Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:24]=[C:25]([C:30]4[CH:35]=[CH:34][N:33]=[CH:32][C:31]=4[NH2:36])[C:26](F)=[N:27][CH:28]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1.O>C1COCC1>[N:10]1([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[N:27][C:26]4[NH:36][C:31]5[CH:32]=[N:33][CH:34]=[CH:35][C:30]=5[C:25]=4[CH:24]=3)=[CH:19][CH:18]=2)[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: Nc1cnccc1-c1cc(-c2ccc(CN3CCCCC3)cc2)cnc1F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: O
Solvent: C1CCOC1
Product: c1cc2c(cn1)[nH]c1ncc(-c3ccc(CN4CCCCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.9 %

Procedure:
A 1N solution of bis(trimethylsilyl)amide in THF (2.78 mL, 2.80 mmol) was added dropwise to a solution of 5-(4-piperidin-1-ylmethyl-phenyl)-2-fluoro-[3,4′]bipyridinyl-3′-ylamine (101 mg, 0.278 mmol) in THF (5.0 mL) at ambient temperature. The mixture was stirred for 1 h at ambient temperature and then treated with water. The resultant brown solution was partitioned between DCM and water, the layers separated, and the aqueous phase extracted into 20% methanol in DCM. The combined organic phase was concentrated in vacuo. The resultant residue was absorbed onto silica gel, and purified by flash chromatography (silica, 1-20% methanol in DCM) to provide a light orange-yellow solid (39.9 mg, 42%). 1H NMR (DMSO-D6, 500 MHz): 12.24 (s, 1H), 8.99 (d, J=1.8 Hz, 1H), 8.93 (s, 1H), 8.92 (d, J=1.8 Hz, 1H), 8.45 (d, J=5.2 Hz, 1H), 8.22 (d, J=5.2 Hz, 1H), 7.77 (d, J=7.5 Hz, 2H), 7.45 (d, J=7.5 Hz, 2H), 3.49 (s, 2H), 2.36 (m, 4H), 1.52 (m, 4H), 1.41 (m, 2H). LCMS (Method D): RT=4.64 min, M+H+=343.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[C:9]([CH:10]=O)=[CH:8][N:7]=[C:6]([S:12][CH3:13])[N:5]=1)[CH3:2].C(O[C:17](=[O:29])[CH2:18][C:19]1[CH:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[CH:20]=1)C.N12CCCN=C1CCCCC2.CC#N>CS(C)=O.C(O)C>[CH3:13][S:12][C:6]1[N:7]=[CH:8][C:9]2[CH:10]=[C:18]([C:19]3[CH:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[CH:24]=3)[C:17](=[O:29])[N:3]([CH2:1][CH3:2])[C:4]=2[N:5]=1
Reactant: CCNc1nc(SC)ncc1C=O
Reactant: CCOC(=O)Cc1cc(OC)cc(OC)c1
Solvent: CC#N
Solvent: CCO
Solvent: CS(C)=O
Product: CCn1c(=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Temperature: 47.5 °C
Yield: 83.9 %

Procedure:
4.8 kg of 4-ethylamino-2-methylsulfanyl-pyrimidine-5-carboxaldehyde and 5.5 kg of (3,5-dimethoxyphenyl)-acetic acid ethyl ester were dissolved in 10 L of DMSO at room temperature and stirred. 4.4 kg of 1,8-diazabicyclo[5.4.0]undec-7-ene was added to the reaction mixture. The mixture was heated at about 45-50° C. for at least 3 hours. The reaction was monitored by reverse-phase HPLC (YMC-AQ column, 60:40 CH3CN/0.02 M SDS, pH 2.2, 1.0 mL/min, 254 nm). When the reaction was completed, ethyl alcohol (3 L) was added to the reaction vessel, which was cooled to 5-15° C. The yellow product was precipitated and collected by filtration, washed with a mixture of isopropyl alcohol and water (3 L+3 L), and dried in a vacuum tray dryer at about 40-45° C. for at least 12 hours using a house vacuum (˜30 in Hg) to provide 7.3 kg (84% yield) of 2-(methylsulfanyl)-6-(3,5-dimethoxyphenyl)-8-ethyl-8H-pyrido[2,3-d]pyrimidine-7-one. Proton NMR is consistent with the structure.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:22]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.O.[NH4+].[Cl-].C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:20]2[CH:21]=[CH:16][CH:17]=[C:18]([CH:22]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: Cc1nnc(C(CC(=O)O)c2cccc(Br)c2)o1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Yield: 57 %

Procedure:
12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97 g (150.3 mmol) and 18.7 g (60.1 mmol) of 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid are heated together with 3 mmol of bis(triphenylphosphine)palladium (II) dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C. The reaction mixture is diluted with conc. NH4Cl solution (200 ml) and extracted with methyl-tetrahydrofurane. The organic phase is filtrated over Celite and 100 g of SiO2 and the solvent is removed in vacuo. The obtained crude 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is used directly in the next step. (Yield=57%, 28 g)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[CH3:10])[NH2:6].[CH:11](=O)/[CH:12]=[CH:13]/[CH3:14].[NH4+].[OH-]>Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:7]([CH:11]=[CH:12][C:13]([CH3:14])=[N:6]2)=[CH:8][C:9]=1[CH3:10]
Reactant: COc1cc(N)ccc1C
Reactant: C/C=C/C=O
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Product: COc1cc2nc(C)ccc2cc1C
Yield: 42.5 %

Procedure:
To 3-methoxy-4-methylaniline (1.0 g, 7.29 mmol) in refluxing in 6N HCl (50 mL) was added dropwise (E)-but-2-enal (1.02 g, 14.6 mmol). The reaction was heated to reflux for 2 hours then cooled down and neutralized with NH4OH. The organic phase was extracted with DCM and the combined organic phases dried over MgSO4, filtered and concentrated under reduced pressure to leave a dark residue. The residue was purified by reverse phase chromatography (SP4, 25M, eluting with a gradient of water/ACN 100:0 to 0:100, 20 column volumes) to yield 7-methoxy-2,6-dimethylquinoline (580 mg, 29.7% yield) as a beige solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]([OH:9])=[O:8])[S:5][CH:6]=1.OS(O)(=O)=O.[OH-].[Na+].[CH3:17]O>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]([O:9][CH3:17])=[O:8])[S:5][CH:6]=1
Reactant: O=C(O)c1cc(Br)cs1
Reactant: CO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)c1cc(Br)cs1
Temperature: 50 °C
Reaction time: 12 h

Procedure:
To a solution of 4-bromo-2-thiophenecarboxylic acid (4 g, 19 mmol) in MeOH (100 mL) was added H2SO4 (5 mL) dropwise at 25° C. The solution was stirred for 12 h at 50° C. and was poured into ice-H2O and the pH was adjusted to 11 with aqueous NaOH. The aqueous phase was extracted several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and used directly (4.27 g, quant.): LCMS (ES) m/z 222 (M+H)+.
Reaction SMILES: C(O)(C(F)(F)F)=O.[NH2:8][C:9]1[C:28]([Br:29])=[CH:27][C:12]2[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([C:16]3(O)[CH2:20][CH2:19][CH2:18][CH2:17]3)[O:15][C:11]=2[CH:10]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl>[NH2:8][C:9]1[C:28]([Br:29])=[CH:27][C:12]2[C:13]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[C:14]([C:16]3[CH2:20][CH2:19][CH2:18][CH:17]=3)[O:15][C:11]=2[CH:10]=1
Reactant: CCOC(=O)c1c(C2(O)CCCC2)oc2cc(N)c(Br)cc12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)c1c(C2=CCCC2)oc2cc(N)c(Br)cc12
Temperature: 25 °C
Reaction time: 12 h
Yield: 94.1 %

Procedure:
TFA (1.5 mL) was added into a solution of ethyl 6-amino-5-bromo-2-(1-hydroxycyclopentyl)benzofuran-3-carboxylate (2.9 g, 7.89 mmol) in DCM (30 mL), then the mixture was stirred at 25° C. for 12 hours. The reaction mixture was poured into ice water, adjusted to pH=7 with NaHCO3 (a.q.), then the residue was extracted with DCM (50 mL*3), dried over Na2SO4, and concentrated to give the product of ethyl 6-amino-5-bromo-2-(cyclopent-1-en-1-yl)benzofuran-3-carboxylate (2.6 g, yield: 94%). 1H-NMR (CDCl3, 400 MHz) δ 7.99 (s, 1H), 7.11 (t, J=7.2 Hz, 1H), 6.83 (s, 1H), 4.43 (q, J=7.2 Hz, 2H), 2.86˜2.91 (m, 2H), 2.59˜2.63 (m, 2H), 2.01 (t, J=8.0 Hz, 2H), 1.46 (t, J=3.2 Hz, 3H). MS (M+H)+: 350/352.
Reaction SMILES: Cl[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])=[O:3].[NH3:54]>C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:47]=[CH:46][C:7]([CH2:8][O:9][CH:10]2[CH:15]([C:16]3[CH:21]=[CH:20][C:19]([O:22][CH2:23][CH2:24][CH2:25][O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[O:34][CH3:35])=[CH:18][CH:17]=3)[CH2:14][CH2:13][N:12]([C:36]([O:38][CH2:39][C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)=[O:37])[CH2:11]2)=[CH:6][C:5]=1[O:48][CH2:49][CH2:50][CH2:51][O:52][CH3:53])(=[O:3])[NH2:54]
Reactant: N
Reactant: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: COCCCOc1cc(COC2CN(C(=O)OCc3ccccc3)CCC2c2ccc(OCCCOCc3ccccc3OC)cc2)ccc1C(N)=O
Reaction time: 0.25 h

Procedure:
The solution of 0.290 g of benzyl 3-[4-chlorocarbonyl-3-(3-methoxypropoxy)benzyloxy]-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 1.0 ml of toluene is added dropwise slowly to 2.30 ml of ammonia solution (7M in methanol, precooled to 0° C.). After 15 minutes, the reaction solution is poured onto water (20 ml) and extracted with tert-butyl methyl ether (2×20 ml). The organic phases are washed with brine (1×30 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.06 (2:1 EtOAc-heptane); Rt=5.56.
Reaction SMILES: [BH4-].[Na+].B(F)(F)F.[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][C:15](=O)[C:16]1[CH:21]=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[C:19]([OH:26])=[C:18]([C:27]([CH3:30])([CH3:29])[CH3:28])[CH:17]=1.Cl>O1CCCC1>[NH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[NH:14][CH2:15][C:16]1[CH:17]=[C:18]([C:27]([CH3:28])([CH3:29])[CH3:30])[C:19]([OH:26])=[C:20]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:21]=1
Reactant: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Agent: Cl
Agent: FB(F)F
Agent: [BH4-]
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(CNc2ccccc2N)cc(C(C)(C)C)c1O
Reaction time: 0.5 h
Yield: 68.2 %

Procedure:
To a suspension of sodium borohydride (2.72 g) in tetrahydrofuran (80 ml) was added dropwise under ice-cooling BF3, Et20 (8.86 ml) and the mixture was stirred for 30 minutes. To this mixture was added by portions N-(2-aminophenyl )-3,5-di-t-butyl-4-hydroxybenzamide (3.06 g ) and the mixture was stirred overnight while returning slowly to room temperature. 6N hydrochloric acid war added and the mixture was heated under reflux for 30 minutes, the solvent was distilled off and the residue was placed into water, neutralized with sodium hydrogen carbonate, extracted with ethyl acetate, washed with water and saturated saline and dried over anhydrous MgSO4. The solvent was distilled off and the residue was purified by a silica gel column chromatography (hexane:ethyl acetate=4:1) to give (2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzylamine (2.00 g, 68%) as crystals.
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH:13]([CH2:17][CH:18]=[CH2:19])[C:14]([OH:16])=O)[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:10])([F:9])[F:8])[N:6]=1.CN(C=O)C.[Cl:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:36]([CH:37]([CH3:39])[CH3:38])=[C:35]([NH2:40])[CH:34]=[N:33]2)=[CH:28][CH:27]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>O.CCN(CC)CC>[Cl:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:36]([CH:37]([CH3:38])[CH3:39])=[C:35]([NH:40][C:14](=[O:16])[CH:13]([N:3]3[C:4]([CH:11]=[CH2:12])=[C:5]([C:7]([F:8])([F:9])[F:10])[N:6]=[C:2]3[CH3:1])[CH2:17][CH:18]=[CH2:19])[CH:34]=[N:33]2)=[CH:30][CH:31]=1
Reactant: C=CCC(C(=O)O)n1c(C)nc(C(F)(F)F)c1C=C
Reactant: CC(C)c1c(N)cnn1-c1ccc(Cl)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: C=CCC(C(=O)Nc1cnn(-c2ccc(Cl)cc2)c1C(C)C)n1c(C)nc(C(F)(F)F)c1C=C
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To 2-[2-methyl-4-(trifluoromethyl)-5-vinylimidazol-1-yl]pent-4-enoic acid (120 mg, 0.42 mmol) was added DMF (3 mL), Et3N (500 μL, excess), 1-(4-chlorophenyl)-5-isopropylpyrazol-4-amine (100 mg, 0.42 mmol), and HATU (250 mg, excess) and the resulting mixture was stirred at room temperature for 1 h. Water (20 mL) was added and the mixture was extracted with EtOAc (2×50 mL). The combined organics were then dried (MgSO4), concentrated in vacuo, and purified by flash chromatography (SiO2, 80% EtOAc/hexanes) to obtain N-[1-(4-chlorophenyl)-5-isopropylpyrazol-4-yl]-2-[2-methyl-4-(trifluoromethyl)-5-vinylimidazol-1-yl]pent-4-enamide (147 mg, 0.3 mmol, 70% yield).
Reaction SMILES: O=S1[O:6][CH:5]([C@@H:7]([N:15]2[C:23](=[O:24])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[C:16]2=[O:25])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:4]O1.[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][NH:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C(=O)([O-])[O-].[Na+].[Na+]>CC(CC(C)C)=O>[C:26]([NH:30][C:31]([C@@H:33]1[CH2:42][C@H:41]2[C@H:36]([CH2:37][CH2:38][CH2:39][CH2:40]2)[CH2:35][N:34]1[CH2:4][C@@H:5]([OH:6])[C@@H:7]([N:15]1[C:16](=[O:25])[C:17]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:23]1=[O:24])[CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:32])([CH3:29])([CH3:27])[CH3:28]
Reactant: O=C1c2ccccc2C(=O)N1[C@@H](Cc1ccccc1)C1COS(=O)O1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)N1C(=O)c2ccccc2C1=O
Yield: 65 %

Procedure:
A suspension of 0.35 g of the above 83:17 mixture of the two 1:1 mixtures of the (2R,4S) and (2S,4S) and respectively (2R,4R) and (2S,4R) isomers of 2-[(S)-1-[2-oxo-1,3,2-dioxathiolan-4-yl]-2-phenylethyl]-2,3-dihydro-1H-isoindol-1,3-dione, 0.24 g of N-tert.butyl-decahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide and 0.21 g of sodium carbonate in 3.5 ml of isobutyl methyl ketone is heated to reflux for 24 hours, thereafter cooled and filtered. The filtrate is purified on silica gel with hexane/ethyl acetate (4:1). After evaporation and drying there is obtained 0.34 g (65%) of pure N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-phthalimidobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide, IR (KBr): 3388m (OH), 1771m and 1708s (C=O of imide).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=2)=[CH:6][CH:7]=1.[C:17](OCC)(=[O:20])[NH:18][NH2:19]>C(O)CCC>[F:16][C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]3[N:3]([C:17](=[O:20])[NH:18][N:19]=3)[N:4]=2)[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: COc1ccc(-c2ccc(Cl)nn2)cc1F
Reactant: CCOC(=O)NN
Solvent: CCCCO
Product: COc1ccc(-c2ccc3n[nH]c(=O)n3n2)cc1F

Procedure:
A mixture comprising 4.0 g. of 3-chloro-6-(3-fluoro-4-methoxyphenyl)-pyridazine (U.S. Pat. No. 4,092,311), 3.54 g. of ethyl carbazate and 100 ml. of butanol is stirred at reflux for 3 days and then cooled in an ice bath. The resulting solid is collected by filtration and dried, giving 2.4 g. of the desired product as a tan solid, m.p. 289°-290° C.
Reaction SMILES: I.[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8](=[NH:11])SC.[NH2:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.C(O)C>O>[Cl:2][C:3]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[C:4]=1[CH:5]=[N:6][NH:7][C:8]([NH:17][CH2:18][C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1)=[NH:11]
Reactant: NCc1cccnc1
Reactant: CSC(=N)NN=Cc1c(Cl)cccc1Cl
Agent: I
Solvent: CCO
Solvent: O
Product: N=C(NCc1cccnc1)NN=Cc1c(Cl)cccc1Cl

Procedure:
A mixture of 5.85 g. of methyl 3-(2,6-dichlorobenzylidene)thiocarbazimidate hydriodide, 3.24 g. of 3-(aminomethyl)pyridine and 25 ml. of absolute ethanol is heated under reflux for 24 hours and diluted while hot with 75 ml. of water. After cooling, an oil separates and crystallizes. The mixture is chilled overnight and the crystals are separated and recrystallized from 100 ml. of 50% aqueous ethanol to give the desired product as pale yellow crystals, m.p. 148°-151° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([S:9][CH2:10][CH2:11][O:12][S:21]([CH3:20])(=[O:23])=[O:22])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CS(=O)(=O)Cl
Reactant: OCCSc1ccc(Cl)c(Cl)c1
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCSc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 117.97 g (0.53 mole) of 2-[(3,4-dichlorophenyl)thio]ethanol (prepared by reacting 3,4-dichlorothiophenol and 2-chloroethanol) and 53.5 g (0.53 mole) of triethylamine in 500 ml of benzene was added dropwise a benzene solution of 60.9 g (0.53 mole) of methanesulfonyl chloride over a one hour period with cooling in an ice bath. The reaction mixture was stirred at room temperature overnight and filtered. Solvent was removed from the filtrate in a rotary evaporator to give an oil which crystallized. A portion was recrystallized from isopropyl ether to give white crystalline solid, m.p. 53°-55° C.
Reaction SMILES: [CH3:1][S:2]([CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12])=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH3:1][S:2][CH:4]=[C:5]1[C:9]([CH3:11])([CH3:10])[CH2:8][CH2:7][C:6]1([CH3:13])[CH3:12]
Reactant: CS(=O)C=C1C(C)(C)CCC1(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSC=C1C(C)(C)CCC1(C)C
Temperature: 25 °C
Reaction time: 10 h
Yield: 75 %

Procedure:
20 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfoxide was dissolved in 200 ml of tetrahydrofuran, and 4.0 g of lithium aluminum hydride was added thereto in small portions. The mixture was stirred at room temperature for 10 hours, and then 100 ml of ethyl acetate was added dropwise thereto. After the mixture was subjected to filtration, the filtrate was concentrated under reduced pressure. The oily substance was subjected to silica gel column chromatography using ethyl acetaten-hexane as an eluent, whereby 13.8 g of 2,2,5,5-tetramethylcyclopentylidenemethyl methyl sulfide was obtained as an oily substance.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1.[C:32](Cl)(=[O:34])[CH3:33].C(N(CC)CC)C>O1CCCC1.CN(C)C1C=CN=CC=1.ClCCl>[C:32]([NH:2][C:3]1[C:4]([C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[F:31])=[O:19])=[CH:13][CH:12]=2)=[C:5]([C:8]([NH2:10])=[O:9])[NH:6][CH:7]=1)(=[O:34])[CH3:33]
Reactant: CC(=O)Cl
Reactant: NC(=O)c1[nH]cc(N)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)Nc1c[nH]c(C(N)=O)c1-c1ccc(NC(=O)Nc2cc(C(F)(F)F)ccc2F)cc1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
To 0.15 g (0.328 mmol) of 4-amino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)-ureido]phenyl}-1H-pyrrole-2-carboxamide hydrochloride dissolved in 4.5 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.023 cm3 of acetyl chloride, 0.091 cm3 of triethylamine and 8 mg of 4-dimethylaminopyridine. After stirring for 16 hours at a temperature in the region of 20° C., the reaction mixture is diluted with 15 cm3 of dichloromethane and then washed with twice 10 cm3 of saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure (2.7 kPa) to give a solid, which is recrystallized while hot from 5 cm3 of dichloromethane. The recrystallized solid is filtered off through a No 3 sinter funnel, washed with twice 3 cm3 of dichloromethane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 40° C. for 5 hours to give 0.084 g of 4-acetylamino-3-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]phenyl}-1H-pyrrole-2-carboxamide in the form of a white solid melting at 228.5° C.; ES+: m/z=464: [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C:6]([CH3:8])([CH3:7])[O:5][B:4]([C:9]2[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=2)[O:3]1.CC1C=CC(S(O[CH2:28][P:29]([O:34][CH2:35][CH3:36])([O:31][CH2:32][CH3:33])=[O:30])(=O)=O)=CC=1>>[CH2:32]([O:31][P:29]([CH2:28][O:15][C:12]1[CH:13]=[CH:14][C:9]([B:4]2[O:3][C:2]([CH3:16])([CH3:1])[C:6]([CH3:7])([CH3:8])[O:5]2)=[CH:10][CH:11]=1)(=[O:30])[O:34][CH2:35][CH3:36])[CH3:33]
Reactant: CC1(C)OB(c2ccc(O)cc2)OC1(C)C
Reactant: CCOP(=O)(COS(=O)(=O)c1ccc(C)cc1)OCC
Product: CCOP(=O)(COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)OCC
Yield: 23 %

Procedure:
Using 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (313 mg, 1.42 mmol) and (diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (550 mg, 1.71 mmol), the desired title compound (121 mg, yield 23%) was obtained by the same method as in Reference Example 2 (2a).
Reaction SMILES: [CH:1]([O:4][Si:5]([CH3:8])([CH3:7])Cl)([CH3:3])[CH3:2].[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Mg]Cl)=[CH:13][CH:12]=1)=[CH2:10].C(C1C=CC(Cl)=CC=1)=C.[Mg]>C1COCC1>[CH:9]([C:11]1[CH:16]=[CH:15][C:14]([Si:5]([CH3:8])([CH3:7])[O:4][CH:1]([CH3:3])[CH3:2])=[CH:13][CH:12]=1)=[CH2:10]
Reactant: CC(C)O[Si](C)(C)Cl
Reactant: C=Cc1ccc([Mg]Cl)cc1
Agent: C=Cc1ccc(Cl)cc1
Agent: [Mg]
Solvent: C1CCOC1
Product: C=Cc1ccc([Si](C)(C)OC(C)C)cc1
Temperature: 10 °C
Reaction time: 18 h
Yield: 45 %

Procedure:
A solution of isopropoxydimethylchlorosilane (15.2 g, 100 mmole) in dry THF (50 mL) was added dropwise over a 1 hour period to a solution of (4-vinylphenyl)magnesium chloride, prepared from 4-vinylphenyl chloride (13.85 g, 100 mmole) and magnesium (3.0 g, 125 mmole) in dry 100 mL THF. The temperature was maintained at 10° C. during the addition. The reaction mixture was stirred at room temperature for over 18 hours. The desired product distilling at 45°-49° C./0.2 mm was obtained in 45% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][CH:15]=[CH:14]2)([O-])=O>C(O)C.[Pd]>[NH:16]1[C:17]2[C:13](=[CH:12][C:11]([O:10][C:9]3[CH:8]=[CH:7][N:6]=[CH:5][C:4]=3[NH2:1])=[CH:19][CH:18]=2)[CH:14]=[CH:15]1
Reactant: O=[N+]([O-])c1cnccc1Oc1ccc2[nH]ccc2c1
Agent: [Pd]
Solvent: CCO
Product: Nc1cnccc1Oc1ccc2[nH]ccc2c1
Reaction time: 1 h
Yield: 94.9 %

Procedure:
To a slurry of 10% Pd/C (1.0 g) in 10 ml of ethanol was added 5-[(3-nitro-4-pyridinyl)oxy]-1H-indole (3.7 g) in 240 ml ethanol and this was shaken on a Parr apparatus for 1 hour. The mixture was filtered and the filtrate concentrated to yield an oil (3.1 g) which was eluted with ethyl acetate on a silica gel column via HPLC. The desired fractions were concentrated to an oil which solidified on standing to yield2.6 g, m.p. 155°-157° C.