Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[C:18]([C:23]([O:25]C(C)(C)C)=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:13][CH:12]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:46])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]>FC(F)(F)C(O)=O.C(Cl)Cl>[CH2:1]([C:5]1[N:9]([CH2:10][C:11]2[CH:12]=[CH:13][C:14]([C:17]3[C:18]([C:23]([OH:25])=[O:24])=[CH:19][CH:20]=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:8]2[CH:30]=[C:31]([N:34]([CH3:46])[C:35]([NH:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])=[O:36])[CH:32]=[CH:33][C:7]=2[N:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)OC(C)(C)C)cc3)c2c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCCCCCNC(=O)N(C)c1ccc2nc(CCCC)n(Cc3ccc(-c4ccccc4C(=O)O)cc3)c2c1

Procedure:
Prepared in analogous manner to Example 9 from tert.butyl 4'-[(2-n-butyl-6-(N-(n-octylaminocarbonyl)-methylamino)-benzimidazol-1-yl)-methyl]biphenyl-2-carboxylate in trifluoroacetic acid/methylene chloride.
Reaction SMILES: C([Si]([O:8][CH2:9][C:10]1[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=1[N:19]=[C:20]=S)(C)C)(C)(C)C.[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]([NH2:34])[CH2:31][CH2:30][CH2:29]2>>[CH3:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[C:28]2[C:33]=1[CH:32]([NH:34][C:20]1[O:8][CH2:9][C:10]3[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=3[N:19]=1)[CH2:31][CH2:30][CH2:29]2
Reactant: CC(C)(C)[Si](C)(C)OCc1cc([N+](=O)[O-])ccc1N=C=S
Reactant: COc1cccc2c1C(N)CCC2
Product: COc1cccc2c1C(NC1=Nc3ccc([N+](=O)[O-])cc3CO1)CCC2
Yield: 79.2 %

Procedure:
Prepared from tert-butyl-(2-isothiocyanato-5-nitro-benzyloxy)-dimethyl-silane (Example C1) (2.76 g, 8.5 mmol; HPLC: 4.446 min) and rac-8-methoxy-1,2,3,4-tetrahydro-naphthalen-1-ylamine (CAS 535935-61-6) (1.51 g, 8.5 mmol; HPLC 0.403 min) according to the procedure described for Example 1. Obtained the title compound as a yellow solid (2.38 g, 79%, HPLC 1.805 min), MS (ISP) m/e=354.2 [(M+H)+].
Reaction SMILES: [CH2:1]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].Br[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43]>C1(C)C=CC=CC=1>[CH2:20]([N:19]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:39][CH2:40][CH2:41][C:42]([O:44][CH2:45][CH3:46])=[O:43])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37]
Reactant: CCOC(=O)CCCBr
Reactant: CCCCCCCCCCCCCCCCCCNCCCCCCCCCCCCCCCCCC
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCCCCCCCN(CCCCCCCCCCCCCCCCCC)CCCC(=O)OCC
Yield: 58.2 %

Procedure:
A solution of dioctadecylamine (5.2 g., 0.01 mole), ethyl 4-bromobutyrate (1.95 g., 0.01 mole) and toluene (50 ml.) is heated at reflux for sixteen hours, then cooled and concentrated in vacuo to a semi-solid oil. The oil is triturated with ethylacetate, filtered, and the filtrate washed with water, then dried (Na2SO4). Removal of the solvent gives the product as an oil (3.7 g.).
Reaction SMILES: [OH-].[K+].[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([C:16]([O:18]CC)=[O:17])[CH2:12][CH2:11]2)=[CH:6][CH:5]=1.Cl>CO>[F:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:11][CH2:12][CH:13]([C:16]([OH:18])=[O:17])[CH2:14][CH2:15]2)=[CH:6][CH:5]=1
Reactant: CCOC(=O)C1CCN(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCN(c2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.4 ml of a 2N potassium hydroxide solution were added to a solution of 1.1 g of ethyl 1-(4-fluorophenyl)piperidine-4-carboxylate in 100 ml of methanol. The mixture was stirred at room temperature overnight. The pH was then adjusted to 6 with 5% hydrochloric acid, and the solution was concentrated in vacuo. The residue was purified by preparative HPLC.
Reaction SMILES: [C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[CH:15]=[CH:14][C:13]=2F)/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[NH:30]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[NH2:31].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:1]([C:5]1[S:9]/[C:8](=[N:10]\[C:11]([C:12]2[CH:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[CH:15]=[CH:14][C:13]=2[NH:31][NH:30][C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:23])/[N:7]([CH2:24][C@H:25]2[CH2:29][CH2:28][CH2:27][O:26]2)[CH:6]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)OC(=O)NN
Reactant: CC(C)(C)c1cn(C[C@H]2CCCO2)/c(=N/C(=O)c2cc(C(F)(F)F)ccc2F)s1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1C(=O)/N=c1\sc(C(C)(C)C)cn1C[C@H]1CCCO1
Yield: 15.7 %

Procedure:
A mixture of Example 1A (203 mg, 0.47 mmol), tert-butyl hydrazinecarboxylate (187 mg, 1.42 mmol) and potassium carbonate (196 mg, 1.42 mmol) in dioxane (15 mL) was warmed to reflux for 24 hours. The mixture was concentrated under reduced pressure and extracted with ethyl acetate. The acetate extract was washed with water, brine, dried with MgSO4 and concentrated under reduced pressure. The residue was purified by chromatography (SiO2) to afford 40 mg of the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 1.31-1.47 (m, 18 H), 1.64-2.04 (m, 4 H), 3.66 (t, J=7.1 Hz, 1 H), 3.75-3.89 (m, 1 H), 4.23-4.40 (m, 3 H), 6.12 (s, 1 H), 6.99 (d, J=9.1 Hz, 1 H), 7.36 (s, 1 H), 7.65 (dd, J=8.9, 1.8 Hz, 1 H), 8.43 (d, J=2.0 Hz, 1 H), 10.11 (s, 1 H). MS (DCI/NH3) m/z 543 (M+H)+.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=3)=[CH:21][C:20]([C:31](O)=[O:32])=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17].[O:34]=[C:35]1[CH2:40][NH:39][CH2:38][CH2:37][NH:36]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C1COCC1>[Cl:10][C:11]1[CH:12]=[C:13]([N:18]2[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[C:27]([O:29][CH3:30])[CH:28]=3)=[CH:21][C:20]([C:31]([N:39]3[CH2:38][CH2:37][NH:36][C:35](=[O:34])[CH2:40]3)=[O:32])=[N:19]2)[CH:14]=[CH:15][C:16]=1[F:17]
Reactant: COc1cncc(-c2cc(C(=O)O)nn2-c2ccc(F)c(Cl)c2)c1
Reactant: O=C1CNCCN1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1cncc(-c2cc(C(=O)N3CCNC(=O)C3)nn2-c2ccc(F)c(Cl)c2)c1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
0.06 ml (0.32 mmol) of N,N-diisopropylethylamine is added to a solution of 150 mg (0.16 mmol, 37% purity) of the compound of Example 64A, 32 mg (0.32 mmol) of 2-oxopiperazine, and 97 mg (0.26 mmol) of HATU in 5 ml of THF, and the mixture that is obtained is stirred for 20 hours at room temperature. After the further addition of 32 mg (0.32 mmol) of 2-oxopiperazine, stirring is continued for 5 hours at 60° C. The crude product is separated by means of preparative HPLC (mobile solvent: acetonitrile/water gradient). The title compound is obtained in a quantitative yield.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1Cl)=[CH:13][CH:12]=[CH:11][C:10]=2[N+:17]([O-])=O)=[O:5])[CH3:2].[Cl:20][C:21]1[CH:28]=[CH:27][CH:26]=[CH:25][C:22]=1[CH2:23][NH2:24]>>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:24][CH2:23][C:22]1[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=1[Cl:20])=[CH:13][CH:12]=[CH:11][C:10]=2[NH2:17])=[O:5])[CH3:2]
Reactant: NCc1ccccc1Cl
Reactant: CCOC(=O)c1cnc2c([N+](=O)[O-])cccc2c1Cl
Product: CCOC(=O)c1cnc2c(N)cccc2c1NCc1ccccc1Cl
Yield: 83 %

Procedure:
The compound prepared in Example 3 was reacted with 2-chloro-benzylamine according to the method as described in Example 4 and the obtained compound was treated as described in Example 14 to prepare the title compound (yield 83%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([Cl:12])=[C:10]([Cl:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[CH3:14][S:15](Cl)(=[O:17])=[O:16]>O>[Cl:12][C:11]1[C:2]([NH:1][S:15]([CH3:14])(=[O:17])=[O:16])=[C:3]([CH:8]=[CH:9][C:10]=1[Cl:13])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(Cl)c(Cl)c1N
Solvent: O
Product: COC(=O)c1ccc(Cl)c(Cl)c1NS(C)(=O)=O
Temperature: 100 °C
Reaction time: 4 h
Yield: 47 %

Procedure:
A mixture of methyl 2-amino-3,4-dichlorobenzoate (2.2 g) and methanesulphonyl chloride (2.86 g) was stirred at 100° C. for 4 hours. A further quantity of methanesulphonyl chloride (2.86 g) was added and the mixture was stirred at 100° C. overnight. The mixture was poured into water then extracted with ethyl acetate. The combined organic extracts were washed with water, dried (magnesium sulphate) and evaporated to yield a brown oil which was crystallised from cyclohexane/ethyl acetate to yield methyl 3,4-dichloro-2-(methylsulphonylamino)benzoate as light brown crystals (1.4 g), m.p. 100°-102° C.
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][N:12]=2)=[C:6]([C:21]#[N:22])[CH:5]=1.O>C1COCC1>[OH:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][N:12]=2)=[C:6]([CH:5]=1)[C:21]#[N:22]
Reactant: COC(=O)c1ccc(Oc2ccc(C(F)(F)F)cn2)c(C#N)c1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1cc(CO)ccc1Oc1ccc(C(F)(F)F)cn1
Temperature: -55 °C
Reaction time: 0.33 h
Yield: 60.7 %

Procedure:
To a solution of 3-cyano-4-(5-trifluoromethyl-pyridin-2-yloxy)-benzoic acid methyl ester (23 g, 0.070 mol) in anhydrous THF (200 mL) was added portionwise LiAH4 (4.07 g, 0.11 mmol) at −78° C. The reaction mixture was warmed to −55° C. slowly and stirred for 20 mins, diluted with water (3 mL 0.16 mmol, slow addition), filtered and concentrated. Purification via column chromatography on silica gel (petroleum ether/ethyl acetate=10/1 to 5/1) afforded the title product (12.5 g) as a colorless oil.
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([NH:16][C:17]4[C:26]5[C:21](=[CH:22][CH:23]=[CH:24][C:25]=5[O:27][C@H:28]([CH3:33])[C:29]([O:31]C)=O)[N:20]=[CH:19][N:18]=4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)[N:3]=[CH:2]1.[CH2:34]([NH2:36])[CH3:35]>>[CH2:34]([NH:36][C:29](=[O:31])[C@H:28]([O:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:17]([NH:16][C:12]1[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=1)[N:7]([CH2:6][C:4]1[N:3]=[CH:2][S:1][CH:5]=1)[N:8]=[CH:9]3)=[N:18][CH:19]=[N:20]2)[CH3:33])[CH3:35]
Reactant: COC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Reactant: CCN
Product: CCNC(=O)[C@@H](C)Oc1cccc2ncnc(Nc3ccc4c(cnn4Cc4cscn4)c3)c12
Yield: 91 %

Procedure:
Using the same procedure as in Example 5, methyl (2R)-2-[(4-{[1-(1,3-thiazol-4-ylmethyl)-1H-indazol-5-yl]amino}quinazolin-5-yl)oxy]propanoate (200 mg, 0.43 mmol) was reacted with ethylamine to give the title compound as a white solid (188 mg, 91%); NMR Spectrum 1.04 (t, 3H), 1.65 (d, 3H), 3.17 (m, 2H), 5.15 (q, 1H), 5.80 (s, 2H), 7.01 (d, 1H), 7.36 (d, 1H), 7.51 (s, 1H), 7.79-7.72 (m, 3H), 8.12 (s, 1H), 8.44 (m, 1H), 8.53 (m, 2H), 9.04 (s, 1H), 10.69 (br s, 1H); Mass spectrum MH+ 474.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[N:12][CH:13]=1)([CH3:7])[CH3:6].[H-].[Na+].[CH3:40]I.CO>CN(C)C=O.CC(O)=O>[CH3:40][O:1][CH2:2][CH2:3][O:4][C:5]([C:8]1[N:9]=[CH:10][C:11]([N:14]2[CH2:18][C@@:17]3([CH2:23][CH2:22][CH2:21][C@@:20]([CH2:25][N:26]4[C:30]5[CH:31]=[C:32]([C:35]#[N:36])[CH:33]=[CH:34][C:29]=5[N:28]=[CH:27]4)([CH3:24])[CH2:19]3)[O:16][C:15]2=[O:37])=[N:12][CH:13]=1)([CH3:7])[CH3:6]
Reactant: CC(C)(OCCO)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CN(C)C=O
Solvent: CO
Product: COCCOC(C)(C)c1cnc(N2C[C@@]3(CCC[C@](C)(Cn4cnc5ccc(C#N)cc54)C3)OC2=O)cn1
Reaction time: 0.17 h
Yield: 40.3 %

Procedure:
To a solution of 1-(((5S,7S)-3-(5-(2-(2-hydroxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile (40 mg, 0.079 mmol) in N,N-Dimethylformamide (DMF) (1 mL) was added sodium hydride (4.76 mg, 0.119 mmol) at RT. After 10 minutes, MeI (0.020 mL, 0.317 mmol) was added and stirred for an hour. To the mixture was added 0.5 mL MeOH and 2 drops 5% AcOH to buffer to pH 10, then filtered and purified by reverse phase HPLC (Waters Sunfire 30×150 mm Acetonitrile:Water 0.1% TFA 50-100%, 50 mL/min, 15 min). The product was free based with PL-HCO3 resin SPE to yield 1-(((5S,7S)-3-(5-(2-(2-methoxyethoxy)propan-2-yl)pyrazin-2-yl)-7-methyl-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl)-1H-benzo[d]imidazole-6-carbonitrile as a white solid (16.5 mg, 39%). 1H NMR (400 MHz, DMSO-d6) δ 9.23 (d, J=1.51 Hz, 1H), 8.57 (d, J=1.51 Hz, 1H), 8.50 (s, 1H), 8.39 (d, J=0.75 Hz, 1H), 7.84 (d, J=8.53 Hz, 1H), 7.60 (dd, J=8.41, 1.38 Hz, 1H), 4.12-4.23 (m, 2H), 3.88 (dd, J=23.09, 10.29 Hz, 2H), 3.43-3.48 (m, 2H), 3.34-3.39 (m, 2H), 3.26 (s, 3H), 2.00 (d, J=13.30 Hz, 1H), 1.89 (d, J=14.31 Hz, 1H), 1.58-1.77 (m, 3H), 1.43-1.56 (m, 8H), 1.30-1.41 (m, 1H), 1.07 (s, 3H). MS (m/z) 519.3 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH2:18])([CH3:4])([CH3:3])[CH3:2].C([O:24][C:25](=O)[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH:30]=1)=[O:28])(C)(C)C>>[C:1]([O:5][C:6](=[O:19])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([Cl:17])=[CH:10][C:9]=1[NH:18][C:25](=[O:24])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]2[O:39][N:38]=[C:37]([CH3:40])[C:36]=2[CH2:41][O:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][O:44]2)[CH:30]=1)=[O:28])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: Cc1noc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)c1COC1CCCCO1
Product: Cc1noc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(N(C)C)cc3NC(=O)OC(C)(C)C)c2)c1COC1CCCCO1

Procedure:
The title compound was prepared from (2-amino-4-chloro-5-dimethylamino-phenyl)-carbamic acid tert.-butyl ester (Example J1) and (RS)-3-{3-[3-methyl-4-(tetrahydro-pyran-2-yloxymethyl)-isoxazol-5-yl]-phenyl}-3-oxo-propionic acid tert.-butyl ester (Example K13) according to the general procedure M. Obtained as a light yellow solid (187 mg).
Reaction SMILES: [NH:1]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[N:8]O/C(=C/C(OC)=O)/C(OC)=O.N1CCCCCC1=N[O:28]/[C:29](=[CH:34]\[C:35]([O:37][CH3:38])=[O:36])/[C:30](OC)=[O:31]>CC1C=CC=CC=1C>[OH:28][C:29]1[C:30](=[O:31])[N:1]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][C:2]2=[N:8][C:34]=1[C:35]([O:37][CH3:38])=[O:36]
Reactant: COC(=O)/C=C(/ON=C1CCCCCN1)C(=O)OC
Reactant: COC(=O)/C=C(\ON=C1CCCCCN1)C(=O)OC
Solvent: Cc1ccccc1C
Product: COC(=O)c1nc2n(c(=O)c1O)CCCCC2

Procedure:
A mixture of dimethyl (2E)-2-[(azepan-2-ylideneamino)oxy]but-2-enedioate and dimethyl (2Z)-2-[(azepan-2-ylideneamino)oxy]but-2-enedioate in ratio 8/1 was dissolved in o-xylene and refluxed. After 16 h the solvent was removed under reduced pressure and the residue, dissolved in ethyl acetate, was extracted with a saturated solution of NaHCO3 in water. The pH of the aqueous phase was adjusted to about 3 adding 6M HCl aq. and the solution was extracted with dichloromethane. The organic phase was dried over sodium sulphate and concentrated.
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][N:9]2[CH:13]=[CH:12][CH:11]=[C:10]2[C:14]([NH2:16])=[O:15])=O)=[CH:4][CH:3]=1>N>[C:2]1([CH3:1])[CH:18]=[CH:17][C:5]([C:6]2[NH:16][C:14](=[O:15])[C:10]3=[CH:11][CH:12]=[CH:13][N:9]3[N:8]=2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)Nn2cccc2C(N)=O)cc1
Agent: N
Product: Cc1ccc(-c2nn3cccc3c(=O)[nH]2)cc1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
A suspension of 1-(4-methyl-benzoylamino)-1H-pyrrole-2-carboxylic acid amide (111 mg, 0.457 mmol) in 25% aqueous ammonia solution (0.7 ml) is heated to 100° C. in a closed reaction vial and stirred at this temperature for 40 hours. The reaction mixture is allowed to cool to room temperature and purged with nitrogen. Aqueous 1 N hydrochloric is added to reach a pH value of 2. The solids are filtered off and washed with water. Chromatography on a silica gel column with methanol/dichloromethane as eluent affords 2-p-tolyl-3H-pyrrolo[2,1-f][1,2,4]triazin-4-one as white crystals; HPLC/MS 2.45 min (B), [M+H] 226;
Reaction SMILES: [CH2:1]([N:8]1[CH:13]2[CH:14]([OH:16])[CH2:15][CH:9]1[CH2:10][CH:11]([C:17]#[N:18])[CH2:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl>[CH2:1]([N:8]1[CH:13]2[C:14](=[O:16])[CH2:15][CH:9]1[CH2:10][CH:11]([C:17]#[N:18])[CH2:12]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#CC1CC2CC(O)C(C1)N2Cc1ccccc1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: N#CC1CC2CC(=O)C(C1)N2Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.8 g of nitrile 150b was dissolved in 10 ml of DCM. Then 3 eq of Dess-Martin reagent was added to the solution and stirred at room temperature overnight. The mixture was filtered and the filtrate was concentrated to give 8-benzyl-6-oxo-8-azabicyclo[3.2.1]octane-3-carbonitrile 150c as a crude product (0.9 g), which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([NH:11][CH3:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].C(N(CC)CC)C.[CH3:20][C:21]1[CH:26]=[C:25]([C:27](Cl)=[O:28])[CH:24]=[CH:23][N:22]=1.S(Cl)(Cl)=O>C(Cl)Cl>[CH3:20][C:21]1[CH:26]=[C:25]([C:27]([N:11]([CH3:12])[C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([CH3:1])[CH:3]=2)=[O:28])[CH:24]=[CH:23][N:22]=1
Reactant: CNc1ccc([N+](=O)[O-])c(C)c1
Reactant: Cc1cc(C(=O)Cl)ccn1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1cc(C(=O)N(C)c2ccc([N+](=O)[O-])c(C)c2)ccn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 16.6 g (0.1 mol) of 3,N-dimethyl-4-nitrobenzenamine and 10.2 g (0.1 mol) of triethylamine in mL of methylene chloride cooled to 0° C. under a nitrogen atmosphere add slowly a solution of 15.6 g (0.1 mol) of 2-methylpyridine-4-carbonyl chloride (prepared from the corresponding acid and thionyl chloride) such that the temperature is maintained between 0°-5° C. After the addition is complete, stir the mixture for 6 h and allow to warm slowly to room temperature. Quench the reaction mixture by the addition of 50 mL of water. Separate the layers and wash the organic layer with two 50 mL portions of water, two 50 mL portions of 5% sodium bicarbonate solution and 50 mL of saturated sodium chloride solution. Dry the methylene chloride solution over anhydrous sodium sulfate. Remove the drying agent by filtration and evaporate the solvent to obtain the title compound.
Reaction SMILES: [F:1][C:2](F)([F:14])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1.ClC1C=CC(C#N)=CN=1.FC(F)(C(F)F)CO>>[F:14][CH:2]([F:1])[CH2:3][O:4][C:5]1[N:10]=[CH:9][C:8]([CH:11]([NH2:13])[CH3:12])=[CH:7][CH:6]=1
Reactant: CC(N)c1ccc(OCC(F)(F)F)nc1
Agent: N#Cc1ccc(Cl)nc1
Agent: OCC(F)(F)C(F)F
Product: CC(N)c1ccc(OCC(F)F)nc1

Procedure:
The title compound was synthesised according to the 2-step procedure described for the synthesis of 1-[6-(2,2,2-trifluoroethoxy)pyridin-3-yl]ethanamine starting from 6-chloronicotinonitrile and 2,2,3,3-tetrafluoropropan-1-ol.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][CH:25]=3)[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Clc1cccc2cc(-c3ccco3)nn12
Solvent: ClCCl
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: O=Cc1c(-c2ccco2)nn2c(Cl)cccc12
Reaction time: 2.5 h
Yield: 79 %

Procedure:
A dry flask charged with dry N,N-dimethylformamide (100 mL) was treated with phosphorous oxychloride (6.0 mL 64.5 mmol). The resultant solution was stirred at room temperature for 1 hour. 7-Chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine (9.4 g, 43 mmol, example 21) was added to the previous solution and stirred for 2.5 hours. Water and dichloromethane were added to quench the reaction. The aqueous phase and organic phase were separated. The aqueous phase was extracted with dichloromethane. The organics were combined and washed with water, dried over magnesium sulfate, filtered and concentrated. Crystallization from a small amount of methanol gave 7-chloro-2-(2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (8.4 g, 79%) as pale yellow crystalline compound. 1H NMR (CDCl3): δ 10.57 (s, 1H), 8.41 (d, 1H), 7.71 (d, 1H), 7.51 (t, 1H), 7.27 (d, 1H), 7.22 (d, 1H), 6.66 (m, 1H). MS m/247 (M+1).
Reaction SMILES: [C:1]([C:9]1[CH:38]=[C:37]([Br:39])[CH:36]=[CH:35][C:10]=1[C:11]([N:13]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[CH2:14][C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N12CCCN=C1CCCCC2>C(O)C>[Br:39][C:37]1[CH:38]=[C:9]2[C:10](=[CH:35][CH:36]=1)[C:11](=[O:12])[N:13]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=1)[C:14]([C:15](=[O:23])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:1]2[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(CN(CC(=O)Cc2ccccc2)C(=O)c2ccc(Br)cc2C(=O)c2ccccc2)cc1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(Cn2c(C(=O)Cc3ccccc3)c(-c3ccccc3)c3cc(Br)ccc3c2=O)cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 1.4 %

Procedure:
[Step 2] To a solution (10 ml) of 2-benzoyl-4-bromo-N-(2-hydroxy-3-phenylpropyl)-N-(4-methanesulfonylbenzyl)benzamide (1.0 g) in DMSO was added triethylamine (2 ml), and pyridine sulfur trioxide complex (1.1 g) was added at room temperature. The mixture was stirred for 1 hr. and the reaction mixture was added to water. 10% Hydrochloric acid was added to acidify the aqueous layer, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (hexane-hexane:ethyl acetate=1:2) to give 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.72 g). [Step 3] To a solution (6 ml) of 2-benzoyl-4-bromo-N-(4-methanesulfonylbenzyl)-N-(2-oxo-3-phenylpropyl)benzamide (0.3 g) in ethanol was added 1,8-diazabicyclo[5.4.0]undeca-7-ene (0.15 g), and the mixture was stirred at 80° C. for 12 hrs. The reaction mixture was concentrated under reduced pressure, water and 10% hydrochloric acid were added to the residue and the mixture was extracted with ethyl acetate. The organic layer was washed with water, saturated aqueous sodium hydrogen carbonate, water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the obtained residue was purified by silica gel thin layer chromatography (hexane:ethyl acetate=2:1) and recrystallized (ethyl acetate-hexane) to give the title compound (4 mg).