Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]([S:8][CH:9](O)[C:10]([O:12][CH3:13])=[O:11])(O)[C:3]([O:5]C)=O.C(OC)(=O)[C:16](OC)=[O:17].[Na]>CO>[OH:17][C:16]1[C:3]([OH:5])=[C:2]([CH3:1])[S:8][C:9]=1[C:10]([O:12][CH3:13])=[O:11]
Reactant: COC(=O)C(O)SC(C)(O)C(=O)OC
Reactant: COC(=O)C(=O)OC
Agent: [Na]
Solvent: CO
Product: COC(=O)c1sc(C)c(O)c1O
Yield: 68.2 %

Procedure:
A mixture of dimethyl α-methyl-thiodiglycolate (Solladie-Cavallo, Bull. Soc. Chim. Fr., 437 (1968)) (10.2 g, 53 mmoles) and dimethyl oxalate (9.4 g, 79 mmoles) in methanol (25 mL) is added slowly to a solution of sodium (3.8 g, 165 mmoles) in methanol (35 mL) under argon and maintained at 10°-15° C. with an ice bath. After the addition, the mixture is slowly heated to reflux for 1 hour, then cooled and concentrated under reduced pressure. The precipitate is filtered off, rinsed with ether, air dried, dissolved in water and acidified with 4N hydrochloric acid. The precipitate is filtered off, rinsed with water and dried to afford the product (6.8 g); mp 116°-117° C.
Reaction SMILES: S(=O)(=O)(O)[OH:2].[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:8]=1[CH2:9][C:10]#N.[OH2:18]>>[CH3:6][C:7]1[CH:15]=[C:14]([CH3:16])[C:13]([CH3:17])=[CH:12][C:8]=1[CH2:9][C:10]([OH:2])=[O:18]
Reactant: Cc1cc(C)c(CC#N)cc1C
Reactant: O=S(=O)(O)O
Reactant: O
Product: Cc1cc(C)c(CC(=O)O)cc1C
Temperature: 90 °C
Reaction time: 8 h
Yield: 90 %

Procedure:
2118 ml of concentrated sulphuric acid are added dropwise to 2662 ml of water at room temperature and the solution is heated to 90° C. 355 g (2.23 mol) of 2,4,5-trimethyl-benzyl cyanide are metered into the half-concentrated sulphuric acid at this temperature and the mixture is subsequently stirred at 100° C. for 8 hours. After cooling, the reaction mixture is poured into ice-water, while stirring vigorously, and filtered with suction. The solid is washed several times with water and then with petroleum ether and dried. 358 g (90% of theory) of 2,4,5-trimethylphenylacetic acid having a melting point of 123-125° C. are obtained.
Reaction SMILES: Cl.[O:2]([NH2:4])[CH3:3].[F:5][C:6]([F:17])([F:16])[C:7]1[CH:8]=[C:9]([C:13](=O)[CH3:14])[CH:10]=[CH:11][CH:12]=1>C(O)C.N1C=CC=CC=1>[CH3:3][O:2][N:4]=[C:13]([C:9]1[CH:10]=[CH:11][CH:12]=[C:7]([C:6]([F:5])([F:16])[F:17])[CH:8]=1)[CH3:14]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: CON
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CON=C(C)c1cccc(C(F)(F)F)c1
Yield: 93 %

Procedure:
Methoxylamine hydrochloride (2.33 g) is added to a solution of 3′-(trifluoromethyl)-acetophenone (1.5 g) in ethanol (20 mL) and pyridine (2 mL). The solution is heated at reflux for 45 minutes. The reaction mixture is then cooled, concentrated under reduced pressure and partitioned between water and ethyl acetate. The aqueous layer is extracted with ethyl acetate. The combined organic layers are washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give the desired product as a colorless oil (1.61 g).
Reaction SMILES: C(C[C:4]([O:6][CH2:7]C)=[O:5])#N.C[O-:10].[Na+].[CH2:12]([O:14][CH:15]=[CH:16][C:17](=O)[CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[CH3:13].Cl.C>C(OCC)(=O)C>[CH3:7][O:6][C:4]([C:18]1[C:19](=[O:20])[O:21][C:22]([CH3:23])=[C:16]([C:15]([O:14][CH2:12][CH3:13])=[O:10])[CH:17]=1)=[O:5]
Reactant: C[O-]
Reactant: CCOC(=O)CC#N
Reactant: CCOC=CC(=O)CC(=O)OCC
Agent: C
Agent: Cl
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cc(C(=O)OC)c(=O)oc1C
Yield: 6 %

Procedure:
Using the procedure described by Baker et al., Journ. of Chem. Soc. Perkin Trans. 1, 3, 677-685 (1979), ethyl cyanoacetate (3.5 g, 0.031 mol) was added to NaOMe solution (prepared from 0.72 g of sodium metal in 50 ml of MeOH), followed by 1 (5.77 g, 0.031 mol). The mixture was refluxed for 15 minutes, cooled and divided into two equal parts. The first portion was acidified with 2N HCl to pH 2-3 and extracted with CH2Cl2. The extracts were washed, dried over MgSO4, and evaporated to give an orange-colored solid. After decolorizing with Nuchar activated carbon in ethyl acetate and recrystallizing from EtOAc-hexane, white, fluffy crystals, of 3-(methoxycarbonyl)-5-(ethoxycarbonyl)-6-methyl-2-pyrone were obtained: 0.22 g, 6% yield; mp=94°-96° C.; NMR (DMSO-d6) δ 1.2-1.5 (t, 3H), 2.7 (s, 3H), 3.8 (s, 3H), 4.1-4.6 (q, 2H), 8.5 (s, 1H); IR (KBr) 1700-1730 cm-1 (C=O of Me and Et ester), 1770 cm-1 (C=O of pyrone).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12](OS(C(F)(F)F)(=O)=O)=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]1.[SH:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:30].C(N(C(C)C)C(C)C)C.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([S:26][CH2:27][CH2:28][C:29]([O:31][CH2:32][CH:33]([CH2:38][CH3:39])[CH2:34][CH2:35][CH2:36][CH3:37])=[O:30])=[CH:11][C:10]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:9]1
Reactant: CCCCC(CC)COC(=O)CCS
Reactant: CCOC(=O)c1cc(OS(=O)(=O)C(F)(F)F)n(-c2ccccc2Cl)n1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCCCC(CC)COC(=O)CCSc1cc(C(=O)OCC)nn1-c1ccccc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
A solution of ethyl 1-(2-chlorophenyl)-5-{[(trifluoromethyl)sulfonyl]oxy}-1H-pyrazole-3-carboxylate (2.85 g), 2-ethylhexyl 3-mercaptopropionate (2.34 g) and N-ethyldiisopropylamine (1.85 g) in toluene (30 mL) was sufficiently deaerated, tris(dibenzylideneacetone)dipalladium (0) (327 mg) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (414 mg) were added, and the mixture was further deaerated. Under an argon atmosphere, the reaction mixture was stirred at 110° C. for 4 hr, and allowed to cool to room temperature. Water was added, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate=19:1→7:1) to give the title compound as a yellow oil (yield 2.87 g, yield 86%).
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[NH:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=P(Cl)(Cl)[Cl:22].CCN(C(C)C)C(C)C>ClCCCl>[CH2:1]([S:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:22])=[N:14][CH:15]=[N:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1[nH]cnc2cc(SCc3ccccc3)ccc12
Reactant: O=P(Cl)(Cl)Cl
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: Clc1ncnc2cc(SCc3ccccc3)ccc12
Reaction time: 2 h

Procedure:
A flask was charged with 7-(benzylthio)quinazolin-4(3H)-one (5.0 g, 18.63 mmol) and DCE (93 ml). POCl3 (5.21 ml, 55.9 mmol) was added, followed by Hunig's base (16.27 ml, 93 mmol). The flask was fitted with a reflux condensor, and the reaction was for two hours at 90° C. The reaction was washed with water and the layers were separated. The aqueous layer was extracted with ethyl acetate, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated. The material was purified via column chromatography (RediSep Gold 80 g, gradient elution 0-75% EtOAc:Heptane) to afford 7-(benzylthio)-4-chloroquinazoline as a light yellow solid. (ESI) 287.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22]O)=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].S(Cl)([Cl:26])=O>C1(C)C=CC=CC=1>[CH2:1]([O:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][Cl:26])=[CH:18][CH:17]=2)=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: O=S(Cl)Cl
Reactant: CCCCCCCCOc1ccc(-c2ccc(CO)cc2)cc1
Solvent: Cc1ccccc1
Product: CCCCCCCCOc1ccc(-c2ccc(CCl)cc2)cc1
Temperature: 70 °C
Reaction time: 8 h

Procedure:
A mixture of 30 g of 4'-octyloxy-4-formylbiphenyl, 2.0 g of sodium borohydride and 300 ml of isopropanol was stirred on a water bath maintained at 70° C. for 3 hours. 20 ml of 6 N hydrochloric acid and 10 ml of water were added, and the resulting mixture was stirred for 2 hours. The reaction mixture was allowed to cool and filtered to collect solids. These solids were recrystallized from 300 ml of ethanol to obtain 30 g of 4'-octyloxy-4-hydroxymethyl-biphenyl. The total of 4'-octyloxy-4-hydroxymethyl-biphenyl, 100 ml of toluene and 40 g of thionyl chloride were uniformly mixed and allowed to stand overnight at room temperature. Then, the mixture was heated for 30 minutes on a water bath maintained at 70° C. After being allowed to cool, the mixture was poured into ice water and then extracted with 300 ml of toluene. The extract was washed with saturated saline water, with a saturated aqueous sodium hydrogen-carbonate and further with saturated saline water to make it neutral. Then, the extract was dried over anhydrous magnesium sulfate, concentrated and then recrystallized from 300 ml of ethanol to obtain 26 g of 4'-octyloxy-4-chloromethyl-biphenyl having a melting point of 97.3 to 98.0° C. Analysis of the compound by HPLC showed that the purity was 99.6%. (ii) Preparation of Objective Compound
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][N:3]=1.C1(C)C=CC=CC=1.CCO.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][C:25]=1[CH3:26].C([O-])([O-])=O.[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:1][C:2]1[CH:7]=[C:6]([C:22]2[CH:23]=[CH:24][C:25]([CH3:26])=[C:20]([F:19])[CH:21]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1cc(Br)ccn1
Reactant: Cc1ccc(B(O)O)cc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Solvent: Cc1ccccc1
Product: Cc1ccc(-c2ccnc(Cl)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a vial was added 2-chloro-4-bromopyridine (96 mg, 0.5 mmol), Pd(PPh3)4 (30 mg), and toluene/EtOH (4:1, 3 mL). After stirring at room temperature for 5 min, 3-fluoro-4-methylphenylboronic acid (115 mg, 0.75 mmol) and 2 M aqueous K2CO3 (1 mL) were added, and the resulting mixture was heated at 90° C. for 16 h. The resulting mixture was poured into water and extracted with EtOAc. The organic layer was dried and concentrated, and the residue was purified by preparative TLC (hexanes/EtOAc) to yield 2-chloro-4-(3-fluoro-4-methyl-phenyl)-pyridine as a solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)=[CH:14][CH:13]=1
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: O=[N+]([O-])c1ccc(Br)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccc(Cl)cc2)nc1
Temperature: 100 °C
Yield: 103.8 %

Procedure:
A flask was charged with 2-bromo-5-nitropyridine (4 g, 19.71 mmol), 4-chlorophenylboronic acid (4.54 g, 27.6 mmol), Pd(PPh3)4 (1.139 g, 0.985 mmol), potassium carbonate (8.16 g, 59.1 mmol), dioxane (40 ml) and water (20 ml) at room temperature. The flask was sealed, flushed with nitrogen for three times and heated at 100° C. for 3 hours. The reaction mixture was diluted with EtOAc (100 ml) and filtered. The filtrate was concentrated. The residue was washed with water by filtration. The afforded solid was dissolved in EtOAc (200 ml) and washed with saturated aqueous sodium bicarbonate solution and brine, dried over Na2SO4, concentrated, and dried under vacuum to afford crude 2-(4-chlorophenyl)-5-nitropyridine (4.8 g, 75% purity, 78% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) ppm 7.27-7.36 (m, 4H) 7.51-7.61 (m, 3H).
Reaction SMILES: [C:1]1([C:7]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[N:8]2[CH:12]=[C:11]([CH:13]=[CH:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:17][CH2:16]3)[N:10]=[CH:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CO.[H][H].[Pd]>[C:33]1([C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=4)[CH2:17][CH2:16]3)[N:10]=[CH:9]2)[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: [H][H]
Reactant: C(=CC1CCN(c2ccccc2)CC1)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: [Pd]
Solvent: CO
Product: c1ccc(N2CCC(CCc3cn(C(c4ccccc4)(c4ccccc4)c4ccccc4)cn3)CC2)cc1

Procedure:
The product from Step E is dissolved in methanol and hydrogenated at 60 psi hydrogen with 10% palladium on carbon. When reaction is complete, the catalyst is filtered and the title compound obtained after evaporation of solvent.
Reaction SMILES: [NH2:1][C:2]1[C:44]([NH2:45])=[CH:43][CH:42]=[CH:41][C:3]=1[C:4]([NH:6][C:7]1[CH:38]=[CH:37][C:10]([C:11]([N:13]([CH3:36])[C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=2[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[O:28])=[O:12])=[CH:9][C:8]=1[O:39][CH3:40])=[O:5].[C:46](O)(=O)[CH3:47]>>[CH3:40][O:39][C:8]1[CH:9]=[C:10]([CH:37]=[CH:38][C:7]=1[NH:6][C:4]([C:3]1[C:2]2[N:1]=[C:46]([CH3:47])[NH:45][C:44]=2[CH:43]=[CH:42][CH:41]=1)=[O:5])[C:11]([N:13]([CH3:36])[C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[O:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][C:27]([N:29]1[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]1)=[O:28])=[O:12]
Reactant: CC(=O)O
Reactant: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc(N)c1N
Product: COc1cc(C(=O)N(C)c2ccc(C)cc2OCCCCCC(=O)N2CCN(C)CC2)ccc1NC(=O)c1cccc2[nH]c(C)nc12

Procedure:
A suspension of 4-(2,3-diaminobenzoyl)amino-3-methoxy-N-methyl-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (100 mg) in acetic acid (1 ml) was refluxed for 8 hours. After being evaporated in vacuo, the residue was dissolved chloroform and the solution was washed with water and saturated aqueous sodium bicarbonate solution. The organic layer was dried over magnesium sulfate and the solvent was evaporated in vacuo. The residue was purified by preparative thin-layer chromatography (chloroform-methanol=10:1) to give 3-methoxy-N-methyl-4-(2-methyl-1H-benzimidazol-4-yl)carbonylamino-N-[4-methyl-2-[5-(4-methylpiperazin-1-yl)carbonylpent-1-yloxy]phenyl]benzamide (84 mg) as a powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[S:17][C:18]([CH:21]([C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([Cl:32])[CH:30]=3)[N:25]([Si](C(C)C)(C(C)C)C(C)C)[CH:24]=2)O)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].FC(F)(F)C(O)=O.C([SiH](CC)CC)C>C(#N)C>[C:1]([O:5][C:6](=[O:43])[N:7]([C:16]1[S:17][C:18]([CH2:21][C:23]2[C:31]3[C:26](=[N:27][CH:28]=[C:29]([Cl:32])[CH:30]=3)[NH:25][CH:24]=2)=[CH:19][N:20]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(C(O)c2cnc(N(Cc3ccc(F)cc3)C(=O)OC(C)(C)C)s2)c2cc(Cl)cnc21
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)OC(=O)N(Cc1ccc(F)cc1)c1ncc(Cc2c[nH]c3ncc(Cl)cc23)s1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
To a solution of {5-[(5-chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-hydroxy-methyl]-thiazol-2-yl}-(4-fluoro-benzyl)-carbamic acid tert-butyl ester (627, 120 mg, 0.186 mmol) in acetonitrile (3 mL) was added trifluoroacetic acid (0.14 mL, 1.86 mmol) and triethylsilane (0.30 mL, 1.86 mmol). The resulting mixture was stirred for 2 hours at 40° C. The solvent was then removed in vacuo and the residue was used directly in the next step.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][CH:7]=1)=[O:5].I[CH2:14][C:15]([CH3:17])=[CH2:16]>C1COCC1>[Cl:1][CH2:2][CH2:3][C:4]([C:6]1[CH:7]=[CH:8][C:9]([F:12])=[CH:10][CH:11]=1)([OH:5])[CH2:16][C:15]([CH3:17])=[CH2:14]
Reactant: C=C(C)CI
Reactant: O=C(CCCl)c1ccc(F)cc1
Solvent: C1CCOC1
Product: C=C(C)CC(O)(CCCl)c1ccc(F)cc1
Reaction time: 1 h
Yield: 76 %

Procedure:
The reaction mixture was mildly exothermic, and began to reflux spontaneously. After the refluxing had ceased, the mixture was stirred for 1 h. TLC showed the 3-chloro-1-(4-fluorophenyl)propan-1-one not reacted completely. A solution of 3-iodo-2-methylprop-1-ene (18.2 g, 0.1 mol) in THF (30 mL) was added, and the mixture was stirred at rt overnight. The mixture was extracted with EtOAc (2×500 mL). The combined organic layer was dried and concentrated. The residue was purified by column chromatography on silica gel eluted with petroleum ether/EtOAc 50:1→30:1→5:1, to give 1-chloro-3-(4-fluorophenyl)-5-methylhex-5-en-3-ol (17 g, yield 76%) as an oil.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[NH2:12])[CH2:3]1.[S:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[C:23]1[CH:28]=[CH:27][C:26]([S:29](Cl)(=[O:31])=[O:30])=[CH:25][CH:24]=1>N1C=CC=CC=1.ClCCl.ClCCl>[CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:10]=[C:11]([NH:12][S:29]([C:26]3[CH:25]=[CH:24][C:23]([C:19]4[S:18][CH:22]=[CH:21][CH:20]=4)=[CH:28][CH:27]=3)(=[O:30])=[O:31])[CH:13]=[CH:14][C:15]=2[O:16][CH3:17])[CH2:3]1
Reactant: O=S(=O)(Cl)c1ccc(-c2cccs2)cc1
Reactant: COc1ccc(N)cc1N1C[C@@H](C)N[C@@H](C)C1
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ccc(NS(=O)(=O)c2ccc(-c3cccs3)cc2)cc1N1C[C@@H](C)N[C@@H](C)C1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 3-(cis-3,5-dimethyl-1-piperazinyl)-4-(methyloxy)aniline (D2) (117 mg, 0.5 mmol) in pyridine:dichloromethane (1:1, 4 ml) was treated with a solution 4-(2-thienyl)benzenesulfonyl chloride (WO 9827069) (143 mg, 0.55 mmol) in dichloromethane (2 ml). The solution was stirred at room temperature for 24 hours, quenched with methanol (2 ml) and concentrated in vacuo. The residue was dissolved in dichloromethane and washed with water (×3). The organic phase was applied to a SCX cartridge (Varian bond-elute, 5 g) and washed with methanol and 2M ammonia in methanol. The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography (dichloromethane to 1:4 2M ammonia in methanol:dichloromethane) to afford the title product (E11). MS (ES+) m/e 458 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]#[N:23])=[CH:12][CH:11]=2)[C:7]2[CH:24]=[C:25]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:26]=[C:27]([CH2:28][CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3].[N-:40]=[N+:41]=[N-:42].[Na+]>CN(C)C=O>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[C:22]3[NH:42][N:41]=[N:40][N:23]=3)=[CH:14][CH:15]=2)[C:7]2[CH:24]=[C:25]([C:30]3[N:34]([CH3:35])[C:33]4[CH:36]=[CH:37][CH:38]=[CH:39][C:32]=4[N:31]=3)[CH:26]=[C:27]([CH2:28][CH3:29])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(CC)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCc1nc2c(CC)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1

Procedure:
Prepared analogously to Example 10 from 4'-[(2-n-propyl-4-ethyl-6-(1-methylbenzimidazol-2-yl)-benzimidazol-1-yl)-methyl]-2-cyano-biphenyl and sodium azide in dimethylformamide.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[C:11]([O:13][CH3:14])=[O:12].[Br:15]Br.S(=O)(=O)(O)O>C(O)(=O)C.CO.CO.ClCCl>[Br:15][C:10]1[CH:9]=[C:8]2[C:4]([C:5]([C:11]([O:13][CH3:14])=[O:12])=[CH:6][NH:7]2)=[CH:3][C:2]=1[I:1]
Reactant: COC(=O)c1c[nH]c2ccc(I)cc12
Reactant: BrBr
Agent: O=S(=O)(O)O
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)c1c[nH]c2cc(Br)c(I)cc12
Temperature: 70 °C
Reaction time: 3 h

Procedure:
To a suspension of methyl 5-iodo-1H-indole-3-carboxylate (1.20 g, 3.09 mmol) in acetic acid (30 ml) was added a solution of bromine (0.15 ml, 2.9 mmol) in acetic acid (5 ml). Reaction was heated to reflux and stirred for 3 hours. The reaction was then cooled and poured onto ice water, then partitioned between water and dichloromethane. The aqueous layer was extracted with 10% MeOH/DCM (2×100 mL). The organics were combined, washed with brine, and dried over sodium sulfate, filtered and concentrated to give a dark red semi solid. The residue was taken up in methanol (30 ml). Concentrated sulfuric acid (0.5 ml) was added and mixture was heated to 70° C. for 2 days. The reaction was cooled then concentrated in vacuo and the residue partitioned between ethyl acetate and aqueous sodium bicarbonate solution. The layers were separated and organic washed with brine, dried over sodium sulfate, filtered and concentrated to give a reddish solid. The residue was dissolved in methanol/dichloromethane and adsorbed onto silica gel and purified by silica gel chromatography (50 g, 20-100% ethyl acetate/heptane). The major peak was isolated to afford a mixture of the title compound and methyl 5-iodo-1H-indole-3-carboxylate confirmed as a brown solid (260 mg) that was taken forward without further purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH:21]=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[C@H:9]1[CH2:21][NH:23][C:24]1[CH:31]=[CH:30][C:27]([C:28]#[N:29])=[C:26]([Cl:32])[C:25]=1[CH3:33])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1c(N)ccc(C#N)c1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](O[Si](C)(C)C(C)(C)C)[C@H]1C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: Cc1c(NC[C@@H]2[C@@H](O[Si](C)(C)C(C)(C)C)CCN2C(=O)OC(C)(C)C)ccc(C#N)c1Cl
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 7B (730 mg, 2.21 mmol) in 10% DMF in CH2Cl2 (5.5 mL) at rt was added 4-amino-2-chloro-3-methyl-benzonitrile (400 mg, 2.4 mmol) followed acetic acid (200 mL) and sodium triacetoxyborohydride (730 mg, 3.5 mmol). The reaction was stirred for 24 h at rt. The reaction was then extracted with EtOAc and washed with saturated aqueous NaHCO3. The organic extracts were dried over MgSO4 filtered and concentrated. Purification by flash chromatography (silica gel, 0-20% EtOAc in hexanes) provided impure (2R,3S)-N-tert-Butyloxycarbonyl-3-(tert-butyldimethylsilanyloxy)-2-[(3-chloro-4-cyano-2-methyl-phenylamino)-methyl]pyrrolidine as a light brown residue. This residue was taken up in 10% TFA in CH2Cl2 (20 mL) and stirred for 2.5 h at rt. Toluene (10 mL) was added and solvents were removed under vacuum. Purification by preperative HPLC (separated into 4 injections, YMC C18 5 μm 30×100 mm, 0-100%B, 10 min grad., 2 min. hold, 25 mL/min: A=10% MeOH/Water+0.1% TFA, B=90% MeOH/Water+0.1% TFA) provided the title compound (267 mg). MS (ES) m/z 380.23 [M+1]+