Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)C=O.[C:6]([C@@H:9]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=2[S:21][CH2:20]1)[CH2:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([OH:8])=[O:7].C(=O)(O)[O-].[Na+].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>O>[CH2:44]([O:7][C:6]([C@@H:9]([NH:18][C@@H:19]1[C:25](=[O:26])[N:24]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:23]2[CH:35]=[CH:36][CH:37]=[CH:38][C:22]=2[S:21][CH2:20]1)[CH2:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:8])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)O)CSc2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)CN1C(=O)[C@@H](N[C@@H](CCc2ccccc2)C(=O)OCc2ccccc2)CSc2ccccc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.9 %

Procedure:
A mixture of 10 ml of N,N-dimethylformamide, 0.3 g of tert-butyl 3(R)-[1(S)-carboxy-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate obtained in Example 43, 0.5 g of sodium bicarbonate and 0.15 g of benzyl bromide is stirred at room temperature overnight. The mixture is diluted with water (100 ml) and extracted with ethyl acetate (200 ml). The extract is washed successively with 0.1N hydrochloric acid and water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 0.35 g of tert-butyl 3(R)-[1(S)-benzyloxycarbonyl-3-phenylpropyl]amino-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetate as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([F:8])[C:5]([Cl:9])=[CH:4][C:3]=1[F:10].C([Mg]Br)(C)C.C(O[B:20]1[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]1)(C)C.[Cl-].[NH4+]>C1COCC1>[Cl:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([B:20]2[O:24][C:23]([CH3:26])([CH3:25])[C:22]([CH3:28])([CH3:27])[O:21]2)=[C:3]([F:10])[CH:4]=1
Reactant: Fc1cc(Br)c(F)cc1Cl
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(C)OB(c2cc(F)c(Cl)cc2F)OC1(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 62.1 %

Procedure:
To a solution of 1-bromo-4-chloro-2,5-difluorobenzene (200 mg, 0.879 mmol) in THF (10 mL) cooled to −10° C. was added isopropylmagnesium bromide (1M in THF, 1.055 mL, 1.055 mmol) dropwise and the reaction mixture was stirred at this temperature for 1 h. The reaction mixture was then warmed to 0° C. and stirred for another 1 h. The resultant mixture was again cooled to −10° C. and treated dropwise with a solution of 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (196 mg, 1.055 mmol). The reaction mixture was allowed to warm up to room temperature and treated with a saturated solution of ammonium chloride (3 mL). The layers were separated and aqueous layer was extracted with dichloromethane (2×2 mL). The combined organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford crude compound which was purified by column chromatography on a silica (7:3-Ethyl acetate:hexane) to afford 2-(4-chloro-2,5-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (150 mg, 0.546 mmol, 62% yield) as an oil. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.46-7.49 (m, 1H), 7.09-7.13 (m, 1H), 1.35 (s, 12H).
Reaction SMILES: O.[OH-].[Li+].C[O:5][C:6](=[O:27])[C@@H:7]1[CH2:11][C@@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][N:8]1[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].CO>O.O1CCCC1>[C:23]([O:22][C:20]([N:8]1[CH2:9][C@H:10]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:11][C@H:7]1[C:6]([OH:27])=[O:5])=[O:21])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)[C@@H]1C[C@@H](NC(=O)OC(C)(C)C)CN1C(=O)OC(C)(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 39.3 %

Procedure:
A solution of lithium hydroxide monohydrate (86 mg) in water (7 mL) was added to a cold (0° C.) stirred solution of N-tert-butoxycarbonyl-trans-4-(tert-butoxycarbonylamino)-L-proline methyl ester (N, 589 mg) in tetrahydrofuran (21 mL)-methanol (7 mL). The mixture was stirred at room temperature for 5 hr and evaporated in vacuo. The residue was diluted with water and washed with ether. The aqueous layer was acidified with 1 N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and evaporated in vacuo to give the title compound (222 mg) as a colorless foam: 1H NMR (400 MHz, CDCl3) δ 1.35-1.57 (m, 18H), 2.05-2.52 (m, 2H), 3.19-3.37 (m, 1H), 3.66-3.81 (m, 1H, 4.17-4.45 (m, 2H), and 4.63-4.87 (m, 1H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CS(O[C@@H:10]([CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])(=O)=O.O>CS(C)=O>[N:1]([C@H:10]([CH3:28])[CH2:11][CH2:12][CH2:13][CH2:14][N:15]1[C:24](=[O:25])[C:23]2[N:22]([CH3:26])[CH:21]=[N:20][C:19]=2[N:18]([CH3:27])[C:16]1=[O:17])=[N+:2]=[N-:3]
Reactant: C[C@@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](CCCCn1c(=O)c2c(ncn2C)n(C)c1=O)N=[N+]=[N-]
Temperature: 50 °C
Reaction time: 12 h
Yield: 78.8 %

Procedure:
Sodium azide (7.11 g, 0.1 mol) was added to a solution of (S)-1-(5-methanesulfonyloxyhexyl)-3,7-dimethylxanthine (19.6 g, 54 mmol) in dimethylsulfoxide (100 ml) and stirred at 50° C. for 12 hours. The mixture was treated with water (200 ml) and extracted with ethyl acetate (3x 100 ml). The combined extracts were washed with water (125 ml), with saturated aqueous sodium chloride solution (150 ml), dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with ethyl acetate to give (R)-1-(5-azidohexyl)-3,7-dimethylxanthine (13 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3([C:22]([NH:24][C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)=[O:23])[CH2:21][CH2:20]3)=[O:18])=[C:11]([F:32])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH2:33]([N:35]([CH2:38][CH3:39])[CH2:36]C)C.ClC(OC1C=CC=CC=1)=[O:42].C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)(=O)C>[N:35]1([C:33]([NH:1][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4([C:22]([NH:24][C:25]5[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=5)=[O:23])[CH2:21][CH2:20]4)=[O:18])=[C:11]([F:32])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:42])[CH2:36][CH2:39][CH2:38]1
Reactant: Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CCN(CC)CC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(Nc1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1)N1CCC1
Reaction time: 0.5 h
Yield: 79 %

Procedure:
N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide (100.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogen atmosphere, and triethylamine (0.0630 ml) and phenyl chloroformate (0.0624 ml) were added dropwise at 0° C. in this order, followed by stirring for 30 min. The reaction mixture was stirred after addition of ethyl acetate (5 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was separated, washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. The residue was dissolved in N,N-dimethylformamide (1.0 ml). Triethylamine(0.315 ml) and azetidine hydrochloride (84.6 mg) were added at room temperature, followed by stirring for 16.5 hr. The reaction mixture was partitioned between ethyl acetate (10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was concentrated under reduced pressure. To the residue were added ethyl acetate (3 ml) and heptane (3 ml) to precipitate a solid. The solid was collected by filtration. The resultant solid was washed with heptane:ethyl acetate=1:1, dried under hot air at 60° C. for 4 hr to provide the titled compound as white powder (94.0 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[N:15])[CH2:10][CH2:9]1.[Li+].[CH3:18]C([N-]C(C)C)C.CI.O>C1COCC1>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[N:8]1[CH2:13][CH2:12][C:11]([CH3:18])([C:14]#[N:15])[CH2:10][CH2:9]1
Reactant: CC(C)[N-]C(C)C
Reactant: N#CC1CCN(c2c(Cl)cncc2Cl)CC1
Agent: [Li+]
Solvent: CI
Solvent: C1CCOC1
Solvent: O
Product: CC1(C#N)CCN(c2c(Cl)cncc2Cl)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 36 %

Procedure:
To a solution of 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile E48 (90 mg, 0.35 mmol) in THF (1.5 mL), at −78° C., was added a 1M solution of LDA in THF (0.38 mL, 0.38 mmol). The mixture was stirred for 30 min at −78° C. before warming to r.t. After 60 min, methyl iodide (31 μL, 0.5 mmol) was added. The mixture was stirred for a further 60 min at r.t. for 1 h, before addition of water (5 mL). The mixture was extracted with CH2Cl2 (3×5 mL) and the combined organic extracts were dried over MgSO4 and concentrated under reduced pressure to dryness. The crude product was purified by flash column chromatography on silica gel (hexane, EtOAc, 100:0-80:20, biotage 25+M) to furnish the title compound as a white solid (34 mg, 36%), along with recovered 1-(3,5-dichloropyridin-4-yl)piperidine-4-carbonitrile (23 mg, 25%), LC-MS (ESI, 4 min) Rt 3.09 min, m/z 270 (100%, W); m/z (ESI) C12H13Cl2N3 requires 269.0487 found [M+H]+ 289.0488.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH:7]([CH2:9][OH:10])[O:6]C1C1C=CC=CC=1.[Cl:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=2)[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=1>CN(C=O)C>[ClH:17].[CH3:3][NH:4][CH2:8][CH:7]([OH:6])[CH2:9][O:10][C:18]1[C:27]2[C:22](=[CH:23][C:24]([CH3:28])=[CH:25][CH:26]=2)[N:21]=[C:20]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)cc(-c3ccccc3)nc2c1
Reactant: CN1CC(CO)OC1c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CNCC(O)COc1cc(-c2ccccc2)nc2cc(C)ccc12
Product: Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 17.4 %

Procedure:
To a 0° C. suspension of NaH (0.11 g, 2.5 mmol, 55% in mineral oil) in DMF (3 ml) was added dropwise a DMF solution (3 ml) of a mixture of (2RS,5RS) and (2RS,5SR) (3-methyl-2-phenyl-oxazolidin-5-yl)-methanol (0.46 g, 2.4 mmol) in DMF (3 ml). After 15 min. at 0° C. and 2 hours at room temperature, reaction mixture was cooled to 0° C. and treated with a solution of 4-chloro-7-methyl-2-phenyl-quinoline (0.3 g, 1.2 mmol) in DMF (3 ml). After 5 min. at 0° C. and 21 hours at room temperature, the reaction mixture was cooled to 0° C., quenched with H2O (0.5 ml), and concentrated. The residue was treated with 1N HCl (6 ml). The so obtained yellow aqueous solution was extracted with CH2Cl2 (3×20 ml). Organic phases were washed with 1N HCl (2×10 ml). Combined aqueous phases were basified to pH 11 with 2N NaOH, and extracted with CH2Cl2 (3×20 ml). Combined organic phases were dried over Na2SO4 and concentrated. The residue was crystallized with Et2O to provide after filtration 95 mg of a white solid which was dissolved in MeOH. HCl-Et2O was added to provide (RS)-1-methylamino-3-(7-methyl-2-phenyl-quinolin-4-yloxy)-propan-2-ol hydrochloride (0.075 g, 16%) as a white solid, MS: m/e=323.3 (M+H+).
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)=S)[CH3:2].[N:17]#[C:18][NH2:19].[Pb]>>[C:18]([NH:19][C:4]([NH:3][CH2:1][CH3:2])=[N:6][CH2:7][CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[N:15][CH:14]=[CH:13][N:12]=1)#[N:17]
Reactant: CCNC(=S)NCCNCc1cnccn1
Reactant: N#CN
Agent: [Pb]
Product: CCNC(=NCCNCc1cnccn1)NC#N

Procedure:
Reacting N-(2-pyrazinylmethyl)ethylenediamine with ethyl isothiocyanate by the procedure of Example 3 and chromatographing gives N-ethyl-N'-[2-(2-pyrazinylmethylamino)ethyl]thiourea. Reacting this thiourea with lead cyanamide by the procedure of Example 3 gives N-cyano-N'-ethyl-N"-[2-(2-pyrazinylmethylamino)ethyl]guanidine.
Reaction SMILES: CS(C)=O.[C:5](Cl)(=O)[C:6](Cl)=O.C(C1C=CC=CC=1[CH2:15][O:16][C:17](=[O:25])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][OH:24])#N.C([N:32]([CH2:35][CH3:36])CC)C>ClCCl>[C:35]([C:36]1[CH:6]=[CH:5][CH:17]=[CH:18][C:19]=1[CH2:20][CH:22]([CH:23]=[O:24])[CH2:21][CH2:20][CH2:19][CH2:18][C:17]([O:16][CH3:15])=[O:25])#[N:32]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CCN(CC)CC
Reactant: N#Cc1ccccc1COC(=O)CCCCCCO
Solvent: ClCCl
Solvent: CS(C)=O
Product: COC(=O)CCCCC(C=O)Cc1ccccc1C#N
Temperature: -60 °C
Reaction time: 0.25 h

Procedure:
At −60° C., a solution of 49.37 mg (0.63 mmol) of dimethyl sulfoxide (DMSO) in 0.5 ml of dichloromethane was added dropwise to a solution of 40.10 mg (0.32 mmol) of oxalyl chloride in 2 ml of dichloromethane. The mixture was stirred at −60° C. for 15 min, and a solution of 58.00 mg (0.21 mmol) of methyl &(2-cyanobenzyl)-7-hydroxyheptanoate from Ex. XXIIId in 1 ml of dichloromethane was then added dropwise. The mixture was stirred at −60° C. for another 15 min, 106.58 mg (1.05 mmol) of triethylamine were added, the cooling bath was removed and the mixture was stirred for 2 h. Water was added, the mixture was extracted with dichloromethane, the combined organic phases were dried over Na2SO4, the solvent was removed and the crude product was dried under high vacuum. The resulting aldehyde could be used without further purification.
Reaction SMILES: CO.[CH2:3]([O:10][C:11]1[CH:16]=[CH:15][C:14]([CH2:17][C:18]#[C:19][Si](C)(C)C)=[CH:13][CH:12]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH2:3]([O:10][C:11]1[CH:12]=[CH:13][C:14]([CH2:17][C:18]#[CH:19])=[CH:15][CH:16]=1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: C[Si](C)(C)C#CCc1ccc(OCc2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#CCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.3 %

Procedure:
To a solution of methanol (20 mL) of (3-(4-benzyloxy-phenyl)-prop-1-ynyl)-trimethyl-silane (910 mg) described in Manufacturing Example 12-1 was added potassium carbonate (850 mg) at room temperature, which was stirred for 4 hours and 10 minutes at room temperature. Water was added to the reaction solution, which was then extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and then the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (heptane:ethyl acetate=20:1) to obtain the titled compound (620 mg).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].Br.[NH2:7][C:8]1[NH:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1.C(=O)(O)[O-].[Na+]>CC(C)=O>[CH3:5][O:4][C:2]([NH:7][C:8]1[NH:9][CH2:10][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:12]=1)=[O:3]
Reactant: COC(=O)Cl
Reactant: NC1=NC(c2ccccc2)CN1
Agent: Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: COC(=O)NC1=NC(c2ccccc2)CN1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
This example illustrates another process embodiment of the invention wherein an alkyl chloroformate is used as one of the reagents. In this example, 0.8 g. of methyl chloroformate is added over a five minute period to a stirring mixture of 2 g. 2-amino-4-phenyl-2-imidazoline hydrobromide, 1.4 g. sodium bicarbonate, and 20 ml. acetone held at 0° C. After addition is complete, the mixture is allowed to warm to room temperature and then stirred for 16 hours at room temperature. The mixture is distilled to a low volume and 50 ml. of water is then added. The mixture is filtered and the precipitate collected and washed with water and then dried affording 4,5-dihydro-2-methoxycarbonylamino-4-phenylimidazole which is then further purified by recrystallizaton from chloroform.
Reaction SMILES: [CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([O:13]C(C)(C)C)=O)[C@H:8]([C:18]([OH:20])=O)[CH2:7]1)[CH:2]=[CH2:3].[N:21]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=1)=C=O.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][C:41]=1[O:42][CH3:43])[CH2:37][NH2:38]>>[CH2:1]([O:4][N:5]=[C:6]1[CH2:10][N:9]([C:11]([NH:21][C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH3:31])[CH:25]=2)=[O:13])[C@H:8]([C:18]([NH:38][CH2:37][C:36]2[CH:39]=[CH:40][C:41]([O:42][CH3:43])=[C:34]([O:33][CH3:32])[CH:35]=2)=[O:20])[CH2:7]1)[CH:2]=[CH2:3]
Reactant: COc1ccc(CN)cc1OC
Reactant: C=CCON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Reactant: COc1cccc(N=C=O)c1
Product: C=CCON=C1C[C@@H](C(=O)NCc2ccc(OC)c(OC)c2)N(C(=O)Nc2cccc(OC)c2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-4-[(allyloxy)imino]-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid, 1-isocyanato-3-methoxybenzene, and 3,4-dimethoxybenzylamine the title compound was obtained in 97% purity by LC/MS. MS(ESI+): m/z=483.2.
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:8])[N:5]=[C:4]([CH:16]2[CH2:18][CH2:17]2)[CH:3]=1.CO.C1(N=C=O)C=CC=CC=1.[OH-].[Na+]>>[CH:16]1([C:4]2[CH:3]=[C:2]([NH:6][C:7]([NH:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)=[O:8])[NH:1][N:5]=2)[CH2:18][CH2:17]1
Reactant: Nc1cc(C2CC2)nn1C(=O)Nc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O=C=Nc1ccccc1
Solvent: CO
Product: O=C(Nc1ccccc1)Nc1cc(C2CC2)n[nH]1
Yield: 20.6 %

Procedure:
To 5-amino-3-cyclopropyl-N-phenyl-1H-pyrazole-l-carboxamide (0.5 g, 2 mmol) in 6 ml of methanol 0.5 ml (4.6 mmol)of phenylisocyanate and 2 ml of 10% NaOH were added. The mixture was refluxed for about 2h, then cooled, quenched with 10% HCl and extracted with ethyl acetate. The organic phase was washed with 10% HCl, water and brine. Concentration and chromatography on silica gel, eluting with 8% to 20% acetone in methylene chloride, afforded 100 mg (20% yield) of N-(3-cyclopropyl-1H-pyrazol-5-yl)-N′-phenylurea as a colorless, glassy solid.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([C:14](OC)=[O:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[CH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1.C(OCC)C>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([CH2:14][OH:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[CH2:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: C=CC1(c2cc(C(=O)OC)ccc2-c2cc(OC)ncc2F)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: C=CC1(c2cc(CO)ccc2-c2cc(OC)ncc2F)CCCC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-vinylcyclopentyl)benzoate 66.67E (51.0 mg, 143 μmol) in THF (2.0 mL) was slowly added LAH, (1.0M solution in diethyl ether) (0.30 mL, 287 μmol) at room temperature. The resulting mixture was stirred at 50° C. for 1 hour. Standard work up conditions were employed and the solvent was removed. The desired product was used in the next step without further purification. MS ESI (pos.) m/e: 328.2 (M+H)+.
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([NH:11][S:12]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[S:21]([CH3:24])(=[O:23])=[O:22])(=[O:14])=[O:13])[CH:9]=2)[N:4](C(OC(C)(C)C)=O)[N:3]=1.[N:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][C:40]=2B(O)O)[CH:35]=[CH:34][CH:33]=1.C(=O)([O-])O.[Na+]>CN(C)C=O>[CH3:24][S:21]([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:12]([NH:11][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[NH:4][N:3]=[C:2]2[C:40]1[CH:39]=[CH:38][CH:37]=[C:36]2[C:41]=1[N:32]=[CH:33][CH:34]=[CH:35]2)(=[O:14])=[O:13])(=[O:22])=[O:23]
Reactant: OB(O)c1cccc2cccnc12
Reactant: CC(C)(C)OC(=O)n1nc(I)c2cc(NS(=O)(=O)c3ccccc3S(C)(=O)=O)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccccc1S(=O)(=O)Nc1ccc2[nH]nc(-c3cccc4cccnc34)c2c1
Yield: 1.8 %

Procedure:
2-Methylsulfonyl-N-(3-quinolin-8-yl-1H-indazol-5-yl)benzenesulfonamide can be obtained as described in Example 59 from 2 g of tert-butyl 3-iodo-5-(2-methylsulfonylbenzenesulfonylamino)indazole-1-carboxylate, 1.17 g of 8-quinolineboronic acid, 80 ml of dimethylformamide, 7.5 ml of a saturated aqueous sodium hydrogencarbonate solution and 98 mg of tetrakis(triphenylphosphine)palladium[0]. 30 mg of 2-methylsulfonyl-N-(3-quinolin-8-yl-1H-indazol-5-yl)benzenesulfonamide are thus obtained in the form of a pale yellow solid melting at 21 g° C. (analysis C23H18N4O4S2 % calculated C, 57.73; H, 3.79; N, 11.71; O, 13.37; S, 13.4. % found C, 57.10; H, 4.11; N, 11.19; S, 11.94).
Reaction SMILES: [C:1]1([C:7]#C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:9]([CH2:12][CH2:13]CCN1C=CC=C(OCC2C=CC=CC=2)C1=O)=[N+:10]=[N-:11].[C:31]1([N:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][C:45]3N=NN[CH:49]=3)=[C:39]([O:50]C)[C:38]2=[O:52])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:31]1([N:37]2[CH:42]=[CH:41][C:40]([CH2:43][CH2:44][CH2:45][CH2:49][C:13]3[N:11]=[N:10][NH:9][CH:12]=3)=[C:39]([O:50][CH2:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[C:38]2=[O:52])[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: C#Cc1ccccc1
Reactant: [N-]=[N+]=NCCCCn1cccc(OCc2ccccc2)c1=O
Reactant: COc1c(CCc2c[nH]nn2)ccn(-c2ccccc2)c1=O
Product: O=c1c(OCc2ccccc2)c(CCCCc2c[nH]nn2)ccn1-c1ccccc1
Yield: 77 %

Procedure:
Reaction of phenylacetylene (0.124 g, 1.21 mmol) and 157c (0.30 g, 1.01 mmol) within 4 h as described for synthesis of 158a gave compound 158c (0.31 g, 77%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.83 (s, 1H), 7.76 (m, 2H), 7.26 (m, 8H), 6.76 (dd, J=6.9, 1.5 Hz, 1H), 6.56 (dd, J=7.4, 1.5 Hz, 1H), 5.91 (t, J=7.1 Hz, 1H), 4.99 (s, 2H), 4.31 (m, 2H), 3.89 (t, J=7.1 Hz, 2H), 1.85 (m, 2H), 1.67 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 157.71, 148.38, 147.20, 135.83, 130.29, 128.45, 128.41, 128.16, 127.68, 127.63, 126.96, 125.25, 119.87, 114.99, 104.60, 70.26, 49.11, 48.02, 26.78, 25.65. HRMS (EI) calcd for C24H24N4O2 [M]+ 400.1899. found 400.1888.
Reaction SMILES: [C:1](OC1C=CC([N+]([O-])=O)=CC=1)(=[O:3])[CH3:2].[CH3:14][C:15]1([CH3:23])[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][C:16]1=[O:22].C(N(CC)CC)C.CC(C)(O)C#N.C([O-])(=O)C>C(#N)C>[C:1]([CH:17]1[C:16](=[O:22])[C:15]([CH3:23])([CH3:14])[CH2:20][CH2:19][C:18]1=[O:21])(=[O:3])[CH3:2]
Reactant: CC1(C)CCC(=O)CC1=O
Reactant: CC(=O)Oc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: CC(C)(O)C#N
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)C1C(=O)CCC(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A 50-mL single neck round bottom flask was charged with 4-nitrophenyl acetate (2.03 g, 11.2 mmol), 4,4-dimethyl-1,3-cyclohexanedione (2.10 g, 15 mmol) and acetonitrile (15 mL). Then triethylamine (2.5 g, 25 mmol) and acetone cyanohydrin (0.14 mL, 1.5 mmol) were added and the mixture was stirred for 2 hours at ambient temperature. NMR analysis of an aliquot showed that 43% of the starting acetate was still unreacted. The mixture was then refluxed for 2 hours after which time NMR analysis of an aliquot showed no starting acetate remaining.