Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:22]=[C:21]([CH3:23])[C:5]([O:6][C:7]2[C:12]([CH3:13])=[C:11]([NH:14][CH:15]([CH2:18][CH3:19])[CH2:16][CH3:17])[CH:10]=[C:9]([CH3:20])[N:8]=2)=[C:4]([CH3:24])[CH:3]=1.C([Li])CCC.C1C[O:33][CH2:32]C1>>[CH2:16]([CH:15]([NH:14][C:11]1[CH:10]=[C:9]([CH3:20])[N:8]=[C:7]([O:6][C:5]2[C:21]([CH3:23])=[CH:22][C:2]([CH:32]=[O:33])=[CH:3][C:4]=2[CH3:24])[C:12]=1[CH3:13])[CH2:18][CH3:19])[CH3:17]
Reactant: C1CCOC1
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(Br)cc2C)c1C
Agent: [Li]CCCC
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C=O)cc2C)c1C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of [2-(4-bromo-2,6-dimethyl-phenoxy)-3,6-dimethyl-pyridin-4-yl]-(1-ethyl-propyl)-amine in dry THF was added n-butyllithium at −78° C. After stirring at −78° C. for 10 min, n,N-dimethylformamide was added and the resulting mixture was stirred at −78° C. for 20 min, the dry-ice bath was removed. After stirring for 5 min, the mixture was quenched with diluted HCl, water and adjusted to pH7.5 and extracted with ethyl acetate. The organic layer was separated, dried, and concentrated to dryness. The residue was purified through silica gel chromatography to give the tiUe compound. 1H NMR(CDCl3) d 9.93(s,1H), 7.60(s,2H), 6.10(s,1H), 3.75(d,1H), 3.35(m1H), 2.17(s,6H), 2.13(s,3H), 2.12(s,3H), 1.4-1.8(m,4H), 0.97(t,6H) ppm.
Reaction SMILES: [C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[N:7](C(OCC)=O)[C:6]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]>C(O)C.CCCCCC>[C:1]([NH:4][C:5]1[C:13]2[C:8](=[CH:9][C:10]([Cl:14])=[CH:11][CH:12]=2)[NH:7][C:6]=1[C:20](=[O:29])[C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)n1c(C(=O)c2ccc(OC)cc2)c(NC(C)=O)c2ccc(Cl)cc21
Solvent: CCCCCC
Solvent: CCO
Product: COc1ccc(C(=O)c2[nH]c3cc(Cl)ccc3c2NC(C)=O)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 2 (Method A) from 3-acetylamino-6-chloro-1-ethoxycarbonyl-2-(4-methoxybenzoyl)indole (step 2). m.p.: 137-139° C. (ethanol/hexane)
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10](F)=[N:11][CH:12]=[C:13]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][N:22]4[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]4)=[CH:17][CH:16]=3)[CH:14]=2)[CH:3]=1.[Br:29][Si](C)(C)C>O1CCOCC1>[Br:29][C:2]1[N:7]=[CH:6][C:5]2[NH:8][C:10]3[N:11]=[CH:12][C:13]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][N:22]5[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]5)=[CH:17][CH:16]=4)=[CH:14][C:9]=3[C:4]=2[CH:3]=1
Reactant: C[Si](C)(C)Br
Reactant: Nc1cnc(Cl)cc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Solvent: C1COCCO1
Product: Brc1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 100 °C
Yield: 65.3 %

Procedure:
To a solution of 6′-chloro-2-fluoro-5-(4-piperidin-1-ylmethyl-phenyl)-[3,4]bipyridinyl-3′-ylamine (1.6 g, 0.004 mol) in 1,4-dioxane (30 mL) was added bromotrimethylsilane (27 mL, 0.2 mol) which immediately produced a white precipitate. The reaction was heated at 100° C. for 48 h. The solid from the cooled reaction mixture was collected by filtration and washed with ethyl acetate (2×20 mL). The resultant solid was then purified by flash chromotagraphy (silica, 25 g column, Biotage, 040% methanol in (DCM containing 1% 2M ammonia in methanol)) to afford the title compound as an off-white solid (1.1 g, 45%). 1H NMR (DMSO-D6, 500 MHz,): 8.62 (s, 1H), 8.25 (d, J=7.3 Hz, 1H), 7.90 (s, 1H), 7.74 (d, J=6.5 Hz, 2H), 7.42 (d, J=6.5 Hz), 7.35 (s, 1H), 5.57 (s, 2H), 3.47 (s, 2H), 2.34 (s, 4H), 1.51 (s, 4H), 1.40 (s, 2H).
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:14])([CH3:13])[NH:10][C:9]2=[O:15])=[N:6][CH:7]=1.[H-].[Na+].IC.[C:20]([O-])(O)=O.[Na+]>CN(C=O)C>[I:1][C:2]1[CH:3]=[N:4][C:5]([N:8]2[CH2:12][C:11]([CH3:13])([CH3:14])[N:10]([CH3:20])[C:9]2=[O:15])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CC1(C)CN(c2ncc(I)cn2)C(=O)N1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: CN1C(=O)N(c2ncc(I)cn2)CC1(C)C
Temperature: 2.5 °C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
(55 mg, 173 μmol) 1-(5-Iodo-pyrimidin-2-yl)-4,4-dimethyl-imidazolidin-2-one (Example 122, step 1) was dissolved in DMF (1 ml) and cooled to 0-5° C. NaH (55%) (9 mg, 225 μmol, 1.3 equiv.) was added and the mixture was stirred for 30 min at 0-5° C. Iodomethane (13 μl, 200 μmol, 1.2 equiv.) was added and the mixture was stirred for 30 min without cooling bath. The reaction mixture was treated with sat. NaHCO3 solution and extracted twice with a small volume of CH2Cl2. The organic layers were loaded directly to silica gel column and the crude material was purified by flash chromatography on silica gel (20 gr, ethyl acetate/heptane gradient, 0:100 to 100:0). The desired 1-(5-iodo-pyrimidin-2-yl)-3,4,4-trimethyl-imidazolidin-2-one (31 mg, 54% yield) was obtained as a white solid, MS: m/e=333.1 (M+H+).
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][NH:29][CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3].C(N(CC)CC)C.Cl[S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41]>C(Cl)Cl>[CH2:1]([C:4]1[CH:5]=[N:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([O:16][C:17]3[S:18][C:19]4[CH:25]=[C:24]([C:26]5[CH2:27][CH2:28][N:29]([S:40]([CH2:43][CH2:44][CH2:45][C:46]([O:48][CH3:49])=[O:47])(=[O:42])=[O:41])[CH2:30][CH:31]=5)[CH:23]=[CH:22][C:20]=4[N:21]=3)[CH2:12][CH2:11]2)=[N:8][CH:9]=1)[CH2:2][CH3:3]
Reactant: COC(=O)CCCS(=O)(=O)Cl
Reactant: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCNCC5)cc4s3)CC2)nc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1cnc(N2CCC(Oc3nc4ccc(C5=CCN(S(=O)(=O)CCCC(=O)OC)CC5)cc4s3)CC2)nc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
To a solution of 2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)-6-(1,2,3,6-tetrahydropyridin-4-yl)benzo[d]thiazole (150 mg, 0.344 mmol) and triethylamine (0.120 mL, 0.861 mmol) in CH2Cl2 (3 mL) at 0° C. was added methyl 4-(chlorosulfonyl)butanoate (104 mg, 0.517 mmol). The reaction mixture was stirred at 0° C. for 15 min, then at rt for 2 h. The reaction mixture was quenched with sat. aq. NaHCO3 (4 mL) and extracted with CH2Cl2 (3×5 mL). The combined organic layers were washed with brine, dried (Na2SO4), filtered, and concentrated. The crude product was purified by column chromatography (silica gel, CH2Cl2-EtOAc gradient 0 to 55% EtOAc) to afford methyl 4-(4-(2-(1-(5-propylpyrimidin-2-yl)piperidin-4-yloxy)benzo[d]thiazol-6-yl)-5,6-dihydropyridin-1(2H)-ylsulfonyl)butanoate (84 mg, 0.14 mmol, 41% yield) as a white solid. LCMS (m/z)=600 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([F:9])[N:3]=1.[N+:10]([O-])([OH:12])=[O:11].OS(O)(=O)=O>>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([N+:10]([O-:12])=[O:11])=[C:4]([F:9])[N:3]=1
Reactant: Fc1ccc(F)c(F)n1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(F)c(F)nc1F
Temperature: 60 °C
Yield: 50.5 %

Procedure:
To neat 2,3,6-trifluoropyridine (12.0 g, 90 mmol) was slowly added fuming HNO3 (142 g, 2254 mmol) and H2SO4 (133 g, 1353 mmol) slow enough to keep the internal temperature below 40° C. Upon completion of the addition, the resulting solution was heated to 60° C. for 30 minutes, and then cooled to 0° C. Ice water (21) was added, and the reaction was extracted with hexanes (2×300 ml) and then DCM (1×300 ml). The combined organic fractions were dried over Na2SO4, filtered, and concentrated to give the title compound (8.1 g, 50%), which was used without further purification.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[N:5]=[C:4]([N:13]2[CH2:19][C:18]3[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=3[S:16](=[O:25])(=[O:24])[CH2:15][CH2:14]2)[CH:3]=1.[CH3:26][NH:27][CH2:28][CH2:29][NH2:30]>>[O:24]=[S:16]1(=[O:25])[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[CH2:19][N:13]([C:4]2[CH:3]=[C:2]([NH:30][CH2:29][CH2:28][NH:27][CH3:26])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=3)[N:5]=2)[CH2:14][CH2:15]1
Reactant: Cc1ccc2nc(N3CCS(=O)(=O)c4ccccc4C3)cc(Cl)c2c1
Reactant: CNCCN
Product: CNCCNc1cc(N2CCS(=O)(=O)c3ccccc3C2)nc2ccc(C)cc12

Procedure:
The title compound was prepared in analogy to Example 3-1 in Scheme 5 by using 4-(4-chloro-6-methylquinolin-2-yl)-2,3,4,5-tetrahydro-1,4-benzothiazepine 1,1-dioxide (prepared in analogy to the one in Example 2-1) and N-methylethane-1,2-diamine. MS obsd. (ESI+) [(M+H)+] 411, 1H NMR (400 MHz, CD3OD) δ ppm 8.03-8.0 (m, 3 H), 7.87-7.84 (d, J=8.8 Hz, 1 H), 7.71-7.70 (d, J=1.2 Hz, 1 H), 7.57-7.53 (m, 2 H), 6.07 (s, 1 H), 5.40 (s, 2 H), 4.56 (s, 2 H), 3.96-3.93 (dd, J=6.0, 6.4 Hz, 2 H), 3.75-3.73 (q, J=4.4 Hz, 2 H), 3.43-3.40 (q, J=6 Hz, 2 H), 2.80 (s, 3 H), 2.46 (s, 3 H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][N:5]([CH2:8][CH2:9][N:10]2[C:19]3[C:14](=[C:15]([F:21])[CH:16]=[C:17]([F:20])[CH:18]=3)[CH:13]=[CH:12][C:11]2=[O:22])[CH2:4][C@@H:3]1[C:23]([O:25][CH3:26])=[O:24].[F:27][C:28]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:29]=1/[CH:35]=[CH:36]/[CH:37]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl.CN(C)C=O>[F:21][C:15]1[CH:16]=[C:17]([F:20])[CH:18]=[C:19]2[C:14]=1[CH:13]=[CH:12][C:11](=[O:22])[N:10]2[CH2:9][CH2:8][N:5]1[CH2:6][CH2:7][C@@H:2]([NH:1][CH2:37]/[CH:36]=[CH:35]/[C:29]2[CH:30]=[C:31]([F:34])[CH:32]=[CH:33][C:28]=2[F:27])[C@@H:3]([C:23]([O:25][CH3:26])=[O:24])[CH2:4]1
Reactant: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1N
Reactant: O=C/C=C/c1cc(F)ccc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC/C=C/c1cc(F)ccc1F
Yield: 48.9 %

Procedure:
Methyl(3S,4R)-4-amino-1-[2-(5,7-difluoro-2-oxoquinolin-1(2H)-yl)ethyl]piperidine-3-carboxylate (Intermediate 34) (120 mg, 0.328 mmol), (2E)-3-(2,5-difluorophenyl)acrylaldehyde (FR 2872164) (54 mg, 0.328 mmol) and sodium triacetoxy borohydride (209 mg, 0.98 mmol) were reacted as described for Example 6. Chromatography on silica gel with dichloromethane/N,N-dimethylformamide (30:1) gave 83 mg (49%) of product as a colorless hard foam.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].CC(C)CC(=O)C.[CH3:14][O:15][CH2:16][C:17]1([N:23]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.[C:34]1([CH2:44][CH2:45]OS(C2C=CC(C)=CC=2)(=O)=O)[C:43]2[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:37]=[CH:36][CH:35]=1>O>[CH3:14][O:15][CH2:16][C:17]1([N:23]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:24](=[O:27])[CH2:25][CH3:26])[CH2:22][CH2:21][N:20]([CH2:45][CH2:44][C:34]2[C:43]3[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=3)[CH:37]=[CH:36][CH:35]=2)[CH2:19][CH2:18]1
Reactant: Cc1ccc(S(=O)(=O)OCCc2cccc3ccccc23)cc1
Reactant: CCC(=O)N(c1ccccc1)C1(COC)CCNCC1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Solvent: O
Product: CCC(=O)N(c1ccccc1)C1(COC)CCN(CCc2cccc3ccccc23)CC1
Temperature: 25 °C
Yield: 43.4 %

Procedure:
A mixture of 6.4 parts of sodium carbonate and 120 parts of 4-methyl-2-pentanone is stirred and refluxed with water-separator. Then there are added 4.1 parts of N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylpropanamide and 5.5 parts of [2-(1-naphthalenyl)ethyl]4-methylbenzenesulfonate and the whole is stirred and refluxed for 20 hours. The reaction mixture is cooled to room temperature and poured onto water. The organic phase is separated, washed with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 7% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The oily residue solidifies on triturating in hexane. The product is filtered off and crystallized from a small amount of 2,2'-oxybispropane, yielding 2.8 parts (43.4%) of N-{4-(methoxymethyl)-1-[2-(1-naphthalenyl)ethyl]-4-piperidinyl}-N-phenylpropanamide; mp. 109.8° C.
Reaction SMILES: CO[CH:3](OC)[CH2:4][C:5](=O)[CH3:6].[NH2:10][C:11]1[NH:15][N:14]=[C:13]([NH:16][S:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:26])(=[O:19])=[O:18])[N:12]=1>C(O)(=O)C>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([NH:16][C:13]1[N:12]=[C:11]2[N:10]=[CH:3][CH:4]=[C:5]([CH3:6])[N:15]2[N:14]=1)(=[O:18])=[O:19]
Reactant: COC(CC(C)=O)OC
Reactant: Nc1nc(NS(=O)(=O)c2ccccc2Cl)n[nH]1
Solvent: CC(=O)O
Product: Cc1ccnc2nc(NS(=O)(=O)c3ccccc3Cl)nn12
Temperature: 25 °C
Yield: 59.3 %

Procedure:
A sample of 3.0 ml (2.7 g, 20 mmol) of acetylacetaldehyde dimethylacetal was added to a solution of 2.74 g (10.0 mmol) of N-(5-amino-1,2,4-triazol-3-yl)-2-chlorobenzenesulfonamide in 20 ml of glacial acetic acid at reflux over 12 hours. After the addition was complete the reaction mixture was heated at reflux for 15 hours and cooled to room temperature. The solid which separated was collected by filtration, washed with acetic acid and dried to yield 1.92 g (59 percent) of the desired product as white solid, mp 267.5°-269° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:12]([C:16]([O:18][CH2:19]C)=[O:17])=[N:11][C:10]([OH:21])=[C:9]([OH:22])[C:8]=2[C:7]1=[O:23].[CH3:28][O-].[Mg+2].C[O-]>CN(C=O)C.CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:24]=[CH:25][C:26]=1[F:27])[CH2:5][N:6]1[CH2:15][CH2:14][C:13]2[C:8](=[C:9]([OH:22])[C:10](=[O:21])[N:11]([CH3:28])[C:12]=2[C:16]([O:18][CH3:19])=[O:17])[C:7]1=[O:23]
Reactant: C[O-]
Reactant: CCOC(=O)c1nc(O)c(O)c2c1CCN(Cc1ccc(F)c(Cl)c1)C2=O
Agent: [Mg+2]
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1c2c(c(O)c(=O)n1C)C(=O)N(Cc1ccc(F)c(Cl)c1)CC2
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a stirred suspension of ethyl 6-(3-chloro-4-fluorobenzyl)-3,4-dihydroxy-5-oxo-5,6,7,8-tetrahydro-2,6-naphthyridine-1-carboxylate (40 g) in DMF (200 mL) was added magnesium methoxide in methanol (100 mL). The mixture heated at 40-50° C. for 3 hours. The excess methanol distilled off, and methyl tosylate (18 mL) was added. The reaction mixture was heated at 50° C. overnight, then cooled to 25° C., and then quenched into 1N HCl (100 mL). The suspension stirred for 1 hour at ambient temperature. The product was isolated by filtration, and the filter cake washed with water (2×100 mL) and then dried on the filter under an atmosphere of nitrogen. The crude product was suspended in methanol (460 mL), heated at reflux temperature for 1 hour, and then allowed to cool to ambient temperature. The product was isolated by filtration and the filter cake washed with cold methanol (2×40 mL) and dried to give the title product.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[C:9](=[O:11])[CH:10]=1.[NH2:27][C:28]1[CH:32]=[CH:31][N:30]([CH2:33][C:34]([CH3:37])([OH:36])[CH3:35])[N:29]=1>>[Cl:1][C:2]1[CH:26]=[CH:25][CH:24]=[CH:23][C:3]=1[O:4][C:5]1[CH:6]=[N:7][N:8]([CH:12]([CH2:16][CH:17]2[CH2:18][CH2:19][O:20][CH2:21][CH2:22]2)[C:13]([NH:27][C:28]2[CH:32]=[CH:31][N:30]([CH2:33][C:34]([OH:36])([CH3:35])[CH3:37])[N:29]=2)=[O:15])[C:9](=[O:11])[CH:10]=1
Reactant: O=C(O)C(CC1CCOCC1)n1ncc(Oc2ccccc2Cl)cc1=O
Reactant: CC(C)(O)Cn1ccc(N)n1
Product: CC(C)(O)Cn1ccc(NC(=O)C(CC2CCOCC2)n2ncc(Oc3ccccc3Cl)cc2=O)n1

Procedure:
Using the method described in Example 49, 2-[4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-3-(tetrahydro-pyran-4-yl)-propionic acid (Intermediate 101) and 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (Intermediate 1) afforded 2-[4-(2-chloro-phenoxy)-6-oxo-6H-pyridazin-1-yl]-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-3-(tetrahydro-pyran-4-yl)-propionamide as a white solid (560 mg); ES+-HRMS m/e calcd for C25H30N5O5Cl [M+H+] 516.2008 found 516.2008. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.05 (s, 3H), 1.06 (s, 3H), 1.14-1.34 (m, 2H), 1.35-1.45 (m, 1H), 1.46-1.57 (m, 2H), 1.84-1.93 (m, 1H), 2.17-2.27 (m, 1H), 3.09-3.27 (m, 2H), 3.74-3.86 (m, 2H), 3.89 (s, 2H), 4.67 (s, 1H), 5.55 (dd, J=11.1, 4.0 Hz, 1H), 5.70 (d, J=2.8 Hz, 1H), 6.40 (d, J=2.1 Hz, 1H), 7.38-7.47 (m, 1H), 7.49-7.56 (m, 3H), 7.71 (d, J=7.9 Hz, 1H), 8.22 (d, J=2.8 Hz, 1H), 10.85 (s, 1H). Separation of enantiomers via supercritical fluid chromatography on a SFC DAICEL AD column, 45% methanol, 70 mL/min.
Reaction SMILES: [CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:36])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@@:21]([CH2:23][OH:24])([CH3:22])[C@@H:20]([OH:25])[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1.[C:37]1(C)[CH:42]=CC(S(O)(=O)=O)=C[CH:38]=1.O.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[CH3:1][C@H:2]1[C@H:30]([CH3:31])[C@@H:29]2[C@@:5]([C:33]([O:35][CH3:36])=[O:34])([CH2:6][CH2:7][C@@:8]3([CH3:32])[C@:13]4([CH3:28])[CH2:14][CH2:15][C@H:16]5[C@:21]6([CH3:22])[CH2:23][O:24][C:37]([CH3:42])([CH3:38])[O:25][C@H:20]6[C@H:19]([OH:26])[CH2:18][C@:17]5([CH3:27])[C@H:12]4[CH2:11][CH:10]=[C:9]32)[CH2:4][CH2:3]1
Reactant: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@H](O)[C@@](C)(CO)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)[C@]12CC[C@@H](C)[C@H](C)[C@H]1C1=CC[C@@H]3[C@@]4(C)C[C@@H](O)[C@@H]5OC(C)(C)OC[C@@]5(C)[C@@H]4CC[C@@]3(C)[C@]1(C)CC2
Yield: 60.3 %

Procedure:
Methyl asiatate 2 (27.7 mg, 0.055 mmole) was dissolved in anhydrous acetone (3 ml), added with p-toluenesulfonic acid (27.7 mg) and then refluxed. Water was added to the reaction mixture, and the solution was neutralized with 5% potassium carbonate and then extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The was chromatographed with benzene and ethyl acetate (3:2) to give pure desired compound (18 mg, 60%).
Reaction SMILES: ClC1C(C(C(F)(F)F)CC(OC)=O)=C(Cl)N=CN=1.COC1C=C(OC)C=CC=1CN.CN(C)C=O.[Cl:36][C:37]1[C:42]([CH:43]([C:49]([F:52])([F:51])[F:50])[CH2:44][C:45]([O:47]C)=O)=[C:41]([NH:53][CH2:54][C:55]2[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=2[O:63][CH3:64])[N:40]=[CH:39][N:38]=1>O>[Cl:36][C:37]1[C:42]2[CH:43]([C:49]([F:51])([F:52])[F:50])[CH2:44][C:45](=[O:47])[N:53]([CH2:54][C:55]3[CH:60]=[CH:59][C:58]([O:61][CH3:62])=[CH:57][C:56]=3[O:63][CH3:64])[C:41]=2[N:40]=[CH:39][N:38]=1
Reactant: COC(=O)CC(c1c(Cl)ncnc1NCc1ccc(OC)cc1OC)C(F)(F)F
Agent: COC(=O)CC(c1c(Cl)ncnc1Cl)C(F)(F)F
Agent: COc1ccc(CN)c(OC)c1
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)CC(C(F)(F)F)c3c(Cl)ncnc32)c(OC)c1
Temperature: 50 °C

Procedure:
Combine methyl 3-(4,6-dichloropyrimidin-5-yl)-4,4,4-trifluorobutanoate (0.71 g, 1.98 mmol) diisopropylethylamine (0.38 mL, 1.1 eq), 2,4-dimethoxybenzylamine (0.32 mL, 1.05 eq), and dimethylformamide (6 mL). Heat at 50° C. overnight. Allow to cool to room temperature. Dilute with water and extract with methyl tert-butyl ether. Wash the organic layer with saturated aqueous sodium chloride. Dry the organics over anhydrous magnesium sulfate, filter, and concentrate in vacuo to give a mixture of the title compound and methyl 3-(4-chloro-6-(2,4-dimethoxybenzylamino)pyrimidin-5-yl)-4,4,4-trifluorobutanoate as an oil. Combine the crude mixture (0.78 g), diisopropylethylamine (0.63 mL), and ethanol (7.8 mL). Heat at reflux for four hours. Allow to cool to room temperature. Filter and rinse with ethanol to obtain the title compound as a white solid (0.43 g, 55%).
Reaction SMILES: I[CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]1[C:10]2[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]1=[O:17].[CH2:19]([CH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]>CCCCCCC.CCOC(C)=O>[CH2:19]([CH:23]1[CH2:28][CH2:27][N:26]([CH2:2][C@@H:3]([CH3:18])[CH2:4][N:5]2[C:10]3[CH:11]=[C:12]([O:15][CH3:16])[CH:13]=[CH:14][C:9]=3[O:8][CH2:7][C:6]2=[O:17])[CH2:25][CH2:24]1)[CH2:20][CH2:21][CH3:22]
Reactant: COc1ccc2c(c1)N(C[C@H](C)CI)C(=O)CO2
Reactant: CCCCC1CCNCC1
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: CCCCC1CCN(C[C@@H](C)CN2C(=O)COc3ccc(OC)cc32)CC1
Yield: 40.9 %

Procedure:
The compound (S)-4-(3-Iodo-2-methylpropyl)-6-methoxy-4H-benzo[1,4]oxazin-3-one (111MF36) (0.636 g, 1.77 mmol) and 4-butylpiperidine (0.226 g, 1.6 mmol) were mixed according to GP16. CC (SiO2; Heptane/EtOAc 4:1-4) and prep HPLC gave the title compound (111MF38) (0.245 g, 27%). 1H NMR (CDCl3) δ 6.89 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.4 Hz, 1H), 6.50 (dd, J=2.8, J=8.8 Hz, 1H), 4.54 (q, J=32.4, J=14.8, 2H), 3.94-3.90 (m, 2H), 3.77 (s, 3H), 2.90 (d, J=11.2 Hz, 1H), 2.72 (d, J=10.8 Hz, 1H), 2.25-2.10 (m, 3H), 1.93 (t, J=11.2 Hz, 1H), 1.80 (t, J=11.2 Hz, 1H), 1.61 (d, J=10.8 Hz, 2H), 1.31-1.19 (m, 9H), 0.90-0.86 (m, 6H); 13C NMR (CDCl3) δ 165.3, 155.5, 139.7, 129.8, 117.2, 107.1, 103.3, 68.0, 64.2, 55.9, 55.7, 54.5, 45.5, 36.5, 36.0, 32.9, 32.5, 29.2, 29.2, 23.1, 16.9, 14.3.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28](Br)[C:29]#[CH:30]>CC(C)=O>[C:28]([O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:21])[C:7]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)=[C:8]([CH3:12])[O:9]2)=[CH:4][CH:3]=1)#[C:29][CH3:30]
Reactant: C#CCBr
Reactant: COc1ccc(-c2c(C)oc3cc(O)ccc3c2=O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#COc1ccc2c(=O)c(-c3ccc(OC)cc3)c(C)oc2c1

Procedure:
A mixture of 7-hydroxy-2-methyl-4′-methoxyisoflavone (2.82 g, 0.01 mol), K2CO3 (2.8 g, 0.02 mol), Kl (0.166 g, 0.001 mol), propargyl bromide (1.78 g, 0.015 mol) and acetone (100 mL) was refluxed 10 h and hot filtered. The solvent was evaporated and the residue was crystallized by toluene. This yields 2.24 g of a product with the following characteristics: m.p. 139-140° C.; 1H NMR (CDCl3) δ: 2.29 (s, 3H), 2.6 (m, 1H), 3.85 (s, 3H), 4.75 (s, 2H), 6.93-8.17 (m, 7H).
Reaction SMILES: [C:1](=[O:3])=[O:2].[O-:4][CH2:5][CH3:6].[Mg+2:7].[O-:8][CH2:9][CH3:10]>C(O)C>[C:1](=[O:2])([O-:3])[O:4][CH2:5][CH3:6].[Mg+2:7].[CH2:9]([O:8][C:1](=[O:2])[O-:3])[CH3:10]
Reactant: CC[O-]
Reactant: O=C=O
Agent: [Mg+2]
Solvent: CCO
Product: CCOC(=O)[O-]

Procedure:
Generally, magnesium hydrocarbyl carbonate is prepared by reacting carbon dioxide with a magnesium alcoholate. For example, magnesium hydrocarbyl carbonate is formed by suspending magnesium ethoxide in ethanol and adding carbon dioxide until the magnesium ethoxide dissolves forming magnesium ethyl carbonate. If, however, the magnesium ethoxide were suspended in 2-ethylhexanol, magnesium 2-ethylhexyl carbonate, magnesium ethyl carbonate and magnesium ethyl/2-ethylhexyl carbonate may be formed. If the magnesium ethoxide is suspended in a liquid hydrocarbon or halohydrocarbon which is free of alcohol, the addition of carbon dioxide results in the breaking apart of the magnesium ethoxide particles and the magnesium hydrocarbyl carbonate reaction product does not dissolve. The reaction of a magnesium alcoholate with carbon dioxide can be represented as:
Reaction SMILES: [OH:1][N:2]=[C:3]1[CH2:10][CH:9]2[N:11](C(OC(C)(C)C)=O)[CH:5]([CH2:6][O:7][CH2:8]2)[CH2:4]1.[Li][CH2:20]CCC.CN(C=O)C.Cl>C1COCC1>[CH:9]12[NH:11][CH:5]([CH2:6][O:7][CH2:8]1)[CH2:4][C:3]1[C:10]2=[CH:20][O:1][N:2]=1
Reactant: CC(C)(C)OC(=O)N1C2COCC1CC(=NO)C2
Reactant: [Li]CCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: c1onc2c1C1COCC(C2)N1
Reaction time: 0.5 h

Procedure:
To a solution of compound 104b (512 mg, 2 mmol, 1.0 eq) in THF (10 mL) was added n-BuLi (5 mL, 2.0 M, 5.0 eq) dropwise at −50° C. After 30 min, dry DMF (740 mg, 10 mmol, 5.0 eq) in THF (2 mL) was added dropwise, the mixture was stirred for another 2 h from −60° C. to room temperature. To it 12 N HCl (1 mL) was added and refluxed for 2 h. The reaction mixture was concentrated to give 4,10-Dioxa-5,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2,5-diene 104a (332 mg) as an oil. MS: calc'd (MH+) 167, measured (MH+) 167.