Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][C:3]=1[F:10].[N:11]([C:14]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:15]=1[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]2)=[C:12]=[O:13].N(C1C=CC=C2C=1C=CN=C2)=C=O>>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:12]([NH:11][C:14]2[CH:23]=[CH:22][CH:21]=[C:20]3[C:15]=2[CH:16]=[C:17]([CH3:24])[N:18]=[CH:19]3)=[O:13])=[CH:4][C:3]=1[F:10]
Reactant: Cc1cc2c(N=C=O)cccc2cn1
Reactant: NCc1ccc(Br)c(F)c1
Agent: O=C=Nc1cccc2cnccc12
Product: Cc1cc2c(NC(=O)NCc3ccc(Br)c(F)c3)cccc2cn1

Procedure:
The title compound was prepared using the procedure described in Example 61B using 4-bromo-3-fluorobenzylamine and the product from Example 154A instead of 4-cyanobenzyl alcohol and the product from Example 61A. 1H NMR (300 MHz, DMSO-d6) δ 9.68 (s, 1H), 9.46 (s, 1H), 8.51 (m, 2H), 8.01 (d, 1H, J=7.8 Hz), 7.80 (t, 1H, J=7.8 Hz), 7.67 (m, 2H), 7.36 (dd, 1H, J=9, 1.5 Hz), 7.18 (dd, 1H, J=9, 1 Hz), 4.39 (d, 2H, J=6 Hz), 2.77 (s, 3H); MS (ESI) 388/390 (M+H)+; Anal. Calcd for C18H15BrFN3O.HCl: C, 50.91; H, 3.80; N, 9.89. Found: C, 50.81; H, 3.74; N, 9.87
Reaction SMILES: [CH2:1]([N:5]1[CH2:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([OH:16])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4].[CH2:18]([N:20]([CH2:24][CH3:25])[CH2:21][CH2:22]Cl)[CH3:19]>>[CH2:1]([N:5]1[CH2:9][C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[C:7]([O:16][CH2:19][CH2:18][N:20]([CH2:24][CH3:25])[CH2:21][CH3:22])[C:6]1=[O:17])[CH2:2][CH2:3][CH3:4]
Reactant: CCN(CC)CCCl
Reactant: CCCCN1CC(c2ccccc2)=C(O)C1=O
Product: CCCCN1CC(c2ccccc2)=C(OCCN(CC)CC)C1=O

Procedure:
23.1 g. 1-n-butyl-3-hydroxy-4-phenyl-3-pyrrolin-2-one is reacted with 20.3 g. β-diethylaminoethyl chloride in a manner analogous to that described in Example 1. The 1-n-butyl-3-(β-diethylaminoethoxy)-4-phenyl-3-pyrrolin-2-one obtained in the form of the free base is reacted in diethyl ether with oxalic acid to give the crystalline oxalate. The yield is 24.2 g. (58% of theory); m.p. 120°-121° C.; after recrystallization from methyl ethyl ketone.
Reaction SMILES: CC(CCCCC)CCCCC1C=CC(C(O)=O)=CC=1.[CH2:21]([O:29][C:30]1[CH:35]=[CH:34][C:33](O)=[CH:32][CH:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]CC.[CH3:37][CH:38]([CH2:54][CH2:55][CH2:56][CH3:57])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][C:45]1[CH:53]=[CH:52][C:48]([C:49]([OH:51])=[O:50])=[CH:47][CH:46]=1.CC(CCCC)CCCCCBr.CC1C=CC(C(O)=O)=CC=1.C(OC1C=CC(O)=CC=1)CCCCC>>[CH2:21]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:50][C:49](=[O:51])[C:48]2[CH:47]=[CH:46][C:45]([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH:38]([CH3:37])[CH2:54][CH2:55][CH2:56][CH3:57])=[CH:53][CH:52]=2)=[CH:34][CH:35]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CCCCCCCCOc1ccc(O)cc1
Reactant: CCCCC(C)CCCCCCc1ccc(C(=O)O)cc1
Agent: CCCCC(C)CCCCCBr
Agent: CCCCCC(C)CCCCc1ccc(C(=O)O)cc1
Agent: CCCCCCOc1ccc(O)cc1
Product: CCCCCCOc1ccc(OC(=O)c2ccc(CCCCCCC(C)CCCC)cc2)cc1

Procedure:
The procedure of Example 1 was followed except that the 4-(5'-methyldecyl)benzoic acid and 4-n-octoxyphenol were replaced by 4-(7'-methylundecyl)benzoic acid prepared by reacting 6-methyldecylbromide with 4-methylbenzic acid and 4-n-hexyloxyphenol to thereby give the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:15])[CH3:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4].O1CCCC1>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13](=[O:15])[CH3:14])[C:10]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][C:26]3[N:27]=[C:28]([C:32]4[O:33][CH:34]=[CH:35][CH:36]=4)[O:29][C:30]=3[CH3:31])=[C:20]([O:37][CH3:38])[CH:19]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(COc2nn(Cc3ccccc3)cc2C(C)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: [Mn+4]
Agent: [O-2]
Solvent: C1CCOC1
Product: COc1cc(COc2nn(Cc3ccccc3)cc2C(C)=O)ccc1OCc1nc(-c2ccco2)oc1C
Temperature: 25 °C
Reaction time: 96 h
Yield: 87 %

Procedure:
A mixture of 1-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-1-ethanol (0.15 g), activated manganese dioxide (0.50 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 days. Manganese dioxide was removed by filtration, and the filtrate was concentrated. The obtained crystals were collected by filtration to give 1-{1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1H-pyrazol-4-yl}-1-ethanone (0.13 g, yield 87%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 144-145° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([Cl:10])=[N:4][C:5]([CH3:9])=[N:6][C:7]=1Cl.Cl.[NH2:12][CH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(N(C(C)C)CC)(C)C>C(O)(C)C>[Cl:10][C:3]1[N:4]=[C:5]([CH3:9])[N:6]=[C:7]([NH:12][CH:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:2]=1[NH2:1]
Reactant: Cc1nc(Cl)c(N)c(Cl)n1
Reactant: NC1CCOCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: Cc1nc(Cl)c(N)c(NC2CCOCC2)n1
Temperature: 100 °C
Yield: 94.5 %

Procedure:
In a 300 mL glass pressure reactor, combine 5-amino-4,6-dichloro-2-methylpyrimidine (20.0 g, 97%, 109.0 mmol), 4-aminotetrahydropyran hydrochloride (21.0 g, 152.6 mmol), di-isopropylethylamine (57.0 mL, 326.9 mmol) and isopropyl alcohol (100 mL). Seal the pressure vessel tightly, start stirring, and adjust the set-point for heat control to 100° C. Stir the mixture at 100° C. for 24 hours. Cool the reactor contents to 60° C., vent the vessel of pressure, and add 4-aminotetrahydropyran hydrochloride (2.25 g, 16.3 mmol). Re-seal the vessel, heat the contents to an internal temperature of 100° C., and stir for an additional 24 hours. Cool the reaction mixture to ambient temperature, vent the reactor of pressure, and transfer the contents to a recovery flask. Concentrate the mixture under reduced pressure to approximately ⅓ of its original volume. Add water (200 mL) and ethyl acetate (200 mL) and transfer the resulting mixture to a separatory funnel Separate the layers, re-extract the aqueous layer with ethyl acetate (100 mL) and combine all organics. Wash with water (2×100 mL) and brine (100 mL), then dry the organic layer over anhydrous sodium sulfate. Concentrate under reduced pressure to afford 6-chloro-2-methyl-N*4*-(tetrahydro-2H-pyran-4-yl)-pyrimidine-4,5-diamine as an off-white solid (25.0 g). MS (m/z): 243/245 (M+1).
Reaction SMILES: C([NH:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[S:11][CH2:12][C@@H:13]2[CH2:19][C@H:18]([CH3:20])[O:17][CH2:16][C@:14]2([C:21]2[S:22][CH:23]=[C:24]([NH:26][C:27]([C:29]3[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[CH:31][N:30]=3)=[O:28])[N:25]=2)[N:15]=1
Reactant: C[C@H]1C[C@H]2CSC(NC(=O)c3ccccc3)=N[C@@]2(c2nc(NC(=O)c3ccc(OC(F)F)cn3)cs2)CO1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: C[C@H]1C[C@H]2CSC(N)=N[C@@]2(c2nc(NC(=O)c3ccc(OC(F)F)cn3)cs2)CO1

Procedure:
A solution of C9 (390 mg, 0.762 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 95%, 132 μL, 0.838 mmol) in methanol (15 mL) was heated at 70° C. for 90 minutes. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 0% to 8% methanol in dichloromethane) to provide the product as a solid. Yield: 191 mg, 0.419 mmol, 55%. LCMS m/z 456.2 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 10.40 (br s, 1H), 8.48 (br dd, J=2.7, 0.6 Hz, 1H), 8.31 (dd, J=8.6, 0.6 Hz, 1H), 7.72 (s, 1H), 7.68 (ddt, J=8.6, 2.7, 0.7 Hz, 1H), 6.65 (t, JHF=72.0 Hz, 1H), 3.93 (AB quartet, downfield doublet is broadened, JAB=11.2 Hz, ΔνAB=45.8 Hz, 2H), 3.75 (dqd, J=11.2, 6.1, 2.3 Hz, 1H), 3.19 (dd, J=12.6, 4.0 Hz, 1H), 2.83-2.90 (m, 1H), 2.61 (dd, J=12.6, 2.8 Hz, 1H), 1.81 (ddd, J=13.2, 12.9, 11.4 Hz, 1H), 1.56 (ddd, J=13.4, 4.2, 2.3 Hz, 1H), 1.30 (d, J=6.1 Hz, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[OH:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12].[Cl:26][C:27]1[C:28](F)=[C:29]([CH:37]=[CH:38][C:39]=1F)[C:30]([N:32]([CH2:34][CH2:35][OH:36])[CH3:33])=[O:31].S(Cl)(Cl)=O>C(#N)C.CO>[Cl:26][C:27]1[C:28]2[O:36][CH2:35][CH2:34][N:32]([CH3:33])[C:30](=[O:31])[C:29]=2[CH:37]=[CH:38][C:39]=1[O:7][C:8]1[CH:9]=[C:10]([CH:15]=[C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(O)cc(OCc2ccccc2)c1
Reactant: CN(CCO)C(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O=S(Cl)Cl
Solvent: CO
Solvent: CC#N
Product: COC(=O)c1cc(OCc2ccccc2)cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)c1
Temperature: 160 °C
Reaction time: 1 h
Yield: 44.5 %

Procedure:
Cesium carbonate (41.2 g, 126.4 mmol) was added to a solution of methyl 3-hydroxy-5-{[phenylmethyl]oxy}benzoate (10.9 g, 42.25 mmol) and 3-chloro-2,4-difluoro-N-(2-hydroxyethyl)-N-methylbenzamide (11.6 g, 46.4 mmol) in acetonitrile (210 mL) and the stirred mixture heated at 160° C. in a microwave reactor for 8 hours. The mixture was cooled to RT and pressure, the acetonitrile evaporated in vacuo, and the residue partitioned between water (500 mL) and ethyl acetate (300 mL). The mixture was adjusted to pH 2, the organic layer washed with brine, dried (MgSO4) and evaporated to a residue (shown to contain a large amount of acid). The mixture was added to a solution of thionyl chloride (11.7 mL, 160 mmol) in methanol (120 mL) at −35° C., the solution stirred at −35° C. for 1 hour then allowed to come to RT and stirred for 18 hours. The methanol was evaporated in vacuo to a residue which was partitioned between ethyl acetate (250 mL) and a saturated sodium hydrogen carbonate solution (175 mL). The organic layer was washed with a saturated sodium hydrogen carbonate solution (3×75 mL), brine, dried (MgSO4) and evaporated in vacuo to a residue which was chromatographed on silica, eluting with 50% ethyl acetate in isohexane, to give the desired compound (8.8 g).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[O:7]=[C:8]1[C@H:13]([CH2:14][CH2:15][C:16](OC)=[O:17])[O:12][C:11]2[CH:20]=[C:21]3[C:26](=[CH:27][C:10]=2[NH:9]1)[CH2:25][CH2:24][CH2:23][CH2:22]3>O1CCCC1>[OH:17][CH2:16][CH2:15][CH2:14][C@@H:13]1[O:12][C:11]2[CH:20]=[C:21]3[C:26](=[CH:27][C:10]=2[NH:9][C:8]1=[O:7])[CH2:25][CH2:24][CH2:23][CH2:22]3
Reactant: COC(=O)CC[C@@H]1Oc2cc3c(cc2NC1=O)CCCC3
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc3c(cc2O[C@H]1CCCO)CCCC3
Yield: 98.7 %

Procedure:
To a stirred and ice-cooled suspension of lithium aluminum hydride (0.51 g) in dry tetrahydrofuran (20 ml), was added dropwise a solution of methyl (S)-3-(3,4,6,7,8,9-hexahydro-3-oxo-2H-naphtho[2,3-b][1,4]oxazin-2-yl)propionate (1.75 g) in dry tetrahydrofuran (10 ml). The whole was stirred at 0° C. for 1.5 hour and quenched with water. After neutralization with 4N-HCl, the insoluble material was filtered off. The filtrate was extracted with ethyl acetate, and the ethyl acetate layer was washed with water and dried over magnesium sulfate. After evaporation of the solvent, the residue was purified by column chromatography on silica gel (60 g) with ethyl acetate-hexane (3:1, v/v) to yield (S)-6,7,8,9-tetrahydro-2-(3-hydroxypropyl)-2H-naphtho[2,3-b][1,4]oxazin-3(4H)-one as colorless needles (1.56 g, 98.7%), m.p. 139°-140° C. [α]D26 +1.4° (c=0.5, CHCl3).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([C:7]1[CH:8]=[C:9]([C:22](Cl)=[O:23])[N:10]([CH:12]([Cl:21])[CH:13]([Cl:20])[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]=1)#[N:6].ClCC(Cl)(Cl)Cl>O>[C:5]([C:7]1[CH:8]=[C:9]2[N:10]([CH:11]=1)[CH:12]([Cl:21])[CH:13]([Cl:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:22]2=[O:23])#[N:6]
Reactant: N#Cc1cc(C(=O)Cl)n(C(Cl)C(Cl)c2ccccc2)c1
Agent: ClCC(Cl)(Cl)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: N#Cc1cc2n(c1)C(Cl)C(Cl)c1ccccc1C2=O
Reaction time: 0.07 h

Procedure:
Aluminum chloride (231 mg.) was added all at once to a mixture of 160 mg. of 4-cyano-N-(1,2-dichloro-2-phenylethyl)pyrrole-2-carbonyl chloride and 0.5 ml. of tetrachloroethane controlled at 140° C. After 4-5 minutes, the mixture is cooled, 15 ml. of water is added and the mixture is extracted with 4 × 10 ml. of chloroform. The extract is washed with water, dried and chromatographed on 10 g. of silica gel by elution with benzene:ethyl acetate (3:1 v/v). The first fraction provided 47 mg. (33%) of 2-cyano-5,6-dichloro-6,11-dihydro-5H-[2,1-b][3]benzazapin-11-one, m.p. 213°-223° C.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:20]=[C:19](SCC2C=CC=C(F)C=2F)[C:18]2[C:13](=[N:14][C:15]([NH2:31])=[CH:16][N:17]=2)[N:12]=1.[NH2:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35]>CN1C=CN=C1>[NH2:31][C:15]1[N:14]=[C:13]2[C:18]([C:19]([NH:32][C:33]([CH3:38])([CH2:36][OH:37])[CH2:34][OH:35])=[N:20][C:11]([S:10][CH2:9][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([F:8])[C:2]=3[F:1])=[N:12]2)=[N:17][CH:16]=1
Reactant: CC(N)(CO)CO
Reactant: Nc1cnc2c(SCc3cccc(F)c3F)nc(SCc3cccc(F)c3F)nc2n1
Agent: Cn1ccnc1
Product: CC(CO)(CO)Nc1nc(SCc2cccc(F)c2F)nc2nc(N)cnc12

Procedure:
A solution of the product from example 1, step (c) (0.25 g) and 2-amino-2-methyl-1,3-propanediol (0.28 ml) in N-methylimidazole (1 ml) was heated in a microwave at 160° C. for 95 minutes. After cooling, the reaction mixture was partitioned between ethyl acetate and saturated aqueous ammonium chloride. The organic phase was dried over magnesium sulphate, filtered and evaporated to give a brown oil which was purified by silica gel flash column chromatography, eluting with 10:1 dichloromethane:methanol to give the title compound as a pale brown solid (0.031 g).
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:24])[C@H:6]([N:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][C:16]=3[N+:20]([O-])=O)[C:11]2=[O:23])[CH:7]([CH3:9])[CH3:8])[CH2:3][CH2:2]1.CO>[Pd]>[NH2:20][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]2[C:17]=1[CH:18]=[CH:19][N:10]([C@H:6]([CH:7]([CH3:9])[CH3:8])[C:5]([NH:4][CH:1]1[CH2:3][CH2:2]1)=[O:24])[C:11]2=[O:23]
Reactant: CC(C)[C@H](C(=O)NC1CC1)n1ccc2c([N+](=O)[O-])cccc2c1=O
Agent: [Pd]
Solvent: CO
Product: CC(C)[C@H](C(=O)NC1CC1)n1ccc2c(N)cccc2c1=O

Procedure:
(R)-N-Cyclopropyl-3-methyl-2-(5-nitro-1-oxoisoquinolin-2(1H)-yl)butanamide (1.3 g, 0.0039 mol) was stirred with palladium 10% wt. on calcium carbonate (0.2 g, 0.0001 mol) in methanol (60 mL, 1 mol) under hydrogen (balloon) for 1 h at room temperature. The catalyst was filtered and the filtrate was concentrated to dryness to give a brown oil. MS m/z 301.1 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=O)=[N:9]2)=[CH:4][CH:3]=1.[CH2:19]([N:21](CC)[CH2:22]C)C.ClC(O)=O.C=C.CNC.[OH-].[Na+]>C1(C)C=CC=CC=1.CO.Cl.O>[CH3:19][N:21]([CH3:22])[C:16]([C:10]1[C:11](=[O:15])[CH:12]=[C:13]([CH3:14])[N:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)=[O:18]
Reactant: CCN(CC)CC
Reactant: Cc1cc(=O)c(C(=O)O)nn1-c1ccc(Cl)cc1
Agent: C=C
Agent: CNC
Agent: Cl
Solvent: CO
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(=O)c(C(=O)N(C)C)nn1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 49.7 %

Procedure:
To an ice cooled suspension of 2.65 g (0.01 mol) 1-(4-chlorophenyl)-1,4-dihydro-4-oxo-6-methylpyridazine-3-carboxylic Acid (see Example 12) and 1.01 g (0.01 mol) of triethylamine in 50 ml of toluene there is added dropwise 1.09 g (0.01 mol) of ethylene chloroformate. The mixture is stirred at room temperature for 15 min. and is cooled to 5° C. To the mixture there is added 3.375 g (0.03 mol) of 40% dimethylamine (aqueous). The solution formed is stirred at room temperature for 18 hrs. and to it there is added 100 ml of water. The mixture is stirred at room temperature for 1 hr. and the aqueous layer is isolated. The aqueous layer is made basic with 50% sodium hydroxide and extracted with toluene. The toluene extract is dried over magnesium sulfate and concentrated in vacuo to afford 1.8 g of colorless tar. The tar is dissolved in 30 ml of methanol, saturated with anhydrous hydrogen chloride and concentrated in vacuo. The concentrate is slurried in 100 ml of ether for 1 hr. and vacuum filtered. The filter cake is air dried to afford 1.45 g (44% yield) of product, mp 125°-135° C. decomp.
Reaction SMILES: C([Li])CCC.CN1[CH2:12][CH2:11][CH2:10][N:9](C)C1=O.[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1COCC1>[CH:19]1[CH:20]=[CH:21][C:16]([CH2:15][C:12]#[C:11][CH2:10][NH2:9])=[CH:17][CH:18]=1
Reactant: BrCc1ccccc1
Reactant: CN1CCCN(C)C1=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: NCC#CCc1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 36.6 %

Procedure:
The compound resulting from Example 60A (4.35 g of -75% pure material, -16.5 mmol) was dissolved in THF (87 mL), cooled to 0° C., then n-butyllithium (16.5 mL of 1.6M hexanes solution) was added dropwise, followed by 1,3-dimethyl-3,4,5,6-tetrahydro-2(1 H)-pyrimidinone (3.20 mL, 3.39 g, 26.5 mmol) and benzyl bromide (3.50 mL, 5.03 g, 29.4 mmol). The reaction was stirred at 0° C. for 3 hours, then 1N HCl was added. After washing with 3×Et2O, the pH was adjusted to 10 with 4N NaOH, then extracted with 4×Et2O. The second set of Et2O layers were combined, dried over Na2SO4, filtered and concentrated to give a residue which was purified by silica gel chromatography eluting with a gradient of 99:1, 98.75:1.25, and 98:2 CHCl3 -MeOH to afford 1.41 g (59%) of the title compound as a light brown oil. 1H NMR (CDCl3) δ 7.35,7.24 (both m, total 5H), 3.60 (t, 2H), 3.47 (t, 2H), 1.38 (br s, 2H). MS (DCl/NH3) m/e 146 (M+H)+, 163 (M+H+NH3)+.
Reaction SMILES: [OH:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[K].[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23]Cl)=[O:19].O>CN(C)C=O>[CH3:16][O:17][C:18]([NH:20][C:21]1[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[C:22]=1[CH2:23][O:1][C:2]1[C:3]2[N:4]([C:8]([CH2:12][C:13]#[CH:14])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:19]
Reactant: C#CCc1c(C)nc2c(O)cccn12
Reactant: COC(=O)Nc1cccc(C)c1CCl
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=O)OC)cccn12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 6.6 %

Procedure:
A mixture of 8-hydroxy-2-methyl-3-(2-propynyl)imidazo[ 1,2-a]pyridine (0.372 g) and potassium carbona (0.276 g) in N,N-dimethylformamide (7.4 ml) was stirred at room temperature for 20 minutes under a nitrogen atmosphere and then 2-methoxycarbonylamino-6-methylbenzylchloride (0.427 g) was added. After being stirred for 2 hours. The mixture was poured into water and the resulting precipitates were collected by filtration. The crude product was purified by column chromatography on silica gel (10 g) with chloroform as eluents to give 8-(2-methoxycarbonylamino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (0.048 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]2[CH2:17][CH2:16][O:15][CH2:14]2)[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].F[C:19]1[CH:30]=[CH:29][C:22]2[C:23](=[O:28])[N:24]([CH3:27])[CH2:25][O:26][C:21]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>C(#N)C>[CH3:27][N:24]1[C:23](=[O:28])[C:22]2[CH:29]=[CH:30][C:19]([O:1][C:2]3[CH:3]=[C:4]([CH:9]=[C:10]([O:12][C@H:13]4[CH2:17][CH2:16][O:15][CH2:14]4)[CH:11]=3)[C:5]([O:7][CH3:8])=[O:6])=[CH:20][C:21]=2[O:26][CH2:25]1
Reactant: CN1COc2cc(F)ccc2C1=O
Reactant: COC(=O)c1cc(O)cc(O[C@H]2CCOC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Oc2ccc3c(c2)OCN(C)C3=O)cc(O[C@H]2CCOC2)c1
Temperature: 160 °C
Reaction time: 10 h
Yield: 39 %

Procedure:
A mixture of methyl 3-hydroxy-5-[(3S)-tetrahydrofuran-3-yloxy]benzoate (184 mg, 0.77 mmol), 7-fluoro-3-methyl-2,3-dihydro-4H-1,3-benzoxazin-4-one (140 mg, 0.77 mmol) and potassium carbonate (214 mg, 1.54 mmol) in acetonitrile (5 mL) was stirred in a microwave reactor at 160° C. for 10 hours then reduced in vacuo and ethyl acetate (50 mL) added. The organics were washed with brine (50 mL), dried (MgSO4), and reduced in vacuo and the crude oil purified by chromatography on silica, eluting with 30%-80% ethyl acetate in isohexane, to give the desired compound as a colourless oil (0.12 g).
Reaction SMILES: [F:1][C:2]1[C:3]([C:33]([F:36])([F:35])[F:34])=[C:4]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[ClH:37]>C(Cl)Cl.CCOCC>[ClH:37].[F:1][C:2]1[C:3]([C:33]([F:35])([F:34])[F:36])=[C:4]([CH:9]2[CH2:10][CH2:11][N:12]([C:15]([C:17]3[C:25]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[NH:19][N:18]=3)=[O:16])[CH2:13][CH2:14]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cc(F)cc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cc(F)cc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 97 %

Procedure:
To a solution of tert-butyl 3-(4-(3,5-difluoro-2-(trifluoro-methyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (59, 94 mg, 0.19 mmol) in CH2Cl2 (3 mL) was added HCl (2.0 N solution in Et2O, 3 mL). The mixture was stirred for 18 h at ambient temperature. The reaction mixture was diluted with Et2O (20 mL) and the mixture concentrated under reduced pressure to yield (4-(3,5-difluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (60) as a white solid (80 mg, 97%).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[CH3:17])[S:9][CH:10]=1)=[O:5])C.[OH-].[Na+]>C1COCC1.CO.C(Cl)Cl>[C:12]1([CH3:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[S:9][CH:10]=[C:6]([C:4]([OH:5])=[O:3])[N:7]=1
Reactant: CCOC(=O)c1csc(-c2ccccc2C)n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: Cc1ccccc1-c1nc(C(=O)O)cs1
Reaction time: 8 h
Yield: 89.2 %

Procedure:
2-o-Tolyl-thiazole-4-carboxylic acid ethyl ester (550 mg, 2.22 mmol) was dissolved in a mixture of THF (1.0 mL) and MeOH (1.0 mL). To this was added NaOH (20% aqueous, 0.444 mL). The reaction mixture was stirred overnight and was then diluted with CH2Cl2 (30 mL) and washed with 1M NaHSO4 (30 mL). The aqueous layer was extracted with CH2Cl2 (2×30 mL), then the combined organic layers were washed with water (1×30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give the product (434 mg, 1.98 mmol, 89%) as a white solid.