Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17].C([Li])CCC.[B:23](OC)([O:26]C)[O:24]C.Cl>C1COCC1.CCCCCC>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:13]=[CH:12][C:11]([B:23]([OH:26])[OH:24])=[C:10]([O:14][CH3:15])[C:9]=1[O:16][CH3:17]
Reactant: COB(OC)OC
Reactant: COc1cccc(-c2ccccc2F)c1OC
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1c(B(O)O)ccc(-c2ccccc2F)c1OC
Temperature: 25 °C
Reaction time: 4 h
Yield: 64.9 %

Procedure:
In the atmosphere of argon, 19.7 g of 2′-fluoro-2,3-dimethoxybiphenyl and 500 mL of anhydrous THF were placed in a flask. 56 mL of a hexane solution of 1.6M n-butyllithium was added, and the reaction solution was stirred at room temperature for 4 hours. After cooling to −78° C., 30 mL of a THF solution of 27.8 g of trimethyl borate was added dropwise. While heating to room temperature, the reaction solution was stirred for 8 hours. 200 mL of 10% HCl was added to the reaction solution, and the resulting mixture was stirred for 2 hours. The reaction solution was extracted with ether. An aqueous phase was removed, and then an organic phase was washed with saturated saline. After drying the organic phase with magnesium sulfate, the organic phase was concentrated, and residues were washed with hexane, whereby 15.2 g (yield: 65%) of 2′-fluoro-2,3-dimethoxybiphenyl-4-boronic acid was obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:21]=[O:22].Cl>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C:9]2[S:10][C:11]([CH:21]=[O:22])=[CH:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: Clc1ccc(Sc2cccs2)cc1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ccc(Sc2ccc(Cl)cc2)s1
Temperature: -30 °C
Reaction time: 2 h

Procedure:
To a solution of 2-(4-chlorophenylthio)thiophene (9.8 g) in dry tetrahydrofuran (75 ml) at -30° C. under nitrogen, was added dropwise, n-butyllithium (17.4 ml, 2.5M) and the solution left to stir at -30° C. for 2 hours. Dry dimethylformamide (5.1 ml) was then added and the solution allowed to stir at -30° C. for a further hour, warmed to room termperature and stirred overnight. The reaction mixture was poured onto 2N hydrochloric acid (75 ml), extracted with ether (2×100 ml), dried over MgSO4 and evaporated under reduced pressure to give a brown oil. The oil was flash chromatographed on a Sorbsil C60-40/60H column using 25% ether-hexane to give an orange oil.
Reaction SMILES: O1CCCCC1[N:7]1[C:15]2[C:10](=[CH:11][C:12]([C:16]3[N:20]=[CH:19][N:18](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:17]=3)=[CH:13][CH:14]=2)[C:9]([C:40]2[CH:41]=[C:42]([NH2:46])[CH:43]=[CH:44][CH:45]=2)=[N:8]1.[CH3:47][C:48]1[CH:56]=[CH:55][C:51]([C:52](Cl)=[O:53])=[CH:50][CH:49]=1.O>N1C=CC=CC=1>[NH:18]1[CH:19]=[N:20][C:16]([C:12]2[CH:11]=[C:10]3[C:15](=[CH:14][CH:13]=2)[NH:7][N:8]=[C:9]3[C:40]2[CH:41]=[C:42]([NH:46][C:52]([C:51]3[CH:55]=[CH:56][C:48]([CH3:47])=[CH:49][CH:50]=3)=[O:53])[CH:43]=[CH:44][CH:45]=2)=[N:17]1
Reactant: Nc1cccc(-c2nn(C3CCCCO3)c3ccc(-c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc23)c1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: c1ccncc1
Solvent: O
Product: Cc1ccc(C(=O)Nc2cccc(-c3n[nH]c4ccc(-c5nc[nH]n5)cc34)c2)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 66.1 %

Procedure:
To a solution of 3-{1-perhydro-2H-pyran-2-yl-5-[1-(triphenylmethyl)(1,2,4-triazol-3-yl)]-1H-indazol-3-yl}phenylamine (0.140 g, 0.23 mmol) in pyridine (2 mL) was 0.35 added 4-methylbenzoyl chloride (0.053 mL, 0.40 mmol). The reaction was stirred at room temperature for 15 h. Water (10 mL) was added and the solid collected by suction filtration. The solid was dried in a vacuum oven for 3 h. The residue was dissolved in 4 N hydrochloric acid in 1,4-dioxane (10 mL) and the mixture was stirred at room temperature for 2 h. After neutralization with aqueous sodium bicarbonate, the reaction mixture was extracted with ethyl acetate. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and evaporated. Addition of dichloromethane (10 mL) to the residue gave the title compound (0.060 g, 65% yield) which was isolated by filtration: 1H NMR (DMSO-d6) δ 10.41 (s, 1H), 8.74 (s, 1H), 8.46 (s, 1H), 8.33 (s, 1H), 8.10 (d, 1H), 7.94 (d, 3H), 7.72 (m, 2H), 7.54 (t, 1H), 7.36 (d, 2H), 2.40 (s, 3H); ES-MS (m/z) 395 [M+1]+.
Reaction SMILES: Cl[C:2]1[C:17]([Cl:18])=[C:16]([OH:19])[CH:15]=[CH:14][C:3]=1[C:4](=[N:12][OH:13])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=1.[H-].[Na+].N#N.[CH3:24]N(C=O)C>>[Cl:18][C:17]1[C:2]2[O:13][N:12]=[C:4]([C:5]3[CH:10]=[CH:9][CH:8]=[C:7]([F:11])[CH:6]=3)[C:3]=2[CH:14]=[CH:15][C:16]=1[O:19][CH3:24]
Reactant: ON=C(c1cccc(F)c1)c1ccc(O)c(Cl)c1Cl
Reactant: CN(C)C=O
Agent: N#N
Agent: [H-]
Agent: [Na+]
Product: COc1ccc2c(-c3cccc(F)c3)noc2c1Cl
Temperature: 100 °C
Reaction time: 18 h

Procedure:
To a solution of 3 g of 2,3-dichloro-4-hydroxy-3'-fluorobenzophenone oxime in 20 ml of DMF, 0.25 g of NaH is added in an atmosphere of N2. The mixture is stirred for 18 hours. The mixture is heated to 100° C. for one hour. The reaction mixture is poured into ice water to yield 7-chloro-3-(3-fluorophenyl)-6-methoxy-1,2-benzisoxazole, mp 149°-150° C.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[CH3:7][CH:8]1[CH:12]=[CH:11][CH:10]([CH3:13])[NH:9]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH3:7][C@H:8]1[CH:12]=[CH:11][C@H:10]([CH3:13])[N:9]1[CH2:2][C:3]([O:5][CH3:6])=[O:4]
Reactant: CC1C=CC(C)N1
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)CN1[C@@H](C)C=C[C@@H]1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
Methyl bromoacetate (16.8 g, 0.11 mol) was added, dropwise, to a stirred mixture of 2,5-dimethyl-3-pyrroline (10 g, 0.1 mol), potassium carbonate (13.8 g, 0.1 mol), and dimethylformamide (25 cm3) maintained below 30° C. by ice cooling. After addition was complete the mixture was cooled in ice for a further 1 h, then stirred at room temperature overnight. The reaction mixture was then diluted with water (50 cm3) and the product extracted into ether. The ether extract was dried and evaporated to yield an oil* which was distilled under vacuum to give methyl (trans-2,5-dihydro-2,5-dimethyl-1H-pyrrol-1-yl)acetate (7 g) b.p. 89°-92° C./15 mm.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1.[CH3:11][O:12][N:13]([CH3:17])[C:14](Cl)=[O:15]>>[CH3:11][O:12][N:13]([CH3:17])[C:14]([NH:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[O:4][N:3]=1)=[O:15]
Reactant: CC(C)(C)c1cc(N)no1
Reactant: CON(C)C(=O)Cl
Product: CON(C)C(=O)Nc1cc(C(C)(C)C)on1
Yield: 94.7 %

Procedure:
Using 3-amino-5-t-butylisoxazole and N-methoxy-N-methylcarbamoyl chloride, the reaction is run as in Example 1, whereby 1-methoxy-1-methyl-3-(5-t-butyl-3-isoxazolyl)urea is obtained. Yield is 94.7%. Melting point is 106.0° to 107.0° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH2:15])[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1.[C:16](O)(=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[N+:19]([O-:23])[CH:18]=1>>[O:1]1[CH:5]=[CH:4][C:3]([C:6]2[N:11]3[N:12]=[C:13]([NH:15][C:16](=[O:24])[C:17]4[CH:22]=[CH:21][CH:20]=[N+:19]([O-:23])[CH:18]=4)[N:14]=[C:10]3[CH:9]=[CH:8][CH:7]=2)=[CH:2]1
Reactant: O=C(O)c1ccc[n+]([O-])c1
Reactant: Nc1nc2cccc(-c3ccoc3)n2n1
Product: O=C(Nc1nc2cccc(-c3ccoc3)n2n1)c1ccc[n+]([O-])c1

Procedure:
The title compound was prepared following procedure described for example 2, but starting from 5-(3-furyl)[1,2,4]triazolo[1,5-a]pyridin-2-amine ((A2), 100 mg; 0.50 mmol; 1.0 eq.) and nicotinic acid N-oxide (83 mg, 0.6 mmol, 1.2 eq.) as a light yellow solid (37.2 mg, 23%). HPLC, Rt: 1.98 min. (purity 98.8%). LC/MS, M+(ESI): 322.1, M−(ESI): 320.1.
Reaction SMILES: [Br:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([C:8]2[CH:13]=[CH:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH:9]=2)=O)=[C:4](F)[CH:3]=1.C[NH:21][NH2:22]>C(O)CCC>[C:14]([N:11]1[CH2:12][CH2:13][CH:8]([C:6]2[C:5]3[C:4](=[CH:3][C:2]([Br:1])=[CH:18][CH:17]=3)[NH:22][N:21]=2)[CH2:9][CH2:10]1)(=[O:16])[CH3:15]
Reactant: CC(=O)N1C=CC(C(=O)c2ccc(Br)cc2F)=CC1
Reactant: CNN
Solvent: CCCCO
Product: CC(=O)N1CCC(c2n[nH]c3cc(Br)ccc23)CC1

Procedure:
A solution of 3.3 g of 4-(4-bromo-2-fluorobenzoyl)-1-acetylpyridine, 1.1 g of (0.013 mole) of methylhydrazine and 30 ml of n-butanol was heated under reflux for 16 hrs. The reaction mixture was concentrated in vacuo and the residue was diluted with water. The aqueous suspension was made basic with ammonium hydroxide solution and extracted with dichloromethane. The extract was washed with water, dried over anhydrous potassium carbonate and the solvent was concentrated to give 3-(1-acetyl-4-piperidinyl)-6-bromo-1H-indazole, as an oil.
Reaction SMILES: [OH-].[Na+].[N+:3]([CH3:6])([O-:5])=[O:4].[CH2:7]([O:9][C:10]1[C:11]([B:19]2[O:23][C:22](C)(C)C(C)(C)[O:20]2)=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])C=O)[CH3:8].Cl>O.C1COCC1>[CH2:7]([O:9][C:10]1[C:11]2[B:19]([OH:20])[O:23][CH:22]([CH2:6][N+:3]([O-:5])=[O:4])[C:12]=2[CH:15]=[CH:16][C:17]=1[F:18])[CH3:8]
Reactant: CCOc1c(F)ccc(C=O)c1B1OC(C)(C)C(C)(C)O1
Reactant: C[N+](=O)[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(F)ccc2c1B(O)OC2C[N+](=O)[O-]
Reaction time: 0.17 h
Yield: 68.6 %

Procedure:
To a cooled solution of sodium hydroxide (80 mg, 2.0 mmol) in water (3.0 mL), nitromethane (244.0 mg, 4.0 mmol) was added at 0° C. and stirred for 10 min. Then 3-ethoxy-4-fluoro-2-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzaldehyde (588.0 mg, 2.0 mmol) in THF (5.0 mL) was added. The reaction mixture was stirred at for 1 h at 0° C. and for 2 h at room temperature. The reaction mixture was acidified with 2.5 M HCl (1.0 mL) and the product was extracted with ethyl acetate (2×20 mL). The organic extracts were combined and washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure and product was chromatographed on a column of silica gel(CH2Cl2:MeOH=95:5) to give the title compound as a solid (350 mg, 69%). 1H NMR (400 MHz, DMSO-d6) δ ppm: 7.40 (dd, J=11.3, 8.2 Hz, 1H), 7.16 (dd, J=8.0, 3.3 Hz, 1H), 5.74 (d, J=9.0 Hz, 1H), 5.30 (dd, J=13.5, 2.2 Hz, 1H), 4.62 (dd, J=13.5, 9.2 Hz, 1H), 4.35 (q, J=6.8 Hz, 2H), 1.28 (t, J=6.8 Hz, 3H); MS (ESI) m/z=254 (M−1, negative).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2I)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.C([Sn](CCCC)(CCCC)[C:27]1[O:28][C:29]2[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:30]=2[CH:31]=1)CCC.C(OCC)(=O)C>CN(C=O)C.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:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]2[C:18]([C:19]#[N:20])=[CH:17][N:16]=[CH:15][C:14]=2[C:27]2[O:28][C:29]3[CH:35]=[CH:34][C:33]([CH:36]=[O:37])=[CH:32][C:30]=3[CH:31]=2)[C:5]([CH3:11])=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2
Reactant: CCCC[Sn](CCCC)(CCCC)c1cc2cc(C=O)ccc2o1
Reactant: Cc1c(Nc2c(I)cncc2C#N)cc(Cl)c2[nH]ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1c(Nc2c(C#N)cncc2-c2cc3cc(C=O)ccc3o2)cc(Cl)c2[nH]ccc12
Temperature: 110 °C
Yield: 82.2 %

Procedure:
To a stirred solution of 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-iodonicotinonitrile (405 mg, 1 mmol) in DMF (7 mL) was added 2-(tributylstannyl)-1-benzofuran-5-carbaldehyde (609 mg, 1.4 mmol) and tetrakis(triphenylphosphine)palladium(0) (110 mg, 0.1 mmol) under nitrogen atmosphere, the reaction mixture was heated at 110° C. for 1.5 h and cooled to room temperature and ethyl acetate was added to the resulting mixture. The organic phase was washed with water, saturated aqueous sodium chloride, dried over magnesium sulfate and concentrated and the residue was purified by flash column chromatography (ethyl acetate/hexane) to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-(5-formyl-1-benzofuran-2-yl)nicotinonitrile as a yellow solid (351 mg, 82%). HPLC retention time: 12.4 min.(g); and MS: 427.3 (M+H).
Reaction SMILES: Br[C:2]1[N:3]=[C:4]([C:20]2[C:21]([CH3:29])=[N:22][N:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=23)[S:5][C:6]=1[C:7]1[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=1.[Cl-].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][Zn+])=[CH:34][CH:33]=1>O1CCCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][C:2]2[N:3]=[C:4]([C:20]3[C:21]([CH3:29])=[N:22][N:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=34)[S:5][C:6]=2[C:7]2[N:11]=[CH:10][N:9]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[N:8]=2)=[CH:34][CH:33]=1
Reactant: Cc1nn2ccccc2c1-c1nc(Br)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Reactant: Clc1ccc(C[Zn+])cc1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nn2ccccc2c1-c1nc(Cc2ccc(Cl)cc2)c(-c2ncn(COCC[Si](C)(C)C)n2)s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
To a solution of 3-[4-bromo-5-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-1,3-thiazol-2-yl]-2-methylpyrazolo[1,5-a]pyridine (0.200 g, 0.407 mmol) in tetrahydrofuran (2.8 mL) were added 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.63 mL, 0.814 mmol) and bis(tri-t-butylphosphine)palladium(0) (0.0156 g, 0.0305 mmol) under argon. The solution was stirred at 60° C. for 3 hours. The reaction was incomplete by LCMS, so additional 4-chlorobenzylzinc chloride (0.50M solution in tetrahydrofuran, 1.0 mL, 0.5 mmole) was added then the reaction was stirred at 60° C. for an additional 3 hours. The reaction was cooled to room temperature then the solvent was evaporated in vacuo. The residue was purified by column chromatography (SiO2, elution with EtOAc in hexanes 10-100% gradient) to yield the title compound (0.188 g, 86%). LCMS: (FA) ES+ , 538. 1H NMR (400 MHz, d6-DMSO) δ: 8.87 (s, 1H), 8.76-8.72 (m, 1H), 8.28-8.24 (m, 1H), 7.54-7.48 (m, 1H), 7.44-7.40 (m, 2H), 7.35-7.30 (m, 2H), 7.09-7.03 (m, 1H), 5.58 (s, 2H), 4.63 (s, 2H), 3.68-3.62 (m, 2H), 2.66 (s, 3H), 0.91-0.84 (m, 2H), 0.050 (s, 9H).
Reaction SMILES: [ClH:1].[NH:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([O:6]CC)=[O:5].[CH2:13](Br)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[ClH:1].[CH2:13]([N:2]1[CH2:12][CH2:11][CH2:10][CH2:9][CH:3]1[C:4]([OH:6])=[O:5])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)C1CCCCN1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(O)C1CCCCN1Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of ethyl pipecolinate hydrochloride (10 g, 52 mmol), benzylbromide (7 mL, 57 mmol) and potassium carbonate (15 g, 114 mmol) in DMF (80 mL) was stirred at room temperature overnight. The solvent was removed in vacuo. The residue was partitioned between dichloromethane (100 mL) and water (50 mL). The aqueous layer was extracted with dichloromethane (2×100 mL), dried over Na2SO4, then evaporated to give a yellow oil. The crude product was chromatographed (500 g silica gel) eluting with a stepgradient of 8%-15% ethyl acetate in hexane. Pure fractions were combined to give title compound (12.3 g, 96%) as a colorless oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=1.CCN(C(C)C)C(C)C.[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH2:30])=[N:26]1>C1COCC1>[CH3:24][N:25]1[CH:29]=[CH:28][C:27]([NH:30][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([S:13][CH3:14])[N:3]=2)=[N:26]1
Reactant: Cn1ccc(N)n1
Reactant: CCOC(=O)c1cnc(SC)nc1Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnc(SC)nc1Nc1ccn(C)n1
Yield: 81.3 %

Procedure:
To a solution of 800 mg of ethyl 4-chloro-2-(methylsulfanyl)pyrimidine-5-carboxylate in 20 mL of THF, 890 mg of DIPEA and 368 mg of 1-methyl-1H-pyrazol-3-amine were added, and the resulting mixture was stirred under reflux for 2 hours, and then, the solvent was distilled off. The thus obtained crude product was purified by silica gel column chromatography, whereby 820 mg the title compound was obtained.
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][O:26][CH2:27][C@@H:28]([O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=2)[CH:39]=1)[C:34](O)=[O:35])[CH3:29].CCN(C(C)C)C(C)C.[NH2:60][C:61]1[CH:65]=[CH:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[N:62]=1>CN(C=O)C>[CH3:25][O:26][CH2:27][C@H:28]([CH3:29])[O:30][C:31]1[CH:32]=[C:33]([CH:37]=[C:38]([O:40][C:41]2[CH:46]=[CH:45][C:44]([S:47]([CH3:50])(=[O:49])=[O:48])=[CH:43][CH:42]=2)[CH:39]=1)[C:34]([NH:60][C:61]1[CH:65]=[CH:64][N:63]([C:66]([O:68][C:69]([CH3:72])([CH3:71])[CH3:70])=[O:67])[N:62]=1)=[O:35]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)O)c1
Reactant: CC(C)(C)OC(=O)n1ccc(N)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)cc2)cc(C(=O)Nc2ccn(C(=O)OC(C)(C)C)n2)c1
Reaction time: 4 h
Yield: 42.9 %

Procedure:
HATU (375 mg, 1.17 mmol) was added to 3-{(1S)-2-methoxy-(1-methylethyl)oxy}-5-{[4-(methylsulfonyl)phenyl]oxy}benzoic acid (300 mg, 0.79 mmol) followed by addition of DMF (5 mL), DIPEA (0.35 mL) and tert-butyl 3-amino-1H-pyrazole-1-carboxylate (155 mg, 0.85 mmol) and the reaction was stirred under argon for 4 h. The solvent was evaporated and the residue was dissolved in saturated aqueous sodium hydrogencarbonate (30 mL) and ethyl acetate (50 mL). The organic layer was separated, washed with saturated aqueous ammonium chloride (30 mL) then dried (MgSO4), filtered and evaporated. Purification by column chromatography, eluting with 50% ethyl acetate in hexanes, afforded the title compound as a colourless oil (185 mg, 43%).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([O:14]C)=[O:13])=[CH:8][NH:9]2)=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)=[C:18]([O:29][CH3:30])[CH:17]=1.O1CCCC1.[OH-].[Na+]>CO>[Cl:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]([OH:14])=[O:13])=[CH:8][NH:9]2)=[CH:5][C:4]=1[C:16]1[CH:21]=[CH:20][C:19]([O:22][CH2:23][C@@H:24]2[CH2:28][CH2:27][CH2:26][NH:25]2)=[C:18]([O:29][CH3:30])[CH:17]=1
Reactant: COC(=O)c1c[nH]c2cc(Cl)c(-c3ccc(OC[C@@H]4CCCN4)c(OC)c3)cc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(-c2cc3c(C(=O)O)c[nH]c3cc2Cl)ccc1OC[C@@H]1CCCN1
Temperature: 65 °C
Reaction time: 41 h

Procedure:
To a solution of (S)-methyl 6-chloro-5-(3-methoxy-4-(pyrrolidin-2-ylmethoxy)phenyl)-1H-indole-3-carboxylate hydrochloride (22.6 mg, 0.050 mmol) in methanol (0.26 mL) was added tetrahydrofuran (0.26 mL) and sodium hydroxide (1N in water, 0.26 mL, 0.26 mmol). The mixture was then sealed and heated to 65° C. After 41 h, the mixture was allowed to cool to 23° C., concentrated in vacuo, diluted with water (1 mL), then acidified to pH 7.5 with hydrochloric acid (1N in water). The solid was filtered and purified by reverse phase HPLC to provide the title compound. MS (ES+) 401.2 (M+H)+. HPLC retention time: 1.44 min, Waters XBridge C18, 5 μm, 4.6×50 mm, 0.03% NH4OH, 5-95% acetonitrile in water gradient over 4.0 min, hold at 95% acetonitrile in water to 5.0 min, flow 2.0 mL/min.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([O:15]C)=[O:14])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:17])[CH:4]=[N:3]1.[OH-].[Na+]>O1CCCC1>[CH3:1][N:2]1[C:6]([C:7]2[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[S:10][C:11]=2[CH3:12])=[C:5]([CH3:17])[CH:4]=[N:3]1
Reactant: COC(=O)c1cc(-c2c(C)cnn2C)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1cnn(C)c1-c1cc(C(=O)O)sc1C
Yield: 95.8 %

Procedure:
A solution of methyl 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylate (240 mg, 0.96 mmol) in 6N sodium hydroxide (3.20 ml, 19.18 mmol) and tetrahydrofuran (4.79 ml) was stirred at 70° C. in a sealed tube for 1 h. The resulting solution was cooled and then partitioned between H2O-DCM. The aqueous phase was adjusted to pH ˜4 and then washed several times with DCM. The combined organic fractions were dried over Na2SO4 and concentrated affording 4-(1,4-dimethyl-1H-pyrazol-5-yl)-5-methyl-2-thiophenecarboxylic acid (217 mg, 0.92 mmol, 96% yield) as a yellow oil: LCMS (ES) m/e 236 (M+H)+.
Reaction SMILES: [CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][OH:22])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:23]([Si:27](Cl)([CH3:29])[CH3:28])([CH3:26])([CH3:25])[CH3:24].N1C=CN=C1>CN(C=O)C>[CH2:1]([NH:8][CH2:9][CH:10]([CH2:21][O:22][Si:27]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:29])[CH3:28])[CH:11]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=1)[OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCC(CNCc1ccccc1)C(O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 64.8 %

Procedure:
To a solution of (1RS,2RS)-2-[(benzylamino)methyl]-1-(3,4-dichlorophenyl)propane-1,3-diol (3.44 g) in DMF (30 ml) were added tert-butylchlorodimethylsilane (1.68 g) and imidazole (1.03 g) under ice-cooling, and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The diluted solution was washed with distilled water, saturated aqueous sodium hydrogen carbonate and brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.98 g).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([Cl:12])[N:8]=[C:7]2[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[F:19][C:20]1[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][N:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:9]1[N:8]=[C:7]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:6]2[C:11](=[C:2]([C:23]3[CH:22]=[N:21][C:20]([F:19])=[CH:25][CH:24]=3)[CH:3]=[CH:4][CH:5]=2)[N:10]=1
Reactant: Clc1nc(N2CCOCC2)c2cccc(Br)c2n1
Reactant: OB(O)c1ccc(F)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Fc1ccc(-c2cccc3c(N4CCOCC4)nc(Cl)nc23)cn1
Temperature: 95 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
To a 50 mL round bottom flask, 8-bromo-2-chloro-4-morpholin-4-yl-quinazoline (150 mg, 0.00046 mol), 2-fluoropyridine-5-boronic acid (58 mg, 0.00041 mol), sodium carbonate (72 mg, 0.00068 mol), DMF (10 mL) and water (3 mL) were added and the reaction vessel was degassed with nitrogen for 5-10 min. To the same reaction mixture, PdCl2(PPh3)2 (16 mg, 0.000023 mol) was added and again degassed with nitrogen for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 60% ethyl acetate in hexane) to yield the desired product [90 mg, 60%]. 1H NMR (300 MHz, CDCl3): δ 8.44 (s, 1H), 8.17-8.24 (m, 1H), 7.89 (d, J=8.1 Hz, 1H), 7.78 (d, J=7.5 Hz, 1H), 7.53 (t, J=7.5 Hz, 1H), 7.75 (dd, J′=2.7, J″=3.0 Hz, 1H), 3.89 (s, 8H). LC-MS (ESI): Calculated mass: 344.1; Observed mass: 345.0 [M+H]+ (RT: 1.63 min).