Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([C:9]2[NH:18][C:17](=[O:19])[C:16]3[C:11](=[CH:12][C:13]([O:22][CH3:23])=[CH:14][C:15]=3[O:20][CH3:21])[N:10]=2)=[CH:4][C:3]=1[CH3:24].[CH:25]([N:28]([CH:31](C)C)[CH2:29]C)(C)C.CS(Cl)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:21][O:20][C:15]1[CH:14]=[C:13]([O:22][CH3:23])[CH:12]=[C:11]2[C:16]=1[C:17](=[O:19])[NH:18][C:9]([C:5]1[CH:6]=[C:7]([CH3:8])[C:2](/[N:1]=[CH:25]/[N:28]([CH3:31])[CH3:29])=[C:3]([CH3:24])[CH:4]=1)=[N:10]2
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(N)c(C)c3)nc2c1
Reactant: CCN(C(C)C)C(C)C
Agent: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C)c(/N=C/N(C)C)c(C)c3)nc2c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 44.7 %

Procedure:
To a solution of 2-(4-amino-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.096 g, 0.295 mmol) and diisopropylethylamine (61.7 μL, 0.354 mmol), in DMF (2.96 mL) was added dropwise methanesulfonyl chloride (25.2 μL, 0.325 mmol). After stirring at room temperature for 18 h, the mixture was diluted with EtOAc (300 mL), washed with saturated aqueous sodium bicarbonate (2×75 mL), saturated aqueous LiCl (2×75 mL), dried over sodium sulfate, filtered and concentrated under vacuum. The residue was purified over silica gel (12 g, CH2Cl2/CH3OH) to provide (E)-N′-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenyl)-N,N-dimethylformimidamide (0.0502 g, 45%) as a white solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 11.68 (s, 1H), 7.87 (s, 2H), 7.40 (s, 1H), 6.72 (d, J=2.31 Hz, 1H), 6.48 (d, J 2.31 Hz, 1H), 3.88 (s, 3H), 3.86 (s, 3H), 2.97 (s, 6H), 2.12 (s, 6H); MS (APCI) m/z 381 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([Br:11])=[CH:7][CH:6]=1)=O.[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]=1.C(=O)([O-])O.[Na+]>C(O)C>[Br:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2[N:12]=[C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][N:14]3[CH:2]=2)=[CH:6][CH:7]=1
Reactant: O=C(CBr)c1ccc(Br)cc1
Reactant: Cc1ccc(N)nc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: Cc1ccc2nc(-c3ccc(Br)cc3)cn2c1
Yield: 81.3 %

Procedure:
Dissolving 5 g (18 mmol) of 2,4′-dibromo acetophenone and 2.0 g (19 mmol) of 2-amino-5-picoline into 30 milliliter of ethanol, adding 2.9 g of sodium hydrogen carbonate, the resultant suspension was refluxed under heating for 6 hours. After completion of the reaction, separation with filtration was carried out and resultant crystals were washed with water and ethanol, thereby obtaining 4.2 g of 2-(4-bromo-phenyl)-6-methyl-imidazo [1,2-a] pyridine (yield: 81%).
Reaction SMILES: CO.[OH-].[Na+].[CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:13]=[C:14]([C:19](=[O:21])[CH:20]=2)[C:15]([O:17]C)=[O:16])[CH2:7][CH:6]=1>C(O)(=O)C>[CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[N:12]([C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[CH:13]=[C:14]([C:19](=[O:21])[CH:20]=2)[C:15]([OH:17])=[O:16])[CH2:7][CH:6]=1
Reactant: COC(=O)c1cn(-c2ccc(O)cc2)c(C2CC=CCC2)cc1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: O=C(O)c1cn(-c2ccc(O)cc2)c(C2CC=CCC2)cc1=O
Yield: 73.2 %

Procedure:
In a mixture consisting of 5 ml of methanol and 5 ml of a 1N aqueous sodium hydroxide solution was dissolved 0.5 g of methyl 6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinate, and they wre reacted at room temperature for 30 minutes. After completion of the reaction, the reaction mixture was adjusted to a pH of 5.5 with acetic acid, and the precipitated crystals were collected by filtration, washed with 30 ml of water, and dried to obtain 0.35 g of 6-(cyclohexen-4-yl)-1-(4-hydroxyphenyl)-4-oxo-1,4-dihydronicotinic acid having a melting point of 250° C. or more.
Reaction SMILES: [Cl-:1].[O:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]1=[CH:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH:28](=O)[C:29]1[O:33][CH:32]=[CH:31][CH:30]=1.C1(C)C(C)=CC=CC=1>C(OCC)(=O)C>[O:33]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH:28]=[CH:8][C:3](=[O:2])[CH2:4][CH2:5][CH2:6][CH2:7][Cl:1]
Reactant: C(=C1CCCCO1)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: [Cl-]
Reactant: O=Cc1ccco1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1C
Product: O=C(C=Cc1ccco1)CCCCCl

Procedure:
2 parts of [(tetrahydro-2H-pyran-2-ylidene)methyl] triphenylphosphonium chloride and 1 part of furfural were combined in 45 parts of xylene. This was maintained under a nitrogen atmosphere and was refluxed for about 24 hours to give a black solution. After cooling the reaction mixture to room temperature xylene was removed from this solution at a temperature of about 40°-60° C. under reduced pressure, leaving a product mixture. This mixture was seprated chromatographically on a silica column using as the elution solvent a solution of 20 percent by volume of ethyl acetate in Skelly B, to yield 1-(2-furyl)7-chloro-1-hepten-3-one which, after a recrystallization from n-pentane, melted at about 50°-52° C.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C1(C)C(S([C:26]2([C:37]3C=CC=C[CH:38]=3)[C:34](=[O:35])[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:27]2=[O:36])(=O)=O)=CC=CC=1>C(#N)C>[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:38][CH2:37][C:26]4([C:2]5[CH:16]=[CH:15][CH:5]=[CH:4][CH:3]=5)[C:34](=[O:35])[C:33]5[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=5)[C:27]4=[O:36])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Cc1ccccc1S(=O)(=O)C1(c2ccccc2)C(=O)c2ccccc2C1=O
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Solvent: CC#N
Product: O=C1c2ccccc2C(=O)C1(CCN1CCC(c2noc3cc(F)ccc23)CC1)c1ccccc1

Procedure:
A mixture of 4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidine (2.2 g, 10 mmol), KCO3 (1.6 g, 11.6 mmol) and 2-toluenesulfonyl-2-phenyl-1,3-indandione (4.2 g, 10 mmol) in acetonitrile (50 ml) was heated at reflux for 3 hours. The mixture was cooled and the insolubles were filtered. The solvent was removed on a rotary evaporator. The residue was purified twice using a flash chromatography column (SiO2, 45 g and 40 g; eluted with DCM). The product thus purified was recrystallized from ethanol (30 ml) and isopropyl ether, yield: 2.8 g, m.p. 149°-150° C.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl-].[OH:8][NH3+:9].[C:10]([C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13])#[N:11]>O.C(O)C>[NH2:11]/[C:10](=[N:9]\[OH:8])/[C:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:14])[CH3:13]
Reactant: [NH3+]O
Reactant: CC(C)(C#N)NC(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C)(C)/C(N)=N/O
Temperature: 25 °C
Reaction time: 18 h
Yield: 94.1 %

Procedure:
Potassium carbonate (3.64 g) was dissolved in water (12 mL) and hydroxylammonium chloride (CAN: 5470-11-1, 1.7 g, mmol) was added. A solution of tert-butyl 2-cyanopropan-2-ylcarbamate (4.84 g, 26 mmol) in ethanol (42 mL) was added and the resulting reaction mixture was stirred for 18 h at ambient temperature. The solvent was removed under reduced pressure and the residue was diluted with ethyl acetate (20 mL). The mixture was filtered and the filtrate was concentrated to yield the crude product (5 g, 87.6%) as yellow solid. MS: m/e=218.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH3:7])=[C:5]([NH:8][C:9](=[O:16])OCC(Cl)(Cl)Cl)[O:4][N:3]=1.[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[S:28][CH:29]=1.C(N(C(C)C)CC)(C)C.O>CS(C)=O>[Cl:17][C:18]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:19]=1[C:25]1[N:26]=[C:27]([N:30]2[CH2:35][CH2:34][N:33]([C:9]([NH:8][C:5]3[O:4][N:3]=[C:2]([CH3:1])[C:6]=3[CH3:7])=[O:16])[CH2:32][CH2:31]2)[S:28][CH:29]=1
Reactant: Clc1cccc(-c2csc(N3CCNCC3)n2)c1Cl
Reactant: Cc1noc(NC(=O)OCC(Cl)(Cl)Cl)c1C
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(NC(=O)N2CCN(c3nc(-c4cccc(Cl)c4Cl)cs3)CC2)c1C
Temperature: 70 °C
Reaction time: 72 h
Yield: 15.6 %

Procedure:
A mixture of 2,2,2-trichloroethyl (3,4-dimethylisoxazol-5-yl)carbamate (121 mg, 0.420 mmol), 1-[4-(2,3-dichlorophenyl)-1,3-thiazol-2-yl]piperazine (120 mg, 0.382 mmol) and diisopropylethylamine (0.133 ml, 0.764 mmol) in dimethyl sulfoxide (1.2 ml) was stirred at 70° C. for 3 days. Water was poured to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:1), and recrystallized from a mixed solvent of hexane and ethyl acetate to give 27.0 mg (15.6%) of the desired product as a solid. mp 175-176° C.
Reaction SMILES: I[C@@:2]1([N:11]2[CH:18]=[CH:17][C:15](=[O:16])[NH:14][C:12]2=[O:13])[O:10][C@H:7]([CH2:8][OH:9])[C@@H:5](O)[C@H:3]1O.[CH2:19]([NH:22][C:23](=[O:28])[C:24]([F:27])([F:26])[F:25])[C:20]#[CH:21].CO>ClCCl>[F:25][C:24]([F:27])([F:26])[C:23]([NH:22][CH2:19][C:20]#[C:21][C:17]1[C:15](=[O:16])[NH:14][C:12](=[O:13])[N:11]([CH:18]=1)[C@@H:2]1[O:10][C@H:7]([CH2:8][OH:9])[CH2:5][CH2:3]1)=[O:28]
Reactant: O=c1ccn([C@]2(I)O[C@H](CO)[C@@H](O)[C@H]2O)c(=O)[nH]1
Reactant: C#CCNC(=O)C(F)(F)F
Solvent: CO
Solvent: ClCCl
Product: O=C(NCC#Cc1cn([C@H]2CC[C@@H](CO)O2)c(=O)[nH]c1=O)C(F)(F)F

Procedure:
Iodouridine 47 was coupled for 3 h to N-propargyltrifluoroacetamide following the general method given in Example 1C. Chomatography with a 0-5% methanol in dichloromethane gradient afforded material which was homogeneous by TLC, but which was difficult to dry. After co-evaporating the chomatographed product several times with chloroform and vacuum-drying, 536.5 mg of alkynylamino nucleoside 48 was obtained as a white foam. This material was homogeneous by TLC and was pure by NMR except for a small amount (39 mole %; corrected yield 66%) of chloroform.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:17](F)=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH2:19][CH3:20])=[CH:10][C:9]=2[F:25])[N:7]=1.[CH3:26][NH2:27]>>[NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[C:17]([NH:27][CH3:26])=[C:16]3[C:11]([C:12](=[O:24])[C:13]([C:21]([OH:23])=[O:22])=[CH:14][N:15]3[CH2:19][CH3:20])=[CH:10][C:9]=2[F:25])[N:7]=1
Reactant: CN
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CN)n3)c(F)c21
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(-c3csc(CN)n3)c(NC)c21
Temperature: 50 °C

Procedure:
To 500 mg (1.37 mmol) of the 7-[2-(aminomethyl)-4-thiazolyl]-1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid was added 15 ml of 40% aqueous methylamine. The mixture was heated at 50° C. for 72 hours. The solution was taken to pH 6.5 and was filtered to give 350 mg of 7-[2-(aminomethyl)-4-thiazolyl]-1-ethyl-6-fluoro-1,4-dihydro-8-methylamino-4-oxo-3-quinolinecarboxylic acid, mp 194°-195° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Fc1ccc(-c2noc(C(F)(F)F)c2-c2c[nH]cn2)cc1
Product: O=[N+]([O-])c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 71 %

Procedure:
As described for Example 24, 3-(4-fluoro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.34 mmol), using 1-fluoro-4-nitrobenzene instead of 4-fluoroacetophenone, was converted to the title compound (100 mg, 71%) which was obtained as a yellow solid. MS: m/e=417.1 [M−H]−.
Reaction SMILES: Cl.[CH2:2]1[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6][CH2:5][CH2:4][N:3]1[C:13]([C:15]1[CH:23]=[C:22]2[C:18]([CH2:19][CH2:20][C@H:21]2[NH:24][C:25](=[O:33])[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[Cl:32])=[CH:17][CH:16]=1)=[O:14].C(N(CC)CC)C.Cl.Cl[C:43]1[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=1.C([O-])(O)=O.[Na+]>C(O)CCC.C(OCC)(=O)C>[Cl:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:25]([NH:24][C@H:21]1[C:22]2[C:18](=[CH:17][CH:16]=[C:15]([C:13]([N:3]3[CH2:4][CH2:5][CH2:6][C:7]4([CH2:8][CH2:9][N:10]([C:43]5[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=5)[CH2:11][CH2:12]4)[CH2:2]3)=[O:14])[CH:23]=2)[CH2:19][CH2:20]1)=[O:33]
Reactant: O=C(N[C@@H]1CCc2ccc(C(=O)N3CCCC4(CCNCC4)C3)cc21)c1ccccc1Cl
Reactant: Clc1ccncc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCCCO
Solvent: CCOC(C)=O
Product: O=C(N[C@@H]1CCc2ccc(C(=O)N3CCCC4(CCN(c5ccncc5)CC4)C3)cc21)c1ccccc1Cl
Temperature: 110 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of (R)—N-(6-(2,9-diazaspiro[5.5]undecane-2-carbonyl)-2,3-dihydro-1H-inden-1-yl)-2-chlorobenzamide hydrochloride (0.491 mmol, 1.0 eq.), triethylamine (5.0 eq.) and 4-chloropyridine hydrochloride (3.0 eq.) in n-butanol (13 ml) was stirred at 110° C. overnight. Ethyl acetate and sat. NaHCO3 solution were added and the aqueous phase was extracted with ethyl acetate a further 4×. The combined organic phases were washed 1× with sat. NaCl solution, dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography (silica, ethyl acetate/ethanol/ammonia (25% aq) 100:10:1) to obtain the desired product (H-54). Yield: 73%
Reaction SMILES: C([Li])CCC.[CH:6]#[C:7][CH2:8][CH2:9][CH3:10].Cl[CH:12]([CH3:15])[CH:13]=[O:14].[Cl-:16].[NH4+]>CCCCCC>[Cl:16][CH2:15][CH2:12][CH:13]([OH:14])[C:6]#[C:7][CH2:8][CH2:9][CH3:10]
Reactant: CC(Cl)C=O
Reactant: [Cl-]
Reactant: C#CCCC
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: CCCC#CC(O)CCCl

Procedure:
To 68 ml. of 1.6M butyllithium in hexane at -50°C. is added dropwise, with stirring, 7.4 g. of 1-pentyne. The resulting white sludge is diluted with 20 ml. of hexane, brought to 10°C. and treated with 11 g. of freshly prepared β -chloropropionaldehyde (Org. Syn., Coll. Vol. I, p. 166) at such a rate that the temperature is maintained at 10°-15°C. The solution is allowed to stir at ambient temperature for 18 hours then treated with saturated ammonium chloride solution. The organic phase is separated, washed with dilute hydrochloric solution, dried with anhydrous magnesium sulfate and taken to dryness. Distillation gives 5.1 g. of product b.p. 65°-66°C. at 0.3 nm.; λ max. 2.95 (--OH) and 4.55 μ (-C≡C-); vapor phase chromatography shows one peak.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH:19][C:20]1[CH:30]=[CH:29][C:28]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[CH:27][C:21]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[O:7]
Reactant: CCOC(=O)c1cc(Oc2ccccc2)ccc1N
Reactant: COc1ccc(C(=O)O)cc1Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)c1cc(Oc2ccccc2)ccc1NC(=O)c1ccc(OC)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.9 %

Procedure:
A solution of 3-chloro-4-methoxy benzoic acid (Lancaster Synthesis Ltd., Windham, N.H.) (100 mg, 0.54 mmol) in CH2Cl2 (5 mL) was cooled to −40° C. DMF (one drop) was added followed by oxalyl chloride (0.32 mL, 0.64 mmol, and 2M solution in CH2Cl2). The reaction was warmed to room temperature and stirred for 1 hour. The mixture was then concentrated to dryness and dried under high vacuum for several hours. The crude acid chloride (38 mg, 0.18 mmol) was dissolved in CH2Cl2 (2 mL) and treated with a solution of 43B (48 mg, 0.18 mmol) in CH2Cl2 (2 mL). Triethylamine (0.13 mL, 0.9 mmol) was added and the reaction was stirred at room temperature until disappearance of the starting material was noted. The reaction was concentrated to dryness and purified by chromatography (SiO2, 5% EtOAc in hexanes) to afford 43C (72 mg, 95%).
Reaction SMILES: [CH3:1][C:2]#[N:3].[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CON(C)[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18]>C1COCC1>[O:18]=[C:17]([C@@H:19]1[CH2:21][C@H:20]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH2:1][C:2]#[N:3]
Reactant: CON(C)C(=O)[C@@H]1C[C@H]1c1ccccc1
Reactant: CC#N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: N#CCC(=O)[C@@H]1C[C@H]1c1ccccc1
Temperature: -60 °C
Reaction time: 3 h
Yield: 51 %

Procedure:
To a stirred solution of MeCN (208.3 mL) and THF (200 mL) at −60° C. under N2 was added dropwise 1M LHMDS in THF (1040 mL). The reaction mixture was stirred at −60° C. for 3 h, and 37 (62.5 g, 304.5 mmol, 1.00 equiv) was then added dropwise. The resulting solution was stirred at −60° C. for 10 min and then quenched with sat'd. aq. NH4Cl solution (400 mL). The reaction mixture was extracted with EtOAc (3×1 L), and the combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by SiO2 chromatography eluting with EtOAc/petroleum ether (10 to 25% EtOAc) to afford 28.5 g (51%) of trans-3-oxo-3-(2-phenylcyclopropyl)propanenitrile (39) as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]#[N:11])=[CH:5][CH:4]=1.[OH-].[Na+].[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=1)([O-:16])=[O:15]>C1(C)C=CC=CC=1.O>[C:10]([C:9]([C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1)=[CH:21][C:20]1[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=1)#[N:11]
Reactant: COc1ccc(CC#N)cc1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: O
Product: COc1ccc(C(C#N)=Cc2ccc([N+](=O)[O-])cc2)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 6.5 %

Procedure:
4-Methoxyphenylacetonitrile (7.63 g, 50 mmol) in toluene (30 mL), PEG(E)-400 (4 g, 10 mmol) and 52% aqueous sodium hydroxide (10.73 g in 12.4 mL water) were placed in a flask equipped with a magnetic stirrer. 4-Nitrobenzaldehyde (7.56 g, 50 mmol) in a minimum of toluene was added dropwise. The mixture was stirred for 1 h at 20° C. and then diluted with water (30 mL). The organic layer was separated, washed with water (3×40 mL) and dried with sodium sulfate. The solvent was removed under reduced pressure and the residue was recrystallized from toluene at -20° C. to give 1-cyano-1-(4-methoxyphenyl)-2-(4-nitrophenyl)ethylene (yield=0.913 g, 6.5%).
Reaction SMILES: [O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>O1CCCC1.B.O1CCCC1>[O:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[CH2:10][OH:11])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccccc1Oc1ccccc1
Agent: B
Solvent: O
Solvent: C1CCOC1
Product: OCc1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of 2-phenoxybenzoic acid (20.8 g) in tetrahydrofuran (400 ml), 14.6 ml of borane-tetrahydrofuran complex (1M tetrahydrofuran solution) was added, and the reaction solution was stirred at 50° C. for 4 hours. The reaction solution was cooled, then water was added, and the mixture was extracted with chloroform. The combined organic layers were washed with 1N aqueous sodium hydroxide and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to afford the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[NH:8][C:7](=[O:12])[C@H:6]3[CH2:13][O:14][CH:15]([CH3:17])[CH2:16][N:5]3[C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:21][CH:22]1[CH2:24][CH2:23]1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:21][CH:22]3[CH2:24][CH2:23]3)[C:7](=[O:12])[C@H:6]3[CH2:13][O:14][CH:15]([CH3:17])[CH2:16][N:5]3[C:4]=2[N:3]=1
Reactant: CC1CN2c3nc(Cl)ncc3NC(=O)[C@H]2CO1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC1CN2c3nc(Cl)ncc3N(CC3CC3)C(=O)[C@H]2CO1
Temperature: 0 °C
Reaction time: 0.58 h
Yield: 99.4 %

Procedure:
To a solution of (R)-2-chloro-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (103 mg, 0.404 mmol) in DMF (2.5 mL) at 0° C. was added sodium hydride (21 mg, 0.526 mmol, 60% in oil). After 35 minutes at 0° C., (bromomethyl)cyclopropane (0.051 mL, 0.526 mmol) was added. The mixture was stirred at 0° C. for 30 minutes, then at room temperature for 45 minutes and then sealed and heated at 90° C. (bath temperature) for 2 hours. More (bromomethyl)cyclopropane (0.250 mL) was added and heated at 90° C. for another 24 hours. The mixture was cooled to room temperature, and more sodium hydride (excess) was added followed by (bromomethyl)cyclopropane (0.1 mL). Heating was continued at 90° C. for another 6 hours. Then the mixture was diluted with EtOAc and water, extracted with EtOAc (3×), and dried over Na2SO4. Solvent was removed in vacuo to give crude (R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one as a brown oil (124 mg). MS [M+H] found 309.2.
Reaction SMILES: I.I.[N:3]1([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH2:18][CH2:19][O:20][CH3:21])[C:13]3[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=3[N:11]=2)[CH2:9][CH2:8][CH2:7][NH:6][CH2:5][CH2:4]1.[CH3:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[CH:38]=[N:37][N:36]=[N:35]2)=[CH:30][C:29]=1[C:39]([N:41]1[CH2:45][CH2:44][C@:43]([CH2:52][CH2:53]OS(C)(=O)=O)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:40].C(N(CC)CC)C>C(#N)C>[CH3:21][O:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][N:14]1[C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[N:11]=[C:10]1[N:3]1[CH2:9][CH2:8][CH2:7][N:6]([CH2:53][CH2:52][C@:43]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:44][CH2:45][N:41]([C:39]([C:29]3[CH:30]=[C:31]([N:34]4[CH:38]=[N:37][N:36]=[N:35]4)[CH:32]=[CH:33][C:28]=3[O:27][CH3:26])=[O:40])[CH2:42]2)[CH2:5][CH2:4]1
Reactant: COc1ccc(-n2cnnn2)cc1C(=O)N1CC[C@](CCOS(C)(=O)=O)(c2ccccc2)C1
Reactant: COCCOCCn1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COCCOCCn1c(N2CCCN(CC[C@]3(c4ccccc4)CCN(C(=O)c4cc(-n5cnnn5)ccc4OC)C3)CC2)nc2ccccc21
Yield: 59.3 %

Procedure:
Heat a mixture of 2-[1,4]diazepan-1-yl-1-[2-(2-methoxy-ethoxy)-ethyl]-1H-benzoimidazole dihydroiodide (0.71 g, 1.24 mmol), methanesulfonic acid 2-{(S)-1-[1-(2-methoxy-5-tetrazol-1-yl-phenyl)-methanoyl]-3-phenyl-pyrrolidin-3-yl}-ethyl ester (0.60 g, 1.27 mmol, example 47.2) and acetonitrile (10 mL), triethylamine (1.2 mL, 8.61 mmol) and acetonitrile (15 mL) at 85° C. for 18 hours. Quench the reaction and purify the crude product as described in Example 113 to afford 0.51 g of the title compound, Rf=0.40 (silica gel, dichloromethane:methanol:30% ammonium hydroxide, 90:10:0.1). The compound may be converted to the dihydrochloride salt by methods well known in the art.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:12])=[C:4]([CH2:8][CH2:9][CH2:10]O)[CH:5]=[CH:6][CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:32]N1C(=O)CCC1=O.O>C(Cl)Cl>[Br:32][CH2:10][CH2:9][CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=1[CH3:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1c(Cl)cccc1CCCO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: ClCCl
Product: Cc1c(Cl)cccc1CCCBr
Yield: 90.9 %

Procedure:
Compound 54-2 (2.10 g) was dissolved in methylene chloride (40 ml), triphenylphosphine (3.30 g) and N-bromosuccinimide (2.23 g) were added under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. Water was added to the reaction mixture, and the mixture was extracted with methylene chloride and washed with saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. Diethyl ether was added, and the precipitated triphenylphosphine oxide was filtered off. The concentrate of the filtrate was purified by silica gel column chromatography (hexane alone) to give the object product (2.56 g) as a colorless oil.