Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[C:23]([O:26][CH2:27][C@@:28]1([CH3:50])[O:32][C@@H:31]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=O)[NH:36][C:34]2=[O:35])[C@H:30]([O:42][C:43](=[O:45])[CH3:44])[C@@H:29]1[O:46][C:47](=[O:49])[CH3:48])(=[O:25])[CH3:24]>ClCCCl>[C:23]([O:26][CH2:27][C@@:28]1([CH3:50])[O:32][C@@H:31]([N:33]2[CH:41]=[C:39]([CH3:40])[C:37](=[S:10])[NH:36][C:34]2=[O:35])[C@H:30]([O:42][C:43](=[O:45])[CH3:44])[C@@H:29]1[O:46][C:47](=[O:49])[CH3:48])(=[O:25])[CH3:24]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(=O)OC[C@@]1(C)O[C@@H](n2cc(C)c(=O)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Solvent: ClCCCl
Product: CC(=O)OC[C@@]1(C)O[C@@H](n2cc(C)c(=S)[nH]c2=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 8 h
Yield: 137.3 %

Procedure:
Lawesson's reagent (119 mg, 0.29 mmol) was added under argon to a solution of 15 (0.167 g, 4.19 mmol) in anhydrous 1,2-dichloroethane (11 mL) and the reaction mixture was stirred overnight under reflux. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography [eluent: stepwise gradient of methanol (1–2%) in chloroform] to give pure 16 (0.165 g, 95%) as a yellow foam. 1H-NMR (DMSO-d6): δ 12.81 (s, 1H, NH), 7.64 (s, 1H, H-6), 5.84 (d, 1H, H-1′, J1′-2′=4.66 Hz), 5.5–5.4 (m, 2H, H-2′ and H-3′), 4.11 (dd, 2H, H-5′ and H-5″, J=11.7 Hz, J=31.3 Hz), 2.0–1.8 (m, 12H, 3 CH3CO2 and CH3), 1.33 (s, 3H, CH3); MS (matrix GT): FAB>0 m/z 829 (2M+H)+, 415 (M+H)+, 273 (S)+, 143 (BH2)+, 43 (CH3CO)+ FAB<0 m/z 827 (2M−H)−, 413 (M−H)−, 141 (B)31 , 59 (CH3CO2)−.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].[Br:15]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[C:8]([CH2:10][Br:15])[CH:7]=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1cc(C)ccc1[N+](=O)[O-]
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1cc(CBr)ccc1[N+](=O)[O-]

Procedure:
5-Methyl-2-nitrobenzoic acid methyl ester (27.1 g, 138.8 mmol) was dissolved in carbon tetrachloride (500 mL), and N-bromosuccinimide (29.6 g, 166.6 mmol) was added, followed by benzoyl peroxide (6.72 g, 27.7 mmol). The mixture was illuminated and gently refluxed for 4 hours. Then, the mixture was cooled and concentrated, then purified by column chromatography silica gel 230-400 mesh; 10% ethyl acetate in hexanes as eluent) to give 5-bromomethyl-2-nitrobenzoic acid methyl ester. Yield: 17.9 g (47%).
Reaction SMILES: [F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6](O)=[O:7].S(Cl)([Cl:12])=O>>[F:1][C:2]1([F:9])[CH2:4][CH:3]1[CH2:5][C:6]([Cl:12])=[O:7]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC1CC1(F)F
Product: O=C(Cl)CC1CC1(F)F

Procedure:
A mixture of 39.8 g (0.29 mmol) 2,2-difluorocyclopropylacetic acid and 38.5 ml (0.53 mmol) thionyl chloride was heated under reflux for 5 hours. Excess thionyl chloride was distilled and the residue was distilled in vacuo.
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)([Cl:12])=O.CP(=O)(C)CCl>ClC1C=CC=CC=1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)Cl
Reactant: O=C(O)c1ccccc1
Agent: CP(C)(=O)CCl
Solvent: Clc1ccccc1
Product: O=C(Cl)c1ccccc1

Procedure:
In the device described for example 1, 122 g of benzoic acid are reacted with phosgene after having added 0.1 g of dimethyl-chloromethyl-phosphine oxide. At the beginning the operation is carried out at a temperature just above the melting point of the benzoic acid (122°C), but while the reaction is continuing the temperature is brought down to approx. 100°C. So as to avoid sublimation, it is useful to add to the reation mixture approx. 20 g of chlorobenzene. The phosgene absorption is terminated after abt. 2 hours. After a postreaction of another hour a more then 99% crude yield of a slightly colored benzoyl chloride is obtained which, for further purification, may be submitted to further distillation under reduced pressure. The net yield is abt. 136 g corresponding to 97% theoretical yield.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8].[N-:15]=[N+:16]=[N-:17].[Na+]>CN(C)C=O.ClCCl>[N:15]([CH2:2][C:3]1[CH:4]=[C:5]([OH:14])[C:6](=[CH:12][CH:13]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N+:16]=[N-:17]
Reactant: CCOC(=O)c1ccc(CBr)cc1O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCOC(=O)c1ccc(CN=[N+]=[N-])cc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Ethyl 4-bromomethylsalicylate (4.8 g, 18.6 mmoles) was dissolved in dry N,N-di-methylformamide (50 mL) and sodium azide (1.2 g, 18.9 mmoles) was added. The suspension was stirred at room temperature for 2 hours. The reaction mixture was then diluted with dichloromethane (150 mL) and extracted with 1N aqueous hydrochloric acid (100 mL), water (100 mL), and saturated aqueous sodium chloride (50 mL). Finally, the solution was then dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness to give ethyl 4-azidomethylsalicylate as an oil.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]3[CH2:38][O:37]C(C)(C)[O:35]3)=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9].Cl>CC(C)=O.O>[CH3:1][C:2]1[NH:3][C:4]([CH3:41])=[C:5]([C:21]([O:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH:34]([OH:35])[CH2:38][OH:37])=[CH:28][CH:27]=2)=[O:22])[CH:6]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([N+:18]([O-:20])=[O:19])[CH:13]=2)[C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCC3COC(C)(C)O3)cc2)C1c1cccc([N+](=O)[O-])c1
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCc2ccc(OCC(O)CO)cc2)C1c1cccc([N+](=O)[O-])c1
Yield: 61.5 %

Procedure:
A solution of 21 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,2-dimethyl-1,3-dioxolan-4-yl)methoxyphenyl]ethoxycarbonyl)-1,4-dihydropyridine (6) in 150 mL of acetone and 50 mL of water was treated with 10 mL of hydrochloric acid and the mixture heated at reflux for 6 h. Water (500 mL) was added and the mixture was extracted with ether. The ether layer was dried over Na2SO4 and evaporated to an oil which was purified by medium pressure chromatography on silica gel (90% ethyl acetate-hexane) to give 12 g of 2,6-dimethyl-3-methoxycarbonyl-4-(3-nitrophenyl)-5-(2-[4-(2,3-dihydroxypropoxy)phenyl]ethoxycarbonyl)-1,4-dihydropyridine (1) as a thick oil which crystallized upon trituration with ethyl acetate, m.p. 117°-118° C.
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(C(C)C)C(C)C)C.[CH2:19](Cl)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C1(C)C=CC=CC=1>[CH2:19]([NH:9][C@@H:2]([CH3:1])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1)[CH:20]=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: C[C@H](N)c1ccccc1
Reactant: ClCC=Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Product: C[C@H](NCC=Cc1ccccc1)c1ccccc1
Yield: 46.5 %

Procedure:
To a solution of (S)-α-methylbenzylamine (1) (0.500 g, 4.13 mmol) in toluene (20 ml) were added N-ethyldiisopropylamine (0.719 ml, 4.13 mmol) and cinnamyl chloride (0.575 ml, 4.13 mmol). The mixture was refluxed overnight, after which the toluene was removed under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and saturated sodium bicarbonate solution (30 ml) and the organic layer was washed with brine (30 ml), dried (magnesium suphate) and removed under reduced pressure to afford a yellow oil. This was purified by flash chromatography on silica gel [ethyl acetate/petroleum ether (1:4) to give the title compound (4) as a colourless oil (0.456 g, 47%). δH (200 MHz; CDCl3) 7.41-7.20 (10H, m, Ph), 6.50 (1H, d, J=15.9, PhCH=CH), 6.30 (1H, dt, J=15.9 and 6.1, PhCH=CH), 3.88 (1H, q, J=6.6, PhCHCH3), 3.29 (2H, d, J=6.5, NCH2), 1.56 (1H, br s, NH), 1.42 (3H, d, J=6.8, PhCHCH3).
Reaction SMILES: Cl.Cl.[CH3:3][N:4]1[CH2:10][C@H:9]2[NH:11][C@H:6]([CH2:7][CH2:8]2)[CH2:5]1.F[C:13]1[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[N:17][CH:18]=1.C(N(CC)CC)C>CS(C)=O.CCOC(C)=O>[CH3:3][N:4]1[CH2:10][C@H:9]2[N:11]([C:13]3[CH:18]=[N:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)[C@H:6]([CH2:7][CH2:8]2)[CH2:5]1
Reactant: O=[N+]([O-])c1ccc(F)cn1
Reactant: CN1C[C@H]2CC[C@@H](C1)N2
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN1C[C@H]2CC[C@@H](C1)N2c1ccc([N+](=O)[O-])nc1
Temperature: 25 °C
Yield: 81.7 %

Procedure:
A solution of (1R,5S)-3-Methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride (981 mg, 4.93 mmol), 5-fluoro-2-nitropyridine (100 mg, 4.93 mmol), and triethylamine (4.99 g, 49.3 mmol) in DMSO (8 ml) was heated to 80° C. for 2 hr. After cooling to room temperature, the reaction mixture was diluted with EtOAc and washed with saturated ammonium chloride, and water. The organic phase was then concentrated and triturated with ether to give desire product as an yellow solid (1 g, 81.8%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C:35]1[CH:40]=[CH:39][C:38]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:37][CH:36]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][OH:34])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:53][S:54](Cl)(=[O:56])=[O:55].[Cl-].[NH4+]>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]([C:35]1[CH:36]=[CH:37][C:38]([O:41][CH2:42][CH2:43][O:44][CH3:45])=[CH:39][CH:40]=1)[C:9]1[N:14]2[N:15]=[CH:16][CH:17]=[C:13]2[N:12]=[C:11]([NH:18][C@H:19]2[CH2:24][CH2:23][CH2:22][N:21]([C:25]([O:27][C:28]([CH3:29])([CH3:30])[CH3:31])=[O:26])[CH2:20]2)[C:10]=1[CH2:32][CH2:33][O:34][S:54]([CH3:53])(=[O:56])=[O:55])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCO)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOc1ccc(N(C(=O)OC(C)(C)C)c2c(CCOS(C)(=O)=O)c(N[C@H]3CCCN(C(=O)OC(C)(C)C)C3)nc3ccnn23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 106.1 %

Procedure:
To a methylene chloride (5 mL) solution containing tert-butyl (S)-3-[7-{tert-butoxycarbonyl-[4-(2-methoxyethoxy)phenyl]amino}-6-(2-hydroxyethyl)pyrazolo[1,5-a]pyrimidin-5-ylamino]piperidine-1-carboxylate (216 mg, 0.345 mmol), triethylamine (480 μL, 3.45 mmol) and methanesulfonyl chloride (80 μL, 1.04 mmol) were added, and this mixture was stirred at room temperature for 30 min. After the reaction, aqueous ammonium chloride was added to the reaction solution, and the mixture was extracted with methylene chloride. The combined methylene chloride layer was dried over sodium sulfate. After the sodium sulfate was filtered off, the filtrate was concentrated to obtain the title compound (258 mg).
Reaction SMILES: [C:1]([CH:4]1[CH:9]([C:10]#[N:11])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])=[CH2:2].C(C1C(CN2C(=O)C(CC3C=CN=CC=3)(CC3C=CN=CC=3)NC2=CC(C2C=CC(C#N)=CC=2)=O)CC2CC1C2(C)C)(C)=C.[N-]=[C:60]=[S:61]>>[C:1]([CH:4]1[CH:9]([CH2:10][N:11]=[C:60]=[S:61])[CH2:8][CH:7]2[CH2:12][CH:5]1[C:6]2([CH3:14])[CH3:13])([CH3:3])=[CH2:2]
Reactant: [N-]=C=S
Reactant: C=C(C)C1C(C#N)CC2CC1C2(C)C
Agent: C=C(C)C1C(CN2C(=O)C(Cc3ccncc3)(Cc3ccncc3)NC2=CC(=O)c2ccc(C#N)cc2)CC2CC1C2(C)C
Product: C=C(C)C1C(CN=C=S)CC2CC1C2(C)C

Procedure:
The same procedure that was used in example 1 was followed except that 2-isopropenyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was used in the place of (+)-3-pinanemethyl isothiocyanate in step D to give the titled compound as a tan solid. 2-Isopropenyl-3-isothiocyanatomethyl-6,6-dimethyl-bicyclo[3.1.1]heptane was prepared by reducing 2-isopropenyl-6,6-dimethyl-bicyclo[3.1.1]heptane-3-carbonitrile to the requisite amine following the procedure in step C of example 42 and subsequently converted to the isothiocyanate using step A of example 15: C.I. m/z 586 [M+1]; 1H NMR (CDCl3)δ 10.47 (br s, 1H), 8.43-8.49 (m, 4H), 7.82 (d, J=8.7 Hz, 2H), 7.69 (d, J=8.7 Hz, 2H), 7.13 (m, 2H), 7.08 (m, 2H), 5.27 (s, 1H), 4.74 (m, 2H), 3.33 (dd, J=11.2, 13.9 Hz, 1H), 3.23 (d, J=13.5 Hz, 2H), 3.03-3.15 (m, 2H), 2.84 (dd, J=3.2, 13.9 Hz, 1H), 1.99-2.15 (m, 2H), 1.70 (m, 3H), 1.63 (s, 3H), 1.20 (m, 2H), 1.15 (s, 3H), 0.77(s, 3H), 0.66 (m, 1H).
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][C:7](=[O:13])[NH:8]2.[CH3:14][C:15]1[N:20]=[C:19]([CH:21]=O)[CH:18]=[CH:17][CH:16]=1.N1CCCCC1>C(O)C>[OH:1][CH2:2][CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[C:6](=[CH:21][C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:14])[N:20]=1)[C:7](=[O:13])[NH:8]2
Reactant: Cc1cccc(C=O)n1
Reactant: O=C1Cc2c(CCO)cccc2N1
Solvent: C1CCNCC1
Solvent: CCO
Product: Cc1cccc(C=C2C(=O)Nc3cccc(CCO)c32)n1
Temperature: 100 °C

Procedure:
A mixture of 4-(2-hydroxy-ethyl)-1,3-dihydro-indol-2-one (89 mg, 0.5 mmol), 6-methyl-2-pyridine-carbaldehyde (61 mg, 0.5 mmol) and piperidine (0.1 mL) in 1.0 mL of ethanol was heated at 100° C. for 1 hour and cooled to room temperature. The precipitate was filtered and recrystallized from ethyl acetate and hexanes to give 4-(2-hydroxy-ethyl)-3-(6-methyl-pyridin-2-ylmethylene)-1,3-dihydro-indol-2-one as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]2[O:8][C:9]3[C:14]([C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:4]=2[CH:3]=1)=[CH:13][C:12]([C:23]1[C:24]([F:29])=[N:25][CH:26]=[CH:27][CH:28]=1)=[CH:11][CH:10]=3.[F:30][C:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[CH:33][N:32]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>>[F:29][C:24]1[C:23]([C:12]2[CH:13]=[C:14]3[C:15]4([CH2:16][O:17][CH2:18][CH2:19][C:20]([NH2:22])=[N:21]4)[C:4]4[CH:3]=[C:2]([C:35]5[CH:34]=[CH:33][N:32]=[C:31]([F:30])[CH:36]=5)[N:7]=[CH:6][C:5]=4[O:8][C:9]3=[CH:10][CH:11]=2)=[CH:28][CH:27]=[CH:26][N:25]=1
Reactant: OB(O)c1ccnc(F)c1
Reactant: NC1=NC2(COCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(Cl)cc12
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Product: NC1=NC2(COCC1)c1cc(-c3cccnc3F)ccc1Oc1cnc(-c3ccnc(F)c3)cc12
Temperature: 110 °C

Procedure:
A vial was charged with (E)-3-chloro-7-(2-fluoropyridin-3-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine (142 mg, 0.346 mmol), 2-fluoropyridin-4-ylboronic acid (122 mg, 0.864 mmol), Pd(AmPhos)2Cl2 (12.24 mg, 0.017 mmol), and potassium phosphate (220 mg, 1.037 mmol). The vial was flushed with Ar (g), then dioxane (1296 μL) and water (432 μL) were added in sequence. The vial was sealed and heated in a microwave reactor for 30 min at 110° C. The mixture was extracted with EtOAc (3×), and the combined organic extracts were concentrated. The crude product was purified by chromatography on silica gel (10-100% of a 90:10:1 mixture of DCM/MeOH/NH4OH in DCM) to give (E)-7-(2-fluoropyridin-3-yl)-3-(2-fluoropyridin-4-yl)-6′,7′-dihydro-2′H-spiro[chromeno[2,3-c]pyridine-5,3′-[1,4]oxazepin]-5′-amine as a yellow solid. 1H NMR (400 MHz, DMSO-d6) δ=8.71 (d, J=0.4 Hz, 1 H), 8.38 (d, J=5.3 Hz, 1 H), 8.26 (td, J=1.5, 4.8 Hz, 1 H), 8.13 (ddd, J=1.9, 7.5, 10.4 Hz, 1 H), 8.07 (s, 1 H), 7.95 (td, J=1.8, 5.2 Hz, 1 H), 7.72 (s, 1 H), 7.69-7.59 (m, 2 H), 7.50 (ddd, J=1.9, 4.9, 7.4 Hz, 1 H), 7.42 (d, J=8.6 Hz, 1 H), 6.16 (br. s., 2 H), 3.86 (t, J=5.6 Hz, 2 H), 3.72 (q, J=12.8 Hz, 2 H), 3.09-2.90 (m, 2 H). MS m/z=472.0. Calc'd for C26H20F2N5O2: 472.2. The racemic material (104 mg) was subjected to chiral SFC separation, using 35% MeOH with diethylamine to afford 45 mg of the (R)-enantiomer (peak 1) and 44 mg of the (S)-enantiomer (peak 2) as white solids.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.C([O-])(=O)C.[Na+].[Br:14][CH2:15][C:16](Br)=[O:17]>C(O)(=O)C>[OH:8][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[NH:1][C:16](=[O:17])[CH2:15][Br:14]
Reactant: Nc1cccc(O)c1
Reactant: O=C(Br)CBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C(CBr)Nc1cccc(O)c1
Temperature: 10 °C

Procedure:
m-Aminophenol, 66.5 g. (0.61 mole), is dissolved in 500 ml. of a 50/50 (v/v) mixture of glacial acetic acid and saturated sodium acetate solution. The mixture is cooled to approximately 10° C. and 200 g. (0.99 mole) of bromoacetyl bromide is added dropwise. The temperature is maintained between 15° and 20° C. When addition is complete, the mixture is stirred while cooling until the temperature is about 5° C. The product is filtered off, washed successively with cold water, saturated sodium bicarbonate solution and finally two portions of water. The product is dried under vacuum. The yield of the title compound is 121 g. (86 percent of theory), m.p. 167°-170° C.
Reaction SMILES: CO[CH2:3][C:4]1[N:39]=[C:7]2[N:8]([CH:35]([CH3:38])[CH2:36][CH3:37])[C:9](=[O:34])[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]2[N:5]=1.B(Br)(Br)[Br:41].C(=O)([O-])O.[Na+].Cl>ClCCl>[Br:41][CH2:3][C:4]1[N:39]=[C:7]2[N:8]([CH:35]([CH3:38])[CH2:36][CH3:37])[C:9](=[O:34])[C:10]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]4[NH:32][C:31](=[O:33])[O:30][N:29]=4)=[CH:18][CH:17]=3)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]2[N:5]=1
Reactant: BrB(Br)Br
Reactant: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(COC)nn12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3noc(=O)[nH]3)cc2)c(=O)n(C(C)CC)c2nc(CBr)nn12
Temperature: 25 °C
Reaction time: 2 h
Yield: 2 %

Procedure:
A mixture of 2-(methoxymethyl)-4-(1-methylpropyl)-6-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-7-propyl[1,2,4]triazolo[1,5-a]pyrimidin-5(4H)-one (0.07 g), boron tribromide (1.0 M dichloromethane solution, 0.4 mL) and dichloromethane (5 mL) was stirred at room temperature for 2 hr, saturated aqueous sodium hydrogen carbonate (10 mL) was added, and the mixture was further stirred for 1 hr. The reaction mixture was adjusted to pH 5 with 1 N hydrochloric acid, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.013 g, 2%).
Reaction SMILES: [O:1]1[CH2:26][CH:2]1[CH2:3][O:4][C:5]1[CH:25]=[CH:24][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH3:27][NH:28][CH3:29].O>C(O)C.CN(C=O)C>[CH3:27][N:28]([CH3:29])[CH2:26][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[CH:18]=3)[N:13]=[CH:12][N:11]=2)=[CH:24][CH:25]=1
Reactant: CNC
Reactant: Cc1cccc(Nc2cc(Nc3ccc(OCC4CO4)cc3)ncn2)c1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCO
Product: Cc1cccc(Nc2cc(Nc3ccc(OCC(O)CN(C)C)cc3)ncn2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 54 %

Procedure:
A mixture of 4-[4'-(2,3-epoxypropoxy)anilino]6-(3'-methylanilino) pyrimidine (0.35 g), 33% dimethylamine in ethanol (10 ml) and DMF (5 ml) was stirred at room temperature for 4 hours. The mixture was poured into water, extracted with ethyl acetate and the organic phase evaporated. The residue was recrystallised from a mixture of methylene chloride, methanol and hexane to give 4-[4'-(3-dimethylamino-2-hydroxypropoxy)anilino]6-(3'-methylanilino) pyrimidine in 54% yield, m.p. 192°-195° C.;
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[K+].[K+].[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27]Br.O>CC(C)=O>[F:24][C:25]1[CH:32]=[CH:31][CH:30]=[CH:29][C:26]=1[CH2:27][O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH:13]([CH3:17])[C:14]([NH2:16])=[O:15])[CH2:6][CH2:5]2
Reactant: CC(C(N)=O)N1CCc2cc(O)ccc2C1=O
Reactant: Fc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CC(C(N)=O)N1CCc2cc(OCc3ccccc3F)ccc2C1=O
Reaction time: 8 h

Procedure:
2-(6-Hydroxy-1-oxo-3,4-dihydro-1H-isoquinolin-2-yl)-propionamide (50 mg, 0.213 mmol), was solved in dry acetone (1 mL) and potassium carbonate (38.3 mg, 0.276 mmol) was added followed by 2-fluorobenzyl bromide (42.36 mg, 0.224 mmol). The mixture was stirred overnight. Water was added and a precipitate appeared. The precipitated was filtrated and the title compound was obtained as a white solid (58 mg, 79%). MS: m/e=343.2 (M+H+).
Reaction SMILES: C[O:2][C:3](=[O:16])[CH2:4][CH2:5][C:6]1[CH:7]=[N:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>[OH-].[K+].CO.O.CO>[N:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[C:6]([CH2:5][CH2:4][C:3]([OH:16])=[O:2])[CH:7]=1
Reactant: COC(=O)CCc1cnc2ccccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCc1cnc2ccccc2c1
Yield: 88.7 %

Procedure:
A solution of 3-quinolinepropanoic acid methyl ester (2.21 g, 10.3 mmol) in 10% KOH/MeOH (48.2 mL), H2O (20 mL) and methanol (134 mL) was stirred at room temperature for 3 h. Upon completion of reaction, the solution was concentrated and the aqueous residue was acidified to pH 5-6 with glacial HOAc. A crystalline solid formed which was filtered, washing with H2O until the filtrate was neutral and dried to give 3-quinolinepropanoic acid (1.84 g, 9.14 mmol) in 89% yield as a solid, mp 180°-181° C.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[B-](F)(F)F.[CH3:27][O+](C)C.CN(C1C2C(N(C)C)=CC=CC=2C=CC=1)C>ClCCl>[CH2:1]([O:8][C:9](=[O:21])[C@@H:10]([NH:13][C:14]([O:16][C:17]([CH3:18])([CH3:20])[CH3:19])=[O:15])[CH2:11][O:12][CH3:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)OCc1ccccc1
Reactant: C[O+](C)C
Agent: CN(C)c1cccc2cccc(N(C)C)c12
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COC[C@H](NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.6 %

Procedure:
To a solution of the compound of Formula XII(a), (S)-2-tert-butoxycarbonylamino-3-hydroxy-propionic acid benzyl ester (1.7 g, 5.76 mmol) in dichloromethane (50 mL) was added trimethyloxonium tetrafluoroborate (1.11 g, 7.50 mmol), followed by the portion-wise addition of proton sponge (1.61 g, 7.50 mmol). After stirring for 24 hrs at RT, the solution was concentrated, and the residue was dissolved in ethyl acetate, and the solution filtered through a pad of celite. The filtrate was washed with 1 M HCl and brine. The organic layers were dried over MgSO4, filtered, and concentrated in vacuo. Silica-gel flash chromatography with 5% to 15% ethyl acetate in hexanes afforded the compound of Formula XIII(b), (S)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid benzyl ester (1.24 g, 69.6%) as a colorless oil. 1H NMR (300 MHz, CDCl3): δ (ppm) 7.35-7.29 (m, 5H), 4.90-4.87 (m, 1H), 4.51 (s, 2H), 3.92-3.87 (m, 1H), 3.80-3.78 (m, 1H), 3.56 (dd, 2H), 3.42 (dd, 1H), 3.33 (s, 3H), 1.42 (s, 9H).
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9]1)=O)(C)(C)C.[ClH:15].O1CCOC[CH2:17]1>CO>[ClH:15].[CH3:17][O:14][C:12]([CH:10]1[CH2:9][NH:8][CH2:11]1)=[O:13]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: COC(=O)C1CNC1

Procedure:
To a solution of 1-(tert-butoxycarbonyl)azetidine-3-carboxylic acid (8.00 g, 39.8 mmol) in MeOH (60 mL) was added 4 M HCl in dioxane (60 mL, 240.0 mmol). The mixture was refluxed for 2 hours. The mixture was concentrated to afford INT 1.