Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]([CH:12]1[N:20](C(OC(C)(C)C)=O)[C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11].C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[NH:9][C:10]([CH:12]1[NH:20][C:15]2=[N:16][CH:17]=[CH:18][CH:19]=[C:14]2[CH2:13]1)=[O:11]
Reactant: CC(C)(C)OC(=O)N1c2ncccc2CC1C(=O)Nc1c(F)cccc1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(Nc1c(F)cccc1F)C1Cc2cccnc2N1
Temperature: 25 °C
Reaction time: 2 h
Yield: 102.2 %

Procedure:
To a solution of tert-butyl 2-(2,6-difluorophenylcarbamoyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (0.2 g, 533 μmol, Eq: 1.00) in DCM (2 mL) was added TFA (2 mL, 26.0 mmol, Eq: 48.7) and the resulting solution was stirred at rt for 2 h. The reaction mixture was concentrated in vacuo and the residue was treated with saturated aqueous NaHCO3 (10 mL). The resulting mixture was extracted with DCM (3×10 mL) and the combined organic layers were dried over Na2SO4 and concentrated in vacuo to give N-(2,6-difluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-2-carboxamide as an off-white solid (0.15 g), m/z=276 (M+H).
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([S:7]([N:10]=[C:11]=[O:12])(=[O:9])=[O:8])=[CH:3][CH:2]=1.[CH3:14][C:15]1[CH:16]=[C:17]([CH:19]=[C:20]([CH3:29])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23])[NH2:18]>C(Cl)Cl>[CH3:29][C:20]1[CH:19]=[C:17]([NH:18][C:11]([NH:10][S:7]([C:4]2[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=2)(=[O:8])=[O:9])=[O:12])[CH:16]=[C:15]([CH3:14])[C:21]=1[S:22]([CH2:25][N+:26]([O-:28])=[O:27])(=[O:24])=[O:23]
Reactant: Cc1cc(N)cc(C)c1S(=O)(=O)C[N+](=O)[O-]
Reactant: Cc1ccc(S(=O)(=O)N=C=O)cc1
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cc(C)c(S(=O)(=O)C[N+](=O)[O-])c(C)c2)cc1
Reaction time: 0.5 h
Yield: 55.5 %

Procedure:
A solution of 1.55 ml (10.2 mmol) of p-toluenesulphonyl isocyanate in 15.5 ml of anhydrous methylene chloride is added dropwise to a suspension, maintained under a nitrogen atmosphere, of 2.6 g (10.6 mmol) of 3,5-dimethyl-4-[(nitromethyl)sulphonyl]aniline in 52 ml of anhydrous methylene chloride. The temperature of the reaction medium rises spontaneously by 2° C. Stirring of the solution obtained is continued for 30 minutes at room temperature. The reaction medium is then concentrated to dryness under reduced pressure; the residue is purified by chromatography on a column of silica (eluent: methylene chloride and then a 9/1 methylene chloride/methanol mixture) and crystallization from methylene chloride, to give 2.5 g (57%) of 1-[3,5-dimethyl-4-[(nitromethyl)sulphonyl]phenyl]-3-[(4-methylphenyl)sulphonyl]urea.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:39])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH:31]=[N:32][C:33]([CH:36]3[CH2:38][CH2:37]3)=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:36]1([C:33]2[N:32]=[CH:31][C:30]([C:26]3[CH:25]=[C:24]([C:22]4[CH2:21][C:20](=[O:39])[NH:19][C:9]5[CH:10]=[C:11]([O:14][C:15]([F:18])([F:16])[F:17])[CH:12]=[CH:13][C:8]=5[N:7]=4)[CH:29]=[CH:28][CH:27]=3)=[CH:35][CH:34]=2)[CH2:37][CH2:38]1
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccc(C3CC3)nc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccc(C4CC4)nc3)c2)=Nc2ccc(OC(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (2-{3-[3-(6-cyclopropyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example M187) (242 mg, 0.436 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a white solid (93 mg, 49%).
Reaction SMILES: C[Si](C)(C)[C:3]([F:6])([F:5])[F:4].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:27]([N:29]1[C:33]([O:34][C:35]2[CH:40]=[CH:39][C:38]([CH:41]=[O:42])=[CH:37][CH:36]=2)=[CH:32][C:31]([C:43]2[CH:44]=[C:45]([C:49]([NH:52][S:53]([CH2:56][C:57]([F:60])([F:59])[F:58])(=[O:55])=[O:54])([CH3:51])[CH3:50])[CH:46]=[CH:47][CH:48]=2)=[N:30]1)[CH3:28].Cl>O1CCCC1>[CH2:27]([N:29]1[C:33]([O:34][C:35]2[CH:36]=[CH:37][C:38]([CH:41]([OH:42])[C:3]([F:6])([F:5])[F:4])=[CH:39][CH:40]=2)=[CH:32][C:31]([C:43]2[CH:44]=[C:45]([C:49]([NH:52][S:53]([CH2:56][C:57]([F:60])([F:58])[F:59])(=[O:54])=[O:55])([CH3:51])[CH3:50])[CH:46]=[CH:47][CH:48]=2)=[N:30]1)[CH3:28]
Reactant: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C=O)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C(C)(C)NS(=O)(=O)CC(F)(F)F)c2)cc1Oc1ccc(C(O)C(F)(F)F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 2.3 %

Procedure:
Trimethyl(trifluoromethyl)silane (0.62 mL, 4.0 mmol, 1.2 equiv) and tetrabutylammonium fluoride (1.0 M in THF, 0.67 mL, 0.67 mmol, 0.20 equiv) were added sequentially to a solution of N-(1-{3-[1-ethyl-5-(4-formylphenoxy)-1H-pyrazol-3-yl]phenyl}-1-methylethyl)-2,2,2-trifluoroethanesulfonamide (1.65 g, 3.33 mmol, 1 equiv) in tetrahydrofuran (3.3 mL) at 0° C. The reaction mixture was stirred for 15 minutes at 0° C., and then was warmed to 22° C. After stirring for 2.5 hours, aqueous hydrochloric acid solution (2 N) was added and the reaction mixture was stirred for an additional 40 minutes. The crude product was partitioned between ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride solution, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (hexanes, grading to 45% ethyl acetate-hexanes) to afford N-[1-(3-{1-ethyl-5-[4-(2,2,2-trifluoro-1-hydroxyethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)-1-methylethyl]-2,2,2-trifluoroethanesulfonamide (43 mg, 2%). Calcd (M+1)+: 566.2. Found: 566.0.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26]#[N:27])=[C:4]([CH:23]=[CH:24][CH:25]=1)[O:5][CH2:6][CH:7]1[CH2:12][CH2:11][N:10](C(OCC2C=CC=CC=2)=O)[CH2:9][CH2:8]1.O=[C:29]([CH3:36])[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[NH2:27][C:26]1[C:3]2[C:2](=[CH:25][CH:24]=[CH:23][C:4]=2[O:5][CH2:6][CH:7]2[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]2)[N:1]=[C:29]([CH3:36])[C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: N#Cc1c(N)cccc1OCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC3CCNCC3)c2c1N

Procedure:
Prepared as in Example 2a from benzyl 4-((3-amino-2-cyanophenoxy)methyl)piperidine-1-carboxylate (Example 35c) and ethyl 3-oxobutanoate as an orange solid (25%). 1H NR (400 MHz, DMSO-d6) δ 1.29-1.37 (m, 5H), 1.77-1.80 (m, 2H), 2.07 (brs, 1H), 2.53 (s, 3H), 2.55-2.65 (m, 3H), 3.06-3.09 (m, 2H), 4.06 (d, J=8.0 Hz, 2H), 4.32 (q, J=8.0 Hz, 2H), 6.92 (d, J=8.0 Hz, 1H), 7.24 (d, J=8.0 Hz, 1H), 7.51 (t, J=8.0 Hz, 1H), 8.08 (s, 2H). MS 344 (MH+).
Reaction SMILES: [C:1]([O:7][CH2:8][C@H:9]([C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1Br)[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].CC1(C)C(C)(C)OB([C:50]2[CH:59]=[CH:58][C:53]3[O:54][CH:55]([CH3:57])[O:56][C:52]=3[CH:51]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:7][CH2:8][C@@H:9]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:15]1[C:39]([CH3:40])=[CH:38][C:18]2[N:19]=[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]4[CH:29]=[C:30]5[C:34](=[CH:35][CH:36]=4)[N:33]([CH3:37])[N:32]=[CH:31]5)[CH:23]=3)[S:21][C:17]=2[C:16]=1[C:50]1[CH:59]=[CH:58][C:53]2[O:54][CH:55]([CH3:57])[O:56][C:52]=2[CH:51]=1)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC1Oc2ccc(B3OC(C)(C)C(C)(C)O3)cc2O1
Reactant: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(Br)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
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
Product: Cc1cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc3c(c2)OC(C)O3)c1[C@@H](COC(=O)C(C)(C)C)OC(C)(C)C
Temperature: 110 °C

Procedure:
To a solution of (S)-2-(7-bromo-5-methyl-2-(3-(1-methyl-1H-indazol-5-yl)phenyl)benzo[d]thiazol-6-yl)-2-tert-butoxyethyl pivalate (16 mg, 0.025 mmol) and 4,4,5,5-tetramethyl-2-(2-methylbenzo[d][1,3]dioxol-5-yl)-1,3,2-dioxaborolane (13 mg, 0.050 mmol) in 1,4-dioxane was added Pd(PPh3)4 (4 mg, 3.1×10−3 mmol) and 2M K2CO3 (66 μL, 0.133 mmol). The reaction was degassed for 5 minutes with N2 and then heated to 110° C. for 1 h. After cooling, the reaction mixture was diluted with EtOAc, extracted with saturated NaHCO3, brine, dried over Na2SO4, filtered and concentrated and purified by flash column chromatography (silica gel, 0 to 10% ethyl acetate/hexanes) to give the product. LCMS-ESI+ (m/z): [M+H]+ calcd for C41H44N3O5S: 690.30; found: 690.4.
Reaction SMILES: Br[C:2]1[C:7]2[C:8](=[O:11])[NH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.[Cu][C:13]#[N:14].O.[C-]#N.[Na+]>CN(C=O)C>[C:13]([C:2]1[C:7]2[C:8](=[O:11])[NH:9][O:10][C:6]=2[CH:5]=[CH:4][CH:3]=1)#[N:14]
Reactant: N#C[Cu]
Reactant: O=c1[nH]oc2cccc(Br)c12
Agent: [C-]#N
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1cccc2o[nH]c(=O)c12
Temperature: 165 °C
Reaction time: 6.5 h
Yield: 51.6 %

Procedure:
To a solution of 4-bromo-1,2-benzoxazolinone (5.0 g, 23 mmol) in DMF (11 mL) was added copper (I) cyanide (3.6 g, 39 mmol) and the reaction heated at 165° C. After 6.5 h, the reaction mixture was cooled to rt and water (20 mL) and sodium cyanide (3.6 g) were added and the reaction heated at 100° C. After 12 h, the reaction mixture was extracted with ethyl acetate and the combined organic layers were filtered through a scrub pad of silica gel eluting with ethyl acetate. The filtrate was concentrated under reduced pressure to give 1.9 g (51%) of 4-cyano-1,2-benzoxazolinone as a brown solid which required no further purification. 1H NMR (400 MHz, DMSO) δ 7.8 (s, 1H), 7.6 (d, 1H), 7.2 (d, 1H).
Reaction SMILES: S(Cl)(Cl)(=O)=O.CS[S:8][CH3:9].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:16]=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30].C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]([S:8][CH3:9])=[C:15]2[CH2:28][C:29]([NH2:31])=[O:30]
Reactant: CSSC
Reactant: COc1ccc2c(c1)c(CC(N)=O)cn2Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=S(=O)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc2c(c1)c(CC(N)=O)c(SC)n2Cc1ccccc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 31 %

Procedure:
Sulfuryl chloride (0.8 mL, 10 mmol) was added to an ice-bath cooled solution of 1.0 mL of dimethyldisulfide in 25 mL of methylene chloride, the cooling bath removed, and the mixture allowed to warm to room temperature. Three mL of this solution (containing methanesulfenyl chloride) was added to 320 mg (1.1 mmol) of 5-methoxy-1-(phenylmethyl)-1H-indole-3-acetamide (Example 3) in 100 mL of methylene chloride, stirred 0.33 hours, saturated NaHCO3 solution added, stirred well, and the methylene chloride solution separated, washed with saturated NaCl, dried (Na2SO4), and concentrated at reduced pressure. The residue chromatographed on silica was eluted with 40% EtOAc/hexane→100% EtOAc to give 115 mg (31% yield) of 5-methoxy-2-(methylthio)-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 195-197° C.
Reaction SMILES: C([Li])CCC.[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:12].C(#N)C.[CH2:16]([O:18]CC)[CH3:17]>>[N:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[CH2:12][C:16]([CH3:17])=[O:18]
Reactant: Cc1ccccn1
Reactant: CCOCC
Agent: [Li]CCCC
Solvent: CC#N
Product: CC(=O)Cc1ccccn1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 960 mg of n-butyllithium in diethyl ether was added dropwise 1480 μl of α-picoline at 0° C. under an argon and the reaction mixture was stirred for 10 minutes at 0° C. To the reaction mixture was added 782 l of acetonitrile and the mixture was stirred for 3 hours at room temperature, followed by extraction with 30 ml of 1.5N-sulfuric acid. The acidic solution was washed with 25 ml of diethyl ether, and made alkaline with a 2N-aqueous sodium hydroxide solution and the solution was extracted with dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure. The residual oil was distilled under reduced pressure to give 700 mg of methyl 2-pyridylmethyl ketone as an oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([O:13]CC)=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[Li+].[OH-]>CO>[O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([C:11]([OH:13])=[O:12])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)C1CCC2(CC1)OCCO2
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)C1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
3.0 g (14 mmol) of the ethyl ester precursor, ethyl 1,4-dioxaspiro[4.5]decane-8-carboxylate, were dissolved in 5 ml of methanol and admixed at RT slowly with 28 ml (2 eq.) of 1 M LiOH solution. The mixture was stirred overnight; HPLC-MS indicated complete reaction. Methanol was distilled off under reduced pressure and the residue was acidified cautiously with 1 ml of HCl such that no acid excess was present. The mixture was extracted with ethyl acetate, and the ethyl acetate phase was dried over sodium sulfate and then concentrated by evaporation under reduced pressure. Yield: 2.25 g, 86% of theory.
Reaction SMILES: C([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)#N.[C:20](=[O:23])(O)[O-:21].[Na+]>S(=O)(=O)(O)O.O>[C:20]([CH2:3][C:4]([C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=1[Cl:19])([OH:11])[CH2:5][N:6]1[CH:10]=[N:9][CH:8]=[N:7]1)([OH:21])=[O:23]
Reactant: O=C([O-])O
Reactant: N#CCC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: O=C(O)CC(O)(Cn1cncn1)c1ccc(Cl)cc1Cl

Procedure:
1-Cyano-2-(2,4-dichlorophenyl)-3-(1H-1,2,4-triazol-1-yl)-2-propanol (4 g, 13.9 mmole) was dissolved in 40% aqueous sulfuric acid (100 ml) and heated in an oil bath at 100°-110° C. for 18 hours. The solution was then cooled, diluted with water (200 ml), and rendered alkaline by the slow addition of solid sodium bicarbonate. The mixture was then extracted several times with ethyl acetate (3×100 ml) and the aqueous phase was rendered acidic (pH 3) by the addition of dilute orthophosphoric acid. The aqueous phase was then extracted with ethyl ether (3×150 ml), the combined ether extracts were washed once with water, and then dried over magnesium sulfate. Evaporation of the ether gave the title compound as a pale yellow solid, 2.7 g, (62%), m.p. 158°-159° C.
Reaction SMILES: [CH3:1][N:2]=[C:3]=[S:4].[F:5][C:6]([F:12])([F:11])[S:7]([NH2:10])(=[O:9])=[O:8].[OH-].[Na+]>CC(C)=O.O>[CH3:1][NH:2][C:3]([NH:10][S:7]([C:6]([F:12])([F:11])[F:5])(=[O:9])=[O:8])=[S:4]
Reactant: NS(=O)(=O)C(F)(F)F
Reactant: CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CNC(=S)NS(=O)(=O)C(F)(F)F
Reaction time: 18 h
Yield: 42.3 %

Procedure:
A solution of methylisothiocyanate (0.21 g.) in acetone (10 ml.) was added to a solution of trifluoromethanesulphonamide (0.45 g.) and sodium hydroxide (0.12 g.) in water (5 ml.), the mixture stirred at 60° for 18 hours and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then adjusted to pH 1 with concentrated hydrochloric acid. The mixture was treated with charcoal and filtered and the filtrate extracted with ethyl acetate. The combined ethyl acetate extracts were dried and evaporated to dryness and the residue recrystallized from petroleum ether (b.p. 60°-80°) to give 1-methyl-3-trifluoromethanesulphonylthiourea (0.27 g.), m.p. 88°-90°.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH:2]=1.C([Li])(C)(C)C.[O:20]=[C:21]1[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1>C1COCC1.CCCCC>[C:10]([O:9][C:8]([NH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][C:4]=1[C:21]1([OH:20])[CH2:25][CH2:24][N:23]([C:26]([O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)=[O:27])[CH2:22]1)=[O:14])([CH3:11])([CH3:13])[CH3:12]
Reactant: O=C1CCN(C(=O)OCc2ccccc2)C1
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: CC(C)(C)OC(=O)Nc1cnccc1C1(O)CCN(C(=O)OCc2ccccc2)C1
Temperature: -78 °C
Reaction time: 2 h
Yield: 25.5 %

Procedure:
To a flame-dried round bottomed flask with thermometer side-arm, equipped with a stir bar, was added tert-butyl pyridin-3-ylcarbamate (1.104 g, 0.005684 mol) in 75 mL THF under inert atmosphere. The solution was cooled to −78° C. and then 1.7 M of tert-butyllithium in pentane (7.4 mL) was added dropwise. The resulting solution was stirred for 2 h at −78° C., followed by the addition of benzyl 3-oxopyrrolidine-1-carboxylate (1.038 g, 0.004736 mol) in 75 mL THF. The reaction was allowed to warm to rt and stirred for 5 hrs. The reaction mixture was quenched with saturated ammonium chloride, diluted with water and extracted with ethyl acetate. The combined organic phases were treated with brine and then magnesium sulfate, filtered, and concentrated. The crude product was purified by combiflash using 50-80% ethyl acetate/hexane to recover the starting material (0.9 g) and then 100% ethyl acetate to obtain the product (0.5 g). The product was verrified by LCMS and NMR data.
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:39][CH2:38][N:37]([C:40]([O:42][CH2:43]C)=[O:41])[CH2:36][CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.[CH3:45][N:46]1[CH2:51][CH2:50][N:49]([C:52]2[CH:58]=CC(N)=[CH:54][CH:53]=2)[CH2:48][CH2:47]1.NC1C=CC=CC=1>>[CH:9]12[O:12][CH:5]([CH2:11][CH2:10]1)[CH2:6][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:58][C:52]([N:49]5[CH2:48][CH2:47][N:46]([CH3:45])[CH2:51][CH2:50]5)=[CH:53][CH:54]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4[CH2:35][CH2:36][N:37]([C:40]([O:42][CH3:43])=[O:41])[CH2:38][CH2:39]4)[N:32]=[CH:33][C:14]=13)[CH2:8]2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: COC(=O)N1CCC(n2ncc3c(N4CC5CCC(C4)O5)nc(-c4ccc(NC(=O)Nc5ccc(N6CCN(C)CC6)cc5)cc4)nc32)CC1

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-(4-methylpiperazino)aniline as the aniline component. (7%, MS=681.4 (M+H))
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH:12]1[CH2:14][CH2:13]1)[CH:5]=[O:6].[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20](B(O)O)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.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>[CH:12]1([CH2:11][O:10][C:9]2[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=2[C:20]2[CH:21]=[CH:22][C:17]([O:16][CH3:15])=[CH:18][CH:19]=2)[CH2:14][CH2:13]1
Reactant: O=Cc1ccc(OCC2CC2)c(Br)c1
Reactant: COc1ccc(B(O)O)cc1
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: Cc1ccccc1
Solvent: CCO
Product: COc1ccc(-c2cc(C=O)ccc2OCC2CC2)cc1
Yield: 89.7 %

Procedure:
To a degassed solution of 3-bromo-4-cyclopropylmethoxybenzaldehyde (1.53 g, 6 mmol), 4-methoxybenzeneboronic acid (1.22 g, 8 mmol) and potassium carbonate (2.74 g, 20 mmol) in toluene/ethanol 2/1 (40 mL), Pd(PPh3)4 (100 mg) was added and the mixture was degassed for further 5 minutes. The mixture was then refluxed for 12 hours. The solid is filtered off, and the solvent partitioned between ethyl acetate and water and extracted. The organic solvent was removed under reduced pressure, dried over sodium sulphate and purified by column chromatography on silica (hexane/ethyl acetate 8/2) to afford 1.52 g of product.
Reaction SMILES: [CH2:1]([OH:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([O:13]C)(=[O:12])[CH:10]=[CH2:11]>[Na]>[CH2:1]([O:8][CH2:11][CH2:10][C:9]([OH:13])=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccccc1
Reactant: C=CC(=O)OC
Agent: [Na]
Product: O=C(O)CCOCc1ccccc1
Reaction time: 0.5 h
Yield: 95.1 %

Procedure:
Sodium metal (249 mg, 10.8 mmol) was added to benzyl alcohol (30 g, 278 mmol) at room temperature under nitrogen and the reaction was stirred for 30 minutes. Methyl acrylate (25.9 ml, 259 mmol) was then added dropwise and the reaction was stirred at room temperature for 18 h. After quenching with saturated aqueous ammonium chloride solution (200 ml) the mixture was extracted with ethyl acetate (2×300 ml) and the combined organic extracts were washed with brine (100 ml), dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in ethanol (300 ml) and 1M aqueous sodium hydroxide solution (300 ml) was added dropwise. After 3 hours the ethanol was removed under reduced pressure and the aqueous residue was washed with dichloromethane (200 ml). The aqueous phase was then acidified with 2N aqueous hydrochloric acid (150 ml), extracted with dichloromethane (2×250 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure. The residual oil was dissolved in 10% aqueous potassium carbonate solution (300 ml), washed with diethylether (300 ml) and the aqueous phase was acidified to pH 1 using concentrated hydrochloric acid. The mixture was then extracted with dichloromethane (2×300 ml) and the combined organic extracts were dried over magnesium sulphate and concentrated under reduced pressure to provide the title compound (44.4 g) as a colourless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[C:26]([O:38][CH3:39])=[CH:27][C:28]2[N:34]([CH3:35])[C:33](=[O:36])[O:32][CH2:31][CH2:30][C:29]=2[CH:37]=1>>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[C:26]([O:38][CH3:39])=[CH:27][C:28]3[N:34]([CH3:35])[C:33](=[O:36])[O:32][CH2:31][CH2:30][C:29]=3[CH:37]=2)=[N:3][CH:4]=1
Reactant: COc1cc2c(cc1N)CCOC(=O)N2C
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCOCC4)cc3OC)n1)CCOC(=O)N2C
Yield: 49 %

Procedure:
In an analogous manner to Example 1503, the product was prepared from (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine and 2-Amino-3-methoxy-5-methyl-8,9-dihydro-5H-7-oxa-5-aza-benzocyclohepten-6-one. Product isolated as an off-white powder (45 mg, 49%). mp: 242-245° C., MS (ESI+): 541 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.24 (s, 1H), 8.04 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.38 (d, J=8 Hz, 1H), 6.96 (s, 1H), 6.69 (s, 1H), 6.50 (s, 1H), 4.25 (t, 2H), 3.84 (s, 3H), 3.76 (br s, 8H), 3.26 (s, 3H), 3.14 (br s, 4H), 2.60 (t, 2H).