Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([N:7]2[C:15]3[CH:14]=[CH:13][NH:12][CH2:11][C:10]=3[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH:13]=[CH:14][C:15]2[N:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: C1=Cc2c(ncn2-c2ccccc2)CN1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1C=Cc2c(ncn2-c2ccccc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.6 %

Procedure:
To a solution of the product of Example 49, Step A (5.5 mg, 0.028 mmol) in DCM (3 mL) was added TEA (11 μL, 0.084 mmol), 2-chloro-3-(trifluoromethyl)benzoic acid (7 mg, 0.031 mmol) and HATU (13 mg, 0.033 mmol). The reaction was stirred at room temperature overnight. The crude reaction mixture was concentrated and purified on 4 g SiO2 column with 0-3% NH3/MeOH CH2Cl2 to give the desired compound (9.9 mg, 87%). MS (ESI): mass calcd. for C20H13ClF3N3O, 403.1. m/z found, 404.3 [M+H]+. 1H NMR (400 MHz, CDCl3) δ 9.06 (s, 1H), 8.09 (m 1H), 7.94-7.84 (m, 1H), 7.76-7.53 (m, 2H), 7.53-7.39 (m, 2H), 7.39-7.22 (m, 4H), 6.96-6.86 (m, 1H), 6.73 (s, 1H), 5.95 (q, J=7.0 Hz, 1H), 5.54 (s, 1H), 3.22 (q, J=7.3 Hz, 2H), 1.37 (t, J=7.3 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21](Br)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[O:23]([C:25]1[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[CH:27][C:26]=1B(O)O)[CH3:24]>>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[CH:19][CH:20]=[C:21]([C:29]4[CH:28]=[CH:27][CH:26]=[C:25]([O:23][CH3:24])[C:30]=4[O:31][CH3:32])[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cccc(Br)c3O2)cc1
Reactant: COc1cccc(B(O)O)c1OC
Product: COc1cccc(-c2cccc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c1OC
Yield: 82 %

Procedure:
Treatment of (±)-(7-bromo-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (0.30 g, 0.783 mmol) with (2,3-dimethoxylphenyl)boronic acid (0.427 g, 2.35 mmol) generally according to the procedure described for Intermediate 184 provided 0.283 g (82%) of (±)-[7-(2,3-dimethoxylphenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. Rf=0.43 (silica, ethyl acetate:hexanes 1:4).
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:10])=[O:9])[CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2]1[C:3]([O:30][C@H:31]2[CH2:36][C:35]([F:38])([F:37])[CH2:34][CH2:33][C@@H:32]2[C:39]2[N:43]([CH3:44])[N:42]=[CH:41][CH:40]=2)=[CH:4][C:5]([F:29])=[C:6]([S:8]([NH:11][C:12]2[CH:17]=[CH:16][N:15]=[CH:14][N:13]=2)(=[O:9])=[O:10])[CH:7]=1
Reactant: COc1ccc(CN(c2ccncn2)S(=O)(=O)c2cc(Cl)c(O[C@H]3CC(F)(F)CC[C@@H]3c3ccnn3C)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cn1nccc1[C@H]1CCC(F)(F)C[C@@H]1Oc1cc(F)c(S(=O)(=O)Nc2ccncn2)cc1Cl
Yield: 82.8 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the 5-chloro-4-{[(1S*,2R*)-5,5-difluoro-2-(1-methyl-1H-pyrazol-5-yl)cyclohexyl]oxy}-N-(2,4-dimethoxybenzyl)-2-fluoro-N-(pyrimidin-4-yl)benzenesulfonamide (212 mg, 0.325 mmol) prepared in Example 141a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (135 mg, 83%) as a colorless solid.
Reaction SMILES: [CH2:1]1[O:11][CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:12]([NH2:16])[CH2:13][CH2:14][NH2:15]>CO>[CH2:12]([NH:16][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH2:13][CH2:14][NH:15][CH2:1][CH:2]([OH:11])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: NCCCN
Reactant: CCCCCCCCC1CO1
Solvent: CO
Product: CCCCCCCCC(O)CNCCCNCC(O)CCCCCCCC

Procedure:
In a manner similar to that of Example 1, condensation of 1-decene oxide (58 g.) and 1,3-propanediamine (13.8 g.) and three recrystallizations of the resulting product from methanol gave N,N'-(1,3-propylene)-bis[2-hydroxydecylamine] (I: R = CH3 (CH2)7, R' = H, X = (CH2)3, Z = H) (8.5 g., m.p. 104.0°-107.6° C.).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([CH3:19])[CH2:15][CH2:14]1.[S:20]([N:30]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([CH:39]=O)=[CH:31]1)([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21].N1CCCCC1>CO>[OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])/[C:7](=[CH:39]/[C:32]3[C:33]4[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=4)[N:30]([S:20]([C:23]4[CH:24]=[CH:25][C:26]([CH3:27])=[CH:28][CH:29]=4)(=[O:22])=[O:21])[CH:31]=3)/[O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:14][CH2:15][N:16]([CH3:19])[CH2:17][CH2:18]1
Reactant: CN1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Solvent: C1CCNCC1
Solvent: CO
Product: Cc1ccc(S(=O)(=O)n2cc(/C=C3\Oc4c(ccc(O)c4CN4CCN(C)CC4)C3=O)c3ccccc32)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.6 %

Procedure:
A solution of 6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]benzofuran-3(2H)-one (0.525 g, 2.00 mol) in methanol (10 mL) was added with 1-tosyl-1H-indole-3-carboxaldehyde (0.599 g, 2.00 mmol) and piperidine (0.017 g, 0.200 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was added with methanol, and the solid was suspended in methanol and thereby washed to obtain the objective (Z)-6-hydroxy-7-[(4-methylpiperazin-1-yl)methyl]-2-[(1-tosyl-1H-indol-3-yl)methylene]benzofuran-3(2H)-one (0.887 g, 81%).
Reaction SMILES: [CH2:1]([O:8][N:9]([CH2:24][C:25]1[C:30]([O:31][CH3:32])=[CH:29][C:28]([O:33][CH3:34])=[CH:27][C:26]=1[O:35][CH3:36])[C:10](=[O:23])[CH2:11][CH2:12][CH:13]1[C:18](=[O:19])[O:17][C:16]([CH3:21])([CH3:20])[O:15][C:14]1=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:38][C:39]1[CH:48]=[CH:47][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:41][CH:40]=1.C(=O)([O-])[O-].[K+].[K+]>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C(#N)C>[CH2:1]([O:8][N:9]([CH2:24][C:25]1[C:26]([O:35][CH3:36])=[CH:27][C:28]([O:33][CH3:34])=[CH:29][C:30]=1[O:31][CH3:32])[C:10](=[O:23])[CH2:11][CH2:12][C:13]1([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([C:43]([O:45][CH3:46])=[O:44])=[CH:47][CH:48]=2)[C:14](=[O:22])[O:15][C:16]([CH3:21])([CH3:20])[O:17][C:18]1=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1cc(OC)c(CN(OCc2ccccc2)C(=O)CCC2C(=O)OC(C)(C)OC2=O)c(OC)c1
Reactant: COC(=O)c1ccc(CBr)cc1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CC#N
Product: COC(=O)c1ccc(CC2(CCC(=O)N(Cc3c(OC)cc(OC)cc3OC)OCc3ccccc3)C(=O)OC(C)(C)OC2=O)cc1
Temperature: 65 °C
Yield: 77.4 %

Procedure:
To stirring acetonitrile were added N-benzyloxy-3-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-yl)-N-(2,4,6-trimethoxybenzyl)-propanamide (10.0 g, 19.9 mmol), methyl 4-(bromomethyl)benzoate (5.02 g, 21.9 mmol), potassium carbonate (4.125 g, 29.9 mmol), and benzyltriethylammonium chloride (6.799 g, 29.9 mmol). This reaction mixture was heated to 65° C. for 5 h. The reaction mixture was then allowed to cool and extracted with 100 mL of 10% KHSO4, 50 mL (3 times) of EtOAc, brine and then dried over Na2SO4. The crude product was purified by flash column chromatography (40% EtOAc in hexanes) to give 10.01 g of 5-{3-[benzyloxy(2,4,6-trimethoxybenzyl)amino]-3-oxopropyl}-2,2-dimethyl-5-[4-(methoxycarbonyl)phenyl]methyl-[1,3]dioxane-4,6-dione as a white powder (78% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[Cl:17])=[N:9][N:10]=2)[CH:7]=1.C([Mg]Cl)(C)C.[CH3:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=[O:29])=[CH:26][CH:25]=1>C1COCC1>[Cl:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:8]1[N:6]2[CH:7]=[C:2]([CH:28]([C:27]3[CH:30]=[CH:31][C:24]([CH3:23])=[CH:25][CH:26]=3)[OH:29])[CH:3]=[CH:4][C:5]2=[N:10][N:9]=1
Reactant: Cc1ccc(C=O)cc1
Reactant: Clc1ccccc1-c1nnc2ccc(Br)cn12
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: Cc1ccc(C(O)c2ccc3nnc(-c4ccccc4Cl)n3c2)cc1
Temperature: 50 °C
Yield: 29 %

Procedure:
In a flame-dried flash under nitrogen a solution of 6-bromo-3-(2-chloro-phenyl)-[1,2,4]triazolo[4,3-a]pyridine (205 mg, 0.66 mmol) in THF (2.5 mL) was cooled to 0° C. A solution of isopropylmagnesium chloride (1.3 eq) was added dropwise, followed by 4-methylbenzaldehyde (1 equivalent), and the resulting mixture was warmed to 50° C. for 3 hours. The reaction was cooled and quenched with water/ethyl acetate. The organic layer was separated, concentrated in vacuo, and the residue purified by flash chromatography (eluting with 80% ethyl acetate/hexane) to give the title compound (67 mg, 29%). MS (M+1)=350.5.
Reaction SMILES: [NH2:1][C:2](=[S:17])[CH2:3][N:4]1[C:8]([CH3:9])=[C:7]([C:10]([O:12]C(C)(C)C)=[O:11])[CH:6]=[N:5]1.Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)=O>>[Cl:29][C:24]1[CH:23]=[C:22]([C:20]2[N:1]=[C:2]([CH2:3][N:4]3[C:8]([CH3:9])=[C:7]([C:10]([OH:12])=[O:11])[CH:6]=[N:5]3)[S:17][CH:19]=2)[CH:27]=[CH:26][C:25]=1[Cl:28]
Reactant: Cc1c(C(=O)OC(C)(C)C)cnn1CC(N)=S
Reactant: O=C(CBr)c1ccc(Cl)c(Cl)c1
Product: Cc1c(C(=O)O)cnn1Cc1nc(-c2ccc(Cl)c(Cl)c2)cs1
Yield: 79.8 %

Procedure:
A reaction similar to Example 1c was performed using the compound (200 mg, 0.783 mmol) obtained in Example 11b and 2-bromo-1-(3,4-dichlorophenyl)ethanone (210 mg, 0.783 mmol). As a result, the title compound (230 mg, 79%) wherein tert-butyl ester was hydrolyzed by hydrobromic acid produced under the reaction conditions was obtained as colorless crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]3[C:14](=[O:22])[N:15]([CH2:18][CH2:19][C:20]#[N:21])[CH2:16][CH2:17][C:12]=3[C:11]([C:23]([F:26])([F:25])[F:24])=[N:10]2)=[CH:5][CH:4]=1.C(O)(=O)C>CO.[Pt]=O>[NH2:21][CH2:20][CH2:19][CH2:18][N:15]1[CH2:16][CH2:17][C:12]2[C:11]([C:23]([F:26])([F:25])[F:24])=[N:10][N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[C:13]=2[C:14]1=[O:22]
Reactant: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCC#N)CC3)cc1
Agent: O=[Pt]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(-n2nc(C(F)(F)F)c3c2C(=O)N(CCCN)CC3)cc1
Yield: 85.2 %

Procedure:
3-[1-(4-Methoxy-phenyl)-7-oxo-3-trifluoromethyl-1,4,5,7-tetrahydro-pyrazolo[3,4-c]pyridin-6-yl]-propionitrile (0.050 g, 0.137 mmol) was dissolved in methanol (20 mL) in a Parr bottle. Platinum oxide (0.005 g, 10%) and acetic acid (5 mL) were added and the reaction was hydrogenated under pressure overnight, filtered over Celite®, washed with methanol, concentrated, and purified with reverse phase HPLC and freeze-drying to afford the title compound (0.043 g, 85%): 1H NMR (CDCl3) δ 8.22 (bs, 2H), 7.39 (d, j=8.8 Hz, 2H), 6.95 (d, j=8.8 Hz, 2H), 3.83 (s, 3H), 3.71 (t, j=6.8 Hz, 2H), 3.61–3.58 (m, 2H), 3.05 (t, j=6.8 Hz, 2H), 2.91 (bs, 2H), 1.99 (bs, 2H) ppm; Mass Spec 369.3(M+H)+.
Reaction SMILES: [Cl:1][CH:2]=[C:3]([O:10]C1C=CC=CC=1)[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6].C(O)=O.Cl>C(Cl)Cl>[Cl:1][CH2:2][C:3](=[O:10])[C:4]([CH3:9])([CH3:8])[CH:5]([CH3:7])[CH3:6]
Reactant: CC(C)C(C)(C)C(=CCl)Oc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: O=CO
Product: CC(C)C(C)(C)C(=O)CCl
Yield: 77 %

Procedure:
238 g (1 mol) of 1-chloro-2-phenoxy-3,3,4-trimethyl-pent-1-ene are stirred with 500 g of formic acid and 50 g of concentrated hydrochloric acid for 2 hours at 80° C. The mixture is diluted with methylene chloride, and is washed once with water and four times with dilute sodium hydroxide solution. After the mixture has been dried over sodium sulphate, the solvent is stripped off in vacuo, and the residue is distilled over a column. 125 to 135 g (77-83% of theory) of 1-chloro-3,3,4-trimethyl-pentan-2-one of boiling point 88°-93° C./16 mbar are obtained. ##STR17##
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]4[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=4[F:32])[CH:20]=[CH:21][CH:22]=3)=[N:10][N:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.[NH2:34][C:35]1[CH:36]=[C:37]2[C:41](=[CH:42][CH:43]=1)[CH2:40][CH:39]([N:44]([CH3:46])[CH3:45])[CH2:38]2.Cl>C(O)(C)C>[CH3:45][N:44]([CH3:46])[CH:39]1[CH2:38][C:37]2[C:41](=[CH:42][CH:43]=[C:35]([NH:34][C:2]3[N:7]=[C:6]([C:8]4[C:9]([C:17]5[CH:18]=[C:19]([NH:23][C:24](=[O:33])[C:25]6[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=6[F:32])[CH:20]=[CH:21][CH:22]=5)=[N:10][N:11]5[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=45)[CH:5]=[CH:4][N:3]=3)[CH:36]=2)[CH2:40]1
Reactant: O=C(Nc1cccc(-c2nn3ccccc3c2-c2ccnc(Cl)n2)c1)c1c(F)cccc1F
Reactant: CN(C)C1Cc2ccc(N)cc2C1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)C1Cc2ccc(Nc3nccc(-c4c(-c5cccc(NC(=O)c6c(F)cccc6F)c5)nn5ccccc45)n3)cc2C1
Temperature: 180 °C

Procedure:
The title compound was synthesized by combining N-{3-[3-(2-chloro-4-pyrimidinyl)pyrazolo[1,5-a]pyridin-2-yl]phenyl}-2,6-difluorobenzamide (152 mg, 0.33 mmol), (5-amino-2,3-dihydro-1H-inden-2-yl)dimethylamine (70 mg, 0.40 mmol), hydrochloric acid (0.033 mmol, 33 uL 1M HCl/diethylether) and 3 mL isopropanol in a sealed vessel. The vial and contents were heated at 180° C. for 30 mins. The reaction was cooled and concentrated. The residue was partitioned between EtOAc and saturated aqueous NaHCO3. The organic layer was washed with brine, dried with MgSO4 and concentrated. The crude material was purified by silica gel column chromatography (0-100% gradient; (90% CH2Cl2:9% MeOH:1% NH4OH/CH2Cl2)) Purification provided 28 mg (14%) of the coupled adduct. ESIMS (M+H)+=603.30.
Reaction SMILES: CC([O-])(C)C.[K+].CS(O[CH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:15][CH:14]=1)(=O)=O.[O:29]1[CH2:34][CH2:33][CH:32]([NH:35][C:36]2[N:41]=[C:40]([C:42]3[CH:47]=[CH:46][NH:45][C:44](=[O:48])[CH:43]=3)[CH:39]=[CH:38][N:37]=2)[CH2:31][CH2:30]1.O>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1COCC1.ClCCl.CC#N>[O:48]=[C:44]1[CH:43]=[C:42]([C:40]2[CH:39]=[CH:38][N:37]=[C:36]([NH:35][CH:32]3[CH2:33][CH2:34][O:29][CH2:30][CH2:31]3)[N:41]=2)[CH:47]=[CH:46][N:45]1[CH2:12][C:13]1[CH:21]=[C:20]2[C:16]([CH:17]=[CH:18][N:19]2[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])=[CH:15][CH:14]=1
Reactant: CC(C)(C)OC(=O)n1ccc2ccc(COS(C)(=O)=O)cc21
Reactant: O=c1cc(-c2ccnc(NC3CCOCC3)n2)cc[nH]1
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1ccc2ccc(Cn3ccc(-c4ccnc(NC5CCOCC5)n4)cc3=O)cc21
Temperature: 70 °C
Reaction time: 2 h
Yield: 23.3 %

Procedure:
KOt-Bu (180 mg, 1.6 mmol) and n-Bu4NI (37 mg, 0.1 mmol) were added to a mixture of tert-butyl 6-((methylsulfonyloxy)methyl)-1H-indole-1-carboxylate (0.8 mmol) and 4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (164 mg, 0.6 mmol) in anhydrous THF (15 mL). The resulting mixture was stirred at 70° C. under microwave irradiation for 2 hours. LC-MS showed the tert-butyl 6-(((methylsulfonyl)oxy)methyl)-1H-indole-1-carboxylate had disappeared. The reaction mixture was treated with water (20 mL) and diluted with dichloromethane. After removal of the insolubles by filtration, the filtrate was extracted with dichloromethane. The combined organic phase was dried with Na2SO4 and concentrated. The residue was purified with Combiflash (A: H2O including 0.5% NH3HCO3, B: CH3CN) to afford tert-butyl 6-((2-oxo-4-(2-((tetrahydro-2H-pyran-4-yl)amino)pyrimidin-4-yl)pyridin-1(2H)-yl)methyl)-1H-indole-1-carboxylate (70 mg, 23% yield).
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15](CC)[CH2:16][C:17]3C=CC(OC)=CC=3)[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][C@H:36]1[OH:45].C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH2:16][CH3:17])[C:12]3=[N:27][CH:28]=[C:29]([C:30]#[N:31])[N:11]3[N:10]=2)=[CH:6][C:5]([C:32]#[N:33])=[CH:4][C:3]=1[NH:34][C@@H:35]1[CH2:40][CH2:39][N:38]([C:41]([O:43][CH3:44])=[O:42])[CH2:37][C@H:36]1[OH:45]
Reactant: CCN(Cc1ccc(OC)cc1)c1nc(Nc2cc(C#N)cc(N[C@@H]3CCN(C(=O)OC)C[C@H]3O)c2Cl)nn2c(C#N)cnc12
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCNc1nc(Nc2cc(C#N)cc(N[C@@H]3CCN(C(=O)OC)C[C@H]3O)c2Cl)nn2c(C#N)cnc12
Temperature: 40 °C
Reaction time: 2 h
Yield: 20.4 %

Procedure:
To (3R,4R)-methyl 4-((2-chloro-5-cyano-3-((7-cyano-4-(ethyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate (30.9 mg, 0.049 mmol) was added DCE (3 mL), anisole (5.35 μl, 0.049 mmol) and TFA (0.5 mL, 6.49 mmol); the reaction stirred 2 hr at 40° C. and solvents removed. The crude material was purified via preparative LC/MS with the following conditions: Column: XBridge C18, 19×200 mm, 5-μm particles; Mobile Phase A: 5:95 acetonitrile: water with 10-mM ammonium acetate; Mobile Phase B: 95:5 acetonitrile: water with 10-mM ammonium acetate; Gradient: 10-60% B over 20 minutes, then a 5-minute hold at 100% B; Flow: 20 mL/min. Fractions containing the desired product were combined and dried via centrifugal evaporation to afford (3R,4R)-methyl 4-((2-chloro-5-cyano-3-((7-cyano-4-(ethylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)amino)-3-hydroxypiperidine-1-carboxylate (5.1 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Mg]Br)[CH:5]=[CH:6][C:7]=1[Cl:8].ClC1C=C(Br)C=CC=1Cl.[Mg].Cl[CH:22]1[S:27][CH2:26][CH2:25][O:24][CH2:23]1.O1CCSCC1.[Cl-].[NH4+]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]2[S:27][CH2:22][CH2:23][O:24][CH2:25]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ClC1COCCS1
Reactant: Clc1ccc([Mg]Br)cc1Cl
Agent: C1CSCCO1
Agent: Clc1ccc(Br)cc1Cl
Agent: [Cl-]
Solvent: c1ccccc1
Product: Clc1ccc(C2COCCS2)cc1Cl
Reaction time: 8 h

Procedure:
A stirred solution of 3,4-dichlorophenylmagnesium bromide [prepared from 3,4-dichlorobromobenzene (10.2 g, 45 mmol) and magnesium (1.1 g, 45 mmol) in the usual fashion] was treated with a solution of 3-chloro-1,4-oxathiane [prepared from 1,4-oxathiane (2.6 g, 25 mmol) using the method of Tuleen and Bennet J. Het. Chem. 1969, 6, 115] in benzene (30 ml), maintaining the temperature of reaction below 10° C. The mixture was allowed to stand at room temperature overnight. It was then poured into ammonium chloride solution (50 ml), the organic phase was separated and the aqueous washed with ether (2×40 ml). The combined organic extracts were dried (MgSO4) and purified by flash chromatography on silica eluting with toluene/hexane (1:1) to give 3-(3,4-dichlorophenyl)-1,4-oxathiane (4.5 g), as colourless crystals, m.p. 65°-68° C.;
Reaction SMILES: [N+:1]([C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][CH:21]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CN(C)C=O.[Pd]>[NH2:1][C:4]1[CH:31]=[CH:30][C:7]([O:8][CH2:9][C:10]([O:12][CH2:13][CH2:14][O:15][C:16](=[O:29])[CH:17]([O:19][C:20]2[CH:21]=[CH:22][C:23]([NH2:26])=[CH:24][CH:25]=2)[CH3:18])=[O:11])=[CH:6][CH:5]=1
Reactant: CC(Oc1ccc([N+](=O)[O-])cc1)C(=O)OCCOC(=O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(Oc1ccc(N)cc1)C(=O)OCCOC(=O)COc1ccc(N)cc1
Reaction time: 3 h
Yield: 53.4 %

Procedure:
2-(4-nitrophenoxy)propionic acid-2-[2-(4-nitrophenoxy)acetoxy]ethyl ester 55 (20 g, 50 mmol) was dissolved in dry dimethylformamide (150 ml) in a pressure vessel, palladium on carbon (5%, 5 g) added, and the mixture stirred under a hydrogen atm. (4 Kg) for 3 hrs. The catalyst was removed by filtration and ice water (1 L) was added to the filtrate. Crude 56 was extracted into ethyl acetate, dried over Na2SO4, distilled and purified by column chromatography on silica gel using chloroform:ethyl acetate (8:2) to give pure 56 (10 g, 58%) as a dark brown syrup.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:17]Br.S(=O)(O)[O-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[NH2:1][C:2]1[C:7]([O:8][C:9]2[CH:16]=[CH:15][C:12]([C:13]#[N:14])=[CH:11][CH:10]=2)=[CH:6][C:5]([Br:17])=[CH:4][N:3]=1
Reactant: BrBr
Reactant: N#Cc1ccc(Oc2cccnc2N)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(Oc2cc(Br)cnc2N)cc1
Temperature: 0 °C
Yield: 66.3 %

Procedure:
Placed 4-(2-aminopyridin-3-yloxy)benzonitrile (13.95 g, 66.05 mmol) in acetic acid (50 mL) and cooled to 0° C. Slowly added bromine (4.229 mL, 82.56 mmol) and stirred for an hour. The reaction mixture was poured onto saturated sodium bisulfite and ice. Extracted with dichloromethane three times, washed with 2N NaOH, water, brine, dried, and concentrated. Purified by MPLC eluting with 3:2 hexane:ethyl acetate to afford the title compound (12.7 g, 66.28% yield) as a light yellow solid.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:16]=[CH:15][C:6]([C:7]([CH2:9][CH2:10][C:11]([O:13]C)=[O:12])=[O:8])=[CH:5][C:4]=1[OH:17].[OH-:18].[K+]>>[OH:17][C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:3]=1[CH2:2][OH:18])[C:7]([CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[O:8]
Reactant: [OH-]
Reactant: COC(=O)CCC(=O)c1ccc(CCl)c(O)c1
Agent: [K+]
Product: O=C(O)CCC(=O)c1ccc(CO)c(O)c1

Procedure:
A mixture of methyl 3-(4-chloromethyl-3-hydroxybenzoyl)-propionate and 3N potassium hydroxide solution was heated under reflux for 4 hours to give 3-(3-hydroxy-4-hydroxymethylbenzoyl)propionic acid.
Reaction SMILES: N[C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)[C:3]([OH:5])=O.[CH:14]1([NH:21][C:22]([NH2:24])=[S:23])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:21][C:22]2[S:23][CH:2]([CH2:6][C:7]3[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=3)[C:3](=[O:5])[N:24]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC(=S)NC1CCCCCC1
Reactant: N[C@@H](Cc1ccc(O)cc1)C(=O)O
Product: O=C1N=C(NC2CCCCCC2)SC1Cc1ccc(O)cc1

Procedure:
Synthesis was performed from (2S)-2-amino-3-(4-hydroxyphenyl)propanoic acid and N-cycloheptylthiourea according to Method E and C.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:6][C:7]1[CH:16]=[CH:15][C:10](/[CH:11]=[CH:12]/[CH2:13][OH:14])=[CH:9][CH:8]=1)[CH3:5])[CH3:2].[CH2:17]=[C:18]1[O:22][C:20](=[O:21])[CH2:19]1>C(N(CC)CC)C>[C:20]([O:14][CH2:13]/[CH:12]=[CH:11]/[C:10]1[CH:9]=[CH:8][C:7]([O:6][CH:4]([O:3][CH2:1][CH3:2])[CH3:5])=[CH:16][CH:15]=1)(=[O:21])[CH2:19][C:18]([CH3:17])=[O:22]
Reactant: CCOC(C)Oc1ccc(/C=C/CO)cc1
Reactant: C=C1CC(=O)O1
Solvent: CCN(CC)CC
Product: CCOC(C)Oc1ccc(/C=C/COC(=O)CC(C)=O)cc1
Yield: 70.9 %

Procedure:
A mixture of 9 g of 4(E)-(1-ethoxyethoxy)cinnamyl alcohol and 0.5 ml of triethylamine was heated at 70°-80° C., and 6 g of diketene was slowly added dropwise thereto. After the addition was finished, the reaction mixture was heated at 110°-120° C. for 30 minutes. After the reaction was completed, the solvent was removed by evaporation under a reduced pressure, and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: diethyl ether: n-hexane=1:3) to yield 8.8 g of 4(E)-[1-ethoxyethoxy)cinnamyl acetoacetate. Refractive index: D24 1.5305
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@H:5]([OH:8])[CH2:4][CH2:3]1.[CH2:9]=[C:10]1[O:14][C:12](=[O:13])[CH2:11]1>O1CCCC1>[OH:8][C@H:5]1[CH2:6][CH2:7][C@H:2]([NH:1][C:12](=[O:13])[CH2:11][C:10](=[O:14])[CH3:9])[CH2:3][CH2:4]1
Reactant: C=C1CC(=O)O1
Reactant: N[C@H]1CC[C@H](O)CC1
Solvent: C1CCOC1
Product: CC(=O)CC(=O)N[C@H]1CC[C@H](O)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 28.8 g (0.25 mol) trans-4-aminocyclohexanol in 200 ml tetrahydrofuran was added dropwise to a solution of 20 g of diketene (0.24 mol) in 200 ml tetrahydrofuran at −5 to 0° C. After 1 h stirring at 0° C. no more starting material was detected by thin layer chromatography. The reaction mixture was evaporated and the residue is recrystallized from 200 ml of ethyl acetate. This gave 33.6 g (0.17 mol, 71% yield) of a colorless solid.