Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CS(O[CH2:6][CH2:7][F:8])(=O)=O.[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH2:38][N:39]6[CH2:44][CH2:43]N(CCF)C[CH2:40]6)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:48])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1>>[CH:9]1([NH:12][C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][C:23]3[CH:28]=[CH:27][N:26]=[C:25]4[CH:29]=[C:30]([C:32]5[CH:37]=[CH:36][C:35]([CH2:38][N:39]6[CH2:44][CH2:43][CH:9]([N:12]([CH2:6][CH2:7][F:8])[CH3:13])[CH2:10][CH2:40]6)=[CH:34][N:33]=5)[S:31][C:24]=34)=[C:18]([F:48])[CH:17]=2)=[O:14])[CH2:11][CH2:10]1
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(CCF)CC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: CS(=O)(=O)OCCF
Product: CN(CCF)C1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1

Procedure:
Compound 421 (example 269) was prepared in one step by reacting the amine precursor 401 (table 31) with compound 419, similarly to compound 420 (example 268, scheme 77). 1H NMR (400 MHz, DMSO-d6) δ (ppm): 8.73 (s, 1H), 8.54 (d, J=1.6 Hz, 1H), 8.52 (d, J=5.6 Hz, 1H), 8.33 (s, 1H), 8.24 (d, J=8.0 Hz, 1H), 7.85 (dd, J=8.0, 2.0 Hz, 1H), 7.73 (dd, J=13.6, 2.4 Hz, 1H), 7.38 (t, J=9.0 Hz, 1H), 7.22-7.18 (m, 1H), 6.64 (d, J=5.2 Hz, 1H), 6.56 (bd, J=2.8 Hz, 1H), 4.51 (t, J=5.2 Hz, 1H), 4.39 (t, J=5.2 Hz, 1H), 3.54 (s, 2H), 2.90-2.82 (m, 2H), 2.77-2.63 (m, 2H), 2.59-2.50 (m, 1H), 2.40-2.30 (m, 1H), 2.22 (s, 3H), 2.02-1.91 (m, 2H), 1.69-1.61 (m, 2H), 1.50-1.38 (m, 2H), 0.68-0.62 (m, 2H), 0.45-0.40 (m, 2H). MS (m/z): 593.59 (M+H).
Reaction SMILES: [F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[NH:6]2.FC(F)(F)S(O[CH2:23][C:24]([F:27])([F:26])[F:25])(=O)=O.C(=O)([O-])[O-].[K+].[K+].CN(C=O)C>O>[F:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:16])([CH3:15])[C:5](=[O:14])[N:6]2[CH2:23][C:24]([F:27])([F:26])[F:25]
Reactant: CC1(C)C(=O)Nc2ccc([N+](=O)[O-])c(F)c21
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC1(C)C(=O)N(CC(F)(F)F)c2ccc([N+](=O)[O-])c(F)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 1610.7 %

Procedure:
A suspension of 4-fluoro-3,3-dimethyl-5-nitro-1,3-dihydro-2H-indol-2-one (0.10 g), 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.16 g), potassium carbonate (0.12 g) and DMF (2 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (2.2 g).
Reaction SMILES: [F:1][C:2]([F:19])([CH:16]([F:18])[F:17])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][C:14]=1C)S([O-])(=O)=O.[OH:20][C:21]1C=C(C=CC=1)C=O.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:19][C:2]([F:1])([CH:16]([F:17])[F:18])[CH2:3][O:4][C:5]1[CH:6]=[C:7]([CH:12]=[CH:13][CH:14]=1)[CH:21]=[O:20]
Reactant: O=Cc1cccc(O)c1
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1OCC(F)(F)C(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=Cc1cccc(OCC(F)(F)C(F)F)c1
Temperature: 20 °C

Procedure:
Combine 3-(2,2,3,3-tetrafluoropropoxy)tosylate (5.72 g, 17.2 mmol), 3-hydroxybenzaldehyde (2.44 g, 20.0 mmol), dimethylformamide (36 ml) and powdered potassium carbonate (3.03 g) and heat at 110° C. for 10 h. Cool to 20° C. Pass through a bed of aluminium-oxide-90 (57.2 g, 70–230 mesh, grade II–III, Brockmann: Merck # 1.01097) and elute with toluene (120 ml). Wash the eluted organic phase with 1N HCl (36 ml) and then water. Evaporate the organic layer under reduced pressure to give the title compound.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6](Cl)(=[O:8])=[O:7].[C:10]([NH2:14])([CH3:13])([CH3:12])[CH3:11].C1(C)C=CC=CC=1>C(Cl)(Cl)Cl>[C:10]([NH:14][S:6]([C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:8])=[O:7])([CH3:13])([CH3:12])[CH3:11]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC(C)(C)N
Solvent: Cc1ccccc1
Solvent: ClC(Cl)Cl
Product: CC(C)(C)NS(=O)(=O)c1cccs1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Thiophene-2-sulfonyl chloride (15 g, 0.082 mol) was dissolved in CHCl3 (200 mL) under N2 atmosphere and then cooled to 0° C. tert-Butylamine (25.9 mL, 0.246 mol) dissolved in CHCl3 (50 mL) was then added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at room temperature and then at reflux for 10 min. Toluene (700 mL) was added and the organic phase was washed with water (3×50 mL), dried, and concentrated in vacuo. The sub-title product was used without further purification in the next step.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Br:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH3:12][CH:13]1[CH2:18][NH:17][C:16](=O)[CH2:15][N:14]1[C:20]([O:22][CH2:23][CH:24]1[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:21].P(Cl)(Cl)(Cl)=O>O1CCOCC1>[Br:11][C:9]1[CH:10]=[C:2]2[C:3]([C:4](=[O:6])[N:17]3[CH2:18][CH:13]([CH3:12])[N:14]([C:20]([O:22][CH2:23][CH:24]4[C:36]5[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=5[C:30]5[C:25]4=[CH:26][CH:27]=[CH:28][CH:29]=5)=[O:21])[CH2:15][C:16]3=[N:1]2)=[CH:7][CH:8]=1
Reactant: CC1CNC(=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: Nc1cc(Br)ccc1C(=O)O
Solvent: C1COCCO1
Solvent: O=P(Cl)(Cl)Cl
Product: CC1Cn2c(nc3cc(Br)ccc3c2=O)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C

Procedure:
A solution of 2-amino-4-bromobenzoic acid (2.8 g, 13.1 mmol, 1.1 equiv), (9H-fluoren-9-yl)methyl 2-methyl-5-oxopiperazine-1-carboxylate (4 g, 11.9 mmol, 1 equiv), and phosphoryl trichloride (4 mL) in 1,4-dioxane (100 mL) was stirred at 80° C. for two hours. After it was cooled to room temperature, the reaction mixture was quenched with water and extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the residue was purified by silica gel chromatography to give the desired product.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:20]1[CH:25]=[CH:24][CH2:23][CH2:22][CH2:21]1>C(Cl)Cl>[O:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH:21]1[N:1]1[CH:5]=[C:4]([C:6]#[N:7])[CH:3]=[N:2]1
Reactant: C1=COCCC1
Reactant: N#Cc1cn[nH]c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: N#Cc1cnn(C2CCCCO2)c1
Temperature: 3 °C
Reaction time: 8 h

Procedure:
The reaction was carried out in a 3 liter three-necked flask with internal thermometer under argon. 50 g (537 mmol) of 1H-pyrazole-4-carbonitrile were suspended in 1.66 liter of methylene chloride and, after 3 h, cooled to 3° C. using an ice bath. At this temperature, 10.2 g (53.7 mmol) of 4-toluenesulphonic acid monohydrate were added. At 3° to 6° C., 58.8 ml (54.2 g, 644 mmol) of 3,4 dihydro-2H-pyran were then added dropwise over a period of 30 min. The reaction was then stirred at RT overnight. The clear reaction solution was then washed with 2 M aqueous sodium carbonate solution and with water, dried over magnesium sulphate, filtered and concentrated. The residue was triturated with cyclohexane and the solid obtained was filtered off with suction and dried in a vacuum drying cabinet at 30° C. for 4 h. This gave 91.8 g (96% of theory) of the title compound as a light-yellow powder.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:5][O:6][C:7]=1[CH3:8])#[CH:2].[Cl:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][N:17]=1.C(N(CC)CC)C>CN(C)C=O.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>[Cl:15][C:16]1[CH:21]=[C:20]([C:2]#[C:1][C:3]2[C:4]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:5][O:6][C:7]=2[CH3:8])[CH:19]=[CH:18][N:17]=1
Reactant: C#Cc1c(-c2ccccc2)noc1C
Reactant: Clc1cc(I)ccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc(-c2ccccc2)c1C#Cc1ccnc(Cl)c1
Temperature: 90 °C
Reaction time: 1.5 h
Yield: 90.5 %

Procedure:
A mixture of 4-ethynyl-5-methyl-3-phenyl-isoxazole (110 mg, 0.60 mmol), 2-chloro-4-iodopyridine (172 mg, 0.72 mmol), triethylamine (209 μl, 1.50 mmol) and bis(triphenylphosphine)palladium(II) chloride (13 mg, 0.02 mmol) in N,N-dimethylformamide (1.2 mL) was evaporated and flushed with argon. Cuprous iodide (2 mg, 0.01 mmol) was added and the reaction mixture was stirred for 1.5 h at 90° C. before it was cooled to ambient temperature and separated between aqueous sodium hydroxide (1 M, 20 mL) and ethyl acetate (30 mL). The aqueous layer was extracted with ethyl acetate (30 mL) and the combined organic layers were washed with aqueous sodium hydroxide (1 M, 20 mL), dried over sodium sulfate and concentrated. Purification by chromatography (SiO2, heptane:ethyl acetate=100:0 to 80:20) afforded the title compound (160 mg, 91%) as a colorless oil. MS: m/e=295.0/297.2 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[C:14]2[C:5]([O:6][C:7]3[C:8]([F:24])=[CH:9][C:10]([O:22][CH3:23])=[CH:11][C:12]=3[C@@:13]32[CH2:20][CH2:19][S:18][C:17]([NH2:21])=[N:16]3)=[CH:4][CH:3]=1.[C:25](=[O:28])(O)[O-:26].[Na+]>O1CCOCC1.C(OCC)(=O)C>[C:12]([O:26][C:25](=[O:28])[NH:21][C:17]1[S:18][CH2:19][CH2:20][C@@:13]2([N:16]=1)[C:12]1[CH:11]=[C:10]([O:22][CH3:23])[CH:9]=[C:8]([F:24])[C:7]=1[O:6][C:5]1[C:14]2=[CH:15][C:2]([Br:1])=[CH:3][CH:4]=1)([CH3:13])([CH3:11])[CH3:7]
Reactant: O=C([O-])O
Reactant: COc1cc(F)c2c(c1)[C@]1(CCSC(N)=N1)c1cc(Br)ccc1O2
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: COc1cc(F)c2c(c1)[C@]1(CCSC(NC(=O)OC(C)(C)C)=N1)c1cc(Br)ccc1O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
(S)-7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-amine (400 mg, 0.977 mmol) was dissolved in dioxane (48870. Saturated aqueous sodium bicarbonate solution (5 mL) was added, followed by addition of Boc-anhydride (681 μl, 2.93 mmol). The reaction mixture was stirred at room temperature for 2 hrs. Then it was diluted with ethyl acetate and washed with water. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were dried with MgSO4, filtered, and concentrated. The material was purified through column chromatography eluting with a gradient of 45% to 60% to 75% EtOAc in Hexane to afford (S)-tert-butyl(7′-bromo-4′-fluoro-2′-methoxy-5,6-dihydrospiro[[1,3]thiazine-4,9′-xanthen]-2-yl)carbamate (490 mg, 0.962 mmol, 98% yield) as a yellow solid.
Reaction SMILES: [N:1]([C@H:4]1[C:12]2[C:7](=[CH:8][C:9]([Br:13])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1)=[N+]=[N-].O.O.Cl[Sn]Cl>CO>[Br:13][C:9]1[CH:8]=[C:7]2[C:12](=[CH:11][CH:10]=1)[C@H:4]([NH2:1])[CH2:5][CH2:6]2
Reactant: [N-]=[N+]=N[C@@H]1CCc2cc(Br)ccc21
Agent: Cl[Sn]Cl
Solvent: CO
Solvent: O
Product: N[C@@H]1CCc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.2 %

Procedure:
A solution of (R)-1-azido-5-bromo-indane (14.0 g, 58.8 mmol) was dissolved in methanol (150 mL) and was treated with SnCl2.2H2O (23.0 g, 106 mmol). The mixture was stirred at room temperature overnight (TLC indicated no starting material) and was concentrated to dryness. The resulting residue was treated with 2N aqueous NaOH (300 mL) and was extracted with EtOAc (2×300 mL). The combined organic extracts were washed with 1N HCl followed by water (2 L). The pH of the combined aqueous layers was adjusted to 11 with cold saturated NaOH solution and the mixture was extracted with EtOAc (2×300 mL). The combined organic extracts were dried over Na2SO4, filtered and concentrated to give 10.0 g (80%) of (1R)-5-bromoindan-1-amine as a dark yellow oil which solidified upon refrigeration. MS (ES+) 213.9 (M+H)+. 1H NMR (CDCl3) δ 1.70-1.75 (m, 1H), 2.40-2.45 (m, 1H), 2.77-2.82 (m, 1H), 2.93-2.97 (m, 1H), 4.28-4.33 (m, 1H), 7.18-7.23 (m, 1H), 7.36-7.41 (m, 2H).
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].Cl.[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:18]3[N:23]=[CH:22][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]5)[CH:28]=4)=[CH:20][N:19]=3)[CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:8]1>CN(C=O)C.C(Cl)Cl>[CH3:6][N:7]1[CH:11]=[C:10]([C:12]2[CH:13]=[C:14]([C:18]3[N:19]=[CH:20][C:21]([C:24]4[CH:25]=[N:26][N:27]([CH:29]5[CH2:34][CH2:33][N:32]([C:1](=[O:3])[CH3:2])[CH2:31][CH2:30]5)[CH:28]=4)=[CH:22][N:23]=3)[CH:15]=[CH:16][CH:17]=2)[CH:9]=[N:8]1
Reactant: Cn1cc(-c2cccc(-c3ncc(-c4cnn(C5CCNCC5)c4)cn3)c2)cn1
Reactant: CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(n2cc(-c3cnc(-c4cccc(-c5cnn(C)c5)c4)nc3)cn2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.8 %

Procedure:
Acetyl chloride (222 μl; 3.1 mmol; 2.0 eq.) was added to a solution of 2-[3-(1-Methyl-1H-pyrazol-4-yl)-phenyl]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyrimidine hydrochloride (example 1, 655 mg; 1.55 mmol; 1.0 eq.) and TEA (503 μl; 3.88 mmol; 2.5 eq.) in dry DMF (12 mL) and the reaction mixture was stirred at RT and under nitrogen for 2 h. The reaction mixture was diluted with DCM and washed with water. Organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by flash chromatography on silica (DCM: MeOH, gradient 100:0 to 80:20) afforded the title compound as a white solid (370 mg, 56%). 1H NMR (300 MHz, DMSO-d6) δ 9.16 (s, 2H), 8.58-8.50 (m, 2H), 8.26 (s, 1H), 8.21 (dt, J=8.0, 1.5 Hz, 1H), 8.15 (s, 1H), 7.92 (s, 1H), 7.71 (dt, J=8.0, 1.5 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 4.58-4.43 (m, 2H), 4.01-3.83 (m, 4H), 3.29-3.17 (m, 1H), 2.74 (dd, J=14.1, 9.2 Hz, 1H), 2.19-2.02 (m, 5H), 1.98-1.69 (m, 2H). HPLC (Condition A): Rt 2.90 min (purity 98.0%). MS (ESI+): 428.36.
Reaction SMILES: Br[CH:2]([CH2:9][CH3:10])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5].[CH3:11][O:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([CH2:36][CH3:37])([C:28]3[CH:33]=[CH:32][C:31]([OH:34])=[C:30]([CH3:35])[CH:29]=3)[CH2:26][CH3:27])[CH:21]=2)[CH:16]=1)=[O:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.C(Cl)Cl>[CH3:11][O:12][C:13]([C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:25]([C:28]3[CH:33]=[CH:32][C:31]([O:34][CH:2]([CH2:9][CH3:10])[C:3](=[O:8])[C:4]([CH3:7])([CH3:6])[CH3:5])=[C:30]([CH3:35])[CH:29]=3)([CH2:36][CH3:37])[CH2:26][CH3:27])[CH:21]=2)[CH:16]=1)=[O:14]
Reactant: CCC(Br)C(=O)C(C)(C)C
Reactant: CCC(CC)(c1ccc(O)c(C)c1)c1ccc2cc(C(=O)OC)ccc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCC(Oc1ccc(C(CC)(CC)c2ccc3cc(C(=O)OC)ccc3c2)cc1C)C(=O)C(C)(C)C
Temperature: 45 °C
Reaction time: 62 h
Yield: 87.6 %

Procedure:
Add 4-bromo-2,2-dimethylhexane-3-one (660 mg, 3.187 mmol) to a mixture of 6-[1-ethyl-1-(4-hydroxy-3-methylphenyl)propyl]naphthalene-2-carboxylic acid methyl ester (1.1 g, 3.035 mmol), and K2CO3 (629 mg, 4.55 mmol) in DMF (10 ml). Maintain the reaction mixture 45° C. for 14 h. Add an additional amount of 4-bromo-2,2-dimethylhexane-3-one (314 mg, 1.52 mmol) and maintain the mixture at 60° C. while stirring for 62 h. Cool the reaction mixture and dilute it with CH2Cl2, filter, and concentrate in vacuo. Chromatograph the resulting residue (CH2Cl2to 1% EtOAc/CH2Cl2) to give the title compound as a colorless viscous oil (1.299 g, 88%). 1NMR (400 MHz, CDCl3) δ ppm: 0.62 (t, J=7.2 Hz, 6H), 1.01 (t, J=7.6 Hz, 3H), 1.16 (s, 9H), 1.88 (m, 2H), 2.16 (m, 4H), 2.19 (s, 3H), 3.97 (s, 3H), 4.86 (dd, J=5.2, 1.6 Hz, 1H), 6.53 (d, J=8.4 Hz, 1H), 6.88 (m, 2H), 7.14 (dd, J=7.2, 1.6 Hz, 1H), 7.73 (d, J=8.8 Hz, 1H), 7.82 (s, 1H), 7.85 (d, J=8.8 Hz, 1H), 8.04 (dd, J=6.4, 2.0 Hz, 1H), 8.52 (s, 1H). High Res. ES-MS: 511.2824; calc. for C32H40O4+Na: 511.2825.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[NH2:27][CH2:28][CH2:29][C:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[NH:32][CH:31]=1>CS(C)=O>[NH:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:30]([CH2:29][CH2:28][NH:27][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31]1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: CS(C)=O
Product: O=C1Cc2c(ccc3c2OC(CNCCc2c[nH]c4ccccc24)CO3)N1
Temperature: 75 °C

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.2 g, 3.2 mmole) and tryptamine (1.5 g, 9.6 mmole) in DMSO (50 ml) were placed in a three-neck flask equipped with a condenser, a thermometer and a nitrogen bubbler immersed into the solution. The reaction mixture was heated at 75° C. for 5 hours, cooled to room temperature and partitioned between water and ethyl acetate. The ethyl acetate layer was separated, dried over anhydrous sodium sulfate, concentrated in vacuum and column chromatographed on silica gel using first ethyl acetate and subsequently 2.5%, 5%, 10% methanol in ethyl acetate as eluants. The free base of the desired product was obtained (0.85 g, 2.3 mmole) as an oil which was dissolved in 50 ml of ethanoldiethyl ether (1/1) solution and treated with 10.3 ml of 0.25 M of fumaric acid in ethanol. Addition of hexane gave 0.30 g of the (S) enantiomer of the title compound as an off-white solid hemi-fumarate, three quarter hydrate, m.p. 175-176° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH:3]=[CH:2]1.[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9]>C(Cl)Cl.CC#N.CC#N.Cl[Pd]Cl>[O:7]=[C:1]1[CH2:6][CH2:5][CH2:4][CH:3]([NH:9][C:8](=[O:18])[O:10][CH2:11][C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:2]1
Reactant: NC(=O)OCc1ccccc1
Reactant: O=C1C=CCCC1
Agent: Cl[Pd]Cl
Solvent: CC#N
Solvent: ClCCl
Product: O=C1CCCC(NC(=O)OCc2ccccc2)C1
Reaction time: 24 h
Yield: 77.6 %

Procedure:
To a solution of 2-cyclohexen-1-one (1.442 g, 15.0 mmol) in anhydrous methylene chloride (15 mL) was added bis(acetonitrile)dichloro-palladium(II) (0.231 g, 1.0 mmol) and benzyl carbamate (1.497 g, 9.9 mmol) and stirred under nitrogen for 24 hrs. The reaction mixture was filtered through a pad of silica gel, washing with ethyl acetate, and concentrated in vacuo. The crude product was purified by silica gel chromatography (20-65% ethyl acetate/hexanes) to give a pale yellow low melting solid (1.9 g). 1H NMR (300 MHz, CDCl3) δ 7.34 (m, 5H), 5.09 (s, 2H), 4.81 (br s, 1H), 3.99 (br s, 1H), 2.73 (m, 1H), 2.36-2.26 (m, 3H), 2.11-1.97 (m, 2H), 1.67-1.64 (m, 2H). ESI m/z: 248.0 (M+H).
Reaction SMILES: [Cl-].[NH3+:2][CH2:3][C@@:4]1([OH:12])[CH:9]2[CH2:10][CH2:11][NH+:6]([CH2:7][CH2:8]2)[CH2:5]1.[Cl-].CCN(C(C)C)C(C)C.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[N:29][C:28]([N:36]=[C:37]=[S:38])=[CH:27]2>CN(C=O)C>[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][C:33]=1[O:34][CH3:35])[CH:30]=[N:29][C:28]([NH:36][C:37]([NH:2][CH2:3][C@@:4]1([OH:12])[CH:9]3[CH2:8][CH2:7][N:6]([CH2:11][CH2:10]3)[CH2:5]1)=[S:38])=[CH:27]2
Reactant: COc1cc2cnc(N=C=S)cc2cc1Cl
Reactant: [NH3+]C[C@]1(O)C[NH+]2CCC1CC2
Agent: [Cl-]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1cc2cnc(NC(=S)NC[C@]3(O)CN4CCC3CC4)cc2cc1Cl
Temperature: 25 °C
Reaction time: 0.58 h

Procedure:
To a stirring suspension of (S)-3-(ammoniomethyl)-3-hydroxy-1-azoniabicyclo[2.2.2]octane chloride (111 mg, 0.484 mmol) in DMF (3 mL) was added Hunig's Base (0.5 mL, 2.86 mmol) and the resulting mixture was stirred at room temperature for 35 minutes. Then was added a suspension of 6-chloro-3-isothiocyanato-7-methoxyisoquinoline (106 mg, 0.423 mmol) in DMF (3 mL) and the reaction mixture was allowed to stir at room temperature overnight. The solvent was evaporated in vacuo and the residue subjected to a silica gel column in 1% NH4OH/9% MeOH/90% CHCl3 to give 140.3 mg (82%) as a white solid, (S)-1-(6-chloro-7-methoxyisoquinolin-3-yl)-3-((3-hydroxyquinuclidin-3-yl)methyl)thiourea. LCMS RT 1.28 min, MH+=407.1, 409.0, 1H NMR (500 MHz, CHLOROFORM-d) δ ppm 11.85 (1H, t, J=5.2 Hz), 9.15 (1H, br. s.), 8.63 (1H, s), 7.76 (1H, s), 6.92 (1H, s), 6.89 (1H, s), 4.14 (1H, dd, J=13.9, 5.6 Hz), 3.99 (2H, s), 3.90 (1H, dd, J=14.0, 5.2 Hz), 3.46 (3H, s), 2.89-3.01 (2H, m), 2.75-2.88 (3H, m), 2.03-2.15 (1H, m), 1.89-1.96 (1H, m), 1.77-1.88 (1H, m), 1.63 (1H, ddd, J=13.4, 6.1, 3.4 Hz), 1.32-1.45 (1H, m).
Reaction SMILES: [C:1](Cl)([Cl:3])=[O:2].[Cl:5][C:6]1[CH:11]=[C:10]([Cl:12])[C:9]([Cl:13])=[CH:8][C:7]=1[OH:14].N1C2C(=CC=CC=2)C=CC=1>ClCCl>[Cl:3][C:1]([O:14][C:7]1[CH:8]=[C:9]([Cl:13])[C:10]([Cl:12])=[CH:11][C:6]=1[Cl:5])=[O:2]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: O=C(Cl)Cl
Solvent: c1ccc2ncccc2c1
Solvent: ClCCl
Product: O=C(Cl)Oc1cc(Cl)c(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
About 7 g of phosgene are passed into a solution of 10.0 g of 2,4,5-trichlorophenol in 50 ml of dichloromethane at 0° C., and the mixture is stirred at 0° C. for 15 min. 7.2 ml of quinoline in 20 ml of dichloromethane are added dropwise over the course of 30 min, and the orange-colored suspension is then stirred in an ice bath for 1 h. Subsequently nitrogen is passed through the suspension for 1 h in order to blow out excess phosgene (absorber tower). The mixture is subsequently filtered, and the filtrate is washed twice with water, dried, again filtered and evaporated to dryness in vacuo. The 4.45 g of oily brownish residue are relatively pure 2,4,5-trichlorophenyl chloroformate, which crystallizes in the refrigerator and can be employed without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([Zn]I)=[CH:8][CH:7]=1)=[O:5])[CH3:2].[CH:14]1([C:17](Cl)=[O:18])[CH2:16][CH2:15]1>C1COCC1.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>[CH:14]1([C:17]([C:9]2[CH:10]=[CH:11][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=2)=[O:18])[CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CC1
Reactant: CCOC(=O)c1ccc([Zn]I)cc1
Agent: Cl[Pd](Cl)([PH](c1ccccc1)(c1ccccc1)c1ccccc1)[PH](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(C(=O)C2CC2)cc1
Reaction time: 0.25 h
Yield: 78.4 %

Procedure:
(4-Ethoxycarbonylphenyl)-iodo-zinc (20 mL of 0.5 M in THF, 10.0 mmol) was added over 10 min to dichloro-bis(triphenylphosphoranyl)palladium (211 mg, 0.3 mmol) in THF (20 mL) under an atmosphere of nitrogen at 0° C. The reaction mixture was stirred for 15 minutes, cyclopropanecarbonyl chloride (941 mg, 817 μL, 9.0 mmol) was added dropwise at 0° C. and stirred for 2 hours. The reaction mixture was quenched with 1M HCl (20 mL), extracted with ethyl acetate (2×50 mL). The organic layer was washed sequentially with sat. aq. NaHCO3 (5 mL) and brine solution (50 mL), dried over MgSO4 and purified by silica gel column chromatography using 0-30% EtOAc/hexanes as eluent to give ethyl 4-(cyclopropanecarbonyl)benzoate (1.54 g, 71%) as a pale yellow oil. ESI-MS m/z calc. 218.0. found 219.3 (M+1)+; Retention time: 1.57 minutes (3 min run).
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]1)[C:2]#[CH:3].[F:10][C:11]1[C:12](I)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cu]I.CN(C=O)C.CCN(CC)CC>[F:10][C:11]1[C:12]([C:3]#[C:2][CH2:1][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5]2)=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15](=[O:20])/[C:14]/2=[CH:21]\[C:22]1[NH:26][CH:25]=[N:24][C:23]=1[CH3:27]
Reactant: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(I)c21
Reactant: C#CCN1CCCCC1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1nc[nH]c1/C=C1\C(=O)Nc2ccc(F)c(C#CCN3CCCCC3)c21

Procedure:
Using Method C above, 1-(2-propynyl)-piperidine (41.3 mg, 0.34 mmol) (prepared according to Kano et al. supra) was coupled with (Z)-1,3-dihydro-5-fluoro-4-iodo-3-[(4-methyl-1H-imidazol-5-yl)methylene]-2H-indol-2-one (Starting Material 3 supra) (50 mg, 0.135 mmol) using (Ph3P)4Pd (16 mg) and CuI (3 mg) as catalyst in DMF (3 mL) and Et3N (3 mL) as solvent at 80° C. for 5 h to give (Z)-1,3-dihydro-5-fluoro-3-[(4-methyl-1H-imidazol-5-yl)methylene]-4-[3-(1-pipendinyl)-1-propynyl]-2H-indol-2-one. (Yield 15 mg, 31%).