Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([N:8]2[C:12]([C:13]3[O:14][C:15](=[O:26])[C:16]4[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[C:19]([CH3:25])[C:17]=4[N:18]=3)=[CH:11][C:10]([C:27]([F:30])([F:29])[F:28])=[N:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Cl.[C:32]1([NH2:38])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1.C(N(CC)CC)C>O1CCCC1>[C:32]1([NH:38][C:15]([C:16]2[CH:22]=[C:21]([C:23]#[N:24])[CH:20]=[C:19]([CH3:25])[C:17]=2[NH:18][C:13]([C:12]2[N:8]([C:3]3[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][N:4]=3)[N:9]=[C:10]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[O:14])=[O:26])([CH:35]2[CH2:37][CH2:36]2)[CH2:34][CH2:33]1
Reactant: NC1(C2CC2)CC1
Reactant: Cc1cc(C#N)cc2c(=O)oc(-c3cc(C(F)(F)F)nn3-c3ncccc3Cl)nc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(C#N)cc(C(=O)NC2(C3CC3)CC2)c1NC(=O)c1cc(C(F)(F)F)nn1-c1ncccc1Cl
Temperature: 60 °C
Yield: 57.4 %

Procedure:
To a solution of 2-[2-(3-chloro-pyridin-2-yl)-5-trifluoromethyl-2H-pyrazol-3-yl]-8-methyl-4-oxo-4H-benzo[d][1,3]oxazine-6-carbonitrile (1.2 g, 2,8 mmol) (prepared according to WO 04/067528) in tetrahydrofuran (40 ml), is added bicyclopropyl-1-ylamine hydrochloride (0.6 g, 4.2 mmol) and 1.2 ml (8.4 mmol) triethylamine, and the solution is heated at a temperature of 60° C. for 8 h. The solution is cooled down to ambient temperature and the solvent is evaporated. Then the mixture is triturated in 100 ml water and the crystals are washed with water and ether to afford 0.85 g of the title compound. The mother liquor is evaporated and a second crop of crystals is obtained by crystallisation in diisopropylether to afford 0.46 g of the title compound (F: 270-272° C.).
Reaction SMILES: [CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31].[OH-].[Li+].Cl>C1COCC1.O.O>[CH3:1][CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[N:5][C:6]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[N:3]1[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([OH:32])=[O:31]
Reactant: CCOC(=O)CCCCCCN1c2nc(-c3ccccc3)c(-c3ccccc3)cc2CCC1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCc2cc(-c3ccccc3)c(-c3ccccc3)nc2N1CCCCCCC(=O)O
Temperature: 25 °C
Reaction time: 96 h

Procedure:
Enantiomer 2 of Ethyl 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoate (37 mg, 0.081 mmol) was dissolved in THF/water (1 ml/2:1) and lithium hydroxide (9.70 mg, 0.405 mmol) was added. The mixture was stirred at room temperature for 4 days and then diluted with water (25 ml). The pH was adjusted to pH 5-6 using 1M HCl. The aqueous portion was extracted with EtOAc (2×20 ml) and the combined organics extracts were washed with brine, dried over MgSO4, filtered and evaporated to afford Enantiomer 1 of 7-(2-methyl-6,7-diphenyl-3,4-dihydro-1,8-naphthyridin-1(2H)-yl)heptanoic acid;
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1.[NH3:25]>C(O)(C)C>[NH2:25][C:2]1[C:3]2[N:4]([C:8]([CH:12]3[CH2:15][CH:14]([N:16]4[CH2:21][CH2:20][N:19]([C:22](=[O:24])[CH3:23])[CH2:18][CH2:17]4)[CH2:13]3)=[N:9][C:10]=2[I:11])[CH:5]=[CH:6][N:7]=1
Reactant: CC(=O)N1CCN(C2CC(c3nc(I)c4c(Cl)nccn34)C2)CC1
Reactant: N
Solvent: CC(C)O
Product: CC(=O)N1CCN(C2CC(c3nc(I)c4c(N)nccn34)C2)CC1
Temperature: 110 °C

Procedure:
1-{4-[3-(8-Chloro-1-iodoimidazo[1,5-a]pyrazin-3-yl)cyclobutyl]piperazin-1-yl}ethanone (13.2 g, 0.029 mol) was dissolved in isopropyl alcohol (100 mL) into a Parr pressure reactor. The vessel was cooled to −78° C. and saturated with ammonia gas and sealed. The reaction was heated for 19 h at 110° C., at which point the reaction was cooled and the solvent concentrated in vacuo. The crude product was purified via silica gel chromatography eluting with 5-10% MeOH (7M NH3): CH2Cl2 to yield the title compounds as an off white solid; MS (ES+): m/z 440.89 (100) [MH], 441.89 (20) [MH++]; HPLC: tR=0.46 min (OpenLynx, polar—5 min); 1H NMR (CDCl3, 400 MHz) δ 2.09 (s, 3 H) 2.28-2.48 (m, 6 H) 2.54-2.71 (m, 2 H) 2.80-2.99 (m, 1 H) 3.27-3.43 (m, 1 H) 3.43-3.54 (m, 2 H) 3.56-3.70 (m, 2 H) 7.02 (d, J=5.05 Hz, 1 H) 7.16 (d, J=5.05 Hz, 2 H).
Reaction SMILES: I[C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:17])[CH3:16].[CH2:29]([OH:34])[CH2:30][CH2:31][C:32]#[CH:33].[Cl-].C(#N)C>C(N(CC)CC)C.[Cu]I>[OH:34][CH2:29][CH2:30][CH2:31][C:32]#[C:33][C:2]1[N:3]([CH2:18][C:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH:22]=[CH:21][CH:20]=2)[CH:4]=[C:5]2[C:10]=1[C:9](=[O:11])[N:8]([CH3:12])[C:7](=[O:13])[N:6]2[CH2:14][CH:15]([CH3:16])[CH3:17]
Reactant: CC(C)Cn1c(=O)n(C)c(=O)c2c(I)n(Cc3cccc4ccccc34)cc21
Reactant: C#CCCCO
Agent: [Cu]I
Agent: [Cl-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)Cn1c(=O)n(C)c(=O)c2c(C#CCCCO)n(Cc3cccc4ccccc34)cc21
Temperature: 25 °C

Procedure:
5-Iodo-3-methyl-1-(2-methylpropyl)-6-(1-naphthalenylmethyl)-1 H-pyrrolo-[3,4-d]pyrimidine-2,4(3 H,6 H)-dione (100 mg), 4-pentyn-1-ol(0.080 ml), bis-triphenylphosphinepalladium (II) chloride (3 mg) and copper (I) iodide (1 mg) were dissolved in triethylamine (3 ml) and acetonitrile (1 ml) and heated to 90° C. in a sealed pressure tube of 3 hours. The reaction mixture was allowed to cool to room temperature and was then evaporated to leave a residue which was recrystallised from ethyl acetate. The resultant brown solid was chromatographed, eluting with ethyl acetate to give a white solid which was triturated with ethyl acetate to give the title compound (45 mg).
Reaction SMILES: [CH2:1]([N:3]1[CH2:9][CH2:8][C:7]2[C:10]([NH2:16])=[CH:11][CH:12]=[C:13]([O:14][CH3:15])[C:6]=2[CH2:5][CH2:4]1)[CH3:2].Cl[C:18]1[N:23]=[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[C:21]([Cl:36])=[CH:20][N:19]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[Na]>O.CC(O)C>[Cl:36][C:21]1[C:22]([NH:24][C@@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[N:23][C:18]([NH:16][C:10]2[C:7]3[CH2:8][CH2:9][N:3]([CH2:1][CH3:2])[CH2:4][CH2:5][C:6]=3[C:13]([O:14][CH3:15])=[CH:12][CH:11]=2)=[N:19][CH:20]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: CCN1CCc2c(N)ccc(OC)c2CC1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: [Na]
Solvent: O
Solvent: CC(C)O
Product: CCN1CCc2c(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)ccc(OC)c2CC1
Temperature: 120 °C

Procedure:
3-Ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamine (50.01 mg, 0.2270 mmol), N-[(1R,2R)-2-(2,5-Dichloro-pyrimidin-4-ylamino)-cyclohexyl]-methanesulfonamide (77.0 mg, 0.227 mmol) and 10-camphorsulfonic acid (79.1 mg, 0.340 mmol) were charged to 2 ml IPA in a microwave tube. The reaction was heated to at 120° C. for 40 minutes. Pour reaction into water (50 ml) and saturated sodium bicarb (90 ml) and extract 3 times with 25 ml portions of methylene chloride. Dry combined organic over magnesium sulfate, filter and evaporate to a brown oil (87 mg). The crude reaction was purified on silica gel (12 g Isco column) using a gradient of 0-20% methanol in methylene chloride and then isocratic 20% methanol in methylene chloride to yield N-{(1R,2R)-2-[5-Chloro-2-(3-ethyl-9-methoxy-2,3,4,5-tetrahydro-1H-benzo[d]azepin-6-ylamino)-pyrimidin-4-ylamino]-cyclohexyl}-methanesulfonamide as an off white foam. 1H-NMR (CDCl3) δ 7.88 (s, 1H), 7.11 (d, J=8.6 Hz, 1H), 6.78 (d, J=8.6 Hz, 1H), 6.38 (s, 1H), 5.18 (br s, 1H), 3.81 (s, 3H), 3.10 (br s, 2H), 2.72 (s, 3H), 2.68-2.49 (m, 6H), 2.18-2.00 (m, 2H), 1.82-1.69 (m, 2H), 1.40-1.18 (m, 4H), 1.07 (t, J=7 Hz, 3H).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]1=2.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:2](=[O:1])[C:3]=2[C:4]=1[C:11]([OH:13])=[O:12])([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Product: O=C1CCCc2[nH]c([N+](=O)[O-])c(C(=O)O)c21
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol) was added in portions over 30 minutes to fuming nitric acid (2 mL) at 0° C. The mixture was stirred an additonal 1.25 hours, then allowed to stir at ambient temperature for 1.25 hours. The mixture was poured into ice water and extracted 2X with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound(0.19 g).
Reaction SMILES: S(Cl)(Cl)=O.[O:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:19]=[CH:18][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[CH3:20]O>>[CH3:20][O:16][C:15](=[O:17])[C:14]1[CH:13]=[CH:12][C:11]([N:8]2[CH2:7][CH2:6][O:5][CH2:10][CH2:9]2)=[CH:19][CH:18]=1
Reactant: CO
Reactant: O=C(O)c1ccc(N2CCOCC2)cc1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(N2CCOCC2)cc1

Procedure:
Under ice cooling, thionyl chloride (436 μL) was added dropwise to methanol (10 mL). 4-Morpholinobenzoic acid (207 mg) was added thereto, and the resultant mixture was heated under reflux for 1.5 hours. The solvent was distilled away under reduced pressure. Methylene chloride and water were added to the residue for partitioning the mixture. The organic layer was dried over sodium sulfate anhydrate. The solvent was distilled away under reduced pressure, whereby the title compound was obtained.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[C:8]([Br:10])[CH:7]=[CH:6][C:5]=1[NH2:11])=[O:3].[N:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[Li]>>[NH2:11][C:5]1[CH:6]=[CH:7][C:8]([Br:10])=[CH:9][C:4]=1[C:2]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][N:12]=1)([OH:3])[CH3:1]
Reactant: [Li]c1ccccn1
Reactant: CC(=O)c1cc(Br)ccc1N
Product: CC(O)(c1ccccn1)c1cc(Br)ccc1N

Procedure:
Prepared from 2-amino-5-bromophenyl methyl ketone and 2-pyridyllithium generally according to the procedure described in example 1. 1H NMR (DMSO-d6): δ 8.5 (d, J=3.99 Hz, 1H), 7.77 (dt, J=7.77, 1.79 Hz, 1H), 7.64 (d, J=7.96 Hz, 1H), 7.30 (d, J=2.37 Hz, 1H), 7.21-7.25 (m, 1H), 7.06 (dd, J=8.49, 2.36 Hz, 1H), 6.47 (d, J=8.51 Hz, 1H), 6.18 (s, 1H), 5.26 (s, 2H), 1.8 (s, 3H); MS (ESI) m/z 293/295, 1 Br pattern ([M+H]+).
Reaction SMILES: [CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([Cl:16])=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17][CH3:18])=[CH:11][CH:10]=3)[CH3:2].ClC1C=C(C=CC=1)C(OO)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl>[CH2:1]([N:3]1[C:7]2=[N:8][C:9]3[C:14]([C:15]([Cl:16])=[C:6]2[CH:5]=[N:4]1)=[CH:13][C:12]([S:17]([CH3:18])=[O:24])=[CH:11][CH:10]=3)[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCn1ncc2c(Cl)c3cc(SC)ccc3nc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCn1ncc2c(Cl)c3cc(S(C)=O)ccc3nc21
Temperature: 0 °C
Yield: 93.9 %

Procedure:
To a solution of 1-ethyl-4-chloro-6-(methylthio)-1H-pyrazolo[3, 4-b]quinoline (2.4 g, 8.7 mmol) in CHCl3 (50 mL) at -40° C. was added m-chloroperoxybenzoic acid (2.75 g, 8.7 mmol). The reaction mixture was slowly warmed to 0° C. and then saturated NaHCO3 (10 mL) was added. The reaction mixture was partitioned between water (20 mL) and CH2Cl2 (20 mL), the layers were separated and then the aqueous layer was extracted with CH2Cl2 (20 ml). The CH2Cl2 extracts were combined, dried over MgSO4 and evaporated. The residue was purified by column chromatography on silica gel eluting with 50% ether/hexane, then 25% ethyl acetate/25% hexane/50% ether and finally ethyl acetate (100%) to afford 2.4 g of 1-ethyl-4-chloro-6-(methylsulfinyl)-1H-pyrazolo[3,4-b]quinoline.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:11][CH:10]=2)[CH:5]=[C:4]([CH3:22])[C:3]=1[C:23]1[N:24]=[C:25]([NH2:28])[S:26][CH:27]=1.C(N(CC)CC)C.Cl.[C:37](Cl)(=[O:44])[C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>C1COCC1>[CH3:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)=[CH:13][CH:14]=2)[CH:5]=[C:4]([CH3:22])[C:3]=1[C:23]1[N:24]=[C:25]([NH:28][C:37](=[O:44])[C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[S:26][CH:27]=1
Reactant: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(N)n1
Reactant: O=C(Cl)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1cc(Oc2ccc(Oc3ccccc3)cc2)cc(C)c1-c1csc(NC(=O)c2ccncc2)n1
Temperature: 60 °C
Reaction time: 8 h
Yield: 80.1 %

Procedure:
To a solution of 4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-amine (26-4, 0.500 g, 1.29 mmol) in THF (6.4 mL) was added triethylamine (0.39 g, 3.86 mmol) followed by isonicotinoyl chloride hydrochloride (0.46 g, 2.58 mmol). The reaction mixture was stirred at 60° C. overnight. The solution was concentrated under reduced pressure and added with water. The resultant precipitate was filtered and dried to give N-{4-(2,6-dimethyl-4-(4-phenoxyphenoxy)phenyl)thiazol-2-yl}isonicotinamide (26, 0.51 g) as light yellow solids in 80% yield: 1H NMR (500 MHz, CDCl3) δ 8.72 (m, 2 H), 7.61 (m, 2 H), 7.31-7.34 (m, 2 H), 7.08-7.10 (m, 1 H), 6.94-7.02 (m, 6 H), 6.80 (s, 1H), 6.49 (s, 2 H), 1.94 (s, 6 H). ESI-MS: m/z 494.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([OH:5])=[O:4].C.[CH2:11](O)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].S([O-])(O)(=O)=O.[Na+]>O.C1(C)C=CC=CC=1>[OH:1][CH:2]([CH2:6][CH2:7][S:8][CH3:9])[C:3]([O:5][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:4]
Reactant: CSCCC(O)C(=O)O
Reactant: CCCCCCCCO
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCCCCCOC(=O)C(O)CCSC
Temperature: 25 °C

Procedure:
To a multi-neck 5 L round bottom flask fitted with a mechanical stirrer, reflux condenser, and dean stark trap was added 2-hydroxy-4-(methylthio)butanoic acid (650 g, 4.33 mol, obtained for example by stirring Alimet over activated charcoal, filtering and concentrating in a rotovap), 1-octanol (845.4 g, 6.49 mol), sodium hydrogen sulfate (10.4 g, 86 mmol), and toluene (2.7 L).The resulting solution was heated to reflux with removal of water (˜146 mL) during the course of about 5.5 hours and the reaction was monitored by GC analysis. The reaction was cooled to room temperature overnight and then washed with saturated NaHCO3 (1×1.5 L), DI water (1×1.5 L) and brine (1×1.5 L), dried over sodium sulfate, filtered and evaporated to give a dark oil (1,525 g). The oil was purified by kugelrohr distillation at 130-150° C. and 0.1 mm Hg vacuum to give a pale yellow oil (507.6 g, 45%). m/z 285 (MNa+).
Reaction SMILES: [H-].[Na+].[CH3:3][S:4]([NH2:7])(=[O:6])=[O:5].[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19](O)=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[C:13]([CH3:35])([CH3:34])[CH2:12]2.C(N1C=CN=C1)(N1C=CN=C1)=O>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[C:11]2[C:16](=[C:17]([C:19]([NH:7][S:4]([CH3:3])(=[O:6])=[O:5])=[O:20])[CH:18]=1)[NH:15][CH:14]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:23]=1)[C:13]([CH3:35])([CH3:34])[CH2:12]2
Reactant: CC1(C)Cc2cc(Cl)cc(C(=O)O)c2NC1c1cccc(N2CCOCC2)c1
Reactant: CS(N)(=O)=O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)Cc2cc(Cl)cc(C(=O)NS(C)(=O)=O)c2NC1c1cccc(N2CCOCC2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 29.8 %

Procedure:
To a suspension of 60% sodium hydride (294 mg, 7.4 mmol) in N,N-dimethylformamide (2.5 mL) was added methanesulfonamide (713 mg, 7.5 mmol) at room temperature. The resulting mixture was stirred at 25° C. for 1 h. A solution of 6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carboxylic acid (300 mg, 0.75 mmol) and 1,1′-carbonyldiimidazole (244 mg, 1.5 mmol) in N,N-dimethylformamide (2.0 mL) was stirred at 70° C. After stirring at 70° C. for 1 h, the above suspension of methanesulfonamide and sodium hydride in N,N-dimethylformamide was added and the mixture was allowed to stir at 25° C. for 1 h. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% ammonium hydroxide in water) afforded N-[6-chloro-3,3-dimethyl-2-(3-morpholin-4-yl-phenyl)-1,2,3,4-tetrahydro-quinoline-8-carbonyl]-methanesulfonamide (107 mg, 30%) as a white solid: LC/MS m/e calcd for C25H30ClN3O4S (M+H)+: 505.05, observed: 504.0.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15].[CH3:17][N:18]1[C:22]([Sn](CCCC)(CCCC)CCCC)=[CH:21][CH:20]=[N:19]1>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[C:8]([C:22]2[N:18]([CH3:17])[N:19]=[CH:20][CH:21]=2)[C:7]([C:11]([F:14])([F:13])[CH3:12])=[CH:6][C:5]=1[NH2:15]
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccnn1C
Reactant: COC(=O)c1cc(I)c(C(C)(F)F)cc1N
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2ccnn2C)c(C(C)(F)F)cc1N
Temperature: 90 °C
Reaction time: 72 h
Yield: 62.1 %

Procedure:
To a solution of 2-amino-4-(1,1-difluoro-ethyl)-5-iodo-benzoic acid methyl ester (0.80 g, 2.35 mmol) in dioxane (10 mL) were added 1-methyl-5-tributylstannanyl-1H-pyrazole (1.05 g, 2.81 mmol) and Pd(PPh3)2Cl2 (168 mg, 0.235 mmol) and the resulting mixture was stirred at 90° C. for 72 h. The solvent was removed in vacuo to afford a dark oil. The crude product was purified by flash chromatography (silica gel, EtOAc/hexanes (0:10 to 3:7)) to give 2-amino-4-(1,1-difluoro-ethyl)-5-(2methyl-2H-pyrazol-3-yl)-benzoic acid methyl ester (430 mg, 1.46 mmol, 62%). ES-MS: m/z 296 [M+H]+, rt 6.05 min.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][C@H:13]([CH2:17][N:18]2[CH:22]=[CH:21][N:20]=[CH:19]2)[CH:14]([CH3:16])[CH3:15])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:23].[C:24]1([C:34](O)=[O:35])[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:27]=[CH:26][N:25]=1.CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[N:18]1([CH2:17][C@@H:13]([O:12][C:11]2[CH:10]=[CH:9][C:8]3[C:7](=[O:23])[CH2:6][CH2:5][CH2:4][C:3]=3[C:2]=2[NH:1][C:34]([C:24]2[C:33]3[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH:27]=[CH:26][N:25]=2)=[O:35])[CH:14]([CH3:16])[CH3:15])[CH:22]=[CH:21][N:20]=[CH:19]1
Reactant: CC(C)[C@@H](Cn1ccnc1)Oc1ccc2c(c1N)CCCC2=O
Reactant: O=C(O)c1nccc2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)[C@@H](Cn1ccnc1)Oc1ccc2c(c1NC(=O)c1nccc3ccccc13)CCCC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 42.1 %

Procedure:
To a solution of 5-amino-6-((S)-1-imidazol-1-ylmethyl-2-methyl-propoxy)-3,4-dihydro-2H-naphthalen-1-one (105 mg, 0.335 mmol) and 1-isoquinoline carboxylic acid (70 mg, 0.402 mmol) in DMF (3 mL) was added Et3N (56 μL, 0.402 mmol) followed by HATU (153 mg, 0.402 mmol). The reaction was stirred at RT overnight. The DMF was removed under reduced pressure. The residue was diluted with EtOAc and washed with H2O, saturated aqueous NaHCO3 and brine, dried over Na2SO4, and concentrated. Purification by chromatography (5% MeOH/EtOAc with 1% NH4OH) afforded the title compound as a foam (66 mg, 0.141 mmol, 42%). The structure was confirmed by NMR and mass spectrometry. MS m/z 469 (M++H).
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CCOCC.[CH2:16]([S:23](Cl)(=[O:25])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[CH2:16]([S:23]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:25])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: On1nnc2ccccc21
Reactant: O=S(=O)(Cl)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=S(=O)(Cc1ccccc1)On1nnc2ccccc21
Yield: 46.7 %

Procedure:
In 1 N aqueous sodium hydroxide (50 ml) is dissolved 1-hydroxy-1,2,3-benzotriazole (5 g) and thereto is added ether (25 ml). To the solution is added benzylsulfonyl chloride (8 g) with stirring under ice-cooling. The mixture is stirred at the same temperature for 3 hours. The reaction mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the oily residue is allowed to stand. The resulting crystals are recrystallized from benzene-petroleum ether to give 1-benzylsulfonyloxy-1,2,3-benzotriazole (5.0 g), melting point: 65°-67° C.
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[C:10](Cl)(=[O:19])[CH:11]=[CH:12]C1C=CC=CC=1.Cl.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl.N1C=CC=CC=1>[F:9][C:6]1[CH:7]=[CH:8][C:2]([F:1])=[C:3]2[C:5]=1[CH:12]=[CH:11][C:10](=[O:19])[NH:4]2
Reactant: Nc1cc(F)ccc1F
Reactant: O=C(Cl)C=Cc1ccccc1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=c1ccc2c(F)ccc(F)c2[nH]1
Yield: 20.7 %

Procedure:
10 g of 2,5-difluoroaniline and 6 g of pyridine in 350 ml of dichloromethane are mixed drop by drop at 0° C. with 12.9 g of cinnamic acid chloride and stirred until conversion is completed at 0° C. The batch is added to 2N hydrochloric acid, and it is extracted with dichloromethane. It is washed with water, dried with sodium sulfate and concentrated by evaporation in a vacuum. The solid that is obtained is mixed with 11.1 g of aluminum chloride and heated for 8 hours to 150° C. After chromatography on silica gel, 2.9 g of 5,8-difluoroquinolin-2(1H)-one is obtained. The latter is reacted in 100 ml of ethylene glycol in the presence of 780 mg of copper(II) oxide for 20 hours at 200° C. in ammonia atmosphere at 60 bar. After chromatography on silica gel, in this case 5-amino-8-fluoroquinolin-2(1H)-one is obtained as fraction A and 2,5-diamino-8-fluoroquinoline is obtained as fraction B.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6].[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([CH:21]3[N:26](C4C=CC=CN=4)[CH2:25][CH2:24][C:23](=O)[CH2:22]3)[CH:12]=[CH:11][C:10]1=2.Cl>>[CH3:8][C:9]1([CH3:34])[CH2:18][CH2:17][C:16]([CH3:20])([CH3:19])[C:15]2[CH:14]=[C:13]([C:21]3[N:26]=[C:25]([N:26]4[CH2:21][CH2:22][CH:23]([NH:1][CH2:2][CH2:3][C@@H:4]([OH:7])[CH2:5][OH:6])[CH2:24][CH2:25]4)[CH:24]=[CH:23][CH:22]=3)[CH:12]=[CH:11][C:10]1=2
Reactant: CC1(C)CCC(C)(C)c2cc(C3CC(=O)CCN3c3ccccn3)ccc21
Reactant: NCC[C@@H](O)CO
Agent: Cl
Product: CC1(C)CCC(C)(C)c2cc(-c3cccc(N4CCC(NCC[C@@H](O)CO)CC4)n3)ccc21

Procedure:
The preparation is carried out analogously to FS1008 starting from 21 mg (0.199 mmol) of (R)-4-aminobutane-1,2-diol and 80 mg (0.199 mmol) of 6-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2,3,5,6-tetrahydro-1,2′-bipyridinyl-4-one. The product is in the form of the hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=S)[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1.[CH2:20]([N:22]([CH2:25][C:26]([NH:28][NH2:29])=O)[CH2:23][CH3:24])[CH3:21]>C(O)CCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:26]([CH2:25][N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[N:28][N:29]=[C:10]3[CH2:9][N:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:19]=1
Reactant: S=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Reactant: CCN(CC)CC(=O)NN
Solvent: CCCCO
Product: CCN(CC)Cc1nnc2n1-c1ccc(Cl)cc1C(c1ccccc1)=NC2

Procedure:
A solution of 1,3-dihydro-7-chloro-5-phenyl-2H-1,4-benzodiazepine-2-thione and (diethylamino)acetic acid hydrazide in n-butyl alcohol was refluxed to give 8-chloro-1-[(diethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a]-[1,4]benzodiazepine, which was recrystallized from ethyl acetate-Skellysolve B hexanes and was identical to the compound obtained in Example 4.