Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][CH:18]2[CH:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1>CC(C)=O.C(O)(C)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[N:11]1[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][C@@H:18]2[C@H:23]([NH:24][C:25]([C:27]3[O:28][C:29]4[CH:35]=[CH:34][CH:33]=[CH:32][C:30]=4[CH:31]=3)=[O:26])[CH:22]3[CH2:36][CH2:37][N:19]2[CH2:20][CH2:21]3)[CH:12]=1
Reactant: O=C(NC1C2CCN(CC2)C1Cc1cccnc1)c1cc2ccccc2o1
Agent: O=C(O)c1ccc(Cl)cc1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: O=C(N[C@@H]1C2CCN(CC2)[C@@H]1Cc1cccnc1)c1cc2ccccc2o1
Temperature: 25 °C
Yield: 94 %

Procedure:
Solid p-chlorobenzoic acid (46.8 mg, 0.299 mmol) was added in one portion to a solution of the earlier eluting isomer of N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl]benzofuran-2-carboxamide from Example 15 (108 mg, 0.299 mmol) in acetone (10 mL). This mixture was warmed to near reflux for 30 min and cooled to ambient temperature. No precipitate formed, so the solution was concentrated to about 20% of its former volume (hot plate), at which point crystals began to form. The mixture was cooled and diluted with isopropanol (2 mL). This mixture was concentrated by slow evaporation of solvent at ambient temperature, and the resulting solids were collected and dried. This produced 145 mg (94% yield) of light yellow crystals, mp 150-152° C. 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 1H), 8.38 (d, 1H), 7.93 (d, 2H, p-chlorobenzoic acid), 7.67 (m, 2H), 7.57 (d, 1H), 7.45 (m, 1H), 7.36 (d, 2H, p-chlorobenzoic acid), 7.30 (m, 1H), 7.27 (s, 1H), 7.16 (m,1H), 7.00 (d, 1H, amide), 6.90 (broad s, quatemary ammonium), 4.62 (m, 1H), 3.85 (dd, 1H), 3.36 (m, 1H), 2.95-3.25 (m, 5H), 2.16 (s, 1H), 1.70-2.10 (m, 4H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:17][CH:16]([OH:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:23][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.O>[C:1]([O:5][C:6]([N:8]1[CH2:17][C:16](=[O:18])[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:19][CH2:20][CH:21]3[CH2:22][CH2:23]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(OCC3CC3)cc2C(O)C1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(=O)c2cc(OCC3CC3)ccc2C1
Temperature: 25 °C

Procedure:
To 600 mg (1.88 mmol) 6-cyclopropylmethoxy-4-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester (example XLIII.1) in 6 mL DCM are added 825 mg (1.88 mmol) Dess-Martin periodinane and the resulting mixture is stirred at r.t. over night. The reaction mixture is diluted with water and extracted with DCM. The organic layer is concentrated by evaporation and the residue is purified by HPLC (ACN/H2O/HCOOH).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH:16]2[OH:28])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29](Br)[CH:30]=[CH2:31]>>[CH2:31]([O:28][CH:16]1[CH:15]([C:12]2[CH:11]=[CH:10][C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[CH:14][CH:13]=2)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:25])([CH3:27])[CH3:26])=[O:22])[CH2:17]1)[CH:30]=[CH2:29]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCc3ccccc3)cc2)C(O)C1
Reactant: C=CCBr
Product: C=CCOC1CN(C(=O)OC(C)(C)C)CCC1c1ccc(OCc2ccccc2)cc1

Procedure:
Analogously to Method D, 12 g of tert-butyl 4-(4-benzyloxyphenyl)-3-hydroxypiperidine-1-carboxylate and 5.4 ml of allyl bromide are reacted. The title compound is obtained as a yellowish oil. Rf=0.31 (1:3 EtOAc-heptane); Rt=5.80.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([OH:11])=O)[CH:5]=[CH:6][CH:7]=1.O.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[Cl:43])[NH2:39]>CN(C=O)C>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:9](=[O:11])[CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([OH:1])[CH:3]=2)[CH:40]=[CH:41][C:42]=1[Cl:43]
Reactant: O=C(O)Cc1cccc(O)c1
Reactant: Nc1ccc(Cl)c(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: O=C(Cc1cccc(O)c1)Nc1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 61.9 %

Procedure:
To a solution of 3-hydroxyphenyl acetic acid (5.0 g, 0.03 mol) in DMF (50 ml) was added 1-hydroxybenzotriazole hydrate (4.86 g, 0.03 mol) and 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (6.9 g, 0.036 mol). To the flask was added 3,4-dichloroaniline (4.86 g, 0.03 mol). The reaction was allowed to stir overnight. Solvent was removed and the reaction was diluted with ethyl acetate. The reaction mixture was washed with 1N HCl, 10% sodium carbonate solution, and brine. The organic layer was dried over MgSO4, filtered and concentrated to provide the title compound (5.5 g, 62% yield): ES-MS (m/z) 296 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C@@H:19]([NH2:21])[CH3:20])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9]2)=[CH:4][CH:3]=1.[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27](Cl)[N:26]=[CH:25][N:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:22][C:23]1[C:28]([C:29]#[N:30])=[C:27]([NH:21][C@H:19]([C:7]2[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[CH:13]=3)=[N:9][C:10]3[C:5]([CH:6]=2)=[CH:4][CH:3]=[C:2]([F:1])[CH:11]=3)[CH3:20])[N:26]=[CH:25][N:24]=1
Reactant: N#Cc1c(N)ncnc1Cl
Reactant: C[C@H](N)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1cc2ccc(F)cc2nc1-c1cccc(F)c1
Temperature: 100 °C
Yield: 16 %

Procedure:
To a solution of 2-((S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethyl)-isoindoline-1,3-dione (60.0 mg, 145 μmol) in EtOH (2 mL) was added NH2NH2 (1.0 mL, 1.45 mmol, 10 eq) and the resulting solution was heated to 80° C. for 2 h. A precipitate was filtered away and the filtrate was removed under reduce pressure to afford (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)ethanamine. To the crude residue of (1S)-1-(7-fluoro-2-(3-fluorophenyl)quinolin-3-yl)-ethanamine in DMF (2 mL) was added 4-amino-6-chloropyrimidine-5-carbonitrile (22 mg, 145 μmol) and DIEA (0.06 mL, 319 μmol). The resulting mixture was heated to 100° C. overnight. Solvent was removed under reduce pressure and purified via preparatory HPLC using 15-60% MeCN/H2O w/0.01% TFA to afford a white solid of 4-amino-6-((S)-1-(7-fluoro-2-(3-fluorophenyl)-quinolin-3-yl)ethylamino)pyrimidine-5-carbonitrile (9.3 mg, 16%). 1H NMR (500 MHz, CD3OD) δ ppm 1.63 (d, J=6.85 Hz, 3H) 5.70 (q, J=7.01 Hz, 1H) 7.25-7.34 (m, 1H) 7.44-7.54 (m, 2H) 7.55-7.63 (m, 2H) 7.74 (dd, J=9.78, 2.45 Hz, 1H) 8.05 (s, 1H) 8.18 (dd, J=9.05, 5.87 Hz, 1H) 8.72 (s, 1H). Mass Spectrum (ESI) m/e=403 (M+1).
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[NH:29][C:28]1[C:36]([CH2:42][CH2:43][OH:44])([CH2:40][CH3:41])[O:37][CH2:38][CH2:39][C:27]2=1.C(N(CC)CC)C.[C:52]([O:56][CH2:57][CH3:58])(=[O:55])[CH:53]=[CH2:54]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:40]([C:36]1([CH2:42][CH2:43][OH:44])[C:28]2[NH:29][C:30]3[C:26]([C:27]=2[CH2:39][CH2:38][O:37]1)=[CH:25][C:24](/[CH:54]=[CH:53]/[C:52]([O:56][CH2:57][CH3:58])=[O:55])=[CH:32][C:31]=3[CH:33]([CH3:35])[CH3:34])[CH3:41]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)/C=C/c1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A suspension of Pd(OAc)2 (0.2 g, 0.8 Mmol), P(o-tolyl)3 (0.25 g, 0.8 mmol), 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol (1.5 g, 4.1 mmol), triethylamine (1.5 ml, 11 mmol), and ethyl acrylate (1.8 ml, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogen atmosphere at 100° C. for 24 hr. The mixture was allowed to cool, quenched with water, worked-up with dichloromethane, and washed with brine. The organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on silica hexane/EtOAc (6:4) to give the product (0.9 g, 56%). %). 1H NMR (300 MHz, CDCl3) δ 8.07 (br, NH), 7.83 (d, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.43 (d, 1H), 4.27 (m, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1H), 2.84 (m, 1), 2.77 (d, 1H), 2.52 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MS m/e=386 (MH+), ESI (−) MS m/e=384 (MH−).
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9]([CH3:11])C)CC1.[Cl:13][C:14]1[C:21]([CH3:22])=[C:20](F)[CH:19]=[CH:18][C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[Cl:13][C:14]1[C:21]([CH3:22])=[C:20]([N:6]2[CH2:7][CH2:8][C@@:4]([OH:12])([CH3:1])[C@@H:5]2[CH2:9][CH3:11])[CH:19]=[CH:18][C:15]=1[C:16]#[N:17]
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Reactant: Cc1c(F)ccc(C#N)c1Cl
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: CC[C@@H]1N(c2ccc(C#N)c(Cl)c2C)CC[C@]1(C)O

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3S)-2-ethyl-3-methylpyrrolidin-3-ol 0.5 oxalate (210 mg), 2-chloro-4-fluoro-3-methylbenzonitrile (300 mg) and lithium carbonate (215 mg), the title compound was obtained as pale-yellow oil (yield: 91.2 mg, yield: 27%).
Reaction SMILES: [Cl:1]C1C2C(=CC=CC=2)N=CC=1C(OCC)=O.[F:17][C:18]1[CH:19]=[C:20]2[C:25](=[CH:26][C:27]=1[F:28])[N:24]=[CH:23][C:22]([C:29]([O:31][CH2:32][CH3:33])=[O:30])=[C:21]2O>>[Cl:1][C:21]1[C:20]2[C:25](=[CH:26][C:27]([F:28])=[C:18]([F:17])[CH:19]=2)[N:24]=[CH:23][C:22]=1[C:29]([O:31][CH2:32][CH3:33])=[O:30]
Reactant: CCOC(=O)c1cnc2cc(F)c(F)cc2c1O
Reactant: CCOC(=O)c1cnc2ccccc2c1Cl
Product: CCOC(=O)c1cnc2cc(F)c(F)cc2c1Cl

Procedure:
The title compound was prepared following the procedure described in Step 2 for the synthesis of 3a using 2c instead of 2a. 1H NMR (CDCl3) δ (ppm): 1.47 (3H, t, J=7.08 Hz), 4.56 (2H, q, J=7.08 Hz), 7.72 (1H, d, J=8.79 Hz), 8.39 (1H, d, J=8.78 Hz), 9.23 (1H, s). m/z 271.6/273.6 (M+/M+2). m/z 272.6 (MH+).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=[C:25]([C:28]4[CH:32]=[C:31]([CH2:33][N:34]([C@@H](C)CO)[CH3:35])[S:30][CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].N[C@H:44]([CH3:47])[CH2:45]O>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH:44]1([CH2:47][N:34]([CH2:33][C:31]2[S:30][CH:29]=[C:28]([C:25]3[CH:26]=[C:27]4[C:22](=[C:23]([C:40]([NH2:42])=[O:41])[CH:24]=3)[NH:21][CH:20]=[C:19]4[CH:16]3[CH2:17][CH2:18][N:13]([S:10]([CH2:8][CH3:9])(=[O:11])=[O:12])[CH2:14][CH2:15]3)[CH:32]=2)[CH3:35])[CH2:2][CH2:45]1
Reactant: C[C@@H](N)CO
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)[C@@H](C)CO)c4)cc23)CC1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4csc(CN(C)CC5CC5)c4)cc23)CC1
Yield: 14.7 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(5-{[[(1S)-2-hydroxy-1-methylethyl](methyl)amino]methyl}-3-thienyl)-1H-indole-7-carboxamide trifluoroacetate (salt), substituting (cyclopropylmethyl)amine (1.20 mmol) for (2R)-2-amino-1-propanol to afford 6.2 mg of the title compound (14.7%).
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:17]1[O:21][C:20](=[O:22])[C@H:19]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=2)[CH2:18]1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[OH-:32].[Li+]>C(COC)OC.O>[C:1]([NH:8][C@@H:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C@@H:17]([OH:21])[CH2:18][C@@H:19]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]#[N:31])[CH:25]=1)[C:20]([OH:22])=[O:32])([O:3][C:4]([CH3:6])([CH3:5])[CH3:7])=[O:2]
Reactant: [OH-]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H]1C[C@@H](Cc2cccc(C#N)c2)C(=O)O1
Agent: [Li+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@@H](Cc1cccc(C#N)c1)C(=O)O

Procedure:
Analogously to Example 1i), 1.6 g (3.8 mmol) of 5(S)-[1(S)-(Boc-amino)-2-phenylethyl]-3(R)-(m-cyanophenylmethyl)-dihydrofuran-2-(3H)-one in 37 ml of dimethoxyethane and 20 ml of water are hydrolysed with 15.2 ml of 1M lithium hydroxide solution to yield the title compound: tRet (I)=13.8 min.
Reaction SMILES: [CH:1]([C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([O:17][CH3:18])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:19])[O:4]1)=O.[C:20]1([C:25]([NH:27][NH2:28])=[O:26])[S:24][CH:23]=[CH:22][CH:21]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[CH3:18][O:17][C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:19])[O:4][C@H:3]1[CH2:1][NH:28][NH:27][C:25](=[O:26])[C:20]1[S:24][CH:23]=[CH:22][CH:21]=1)=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1C=O
Reactant: NNC(=O)c1cccs1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCO
Product: COC(=O)CCC/C=C\C[C@H]1CO[C@@H](C)O[C@H]1CNNC(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-formyl-5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-1,3-dioxane (47 mg) in ethanol (1 ml) was added thenohydrazide (27 mg) and the mixture was stirred at room temperature for 1 hour, and then added sodium cyanoborohydride (20 mg) and acetic acid (0.25 ml) and the mixture was stirred for 1 hour. Aqueous sodium bicarbonate was added and extracted with chloroform and the organic layers were combined and dried over anhydrous sodium sulfate. The solvent was evaporated in vacuo to give (2R,4R,5S) -5-[(Z)-6-methoxycarbonyl-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane as a residue and the residue was dissolved in methanol (2 ml) and added 1N aqueous sodium hydroxide (0.4 ml) and stirred at room temperature for 4 hours. The reaction mixture was evaporated in vacuo and the residue was neutralized with 1N hydrochloric acid and extracted with chloroform. The organic layers were combined and dried over sodium sulfate. The solvent was evaporated in vacuo and the crude product was purified with preparative TLC (ethyl acetate as an eluent) to give (2R,4R,5S)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(N'-thenoylhydrazino)methyl-1,3-dioxane (55 mg).
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[C:4](Cl)[N:3]=1.[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1.C(O)C>O>[Cl:1][C:2]1[C:7]([C:8]2[O:9][C:10]3[CH:16]=[C:15]([C:17]4[CH:18]([CH3:24])[CH2:19][C:20](=[O:23])[NH:21][N:22]=4)[CH:14]=[CH:13][C:11]=3[N:12]=2)=[CH:6][CH:5]=[C:4]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[N:3]=1
Reactant: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(Cl)nc3Cl)oc2c1
Reactant: C1COCCN1
Solvent: CCO
Solvent: O
Product: CC1CC(=O)NN=C1c1ccc2nc(-c3ccc(N4CCOCC4)nc3Cl)oc2c1

Procedure:
1.1 g (2.9 mmol) 6-[2-(2,6-dichloro-pyridin-3-yl)-benzoxazol-6-yl]-5-methyl-4,5-dihydro-2H-pyridazin-3-one, 1 ml morpholine and 50 ml of ethanol are refluxed together for 3 h, then the solv. is eliminated by rotary evaporation i.V., the residue is stirred with water and filtered off. The crude product is recrystallised from aqueous isopropanol.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4](/[CH:6]=[CH:7]/[CH2:8]P(OCC)(OCC)=O)=[O:5].[N+:17]([C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1)([O-:19])=[O:18].[H-].[Na+]>C1(C)C=CC=CC=1.O1CCCC1>[CH2:2]([O:3][C:4](=[O:5])[CH:6]=[CH:7][CH:8]=[CH:24][C:23]1[CH:26]=[CH:27][C:20]([N+:17]([O-:19])=[O:18])=[CH:21][CH:22]=1)[CH3:1]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C=CC=Cc1ccc([N+](=O)[O-])cc1

Procedure:
Triethyl 4-phosphonocrotonate is condensed with p-nitrobenzaldehyde in the presence of sodium hydride in toluene/tetrahydrofuran to yield 5-(p-nitrophenyl)-penta-2,4-dienoic acid ethyl ester, m.p. 150°-152°. Hydrogenation in ethyl acetate at one atmosphere pressure and room temperature using Adams catalyst yields ethyl 5-(4-amino-phenyl)-valerate. Condensation with acetonylacetone yields ethyl 5-[4-(2,5-dimethyl-1H-pyrrol-1-yl)-phenyl]-valerate.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[Br:43][C:44]1[CH:45]=[C:46]([NH2:53])[C:47]2[CH:48]=[N:49][NH:50][C:51]=2[CH:52]=1>CN(C=O)C>[Br:43][C:44]1[CH:52]=[C:51]2[C:47]([CH:48]=[N:49][NH:50]2)=[C:46]([NH:53][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[S:3][CH:4]=2)=[O:9])[CH:45]=1
Reactant: Cc1nc(C(=O)O)cs1
Reactant: Nc1cc(Br)cc2[nH]ncc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1nc(C(=O)Nc2cc(Br)cc3[nH]ncc23)cs1
Temperature: 20 °C
Reaction time: 48 h
Yield: 18.9 %

Procedure:
2-Methyl-1,3-thiazole-4-carboxylic acid (4.59 g, 32.1 mmol), HATU (13.4 g, 35.3 mmol) and DIPEA (16.8 ml, 96 mmol) were stirred in DMF (140 ml) for 30 mins at 20° C. 6-Bromo-1H-indazol-4-amine (3.40 g, 16.03 mmol) was added and the reaction stirred at 20° C. for 2 days. The solvent was reduced to ˜40 ml and the reaction mixture applied to 5×70 g aminopropyl SPE cartridges and left to stand for 3 h. The cartridges were eluted with DCM:MeOH (1:1, v/v) and the solvent was evaporated in vacuo. The residue was purified by silica gel chromatography, eluting with 0-15% MeOH (containing 1% Et3N) in DCM. Appropriate fractions were evaporated to give the title compound 1.02 g.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([C:12]2[NH:16][C:15](=[O:17])[N:14]([C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[N:13]=2)[C:6]([CH:9]([F:11])[F:10])=[N:7][CH:8]=1.[CH:28]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][CH2:29]1>C(Cl)Cl>[F:10][CH:9]([F:11])[C:6]1[N:7]=[CH:8][C:3]([CH2:2][NH:1][C:32]([CH:28]2[CH2:31][CH2:30][CH2:29]2)=[O:33])=[CH:4][C:5]=1[C:12]1[NH:16][C:15](=[O:17])[N:14]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:25])[F:27])=[CH:20][CH:19]=2)[N:13]=1
Reactant: NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=C(Cl)C1CCC1
Solvent: ClCCl
Product: O=C(NCc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1)C1CCC1
Yield: 22.5 %

Procedure:
The title compound was prepared by following the procedure as described in Example-108 by using 3-(5-(aminomethyl)-2-(difluoromethyl)pyridin-3-yl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (step-1 of Example-186, 0.75 g, 0.19 mmol), cyclobutane carbonyl chloride (0.035 g, 0.29 mmol), TEA (0.059 g, 0.58 mmol) and DCM (10 mL) to afford 0.020 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.89-2.29 (m, 7H), 4.45 (s, 2H), 7.31-7.52 (m, 1H), 7.72 (d, J=8.4 Hz, 2H), 8.05 (s, 1H), 8.18 (d, J=8.4 Hz, 2H), 8.66 (s, 1H); MS (m/z): 468.26 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([CH:12]2[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]2)=[CH:4][NH:5][C:6]=1[C:7]([O:9]CC)=O.C(O)(=O)C.[CH:29](N)=[NH:30]>C(O)C>[O:9]=[C:7]1[NH:30][CH:29]=[N:1][C:2]2[C:3]([CH:12]3[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:23])([CH3:24])[CH3:22])=[O:19])[CH2:14][CH2:13]3)=[CH:4][NH:5][C:6]1=2
Reactant: N=CN
Reactant: CCOC(=O)c1[nH]cc(C2CCN(C(=O)OC(C)(C)C)CC2)c1N
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCC(c2c[nH]c3c(=O)[nH]cnc23)CC1
Yield: 102.9 %

Procedure:
tert-Butyl 4-[4-amino-5-(ethoxycarbonyl)-1H-pyrrol-3-yl]piperidine-1-carboxylate (466 mg, 1.38 mmol) was dissolved in ethanol (8 mL), and then formamidine acetate (863 mg, 8.29 mmol) was added, followed by heating under reflux for 14 hours. The reaction liquid was cooled, and the precipitated solid was filtered and washed with ethanol to give tert-butyl 4-(4-oxo-4,5-dihydro-3H-pyrrolo[3,2-d]pyrimidin-7-yl)piperidine-1-carboxylate (452 mg, >1000) as a pale yellow solid.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].[Br:17]Br.C(OCC)(=O)C>C(O)(=O)C>[Br:17][C:5]1[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2](=[O:1])[N:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(Br)c2ccccn2c1=O
Reaction time: 0.08 h
Yield: 66.3 %

Procedure:
To a solution of ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (2.33 g, 10.7 mmol) in 20 ml acetic acid was rapidly added a solution of bromine (1.9 g, 12 mmol) in 10 ml acetic acid. The reaction was complete after 5 min, as indicated by thin layer chromatography (ethyl acetate). The solvent was evaporated in vacuo and the remaining yellow solid was dissolved in 20 ml dichloromethane. To this solution, silica gel (3 g) was added and the solvent was evaporated in vacuo. The silica gel was poured on a prepacked column and eluted with ethyl acetate to give ethyl 1-bromo-4-oxo-4H-quinolizine-3-carboxylate (9) as a bright yellow solid (2.1 g, 71%). M.p. 156-158° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz, 3H), 4.43 (q, J=7 Hz, 2H), 7.03 (dd, J=7 Hz, J=7 Hz, 1H), 7.30 (dd, J=7 Hz, 2H), 7.80 (dd, J=7 Hz, J=7 Hz, 1H), 8.63 (s, 1H), 9.49 (d, J=7 Hz). MS: m/z 294.9839; required for C12H10BrNO3: 294.9843.
Reaction SMILES: [CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([OH:11])=[O:10])=[CH:7][C:6]=1[C:14]([F:17])([F:16])[F:15])[CH:2]([CH3:4])[CH3:3].[CH3:18][Si](C=[N+]=[N-])(C)C>ClCCl.CO>[CH2:1]([C:5]1[CH:13]=[CH:12][C:8]([C:9]([O:11][CH3:18])=[O:10])=[CH:7][C:6]=1[C:14]([F:15])([F:16])[F:17])[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(C(=O)O)cc1C(F)(F)F
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1ccc(CC(C)C)c(C(F)(F)F)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 89.4 %

Procedure:
To 4-isobutyl-3-(trifluoromethyl)benzoic acid (Preparation 23A, 0.55 g, 2.234 mmol) in dichloromethane (5 mL) and methanol (2.00 mL) was added trimethylsilyldiazomethane (1.452 mL, 2.90 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Excess trimethylsilyldiazomethane was quenched by the slow addition of acetic acid (˜0.5 ml) at room temperature. The reaction mixture was concentrated and partitioned between ethyl acetate (20 mL) and sat. aq. sodium bicarbonate (10 mL). The ether layer was washed with brine (10 mL), dried over sodium sulfate, and concentrated. The resulting dark oil was subjected to silica gel column chromatography (hexane/ethyl acetate). Fractions corresponding to the product were collected and concentrated to yield an oil. The oil was azeotroped with THF (2×5 mL) and dried under high vacuum to yield methyl 4-isobutyl-3-(trifluoromethyl)benzoate (0.52 g, 1.998 mmol, 89% yield) as a clear liquid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([CH3:12])[CH:3]=1.Br[CH2:14][CH:15]1[CH2:17][CH2:16]1>>[CH:17]1([CH2:16][O:1][C:2]2[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([O:8][CH2:14][CH:15]3[CH2:17][CH2:16]3)=[O:7])=[C:4]([CH3:12])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc(O)cc(C)c1C(=O)O
Reactant: BrCC1CC1
Product: Cc1cc(OCC2CC2)cc(C)c1C(=O)OCC1CC1

Procedure:
Using 4-hydroxy-2,6-dimethylbenzoic acid and (bromomethyl)cyclopropane, and in the same manner as in Example 5, the title compound was obtained.