Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:10][CH3:11])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O-:8])=O.S(Cl)(Cl)=O.[NH2:16][C:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2[O:19][C:18]=1[C:26]([NH:28][C:29]1[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][N:30]=1)=[O:27].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.CN(C)C=O.N1C=CC=CC=1>[Cl:35][C:32]1[CH:33]=[CH:34][C:29]([NH:28][C:26]([C:18]2[O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:17]=2[NH:16][C:6](=[O:8])[CH2:5][CH2:4][CH2:3][CH2:2][C:1]([O:10][CH3:11])=[O:9])=[O:27])=[N:30][CH:31]=1
Reactant: Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Reactant: COC(=O)CCCCC(=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: COC(=O)CCCCC(=O)Nc1c(C(=O)Nc2ccc(Cl)cn2)oc2ccccc12
Reaction time: 0.33 h
Yield: 90.3 %

Procedure:
Monomethyl adipate (2.55 g) is dissolved in chloroform (35 ml) and there to are added thionyl chloride (1.25 ml) and N,N-dimethylformamide (2 drops) at room temperature. The mixture is stirred at the same temperature for 3 hours and 20 minutes, and thereto are added 3-amino-N-(5-chloropyridin-2-yl)benzofuran-2-carboxamide (3.50 g) obtained in Reference Example 80 and pyridine (5.0 ml). After stirring for 14.5 hours at room temperature, a saturated aqueous sodium hydrogen carbonate solution is added to the reaction solution, and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate, and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diisopropyl ether and the precipitates are collected by filtration to give methyl 6-[(2-{[(5-chloropyridin-2-yl)amino]carbonyl}benzofuran-3-yl)amino]-6-oxohexanoate (4.72 g).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]#[N:11].[OH-:14].[Na+].OO>>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:13])([CH3:12])[C:10]([NH2:11])=[O:14]
Reactant: CC(C)(C#N)c1cccc(F)c1F
Reactant: [OH-]
Agent: OO
Agent: [Na+]
Product: CC(C)(C(N)=O)c1cccc(F)c1F

Procedure:
Hydrolysis of 2-(2,3-difluorophenyl)-2-methylpropionitrile was performed according to the procedure of Example 10 using sodium hydroxide in the presence of hydrogen peroxide to provide 2-(2,3-difluorophenyl)isobutyramide [1H-NMR (CDCl3): δ 7.17-7.08 (m, 3H), 5.98 (br s, 1H), 5.45 (br s, 1H), 1.60 (s, 6H)].
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH:24]3[CH2:26][CH2:25]3)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29](B(O)O)[CH:28]=1>>[CH:24]1([C:10]2[CH:11]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:13]=[C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([C:29]4[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=4)[CH:3]=3)[N:9]=2)[CH2:26][CH2:25]1
Reactant: FC(F)(F)c1ccc(-c2cc(-c3cccc(Br)c3)nc(C3CC3)c2)cc1
Reactant: OB(O)c1cccnc1
Product: FC(F)(F)c1ccc(-c2cc(-c3cccc(-c4cccnc4)c3)nc(C3CC3)c2)cc1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-6-cyclopropyl-4-(4-trifluoromethyl-phenyl)-pyridine (example E.22) (0.392 g, 0.72 mmol) and commercially available 3-pyridineboronic acid (0.115 g, 0.93 mmol) according to the general procedure VI. Obtained as a white solid (0.120 g, 40%). MS (ISP) 417.3 [(M+H)+]; mp 100-104° C.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-:17])=[O:16])[C:10]=1[O:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=O)(C)(C)C.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>CO>[CH2:19]([O:18][C:10]1[C:11]([N+:15]([O-:17])=[O:16])=[CH:12][CH:13]=[CH:14][C:9]=1[NH2:8])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc([N+](=O)[O-])c1OCc1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Nc1cccc([N+](=O)[O-])c1OCc1ccccc1
Temperature: 50 °C
Reaction time: 12 h
Yield: 96.9 %

Procedure:
N-tert-Butoxycarbonyl-2-benzyloxy-3-nitroaniline (9.37 g, 27.2 mmol) was dissolved in methanol (150 ml), p-toluenesulfonic acid monohydrate (7.84 g, 45.5 mmol) was added thereto and the mixture was stirred at 50° C. for 12 hours. The reaction solution was neutralized with a saturated aqueous solution of sodium bicarbonate and extracted with chloroform. The organic layer was washed with water and a saturated sodium chloride solution successively and dried over anhydrous sodium sulfate and the solvent was evaporated. The residue was purified by a silica gel column chromatography (50 g of silica gel; developing solvent, hexane:ethyl acetate=6:1) to provide 6.44 g (yield 96.9%) of 2-benzyloxy-3-nitroaniline as pale yellowish brown oil.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:15]#[N:16].[Cl:17][C:18]1[CH:19]=[C:20]([NH2:31])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:17][C:18]1[CH:19]=[C:20]([NH:31][C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:14])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:15]#[N:16])[CH:21]=[CH:22][C:23]=1[S:24][C:25]1[N:26]([CH3:30])[CH:27]=[CH:28][N:29]=1
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1F
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Temperature: 120 °C
Reaction time: 0.75 h

Procedure:
A mixture of 1.0 g (4.23 mmol) of 4-chloro-7-fluoro-6-methoxyquinoline-3-carbonitrile (AM100856), 1.114 g (4.65 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine and 0.489 g (4.23 mmol) of pyridine hydrochloride in 10 mL of 2-ethoxyethanol is heated at 120° C. for 1.5 hours, then cooled to room temperature. The resulting solid is filtered, washed with cold 2-ethoxyethanol, then ethyl acetate. After drying in vacuo, the solid is suspended in a saturated solution of sodium bicarbonate, stirred for 45 minutes and collected by filtration. The reaction product is washed with water and dried in vacuo, to provide 4-[3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)-phenylamino]-7-fluoro-6-methoxyquinoline-3-carbonitrile as a tan solid, mp 295-297° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:5]=[CH:6][CH:7]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].[ClH:38].[N:39]12[CH2:46][CH2:45][CH:42]([CH2:43][CH2:44]1)[C@@H:41]([NH:47][C:48]([C:50]1[S:51][C:52]3[C:58](Br)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2.C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C.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]>[ClH:38].[N:39]12[CH2:44][CH2:43][CH:42]([CH2:45][CH2:46]1)[C@@H:41]([NH:47][C:48]([C:50]1[S:51][C:52]3[C:58]([C:2]4[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9](=[O:14])[C:10]([CH3:13])([CH3:12])[CH3:11])[CH:3]=4)=[CH:57][CH:56]=[CH:55][C:53]=3[CH:54]=1)=[O:49])[CH2:40]2
Reactant: O=C(N[C@H]1CN2CCC1CC2)c1cc2cccc(Br)c2s1
Reactant: CC(C)(C)C(=O)Nc1cccc(Br)c1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)Nc1cccc(-c2cccc3cc(C(=O)N[C@H]4CN5CCC4CC5)sc23)c1

Procedure:
143.5 mg (0.56 mmol) of N-(3-bromophenyl)-2,2-dimethylpropanamide, 142.2 mg (0.56 mmol) of bis(pinacolato)diboron, 119.1 mg (1.21 mmol) of potassium acetate, 13.7 mg (0.02 mmol) of PdCl2(dppf), 150.0 mg (0.37 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-7-bromo-1-benzothiophene-2-carboxamide hydrochloride (Example 8A), 0.93 ml of 2 M sodium carbonate solution and a further 13.7 mg (0.02 mmol) of PdCl2(dppf) in 2.0 ml of DMF are reacted by general method D. An initial purification by preparative HPLC is followed by column chromatography on silica gel (mobile phase: dichloromethane/methanol/ammonia 90:9:1). Drying under high vacuum results in 32.4 mg (17% of theory) of the title compound.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[N+:38]([C:41]1[CH:46]=[CH:45][C:44](B2OC(C)(C)C(C)(C)O2)=[CH:43][CH:42]=1)([O-:40])=[O:39].C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[N+:38]([C:41]1[CH:46]=[CH:45][C:44]([C:2]2[N:3]=[C:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[NH:8][C:7]4[N:15]=[CH:16][CH:17]=[CH:18][C:6]=4[N:5]3[C:19]=2[C:20]2[CH:25]=[CH:24][C:23]([C:26]3([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:35])([CH3:34])[CH3:36])[CH2:27][CH2:28][CH2:29]3)=[CH:22][CH:21]=2)=[CH:43][CH:42]=1)([O-:40])=[O:39]
Reactant: CC1(C)OB(c2ccc([N+](=O)[O-])cc2)OC1(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Cl)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccc([N+](=O)[O-])cc4)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Temperature: 160 °C
Yield: 17.6 %

Procedure:
A mixture of tert-butyl {1-[4-(2-chloro-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (250 mg, 0.486 mmol), 4-nitrophenylboronic acid pinacol ester (152 mg, 0.730 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (34.4 mg, 0.0486 mmol) and 2M Na2CO3 aq. (0.485 mL, 0.970 mmol) in DMF (1.00 mL) was heated at 160° C. under microwave irradiation for 1 hour under nitrogen. After cooling to room temperature, the mixture was diluted with EtOAc and washed with water (×3). The organic layer was dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (EtOAc/hexane=1:4→1:2) and TLC (EtOAc/hexane=1:1, DCM/EtOAc=1:1) to afford desired product (51.4 mg, 17.6%) as yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.19-8.08 (m, 3H), 8.06-8.01 (m, 1H), 7.80-7.70 (m, 2H), 7.47-7.40 (m, 2H), 7.36-7.30 (m, 1H), 7.22-7.14 (m, 3H), 7.00-6.93 (m, 1H), 6.85-6.78 (m, 1H), 6.65-6.58 (m, 1H), 6.38 (s, 1H), 5.19 (s, 1H), 2.67-2.30 (m, 4H), 2.25-2.09 (m, 1H), 1.98-1.84 (m, 1H), 1.39 (br s, 9H).
Reaction SMILES: [C:1]1([NH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F-].[Cs+].[CH3:15][O:16][CH2:17]C1COC(=O)O1>CN(C)C=O>[C:1]1([N:7]2[CH2:12][CH:11]([CH2:15][O:16][CH3:17])[O:10][C:8]2=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CCOC(=O)Nc1ccccc1
Reactant: COCC1COC(=O)O1
Agent: [Cs+]
Agent: [F-]
Solvent: CN(C)C=O
Product: COCC1CN(c2ccccc2)C(=O)O1
Temperature: 140 °C
Reaction time: 50 h
Yield: 68 %

Procedure:
Phenylurethane (15.0 g, 90.9 mmol) was dissolved in N,N-dimethylformamide (40 mL), and thereto were added cesium fluoride (1.15 g, 7.57 mmol) and 4-methoxymethyl-1,3-dioxolan-2-one (10.0 g, 75.7 mol), in order. The mixture was stirred for 50 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by silica gel chromatography to give the subject 3-phenyl-5-methoxymethyloxazolidin-2-one (12.8 g, yield 81.6%).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=O)C=1.[CH2:12]([O:19][C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:43])([CH3:42])[CH3:41])[C:31]([CH2:45][CH3:46])=[N:30][C:25]=3[CH:26]=[N:27][C:28]=2[CH:29]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-].[NH4+:48].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>C(Cl)(Cl)Cl>[NH2:48][C:26]1[C:25]2[N:30]=[C:31]([CH2:45][CH3:46])[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:38](=[O:44])[O:39][C:40]([CH3:41])([CH3:42])[CH3:43])[C:24]=2[C:23]2[CH:22]=[CH:21][C:20]([O:19][CH2:12][C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[CH:29][C:28]=2[N:27]=1
Reactant: CCc1nc2cnc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: CCc1nc2c(N)nc3cc(OCc4ccccc4)ccc3c2n1CCCCNC(=O)OC(C)(C)C
Reaction time: 1.5 h

Procedure:
mCPBA (10.6 g, 33.7 mmol) was added in one portion to a solution of tert-butyl [4-(7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate (16.0 g, 33.7 mmol) in chloroform (270 mL). After the reaction was stirred for 1.5 hours, ammonium hydroxide (270 mL) was added. The mixture was stirred for 15 minutes, and p-toluenesulfonyl chloride (6.42 g, 33.7 mmol) was added in three portions. The reaction was stirred for 18 hours. The layers were separated, and the aqueous layer was extracted with dichloromethane. The combined organic fractions were washed with water and brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile to afford 9.73 g of tert-butyl [4-(4-amino-7-benzyloxy-2-ethyl-1H-imidazo[4,5-c]quinolin-1-yl)butyl]carbamate as a gray powder.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([O:11]C)=O.[NH2:13][NH2:14]>>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][O:7][CH2:8][C:9]([NH:13][NH2:14])=[O:11]
Reactant: COC(=O)COCc1cccs1
Reactant: NN
Product: NNC(=O)COCc1cccs1

Procedure:
2-(2-thienylmethoxy)acetic acid, hydrazide (20) was prepared from methyl 2-(2-thienylmethoxy)acetate (19) (3.6 mmol), prepared in the manner described above in Example 19, and hydrazine (3.6 mmol) in the manner described above in Example 12 to yield 0.60 g (90%) of product.
Reaction SMILES: C1(N2C(=O)C3S[CH:15]=[C:16]([C:17]4C=CC=CC=4)[C:10]=3[N:9]=[CH:8]2)C=CC=CC=1.[NH2:23][C:24]1[C:28]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[F:35])=[CH:27][S:26][C:25]=1[C:36]([O:38]C)=O.C(OCC)(OCC)OCC.C(N)C(C)C>C(O)(=O)C>[F:35][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=1[C:28]1[C:24]2[N:23]=[CH:8][N:9]([CH2:10][CH:16]([CH3:17])[CH3:15])[C:36](=[O:38])[C:25]=2[S:26][CH:27]=1
Reactant: O=c1c2scc(-c3ccccc3)c2ncn1-c1ccccc1
Reactant: COC(=O)c1scc(-c2ccccc2F)c1N
Solvent: CC(C)CN
Solvent: CC(=O)O
Solvent: CCOC(OCC)OCC
Product: CC(C)Cn1cnc2c(-c3ccccc3F)csc2c1=O
Yield: 83.5 %

Procedure:
In the same manner as the synthesis of Compound 1, methyl 3-amino-4-(2-fluorophenyl)thiophene-2-carboxylate (100 mg, 0.40 mmol), triethyl orthoformate (1 ml), isobutylamine (0.076 ml, 0.76 mmol), and acetic acid (0.1 ml) were used to give 101 mg (0.33 mmol, 83.5% yield) of the title compound.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:27])=[O:26])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15](=[S:17])[NH2:16])=[CH:11]2.[C:32]([O:37][CH2:38][CH3:39])(=[O:36])[C:33]#[C:34][CH3:35].C(P(CCCC)CCCC)CCC.O1CCCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH:4]([CH2:29][O:30][CH3:31])[O:5][C:6]1[CH:7]=[C:8]([O:18][C:19]2[CH:20]=[N:21][C:22]([S:25]([CH3:28])(=[O:26])=[O:27])=[CH:23][CH:24]=2)[CH:9]=[C:10]2[C:14]=1[NH:13][C:12]([C:15]1[S:17][CH:34]([CH2:33][C:32]([O:37][CH2:38][CH3:39])=[O:36])[CH2:35][N:16]=1)=[CH:11]2
Reactant: CC#CC(=O)OCC
Reactant: COCC(COC)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc2cc(C(N)=S)[nH]c12
Agent: CCCCP(CCCC)CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCOC(=O)CC1CN=C(c2cc3cc(Oc4ccc(S(C)(=O)=O)nc4)cc(OC(COC)COC)c3[nH]2)S1
Temperature: 60 °C
Reaction time: 0.83 h
Yield: 52 %

Procedure:
A mixture of 7-[2-methoxy-1-(methoxymethyl)ethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}-1H-indole-2-carbothioamide (940 mg), ethyl 2-butynoate (0.6 mL), tributylphosphine (0.5 mL), tetrahydrofuran (15 mL) and toluene (20 mL) was stirred at 60° C. for 50 min. The mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography (methanol/ethyl acetate/hexane=0/5/95 to 5/95/0, volume ratio) to give the title compound (610 mg, 52%) as a yellow amorphous solid. MS 578 (MH+).
Reaction SMILES: [O:1]1[CH:3]2[C:4]3[CH:13]=[CH:12][CH:11]=[CH:10][C:5]=3[O:6][C:7]([CH3:9])([CH3:8])[CH:2]12.[N-:14]=[N+:15]=[N-:16].[Na+].O>O1CCOCC1>[N:14]([C@H:3]1[C@H:2]([OH:1])[C:7]([CH3:9])([CH3:8])[O:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]1=2)=[N+:15]=[N-:16]
Reactant: [N-]=[N+]=[N-]
Reactant: CC1(C)Oc2ccccc2C2OC21
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC1(C)Oc2ccccc2[C@@H](N=[N+]=[N-])[C@@H]1O

Procedure:
3,4-Epoxy-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran (3.00g.) and sodium azide (1.23g.; an excess) were refluxed in dioxane (25 ml.) and water (5 ml.) mixture for 24 hours. Dilution with water and extraction via diethyl ether gave trans-4-azido-3,4-dihydro-2,2-dimethyl-2H-benzo[b]-pyran-3-ol (3.06 g.) as needles from 60°-80° petroleum ether m.p. 70°°- 71°. To a solution of the hydroxy azide (2.90g.) in acetone (50 ml.) containing concentrated hydrochloric acid (10 ml.) was added with stirring and in portions, zinc dust (10 g.). Stirring was continued until gas evolution ceased. The zinc was filtered and washed with acetone. The combined washings and filtrate were diluted with water and extracted with diethyl ether. Basification of the aqueous layer and isolation via diethyl ether gave trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol (2.70 g.), re-crystallised from ethanol m.p. 138°. Treatment with anhydrous hydrochloric acid as in Example 1 yielded trans-4-amino-3,4-dihydro-2,2-dimethyl-2H-benzo[b]pyran-3-ol hydrochloride, m.p. 223°-225°.
Reaction SMILES: [CH3:1][N:2]([C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[C:23]([NH:28][C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)[N:22]=1)[CH:3]1[CH2:20][CH2:19][C:6]2([CH2:11][CH2:10][N:9](C(OC(C)(C)C)=O)[CH2:8][CH2:7]2)[CH2:5][CH2:4]1.Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>ClCCl.O.C(Cl)Cl.CO>[CH3:1][N:2]([CH:3]1[CH2:20][CH2:19][C:6]2([CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4]1)[C:21]1[C:26]([CH3:27])=[CH:25][N:24]=[C:23]([NH:28][C:29]2[CH:30]=[N:31][N:32]([CH3:34])[CH:33]=2)[N:22]=1
Reactant: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CC1)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: Cc1cnc(Nc2cnn(C)c2)nc1N(C)C1CCC2(CCNCC2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
To a suspension of tert-butyl 9-(methyl(5-methyl-2-((1-methyl-1H-pyrazol-4-yl) amino)pyrimidin-4-yl)amino)-3-azaspiro[5.5]undecane-3-carboxylate (250 mg, 0.53 mmol) in dichloromethane (15 mL) was added the solution of HCl in EtOAc (3 mL, 12 mmol). The reaction mixture was stirred at rt for 2 h. The mixture was adjust to pH=8-9 with the saturated solution of NaHCO3, then the mixture was diluted with 20 mL H2O and exacted with DCM/MeOH (10/1, 10 mL×3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash silica gel column chromatography (DCM/MeOH (v/v)=10/1 to 5/1) to give the title compound as a yellow solid (135 mg, 68.6%).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:20])([CH3:19])[CH3:18])[C:12]([OH:14])=[O:13])(=[O:7])=[O:6].C(Cl)(=O)C(Cl)=O.O[C@H:32]([C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])[CH3:33].N1C=CC=CC=1>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:24])([CH3:23])[C@@H:11]([O:15][Si:16]([CH3:22])([CH3:21])[C:17]([CH3:19])([CH3:18])[CH3:20])[C:12]([O:14][C@@H:32]([CH3:33])[C:34](=[O:38])[CH:35]([CH3:37])[CH3:36])=[O:13])(=[O:7])=[O:6]
Reactant: CC(C)C(=O)[C@H](C)O
Reactant: CC(C)(COS(=O)(=O)CCCCl)[C@@H](O[Si](C)(C)C(C)(C)C)C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)C(=O)[C@H](C)OC(=O)[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCCl
Yield: 35.9 %

Procedure:
Following the general procedure for the preparation of carboxylic esters from carboxylic acids of Description 15, (2R)-4-[(3-chloropropyl)sulfonyloxy]-3,3-dimethyl-2-(1,1,2,2-tetramethyl-1-silapropoxy)butanoic acid (15) (2.0 g, 5.0 mmol) dissolved in 25 mL of anhydrous dichloromethane (DCM) was reacted with 0.90 mL (1.31 g, 10 mmol) of oxalyl chloride. Upon completion of the reaction, a solution of 2 mL (1.2 g, 10.0 mmol) of (2S)-2-hydroxy-4-methylpentan-3-one (synthesized following procedures according to Gallop et al., U.S. Pat. No. 6,927,036) and 0.85 mL of pyridine (0.79 g, 10.0 mmol) in 20 mL of anhydrous dichloromethane (DCM) was added to the acid chloride. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:9) as eluent to provide 0.9 g (36% yield) of the title compound (30a) as a colorless oil. Rf=0.39 (EtOAc/Hxn=1:4). 1H NMR (400 MHz, CDCl3): δ=0.05 (s, 3H), 0.10 (s, 3H), 0.94 (s, 9H), 1.09 (s, 6H), 1.12 (d, J=7.2 Hz, 3H), 1.19 (d, J=7.2 Hz, 3H), 1.46 (d, J=7.2 Hz, 3H), 2.32-2.39 (m, 2H), 2.83 (sept., J=7.2 Hz, 1H), 3.31-3.35 (m, 2H), 3.69-3.72 (m, 2H), 4.10-4.13 (m, 3H), 5.24 (q, J=7.2 Hz, 1H) ppm. MS (ESI) m/z 501.09 (M+H)+, 523.03 (M+Na)+. The analytical data was consistent with the proposed structure.
Reaction SMILES: C(OC(N1CCC2(NC(=O)N(C)C2=O)CC1)=O)(C)(C)C.[Br-].C(O[C:27]([N:29]1[CH2:44][CH2:43][C:32]2([N:36]([CH2:37][CH2:38][CH3:39])[C:35](=[O:40])[N:34]([CH3:41])[C:33]2=[O:42])[CH2:31][CH2:30]1)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+].BrC[C:53]1[N:63]([CH2:64][C:65]([CH3:68])([CH3:67])[CH3:66])[C:56]2[N:57]=[C:58]([C:61]#[N:62])[N:59]=[CH:60][C:55]=2[CH:54]=1>CN(C=O)C.C(Cl)Cl.C(O)(C(F)(F)F)=O.CS(C)=O>[CH3:66][C:65]([CH3:68])([CH3:67])[CH2:64][N:63]1[C:56]2[N:57]=[C:58]([C:61]#[N:62])[N:59]=[CH:60][C:55]=2[CH:54]=[C:53]1[CH2:27][N:29]1[CH2:30][CH2:31][C:32]2([N:36]([CH2:37][CH2:38][CH3:39])[C:35](=[O:40])[N:34]([CH3:41])[C:33]2=[O:42])[CH2:43][CH2:44]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: CCCN1C(=O)N(C)C(=O)C12CCN(C(=O)OC(C)(C)C)CC2
Agent: CN1C(=O)NC2(CCN(C(=O)OC(C)(C)C)CC2)C1=O
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCN1C(=O)N(C)C(=O)C12CCN(Cc1cc3cnc(C#N)nc3n1CC(C)(C)C)CC2
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.5 %

Procedure:
To a solution of 3-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (1 g, 3.53 mmol) in DMF (10 ml), Na (211 mg, 5.4 mmol) and n-propryl bromide (384 □1, 4.24 mmol) are added at 0° C. The reaction mixture is stirred at ambient temperature for 4 h, quenched with saturated ammonium chloride and extracted with AcOEt. The organic layer is washed with brine, dried over magnesium sulfate and filtrated. To a solution of 3-methyl-2,4-dioxo-1-propyl-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (3.53 mmol) in CH2Cl2 (5 ml), TFA (5 ml) are added at 0° C. The reaction mixture is stirred at room temperature for 1 h. After removal of the solvent, H2O is added to the residue and lyophilized. To the crude product (1.5 g, 4.42 mmol) in DMSO (10 ml), potassium carbonate (1.2 g, 8.82 mmol) and 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.7 g, 2.28 mmol) are added to the mixture at ambient temperature. The reaction mixture is stirred at ambient temperature for 3 h, quenched with saturated ammonium chloride and extracted with AcOEt. The combined extracts are washed with H2O, brine and dried over magnesium sulfate. The combined extracts are concentrated and the residue is purified by column chromatography on silica gel using n-hexane:AcOEt=3:1 to give 386 mg of desired product in 24% yield.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:21]=[C:22]([C:29]#[C:30][Si](C)(C)C)[CH:23]=[C:24]([F:28])[C:25]=1[O:26][CH3:27]>C1COCC1>[C:29]([C:22]1[CH:21]=[C:20]([F:19])[C:25]([O:26][CH3:27])=[C:24]([F:28])[CH:23]=1)#[CH:30]
Reactant: COc1c(F)cc(C#C[Si](C)(C)C)cc1F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cc(F)c(OC)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
1N tetrabutylammonium fluoride (TBAF) in THF was added to 1.71 g (3,5-Difluoro-4-methoxy-phenylethynyl)-trimethyl-silane and the mixture stirred at 25° C. overnight. The solvent was removed in vacuo and the residue purified by flash chromatography over silica eluting with 20:1 heptane:ethyl acetate to give 866 mg 5-Ethynyl-1,3-difluoro-2-methoxy-benzene in 72% yield.