Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS[C:3]1[N:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1.[CH3:20][O-:21].[Na+]>>[CH3:20][O:21][C:3]1[N:8]2[C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[N:10][CH:11]=[C:7]2[CH:6]=[C:5]([S:18][CH3:19])[N:4]=1
Reactant: C[O-]
Reactant: CSc1cc2cnc(-c3ccccc3)n2c(SC)n1
Agent: [Na+]
Product: COc1nc(SC)cc2cnc(-c3ccccc3)n12

Procedure:
Using the method of Example 61, 5,7-bis(methylthio)-3-phenylimidazo[1,5-c]pyrimidine (from Example 30) was reacted with sodium methoxide to provide 5-methoxy-7-methylthio-3-phenylimidazo[1,5-c]pyrimidine as a pale yellow solid after recrystallization from cyclohexane, m.p. 134°-135° C. Analysis: Calculated for C14H13N3OS: %C, 62.0; %H, 4.8; %N, 15.5; Found; %C, 62.0; %H, 4.7; %N, 15.7.
Reaction SMILES: C1(=N[NH:10][C:11](N)=[O:12])CCCCCCC1.[CH:14]1([NH2:19])[CH2:18][CH2:17][CH2:16][CH2:15]1.N>O1CCOCC1>[CH:14]1([NH:19][C:11](=[O:12])[NH2:10])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCC1
Reactant: NC(=O)NN=C1CCCCCCC1
Agent: N
Solvent: C1COCCO1
Product: NC(=O)NC1CCCC1

Procedure:
1.8 g of 4-[4-(β-<2-methoxy-5-chloro-benzamido>-ethyl)-benzenesulfonyl]-cyclooctanone-semicarbazone, 50 ml of dioxane and 0.29 g of cyclopentyl-amine were refluxed for 1 hour. The clear solution was concentrated in vacuo and the residue obtained was treated with about 0.5 %-aqueous ammonia. After filtration the filtrate was acidified. A crystalline precipitate of N-[4-(β-<2-methoxy-5-chlorobenzamido>-ethyl)-benzenesulfonyl]-N'-cyclopentyl-urea was obtained, separated by suction-filtration, dried and recrystallized from methanol. The melting point of the substance was 182° - 184°C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:20]=[CH:19][C:11]3[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=3[CH:9]=2)[CH:5]=[CH:4][N:3]=1.[C:21]1([CH:27]2[CH2:31][CH2:30][CH2:29][NH:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([CH:27]2[CH2:31][CH2:30][CH2:29][N:28]2[C:2]2[N:7]=[C:6]([C:8]3[CH:20]=[CH:19][C:11]4[N:12]=[C:13]([NH:15][C:16](=[O:18])[CH3:17])[S:14][C:10]=4[CH:9]=3)[CH:5]=[CH:4][N:3]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: c1ccc(C2CCCN2)cc1
Reactant: CC(=O)Nc1nc2ccc(-c3ccnc(Cl)n3)cc2s1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(=O)Nc1nc2ccc(-c3ccnc(N4CCCC4c4ccccc4)n3)cc2s1
Temperature: 140 °C
Yield: 20.1 %

Procedure:
A mixture of N-(6-(2-chloropyrimidin-4-yl)benzo[d]thiazol-2-yl)acetamide (0.100 g, 0.3 mmol), 2-phenylpyrrolidine (0.05 ml, 0.3 mmol), diisopropylethylamine (0.1 ml, 0.7 mmol) in DMSO (1.0 g, 11 mmol) was heated under CEM microwave at 140° C., 130 W (Powermax® off). The resultant was diluted with 5 ml of water and filtered. The solid was diluted with DCM and filtered. The filterate was recrystallized from DCM to give a brown solid (25 mg). MS (ESI pos. ion) Found m/z: 416, (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25](O)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.ClC1C=C(C2N(C3C=CC=CN=3)N=C([C:47]([N:49]3[CH2:53][C:52](=[O:54])[NH:51][CH2:50]3)=O)C=2)C=C(F)C=1.O=C1CNCCN1>>[Br:1][C:2]1[CH:3]=[C:4]([C:13]2[N:17]([C:18]3[CH:19]=[N:20][C:21]([F:24])=[CH:22][CH:23]=3)[N:16]=[C:15]([C:25]([N:49]3[CH2:47][CH2:50][NH:51][C:52](=[O:54])[CH2:53]3)=[O:26])[CH:14]=2)[CH:5]=[C:6]([O:8][C:9]([F:11])([F:12])[F:10])[CH:7]=1
Reactant: O=C(O)c1cc(-c2cc(Br)cc(OC(F)(F)F)c2)n(-c2ccc(F)nc2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cc(F)cc(Cl)c3)n(-c3ccccn3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cc(Br)cc(OC(F)(F)F)c3)n(-c3ccc(F)nc3)n2)CCN1

Procedure:
50 mg (0.11 mmol) of the compound of Example 42A is reacted analogously to the synthesis of the compound of Example 1 with 12 mg (0.12 mmol) of 2-oxopiperazine. 51 mg (85% of theory) of the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][NH2:10].Cl.C(=O)([O-])[O-].[K+].[K+].C([O:20][CH:21]=[C:22]([C:28](OCC)=O)[C:23]([O:25][CH2:26][CH3:27])=[O:24])C>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:21](=[O:20])[C:22]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:28][NH:10]1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: NNc1c(Cl)cccc1Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1c[nH]n(-c2c(Cl)cccc2Cl)c1=O
Yield: 72.2 %

Procedure:
In the same manner as in Reference Example 63 and using (2,6-dichlorophenyl)hydrazine•hydrochloride (4.8 g, 23 mmol), water (100 mL), potassium carbonate (6.9 g, 50 mmol) and diethyl ethoxymethylenemalonate (5.9 g, 27 mmol) as starting materials, the title compound (5.0 g, 73%) was obtained as a pale-yellow solid.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:14][NH2:15]>C1(C)C=CC=CC=1>[CH3:14][NH:15][C@H:10]1[CH2:11][CH2:12][C@H:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH2:9]1
Reactant: O=C1CCC(c2ccccc2)CC1
Reactant: CN
Solvent: Cc1ccccc1
Product: CN[C@H]1CC[C@H](c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
26 g (0.15 mol) of 4-phenylcyclohexanone are stirred with 160 ml of a 6 % methylamine solution in toluene in the presence of 30 g of molecular sieve M 3 Å overnight in a sealed flask. After filtering and concentration by evaporation the residue is dissolved in 200 ml of methanol and at −20° C. 7.8 g sodium borohydride are added batchwise. After it has all been added the mixture is stirred overnight at ambient temperature. After evaporation of the methanol the remainder is taken up in 150 ml of ice water and made strongly acidic with conc. hydrochloric acid. After saturation with common salt the hydrochloride precipitated is suction filtered, the mother liquor is made strongly alkaline with 6N sodium hydroxide solution, extracted with ethyl acetate, dried and evaporated down. The hydrochloride precipitated is suspended in a mixture of water and ethyl acetate and, under cooling, made strongly alkaline with 6N sodium hydroxide solution. The ethyl acetate phase is washed with water and saturated saline solution, dried and evaporated down. Crystallisation of the residue from petroleum ether yields 15.1 g trans-N-methyl-4-phenylcyclohexylamine (colourless crystals). The petroleum ether mother liquor is evaporated down and combined with the evaporation residue from the hydrochloride precipitation. Separation on aluminium oxide (activity stage III, ethyl acetate/petroleum ether=1:1 to 2:1, v:v) yields 2.4 g cis-N-methyl-4-phenylcyclohexylamine,
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=O)[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1.[S:25]1[CH2:31][C:29](=[O:30])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:26]1=[S:27].[Cl-].[NH4+].N>C(O)C>[OH2:2].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][C:10](=[O:24])[NH:11][C:12]1[S:13][CH:14]=[C:15]([C:17](=[C:31]2[S:25][C:26](=[S:27])[N:28]([CH2:32][C:33]([OH:35])=[O:34])[C:29]2=[O:30])[C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:16]=1
Reactant: O=C(O)CN1C(=O)CSC1=S
Reactant: CCOC(=O)C(=O)c1csc(NC(=O)Nc2ccccc2OC)n1
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Product: CCOC(=O)C(=C1SC(=S)N(CC(=O)O)C1=O)c1csc(NC(=O)Nc2ccccc2OC)n1
Product: O

Procedure:
Following a procedure similar to that described in Example 1, the desired compound was prepared from 1.75 g of ethyl 2-(3-o-methoxyphenylureido)thiazol-4-ylglyoxylate, 0.95 g of rhodanine-3-acetic acid, 0.5 g of ammonium chloride, 0.5 ml of 28% v/v aqueous ammonia and 25 ml of ethanol. The resulting product was a yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][OH:14].[CH3:15][O:16][C:17]([C:19]1[O:23][NH:22][C:21](=O)[CH:20]=1)=[O:18]>>[CH3:15][O:16][C:17]([C:19]1[O:23][N:22]=[C:21]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])[CH:20]=1)=[O:18]
Reactant: Cc1onc(-c2ccccc2)c1CO
Reactant: COC(=O)c1cc(=O)[nH]o1
Product: COC(=O)c1cc(OCc2c(-c3ccccc3)noc2C)no1
Yield: 62.4 %

Procedure:
As described for Intermediate 1, (5-methyl-3-phenyl-isoxazol-4-yl)-methanol (1.0 g, 5.3 mmol) was converted, using 3-oxo-2,3-dihydro-isoxazole-5-carboxylic acid methyl ester (756 mg, 5.3 mmol) instead of 3-hydroxy-5-methylisoxazole, to the title compound (1.04 g, 63%) which was obtained as a colourless gum after purification by chromatography (silica, heptane:ethyl acetate=4:1 to 0:1). MS: m/e=315.0 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].CS(O[CH2:31][CH2:32][C:33]1[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[C:35]([C@@H:47]([C:57]2[CH:62]=[CH:61][CH:60]=[CH:59][CH:58]=2)[CH2:48][CH2:49][N:50]([CH:54]([CH3:56])[CH3:55])[CH:51]([CH3:53])[CH3:52])[CH:34]=1)(=O)=O>CN(C)C=O.C(OCC)C.O>[NH3:7].[C:1]([O:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:31][CH2:32][C:33]2[CH:38]=[CH:37][C:36]([O:39][CH2:40][C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)=[C:35]([C@@H:47]([C:57]3[CH:58]=[CH:59][CH:60]=[CH:61][CH:62]=3)[CH2:48][CH2:49][N:50]([CH:54]([CH3:55])[CH3:56])[CH:51]([CH3:52])[CH3:53])[CH:34]=2)[CH:11]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCCc1cccc(O)c1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOS(C)(=O)=O)ccc1OCc1ccccc1)C(C)C
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Solvent: O
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(CCOc2cccc(CCNC(=O)OC(C)(C)C)c2)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 60 °C
Reaction time: 8 h

Procedure:
tert-butyl[2-(3-hydroxyphenyl)ethyl]carbamate (Preparation 35, 1.7 g, 5.96 mmol), potassium carbonate (1.65 g, 11.9 mmol), potassium iodide (5.0 g, 0.03 mmol) and 2-{4-(benzyloxy)-3-[(1R)-3-(diisopropylamino)-1-phenylpropyl]phenyl)ethyl methanesulfonate (Preparation 36, 1.56 g, 2.98 mmol) were stirred in dimethylformamide (20 ml) and stirred at 60° C. overnight. After cooling, water (250 ml) and diethyl ether (250 ml) were added, organics separated and washed with water (100 ml×3), brine (150 ml) then dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (100/0/0 to 90/10/1.0 by volume) to furnish the title compound as an oil, 1.3 g.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][CH:4]([OH:8])[CH2:5][C:6]=1[CH3:7].N1C=CC=CC=1.[Cl:15]/[C:16](/[C:26]([F:29])([F:28])[F:27])=[CH:17]\[C@@H:18]1[C@H:20]([C:21](Cl)=[O:22])[C:19]1([CH3:25])[CH3:24]>C(C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)C.C1(C)C=CC=CC=1>[Cl:15]/[C:16](/[C:26]([F:27])([F:28])[F:29])=[CH:17]\[C@@H:18]1[C@H:20]([C:21]([O:8][CH:4]2[CH2:5][C:6]([CH3:7])=[C:2]([CH3:1])[CH2:3]2)=[O:22])[C:19]1([CH3:25])[CH3:24]
Reactant: CC1=C(C)CC(O)C1
Reactant: CC1(C)[C@H](/C=C(\Cl)C(F)(F)F)[C@@H]1C(=O)Cl
Agent: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CC1=C(C)CC(OC(=O)[C@H]2[C@@H](/C=C(\Cl)C(F)(F)F)C2(C)C)C1
Yield: 86.5 %

Procedure:
To a mixture of 3,4-dimethyl-3-cyclopenten-1-ol (175 mg), 2,6-di-tert-butyl-4-methylphenol (5 mg), pyridine (150 mg) and toluene (10 ml), (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarbonyl chloride (395 mg) was added under ice-cooling. The resulting reaction mixture was further allowed to react for 8 hours at room temperature. Then the reaction mixture was subjected to the same post-treatment as in Example 1 to afford 441 mg of 3,4-dimethyl-3-cyclopenten-1-yl (1RS)-cis-3-(Z-2-chloro-3,3,3-trifluoro-1-propenyl)-2,2-dimethylcyclopropanecarboxylate (Compound No. 3). Yield 84% nD25 1.4620
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[C:33]([O:36]C)[N:34]=5)[N:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Br.C(O)(=O)C.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([NH:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][C:26]4[CH:27]=[CH:28][N:29]=[C:30]5[C:35]=4[NH:34][C:33](=[O:36])[CH:32]=[CH:31]5)=[CH:23][CH:24]=3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: COc1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2n1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: O=c1ccc2nccc(Oc3ccc(Nc4nnc(-c5ccc(Cl)cc5)c5ccccc45)cc3)c2[nH]1
Temperature: 85 °C
Reaction time: 1 h

Procedure:
In a 48 mL sealed pressure vessel, was added 4-(4-chlorophenyl)-N-(4-(6-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine (0.280 g, 0.553 mmol), HBr (6.01 mL, 11.1 mmol), and acetic acid (6.34 mL, 11.1 mmol). The mixture was stirred at 85° C. for 1 hour. The reaction was monitored and found complete by LC/MS. The reaction mixture was cooled to RT, carefully basified with 6 N NaOH. Light yellow solids crashed out, which were filtered, rinsed with water and dried in vacuum oven to yield 8-(4-(4-(4-chlorophenyl)phthalazin-1-ylamino)phenoxy)-1,5-naphthyridin-2(1H)-one. The product was used without further purification. MS: [M+H]=492.1; Calc'd 491.9 for C28H18ClN5O2
Reaction SMILES: [NH2:1][C:2]1[C:3](=[O:14])[N:4]([CH2:12][CH3:13])[C:5](=[O:11])[N:6]([CH2:9][CH3:10])[C:7]=1[NH2:8].[CH2:15]([O:18][C:19]1[CH:29]=[CH:28][C:22]([CH:23]=[CH:24][C:25](O)=O)=[CH:21][CH:20]=1)[CH2:16][CH3:17]>>[CH2:12]([N:4]1[C:3](=[O:14])[C:2]2[NH:1][C:25](/[CH:24]=[CH:23]/[C:22]3[CH:21]=[CH:20][C:19]([O:18][CH2:15][CH2:16][CH3:17])=[CH:29][CH:28]=3)=[N:8][C:7]=2[N:6]([CH2:9][CH3:10])[C:5]1=[O:11])[CH3:13]
Reactant: CCn1c(N)c(N)c(=O)n(CC)c1=O
Reactant: CCCOc1ccc(C=CC(=O)O)cc1
Product: CCCOc1ccc(/C=C/c2nc3c([nH]2)c(=O)n(CC)c(=O)n3CC)cc1
Yield: 54.3 %

Procedure:
Substantially the same procedure as in Reference Example 70 was repeated using 3.00 g (15.1 mmol) of 5,6-diamino-1,3-diethyluracil and 3.43 g (16.6 mmol) of 4-propoxycinnamic acid. Then, the resultant crude crystals were recrystallized from dioxane/water to give 3.02 g (yield 54%) of Compound 125 as pale yellow needles.
Reaction SMILES: [C:1]1(=[O:6])[O:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH2:11]>O1CCCC1>[CH3:7][O:8][CH:9]([O:12][CH3:13])[CH2:10][NH:11][C:1](=[O:6])[CH2:2][CH2:3][CH2:4][OH:5]
Reactant: COC(CN)OC
Reactant: O=C1CCCO1
Solvent: C1CCOC1
Product: COC(CNC(=O)CCCO)OC

Procedure:
A mixture of 4-butyrolactone (54 g) and aminoacetaldehyde dimethylacetal (55 g) in tetrahydrofuran (THF) (500 mL) was refluxed for 4 h. A further portion of aminoacetaldehyde dimethylacetal (27 g) was added followed by reflux for 2 h. Reflux was continued and two further portions of acetal were added at 2 h intervals. Concentration of the reaction mixture in vacuo followed by destillation of the remaining oil gave N-(2,2-dimethoxyethyl)-4-hydroxybutyramide as an oil, bp. 230° C./10 torr, yield 72 g. The oil was dissolved in dry THF (800 mL) and added slowly to a suspension of of lithium aluminium hydride in THF (200 mL). After reflux for 16 h, the reaction mixture was cooled and subsequently quenched with water (88 mL), 15% NaOH solution (44 mL), and water (220 mL). Filtration and removal of solvent in vacuo gave an oil which was dissolved in methylene chloride (500 mL) and dried over magnesium sulfate. Filtration and removal of solvent in vacuo gave 4-(2,2-dimethoxyethylamino)-1-butanol as an oil, yield 62 g. A portion of the oil (20 g) was dissolved in methylene chloride (100 mL) and added dropwise to a solution of cyclohexylisocyanate in methylene chloride (50 mL) at 5° C. Reflux for 3 h and concentration in vacuo gave N-cyclohexyl-N′-(2,2-dimethoxyethyl)-N′-(4-hydroxy-1-butyl)urea as an oil, yield 35 g. The oil was dissolved in a mixture of THF (200 mL) and 2 M hydrochloric acid (200 mL) followed by reflux for 24 h. The reaction mixture was concentrated in vacuo followed by addition of ethyl acetate (300 mL) and 4 M NaOH (300 mL). The organic phase was dried over magnesium sulfate. Removal of solvent gave 1-cyclohexyl-3-(4-hydroxy-1-butyl)-1,3-dihydroimidazol-2-one as an oil, yield 29 g. The oil was dissolved in methylene chloride (250 mL) and triethylamine (13 g) was added followed by cooling to 5° C. A solution of methanesulfonyl chloride (14 g) in methylene chloride (20 mL) was added dropwise followed by stirring for 1.5 h at room temperature. The reaction mixture was washed with water, dried over magnesium sulfate and concentrated in vacuo giving the title compound as an oil, yield 36 g. 1H NMR (CDCl3): δ 1.05-1.25 (m, 1H), 1.30-1.50 (m, 4H), 1.60-2.00
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[C:22]([C:27]#[N:28])=[CH:23][CH:24]=[CH:25][CH:26]=4)=[CH:17][CH:16]=3)[C:8](=[O:29])[N:7]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:6]=12.C([Sn](=O)CCCC)CCC.[N:46]([Si](C)(C)C)=[N+:47]=[N-:48].C1(C)C=CC=CC=1>C(OCC)(=O)C>[CH3:1][C:2]1[CH:3]=[N:4][N:5]2[C:10]([CH2:11][CH2:12][CH3:13])=[C:9]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[C:27]4[NH:48][N:47]=[N:46][N:28]=4)=[CH:19][CH:20]=3)[C:8](=[O:29])[N:7]([CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:6]=12
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)c(=O)n(C2CCOCC2)c2c(C)cnn12
Temperature: 110 °C
Reaction time: 48 h
Yield: 41.6 %

Procedure:
A mixture of 4′-{[3-methyl-5-oxo-7-propyl-4-(tetrahydro-2H-pyran-4-yl)-4,5-dihydropyrazolo[1,5-a]pyrimidin-6-yl]methyl}biphenyl-2-carbonitrile (0.33 g), dibutyltin oxide (0.088 g), azidotrimethylsilane (3.5 g) and toluene (30 mL) was stirred at 110° C. for 48 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as colorless crystals (0.15 g, 41%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([S:15]([NH:18][C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[C:5]([CH3:26])[O:4][N:3]=1.[C:27](N=C(N(C)C)N(C)C)([CH3:30])([CH3:29])[CH3:28].BrCC(C)C>C(#N)C>[CH3:1][C:2]1[C:6]([CH2:7][O:8][C:9]2[CH:10]=[CH:11][C:12]([S:15]([N:18]([CH2:28][CH:27]([CH3:30])[CH3:29])[C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][N:20]=3)(=[O:17])=[O:16])=[CH:13][CH:14]=2)=[C:5]([CH3:26])[O:4][N:3]=1
Reactant: CN(C)C(=NC(C)(C)C)N(C)C
Reactant: Cc1ccc(NS(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Solvent: CC#N
Solvent: CC(C)CBr
Product: Cc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(OCc3c(C)noc3C)cc2)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 4 %

Procedure:
To a solution of 4-((3,5-dimethylisoxazol-4-yl)methoxy)-N-(5-methylpyridin-2-yl)benzenesulfonamide (187 mg, 0.5 mmol) in acetonitrile (5 mL) stirred at room temperature, was added 2-(tert-butyl)-1,1,3,3-tetramethylguanidine (0.261 mL, 1.250 mmol). The mixture was stirred at room temperature for 1 hour, then 1-bromo-2-methylpropane (0.190 mL, 1.750 mmol) added. The reaction was then heated by microwaves to 160° C., for 25 minutes. After cooling, dicholormethane (5 mL) was added to the mixture and the organic phase washed with water (5 mL) then separated using a hydrophobic frit. The solvent was removed under a stream of nitrogen and the crude sample purified by mass directed autoprep (ammonium carbonate modifier) to give the title product (8.5 mg). LCMS (3 min, High pH) Rt 1.88 min, m/z (ES+) 430 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:31])[N:7]([C:9]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([CH2:15][N:16]([C:18](=[O:22])[CH:19]([CH3:21])[CH3:20])[CH3:17])[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:31])[N:7]([C:9]([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[C:25]([Cl:30])[CH:24]=1)([CH2:15][N:16]([C:18](=[O:22])[CH:19]([CH3:20])[CH3:21])[CH3:17])[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)C(=O)N(C)CC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)C(=O)N(C)CC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.1 %

Procedure:
tert-Butyl{1-(3,4-dichlorophenyl)-3,4-dihydroxy-1-[(isobutyryl-methylamino)-methyl]-butyl}-methyl-carbamate (1.41 g) was dissolved in a mixture solvent of tetrahydrofuran (8 mL) and water (8 mL). Sodium periodate (1.3 g) was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (1.33 g, quantative amount). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]([CH2:11][NH:12]C(C(F)(F)F)=O)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+:20].[ClH:21]>C1COCC1>[ClH:21].[NH2:12][CH2:11][C:8]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5].[Na+:20].[Cl-:21]
Reactant: Cc1ccc(CNC(=O)C(F)(F)F)cc1C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(CN)cc1C(=O)O
Product: [Cl-]
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A mixture of 2-methyl-5-(trifluoromethylcarbonylamino-methyl)benzoic acid (15 mmol; 4.00 g), 1 M NaOH (36 mL) and THF (40 mL) was stirred at rt for 3 h. 4 M aq. HCl solution (5 mL) was added. Concentration under reduced pressure gave the sub-title compound as a mixture with NaCl which was used without further purification in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:40])[C:15]([O:32]CC2C=CC=CC=2)=[C:16]2[C:29](=[O:30])[N:20]3[CH:21]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]4[CH2:23][O:24][CH:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12].[H][H].CO.ClCCl>O1CCCC1.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH2:9][NH:10][C:11]([C:13]1[C:14](=[O:40])[C:15]([OH:32])=[C:16]2[C:29](=[O:30])[N:20]3[CH:21]4[CH2:28][CH2:27][CH2:26][CH2:25][CH:22]4[CH2:23][O:24][CH:19]3[CH2:18][N:17]2[CH:31]=1)=[O:12]
Reactant: O=C(NCc1ccc(F)cc1F)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1C(C2)OCC2CCCCC21
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CO
Product: O=C(NCc1ccc(F)cc1F)c1cn2c(c(O)c1=O)C(=O)N1C(C2)OCC2CCCCC21
Yield: 67.3 %

Procedure:
racemic-(4aR,6aR,14aS)—N-[(2,4-Difluorophenyl)methyl]-11,13-dioxo-12-[(phenylmethyl)oxy]-1,3,4,4a,5,6a,7,11,13,14a-decahydro-2H-pyrido[1′,2′:4,5]pyrazino[1,2-a][3,1]benzoxazine-10-carboxamide (13 mg, 0.0236 mmol) was dissolved in tetrahydrofuran and 10 w.t. % Pd/C (13 mg) was added. Hydrogen was passed through the solution several times and the mixture was stirred at 1 atm hydrogen for 18 hours until the reaction was determined complete by TLC (5% methanol/dichloromethane). The mixture was filtered through Celtite, eluting with methanol/chloroform and the filtrate was concentrated under reduced pressure and purified by HPLC to yield the title compound (7.3 mg, 73%) 1H NMR (CDCl3) δ 12.45 (m, 1H), 10.38 (s, 1H), 8.30 (s, 1H), 7.32 (m, 1H), 6.83-6.76 (m, 2H), 5.23 (m, 1H), 4.75 (m, 1H), 4.63 (m, 2H), 4.26 (m, 1H), 4.12-4.01 (m, 2H), 3.83 (m, 1H), 2.30 (m, 1H), 1.91 (m, 1H), 1.80 (m, 1H), 1.67-1.40 (m, 5H), 1.20 (m, 1H); ES+ MS: 460 (M+1).