Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([NH:18][CH3:19])[C:5]2[CH2:10][CH2:9][CH:8]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]=2[N:7]=1.[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[N:29]1[CH:33]=[N:32][C:31]([CH3:34])=[N:30]1)[NH2:25].OS(O)(=O)=O.C([O-])(O)=O.[Na+]>CN1CCCC1=O.O>[F:17][C:14]1[CH:15]=[CH:16][C:11]([CH:8]2[C:6]3[N:7]=[C:2]([NH:25][C:24]4[CH:26]=[CH:27][C:28]([N:29]5[CH:33]=[N:32][C:31]([CH3:34])=[N:30]5)=[C:22]([O:21][CH3:20])[CH:23]=4)[N:3]=[C:4]([NH:18][CH3:19])[C:5]=3[CH2:10][CH2:9]2)=[CH:12][CH:13]=1
Reactant: COc1cc(N)ccc1-n1cnc(C)n1
Reactant: CNc1nc(Cl)nc2c1CCC2c1ccc(F)cc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: CNc1nc(Nc2ccc(-n3cnc(C)n3)c(OC)c2)nc2c1CCC2c1ccc(F)cc1
Temperature: 100 °C

Procedure:
To a solution of 2-chloro-7-(4-fluorophenyl)-N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (Preparation Hh) (141.2 mg, 0.508 mmol) and 3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)aniline (Preparation D) (208 mg, 1.017 mmol) in N-Methyl-2-pyrrolidinone (4067 μL) was added H2SO4 (43.4 μL, 0.813 mmol). The solution was heated to 100° C. When the reaction was complete, water and NaHCO3 were added. After extraction into CH2Cl2, the organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. Applied the residue to SG and eluted with a EtOAc/Hex gradient, which yielded 7-(4-fluorophenyl)-N2-(3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl)-N4-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine-2,4-diamine (Example 44).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[OH-].[K+].[I:13]I>CN(C=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([I:13])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: II
Reactant: Fc1ccc2cn[nH]c2c1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: Fc1ccc2c(I)n[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.2 %

Procedure:
To a solution of 6-fluoro-1H-indazole (5.50 g, 40.4 mmol) in DMF (150 ml) at room temperature was added potassium hydroxide (6.8 g, 121 mmol) and iodine (15.4 g, 60.6 mmol). The maroon reaction mixture was stirred at room temperature for 8 h then quenched with 10% aqueous Na2S2O3 and diluted with water. The mixture was extracted with EtOAc (2×). The combined organics were washed with water, sat LiCl, and sat NaCl, then dried over MgSO4 and concentrated to afford 8.6 g (81%) of 6-fluoro-3-iodo-1H-indazole as a light yellow solid. 1H NMR (CDCl3, 300 MHz): δ (ppm) 7.48 (dd, J=8.9, 5.1 Hz, 1H), 7.20 (dd, J=8.9, 2.1 Hz, 1H), 7.02 (td, J=9.1, 2.1 Hz, 1H)
Reaction SMILES: [NH2:1][C@H:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5].[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:16](O[C:19](=O)[C:14]=12)=[O:17])([O-:12])=[O:11]>C(O)(=O)C>[N+:10]([C:13]1[CH:23]=[CH:22][CH:21]=[C:15]2[C:14]=1[CH2:19][N:1]([CH:2]([C:7](=[O:9])[NH2:8])[CH2:3][C:4]([OH:6])=[O:5])[C:16]2=[O:17])([O-:12])=[O:11]
Reactant: NC(=O)[C@@H](N)CC(=O)O
Reactant: O=C1OC(=O)c2c1cccc2[N+](=O)[O-]
Solvent: CC(=O)O
Product: NC(=O)C(CC(=O)O)N1Cc2c(cccc2[N+](=O)[O-])C1=O

Procedure:
A mixture of isoaspargine (10 mmol) and 3-nitrophthalic anhydride (10 mmol) in 15 ml of acetic acid is heated to reflux. The cooled reaction mixture is concentrated and the residue is purified by chromatography to afford 3-(4-nitro-1-oxoisoindolin-2-yl)-3-carbamoylpropanoic acid.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[OH-].[K+].[CH3:6][O:7][C:8]1[CH:9]=[C:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=3)=[CH:21][C:20]2=[O:35])[CH:11]=[CH:12][C:13]=1[O:14][CH2:15][C@H:16]1[CH2:18][O:17]1>C1COCC1.CCOC(C)=O>[CH2:1]([S:3][CH2:18][C@@H:16]([OH:17])[CH2:15][O:14][C:13]1[CH:12]=[CH:11][C:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:33])([F:34])[F:32])=[CH:27][CH:26]=3)=[CH:21][C:20]2=[O:35])=[CH:9][C:8]=1[O:7][CH3:6])[CH3:2]
Reactant: CCS
Reactant: COc1cc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)ccc1OC[C@H]1CO1
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCSC[C@@H](O)COc1ccc(-n2ccc(-c3ccc(C(F)(F)F)cc3)cc2=O)cc1OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
Ethanethiol (47.6 mg, 0.76 mmol) and 25% aq. potassium hydroxide (172 mg, 0.77 mmol) were added to a solution of (R)-1-(3-methoxy-4-(oxiran-2-ylmethoxy)phenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one (32 mg, 0.08 mmol) Part A in THF (1.5 mL). The mixture was stirred overnight at RT. Diluted with EtOAc, washed with sat. NaHCO3, dried (Na2SO4), and concentrated. The residue was purified using ISCO flash chromatography (silica gel/hexanes/ethyl acetate 100:0 to 0:100 gradient) to afford the desired product (S)-1-(4-(3-(ethylthio)-2-hydroxypropoxy)-3-methoxyphenyl)-4-(4-(trifluoromethyl)phenyl)pyridin-2(1H)-one 15B (28 mg, 0.06 mmol, 76% yield) as a light yellow solid. LC/MS 480 (M+H)+, tR 0.97 min (method 5).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:34]N1C(=O)CCC1=O>C(Cl)Cl>[Br:34][CH2:2][CH2:3][CH2:4][CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:8][CH2:7][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: OCCCC1CCCc2ccccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCCCC1CCCc2ccccc21
Yield: 102 %

Procedure:
Compound 94-1 (140 mg) was dissolved in methylene chloride (10 ml), triphenylphosphine (212 mg) and N-bromosuccinimide (144 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr, and at room temperature 16 hr. The reaction mixture was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether (50 ml) was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography to give the object product (190 mg) as a colorless oil.
Reaction SMILES: CS([C:4]1[N:9]=[CH:8][C:7]2=[CH:10][CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[O:19][CH3:20])[N:6]2[N:5]=1)=O.C(N(CC)C(C)C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:37]2[CH:38]=[C:39]([CH:41]=[CH:42][CH:43]=2)[NH2:40])[CH2:33][CH2:32]1>COCCO>[CH3:20][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[C:12]1[N:6]2[C:7]([CH:8]=[N:9][C:4]([NH:40][C:39]3[CH:41]=[CH:42][CH:43]=[C:37]([N:34]4[CH2:33][CH2:32][N:31]([CH3:30])[CH2:36][CH2:35]4)[CH:38]=3)=[N:5]2)=[CH:10][CH:11]=1
Reactant: COc1ccccc1-c1ccc2cnc(S(C)=O)nn12
Reactant: CN1CCN(c2cccc(N)c2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: COCCO
Product: COc1ccccc1-c1ccc2cnc(Nc3cccc(N4CCN(C)CC4)c3)nn12
Temperature: 180 °C
Yield: 7.9 %

Procedure:
2-Methanesulfinyl-7-(2-methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine (75.0 mg, 0.000261 mol), N,N-Diisopropylethylamine (0.0682 mL, 0.000392 mol) and 3-(4-Methylpiperazin-1-yl)aniline (99.8 mg, 0.000522 mol) were dissolved in 2-Methoxyethanol (1.83 mL) and the reaction was heated under 300 W microwave conditions at 180° C. until HPLC showed consumption of starting material. The reaction mixture was then reduced en vacuo and the product was isolated and purified by Gilson prep HPLC to afford 8.59 mg of [7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazin-2-yl]-[3-(4-methyl-piperazin-1-yl)-phenyl]-amine as lyophilated powder. (M+H)=415.18. 1H NMR (400 MHz, CDCl3) δ 10.42 (s, 1H), 8.55 (s, 1H), 7.87 (d, 1H, J=6.57 Hz), 7.52 (s, 1H), 7.30 (m, 3H), 7.18 (m, 2H), 7.09 (m, 2H), 6.57 (s, 1H), 3.84 (s, 3H), 3.55 (d, 2H, J=11.12 Hz), 3.45 (d, 2H, J=13.64 Hz), 3.18 (m, 2H), 2.90 (m, 2H), 2.86 (s, 3H).
Reaction SMILES: CCO.Cl[C:5]1[O:9][C:8]([C:10]2[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[C:13]([CH3:21])[O:12][N:11]=2)=[CH:7][CH:6]=1.[K+].[Br-]>O=[Pt]=O.CCCCCC>[O:9]1[CH:5]=[CH:6][CH:7]=[C:8]1[C:10]1[C:14]([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[C:13]([CH3:21])[O:12][N:11]=1
Reactant: Cc1onc(-c2ccc(Cl)o2)c1-c1ccccc1
Agent: O=[Pt]=O
Agent: [Br-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCO
Product: Cc1onc(-c2ccco2)c1-c1ccccc1
Reaction time: 7 h
Yield: 89 %

Procedure:
A solution of EtOH (2 ml) containing 3-(5-chlorofuran-2-yl)-4-phenyl-5-methylisoxazole (97 mg, 0.374 mmoles), PtO2 (5 mg) is kept in an atmosphere of H2 (1 atm) at ambient temperature, stirring for 7 h. The catalyst is then filtered on celite and the solvent is evaporated at reduced pressure. The residue is crystallised from hexane. A white powder is obtained with 89% yield and a m.p. 93-96° C. (hexane). FT-IR (KBr): 3149, 3122, 3059, 2962, 2925, 2853, 1633, 1605, 1511, 1496, 1448, 1438, 1417, 1239, 1225, 1176, 1070, 1020, 976, 923, 891, 782, 714, 700 cm−1. 1H NMR (400 MHz, CDCl3, δ): 7.47-7.41 (m, 4H, aromatic protons); 7.31-7.28 (m, 2H, aromatic protons); 6.37-6.35 (dd, 1H, J=3.3 Hz, J=1.8 Hz, furyl proton); 6.34-6.33 (d, 1H, J=3.3 Hz, furyl proton); 2.39 (s, 3H). 13C NMR (100 MHz, CDCl3, δ): 166.6, 153.1, 144.0, 143.6, 130.0, 129.8, 128.7, 128.1, 114.9, 111.5, 111.1, 11.2. GC-MS (70 eV) m/z (rel.int.): 225 (M+, 40), 184 (14), 183 (100), 154 (17), 127 (13), 102 (12), 43 (11). Anal. Calc. for C14H11NO2: C, 74.65; H, 4.92; N, 6.22; O, 14.21. Found: C, 74.48; H, 4.94; N, 6.19.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2([O:15][CH3:16])[C:12]#[C:13][CH3:14].[Cl:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(COC)OC.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>[Cl:17][C:18]1[CH:23]=[C:22]([C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][C:6](=[O:11])[C:5]3([O:15][CH3:16])[C:12]#[C:13][CH3:14])[CH:21]=[CH:20][CH:19]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: CC#CC1(OC)C(=O)Nc2ccc(Br)cc21
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: [Na+]
Solvent: O
Solvent: COCCOC
Product: CC#CC1(OC)C(=O)Nc2ccc(-c3cccc(Cl)c3)cc21
Reaction time: 0.25 h
Yield: 15 %

Procedure:
5-bromo-3-methoxy-3-prop-1-ynyl-1,3-dihydroindol-2-one (0.56 g, 2.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.12 g, 0.10 mmol) were stirred at room temperature in dimethoxyethane (22 cm3). After 15 min. 3-chlorophenylboronic acid (0.63 g, 4.0 mmol) and sodium carbonate (1.06 g, 10 mmol) in water (11 cm3) were added and the mixture heated under reflux. After 16 h, the mixture was cooled, poured into water and extracted with EtOAc (×3). The combined organic layers were washed with sodium hydroxide (1N, ×2), brine, dried (MgSO4) and evaporated. The residue was subjected to column chromatography (SiO2, EtOAc:hexane, gradient elution) and the product triturated with hexane to afford the title compound (0.095 g, 0.30 mmol, 15%) as a solid: mp. >190° C. (decomp.); (CDCl3) δ 1.88 (s, 3H), 3.25 (s, 3H), 3.30 (s, 1H), 6.91 (d, 1H, J=8.1 Hz), 7.29-7.39 (m, 2H), 7.44-7.47 (m, 1H), 7.54-7.57 (m, 2H), 7.74 (d, 1H, J=1.7 Hz); MS (EI) m/z 311 (M+).
Reaction SMILES: [C:1]([N:9]1[CH:22]([C:23](O)=[O:24])[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH2:62])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1>>[CH3:44][O:45][C:46](=[O:63])[C@@H:47]([NH:62][C:23]([CH:22]1[CH2:21][C:20]2[CH:19]=[C:18]3[C:13]([O:14][C@@H:15]([C:27]4[CH:32]=[CH:31][C:30]([O:33][CH2:34][C:35]5[CH:40]=[CH:39][C:38]([Cl:41])=[C:37]([Cl:42])[CH:36]=5)=[CH:29][CH:28]=4)[C:16](=[O:26])[NH:17]3)=[CH:12][C:11]=2[CH2:10][N:9]1[C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:24])[CH2:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[CH:60]=[CH:59][C:58]([Cl:61])=[CH:57][CH:56]=2)=[CH:51][CH:50]=1
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccc(Cl)cc2)cc1
Reactant: O=C(O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3
Agent: Cl
Product: COC(=O)[C@H](Cc1ccc(-c2ccc(Cl)cc2)cc1)NC(=O)C1Cc2cc3c(cc2CN1C(=O)c1ccccc1)O[C@@H](c1ccc(OCc2ccc(Cl)c(Cl)c2)cc1)C(=O)N3

Procedure:
(S)-2-({(S)-6-Benzoyl-3-[4-(3,4-dichloro-benzyloxy)-phenyl]-2-oxo-2,3,5,6,7,8-hexahydro-1H-4-oxa-1,6-diaza-anthracene-7-carbonyl}-amino)-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester (71 mg, LC/MS: m/z 878) was prepared from Intermediate D (100 mg) and (S)-2-amino-3-(4′-chloro-biphenyl-4-yl)-propionic acid methyl ester hydrochloride according to general procedure A.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH2:22])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(N(C(C)C)CC)(C)C>CN1CCCC1=O>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([NH:22][C:2]2[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=2)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Brc1ccc(Br)nc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCC(Nc2ccc(Br)cn2)CC1
Temperature: 80 °C
Yield: 10.1 %

Procedure:
A tube was charged with 2,5-dibromopyridine (0.24 g, 1.0 mmol), 4-Amino-piperidine-1-carboxylic acid tert-butyl ester (0.22 g, 1.1 mmol), di-isopropylethylamine (0.19 mL, 1.1 mmol) and N-methylpyrrolidinone (1.0 mL). The tube was sealed and the mixture was heated at 80° C. overnight. The temperature was increased to 120° C. and heated overnight. The reaction was partitioned between ethyl acetate and water. The phases were separated and the aqueous phase was extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated by rotary evaporation. The residue was purified by silica gel chromatography using gradient elution of ethyl acetate and hexanes to afford 4-(5-bromo-pyridin-2-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (36 mg, 10%).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[C:6]([CH:15]=[CH2:16])=[CH:7][N+:8]([O-])=[CH:9]2)([O-:3])=[O:2].P(Cl)(Cl)([Cl:19])=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Cl:19][C:9]1[C:10]2[C:5](=[C:4]([N+:1]([O-:3])=[O:2])[CH:13]=[CH:12][CH:11]=2)[C:6]([CH:15]=[CH2:16])=[CH:7][N:8]=1
Reactant: C=Cc1c[n+]([O-])cc2cccc([N+](=O)[O-])c12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: C=Cc1cnc(Cl)c2cccc([N+](=O)[O-])c12
Temperature: 60 °C
Reaction time: 1 h

Procedure:
The 5-nitro-4-vinylisoquinoline N-oxide (27 g) obtained in Step B mentioned above was suspended in chloroform (300 ml), and added dropwise with phosphorus oxychloride (22.3 ml, Wako Pure Chemical Industries) under ice cooling. After the addition, the reaction mixture was warmed to 60° C., and stirred at the same temperature for one hour. The reaction mixture was poured into in ice water, and neutralized with 2 N sodium hydroxide with stirring. The organic layer was separated, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain the title compound (15 g).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]2=[C:8]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[F:22])[N:7]=1)=O)C.[NH3:23]>CO>[F:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[CH2:15][C:8]1[N:7]=[C:6]([C:4]([NH2:23])=[O:3])[N:10]2[CH:11]=[CH:12][CH:13]=[N:14][C:9]=12
Reactant: CCOC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(Cc2ccccc2F)c2ncccn12
Temperature: 150 °C
Reaction time: 1.33 h

Procedure:
8.200 g (27.40 mmol) of ethyl-8-(2-fluorobenzyl)imidazo[1,5-a]pyrimidine-6-carboxylate was distributed in 8 microwave vessels. Each vessel was charged with 10 ml of 7N solution of ammonia in methanol and stirred for 80 min at 150° C. in the microwave. After cooling, the contents of the vessels were combined, the resultant precipitate was filtered with suction, washed with a little methanol and dried under high vacuum. 8.42 g (quant.) of the target compound was obtained.
Reaction SMILES: Cl[C:2]1[C:6](=[CH:7][CH2:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[CH2:5][CH2:4][C:3]=1[C:16]([O:18][CH3:19])=[O:17].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([SH:30])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29].C(=O)([O-])[O-].[K+].[K+].O>CO>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([S:30][C:2]2[C:6](=[CH:7][CH2:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:5][CH2:4][C:3]=2[C:16]([O:18][CH3:19])=[O:17])[CH:25]=[CH:26][C:27]=1[O:28][CH3:29]
Reactant: COC(=O)C1=C(Cl)C(=CCCc2ccccc2)CC1
Reactant: COc1ccc(S)cc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COC(=O)C1=C(Sc2ccc(OC)c(OC)c2)C(=CCCc2ccccc2)CC1
Reaction time: 48 h
Yield: 57.5 %

Procedure:
A mixture of Methyl 2-chloro-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.2 g, 0.72 mmol), 3,4-dimethoxythiophenol (0.12 g, 0.72 mmol) and potassium carbonate (0.1 g, 0.72 mmol) in methanol (20 mL) is heated under reflux for 6 hours. After standing at room temperature for 2 days, the mixture is heated under reflux for another 4 hours. The mixture is poured into water and is extracted with ether. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (4:1 hexane:ethyl acetate) to provide methyl 2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylate (0.17 g, 58%): 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.10-1.70 (m, 5H), 1.88-1.98 (m, 1H), 2.31-2.40 (t, 3H), 2.58-2.70 (t, 3H), 3.78 (s, 3H), 3.84 (s, 3H), 3.90 (s, 3H), 6.68-6.75 (d, 1H), 6.95-7.09 (m, 4H), 7.17-7.30 (m, 3H); MS (EI) m/e 412 (M+).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([CH3:8])[CH:7]=1.[CH2:10](Br)[CH:11]=[CH2:12]>>[CH2:12]([O:9][C:4]1[CH:5]=[C:6]([CH3:8])[CH:7]=[C:2]([CH3:1])[CH:3]=1)[CH:11]=[CH2:10]
Reactant: C=CCBr
Reactant: Cc1cc(C)cc(O)c1
Product: C=CCOc1cc(C)cc(C)c1
Yield: 78 %

Procedure:
Using 3,5-dimethylphenol and allyl bromide, the title compound was synthesized in the same manner as in Reference Example 213. Yield 78%. Oily matter.
Reaction SMILES: [OH-].[Na+].O=[CH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:8]([O:9][CH3:10])[C:6]=1[OH:7].Br[CH2:15][C:16]([C:18]1[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=1)=[O:17]>C(O)C>[CH3:10][O:9][C:8]1[C:6]2[O:7][C:15]([C:16]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)=[O:17])=[CH:4][C:5]=2[CH:13]=[CH:12][CH:11]=1
Reactant: COc1cccc(C=O)c1O
Reactant: O=C(CBr)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1cccc2cc(C(=O)c3ccncc3)oc12
Temperature: 55 °C
Reaction time: 0.17 h
Yield: 27 %

Procedure:
Sodium hydroxide (1.22 g) was added to a solution of o-vanillin (2.11 g) in ethanol (50 ml) at 55° C. under a nitrogen atmosphere. The reaction mixture was stirred for 10 minutes to give a yellow suspension. 4-(Bromoacetyl)pyridine hydrobomide (5 g) was then added portionwise and the solution heated at 55° C. for 12 h, then at 65-70° C. for a further 12 h. The reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between water (250 ml, containing sodium hydroxide (0.5 g)) and dichloromethane (2×200 ml). The combined organic phases were washed with water (100 ml), dried over magnesium sulphate, filtered and evaporated in vacuo onto silica gel. The compound was washed through a pad of silica with ethyl acetate, the ethyl acetate was removed in vacuo and the residue azeotroped with hexane. The resulting solid was washed with hexane and filtered to furnish the title compound (0.95 g) as a yellow solid. TLC Rf 0.53 (ethyl acetate)
Reaction SMILES: [CH3:1][NH2:2].[F:3][C:4]([F:33])([F:32])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:31])[C:13]([N:16]2[C:21](=[O:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH2:29]Br)[O:18][CH2:17]2)([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1.C(OCC)(=O)C>C(O)C>[F:3][C:4]([F:33])([F:32])[C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:31])[C:13]([N:16]2[C:21](=[O:22])[C:20]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[C:19]([CH2:29][NH:2][CH3:1])[O:18][CH2:17]2)([CH3:15])[CH3:14])[CH:8]=[CH:9][CH:10]=1
Reactant: CC(C)(C(=O)Nc1cccc(C(F)(F)F)c1)N1COC(CBr)=C(c2ccccc2)C1=O
Reactant: CN
Solvent: CCOC(C)=O
Solvent: CCO
Product: CNCC1=C(c2ccccc2)C(=O)N(C(C)(C)C(=O)Nc2cccc(C(F)(F)F)c2)CO1
Temperature: 25 °C

Procedure:
Methylamine (2 ml of a 33% solution in ethanol) was added to a stirred suspension of N-(3-trifluoromethylphenyl)-2-(6-bromomethyl-2,3-dihydro-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (0.5 g) in ethanol. Stirring was maintained at room temperature for 1 hour. The solution was diluted (ethyl acetate), washed (water), dried (magnesium sulphate) and evaporated. The residue was purified by dry column chromatography on silica gel, eluting with methanol/hexane to give N-(3-trifluoromethylphenyl)-2-(2,3-dihydro-6-methylaminomethyl-4-oxo-5-phenyl-4H-1,3-oxazin-3-yl)-2-methylpropanamide (compound 105, 0.21 g) as an orange gum, NMR (CDCl3)δ 1.6(s,6H), 2.25(s,3H), 3.25(s,2H), 5.3(s,2H), 7.1-7.3(m,8H), 7.55(m,1H), 7.75(s,1H), 8.45(s,1H);
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=[O:11].C1COCC1.S(Cl)([Cl:21])(=O)=O>O>[Cl:21][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: COc1ccccc1CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(Cl)cc1CC(=O)O
Temperature: -15 °C
Yield: 95 %

Procedure:
A flame dried three-necked 3-L round-bottomed flask, equipped with a septa, stirring bar, argon inlet, thermocouple and addition funnel capped with a septa, was vacuum/argon purged. The flask was charged with commercially available 2-methoxy phenylacetic acid (300 g, 1.81 mol) and anhydrous THF (2 L). The mixture was cooled to approximately -15° C. and stirred until the solution became homogeneous. Neat sulfuryl chloride (205 mL, 2.55 mol) was added dropwise via an additional funnel while stirring over an hour. The internal temperature was maintained below -5° C. (ranging between -15° and -5° C.). Immediately after the complete addition of sulfuryl chloride, HPLC analysis showed the reaction was complete. The reaction mixture was poured into cold water (16 L) with vigorous stirring. The resultant slurry was stirred for 3 hours and the white precipitate was collected by filtration, washed with water (2 L), air dried for about 24 h, and vacuum dried to afford 345.3 g (95% yield, 97% by HPLC) of the title compound as an off-white solid that was used without further purification in the next step.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:12]1[N:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:15]2[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:14]=2[N:13]=1)[CH2:9][O:10][CH3:11])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:27][C:24]1[CH:25]=[CH:26][C:14]2[N:13]=[C:12]([C@@H:8]([NH2:7])[CH2:9][O:10][CH3:11])[N:16]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:15]=2[CH:23]=1
Reactant: COC[C@H](NC(=O)OC(C)(C)C)c1nc2ccc(F)cc2n1-c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC[C@H](N)c1nc2ccc(F)cc2n1-c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 65.3 %

Procedure:
To a solution of [(R)-1-(6-fluoro-1-phenyl-1H-benzoimidazol-2-yl)-2-methoxyethyl]carbamic acid tert-butyl ester (0.227 g, 0.59 mmol) in DCM (4.5 mL) was added TFA (2.5 mL) and the mixture stirred at RT for 2 h. The volatiles were removed in vacuo and the resulting residue partitioned between DCM and a saturated aqueous solution of NaHCO3. The two phase system was stirred for 10 min, then the organic fraction was dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% MeOH in DCM) to afford the title compound as a colourless oil (110 mg, 65%). LCMS (Method B): RT 1.90 min [M+H]+ 286.0.