Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15](Cl)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6].[NH2:21][C:22]1[CH:23]=[CH:24][C:25]2[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=2[CH:37]=1.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.C(O)(C)C>O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[C:3]([NH:12][C:13]2[C:18]([Cl:19])=[CH:17][N:16]=[C:15]([NH:21][C:22]3[CH:23]=[CH:24][C:25]4[N:31]([CH2:32][CH2:33][O:34][CH3:35])[C:30](=[O:36])[CH2:29][CH2:28][CH2:27][C:26]=4[CH:37]=3)[N:14]=2)=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([NH:7][CH3:8])=[O:6]
Reactant: COCCN1C(=O)CCCc2cc(N)ccc21
Reactant: CNC(=O)c1cccc(Cl)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CNC(=O)c1cccc(Cl)c1Nc1nc(Nc2ccc3c(c2)CCCC(=O)N3CCOC)ncc1Cl
Temperature: 120 °C
Yield: 29.9 %

Procedure:
A microwave vessel was charged with 3-chloro-2-(2,5-dichloro-pyrimidin-4-ylamino)-N-methyl-benzamide (50.00 mg, 0.1508 mmol), 7-amino-1-(2-methoxy-ethyl)-1,3,4,5-tetrahydro-1-benzazepin-2-one (39 mg, 0.16 mmol), 10-camphorsulfonic acid (6.0 mg, 0.026 mmol) and isopropyl alcohol (2 mL) and heated to at 120° C. for 70 minutes in a microwave reactor (sealed vessel). The reaction was diluted with water (10 mL) and saturated aqueous solution of NaHCO3 before extracting into DCM. The organic layer was dried by passing through a filter funnel loaded with MgSO4; the filtrate was evaporated onto celite prior to purification by chromatography (amine modified silica gel, 30% EtOAc/Hexane→80% EtOAc gradient). The appropriate fractions were combined, evaporated to afford a solid that was triturated with ether (2×2 mL) and yielded product (23.9 mg, 30%) as a white foam that had the following properties: m.p.=136-157° C., bubbled; LC/MS (ESI+): 529 (M+H); 1H-NMR (CDCl3, 400 MHz): δ 8.12 (s, 1H), 8.03 (s, 1H), 7.62 (d, J=8.0, 1H), 7.52 (d, J=8.0, 1H), 7.31 (dd, J=8.0, 7.8, 1H), 7.27 (m, 1H), 7.220 (d, J=8.6, 1H), 7.09 (d, J=8.6, 1H), 6.98 (s, 1H), 6.10, (s, 1H), 3.7-4.2 (m, 2H), 3.55-3.47 (m, 2H), 3.30 (s, 3H), 2.95 (d, J=4.9, 3H), 2.9-2.4 (m, 2H), 2.3-2.2 (m, 2H), 1.8-2.3 (m, 2H).
Reaction SMILES: [S:1]1(=[O:13])(=[O:12])[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4](=[O:11])[CH2:3][NH:2]1.O.[C:15]1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])([O-])OC>CO>[CH3:15][O:11][C:4]1[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[S:1](=[O:12])(=[O:13])[NH:2][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C1CNS(=O)(=O)c2ccccc21
Agent: COC([O-])[O-]
Solvent: O
Solvent: CO
Product: COC1=CNS(=O)(=O)c2ccccc21
Yield: 375.1 %

Procedure:
A mixture of 1.97 g (10 mmol) of 3,4-dihydro-2H-1,2-benzothiazin-4-one 1,1-dioxide, 500 mg (2.6 mmol) of p-toluenesulfonic acid monohydrate, 20 ml of methyl orthoformate and 20 ml of methanol was refluxed for 3 hours. The solvent was distilled off and the residue was purified by chromatography on a silica gel column (eluent: methylene chloride:ethyl acetate=40:1), whereby 2.06 g of the title compound were obtained (yield: 97%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[NH:23][C:22](=[O:24])[C:21]4[C:16](=[CH:17][C:18]([O:27][CH3:28])=[CH:19][C:20]=4[O:25][CH3:26])[N:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH3:29][S:30](Cl)(=[O:32])=[O:31].CCN(CC)CC>C(Cl)Cl>[CH3:26][O:25][C:20]1[CH:19]=[C:18]([O:27][CH3:28])[CH:17]=[C:16]2[C:21]=1[C:22](=[O:24])[NH:23][C:14]([C:11]1[CH:12]=[CH:13][C:8]([N:5]3[CH2:4][CH2:3][CH:2]([NH:1][S:30]([CH3:29])(=[O:32])=[O:31])[CH2:7][CH2:6]3)=[CH:9][CH:10]=1)=[N:15]2
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(N)CC4)cc3)nc2c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCC(NS(C)(=O)=O)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
A mixture of 2-(4-(4-aminopiperidin-1-yl)phenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.105 g, 0.28 mmol), methanesulfonylchloride (0.035 g, 0.30 mmol), and Et3N (0.057 g. 0.56 mmol) in CH2Cl2 (10 mL) was stirred at room temperature under nitrogen for 2 hours. The mixture was concentrated, redissolved in THF (5 mL), 2 M NaOH (5 mL) added and stirred for 20 minutes. The pH was adjusted to 8 with 1 M HCl and the mixture extracted with CH2Cl2 (3×150 mL). The organic phase was dried over anhydrous MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography, eluting with 1:1 CH2Cl2/(92:7:1 CHCl3/MeOH/concentrated NH4OH) to 100% 92:7:1 CHCl3/MeOH/concentrated NH4OH. Further purification by reverse-phase HPLC. eluting with 10% to 90% CH3CN in H2O with 0.1% TFA. afforded the title compound as a yellow solid (0.075 g, 58%). 1H NMR (300 MHz, DMSO-d6): δ11.75 (s, 1H), 8.08 (d, J=9.0 Hz, 2H), 7.13 (d, J=7.3 Hz, 1H), 7.00 (d, J=9.0 Hz, 2H), 6.66 (d, J=2.3 Hz, 1H), 6.46 (d, J=2.3 Hz, 1H), 3.81-3.94 (m, 8H), 3.34-3.47 (m, 1H), 2.90 (m, 6H), 1.87-1.95 (m, 2H), 1.42-1.54 (m, 2H); ESI MS m/z 459 [M+H]+.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:11])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.C([Li])CCC.[CH2:17]1[O:27][C:20]2([CH2:25][CH2:24][C:23](=[O:26])[CH2:22][CH2:21]2)[O:19][CH2:18]1>C1COCC1.CCOCC>[OH:11][C:8]([C:5]1[CH:4]=[CH:3][C:2]([C:23]2([OH:26])[CH2:24][CH2:25][C:20]3([O:27][CH2:17][CH2:18][O:19]3)[CH2:21][CH2:22]2)=[N:7][CH:6]=1)([CH3:10])[CH3:9]
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: CC(C)(O)c1ccc(Br)nc1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccc(C2(O)CCC3(CC2)OCCO3)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 32.7 %

Procedure:
2-(6-Bromopyridin-3-yl)propan-2-ol (1.08 g, 5 mmol) was dissolved in 10 mL of THF and 50 mL of anhydrous ether. After the solution was cooled to −78° C., 4.20 ml n-butyllithium (2.5 M, 11 mmol) was slowly dropped through a syringe in 10 min. After being stirred at −78° C. for 30 minutes, 1,4-cyclohexanedione mono-ethylene ketal (0.80 g, 5 mmol) was added. The reaction mixture was warmed up to room temperature during two hours and then quenched by addition of 5 mL of water. The mixture was extracted twice using EtOAc. The combined extracts were dried and concentrated. After flash column using 40-70% EtOAc in hexane, 0.48 g of white crystals were obtained (42% yield), MS: 294.1 (M+-1-1).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[NH2:25])[CH2:12][CH2:11]2)=[N:2]1.[C:26](Cl)(=[O:28])[CH3:27]>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=3[NH:25][C:26](=[O:28])[CH3:27])[CH2:12][CH2:11]2)=[N:2]1
Reactant: Cc1cccc(CCN2CCN(c3nsc4ccccc34)CC2)c1N
Reactant: CC(=O)Cl
Product: CC(=O)Nc1c(C)cccc1CCN1CCN(c2nsc3ccccc23)CC1
Yield: 63 %

Procedure:
Starting from 2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-6-methyl-phenylamine (65 mg, 0.185 mmol) and acetyl chloride (14 μL, 0.194 mmol) and following the procedure as outlined in Example 1, 46 mg of N-{2-[2-(4-1,2-benzisothiazol-3-yl-piperazin-1-yl)-ethyl]-6-methyl-phenyl}-acetamide was isolated as a pink foam in 100% purity @ 254 nm; LCMS (APCI): 395 [M+H]+.
Reaction SMILES: [H-].[Na+].[CH2:3]([N:5]1[CH2:9][CH2:8][CH:7]([OH:10])[CH2:6]1)[CH3:4].[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[S:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[C:26]=3[C:34]([C:36]3[CH:41]=[CH:40][C:39](F)=[CH:38][CH:37]=3)=[O:35])=[CH:21][CH:20]=2)[CH2:15][CH2:14][CH2:13][CH2:12]1>CN(C=O)C.[Cl-].[Na+].O>[N:11]1([CH2:16][CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[S:29][C:28]4[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=4[C:26]=3[C:34]([C:36]3[CH:41]=[CH:40][C:39]([O:10][CH:7]4[CH2:8][CH2:9][N:5]([CH2:3][CH3:4])[CH2:6]4)=[CH:38][CH:37]=3)=[O:35])=[CH:23][CH:24]=2)[CH2:12][CH2:13][CH2:14][CH2:15]1
Reactant: O=C(c1ccc(F)cc1)c1c(-c2ccc(OCCN3CCCC3)cc2)sc2ccccc12
Reactant: CCN1CCC(O)C1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN1CCC(Oc2ccc(C(=O)c3c(-c4ccc(OCCN5CCCC5)cc4)sc4ccccc34)cc2)C1
Reaction time: 0.25 h
Yield: 63 %

Procedure:
Sodium hydride (60% oil dispersion, 38 mg) was suspended in DMF (1 mL) and stirred at ambient temperature for 15 min under argon before 1-ethyl-3-pyrrolidinol (92 μL) was added. After stirring for 15 min, 4-fluorophenyl 2-[4-[2-(1-pyrrolidinyl)ethoxy]phenyl]benzo[b]thiophen-3-yl ketone (223 mg) in 1 mL of DMF was introduced and the resulting solution was stirred at ambient temperature for 4 h. The reaction mixture was diluted with brine (50 mL) and extracted with EtOAc (3×50 mL). The combined organic layers were dried (Na2SO4) and concentrated under reduced pressure. Chromatography with Et3N:MeOH:EtOAc (5:5:90) afforded the product as a colorless oil (171 mg, 63%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:21]#[N:22])([C:14]2[C:15](Cl)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(O[AlH-](OC(C)(C)C)OC(C)(C)C)(C)(C)C.[Li+].[OH-].[Na+].O>C1COCC1.O1CCOCC1.ClCCl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:14]3[C:15](=[N:16][CH:17]=[CH:18][CH:19]=3)[NH:22][CH2:21]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)(c2cccnc2Cl)CC1
Agent: CC(C)(C)O[AlH-](OC(C)(C)C)OC(C)(C)C
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC2(CC1)CNc1ncccc12
Yield: 101.9 %

Procedure:
A mixture of 2-chloro-4′-cyano-3′,4′,5′,6′-tetrahydro-2′H-[3,4′]bipyridinyl-1′-carboxylic acid tert-butyl ester (6 g) and lithium tri-tert-butoxyaluminohydride (72.34 ml), 1M solution in THF) in 1-4-dioxane (90 ml) was refluxed overnight. After cooling, 1 N NaOH (100 ml) and H2O (100 ml) were added slowly at 0° C. Dichloromethane was added to the mixture. The aqueous phase was extracted twice with dichloromethane and the combined organic layers were washed with saturated sodium bicarbonate, dried (magnesium sulfate), filtered and concentrated in vacuo. The crude product was purified by chromatography [SiO2; dichloromethane-methanol (95:5)] to give 5.5 g (46%) of 7-Aza- spiro[indoline-3,4′-piperidine]-1′-carboxylic acid tert-butylester; MS (ES+) 290 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=O)=[CH:4][CH:3]=1.[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br.Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1COCC1>[CH3:12][O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([Cl:1])[CH:10]=2)[CH2:6][CH:7]=1
Reactant: O=C1CCc2ccc(Cl)cc21
Reactant: COc1ccccc1[Mg]Br
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: COc1ccccc1C1=CCc2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Under an argon atmosphere, a solution of 12.80 g of 6-chloroindan-1-one (73.45 mol) from Example 16A in 60 ml of THF is added drop wise to 88 ml of a 1 M solution of 2-methoxyphenylmagnesium bromide in THF (88.0 mol) at 0° C. The reaction mixture is stirred at room temperature for 1.5 h and 200 ml of 1 N hydrochloric acid are added for working up. The mixture is extracted three times with ethyl acetate, the combined organic phases are dried over sodium sulphate, and the solvent is removed in a rotary evaporator. The residue is dissolved in 400 ml of dichloromethane, mixed with 0.10 g of 4-toluenesulphonic acid monohydrate (0.53 mol) and stirred at room temperature for 16 h. The reaction mixture is washed with saturated sodium bicarbonate solution and saturated sodium chloride solution and dried over sodium sulphate. The solvent is removed in a rotary evaporator, and the residue is purified by chromatography on silica gel (mobile phase: cyclohexane/ethyl acetate 150:1). 12.02 g (61% of theory) of the title compound are obtained.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:42]=[CH:43][CH:44]=1)[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[C:19]3[C:14](=[N:15][CH:16]=[C:17]([C:20]4[CH:25]=[CH:24][C:23]([N:26]5[CH2:31][CH2:30][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:28][CH2:27]5)=[C:22]([N+:39]([O-])=O)[CH:21]=4)[CH:18]=3)[NH:13][CH:12]=2)[CH:8]=[N:7]1>[Pd].CO>[NH2:39][C:22]1[CH:21]=[C:20]([C:17]2[CH:18]=[C:19]3[C:11]([C:9]4[CH:8]=[N:7][N:6]([CH2:5][C:4]5[CH:42]=[CH:43][CH:44]=[C:2]([F:1])[CH:3]=5)[CH:10]=4)=[CH:12][NH:13][C:14]3=[N:15][CH:16]=2)[CH:25]=[CH:24][C:23]=1[N:26]1[CH2:27][CH2:28][N:29]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:30][CH2:31]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2[N+](=O)[O-])CC1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6cccc(F)c6)c5)c4c3)cc2N)CC1
Yield: 105.7 %

Procedure:
Using similar reaction conditions as described in example-8, tert-butyl 4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-nitrophenyl)piperazine-1-carboxylate (90 mg, 0.15 mmol) was reduced by 10% palladium on carbon (10 mg, 10% W/W) in methanol (10 mL) to yield crude 90 mg of the titled compound. MS: m/z=567.8 (M+1).
Reaction SMILES: Br[C:2]1[C:9]2[S:8][CH:7]=[N:6][C:5]=2[N:4]([CH:10]([CH3:14])[CH2:11][O:12][CH3:13])[C:3]=1[CH3:15].[C:16]([Cu])#[N:17]>CN(C)C=O>[CH3:13][O:12][CH2:11][CH:10]([N:4]1[C:5]2[N:6]=[CH:7][S:8][C:9]=2[C:2]([C:16]#[N:17])=[C:3]1[CH3:15])[CH3:14]
Reactant: COCC(C)n1c(C)c(Br)c2scnc21
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: COCC(C)n1c(C)c(C#N)c2scnc21
Temperature: 150 °C
Reaction time: 2 h
Yield: 61.4 %

Procedure:
To a solution of 6-bromo-4-(1-methoxypropan-2-yl)-5-methyl-4H-pyrrolo[2,3-d]thiazole (2.0 g, 6.92 mmol) in anhydrous N,N-dimethylformamide (15 mL) was added cyano copper (1.24 g, 13.84 mmol). The resulting reaction mixture was heated to 150° C. and allowed to stir for 2 hours at 150° C. The reaction mixture was washed with water and brine, and extracted with acetic ester (30 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel eluted with (petrol ether/acetic ester 30:1→20:1→10:1) to give the title compound (1.0 g, 62%) as yellow oil. LCMS (M+H+) m/z: calc'd. 235.08. found 236.0.
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:27][CH2:28][Cl:29])[N:21](COCC)[C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+]>Cl>[C:1]1([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:9]2[C:18]3[N:19]=[C:20]([CH2:26][CH2:27][CH2:28][Cl:29])[NH:21][C:17]=3[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOCn1c(CCCCl)nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: ClCCCc1nc2c(N(Cc3ccccc3)Cc3ccccc3)nc3ccccc3c2[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.7 %

Procedure:
A suspension of N,N-bis(phenylmethyl)-2-(3-chloropropyl)-1-ethoxymethyl-1H-imidazo[4,5-c]quinolin-4-amine (1 g, 2.0 mmole) in 6N hydrochloric acid (80 mL) was heated at reflux for 2 hours and then stirred at ambient temperature overnight. The reaction mixture was neutralized with 10% sodium hydroxide then extracted with methylene chloride. The extract was dried over magnesium sulfate then concentrated under vacuum to provide 0.8 g of N,N-bis(phenylmethyl)-2-(3-chloropropyl)-1H-imidazo[4,5-c]quinolin-4-amine.
Reaction SMILES: [CH:1]([CH:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([OH:7])=[O:6])([CH3:3])[CH3:2].[C:12]([CH:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:16]=1)#[N:13].C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O>[CH:1]([CH:4]([CH2:8][C:9]([CH3:11])=[CH2:10])[C:5]([O:7][CH:14]([C:12]#[N:13])[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:16]=1)=[O:6])([CH3:3])[CH3:2]
Reactant: N#CC(Br)c1cccc(Oc2ccccc2)c1
Reactant: C=C(C)CC(C(=O)O)C(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: C=C(C)CC(C(=O)OC(C#N)c1cccc(Oc2ccccc2)c1)C(C)C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of 2-isopropyl-4-methylpent-4-enoic acid (1.0g), alpha-cyano-3-phenoxybenzyl bromide (1.9g) and potassium carbonate (1.0g) in anhydrous acetone (40ml) was stirred at room temperature for 4 hours. Water was added to the reaction mixture and the product extracted with ether, the ethereal extracts washed with water (X2) and dried over magnesium sulphate. Evaporation of the solvent gave a crude product which was purified by chromatography on silica gel using 3% acetone in 60°-80° C. petroleum ether as eluent to give the desired ester. R.I. nD20 1.5343.
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6][CH:7]1[CH2:15][C:14]2[C:9](=[C:10]([Cl:21])[C:11]([Cl:20])=[C:12]([O:16][CH2:17][C:18]#[N:19])[CH:13]=2)[C:8]1=[O:22])(=[O:3])[CH3:2].N12CCCC1=CCCN2.[CH:32]([C:34]([CH3:36])=[O:35])=[CH2:33].C(OCC)(=O)C>O1CCCC1.N12CCCC1=CCCN2.C(O)(=O)C>[C:1]([O:4][CH2:5][CH2:6][C:7]1([CH2:33][CH2:32][C:34](=[O:35])[CH3:36])[CH2:15][C:14]2[C:9](=[C:10]([Cl:21])[C:11]([Cl:20])=[C:12]([O:16][CH2:17][C:18]#[N:19])[CH:13]=2)[C:8]1=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)OCCC1Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Reactant: C=CC(C)=O
Agent: C1=C2CCCN2NCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(=O)CCC1(CCOC(C)=O)Cc2cc(OCC#N)c(Cl)c(Cl)c2C1=O
Temperature: 40 °C
Reaction time: 2 h

Procedure:
{[2-(2-Acetoxyethyl)-6,7-dichloro-2,3-dihydro-1-oxo-1H-inden-5-yl]oxy}acetonitrile (3.42 g, 10 mMole) is dissolved in tetrahydrofuran (30 ml), warmed to 40° C. and diazabicyclo[4.3.0]non-5-ene (50 microliters) added. Then methyl vinyl ketone (1.2 g, 17 mMole) is added and the mixture stirred at 50°-52° C. for two hours. More methyl vinyl ketone (600 mg) and diazabicyclo[4.3.0]non-5-ene (2 drops) are added and stirring and heating continued for another 2 hours. The solution is cooled, treated with ethyl acetate (50 ml) and poured into ice water (250 ml) containing acetic acid (1 ml). The organic layer is separated and the aqueous layer extracted first with methylene chloride and then with ether. The combined organic layers were dried over MgSO4 and the solvent removed by evaporation in vacuo to give the desired product.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH:21]1[CH2:25][CH2:24][O:23][C:22]1=[O:26]>CN(C)C=O>[O:26]=[C:22]1[CH:21]([N:4]2[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]2)[CH2:25][CH2:24][O:23]1
Reactant: O=C1OCCC1Br
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(C2CCOC2=O)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 74 %

Procedure:
To a stirred solution of 2.0 g (11 mmol) of tert-butyl piperazine-1-carboxylate in 30 mL of anhydrous N,N-dimethylformamide was added 1.9 g (14 mmol) of potassium carbonate followed by 0.09 mL (11 mmol) of 3-bromodihydrofuran-2(3H)-one. The resulting heterogeneous mixture was stirred at ambient temperature of 12 h, quenched with water, then extracted with ethyl acetate. The combined organic layers were washed with water then brine, dried over magnesium sulfate and evaporated to dryness in vacuo. The residue was purified by silica gel chromatography eluting with a 0-75% acetone in hexanes gradient to afford the title compound as clear gum (2.2 g, 75%). LC-MS: m/z (ES) 271.2 (MH)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[N:22]([CH3:24])[C:21]([C:25](=[O:44])[NH:26][C:27]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=2[O:42][CH3:43])=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])(C)(C)[CH3:2].CCOC(N1CCNCC1)=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClC(Cl)C>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:23]=2[N:22]([CH3:24])[C:21]([C:25](=[O:44])[NH:26][C:27]2[CH:32]=[C:31]([C:33]([CH3:35])([CH3:36])[CH3:34])[CH:30]=[C:29]([NH:37][S:38]([CH3:41])(=[O:40])=[O:39])[C:28]=2[O:42][CH3:43])=[CH:20]3)[CH2:12][CH2:13]1)=[O:7])[CH3:2]
Reactant: COc1c(NC(=O)c2cc3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3n2C)cc(C(C)(C)C)cc1NS(C)(=O)=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CCOC(=O)N1CCNCC1
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: CC(=O)O
Product: CCOC(=O)N1CCN(Cc2cccc3cc(C(=O)Nc4cc(C(C)(C)C)cc(NS(C)(=O)=O)c4OC)n(C)c23)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 37.9 %

Procedure:
To a solution of 7-formyl-1-methyl-1H-indole-2-carboxylic acid (5-tert-butyl-3-methanesulfonylamino-2-methoxy-phenyl)-amide (see Example 2, 30 mg, 0.066 mmol) and ethyl N-piperazinocarboxylate (104 mg, 0.66 mmol) in dichloroethane (2 mL) was added acetic acid (0.1 mL). The mixture was stirred at room temperature for 4 h. Sodium triacetoxyborohydride (35 mg, 0.156 mmol) was then added to the reaction mixture. The reaction was stirred overnight at room temperature and then quenched with saturated NaHCO3 solution. The mixture was then extracted with EtOAc and dichloromethane in sequence, dried over Na2SO4 and concentrated. The residue was purified by preparative-TLC, eluting with EtOAc-hexane, 1:1, providing 15 mg (38%) of the title compound. ESI MS m/z 600.37 [M+H]+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18])=[O:14])[CH3:11]>>[CH2:10]([O:12][C:13]([C:15]1[CH:16]=[C:17]([NH:18][C:2]2[N:7]=[C:6]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[C:15]([C:13]([O:12][CH2:10][CH3:11])=[O:14])[CH:16]=3)[C:5]([F:9])=[CH:4][N:3]=2)[CH:19]=[CH:20][CH:21]=1)=[O:14])[CH3:11]
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: Fc1cnc(Cl)nc1Cl
Product: CCOC(=O)c1cccc(Nc2ncc(F)c(Nc3cccc(C(=O)OCC)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-fluoropyrimidine and 3-ethoxycarbonylaniline gave N2,N4-bis(3-ethoxycarbonylphenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 26.55 min.; purity: 100%; MS (m/e): 425 (MH+).
Reaction SMILES: [H-].[Na+].[C:3]([OH:8])#[C:4][CH2:5][CH2:6][CH3:7].[CH:9]1[CH:14]=[CH:13][C:12]([CH2:15]Br)=[CH:11][CH:10]=1>C1COCC1>[CH2:3]([O:8][CH2:15][C:12]1[CH:13]=[CH:14][CH:9]=[CH:10][CH:11]=1)[CH2:4][CH2:5][C:6]#[CH:7]
Reactant: BrCc1ccccc1
Reactant: CCCC#CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCCCOCc1ccccc1
Temperature: 0 °C
Yield: 94.5 %

Procedure:
To a flame-dried round-bottomed flask was added NaH (2 equiv., 47.6 mmol, 1.9 g of a 60% dispersion in mineral oil). The solid was washed with hexanes (15 mL), THF (95 mL) was added and the suspension was cooled to 0° C. Pentynol (1 equiv., 23.8 mmol, 2.0 g) was added drop wise in THF (5 mL), followed by drop wise addition of BnBr (0.92 equiv., 21.9 mmol, 2.60 mL). The reaction was warmed to ambient temperature over 16 h, quenched with saturated aqueous NH4Cl (25 mL), and diluted with water (20 mL). The organic layer was extracted with EtOAc (2×40 mL), washed with brine (40 mL) and dried with Na2SO4. Product isolation was achieved by concentration in vacuo and purification by flash column chromatography to afford ((pent-4-yn-1-yloxy)methyl)benzene (3.60 g, 20.7 mmol, 94%). TLC Rf=0.41 (5% EtOAc/Hex); 1HNMR (300 MHz): δ 7.29-7.44 (5H), 4.55 (s, 2H), 3.61 (t, 2H, J=6.2 Hz), 2.36 (td, 2H, J=7.1, 2.6 Hz), 1.97 (t, 1H, J=2.6 Hz), 1.81-1.93 (m, 2H). 13CNMR (75 MHz): δ 138.5, 128.4, 127.63, 127.58, 84.0, 73.0, 68.7, 68.5, 28.7, 15.3.