Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:8])[CH2:6][CH2:5][CH2:4][C:3](=[O:7])[CH2:2]1.[CH3:9][CH2:10][O:11][C:12](/[C:14](/[C:22]#[N:23])=[CH:15]/[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]>C(O)C>[NH2:23][C:22]1[O:7][C:3]2[CH2:4][CH2:5][CH2:6][C:1](=[O:8])[C:2]=2[CH:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]=1[C:12]([O:11][CH2:10][CH3:9])=[O:13]
Reactant: CCOC(=O)/C(C#N)=C/c1ccccc1
Reactant: O=C1CCCC(=O)C1
Solvent: CCO
Product: CCOC(=O)C1=C(N)OC2=C(C(=O)CCC2)C1c1ccccc1
Temperature: 25 °C
Yield: 83 %

Procedure:
To a solution of 1,3-cyclohexane dione (0.56 g, 5.0 mmole) in hot ethanol (10 ml) was added ethyl trans-a-cyanocinnamate (1.0 g, 5.0 mmole) and the mixture heated at reflux for 18 h. The mixture was cooled to room temperature, filtered and washed with ethanol to provide the desired product (1.30 g, 83%) as a white powder. 1H NMR (400 MHz; CDCl3) d 7.29-7.0 (m, 5H); 6.2 (bs, 2H); 4.72 (s, 1H); 4.09-3.96 (m, 2H); 2.64-2.48 (m, 2H); 2.40-2.26 (m, 2H); 2.06-1.88 (m, 2H); 1.14 (t, 3H, J=7.4 Hz). LC MS shows MH+ at 314.
Reaction SMILES: [N+:1]([C:4]1[O:8][C:7]([CH:9]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:11][CH:12](C)[C:13](Cl)=O.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:11][C:12]([CH3:13])=[CH:9][C:7]1[O:8][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])o1
Reactant: CC(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CC(Cl)=Cc1ccc([N+](=O)[O-])o1
Reaction time: 0.67 h

Procedure:
To a solution of 9 g of 5-nitro-2-furaldehyde and 11.0 g of 2-chloropropionyl chloride in 100 ml of benzene was added dropwise at 25°-30° over a 20-minute period a solution of 10 g of triethylamine in 30 ml of benzene. After an additional 40 minutes, the mixture was stirred at reflux for 1.5 hours. The cooled mixture was washed with water, dried and concentrated under reduced pressure to leave a residue which was distilled to give a liquid product, b.p.: 92°-100° at 0.15 torr. This product was triturated with n-hexane to give 3 as a mixture of stereisomers, a tan solid, m.p.: 55°-65°.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([CH2:23][CH2:24][CH2:25][NH2:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:7]=[C:8]([NH2:16])[N:9]=[C:10]([NH:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:11]=1[I:12]
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: NCCCc1ccccc1
Solvent: C1CCOC1
Product: Nc1nc(NCCCc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine and 3-phenylpropylamine in THF. ES-MS m/e (%): 421 (M+H+, 100).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([O:14][CH3:15])[N:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7].[CH:16]1[C:28]2[CH:27]([CH2:29][O:30][C:31]([N:33]=[C:34]=[S:35])=[O:32])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C:20]=2[CH:19]=[CH:18][CH:17]=1>C1(C)C=CC=CC=1>[CH2:9]([O:8][C:6]([C:5]1[CH:11]=[C:12]([O:14][CH3:15])[N:13]=[C:3]([CH2:2][NH:1][C:34]([NH:33][C:31]([O:30][CH2:29][CH:27]2[C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:20]3[C:28]2=[CH:16][CH:17]=[CH:18][CH:19]=3)=[O:32])=[S:35])[CH:4]=1)=[O:7])[CH3:10]
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1cc(CN)nc(OC)c1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)nc(OC)c1
Reaction time: 0.25 h
Yield: 29.5 %

Procedure:
6.67 g (31.7 mmol) of ethyl 2-aminomethyl-6-methoxyisonicotinate (20d) were dissolved in 175 ml of toluene and treated at RT with 8.93 g (281.3 mmol) of fluoren-9-ylmethyloxycarbonyl isothiocyanate. After 15 minutes, the resulting precipitate was filtered off and dried at 50° C., 4.6 g of the title compound being isolated. The filtrate was concentrated, and the residue was taken up in DCM and washed three times with water. The organic phase was dried with MgSO4 and concentrated. The crude product thus obtained was chromatographed on silica gel (heptane/ethyl acetate 90:10→75:25), it being possible to isolate a further 8.1 g of the title compound.
Reaction SMILES: [CH2:1]1[C@@H:9]2[N:4]([C:5](=[O:11])[CH2:6][C:7](=O)[CH2:8]2)[CH2:3][CH2:2]1.[NH:12]1[CH2:16][CH2:15][CH2:14][CH2:13]1>C(O)C>[NH:4]1[CH2:9][CH2:1][CH2:2][CH2:3]1.[N:12]1([C:7]2[CH2:8][C@H:9]3[N:4]([CH2:3][CH2:2][CH2:1]3)[C:5](=[O:11])[CH:6]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CC(=O)N2CCC[C@H]2C1
Solvent: C1CCNC1
Solvent: CCO
Product: O=C1C=C(N2CCCC2)C[C@@H]2CCCN12
Reaction time: 0.08 h
Yield: 204.1 %

Procedure:
(S)-1,2,3,5,6,7,8,8a-octahydroindolizin-5,7-dione (117 mg (0.76 mmol), prepared as described in 3)) was dissolved in ethanol (1.2 ml). To the solution was added pyrrolidine (128 μl, 1.53 mmol), and the resulting mixture was allowed to stand at room temperature for 5 minutes. At the end of this time, the reaction mixture was concentrated by distillation under reduced pressure to remove solvents and any excess of pyrrolidine, to give the title compound (160 mg) as a light yellow powder (yield quantitative).
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1([CH2:19][O:20][C:21]([NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C:26](O)=[O:27])=[O:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C.[NH2:44][C:45]1[S:49][C:48]([SH:50])=[N:47][N:46]=1>C1COCC1>[C:13]1([CH2:19][O:20][C:21](=[O:22])[NH:23][C@@H:24]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:25][C:26]([NH:44][C:45]2[S:49][C:48](=[S:50])[NH:47][N:46]=2)=[O:27])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1nnc(S)s1
Reactant: O=C(O)C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=C(C[C@@H](NC(=O)OCc1ccccc1)c1ccccc1)Nc1n[nH]c(=S)s1
Reaction time: 0.5 h
Yield: 14.5 %

Procedure:
Carbonyldiimidazole (0.879 g, 5.42 mmol) is added to a solution of (R)-β-[[(phenylmethoxy)carbonyl]amino]benzenepropanoic acid (1.08 g, 3.62 mmol) in 25 mL THF under N2 at room temperature and allowed to stir for 0.5 hours. Diisopropylethylamine (0.63 mL, 3.6 mmol) and 5-amino-1,3,4-thiadiazole-2-thiol (0.482 g, 3.62 mmol) are added and the reaction is stirred at ambient temperature for 18 hours. The reaction is concentrated in vacuo, diluted with 50 mL CH2Cl2, and washed with (3×25 mL) 1 M citric acid. The organic phase is dried (Na2SO4), combined with the precipitate that formed in the aqueous phase, absorbed onto silica gel and chromatographed (2-5% MeOH/CH2 Cl2). The precipitate which formed in the fractions containing product is collected and dried to afford 0.217 g product as white needles.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:16][CH:15]=2)[C:7](=[O:12])[CH:8]=[C:9]([CH3:11])[N:10]=1)[CH2:2][CH2:3][CH3:4].[Br:28]Br>C(O)(=O)C.C(OCC)(=O)C>[Br:28][C:8]1[C:7](=[O:12])[N:6]([CH2:13][C:14]2[CH:15]=[CH:16][C:17]([C:20]3[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:18][CH:19]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:10][C:9]=1[CH3:11]
Reactant: CCCCc1nc(C)cc(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: BrBr
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 70 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of 4′-[(2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.8 g) in acetic acid (40 mL) was added bromine (0.77 mL), and the mixture was stirred at 70° C. for 2 hr. The reaction mixture was allowed to cool to room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate 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 to give the title compound (1.96 g, 88%) as a colorless solid.
Reaction SMILES: [CH2:1]([C:7]1[S:11][C:10]([C:12]([OH:14])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:15]([O:21][C:22]1[CH:28]=[CH:27][C:25](O)=[C:24]([C:29]#[N:30])[C:23]=1[C:31]#[N:32])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20].C1(N=C=NC2CCCCC2)CCCCC1.N1(C2C=CC=CN=2)CCCC1>C1COCC1>[CH2:1]([C:7]1[S:11][C:10]([C:12]([O:14][C:25]2[CH:27]=[CH:28][C:22]([O:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[C:23]([C:31]#[N:32])[C:24]=2[C:29]#[N:30])=[O:13])=[CH:9][CH:8]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(O)c(C#N)c1C#N
Reactant: CCCCCCc1ccc(C(=O)O)s1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: c1ccc(N2CCCC2)nc1
Solvent: C1CCOC1
Product: CCCCCCOc1ccc(OC(=O)c2ccc(CCCCCC)s2)c(C#N)c1C#N
Yield: 53.2 %

Procedure:
0.50 g (2.36 mM) of 5-hexylthiophene-2-carboxylic acid (M.W.: 212), 0.58 g (2.36 mM) of 2,3-dicyanohydroquinone monohexyl ether (M.W.: 244) and 20 ml of THF were mixed and stirred. To the mixture, 0.49 g (2.36 mM) of dicyclohexylcarbodiimide (M.W.: 206) and 0.05 g of pyrrolidinopyridine were added, followed by stirring overnight at room temperature. After the reaction, the reaction mixture was subjected to filtration and the filtrate was subjected to distillation to obtain a crude product. The crude product was purified by silica gel column chromatography with the use of benzene and recrystallized from ethanol to obtain 0.55 g of an objective product (yield: 53.4%).
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7](Cl)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]([CH3:16])[CH3:15])[N:4]=1)[CH3:2].[CH:17]1([SH:23])[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>C(N(CC)CC)C>[CH2:1]([C:3]1[N:8]=[C:7]([S:23][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:6]([N+:10]([O-:12])=[O:11])=[C:5]([NH:13][CH:14]([CH3:16])[CH3:15])[N:4]=1)[CH3:2]
Reactant: SC1CCCCC1
Reactant: CCc1nc(Cl)c([N+](=O)[O-])c(NC(C)C)n1
Solvent: CCN(CC)CC
Product: CCc1nc(NC(C)C)c([N+](=O)[O-])c(SC2CCCCC2)n1
Yield: 74.8 %

Procedure:
12.1 g (50 m-moles) of 2-ethyl-4-chloro-5-nitro-6-isopropylamino-pyrimidine (vide Ex. 9a) are reacted with 7.0 g (60 m-moles) of cyclohexylmercaptan and 6.1 g (60 m-moles) of triethylamine to yield 12.0 g of 2-ethyl-4-cyclohexylthio-5-nitro-6-isopropylamino-pyrimidine of m.p. 69°-71° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9]C)=O)=[CH:5][CH:4]=1.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][C:22]#[N:23])=[CH:17][CH:16]=1.[Li+].CC([N-]C(C)C)C>C1COCC1>[NH2:23][C:22]1[C:5]2[C:6](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:7](=[O:9])[C:21]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COc1ccc(CC#N)cc1
Reactant: COC(=O)c1ccc(OC)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2=C(N)c3cc(OC)ccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65 %

Procedure:
A mixture of methyl 4-methoxybenzoate (1.47 g, 7.47 mmole) and 4-methoxy phenylacetonitrile (1.00 g, 6.79 mmole) in dry THF (15 mL) was slowly added to 20 ml of 2.0 M of LDA at −10° C. The mixture was gradually allowed to warm to room temperature and left to stir overnight. The reaction was quenched with water and most of the THF was removed via vacuum. The crude aminoindenone was then filtered, dried and recrystallized from isopropanol to give a red orange solid (65% yield, m.p. 213° C.); MS m/e 281 (M+)+.
Reaction SMILES: [CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](Cl)=[O:19])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].N1C=CC=CC=1.[CH3:29][NH:30][O:31][CH3:32]>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:22]=[CH:21][C:7]([CH2:8][CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:19])[N:30]([O:31][CH3:32])[CH3:29])=[CH:13][CH:12]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(CCOc2ccc(NC(=O)Cl)cc2)cc1
Reactant: CNOC
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: CON(C)C(=O)Nc1ccc(OCCc2ccc(C(C)C)cc2)cc1
Temperature: 0 °C
Yield: 42 %

Procedure:
Into a solution of 10.6 g of 4-(4-isopropylphenethyloxy)phenylcarbamyl chloride in 200 ml of toluene are added 4 ml of pyridine and a solution of 2.5 g of N,O-dimethylhydroxylamine in 50 ml of toluene at a temperature below 20° C. The mixture is heated under reflux for 4 hours. The reaction mixture is then poured into ice water, and the separated organic layer is washed with dilute hydrochloric acid, thoroughly washed with water and dried over anhydrous sodium sulfate. The solvent is removed under reduced pressure, and the crude crystals are recrystallized from ethanol to obtain 4.8 g of N'-[4-(4-isopropylphenethyloxy)phenyl]-N-methoxy-N-methylurea as white needles, M.P. 81°-82° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][OH:8])[O:3][CH2:2]1.C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:8][CH2:7][CH:4]1[CH2:5][CH2:6][O:1][CH2:2][O:3]1)(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: OCC1CCOCO1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCC1CCOCO1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
A stirred solution of 16.2 grams (0.137 mole) of 1,3-dioxan-4-ylmethanol and 16.7 grams (0.165 mole) of triethylamine in 250 mL of methylene chloride was cooled to about -20° C., and a solution of 17.3 grams (0.151 mole) of methanesulfonyl chloride in about 25 mL of methylene chloride was added dropwise. Upon completion of addition the reaction mixture was allowed to warm to ambient temperature as it stirred for one hour. The reaction mixture was then washed with water and dried with magnesium sulfate. The mixture was filtered and concentrated under reduced pressure to a residue. The residue was purified using column chromatography on silica gel, yielding 18.1 grams of the subject compound. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:10]([C:12]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:21]=1[NH:20][C:19](=[O:22])[CH:18]=[CH:17]2)[CH3:11]>C(=S)=S>[Cl:1][CH2:2][C:3]([C:14]1[CH:15]=[C:16]2[C:21](=[C:12]([CH2:10][CH3:11])[CH:13]=1)[NH:20][C:19](=[O:22])[CH:18]=[CH:17]2)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: CCc1cccc2ccc(=O)[nH]c12
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: CCc1cc(C(=O)CCl)cc2ccc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 62 ml of chloroacetyl chloride in 600 ml of carbon disulfide were added, with ice-cooling, 173 g of aluminum chloride and 44 g of 8-ethylcarbostyril in this order. The mixture was refluxed for 6 hours. The reaction mixture was subjected to distillation to remove carbon disulfide. The residue was poured into ice water. The mixture was stirred at room temperature overnight. The insoluble portion was collected by filtration, washed with water and dried to obtain 55 g of 6-chloroacetyl-8-ethylcarbostyril as a brown powder.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.Cl.[CH3:24][O:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)=[CH:28][CH:27]=1.C(O)C.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:35]2[CH2:34][CH2:33][N:32]([C:29]3[CH:28]=[CH:27][C:26]([O:25][CH3:24])=[CH:31][CH:30]=3)[CH2:37][CH2:36]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Reactant: COc1ccc(N2CCNCC2)cc1
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CC(C)=O
Solvent: CCO
Product: COc1ccc(N2CCN(CCCOc3cc4c5c(c(=O)oc4cc3OC)CCC5)CC2)cc1
Yield: 45 %

Procedure:
Method A (60 h at 40° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(4-methoxyphenyl)piperazine dihydrochloride; yield 45%; fusion point 155°-156° C. (from ethanol). Fumarate: method E; yield 96%; fusion point 207°-210° C. (from acetone).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3I)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C@@H:22]12[CH2:28][N:27](C(OC(C)(C)C)=O)[C@@H:26]1[CH2:25][NH:24][CH2:23]2.[ClH:36]>C(O)(C)C>[ClH:36].[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:12]=[N:13][C:14]3[C:19]([CH:20]=2)=[CH:18][CH:17]=[CH:16][C:15]=3[N:24]2[CH2:25][C@@H:26]3[C@@H:22]([CH2:28][NH2+:27]3)[CH2:23]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CNC[C@H]21
Reactant: O=S(=O)(c1cccc(F)c1)c1cnc2c(I)cccc2c1
Agent: Cl
Solvent: CC(C)O
Product: O=S(=O)(c1cccc(F)c1)c1cnc2c(N3C[C@@H]4C[NH2+][C@@H]4C3)cccc2c1

Procedure:
0.081 g of (1S,5S)-3-(3-(3-fluorophenylsulfonyl)quinolin-8-yl)-3-aza-6-azoniabicyclo[3.2.0]heptane hydrochloride were prepared by analogy to the methods of Examples 27 and 28 by coupling of 3-(3-fluorophenylsulfonyl)-8-iodoquinoline with (1R,5S)-tert-butyl 3,6-diazabicyclo[3.2.0]heptane-6-carboxylate and subsequent deprotection of the tert-butyl-oxycarbonyl derivative with HCl in isopropanol.
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]=1[C:16]([OH:18])=O>>[Cl:5][C:6]1[CH:15]=[CH:14][C:9]2[O:10][CH2:11][CH2:12][O:13][C:8]=2[C:7]=1[C:16]([Cl:3])=[O:18]
Reactant: O=C(O)c1c(Cl)ccc2c1OCCO2
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1c(Cl)ccc2c1OCCO2
Yield: 93 %

Procedure:
56 ml of thionyl chloride, 28 g of 6-chloro-1,4-benzodioxane-5-carboxylic acid were introduced into a 250 ml balloon flask provided with a stirrer, a condenser and a thermometer. The mixture was heated at the reflux temperature for 30 minutes. The excess of thionyl chloride was removed by distillation under reduced pressure. 28.5 g of 6-chloro-1,4-benzodioxane-5-carbonyl chloride were obtained (M.P.: 50° C.; yield: 93%).
Reaction SMILES: C1(C)C=CC(S(O[C:11]2[C:12](Br)=[CH:13][CH:14]=[C:15]3[C:20]=2[N:19]=[CH:18][CH:17]=[CH:16]3)(=O)=O)=CC=1.[O:23]1[CH:27]=[CH:26][CH:25]=[CH:24]1.C([Li])CCC.O>C1COCC1>[O:23]1[CH:27]2[C:11]3[C:12](=[CH:13][CH:14]=[C:15]4[C:20]=3[N:19]=[CH:18][CH:17]=[CH:16]4)[CH:24]1[CH:25]=[CH:26]2
Reactant: Cc1ccc(S(=O)(=O)Oc2c(Br)ccc3cccnc23)cc1
Reactant: c1ccoc1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: C1=CC2OC1c1ccc3cccnc3c12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A stirred solution of the tosyl ester (4a) (5.00 g, 13.2 mmol) in dry THF (150 mL) and freshly distilled furan (24.3 mL, 22.6 g, 0.33 mol, 25 equiv.) cooled at −78° C. under nitrogen was treated dropwise with n-butyllithium in hexanes (2.5 M, 5.55 mL, 13.8 mmol, 1.05 equiv.). The reaction was stirred for 1 hr at −78° C. and then allowed to warm to room temperature over 3 hours. The reaction mixture was treated with water (5 mL) and then heated under reduced pressure to remove most of the THF. This mixture was then diluted with water (150 mL), extracted with dichloromethane (3×100 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a crude brown solid (2.31 g). This material was dissolved in the minimum amount of dichloromethane/petroleum and absorbed onto a pad of neutral alumina. Gradient elution with ethyl acetate/petroleum ether afforded the product, which was recrystallized from dichloromethane/ether/petroleum ether to afford the endoxide (7,10-epoxy-7,10-dihydrobenzo[h]quinoline (6) as cream colored crystals (1.07 g, 42%). 1H NMR (CDCl3, 300 MHz) δ ppm 8.88 (dd, 1H, J=4.1, 1.7 Hz); 8.14 (dd, 1H, J=8.4, 1.7 Hz); 7.60 and 7.57 (ABq, 2H, J=7.8 Hz); 7.27-7.33 (m, 2H); 7.21 (dd, 1H, J=5.5, 1.8 Hz); 6.54 (bs, 1H); 5.95 (m, 1H).
Reaction SMILES: [CH2:1]([N:3]([S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:18])=[O:17])[C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13](=[S:15])[NH2:14])=[CH:9]2)[CH3:2].Br[CH:25]([CH:28]=O)[CH:26]=[O:27].CN(C)C(=O)C>O>[CH2:1]([N:3]([C:4]1[CH:5]=[CH:6][CH:7]=[C:8]2[C:12]=1[NH:11][C:10]([C:13]1[S:15][C:25]([CH2:26][OH:27])=[CH:28][N:14]=1)=[CH:9]2)[S:16]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)(=[O:17])=[O:18])[CH3:2]
Reactant: O=CC(Br)C=O
Reactant: CCN(c1cccc2cc(C(N)=S)[nH]c12)S(=O)(=O)c1cccs1
Solvent: O
Solvent: CC(=O)N(C)C
Product: CCN(c1cccc2cc(-c3ncc(CO)s3)[nH]c12)S(=O)(=O)c1cccs1
Temperature: 95 °C
Reaction time: 1.5 h
Yield: 17 %

Procedure:
A mixture of 7-[ethyl(2-thienylsulfonyl)amino]-1H-indole-2-carbothioamide (4.10 g), bromomalonaldehyde (3.55 g) and N,N-dimethylacetamide (30 ml) was stirred at 95° C. for 1.5 hr. Water was added to the reaction mixture, and the obtained precipitate was collected by filtration and dissolved in tetrahydrofuran (30 ml) and methanol (30 ml). After cooling with an ice bath, sodium borohydride (508 mg) was added, and the mixture was stirred at room temperature for 16 hr. The reaction mixture was concentrated, and diluted with ethyl acetate-tetrahydrofuran mixture. The organic layer was washed successively with aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, and filtrated, and the filtrate was concentrated. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (2:1) mixture to give the title compound (800 mg, yield 17%) as a solid.
Reaction SMILES: [F:1][C:2]1[C:31]([F:32])=[CH:30][CH:29]=[CH:28][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[N:17][C:18]=3[NH2:20])[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][NH:23]3)[N:12]=2)=[C:7]([F:27])[CH:6]=1.[C:33]([CH2:35][C:36](O)=[O:37])#[N:34]>C(Cl)Cl.O>[NH2:20][C:18]1[N:17]=[CH:16][N:15]=[C:14]2[N:13]([CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][N:23]3[C:36](=[O:37])[CH2:35][C:33]#[N:34])[N:12]=[C:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][C:3]4[CH:28]=[CH:29][CH:30]=[C:31]([F:32])[C:2]=4[F:1])=[CH:6][C:7]=3[F:27])[C:19]=12
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3cccc(F)c3F)cc1F)nn2C[C@@H]1CCCN1
Reactant: N#CCC(=O)O
Solvent: O
Solvent: ClCCl
Product: N#CCC(=O)N1CCC[C@H]1Cn1nc(-c2ccc(Oc3cccc(F)c3F)cc2F)c2c(N)ncnc21
Yield: 69.1 %

Procedure:
A solution of 3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1-((S)-pyrrolidin-2-ylmethyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine (2.4 g Crude, 3.65 mmol, 1.00 equiv), 2-cyanoacetic acid (0.47 g, 5.48 mmol, 1.50 equiv), HAW (2.08 g, 5.48 mmol, 1.50 equiv), TEA (2.54 ml, 18.25 mmol, 5.00 equiv) in DCM (40 mL) was stirred overnight at room temperature. The resulting mixture was diluted with water, and extracted with DCM. The DCM layers were combined and washed with brine, dried over Na2SO4 and concentrated. The residue was submitted to flash chromatography (SiO2, PE:EtOAc=2:1 to 1:1) to give 1.28 g (69%) of 3-((S)-2-((4-amino-3-(4-(2,3-difluorophenoxy)-2-fluorophenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)pyrrolidin-1-yl)-3-oxopropanenitrile as a yellow solid.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13](=O)[CH:12](Br)[CH2:11][CH2:10][C:9]=2[N:8](C(OC(C)(C)C)=O)[CH:7]=1)=[O:5])[CH3:2].[C:24]([NH2:27])(=[S:26])[CH3:25]>CO>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:13]3[N:27]=[C:24]([CH3:25])[S:26][C:12]=3[CH2:11][CH2:10][C:9]=2[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cn(C(=O)OC(C)(C)C)c2c1C(=O)C(Br)CC2
Reactant: CC(N)=S
Solvent: CO
Product: CCOC(=O)c1c[nH]c2c1-c1nc(C)sc1CC2
Yield: 34 %

Procedure:
To a solution of 5-bromo-4-oxo-4,5,6,7-tetrahydro-indole 1,3-dicarboxylic acid 1-tert-butyl ester 3-ethyl ester (0.78 mmol) in 10 mL CH3OH is added thioacetamide (1.55 mmol). After stirring under refluxing for 16 hours the solvent is removed in vacuo. The brown oil is chromatographed using EtOAc 1: hexane 1, followed by 5% MeOH in CH2Cl2 as mobile phases to yield 2-methyl-5,6-dihydro-4H-thiazolo[4,5-e]indole-8-carboxylic acid ethyl ester as a white solid (34%). 1H NMR (DMSO-d6) 1.27 (t, 3H), 2.60 (s, 3H), 2.78(t, 2H), 2.96 (t, 2H), 4.19 (q, 2H), 7.21 (s, 1H), 11.44 (s, 1H).