Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([C:19]#N)=[CH:17][N:16]=1.C1(C)C=CC=CC=1.[H-].C([Al+]CC(C)C)C(C)C.[Cl-].[NH4+].C(OCC)(=[O:44])C>CCCCCC>[CH3:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH:19]=[O:44])=[CH:17][N:16]=1
Reactant: Cc1sc(-c2ccccc2)nc1COc1ccc(C#N)cn1
Reactant: CCOC(C)=O
Agent: CC(C)C[Al+]CC(C)C
Agent: [Cl-]
Agent: [H-]
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: Cc1sc(-c2ccccc2)nc1COc1ccc(C=O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 78 %

Procedure:
To a mixture of 6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinonitrile (5.45 g) and anhydrous toluene (150 mL) was dropwise added a solution (0.95 M, 41.0 mL) of diisobutylaluminum hydride in hexane at −78° C. The reaction mixture was allowed to warm to room temperature with stirring for 1.5 hrs. A saturated aqueous ammonium chloride solution (100 mL) was dropwise added to the mixture, and the mixture was further stirred at room temperature for 30 min. Ethyl acetate was added to the mixture and the mixture was stirred at room temperature for 30 min. Insoluble materials were filtered away. The filtrate was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give crystals (4.30 g, 78%) of 6-[(5-methyl-2-phenyl-4-thiazolyl)methoxy]nicotinaldehyde from a fraction eluted with ethyl acetate-hexane (1:4, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 120-121° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:17]([CH2:24][CH2:25][C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C[O-].[Na+]>CS(C)=O>[NH:17]([CH:24]=[C:25]([CH2:13][C:12]1[CH:15]=[CH:16][C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[CH:10][CH:11]=1)[C:26]#[N:27])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1
Reactant: N#CCCNc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CC(=CNc1ccccc1)Cc1ccc(OCc2ccccc2)cc1
Temperature: 0 °C

Procedure:
p-Benzyloxybenzaldehyde (25g.), β-anilinopropionitrile (22 g.), and dimethylsulphoxide (25 ml.) were heated together to 95° C, and a slurry of sodium methoxide (1 g.) in dimethylsulphoxide (20 ml.) was carefully added such that the temperature rose to 105° C. The mixture was heated to 125°-130° and held at that temperature for 11/2 hr. The reaction mixture was poured into ice-water (500 ml.), and the resulting solid was collected and washed by decantation. The crude product was slurried in cold ethanol to give β-anilino-α-(p-benzyloxybenzyl) acrylonitrile. Wt.= 27g.
Reaction SMILES: [CH3:1][Si:2]([CH3:13])([CH3:12])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH3:10])[CH:6]=[CH:7][CH:8]=1.[CH:14]([C:16]1[CH:25]=[CH:24][C:19]([C:20]([O:22]C)=[O:21])=[CH:18][CH:17]=1)=O.[OH-].[Na+].Cl>O1CCCC1.O>[CH3:13][Si:2]([CH3:12])([CH3:1])[C:3]1[CH:4]=[C:5]([C:9](=[O:11])[CH:10]=[CH:14][C:16]2[CH:25]=[CH:24][C:19]([C:20]([OH:22])=[O:21])=[CH:18][CH:17]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1cccc([Si](C)(C)C)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)c1cccc(C(=O)C=Cc2ccc(C(=O)O)cc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60.6 %

Procedure:
To a solution of 130 mg (0.676 mmol) of 3'-trimethylsilylacetophenone and 127 mg (0.774 mmol) of methyl 4-formylbenzoate in 4.5 ml of tetrahydrofuran (THF) were added 128 mg (3.20 mmol) of NaOH and 3 ml of hot water, and the mixture was stirred at room temperature overnight. The reaction mixture was adjusted with 7 ml of 0.5N-HCl to pH6, and then the aqueous solution was extracted with ethyl acetate. The extract was washed with 0.05N-HCl and H2O, dried and evaporated. The residue was purified by column chromatography affording 133 mg of pale yellow powder (yield 61%), which was recrystallized from a mixture of methylene chloride, methanol and n-hexane to give 98 mg of pale yellow needles, m.p. 179°-180° C. (yield 45%).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].C1(N=C=NC2CCCCC2)CCCCC1.[F:28][C:29]1[C:34](O)=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]>ClCCl>[F:28][C:29]1[C:34]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:33]([F:36])[C:32]([F:37])=[C:31]([F:38])[C:30]=1[F:39]
Reactant: N#CC(C(=O)O)c1ccccc1
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: N#CC(C(=O)Oc1c(F)c(F)c(F)c(F)c1F)c1ccccc1
Reaction time: 4 h

Procedure:
8 g. (0.05 moles) of α-cyano-phenylacetic acid are dissolved in dichloromethane. Under mild heating 10.3 g. (0.05 moles) of dicyclohexylcarbodiimide and 0.2 g. (0.05 moles) of pentafluorophenol dissolved in 50 ml. of dichloromethane are added dropwise. The mixture is stirred for 4 hours at 30° to 35° C. It is cooled, and the precipitated dicyclohexylurea is filtered. The substance on the filter is washed twice with 10 ml. of dichloromethane. The combined organic layers are evaporated while petrolether is added. The crystalline ester is precipitated from petrolether.
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.CS(C)=O.C1([O:15][C:16](=O)[NH:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][C:25]3[C:34]4[C:29](=[CH:30][C:31]([O:37][CH2:38][C@H:39]5[CH2:41][O:40]5)=[C:32]([C:35]#[N:36])[CH:33]=4)[N:28]=[CH:27][CH:26]=3)=[CH:20][C:19]=2[F:42])C=CC=CC=1.O>C(OCC)(=O)C>[F:42][C:19]1[CH:20]=[C:21]([O:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:38][C@H:39]4[CH2:41][O:40]4)=[C:32]([C:35]#[N:36])[CH:33]=3)[N:28]=[CH:27][CH:26]=2)[CH:22]=[CH:23][C:18]=1[NH:17][C:16]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:15]
Reactant: NC1CC1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)Oc4ccccc4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Solvent: O
Product: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(F)c3)ccnc2cc1OC[C@H]1CO1
Reaction time: 0.17 h

Procedure:
Cyclopropylamine (0.04 ml) was added to dimethylsulfoxide (3 ml), and then [2-fluoro-4-([6-cyano-7-([(2R)-oxiran-2-yl]methoxy)-4-quinolyl]oxy)phenyl]carbamic acid phenyl ester (212 mg) was dissolved therein and the solution was stirred for 10 minutes. Water and ethyl acetate were added to the reaction solution, and the precipitated crystals were filtered out to obtain the title compound (150 mg).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]2[CH:11]=[CH:12][S:13][C:3]=12.[NH2:14][C@H:15]1[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]1.C(N(CC)C(C)C)(C)C>C(O)(C)C>[N+:8]([C:7]1[C:2]([NH:14][C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][OH:22])[CH2:17][CH2:16]2)=[C:3]2[S:13][CH:12]=[CH:11][C:4]2=[N:5][CH:6]=1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1cnc2ccsc2c1Cl
Reactant: N[C@H]1CC[C@H](CO)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: O=[N+]([O-])c1cnc2ccsc2c1N[C@H]1CC[C@H](CO)CC1
Temperature: 90 °C

Procedure:
A mixture of 7-chloro-6-nitrothieno[3,2-b]pyridine (0.21 g, 0.98 mmol) (Example 1, Step 2), (trans-4-aminocyclohexyl)methanol (from J&W Pharmatech, 0.25 g, 2.0 mmol) and N,N-diisopropylethylamine (0.51 mL, 2.9 mmol) in isopropyl alcohol (3.3 mL) was heated at 90° C. for 2 h. The resulting mixture was concentrated and purified on silica gel (eluting with 0 to 60% EtOAc in hexanes) to give the desired product (0.26 g, 86%). LCMS calculated for C14H18N3O3S (M+H)+: m/z=308.1. Found: 308.0.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=2)[N:15]2[CH2:18][C:17](=O)[CH2:16]2)=[CH:10][CH:9]=1.[CH3:27][S:28]([CH2:31][C:32]1[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=1)(=[O:30])=[O:29].CS(Cl)(=O)=O>O1CCCC1.C(OCC)C.O>[Cl:26][C:23]1[CH:22]=[CH:21][C:20]([CH:14]([C:11]2[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=2)[N:15]2[CH2:18][C:17](=[C:31]([S:28]([CH3:27])(=[O:29])=[O:30])[C:32]3[S:36][C:35]([C:37]([O:39][CH3:40])=[O:38])=[CH:34][CH:33]=3)[CH2:16]2)=[CH:25][CH:24]=1
Reactant: COC(=O)c1ccc(CS(C)(=O)=O)s1
Reactant: O=C1CN(C(c2ccc(Cl)cc2)c2ccc(Cl)cc2)C1
Agent: CC(C)(C)[O-]
Agent: CS(=O)(=O)Cl
Agent: [K+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(C(=C2CN(C(c3ccc(Cl)cc3)c3ccc(Cl)cc3)C2)S(C)(=O)=O)s1
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 15.3 %

Procedure:
2.47 g of potassium tert-butoxide are added to a suspension of 6.12 g of 1-[bis(4-chlorophenyl)methyl]azetidin-3-one and 5.15 g of methyl 5-(methylsulfonylmethyl)thiophene-2-carboxylate in 200 cm3 of tetrahydrofuran, under an argon atomosphere, cooled to −70° C. The mixture is stirred for 1 hour 30 min at a temperature close to −70° C., and then 1.7 cm3 of methanesulfonyl chloride in solution in 8 cm3 of ethyl ether is added. After stirring for 1 hour at a temperature close to −70° C., the mixture is allowed to return to room temperature and then 80 cm3 of distilled water are added. The mixture is concentrated in a rotary evaporator to one third of its initial volume, and is then extracted with 500 cm3 of dichloromethane. The organic phase is washed with three times 80 cm3 of distilled water, dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). The residue obtained is chromatographed on a silica gel column (particle size 0.02-0.04 mm, diameter 7.5 cm, height 35 cm), eluting at a nitrogen pressure of 0.5 bar with a cyclohexane and ethyl acetate mixture (70/30 by volume) and collecting 40 cm3 fractions. Fractions 19 to 29 are combined and then concentrated to dryness under reduced pressure (2.7 kPa). 1.6 g of 1-[bis(4-chlorophenyl)methyl]-3-[(methylsulfonyl)(2-methoxycarbonylthien-5-yl)methylene]azetidine are obtained in the form of a cream-colored foam [1H NMR spectrum (400 MHz, CDCl3, δ in ppm): 2.91 (s, 3H), 3.88 (s, 3H), 4.08 (mt, 2H), 4.37 (mt, 2H), 4.53 (s, 1H), from 7.25 to 7.45 (mt, 9H), 7.71 (d, J=3.5 Hz, 1H)].
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:22][N:12]3[C:13](=[O:21])[NH:14][C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[C:11]3=[N:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:31]=[C:32]=[O:33])[CH:28]=[CH:29][CH:30]=1>>[CH3:23][O:24][C:25]1[CH:26]=[C:27]([NH:31][C:32]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([CH:8]3[CH2:22][N:12]4[C:13](=[O:21])[NH:14][C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[C:11]4=[N:10][CH2:9]3)=[CH:4][CH:3]=2)=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: COc1cccc(N=C=O)c1
Reactant: Nc1ccc(C2CN=C3c4ccccc4NC(=O)N3C2)cc1
Product: COc1cccc(NC(=O)Nc2ccc(C3CN=C4c5ccccc5NC(=O)N4C3)cc2)c1
Yield: 66 %

Procedure:
In a manner similar to the procedure described in Example 7, 3-(4-aminophenyl)-2,3,4,7-tetrahydro-6H-pyrimido[1,2-c]quinazolin-6-one (20.2 mg, 0.069 mmol) and 3-methoxyphenyl isocyanate (0.0098 mL, 0.076 mmol) were reacted to give the title compound as a white solid (20.1 mg, 66%). 1H NMR (DMSO-d6) δ: 10.69 (s, 1H), 8.65 (s, 1H), 8.62 (s, 1H), 7.98 (d, J=7.3 Hz, 1H), 7.39-7.47 (m, 3H), 7.13-7.27 (m, 4H), 6.98-7.10 (m, 2H), 6.93 (d, J=7.6 Hz, 1H), 6.55 (dd, J=8.4, 2.2 Hz, 1H), 4.18-4.26 (m, 1H), 3.73 (s, 4H), 3.48-3.62 (m, 2H), 2.90-3.02 (m, 1H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:22]([OH:23])=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[CH:15][N:14]=1)=[O:12].CO.CO.O>C(Cl)(Cl)Cl>[CH3:9][O:10][C:11]([C:13]1[C:22]([OH:23])=[C:21]2[C:16]([CH:17]=[CH:18][CH:19]=[N:20]2)=[C:15]([Br:1])[N:14]=1)=[O:12]
Reactant: COC(=O)c1ncc2cccnc2c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COC(=O)c1nc(Br)c2cccnc2c1O
Temperature: 35 °C
Reaction time: 0.5 h
Yield: 92.6 %

Procedure:
N-bromosuccinimide (7.83 g, 44.0 mmol) was added to a solution of 8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (5, 8.17 g, 40.0 mmol) in chloroform (32 mL) over 20 min maintaining the temperature at 20-50° C. and the mixture was aged for 30 min at 50° C. The mixture became a thick, stirrable slurry and HPLC analysis indicated <2% starting material remaining. The mixture was cooled to 30° C. over 15 min. MeOH (64 mL) was added over 30 min then a 1:1 mixture of MeOH-water (64 mL) was added over 30 min. The mixture was cooled to −40° C. over 30 min and aged at −40° C. for 30 min. The cold mixture was filtered and the solid was washed with 1:1 MeOH:water (100 mL) at 10-20° C. The off white crystalline solid was dried under a stream of nitrogen to provide 10.48 g (93% yield) of 5-bromo-8-hydroxy-1,6-naphthyridine-7-carboxylic acid methyl ester (6).
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=O)[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.Cl.[NH2:33][OH:34].C([O-])(=O)C.[NH4+].C(O)C.O>O>[F:1][C:2]1[CH:31]=[CH:30][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:15][CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:25](=[N:33][OH:34])[CH3:26])=[CH:21][C:20]=4[O:28][CH3:29])[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: NO
Reactant: COc1cc(C(C)=O)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1cc(C(C)=NO)ccc1OCCCN1CCC(c2noc3cc(F)ccc23)CC1

Procedure:
A mixture of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-piperidinyl]propoxy]-3-methoxyphenyl]ethanone (4.3 g, 10 mmol), prepared as in Example 3 above, hydroxylamine hydrochloride (1.3 g, 18 mmol), ammonium acetate (1.7 g, 22 mmol) and ethanol-H2O was stirred and refluxed for 16 hours. The reaction was poured into water, and the mixture was cooled in an ice bath for 2 hours. The resultant, white solid was collected washed with water, and dried to yield 4,6 g or hydrochloride salt of the oxime, m.p.=216°-218° C. The compound was dispersed in water, and ammonium hydroxide was added until the suspension was decidedly basic. The basic suspension was then extracted with dichloromethane, and after washing with water, drying (MgSO4) and concentrating the extract, 3.0 g of white solid melting at 168°-170° C. were harvested. The compound, was recrystallized from dimethylformamide to yield 2.3 g (52%) of 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone oxime as a white solid, m.p.=168°-170° C. ANALYSIS: Calculated for C24H28FN3O4: 65.29%C 6.39%H 9.52%N Found: 65.27%C 6.44%H 9.46%N
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[C:5]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[CH:14]=1.[CH2:19]=O>C(O)C.[Pt]=O>[ClH:1].[CH3:19][N:11]1[CH2:10][CH2:9][C:8]2[CH:14]=[C:4]([O:3][CH3:2])[C:5]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:6][C:7]=2[CH2:13][CH2:12]1
Reactant: C=O
Reactant: COc1cc2c(cc1S(C)(=O)=O)CCNCC2
Agent: O=[Pt]
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1S(C)(=O)=O)CCN(C)CC2

Procedure:
A mixture of 8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (1 g, 3.5 mmol), 37% aqueous formaldehyde (1.1 g) and platinum oxide (0.1 g) in ethanol (25 ml) was shaken under an atmosphere of hydrogen (60 psi). The mixture was degassed, filtered and concentrated at reduced pressure to give 3-methyl-8-methoxy-7-methylsulfonyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][C:10]([O:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:9]([C:8]([C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=1)=[O:14])[C:10]([O:12][CH3:13])=[O:11]
Reactant: BrBr
Reactant: COC(=O)CC(=O)c1ccc(C)cc1
Solvent: ClC(Cl)Cl
Product: COC(=O)C(Br)C(=O)c1ccc(C)cc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
To a chloroform (20 mL) solution of methyl 3-(4-methylphenyl)-3-oxopropanoate (1.0 g), bromine (0.12 mL) was added, and the resultant was stirred at 70° C. for 1 hour under sealed conditions. Then, bromine (0.12 mL) was further added thereto, and the resultant was further stirred at 70° C. for 1 hour under sealed conditions. The reaction solution was concentrated under reduced pressure to obtain the title compound (1.3 g) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[C:13][Si](C)(C)C)[CH:10]=2)[NH:5][C:4](=[O:18])[CH2:3]1>CO>[CH3:1][C:2]1([CH3:19])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[CH:13])[CH:10]=2)[NH:5][C:4](=[O:18])[CH2:3]1
Reactant: CC1(C)CC(=O)Nc2ccc(C#C[Si](C)(C)C)cc21
Solvent: CO
Product: C#Cc1ccc2c(c1)C(C)(C)CC(=O)N2
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2.64 g (9.7 mmol) of 4,4-dimethyl-2-oxo-1,2,3,4-tetrahydro-6[(trimethylsilyl)ethynyl]quinoline (Compound 2) in 200 ml of methanol was added 0.269 g (1.95 mmol) of K2CO3The reaction was stirred at room temperature for 12 h. The reaction was then concentrated in vacuo and water was added to the residue. The aqueous layer was extracted with methylene chloride (2×). The organic layers were dried (MgSO4), filtered and concentrated in vacuo to give the title compound as a white solid.
Reaction SMILES: ClC(N(C)C)=C(C)C.[F:9][CH:10]([F:33])[O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:19]([OH:21])=O)[CH3:14].[CH3:34][C:35]1[N:36]=[CH:37][C:38]([NH2:41])=[N:39][CH:40]=1.N1C=CC=CC=1>C(Cl)Cl>[F:33][CH:10]([F:9])[O:11][CH2:12][C@@H:13]([O:15][C:16]1[CH:17]=[C:18]([CH:22]=[C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:24]=1)[C:19]([NH:41][C:38]1[CH:37]=[N:36][C:35]([CH3:34])=[CH:40][N:39]=1)=[O:21])[CH3:14]
Reactant: Cc1cnc(N)cn1
Reactant: C[C@@H](COC(F)F)Oc1cc(OCc2ccccc2)cc(C(=O)O)c1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cc(OCc3ccccc3)cc(O[C@@H](C)COC(F)F)c2)cn1
Reaction time: 1 h

Procedure:
1-Chloro-N,N,2-trimethyl-prop-1-en-1-amine (0.26 mL, 2.0 mmol) was added to a solution of 3-[(2S)-1-(difluoromethoxy)propan-2-yl]oxy-5-phenylmethoxy-benzoic acid (0.54 g, 1.5 mmol) in DCM (20 mL) and stirred for 1 hour. 5-Methylpyrazin-2-amine (CAS no. 5521-58-4) (335 mg, 3.1 mmol) then pyridine (0.25 mL, 3.1 mmol) were added and the reaction stirred for a further 30 minutes before being reduced in vacuo and partitioned between ethyl acetate (50 mL) and water (50 mL). The aqueous layer was further extracted into ethyl acetate (50 mL) and the combined organics washed with water (50 mL), brine (50 mL), dried (MgSO4), and reduced in vacuo. The crude residue was chromatographed on silica, eluting with 40-100% ethyl acetate in isohexane, to give the desired compound (0.48 g).
Reaction SMILES: S(=O)(=O)(O)O.ClC1C=CC=CC=1C[N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[C:12](C#N)=[C:11]1[N:25]1[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:22][N:14]1[C:13]2[CH:12]=[C:11]([N:25]3[CH2:30][CH2:29][CH2:28][C@@H:27]([NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH2:26]3)[NH:10][C:18]=2[C:17](=[O:19])[N:16]([CH3:20])[C:15]1=[O:21]
Reactant: Cn1c(=O)c2c(c(C#N)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: O
Product: Cn1c(=O)c2[nH]c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)cc2n(C)c1=O
Temperature: 140 °C
Reaction time: 3 h
Yield: 93.1 %

Procedure:
Under ice-cooling, water (2 ml) and concentrated sulfuric acid (4 ml) were added to tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-cyano-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (300 mg), and the resulting mixture was stirred at 140° C. After 3 hours, the reaction solution was cooled to 0° C. and adjusted to pH 8 or higher by dropwise addition of a 5N aqueous potassium carbonate solution. The reaction solution was extracted with chloroform and the organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure. To the resulting residue were added di-tert-butyl dicarbonate (372 mg), 1,4-dioxane (5 ml) and a saturated aqueous sodium hydrogencarbonate solution (5 ml), and the resulting mixture was stirred at room temperature for 8 hours. Water was added to the reaction solution, followed by extraction with chloroform. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. To the resulting residue was added diethyl ether, followed by filtration, and the precipitate was washed with hexane to obtain the title compound (200 mg) as a light-yellow solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[C:13]([CH2:14][C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[C:10]([CH3:22])[N:9]=1)([CH3:3])[CH3:2].C([O:30][N:31]=O)(C)(C)C>COCCOC>[CH:1]([C:4]1[CH:5]=[C:6]([CH:23]=[CH:24][CH:25]=1)[O:7][C:8]1[C:13]([C:14](=[N:31][OH:30])[C:15]([O:17][CH3:18])=[O:16])=[C:12]([N:19]([CH3:21])[CH3:20])[N:11]=[C:10]([CH3:22])[N:9]=1)([CH3:3])[CH3:2]
Reactant: CC(C)(C)ON=O
Reactant: COC(=O)Cc1c(Oc2cccc(C(C)C)c2)nc(C)nc1N(C)C
Solvent: COCCOC
Product: COC(=O)C(=NO)c1c(Oc2cccc(C(C)C)c2)nc(C)nc1N(C)C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of methyl 4-(3-isopropylphenoxy)-6-dimethylamino-2-methyl-pyrimidin-5-yl-acetate (28 g, 0.08 mol) in t-butylnitrite (40 ml) and 1,2-dimethoxyethane (40 ml) is added at -30° C. to a solution of potassium tert.butylate (14 g, 0.12 mol) in 1,2-dimethoxyethane (50 ml). The reaction mixture is allowed to warm to 0° C. and is the quenched with a solution of ammonium chloride. After stirring for 2 hours at room temperature the product is extracted with diethylether. Drying (MgSO4) and evaporation of the solvent gives crude methyl 2-[4-(3-isopropylphenoxy)-6-dimethylamino-2-methyl-pyrimidin-5-yl]-2-hydroximino-acetate (30 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[NH:9]1[CH2:14][CH2:13][CH:12]([C:15](O)=O)[CH2:11][CH2:10]1.[OH-].[K+]>O>[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[O:8][C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[N:1]=2)[CH2:11][CH2:10]1
Reactant: Nc1ccccc1O
Reactant: O=C(O)C1CCNCC1
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: c1ccc2oc(C3CCNCC3)nc2c1
Temperature: 180 °C
Yield: 84.3 %

Procedure:
2-Aminophenol (200 mg) and 4-piperidinecarboxylic acid (236 mg) were mixed with polyphosphoric acid (1 g) and stirred with heating at 180° C. for 2 hours. After cooling to room temperature, the reaction was stopped by adding water. The filtrate was adjusted to pH 12 with 50% potassium hydroxide aqueous solution and then extracted with methylene chloride. The organic layer was washed with saturated brine and dried with magnesium sulfate, and then the solvent was evaporated under a reduced pressure to obtain the title compound 2-(4-piperidyl)benzoxazole (311.5 mg).