Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:19]([CH3:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[N:16][CH:17]=2)[N:12]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]#[N:32])[C:11]1=[O:36].[OH-:37].[Na+].OO.O>CS(C)=O>[F:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[N:10]1[CH:19]([CH3:20])[C:18]2[C:13](=[N:14][C:15]([NH:21][C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)=[N:16][CH:17]=2)[N:12]([C:28]2[CH:29]=[C:30]([CH:33]=[CH:34][CH:35]=2)[C:31]([NH2:32])=[O:37])[C:11]1=[O:36]
Reactant: COc1ccc(N2C(=O)N(c3cccc(C#N)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1ccc(N2C(=O)N(c3cccc(C(N)=O)c3)c3nc(Nc4ccccc4)ncc3C2C)c(F)c1
Reaction time: 0.75 h

Procedure:
(±)-3-[3-(2-Fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzonitrile (0.80 g; 1.67 mmol) (from Example 9b supra) was dissolved in dimethyl sulfoxide (25 mL). Most of the material went into solution. Aqueous sodium hydroxide (1.0 N; 3.34 mL; 3.34 mmol) was added followed by hydrogen peroxide (30% in water; 0.51 mL, 4.99 mmol) at room temperature. After stirring for 45 minutes, water was added and a white solid precipitated out of solution. The solid was collected, washed with water and dried. Dissolution of the solid required significant volumes of dichloromethane-methanol-acetonitrile. The solvent mixture was then distilled off until solid began to crystallize out of solution. Cooling and filtration gave (±)-3-[3-(2-fluoro-4-methoxy-phenyl)-4-methyl-2-oxo-7-phenylamino-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-benzamide as a white solid. (Yield 0.56 g; 67.6%).
Reaction SMILES: CCN(C(C)C)C(C)C.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[NH:29][C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]4[CH2:34][CH2:33][CH2:32][CH2:31][C:25]=4[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11].C(OC(C1C=NN(C2NC(=O)C3C4CCCCC=4C=CC=3N=2)C=1)=O)C.Cl[CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66]>C1COCC1.CCOC(C)=O>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([C:20]2[N:29]([CH2:61][O:62][CH2:63][CH2:64][O:65][CH3:66])[C:28](=[O:30])[C:27]3[C:22](=[CH:23][C:24]4[CH2:34][CH2:33][CH2:32][CH2:31][C:25]=4[CH:26]=3)[N:21]=2)[CH:19]=1)=[O:14])[CH3:11]
Reactant: COCCOCCl
Reactant: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)[nH]2)CCCC4)c1
Agent: CCOC(=O)c1cnn(-c2nc3ccc4c(c3c(=O)[nH]2)CCCC4)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnn(-c2nc3cc4c(cc3c(=O)n2COCCOC)CCCC4)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 41 %

Procedure:
DIEA (0.76 mL, 4.4 mmol) was added to a 2:1 mixture of 1-(4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester and 1-(1-oxo-1,2,7,8,9,10-hexahydro-benzo[f]quinazolin-3-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (0.500 g, 1.478 mmol) in THF (7.4 mL), followed by 1-chloromethoxy-2-methoxy-ethane (0.186 mL, 1.63 mmol). The reaction mixture was stirred at room temperature for 18 h, diluted with EtOAc (40 mL), and washed with water (30 mL). The aqueous layer was extracted with EtOAc (2×30 mL) and the combined organic layers were washed with brine (40 mL), dried (MgSO4), and concentrated. The residue was purified by FCC (5-60% EtOAc/hexanes) to yield 1-[3-(2-methoxy-ethoxymethyl)-4-oxo-3,4,6,7,8,9-hexahydro-benzo[g]quinazolin-2-yl]-1H-pyrazole-4-carboxylic acid ethyl ester (0.257 g, 41% yield) and the titled compound (69.0 mg, 11% yield).
Reaction SMILES: [Na].[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([OH:24])(=O)=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.C(Cl)(=O)C([Cl:28])=O>CN(C)C=O.ClCCl>[ClH:28].[CH3:2][C:3]1[CH:12]=[C:11]([CH2:13][O:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([Cl:28])(=[O:24])=[O:22])=[CH:17][CH:16]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1cc(COc2ccc(S(=O)(=O)O)cc2)c2ccccc2n1
Agent: [Na]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(COc2ccc(S(=O)(=O)Cl)cc2)c2ccccc2n1
Product: Cl
Temperature: -10 °C
Reaction time: 18 h
Yield: 92 %

Procedure:
76 g (216 mmol) of the sodium salt of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonic acid in 500 ml of dimethylformamide are added dropwise to a solution of 55 ml (649 mmol) of oxalyl chloride in 100 ml of dichloromethane, cooled beforehand to −10° C. After the addition, the reaction medium is stirred at ambient temperature for 18 h. The reaction medium is then poured into 1 l of ice and then extracted with ethyl acetate. The organic phases are combined, washed with water and then with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, filtered and concentrated under vacuum. 77 g (92%) of 4-(2-methylquinolin-4-ylmethoxy)benzenesulfonyl chloride hydrochloride are obtained in the form of a beige solid.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][CH:5]=[N:4][C:3]=1[C:8]1([OH:16])[CH2:14][CH:13]2[NH:15][CH:10]([CH2:11][CH2:12]2)[CH2:9]1.Br[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[Cl:25].C([O-])([O-])=O.[K+].[K+].O>CC#N>[Cl:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=1[CH:18]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[Cl:32])[N:15]1[CH:13]2[CH2:12][CH2:11][CH:10]1[CH2:9][C:8]([C:3]1[N:4]=[CH:5][CH:6]=[CH:7][N:2]=1)([OH:16])[CH2:14]2
Reactant: Clc1ccccc1C(Br)c1ccccc1Cl
Reactant: OC1(c2ncccn2)CC2CCC(C1)N2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: OC1(c2ncccn2)CC2CCC(C1)N2C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 22.5 °C

Procedure:
Under N2, a well stirred mixture of 3-pyrimidin-2-yl-8-azabicyclo[3.2.1]octan-3-ol hydrochloride (4.5 g, 14 mmol), 1,1′-(bromomethylene)bis(2-chlorobenzene) (5.0 g, 16 mmol) and K2CO3 (10.0 g, 72 mmol) in CH3CN (50 ml) was stirred under reflux and the reaction was followed by HPLC. After complete reaction (36 to 48 h) the mixture was cooled to 20-25° C., water (50 ml) was added and the suspension was stirred for 3 h. The product was filtered off, washed with water (2×25 ml) and dried to constant weight under vacuum and a slight stream of N2 at 50° C. Yield: 5.5 g (87% abs.). Assay (HPLC): 97% pure vs. standard.
Reaction SMILES: Cl.[NH2:2][OH:3].C(N(C(C)C)CC)(C)C.[C:13]1([P:19](Cl)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>ClCCl>[NH2:2][O:3][P:19](=[O:20])([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=P(Cl)(c1ccccc1)c1ccccc1
Reactant: NO
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NOP(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 77.6 %

Procedure:
To a suspension of hydroxylamine hydrochloride (29.4 g) in dichloromethane (200 mL) was added diisopropylethylamine (54.6 g) over 3 minutes in a methanol-ice bath under a nitrogen atmosphere. A white precipitate was formed upon the addition. After stirring for 1 hour under the bath, a solution of diphenylphosphinic chloride (20.0 g) in dichloromethane (20 mL) was added over 60 minutes. A white crystal was formed upon the addition. The mixture was warmed to 0° C. over 1 hour with stirring. The reaction was quenched by adding water (200 mL) over 3 minutes. After stirring the mixture for 0.5 hour, the crystal was collected by filtration. The crystal was washed with water (50×3 mL) followed by diisopropyl ether (50×3 mL). The collected crystal was dried overnight in the air and 3 hours under a reduced pressure with slight warming (4° C.) to give a crude product. The crude product was triturated in EtOH (ethanol) to give (aminooxy)(diphenyl)phosphine oxide as a white crystal (15.3 g).
Reaction SMILES: C(N=C=NCCCN(C)C)C.[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[NH:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[O:25]1[CH2:29][CH2:28][CH:27]([C:30](O)=[O:31])[CH2:26]1.O>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:12]([C@@H:19]1[CH2:23][O:22][C:21](=[O:24])[N:20]1[C:30]([C@H:27]1[CH2:28][CH2:29][O:25][CH2:26]1)=[O:31])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Reactant: O=C(O)C1CCOC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: ClCCl
Product: O=C1OC[C@@H](Cc2ccccc2)N1C(=O)[C@H]1CCOC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.6 %

Procedure:
1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI; 362 mg, 1.90 mmol) and DMAP (202 mg, 1.90 mmol) were added to a solution of (R)-4-benzyl-oxazolidin-2-one (333 mg, 1.90 mmol) and tetrahydrofuran-3-carboxylic acid (200 mg, 1.70 mmol) in CH2Cl2 (20 mL) at ambient temperature. The reaction mixture was stirred for 3 h at ambient temperature and water (20 mL) was added. The two layers were separated and the aqueous phase was extracted with CH2Cl2 (20 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash column chromatography on silica gel (CH2Cl2/EtOAc=100:2) to afford (R)-4-benzyl-3-((S)-tetrahydrofuran-3-carbonyl)oxazolidin-2-one (120 mg, 25% yield).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].O1CCCC1.CCCCCCC.C(C1C=CC=CC=1)C.[Br:29][C:30]1[CH:35]=[C:34]([Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[C:33]([F:43])=[CH:32][N:31]=1.[F:44][CH:45]([F:51])[C:46](OCC)=[O:47]>C1COCC1>[Br:29][C:30]1[N:31]=[C:32]([C:46](=[O:47])[CH:45]([F:51])[F:44])[C:33]([F:43])=[C:34]([Si:36]([CH2:41][CH3:42])([CH2:39][CH3:40])[CH2:37][CH3:38])[CH:35]=1
Reactant: CCOC(=O)C(F)F
Reactant: CC[Si](CC)(CC)c1cc(Br)ncc1F
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CCc1ccccc1
Solvent: C1CCOC1
Product: CC[Si](CC)(CC)c1cc(Br)nc(C(=O)C(F)F)c1F
Temperature: -78 °C
Reaction time: 3 h
Yield: 22.1 %

Procedure:
To 3-neck 250-mL round bottomed flask was added THF (15 mL). The mixture was cooled to −78° C. and lithium diisopropylamide, 2.0 m solution in tetrahydrofuran/heptane/ethylbenzene (5.73 ml, 11.45 mmol) was added over 1 min. To the solution was then added 2-bromo-5-fluoro-4-(triethylsilyl)pyridine (2.89 g, 9.96 mmol) in 16 mL THF over 5 min. The temperature was not allowed to go above −70° C. during the addition. After 3 h at −78° C., ethyl difluoroacetate (1.099 ml, 10.45 mmol) was added dropwise and the resulting reaction mixture was stirred at −78° C. for 2 h. The cold bath was removed and the solution was allowed to warm to −40° C. At that point the solution was quenched with a solution of saturated NH4Cl. The solution was extracted with EtOAc (2×100 mL) and the combined extracts were washed with brine, dried (Na2SO4) and concentrated. Purification by silica gel chromatography (0.0 to 20% EtOAc/hexane, 120 g Grace column) afforded 1-(6-bromo-3-fluoro-4-(triethylsilyl)pyridin-2-yl)-2,2-difluoroethanone (0.81 g, 2.2 mmol, 22.1% yield) as a dark orange oil. MS m/z=386, 388 M+18, Calculated for C13H17BrF3NOSi: 368.26.
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([F:11])=[CH:4][C:3]=1[NH2:12].O.O.[C:15](O)(=[O:19])[C:16](O)=[O:17]>Cl>[F:11][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:15](=[O:19])[C:16](=[O:17])[NH:12]2)=[C:7]([N+:8]([O-:10])=[O:9])[CH:6]=1
Reactant: Nc1cc(F)cc([N+](=O)[O-])c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Solvent: O
Product: O=c1[nH]c2cc(F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 62.5 °C
Yield: 43.5 %

Procedure:
A mixture of 1,2-diamino4-fluoro-6-nitrobenzene (80 mg, 0.46 mmole) and oxalic acid dihydrate (70 mg, 0.56 mmole, used as received) in 4N HCl (4 mL) was refluxed at 120-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the supernatant was removed. The yellow solid was washed with cold water (2×2 mL), collected by filtration, and dried in vacuo for 2 h, affording 45 mg (42%) of crude 7-fluoro-5-nitro-1,4-dihydro-2,3-quinoxalinedione as a yellow powder. The crude product was taken up in 1N NaOH (1 mL) and filtered. The filtrate was acidified to pH=3, affording 35 mg (33%) of 7-fluoro-5-nitro-1,4-dihydro-2,3-quinoxalinedione; mp: 333-335° C. (dec.); IR (KBr, cm-1): 3427, 3328, 3104, 3072, 1716, 1545. 1H NMR (DMSO-d6): δ 12.418 (s, 1H), 11.149 (s, 1H), 7.819 (dd, J1 =2.4 Hz, J2 =9.0 Hz, 1H), 7.297 (dd, J1 =2.4 Hz, J2 =9.0 Hz, 1H); HRMS: calcd for C8H4FN3O4 (M+) m/z: 225.0185; found: 225.0188.
Reaction SMILES: O=[C:2]([CH3:10])[CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].[C:11]1([C@H:17]([NH2:19])[CH3:18])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[C:20]1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1(C)C=CC=CC=1>[CH3:20][O:9][C:7](=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]([NH:19][C@@H:17]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:18])[CH3:10]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(=O)CCCCC(=O)O
Reactant: C[C@@H](N)c1ccccc1
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)CCCCC(C)N[C@H](C)c1ccccc1
Reaction time: 48 h

Procedure:
Put 8.80 g (55.63 mmol) 6-oxoheptanoic acid and 6.741 g (55.63 mmol) (R)-(+)-1-phenylethylamine together in 100 ml toluene at RT. Add a catalytic amount (approx. 50 mg) of p-toluenesulphonic acid and heat overnight with stirring on a water separator. Then partially concentrate by evaporation, filter off any solids using a paper filter, and fully concentrate the filtrate by evaporation. Dissolve the residue in 170 ml methanol. Add approx. 1.7 g Raney Nickel (moist with water) and hydrogenate for 48 h at 4 bar. Next, filter on diatomite and concentrate the filtrate by evaporation. Purify the residue by column chromatography on silica gel (solvent: dichloromethane/methanol 95:5), obtaining 4.15 g (48.5% of theor.) of the target compound, which is reacted without further characterization.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH:52]=[CH:53][C:54]3[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2].[H][H]>[Rh]>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:62])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([O:50][CH2:51][CH2:52][CH2:53][C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=3)[CH:46]([O:60][CH3:61])[CH2:45]2)[CH:7]([CH3:63])[CH2:6][CH2:5][C:4]1=[O:64])[CH3:2]
Reactant: [H][H]
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCC=Cc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Agent: [Rh]
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(OCCCc4ccccc4)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
To a solution of 17-ethyl-1-hydroxy-12-[2'-(4"-cinnamyloxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone (16 mg in 2 ml ethanol) was added 2 mg of 5% rhodium on carbon catalyst. The reaction flask was fitted with a hydrogen balloon, evacuated and recharged with hydrogen (3 times) and stirred at room temperature. After 30 minutes, the mixture was filtered over diatomacous earth, concentrated and purified by preparative TLC on silica gel (ethyl acetate:hexane (1:2)+1% methanol) to give the title compound (5.5 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1([CH:25](O)[CH3:26])[CH2:24][CH2:23][CH2:22][CH2:21]1.CCOC(/N=N/C(OCC)=O)=O.O1CCCCC1[N:46]1[C:54]2[C:49](=[CH:50][C:51]([C:55]3[N:59]=[CH:58][N:57](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:56]=3)=[CH:52][CH:53]=2)[C:48]([C:79]2[CH:80]=[C:81]([OH:85])[CH:82]=[CH:83][CH:84]=2)=[N:47]1.Cl>O1CCCC1>[NH:56]1[C:55]([C:51]2[CH:50]=[C:49]3[C:54](=[CH:53][CH:52]=2)[NH:46][N:47]=[C:48]3[C:79]2[CH:84]=[CH:83][CH:82]=[C:81]([O:85][CH2:26][CH2:25][N:20]3[CH2:24][CH2:23][CH2:22][CH2:21]3)[CH:80]=2)=[N:59][CH:58]=[N:57]1
Reactant: CC(O)N1CCCC1
Reactant: Oc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1cc(OCCN2CCCC2)cc(-c2n[nH]c3ccc(-c4ncn[nH]4)cc23)c1
Temperature: 25 °C
Reaction time: 23 h
Yield: 46 %

Procedure:
Triphenylphosphine (0.694 g, 2.65 mmol), tetrahydrofuran (2.12 mL), pyrrolidinylethanol (0.310 mL, 2.65 mmol) and diethylazodicarboxylate (0.418 mL, 2.65 mmol) were added to 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenol (0.400 g, 0.662 mmol). The mixture was stirred at ambient temperature for 23 h and poured into aqueous 6 N hydrochloric acid (30 mL). After stirring at ambient temperature for 4 h, the mixture was extracted with ether (3×). The aqueous fraction was added to aqueous 6 N sodium hydroxide (30 mL) and the pH adjusted to 11. The solution was extracted with ethyl acetate (3×) and the organic fractions were combined and dried over anhydrous sodium sulfate, filtered and evaporated. The residue was purified by flash chromatography on silica pretreated with 2% triethylamine/ethyl acetate followed by 0-20% methanol/ethyl acetate. The desired fractions were concentrated, dissolved in ethyl acetate, washed with aqueous sodium bicarbonate, dried over anhydrous sodium sulfate, filtered and evaporated which gave the title compound (0.114 g, 46% yield). 1H NMR (CD3OD) δ 8.72 (s, 1H), 8.34 (s, 1H), 8.09 (dd, 1H), 7.67 (d, 1H), 7.62 (d, 1H), 7.57 (m, 1H), 7.47 (t, 1H), 7.04 (m, 1H), 4.26 (t, 2H), 3.02 (t, 2H), 2.73 (m, 4H), 1.87 (m, 4H). ES-MS (m/z) 375 [M+1]+.
Reaction SMILES: [S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6](O)=[O:7])([OH:4])(=[O:3])=[O:2].S(Cl)([Cl:20])=O.CN(C)C=O>C(OCC)C.CCCCCC>[S:1]([CH:5]([C:9]1[CH:10]=[CH:11][C:12]2[O:16][CH2:15][CH2:14][C:13]=2[CH:17]=1)[C:6]([Cl:20])=[O:7])([OH:4])(=[O:3])=[O:2]
Reactant: O=C(O)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Reactant: O=S(Cl)Cl
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=C(Cl)C(c1ccc2c(c1)CCO2)S(=O)(=O)O
Temperature: 25 °C

Procedure:
α-Sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride is prepared according to the general method described in J. Med. Chem., 15, 1105 (1972). α-Sulfo(2,3-dihydro-5-benzofuranyl)acetic acid 20 mmole is added slowly to a solution of diethyl ether (4 ml) and thionyl cloride (150 mmole). The mixture is stirred at room temperature until the gas evolution stops. Then about 0.2 ml of dimethylformamide is added and the solution heated at 40° C. for 4 hours. The mixture is diluted with 30 ml of diethyl ether and 30 ml of hexane and then cooled to about -25° C. The α-sulfo(2,3-dihydro-5-benzofuranyl)acetyl chloride is recovered from the mixture and used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)(=[O:18])=[O:17])[CH2:12][CH2:11]2)[C:5]([CH3:27])=[CH:4][N:3]=1.[H][H]>C(O)C.C(N(CC)CC)C.[Pd]>[CH3:27][C:5]1[C:6]([NH:8][CH2:9][CH:10]2[CH2:11][CH2:12][N:13]([S:16]([CH2:19][CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)(=[O:17])=[O:18])[CH2:14][CH2:15]2)=[N:7][CH:2]=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)nc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCN(CC)CC
Solvent: CCO
Product: Cc1cncnc1NCC1CCN(S(=O)(=O)CCc2ccccc2)CC1

Procedure:
EXAMPLE 92 was prepared from (2-chloro-5-methyl-pyrimidin-4-yl)-[1-(2-phenyl-ethanesulfonyl)-piperidin-4-ylmethyl]-amine by hydrogenation in ethanol-triethylamine over 5% palladium on carbon, 1 atm of hydrogen: MS (m+1)=375.5.
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[CH3:35][O:36][CH2:37][C:38](Cl)=[O:39]>>[CH:2]1([CH2:5][O:6][C:7]2[CH:15]=[CH:14][C:10]3[O:11][CH2:12][O:13][C:9]=3[C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][CH:29]4[CH2:30][CH2:31][N:32]([C:38](=[O:39])[CH2:37][O:36][CH3:35])[CH2:33][CH2:34]4)=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1
Reactant: Cc1[nH]c2c(-c3c(OCC4CC4)ccc4c3OCO4)ncnc2c1C(=O)NC1CCNCC1
Reactant: COCC(=O)Cl
Agent: Cl
Product: COCC(=O)N1CCC(NC(=O)c2c(C)[nH]c3c(-c4c(OCC5CC5)ccc5c4OCO5)ncnc23)CC1

Procedure:
Starting from 4-[5-(cyclopropylmethoxy)-1,3-benzodioxol-4-yl]-6-methyl-N-piperidin-4-yl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f1) and commercially available methoxy-acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]2[CH2:12][C:11](=O)[CH2:10][C:9](=[O:14])[CH2:8]2)=[CH:3][CH:2]=1.Cl.[NH2:16][CH2:17][C:18]#[C:19][CH3:20].O1CCCC1>C(N(CC)CC)C>[CH3:20][C:19]1[C:10]2[C:9](=[O:14])[CH2:8][CH:7]([C:4]3[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=3)[CH2:12][C:11]=2[N:16]=[CH:17][CH:18]=1
Reactant: O=C1CC(=O)CC(c2ccncc2)C1
Reactant: CC#CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccnc2c1C(=O)CC(c1ccncc1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 8.9 %

Procedure:
To a mixture of 5-(4-pyridyl)cyclohexane-1,3-dione (0.90 g), 1-amino-2-butyne hydrochloride (0.5 g), molecular sieves 4A (2 g) and tetrahydrofuran (20 ml) was added triethylamine (0.48 g), and the mixture was stirred at room temperature for 1 hour, refluxed for 15 hours and cooled, insoluble materials were filtered off. Under reduced pressure, the solvent was evaporated, and the residue was stirred for 3.5 hours at 220° C. and cooled, to which were added ethyl acetate and sodium hydrogen carbonate solution. The organic layer was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/MeOH) to give oil of 4-methyl-7-(4-pyridyl)-5,6,7,8-tetrahydroquinolin-5-one (0.1 g).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C-:18]#[N:19].[Na+]>C(O)C>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:18]#[N:19])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [C-]#N
Reactant: ClCc1ccc(OCc2ccccc2)cn1
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(OCc2ccccc2)cn1
Reaction time: 0.42 h
Yield: 86.6 %

Procedure:
To a solution of 5-benzyloxy-2-chloromethyl-pyridine (2.13 g, 9.11 mmol) described in Manufacturing Example 127-1-3 in ethanol (30 mL) and water (10 mL) was added sodium cyanide (580 mg, 11.8 mmol), which was stirred for 4 hours and 25 minutes under reflux. Water was added to the reaction mixture at room temperature, which was extracted with ethyl acetate. The organic layer was separated, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=1:1) to obtain the title compound (1.77 g, 87%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([N:7]2[CH:11]=[C:10]([C:12]3[N:17]=[C:16]4[C:18](=O)[CH2:19][CH2:20][O:21][C:15]4=[CH:14][CH:13]=3)[CH:9]=[N:8]2)[CH:2]=1.[CH3:23][O:24][NH2:25].Cl.CC([O-])=O.[K+]>CO>[CH3:23][O:24][N:25]=[C:18]1[C:16]2=[N:17][C:12]([C:10]3[CH:9]=[N:8][N:7]([C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)[CH:11]=3)=[CH:13][CH:14]=[C:15]2[O:21][CH2:20][CH2:19]1
Reactant: CON
Reactant: O=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21
Agent: CC(=O)[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CON=C1CCOc2ccc(-c3cnn(-c4cccnc4)c3)nc21

Procedure:
6-[1-(3-Pyridyl)pyrazol-4-yl]-2,3-dihydropyrano[3,2-b]pyridin-4-one (120 mg, 0.41 mmol), CH3ONH2.HCl (38 mg, 0.82 mmol) and KOAc (81 mg, 0.82 mmol) were suspended in methanol (3 ml) under N2. The reaction mixture was refluxed overnight and purified by chromatography on silica (EtOAc) to get the title compound as a yellow solid.