Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:8]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][C:12]=3[N:7]2[N:6]=[C:5]1[C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])[CH:2]=[CH2:3].B1C2CCCC1CCC2.[OH-:39].[Na+].OO>C1COCC1.O>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]2[O:10][CH2:9][CH:8]3[C:4]([CH2:1][CH2:2][CH2:3][OH:39])([C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:5]([C:18]([N:20]([O:22][CH3:23])[CH3:21])=[O:19])=[N:6][N:7]3[C:12]=2[CH:13]=1
Reactant: [OH-]
Reactant: C=CCC1(c2ccccc2)C(C(=O)N(C)OC)=NN2c3cc(Cl)ccc3OCC21
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CON(C)C(=O)C1=NN2c3cc(Cl)ccc3OCC2C1(CCCO)c1ccccc1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
3-Allyl-8-chloro-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-2; a racemic mixture, 0.26 g, 0.64 mmol) was dissolved in anhydrous THF (5 mL) and treated with a 0.5M solution of 9-BBN (5.1 mL, 2.6 mmol) and stirred at 50° C. for 2 h. The reaction was cooled to 0° C. and treated with 3N NaOH (1 mL) and 30% H2O2 in water (1 mL), and stirred an additional hour. Upon completion, the reaction was quenched with the addition of brine (5 mL), and extracted with EtOAc (3×10 mL). The combined organic extracts were dried (MgSO4), filtered and concentrated. The crude residue was subjected to flash column chromatography (ISCO Redisep 40 g SiO2 column, 0-100% EtOAc/hexanes gradient) to provide pure 8-chloro-3-(3-hydroxypropyl)-N-methoxy-N-methyl-3-phenyl-3a,4-dihydro-3H-pyrazolo[5,1-c][1,4]benzoxazine-2-carboxamide (4-3; a racemic mixture): 1H NMR (300 MHz, CDCl3) δ 7.42 (d, J=2.1 Hz 1H), 7.43-7.24 (m, 5H), 6.83 (d, J=8.5, 2.1 Hz, H), 6.77 (d, J=12.5 Hz, 1H), 3.99 (dd, J=10.5, 3.5 Hz, 1H), 3.91 (s, 3H), 3.76 (br s, 1H), 3.56 (dd, J=11.0, 3.7 Hz, 1H), 3.32 (s, 3H), 2.93 (t, J=10.7 Hz, 1H), 2.59 (dt, J=12.2, 4.9 Hz, 1H), 2.42 (dt, J=12.2, 4.6 Hz, 1H), 1.90-1.60 (m, 4H); MS (M+H+, C22H24ClN3O4) 430.4 found 430.9 required.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([C:24]#[N:25])=[C:21]([CH3:23])[CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.Cl>O1CCOCC1>[C:24]([C:20]1[C:21]([CH3:23])=[CH:22][C:17]([C:15]([NH:14][CH:11]2[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]2)=[O:16])=[CH:18][N:19]=1)#[N:25]
Reactant: Cc1cc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cnc1C#N
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cc(C(=O)NC2CCNCC2)cnc1C#N
Temperature: 25 °C

Procedure:
To the above prepared 4-[(6-cyano-5-methyl-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.363 g, 1.05 mmol), dissolved in 3 ml of dioxane, was added 5.27 ml of 4N HCl (dioxane) and the resulting suspension stirred at ambient temperature for another h. Careful evaporation left 0.375 g of the title compound as hydrochloride as off-white crystals.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:3][CH2:2]1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26](Cl)=[O:27]>>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[Cl:32])[C:26]([N:1]1[CH2:2][CH2:3][C:4]2([O:11][C:10]3[C:12]4[C:17]([C:18](=[O:21])[C:19](=[O:20])[C:9]=3[S:8][CH2:7]2)=[CH:16][CH:15]=[CH:14][CH:13]=4)[CH2:5][CH2:6]1)=[O:27]
Reactant: O=C1C(=O)c2ccccc2C2=C1SCC1(CCNCC1)O2
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Product: O=C1C(=O)c2ccccc2C2=C1SCC1(CCN(C(=O)c3ccc(Cl)c(Cl)c3)CC1)O2

Procedure:
Compound 53 was synthesized using spiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, 3,4-dichlorobenzoyl chloride and conditions outlined in procedure N. M.p.=221° C.; 300 MHz 1H NMR (DMSO-d6) δ 7.89 (m, 2H), 7.74 (m, 3H), 7.58 (t, 1H), 7.46 (d, J=8.1 Hz, 1H), 4.40 (m, 1H), 3.56 (brm, 2H), 3.30 (m, 1H), 3.10 (s, 2H), 2.08 (m, 2H), 1.85 (m, 2H); LCMS: 474 [M+H].
Reaction SMILES: [CH2:1]([N:8]1[C:12](=[O:13])[CH2:11][S:10][C:9]1=[S:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:15](=O)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC#N>[CH2:1]([N:8]1[C:12](=[O:13])[C:11](=[CH:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[S:10][C:9]1=[S:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=Cc1ccccc1
Reactant: O=C1CSC(=S)N1Cc1ccccc1
Solvent: CC#N
Product: O=C1C(=Cc2ccccc2)SC(=S)N1Cc1ccccc1

Procedure:
A mixture of 3-benzylrhodanine (0.50 g, 2.2 mmol), benzaldehyde (0.23 mL, 2.3 mmol) and TEA (0.68 mL, 4.9 mmol) in MeCN (5 mL, anhyd) was heated at reflux. After 2 h the reaction mixture was cooled. Precipitated solids were collected by filtration, triturated with MeCN-Hex and dried under vacuum to yield 3-benzyl-5-benzylidene-2-thioxothiazolidin-4-one, which was used without further purification.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)=[O:4].[BH4-].[Na+]>C(O)C.O>[Br:1][CH2:2][CH:3]([C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]2([CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1)[OH:4]
Reactant: O=C(CBr)C1=CC2(CCCC2)c2ccccc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC(CBr)C1=CC2(CCCC2)c2ccccc21

Procedure:
3'-Bromoacetylspiro(cyclopentane-1,1'-indene) (7.5 g) in ethanol (150 ml) is stirred at about 20° C. with sodium borohydride (3.0 g) for 15 minutes. The solution is diluted with water and extracted three times with diethyl ether. The extracts are dried and the solvent removed, giving crude 2-bromo-1-[spiro(cyclopentane-1,1'-indene)-3'-yl]ethanol. This bromohydrine is dissolved in dioxane (75 ml) and dimethylamine (10 g) is added. The solution is heated in an autoclave at 90° C. for 2 hours. Evaporation of excess of dimethylamine and solvent gives an oily residue, which is treated with 2 N sodium hydroxide solution. Extraction with dichloromethane, drying of the extract and evaporation of the solvent gives the title amine as a colourless oil, which on treatment with oxalic acid in acetonitrile solution is converted to the crystalline hydrogen oxalate; m.p. 133°-134° C. after crystallization from acetonitrile.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].C(=O)C.C(N(CC)CC)C.[CH3:18][C:19]1[CH:23]=[C:22]([CH3:24])[NH:21][C:20]=1[CH:25]=[C:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[NH:28][C:27]1=[O:35]>CN(C=O)C>[C:5]([O:4][CH:1]([N:28]1[C:29]2[C:34](=[CH:33][CH:32]=[CH:31][CH:30]=2)/[C:26](=[CH:25]/[C:20]2[NH:21][C:22]([CH3:24])=[CH:23][C:19]=2[CH3:18])/[C:27]1=[O:35])[CH3:2])(=[O:7])[CH3:6]
Reactant: Cc1cc(C)c(C=C2C(=O)Nc3ccccc32)[nH]1
Reactant: CC(=O)OC(C)=O
Agent: CC=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)OC(C)N1C(=O)/C(=C\c2[nH]c(C)cc2C)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 64.7 %

Procedure:
A mixture of acetic anhydride (2.1 g, 20 mmol), acetaldehyde (4.4 g, 100 mmol), triethylamine (2.0 g, 20 mmol) and 3-(3,5-dimethyl-1H-pyrrol-2-ylmethylidene)-1,3-dihydro-indol-2-one (2.38 g, 10 mmol) in DMF (30 mL) was stirred at room temperature for 3 days. The solvents were removed and the residual oil was chromatographed on silica gel to give, as the first product eluted from the column, 2.5 g of product, which was crystallized from ether to give 2.1 g of the title compound, mp 107–110° C. HPLC Rt 6.78 min. 1H NMR (CDCl3) δ 1.81 (d, 3H), 2.09 (s, 3H), 2.33 (s, 3H), 2.38 (s, 3H), 5.98 (s, 2H), 7.00–7.20 (m, 3H), 7.25 (dd, 1H), 7.39 (s, 1H), 7.51 (dd, 1H) and 13.0 (br s, 1H). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.33; H, 6.18; N, 8.60.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[N:30]=[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][NH:26][C:25](=O)[CH2:24]5)[N:16]4[N:15]=3)=[CH:10][CH:11]=2)[NH:6][N:5]=1.Cl.[OH2:32]>C(O)C>[CH3:1][O:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][C:9]([NH:13][C:14]3[N:30]=[C:17]4[CH:18]=[CH:19][CH:20]=[C:21]([CH2:22][N:23]5[CH2:28][CH2:27][NH:26][CH2:25][C:24]5=[O:32])[N:16]4[N:15]=3)=[CH:10][CH:11]=2)[NH:6][N:5]=1
Reactant: COCc1n[nH]c2cc(Nc3nc4cccc(CN5CCNC(=O)C5)n4n3)ccc12
Reactant: O
Agent: Cl
Solvent: CCO
Product: COCc1n[nH]c2cc(Nc3nc4cccc(CN5CCNCC5=O)n4n3)ccc12
Temperature: 60 °C
Yield: 12 %

Procedure:
4-((2-(3-(Methoxymethyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-a]pyridin-5-yl)methyl)piperazin-2-one. 6 M HCl in water (0.410 mL, 2.459 mmol) was added to a stirred mixture of 4-((2-(3-(methoxymethyl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazol-6-ylamino)-[1,2,4]triazolo[1,5-c]pyridin-5-yl)methyl)piperazin-2-one (0.132 g, 0.246 mmol) in ethanol (5 mL) at 60° C. The resulting mixture was stirred vigorously and heated at 60° C. under a reflux condenser under nitrogen for 12 h. The solvent was removed on a rotary evaporator. The residue was dissolved in hot DMSO, diluted with methanol, filtered, and purified using reverse-phase semi-preparatory HPLC (5-30% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 30 min). Fractions containing the desired product were loaded onto a Strata X—C ion exchange column from Phenomenex. The column was washed successively with water, acetonitrile, methanol, and then 5% ammonium hydroxide in methanol. The product came off with the 5% ammonium hydroxide in methanol eluent and was concentrated on a rotary evaporator and dried under high vacuum at 45° C. to give the desired product (0.012 g, 0.030 mmol, 12% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 12.67 (s, 1H), 9.86 (s, 1H), 8.19 (d, J=1.17 Hz, 1H), 7.86 (s, 1H), 7.51-7.65 (m, 3H), 7.24 (dd, J=1.76, 8.79 Hz, 1H), 7.11 (d, J=7.03 Hz, 1H), 4.66 (s, 2H), 4.11 (s, 2H), 3.29 (s, 3H), 3.17-3.27 (m, 4H), 2.80 (t, J=5.27 Hz, 2H); MS (ESI) m/z 407.5 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH2:25])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N[CH2:34][CH2:35][OH:36].C(OCC)(=O)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@H:10]([NH:14][C:15]([C:17]2[C:21]([NH:22][C:23]([NH:25][CH2:34][CH2:35][OH:36])=[O:24])=[CH:20][N:19]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)[CH:18]=2)=[O:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: NCCO
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(N)=O)C1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC[C@H](NC(=O)c2cn(-c3cccc(F)c3)cc2NC(=O)NCCO)C1
Yield: 55 %

Procedure:
Following general method 6, employing (S)-3-{[1-(3-fluorophenyl)-4-ureido-1H-pyrrole-3-carbonyl]-amino}-piperidine-1-carboxylic acid tert-butyl ester and 2-amino-ethanol, afforded the crude desired product. Column chromatography (silica, 12 g column, ISCO, 0-100% ethyl acetate in DCM) afforded the title compound as a glass (60 mg, 55%); LCMS (method B): RT=3.25 min, M+H+=490.
Reaction SMILES: [OH:1][C:2]([CH3:14])([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])[C:3](O)=[O:4].[NH2:15][C@@H]1C(=O)N(CC(F)(F)F)C2C=C(F)C=CC=2O[C@@H]1CC>>[OH:1][C:2]([CH3:14])([C:6]([NH:8][CH2:9][C:10]([F:13])([F:12])[F:11])=[O:7])[C:3]([NH2:15])=[O:4]
Reactant: CC[C@H]1Oc2ccc(F)cc2N(CC(F)(F)F)C(=O)[C@H]1N
Reactant: CC(O)(C(=O)O)C(=O)NCC(F)(F)F
Product: CC(O)(C(N)=O)C(=O)NCC(F)(F)F

Procedure:
N-[(6R,7S)-6-Ethyl-2-fluoro-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-(R or S)-2-hydroxy-2-methyl-N′-(2,2,2-trifluoro-ethyl)-malonamide, entity A, was obtained according to the procedures described for example 2b using (S or R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, entity B (example 72), and (6R,7S)-7-amino-6-ethyl-2-fluoro-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, MS m/e (%): 504.0 (M+H+, 100). N-[(6R,7S)-6-Ethyl-2-fluoro-8-oxo-9-(2,2,2-trifluoro-ethyl)-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl]-(R or S)-2-hydroxy-2-methyl-N′-(2,2,2-trifluoro-ethyl)-malonamide, entitiy B, was obtained according to the procedures described for example 2b using (S or R)-2-hydroxy-2-methyl-N-(2,2,2-trifluoro-ethyl)-malonamic acid, entity A (example 72), and (6R,7S)-7-amino-6-ethyl-2-fluoro-9-(2,2,2-trifluoro-ethyl)-6,7-dihydro-9H-5-oxa-9-aza-benzocyclohepten-8-one, MS m/e (%): 504.0 (M+H+, 100).
Reaction SMILES: [F:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[C:6]([N+]([O-])=O)[C:3]=1[C:4]#[N:5].[Cl-:14].[Ca+2].[Cl-].ClCl>>[Cl:14][C:6]1[CH:7]=[CH:8][C:9]([F:10])=[C:2]([F:1])[C:3]=1[C:4]#[N:5]
Reactant: N#Cc1c([N+](=O)[O-])ccc(F)c1F
Reactant: [Cl-]
Agent: ClCl
Agent: [Ca+2]
Product: N#Cc1c(Cl)ccc(F)c1F
Temperature: 190 °C
Yield: 987.8 %

Procedure:
24.8 g (0.135 mol) of 2,3-difluoro-6-nitrobenzonitrile and 1 g of anhydrous calcium chloride are placed in a 50 ml flask with a finely drawn-out gas inlet tube, and heated to 190° C. Chlorine is introduced at this temperature with a throughput of 2-3 l/h so that a uniform production of nitrous gases occurs. After a reaction time of 12 h, the starting material has been substantially converted (<10% residual content of nitro compound). The remaining nitrous gases are purged with air and the residue is distilled off under vacuum over a short Vigreux column to give 15.5 g (89 mmol, 66%) of 2-chloro-5,6-difluorobenzonitrile as a light yellowish, oily liquid boiling at 70°-75° C./3 Torr (purity (GC)>95%).
Reaction SMILES: CC1(C)[O:6][CH:5]([CH2:7][N:8]2[CH:12]=[C:11]([C:13]3[CH:14]=[C:15]4[C:20](=[CH:21][CH:22]=3)[CH:19]=[N:18][C:17]([NH:23][C:24]3[CH:29]=[CH:28][C:27]([C:30]5[N:34]([CH3:35])[C:33]([CH3:36])=[N:32][CH:31]=5)=[CH:26][C:25]=3[O:37][CH3:38])=[CH:16]4)[CH:10]=[N:9]2)[CH2:4][O:3]1.C(O)(C(F)(F)F)=O>C1COCC1>[CH3:35][N:34]1[C:30]([C:27]2[CH:28]=[CH:29][C:24]([NH:23][C:17]3[N:18]=[CH:19][C:20]4[C:15]([CH:16]=3)=[CH:14][C:13]([C:11]3[CH:10]=[N:9][N:8]([CH2:7][CH:5]([OH:6])[CH2:4][OH:3])[CH:12]=3)=[CH:22][CH:21]=4)=[C:25]([O:37][CH3:38])[CH:26]=2)=[CH:31][N:32]=[C:33]1[CH3:36]
Reactant: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(CC4COC(C)(C)O4)c3)ccc2cn1
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(-c2cnc(C)n2C)ccc1Nc1cc2cc(-c3cnn(CC(O)CO)c3)ccc2cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.8 %

Procedure:
To a solution of 6-(1-((2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-1H-pyrazol-4-yl)-N-(4-(1,2-dimethyl-1H-imidazol-5-yl)-2-methoxyphenyl)isoquinolin-3-amine (Example 40, 20 mg, 0.038 mmol) in THF (8 mL) at 0° C. was added TFA (1 mL). the reaction was stirred at room temperature for 16 hours before concentrating in vacuo. The residue was purified by elution through an SCX-2 column using 2M NH3/MeOH to afford the title compound (18 mg, 97%).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH2:17])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:19][C:20]1[C:21]([CH3:26])=[CH:22][CH:23]=[CH:24][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[CH3:26])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1=NC(=O)CN1C(=O)OCc1ccccc1
Reactant: Cc1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccccc1CNC1=NC(=O)CN1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 43 %

Procedure:
A suspension of 2-amino-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (93.2 mg, 0.40 mmol), alpha-bromo-o-xylene (74.02 mg, 0.40 mmol) and K2CO3 (166.0 mg, 1.20 mmol) in acetonitrile (10 mL) was heated to reflux under argon for 1 hr. Cool to r.t., the reaction mixture was partitioned between EtOAc and water. The organic layer was dried over Na2SO4 and concentrated to give an oil which was purified by preparative TLC, eluted with 50% nHex/EtOAc to give 2-(2-methyl-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester as a white solid (58.0 mg, 42.9%).
Reaction SMILES: C[S:2][C:3](=S)[NH:4][N:5]=[CH:6][C:7]1[N:8]=[C:9]([CH2:13][CH2:14][CH3:15])[NH:10][C:11]=1[CH3:12].C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:12][C:11]1[N:10]=[C:9]([CH2:13][CH2:14][CH3:15])[N:8]2[C:7]=1[CH:6]=[N:5][NH:4][C:3]2=[S:2]
Reactant: CCCc1nc(C=NNC(=S)SC)c(C)[nH]1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCCc1nc(C)c2cn[nH]c(=S)n12

Procedure:
A mixture of 32.12 gm. of 3-[(5-methyl-2-n-propyl-4-imidazolyl)methylene]dithiocarbazic acid methyl ester and 200 ml. of diphenyl ether is reacted as described in Example 23 giving the desired product, m.p. 183°-186° C.
Reaction SMILES: COP([CH:7]([CH:13]([CH3:15])[CH3:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])(OC)=O.C([Li])CCC.[CH3:21][C:22](=[CH:24][CH2:25][CH2:26]/[C:27](=[CH:29]/[CH:30]=O)/[CH3:28])[CH3:23].[Cl-].[NH4+]>O1CCCC1.CCCCCC>[CH3:14][CH:13]([C:7](=[CH:30][CH:29]=[C:27]([CH3:28])[CH2:26][CH2:25][CH:24]=[C:22]([CH3:23])[CH3:21])[C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH3:15]
Reactant: CC(C)=CCC/C(C)=C/C=O
Reactant: CCOC(=O)C(C(C)C)P(=O)(OC)OC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C(=CC=C(C)CCC=C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 44.1 %

Procedure:
To a solution of ethyl 2-(dimethylphosphono)-3-methylbutyrate (11.0 g, 41.3 mmol) in tetrahydrofuran (50 ml) chilled at -68° C. was dropwise added 1.62M solution of n-butyllithium in hexane (21.6 ml, 35.0 mmol) with stirring in 15 minutes under argon atmosphere. After stirring at -72° C. for 15 minutes, the mixture was mixed with geranial (4.0 g, 26.3 mmol), warmed up to room temperature in 30 minutes and stirred for 5 hours. The reaction mixture was chilled on an ice bath and mixed with saturated aqueous ammonium chloride (100 ml) and hexane (100 ml). The organic layer was separated, washed with saturated aqueous sodium chloride (50 ml), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to remove the solvent. The resulting residue was chromatographed on a silica gel column (Eluent: n-hexane:ether=30:1) to give ethyl 2-(1-methylethyl)-5,9-dimethyl-2,4,8-decatrienate (3,07 g, 48%).
Reaction SMILES: O[C:2]1[C:7]([OH:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10]([C:12]1[CH:17]=[C:16]([OH:18])[C:15]([O:19][CH2:20][C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:14]([OH:29])[CH:13]=1)=[O:11].[CH2:30]([OH:37])[C:31]([NH2:36])([CH2:34][OH:35])[CH2:32][OH:33]>[Ag]=O>[OH:29][C:14]1[CH:13]=[C:12]([CH:17]=[C:16]([OH:18])[C:15]=1[O:19][CH2:20][C:21](=[O:28])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:10]([C:3]1[CH:4]=[CH:5][C:6](=[O:9])[C:7]2([OH:8])[O:37][CH2:30][C:31]([CH2:34][OH:35])([CH2:32][OH:33])[NH:36][C:2]=12)=[O:11]
Reactant: O=C(COc1c(O)cc(C(=O)c2ccc(O)c(O)c2O)cc1O)c1ccccc1
Reactant: NC(CO)(CO)CO
Agent: O=[Ag]
Product: O=C(COc1c(O)cc(C(=O)C2=C3NC(CO)(CO)COC3(O)C(=O)C=C2)cc1O)c1ccccc1
Yield: 40.3 %

Procedure:
The procedure is analogous to that described in Example 8a), but starting with 0.79 g of [2,3,4-trihydroxy-phenyl][3',5'-dihydroxy-4'-(2-oxo-2-phenylethoxy)phenyl] methanone (compound VIIIb described in Example 2), 12.10 g of Tris and 2.30 g of silver oxide (Ag2O). After purification by chromatography on a 30 g silica gel column (diameter: 2.0 cm, height: 60 cm) eluted with an ethyl acetate/methanol mixture (97/3 by volume), 0.40 g of (RS)-5-[3,5-dihydroxy-4-(2-oxo-2-phenylethoxy)-benzoyl]-3,3-bis(hydroxymethyl)-8a-hydroxy-3,4-dihydro-2H-1,4-benzoxazin-8(8aH)-one is obtained in the form of an orange powder melting at around 185° C. (with decomposition).
Reaction SMILES: C1CCCC([O:7][C:8]2[CH:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[C:15]([Cl:22])=[CH:14][C:9]=2[C:10]([O:12][CH3:13])=[O:11])C=1.CCN([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)CC>C(OC(=O)C)C.CCCCCC>[CH2:30]([C:17]1[C:16]([NH:18][C:19](=[O:21])[CH3:20])=[C:15]([Cl:22])[CH:14]=[C:9]([C:10]([O:12][CH3:13])=[O:11])[C:8]=1[OH:7])[CH2:29][CH:28]=[CH:33][CH2:32][CH3:31]
Reactant: CCN(CC)c1ccccc1
Reactant: COC(=O)c1cc(Cl)c(NC(C)=O)cc1OC1C=CCCC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CCC=CCCc1c(O)c(C(=O)OC)cc(Cl)c1NC(C)=O
Temperature: 220 °C

Procedure:
A mixture of 0.6 g of methyl 2-(cyclohexen-3-yloxy)-4-acetylamino-5-chlorobenzoate and 0.5 ml diethylaniline is placed under house vaccum and heated to 220° C. for 2 hours. This reaction mixture is then diluted with 40% ethylacetate/hexane and purified by dry column chromatography using the same solvent system as eluent. Three fractions are separated: 1. diethylaniline; 2. starting benzoate compound and 3. methyl 3-(3-hexenyl)-4-acetylamino-5-chlorosalicylate. The latter is used directly in the next step.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11]C)=O)=[CH:7][N:6]=[C:5]([Cl:13])[CH:4]=1.Cl.[NH2:15][C@@H:16]([CH2:29][CH:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1)[CH2:17][N:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]1=[O:28].C(N(CC)C(C)C)(C)C.C(O)CCC>>[Cl:13][C:5]1[N:6]=[CH:7][C:8]2[C:9](=[O:11])[N:15]([C@@H:16]([CH2:29][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)[CH2:17][N:18]3[C:19](=[O:28])[C:20]4[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=4)[C:26]3=[O:27])[CH2:2][C:3]=2[CH:4]=1
Reactant: COC(=O)c1cnc(Cl)cc1CBr
Reactant: N[C@@H](CC1CCCCC1)CN1C(=O)c2ccccc2C1=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: O=C1c2ccccc2C(=O)N1C[C@H](CC1CCCCC1)N1Cc2cc(Cl)ncc2C1=O
Temperature: 140 °C
Reaction time: 2 h
Yield: 55.1 %

Procedure:
A mixture of methyl 4-(bromomethyl)-6-chloronicotinate (200.0 mg, 0.7561 mmol) (prepared according to Example 119, Steps A, B and C), 2-[(2S)-2-amino-3-cyclohexylpropyl]-1H-isoindole-1,3(2H)-dione hydrochloride (244 mg, 0.754 mmol) (prepared from Example 79, Step A) and N,N-diisopropylethylamine (0.526 mL, 3.02 mmol) in 1-butanol (5.0 mL, 55 mmol) was stirred at 140° C. for 2 h under microwave irradiation. Direct purification on prep.HPLC afforded 182 mg (55.1% yield) of the desired product. LC-MS found: 438.1 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[N:6]2[C:7](Br)=[CH:8][N:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[CH2:12]([NH2:16])[CH2:13][CH2:14][CH3:15]>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][N:9]=[C:10]([NH:16][CH2:12][CH2:13][CH2:14][CH3:15])[C:5]2=[N:4][CH:3]=1
Reactant: Brc1cncc2ncc(Br)n12
Reactant: CCCCN
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCCCNc1nccn2c(Br)cnc12
Temperature: 70 °C
Yield: 51.1 %

Procedure:
To a solution of 3,5-dibromo-imidazo[1,2-a]pyrazine (D) (200 mg, 0.72 mmol) in THF (3.6 ml) was added butylamine (2.2 ml, 21.6 mmol). The mixture was heated at 70° C. for 3 hr. The mixture was then cooled to rt, and diluted with DCM. The organic layer was washed with water, brine, dried and concentrated. The residue was purified on a silica gel column to afford 99 mg (yield 51%) of (3-bromo-imidazo[1,2-a]pyrazin-8-yl)-butyl-amine.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([Cl:23])[C:5]([Cl:22])=[C:6]([CH2:8][N:9]2[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]2=[O:21])[CH:7]=1.[I:24]I.N(OC(C)(C)C)=O>CS(C)=O>[Cl:22][C:5]1[C:4]([Cl:23])=[CH:3][C:2]([I:24])=[CH:7][C:6]=1[CH2:8][N:9]1[C:14](=[O:15])[CH:13]=[C:12]([C:16]([F:19])([F:18])[F:17])[N:11]([CH3:20])[C:10]1=[O:21]
Reactant: II
Reactant: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(N)cc(Cl)c2Cl)c1=O
Agent: CC(C)(C)ON=O
Solvent: CS(C)=O
Product: Cn1c(C(F)(F)F)cc(=O)n(Cc2cc(I)cc(Cl)c2Cl)c1=O
Yield: 110.3 %

Procedure:
By the method of Example 2, Step B, 2.67 grams (0.00725 mole) of 3-(5-amino-2,3-dichlorophenylmethyl)-1-methyl-6-trifluoromethyluracil, 1.84 grams (0.00725 mole) of iodine, and 1.12 grams (0.0109 mole) of tertiarybutyl nitrite were reacted in 10 mL of dimethyl sulfoxide, yielding 3.83 grams of 3-(2,3-dichloro-5-iodophenylmethyl)-1-methyl-6-trifluoromethyluracil as a light brown solid, m.p. 142°-144° C. The NMR and IR spectra were consistent with the proposed structure.