2:55][CH3:56])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OS(=O)(=O)C(F)(F)F)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1c2ccc(C#N)nc2[C@@H](NC(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2ncc(N3CCN(C(C)=O)CC3)cn2)C[C@H]1CC
Temperature: 100 °C
Reaction time: 6 h

Procedure:
(2R,4S)-4-{[5-(4-Acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis-(trifluoromethyl)benzyl]}amino-2-ethyl-6-trifluoromethanesulfonyloxy-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (200 mg), a catalytic amount of tetrakis(triphenylphosphine)palladium, zinc cyanide (37 mg) are dissolved in N,N-dimethylformamide (2 ml), and the mixture is stirred at 100° C. for 6 hours under nitrogen flow. The reaction solution is cooled to room temperature, and thereto are added water and ethyl acetate. The mixture is washed with saturated brine and dried over magnesium sulfate, then concentrated under reduced pressure. The resulting residue is purified by column chromatography (silica gel; hexane:ethyl acetate=3:7→0:1) to give (2R,4S)-4-{[5-(4-acetylpiperazin-1-yl)pyrimidin-2-yl]-[3,5-bis(trifluoromethyl)benzyl]}amino-6-cyano-2-ethyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (149 mg). MS (m/z): 705 [M+H]+.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[Pt]>[I:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([NH2:9])[CH:3]=1
Reactant: Cc1ccc(I)cc1[N+](=O)[O-]
Agent: [Pt]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1ccc(I)cc1N
Temperature: 22 °C

Procedure:
To a solution of 4-iodo-1-methyl-2-nitro-benzene (25.0 g, 107 mmol) in 300 mL of ethanol was added sulfided platinum (3.00 g) and ammonium formate (20.3 g, 321 mmol). The mixture was heated to reflux for 12 h and then cooled to 22° C., filtered through Celite® and concentrated in vacuo. The resulting residue was diluted with H2O (300 mL) and extracted with 3×200 mL CH2Cl2. The organic fractions were combined, washed with brine, dried over Na2SO4 and concentrated in vacuo to give b (21.1 g, 95%): MS m/z=234 (M+H).
Reaction SMILES: [CH3:1][C@@H:2]([CH2:7][OH:8])[C:3]([O:5][CH3:6])=[O:4].[C:9](Cl)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CO.O>CN(C)C=O>[C:9]([O:8][CH2:7][C@H:2]([CH3:1])[C:3]([O:5][CH3:6])=[O:4])([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)([C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: COC(=O)[C@@H](C)CO
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CO
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)[C@@H](C)COC(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
Methyl (S)-(+)-2-methyl-3-hydroxypropionate (1.18 g; 10 mmole), trityl chloride (3.1 g; 11.13 mmole) and N,N-dimethylaminopyridine (1.34 g; 11 mmole) were dissolved in dry dimethylformamide (10 ml), and the resultant mixture was stirred at room temperature overnight. Methanol (5 ml) was added thereto to decompose the unreacted trityl chloride, and the resultant mixture was stirred for 3 hours. Water (20 ml) was added to the reaction mixture, which was extracted with toluene (20 ml) three times. The extracts were combined together, washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give methyl (S)-3-trityloxy-2-methylpropionate.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[C:29](Cl)(=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31]>C(Cl)Cl>[C:16]1([CH:4]([NH:3][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: CC(C)(C)C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.7 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (140 mg, 0.42 mmol) in DCM (5 ml), were sequentially added triethylamine (175 μl, 1.26 mmol) and pivaloyl chloride (62.1 μl, 0.50 mmol). The reaction was stirred at RT for 2 hours, and then the solvent was evaporated. The residue was taken up with EtOAc and washed with Na2CO3, water and brine, dried over Na2SO4, filtered and evaporated to obtain (R)-quinuclidin-3-yl 2-phenyl-2-pivalamidoacetate (95 mg; 66% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]1[CH3:15].[CH3:17][N:18]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[S:19]([C:22]1[C:27]([CH:28]=O)=[CH:26][CH:25]=[CH:24][N:23]=1)(=[O:21])=[O:20]>>[CH3:1][O:2][C:3](=[O:16])[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][C:10]([F:14])=[CH:11][CH:12]=2)[C:7]([CH2:28][C:27]2[C:22]([S:19](=[O:21])(=[O:20])[N:18]([CH3:17])[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[N:23][CH:24]=[CH:25][CH:26]=2)=[C:6]1[CH3:15]
Reactant: CN(c1ccccc1)S(=O)(=O)c1ncccc1C=O
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2cccnc2S(=O)(=O)N(C)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 29a using (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester and 3-formylpyridine-2-sulfonic acid methylphenylamide.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13].CNCC1C=CC2C(=CC=CC=2)C=1CCC.[ClH:30].[N:31]1([CH2:37][CH2:38][N:39]2[CH2:45][C:44]3[CH:46]=[C:47](/[CH:50]=[CH:51]/[C:52](O)=[O:53])[CH:48]=[N:49][C:43]=3[NH:42][C:41](=[O:55])[CH2:40]2)[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[ClH:30].[CH3:1][N:2]([CH2:3][C:4]1[S:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[C:5]=1[CH3:13])[C:52](=[O:53])/[CH:51]=[CH:50]/[C:47]1[CH:48]=[N:49][C:43]2[NH:42][C:41](=[O:55])[CH2:40][N:39]([CH2:38][CH2:37][N:31]3[CH2:32][CH2:33][O:34][CH2:35][CH2:36]3)[CH2:45][C:44]=2[CH:46]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(CCN1CCOCC1)CC(=O)N2
Reactant: CNCc1sc2ccccc2c1C
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: Cc1c(CN(C)C(=O)/C=C/c2cnc3c(c2)CN(CCN2CCOCC2)CC(=O)N3)sc2ccccc12
Yield: 74 %

Procedure:
According to the procedure of Example 1, except substituting methyl-(3-methyl-benzo[b]thiophen-2-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-3-[4-(2-morpholin-4-yl-ethyl)-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl]acrylic acid hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (90 mg, 74%) was prepared as a tan solid: 1H NMR (300 MHz, DMSO-d6) δ 10.58 (br s, 2H), 8.62 (s, 1H), 8.27-8.25 (m, 1H), 7.88-7.86 (m, 1H), 7.75-7.72 (m, 1H), 7.61-7.53 (m, 1H), 7.42-7.29 (m, 3H), 5.15-4.89 (m, 2H), 4.03-3.65 (m, 12H), 3.28-3.17 (m, 4H), 3.01-2.64 (m, 3H), 2.42 (s, 3H); MS (ESI) m/e 520 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([Li])CCC.[CH3:22][S:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1.O>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[C:5]2[S:10][C:9]([CH:28]([C:27]3[CH:30]=[CH:31][C:24]([S:23][CH3:22])=[CH:25][CH:26]=3)[OH:29])=[CH:8][C:6]=2[N:7]=1
Reactant: Clc1nc(N2CCOCC2)c2sccc2n1
Reactant: CSc1ccc(C=O)cc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: CSc1ccc(C(O)c2cc3nc(Cl)nc(N4CCOCC4)c3s2)cc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (2.74 g) in THF (40 mL) at −78° C. was added n-butyllithium (5.15 mL of a 2.5 M solution in hexanes) and the reaction stirred at −78° C. for 1 h. 4-Methylmercaptobenzaldehyde (1.43 mL) was then added and the reaction mixture was lowly warmed to room temperature. Water was added and the resulting precipitate was collected by filtration. Recyrstallisation from EtOAc/hexane yielded (2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-yl)-(4-methylsulfanyl-phenyl)-methanol (2.53 g).
Reaction SMILES: [CH:1]([NH:4][C:5]1[C:6]2[CH:13]=[CH:12][S:11][C:7]=2[N:8]=[CH:9][N:10]=1)([CH3:3])[CH3:2].[N+:14]([O-])([OH:16])=[O:15].C(=O)([O-])[O-].[Na+].[Na+]>S(=O)(=O)(O)O>[CH:1]([NH:4][C:5]1[C:6]2[CH:13]=[C:12]([N+:14]([O-:16])=[O:15])[S:11][C:7]=2[N:8]=[CH:9][N:10]=1)([CH3:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CC(C)Nc1ncnc2sccc12
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: CC(C)Nc1ncnc2sc([N+](=O)[O-])cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-isopropylaminothieno[2,3-d]pyrimidine (4.0 g, prepared as described in Example 5) and concentrated sulphuric acid (20 ml) was cooled to 0° and treated dropwise with a mixture of concentrated nitric acid (2.2 ml) and concentrated sulphuric acid (2.0 ml) whilst maintaining the temperature below 12° C. The mixture was allowed to stir at room temperature for a further one hour, poured into ice-water and neutralised with sodium carbonate. The precipitate was filtered off, washed with water and dried to give 4-isopropylamino-6-nitrothieno[2,3-d]pyrimidine (4.58 g, m.p. 200°) (Compound No. 134).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:11]([CH3:22])([CH3:21])[CH2:12][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH:14]=O)[C:5]2[O:9][CH2:8][CH2:7][C:6]=2[CH:10]=1.[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[NH2:37])[N:28]=1)=[O:26]>C(O)(=O)C.C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([C:27]1[CH:36]=[CH:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][C:33]=2[N:37]=[CH:14][C:13]([OH:20])([C:16]([F:19])([F:18])[F:17])[CH2:12][C:11]([C:4]2[C:5]3[O:9][CH2:8][CH2:7][C:6]=3[CH:10]=[C:2]([Cl:1])[CH:3]=2)([CH3:21])[CH3:22])[N:28]=1)=[O:26]
Reactant: COC(=O)c1ccc2c(N)cccc2n1
Reactant: CC(C)(CC(O)(C=O)C(F)(F)F)c1cc(Cl)cc2c1OCC2
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1ccc2c(N=CC(O)(CC(C)(C)c3cc(Cl)cc4c3OCC4)C(F)(F)F)cccc2n1

Procedure:
Analogously to Example 37, 160 mg (0.47 mmol) of 4-(5-chloro-2,3-dihydrobenzofuran-7-yl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal is reacted with 116 mg (0.57 mmol) of 5-aminoquinoline-2-carboxylic acid methyl ester in 1.0 ml of concentrated acetic acid and 20 ml of toluene. After working-up and purification on silica gel with hexane-ethyl acetate (0-100%), 110 mg (45% of theory) of the product is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1[C:15](=[O:16])[CH2:14][CH:13]2[C:17](=[O:18])[CH:10]1[CH:11]=[CH:12]2.[N-:19]=[N+:20]=[N-:21].[Na+]>CN(C=O)C.O>[N:19]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][N:9]1[C:15](=[O:16])[CH2:14][CH:13]2[C:17](=[O:18])[CH:10]1[CH:11]=[CH:12]2)=[N+:20]=[N-:21]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1C2C=CC1N(OCCCCCCBr)C(=O)C2
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCCCCCCON1C(=O)CC2C=CC1C2=O
Temperature: 65 °C
Reaction time: 8 h
Yield: 86.9 %

Procedure:
To a stirring solution of 3b (100 mg, 0.302 mmol) in DMF (10 mL) was added sodium azide (98 mg, 1.51 mmol). The solution was allowed to stir at 65° C. overnight. After cooling to room temperature, the solution was diluted with water (10 mL) and extracted with EtOAc (3×15 mL). The combined organic phase was dried over Na2SO4. The drying agent was removed by filtration and the solvent was removed under reduced pressure to afford 3c as a clear oil (73 mg, 83%). The oil was taken on without further purification immediately, as 3c was found to be unstable. 1H-NMR (CDCl3, 300 MHz): δ 6.70 (dd, J=5.8, 1.0 Hz, 1H), 6.49 (dd, J=6.0, 1.7 Hz, 1H), 5.47 (d, J=1.1 Hz, 1H), 4.50 (d, J=1.6 Hz, 1H), 3.92 (ABX2, JAX=JBX=6.7 Hz, JAB=9.2 Hz, 2H), 3.27 (t, J=7.0 Hz, 2H), 1.71-1.56 (m, 4H), 1.48 (s, 3H), 1.48-1.39 (m, 4H), 1.04 (s, 3H). 13C-NMR (CDCl3, 75 MHz): δ 175.4, 135.3, 134.6, 90.6, 87.1, 75.3, 51.2, 48.8, 28.5, 27.9, 26.7, 26.3, 25.3, 19.6. HRESI-MS calcd for C14H22N4O3 [M+H]+ 295.1765. found 295.1758.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:32])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]([O:20]C2C(F)=C(F)C(F)=C(F)C=2F)=O)=[CH:13][CH:12]=1.[NH2:33][C@@H:34]([CH3:47])[CH2:35][O:36][C:37]1[CH:46]=[CH:45][C:40]([C:41]([O:43]C)=[O:42])=[CH:39][CH:38]=1.CCN(CC)CC.CN([CH:58]=[O:59])C>CCOC(C)=O>[CH3:58][O:59][C:16]1[CH:15]=[C:14]([CH2:17][C:18]([NH:33][C@@H:34]([CH3:47])[CH2:35][O:36][C:37]2[CH:46]=[CH:45][C:40]([C:41]([OH:43])=[O:42])=[CH:39][CH:38]=2)=[O:20])[CH:13]=[CH:12][C:11]=1[NH:10][C:9]([NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])=[O:32]
Reactant: CN(C)C=O
Reactant: Cc1ccccc1NC(=O)Nc1ccc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)cc1
Reactant: COC(=O)c1ccc(OC[C@H](C)N)cc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1cc(CC(=O)N[C@@H](C)COc2ccc(C(=O)O)cc2)ccc1NC(=O)Nc1ccccc1C
Temperature: 25 °C
Reaction time: 3 h
Yield: 36 %

Procedure:
A mixture of pentafluorophenyl 4-[N′-(2-methylphenyl)ureido]phenylacetate (560 mg, 1.24 mmol), methyl (S)-4-(2-amino-1-propoxy)benzoate (260 mg, 1.24 mmol), Et3N (0.260 mL, 1.87 mmol) in DMF (8 mL) was stirred at room temp for 3 hr. The mixture was diluted with EtOAc and the solution was washed with 0.5 N HCl, brine, and dried over Na2SO4. After removal of the solvent, the residue was purified by recrystallization from MeOH—CHCl3-n-hexane to give 210 mg (36%) (S)-4-[2-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetylamino]-1-propoxy]benzoic acid as a white crystalline powder. 1H-NMR (DMSO-d6) δ1.17 (d, 3 H, J=6.8 Hz), 2.24 (s, 3 H), 3.32 (s, 2 H), 3.81 (s, 3 H), 3.92-4.03 (m, 2 H), 4.08-4.15 (m, 1 H), 6.92-6.95 (m, 1 H), 7.04-7.06 (m, 2 H), 7.12-7.18 (m, 4 H), 7.35-7.39 (m, 2 H), 7.83-7.85 (m, 1 H), 7.89-7.92 (m, 3 H), 8.12-8.14 (m, 1 H), 8.97 (s, 1 H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH:9]1[CH2:11][O:10]1.[OH:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1.[OH-].[Na+]>C1(C)C=CC=CC=1>[OH:10][CH:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH2:11][O:12][C:13]1[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][CH:14]=1
Reactant: COc1ccccc1C1CO1
Reactant: O=Cc1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1ccccc1C(O)COc1ccc(C=O)cc1
Temperature: 78 °C
Yield: 20.2 %

Procedure:
To a stirring solution of 2-(2-methoxyphenyl)oxirane (5.60 g, 37.3 mmol) in toluene (65 mL) was added 4-hydroxybenzaldehyde (6.80 g, 56.0 mmol), 1M NaOH (65 mL) and PEG4000 (polyethylene glycol, 0.85 g) and the stirring mixture was heated at 78° C. overnight. The reaction was allowed to cool to RT and it was then extracted with EtOAc (2×150 mL). The combined extracts were washed with brine, dried (Na2SO4), filtered and evaporated in vacuo. The resulting light oil was adsorbed onto silica gel and chromatographed eluting with 30-40% EtOAc/hexanes to give 2 major spots. Fractions containing the higher Rf spot were combined and evaporated in vacuo to give 1.71 g (17%) the regioisomer as a brown oil. Fractions containing the lower Rf spot were combined and evaporated in vacuo to give 2.05 g (20%) of the title compound as a yellow solid.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.Cl[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].BrCC(OC(C)(C)C)=O>>[CH2:15]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCCCCCl
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: CC(C)(C)OC(=O)CBr
Product: CCCCCCCCCCOc1ccc(C=O)c2ccccc12

Procedure:
The desired product was prepared by substituting 4-hydroxy-1-naphthaldehyde and 1-chlorodecane for Example 20C and tert-butyl bromoacetate, respectively, in Example 20D.