Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH:2]([CH2:7][C:8](Cl)=[O:9])[C:3]([O:5][CH3:6])=[O:4].[Cl:11][C:12]1[C:13](=[N:18][NH2:19])[NH:14][CH:15]=[CH:16][CH:17]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[Cl:11][C:12]1[C:13]([N:18]2[CH:2]([C:3]([O:5][CH3:6])=[O:4])[CH2:7][C:8](=[O:9])[NH:19]2)=[N:14][CH:15]=[CH:16][CH:17]=1
Reactant: COC(=O)C(Br)CC(=O)Cl
Reactant: NN=c1[nH]cccc1Cl
Agent: NNc1ncccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: COC(=O)C1CC(=O)NN1c1ncccc1Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 89.8 %

Procedure:
The crude product of Step B (i.e. methyl 2-bromo-4-chloro-4-oxobutanoate) (11.00 g, ˜47.4 mmol) in acetonitrile (25 mL) was added over 65 minutes to a mixture of 3-chloro-2(1H)-pyridinone hydrazone (alternatively named (3-chloro-pyridin-2-yl)-hydrazine) (6.55 g, 45.6 mmol) and sodium bicarbonate (9.23 g, 0.110 mol) in acetonitrile (60 mL) at 0° C. The mixture was then allowed to warm to room temperature and was stirred for 3 h. The mixture was then warmed and maintained at 38° C. for 8 h. Then the mixture was allowed to cool, and the solvent was removed by evaporation under reduced pressure. Water (25 mL) was added, and acetic acid (about 1.9 mL) was added until the slurry had a pH of about 5. After 2 h, the product was isolated by filtration, rinsed with water (10 mL) and dried in vacuo to provide the title compound as a pale yellow solid (11 g, 89.8% yield). A sample recrystallized from ethanol melted at 147-148° C.
Reaction SMILES: Cl[C:2]1[N:27]=[CH:26][C:5]2[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[CH:13][CH:12]=3)[C:4]=2[CH:3]=1.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([Sn](CCCC)(CCCC)CCCC)=[CH:35][CH:34]=1>O1CCOCC1>[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[O:37][C:36]([C:2]2[N:27]=[CH:26][C:5]3[N:6]=[CH:7][N:8]=[C:9]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]5[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=5)=[CH:13][CH:12]=4)[C:4]=3[CH:3]=2)=[CH:35][CH:34]=1
Reactant: Fc1ccc(COc2ccc(Nc3ncnc4cnc(Cl)cc34)cc2)cc1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C2OCCO2)o1
Solvent: C1COCCO1
Product: Fc1ccc(COc2ccc(Nc3ncnc4cnc(-c5ccc(C6OCCO6)o5)cc34)cc2)cc1

Procedure:
(6-Chloropyrido[3,4-d]pyrimidin-4-yl)-(4-(4-fluorobenzyloxy)-phenyl)-amine (1.82 g) and 5-(1,3-dioxolan-2-yl)-2-(tributylstannyl)-furan (3.75 g) in dioxan (40 ml) were reacted together as in Procedure B. The mixture was evaporated and the residue suspended in dichloromethane. This was then filtered through celite and the solvent evaporated. The gummy residue was then triturated with hexane giving a beige solid (1.21 g); m/z 485 (M+1)+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17](=O)[CH3:18].O>CCOCC.[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[I:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[CH2:14][CH2:15][CH2:16][C:17]([CH3:18])=[CH2:1]
Reactant: CC(C)(C)[O-]
Reactant: CC(=O)CCCc1ccccc1I
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Product: C=C(C)CCCc1ccccc1I
Yield: 90.2 %

Procedure:
To a stirred solution of potassium t-butoxide (7.96 g, 71 mmol) in anhydrous ether (100 ml) under nitrogen, was added methyltriphenylphosphonium bromide (25.6 g, 71 mmol). The yellow mixture was stirred under reflux for 0.5 h, allowed to cool for 10 min, and then a solution of 5-(2-iodophenyl)pentan-2-one (Intermediate 1) (9.3 g, 32.3 mmol) in anhydrous ether (70 ml) was added over 20 min. The reaction mixture was refluxed for 1 h, allowed to cool and then poured onto ice. Ether (100 ml) and water (100 ml) were added and the layers were separated. The aqueous layer was re-extracted with ether (100 ml) and the combined organic layers were washed successively with water (100 ml) and saturated brine (100 ml), dried over anhydrous magnesium sulphate and evaporated to dryness. The residue was treated with heptane (200 ml), solid was filtered off and washed with heptane and the filtrate was evaporated. The oil obtained was purified on a 90 g silica cartridge eluted with heptane to give the title compound as a liquid (8.34 g, 90%).
Reaction SMILES: [O:1]1[C@H:3]2[CH2:4][C@H:5]3[C@:18]([CH3:20])([CH2:19][C@@H:2]12)[C@@H:17]1[C@H:8]([C@H:9]2[C@@:13]([CH2:15][C@H:16]1[NH:21][C:22]([O:24][CH2:25][C:26]([Cl:29])([Cl:28])[Cl:27])=[O:23])([CH3:14])[C@@H:12]([C:30]([O:32][CH3:33])=[O:31])[CH2:11][CH2:10]2)[CH2:7][CH2:6]3.S(=O)(=O)(O)[OH:35]>O1CCOCC1.O>[OH:1][C@H:2]1[CH2:19][C@@:18]2([CH3:20])[C@@H:5]([CH2:6][CH2:7][C@@H:8]3[C@@H:17]2[C@H:16]([NH:21][C:22]([O:24][CH2:25][C:26]([Cl:28])([Cl:29])[Cl:27])=[O:23])[CH2:15][C@@:13]2([CH3:14])[C@H:9]3[CH2:10][CH2:11][C@@H:12]2[C:30]([O:32][CH3:33])=[O:31])[CH2:4][C@@H:3]1[OH:35]
Reactant: O=S(=O)(O)O
Reactant: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H]5O[C@@H]5C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)[C@@H](O)C[C@]4(C)[C@H]3[C@H](NC(=O)OCC(Cl)(Cl)Cl)C[C@]12C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Methyl 2α,3α-epoxy-11α-(2,2,2-trichloroethoxycarbonylamino)-5α-androstane-17β-carboxylate (522 mg) in dioxan (5 ml) was treated with 2N sulphuric acid (1 ml) and stirred at ambient temperature for 18 h. The mixture was diluted with water (50 ml) and extracted with ethyl acetate (3×). The extract was washed with water, dried and evaporated to give a foam. This was purified by preparative t.l.c. in ethyl acetate/petrol (1:1) and crystallised from ether to give the title compound (217 mg) m.p. 228°-230°, [α]D +27.6.
Reaction SMILES: [CH2:1]([C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[O:14]CC=C)[C:7]([O:9][CH3:10])=[O:8])[CH:2]=[CH2:3].C(OCC)(=O)C.Cl[C:25]1[CH:30]=CC=C[C:26]=1Cl>CCCCCC>[OH:14][C:13]1[C:12]([CH2:30][CH:25]=[CH2:26])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[CH2:1][CH:2]=[CH2:3]
Reactant: Clc1ccccc1Cl
Reactant: C=CCOc1ccc(C(=O)OC)cc1CC=C
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: C=CCc1cc(C(=O)OC)cc(CC=C)c1O
Yield: 97 %

Procedure:
The product of Step A (3.2g, 13.8 mmol) was refluxed in 1,2-dichlorobenzene for 3 days in the presence of a catalytic amount of BHT (10 mg). Flash column chromatography of the mixture using hexane and then 10% and 20% ethyl acetate in hexane afforded 3.1 g (97%) of the title compound.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[C:18]([F:20])[CH:17]=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9]1)=O)(C)(C)C.ClCCl.FC(F)(F)C(O)=O>>[F:20][C:18]1[CH:17]=[CH:16][C:15]([CH3:21])=[C:14]([N:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[CH:19]=1
Reactant: Cc1ccc(F)cc1N1CCN(C(=O)OC(C)(C)C)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(F)cc1N1CCNCC1
Reaction time: 1 h
Yield: 118.8 %

Procedure:
In a 20 ml scintillation vial equipped with a magnetic stir bar and fitted with a nitrogen inlet, the 4-(5-fluoro-2-methyl-phenyl)-piperazine-1-carboxylic acid tert-butyl ester 16c (203.70 mg, 0.69 mmol) was taken up in clean, dry, reagent grade dichloromethane (5.00 ml, 77.53 mmol). The mixture was stirred until all solids were in solution and the trifluoroacetic acid (0.50 ml, 6.73 mmol) was added in one portion. The reaction stirred at room temperature for 1 h. After 1 h, the volatiles were removed under reduced pressure. The yellow oil was then taken back up in 5 ml of dichloromethane and the volatiles were removed once more under reduced pressure. The resultant yellow oil was further dried under high vacuum. The product, 1-(5-fluoro-2-methyl-phenyl)-piperazine 16d (160.10 mg, 0.82 mmol), was isolated as a yellow oil and was carried on without further purification.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[N:7]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([F:20])[CH:14]=2)[CH2:11][N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1)[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CN(Cc2ccccc2)C[C@H]1c1ccc(Cl)c(F)c1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
A mixture of 5.7 g (14.1 mmol) [(3S,4R)-1-Benzyl-4-(4-chloro-3-fluoro-phenyl)-pyrrolidin-3-yl]-carbamic acid tert-butyl ester, 676 mg (17 mmol) NaH (55%) in DMF was stirred for 20 minutes at room temperature and 1 h at 60° C. 3 g (21 mmol) iodomethane in DMF was added and the mixture was stirred at 60° C. for 1 h and evaporated. The residue was taken up in ethyl acetate and water, the organic layer washed with brine and back-extracted with ethyl acetate. The combined organic layers were dried with Na2SO4, filtered off and evaporated. The residue was taken up on isolute and subjected to column chromatography on silica eluting with a gradient formed from ethyl acetate and heptane to yield after evaporation of the product containing fractions 2.67 g (45%) of the title compound as light yellow oil. MS m/e: 419.2 [M+H]+.
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[C:9]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][C:15]([CH3:22])([CH3:21])[CH2:14]2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:29](=O)[CH2:30][CH2:31][CH3:32].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O1CCCC1>[CH2:29]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[C:9]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)[CH:10]=[CH:11][C:12]=2[CH:13]2[CH2:14][C:15]([CH3:21])([CH3:22])[CH2:16][C:17]([CH3:20])([CH3:19])[CH2:18]2)[CH2:6][CH2:5]1)[CH2:30][CH2:31][CH3:32]
Reactant: CCCC=O
Reactant: CC1(C)CC(c2ccc(N3CCOCC3)cc2N2CCNCC2)CC(C)(C)C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCN1CCN(c2cc(N3CCOCC3)ccc2C2CC(C)(C)CC(C)(C)C2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 4-[3-piperazin-1-yl-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine (14 mg, 0.0363 mmol) produced in Example (81e), butyraldehyde (0.0097 mL, 0.109 mmol) and tetrahydrofuran (0.5 mL) was added sodium triacetoxyborohydride (23 mg, 0.109 mmol), followed by stirring for 1 hour and 30 minutes at room temperature. Saturated aqueous solution of sodium hydrogencarbonate was added to the reaction mixture and extraction was performed with ethyl acetate. The solvent was distilled of by nitrogen stream to the separated organic layer. The resultant residue was purified by NH silica gel column chromatography (ethyl acetate/heptane) to give 4-[3-(4-butylpiperazine-1-yl)-4-(3,3,5,5-tetramethylcyclohexyl)phenyl]morpholine.
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[F:46][C:47]1[CH:48]=[C:49]([CH:96]=[CH:97][CH:98]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:76][CH2:75][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:73][CH2:72]5)=[C:67]([NH:81][S:82]([CH3:85])(=[O:84])=[O:83])[CH:66]=4)[CH:63]=3)[N:58](S(C3C=CC(C)=CC=3)(=O)=O)[CH:57]=2)[CH:53]=[N:52]1.[OH-].[Li+]>C1COCC1.CO.O>[F:46][C:47]1[CH:48]=[C:49]([CH:96]=[CH:97][CH:98]=1)[CH2:50][N:51]1[CH:55]=[C:54]([C:56]2[C:64]3[C:59](=[N:60][CH:61]=[C:62]([C:65]4[CH:70]=[CH:69][C:68]([N:71]5[CH2:72][CH2:73][N:74]([CH2:77][C:78]([NH2:80])=[O:79])[CH2:75][CH2:76]5)=[C:67]([NH:81][S:82]([CH3:85])(=[O:83])=[O:84])[CH:66]=4)[CH:63]=3)[NH:58][CH:57]=2)[CH:53]=[N:52]1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(N5CCN(CC(N)=O)CC5)c(NS(C)(=O)=O)c4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CS(=O)(=O)Nc1cc(-c2cnc3[nH]cc(-c4cnn(Cc5cccc(F)c5)c4)c3c2)ccc1N1CCN(CC(N)=O)CC1
Yield: 23.6 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, 2-(4-(4-(3-(1-(3-fluorobenzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)-2-(methylsulfonamido)phenyl)piperazin-1-yl)acetamide (80 mg, 0.1 mmol) was hydrolyzed with lithium hydroxide (13 mg, 0.3 mmol) in THF/methanol/Water (2/2/1 mL) to yield 15 mg (23.6% yield. 1H NMR (DMSO-d6, 400 MHz): δ 8.45-8.40 (m, 3H), 8.3 (s, 1H), 7.94 (s, 1H), 7.767-7.761 (d, 1H), 7.615-7.610 (d, 1H), 7.53-7.51 (d, 1H), 7.40-7.33 (m, 2H), 7.24-7.07 (m, 4H), 5.38 (s, 2H), 3.18 (s, 3H), 2.95-2.92 (m, 6H), 2.657 (s, 5H). MS: m/z=603.15 (M+1), HPLC: 93.36% in method A.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([O:27]CC)[CH:20]=2)=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[C:2]1C=CC=CC=1>C(O)C.[Pd]>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([C:17]([C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[C:21]([OH:27])[CH:20]=2)=[O:18])[CH:12]=[CH:13][C:14]=1[O:15][CH3:16])[CH3:2]
Reactant: CCOc1cc(C(=O)c2ccc(OC)c(OCc3ccccc3)c2)ccc1OC
Agent: [Pd]
Solvent: CCO
Product: CCOc1cc(C(=O)c2ccc(OC)c(O)c2)ccc1OC
Yield: 94.1 %

Procedure:
A mixture of (3-benzyloxy-4-methoxy-phenyl)-(3-ethoxy-4-methoxy-phenyl)-methanone (7.24 g), 20% palladium on charcol (0.22 g, 3% weight), and cyclohexcene (24 mL) in ethanol (48 mL) was refluxed overnight. The black suspension was filtered through a Celite pad, and the filtrate was evaporated to give (3-ethoxy-4-methoxy-phenyl)-(3-hydroxy-4-methoxy-phenyl)-methanone as an off-white solid (5.25 g, 94% yield): 1H NMR (DMSO-d6) δ 1.49 (t, J=7 Hz, 3H, CH2CH3), 3.95 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 4.16 (q, J=7 Hz, 2H, CH2CH3), 5.69 (s, 1H, OH), 6.87-6.93 (m, 2H, Ar), 7.35-7.43 (m, 4H, Ar). The product was used in the next step without further purification.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=3[O:11][C:10]=2[CH3:20])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CO.[BH4-].[Na+].Cl>O1CCCC1>[CH:1]1([CH:7]([C:9]2[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH3:19])=[CH:17][C:12]=3[O:11][C:10]=2[CH3:20])[OH:8])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: COc1ccc2c(C(=O)C3CCCCC3)c(C)oc2c1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(C(O)C3CCCCC3)c(C)oc2c1
Reaction time: 0.5 h
Yield: 76.2 %

Procedure:
To a mixture of cyclohexyl(6-methoxy-2-methyl-1-benzofuran-3-yl)methanone (1.18 g) synthesized above, methanol (1 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (246 mg) at 0° C., and the mixture was stirred for 30 min. 1N Hydrochloric acid was added to quench the reaction, the organic solvent was evaporated in an evaporator, and the residue was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (906 mg, 76%) as a pale-yellow oil.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH2:4][CH2:3]1.C1(=O)CCCC1.[C-]#N.[K+].CN(C)[C:17]1([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]1>O>[N:2]1([C:17]2([C:22]#[N:23])[CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:5][CH2:4][CH2:3]1
Reactant: C1CNC1
Reactant: CN(C)C1(C#N)CCCC1
Agent: Cl
Agent: [C-]#N
Agent: [K+]
Solvent: O=C1CCCC1
Solvent: O
Product: N#CC1(N2CCC2)CCCC1
Yield: 43 %

Procedure:
The title compound (1.29 g, 43%) was prepared from azetidine hydrochloride (1.85 g, 20 mmol), cyclopentanone (1.68 g, 20 mmol) and potassium cyanide (1.30 g, 20 mmol) in water (10 ml) in a similar manner to that described in D1. 1H NMR (CDCl3) δ: 1.70-1.82 (6H, m), 1.86 (2H, m), 2.07 (2H, quin, J=7 Hz), 3.32 (4H, t, J=7 Hz).
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6](=[N:13][C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC.CCOCC>[C:7]1([CH:6]([NH:13][C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)[CH2:1][CH2:2][CH2:3][CH3:4])[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: C(=Nc1ccncc1)c1ccccc1
Reactant: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: CCCCC(Nc1ccncc1)c1ccccc1
Temperature: 25 °C
Yield: 32.7 %

Procedure:
0.03 Mole of butyl lithium in hexane as a 15% w/w solution was added dropwise to a stirred, cooled (-10° C.) solution of 5.46 grams (0.03 mole) of 4-benzylideneamino pyridine in 10 milliliters of dry ether. The mixture was allowed to warm to room temperature and then poured onto ice and extracted with methylene chloride. The organic phase was separated and extracted with 2 N hydrochloric acid. The extracts were basified with 2 N sodium hydroxide and extracted into methylene chloride. The resulting methylene chloride solution was dried (MgSO4) and decolourised with charcoal. The solvent was removed and the resulting light oil (5.75 grams) was crystallised and recrystallised from a toluene/petrol 60°-80° C.) mixture affording 2.36 grams of N-([α-phenyl]-n-pentyl)-4-pyridinamine, melting point 118°-8.5°.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C:8](=O)[CH2:9][CH3:10])[CH2:4][CH2:3]1.[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=O)=[CH:18][CH:17]=1>>[Cl:12][CH2:13][CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)=[C:8]([CH:5]2[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]2)[CH2:9][CH3:10])=[CH:18][CH:17]=1
Reactant: CCC(=O)C1CCC(O)CC1
Reactant: O=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1
Product: CCC(=C(c1ccc(O)cc1)c1ccc(OCCCl)cc1)C1CCC(O)CC1
Yield: 52 %

Procedure:
Following general procedure of McMurry reaction as described in example 1, step B, 1-(4-hydroxycyclohexyl)propan-1-one (0.6 g, 1.0 eq) was reacted with (4-(2-chloroethoxy)phenyl)(4-hydroxyphenyl)methanone (1.6 g, 1.5 eq) to give 0.8 g desired product (52% yield, Z/E=1/1). 1H NMR (400 MHz, CDCl3) δ 7.11-7.20 (m, 1H), 7.00-7.10 (m, 2H), 6.90-6.70 (m, 1H), 6.60-6.89 (m, 3H), 6.58 (d, J=7.6 Hz, 1H), 4.08-4.20 (m, 2H), 3.70-3.80 (m, 2H), 3.60 (brs, 1H), 2.47 (q, J=7.6 Hz, 2H), 2.28-2.38 (m, 1H), 2.00-2.08 (m, 2H), 1.86-1.94 (m, 2H), 1.72-1.80 (m, 1H), 1.20-1.49 (m, 4H), 1.04 (t, J=7.6 Hz, 3H)
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11](C=O)[CH2:10][CH2:9]2)(=[O:5])=[O:4].Cl>CO.C(Cl)(Cl)Cl>[CH3:1][NH:2][S:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH2:10][CH2:9]2)(=[O:5])=[O:4]
Reactant: CNS(=O)(=O)c1ccc2c(c1)CCN2C=O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CNS(=O)(=O)c1ccc2c(c1)CCN2
Yield: 82.1 %

Procedure:
To a stirred solution of 23.42 g (0.0975 mol) of 5-methylsulfamoyl-N-formylindoline in 500 ml of methanol was added 40 ml of concentrated hydrochloric acid. The solution was heated to reflux for one hour. Thin layer chromatography in chloroform showed the reaction was complete. The solution was allowed to cool, and then the methanol was removed under reduced pressure. The aqueous slurry remaining was dissolved ice water and neutralized by the addition of sodium hydroxide solution. The precipitate was extracted with methylene chloride, washed with water and saturated aqueous sodium chloride solution. The solution was dried over sodium sulfate and then concentrated under reduced pressure. The residue was allowed to air dry to give 17.02 g (0.08 mol) (82% by weight yield) of 5-methylsulfamoylindoline.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:48]1[CH:53]=[CH:52][C:51]([CH:54]([CH3:73])[C:55]([C:61]2[CH:62]=[CH:63][C:64]3[O:69][CH2:68][C:67](=[O:70])[N:66]([CH3:71])[C:65]=3[CH:72]=2)([OH:60])[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:74])[CH:49]=1.[NH:75]1[CH2:80][CH2:79][CH:78]([C:81]([O:83][CH2:84][CH3:85])=[O:82])[CH2:77][CH2:76]1>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[CH2:84]([O:83][C:81]([CH:78]1[CH2:79][CH2:80][N:75]([C:48]2[CH:53]=[CH:52][C:51]([CH:54]([CH3:73])[C:55]([OH:60])([C:61]3[CH:62]=[CH:63][C:64]4[O:69][CH2:68][C:67](=[O:70])[N:66]([CH3:71])[C:65]=4[CH:72]=3)[C:56]([F:59])([F:58])[F:57])=[C:50]([Cl:74])[CH:49]=2)[CH2:76][CH2:77]1)=[O:82])[CH3:85]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(c1ccc(Br)cc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccc3ccccc3c2-c2c(P(c3ccccc3)c3ccccc3)ccc3ccccc23)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN(c2ccc(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 3.2 %

Procedure:
To a suspension of 2,2′-bis(diphenylphosphino)-1,1′binaphthyl (3.1 mg), tris(dibenzylideneacetone)dipalladium (0) (1.5 mg) and sodium-tert.-butylate (19 mg) in toluene (15 ml) were added 6-[2-(4-bromo-2-chloro-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 22, step 3, 80 mg) and ethyl piperidine-4-carboxylate (29 mg). The mixture was stirred at room temperature overnight. 2,2′-Bis(diphenylphosphino)-1,1′binaphthyl (3.1 mg), ethyl piperidine-4-carboxylate (29 mg) and tris(dibenzylideneacetone)dipalladium (0) (1.5 mg) were added and the mixture was stirred at 80° C. for 4 h. After cooling to room temperature, the mixture was diluted with EtOAc. The organic phase was washed with water, dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>4:1) to give the title compound (3 mg) as light yellow oil. MS (m/e)=555.3 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[N:7]3[CH2:16][CH2:15][CH:14]([OH:17])[CH2:13][CH2:12][C:8]3=[N:9]2)=[CH:4][CH:3]=1.CCN(CC)CC.[S:26](Cl)([CH3:29])(=[O:28])=[O:27]>C(Cl)Cl.O>[CH3:29][S:26]([O:17][CH:14]1[CH2:15][CH2:16][N:7]2[C:8](=[N:9][C:10]3[C:5]([C:6]2=[O:18])=[CH:4][CH:3]=[C:2]([Br:1])[CH:11]=3)[CH2:12][CH2:13]1)(=[O:28])=[O:27]
Reactant: CS(=O)(=O)Cl
Reactant: O=c1c2ccc(Br)cc2nc2n1CCC(O)CC2
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC1CCc2nc3cc(Br)ccc3c(=O)n2CC1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of 3-bromo-8-hydroxy-7,8,9,10-tetrahydroazepino[2,1-b]quinazolin-12(6H)-one (290 mg, 0.938 mmol) and excess Et3N in DCM (10 mL) was added Ms-Cl (0.76 mL). The mixture was stirred for 1.5 h at room temperature. Then the reaction mixture was diluted with water and extracted with EtOAc (3×50 mL). The combined organic layers were dried over Na2SO4. After filtration and concentration, the crude product was directly used for the next step. MS (ESI): 387, 389 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[Br:10][C:11]1[CH:16]=[C:15](Br)[CH:14]=[C:13]([Br:18])[CH:12]=1>>[Br:10][C:11]1[CH:16]=[C:15]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=2)[CH:14]=[C:13]([Br:18])[CH:12]=1
Reactant: Brc1cc(Br)cc(Br)c1
Reactant: N#Cc1ccc(N)cn1
Product: N#Cc1ccc(Nc2cc(Br)cc(Br)c2)cn1

Procedure:
5-Amino-pyridine-2-carbonitrile was coupled with 1,3,5-tribromobenzene to give 5-(3,5-dibromo-phenylamino)-pyridine-2-carbonitrile by the method described in Example 44. 5-(3,5-Dibromo-phenylamino)-pyridine-2-carbonitrile was converted to [3-bromo-5-(6-cyano-pyridin-3-ylamino)-phenyl]-carbamic acid methyl ester using the conditions in Example 86, replacing methylsulfonamide with carbamic acid methyl ester. [3-Bromo-5-(6-cyano-pyridin-3-ylamino)-phenyl]-carbamic acid methyl ester was converted to [3-(6-cyano-pyridin-3-ylamino)-5-(1H-indol-4-yl)-phenyl]-carbamic acid methyl ester as described in Example 102. 1H NMR (400 MHz, acetone-d6): δ 10.41 (s, 1H), 8.84 (s, 1H), 8.50 (d, J=2.5 Hz, 1H), 8.44 (s, 1H), 7.72-7.63 (m, 4H), 7.46 (d, J=7.6 Hz, 1H), 7.42 (t, J=2.7 Hz, 1H), 7.26 (s, 1H), 7.23-7.14 (m, 2H), 6.75 (s, 1H), 3.73 (s, 3H).