Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][CH2:2][C:3](Br)=[O:4].[CH3:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C.CCOCC>C(Cl)Cl>[CH3:6][N:7]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3](=[O:4])[CH2:2][Br:1]
Reactant: O=C(Br)CBr
Reactant: CNCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CN(Cc1ccccc1)C(=O)CBr
Yield: 100.1 %

Procedure:
At 0° C., a solution of 10 g of bromoacetyl bromide in 20 ml of DCM is added to a solution of 6 g of methylbenzylamine and 5 g of triethylamine in 50 ml of DCM. After one night at RT, ether is added, the precipitate formed is filtered off and the filtrate is concentrated to give 12 g of the expected product in crude form.
Reaction SMILES: C(C1N=C(N2CCOCC2)C2N=NN([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=C[C:16]=3Cl)C=2N=1)(C)(C)C.[C:28]([C:32]1[N:33]=[C:34](Cl)[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29].CC1CCC[NH:52]1>>[C:28]([C:32]1[N:33]=[C:34]([N:52]2[CH2:18][CH2:19][CH2:20][C:15]2([CH3:14])[CH3:16])[C:35]2[N:40]=[N:39][N:38]([CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[Cl:48])[C:36]=2[N:37]=1)([CH3:31])([CH3:30])[CH3:29]
Reactant: CC1CCCN1
Reactant: CC(C)(C)c1nc(Cl)c2nnn(Cc3ccccc3Cl)c2n1
Reactant: CC(C)(C)c1nc(N2CCOCC2)c2nnn(Cc3ccccc3Cl)c2n1
Product: CC(C)(C)c1nc(N2CCCC2(C)C)c2nnn(Cc3ccccc3Cl)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-3-(2-chloro-benzyl)-7-morpholin-4-yl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 1, step c), the title compound was prepared from 5-tert-butyl-7-chloro-3-(2-chlorobenzyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 2-methylpyrrolidine and isolated as white solid (13.2 mg, 70%). MS(m/e): 399.4 (MH+).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20](=[O:22])[CH3:21])=[CH:16][CH:15]=1.CCN=C=NCCCN(C)C.Cl>CN(C=O)C.CN(C1C=CN=CC=1)C>[C:20]([C:17]1[CH:18]=[CH:19][C:14]([NH:13][C:10](=[O:12])[CH2:9][O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[CH:15][CH:16]=1)(=[O:22])[CH3:21]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: O=C(O)COCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(NC(=O)COCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91.5 %

Procedure:
A solution of 2 g of (benzyloxy)acetic acid in 30 ml of DMF was cooled to 0° C., and 2.44 g of 1-(4-aminophenyl)ethanone, 294 mg of DMAP, and 3.73 g of WSC/hydrochloride were added thereto, followed by stirring at room temperature for 3 hours. Liquid separation was carried out with ethyl acetate-1 M hydrochloric acid. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure to obtain 3.12 g of N-(4-acetylphenyl)-2-(benzyloxy)acetamide.
Reaction SMILES: [H-].[Na+].[CH3:3][CH2:4][O:5][C:6](/[CH:8]=[CH:9]/[CH2:10]P(OCC)(OCC)=O)=[O:7].[CH2:19]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=O)=[CH:27]1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>O1CCCC1.O>[CH2:19]([N:26]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:28]([CH:35]=[CH:10][CH:9]=[CH:8][C:6]([O:5][CH2:4][CH3:3])=[O:7])=[CH:27]1)[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CCOC(=O)/C=C/CP(=O)(OCC)OCC
Reactant: O=Cc1cn(Cc2ccccc2)c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)C=CC=Cc1cn(Cc2ccccc2)c2ccccc12
Yield: 62 %

Procedure:
To a suspension of 1.08 g (60% reagent, 27 mmol) of sodium hydride in 20 ml of tetrahydrofuran (THF), stirred in an ice bath, was added dropwise 6 ml (6.7 g, 27 mmol) of triethyl 4-phosphonocrotonate. The resulting mixture was stirred for an additional 1 hour in the cooling bath and a solution of 4.2 g (18 mmol) of 1-benzylindol-3-carboxaldehyde in 25 ml of water. This mixture was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with two 50 ml portions of ethyl acetate. The combined organic layer was washed with two 25 ml portions of brine, dried (magnesium sulfate) and concentrated on a rotary evaporator to give an oil. Purification on a dry column (25% ethyl acetate in hexane) followed by crystallization (acetone-ether) gave 3.7 g of product as orange crystals, m.p. 110-112. MS (EI): 331 (M+), 240 (M+--C7H7), 167 (M+--C7H7 --CO2C2H5). NMR spectrum (CDCl3) shows a triplet centered at δ1.26 (J=7 Hz), a singlet at δ5.21, a doublet centered at δ5.8 which is the signal of the olefinic proton adjacent to the carbonyl group. The remainder of the proton signals cluster around 7.25 ppm.
Reaction SMILES: [F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]([O-])=O.[Na+].[NH2:15][C:16]1[C:24]([CH3:25])=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C[Si](OP(=O)=O)(C)C>>[F:1][C:2]([F:13])([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][N:7]=1)[C:3]1[NH:20][C:18](=[O:19])[C:17]2[C:16](=[C:24]([CH3:25])[CH:23]=[CH:22][CH:21]=2)[N:15]=1
Reactant: Cc1cccc(C(N)=O)c1N
Reactant: O=C([O-])C(F)(F)c1ccc(F)cn1
Agent: C[Si](C)(C)OP(=O)=O
Agent: [Na+]
Product: Cc1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Temperature: 115 °C
Yield: 49.1 %

Procedure:
Sodium 2,2-difluoro-2-(5-fluoropyridin-2-yl)acetate from Example 2 Step B (1.02 g, 4.8 mmol) and 2-amino-3-methyl-benzamide (0.6 g, 4.0 mmol) were combined with trimethylsilyl polyphosphate (8.0 mL) and the mixture was heated at 115° C. for 18 h with vigorous stirring. The mixture was allowed to cool to rt, then the mixture was partitioned between water (15 mL) and ethyl acetate (15 mL). The organic layer was separated and the aqueous layer (pH˜1) was extracted with ethyl acetate (30 mL×3). The combined organic layers were separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with 1:10 to 1:1 EtOAc/hexanes to afford 2-[difluoro-(5-fluoro-pyridin-2-yl)-methyl]-8-methyl-3H-quinazolin-4-one as an off-white solid (0.6 g, 29%).
Reaction SMILES: [CH:1]1[C:6]([CH:7]([CH2:12][NH2:13])[CH2:8][C:9](O)=[O:10])=[CH:5][CH:4]=[C:3]([Cl:14])[CH:2]=1.S(Cl)(Cl)=O.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[Cl:14][C:3]1[CH:4]=[CH:5][C:6]([CH:7]2[CH2:12][NH:13][C:9](=[O:10])[CH2:8]2)=[CH:1][CH:2]=1
Reactant: NCC(CC(=O)O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O=S(Cl)Cl
Product: O=C1CC(c2ccc(Cl)cc2)CN1
Reaction time: 0.17 h

Procedure:
To Baclofen (1.0 g, 4.7 mmol) in CH2Cl2 (20 mL) was added thionyl chloride (0.38 mL, 5.2 mmol), and the reaction was stirred for 10 minutes. Diisopropylethylamine (1.5 mL) was added, and the mixture was worked-up to give the title compound.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5](Cl)=[O:6].[CH3:21][NH:22][CH3:23]>O1CCCC1>[I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([I:20])[C:10]=1[O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=1)[C:5]([N:22]([CH3:23])[CH3:21])=[O:6]
Reactant: CNC
Reactant: COc1ccc(Oc2c(I)cc(C(=O)Cl)cc2I)cc1
Solvent: C1CCOC1
Product: COc1ccc(Oc2c(I)cc(C(=O)N(C)C)cc2I)cc1

Procedure:
3,5-diiodo-4-(4′-methoxyphenoxy)-N,N-dimethyl benzamide (Compound 9) was prepared way of 3,5-diiodo-4-(4′-methoxyphenoxy)benzoyl chloride (see, Example 1.5). The acid chloride was reacted with excess dimethylamine in tetrahydrofuran at ambient temperature (1 hour), filtered to remove dimethylamine-hydrochloride precipitate, the solvent evaporated and the product crystallized from absolute ethanol.
Reaction SMILES: [CH:1]1([N:4]2[C:8]3[C:9](I)=[CH:10][C:11]([C:13]4[C:14]([CH3:19])=[N:15][O:16][C:17]=4[CH3:18])=[CH:12][C:7]=3[NH:6][C:5]2=[O:21])[CH2:3][CH2:2]1.[CH2:22](Cl)Cl.[CH2:25]1[CH2:35][CH2:34][N:33]2[C:28](=N[CH2:30][CH2:31][CH2:32]2)[CH2:27][CH2:26]1>CS(C)=O.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH:1]1([N:4]2[C:8]3[C:9]([C:26]4[C:25]([CH3:22])=[CH:35][CH:34]=[C:28]5[C:27]=4[CH:30]=[CH:31][CH:32]=[N:33]5)=[CH:10][C:11]([C:13]4[C:14]([CH3:19])=[N:15][O:16][C:17]=4[CH3:18])=[CH:12][C:7]=3[NH:6][C:5]2=[O:21])[CH2:3][CH2:2]1
Reactant: C1CCC2=NCCCN2CC1
Reactant: ClCCl
Reactant: Cc1noc(C)c1-c1cc(I)c2c(c1)[nH]c(=O)n2C1CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2ncccc2c1-c1cc(-c2c(C)noc2C)cc2[nH]c(=O)n(C3CC3)c12
Temperature: 140 °C

Procedure:
To a microwave vial containing 1-cyclopropyl-5-(3,5-dimethylisoxazol-4-yl)-7-iodo-1H-benzo[d]imidazol-2(3H)-one (25 mg, 0.063 mmol, 1 equiv.) was added 3,5-6-methylquinolin-5-ylboronic acid (71 mg, 0.38 mmol, 6 equiv.), Pd(dppf)Cl2.CH2Cl2 (11 mg, 0.013 mmol, 0.1 equiv.) and DBU (76 mL, 0.51 mmol, 8 equiv.) and dissolved in DMSO-H2O (4 mL, 0.2 M, 2/1, v/v). The mixture was heated to 140° C. for 30 minutes in the microwave reactor. Purification was carried out by reverse phase HPLC.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.BrN1C(=O)CCC1=O.[Cl:28][C:29]1[CH:37]=[C:36]2[C:32]([C:33]([C:41]([OH:43])=O)=[CH:34][N:35]2[CH:38]([CH3:40])[CH3:39])=[CH:31][CH:30]=1.[CH3:44][C:45]1[S:49][C:48]([NH2:50])=[N:47][CH:46]=1.Cl>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:44][C:45]1[S:49][C:48]([NH:50][C:41]([C:33]2[C:32]3[C:36](=[CH:37][C:29]([Cl:28])=[CH:30][CH:31]=3)[N:35]([CH:38]([CH3:39])[CH3:40])[CH:34]=2)=[O:43])=[N:47][CH:46]=1
Reactant: Cc1cnc(N)s1
Reactant: CC(C)n1cc(C(=O)O)c2ccc(Cl)cc21
Agent: Cl
Agent: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: Cc1cnc(NC(=O)c2cn(C(C)C)c3cc(Cl)ccc23)s1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 57.1 %

Procedure:
A solution of triphenylphosphine (251 mg, 0.82 mmol) in methylene chloride (3 mL) cooled to 0° C. was treated with N-bromosuccinimide (146 mg, 0.82 mmol). This solution was stirred at 0° C. for 5 min. At this time, the reaction was treated with 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (150 mg, 0.63 mmol). This solution was stirred at 0° C. for 5 min and then was allowed to warm to 25° C. where it was stirred for 30 min. The reaction was then treated with 5-methyl-thiazol-2-ylamine (166 mg, 1.45 mmol) and was stirred at 25° C. for 2 d. At this time, the reaction was diluted with water (25 mL) and ethyl acetate (25 mL). This mixture was treated with a 1N aqueous hydrochloric acid solution (5 mL). The organic layer was separated and was washed with a saturated aqueous sodium bicarbonate solution (1×10 mL) and a saturated aqueous sodium chloride solution (1×10 mL). The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 1/1 hexanes/ethyl acetate) afforded 6-chloro-1-isopropyl-1H-indole-3-carboxylic acid (5-methyl-thiazol-2-yl)-amide (120 mg, 57%) as a pink solid: mp 216-219° C.; (ES)+-HRMS m/e calcd for C16H16ClN3OS (M+) 333.0703, found 333.0708.
Reaction SMILES: C(C1C=CC(O[CH2:8][C@H:9]2[CH2:14][CH2:13][C@H:12]([CH2:15][O:16][C:17]3[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19][CH:18]=3)[CH2:11][CH2:10]2)=CC=1)=O.[O:27]=[C:28]1[CH2:32][O:31][C:30](=[S:33])[NH:29]1.[C:34]([O-:37])(=O)[CH3:35].[Na+]>C(O)(=O)C>[O:27]=[C:28]1[C:32](=[CH:14][C:9]2[CH:8]=[CH:35][C:34]([O:37][CH2:8][C@H:9]3[CH2:10][CH2:11][C@H:12]([CH2:15][O:16][C:17]4[CH:18]=[CH:19][C:20]([CH:23]=[C:32]5[O:31][C:30](=[S:33])[NH:29][C:28]5=[O:27])=[CH:21][CH:22]=4)[CH2:13][CH2:14]3)=[CH:11][CH:10]=2)[O:31][C:30](=[S:33])[NH:29]1
Reactant: CC(=O)[O-]
Reactant: O=C1COC(=S)N1
Reactant: O=Cc1ccc(OC[C@H]2CC[C@H](COc3ccc(C=O)cc3)CC2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)OC1=Cc1ccc(OC[C@H]2CC[C@H](COc3ccc(C=C4OC(=S)NC4=O)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
A mixture consisting of 3.52 g of trans-1,4-bis[(4-formylphenoxy)methyl]cyclohexane, 2.34 g of 4-oxo-2-thioxooxazolidine, 0.31 g of sodium acetate and 50 ml of acetic acid was subjected to overnight reflux. After spontaneous cooling, crystals thus formed were collected by filtration and recrystallized from dimethylformamide to obtain 3.75 g of trans-1,4-bis[[4-[(4-oxo-2-thioxo-5-oxazolidinylidene)methyl]phenoxy]methyl]cyclohexane (19-a).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9](S(C)=O)[N:8]=1.[NH:41]1[CH2:47][CH2:46][CH2:45][C@H:42]1[CH2:43][OH:44].C(N(CC)CC)C.CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:36]=[CH:37][C:38]=1[O:39][CH3:40])[CH2:5][NH:6][C:7]1[C:12]([C:13]([O:15][CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:14])=[C:11]([N:26]2[CH2:31][CH2:30][CH:29]([OH:32])[CH2:28][CH2:27]2)[N:10]=[C:9]([N:41]2[CH2:47][CH2:46][CH2:45][CH:42]2[CH2:43][OH:44])[N:8]=1
Reactant: OC[C@@H]1CCCN1
Reactant: COc1ccc(CNc2nc(S(C)=O)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1ccc(CNc2nc(N3CCCC3CO)nc(N3CCC(O)CC3)c2C(=O)OCCOCc2ccccc2)cc1Cl
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A mixture of whole amount of 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-methylsulfinylpyrimidine (prepared in the above (4)), L-prolinol 53 mg, triethylamine 53 mg and dimethylformamide 4 ml is stirred at room temperature for 1.5 hours and then at 65° C. for 3.5 hours. After cooling the reaction mixture is diluted with water and extracted with ethyl acetate. The ethyl acetate layer is washed, dried and concentrated in vacuo. The residue is separated with silica gel chromatography (solvent; chloroform: ethyl acetate=1:2) to give 4-(3-chloro-4-methoxybenzylamino)-5-(2-benzyloxyethoxycarbonyl)-6-(4-hydroxypiperidin-1-yl)-2-(2-hydroxymethyl-1-pyrrolidinyl)pyrimidine as a colorless caramel 96 mg.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([O:13]C)=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:24][CH2:23][N:22]2[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:17][CH:16]=1.[OH-].[Na+]>CO>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([OH:13])=[O:12])=[CH:7][NH:8]2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([CH:21]2[CH2:24][CH2:23][N:22]2[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(C4CCN4S(C)(=O)=O)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CS(=O)(=O)N1CCC1c1ccc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)cc1
Temperature: 70 °C
Reaction time: 24 h
Yield: 22.5 %

Procedure:
To a solution of methyl 6-chloro-5-{4-[1-(methylsulfonyl)azetidin-2-yl]phenyl}-1H-indole-3-carboxylate (80 mg, 0.22 mmol) in methanol (8 mL) was added 1.0M aq. NaOH (2.0 mL, 2.0 mmol). The mixture was stirred at 70° C. for 24 hours. The mixture was adjusted to pH 7 and purified by prep-HPLC to give the title compound (20 mg, 13% yield) as a white solid. MS (ES+) 445.0 (M+CH3CN)+. 1H NMR (400 MHz, DMSO-d6): δ 8.05 (s, 1H), 7.95 (s, 1H), 7.65 (s, 1H), 7.50-7.30 (m, 4H), 4.70 (m, 1H), 3.10 (m, 2H), 2.89 (s, 3H), 1.90-1.80 (m, 2H).
Reaction SMILES: [N+]([O-])(O)=O.[F:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]([NH2:21])=[NH:20])[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1.[CH3:22][CH:23]([CH3:34])[C:24](=O)[CH2:25][C:26](=O)[C:27]([O:29][CH2:30][CH3:31])=[O:28].C(=O)([O-])[O-].[K+].[K+]>C(O)C.C(OCC)(=O)C>[F:5][C:6]1[CH:7]=[C:8]([NH:18][C:19]2[N:21]=[C:26]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:25]=[C:24]([CH:23]([CH3:22])[CH3:34])[N:20]=2)[CH:9]=[CH:10][C:11]=1[N:12]1[CH:16]=[C:15]([CH3:17])[N:14]=[CH:13]1
Reactant: Cc1cn(-c2ccc(NC(=N)N)cc2F)cn1
Reactant: CCOC(=O)C(=O)CC(=O)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(C)C)nc(Nc2ccc(-n3cnc(C)c3)c(F)c2)n1
Temperature: 170 °C
Yield: 20 %

Procedure:
A mixture of N-[3-fluoro-4-(4-methyl-imidazol-1-yl)-phenyl]-guanidine nitrate (719 mg, 2.0 mmol), ethyl 5-methyl-2,4-dioxo-hexanoate (372 mg, 2.0 mmol) and potassium carbonate (138 mg, 1.0 mmol) in ethanol (5 mL) was heated in a sealed tube in a microwave oven to 170° C. for 0.5 h. The mixture was cooled, diluted with ethyl acetate (50 mL), and then washed with water (20 mL) and with brine (20 mL). The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residual material was purified by chromatography on silica gel using dichloromethane/0-10% methanol as eluent to give the title compound (153 mg, 20%) as a light yellow solid. MS ISP (m/e): 384.3 [(M+H)+]. 1H NMR (CDCl3, 300 MHz): 8 (ppm)=8.11 (dd, 1H), 7.68 (s, 1H), 7.47 (s, 1H), 7.38 (s, 1H), 7.25-7.30 (2H), 6.94 (s, 1H), 4.48 (q, 2H), 3.05 (m, 1H), 2.31 (s, 3H), 1.46 (t, 3H), 1.36 (d, 6H).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[P:6]([OH:8])[OH:7].[CH2:9](N(CC)CC)[CH3:10].ClC(OCC)=O>ClCCl>[CH2:9]([O:7][P:6]([CH:2]1[CH2:3][CH2:4][CH2:5][O:1]1)[OH:8])[CH3:10]
Reactant: CCN(CC)CC
Reactant: OP(O)C1CCCO1
Agent: CCOC(=O)Cl
Solvent: ClCCl
Product: CCOP(O)C1CCCO1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 2.6 g of P-tetrahydrofuran-2-yl-phosphonous acid in 20 ml of anhydrous dichloromethane is cooled to 5° under inert gas and treated with 2.03 g of triethylamine. A dichloromethane solution of 2.17 g of ethyl chloroformate is added dropwise whereupon an exothermic reaction and a gas evolution ensues. The suspension is warmed to room temperature and stirred for 3 hours. The reaction mixture is then diluted with dichloromethane and washed with water. Drying of the organic phase with anhydrous magnesium sulphate and removal of the solvent in vacuo affords P-tetrahydrofuran-2-yl phosphonous acid ethyl ester, b.p. 90°/8×10-2 mbar.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8](Br)=[CH:7]2.[I-:15].[Na+].CNCCNC>O1CCOCC1.[Cu](I)I>[NH2:1][C:2]1[CH:3]=[C:4]([O:13][CH3:14])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][C:8]([I:15])=[CH:7]2
Reactant: [I-]
Reactant: COc1cc(N)c2ncc(Br)cc2c1
Agent: I[Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1cc(N)c2ncc(I)cc2c1

Procedure:
In a similar procedure to Step 2 of Example 1 8-amino-3-bromo-6-methoxyquinoline (preparation described in Journal of Pharmaceutical Sciences (1984), 73(12), 1854-6) (6.0 g) is treated with sodium iodide, copper iodide and N,N′-dimethyl-ethane-1,2-diamine in dioxane in a sealed tube under argon, at 120° C. for 14 h. After work-up the crude is purified by flash chromatography (ethyl acetate: cyclohexane, 1:4) to provide 8-amino-3-iodo-6-methoxyquinoline (4.6 g) as a pure product. 1H NMR (CDCl3) δ ppm: 8.70 (1H, d); 8.30 (1H, d); 6.55 (1H, d); 6.35 (1H, d); 5.00 (2H, br s); 3.85 (3H, s). (M+1)+: 301
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]1=[S:8].[CH3:9][C:10]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:11]=1[CH2:12][Cl:13]>C1(C)C=CC=CC=1>[Cl-:13].[CH3:9][C:10]1[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][C:11]=1[CH2:12][S:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][N+:2]=1[CH3:1]
Reactant: Cn1ccccc1=S
Reactant: Cc1ccc(C)c(CCl)c1
Solvent: Cc1ccccc1
Product: Cc1ccc(C)c(CSc2cccc[n+]2C)c1
Product: [Cl-]
Temperature: 70 °C

Procedure:
A mixture of 5.0 g of 1-methyl-2(1H)-pyridinethione and 6.2 g of 2,5-dimethylbenzyl-chloride in 40 ml of toluene was heated for five hours at 70° C. A pale yellow solid was filtered from the cooled mixture. Yield was 5 g having a melting point of 130-137° C. NMR and infrared spectra were consistent with the structure.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2].O1CCCC1.CO.O.[OH-].[Li+]>O>[C:1]([C:3]1[CH:4]=[C:5]([CH:22]([CH3:24])[CH3:23])[C:6]2[O:10][C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:19][CH:20]=3)=[N:8][C:7]=2[CH:21]=1)#[N:2]
Reactant: COC(=O)c1ccc(-c2nc3cc(C#N)cc(C(C)C)c3o2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1cc(C#N)cc2nc(-c3ccc(C(=O)O)cc3)oc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a 5-l, round-bottom flask fitted with a stir bar and a Claisen adapter fitted with a thermocouple and a nitrogen line was added was added methyl 4-(5-cyano-7-isopropyl-1,3-benzoxazol-2-yl)benzoate (40.5 g, Step B) tetrahydrofuran (1.25 l), methanol (630 ml), water (315 ml), and lithium hydroxide monohydrate (10.7 g). The mixture was heated to 50° C. and stirred at this temperature for 1 h. The mixture was then cooled and concentrated to a thick slurry. 1N HCl (3.2 l) was added and an off-white solid formed. The mixture was stirred for 5 min and then filtered, washing with water (2×500 ml). The solid was transferred to a 2-l round-bottom flask, concentrated from toluene (1 l) and then dried in vacuo. Mass spectrum (ESI) 307.0 (M+1). 1H NMR (500 MHz, DMSO-d6): δ 8.69 (d, J=7.5 Hz, 2H), 8.28 (s, 1H), 8.16 (d, J=8.0 Hz, 2H), 7.81 (s, 1H), 3.46 (septet, J=6.5 Hz, 1H), 1.40 (d, H=7.0 Hz, 6H).
Reaction SMILES: C(N(CC)C1C=CC=CC=1)C.[CH3:12][C:13]1[C:28]([CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=2[CH3:40])=[C:16]2[NH:17][C:18]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[CH:19][C:20](=O)[N:15]2[N:14]=1.P(Cl)(Cl)([Cl:43])=O>>[Cl:43][C:20]1[N:15]2[N:14]=[C:13]([CH3:12])[C:28]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[C:31]=3[CH3:40])=[C:16]2[N:17]=[C:18]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:19]=1
Reactant: Cc1nn2c(=O)cc(C3CCOCC3)[nH]c2c1Cc1cccc(C(F)(F)F)c1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: CCN(CC)c1ccccc1
Product: Cc1nn2c(Cl)cc(C3CCOCC3)nc2c1Cc1cccc(C(F)(F)F)c1C
Temperature: 0 °C

Procedure:
To a suspension of N,N-diethylaniline (0.83 g, 5.54 mmol) and 2-methyl-3-{[2-methyl-3-(trifluoromethyl)phenyl]methyl}-5-(tetrahydro-2H-pyran-4-yl)pyrazolo[1,5-a]pyrimidin-7(4H)-one (1.02 g, 2.52 mmol) stirred under nitrogen at 0° C. was added neat phosphoric trichloride (1.93 g, 12.6 mmol) dropwise during 5 minutes. The reaction mixture was stirred at 80° C. for 2 hr. Reaction mixture was concentrated. The residue was dissolved with DCM (50 mL) and icy water (15 mL). The pH of aqueous layer was adjusted by 10 N NaOH solution to 5. Two layers were separated. Organic layer was washed with brine (15 mL) again. Organic layer was dried, concentrated to dryness. Product was purified on a silica gel column (ethyl acetate/hexane gradient solvents). The product was obtained and used in subsequent steps. (463 mg, 43%); LC/MS: MS (ES+) m/e 424 (MH+).
Reaction SMILES: N1(CC2N3C=C(C)C=CC3=NC=2C2C=CC(C)=CC=2)C=CN=C1.Cl.Cl[CH2:26][C:27]1[N:31]2[CH:32]=[CH:33][CH:34]=[CH:35][C:30]2=[N:29][C:28]=1[C:36]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][CH:37]=1.[NH:43]1[C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[C:45]([C:52]([O:54][CH3:55])=[O:53])=[CH:44]1>>[Cl:42][C:39]1[CH:40]=[CH:41][C:36]([C:28]2[N:29]=[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]3[C:27]=2[CH2:26][N:43]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=3)[C:45]([C:52]([O:54][CH3:55])=[O:53])=[CH:44]2)=[CH:37][CH:38]=1
Reactant: ClCc1c(-c2ccc(Cl)cc2)nc2ccccn12
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: Cc1ccc(-c2nc3ccc(C)cn3c2Cn2ccnc2)cc1
Agent: Cl
Product: COC(=O)c1cn(Cc2c(-c3ccc(Cl)cc3)nc3ccccn23)c2ccccc12

Procedure:
The title compound was prepared according to Method A and the experimentals described for compound 1 from 3-(chloromethyl)-2-(4-chlorophenyl)imidazo[1,2-a]pyridine hydrochloride and methyl 1H-indole-3-carboxylate. M/e+ 430 for C25H21ClN3O2 (M+H)+; 1H-NMR (400 MHz, CDCl3) δ 8.24 (dd, J=5.8, 2.5 Hz, 1H), 7.74 (d, J=9.1 Hz, 2H), 7.66 (d, J=8.4 Hz, 1H), 7.64 (m, 1H), 7.51 (s, 1H), 7.48 (m, 1H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (m, 2H), 7.29 (t, J=5.8 Hz, 1H), 6.80 (t, J=6.9 Hz, 1H), 5.67 (s, 2H), 3.83 (s, 3H) ppm.