Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH:27]1([C:30](O)=[O:31])[CH2:29][CH2:28]1.C(N(CC)CC)C.Cl.C(N=C=NCCCN(C)C)C>CN(C)C1C=CN=CC=1.O1CCCC1.O>[CH:27]1([C:30]([O:26][CH:23]([C:5]2[C:6]3[N:7]4[CH2:14][CH2:13][CH2:12][N:11]([C:15]5[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=5[Cl:22])[C:8]4=[N:9][C:10]=3[C:2]([Cl:1])=[CH:3][CH:4]=2)[CH2:24][CH3:25])=[O:31])[CH2:29][CH2:28]1
Reactant: O=C(O)C1CC1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: CCC(OC(=O)C1CC1)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 15 h
Yield: 53.5 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol), cyclopropanecarboxylic acid (0.0272 mL, 0.342 mmol), triethylamine (0.0733 mL, 0.526 mmol) and 4-dimethylaminopyridine (41.0 mg, 0.336 mmol) in tetrahydrofuran (5.0 mL) was added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride 08.0 mg, 0.511 mmol) at room temperature. The mixture was stirred at room temperature for 15 hr. Cyclopropanecarboxylic acid (0.0147 mL, 0.185 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (53.2 mg, 0.278 mmol) were added to the reaction mixture at room temperature. The mixture was stirred at room temperature for 8 hr. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-80% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (61.6 mg, 0.13 mmol, 53%) as colorless crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[C:9](=O)[CH2:8][CH2:7][CH2:6][N:5]2[CH:11]=1.[NH2:12][C@H:13]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C@@H:14]([O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])[C:15](OCC)=[O:16].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([N-]C(C)C)(C)C.[Li+]>C1(C)C=CC=CC=1.O1CCCC1.O>[Si:21]([O:20][C@H:14]1[C:15](=[O:16])[C:8]2[CH2:7][CH2:6][N:5]3[CH:11]=[C:2]([CH3:1])[N:3]=[C:4]3[C:9]=2[NH:12][C@@H:13]1[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22]
Reactant: Cc1cn2c(n1)C(=O)CCC2
Reactant: CCOC(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](N)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Li+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cn2c(n1)C1=C(CC2)C(=O)[C@H](O[Si](C)(C)C(C)(C)C)[C@@H](c2ccccc2)N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
19.4 g (128.3 mmol) of 2-methyl-6,7-dihydro-5H-imidazo[1,2-a]pyridin-8-one, 42.07 g (130.2 mmol) of ethyl (2R,3R)-3-amino-2-(t-butyldimethylsilanyloxy)-3-phenylpropionate and 0.65 g of p-toluenesulfonic acid monohydrate are boiled under reflux in a water separator for 1.5 h in 100 ml of absolute toluene. The solution is cooled to room temperature and treated with 100 ml of absolute tetrahydrofuran. 154 ml of 2M LDA (lithium diisopropylamide) solution (THF) are then added dropwise to the reaction solution, which is cooled to −25° C. After the LDA addition, the temperature is allowed to rise to 0° C. and the mixture is stirred further at 0° C. for 1 h. The reaction solution is washed once at room temperature with 200 ml of saturated ammonium chloride solution, once with 50 ml of saturated ammonium chloride solution and once with water. The organic phase is concentrated and chromatographed on silica gel (petroleum ether/ethyl acetate 2:1). The concentrated product fractions are dried in a high vacuum. 50.8 g (97% of theory) of the title compound are obtained.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14])=O)(C)(C)C.[ClH:19].CCOCC>O1CCOCC1>[ClH:19].[NH2:8][CH2:9][C:10]1([C:16]([OH:18])=[O:17])[CH2:12][CH:11]1[CH:13]([CH3:15])[CH3:14]
Reactant: CC(C)C1CC1(CNC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC(C)C1CC1(CN)C(=O)O
Temperature: 25 °C
Reaction time: 8 h
Yield: 88 %

Procedure:
To a solution of 1-(tert-butoxycarbonylamino-methyl)-2-isopropyl-cyclopropanecarboxylic acid (2.05 g, 8.0 mmol) in dry 1,4-dioxane (40 mL) was added 4N HCl (40 mL, in. 1,4-dioxane). The reaction mixture was stirred at room temperature overnight and ether was added (100 mL). The white solid was collected and dried to give 1-aminomethyl-2-isopropyl-cyclopropanecarboxylic acid hydrochloride (1.35 g, 88%): mp: 245-246° C.; 1H NMR (300 MHz, D2O) δ 0.94 (d, J=6.5 Hz, 3H), 0.96 (m, 1H), 1.05 (d, J=6.4 Hz, 3H), 1.23-1.31 (m, 1H), 1.49-1.59 (m, 2H), 2.85 (d, J=13.7 Hz, 1H), 3.83 (d, J=13.7 Hz, 1H); 13C NMR (75 MHz, D2O) δ 22.3, 23.9, 27.8, 30.8, 39.6, 41.7, 179.6; MS (APCI) m/z 158 [M+H]+. Anal. Calc'd For C8H15NO2—HCl: C, 49.61; H, 8.33; N, 7.23; Cl, 18.31. Found: C, 49.76; H, 8.44; N, 7.11; Cl, 18.48.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([NH2:17])[C:7]=1[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2].[C:28]1([C:34]2[N:35]([N:45]=[C:46]([CH3:50])[C:47](=O)[CH3:48])[C:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)=[CH:37][CH:38]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1.S(NN)(C1C=CC(C)=CC=1)(=O)=O>C1(C)C=CC=CC=1.O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:8]([N:17]=[C:47]([CH3:48])[C:46](=[N:45][N:35]2[C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:38][CH:37]=[C:36]2[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:50])[C:7]=1[C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)=[O:5])[CH3:2]
Reactant: CC(=O)C(C)=Nn1c(-c2ccccc2)ccc1-c1ccccc1
Reactant: CCOC(=O)c1cc(-c2ccccc2)n(N)c1-c1cccc2ccccc12
Agent: Cc1ccc(S(=O)(=O)NN)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cc(-c2ccccc2)n(N=C(C)C(C)=Nn2c(-c3ccccc3)ccc2-c2ccccc2)c1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
A solution of 1-Amino-2-naphthalen-1-yl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester (434 mg, 1.22 mmol) in toluene (7.2 mL) was treated with 3-(2,5-Diphenyl-pyrrol-1-ylimino)-butan-2-one (308 mg, 1.02 mmol) and p-toluene sulfonic acid (8 mg). A Dean Stark trap was attached, and the resulting solution heated to reflux under Ar with the azeotropic removal of water for 18 h, then another portion of p-toluene sulfonic acid (8 mg) was added and the azeotropic removal of water was continued for an additional 75 min. The solution was cooled to rt and concentrated in vacuo. The residue was dissolved in THF/Acetic acid (10/1) and treated with PS-TsNHNH2 resin (Argonaut Technologies, 1.039 g, 2.6 mmol). The suspension was stirred under Ar overnight, then filtered through a polyethylene frit, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, 50-100% CH2Cl2/heptane) to afford 1-[2-(2,5-Diphenyl-pyrrol-1-ylimino)-1-methyl-propylideneamino]-2-naphthalen-1-yl-5-phenyl-1H-pyrrole-3-carboxylic acid ethyl ester a66 (240 mg, 37%): 11H NMR (DMSO, chemical shifts relative to TMS, 80° C.): 0.82 (t, 3H, J=7.3 Hz), 1.08 (s, 3H), 1.74 (s, 3H), 3.91 (q, 2H, J=6.9 Hz), 6.42 (s, 2H), 7.03 (s, 1H), 7.11 (d, 4H, J=7.3 Hz), 7.18 (t, 4H, J=7.3 Hz), 7.22-7.25 (m, 2H), 7.32-7.37 (m, 5H), 7.39-7.41 (m, 2H), 7.44-7.47 (m, 2H), 7.53 (d, 1H, J=8.2 Hz), 7.93 (t, 2H, J=8.7 Hz).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].[Br:8][C:9]1[CH:10]=[C:11](C=O)[S:12][CH:13]=1.[OH-].[K+].Cl>N1C=CC=CC=1.N1CCCCC1.O>[Br:8][C:9]1[CH:10]=[C:11](/[CH:1]=[CH:2]/[C:3]([OH:5])=[O:4])[S:12][CH:13]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C(O)CC(=O)O
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCNCC1
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)/C=C/c1cc(Br)cs1
Temperature: 100 °C

Procedure:
Malonic acid (16.2 g) was added to a solution of 4-bromothiophen-2-aldehyde (25.1 g) in pyridine (100 cm3) and piperidine (3.2 cm3) and the resulting mixture was heated at 100° C. for 6.5 hours, allowed to cool to room temperature overnight and was then evaporated down to give a beige semi-solid. The semi-solid was treated with aqueous potassium hydroxide solution and the resulting mixture was diluted with water (50 cm3), acidified with concentrated hydrochloric acid (90 cm3) and then cooled to yield a precipitate which was filtered off, washed with ether/40-60 petrol and was then sucked dry (26.1 g) m.p. 167°-169° C. (aqueous methanol) Analysis; Calculated; C, 36.05; H, 2.15; Found; C, 36.30; H, 2.03.
Reaction SMILES: [NH2:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][CH:6]=1.[C:20]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]1[O:28][CH2:27]1)#[N:21]>C(O)(C)C>[C:20]([C:22]1[CH:32]=[CH:31][CH:30]=[CH:29][C:23]=1[O:24][CH2:25][CH:26]([OH:28])[CH2:27][NH:1][C:2]([CH3:19])([CH3:18])[CH2:3][NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:9][CH:10]=1)#[N:21]
Reactant: N#Cc1ccccc1OCC1CO1
Reactant: CC(C)(N)CNc1ccc(C2=NNC(=O)CC2)cc1
Solvent: CC(C)O
Product: CC(C)(CNc1ccc(C2=NNC(=O)CC2)cc1)NCC(O)COc1ccccc1C#N
Reaction time: 24 h

Procedure:
2.6 g of 6-[4-(2-amino-2-methylpropylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone and 1.5 g of -(2-cyanophenoxy)-2,3-epoxypropane obtained in Example 1, (3) were dissolved in 20 ml of isopropanol, and heated with stirring for 24 hours. The solution was then worked up in the same way as in Example 1, (5). Recrystallization from dichloromethane-ether gave 2.93 g of 6-[4-[2-[3-(2-cyanophenoxy)-2-hydroxypropylamino]-2-methylpropylamino]phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.C1CCC(N=C=NC2CCCCC2)CC1.C1C=CC2N(O)N=NC=2C=1.[C:54]([O:58][C:59]([NH:61][CH:62]([C:66]1[CH:71]=[CH:70][CH:69]=[CH:68][CH:67]=1)[C:63](O)=[O:64])=[O:60])([CH3:57])([CH3:56])[CH3:55]>C1COCC1.C(Cl)Cl>[C:54]([O:58][C:59]([NH:61][CH:62]([C:66]1[CH:67]=[CH:68][CH:69]=[CH:70][CH:71]=1)[C:63]([NH:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]2)[CH2:9]1)=[O:6])=[O:64])=[O:60])([CH3:57])([CH3:55])[CH3:56]
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1ccccc1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC(C(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 34 %

Procedure:
To a suspension of (R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (500 mg, 1.50 mmol) in THF (15 ml) and DCM (5 ml), was added triethylamine (591 μl, 4.25 mmol), and the reaction was stirred at RT for 10 minutes. Then DCC (309 mg, 1.50 mmol), HOBT (203 mg, 1.50 mmol), and 2-(tert-butoxycarbonylamino)-2-phenylacetic acid (314 mg, 1.25 mmol) were added, and the reaction was stirred at RT for 15 hours. The solvent was evaporated, the residue was taken up with DCM, and the insoluble was removed by filtration. The organic solution was washed twice with 1N Na2CO3 and brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography (DCM/MeOH=95/5) to obtain (R)-quinuclidin-3-yl 2-(2-(tert-butoxycarbonylamino)-2-phenylacetamido)-2-phenylacetate (210 mg, 34% yield).
Reaction SMILES: OO.[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[C:24]4[CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][C:16]=3[N:17]=2)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.C(O)(C(F)(F)F)=[O:27]>C(Cl)Cl.N>[N:3]1([CH2:9][CH2:10][NH:11][C:12]2[N:13]=[N+:14]([O-:25])[C:15]3[C:24]4[CH2:23][CH2:22][CH2:21][C:20]=4[CH:19]=[CH:18][C:16]=3[N+:17]=2[O-:27])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1
Reactant: O=C(O)C(F)(F)F
Reactant: [O-][n+]1nc(NCCN2CCCCC2)nc2ccc3c(c21)CCC3
Agent: N
Agent: OO
Solvent: ClCCl
Product: [O-][n+]1nc(NCCN2CCCCC2)[n+]([O-])c2ccc3c(c21)CCC3
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 54 %

Procedure:
H2O2 (70%, 0.27 mL, ca. 5.4 mmol) was added dropwise to a stirred solution of TFM (0.8 mL, 5.4 mmol) in DCM (10 mL) at 0° C. The solution was stirred at 0° C. for 5 min, warmed to 20° C. for 10 min, then cooled to 0° C. and added to a stirred solution of 1-oxide 12 (170 mg, 0.5 mmol) and TFA (0.21 mL, 2.7 mmol) in DCM (15 mL) at 0° C. The solution was stirred at 20° C. for 16 h, diluted with dilute aqueous NH3 solution (10 mL) and extracted with CHCl3 (4×50 mL). The combined organic fraction was dried and the solvent evaporated. The residue was purified by chromatography, eluting with a gradient (0-10%) of MeOH/DCM, to give 1,4-dioxide 13 (89 mg, 50%) as a red solid: mp (MeOH/EtOAc) 138-141° C.; 1H NMR δ 8.12 (d, J=8.7 Hz, 1H, H-5), 7.70 (d, J=8.7 Hz, 1H, H-6), 7.44 (br s, 1H, NH), 3.70 (br t, J=7.6 Hz, 2H, H-9), 3.60-3.64 (m, 2H, CH2N), 3.04 (br t, J=7.7 Hz, 2H, H-7), 2.64 (br t, J=6.1 Hz, 2H, CH2N), 2.43-2.50 (m, 4H, 2×CH2), 2.21 (br p, J=7.7 Hz, 2H, H-8), 1.59-1.65 (m, 4H, 2×CH2), 1.42-1.48 (m, 2H, CH2); 13C NMR δ 149.1, 144.7, 138.6, 138.4, 132.7, 129.0, 115.7, 56.9, 54.4 (2), 38.1, 35.1, 32.9, 25.9 (2), 24.6, 24.3. Anal. calcd for C17H23N5O2.½H2O: C, 60.3; H, 7.2; N, 20.7. Found: C, 59.9; H, 7.0; N, 20.3%.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([CH3:12])=[N+:7]([O-])[CH:8]=[CH:9][N:10]=1)=[O:4].P(Cl)(Cl)([Cl:15])=O>CN(C=O)C>[Cl:15][C:8]1[N:7]=[C:6]([CH3:12])[C:5]([C:3]([O:2][CH3:1])=[O:4])=[N:10][CH:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ncc[n+]([O-])c1C
Solvent: CN(C)C=O
Product: COC(=O)c1ncc(Cl)nc1C
Temperature: 100 °C
Reaction time: 1 h
Yield: 21.7 %

Procedure:
In a 1-L flask, the crude 3-(methoxycarbonyl)-2-methylpyrazine 1-oxide (step 2, 17.77 g, 106 mmol) was dissolved in DMF (300 mL). Neat phosphoryl trichloride (29.6 mL, 317 mmol) was added. The reaction mixture was heated to 100° C. After 1 h, the reaction mixture was concentrated to remove most of the DMF. The flask was cooled in an ice water bath, and 1 M aqueous Na2CO3 (300 mL) was added slowly, followed by 80% EtOAc-hexane (400 mL). The mixture was filtered through Celite. The resulting filtrate was partitioned and the aqueous phase was extracted further with 80% EtOAc-hexane (2×250 mL). The combined organic layers were dried over MgSO4 and concentrated. The material was purified through silica gel using 11% EtOAc-hexane to afford the title compound (4.29 g, 23 mmol, 22%). MS m/z=187 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([C:19](Cl)=[O:20])[CH:13]=2)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[NH3:22]>C(Cl)Cl>[C:19]([C:14]1[CH:13]=[C:12]([C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=2)[CH:17]=[CH:16][C:15]=1[Cl:18])(=[O:20])[NH2:22]
Reactant: O=C(Cl)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Reactant: N
Solvent: ClCCl
Product: NC(=O)c1cc(-c2ncc(C(F)(F)F)cc2Cl)ccc1Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of 4.0 g of 3-chloro-2-(4-chloro-3-chloroformylphenyl)-5-trifluoromethylpyridine in 10 ml of methylene chloride was added dropwise to 100 ml of a 25% by weight aqueous ammonia solution cooled to 0° C. After 3 hours, the crystals which had formed were separated off, stirred with n-hexane, again separated off, washed with n-hexane and finally dried. Yield: 2.8 g (75%) of colorless crystals; melting point: 167°-168° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([O:8][C:9]([F:12])([F:11])[F:10])[CH:5]=[CH:4][C:3]=1[OH:13].[Cl:14][CH2:15][CH2:16]OS(C1C=CC(C)=CC=1)(=O)=O.CN(C=O)C.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:14][CH2:15][CH2:16][O:13][C:3]1[CH:4]=[CH:5][C:6]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:7][C:2]=1[I:1]
Reactant: Cc1ccc(S(=O)(=O)OCCCl)cc1
Reactant: Oc1ccc(OC(F)(F)F)cc1I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: FC(F)(F)Oc1ccc(OCCCl)c(I)c1
Yield: 100 %

Procedure:
2-Iodo-4-(trifluoromethoxy)phenol (10 g, 33 mmol), 2-chloroethyl-p-toluenesulfonate (7.9 g, 34 mmol), N,N′-dimethylformamide (50 mL) and potassium carbonate (9.1 g, 66 mmol) were stirred together at 50° C. for 16 hours and then cooled. The suspension was diluted with water (100 mL) and extracted with 60% diethyl ether/hexane (2×100 mL). The extracts were dried (MgSO4) and concentrated to give the title compound as a solid (12.1 g, 33 mmol).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([O:14][CH:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)=[CH:12][CH:11]=[C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH:9]=2)=[CH:4][C:3]=1[CH3:26].[N:27]([O-])=O.[Na+].NC(N)=O.C1(C)C=CC=CC=1>C(O)(=O)C.O>[CH:15]1([O:14][C:13]2[CH:12]=[CH:11][C:10]([CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:9][C:8]=2[C:5]2[CH:4]=[C:3]3[C:2](=[CH:7][CH:6]=2)[NH:1][N:27]=[CH:26]3)[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=N[O-]
Reactant: COC(=O)CCc1ccc(OC2CCCC2)c(-c2ccc(N)c(C)c2)c1
Agent: NC(N)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)CCc1ccc(OC2CCCC2)c(-c2ccc3[nH]ncc3c2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.4 %

Procedure:
A solution of Intermediate 72 (760 mg) in acetic acid (4 ml) was added with an aqueous solution (0.7 ml) of sodium nitrite (156 mg) under ice cooling, and stirred for 30 minutes. This reaction mixture was added with urea (350 mg), warmed to room temperature, stirred for 30 minutes, then added with toluene (8 ml) and water (4 ml), and further stirred for 60 hours. The reaction mixture was extracted with toluene (50 ml×2). The organic layer was washed successively with saturated aqueous sodium hydrogencarbonate, and saturated brine and dried, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography (Quad, hexane:ethyl acetate=6:1) to obtain the title compound (Compound No. V-57, 411 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20](I)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1.OC(C(O)(C)C)(C)C.[N:34]1[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[C:6]([CH3:13])=[C:5]2[N:14]1[C:22]2[C:17](=[CH:18][CH:19]=[C:20]([C:37]3[CH:38]=[CH:39][N:34]=[CH:35][CH:36]=3)[CH:21]=2)[C:16]([CH3:25])([CH3:24])[CH2:15]1
Reactant: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(I)cc32)c1C
Reactant: OB(O)c1ccncc1
Agent: CC(C)(O)C(C)(C)O
Product: Cc1nc2ccc(Cl)cc2c(N2CC(C)(C)c3ccc(-c4ccncc4)cc32)c1C

Procedure:
Prepared according to procedure W using 6-chloro-4-(6-iodo-3,3-dimethylindolin-1-yl)-2,3-dimethylquinoline (0.15 g, 0.32 mmol) and pyridine-4-boronic acid pinacol (0.1329 g, 0.65 mmol) to give 6-chloro-4-(3,3-dimethyl-6-(4-pyridinyl)-2,3-dihydro-1H-indol-1-yl)-2,3-dimethylquinoline as a brown solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (2H, d, J=4.3 Hz), 8.02 (1H, d, J=9.0 Hz), 7.82 (1H, d, J=2.3 Hz), 7.60 (1H, dd, J=9.0, 2.3 Hz), 7.28-7.35 (3H, m), 7.04 (1H, dd, J=7.6, 1.4 Hz), 6.12 (1H, d, J=1.2 Hz), 3.63-3.88 (2H, m), 2.75 (3H, s), 2.27 (3H, s), 1.60 (3H, s), 1.54 (3H, s); Mass Spectrum (ESI) m/e=414.1 (M+1).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([F:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[N:31]=[CH:30][CH:29]=[CH:28][N:27]=1>>[F:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[N:31]=[CH:30][CH:29]=[CH:28][N:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: Brc1ncccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3cccnc3F)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12i and 2-bromopyrimidine
Reaction SMILES: [CH:1]1([N:6]2[C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[C:8]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([N+:25]([O-])=O)[CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[F:28][C:29]1[CH:30]=[C:31]([S:35](Cl)(=[O:37])=[O:36])[CH:32]=[CH:33][CH:34]=1>CS(C)=O>[NH2:15][C:14]1[C:9]2[C:8]([C:16]3[NH:20][C:19]4[CH:21]=[C:22]([NH:25][S:35]([C:31]5[CH:32]=[CH:33][CH:34]=[C:29]([F:28])[CH:30]=5)(=[O:37])=[O:36])[CH:23]=[CH:24][C:18]=4[N:17]=3)=[CH:7][N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[C:10]=2[N:11]=[CH:12][N:13]=1
Reactant: Nc1ncnc2c1c(-c1nc3ccc([N+](=O)[O-])cc3[nH]1)cn2C1CCCC1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Solvent: CS(C)=O
Product: Nc1ncnc2c1c(-c1nc3ccc(NS(=O)(=O)c4cccc(F)c4)cc3[nH]1)cn2C1CCCC1

Procedure:
The title compound was prepared by treatment of 5-(6-Amino-1H-benzoimidazol-2-yl)-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (1E, 20 mg in 1.0 mL NMP) with 1.2 equiv. of 3-fluoro-benzenesulfonyl chloride (14.3 mg) at 80° C. for 2.5 h. LCMS was used to confirm product formation and the resulting reaction mixture was diluted with 1.0 mL DMSO and purified via preparative HPLC to furnish the desired product (M/Z 491.2, retention time 2.3 min. with analytical HPLC method 2).
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.[OH:17][CH2:18][CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH2:22][CH2:21]1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:17][CH2:18][CH2:19][N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: OCCN1CCOCC1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCN2CCOCC2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, N-(2-hydroxyethyl)morpholine and DBU in THF. ES-MS m/e (%): 417 (M+H+, 100).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH2:17][CH:18]([OH:23])[CH:19]([CH3:22])[CH2:20][CH3:21])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([O:15][CH3:16])=[CH:10][C:9]=1[CH2:17][CH:18]([OH:23])[CH:19]([CH3:22])[CH2:20][CH3:21]
Reactant: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCC(C)C(O)Cc1cc(OC)c(Cl)cc1N
Reaction time: 9 h
Yield: 95.9 %

Procedure:
To a solution of tert-butyl[5-chloro-2-(2-hydroxy-3-methylpentyl)-4-methoxyphenyl]carbamate (873 mg) in dichloromethane (12.2 mL) was added dropwise trifluoroacetic acid (3.76 mL) under ice-cooling, and this mixture was stirred for 9 hours. The reaction mixture was concentrated under reduced pressure. To the residue were added ethyl acetate and saturated aqueous sodium hydrogen carbonate solution to separate the organic layer. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluting solvent: ethyl acetate-hexane) to obtain the title compound (603 mg). 1H-NMR (CDCl3) δ ppm: 0.75-1.75 (9H, m), 2.45-2.85 (2H, m), 3.30-4.10 (6H, m), 6.60-6.80 (2H, m). ESI-MS (m/z): 258, 260 (M+H)+