Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28]OS(C)(=O)=O)=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:34])([CH3:3])[CH3:2].[C-:35]#[N:36].[K+]>CN(C=O)C>[CH:1]([N:4]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[N:6]([CH2:13][C:14]2[N:18]([CH2:19][CH2:20][CH:21]([CH3:23])[CH3:22])[C:17]3[CH:24]=[CH:25][C:26]([CH2:28][C:35]#[N:36])=[CH:27][C:16]=3[N:15]=2)[C:5]1=[O:34])([CH3:2])[CH3:3]
Reactant: [C-]#N
Reactant: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(COS(C)(=O)=O)ccc21
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CCn1c(Cn2c(=O)n(C(C)C)c3ccccc32)nc2cc(CC#N)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 87.5 %

Procedure:
A mixture of methanesulfonic acid 2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-ylmethyl ester (16 mg, 0.033 mmol) and KCN (21 mg, 0.33 mmol) in DMF was stirred for 24 h at ambient temperature. The solvent was evaporated and the residue was purified by prep-HPLC (gradient 10%-100% B) to give 12 mg (88%) of [2-(3-isopropyl-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl)-1-(3-methyl-butyl)-1H-benzoimidazol-5-yl]-acetonitrile as a colorless gum.
Reaction SMILES: [C:1]1([CH:7]([SeH:12])[CH2:8][O:9][CH2:10]Cl)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[P:13]([O:20]CC)([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16]>>[C:1]1([CH:7]([SeH:12])[CH2:8][O:9][CH2:10][P:13](=[O:20])([O:17][CH2:18][CH3:19])[O:14][CH2:15][CH3:16])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOP(OCC)OCC
Reactant: ClCOCC([SeH])c1ccccc1
Product: CCOP(=O)(COCC([SeH])c1ccccc1)OCC
Yield: 81 %

Procedure:
A solution of 27 (25g, 0.1 mol) and triethyl phosphite was heated at 110° C. for 2.5 hours. After evaporation of volatile in vacuo, the residual oil was chromatographed on silica gel using CH2Cl2 -6% MeOH as eluant to give 28 (30 g, 81%) as a slightly yellow oil. 1H-NMR (300 MHz, CDCl3) 1.27 (t, J=7.24Hz, 6H), 3.01 (t, J=7.5Hz, 2H), 3.70-3.75 (m, 4H), 4.10-4.18 (m, 4H), 7.2-7.5 (m, 5H).
Reaction SMILES: [CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][C:6](OCC)=[O:7].[BH4-].[Li+]>C1COCC1>[CH3:1][C:2]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:3]=1[O:4][CH2:5][CH2:6][OH:7]
Reactant: CCOC(=O)COc1cccc(C)c1C
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cccc(OCCO)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.2 %

Procedure:
To a solution of ethyl 2-(2,3-dimethylphenoxy)acetate (1.7 g, 8.16 mmol) in THF (50 mL) at 0° C. was added lithium borohydride (2 M in THF, 8.16 mL, 16.33 mmol) dropwise over a period of 10 min. At the conclusion of this period, the reaction mixture was slowly warmed to room temperature where it stirred for 16 h. After this time, the reaction mixture was quenched slowly with saturated NH4Cl, and the organic layer was separated, washed with water and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound (1.06 g, 78% yield). LCMS, [M+H]+=167.0.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[NH:10]2)=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2].[H-].[Na+].[CH3:35][CH:36]([S:38](Cl)(=[O:40])=[O:39])[CH3:37]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@@H:9]2[C:14]([C:15]#[N:16])=[C:13]([CH3:17])[N:12]([C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=3)[C:11](=[O:28])[N:10]2[S:38]([CH:36]([CH3:37])[CH3:35])(=[O:40])=[O:39])=[C:5]([S:29]([CH3:32])(=[O:31])=[O:30])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)NC(=O)N1c1cccc(C(F)(F)F)c1
Reactant: CC(C)S(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2S(C)(=O)=O)N(S(=O)(=O)C(C)C)C(=O)N1c1cccc(C(F)(F)F)c1
Yield: 71.6 %

Procedure:
Analogously to the preparation of Example 27, (4S)-4-[4-cyano-2-(methylsulfonyl)phenyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (100 mg, 217 μmol; Example 6), sodium hydride (60%, 11.2 mg, 282 μmol) and 2-propanesulfonyl chloride (40.3 mg, 282 μmol) were reacted with one another for 16 h. This gave the title compound as a colorless solid (88 mg, 72% of theory).
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH:3]=[CH:4][C:5]([OH:7])=[O:6].C([O-])([O-])=O.[K+].[K+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CC(C)=O>[CH2:15]([O:6][C:5](=[O:7])[CH:4]=[CH:3][CH:2]([CH3:8])[CH3:1])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)C=CC(=O)O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(C)C=CC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a solution of 4-methyl-2-pentenoic acid (24.0 g, 210 mmol; commercially available from TCI America) in acetone (300 mL) was added K2CO3 (55.8 g, 404 mmol) and the reaction was stirred at 25° C. for 30 min. A solution of benzyl bromide (25.2 mL, 212 mmol; commercially available from Sigma Aldrich) in acetone (100 mL) was then added drop-wise. The reaction mixture was subsequently heated to reflux for 16 hrs. After cooling to 25° C., the acetone was removed under reduced pressure and ether (300 mL) and water (300 mL) were added and the organic layer was separated, washed with brine and dried over Na2SO4. After concentration, the crude product was subjected to silica gel chromatography (1-5% Ether/Hex) to afford 4-methyl-pent-2-enoic acid benzyl ester (40.5 g, 98%): H-NMR (CDCI3) δ 7.36-7.28 (m, 5 H), 6.96 (dd, 1 H), 5.79 (d, 1 H), 5.14 (s, 2 H), 2.45-2.40 (m, 1 H), 1.01 (d, 6 H).
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][CH:5]=[N:4]1.Cl[C:9]1[C:14]([CH2:15][CH2:16][CH3:17])=[C:13]([CH2:18][N:19]2[CH:23]=[CH:22][N:21]=[C:20]2[C:24]2[C:29]([F:30])=[CH:28][CH:27]=[CH:26][N:25]=2)[N:12]=[CH:11][N:10]=1>C1COCC1>[F:30][C:29]1[C:24]([C:20]2[N:19]([CH2:18][C:13]3[C:14]([CH2:15][CH2:16][CH3:17])=[C:9]([N:3]4[CH:7]=[CH:6][CH:5]=[N:4]4)[N:10]=[CH:11][N:12]=3)[CH:23]=[CH:22][N:21]=2)=[N:25][CH:26]=[CH:27][CH:28]=1
Reactant: c1cn[nH]c1
Reactant: CCCc1c(Cl)ncnc1Cn1ccnc1-c1ncccc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCc1c(Cn2ccnc2-c2ncccc2F)ncnc1-n1cccn1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a suspension of NaH (15 mg, 60% in mineral oil, 0.37 mmol) in anhydrous THF (4 mL), a solution of pyrazole (20 mg, 0.3 mmol) in THF (3 mL) is added dropwise. The mixture is stirred at room temperature for 20 minutes. To the mixture, a solution of 4-chloro-6-[2-(3-fluoro-pyridin-2-yl)-imidazol-1-ylmethyl]-5-propyl-pyrimidine (100 mg, 0.3 mmol) in THF (3 mL) is added. The mixture is stirred at room temperature overnight. The solvent is removed in vacuo. The residue is dissolved in DCM, and the mixture is washed with brine, dried over (MgSO4), filtered, and the solvent is evaporated. The residue is purified by preparative TLC with 10% MeOH/DCM to give the title compound. 1H-NMR (CDCl3) δ: 0.95 (t, 3H), 1.55-1.61 (m, 2H), 3.11 (t, 2H), 5.94 (s, 2H), 6.46-6.47 (m, 1H), 7.16 (s, 1H), 7.22 (s, 1H), 7.34 (s, 1H), 7.51 (t, 1H), 7.77 (d, 1H), 8.26 (s, 1H), 8.45 (d, 1H), 8.71 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[NH2:12][C:13]1[S:14][CH:15]=[CH:16][N:17]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:12][C:13]2[S:14][CH:15]=[CH:16][N:17]=2)=[S:10])[CH:7]=1
Reactant: Nc1nccs1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1nccs1
Yield: 77.4 %

Procedure:
Prepared using Method C from 3.0 g (16.3 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 1.7 g (16.3 mmol) of 2-amino-thiazole to give 3.58 g of title compound as a beige solid, m.p. 197-198° C. (77% yield).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([C:6]1(O)[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH2:7]1)=[CH2:5].C1C=CC=CC=1.P(Cl)(Cl)(Cl)=O.[OH-].[Na+]>CCOCC.O.N1C=CC=CC=1>[CH3:19][N:2]([CH3:1])[CH2:3][C:4]([C:6]1[C:15]2[CH:14]=[N:13][C:12]([O:16][CH3:17])=[CH:11][C:10]=2[CH2:9][CH2:8][CH:7]=1)=[CH2:5]
Reactant: C=C(CN(C)C)C1(O)CCCc2cc(OC)ncc21
Agent: [Na+]
Agent: [OH-]
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccccc1
Solvent: CCOCC
Product: C=C(CN(C)C)C1=CCCc2cc(OC)ncc21
Temperature: 25 °C

Procedure:
To 7.1 parts of N,N-dimethyl-N-(2-[5,6,7,8tetrahydro-8-hydroxy-3-methoxyisoquinol-8-yl]prop-2-en1-yl)amine in 31 parts of benzene and 34.5 parts of pyridine is added 4.5 parts of phosphorous oxychloride, dropwise and at room temperature. That solution is stirred at room temperature for several hours, then cooled in an ice bath. 25 Parts of water slowly is added followed by enough 5% aqueous sodium hydroxide solution to bring the pH of the solution to about 10. Ether is added and the organic and aqueous layers separated. The aqueous layer is extracted with ether and the extracts washed with saturated sodium chloride and dried over anhydrous sodium sulfate. Approximately 200 parts of n-hexane is added to the solution, followed by a portion of charcoal. That mixture is filtered through diatomaceous earth to give a light yellow solution which, upon solvent removal, affords a yellow oil yielding upon crystallization N,N-dimethyl-N-(2-[5,6dihydro-3-methoxyisoquinol-8-yl]prop-2-en-1-yl)amine. A portion of that material is distilled and the distillate is taken up into methanol-water and upon standing yields crystals melting at about 42°-45°. That compound further exhibits an ultraviolet maximum in methanol at about 262 milimicrons with a molecular extinction coefficient of 12,900. It is further characterized by peaks in the nuclear magnetic resonance spectrum in deuteriochloroform at 134, 286, 336, 318, 357, 395 and 480 Hertz.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[C:5]1([C@H:8]([NH:11][C@H:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH3:13])[C:9]#[N:10])[CH2:7][CH2:6]1)[CH3:2]>C(O)C>[CH2:1]([O:3][CH:4]([O:20][CH2:21][CH3:22])[C:5]1([C@@H:8]([NH:11][C@H:12]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH3:13])[C:9]#[N:10])[CH2:7][CH2:6]1)[CH3:2]
Reactant: CCOC(OCC)C1([C@@H](C#N)N[C@@H](C)c2ccccc2)CC1
Solvent: CCO
Product: CCOC(OCC)C1([C@H](C#N)N[C@@H](C)c2ccccc2)CC1

Procedure:
Anhydrous ethanol (1.0 ml) was added to a mixture of the title compound and its diastereomer, (2S)-2-[1-(diethoxymethyl)cyclopropyl]-2-{[(1S)-1-phenylethyl]amino}acetonitrile (the mixture: 16 mg, mixing ratio=1:1.8, (2S)-2-[1-(diethoxymethyl)cyclopropyl]-2-{[(1S)-1-phenylethyl]amino}acetonitrile was a main component). After stirring at 60° C. for 30 minutes in an argon gas stream, the reaction mixture was concentrated under reduced pressure. The diastereomer mixing ratio of the reuslting colorless crystals (16 mg) was found to be 3.4:1 based on the integral ratio of 1H-NMR ((2S)-2-[1-(diethoxymethyl)cyclopropyl]-2-{[(1S)-1-phenylethyl]amino}acetonitrile was a main component).
Reaction SMILES: [OH:1][CH:2]1[C:9](=[CH2:10])[CH2:8][C@H:7]2[C@@H:3]1[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:34])([CH3:33])[CH3:32])([CH3:30])[CH3:29])[C@H:6]2/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41](Cl)(=[O:43])=[O:42])=[CH:37][CH:36]=1>>[C:35]1([CH3:45])[CH:40]=[CH:39][C:38]([S:41]([O:1][CH:2]2[C:9](=[CH2:10])[CH2:8][C@H:7]3[C@@H:3]2[CH2:4][C@@H:5]([O:27][Si:28]([C:31]([CH3:33])([CH3:32])[CH3:34])([CH3:29])[CH3:30])[C@H:6]3/[CH:11]=[CH:12]/[C@@H:13]([O:19][Si:20]([C:23]([CH3:24])([CH3:25])[CH3:26])([CH3:21])[CH3:22])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:43])=[O:42])=[CH:37][CH:36]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1O
Product: C=C1C[C@@H]2[C@H](/C=C/[C@H](CCCCC)O[Si](C)(C)C(C)(C)C)[C@H](O[Si](C)(C)C(C)(C)C)C[C@@H]2C1OS(=O)(=O)c1ccc(C)cc1
Yield: 77.1 %

Procedure:
In the same way as in Example 8, (1S,2RS,5S,6S,7R)-2-hydroxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy- 1-octenyl]-7-t-butyldinmethylsilyloxybicyclo[3.3.0]octane (178 mg, 0.35 mmole) obtained in Example 3 was reacted with p-toluenesulfonyl chloride (133 mg, 0.70 mmole). The reaction mixture was worked up and column-chromatographed to give (1S,2RS,5S,6S,7R)-2-p-toluenesulfonyloxy-3-methylene-6-[(E,3S)-3-t-butyldimethylsilyloxy-l-octenyl]-7-t-butyldimethylsilyloxybicyclo[3.3.0]octane (179 mg, 0.27 mmole, 78%).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][NH:14][C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1.[C:17]([O-])([O-])=O.[Cs+].[Cs+].IC>CN(C=O)C>[Cl:1][C:2]1[C:3]2[CH:16]=[CH:15][N:14]([CH3:17])[C:4]=2[N:5]=[C:6]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[N:7]=1
Reactant: O=C([O-])[O-]
Reactant: Clc1nc(-c2cccnc2)nc2[nH]ccc12
Agent: [Cs+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1ccc2c(Cl)nc(-c3cccnc3)nc21
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 56.7 %

Procedure:
To a solution of 4-chloro-2-(pyridin-3-yl)-7H-pyrrolo[2,3-d]pyrimidine (80 mg, 0.34 mmol, 1.0 eq.) in dry DMF (20 mL) was added Cs2CO3 (221 mg, 0.68 mmol, 2.0 eq.) and iodomethane (54.3 mg, 0.38 mmol, 1.1 eq.) at 0° C. The reaction mixture was warmed to room temperature and stirred for 2.5 h. The reaction mixture was poured into ice water and extracted with EtOAc (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4. After filtration and concentration, the residue was purified by chromatography on silica gel (petroleum ether/ethyl acetate 8:1) to give 65 mg of xlvi-a as brown solid (56.7%).
Reaction SMILES: [NH2:1][C:2]1[C:27]([Cl:28])=[CH:26][C:5]([C:6]([NH:8][CH2:9][CH2:10][CH2:11][N:12]2[CH2:16][CH2:15][CH:14]([CH2:17][NH:18][C:19]([O:21]C(C)(C)C)=O)[CH2:13]2)=[O:7])=[C:4]([O:29][CH3:30])[CH:3]=1.[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35](C(O)=O)=[C:34]([O:42][CH3:43])[CH:33]=1>>[NH2:31][C:32]1[C:40]([Cl:41])=[CH:39][C:35]([C:19]([NH:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:12]([CH2:11][CH2:10][CH2:9][NH:8][C:6](=[O:7])[C:5]3[CH:26]=[C:27]([Cl:28])[C:2]([NH2:1])=[CH:3][C:4]=3[O:29][CH3:30])[CH2:13]2)=[O:21])=[C:34]([O:42][CH3:43])[CH:33]=1
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCCCN1CCC(CNC(=O)OC(C)(C)C)C1
Reactant: COc1cc(N)c(Cl)cc1C(=O)O
Product: COc1cc(N)c(Cl)cc1C(=O)NCCCN1CCC(CNC(=O)c2cc(Cl)c(N)cc2OC)C1

Procedure:
4-Amino-N-(3-(3-tert-butoxycarbonylaminomethylpyrrolidin-1-yl)-propyl)-5-chloro-2-methoxybenzamide (1.70 g) as starting compound was reacted and treated in the same manner as in Example 67 using 4-amino-5-chloro-2-methoxybenzoic acid (0.76 g) to give 4-amino-N-(1-(3-(4-amino-5-chloro-2-methoxybenzoylamino)propyl)pyrrolidin-3-ylmethyl)-5-chloro-2-methoxybenzamide.
Reaction SMILES: [CH2:1](Br)[CH2:2]Br.[Cl:5][C:6]1[CH:7]=[C:8]([CH:10]=[CH:11][CH:12]=1)[NH2:9].C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:5][C:6]1[CH:7]=[C:8]([NH:9][CH2:10][CH2:8][NH:9][C:2]2[CH:1]=[CH:11][CH:12]=[C:6]([Cl:5])[CH:7]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Nc1cccc(Cl)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Clc1cccc(NCCNc2cccc(Cl)c2)c1
Temperature: 140 °C
Reaction time: 5 h
Yield: 72.9 %

Procedure:
A mixture consisting of 188 gm of ethylene bromide, 383 gm of 3-chloro-aniline and 300 gm of sodium carbonate was stirred at 140° C. for five hours. Thereafter, the reaction mixture was cooled to about 80° C., and by addition of water the inorganic substances were caused to go into solution. The mixture was then extracted with ethyl acetate, the organic extract was dried over sodium sulfate, and the solvent as well as unreacted 3-chloroaniline were distilled off in vacuo, leaving 205 gm (76% of theory) of raw N,N'-bis-(3-chlorophenyl)-ethylenediamine. The raw product may be purified by distillation at 16 mm Hg and about 285° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][C:2]1=[CH:7][C:8]([O:10][CH3:11])=[O:9].C(C1(C)[O:19][C:18](=O)[CH:17]=[C:16]([CH3:21])O1)C>C1(C)C(C)=CC=CC=1>[CH3:21][C:16]1[N:1]2[C:2]([CH2:3][CH2:4][CH2:5][CH2:6]2)=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:18](=[O:19])[CH:17]=1
Reactant: COC(=O)C=C1CCCCN1
Reactant: CCC1(C)OC(=O)C=C(C)O1
Solvent: Cc1ccccc1C
Product: COC(=O)c1c2n(c(C)cc1=O)CCCC2
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 93 %

Procedure:
A mixture of 3.10 g of methyl α-(hexahydro-2-pyridinylidene)acetate and 10 ml of xylene was gently refluxed, to which a solution of 7.81 g of 2-ethyl-2,6-dimethyl-4H-1,3-dioxin-4-one in 10 ml of xylene was dropwise added, taking 20 minutes. The mixture was further refluxed for 2 hours, removing the by-product a methyl ethyl ketone through Dean-Stark apparatus. The reaction mixture was cooled to room temperature. The resultant crystals were filtered, washed and dried under reduced pressure to obtain 4.11 g (Yield 93%) of methyl 6,7,8,9-tetrahydro-4-methyl-2-oxo-2H-quinolizine-1-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C([O-])(O)=O.[Na+].[N:23]#[C:24]Br>CCO>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:12]3[CH2:17][CH2:16][N:15]([C:24]#[N:23])[CH2:14][CH2:13]3)=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(N3CCNCC3)ccnc2c1
Reactant: N#CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: N#CN1CCN(c2ccnc3cc(Cl)ccc23)CC1
Reaction time: 2 h

Procedure:
A suspension of 7-Chloro-4-(piperazin-1-yl)quinoline (496 mg, 2.0 mmol) and NaHCO3 (504 mg, 6.0 mmol) in EtOH is treated with cyanogen bromide (5 M in MeCN, 440 μL, 2.2 mmol) and stirred at room temp. for 2 h. The solvent is removed, and the residue suspended in CH2Cl2 and filtered. The filtrate is concentrated, and the residue is purified by column chromatography with hexane-EtOAc giving 221 mg of the product as a colorless solid.
Reaction SMILES: [C:1]1([C:14](O)=[O:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[C:1]1([CH2:14][OH:15])[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: OCc1cccc2c1Cc1ccccc1-2
Reaction time: 1 h

Procedure:
To a cooled (0°), stirred, solution of 1-fluorenecarboxylic acid (2.10 g, 10.0 mmol) in dry tetrahydrofuran (20 ml) under argon was added lithium aluminium hydride (0.19 g, 5 mmol) added in portions over 10 minutes. After a further 1 hour, water was added cautiously until effervescence ceased. The reaction mixture was partitioned between ethyl acetate and water and filtered. The organic layer was washed with saturated sodium hydrogen carbonate solution followed by water and dried over MgSO4. Evaporation of solvent gave crude product. δH (CDCl3 containing CD3OD) 3.87 (2H, s), 4.81 (2H, s), 7.2-7.75 (7H, m) ppm
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:13]=[CH:12][C:11]([OH:14])=[C:10]2[C:5]=1[CH:6]=[CH:7][CH:8]=[N:9]2.C([O-])([O-])=O.[K+].[K+].Cl[C:22]1[CH:27]=[CH:26][N:25]=[C:24]([NH2:28])[C:23]=1[N+:29]([O-:31])=[O:30]>CS(C)=O.O>[NH2:28][C:24]1[C:23]([N+:29]([O-:31])=[O:30])=[C:22]([O:14][C:11]2[C:10]3[N:9]=[CH:8][CH:7]=[CH:6][C:5]=3[C:4]([NH2:3])=[CH:13][CH:12]=2)[CH:27]=[CH:26][N:25]=1
Reactant: Nc1nccc(Cl)c1[N+](=O)[O-]
Reactant: Nc1ccc(O)c2ncccc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: Nc1nccc(Oc2ccc(N)c3cccnc23)c1[N+](=O)[O-]
Temperature: 70 °C

Procedure:
To a stirred solution of 5-aminoquinolin-8-ol dihydrochloride (2.00 g, 8.60 mmol) in DMSO (30 mL) under N2 was added K2CO3 (3.79 g, 27.5 mmol) and after 1 hr at RT the mixture was treated with 4-chloro-3-nitropyridin-2-amine (1.34 g, 7.72 mmol) in a single portion. The reaction mixture was heated to 70° C. for 2 hr and was then cooled to RT and diluted with water (500 mL). A precipitate formed which was isolated by filtration, washed with water (2×20 mL) and then dried in vacuo at 40° C. to afford the title compound, Intermediate H1 as a dark brown solid (1.50 g, 53%); Rt 0.99 min (Method 2); m/z 298 (M+H)+ (ES+).
Reaction SMILES: [C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH:10](C(O)=O)[C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2].C(=O)=O.C(=O)(O)[O-].[Na+]>O.CCCCCC>[C:1]([C:5]1[CH:18]=[C:17]([CH3:19])[C:8]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[C:7]([CH3:20])[C:6]=1[OH:21])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C)c1CC(C(=O)O)C(=O)O
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Product: Cc1cc(C(C)(C)C)c(O)c(C)c1CCC(=O)O

Procedure:
17.9 grams of the compound of Example 16 was stirred together with white oil at 165° to 180° for two hours until little CO2 evolution could be detected. The reaction mixture was cooled to 50° and stirred thoroughly together with 5.2 grams of sodium bicarbonate dissolved in 100 ml of water until no foaming took place and all solids had dissolved. The reaction mixture was diluted with 50 ml of n-hexane and the upper organic phase separated from the lower aqueous phase. The organic phase was washed with water, the wash water being combined with the aqueous phase. The combined aqueous phase was then washed with n-hexane, clarified by filtration through filtercel, and added dropwise to about 150 ml of cold 6N aqueous hydrochloric acid so that a granular off-white precipitate was obtained. The product was used as such after drying in the vacuum oven at 60° and 3mm Hg. overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([C:12]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)=[O:13])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl[CH2:21][C:22]([C:24]1[CH:33]=[CH:32][C:27]2[O:28][CH2:29][CH2:30][O:31][C:26]=2[CH:25]=1)=[O:23].CCN(C(C)C)C(C)C>CN(C=O)C>[O:28]1[C:27]2[CH:32]=[CH:33][C:24]([C:22](=[O:23])[CH2:21][N:17]3[CH2:18][CH2:19][CH:14]([C:12]([C:10]4[S:11][C:7]5[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=5[N:9]=4)=[O:13])[CH2:15][CH2:16]3)=[CH:25][C:26]=2[O:31][CH2:30][CH2:29]1
Reactant: COc1cccc2sc(C(=O)C3CCNCC3)nc12
Reactant: O=C(CCl)c1ccc2c(c1)OCCO2
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cccc2sc(C(=O)C3CCN(CC(=O)c4ccc5c(c4)OCCO5)CC3)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A mixture of (4-methoxy-benzothiazol-2-yl)-piperidin-4-yl-methanone (333 mg, 1.2 mmol) and 2-chloro-1-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-ethanone (256 mg, 1.2 mmol) in DMF (4 ml) was treated with DIPEA (199 ul, 1.2 mmol) and the mixture was stirred at RT overnight. The mixture was poured on water and extracted with EtOAc. The organic layers were dried over MgSO4 and concentrated. Chromatography on SiO2 (hex/EtOAc 1:1, EtOAc) and crystallisation from ether gave 350 mg (65%) of title compound as a yellowish solid.
Reaction SMILES: [NH2:1][C@@H:2]([CH3:21])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=2)=[N:5]1.[C:22]([C:25]1[CH:29]=[C:28]([C:30](O)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]>>[C:22]([C:25]1[CH:29]=[C:28]([C:30]([NH:1][C@@H:2]([CH3:21])[CH2:3][N:4]2[CH:8]=[CH:7][C:6]([C:9]3[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[C:11]([C:17]([F:20])([F:19])[F:18])[CH:10]=3)=[N:5]2)=[O:31])[NH:27][N:26]=1)(=[O:24])[CH3:23]
Reactant: CC(=O)c1cc(C(=O)O)[nH]n1
Reactant: C[C@H](N)Cn1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1
Product: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(C(F)(F)F)c3)n2)[nH]n1

Procedure:
The title compound was prepared using the method of Example 34(d) starting from (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-(trifluoromethyl)-benzonitrile (110 mg, 0.374 mmol) and 3-acetyl-1H-pyrazole-5-carboxylic acid (58 mg, 0.374 mmol). The product was purified twice with flash-chromatography. Yield 8 mg (4%). 1H-NMR (400 MHz; d6-DMSO): δ 1.17 (d, 3H), 2.48 (m, 3H), 4.29-4.38 (m, 2H), 4.41-4.50 (m, 1H), 7.01 (d, 1H), 7.29 (s, 1H), 7.84 (d, 1H), 8.15-7.19 (m, 1H), 8.24 (s, 1H), 8.44-8.50 (m, 2H), 14.13 (m, 1H).