Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[Cl:13][C:14]1[S:18][C:17]([CH2:19][NH2:20])=[CH:16][CH:15]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:13][C:14]1[S:18][C:17]([CH2:19][N:20]=[C:2]=[O:4])=[CH:16][CH:15]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: NCc1ccc(Cl)s1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C=NCc1ccc(Cl)s1
Temperature: 25 °C

Procedure:
To a solution of triphosgene (1.15 g, 3.9 mmol) in CH2Cl2 (30 mL) was added dropwise a mixture of (5-chlorothiophen-2-yl)methanamine (1.14 g, 7.8 mmol) and DIPEA (2.0 g, 15.6 mmol) in CH2Cl2 (32 mL) over 2 hours at 0 C under N2 atmosphere. After addition was complete, the mixture was refluxed for 1 hour and then cooled to ambient temperature. The mixture was washed with aq. KHSO4, brine, dried over Na2SO4, and concentrated to give 5-chlorothiophen-2-yl-methyl isocynate a yellow liquid (1.34 g, yield 100%), which was used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[O:12]1[CH2:17]COC[CH2:13]1.O.C(=O)([O-])[O-].[Cs+].[Cs+]>C(Cl)Cl>[CH3:13][O:12][CH2:17][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(Br)cc1
Reactant: C1COCCO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: ClCCl
Solvent: O
Product: COCc1ccc(C(=O)OC)cc1
Temperature: 100 °C
Reaction time: 4.5 h
Yield: 33 %

Procedure:
To a mixture of methyl 4-bromobenzoate (50 mg, 0.233 mmol) and 1,4-dioxane (1 ml) were added water (0.1 ml), cesium carbonate (228 mg, 0.7 mmol), potassium methoxymethyl trifluoroborate (71 mg, 0.467 mmol) and 1′,1′-bis(diphenylphosphino)ferrocenedichloropalladium (II) (17 mg, 0.023 mmol). Then, the reaction mixture was stirred at 100° C. (external temperature) for 4.5 hours. After the reaction mixture was cooled at room temperature, water and methylene chloride were added to the mixture, followed by filtration using celite. The separated organic layer was washed with an aqueous saturated sodium chloride solution. The organic layer was separated, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethylacetate=10:1) to obtain the title compound (13.9 mg, 33%).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[N:11][C:12]=2[NH:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]3[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=3)=[C:17]([Cl:29])[CH:16]=2)[NH:7][N:6]=1.[C:30]([N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1)(=[O:32])[CH3:31]>>[C:30]([N:33]1[CH2:38][CH2:37][N:36]([CH2:2][CH2:3][O:4][C:5]2[C:13]3[C:8](=[N:9][CH:10]=[N:11][C:12]=3[NH:14][C:15]3[CH:20]=[CH:19][C:18]([O:21][C:22]4[CH:23]=[N:24][C:25]([CH3:28])=[CH:26][CH:27]=4)=[C:17]([Cl:29])[CH:16]=3)[NH:7][N:6]=2)[CH2:35][CH2:34]1)(=[O:32])[CH3:31]
Reactant: CC(=O)N1CCNCC1
Reactant: Cc1ccc(Oc2ccc(Nc3ncnc4[nH]nc(OCCCl)c34)cc2Cl)cn1
Product: CC(=O)N1CCN(CCOc2n[nH]c3ncnc(Nc4ccc(Oc5ccc(C)nc5)c(Cl)c4)c23)CC1
Yield: 32 %

Procedure:
The procedure described in Example 23 was repeated using 3-(2-chloroethoxy)-N-{3-chloro-4-[(6-methylpyridin-3-yl)oxy]phenyl}-1H-pyrazolo[3,4-d]pyrimidin-4-amine and N-acetylpiperazine to give the title compound in 32% yield; NMR Spectrum: 1.96 (s, 3H), 2.45 (s, 3H), 2.46-2.53 (m, partially hidden by DMSO, 8H), 2.86 (t, 2H), 4.47 (t, 2H), 6.05 (br s, 1H), 7.20 (d, 1H), 7.26 (br s, 2H), 7.71 (d, 1H), 8.12 (s, 1H), 8.20 (s, 1H), 8.36 (s, 1H); Mass Spectrum: 523 (MH+).
Reaction SMILES: [CH:1]1([CH:9]=O)[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:11][C:12]1[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=1.C(O)(=O)C>[Zn].C1C=CC=CC=1>[CH:1]1([CH2:9][NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]1
Reactant: Nc1ccc(C(=O)O)cc1
Reactant: O=CC1CCCCCCC1
Agent: [Zn]
Solvent: CC(=O)O
Solvent: c1ccccc1
Product: O=C(O)c1ccc(NCC2CCCCCCC2)cc1

Procedure:
Cyclooctane carboxaldehyde (14.72 g, 0.105 mole) was added dropwise to a stirred and refluxing mixture of 13.7 g (0.1 mole) p-aminobenzoic acid, 25 g zinc dust, 25 ml glacial acetic acid and 125 ml of benzene. Water which evolved was collected in a Dean-Stark trap as the reaction mass was refluxed overnight. Following the reflux period, the resulting product mass was filtered while still hot. Upon cooling the filtrate, crystals formed therein. The benzene was evaporated and the residue recrystallized from acetonitrile. The crude product weighed 18.77 g. It was decolorized and recrystallized from benzene. The resulting purified 4-[(cyclooctylmethyl)amino]benzoic acid product weighed 12.93 g. It had a melting point of 160°-162° C.
Reaction SMILES: [N:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH3:11])=[C:2]=[S:3].C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=1[NH2:22].C(O)(=O)C>C(O)C>[SH:3][C:2]1[N:1]([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[O:10][CH3:11])[C:14](=[O:13])[C:15]2[C:16](=[CH:17][C:18]([CH3:21])=[CH:19][CH:20]=2)[N:22]=1
Reactant: COC(=O)c1ccc(C)cc1N
Reactant: COc1ccccc1N=C=S
Solvent: CC(=O)O
Solvent: CCO
Product: COc1ccccc1-n1c(S)nc2cc(C)ccc2c1=O
Temperature: 25 °C
Yield: 61.5 %

Procedure:
1-Isothiocyanato-2-methoxy-benzene (0.76 mL, 5.45 mmol) was added to a solution of 2-amino-4-methyl-benzoic acid methyl ester (900 mg, 5.45 mmol) and acetic acid (1.5 mL) in ethanol (10 mL), and heated at reflux for 16 hr. The reaction mixture was cooled to room temperature and diluted with ethanol. The precipitated solid was filtered, washed with ethanol and dried to afford 2-mercapto-3-(2-methoxy-phenyl)-7-methyl-3H-quinazolin-4-one (1.0 g, 62%) as white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[C:8]1([CH3:15])[CH:13]=[CH:12][C:11](Br)=[CH:10][CH:9]=1.[Mg].[Cl-].[NH4+]>CCOCC>[Br:1][C:2]1[C:3]([C:11]2[CH:12]=[CH:13][C:8]([CH3:15])=[CH:9][CH:10]=2)=[N:4][CH:5]=[N:6][CH:7]=1
Reactant: Cc1ccc(Br)cc1
Reactant: Brc1cncnc1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: CCOCC
Product: Cc1ccc(-c2ncncc2Br)cc1
Reaction time: 8 h

Procedure:
To a solution of 5-bromopyrimidine (15.9 g, 0.1 mmol) in ether (200 ml) was added a Grignard reagent (prepared from p-tolyl bromide (20.52 g, 0.12 mmol), magnesium (2.92 g, 0.1 mmol) and ether (100 ml) dropwise at room temperature during 10 minutes. After the addition, the resulting suspension was heated under reflux for 1 hour and allowed to stand overnight. The reaction mixture was treated with aqueous ammonium chloride and then the ether layers were collected. The aqueous layers were extracted with methylene chloride and the extracts were combined with the ether layers and concentrated to dryness. The residue was purified by column chromatography on silica gel and then dissolved in acetone (100 ml). To the acetone solution was added a solution of potassium permanganate in acetone until red color disappeared, manganese dioxide was removed from the reaction mixture by filtration. The filtrate was concentrated to dryness and the residue was purified by column chromatography on silica gel. Recrystallization from hexane afforded colorless needles (12.8 g, 51%), m.p. 81°-82° C.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.FC(F)(F)S(O[Si:26]([CH3:29])([CH3:28])[CH3:27])(=O)=O>C1(C)C=CC=CC=1>[CH3:27][Si:26]([N:1]([Si:26]([CH3:29])([CH3:28])[CH3:27])[C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:11][CH:12]=1)([CH3:29])[CH3:28]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(N([Si](C)(C)C)[Si](C)(C)C)cc1
Yield: 92.6 %

Procedure:
About 9.24 g of ethyl 4-aminobenzoate, 14.88 g of triethylamine, and 10 ml of toluene were mixed in a round-bottom reaction flask cooled with an ice bath. To this mixture was added, in a dropwise fashion, a solution of 32.68 g of trimethylsilyl trifluoromethanesulfonate in 50 ml of toluene. The resulting mixture was heated to reflux for 8 hours to give a biphasic mixture. The top layer was transferred to another flask, and the bottom layer was extracted with 40 ml of toluene. The combined toluene solution was evaporated under vacuum. The residue was extracted with 100 ml of hexane, and the hexane layer was evaporated under vacuum, yielding ethyl 4-[bis(trimethylsilyl)amino]benzoate (4-BTMSAEBz) as a yellow oil (16.04 g, 93% yield). The 1H NMR data (C6D6, 25° C., referenced to tetramethylsilane) of the product are listed as follows: δ 8.07 (doublet, 2 H, aromatic protons), 6.76 (doublet, 2 H, aromatic protons), 4.12 (quartet, 2 H, CH2 protons), 1.00 (triplet, 3 H, CH3 protons), 0.02 (singlet, 18 H, Si—CH3 protons). From the 1H NMR data, the structure of the product was determined to be as follows:
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]=[O:14])=[CH:11][N:12]=1)([CH3:4])([CH3:3])[CH3:2].C[Si]([C:20]#[N:21])(C)C>ClCCl.[Zn+2].[I-].[I-]>[C:1]([O:5][C:6](=[O:15])[NH:7][C:8]1[S:9][C:10]([CH:13]([OH:14])[CH2:20][NH2:21])=[CH:11][N:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ncc(C=O)s1
Reactant: C[Si](C)(C)C#N
Agent: [I-]
Agent: [Zn+2]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1ncc(C(O)CN)s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of compound 62.3 (4.5 mmol) in dichloromethane is added trimethylsilyl cyanide (“TMSCN”; 2.1 equivalents) and ZnI2 (10% mol). After stirring at room temperature overnight, the reaction is concentrated under vacuum. The crude cyanohydrin is dissolved in THF and treated with AlH3 (2.2 equivalents of a 0.5 M solution in THF). After stirring for 15 minutes, the reaction is quenched with the addition of saturated aqueous Na2SO4, is filtered through a pad of Celite, is dried and concentrated. Purification by flash column chromatography on silica gel (10% 7.0 M NH3/MeOH in dichloromethane) provides [5-(2-amino-1-hydroxy-ethyl)-thiazol-2-yl]-carbamic acid tert-butyl ester (compound 62.4).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[C:9]([C:18](OCC)=[O:19])[CH:8]=1)=[O:5].[CH2:34]([CH2:36][NH2:37])[OH:35].C(N(CC)C(C)C)(C)C>CO>[Cl:1][C:2]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([F:33])=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:23][C:3]=1[C:4]([NH:6][C:7]1[N:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:10]=[C:9]([C:18]([NH:37][CH2:36][CH2:34][OH:35])=[O:19])[CH:8]=1)=[O:5]
Reactant: NCCO
Reactant: CCOC(=O)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: CO
Product: O=C(NCCO)c1cc(NC(=O)c2cc(-c3ncccc3F)ccc2Cl)n(-c2ccccc2)n1
Yield: 41.7 %

Procedure:
Ethyl 5-(2-chloro-5-(3-fluoropyridin-2-yl)benzamido)-1-phenyl-1H-pyrazole-3-carboxylate (Example 113, 40 mg, 0.09 mmol), ethanolamine (15.7 mg, 0.26 mmol) and N,N-diisopropylethylamine (33.3 mg, 0.26 mmol) in methanol (1 mL) was heated at 50° C. in a sealed vial for 17 hours. The reaction was cooled and purified using reverse phase column chromatography eluting with 3-50% MeCN in water with 0.1% ammonia to afford the title compound as a white solid (18 mg, 44%).
Reaction SMILES: [F:1][C:2]1[CH:16]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:14]=[CH:13][C:3]=1[O:4][C:5]1[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=1.C([O-])(O)=O.[Na+].Br[C:32]1[CH:37]=[CH:36][N:35]([CH2:38][CH:39]2[CH2:41][CH2:40]2)[C:34](=[O:42])[C:33]=1[C:43]#[N:44]>O1CCOCC1.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>[CH:39]1([CH2:38][N:35]2[CH:36]=[CH:37][C:32]([C:15]3[CH:14]=[CH:13][C:3]([O:4][C:5]4[C:6]([CH3:12])=[N:7][C:8]([CH3:11])=[CH:9][CH:10]=4)=[C:2]([F:1])[CH:16]=3)=[C:33]([C:43]#[N:44])[C:34]2=[O:42])[CH2:40][CH2:41]1
Reactant: Cc1ccc(Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2F)c(C)n1
Reactant: N#Cc1c(Br)ccn(CC2CC2)c1=O
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: C1COCCO1
Product: Cc1ccc(Oc2ccc(-c3ccn(CC4CC4)c(=O)c3C#N)cc2F)c(C)n1
Yield: 57.1 %

Procedure:
To a solution of intermediate 12 (2 mmol) in 1,4-dioxane (6 ml) and a saturated solution of NaHCO3 (6 ml) was added intermediate 5 (0.51 g, 2 mmol). The resulting solution was degassed using a stream of nitrogen and to this was added Pd(PPh3)4 (0.231 mg, 0.2 mmol). The reaction was then microwaved in a sealed tube at 150° C. for 10 minutes. The resulting cooled reaction mixture was filtered through a pad of diatomaceous earth and concentrated in vacuo. The crude reaction mixture was then purified by column chromatography (silica gel; DCM to DCM/MeOH up to 3% as eluent). The desired fractions were collected and evaporated in vacuo to yield compound 3 (0.445 g, 58%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15](Cl)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[O:24]1[C:29]2[CH:30]=[CH:31][C:32]([NH2:34])=[CH:33][C:28]=2[O:27][CH2:26][CH2:25]1>>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[C:15]([NH:34][C:32]3[CH:31]=[CH:30][C:29]4[O:24][CH2:25][CH2:26][O:27][C:28]=4[CH:33]=3)[N:14]=[N:13][C:12]=2[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc2c(c1)OCCO2
Reactant: CC(C)(C)c1ccc(-c2cc(Cl)nnc2-c2ccccc2)cc1
Product: CC(C)(C)c1ccc(-c2cc(Nc3ccc4c(c3)OCCO4)nnc2-c2ccccc2)cc1

Procedure:
Analogous to the procedure used to prepare Example 5(b), 4-(4-tert-butyl-phenyl)-6-chloro-3-phenylpyridazine, Example 78(d), (155 mg, 0.5 mmol) and 1,4-benzodioxan-6-amine (80 mg, 0.5 mmol, Aldrich) to give the product as a light yellow crystalline solid. MS (ESI, pos. ion) m/z: 438 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>C(#N)C.ClCCl>[CH2:9]([NH:16][C:2]1[CH:7]=[N:6][CH:5]=[C:4]([Cl:8])[N:3]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Clc1cncc(Cl)n1
Reactant: NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: Clc1cncc(NCc2ccccc2)n1
Temperature: 85 °C
Yield: 80.2 %

Procedure:
A mixture of 2,6-dichloropyrazine (1.31 g, 8.8 mmol), benzylamine (1.15 g, 10.7 mmol) and K2CO3 (1.65 g, 11.9 mmol) in acetonitrile (6 mL) was heated at 85° C. for 13 h in a sealed pyrex flask. The reaction mixture was diluted with dichloromethane, filtered and concentrated in vacuo. The yellow solid residue was dissolved in a small volume of methanol and purified by silica gel chromatography (18×4 cm) using CHCl3/MeOH (98:2) as eluent. A second purification (SiO2; 16×4 cm) using CHCl3 as eluent furnished 1.55 g (81%) of the title compound as a light yellow solid. HRMS m/z calcd for C11H10ClN3 (M)+ 219.0563, found 219.0568. Anal. (C11H10ClN3) C, H, N.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([CH2:18][CH2:17][N:16]([C:19]([N:21](CC)[CH:22]([CH3:24])C)=[O:20])[CH2:15]3)[O:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1.[CH2:27]([NH:29][CH:30](C)C)[CH3:28]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[CH2:14][C:13]3([O:12][N:11]=2)[CH2:18][CH2:17][N:16]([C:19]([NH:21][C:22]2[CH:28]=[CH:27][N:29]=[CH:30][CH:24]=2)=[O:20])[CH2:15]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CCNC(C)C
Reactant: CCN(C(=O)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1)C(C)C
Product: O=C(Nc1ccncc1)N1CCC2(CC(C#Cc3cccc(Cl)c3)=NO2)C1
Yield: 16.4 %

Procedure:
The title compound was synthesized using the method described for the compound of Example 109, replacing 4-aminopyridine for ethylisopropylamine. After the usual work-up procedure evaporation, the crude was purified by means of automated flash chromatography (SP01®TM-Biotage; gradient EtOAc-MeOH/NH3 from 98:2 to 85:15) to afford a pale yellow solid. Yield: 16.4%.
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=O)[NH:7][C:6]1=[S:15])[CH:2]([CH3:4])[CH3:3].COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>C1(C)C=CC=CC=1>[CH2:1]([N:5]1[C:13]2[N:12]=[CH:11][NH:10][C:9]=2[C:8](=[S:25])[NH:7][C:6]1=[S:15])[CH:2]([CH3:4])[CH3:3]
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)Cn1c(=S)[nH]c(=O)c2[nH]cnc21
Solvent: Cc1ccccc1
Product: CC(C)Cn1c(=S)[nH]c(=S)c2[nH]cnc21
Temperature: 120 °C
Reaction time: 0.17 h
Yield: 74.8 %

Procedure:
3-Isobutyl-2-thioxanthine (0.20 g, 0.89 mmol) and Lawesson's reagent (1.1 g, 2.7 mmol) were suspended in toluene (8 mL). This mixture was heated at 120° C. for 17 h. The reaction mixture was cooled and the solvent removed under reduced pressure. 10% Sodium hydroxide (20 mL) was added and the mixture stirred for 10 minutes. This solution was filtered to remove insoluble solids and the solid washed with 10% sodium hydroxide solution. The basic filtrate was treated with dilute acetic acid until pH 4 was reached. The resulting precipitate was collected by filtration and washed with water. Drying of the substance afforded the title compound (0.16 g, 73%).
Reaction SMILES: Cl[CH2:2][CH:3]1[CH:5]([C:6]([O:8]CC)=O)[C:4]1([CH3:20])[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=1.[CH:21]1([CH2:27][CH2:28][CH2:29][NH2:30])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>Cl>[CH:21]1([CH2:27][CH2:28][CH2:29][N:30]2[CH2:2][CH:3]3[CH:5]([C:4]3([CH3:20])[C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=3)[C:6]2=[O:8])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: NCCCC1CCCCC1
Reactant: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC1(c2cccc([N+](=O)[O-])c2)C2CN(CCCC3CCCCC3)C(=O)C21
Yield: 72.7 %

Procedure:
A solution of ethyl 3-(chloromethyl)-2-methyl-2-(3-nitrophenyl)cyclopropane carboxylate (Preparation 5, 1 g, 3.36 rmnol) in 3-cyclohexylpropylamine ([Preparation—Eur. J. Med. Chem. (1992), 27, 321-330], 2.9 g, 20.5 mmol) was heated to 160° C. for 16 h. The mixture was cooled, 2N hydrochloric acid solution (20 ml) was added and the mixture was extracted with dichloromethane (3×20 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (200 g) column chromatography eluting with dichloromethane then diethyl ether. Appropriate fractions were combined and concentrated in vacuo to give the title compound as an amber oil (870 mg, 73%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[N:7]([CH2:11][CH2:12]Cl)[CH2:8][CH2:9]Cl)([CH3:4])([CH3:3])[CH3:2].[Cl:15][C:16]1[CH:28]=[CH:27][C:19]([CH2:20][C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:18][CH:17]=1.C[Si](C)(C)[N-][Si](C)(C)C.[Na+].CO>C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:7]1[CH2:11][CH2:12][C:20]([C:19]2[CH:27]=[CH:28][C:16]([Cl:15])=[CH:17][CH:18]=2)([C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)[CH2:9][CH2:8]1)=[O:14])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N(CCCl)CCCl
Reactant: Clc1ccc(Cc2ccncc2)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC(c2ccncc2)(c2ccc(Cl)cc2)CC1
Temperature: 0 °C
Reaction time: 3.5 h
Yield: 0.7 %

Procedure:
Under nitrogen, a solution of bis-(2-chloro-ethyl)-carbamic acid tert-butyl ester* (1.54 g, 6.36 mmol) in toluene (10 mL) was cooled in ice. 4-(4-Chloro-benzyl)-pyridine (1.30 g, 6.36 mmol) was added, followed over two minutes by sodium hexamethyldisilazide solution (10 mL, 20 mmol, 2M in THF). The mixture was stirred at 0° C. for 3.5 hours then allowed to warm to room temperature and stirred for a further 20 hours. Methanol was added then the mixture was concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 1N hydrochloric acid (×3) and brine, dried (MgSO4), filtered and concentrated to afford a residue which was purified by column chromatography (SiO2), eluting with gradient of 2M methanolic ammonia in dichloromethane (1% to 5%). A second purification by column chromatography (SiO2), eluting with 50% ethyl acetate/petrol gave the title compound (16 mg, 0.7%). LCMS (PS-A2) Rt 2.65 min [M+H]+ 373. *This starting material can be made by the method described in J. Chem. Soc., Perkin Trans 1, 2000, p3444-3450
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16]([CH2:17][C:18]([OH:20])=O)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[C:21](N1C=CN=C1)([N:23]1C=CN=[CH:24]1)=O.CNC>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:16]([CH2:17][C:18]([N:23]([CH3:24])[CH3:21])=[O:20])[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Agent: CNC
Solvent: C1CCOC1
Product: CN(C)C(=O)Cn1c(-c2ccc(F)cc2)nc2cccnc21
Temperature: 45 °C
Reaction time: 8 h
Yield: 39.1 %

Procedure:
A mixture of 2-(4-fluorophenyl-3H-imidazo[4,5-b]pyridine-3-acetic acid (5.0 g, 0.01845 mole) and 1,1'-carbonyldiimidazole (2.99 g, 0.01845 mole) was stirred at room temperature in dry tetrahydrofuran (100 ml) for three hours with a stream of nitrogen bubbling through it. A solution of dimethylamine in tetrahydrofuran (48 ml of 2.29 M solution, 0.111 mole) was added and the reaction mixture was stirred at 45° C. under nitrogen overnight. The solvents were removed under reduced pressure and the residue was triturated in water (100 ml), the solid was collected by filtration, rinsed twice with water, twice with a 5% potassium hydroxide solution and twice again with water. The solid was dissolved in hot isopropyl alcohol, filtered hot, cooled to room temperature and isopropyl ether was added to the cloud point. The resulting solid was collected by filtration, rinsed with isopropyl ether and dried under high vacuum at 42° C. overnight to give 2.15 g (39%) of title compound, mp. 180°-183° C.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:9][N:8]=1)(=O)=O.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1.C([O-])([O-])=O.[K+].[K+].O>C(#N)C>[O:24]1[CH2:25][CH2:26][N:21]([CH2:6][C:7]2[N:8]=[CH:9][C:10]([NH:13][C:14](=[O:15])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:11][CH:12]=2)[CH2:22][CH2:23]1
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)Nc1ccc(COS(C)(=O)=O)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CN2CCOCC2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 72.8 %

Procedure:
A mixture containing (5-(tert-butoxycarbonylamino)pyridin-2-yl)methyl methanesulfonate (114; 1.70 g), morpholine (48; 1.0 g, 11.3 mmol) and K2CO3 (2.30 g, 16.9 mmol) in acetonitrile (30 mL) was stirred at room temperature for 12 h. Water (30 mL) was added and the mixture was extracted with ethyl acetate (3×30 mL). The combined organic layers were dried (MgSO4) and concentrated under reduced pressure. The resulting residue was purified by chromatography (petroleum ether:ethyl acetate=1:1 to 1:3) to afford tert-butyl 6-(morpholinomethyl)pyridin-3-ylcarbamate 115 (1.20 g, 71% for two steps).
Reaction SMILES: [NH:1]([C:3]1[C:8]([CH2:9][CH2:10][CH3:11])=[N:7][C:6]([C:12]2[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=2)=[CH:5][N:4]=1)[NH2:2].[CH3:18][CH:19]([C:25](OCC)=O)[C:20]([O:22][CH2:23][CH3:24])=[O:21]>>[CH3:18][CH:19]([C:25]1[N:4]2[CH:5]=[C:6]([C:12]3[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=3)[N:7]=[C:8]([CH2:9][CH2:10][CH3:11])[C:3]2=[N:1][N:2]=1)[C:20]([O:22][CH2:23][CH3:24])=[O:21]
Reactant: CCCc1nc(-c2cccnc2)cnc1NN
Reactant: CCOC(=O)C(C)C(=O)OCC
Product: CCCc1nc(-c2cccnc2)cn2c(C(C)C(=O)OCC)nnc12

Procedure:
In a manner analogous to that described in Example 1, by condensing 2-hydrazino-3-propyl-5-(3-pyridyl)pyrazine with diethyl methylmalonate there is obtained ethyl rac-α-methyl-8-propyl-6-(3-pyridyl)-s-triazolo[4,3-a]pyrazine-3-acetate, MS: 339 (M)+, which by saponification analogously to Example 1 is converted into the above acid which is used directly in the next step.