Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:20]([CH2:22][CH3:23])[CH3:21])=[N:4][C:5]([O:8][C:9]2[CH:14]=[C:13]([CH3:15])[C:12]([N+:16]([O-])=O)=[CH:11][C:10]=2[CH3:19])=[N:6][CH:7]=1.CO>Cl>[NH2:16][C:12]1[C:13]([CH3:15])=[CH:14][C:9]([O:8][C:5]2[N:4]=[C:3]([N:20]([CH2:22][CH3:23])[CH3:21])[C:2]([Cl:1])=[CH:7][N:6]=2)=[C:10]([CH3:19])[CH:11]=1
Reactant: CCN(C)c1nc(Oc2cc(C)c([N+](=O)[O-])cc2C)ncc1Cl
Agent: Cl
Solvent: CO
Product: CCN(C)c1nc(Oc2cc(C)c(N)cc2C)ncc1Cl
Temperature: 25 °C

Procedure:
To a solution of 8.86 g (20 mmol) 5-chloro-2-(2,5-dimethyl-4-nitrophenoxy)-N-ethyl-N-methylpyrimidin-4-amine in 50 ml hydrochloric acid and 50 ml methanol 13.5 g (60 mmol) tin-(II)-dichloro dihydrate was added and the mixture was refluxed for 4 h. After cooling down to ambient temperature the formed precipitate was filtered by suction, solved in water and brought to pH 8 with aqueous solution of sodium hydroxide. Ethyl acetate was added and the organic layer was separated, dried over magnesium sulfate, concentrated in vacuo and column chromatography (cyclohexane/ethyl acetate, 1:1) yielded 4.6 g (72%) with a purity of 96% log P (pH=2.3)=1.88.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][NH2:10].C(O[CH:14]=[C:15]([C:18]#[N:19])[C:16]#[N:17])C.C(N(CC)CC)C>CO>[NH2:19][C:18]1[N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH3:2])[N:10]=[CH:14][C:15]=1[C:16]#[N:17]
Reactant: Cc1ccccc1NN
Reactant: CCOC=C(C#N)C#N
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1ccccc1-n1ncc(C#N)c1N

Procedure:
10.2 g (64.4 mmol) of 2-methylphenylhydrazine hydrochloride are suspended with 7.8 g (64.4 mmol) of ethoxymethylenemalononitrile in 100 ml of methanol, and 26.9 ml (193.3 mmol) of triethylamine are added. The reaction mixture is heated to reflux overnight, during which a clear solution forms. The solution is subsequently distilled off under reduced pressure, and the crude product is purified by column chromatography (silica gel, mobile phase dichloromethane). 10.8 g (85% of theory) of the desired product are obtained.
Reaction SMILES: [F:1][CH:2]([F:44])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36]O)[CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=2[N:4]=1.C[CH2:46][N:47](CC)[CH2:48]C.CS(Cl)(=O)=O.CNC>C(Cl)Cl>[F:44][CH:2]([F:1])[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([N:20]([CH2:34][CH2:35][CH2:36][N:47]([CH3:48])[CH3:46])[CH:21]3[CH2:26][CH2:25][CH2:24][N:23]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22]3)[N:9]=2)[C:6]2[CH:38]=[CH:39][CH:40]=[C:41]([O:42][CH3:43])[C:5]=2[N:4]=1
Reactant: CCN(CC)CC
Reactant: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCO)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Agent: CNC
Agent: CS(=O)(=O)Cl
Solvent: ClCCl
Product: COc1cccc2c1nc(C(F)F)n2-c1nc(N2CCOCC2)nc(N(CCCN(C)C)C2CCCN(C(=O)OC(C)(C)C)C2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
To a solution of tert-butyl 3-[[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl](3-hydroxypropyl)-amino]-1-piperidinecarboxylate (420 mg, 0.72 mmol) in CH2Cl2 (12 mL) at 0° C. was added Et3N (0.2 mL, 1.4 mmol) and methanesulfonyl chloride (0.1 mL, 1.08 mmol). The reaction mixture was stirred at 0° C. for 30 min, and a solution of 40% aqueous dimethylamine (5 mL) was then added. The reaction mixture was stirred at room temperature for 2 days and the solvent was removed under vacuum. The residue was diluted with water and stirred for 30 min to give a precipitate, which was collected by filtration, washed with water, and dried. Chromatography on SiO2 eluting first with CH2Cl2/EtOAc (4:1), and then with CH2Cl2/MeOH (95:5) containing 1% aqueous NH3, gave tert-butyl 3-{[4-[2-(difluoromethyl)-4-methoxy-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-1,3,5-triazin-2-yl][3-(dimethylamino)propyl]amino}-1-piperidinecarboxylate (465 mg; 100%) as a white solid: mp (CH2Cl2/MeOH) 133-136° C.; 1H NMR (DMSO-d6) (rotamers) δ 7.96 and 7.88 (2d, J=8.3 Hz, 1H), 7.77 and 7.68 (2t, JHF=53.0, 52.9 Hz, 1H), 7.40-7.34 (m, 1H), 6.96-6.93 (m, 1H), 4.56-4.88 and 4.30-4.27 (2 m, 1H), 3.98 and 3.97 (2s, 3H), 3.97-3.49 (m, 13H), 2.93-2.88 and 2.77-2.63 (2m, 2H), 2.35-2.27 (m, 2H), 2.15 and 2.13 (2s, 6H), 1.93-1.71 (m, 4H), 1.48-1.16 (m, 1H), 1.40 (s, 9H); Anal. Calcd. for C31H45F2N9O4C, 57.7; H, 7.0; N, 19.5. Found: C, 57.7; H, 7.1; N, 19.7%.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10](OCC)(OCC)[CH2:11][NH2:12])[CH:7]=[CH:6][N:5]=1)[CH3:2].Cl.[C:20](=[NH:25])(OCC)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([C:10]2[N:25]=[C:20]([CH3:21])[NH:12][CH:11]=2)[CH:7]=[CH:6][N:5]=1)[CH3:2]
Reactant: CCNc1cc(C(CN)(OCC)OCC)ccn1
Reactant: CCOC(C)=N
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCNc1cc(-c2c[nH]c(C)n2)ccn1

Procedure:
A mixture of 2.0 g. (8 mmoles) of 2-(2-ethylamino-4-pyridyl)-2,2-diethoxyethylamine, 1.0 g. (8.3 mmoles) of ethyl acetimidate hydrochloride and 30 ml. of absolute ethanol was heated at reflux for 1.3 hours. The mixture was concentrated, and the residue taken up in 10 ml. of concentrated hydrochloric acid. The acid solution was heated on a steam bath for one hour and the cooled reaction made basic by the addition of solid potassium carbonate. The product was extracted with chloroform (4×15 ml.) and the combined extracts dried and concentrated to give 1.1 g. of crude product. The product was chromatographed over 35 g. of silica gel using chloroform-methanol (19:1, v:v) as the eluent to give 510 mg. (30%), m.p. 214°-216° C.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[CH:24][C:10]([O:11][CH:12]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:13]([OH:18])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:26]([Si:28]([CH2:32][CH3:33])([CH2:30][CH3:31])Cl)[CH3:27].C(N(CC)CC)C>C1COCC1.CN(C)C1C=CN=CC=1>[C:1]1([C:7]2[CH:8]=[CH:9][C:10]([O:11][CH:12]([N:19]3[CH:23]=[N:22][CH:21]=[N:20]3)[CH:13]([O:18][Si:28]([CH2:32][CH3:33])([CH2:30][CH3:31])[CH2:26][CH3:27])[C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)C(O)C(Oc1ccc(-c2ccccc2)cc1)n1cncn1
Reactant: CC[Si](Cl)(CC)CC
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)OC(C(Oc1ccc(-c2ccccc2)cc1)n1cncn1)C(C)(C)C
Temperature: 45 °C
Reaction time: 14 h
Yield: 40.7 %

Procedure:
5.5 g of 1-p-phenylphenoxy-3,3-dimethyl-1-(1,2,4-triazol-1-yl)-butan-2-ol is dissolved in 25 ml of THF. 2.9 g of triethylchlorosilane and 0.2 g of 4-dimethylaminopyridine are added under a nitrogen blanket. The mixture is heated to 45° C., and 3.3 g of triethylamine is added in portions. After the mixture has been stirred for 14 hours at from 40° to 50° C. it is cooled to room temperature, undissolved matter is filtered off, and the filtrate is concentrated. The product is further purified either by adding petroleum ether, followed by filtration and concentration, or by gel filtration (SiO2, CHCl3). There is obtained 3 g of 1-p-phenylphenoxy-3,3-dimethyl-2-triethylsiloxy-1-(1,2,4-triazol-1-yl)-butane.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([O:29][CH3:30])[CH2:28][CH2:27][NH:26][CH2:25]4)=[O:23])[CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1.Cl[CH2:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([C:41]2[CH:46]=[CH:45][C:44]([C:47]3[N:52]=[CH:51][CH:50]=[CH:49][N:48]=3)=[C:43]([F:53])[CH:42]=2)[CH2:37][CH2:36]1)=[O:34].C(N(C(C)C)CC)(C)C>CN(C)C=O>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:20]3[C:15](=[CH:16][CH:17]=[C:18]([NH:21][C:22]([C:24]4([O:29][CH3:30])[CH2:28][CH2:27][N:26]([CH2:32][C:33]([N:35]5[CH2:40][CH2:39][N:38]([C:41]6[CH:46]=[CH:45][C:44]([C:47]7[N:48]=[CH:49][CH:50]=[CH:51][N:52]=7)=[C:43]([F:53])[CH:42]=6)[CH2:37][CH2:36]5)=[O:34])[CH2:25]4)=[O:23])[CH:19]=3)[NH:14][N:13]=2)=[CH:8][CH:7]=1
Reactant: COCCOc1ccc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCNC4)cc23)cc1
Reactant: O=C(CCl)N1CCN(c2ccc(-c3ncccn3)c(F)c2)CC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1ccc(-c2n[nH]c3ccc(NC(=O)C4(OC)CCN(CC(=O)N5CCN(c6ccc(-c7ncccn7)c(F)c6)CC5)C4)cc23)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-pyrrolidine-3-carboxylic acid {3-[4-(2-methoxy-ethoxy)-phenyl]-1H-indazol-5-yl}-amide (10AB) (50 mg, 0.103 mmol, 1 equiv) and 2-Chloro-1-[4-(3-fluoro-4-pyrimidin-2-yl-phenyl)-piperazin-1-yl]-ethanone (7AB) (42 mg, 0.124 mmol, 1.2 equiv) were weighed out in a flask and to it was added N,N-dimethylformamide (3 mL) and diisopropylethylamine (26.6 mg, 36 uL, 0.206 mmol, 2 equiv). The reaction content was stirred at room temperature, overnight.
Reaction SMILES: C([O:3][C:4](=[O:39])[C@@H:5]([NH:15][C@H:16]([C:31](=[O:38])[NH:32][C:33]1[NH:37][N:36]=[N:35][N:34]=1)[CH2:17][C:18]1[CH:23]=[CH:22][C:21]([C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=2)=[CH:20][CH:19]=1)[CH2:6][O:7]CC1C=CC=CC=1)C>CCOC(C)=O.CCO.[Pd]>[Cl:30][C:26]1[CH:25]=[C:24]([C:21]2[CH:20]=[CH:19][C:18]([CH2:17][C@H:16]([NH:15][C@@H:5]([CH2:6][OH:7])[C:4]([OH:39])=[O:3])[C:31](=[O:38])[NH:32][C:33]3[NH:37][N:36]=[N:35][N:34]=3)=[CH:23][CH:22]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)[C@H](COCc1ccccc1)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)[C@H](CO)N[C@@H](Cc1ccc(-c2cccc(Cl)c2)cc1)C(=O)Nc1nnn[nH]1
Temperature: 50 °C
Reaction time: 6 h

Procedure:
To a solution of (S)-3-benzyloxy-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-propionic acid ethyl ester (Example 32-8: 47 mg, 0.090 mmol) in EtOAc (1 mL) and EtOH (1 mL) was added 5% Pd—C (9.6 mg, 0.0045 mmol). H2 gas was loaded with a balloon and the reaction mixture was stirred at 50° C. for 6 hours. The reaction mixture was filtered through celite pad and the filtrate was concentrated. The residue was purified by reverse phase HPLC (Sunfire C-18 column, eluent: 0.1% TFA in H2O/CH3CN) to give (S)-2-[(S)-2-(3′-chloro-biphenyl-4-yl)-1-(1H-tetrazol-5-ylcarbamoyl)-ethylamino]-3-hydroxy-propionic acid and (S)-2-[(S)-2-biphenyl-4-yl-1-(1H-tetrazol-5-ylcarbamoyl): ethylamino]-3-hydroxy-propionic acid.
Reaction SMILES: [CH3:1][S:2][CH:3]1[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:4]1=2.[CH3:22]C(C)([O-])C.[K+].CI>CS(C)=O.C(OCC)(=O)C>[CH3:22][C:3]1([S:2][CH3:1])[C:9]2[N:10]=[CH:11][CH:12]=[CH:13][C:8]=2[C:7](=[O:14])[N:6]([CH3:15])[C:5]2[CH:16]=[CH:17][C:18]([O:20][CH3:21])=[N:19][C:4]1=2
Reactant: CC(C)(C)[O-]
Reactant: COc1ccc2c(n1)C(SC)c1ncccc1C(=O)N2C
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc2c(n1)C(C)(SC)c1ncccc1C(=O)N2C
Reaction time: 0.02 h

Procedure:
To a solution of 5,11-dihydro-11-methylthio-2-methoxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.031 g) in DMSO (0.5 mL) stirred under argon was added potassium tert-butoxide (1M in tetrahydrofuran, 0.012 mL). After 1 minute, methyl iodide (0.05 mL) was added. After 5 minutes the mixture was diluted with ethyl acetate, washed with water, dried, filtered and evaporated. Fractionation of the residue by preparative layer chromatography (developer, ethyl acetate/hexane) gave 5,11-dihydro-11-methyl-11-methylthio-2-methoxy-5-methyl-dipyrido[3,2-b:2',3'-e]azepine-6-one (0.029).
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24]C)=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:8]=1)(=[O:5])=[O:4].B(Br)(Br)Br>C(Cl)Cl>[F:33][C:2]([F:1])([F:34])[S:3]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([OH:24])=[CH:21][CH:22]=3)[CH:17]=[C:16]([CH3:26])[C:15]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:9][CH:8]=1)(=[O:4])=[O:5]
Reactant: COc1ccc2c(Oc3ccc(NS(=O)(=O)C(F)(F)F)cc3)c(-c3ccccc3)c(C)cc2c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cc2cc(O)ccc2c(Oc2ccc(NS(=O)(=O)C(F)(F)F)cc2)c1-c1ccccc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 63.4 %

Procedure:
Compound 31 (47 mg, 0.10 mmol, 1 equiv) was dissolved in CH2Cl2 (5 mL) and cooled to 0° C. under N2. BBr3 (46 μL, 0.49 mmol, 5 equiv) was added dropwise and the resulting solution was allowed to stir at 0° C. for 4 h. The reaction mixture was then poured into ice and product extracted into EtOAc (250 mL). The organics were washed with saturated aqueous NaCl (100 mL), dried over Na2SO4, filtered and concentrated to dryness. The residue was purified by silica gel flash column chomatography (1:1 EtOAc:hexanes) to provide the title compound (32) (30 mg, 66%) as a yellow solid. 1HNMR (400 MHz, DMSO-d6): δ 11.53 (br s, 1H), 10.69 (br s, 1H), 7.88 (m, 1H), 7.60 (m, 1H), 7.27-7.14 (m, 7H), 6.98 (m, 2H), 6.59 (m, 2H), 2.20 (s, 3H). MS m/z 472.3 (M−H)−.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2Br)[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[CH:29](/B(O)O)=[CH:30]/[CH3:31].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:26]=[CH:25][C:20]([C:21]([O:23][CH3:24])=[O:22])=[CH:19][C:18]=2/[CH:29]=[CH:30]\[CH3:31])[CH2:13][CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C/C=C\B(O)O
Reactant: COC(=O)c1ccc(N2CCN(CCOCc3ccccc3)CC2)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: C/C=C\c1cc(C(=O)OC)ccc1N1CCN(CCOCc2ccccc2)CC1
Temperature: 80 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
Methyl 4-{4-[2-(benzyloxy)ethyl]piperazin-1-yl}-3-bromobenzoate (78 mg, 0.180 mmol) was dissolved in N,N-dimethylformamide: water=3:1 (1.8 mL). At room temperature, (Z)-propenylboronic acid (containing about 10% E-isomer; Hereinafter the same is used for all) (37 mg, 0.433 mmol), tetrakistriphenylphosphine palladium (10 mg, 0.00902 mmol) and sodium carbonate (76 mg, 0.722 mmol) were added sequentially, and the mixture was stirred at 80° C. for 1 hour under microwave irradiation. The reaction solution was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The obtained residue was purified by silica-gel column chromatography (hexane/acetone). The title compound (61 mg (yield 86%)) was obtained as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([CH2:13][CH2:14][C:15]3[S:16][C:17]([C:21]([OH:23])=O)=[C:18]([CH3:20])[N:19]=3)=[C:11]([CH3:24])[O:10][N:9]=2)=[N:6][CH:7]=1.[CH:25]([NH2:28])([CH3:27])[CH3:26]>>[CH:25]([NH:28][C:21]([C:17]1[S:16][C:15]([CH2:14][CH2:13][C:12]2[C:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][N:6]=3)=[N:9][O:10][C:11]=2[CH3:24])=[N:19][C:18]=1[CH3:20])=[O:23])([CH3:27])[CH3:26]
Reactant: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)O
Reactant: CC(C)N
Product: Cc1nc(CCc2c(-c3ccc(F)cn3)noc2C)sc1C(=O)NC(C)C
Yield: 91 %

Procedure:
As described for example 31b, 2-{2-[3-(5-fluoro-pyridin-2-yl)-5-methyl-isoxazol-4-yl]-ethyl}-4-methyl-thiazole-5-carboxylic acid (69 mg, 0.20 mmol) was converted, using isopropylamine instead of 4-aminotetrahydropyran, to the title compound (71 mg, 91%) which was obtained as an off white solid. MS: m/e=389.2 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH:14]C(=O)C)([O-:3])=[O:2].N>Cl.O>[N+:1]([C:4]1[C:13]2[CH2:12][CH2:11][CH2:10][CH2:9][C:8]=2[CH:7]=[CH:6][C:5]=1[NH2:14])([O-:3])=[O:2]
Reactant: CC(=O)Nc1ccc2c(c1[N+](=O)[O-])CCCC2
Agent: Cl
Agent: N
Solvent: O
Product: Nc1ccc2c(c1[N+](=O)[O-])CCCC2
Temperature: 100 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
A suspension of acetamide 168 (835 mg, 4.4 mmol) in 6 M HCl (50 mL) was stirred at 100° C. for 16 h. The suspension was cooled to 20° C., diluted with water (50 mL) and the pH adjusted to 8 with dilute aqueous NH3 solution. The mixture was extracted with DCM (3×50 mL), the combined organic fraction dried and the solvent evaporated. The residue was purified by chromatography, eluting with 20% EtOAc/pet. ether, to give amine 169 (755 mg, 56%) as an orange solid: mp (EtOAc/pet. ether) 76-78° C.; 1H NMR δ 6.98 (d, J=8.4 Hz, 1H, H-4), 6.58 (d, J=8.4 Hz, 1H, H-3), 4.73 (br s, 2H, NH2), 2.76-2.81 (m, 2H, CH2), 2.65-2.69 (m, 2H, CH2), 1.69-1.78 (m, 2H, CH2). Anal. calcd for C10H12N2O2: C, 62.5; H, 6.3; N, 14.6. Found: C, 62.8; H, 6.1; N, 14.6%.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C@H:8]([CH2:18]OS(C)(=O)=O)[CH2:7]1.[CH3:30][NH2:31]>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([N+:27]([O-:29])=[O:28])[CH:26]=1)[O:5][C@H:6]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:16])([CH3:17])[CH3:15])=[O:12])[C@H:8]([CH2:18][NH:31][CH3:30])[CH2:7]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(F)cc([N+](=O)[O-])c2)C[C@H]1COS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNC[C@@H]1C[C@@H](Oc2cc(F)cc([N+](=O)[O-])c2)CN1C(=O)OC(C)(C)C
Temperature: 55 °C

Procedure:
To a solution of (2S,4R)-tert-butyl 4-(3-fluoro-5-nitrophenoxy)-2-((methylsulfonyloxy)methyl)pyrrolidine-1-carboxylate (1.0 equiv) in THF (0.4 M) was added 40% aq. methylamine (90 equiv). The resulting solution was heated to 55° C. overnight. The reaction mixture was cooled to room temperature and diluted with EtOAc (20 volume equivalents) and washed twice with sat. aq. NaHCO3 (10 volume equivalents) and once with brine (10 volume equivalents). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to provide the title compound as a dark oil with 119% mass balance; the material was used without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([CH2:16][CH:17](Br)[CH2:18]Br)[C:11]=1[O:12]C(=O)C)[O:8][C:7](=[O:21])[CH:6]=[CH:5]2.[OH-].[K+].O1C2C(=CC=CC=2)C=CC1=O.[OH-].[K+]>O>[CH3:18][C:17]1[O:12][C:11]2[C:10](=[C:9]3[O:8][C:7](=[O:21])[CH:6]=[CH:5][C:4]3=[CH:3][C:2]=2[CH3:1])[CH:16]=1
Reactant: CC(=O)Oc1c(C)cc2ccc(=O)oc2c1CC(Br)CBr
Agent: O=c1ccc2ccccc2o1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1cc2c(o1)c(C)cc1ccc(=O)oc12

Procedure:
To an ethanolic solution (100 ml) of 6-methyl-7-acetoxy-8-(2',3'-dibromopropyl) coumarin (XIII) (1.5 g) a volume of ethanolic 4% KOH solution was added, equivalent to a molar ratio coumarin/KOH 1:10. The mixture was refluxed for 80 min. in the dark, chilled, diluted with H2O (200 ml) and acidified with dil. HC1. The precipitate thus obtained was filtered, washed with H2O, dried and chromatographed on a silica gel column by eluting with CHC13, yielding the 6,5'-dimethylangelicin (XVI), crystallized from MeOH (0.52 g; m.p. 175-6° C.). ##STR22##
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[C:13](=[O:20])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].[Cl-].[Na+]>O.C(O)(=O)C>[F:5][C:6]1[CH:11]=[CH:10][C:9]([I:12])=[CH:8][C:7]=1[C:13](=[O:20])[C:14](=[N:1][OH:3])[C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: O=N[O-]
Reactant: CCOC(=O)CC(=O)c1cc(I)ccc1F
Agent: [Cl-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)C(=NO)C(=O)c1cc(I)ccc1F
Reaction time: 1.5 h
Yield: 50.2 %

Procedure:
Employing the method utilized by Fray (Fray, J. M., Cooper, K., Parry, M. J., Richardson, K., Steele, J. J. Med. Chem. 1995, 38, 3514-3523), a solution of sodium nitrite (0.52 g) in water (3 mL) is added dropwise to a solution of ethyl 3-(2-fluoro-5-iodophenyl)-3-oxopropanoate (Preparation 15, 2.4 g) in glacial acetic acid (3 mL) at 5° C. with stirring. After 1.5 h, the mixture is poured into saturated aqueous sodium chloride and extracted with dichloromethane. The organic extracts are washed with saturated aqueous sodium chloride and saturated aqueous sodium bicarbonate, dried (Na2SO4), and concentrated in vacuo to give a sticky oil which is flash chromatographed on silica gel (230-400 mesh, 10 g) eluting with 20% ethyl acetate and hexane to give, after concentration of product fractions, 1.31 g of the title compound as a yellow liquid (˜3/1 ratio of oxime isomers). Physical characteristics: MS (ESI+) m/z 366 (M+H)+.
Reaction SMILES: C([O:4][C:5]1[C:32]([CH:33]([CH3:35])[CH3:34])=[CH:31][C:8]([C:9]([NH:11][C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[Cl:28])=[CH:19][C:18]([CH3:29])=[CH:17][C:16]=3[CH3:30])=[O:10])=[CH:7][C:6]=1[CH:36]([CH3:38])[CH3:37])(=O)C.[OH-].[Na+]>CO>[Cl:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:21]1[C:20]2[C:15](=[C:16]([CH3:30])[CH:17]=[C:18]([CH3:29])[CH:19]=2)[N:14]=[CH:13][C:12]=1[NH:11][C:9](=[O:10])[C:8]1[CH:7]=[C:6]([CH:36]([CH3:38])[CH3:37])[C:5]([OH:4])=[C:32]([CH:33]([CH3:35])[CH3:34])[CH:31]=1
Reactant: CC(=O)Oc1c(C(C)C)cc(C(=O)Nc2cnc3c(C)cc(C)cc3c2-c2ccccc2Cl)cc1C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(C)c2ncc(NC(=O)c3cc(C(C)C)c(O)c(C(C)C)c3)c(-c3ccccc3Cl)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.4 %

Procedure:
A mixture of 3-(4-acetoxy-3,5-diisopropylbenzamido)-4-(2-chlorophenyl)-6,8-dimethylquinoline (600 mg), methanol (40 ml) and 1N-sodium hydroxide (4 ml) was stirred at room temperature for 3 hours. After concentrating, the mixture was diluted with water and made acidic with 2N-hydrocloric acid. Thereafter, the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO4). The solvent was removed and the residue was recrystallized from acetone-isopropyl ether to give 4-(2-chlorophenyl)-3-(4-hydroxy-3,5-diisopropyl benzamido)-6,8-dimethylquinoline (494 mg, 89.5%) as colorless prisms.
Reaction SMILES: Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[CH:12]=[CH:11][C:7]([C:8]([NH2:10])=[NH:9])=[CH:6][CH:5]=1.C[O-].[Na+].[Na]>CO>[CH2:5]([C:4]1[CH:3]=[N:9][C:8]([C:7]2[CH:11]=[CH:12][C:4]([C:3]([F:13])([F:14])[F:2])=[CH:5][CH:6]=2)=[N:10][CH:12]=1)[CH2:6][CH3:7]
Reactant: N=C(N)c1ccc(C(F)(F)F)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1
Yield: 100 %

Procedure:
4-Trifluoromethylbenzamidine hydrochloride (5 g, 0.02 mol) and α-propyl-β-dimethylaminoacrolein (3 g, 0.02 mol) were added to a sodium methylate solution having metallic sodium (1 g) dissolved in anhydrous methanol (50 ml), followed by boiling the mixture for 4 hours with stirring, distilling off methanol, adding toluene (50 ml) to the reaction residue to extract the product, washing the resulting extract with water, drying the toluene layer with anhydrous sodium sulfate, distilling off toulene and three times recrystallizing the residue from methanol to obtain 5-propyl-2-(4-trifluoromethylphenyl)pyrimidine (3 g, 0.01 mol).