Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([NH:35][C:36]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)=[O:37])[N:34]=3)[C:10]([C:13]3[CH:14]=[CH:15][C:16]([N:19]4[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]4)=[N:17][CH:18]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1.C(Cl)[Cl:49]>C(O)(C(F)(F)F)=O.CO>[ClH:49].[O:1]1[CH2:6][CH2:5][N:4]([C:7]2[C:8]3[N:9]([CH:32]=[C:33]([NH:35][C:36]([C:38]4[CH:47]=[CH:46][C:45]5[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=5)[N:39]=4)=[O:37])[N:34]=3)[C:10]([C:13]3[CH:18]=[N:17][C:16]([N:19]4[CH2:20][CH2:21][NH:22][CH2:23][CH2:24]4)=[CH:15][CH:14]=3)=[CH:11][N:12]=2)[CH2:3][CH2:2]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc(N4CCOCC4)c4nc(NC(=O)c5ccc6ccccc6n5)cn34)cn2)CC1
Reactant: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: O=C(Nc1cn2c(-c3ccc(N4CCNCC4)nc3)cnc(N3CCOCC3)c2n1)c1ccc2ccccc2n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of compound 21d (170 mg, 0.26 mmol) in DCM (6.8 mL), TFA (2.2 mL) was added. The resulting mixture was stirred at rt for 1 h and concentrated under reduced pressure. The residue obtained was dissolved in MeOH (20 mL) and passed through a MeOH pre-washed Bio-Rad AG-2X8 Cl-exchange column (50 g). The eluent was concentrated and dried under reduced pressure to obtain the title compound 125. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 11.11 (s, 1H), 9.19 (br. s., 2H), 8.66 (d, J=8.2 Hz, 1H), 8.43 (d, J=2.3 Hz, 1H), 8.29 (d, J=8.6 Hz, 1H), 8.20 (d, J=8.6 Hz, 1H), 8.10-8.16 (m, 2H), 8.00 (dd, J=8.8, 2.5 Hz, 1H), 7.91-7.97 (m, 1H), 7.78 (t, J=8.0 Hz, 1H), 7.45 (s, 1H), 7.20 (d, J=9.0 Hz, 1H), 4.22 (d, J=3.9 Hz, 4H), 3.87-3.94 (m, 4H), 3.79-3.86 (m, 4H), 3.24 (none, 4H). Mass Spectrum (LCMS, ESI pos.) Calcd. For C29H29N9O2: 536.2 (M+H). Found 536.3.
Reaction SMILES: [CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][NH:6][C@H:5]2[CH:9](C)C)[CH2:3][CH2:2]1.[F:13][C:14]1[CH:21]=[C:20](F)[CH:19]=[C:18]([F:23])[C:15]=1[C:16]#[N:17].C(=O)([O-])[O-].[Li+].[Li+]>>[CH:1]1([C@:4]2([OH:12])[CH2:8][CH2:7][N:6]([C:20]3[CH:21]=[C:14]([F:13])[C:15]([C:16]#[N:17])=[C:18]([F:23])[CH:19]=3)[C@H:5]2[CH3:9])[CH2:2][CH2:3]1
Reactant: N#Cc1c(F)cc(F)cc1F
Reactant: CC(C)[C@@H]1NCC[C@@]1(O)C1CC1
Agent: O=C([O-])[O-]
Agent: [Li+]
Product: C[C@@H]1N(c2cc(F)c(C#N)c(F)c2)CC[C@@]1(O)C1CC1

Procedure:
By an operation in the same manner as in Example 1 and using (2S,3R)-3-cyclopropyl-2-methylpyrrolidin-3-ol 0.5 oxalate (200 mg), 2,4,6-trifluorobenzonitrile (288 mg) and lithium carbonate (180 mg), the title compound was obtained as a colorless solid (yield: 172 mg, yield: 51%).
Reaction SMILES: [C:1]([O:5][N:6]=[C:7]([C:9]1[N:10]=[CH:11][C:12]([NH:15]C(=O)C(C)(C)C)=[N:13][CH:14]=1)[CH3:8])([CH3:4])([CH3:3])[CH3:2]>O1CCOCC1.O.NN.C(OCC)(=O)C>[C:1]([O:5][N:6]=[C:7]([C:9]1[CH:14]=[N:13][C:12]([NH2:15])=[CH:11][N:10]=1)[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(=NOC(C)(C)C)c1cnc(NC(=O)C(C)(C)C)cn1
Agent: NN
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(=NOC(C)(C)C)c1cnc(N)cn1
Temperature: 25 °C
Yield: 101606.6 %

Procedure:
A solution of N-[5-(1-tert-butoxyimino-ethyl)-pyrazin-2-yl]-2,2-dimethyl-propionamide (563.4 mg, 1.93 mmol) in dioxane (5.8 mL) and hydrazine monohydrate (9.6 mL) was heated under reflux for 48 h. The reaction mixture was allowed to cool to 25° C. and then was diluted with ethyl acetate (100 mL). The organic layer was washed with a saturated aqueous sodium chloride solution (1×100 mL), dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40L, Silica, 3/7 ethyl acetate/hexanes) afforded 1-(5-amino-pyrazin-2-yl)-ethanone O-tert-butyl-oxime (408.4 g, quant.) as a light yellow solid: mp 113–115° C.; EI-HRMS m/e calcd for C10H16N4O (M+) 208.1324, found 208.1325.
Reaction SMILES: [NH2:1][C:2]1[NH:3][CH2:4][CH2:5][CH2:6][N:7]=1.[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29](OCC)=[O:30])=[CH:21][CH:20]=3)[S:15][C:11]=2[CH:10]=1.NN1C=CCNC1>C1COCC1>[Br:8][C:9]1[CH:42]=[CH:41][C:12]2[N:13]=[C:14]([NH:16][C@H:17]([C:34]([O:36][C:37]([CH3:38])([CH3:39])[CH3:40])=[O:35])[CH2:18][C:19]3[CH:20]=[CH:21][C:22]([O:25][CH2:26][CH2:27][CH2:28][C:29](=[O:30])[NH:1][C:2]4[NH:7][CH2:6][CH2:5][CH2:4][N:3]=4)=[CH:23][CH:24]=3)[S:15][C:11]=2[CH:10]=1
Reactant: NC1=NCCCN1
Reactant: CCOC(=O)CCCOc1ccc(C[C@H](Nc2nc3ccc(Br)cc3s2)C(=O)OC(C)(C)C)cc1
Agent: NN1C=CCNC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)[C@H](Cc1ccc(OCCCC(=O)NC2=NCCCN2)cc1)Nc1nc2ccc(Br)cc2s1
Reaction time: 20 h

Procedure:
80 mg of 2-amino-1,4,5,6-tetrahydropyrimidine is added to a solution of the ester 8-2 (123 mg) in 3 ml of THF, agitation is carried out for 20 hours at ambient temperature, 48 mg of tetrahydroaminopyrimidine is also added and agitation is carried out for 5 hours. After evaporating under reduced pressure, the mixture is chromatographed eluting with a CH2Cl2/AcOEt 80/20 then CH2Cl2/MeOH 90/10 mixture. 68 mg of the expected 8-3 is obtained.
Reaction SMILES: [CH2:1]([S:5]Cl)[CH2:2][S:3]Cl.[CH2:7]([NH:14][C:15](=[S:17])[S-:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[Na+]>>[CH2:7]([NH:14][C:15]([S:16][S:3][CH2:2][CH2:1][S:5][S:17][C:15](=[S:16])[NH:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[S:17])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClSCCSCl
Reactant: S=C([S-])NCc1ccccc1
Agent: [Na+]
Product: S=C(NCc1ccccc1)SSCCSSC(=S)NCc1ccccc1

Procedure:
Bis-dithiocarbamates from primary amines are similarly prepared. For example, addition of 1,2-ethanedisulfenyl chloride solution to an aqueous solution of sodium benzyldithiocarbamate gives nearly a quantitative yield of 1,2-bis(N-benzylthiocarbamoyldithio)ethane, m.p. 105°-110°C, decom., NMR 7.3 singlet, 4.9 mult., 3.4 singlet and 3.15 singlet.
Reaction SMILES: [CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10]CC.S(Cl)(Cl)=O.C(OC1C=CC(CO)=CC=1)CCCCCCCCC>C(Cl)Cl>[CH2:1]([O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][Cl:19])=[CH:16][CH:15]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCCCCCCCCOc1ccc(CCl)cc1
Agent: CCCCCCCCCCOc1ccc(CO)cc1
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: CCCCCCCCCCOc1ccc(CCl)cc1

Procedure:
Was synthesized following the same general procedure as that for the preparation of 4-dodecyloxybenzyl chloride; thionyl chloride (5.00 g, 42.4 mmol), 4-decyloxybenzyl alcohol (10.2 g, 38.6 mmol), CH2Cl2 (100 mL). 9.87 g (90%) white solid which decomposes upon melting.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.C(O[C:17]1(O[Si](C)(C)C)[CH2:19][CH2:18]1)C.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[CH:17]1([N:1]2[CH2:5][CH2:4][C@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)[CH2:19][CH2:18]1
Reactant: CCOC1(O[Si](C)(C)C)CC1
Reactant: CC(C)(C)OC(=O)N[C@H]1CCNC1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N[C@H]1CCN(C2CC2)C1

Procedure:
(S)-tert-butyl pyrrolidin-3-ylcarbamate (415 mg), (1-ethoxycyclopropoxy)trimethylsilane (1.8 mL) and molecular sieves (500 mg) were combined in methanol (4.5 mL). Acetic acid (1.3 mL) was added, followed by sodium cyanoborohydride (420 mg). The resulting mixture was heated to reflux for 4 hours. Insoluble material was filtered off and reaction was made basic to pH 14 with addition of 6M aqueous NaOH solution. The solution was extracted three times with diethyl ether, and the combined extracts were dried over MgSO4, filtered and concentrated to obtain an oil, which was purified by flash chromatography, eluting first with 100% dichloromethane, followed by 5% methanol/dichloromethane and 10% methanol/dichloromethane.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]([CH3:17])([CH3:16])[C:13]([OH:15])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[NH2:49][C:50]1[S:51][C:52]([O:58][C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)=[C:53]([CH:55]2[CH2:57][CH2:56]2)[N:54]=1>CN(C=O)C>[CH2:1]([O:8][C:9](=[O:10])[NH:11][C:12]([C:13](=[O:15])[NH:49][C:50]1[S:51][C:52]([O:58][C:59]2[CH:66]=[CH:65][C:62]([C:63]#[N:64])=[CH:61][CH:60]=2)=[C:53]([CH:55]2[CH2:57][CH2:56]2)[N:54]=1)([CH3:17])[CH3:16])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Reactant: N#Cc1ccc(Oc2sc(N)nc2C2CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(NC(=O)OCc1ccccc1)C(=O)Nc1nc(C2CC2)c(Oc2ccc(C#N)cc2)s1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-Benzyloxycarbonylamino-2-methyl-propionic acid (360 mg, 1.52 mmol), HBTU (576 mg, 1.52 mmol) and Et3N (0.21 mL, 1.5 mmol) in DMF (4 mL) was stirred at room temperature for 30 min. To this was added a solution of 4-(2-Amino-4-cyclopropyl-thiazol-5-yloxy)-benzonitrile (260 mg, 1.01 mmol) in DMF (4 mL). The mixture was heated at 85° C. for 18 h and partitioned between EtOAc and 3M HCl. The organic extract was dried over MgSO4, concentrated and chromatographed to give the title compound. m/z 477.1 (MH+).
Reaction SMILES: C(Br)C1C=CC=CC=1.[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[N:14][CH:15]=1.C(N(CC)CC)C.[H][H]>C(O)(C)C>[CH3:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH:17]=2)=[N:14][CH:15]=1
Reactant: Cc1ccc(-c2ccncc2)nc1
Reactant: [H][H]
Agent: BrCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: Cc1ccc(C2=CCNCC2)nc1
Temperature: 50 °C
Reaction time: 5 h
Yield: 40.1 %

Procedure:
Benzyl bromide in an amount of 10.5 g was added to a solution of 10 g of 5-methyl-2,4′-bipyridine in 70 mL of isopropyl alcohol, and stirred for 5 hours at 50° C. To the resulting reaction solution, 1.0 g of 2% palladium-S carbon and 6.0 g of triethylamine were added. This admixture was put in an autoclave, the autoclave's atmosphere was replaced twice with nitrogen gas under a nitrogen pressure of 196 kPa, and then hydrogen gas was blown into the autoclave over 3 hours at 80° C. under a hydrogen pressure of 196 kPa until the absorption of hydrogen gas in a volume of 4,200 mL was completed. After the replacement with nitrogen, the catalyst was filtered out and the resulting filtrate was concentrated under a reduced pressure of 1.33 kPa until the quantity thereof was reduced to 18.0 g. Further thereto, 50 mL of water and 10 g of a 25% aqueous solution of sodium hydroxide were added. The resulting solution was extracted with three 200 mL portions of ethyl acetate, and the organic layer was concentrated. The thus obtained solid was adsorbed to NH2-modified silica gel (produced by Biotage Japan, Ltd.), and eluted with ethylacetate. The fraction obtained was concentrated, and the crystals thus deposited were dried to give 4.1 g of the intended compound as light yellow crystals. Yield rate: 40%, EI-MS: (m/z) 174 (M+), melting point: 78-80° C.
Reaction SMILES: [C:1]([C:5]1[N:6]=[CH:7][C:8]2[N:9]=[CH:10][N:11]=[C:12](O)[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O>>[C:1]([C:5]1[N:6]=[CH:7][C:8]2[N:9]=[CH:10][N:11]=[C:12]([Cl:18])[C:13]=2[N:14]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ncc2ncnc(O)c2n1
Reactant: O=P(Cl)(Cl)Cl
Product: CC(C)(C)c1ncc2ncnc(Cl)c2n1
Reaction time: 0.17 h

Procedure:
6-tert-Butyl-pyrimido[5,4-d]pyrimidin-4-ol (210 mg, 1.03 mMol) was dissolved in phosphorous oxychloride (10 mL), and the mixture was heated at reflux for 4 hours. The solution was concentrated in-vacuo, then stripped from methylene chloride (3×50 mL) to remove excess phosphorous oxychloride. The residue was stirred for 10 minutes in saturated sodium bicarbonate (50 mL), then extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (30 mL), followed by brine (30 mL), dried over sodium sulfate, then concentrated in-vacuo. The residue was purified over silica gel, eluting with 50% ethyl acetate/heptane, to yield 150 mg of a white solid as product. NMR (500 MHz, CDCl3) δ 9.61 (s, 1H), 9.15 (S, 1H), 1.52 (s, 9H).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:11]([OH:13])=[O:12])=[CH:5][CH:4]=1.[N:20]12[CH2:27][CH2:26][CH:23]([CH2:24][CH2:25]1)[C@@H:22](O)[CH2:21]2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1>C1COCC1>[F:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][CH:10]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:11]([O:13][C@@H:22]2[CH:23]3[CH2:26][CH2:27][N:20]([CH2:25][CH2:24]3)[CH2:21]2)=[O:12])=[CH:5][CH:4]=1
Reactant: O[C@H]1CN2CCC1CC2
Reactant: O=C(O)C(Nc1ccc(F)cc1)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: O=C(O[C@H]1CN2CCC1CC2)C(Nc1ccc(F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 38.1 %

Procedure:
2-(4-Fluorophenylamino)-2-phenylacetic acid hydrochloride (I7) (2.00 g, 8.15 mmol), (R)-quinuclidin-3-ol (1.14 g, 8.97 mmol), HOBt (1.10 g, 8.15 mmol) and DCC (0.841 g, 4.08 mmol) were dissolved in THF (25 ml), and the mixture was stirred at room temperature for three days. Then a second portion of HOBt (0.55 g, 4.08 mmol), DCC (0.84 g, 4.08 mmol) and (R)-quinuclidin-3-ol (0.52 g, 4.08 mmol) were added and the mixture was stirred at room temperature overnight. THF was removed under vacuum, and the residue was treated with H2O and extracted twice with EtOAc. The organic phase was washed with saturated Na2CO3 and dried over Na2SO4, filtered and the solvent was evaporated in vacuo. The crude was purified by flash chromatography (EtOAc/MeOH=9/1 to 75/25) to obtain (R)-quinuclidin-3-yl 2-(4-fluorophenylamino)-2-phenylacetate (1.1 g, 38.1% yield, mixture of diasteromers).
Reaction SMILES: [OH:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3].Cl[Si:27]([CH3:30])([CH3:29])[CH3:28].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:28][Si:27]([CH3:30])([CH3:29])[O:1][C@@H:2]([C@@H:4]1[C@@H:7]([C@H:8]([C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[S:11])[CH3:9])[N:6]([CH2:18][C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:5]1=[O:25])[CH3:3]
Reactant: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O)[C@H]1[C@@H](C)C(=S)c1ccccc1
Reactant: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C=CCOC(=O)CN1C(=O)[C@H]([C@@H](C)O[Si](C)(C)C)[C@H]1[C@@H](C)C(=S)c1ccccc1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 92.7 %

Procedure:
(3S,4S)-3-[(1R)-1-Hydroxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (content, 90.6%; 14.7 g) was dissolved in dry toluene (60 ml), and chlorotrimethylsilane (7.8 g) and triethylamine (7.8 g) were added thereto under ice-cooling, followed by stirring at room temperature for 40 minutes. The reaction mixture was diluted with toluene (300 ml), washed with 2% sodium bicarbonate solution (300 ml) and aqueous sodium chloride (300 ml×2) and dried over magnesium sulfate to give (3S,4S)-3-[(1R)-1-trimethylsilyloxyethyl]-4-[(1R)-1-phenylthiocarbonylethyl]-1-allyloxycarbonylmethyl-2-azetidinone (16.35 g; yield, 90%).
Reaction SMILES: [F:1][CH:2]([F:16])[O:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([N:13]=[C:14]=[O:15])(=[O:12])=[O:11].[NH2:17][C:18]1[N:23]=[C:22]([CH:24]2[CH2:26][CH2:25]2)[N:21]=[C:20]([C:27]([Cl:30])([Cl:29])[Cl:28])[N:19]=1>CCCCCC>[CH:24]1([C:22]2[N:21]=[C:20]([C:27]([Cl:29])([Cl:28])[Cl:30])[N:19]=[C:18]([NH:17][C:14]([NH:13][S:10]([C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[O:3][CH:2]([F:1])[F:16])(=[O:12])=[O:11])=[O:15])[N:23]=2)[CH2:25][CH2:26]1
Reactant: O=C=NS(=O)(=O)c1ccccc1OC(F)F
Reactant: Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1
Solvent: CCCCCC
Product: O=C(Nc1nc(C2CC2)nc(C(Cl)(Cl)Cl)n1)NS(=O)(=O)c1ccccc1OC(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
2.7 g of 2-difluoromethoxybenzenesulfonylisocyanate are added to a solution of 2.54 g of 2-amino-4-cyclopropyl-6-trichloromethyl-1,3,5-triazine, and the whole is stirred at room temperature for 14 hours. Hexane is then added until the reaction product precipitates. Filtration is carried out and the filtration residue is dried to thus obtain 3 g of the above urea, which melts at 103°-105° C.
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:12][CH:11]=2)[C:7]2[C:28]([C:32]([OH:34])=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2].C(N(CC)CC)C.ClC1C=C(Cl)[CH:49]=[C:48](Cl)[C:44]=1[C:45](Cl)=[O:46].C1C[O:57]CC1>>[CH2:1]([O:3][C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:26][C:25](=[O:27])[O:24][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[C:28]([C:32]([O:34][CH:49]3[CH2:48][CH2:44][C:45](=[O:46])[O:57]3)=[O:33])=[CH:29][CH:30]=[CH:31][C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cccc(C(=O)O)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Reactant: C1CCOC1
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Solvent: CCN(CC)CC
Product: CCOc1nc2cccc(C(=O)OC3CCC(=O)O3)c2n1Cc1ccc(-c2ccccc2-c2noc(=O)[nH]2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 3.3 %

Procedure:
To a solution of 2-ethoxy-1-{[2′-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl}-1H-benzimidazole-7-carboxylic acid (4.0 g) and triethylamine (1.3 mL) in THF (50 mL) was added dropwise 2,4,6-trichlorobenzoyl chloride (1.4 mL) under ice-cooling. After stirring at room temperature for 12 hrs., insoluble material was filtered off and the filtrate was concentrated. The residue was dissolved in methylene chloride (50 mL) and 5-oxotetrahydro-2-furanyl (0.67 g) and N,N-dimethylaminopyridine (1.0 g) were added under ice-cooling. After stirring at room temperature for 4 hrs., the reaction mixture was diluted with chloroform (150 mL), washed with water, saturated aqueous sodium hydrogen carbonate, 1 N hydrochloric acid and saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column chromatography to give the title compound (0.16 g, 3.3%) as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].[F:14][C:15]([F:25])([F:24])[C:16]1[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Cl.[H-].[Na+]>>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:18][C:17]1[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=1[C:15]([F:14])([F:24])[F:25])[N:8]1[CH:12]=[CH:11][CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: FC(F)(F)c1ccccc1CCl
Reactant: CC(C)(C)OC(=O)Nn1cccc1
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N(Cc1ccccc1C(F)(F)F)n1cccc1

Procedure:
Prepared according to the benzylation condition used in Example 1 step b) from pyrrol-1-yl-carbamic acid tert-butyl ester (1.0 eq.), 2-trifluoromethylbenzyl chloride (1.0 eq.) and sodium hydride (1.3 eq.). ESI (m/z): 341 (M+H)+.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:20]([Br:24])(Br)(Br)Br.OC[C:27]#[C:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:46])([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([CH3:45])[CH3:44])=[CH:38][CH:37]=2)[NH:32][C:31]1=[O:47]>ClCCl>[Br:24][CH2:20][C:27]#[C:28][CH2:29][N:30]1[C:34](=[O:35])[C:33]([CH3:46])([C:36]2[CH:41]=[CH:40][C:39]([O:42][CH:43]([CH3:44])[CH3:45])=[CH:38][CH:37]=2)[NH:32][C:31]1=[O:47]
Reactant: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCO)C2=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(C)Oc1ccc(C2(C)NC(=O)N(CC#CCBr)C2=O)cc1
Yield: 87.4 %

Procedure:
Triphenylphosphine (196 mg) and carbon tetrabromide (247 mg) were added to a mixed solution of 3-(4-hydroxy-2-butynyl)-5-methyl-5-[4-(1-methylethoxy)phenyl]imidazolidine-2,4-dione (157 mg, 498 μmol) in dichloromethane (10 mL) at room temperature. After completion of the reaction, the solvent was evaporated, and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to obtain 165 mg of the title compound (yield: 87%) as a colorless oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13](I)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.CC1(C)C(C)(C)OB([C:30]2[CH:42]=[CH:41][C:33]([O:34][C:35]3[N:40]=[CH:39][CH:38]=[CH:37][N:36]=3)=[CH:32][CH:31]=2)O1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([N:11]3[C:15]4=[N:16][CH:17]=[N:18][C:19]([NH2:20])=[C:14]4[C:13]([C:30]4[CH:42]=[CH:41][C:33]([O:34][C:35]5[N:36]=[CH:37][CH:38]=[CH:39][N:40]=5)=[CH:32][CH:31]=4)=[N:12]3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CC1(C)OB(c2ccc(Oc3ncccn3)cc2)OC1(C)C
Reactant: Nc1ncnc2c1c(I)nn2C1CCC2(CC1)OCCO2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Nc1ncnc2c1c(-c1ccc(Oc3ncccn3)cc1)nn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Yield: 75.7 %

Procedure:
A mixture of 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (Intermediate N) (1.50 g, 0.00374 mol), 2-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]-pyrimidine (intermediate BA) (1.23 g, 0.00412 mol), tetrakis(triphenylphosphine)palladium(0) (0.26 g, 0.00022 mol) and sodium carbonate (0.993 g, 0.00937 mol) in 40 mL 1,2-dimethoxyethane and 20 mL water was heated at 80° C. for eighteen hours, after which time additional 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (0.15 g, 0.00037 mol) was added. The mixture was stirred for an additional hour and then allowed to cool to ambient temperature. The precipitate was filtered and washed with 1,2-dimethoxyethane and dried in vacuo, to give 1-(1,4-dioxaspiro[4.5]dec-8-yl)-3-[4-(2-pyrimidinyloxy)phenyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine as a white solid (1.26 g, 0.00283 mol):1H NMR (DMSO-d6, 400 MHz) 8.68(d, 2H), 8.254(s, 1H), 7.73 (d, 2H), 7.37 (d, 2H), 7.31 (t, 1H), 6.30-7.20 (bs, 2H), 4.78-4.84 (m, 1H), 3.91 (s, 4H), 2.22-2.30 (m, 2H), 1.73-1.92 (m, 6H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13](OCC)=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][NH2:22]>CO>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([C:13]([NH:21][NH2:22])=[O:14])=[CH:11][C:10]=1[Cl:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Reactant: NN
Solvent: CO
Product: NNC(=O)c1ccc(OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
Ethyl 4-benzyloxy-3-chlorobenzoate [c.f., Jones & Robinson, J. Chem. Soc. 3845 (1955)] (32.0 g., 0.11 mole), 25 ml. methanol and 20 ml. 95% hydrazine are stirred under reflux for 8 hours and cooled to room temperature. The mixture is filtered and the resulting solid dried in vacuo to give 29.4 g. 4-benzyloxy-3-chlorobenzoic acid hydrazide (96.7% yield), m.p. 168°-171° C.
Reaction SMILES: [OH-].[Na+].[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([O:8]CC)=[O:7].C(OCC)C.O.Cl>O.C1COCC1>[CH3:3][C:4]([C:11]#[C:12][S:13]([C:16]1[CH:25]=[CH:24][C:23]2[C:22]([CH3:27])([CH3:26])[CH2:21][CH2:20][C:19]([CH3:29])([CH3:28])[C:18]=2[CH:17]=1)(=[O:15])=[O:14])=[CH:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)C=C(C)C#CS(=O)(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C#CS(=O)(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C)=CC(=O)O

Procedure:
NaOH (100 mg, 2.5 mmol) in water is added to a solution of ethyl 3-methyl-5-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-ylsulphonyl)pent-2-en-4-ynoate (605 mg, 1.7 mmol) in 15 ml of THF. The medium is then refluxed for 6 h. Next, it is poured into an ethyl ether/water mixture, acidified to pH 1 with concentrated hydrochloric acid solution and extracted with ethyl ether. After separation of the phases by settling, the organic phase is washed twice with water, dried over anhydrous magnesium sulphate and concentrated on a rotary evaporator under vacuum at 40° C. The residue is then crystallized from methanol.