Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[C:18]([CH3:23])[C:17]=1[CH3:24].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.[CH2:37]([N:39]([CH2:47][CH3:48])[CH2:40][CH2:41][CH:42]([OH:46])[CH2:43][CH2:44][CH3:45])[CH3:38].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:26](=[O:28])[O:46][CH:42]([CH2:41][CH2:40][N:39]([CH2:37][CH3:38])[CH2:47][CH3:48])[CH2:43][CH2:44][CH3:45])=[C:18]([CH3:23])[C:17]=1[CH3:24]
Reactant: CCCC(O)CCN(CC)CC
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)c(C)c3C)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CCCC(CCN(CC)CC)OC(=O)Nc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C)c1C
Yield: 37.2 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]-2,3-dimethylaniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (68 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-(diethylamino)-3-hexanol (40 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, and the extract was washed with water and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (30 mg, yield 34%).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1.[F:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[CH:27][C:28]=1[F:29].C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[F:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][C:28]=1[F:29])[O:30][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[CH:13]=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[N:9][N:10]=2)[N:7]=1
Reactant: Clc1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: Oc1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: Fc1ccc(Oc2ccc3nnc(Cc4ccc5ncccc5c4)n3n2)cc1F
Yield: 34.5 %

Procedure:
A solution of 6-(6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylmethyl)-quinoline (60 mg, 0.203 mmol, 1.0 equiv.), 3,4-difluorophenol (0.223 mmol, 1.1 equiv.), Cs2CO3 (86 mg, 0.264 mmol, 1.3 equiv) and dimethylsulfoxide (1 mL) were mixed in a microwave tube and capped. The microwave tube was reacted in a microwave reactor (Personel Chemistry, Emrys Optimizer) at 70° C. for 10 minutes. The solvent was removed by rotary evaporation and the crude product purified via flash column chromatography (SiO2, CH2Cl2:CH3OH 100:0-80:20) to return the title compound as a white solid (27.2 mg, 0.07 mmol, 34% yield). Analytical data presented in Table 1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][CH:27]([CH2:30]O)[CH2:26][CH2:25]2)[O:21][N:20]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:18][C:19]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][O:17][C:14]3[CH:15]=[CH:16][C:11]([C:8]4[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=4)=[CH:12][CH:13]=3)[CH2:28][CH2:29]2)[O:21][N:20]=1
Reactant: Cc1noc(N2CCC(CO)CC2)n1
Reactant: CS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1noc(N2CCC(COc3ccc(-c4ccc(S(C)(=O)=O)cc4)cc3)CC2)n1
Yield: 21 %

Procedure:
The title compound (43 mg, 21%) was prepared as a white solid from 4′-(methylsulfonyl)-4-biphenylol (prepared as in Example 1, Step 1, 120 mg, 0.48 mmol), [1-(3-methyl-1,2,4-oxadiazol-5-yl)-4-piperidinyl]methanol (143 mg, 0.73 mmol) and Ph3P (191 mg, 0.73 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.144 mL, 0.73 mmol) in a manner similar to Example 1, Step 2, and worked up in a manner similar to Example 9, Step 3. 1H NMR (400 MHz, CDCl3): δ 7.97 (d, 2H, J=8.6 Hz), 7.72 (d, 2H, J=8.4 Hz), 7.55 (d, 2H, J=8.8 Hz), 6.99 (d, 2H, J=8.8 Hz), 4.25-4.15 (m, 2H), 3.89 (d, 2H, J=6.4 Hz), 3.22-3.08 (m, 2H), 3.08 (s, 3 H), 2.24 (s, 3H), 2.04-1.94 (m, 2H), 1.55-1.42 (m, 3H); LRMS (ESI), m/z 428 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15]Cl)[CH:6]=[C:5]2[CH:19]=[O:20].C([O-])(=[O:23])C.[Na+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[N:7]([CH2:13][C:14]([CH3:18])([CH3:17])[CH2:15][OH:23])[CH:6]=[C:5]2[CH:19]=[O:20]
Reactant: CC(=O)[O-]
Reactant: CC(C)(CCl)Cn1cc(C=O)c2cc(Br)ccc2c1=O
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)(CO)Cn1cc(C=O)c2cc(Br)ccc2c1=O

Procedure:
A solution of 6-bromo-2-(3-chloro-2,2-dimethylpropyl)-1-oxo-1,2-dihydroisoquinoline-4-carbaldehyde (Example 26c, 20 g) in DMSO (140 mL) was treated with sodium acetate (55 g) under nitrogen. The resulting mixture was stirred at 135° C. for 48 h during which more sodium acetate was added after 6 h (55 g), 24 h (55 g) then 30 h (22.5 g).
Reaction SMILES: B.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([OH:24])[C@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:11]2=O)=[CH:5][CH:4]=1.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([C@@H:32]([OH:47])[C@@H:33]2[O:38][CH2:37][CH2:36][N:35]([CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:34]2=O)=[CH:28][CH:27]=1>O1CCCC1>[Cl:2][C:3]1[CH:4]=[CH:5][C:6]([C@H:9]([C@@H:10]2[O:15][CH2:14][CH2:13][N:12]([CH2:16][C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11]2)[OH:24])=[CH:7][CH:8]=1.[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([C@@H:32]([C@H:33]2[O:38][CH2:37][CH2:36][N:35]([CH2:39][C:40]3[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=3)[CH2:34]2)[OH:47])=[CH:30][CH:31]=1
Reactant: O=C1[C@@H]([C@@H](O)c2ccc(Cl)cc2)OCCN1Cc1ccccc1
Reactant: O=C1[C@H]([C@H](O)c2ccc(Cl)cc2)OCCN1Cc1ccccc1
Agent: B
Solvent: C1CCOC1
Product: O[C@@H](c1ccc(Cl)cc1)[C@@H]1CN(Cc2ccccc2)CCO1
Product: O[C@H](c1ccc(Cl)cc1)[C@H]1CN(Cc2ccccc2)CCO1
Temperature: 60 °C

Procedure:
A solution of borane in tetrahydrofuran (1M, 29 ml) was added dropwise to a stirred solution of diastereomer 1 (2R)-2-[(S)-(4-chlorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one and (2S)-2-[(R)-(4-chlorophenyl)(hydroxy)methyl]-4-benzylmorpholin-3-one (2.40 g 7.24 mmol) in dried tetrahydrofuran (30 ml) at room temperature under nitrogen causing effervesence. The solution was heated to 60° C. for 2 h, allowed to cool to room temperature and excess borane quenched by adding methanol (14 ml) slowly. Aqueous hydrochloric acid (1M, 14 ml) was added, heated to 60° C. for 1 h and then evaporated to a white solid. Added saturated aqueous sodium carbonate (50 ml) and diethyl ether (50 ml) to dissolve the solid and extracted with diethyl ether (2×50ml). The extracts were washed with brine solution, dried, filtered and evaporated to a colourless oil (2.38 g). The oil was purified by chromatography on silica eluting with diethyl ether:hexane 75:25 to give (R)-[4-chlorophenyl][(2R)-4-benzylmorpholin-2-yl]methanol and (S)-[4-chlorophenyl][(2S)-4-benzylmorpholin-2-yl]methanol as a colourless oil (2.08 g)
Reaction SMILES: [C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)(=O)C(Cl)=O.C(Cl)Cl.C(N(CC)CC)C.[C:34]1([CH:40]([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH2:41][N:42]([CH3:60])[C:43](=[O:59])[CH:44]([NH:51][CH2:52][CH2:53][C:54]2[N:55]=[CH:56][NH:57][CH:58]=2)[C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C)C=O>[C:1]([C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([N:51]([CH:44]([C:43](=[O:59])[N:42]([CH2:41][CH:40]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:61]1[CH:62]=[CH:63][CH:64]=[CH:65][CH:66]=1)[CH3:60])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH2:52][CH2:53][C:54]1[N:55]=[CH:56][NH:57][CH:58]=1)=[O:13])(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(NCCc1c[nH]cn1)c1ccccc1
Reactant: O=C(O)c1ccccc1C(=O)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(CC(c1ccccc1)c1ccccc1)C(=O)C(c1ccccc1)N(CCc1c[nH]cn1)C(=O)c1ccccc1C(=O)c1ccccc1
Reaction time: 8 h
Yield: 70.5 %

Procedure:
2-Benzoylbenzoic acid (0.341 g, 1.51 mmol) was taken up in a 2M solution of oxalyl chloride in methylene chloride (1.5 mL, 3.0 mmol). One drop of N,N-dimethylformamide was added and the frothy mixture was stirred overnight and concentrated. A solution of the crude 2-benzoylbenzoyl chloride in methylene chloride (4 mL) followed by triethylamine (0.25 mL, 1.8 mmol) was added to the product of step 2 (0.220 g, 0.502 mmol). The mixture was heated at reflux for 2 hours and concentrated. The residue was taken up in 5:1 methanol/1 N aqueous lithium hydroxide (12 mL) and stirred for 1 hour. The reaction was again concentrated and the residue was partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The organic layer was dried (sodium sulfate) and concentrated to afford a foamy amber solid. Flash chromatography over silica (methylene chloride/methanol) provided 0.229 g (71%) of product as a foamy pale amber solid: 1H NMR (CDCl3) δ 7.91-6.92 (m, 26H), 6.54-6.39 (m, 1H), 6.34-6.06 (m, 1H), 4.83-4.31 (m, 2H), 3.97-2.82 (m, 3H), 2.70-2.39 (m, 3H), 2.35-2.09 (m, 2H) ppm. MS (ESI) m/z 648 (M+H+).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:24]=[CH:23][C:12]([O:13][CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]#[N:22])=[N:19][CH:20]=3)=[CH:11][CH:10]=2)O1.Br[C:27]1[N:32]2[N:33]=[C:34]([NH:36][C:37]([CH:39]3[CH2:41][CH2:40]3)=[O:38])[N:35]=[C:31]2[CH:30]=[CH:29][CH:28]=1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[C:21]([C:18]1[N:19]=[CH:20][C:15]([CH2:14][O:13][C:12]2[CH:11]=[CH:10][C:9]([C:27]3[N:32]4[N:33]=[C:34]([NH:36][C:37]([CH:39]5[CH2:40][CH2:41]5)=[O:38])[N:35]=[C:31]4[CH:30]=[CH:29][CH:28]=3)=[CH:24][CH:23]=2)=[CH:16][CH:17]=1)#[N:22]
Reactant: CC1(C)OB(c2ccc(OCc3ccc(C#N)nc3)cc2)OC1(C)C
Reactant: O=C(Nc1nc2cccc(Br)n2n1)C1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: N#Cc1ccc(COc2ccc(-c3cccc4nc(NC(=O)C5CC5)nn34)cc2)cn1
Temperature: 90 °C

Procedure:
5-[4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-pyridine-2-carbonitrile (10 g, 0.03 mol, 1.1 equiv.) was added to a solution of cyclopropanecarboxylic acid (5-bromo-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-amide (7.6 g, 0.027 mol) in 1,4-dioxane/water (4:1; 70 mL). K2CO3 (7.45, 0.054 mol, 2 eq.) and PdCl2dppf (5%) were added to the solution. The resulting mixture was then heated in an oil bath at 90° C. under N2 until completion (monitored by LCMS). 1,4-Dioxane was removed under vacuum, and water/EtOAc were added and the solid was filtered. The obtained solid was dissolved in methanol/DCM, dried over MgSO4 and the final compound was obtained after purification by flash chromatography, eluted with neat EtOAc as a white solid
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([OH:18])[N:13]=[C:12]2[CH3:19])[CH:5]=1.[CH3:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][CH:29]=1)[CH2:25]Br.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C)C=O>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N:11]2[C:16](=[O:17])[CH:15]=[C:14]([O:18][CH2:21][C:22]3[CH:29]=[CH:28][CH:27]=[C:24]([CH3:25])[CH:23]=3)[N:13]=[C:12]2[CH3:19])[CH:5]=1
Reactant: Cc1cccc(CBr)c1
Reactant: COC(=O)c1ccc(C)c(-n2c(C)nc(O)cc2=O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C)c(-n2c(C)nc(OCc3cccc(C)c3)cc2=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
To a solution of Intermediate 2 (460 mg, 1.68 mmol) in N,N-dimethylformamide (2 mL) was added 3-methylbenzyl bromide (0.22 mL, 1.68 mmol), potassium carbonate (350 mg, 2.53 mmol) and 18-crown-6 (40 mg). The slurry was stirred at ambient temperature for one hour. The reaction was partitioned between ethyl acetate and water. The organic layer was washed with water and brine and dried over magnesium sulfate. The slurry was filtered and concentrated in vacuo. The crude material was purified using normal phase chromatography (ethyl acetate/heptane) to provide the alkylated product as a white semi-solid (138 mg, 22% yield). MS (M+H): 379
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:8]O)=[N:4][CH:5]=[CH:6][N:7]=1.C1(=O)[NH:14]C(=O)C2=CC=CC=C12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.NN>C1COCC1.CO>[ClH:1].[ClH:1].[Cl:1][C:2]1[C:3]([CH2:8][NH2:14])=[N:4][CH:5]=[CH:6][N:7]=1
Reactant: OCc1nccnc1Cl
Reactant: O=C1NC(=O)c2ccccc21
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: NN
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CO
Product: Cl
Product: NCc1nccnc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 232.7 %

Procedure:
To a solution of (3-chloropyrazin-2-yl)methanol (B. Klein et al. J. Org. Chem. 1963, 28, 1682.) (10.78 g, 74.6 mmol), phthalimide (13.18 g, 89.7 mmol) and triphenylphosphine (23.78 g, 90.8 mmol) in THF (350 mL) was added DIAD (17.8 mL, 90.8 mmol) and the mixture stirred at ambient temp for 16 h. The mixture was concentrated by rotary evaporation. The intermediate 2-((3-chloropyrazin-2-yl)methyl)isoindoline-1,3-dione was taken up in CH2Cl2 (300 mL) and methanol (450 mL) and treated with anhydrous hydrazine (6.0 mL, 190 mmol) at ambient temperature for 18 h. The mixture was filtered and the precipitate discarded. The filtrate was concentrated by rotary evaporation, then taken up in EtOAc and refiltered. The filtrate was concentrated to dryness, dissolved in 600 mL EtOAc, then treated with 40 mL of 4N HCL in dioxane. The precipitated solids were collected, washed with ether and vacuum dried to give 12.53 g tan solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[CH2:14][S:13][C:12]1=[S:17].[CH:18](=O)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C([O-])(=O)C.[NH+]1C=CC=CC=1>CCOCC>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][N:11]1[C:15](=[O:16])[C:14](=[CH:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[S:13][C:12]1=[S:17]
Reactant: O=Cc1ccccc1
Reactant: O=C1CSC(=S)N1N=c1sc2ccccc2s1
Agent: CC(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Product: O=C1C(=Cc2ccccc2)SC(=S)N1N=c1sc2ccccc2s1
Temperature: 120 °C

Procedure:
A mixture of 2.0 g of 3-[(1,3-benzodithiol-2-ylidene)amino]-2-thioxo-4-thiazolidinone (see example 37), benzaldehyde (20 ml, excess) and pyridinium acetate (5 ml) is prepared and heated at 120° C for 3 days under nitrogen with stirring. The mixture is then cooled, diluted with ether and filtered. The residue is washed with water and recrystallized from dimethylformamide to yield 2.2 g of the title compound, melting point 288°-289° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](S(C)=O)[N:5]=[C:4]2[N:11]([C:16]3[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=3[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]=12.[N:24]1([CH:30]2[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[N:24]1([CH:30]2[CH2:35][CH2:34][N:33]([C:6]3[N:5]=[C:4]4[N:11]([C:16]5[C:21]([F:22])=[CH:20][CH:19]=[CH:18][C:17]=5[F:23])[C:12](=[O:15])[NH:13][CH2:14][C:3]4=[C:2]([Cl:1])[N:7]=3)[CH2:32][CH2:31]2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: CS(=O)c1nc(Cl)c2c(n1)N(c1c(F)cccc1F)C(=O)NC2
Reactant: C1CCN(C2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1NCc2c(Cl)nc(N3CCC(N4CCCCC4)CC3)nc2N1c1c(F)cccc1F
Yield: 115 %

Procedure:
To a solution of 5-chloro-1-(2,6-difluorophenyl)-7-(methylsulfinyl)-3,4-dihydropyrimido[4,5-d]pyrimidin-2(1H)-one (200 mg, 0.56 mmol) in DCM (10 mL) were added 1,4′-bipiperidine (270 mg, 1.61 mmol) and N,N-diisopropylethylamine (0.3 mL, 1.7 mmol). The resultant solution was stirred at room temperature over night. The result mixture was concentrated. CombiFlash chromatography (mobile phase DCM/DCM[90]+MeOH[7]+NH4OH[3]) provided the title compound as a white solid (298 mg, 83%). LC-MS m/z 463 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4](=O)[CH2:5][C:6]#[N:7].[CH2:9]([NH:11][NH2:12])[CH3:10].Cl>C(O)C>[CH2:9]([N:11]1[C:6]([NH2:7])=[CH:5][C:4]([CH2:3][O:2][CH3:1])=[N:12]1)[CH3:10]
Reactant: COCC(=O)CC#N
Reactant: CCNN
Agent: Cl
Solvent: CCO
Product: CCn1nc(COC)cc1N
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.8 %

Procedure:
To a 25 mL round bottom was added 4-(methyloxy)-3-oxobutanenitrile (500 mg, 4.42 mmol), ethyl hydrazine (655 mg, 4.42 mmol), and 2 M HCl (2.210 mL, 4.42 mmol) in ethanol (10 mL). The reaction mixture was stirred at the room temperature overnight. The reaction mixture was then evaporated and pardoned between 20 mL of ethyl acetate and 20 mL of 1 M Na2CO3. The organic layer was washed with brine, filtered and evaporated to obtain 1-ethyl-3-[(methyloxy)methyl]-1H-pyrazol-5-amine (450 mg, 2.465 mmol, 55.8% yield) as a yellow oil. The product was used in the next step without further purification. LCMS (M+H)+=156.1; 1H NMR (400 MHz, DMSO-d6) ppm 1.20 (t, J=7.20 Hz, 3 H) 3.19 (s, 3 H) 3.82 (q, J=7.33 Hz, 2 H) 4.11 (s, 2 H) 5.11 (s, 2 H) 5.22 (s, 1H).
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=O.[NH:34]1[CH2:38][CH2:37][CH2:36][C@@H:35]1[CH2:39][NH2:40].C(O)(=O)C>ClCCl>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH2:22][NH:21][C:20]([C:8]2[C:9](=[O:19])[C:10]([O:11][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:5]3[C:3](=[O:2])[N:40]4[CH2:39][C@H:35]5[CH2:36][CH2:37][CH2:38][N:34]5[C@@H:32]4[CH2:31][N:6]3[CH:7]=2)=[O:30])=[CH:28][CH:27]=1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Reactant: NC[C@H]1CCCN1
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(NCc1ccc(F)cc1)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C[C@H]3CCCN3[C@@H]1C2
Yield: 91.8 %

Procedure:
The title compound was made in two steps using a similar process to that described in example Z-2. 16 (60 mg, 0.13 mmol) and [(2R)-2-pyrrolidinylmethyl]amine (100 mg, 1.0 mmol) were reacted in dichloromethane (2 mL) with acetic acid to give (4aS,13aR)-N-[(4-fluorophenyl)methyl]-9,11-dioxo-10-[(phenylmethyl)oxy]-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (60 mg, 91%). This material was hydrogenated in a second step as described in example Z-2 to give (4aS,13aR)-N-[(4-fluorophenyl)methyl]-10-hydroxy-9,11-dioxo-2,3,4a,5,9,11,13,13a-octahydro-1H-pyrido[1,2-a]pyrrolo[1′,2′:3,4]imidazo[1,2-d]pyrazine-8-carboxamide (21 mg, 42%) as a white solid. 1H NMR (CDCl3) δ 11.72 (m, 1H), 1.37 (m, 1H), 8.33 (s, 1H), 7.29 (m, 2H), 6.97 (m, 2H), 4.57 (m, 2H), 4.52 (m, 1H), 4.24-4.19 (m, 2H), 3.87-8.76 (m, 2H), 3.14-3.07 (m, 2H), 2.82 (m, 1H), 2.11-1.89 (m, 3H), 1.68 (m, 1H); ES+ MS: 413 (M+1).
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:8][C:7](=[O:9])[NH:6][C:5](=[O:10])[CH:4]=1.S(Cl)([Cl:14])(=O)=O>C(O)(=O)C>[Cl:14][C:4]1[C:5](=[O:10])[NH:6][C:7](=[O:9])[NH:8][C:3]=1[CH2:2][Cl:1]
Reactant: O=S(=O)(Cl)Cl
Reactant: O=c1cc(CCl)[nH]c(=O)[nH]1
Solvent: CC(=O)O
Product: O=c1[nH]c(CCl)c(Cl)c(=O)[nH]1
Temperature: 0 °C
Reaction time: 3 h
Yield: 92 %

Procedure:
To a suspension of 6-chloromethyluracil (163 g) in acetic acid (500 ml), sulfuryl chloride (120 ml) was added dropwise at room temperature over 20 minutes, followed by stirring at the same temperature for 3 hours. The reaction mixture was poured into ice water (500 ml), and a crystallized matter was collected by filtration, whereby 182.3 g of the title compound were obtained (yield: 92%).
Reaction SMILES: [CH:1]1[C:6]([Cl:7])=[C:5]([Cl:8])[CH:4]=[C:3]([NH2:9])[C:2]=1[NH2:10].O.O.[C:13](O)(=[O:17])[C:14](O)=[O:15].O>Cl>[Cl:7][C:6]1[C:5]([Cl:8])=[CH:4][C:3]2[C:2](=[N:10][C:13](=[O:17])[C:14](=[O:15])[N:9]=2)[CH:1]=1
Reactant: O=C(O)C(=O)O
Reactant: Nc1cc(Cl)c(Cl)cc1N
Agent: Cl
Solvent: O
Product: O=C1N=c2cc(Cl)c(Cl)cc2=NC1=O
Temperature: 125 °C
Reaction time: 2.5 h
Yield: 93982360 %

Procedure:
A suspension of 2.655 g (15.0 mmol) of 4,5-dichlorophenylene-1,2-diamine and 1.986 g (15.75 nmol) oxalic acid dihydrate (Fisher Scientific Co., used as received) in 22.5 mL of 2N aq. HCl was refluxed with stirring at 125° C. (bath temperature) for 2.5 h, (during the first 5 min heating, the suspension almost turned into a solution, then began to form a precipitate). The reaction mixture was allowed to cool to 22° C., and H2O (50 mL) was added. The precipitate was collected on a Hirsh funnel by vacuum filtration, washed with H2O (6×25 mL) and dried at 60° C. under 0.1 mmHg for 12 h affording 3.39 g (98%) of 6,7-dichloroquinoxaline-2,3-dione as a deep pink powder. Mp. >400° C. 1H NMR (DMSO-d6): δ12.016 (s, 2H), 7.234 (s, 2H). This product was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[Na+].[Na+].C(O)C.FC1C=C([C:31]2[C:36](=[O:37])[N:35]3[CH:38]=[CH:39][S:40][C:34]3=[N:33][C:32]=2[CH3:41])C=C(F)C=1>C1(C)C=CC=CC=1.CC1N=C2SC=CN2C(=O)C=1C1C=CC(C#N)=CC=1.O>[CH3:41][C:32]1[N:33]=[C:34]2[S:40][CH:39]=[CH:38][N:35]2[C:36](=[O:37])[C:31]=1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:13])([F:12])[F:1])[CH:4]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1nc2sccn2c(=O)c1-c1cc(F)cc(F)c1
Agent: Cc1nc2sccn2c(=O)c1-c1ccc(C#N)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1nc2sccn2c(=O)c1-c1cccc(C(F)(F)F)c1

Procedure:
The title compound was prepared by coupling reaction of Step 2 intermediate from Intermediate 4 (600 mg, 2.001 mmol) with 3-(trifluoromethyl)phenyl boronic acid (585 g, 3.020 mmol) in the presence of Pd[(C6H5)3P]4 (92 mg, 0.0812 mmol) and sodium carbonate (1.27 g, 12.061 mol) in a mixture of toluene, ethanol and water according to the procedure described in Intermediate 3, step 3 1.21 g yielded 18.5 g of the desired compound as a light yellow solid; 1H NMR (300 MHz, DMSO-d6) δ 2.18 (s, 3H), 7.53-7.59 (m, 4H), 7.58-7.80 (m, 1H), 8.01 (d, J=4.8 Hz, 1H); ESI-MS (m/z) 311.28 (M+H)+.
Reaction SMILES: [C:1]1([N:7]=[C:8]=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH2:15])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]>C(OCC)(=O)C>[F:10][C:11]1[CH:17]=[CH:16][C:14]([NH:15][C:8]([NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[O:9])=[CH:13][C:12]=1[N+:18]([O-:20])=[O:19]
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Reactant: O=C=Nc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccccc1)Nc1ccc(F)c([N+](=O)[O-])c1
Reaction time: 8 h
Yield: 52 %

Procedure:
Phenylisocyanate (12.0 g, 0.1 mol) was added to 4-fluoro-3-nitroaniline (15.6 g, 0.1 mol) in ethyl acetate (400 mL) at room temperature. The reaction mixture was stirred overnight, then the volume was reduced to approximately 200 mL and the resulting suspension filtered to afford the product (14.3 g); m.p. 200-202° C. Concentration of the filtrate followed by filtration afforded an additional crop of product (5.4 g).