Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].F[C:12]1[CH:20]=[N:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[Cl:1][C:2]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:17]1[CH:18]=[N:19][CH:20]=[CH:12][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: NCc1ccc(Cl)cc1Cl
Reactant: O=C(O)c1ccncc1F
Product: O=C(O)c1ccncc1NCc1ccc(Cl)cc1Cl
Yield: 42 %

Procedure:
The title compound was prepared in 42% yield from 2,4-dichlorobenzylamine and 3-fluoroisonicotinic acid according to the procedure for the preparation of Example 3. 1H NMR (400 MHz, DMSO-d6): δ 13.49 (br s, 1H), 8.04 (s, 1H), 7.87 (d, 1H, J=5.0 Hz), 7.66 (s, 1H), 7.59 (d, 1H, J=5.0 Hz), 7.38-7.42 (m, 2H), 4.63 (s, 2H). [M+H] calc'd for C13H10Cl2N2O2, 297, 299. found 297, 299.
Reaction SMILES: [F:1][C:2]1[CH:3]=C(C#N)[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:8]=[C:7]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1.[OH-:40].[K+].Cl.[CH2:43]([OH:45])[CH3:44]>>[F:1][C:2]1[CH:3]=[C:44]([C:43]([OH:40])=[O:45])[CH:5]=[C:6]2[C:10]=1[N:9]([C:11]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[N:8]=[C:7]2/[CH:30]=[CH:31]/[C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1
Reactant: N#Cc1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCO
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Product: O=C(O)c1cc(F)c2c(c1)c(/C=C/c1cccnc1)nn2C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
3.60 g of 7-fluoro-3-[(E)-2-(pyridin-3-yl)-vinyl]-1-trityl-1H-indazole-5-carbonitrile was dissolved in 500 mL of ethanol, added with 154 g of potassium hydroxide, and stirred at 80° C. overnight. After cooling to room temperature, the solution was adjusted to pH 3 by 5N hydrochloric acid, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over magnesium sulfate, and the solvent was evaporated. The obtained crude product was purified by silica gel column chromatography, and the resultant dark brown solid was washed with 10 mL of diethyl ether, to afford 3.58 g of the title compound as dark brown crystals.
Reaction SMILES: [CH:1]1([CH2:6][O:7][C:8]2[CH:13]=[CH:12][C:11]([C@H:14]3[CH2:39][O:38][C:17]4=[CH:18][C:19]5[CH2:20][C@@H:21]([C:35](O)=[O:36])[N:22]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:23][C:24]=5[CH:25]=[C:16]4[O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.Cl.C[O:43][C:44](=[O:62])[C@@H:45]([NH2:61])[CH2:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=2[CH3:60])=[CH:49][CH:48]=1>>[CH:1]1([CH2:6][O:7][C:8]2[CH:9]=[CH:10][C:11]([C@H:14]3[CH2:39][O:38][C:17]4=[CH:18][C:19]5[CH2:20][C@@H:21]([C:35]([NH:61][C@@H:45]([CH2:46][C:47]6[CH:52]=[CH:51][C:50]([C:53]7[CH:58]=[CH:57][N:56]=[C:55]([CH3:59])[C:54]=7[CH3:60])=[CH:49][CH:48]=6)[C:44]([OH:43])=[O:62])=[O:36])[N:22]([C@H:26]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)[CH2:27][CH3:28])[CH2:23][C:24]=5[CH:25]=[C:16]4[O:15]3)=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)O)OC[C@H](c1ccc(OCC2CCCC2)cc1)O3
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2ccnc(C)c2C)cc1
Agent: Cl
Product: CC[C@@H](c1ccccc1)N1Cc2cc3c(cc2C[C@H]1C(=O)N[C@@H](Cc1ccc(-c2ccnc(C)c2C)cc1)C(=O)O)OC[C@H](c1ccc(OCC2CCCC2)cc1)O3

Procedure:
(3S,8S)-3-(4-Hydroxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid methyl ester (20 mg) was reacted with cyclopentylmethanol according to General Procedure K and the resulting ester was hydrolyzed according to General Procedure AB to provide (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg). The title compound (17 mg) was prepared from (3S,8S)-3-(4-cyclopentylmethoxy-phenyl)-7-((S)-1-phenyl-propyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carboxylic acid (18 mg) and (S)-2-amino-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride according to General Procedures L and B. LCMS (m/z): 781.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11].[C:33](Cl)(=[O:36])[CH:34]=[CH2:35]>C1COCC1>[C:10]([O:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([S:23]([C:26]2[CH:31]=[CH:30][C:29]([NH:32][C:33](=[O:36])[CH:34]=[CH2:35])=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:11])[CH3:12]
Reactant: C=CC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCC(S(=O)(=O)c2ccc(N)cc2)CC1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: C=CC(=O)Nc1ccc(S(=O)(=O)C2CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 15.4 %

Procedure:
Diisopropylethylamine (0.09 ml, 0.5 mmol) was added in one portion to a stirred solution of 4-(4-Amino-benzenesulfonyl)-piperidine-1-carboxylic acid tert-butyl ester (0.11 g, 0.33 mmol) in THF (3 ml) at room temperature. To this mixture was added acryloyl chloride (0.03 ml, 0.5 mmol) in one portion and the mixture was stirred at room temperature under a nitrogen atmosphere for 1 hour. After this time, the mixture was concentrated under vacuum and the resulting residue was purified by column chromatography (elution: 40% heptane, 60% ethyl acetate) to give the title compound (0.02 g, 17% yield) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.[C:30](Cl)(=[O:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.N1C=CC=CC=1>C(N(CC)CC)C>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][C:30](=[O:37])[C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: c1ccncc1
Product: O=C(Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1)c1ccccc1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and benzoyl chloride in substantially the same manner as described in Example 61 with one change: pyridine was used as a base instead of triethylamine; off-white solid: MS (EI) m/z 497.2 (M+H)+; 1H NMR (DMSO-d6): δ 7.03 (d, J=7.6 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 7.39 (t, J=8.0 Hz, 2H), 7.50-7.95 (m, 10H), 8.05 (d, J=7.7 Hz, 1H), 8.36 (d, J=7.0 Hz, 1H), 9.16 (s, 1H), 10.33 (s, 1H).
Reaction SMILES: [C:1]([C:6]1[NH:7][C:8]([CH3:18])=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][Cl:15])([O:3][CH2:4][CH3:5])=[O:2].[OH:19][C:20]1([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O1CCOCC1>[ClH:15].[CH2:4]([O:3][C:1]([C:6]1[NH:7][C:8]([CH3:18])=[C:9]([CH3:17])[C:10]=1[O:11][CH2:12][CH:13]([OH:16])[CH2:14][N:23]1[CH2:22][CH2:21][C:20]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)([OH:19])[CH2:25][CH2:24]1)=[O:2])[CH3:5]
Reactant: OC1(c2ccccc2)CCNCC1
Reactant: CCOC(=O)c1[nH]c(C)c(C)c1OCC(O)CCl
Solvent: C1COCCO1
Product: CCOC(=O)c1[nH]c(C)c(C)c1OCC(O)CN1CCC(O)(c2ccccc2)CC1
Product: Cl
Yield: 35.8 %

Procedure:
6.0 g of 1-(2-carboethoxy-4,5-dimethyl-pyrrol-3-oxy)-3-chloro-propan-2-ol and 3.5 g of 4-hydroxy-4-phenylpiperidine in 150 ml of dioxane are heated for 15 hours in an autoclave at 120° C. The volatile constituents are then distilled off under reduced pressure, and the very viscous crude product is partitioned between ether and 2 N sulfuric acid. The aqueous phase is cautiously rendered alkaline with 4 N sodium hydroxide solution and is then extracted with ether. The ether phase is dried over magnesium sulfate, the solvent is removed and the residue which remains is, as described in Example 2, dissolved in a small amount of methanol and treated with a solution of hydrogen chloride in ether, to give 3.2 g of 3-[2-hydroxy-3-(4-phenyl-4-hydroxy-piperidino)-propoxy]-4,5-dimethylpyrrole-2-carboxylic acid ethyl ester hydrochloride, of melting point 210°-212° C.
Reaction SMILES: NOS(O)(=O)=O.[C:7]1(=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[Cl-].[NH4+:17].O>C(O)=O>[C:7]1(=[O:15])[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][NH:17]1
Reactant: O=C1CCCCCCC1
Reactant: [NH4+]
Agent: NOS(=O)(=O)O
Agent: [Cl-]
Solvent: O
Solvent: O=CO
Product: O=C1CCCCCCCN1
Temperature: 105 °C
Yield: 65 %

Procedure:
A 5 L three-neck round bottom flask was fitted with a heating mantle, an overhead mechanical stirrer, an addition funnel , a nd a thermometer. The reaction was performed under an argon atmosphere. Hydroxylamine-O-sulfonic acid (196.7 g, 1.74 moles, 1.10 equiv.) and formic acid (1 L) were charged into the round bottom flask and stirred to form a white slurry. A solution of cyclooctanone (200.0 g 1.58 moles, 1.0 equiv.) in formic acid (600 mL) was added dropwise to the white slurry via the addition funnel. After the addition, the addition funnel was replaced by a reflux condenser, and the reaction was heated to reflux (internal temperature about 105° C.) for 1 hour to give a brown solution. After the solution was cooled to room temperature, it was poured into a mixture of saturated aqueous ammonium chloride (1.5 L) and water (1.5 L). The aqueous mixture was extracted with chloroform (3×1200 mL). The combined chloroform layers were transferred into a beaker, and saturated sodium bicarbonate (2 L) was added slowly. The chloroform layer was then separated, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to afford a brown oil. The oil was placed in a 500 mL round bottom flask with a magnetic stirrer. The round bottom flask was placed in a silicon oil bath and was fitted with a short path vacuum distillation head equipped with a thermometer. A Cow-type receiver was connected to three 250 mL flasks. 2-Azacyclononanone (145 g, 65%, mp 64-69° C.) was obtained by vacuum distillation (fraction with head temperature range from 80 to 120° C. at pressures between 3.0 and 3.4 mmHg).
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].CON(C)[C:8](=[O:21])[C@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]([CH3:12])[CH3:11].C(OC(=O)C)(=O)C.CO>O1CCCC1>[CH3:12][CH:10]([C@@H:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:8](=[O:21])[CH:1]=[CH2:2])[CH3:11]
Reactant: C=C[Mg]Br
Reactant: CON(C)C(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Solvent: CO
Solvent: C1CCOC1
Product: C=CC(=O)[C@H](NC(=O)OC(C)(C)C)C(C)C
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 64.1 %

Procedure:
Vinylmagnesium bromide (1M soln in THF, 34.6 mL, 34.6 mmol) was added to a solution of (R)-tert-butyl 1-(methoxy(methyl)amino)-3-methyl-1-oxobutan-2-ylcarbamate (4.5 g, 17.30 mmol) in anhydrous tetrahydrofuran (50 mL) under nitrogen at −78° C., dropwise, over 20 min. The reaction was slowly warmed to 0° C. and then stirred for an hour at 0° C. The reaction warmed to room temperature and then stirred for 10 h. Acetic anhydride (10 mL) was added to the reaction mixture at 0° C. After several minutes methanol (10 mL) was added to the reaction. The mixture was allowed to stir for 10 min, and then concentrated to a volume of 25 mL. The reaction mixture was washed with water (100 mL) and the aqueous layer was extracted with ethyl acetate (150 mL). The combined organic layers were washed successively with aqueous sodium bicarbonate (2×100 mL) and brine (2×100 mL), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure at less than 40° C. The resulting residue was purified by flash column chromatography on silica gel, eluting with 85:15 hexanes:ethyl acetate to provide (R)-tert-butyl 2-methyl-4-oxohex-5-en-3-ylcarbamate (2.52 g) as a white solid. 1H NMR (CDCl3): 6.50-6.32 (m, 2H), 5.85 (d, 1H), 5.22 (d, 1H), 4.56 (dd, 1H), 2.18 (m, 1H), 1.44 (s, 9H), 1.01 (d, 3H), 0.80 ppm (d, 3H).
Reaction SMILES: F[C:2](F)(F)C(O)=O.N[C@@H:9]([C:12]([NH2:14])=[O:13])[CH2:10][OH:11].C(=O)(O)[O-].[Na+].C=O.[C:22]([BH3-])#[N:23].[Na+]>O.C(#N)C>[CH3:2][N:23]([CH3:22])[C@H:9]([CH2:10][OH:11])[C:12]([NH2:14])=[O:13]
Reactant: [BH3-]C#N
Reactant: NC(=O)[C@H](N)CO
Reactant: O=C(O)C(F)(F)F
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CN(C)[C@H](CO)C(N)=O
Temperature: -5 °C
Reaction time: 0.17 h
Yield: 92.9 %

Procedure:
D-serine amide trifluoroacetate (9.0 g) was dissolved in water (12.6 ml). Under ice cooling, sodium bicarbonate (3.47 g) was added, followed by stirring for 10 minutes. The resulting mixture was added with acetonitrile (66.6 ml) to form a suspension. Under cooling at -5° C., were added a 37% aqueous solution (7.37 g) of formaldehyde and sodium cyanoborohydride (1.74 g), followed by stirring for 1 hour. An insoluble matter deposited was filtered off and the filtrate was concentrated under reduced pressure. The residue was purified by chromatography on a column packed with alumina (450 g), thereby obtaining the target product (3.4 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:35]=[CH:36][C:37]=1[F:38])[CH2:5][N:6]1[CH:11]=[CH:10][CH:9]=[C:8]([C:12]([NH:14][CH2:15][C:16]2[CH:17]=[C:18]([C:22]3[C:30]4[C:25](=[N:26][CH:27]=[C:28]([C:31]([NH2:33])=[O:32])[CH:29]=4)[NH:24][CH:23]=3)[CH:19]=[CH:20][CH:21]=2)=[O:13])[C:7]1=[O:34].F[C:40]1C=C(C=C[C:75]=1F)CN1C=CC=C(C(NCC2C=C(C3C4C(=NC=C(C(O)=O)C=4)NC=3)C=CC=2)=O)C1=O.Cl.C(N)C>>[CH2:40]([NH:33][C:31]([C:28]1[CH:29]=[C:30]2[C:22]([C:18]3[CH:19]=[CH:20][CH:21]=[C:16]([CH2:15][NH:14][C:12]([C:8]4[C:7](=[O:34])[N:6]([CH2:5][C:4]5[CH:35]=[CH:36][C:37]([F:38])=[C:2]([F:1])[CH:3]=5)[CH:11]=[CH:10][CH:9]=4)=[O:13])[CH:17]=3)=[CH:23][NH:24][C:25]2=[N:26][CH:27]=1)=[O:32])[CH3:75]
Reactant: O=C(O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Reactant: NC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1
Agent: CCN
Agent: Cl
Product: CCNC(=O)c1cnc2[nH]cc(-c3cccc(CNC(=O)c4cccn(Cc5ccc(F)c(F)c5)c4=O)c3)c2c1

Procedure:
Except where indicated, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid ethylamide was synthesized as per Example 81, 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid amide using 3-[3-({[1-(3,4-Difluoro-benzyl)-2-oxo-1,2-dihydro-pyridine-3-carbonyl]-amino}-methyl)-phenyl]-1H-pyrrolo[2,3-b]pyridine-5-carboxylic acid (53 mg, 0.00010 mol) as carboxylic acid and ethylamine hydrochloride (15 mg, 0.00018 mol; Aldrich) as amine, to yield the product. 1H NMR (400 MHz, CDCl3) d ppm 12.550 (s, 1H) 10.727 (s (br), 1H) 9.373 (s, 1H) 9.026 (s, 1H) 8.682-8.286 (m, 2H) 7.917 (s, 1H) 7.705 (s, 1H) 7.633-7.293 (m, 4H) 7.218-7.091 (m, 2H) 7.030 (m, 1H) 6.511 (m, 1H) 5.163 (s, 2H) 4.756 (m, 2H) 3.603 (m, 2H) 1.339 (t, J=7.5 Hz, 3H); MS m/z=542.38 M+H.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Al](C)C.CCCCCC.[C:32]([C:34]1[CH:35]=[C:36]([C:40]2[CH2:44][CH2:43][CH2:42][C:41]=2[C:45](OCC)=[O:46])[CH:37]=[CH:38][CH:39]=1)#[N:33]>ClCCl>[C:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:45]([C:41]2[CH2:42][CH2:43][CH2:44][C:40]=2[C:36]2[CH:37]=[CH:38][CH:39]=[C:34]([C:32]#[N:33])[CH:35]=2)=[O:46])=[CH:17][CH:16]=1)(=[O:8])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(N)cc1
Reactant: CCOC(=O)C1=C(c2cccc(C#N)c2)CCC1
Agent: C[Al](C)C
Solvent: ClCCl
Solvent: CCCCCC
Product: CC(C)(C)NS(=O)(=O)c1ccccc1-c1ccc(NC(=O)C2=C(c3cccc(C#N)c3)CCC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.3 %

Procedure:
To a solution of 2′-tert-butylaminosulfonyl-4-amino-[1,1′]-biphenyl (60 mg, 0.197 mmol) in 4 ml anhydrous dichloromethane was added a solution of 2M trimethylaluminum in hexane (0.3 ml, 0.59 mmol). Reaction was stirred at room temperature for 20 minutes to which a solution of ethyl 2-(3-cyanophenyl)-1-cyclopentene-1-carboxylate (48 mg, 0.197 mmol) in lml anhydrous dichloromethane. Reaction was stirred at room temperature overnight. Reaction was quenched with 15 ml 1N HCl after which an additional 10 ml dichloromethane was added. Organic was washed with 2×20 ml water, dried over magnesium sulfate and concentrated to give N-[4-(2-{[(tert-butyl)amino]sulfonyl}phenyl)phenyl][2-(3-cyanophenyl)cyclopent-1-enyl]carboxamide (80 mg, 80%) as a white powder which was sufficiently pure to be used without further purification.
Reaction SMILES: Br[C:2]1[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:5]2[CH:6]=[N:7][NH:8][C:9](=[O:10])[C:4]=2[C:3]=1[Cl:20].BrC1N(COCC[Si](C)(C)C)C2C=NNC(=O)C=2C=1.[CH:40]1([CH2:43][O:44][C:45]2[CH:46]=[C:47](B3OC(C)(C)C(C)(C)O3)[CH:48]=[CH:49][C:50]=2[O:51][CH3:52])[CH2:42][CH2:41]1.C1(OC2C=C(B3OC(C)(C)C(C)(C)O3)C=CC=2OC(F)F)CC1>>[Cl:20][C:3]1[C:4]2[C:9](=[O:10])[NH:8][N:7]=[CH:6][C:5]=2[N:11]([CH2:12][O:13][CH2:14][CH2:15][Si:16]([CH3:19])([CH3:18])[CH3:17])[C:2]=1[C:47]1[CH:48]=[CH:49][C:50]([O:51][CH3:52])=[C:45]([O:44][CH2:43][CH:40]2[CH2:42][CH2:41]2)[CH:46]=1
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1OCC1CC1
Reactant: C[Si](C)(C)CCOCn1c(Br)c(Cl)c2c(=O)[nH]ncc21
Agent: CC1(C)OB(c2ccc(OC(F)F)c(OC3CC3)c2)OC1(C)C
Agent: C[Si](C)(C)CCOCn1c(Br)cc2c(=O)[nH]ncc21
Product: COc1ccc(-c2c(Cl)c3c(=O)[nH]ncc3n2COCC[Si](C)(C)C)cc1OCC1CC1
Yield: 64.9 %

Procedure:
Reaction and post treatment were carried out in the same manner as in Example 1-(a) except for using 0.40 g (1.1 mmol) of 2-bromo-3-chloro-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo[2,3-d]pyridazin-4-one obtained in the following Reference example 16-(d) in place of 2-bromo-1-(2-trimethylsilylethoxymethyl)-1,5-dihydropyrrolo-[2,3-d]pyridazin-4-one, and using 0.57 g (1.9 mmol) of 2-(3-cyclopropylmethoxy-4-methoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane obtained in the following Reference example 2-(a) in place of 2-(3-cyclopropoxy-4-difluoromethoxyphenyl)-4,4,5,5-tetramethyl-[1,3,2]dioxaborolane, whereby 0.34 g of the title compound was obtained as a pale yellowish solid. (Yield: 67%)
Reaction SMILES: N(C1CC1)=C=S.N.[CH:8]1([NH:11][C:12]([NH2:14])=[S:13])[CH2:10][CH2:9]1.Br[CH2:16][C:17]([C:19]1[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=1)=O>C1COCC1.CO>[CH:8]1([NH:11][C:12]2[S:13][CH:16]=[C:17]([C:19]3[CH:27]=[CH:26][C:22]([C:23]([OH:25])=[O:24])=[CH:21][CH:20]=3)[N:14]=2)[CH2:10][CH2:9]1
Reactant: O=C(O)c1ccc(C(=O)CBr)cc1
Reactant: NC(=S)NC1CC1
Agent: N
Agent: S=C=NC1CC1
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2csc(NC3CC3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Isothiocyanato-cyclopropane (4 g) was mixed with ammonia (37% in water, 8 mL) and methanol (32 mL) at 0° C. and then stirred for 16 hours at room temperature. The mixture was then cooled to 0° C., filtered, washed with a little water and dried. The Cyclopropyl-thiourea (2.06 mmol) and 4-(2-Bromo-acetyl)-benzoic acid (2.06 mmol) were mixed in THF (12 mL). After stirring at room temperature for 5 minutes the mixture was heated to 80° C. for 2 hours. The mixture was then cooled to room temperature and filtered. The solid was washed with a small amount of diethylether and dried. m/z=261.0 in MS ES+, which was characterized by hplc and MS and used in the next step without any further purification.
Reaction SMILES: Br.[N:2]1([C:8]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:9]=2[CH2:10][CH2:11][C:12](=[O:18])[NH:13]3)[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1.O>CN(C=O)C>[CH3:26][O:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([N:5]2[CH2:6][CH2:7][N:2]([C:8]3[CH:17]=[CH:16][CH:15]=[C:14]4[C:9]=3[CH2:10][CH2:11][C:12](=[O:18])[NH:13]4)[CH2:3][CH2:4]2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C1CCc2c(cccc2N2CCNCC2)N1
Reactant: COc1ccc(C(=O)Cl)cc1
Agent: Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(=O)N2CCN(c3cccc4c3CCC(=O)N4)CC2)cc1
Temperature: 25 °C
Yield: 36.1 %

Procedure:
5-(1-Piperazinyl)-3,4-dihydrocarbostyril monohydrobromide (2.6 g) and 2.34 ml of triethylamine were dissolved in 40 ml of DMF. The mixture was stirred at room temperature while slowly adding dropwise 10 ml of DMF solution containing 2.5 g of 4-methoxybenzoyl chloride. After completion of addition the reaction mixture was stirred for 30 minutes. The reaction mixture was poured into a large amount of water and extracted with chloroform. The extract was washed with saturated sodium hydrogencarbonate solution and subsequently with water and dried over anhydrous sodium sulfate. Chloroform was distilled off and residual crystals were recrystallized from methanol-chloroform to give 1.1 g of 5-[4-(4-methoxybenzoyl)-1-piperazinyl]-3,4-dihydrocarbostyril, m.p. 219°-220° C., colorless needles.
Reaction SMILES: [C:1]([C:5]1ON=[C:7]([C:10]([NH:12][CH:13]=[O:14])=O)[CH:6]=1)([CH3:4])(C)C.CN.[C:17]([NH2:25])(=O)C1C=CC=CC=1.[CH3:26]NC>>[CH3:17][NH:25][C:13]([N:12]([CH3:26])[C:10]1[CH:4]=[CH:1][CH:5]=[CH:6][CH:7]=1)=[O:14]
Reactant: CC(C)(C)c1cc(C(=O)NC=O)no1
Reactant: CNC
Reactant: NC(=O)c1ccccc1
Agent: CN
Product: CNC(=O)N(C)c1ccccc1
Yield: 64.7 %

Procedure:
The procedures of Example 1 were repeated except that (5-t-butyl-3-isooxazoyl)formamide and methylamine were replaced with benzamide and dimethylamine, respectively, to give N,N'-dimethyl-N'-phenylurea in 64.70% yield.
Reaction SMILES: C([Si](C1C=CC=CC=1)(C1C=CC=CC=1)[O:6][C:7]1[CH:8]=[C:9]([C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:16]=2)=[O:14])[CH:10]=[CH:11][CH:12]=1)(C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:6][C:7]1[CH:8]=[C:9]([C:13]([C:15]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH2:24][CH:25]([CH3:27])[CH3:26])[N:16]=2)=[O:14])[CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)Cn1nc(C(=O)c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)c2ccccc21
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CC(C)Cn1nc(C(=O)c2cccc(O)c2)c2ccccc21

Procedure:
[3-(tert-Butyl-diphenyl-silanyloxy)-phenyl]-(1-isobutyl-1H-indazol-3-yl)-methanone (0.650 g, 0.0012 mol) was dissolved in dry THF (1 mL) in a glass vial. The vial was cooled to −78 C in a dry ice/acetone bath. TBAF (1.8 mL of a 1 M soln., 0.0018 mol) was added. The vial was removed from the bath and stirred until a dark yellow color persisted (approx. 1 minute). The vial was placed back in the bath and the progress of the reaction was followed by TLC. When complete, the reaction was quenched with aqueous HCl (1-2N), adsorbed on a small plug of silica gel, and chromatographed with hexane/ethyl acetate (10:1) to give the desired product.