Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[C:8]([NH:16][C:17]1[CH:29]=[C:28]([N:30]2[CH2:35][CH2:34][CH:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:32][CH2:31]2)[CH:27]=[CH:26][C:18]=1[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>>[C:8]([NH:16][C:17]1[CH:29]=[C:28]([N:30]2[CH2:31][CH2:32][CH:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH2:34][CH2:35]2)[CH:27]=[CH:26][C:18]=1[C:19]([OH:21])=[O:20])(=[O:15])[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CCC(c3ccccc3)CC2)cc1NC(=O)c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(Nc1cc(N2CCC(c3ccccc3)CC2)ccc1C(=O)O)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mL of trifluoroacetic acid was added to the obtained tert-butyl 2-(benzamido)-4-(4-phenylpiperidin-1-yl)benzoate and stirred at room temperature for 3 hours, the solvent was evaporated under reduced pressure, ethyl acetate and water were added and pH was adjusted to pH 6.5 with a saturated sodium hydrogen carbonate aqueous solution. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with water and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Diisopropyl ether was added to the obtained residue and a solid substance was separated by filtration to obtain 20 mg of 2-(benzamido)-4-(4-phenylpiperidin-1-yl)benzoic acid as white solid.
Reaction SMILES: P(=O)(O)(O)O.[CH3:6][C:7](=[CH:9][CH2:10][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:12](=[O:15])[CH2:13][CH3:14])[CH3:8]>C1(C)C=CC=CC=1>[CH3:6][C:7]1([CH3:8])[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:11]([C:12](=[O:15])[CH2:13][CH3:14])[CH2:10][CH2:9]1
Reactant: CCC(=O)C(CC=C(C)C)c1ccccc1
Agent: O=P(O)(O)O
Solvent: Cc1ccccc1
Product: CCC(=O)C1CCC(C)(C)c2ccccc21
Temperature: 0 °C
Yield: 69.4 %

Procedure:
36 g of 85% phosphoric acid, 36 g of polyphosphoric acid, 175 ml of toluene and 72 g of 2-methyl-5phenyl-oct-2-en-6-one are heated together at 100° C. for 2 hours under a nitrogen atmosphere and while stirring. The mixture is left to cool, 250 ml of ice/water are added, the aqueous phase is separated and the organic phase is subjected to a steam distillation. The distillate is separated from the water and distilled in vacuo. There are obtained 50 g of 1,1-dimethyl-4-propionyl-tetralin of boiling point 75° C./0.05 mmHg; nD20 =1.5263; yield 70%. Odour: see (3).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[N:17]=[C:16]([NH:18][C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]4)[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.C(OC([N:42]1[CH2:47][CH2:46][CH:45]([C:48](O)=[O:49])[CH2:44][CH2:43]1)=O)(C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[NH:42]1[CH2:47][CH2:46][CH:45]([C:48]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[N:17]=[C:16]([NH:18][C:19]4[CH:20]=[C:21]5[C:25](=[CH:26][CH:27]=4)[N:24]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[N:23]=[CH:22]5)[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[N:9]=3)[CH:5]=[CH:6][CH:7]=2)=[O:49])[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(N)c4)nc4ccccc34)ccc21
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1ncc2cc(Nc3nc(-c4cccc(NC(=O)C5CCNCC5)c4)nc4ccccc34)ccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A suspension of tert-butyl 5-(2-(3-aminophenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (126 mg, 0.278 mmol), 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid (79 mg, 0.347 mmol), PyBOP® (212 mg, 0.455 mmol) and DIEA (250 μL, 1.43 mmol) in CH2Cl2 (10 mL) was stirred at RT for 72 h. Reaction mixture was diluted with more CH2Cl2 (50 mL) and extracted with H2O (3×). Organic layer was dried under Na2SO4 and concentrated in vacu. Crude product was purified by prep TLC to give the desired product tert-butyl 5-(2-(3-(piperidine-4-carboxamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][NH:9]2)=[CH:4][CH:3]=1.Cl[C:13]1[C:22]2[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=2)[N:16]=[CH:15][N:14]=1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][N:9]2[C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH3:26])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[CH:4][CH:3]=1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Brc1ccc2c(c1)NCCC2
Product: COc1cc2ncnc(N3CCCc4ccc(Br)cc43)c2cc1OC
Yield: 11 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 11% yield from 7-bromo-1,2,3,4-tetrahydroquinoline and 4-chloro-6,7-dimethoxy-quinazoline. (film; LC-MS: 399 (MH+)).
Reaction SMILES: [CH:1]([C@@H:3]1[C@@H:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:6][N:5]([C@H:14]([CH:27]2[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=2)=[O:16])[CH2:4]1)=O.[CH2:33]([C:40]1[C:41](=[O:52])[N:42]([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[NH:43][C:44]=1[CH3:45])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.CO.CC(O)=O.C(OCC)(=O)C>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][O:17][C:15](=[O:16])[C@H:14]([N:5]2[CH2:6][C@H:7]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[C@@H:3]([CH2:1][N:49]3[CH2:50][CH2:51][CH:46]([N:42]4[C:41](=[O:52])[C:40]([CH2:33][C:34]5[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=5)=[C:44]([CH3:45])[NH:43]4)[CH2:47][CH2:48]3)[CH2:4]2)[CH:27]2[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32]2)=[CH:24][CH:23]=1
Reactant: Cc1[nH]n(C2CCNCC2)c(=O)c1Cc1ccccc1
Reactant: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](c3ccccc3)[C@@H](C=O)C2)cc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCCl
Product: COc1ccc(COC(=O)[C@@H](C2CCCCC2)N2C[C@H](CN3CCC(n4[nH]c(C)c(Cc5ccccc5)c4=O)CC3)[C@@H](c3ccccc3)C2)cc1
Reaction time: 0.25 h
Yield: 9.7 %

Procedure:
To a stirred solution of 0.44 g of α-(R)-(3-(R)-formyl-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester (prepared above as Aldehyde 5) and 0.55 g of 4-(4-benzyl-5-methyl-1H-pyrazole-3(2H)-on-2-yl)-piperidine in 3 mL 1,2-dichloroethane, 0.5 mL MeOH and 0.1 mL HOAc is added 0.3 g of powdered molecular sieves (4A). After 15 minutes, 0.1 g of sodium triacetoxyborohydride was added and stirring was continued overnight. The reaction mixture was poured into a rapidly stirred mixture of ethyl acetate and saturated sodium bicarbonate solution (˜15 mL each). After 15 minutes the mixture was filtered through Celite, the aqueous layer separated and extracted with 25 mL ethyl acetate. The combined organic layers were washed with saturated sodium bicarbonate solution, water, then brine, dried with sodium sulfate and concentrated under reduced pressure to give 0.068 g of α-(R)-(3-(S)-((4-(4-benzyl-5-methyl-1H-pyrazol-3(2H)-on-2-yl)-piperidin-1-yl)methyl)-4-(S)-phenylpyrrolidin-1-yl)-cyclohexaneacetic acid 4-methoxybenzyl ester suitable for use in the next step. ESI-MS 691.3 (M+H); HPLC A: 3.20 min.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:24]=[C:8]2[CH2:9][N:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[C:11]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:7]2[N:6]=1)=O.[BH4-].[Na+]>>[Cl:23][C:19]1[CH:18]=[C:17]([N:10]2[C:11]3[N:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:7]3[N:6]=[C:5]([CH2:3][OH:2])[N:24]=[C:8]3[CH2:9]2)[CH:22]=[CH:21][CH:20]=1
Reactant: COC(=O)c1nc2n(n1)-c1cccnc1N(c1cccc(Cl)c1)C2
Agent: [BH4-]
Agent: [Na+]
Product: OCc1nc2n(n1)-c1cccnc1N(c1cccc(Cl)c1)C2

Procedure:
using 3.80 g (0.011 mol) of 5-(3-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-carboxylic acid methyl ester and 4.20 g (0.112 mol) of sodium borohydride there is obtained 5-(3-chlorophenyl)-4,5-dihydropyrido[2,3-e][1,2,4]triazolo[1,5-a]pyrazine-2-methanol having a melting point of 204°-206°;
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[Br:34]C1C=CC(OC2C=CC(S(Cl)(=O)=O)=CC=2)=CC=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([S:17]([C:20]1[CH:25]=[CH:24][C:23]([O:26][C:27]2[CH:32]=[CH:31][C:30]([Br:34])=[CH:29][CH:28]=2)=[CH:22][CH:21]=1)(=[O:19])=[O:18])[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Br)cc2)cc1
Reactant: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccccc2)cc1
Product: CC(C)(C)OC(=O)CN(CC(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Oc2ccc(Br)cc2)cc1

Procedure:
Compound 4d was prepared similar to the procedure described for 4a using 4-(4-bromophenoxy)-benzenesulphonyl chloride (3d) (3.00 g, 8.63 mmol). Yield: 4.13 g, 7.42 mmol, 86% (light yellow solid). 1H NMR (DMSO-d6): δ 7.70 (d, J=8.2 Hz, 2H, ArH), 7.52 (d, J=8.8 Hz, 2H, ArH), 7.01 (d, 3J=8.8 Hz, 2H, ArH), 6.67 (d, 3J=8.9 Hz, 2H, ArH) 4.05 (s, 4H, 2×CH2CO2 tBu), 1.46 (s, 18H, 2×CO2tBu).
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[N+:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[C:20]([OH:22])=[O:21])([O-:9])=[O:8].IC.O>CN(C)C=O>[N+:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH:12]=[CH:13][N:14]=[C:15]2[C:20]([O:22][CH3:1])=[O:21])([O-:9])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: O=C(O)c1nccc2c([N+](=O)[O-])cccc12
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1nccc2c([N+](=O)[O-])cccc12
Temperature: 25 °C
Reaction time: 20 h
Yield: 19.4 %

Procedure:
Potassium carbonate (23 g, 167 mmol) was added to a solution of 5-nitro-isoquinoline-1-carboxylic acid (Description 104, 2.7 g, 12.4 mmol) in N,N-dimethylformamide (50 ml) at room temperature. Iodomethane (1.0 ml, 16.1 mmol) was then added and the reaction stirred at room temperature for 20 h. Water (300 ml) was added and the mixture was extracted with ethyl acetate (2×200 ml). The combined organic phases were washed with water (2×100 ml), brine (100 ml) then dried (Na2SO4) and evaporated. Purification of the residue by column chromatography eluting with ethyl acetate-isohexane (7:13 increasing to 1:1) gave the title compound (558 mg, 19%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][N:3]=1.[H-].[Na+].I[CH:12]([CH3:14])[CH3:13].O>CN(C)C=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:12]([CH3:14])[CH3:13])=[CH:4][N:3]=1
Reactant: Oc1ccc(F)nc1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(F)nc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-fluoro-5-hydroxypyridine (6.000 g, 53.05 mmol) in N,N-dimethyl formamide (50 mL) cooled with an ice bath was added NaH (2.80 g, 60%, 70.0 mml) in several potions. After the addition, the mixture was stirred at 0° C. for 10 minutes. 2-iodopropane (6.5 mL, 65.00 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was poured into water, extracted with ether (2×), the combined extracts were washed with 1N NaOH (1×), water (1×), brine (1×), dried over MgSO4 and concentrated to give the product that was used directly without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23](Br)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH3:33][N:34]1[C:42]2[C:37](=[CH:38][C:39](B(O)O)=[CH:40][CH:41]=2)[CH:36]=[CH:35]1>O1CCOCC1.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>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[O:15][C:16]([C:19]3[C:20]([NH2:26])=[N:21][CH:22]=[C:23]([C:39]4[CH:38]=[C:37]5[C:42](=[CH:41][CH:40]=4)[N:34]([CH3:33])[CH:35]=[CH:36]5)[CH:24]=3)=[N:17][N:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(c2nnc(-c3cc(Br)cnc3N)o2)CC1
Reactant: Cn1ccc2cc(B(O)O)ccc21
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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ccc2cc(-c3cnc(N)c(-c4nnc(C5CCN(C(=O)OC(C)(C)C)CC5)o4)c3)ccc21
Temperature: 100 °C
Reaction time: 18 h
Yield: 73.2 %

Procedure:
To a solution of 4-[5-(2-amino-5-bromo-pyridin-3-yl)-[1,3,4]oxadiazol-2-yl]-piperidine-1-carboxylic acid tert-butyl ester (1.1 g, 2.59 mmol) in dioxane (20 mL) and water (10 mL) were added K2CO3 (1.07 g, 7.77 mmol) and N-methylindole-5-boronic acid (0.50 g, 2.85 mmol) in a sealed tube. The reaction mixture was degassed with argon for 20 min, then Pd(PPh3)4 (0.15 g, 0.13 mmol) was added to the reaction mixture. The reaction mixture was stirred for 18 h at 100° C. The reaction was diluted with water (100 mL), extracted with ethyl acetate (2×150 mL) and organic layer was washed with brine, dried over anhydrous sodium sulphate and concentrated under reduced pressure to get crude compound. Crude compound was purified by column chromatography using 100-200 mesh silica gel compound eluted with 60% ethyl acetate in petroleum ether to afford 900 mg of the title compound which is further purified by washing with 20% chloroform in hexane to afford the title compound as a pale yellow solid.
Reaction SMILES: C(OC(=O)[N:7]([S:13]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27](Cl)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]=1[F:37])(=[O:15])=[O:14])[C:8]1[S:9][CH:10]=[CH:11][N:12]=1)(C)(C)C.[F:39][C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1.C([O-])([O-])=O.[Na+].[Na+].O>CN(C)C=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>[Cl:22][C:20]1[C:19]([O:23][C:24]2[CH:25]=[N:26][C:27]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([F:39])[CH:45]=3)=[CH:28][C:29]=2[C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:18][C:17]([F:37])=[C:16]([S:13]([NH:7][C:8]2[S:9][CH:10]=[CH:11][N:12]=2)(=[O:15])=[O:14])[CH:21]=1
Reactant: CC(C)(C)OC(=O)N(c1nccs1)S(=O)(=O)c1cc(Cl)c(Oc2cnc(Cl)cc2-c2cccnc2)cc1F
Reactant: OB(O)c1cccc(F)c1
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: CN(C)C=O
Product: O=S(=O)(Nc1nccs1)c1cc(Cl)c(Oc2cnc(-c3cccc(F)c3)cc2-c2cccnc2)cc1F
Reaction time: 0.17 h
Yield: 29.9 %

Procedure:
20 mg (0.03 mmol) of tert-butyl((5-chloro-4-((6′-chloro-[3,4′-bipyridin]-3′-yl)oxy)-2-fluorophenyl)sulfonyl)(thiazol-2-yl)carbamate was dissolved in 3 mL of N,N-dimethylformamide, and 7 mg (0.05 mmol) of (3-fluorophenyl)boronic acid was added thereto, and then 3.8 mg (10 mol %) of Pd(PPh3)4, 10.6 mg (0.10 mmol) of Na2CO3, and 1 mL of H2O were added thereto. After reacting with microwave reactor at 120° C. for 10 minutes, the solvent was removed, and the remaining material was diluted with ethyl acetate and the organic layer was separated, and washed with saturated sodium chloride. The organic layer was collected, dried with magnesium sulfate to remove water, and concentrated under reduced pressure, and the residue was purified by column chromatography (developing solvent, hexane:ethyl acetate=3:1) to obtain 5 mg (27% yield) of the title compound.
Reaction SMILES: II.[CH2:3](Br)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:11]([O:13][C:14](=[O:22])[C:15]1[CH:20]=[C:19](Br)[CH:18]=[N:17][CH:16]=1)[CH3:12].C([O-])(O)=O.[Na+]>CC(N(C)C)=O.C1C=CC=CC=1.CCOC(C)=O.[Zn]>[CH2:11]([O:13][C:14](=[O:22])[C:15]1[CH:20]=[C:19]([CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:18]=[N:17][CH:16]=1)[CH3:12]
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)c1cncc(Br)c1
Agent: II
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cncc(Cc2ccccc2)c1
Temperature: 80 °C

Procedure:
A suspension of Zn (1.0 g, 15 mmol) and I2 (130 mg, 0.5 mmol) in DMA (15 mL) was stirred vigorously until the red color dissipated (3-5 min). Benzyl bromide (1.7 g, 10 mmol) was introduced and the resulting slurry was heated at 80° C. for 2.5 h at which point Cl2Pd(PPh3)2 (250 mg, 0.35 mmol) and a solution of ethyl-5-bromonicotinate (1.1 g, 5.0 mmol) in benzene (10 mL) were introduced and the reaction was heated at 80° C. for 1 h. The reaction was allowed to cool to room temperature and was diluted with EtOAc (100 mL). The mixture was poured into NaHCO3 (5% aqueous, 100 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2×50 mL). The combined organic layers were sequentially washed with H2O (3×100 mL) and brine before being dried over Na2SO4. Concentration and purification by silica gel chromatography (hexane→50% EtOAc/hexane) provided the title compound as a brown oil. MS m/z: 242.1 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20](F)(F)F)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1.BrC1C=C[C:30]2[C:31]3[N:32]=[C:33]([C:39](N)=O)SC=3CCOC=2C=1.N1C=CC(CNN)=CC=1>>[Br:1][C:2]1[CH:25]=[CH:24][C:5]2[C:6]3[N:7]=[C:8]([C:14]4[N:15]([CH2:19][C:20]5[CH:39]=[CH:33][N:32]=[CH:31][CH:30]=5)[N:16]=[CH:17][N:18]=4)[S:9][C:10]=3[CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1
Reactant: NC(=O)c1nc2c(s1)CCOc1cc(Br)ccc1-2
Reactant: FC(F)(F)Cn1ncnc1-c1nc2c(s1)CCOc1cc(Br)ccc1-2
Agent: NNCc1ccncc1
Product: Brc1ccc2c(c1)OCCc1sc(-c3ncnn3Cc3ccncc3)nc1-2

Procedure:
Following the procedure for 8-Bromo-2-[2-(2,2,2-trifluoro-ethyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene, 8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid amide 25 was reacted with pyridin-4-ylmethyl-hydrazine to give 8-Bromo-2-(2-pyridin-4-ylmethyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:6]=[N:7][N:8]([CH3:13])[C:9](=[O:12])[C:10]=1[Cl:11]>CO>[Cl:11][C:10]1[C:9](=[O:12])[N:8]([CH3:13])[N:7]=[CH:6][C:5]=1[O:2][CH3:1]
Reactant: Cn1ncc(Cl)c(Cl)c1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1cnn(C)c(=O)c1Cl
Temperature: 25 °C
Reaction time: 12 h
Yield: 84.3 %

Procedure:
295 g of 30% strength sodium methylate solution was added to 293 g (1.64 mol) of 4,5-dichloro-1-methyl-6-pyridazone in 690 ml of methanol in such a manner that a temperature of 30° C. was not exceeded. After cooling and stirring for 12 hours at 25° C., the precipitate which had formed was filtered off, washed and dried. There was obtained 241 g (84.3%) of 5-chloro-4-methoxy-1-methyl-6-pyridazone of melting point 189°-191° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH2:7][N:8]2[C:12](=[O:13])[CH2:11][CH:10](C(N)=O)[CH2:9]2)=[CH:5][CH:4]=1.C(OI(OC(=O)C)C1C=CC=CC=1)(=O)C.Cl.CC#[N:37]>O>[NH2:37][CH:10]1[CH2:9][N:8]([CH2:7][C:6]2[CH:17]=[CH:18][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:12](=[O:13])[CH2:11]1
Reactant: COc1ccc(CN2CC(C(N)=O)CC2=O)cc1
Reactant: CC#N
Agent: CC(=O)OI(OC(C)=O)c1ccccc1
Agent: Cl
Solvent: O
Product: COc1ccc(CN2CC(N)CC2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.2 %

Procedure:
To a solution of 1-(4-methoxy-benzyl)-5-oxo-pyrrolidine-3-carboxylic acid amide (50.0 g, 201 mmol) in 560 mL of CH3CN and 560 mL of H2O was added bis(acetyloxy)(phenyl)-λ3-iodane (84.0 g, 261 mmol). The color of the mixture turned to light red. After being stirred at room temperature overnight, the reaction mixture was diluted with 1000 mL of H2O and acidified to pH 2 with concentrated HCl, then extracted with DCM (300 mL×3). The aqueous layer was then basified to pH 10 with 1 N aqueous solution of KOH and then extracted with DCM (400 mL×3). The combined organic layers were dried over Na2SO4 and then concentrated in vacuo to afford 4-amino-1-(4-methoxybenzyl)pyrrolidin-2-one as light yellow oil (28.0 g, yield: 63.2%), which solidified after being cooled down to room temperature and was used without further purification.
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:10]([O:11]C(=O)C)[C@H:9]([O:15]C(=O)C)[C@@H:8]([CH2:19][O:20]C(=O)C)[O:7][C@H:6]1[O:24][C:25]1[C:29]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH2:38][CH2:39][CH2:40][N:41]([CH2:47][C:48]3[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=3)[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])=[CH:33][C:32]=2[CH3:54])=[C:28]([CH:55]([CH3:57])[CH3:56])[NH:27][N:26]=1)(=O)C.C[O-].[Na+]>CO>[CH2:47]([N:41]([CH2:40][CH2:39][CH2:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:29]2[C:25]([O:24][C@@H:6]3[O:7][C@H:8]([CH2:19][OH:20])[C@@H:9]([OH:15])[C@H:10]([OH:11])[C@H:5]3[OH:4])=[N:26][NH:27][C:28]=2[CH:55]([CH3:57])[CH3:56])=[C:32]([CH3:54])[CH:33]=1)[CH2:42][CH2:43][C:44](=[O:46])[NH2:45])[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Oc2n[nH]c(C(C)C)c2Cc2ccc(OCCCN(CCC(N)=O)Cc3ccccc3)cc2C)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(OCCCN(CCC(N)=O)Cc2ccccc2)ccc1Cc1c(O[C@@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)n[nH]c1C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 93 %

Procedure:
To a solution of 3-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-4-[(4-{3-[N-benzyl-N-(2-carbamoylethyl)-amino]propoxy}-2-methylphenyl)methyl]-5-isopropyl-1H-pyrazole (45.3 g) in methanol (400 mL) was added sodium methoxide (28% methanol solution, 2.2 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol=5/1-4/1) to give the title compound (33.2 g).
Reaction SMILES: Br[C:2]1[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1.C([O-])([O-])=O.[K+].[K+].[Br-]>C(#N)C.[Pd](Cl)Cl.C(P(C(C)(C)C)[C-]1C=CC=C1)(C)(C)C.[C-]1(P(C(C)(C)C)C(C)(C)C)C=CC=C1.[Fe+2]>[Cl:12][C:13]1[CH:14]=[C:15]([C:2]2[C:3]([CH2:10][OH:11])=[N:4][C:5]([S:8][CH3:9])=[N:6][CH:7]=2)[C:16]([O:19][CH3:20])=[N:17][CH:18]=1
Reactant: CSc1ncc(Br)c(CO)n1
Reactant: COc1ncc(Cl)cc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(C)(C)P([c-]1cccc1)C(C)(C)C
Solvent: CC#N
Product: COc1ncc(Cl)cc1-c1cnc(SC)nc1CO
Temperature: 50 °C

Procedure:
[5-Bromo-2-(methylthio)pyrimidin-4-yl]methanol (INTERMEDIATE 1, 1.9 g, 8.08 mmol), 5-chloro-2-methoxypyridin-3-ylboronic acid (1.51 g, 8.08 mmol) and K2CO3 (3.35 g, 24.24 mmol) were added to a round bottom flask, which was then evacuated and charged with nitrogen 3 times. THF (30 mL) and water (6 mL) were then added. After evacuating and charging again with nitrogen, 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (0.527 g, 0.808 mmol) was added and the reaction heated for 30 minutes at 50° C. LCMS showed 80% conversion to product plus 20% unreacted bromide. The reaction was diluted with 15 mL acetonitrile and filtered through a 4 g C18 cartridge, eluting with 50 mL acetonitrile until the filtrate was colorless. The filtrate was then concentrated. Silica gel chromatography using a 0-50% isopropyl acetate/hexanes linear gradient followed by an isocratic hold of 50% isopropyl acetate/hexanes gave an 80/20 inseparable mixture of title compound and recovered starting material, which was more thoroughly purified later in the synthetic route. LCMS (M+H)+: 298.3 Title compound. LCMS (M+H)+: 237.1 Starting material (INTERMEDIATE 1).