Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]1[C:30]2[C:25](=[C:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[CH:27]=[C:28]([OH:31])[CH:29]=2)[CH2:24][NH:23][C:22]1=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH2:60][CH2:61][N:62]1[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]1>O1CCCC1>[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[N:21]1[C:30]2[C:25](=[C:26]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=3[Cl:38])[CH:27]=[C:28]([O:31][CH2:60][CH2:61][N:62]3[CH2:67][CH2:66][CH2:65][CH2:64][CH2:63]3)[CH:29]=2)[CH2:24][NH:23][C:22]1=[O:39]
Reactant: OCCN1CCCCC1
Reactant: O=C1NCc2c(-c3ccccc3Cl)cc(O)cc2N1c1c(Cl)cccc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: O=C1NCc2c(-c3ccccc3Cl)cc(OCCN3CCCCC3)cc2N1c1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
Diethyl azodicarboxylate (50 μL, 0.32 mmol) was added dropwise to a solution of 1-(2,6dichlorophenyl)-5-(2-chlorophenyl)-7-hydroxy-3,4-dihydro-2(1H)-quinazolinone (30 mg, 0.07 mmol) INTERMEDIATE 49), triphenylphosphine (95 mg, 0.36 mmol) and 1-(2-hydroxyethyl)piperidine (55 mg, 0.43 mmol) in 1 mL tetrahydrofuran at 65° C. under an argon atmosphere. After 1 h the solution was cooled to RT and partitioned between saturated NaHCO3 (5 mL) and EtOAc (15 mL). The organic phase was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by thin layer chromatography using EtOAc followed by CHCl3/MeOH/NH4OH (87/12/1) as the eluent to give 1-(2,6-dichlorophenyl)-5-(2-chlorophenyl)-7-[2-(1-piperidinyl)ethoxy]-3,4-dihydro-2(1H)-quinazolinone. 1H NMR(CDCl3, 500 MHz): δ 1.44 (m, 2H), 1.62 (m, 4H), 2.48 (m, 4H), 2.72 (m, 2H), 4.00 (t, 2H, J=6.0 Hz), 4.18 (d, 1H, J=14.0 Hz), 4.36 (d, 1H, J-14.0 Hz), 5.22 (s, 1H), 5.76 (d, 1H, J=1.8 Hz), 6.45 (d, 1H, J=2.0 Hz), 7.28-7.39 (m, 4H), 7.45-7.53 (m, 3H). MS(ES) 530 (M+H); LC 1: 2.28 min.
Reaction SMILES: [CH3:1][P:2]([O-:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6].[CH3:9][C:10]([O:12][CH:13]([C:16]#[N:17])[CH:14]=[CH2:15])=[O:11]>>[C:10]([O:12][CH:13]([C:16]#[N:17])[CH2:14][CH2:15][P:2]([CH3:1])(=[O:8])[O:3][CH2:4][CH:5]([CH3:7])[CH3:6])(=[O:11])[CH3:9]
Reactant: CC(C)COP(C)[O-]
Reactant: C=CC(C#N)OC(C)=O
Product: CC(=O)OC(C#N)CCP(C)(=O)OCC(C)C
Temperature: 80 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
208 g of isobutyl methanephosphonite are heated to 80° C. under nitrogen. 0.5 g of tert.-butyl perpivalate is added to the hot reaction solution, and 63.9 g of acrolein cyanohydrin acetate and 2.5 g of tert.-butyl perpivalate are added dropwise within 2.3 hours. The mixture is stirred at 80° C. for 5 min, and 133.9 g of isobutyl methanephosphonite are distilled out under high vacuum (recovery: 91.3%; purity: 97%). 134.6 g of isobutyl (3-acetoxy-3-cyanopropyl)methylphosphinate (yield: 97.8%, purity 95%) are obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([O:15]C)=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].CO>O>[CH2:1]([O:8][C:9]([NH:11][CH:12]([CH2:17][C:18]1([CH3:24])[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1)[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)C(CC1(C)CCCCC1)NC(=O)OCc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC1(CC(NC(=O)OCc2ccccc2)C(=O)O)CCCCC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 36 %

Procedure:
A mixture of methyl 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoate, 10.00 g of KOH, 100 mL of MeOH, and 20 mL of water was vigorously stirred at rt for 17 h. After methanol was evaporated under reduced pressure, the residue was diluted with water and extracted with Et2O (2×). The aqueous phase was treated with 100 mL of 2 NHCl, extracted with EtOAc (3×), and dried over Na2SO4. The extracts were evaporated under reduced pressure to afford 1.5150 g (36% in two steps) of 2-(benzyloxycarbonylamino)-3-(1-methylcyclohexyl)propanoic acid. MS ESI +ve m/z 320 (M+H).
Reaction SMILES: [CH3:1][S-:2].[Na+].[Cl:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13]Cl)=[CH:7][N:6]=1>C(O)C>[Cl:4][C:5]1[C:10]([O:11][CH3:12])=[CH:9][C:8]([CH2:13][S:2][CH3:1])=[CH:7][N:6]=1
Reactant: C[S-]
Reactant: COc1cc(CCl)cnc1Cl
Agent: [Na+]
Solvent: CCO
Product: COc1cc(CSC)cnc1Cl
Reaction time: 8 h

Procedure:
To a suspension of sodium thiomethoxide (0.24 g, 3.5 mmol) in ethanol (10 mL) at 25° C. was added solution of 2-chloro-5-chloromethyl-3-methoxypyridine (0.55 mg, 2.9 mmol) in EtOH (4 mL). The solution was stirred overnight, after which the reaction was concentrated under vacuum. The crude reaction mixture was partitioned between H2O and Et2O and the layers separated. The aqueous phase was further extracted with Et2O (3×) and the combined organic phases dried over MgSO4 and concentrated to furnish 2-chloro-3-methoxy-5-methylthiomethylpyridine as a yellow oil (0.42 g, 71% over two steps). GC-MS: Exact mass calcd for C8H10ClNOS [M]+, 203. Found 203.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH2:22])=[CH:18][CH:17]=1.[NH:23]1[CH:27]=[C:26]([CH:28]=O)[N:25]=[N:24]1>>[CH3:15][C:16]1[O:20][C:19]([CH2:21][NH:22][C:8]2[CH:7]=[CH:6][C:5]3[C:4]([NH:1][CH2:28][C:26]4[NH:25][N:24]=[N:23][CH:27]=4)=[CH:13][CH:12]=[CH:11][C:10]=3[N:9]=2)=[CH:18][CH:17]=1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=Cc1c[nH]nn1
Reactant: Cc1ccc(CN)o1
Product: Cc1ccc(CNc2ccc3c(NCc4cnn[nH]4)cccc3n2)o1

Procedure:
The title compound, MS: m/e=335.4 (M+H+), was prepared from 5-nitro-2-chloroquinoline, 5-methyl-2-furanmethanamine and 1H-1,2,3-triazole-4-carbaldehyde as described in example 26.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:16]3[C:15]4[CH2:17][NH:18][CH2:19][CH2:20][C:14]=4[NH:13][C:12]=3[N:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCCl>[Cl:21][C:22]1[CH:23]=[C:24]([C:25]([N:18]2[CH2:19][CH2:20][C:14]3[NH:13][C:12]4[N:11]=[CH:10][CH:9]=[C:8]([NH:7][C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)[C:16]=4[C:15]=3[CH2:17]2)=[O:26])[CH:28]=[CH:29][CH:30]=1
Reactant: c1ccc(Nc2ccnc3[nH]c4c(c23)CNCC4)cc1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: O=C(c1cccc(Cl)c1)N1CCc2[nH]c3nccc(Nc4ccccc4)c3c2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
Phenyl-(6,7,8,9-tetrahydro-5H-dipyrido[2,3-b;3′,4′-d]pyrrol-4-yl)-amine (40 mg, 0.15 mmol), 3-chlorobenzoyl chloride (32 mg, 0.18 mmol), and triethylamine (0.06 mL, 0.45 mmol) were dissolved in 1,2-dichloroethane (2.0 mL), and stirred overnight at room temperature. The reaction mixture was added directly to a Biotage column. The crude product was purified via Biotage eluting with CH2Cl2/MeOH (9/1, v/v) to provide 9 (16 mg, 26% yield) as a tan solid. LC-MS (M+H=403, obsd.=403).
Reaction SMILES: [NH:1]1[C:10]2[NH:9][C:8](=[O:11])[CH:7]=[CH:6][C:5]=2[CH:4]=[CH:3][C:2]1=[O:12].[H-].[Na+].[CH2:15](Br)[CH:16]=[CH2:17].[CH2:19](I)[CH:20]=[CH2:21]>CN(C=O)C>[CH2:15]([N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:11][CH2:21][CH:20]=[CH2:19])[N:9]=2)[CH:4]=[CH:3][C:2]1=[O:12])[CH:16]=[CH2:17]
Reactant: C=CCI
Reactant: O=c1ccc2ccc(=O)[nH]c2[nH]1
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOc1ccc2ccc(=O)n(CC=C)c2n1
Temperature: 40 °C

Procedure:
A suspension of 1,8-naphthyridine-2,7(1H,8H)-dione (8.0 g, 49.4 mmol)(prepared according to the method of Newkome, George R et al, Journal of Organic Chemistry (1981), 46(5), 833-9) in DMF (200 ml) was treated under argon with sodium hydride (2.2 g of 60% dispersion with mineral oil, 1.3 g, 55 mmol) then heated to 40° C. for 20 minutes. Allyl bromide (˜5 ml) was added. After 2 hours at 40° C. more sodium hydride (2.2 g of 60% dispersion with mineral oil, 1.3 g, 55 mmol) and allyl iodide (˜5 ml) were added. After a further 1 hour at 40° C. the mixture was cooled to room temperature and quenched with saturated aqueous ammonium chloride (5 ml). The mixture was evaporated and the residue chromatographed eluting with 0-10% ethyl acetate in hexane affording the product as a yellow oil (5.2 g, 45%).
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.[F:11][C:12]([F:24])([F:23])[S:13]([O:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=[O:15])=[O:14].[Te]1C2C=CC=CC=2N=C1>ClCCl.C(Cl)(Cl)(Cl)Cl>[F:11][C:12]([F:24])([F:23])[S:13]([O-:16])(=[O:15])=[O:14].[CH2:21]([O:20][C:18]([CH2:17][N+:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[Te:3][C:2]=1[CH3:1])=[O:19])[CH3:22]
Reactant: CCOC(=O)COS(=O)(=O)C(F)(F)F
Reactant: Cc1nc2ccccc2[te]1
Agent: c1ccc2[te]cnc2c1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCOC(=O)C[n+]1c(C)[te]c2ccccc21
Product: O=S(=O)([O-])C(F)(F)F
Temperature: 25 °C

Procedure:
2-Methylbenzotellurazole (Example 18) (0.81 g, 0.0033 mole) was dissolved in dichloromethane (30 ml). The solution of ethoxycarbonylmethyl trifluoromethanesulfonate (0.004 mole) in carbon tetrachloride prepared as described above, was placed in a dropping funnel and added to the benzotellurazole solution at room temperature under a nitrogen atmosphere. After the addition was complete, the mixture was stirred at room temperature, while maintaining a nitrogen atmosphere for 22 hours. The solid was isolated by filtration and dried at room temperature under vacuum. Yield was 0.62 g (39% of theory) of a white powder, m.p. 156°-158° C. The C, H, N and S elemental analyses and the infrared, nuclear magnetic resonance, and mass spectra were all in agreement with that expected for the structural formula.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:23](=[O:24])[C:22]2[N:25]3[C:15](=[CH:16][N:17]=[C:18]3[CH:19]=[CH:20][CH:21]=2)[C:14]1=[O:26])=O)(C)(C)C.[ClH:27]>CO>[ClH:27].[ClH:27].[NH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:23](=[O:24])[C:22]2[N:25]3[C:15](=[CH:16][N:17]=[C:18]3[CH:19]=[CH:20][CH:21]=2)[C:14]1=[O:26]
Reactant: CC(C)(C)OC(=O)NCCCCn1c(=O)c2cccc3ncc(c1=O)n32
Agent: Cl
Solvent: CO
Product: NCCCCn1c(=O)c2cccc3ncc(c1=O)n32
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.1 %

Procedure:
To a solution of 3.58 g (10.0 mmol) of 4,5-dihydro-4-[4-(tert-butoxycarbonylamino)butan-1-yl]-3H-1,4,8b-triazaacenaphthylene-3,5-dione in 30 ml of methanol was added 15 ml of conc. HCl. The mixture was stirred for one hour at room temperature. The solvent was distilled off. To the residue were added ethanol and ether. The resulting precipitate was collected by filtration and dried to give 3.28 g of the desired compound (99.1%, white solid), m.p.250.0-252.0° C.
Reaction SMILES: C([NH:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:8]([O:10][C:11](=[O:12])[C:6]=12)=O)(=O)C.[F:19][C:20]1[CH:26]=[CH:25][C:23]([OH:24])=[CH:22][C:21]=1[OH:27].CS(O)(=O)=O>O>[NH2:4][C:5]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][CH:13]=[C:7]2[C:6]=1[C:11](=[O:12])[O:10][C:8]12[C:25]2[CH:26]=[C:20]([F:19])[C:21]([OH:27])=[CH:22][C:23]=2[O:24][C:23]2[C:25]1=[CH:26][C:20]([F:19])=[C:21]([OH:27])[CH:22]=2
Reactant: Oc1ccc(F)c(O)c1
Reactant: CC(=O)Nc1c([N+](=O)[O-])ccc2c1C(=O)OC2=O
Agent: CS(=O)(=O)O
Solvent: O
Product: Nc1c([N+](=O)[O-])ccc2c1C(=O)OC21c2cc(F)c(O)cc2Oc2cc(O)c(F)cc21
Temperature: 80 °C
Reaction time: 60 h
Yield: 60.7 %

Procedure:
3-Acetamido-4-nitrophthalic anhydride (1.3 g, 5.0 mmol) and 4-fluororesorcinol (1.3 g, 10 mmol) were added to methanesulfonic acid (10 ml), and the mixture was stirred at 80° C. under an argon atmosphere for 60 hours. The reaction mixture was added with water (120 ml) and refluxed for 2 hours. The reaction mixture was adjusted to pH 2, and precipitates were collected by filtration. The obtained product was dried and purified by silica gel chromatography (3% methanol/97% dichloromethane, v/v) to obtain the title compound (1.3 g, 61%).
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:21])[C:4](=[O:20])[C:5]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:6]([C:8]([O:10]C)=O)[N:7]=1.[CH3:22][NH2:23].C1COCC1>>[CH3:22][NH:23][C:8]([C:6]1[N:7]=[C:2]([NH2:1])[N:3]([CH3:21])[C:4](=[O:20])[C:5]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:10]
Reactant: CN
Reactant: COC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Solvent: C1CCOC1
Product: CNC(=O)c1nc(N)n(C)c(=O)c1OCc1ccccc1
Temperature: 140 °C
Yield: 100 %

Procedure:
To a mixture of methyl 2-amino-5-(benzyloxy)-1-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate (0.907 g, 3.14 mmol, Eq: 1.00), methylamine 2M in THF (12 ml, 24.0 mmol) was added. The mixture was heated in a microwave oven at 140° C. for 2 h. The crude reaction mixture was concentrated in vacuo to give the title product as an off-white solid (0.90 g; 100%). LCMS: m/z=289 (MH+).
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][CH3:9])[CH2:4][CH2:3]1.[CH3:10][S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C>O1CCCC1>[CH3:10][S:11]([O:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([N:8]([S:11]([CH3:10])(=[O:13])=[O:12])[CH3:9])[CH2:4][CH2:3]1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)Cl
Reactant: CN[C@H]1CC[C@@H](O)CC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN([C@H]1CC[C@@H](OS(C)(=O)=O)CC1)S(C)(=O)=O

Procedure:
Prepared by reacting cis-1-hydroxy-4-methylamino-cyclohexane with methanesulphonic acid chloride in tetrahydrofuran in the presence of triethylamine.
Reaction SMILES: [C:1]1([C:7]#[CH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Si]([N:13]=[N+:14]=[N-:15])(C)(C)C.CCCCCC>CCOCC>[C:1]1([C:7]2[N:13]=[N:14][NH:15][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#Cc1ccccc1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Solvent: CCOCC
Solvent: CCCCCC
Product: c1ccc(-c2c[nH]nn2)cc1
Temperature: 150 °C
Yield: 76.3 %

Procedure:
##STR9## Phenylethyne (12.0 g) and Me3SiN3 (7.8 g) were sealed into a heavy-walled glass reactor at -70° C. and 0.6 mm Hg. The mixture was heated at 150° C. for 10 hrs., cooled, and dissolved in Et2O. The Et2O was treated exactly as in Example 2, reduced to 100 ml total volume, a little hexane added and chilled in a refrigerator overnight. Filtration gave 7.5 g (76%) white crystals mp 146.9-149.0.
Reaction SMILES: Cl[C:2]1[N:14]=[CH:13][C:5]2[S:6][C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[C:4]=2[CH:3]=1.[C:15]1(B(O)O)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.O>[C:15]1([C:2]2[N:14]=[CH:13][C:5]3[S:6][C:7]4[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=4[C:4]=3[CH:3]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1ccccc1
Reactant: Clc1cc2c(cn1)sc1ccccc12
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc(-c2cc3c(cn2)sc2ccccc23)cc1
Yield: 26.9 %

Procedure:
2-chloro-3-azadibenzothiophene (1.3 g, 5.7 mmol), phenylboronic acid (0.87 g, 7.1 mmol), dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine (S-Phos) (0.09 g, 0.23 mmol), and potassium phosphate (3.3 g, 14.3 mmol) were mixed in 60 mL of toluene and 6 mL of water. Nitrogen is bubbled directly into the mixture for 30 minutes. Next, Pd2(dba)3 was added (0.05 g, 0.05 mmol) and the mixture was heated to reflux under nitrogen for 3 days. The mixture was cooled and the organic layer was separated. The organic layers are washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 5% ethyl acetate/hexanes. 0.4 g of desired product was obtained after purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.CCN(C(C)C)C(C)C>CC(O)C>[CH3:9][O:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:7]=1
Reactant: Nc1ccccc1
Reactant: COc1ccnc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: COc1ccnc(Nc2ccccc2)n1
Temperature: 100 °C
Yield: 11.8 %

Procedure:
A sealed tube was charged with 2-chloro-4-methoxypyrimidine (1.00 g, 6.92 mmol) in 2-propanol (5 mL). Aniline (0.757 ml, 8.30 mmol) and DIEA (1.45 ml, 8.30 mmol) were added and the reaction mixture was heated at 100° C. until the reaction was complete by HPLC. The reaction mixture was cooled to room temperature. The resulting thick suspension was filtered, washed with ethanol, collected and dried under vacuum to yield the desired product (0.164 g) as a white solid. The filtrate was concentrated and then partitioned between EtOAc and saturated aqueous NaCl. The phases were separated, and the aqueous phase was re-extracted with EtOAc (1×). The combined organic layers were dried (Na2SO4), filtered and concentrated to yield a yellow solid. The crude product was purified by flash column chromatography, eluting with 25:1 dichloromethane/EtOAc. The desired product (0.548 g) was obtained as a white solid which was combined with the filtered product to yield 0.712 g (51%) total desired product. 1H-NMR (400 MHz, DMSO-d6) δ 9.51 (s, 1H), 8.20 (d, 1H), 7.77 (d, 2H), 7.27 (t, 2H), 6.94 (t, 1H), 6.28 (d, 1H), 3.91 (s, 3H). LRMS (ESI pos) m/e 202 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([O:15]C)[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4.B(Br)(Br)Br.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]3[CH:19]=[C:18]([CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:17](=[O:27])[C:8]4[CH:9]=[C:10]([OH:15])[CH:11]=[C:12]([C:13]=2[CH:14]=1)[C:7]3=4
Reactant: COc1cc2c(=O)c(Cc3ccccn3)cn3c4ccc(Br)cc4c(c1)c23
Agent: BrB(Br)Br
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: O=c1c(Cc2ccccn2)cn2c3ccc(Br)cc3c3cc(O)cc1c32
Temperature: 25 °C
Reaction time: 12 h
Yield: 33.1 %

Procedure:
10-bromo-2-methoxy-5-(2-pyridylmethyl)-4H-pyrido [3,2,1-jk]carbazole-4-one (0.54 g) obtained in Example 84 was suspended in anhydrous methylene chloride (30 ml), and boron tribromide (5 ml) was added dropwise at room temperature. The mixture was stirred at room temperature for 12 hours, and the reaction mixture was poured into ice wacer, and to this mixture was added saturated aqueous solution of sodium carbonate until the termination of foaming. The crystals precipitated were recovered by filtration, and the resulting crude crystals were washed with a mixed solution of methylene chloride and methanol to obtain the title compound (0.173 g, 33%).
Reaction SMILES: [O:1]=[C:2]1[C:10](=[C:11]2[C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]([CH2:20][CH2:21]OS(C)(=O)=O)[O:12]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>O1CCOCC1>[N:27]1([CH2:21][CH2:20][CH:13]2[C:14]3[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11](=[C:10]3[C:9]4[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=4)[NH:3][C:2]3=[O:1])[O:12]2)[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1
Reactant: CS(=O)(=O)OCCC1OC(=C2C(=O)Nc3ccccc32)c2ccccc21
Reactant: C1COCCN1
Solvent: C1COCCO1
Product: O=C1Nc2ccccc2C1=C1OC(CCN2CCOCC2)c2ccccc21
Reaction time: 18 h
Yield: 75.6 %

Procedure:
A solution of methanesulfonic acid 2-[3-(2-oxo-1,2-dihydro-indol-3-ylidene)-1,3-dihydro-isobenzofuran-1-yl]-ethyl ester (50 mg, 0.135 mmol) and morpholine (118 μl, 1.35 mmol) in dioxane (0.8 ml) was heated at 70° C. for 40 minutes and then at 60° C. for 18 hours. The reaction was partitioned between EtOAc and water. The EtOAc layer was washed with water, brine, dried with anhydrous Na2SO4 and rotary evaporated to give a yellow film. The yellow film was chromatographed (CHCl3 to 2% MeOH/CHCl3 gradient) to give 3-[3-(2-morpholin-4-yl-ethyl)-3H-isobenzofuran-1-ylidene]-1,3-dihydro-indol-2-one as a yellow solid (37 mg, 76%).
Reaction SMILES: [H-].[Li+].[F:3][C:4]([F:17])([F:16])[C:5]([C:7]1[CH:12]=[C:11]([Cl:13])[C:10]([Cl:14])=[C:9]([Cl:15])[CH:8]=1)=[O:6].[CH3:18][O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27](=[O:29])[CH3:28])[O:24][C:23]=1[CH3:30])=[O:21].CC(OC)(C)C>C1COCC1>[CH3:18][O:19][C:20]([C:22]1[CH:26]=[C:25]([C:27](=[O:29])[CH2:28][C:5]([OH:6])([C:7]2[CH:8]=[C:9]([Cl:15])[C:10]([Cl:14])=[C:11]([Cl:13])[CH:12]=2)[C:4]([F:3])([F:16])[F:17])[O:24][C:23]=1[CH3:30])=[O:21]
Reactant: COC(=O)c1cc(C(C)=O)oc1C
Reactant: O=C(c1cc(Cl)c(Cl)c(Cl)c1)C(F)(F)F
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Product: COC(=O)c1cc(C(=O)CC(O)(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)oc1C
Reaction time: 1 h
Yield: 123.5 %

Procedure:
LiH (1.76 g) is added to a solution of 2,2,2-trifluoro-1-(3,4,5-trichloro-phenyl)-ethanone (35.33 g) and 5-acetyl-2-methyl-furan-3-carboxylic acid methyl ester (20 g) in THF (300 ml). After 1 hour 30 at 60° C. MTBE is added (450 ml) and the reaction mixture is poured onto water (750 ml) at 0° C. The organic phase is washed with water and a saturated aqueous solution of NaCl dried over MgSO4 and concentrated in vacuo to yield 62.3 g of 2-methyl-5-[4,4,4-trifluoro-3-hydroxy-3-(3,4,5-trichloro-phenyl)-butyryl]-furan-3-carboxylic acid methyl ester. The crude product is used without further purification. MS (HPLC/MS): 459 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:12][N:13]([O:16]C2CCCCO2)[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][CH2:33][C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)[N:3]=1>C(O)(=O)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][NH:9][C:10](=[O:29])[C@H:11]([CH2:23][CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28]2)[CH2:12][N:13]([OH:16])[CH:14]=[O:15])[C:5]([F:30])=[C:4]([NH:31][CH2:32][CH2:33][C:34]2[CH:38]=[CH:37][S:36][CH:35]=2)[N:3]=1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCCc2ccsc2)c1F)OC1CCCCO1
Solvent: CC(=O)O
Solvent: O
Product: O=CN(O)C[C@@H](CC1CCCC1)C(=O)NNc1nc(Cl)nc(NCCc2ccsc2)c1F
Reaction time: 8 h
Yield: 50 %

Procedure:
[(2R)-3-[2-(2-Chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl](tetrahydro-2H-pyran-2-yloxy)formamide (0.1677, 0.295 mmol) was dissolved in acetic acid (8 mL) and water (2 mL). This reaction mixture was left to stir overnight. The volatiles were evaporated, and the resulting residue was purified by RP-HPLC to provide [(2R)-3-[2-(2-chloro-5-fluoro-6-{[2-(3-thienyl)ethyl]amino}-4-pyrimidinyl)hydrazino]-2-(cyclopentylmethyl)-3-oxopropyl]hydroxyformamide as a beige solid (0.0715 g, 50%). LCMS: (M+H)+=485.1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:16][O:15][CH2:14][CH:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[N:22][CH:23]=1.F[C:25]1C=CC(C2C=NC=NC=2)=CC=1C12COCC1CSC(N)=N2>>[CH3:25][N:20]([CH3:21])[CH2:19][CH3:18].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@:8]23[CH2:16][O:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH2:17])=[N:9]3)=[CH:4][C:3]=1[C:18]1[CH:19]=[N:20][CH:21]=[N:22][CH:23]=1
Reactant: NC1=NC2(c3cc(-c4cncnc4)ccc3F)COCC2CS1
Reactant: NC1=NC2(c3ccc(F)c(-c4cncnc4)c3)COCC2CS1
Product: CCN(C)C
Product: NC1=N[C@@]2(c3ccc(F)c(-c4cncnc4)c3)COC[C@H]2CS1
Yield: 0.2 %
Yield: 14 %

Procedure:
The mixture of racemic (4aSR,7aSR)-7a-(4-fluoro-3-(pyrimidin-5-yl)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine and racemic (4aSR,7aSR)-7a-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (0.231 g, 0.697 mmol) are separated using a Chiralpak AD-H 3×25 cm column eluting with 3/2 EtOH:acetonitrile with 0.2% dimethylethylamine at a flow rate of 30 mL/min., 225 nM to give (4aS,7aS)-7a-(4-fluoro-3-(pyrimidin-5-yl)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (TR=3.12) (0.032 g, 14%): ES/MS m/e: 331 (M+1) and (4aS,7aS)-7a-(2-fluoro-5-(pyrimidin-5-yl)phenyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine (TR=4.479) (0.058 g, 25%). ES/MS m/e: 331 (M+1).