Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:30])[CH2:4][CH2:5][NH:6][C:7](=[O:29])[C:8]1[CH:13]=[CH:12][C:11]([CH:14]([S:19][C:20]2[CH:25]=[C:24]([CH3:26])[C:23](Br)=[C:22]([CH3:28])[CH:21]=2)[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:10][CH:9]=1.[C:31]([C:35]1[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([C:35]1[CH:40]=[CH:39][C:38]([C:23]2[C:24]([CH3:26])=[CH:25][C:20]([S:19][CH:14]([C:11]3[CH:10]=[CH:9][C:8]([C:7]([NH:6][CH2:5][CH2:4][C:3]([OH:2])=[O:30])=[O:29])=[CH:13][CH:12]=3)[CH2:15][CH:16]([CH3:17])[CH3:18])=[CH:21][C:22]=2[CH3:28])=[CH:37][CH:36]=1)([CH3:34])([CH3:33])[CH3:32]
Reactant: COC(=O)CCNC(=O)c1ccc(C(CC(C)C)Sc2cc(C)c(Br)c(C)c2)cc1
Reactant: CC(C)(C)c1ccc(B(O)O)cc1
Product: Cc1cc(SC(CC(C)C)c2ccc(C(=O)NCCC(=O)O)cc2)cc(C)c1-c1ccc(C(C)(C)C)cc1

Procedure:
The title compound is prepared in a manner substantially similar to Example 358 starting from 3-{4-[1-(4-bromo-3,5-dimethyl-phenylsulfanyl)-3-methyl-butyl]-benzoylamino}-propionic acid methyl ester and 4-tert-butyl phenyl boronic acid. MS: 530.2 [M−H]−.
Reaction SMILES: [ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[CH2:31][C:32]([NH:34][C:35]2[CH:40]=[CH:39][C:38]([F:41])=[CH:37][CH:36]=2)=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:27][CH2:26]O[CH2:24][CH2:23]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1.FC1C=C(N)C=CC=1O[C:51]1C2=C(C)C(OCCN3CCN(C)CC3)=CN2N=C[N:52]=1>>[ClH:1].[ClH:1].[F:2][C:3]1[CH:4]=[C:5]([NH:29][C:30](=[O:42])[CH2:31][C:32]([NH:34][C:35]2[CH:36]=[CH:37][C:38]([F:41])=[CH:39][CH:40]=2)=[O:33])[CH:6]=[CH:7][C:8]=1[O:9][C:10]1[C:15]2=[C:16]([CH3:28])[C:17]([O:19][CH2:20][CH2:21][N:22]3[CH2:23][CH2:24][N:52]([CH3:51])[CH2:26][CH2:27]3)=[CH:18][N:14]2[N:13]=[CH:12][N:11]=1
Reactant: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: Cc1c(OCCN2CCOCC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Agent: Cl
Product: Cc1c(OCCN2CCN(C)CC2)cn2ncnc(Oc3ccc(NC(=O)CC(=O)Nc4ccc(F)cc4)cc3F)c12
Yield: 46 %

Procedure:
Following a procedure similar to that for the synthesis of Compound D of Example 36, 3-fluoro-4-(5-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyrrolo[2,1-f][1,2,4]triazin-4-yloxy)benzenamine (60 mg, 0.15 mmol) was converted the title compound (30 mg, 46%) as a 2.HCl salt. 1H NMR (DMSO-d6) δ 10.63 (s, 1H), 10.37 (s, 1H), 8.04 (s, 1H), 7.99 (s, 1H), 7.80 (d, 1H), 7.61 (m, 2H), 7.40 (m, 2H), 7.16 (m, 2H), 4.42 (br s, 2H), 3.38-3.60 (m, 10H), 2.81 (s, 3H), 2.40 (s, 3H); ).
Reaction SMILES: C[O-].[Na+].[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[SH:10].[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.O>CO.Cl.CCCCCC>[CH3:4][C:5]1[O:6][CH:7]=[CH:8][C:9]=1[S:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Cc1occc1S
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCCCCC
Product: Cc1occc1SCc1ccccc1
Temperature: 25 °C

Procedure:
Into a 25 ml round bottom flask equipped with magnetic stirrer, thermometer, reflux condenser and heating mantle is placed a solution containing 0.27 g (0.005 moles) of sodium methoxide in 3 ml of absolute methanol. With stirring and while maintaining the temperature at 25° - 30° C, 0.57 g (0.005 moles) of 2-methyl-3-furan thiol in 3 ml absolute methanol is added. The reaction mass is stirred for a period of 10 minutes. 0.86 g of benzyl bromide dissolved in 2 ml absolute methanol is then added to the reaction mass with stirring at 25° C. The reaction mass is heated to reflux (50° - 60° C) and maintained at this temperature with stirring for a period of 4 hours. The reaction mass is then allowed to cool down to room temperature and is admixed with 10 ml of water with stirring. The reaction mass is neutralized to a pH of 5 - 6 with one drop of 10% hydrochloric acid and 5 ml hexane is added with stirring. The mass is then transferred to a separatory funnel and the organic and aqueous phases are separated. The aqueous phase is diluted with 5 ml water and extracted with 7 ml of n-hexane. The hexane extracts are combined, washed with 5 ml saturated sodium chloride, dried over anhydrous sodium sulfate, and gravity filtered. The resulting solution is then concentrated to an amber oil using rotary evaporation under a water aspirator vacuum. NMR, IR and Mass Spectral analyses confirm that the major product isolated by GLC trapping has the structure: ##SPC23##
Reaction SMILES: [C:1]([CH2:6][CH:7]1[CH:11]([CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH2:10][CH2:9][C:8]1=O)([O:3][CH2:4][CH3:5])=[O:2].[CH2:21]([OH:24])[CH2:22]O.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C1C=CC=CC=1>O>[C:1]([CH2:6][CH:7]1[O:24][CH:21]2[CH2:22][CH2:8][CH2:9][CH:10]2[CH:11]1/[CH:12]=[CH:13]/[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])([O:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCCCC=CC1CCC(=O)C1CC(=O)OCC
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCCCC/C=C/C1C(CC(=O)OCC)OC2CCCC21

Procedure:
A mixture of 10.142 g. (0.0362 mole) of 2-(carbethoxymethyl)-3-(1-octenyl)cyclopentanone (ethyl 9-oxo-3,4,5,6,7-pentanor-13-trans-prostenoate, Example 63), 3.49 g. (0.0562 mole) of ethylene glycol, 0.344 g. of p-toluenesulfonic acid monohydrate, and 30 ml. of benzene is refluxed for 4.5 hours with azeotropic removal of water. The mixture is cooled, placed onto a column of 130 g. of Florisil in benzene and the ketal is eluted off with benzene. The filtrate is evaporated to yield 9.53 g. of a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](=[O:35])[NH:31][CH:32]4[CH2:34][CH2:33]4)[C:23]=3[CH:22]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH:15]2[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]2)=[O:14])=[N:6][CH:7]=1.C=O.[C:38](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CO>[Cl:1][C:2]1[C:3]([C:21]2[S:25][C:24]3[CH:26]=[CH:27][CH:28]=[C:29]([C:30](=[O:35])[NH:31][CH:32]4[CH2:34][CH2:33]4)[C:23]=3[CH:22]=2)=[N:4][C:5]([NH:8][CH2:9][CH2:10][CH2:11][NH:12][C:13]([CH:15]2[CH2:16][CH2:17][N:18]([CH3:38])[CH2:19][CH2:20]2)=[O:14])=[N:6][CH:7]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(NCCCNC(=O)C4CCNCC4)ncc3Cl)cc12
Agent: C=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CO
Product: CN1CCC(C(=O)NCCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Yield: 16.9 %

Procedure:
A stirred suspension of piperidine-4-carboxylic acid {3-[5-chloro-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-propyl}-amide (231 mg, 0.450 mmol) in 1,2-dichloroethane (3 mL) and methanol (3 mL) is treated at room temperature with aqueous 37% formaldehyde (0.200 mL, 3.02 mmol) in the presence of sodium triacetoxyborohydride (165 mg, 0.779 mmol) for 24 hours. The mixture is then concentrated under reduced pressure, and subjected to chromatographic purification on silica gel, eluting with 2 M NH3/MeOH in dichloromethane: 8-15%, to provide the title compound (40 mg, 17% yield). ES+(m/z) 527 (35Cl) and 529 (37Cl) [M+H].
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:48][O:47][CH2:46]6)[CH2:41][C@@H:40]5[CH3:49])=[CH:35][N:34]=4)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=3)[C:18]=1[CH:19]=[O:20])[N:9]=[CH:8]2)([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+]>CO>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[C:13]([F:15])[CH:14]=1)[C:11](=[O:16])[N:10]([C:17]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([C:26]3[CH:31]=[C:30]([NH:32][C:33]4[CH:38]=[CH:37][C:36]([N:39]5[CH2:44][CH2:43][N:42]([CH:45]6[CH2:46][O:47][CH2:48]6)[CH2:41][C@@H:40]5[CH3:49])=[CH:35][N:34]=4)[C:29](=[O:50])[N:28]([CH3:51])[CH:27]=3)[C:18]=1[CH2:19][OH:20])[N:9]=[CH:8]2)([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3C=O)cn(C)c2=O)nc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(-c3cc(F)cc(-n4ncc5cc(C(C)(C)C)cc(F)c5c4=O)c3CO)cn(C)c2=O)nc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.9 %

Procedure:
A mixture of (S)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)-4-fluoro-6-(1-methyl-5-(5-(2-methyl-4-(oxetan-3-yl)piperazin-1-yl)pyridin-2-ylamino)-6-oxo-1,6-dihydropyridin-3-yl)benzaldehyde 104a (80 mg, 0.12 mmol), NaBH4 (14 mg, 0.36), and methanol (20 mL) was stirred at 25° C. for 1 h. Then the reaction mixture was quenched with water (10 mL) and concentrated under reduced pressure. The residue was extracted with dichloromethane (2×30 mL) and the combined dichloromethane extract was concentrated under reduced pressure. The residue was purified by reverse-phase prep-HPLC to afford 104 (46 mg, 55%) as a yellow solid. MS: [M+H]+ 698.3. 1H NMR (500 MHz, DMSO-d6) δ 8.54 (d, J=2.0 Hz, 1H), 8.52 (d, J=2.0 Hz, 1H), 8.42 (s, 1H), 7.88 (s, 1H), 7.86 (d, J=3.0 Hz, 1H), 7.77-7.74 (m, 1H), 7.40-7.34 (m, 3H), 7.30 (dd, J=2.5, 9.5 Hz, 1H), 7.23 (d, J=9.0 Hz, 1H), 4.57-4.54 (m, 2H), 4.49-4.45 (m, 1H), 4.43-4.40 (m, 1H), 4.34-4.29 (m, 2H), 3.70-3.65 (m, 1H), 3.58 (s, 3H), 3.40-3.38 (m, 2H), 3.12-3.06 (m, 1H), 2.97-2.91 (m, 1H), 2.36-2.29 (m, 3H), 2.19-2.15 (m, 1H), 1.38 (s, 9H), 0.93 (d, J=6.5 Hz, 3H),
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[O:8][C:7]([CH3:10])([CH3:9])[O:6][C@@H:5]([CH2:11][C:12]([O:14]C(C)(C)C)=O)[CH2:4]1.[CH2:19]([NH2:23])[CH2:20][CH2:21][CH3:22].[Na].CC(C)([O-])C>CO>[CH2:19]([NH:23][C:12](=[O:14])[CH2:11][C@H:5]1[CH2:4][C@@H:3]([CH2:2][OH:1])[O:8][C:7]([CH3:9])([CH3:10])[O:6]1)[CH2:20][CH2:21][CH3:22]
Reactant: CCCCN
Reactant: CC(C)(C)OC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Agent: CC(C)(C)[O-]
Agent: [Na]
Solvent: CO
Product: CCCCNC(=O)C[C@H]1C[C@@H](CO)OC(C)(C)O1
Temperature: 42.5 °C

Procedure:
Mixture of tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate (100 grams), methanol (1 L), n-butyl amine (200 ml) and sodium, tertiary butoxide (74 grams) was heated to 40-45° C. and stirred up to completion of the reaction. Distilled off the reaction mixture completely under reduced pressure and water (300 ml) was added to it at 25-30° C. The reaction mixture was cooled and acidified with aqueous acetic acid. The reaction mixture washed with cyclohexane and product from aqueous layer was extracted into methylene chloride. The organic layer was washed with saturated sodium chloride solution and the solvent from it was distilled off under reduced pressure to get the title compound.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:13]([SH:16])[CH2:14][SH:15]>C1(C)C=CC=CC=1>[C:1]([O:9][CH2:10][CH:11]1[S:16][CH2:13][CH2:14][S:15]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCS
Reactant: O=CCOC(=O)c1ccccc1
Solvent: Cc1ccccc1
Product: O=C(OCC1SCCS1)c1ccccc1
Temperature: 25 °C

Procedure:
A mixture of 2-benzoyloxyacetaldehyde (example (5.65 g), 1,2-ethanedithiol (3 ml) and paratoluenesulfonic acid (200 mg) in toluene (250 ml) was heated at refluxing under water removal conditions using a Dean Stark apparatus for 4 hours. The mixture was cooled to room temperature, washed first with saturated aqueous NaHCO3 solution (1×60 ml), then with water (2×60 ml), and dried over reduced pressure. The residue was purified by chromatography on silica gel using hexane:ethyl acetate (9:1) as eluant to give 5.2 g of pure product which was characterized by 1H- and 13C-NMR spectroscopy.
Reaction SMILES: CO[C:3]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:4]=1[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[CH2:18]([Mg]Cl)[CH2:19][CH3:20].CCOCC.C(O)(=O)C>C1COCC1.O>[CH3:17][O:16][C:15]1[C:3]([CH2:18][CH2:19][CH3:20])=[C:4]([CH:12]=[CH:13][CH:14]=1)[C:5]([O:7][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:6]
Reactant: COc1cccc(C(=O)OC(C)(C)C)c1OC
Reactant: CCC[Mg]Cl
Solvent: O
Solvent: CC(=O)O
Solvent: CCOCC
Product: CCCc1c(OC)cccc1C(=O)OC(C)(C)C
Temperature: -12 °C
Reaction time: 3.5 h

Procedure:
To a chilled solution (−34° C.) of tert-butyl 2,3-dimethoxybenzoate (171 g, 718 mmol) in THF (855 mL) add 2 M propylmagnesium chloride in ether (448.5 mL, 897 mmol) dropwise at a rate sufficient to keep the internal temperature below −10° C. Stir the mixture 3.5 h maintaining the temperature near −12° C. Add acetic acid (51.4 mL) dropwise to the mixture while maintaining the temperature below −10° C. and then dilute with water (340 mL). Separate the phases and extract the aqueous phase with methyl-tert-butylether (3×100 mL). Wash the combined organic extracts with brine and concentrate the organic phase in vacuo to yield the title compound (190 g, quantitative) as a colorless oil containing traces of THF and methyl-tert-butylether. 1H NMR (300 MHz, CDCl3) δ 7.24-7.14 (m, 2H), 6.93 (dd, J=1.4, 8.0 Hz, 1H), 3.82 (s, 3H), 2.84-2.79 (m, 2H), 1.59 (m, 11H), 0.97 (t, J=7.4 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[CH:3]([C:28]1[CH:33]=[C:32]([Cl:34])[C:31]([Cl:35])=[C:30]([Cl:36])[CH:29]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][N:17]2C(=O)C3C(=CC=CC=3)C2=O)=[CH:8][CH:7]=1.O.NN>CCO>[F:38][C:2]([F:1])([F:37])[CH:3]([C:28]1[CH:29]=[C:30]([Cl:36])[C:31]([Cl:35])=[C:32]([Cl:34])[CH:33]=1)/[CH:4]=[CH:5]/[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][NH2:17])=[CH:8][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1ccc(/C=C/C(c2cc(Cl)c(Cl)c(Cl)c2)C(F)(F)F)c2ccccc12
Temperature: 80 °C

Procedure:
To a stirred solution of (E)-2-((4-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-en-1-yl)naphthalen-1-yl)methyl)isoindoline-1,3-dione (CI.4 g, 0.7 mmol) in EtOH was added hydrazine hydrate (0.18 g, 3.5 mmol), and the resultant reaction mixture was heated at 80° C. for 2 h. The reaction mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2, and the solution was washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The title compound was isolated as a gummy liquid (150 mg, 50%). The product obtained in this reaction was carried on to the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[F:17][C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20]([C:19]([F:24])([F:23])[C:18]([F:26])([F:25])[F:17])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: O=C(O)C(F)(F)C(F)(F)F
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Product: N#Cc1ccccc1-c1ccc2[nH]c(C(F)(F)C(F)(F)F)nc2c1
Temperature: 115 °C

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (9.6 mmoles, 2.0 g) was dissolved in 40 ml of pentafluoropropionic acid and heated at 115° C. for 20 hours. After cooling, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was added slowly to saturated sodium bicarbonate. The intermediate was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed over silica gel eluted with 25% ethyl acetate in hexane to yield 1.1 g of 5-(2-cyanophenyl)-2-pentafluoroethyl-1H-benzimidazole. (MS).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]([CH3:12])=[C:6]2[CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16].C[Si]([N-][Si](C)(C)C)(C)C.[K+].[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39]Br)=[CH:37][CH:36]=1.Cl>C1COCC1>[Br:34][C:35]1[CH:42]=[CH:41][C:38]([CH2:39][N:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[C:6]([CH:13]([C:20]([F:23])([F:22])[F:21])[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])=[C:7]2[CH3:12])=[CH:37][CH:36]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: CCOC(=O)CC(c1c(C)[nH]c2ccc(OC)cc12)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)CC(c1c(C)n(Cc2ccc(Br)cc2)c2ccc(OC)cc12)C(F)(F)F
Temperature: 0 °C
Yield: 64 %

Procedure:
To a -78° C. solution of the indole from Step 3 (3.1 g, 9.4 mmol) in 65 mL of THF was added KHMDS (0.6M toluene solution, 18.8 mL, 11.3 mmol) dropwise. The solution was warmed to 0° C., then cooled to -78° C. A solution of p-bromobenzyl bromide (3.0 g, 12.2 mmol) was then added, and the solution was allowed to warm to room temperature. The solution was then poured into 1M HCl and extracted with ether. The organic extracts were washed with brine, dried over MgSO4 and evaporated. The residue was purified by flash chromatography (20% ethyl acetate/hexanes) to provide 3.0 g of the title compound.
Reaction SMILES: [CH3:1][C:2](=[CH2:20])[CH2:3][O:4][C@H:5]([C@@H:10]([O:15][CH2:16][C:17]([CH3:19])=[CH2:18])[C:11](OC)=[O:12])[C:6](OC)=[O:7].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:20][C:2](=[CH2:1])[CH2:3][O:4][C@H:5]([C@@H:10]([O:15][CH2:16][C:17]([CH3:19])=[CH2:18])[CH2:11][OH:12])[CH2:6][OH:7]
Reactant: C=C(C)CO[C@@H](C(=O)OC)[C@@H](OCC(=C)C)C(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)CO[C@@H](CO)[C@H](CO)OCC(=C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 92 %

Procedure:
To a solution of (2R,3R)-dimethyl 2,3-bis((2-methylallyl)oxy)succinate (14.7 g, 51.3 mmol) in THF (130 mL) at 0° C. was added slowly a 1.0 M solution of LAH in THF (257 mL, 257 mmol). The mixture was warmed to room temperature and stirred for 2 h, carefully quenched by the addition of EtOAc at 0° C., and then treated with a saturated aqueous solution of potassium sodium tartrate (Rochelle's salt). The phases were separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc gradient) to yield the title compound as a colorless oil (10.87 g, 92%): IR (neat) 3388, 2918, 2880, 1656, 1452, 1046 cm−1; 1H NMR (400 MHz, CDCl3) δ 4.98 (s, 2H), 4.90 (s, 2H), 4.03 (s, 4H), 3.81 (d, J=11.7 Hz, 2H), 3.71 (d, J=11.9 Hz, 2H), 3.64-3.59 (m, 2H), 2.57-2.47 (m, 2H), 1.75 (s, 6H); 13C NMR (101 MHz, CDCl3) δ 142.16, 112.85, 78.75, 74.52, 60.85, 19.68; HRMS-ESI (m/z) [M]+ calcd for C12H22O4, 230.1518; found, 230.1519.
Reaction SMILES: Cl[C:2]1[C:8]2[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=2[S:6][C:5]2[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=2[N:3]=1.[NH:21]1[CH2:26][CH2:25][O:24][CH2:23][CH2:22]1>C(#N)C>[O:24]1[CH2:25][CH2:26][N:21]([C:2]2[C:8]3[CH:9]=[CH:10][C:11]([C:13]([O:15][CH3:16])=[O:14])=[CH:12][C:7]=3[S:6][C:5]3[CH:17]=[CH:18][CH:19]=[CH:20][C:4]=3[N:3]=2)[CH2:22][CH2:23]1
Reactant: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2Cl
Reactant: C1COCCN1
Solvent: CC#N
Product: COC(=O)c1ccc2c(c1)Sc1ccccc1N=C2N1CCOCC1

Procedure:
Reflux a mixture of 3.035 gm. (10 mmole) of the 11-chloro ester of Example 6, 2.61 mg. (30 mmmole) of morpholine and 30 ml. of dry acetonitrile under an argon atmosphere for 40 hours. Add 50 ml. of ice-water to the reaction mixture and extract twice with 50 ml. portions of ethyl acetate. Wash the combined extracts with 50 ml. of water and then with 50 ml. of saturated aqueous sodium chloride solution. Dry over magnesium sulfate and evaporate. Chromatograph the residue over silica gel eluting with 1:9 ethyl acetate in toluene. Recrystallize from diisopropyl ether to obtain the title product, (m.p. 114°-115° C.).
Reaction SMILES: [C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17](Br)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2].[CH3:23][C:24]1[CH:25]=[C:26]([SH:30])[CH:27]=[CH:28][CH:29]=1.C(N(CC)CC)C.N#N>>[C:1]([C:3]1[CH:22]=[CH:21][C:6]([CH2:7][C:8]2[N:12]([CH2:13][C:14]3[CH:15]=[CH:16][C:17]([S:30][C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([CH3:23])[CH:25]=4)=[N:18][CH:19]=3)[CH:11]=[N:10][CH:9]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cccc(S)c1
Reactant: N#Cc1ccc(Cc2cncn2Cc2ccc(Br)nc2)cc1
Agent: N#N
Solvent: CCN(CC)CC
Product: Cc1cccc(Sc2ccc(Cn3cncc3Cc3ccc(C#N)cc3)cn2)c1
Temperature: 105 °C

Procedure:
The compound from Step 3 (0.28 mmol, 0.164 g), 3-methyl thiophenol (0.85 mmol, 0.106 g) and triethylamine (3.59 mmol, 0.36 g) were placed in an N2 purged sealed tube. This was heated at 105° C. for 15 hr. The residue was dissolved in methanol and purified on a C18 preperative hplc column. Lyophilized from dioxane/HCl to provide the title compound. FAB-MS: calc: 396.4 found: 397.2 1H-NMR (CD3OD): 2.4 ppm (s, 3H); 4.2 ppm (s, 2H); 5.4 ppm (s, 2H); 7.2-7.6 ppm (1OH); 8.1 ppm (s, 1H); 9.1 ppm (s, 1H).
Reaction SMILES: [ClH:1].[CH3:2][N:3]([CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9]#[N:10].[CH2:18]([OH:20])[CH3:19]>>[ClH:1].[CH3:2][N:3]([CH3:17])[CH2:4][CH2:5][O:6][C:7]1[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:8]=1[C:9](=[NH:10])[O:20][CH2:18][CH3:19]
Reactant: COc1ccc(C#N)c(OCCN(C)C)c1
Reactant: CCO
Agent: Cl
Product: CCOC(=N)c1ccc(OC)cc1OCCN(C)C
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 96 %

Procedure:
Hydrogen chloride gas was passed through a solution of 2-(2-dimethylamino-ethoxy)-4-methoxy-benzonitrile (200 mg, 0.908 mmol) in anhydrous ethanol (10 mL) at 0° C. After 45 min, hydrogen chloride gas was stopped and the reaction vessel was sealed with a septum. After stirring at room temperature for 3 d, the reaction vessel was cooled to 0° C. and the septum was removed. The solvent was removed in vacuo to afford ethyl 2-(2-dimethylamino-ethoxy)-4-methoxy-benzimidate hydrochloride as a pale-yellow foam (310 mg, 96%). It was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[C:5]([NH:7][C:8]1[C:9](=[C:13]([Cl:17])[CH:14]=[CH:15][CH:16]=1)[C:10]([OH:12])=[O:11])=O.C(OC(=O)C)(=O)C>>[F:1][C:2]1[CH:3]=[C:4]([C:5]2[O:11][C:10](=[O:12])[C:9]3[C:13]([Cl:17])=[CH:14][CH:15]=[CH:16][C:8]=3[N:7]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: O=C(Nc1cccc(Cl)c1C(=O)O)c1cccc(F)c1
Solvent: CC(=O)OC(C)=O
Product: O=c1oc(-c2cccc(F)c2)nc2cccc(Cl)c12
Yield: 86.7 %

Procedure:
29 parts of N-(3'-fluorobenzoyl)-6-chloroanthranilic acid in 250 parts of acetic anhydride are stirred under reflux for 21/2 hours. The mixture is evaporated down under reduced pressure, the residue is taken up in methylene chloride and this solution is washed with twice 100 parts by volume of 0.5 N sodium hydroxide solution and then with water. Thereafter, the solution is chromatographed on neutral alumina, giving 23.6 parts of 2-(3'-fluorophenyl)-5-chloro-4H-3,1-benzoxazin-4-one, of melting point 123°-125° C.; yield: 86.7% of theory.