Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:26])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([OH:25])[CH:20]=[CH:21][C:22]=4F)[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[CH3:27][N:28]([CH3:38])[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][NH:30]1>>[CH3:27][N:28]([CH3:38])[C:29]1[CH:34]=[CH:33][C:32]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]3[C:18]=2[CH2:17][CH2:16][C@H:15]3[O:14][C:12]2[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:26])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=2)=[CH:31][N:30]=1
Reactant: CN(C)C1(B(O)O)C=CC=CN1
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(O)ccc(F)c43)ccc21
Product: CN(C)c1ccc(Oc2cccc3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cn1

Procedure:
The methyl ester of the title compound is prepared from {(S)-6-[(R)-7-fluoro-4-hydroxy-indan-1-yloxy]-2,3-dihydro-benzofuran-3-yl}-acetic acid methyl ester and 2-dimethylamino-pyridineboronic acid following a procedure analogous to that described for Intermediate 6. The title compound is obtained after saponification of the methyl ester as described for Example 1. LC (method 2): tR=0.91 min; Mass spectrum (ESI+): m/z=465 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[CH:3]([CH3:27])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:12][CH:11]=1)[C:5]([O:7]CC)=[O:6].CO.[OH-].[Li+].Cl>C1COCC1.O>[F:29][C:2]([F:1])([F:28])[CH:3]([CH3:27])[CH:4]([C:10]1[CH:15]=[CH:14][C:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:18]2=[O:26])=[CH:12][CH:11]=1)[C:5]([OH:7])=[O:6]
Reactant: CCOC(=O)C(c1ccc(CN2Cc3ccccc3C2=O)cc1)C(C)C(F)(F)F
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CC(C(C(=O)O)c1ccc(CN2Cc3ccccc3C2=O)cc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Under argon, 270 mg (0.66 mmol) of ethyl 4,4,4-trifluoro-3-methyl-2-{4-[(1-oxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phenyl}butanoate were dissolved in 1 ml each of THF, methanol and water, and 69.9 mg (1.66 mmol) of lithium hydroxide were added. The mixture was stirred at RT overnight. The reaction mixture was diluted with water and acidified with 1 N hydrochloric acid, and the resulting precipitate was filtered off with suction. The solid was washed with water until the washings remained neutral. This gave 222 mg (88.3% of theory) of the target compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2].[F:17][B-](F)(F)F.F[N+]1C(Cl)=CC=CC=1Cl>ClCCl>[CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:15]=[CH:14][C:13]([F:17])=[C:12]([OH:16])[C:9]=2[C:10]=1[CH3:11])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1oc2cccc(O)c2c1C
Reactant: F[B-](F)(F)F
Agent: F[n+]1c(Cl)cccc1Cl
Solvent: ClCCl
Product: CCOC(=O)c1oc2ccc(F)c(O)c2c1C
Reaction time: 8 h
Yield: 27.7 %

Procedure:
To a solution of 4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (Joseph G. Atkinson et al., European patent application 0146243 (1985)) (700 mg) in dichloromethane (20 ml) was added 1-fluoro-2,6-dichloropyridinium tetrafluoroborate (807 mg) at room temperature and the mixture was stirred overnight. The reaction was quenched by the addition of water (10 ml), extracted with ethyl acetate (20 ml), washed with brine and dried over anhydrous magnesium sulfate. The mixture was separated by silica gel column chromatography developed by dichloromethane and methanol. 5-fluoro-4-hydroxy-3-methyl-benzofuran-2-carboxylic acid ethyl ester (210 mg) was obtained as a white solid. EI-MS: m/z 238 (MH+); 1H-NMR (CDCl3): δ 1.50 (3H, t, J=7.3 Hz), 2.82 (3H, s), 4.46 (2H, q, J=7.3 Hz), 6.99 (1H, dd, J=3.3 Hz, 8.9 Hz), 7.15 (1H, dd, J=8.9 Hz, 10.6 Hz). And 7-fluoro-4-methyl-benzofuran-2-carboxylic acid ethyl ester was obtained as a colorless oil. EI-MS: m/z 238 (MH+); 1H-NMR (CDCl3): δ 1.44 (3H, t, J=7.3 Hz), 2.76 (3H, s), 4.46 (2H, q, J=7.3 Hz), 6.47 (1H, dd, J=3.0 Hz, 8.6 Hz), 6.97 (1H, dd, J=8.6 Hz, 10.2 Hz).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][N:6]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]2[O:24][CH2:25][O:26][C:20]=2[C:19]=1[O:27][CH3:28])S(C1C=CC(C)=CC=1)(=O)=O)C.[ClH:32].O>O1CCOCC1>[ClH:32].[CH3:28][O:27][C:19]1[C:20]2[O:26][CH2:25][O:24][C:21]=2[CH:22]=[C:23]2[C:18]=1[CH:17]=[N:6][CH:5]=[CH:4]2
Reactant: CCOC(CN(Cc1ccc2c(c1OC)OCO2)S(=O)(=O)c1ccc(C)cc1)OCC
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: COc1c2c(cc3ccncc13)OCO2
Temperature: 5 °C
Yield: 61.8 %

Procedure:
N-(2-methoxy-3,4-methylenedioxybenzyl)-N-(p-toluenesulfonyl)aminoacetaldehyde diethylacetal (3) in an amount of 69.89 g (0.155 mol) was dissolved in 0.194 ml of dioxane, to which 14.7 ml (0.169 mol) of concentrated hydrochloric acid and 47.1 ml of water were added and heated under reflux for two hours and 40 minutes. After the mixture were cooled to about 5° C., deposited crystals were collected by filtration, washed with 30 ml of cold dioxcane and then dried to obtain 22.95 g of 8-methoxy-6,7-methylenedioxyisoquinoline hydrochloride (4) as yellow crystals. Yield 61.8%.
Reaction SMILES: Cl.[F:2][C:3]([F:12])([F:11])[C:4]1[CH:5]=[C:6]([NH2:10])[CH:7]=[CH:8][CH:9]=1.[C:13](#[N:16])[CH:14]=[CH2:15].C(NCC)C.[OH-].[Na+]>>[F:2][C:3]([F:11])([F:12])[C:4]1[CH:5]=[C:6]([NH:10][CH2:15][CH2:14][C:13]#[N:16])[CH:7]=[CH:8][CH:9]=1
Reactant: C=CC#N
Reactant: Nc1cccc(C(F)(F)F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCNCC
Product: N#CCCNc1cccc(C(F)(F)F)c1
Temperature: 180 °C
Reaction time: 2.5 h
Yield: 45 %

Procedure:
A mixture of 70 parts of 3-(trifluoromethyl)benzenamine hydrochloride, 26.5 parts of 2-propenenitrile and 36.5 parts of N-ethylethanamine was stirred for 2.5 hours at 180° C. After cooling to 0° C., the whole was treated with a sodium hydroxide solution. The product was extracted with dichloromethane. The extract was washed with water, dried, filtered and evaporated, yielding 34.5 parts (45%) of 3-[[3-(trifluoromethyl)phenyl]amino]propanenitrile as a residue (int. 105).
Reaction SMILES: [N:1]1([C:7]2[CH:17]=[CH:16][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:18][C:19]([F:44])([F:43])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41]Br)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]>>[F:18][C:19]([F:43])([F:44])[CH2:20][NH:21][C:22]([C:24]1([CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:16][CH:17]=3)[CH2:6][CH2:5]2)[C:36]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[C:30]2[C:25]1=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:23]
Reactant: O=C(NCC(F)(F)F)C1(CCCCCBr)c2ccccc2-c2ccccc21
Reactant: CCOC(=O)c1ccc(N2CCNCC2)cc1
Product: CCOC(=O)c1ccc(N2CCN(CCCCCC3(C(=O)NCC(F)(F)F)c4ccccc4-c4ccccc43)CC2)cc1

Procedure:
Step (b) of Example 1 was repeated, except that the compound prepared in step (a) of Example 80 and the compound prepared in step (a) of Example 94 were used as the starting compounds. Thus, ethyl 4-[4-[5-[9-(2,2,2-trifluoroethylcarbamoyl)-9H-fluoren-9-yl]pentyl]-piperazin-1-yl]benzoate was obtained.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1.[NH2:19][CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][C:25]([NH:28][S:29]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)(=[O:31])=[O:30])=[CH:24][CH:23]=1.[CH2:38](O)C>C(O)(=O)C>[OH:1][C@@H:2]([CH2:3][NH:19][CH2:20][CH:21]([C:22]1[CH:23]=[CH:24][C:25]([NH:28][S:29]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)(=[O:31])=[O:30])=[CH:26][CH:27]=1)[CH3:38])[CH2:4][O:5][C:6]1[C:18]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: c1ccc2c(c1)[nH]c1cccc(OC[C@@H]3CO3)c12
Reactant: CCO
Reactant: NCCc1ccc(NS(=O)(=O)c2ccccc2)cc1
Solvent: CC(=O)O
Product: CC(CNC[C@H](O)COc1cccc2[nH]c3ccccc3c12)c1ccc(NS(=O)(=O)c2ccccc2)cc1
Temperature: 45 °C
Yield: 29 %

Procedure:
A stirred mixture of (S)-4-(oxiranylmethoxy)-9H-carbazole (478.5 mg, 2.0 mmol), N-(4-[2-aminoethyl]phenyl)benzenesulfonamide (829.1 mg, 3.0 mmol), acetic acid (1 drop), and ethanol (50 mL) was heated at 45° C. for 16 h with a slow stream of nitrogen bubbling through the reaction mixture. The mixture was cooled and concentrated in vacuo to an amorphous solid. The solid was taken up in ethyl acetate (150 mL) and washed once with 1N HCl (20 mL) and twice with aqueous saturated sodium bicarbonate solution and finally with water. The organic layer was then dried over anhydrous magnesium sulfate, filtered, and concentrated to dryness. The resulting white amorphous product was purified by radial chromatography (Chromatatron) using EtOAc:MeOH (9:1). Concentration of the appropriate fractions and drying under vacuum gave 290 mg (29%) of the desired product as an amorphous white solid. Anal. Calcd. for C29H29N3O4S.0.5 mol H2O: C, 66.39; H, 5.76; N, 8.01. Found: C, 66.49; H, 5.81; N, 7.77.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([CH:37]2[CH2:39][CH2:38]2)[CH:34]=[CH:33][C:4]=1[CH2:5][CH2:6][NH:7][C:8]([C:10]1[CH:32]=[CH:31][C:13]([O:14][C:15]2[CH:24]=[C:23]3[C:18]([CH:19]([C:25]([O:27]CC)=[O:26])[CH2:20][CH2:21][O:22]3)=[CH:17][C:16]=2[Cl:30])=[CH:12][CH:11]=1)=[O:9].[OH-].[Na+]>C1COCC1.C(O)C.CCOC(C)=O.Cl>[Cl:30][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:15]=1[O:14][C:13]1[CH:31]=[CH:32][C:10]([C:8](=[O:9])[NH:7][CH2:6][CH2:5][C:4]3[CH:33]=[CH:34][C:35]([CH:37]4[CH2:39][CH2:38]4)=[CH:36][C:3]=3[O:2][CH3:1])=[CH:11][CH:12]=1)[O:22][CH2:21][CH2:20][CH:19]2[C:25]([OH:27])=[O:26]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(C5CC5)cc4OC)cc3)c(Cl)cc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: COc1cc(C2CC2)ccc1CCNC(=O)c1ccc(Oc2cc3c(cc2Cl)C(C(=O)O)CCO3)cc1
Temperature: 25 °C
Yield: 89.3 %

Procedure:
To a stirred solution of ethyl 7-(4-(2-methoxy-4-cyclopropylphenethylcarbamoyl)phenoxy)-6-chlorochroman-4-carboxylate (0.07 g; 0.133 mmol) in a mixture of 1.2 mL THF and 0.6 mL ethanol at ambient temperature was added 0.53 mL of 1M aqueous NaOH. The resulting slightly cloudy mixture was vigorously stirred at ambient temperature. After 1 hour the reaction mixture was diluted with 6 mL EtOAc and 3 mL of 1M aqueous HCl, then transferred to a separatory funnel. After shaking, the organic layer was washed with 2 mL brine, then dried over sodium sulfate and evaporated to give 62 mg of 6-chloro-7-(4-(4-cyclopropyl-2-methoxyphenethylcarbamoyl)phenoxy)chroman-4-carboxylic acid as a colorless oil. MS (apci, pos) m/z=523.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][S:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C(N(CC)CC)C.[C:19]1([CH3:31])[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH2:27][C:28](Cl)=[O:29].Cl>O.C1COCC1>[CH3:31][C:19]1[CH:24]=[C:23]([CH3:25])[CH:22]=[C:21]([CH3:26])[C:20]=1[CH2:27][C:28]([N:1]1[CH2:6][CH2:5][S:4][CH2:3][CH:2]1[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:29]
Reactant: CCOC(=O)C1CSCCN1
Reactant: Cc1cc(C)c(CC(=O)Cl)c(C)c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1CSCCN1C(=O)Cc1c(C)cc(C)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 94.6 %

Procedure:
175.3 g (1 mol) of ethyl thiomorpholine-3-carboxylate are dissolved in 1000 ml of abs. THF, 140 ml (1 mol) of triethylamine are added and 198.5 g (1 mol) of mesitylene acetyl chloride are added dropwise at 0° to 10° C. The mixture is subsequently stirred at room temperature for a further 1 h and poured into 4.5 1 of ice water and 500 ml of 1 N HCl, and a flocculant, strongly water-containing product is filtered off with suction, taken up in methylene chloride, dried using MgSO4 and concentrated on a rotary evaporator. In this manner, 317.2 g (=94.7% of theory) of ethyl N-(2,4,6-trimethylphenyl-acetyl)-thiomorpholine-3-carboxylate are obtained as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34]Br>CN(C=O)C>[Cl:30][C:31]1[CH:32]=[C:33]([CH:36]=[CH:37][CH:38]=1)[CH2:34][N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][O:8][C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[C:11]([NH2:20])=[N:12][C:13]([NH2:19])=[N:14]3)[CH2:3][CH2:2]1
Reactant: Nc1nc(N)c2c(OCC3CCNCC3)cccc2n1
Reactant: Clc1cccc(CBr)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Nc1nc(N)c2c(OCC3CCN(Cc4cccc(Cl)c4)CC3)cccc2n1
Temperature: 60 °C
Reaction time: 20 h

Procedure:
To a stirred solution of 5-(piperidin-4-ylmethoxy)quinazoline-2,4-diamine (2.5 g, 9.15 mmol) and diisopropylethylamine (2.96 g, 22.87 mmol) in DMF (16 mL) was added a solution of 3-chlorobenzyl bromide in DMF (4 mL). The reaction mixture was heated at 60° C. with stirring for 20 h. The mixture was concentrated, water was added stirred for 1 h. The precipitate was filtered, washed with water, dried. Purified by silica gel column chromatography using 3-10% methanol in dichloromethane afforded 1.82 g of 5-[1-(3-chlorobenzyl)piperidin-4-ylmethoxy]quinazoline-2,4-diamine 1H NMR (400 MHz, DMSO-d6) δ 7.25-7.38 (m, 5H), 7.2 (s, 2H), 6.77 (dd, J=8.0, 1.2 Hz, 1H), 6.53 (dd, J=8.0, 0.8 Hz, 1H), 5.95 (s, 2H), 3.99 (d, J=6.4 Hz, 2H), 3.48 (s, 2H), 2.84 (d, J=11.2 Hz, 2H), 1.7-2.07 (m, 5H), 1.3-1.42 9m, 2H). MS m/z (ESI) 399 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[CH:28]=[CH:27][C:5]([C:6](C2C(NC(=O)C3C=CC=CC=3)=CC3CCCCC=3C=2)=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+]>O1CCCC1.C(O)C.O>[C:2]1([CH3:1])[CH:28]=[CH:27][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=O)c2cc3c(cc2NC(=O)c2ccccc2)CCCC3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C=O)cc1

Procedure:
To a 50 mL flask containing a stirred solution of N-[3-(4-methyl-benzoyl)-5,6,7,8-tetrahydro-naphthalen-2-yl]-benzamide (191 mg, 517 μmol) in tetrahydrofuran (5 mL), ethanol (5 mL) and water (1 mL) under nitrogen was added sodium hydroxide (340 mg, 8.5 mmol) and heated at reflux overnight. Heating was discontinued and solvents removed in vacuo. Added water (20 mL) and extracted with ethyl acetate (3×20 mL). Combined organics were dried with magnesium sulphate and evaporated in vacuo to give 3-amino-5,6,7,8-tetrahydro-naphthalen-2-yl)-p-tolyl-methanone as a partially crystalline red oil 146 mg (107% Yield). LCMS (5 min acidic) 2.99 min 100% pure by ELSD and UV ES+ and AP+ 266. HNMR (CDCl3) >90% pure 7.57-7.55 (m, 2H), 7.27-7.24 (m, 2H), 7.16 (s, 1H), 6.46 (s, 1H), 5.63 (br-s, 2H), 2.72-2.69 (m, 2H), 2.59-2.56 (m, 2H), 2.43 (s, 3H), 1.77-1.73 (m, 4H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]#[N:15].[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[OH:23][C:21]1[CH:22]=[C:17]([NH:16][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=3)[N:5]=[CH:4][C:3]=2[C:14]#[N:15])[CH:18]=[CH:19][C:20]=1[CH3:24]
Reactant: Cc1ccc(N)cc1O
Reactant: COc1ccc2c(Cl)c(C#N)cnc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2c1

Procedure:
To a suspension of 200 mg (0.91 mmol) of 4-chloro-7-methoxy-3-quinolinecarbonitrile and 135.5 mg (1.10 mmol) of 5-amino-o-cresol in 10 mL of 2-ethoxy ethanol was added 105.6 mg (0.91 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr, and then the solvent was removed to give a residue. To the residue was added about 30 mL of water and neutralized to pH 7-8 by addition of diluted sodium carbonate solution. The precipitate was collected by filtration and washed with water and ether. After drying in vacuo, this afforded 277 mg (99%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 305.9.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=1.C(N(C(C)C)CC)(C)C.[N:18]1([CH2:23][CH2:24][N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH2:22][CH2:21][CH2:20][CH2:19]1>C(O)CCC>[N:18]1([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][N:28]([C:2]3[N:7]=[CH:6][N:5]=[C:4]([NH2:8])[CH:3]=3)[CH2:29][CH2:30]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: Nc1cc(Cl)ncn1
Reactant: C1CCN(CCN2CCNCC2)C1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Nc1cc(N2CCN(CCN3CCCC3)CC2)ncn1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
6-Chloropyrimidin-4-amine 7-2 (0.317 g, 2.44 mmol) and diisopropylethylamine (0.0.316 g, 2.44 mmol) were suspended in n-butanol and 1-(2-pyrrolidin-1-ylethyl)piperazine 11-1 (0.448 g, 2.44 mmol) was added. The reaction was stirred at 125° C. for 18 hours. Upon cooling the reaction was purified on a silica column (DCM:MeOH:NH4OH) to afford 11-2. 1NMR (CD3OD): 7.96 ppm (s, 1H); 5.71 ppm (s, 1H); 3.53 ppm (t, 4H); 2.69 ppm (m, 2H); 2.58 ppm (m, 10H); 1.82 ppm (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]([NH2:17])=O)[CH:13]=2)[C:8]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:7]1.CCN(CC)CC.O(S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:28]=[C:29]([F:31])[CH:30]=1)[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([C:15]#[N:17])[CH:13]=2)[C:8]([S:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[N+:25]([O-:27])=[O:26])=[CH:7]1
Reactant: NC(=O)c1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: N#Cc1ccc2c(Sc3ccccc3[N+](=O)[O-])cn(Cc3cc(F)cc(F)c3)c2c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 90.7 %

Procedure:
To a cooled (0° C.) suspension of 1-(3,5-Difluoro-benzyl)-3-(2-nitro-phenylsulfanyl)-1H-indole-6-carboxylic acid amide (15 mg, 0.034 mmol) and Et3N (10 μL, 0.072 mmol) in CH2Cl2 (1.5 mL) was added Tf2O (13 μL, 0.077 mmol). The mixture was stirred at 0° C. for 2 h and then at room temperature for 20 h. Water (25 mL) was added and the mixture was extracted with CH2Cl2 (2×25 mL). The combined organic phases were dried (Na2SO4) and concentrated to give the title compound as a yellow solid (13 mg, yield: 91%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20].[Cl:21][C:22]1[CH:23]=[C:24]([NH2:35])[CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1.Cl.N1C=CC=CC=1>C(OCCO)C>[Cl:21][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:27]=1[S:28][C:29]1[N:30]([CH3:34])[CH:31]=[CH:32][N:33]=1)[NH:35][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][Cl:18])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:19]#[N:20]
Reactant: COc1cc2c(Cl)c(C#N)cnc2cc1OCCCCl
Reactant: Cn1ccnc1Sc1ccc(N)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCCO
Product: COc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1OCCCCl

Procedure:
A 2.0 g (6.43 mmol) portion of 4-chloro-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile (Boschelli, Diane H.; Ye, Fei; Wang, Yanong D.; Dutia, Minu; Johnson, Steve L.; Wu, Biqi; Miller, Karen; Powell, Dennis W.; Yaczko, Deanna; Young, Mairead; Tischler, Mark; Arndt, Kim; Discafani, Carolyn; Etienne, Carlo; Gibbons, Jay; Grod, Janet; Lucas, Judy; Weber, Jennifer M.; Boschelli, Frank. J. Med. Chem. 2001, 44, 3965-3977) in 2-ethoxyethanol (20 mL) is heated to 60° C. To this is added 1.7 g (7.10 mmol) of 3-chloro-4-(1-methyl-1H-imidazole-2-ylsulfanyl)phenylamine (U.S. Pat. No. 4,973,599) and 0.74 g (6.43 mmol) of pyridine hydrochloride, and the resulting mixture is refluxed for 2 hours. After cooling, the precipitated solid is filtered, washed with aqueous sodium bicarbonate and dried in vacuo to give 2.93 g of 4-{3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]anilino}-7-(3-chloropropoxy)-6-methoxy-3-quinolinecarbonitrile as a tan solid, mp 271-276° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5](O)=[O:6].C(Cl)(=O)C([Cl:16])=O>C(Cl)Cl.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:11][CH3:12])[CH:10]=1)[C:5]([Cl:16])=[O:6]
Reactant: COc1cc(F)cc(C(=O)O)c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(F)cc(C(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-fluoro-5-methoxybenzoic acid (5 g, 0.029 mol) was stirred in CH2Cl2 (50 ml) at 0° C. under an argon atmosphere. DMF (9 drops, catalytic) was added, followed by oxalyl chloride (12.7 ml, 0.147 mol). Reaction was warmed to room temperature then stirred under argon for one hour. Reaction was concentrated in vacuo to yield 3-fluoro-5-methoxybenzoyl chloride (BA67).
Reaction SMILES: [CH3:1][C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][C@:8]([CH2:14][CH2:15][CH2:16][C@@H:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH3:23])[CH3:18])([CH3:13])[O:9]2)=[C:4]([CH3:30])[C:3]=1[OH:31].[H-].[Na+].[H][H].CN(C)[CH:38]=[O:39]>>[O:39]1[CH2:38][CH2:10][O:9][CH:8]1[CH2:7][CH2:6][CH2:5][CH2:4][O:31][C:3]1[C:4]([CH3:30])=[C:5]2[C:10](=[C:11]([CH3:12])[C:2]=1[CH3:1])[O:9][C@:8]([CH3:13])([CH2:14][CH2:15][CH2:16][C@H:17]([CH3:18])[CH2:19][CH2:20][CH2:21][C@H:22]([CH3:23])[CH2:24][CH2:25][CH2:26][CH:27]([CH3:29])[CH3:28])[CH2:7][CH2:6]2
Reactant: [H][H]
Reactant: Cc1c(C)c2c(c(C)c1O)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Reactant: CN(C)C=O
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C)c2c(c(C)c1OCCCCC1OCCO1)CC[C@@](C)(CCC[C@H](C)CCC[C@H](C)CCCC(C)C)O2
Temperature: 25 °C
Reaction time: 1 h
Yield: 86 %

Procedure:
To a stirred solution of (+)-α-tocopherol (1.54 g, 3.6 mmol, 1.1 equiv.) in N,N-dimethylformamide (DMF, 30 mL) at 0° C. (ice/water bath) was added NaH (60% in mineral oil, 0.30 g, 7.5 mmol, 2.2 equiv.) in a single portion. After hydrogen gas was no longer being visibly evolved, the cooling bath was removed, and the mixture stirred at room temperature for 1 h. A solution of tosylated compound of Step 5 (crude from previous step, assumed 3.4 mmol, 1.0 equiv) in DMF (10 mL) was added to the reaction mixture at room temperature. The mixture was stirred at 80° C. for 20 h. Solvent was removed by coevaporation with PhMe (3×50 mL). The residue was taken up in EtOAc (250 mL). The solution was then washed with sat. aq. NaHCO3 (50 mL) and brine (50 mL). The combined aqueous fractions were extracted with EtOAc (2×50 mL). The combined organic fractions were then dried (MgSO4), filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica gel, pet ether to EtOAc:pet ether=1:9) to give the resulting compound (1.65 g, 3.0 mmol, 86% yield) as colorless oil. XX: 1H NMR (500 MHz, CDCl3) δ=4.93 (t, J=4.7 Hz, 1H), 4.05-3.94 (m, 2H), 3.92-3.84 (m, 2H), 3.68 (t, J=6.6 Hz, 2H), 2.60 (t, J=6.9 Hz, 2H), 2.20 (s, 3H), 2.16 (s, 3H), 2.12 (s, 3H), 1.93-1.05 (m, 29H), 1.27 (s, 3H), 0.97-0.83 (m, 12H) ppm; 13C NMR (125 MHz, CDCl3) δ=148.6, 147.8, 127.9, 125.9, 122.9, 117.6, 104.7, 74.8, 72.9, 65.0, 40.3, 39.6, 37.67, 37.65, 37.6, 37.5, 34.1, 33.0, 32.9, 31.5, 30.4, 28.2, 25.0, 24.6, 24.1, 22.9, 22.8, 21.2, 21.0, 20.8, 19.94, 19.85, 12.9, 12.03, 11.9 ppm; HRMS (ESI+ve) m/z: 559.4719 ([M+H]+); C36H63O4 requires 559.4721.