Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1)#[N:2].Br[C:13]1[CH:19]=[CH:18][C:16]([NH2:17])=[C:15]([N+:20]([O-:22])=[O:21])[CH:14]=1>O1CCCC1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[NH2:17][C:16]1[CH:18]=[CH:19][C:13]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:14][C:15]=1[N+:20]([O-:22])=[O:21]
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: Nc1ccc(Br)cc1[N+](=O)[O-]
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: N#Cc1cccc(-c2ccc(N)c([N+](=O)[O-])c2)c1
Temperature: 85 °C

Procedure:
A stirred solution of 3-cyanophenyl boronic acid (812 mg) and tetrakis(triphenylphosphine) palladium (150 mg) in tetrahydrofuran (4 mL) under at atmosphere of nitrogen was treated with 4-bromo-2-nitroaniline in tetrahydrofuran (10 mL). The reaction mixture was heated at 85° C. for 48 hours, then cooled to ambient temperature and then partitioned between ethyl acetate and water. The organic layer was washed with brine, then dried over magnesium sulfate and then evaporated. The residue was subjected to flash column chromatography on silica eluting with a mixture of ethyl acetate and hexane (1:2, v/v) to give 4′-amino-3′-nitro-biphenyl-3-carbonitrile (224 mg) as a yellow solid. LC-MS (METHOD B): RT=3.21 minutes, 240.3 (M+H)+. (b) 2-nitro-4-pyridine-3-yl-phenylamine
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH2:24])[CH2:20][CH:21]([CH3:23])[CH3:22])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:26]1[C:38]2[C:37](=[O:39])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]=2[C:29]([C:40](Cl)=[O:41])=[CH:28][CH:27]=1>>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:25])[C@@H:13]2[CH2:17][CH2:16][CH2:15][N:14]2[CH2:18][C@@H:19]([NH:24][C:40]([C:29]2[C:30]3[C:31]4[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:37](=[O:39])[C:38]=3[CH:26]=[CH:27][CH:28]=2)=[O:41])[CH2:20][CH:21]([CH3:22])[CH3:23])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(Cl)c1cccc2c1-c1ccccc1C2=O
Reactant: CC(C)C[C@H](N)CN1CCC[C@H]1C(=O)NCCCCc1ccccc1
Product: CC(C)C[C@@H](CN1CCC[C@H]1C(=O)NCCCCc1ccccc1)NC(=O)c1cccc2c1-c1ccccc1C2=O
Yield: 16.4 %

Procedure:
Using the procedure described in Example 7, treatment of 1-[2-(S)-amino-4-methylpentyl ]-L-proline 4-phenylbutylamide (134 mg) with 9-fluorenone-4-carbonyl chloride (131 mg) provided 35 mg(18%) of the title compound. The 1H NMR and Mass spectrum analysis of this compound was consistent with the structure.
Reaction SMILES: [CH3:1][C:2]([CH3:23])([O:4][C:5]([NH:7][C@@H:8]([C:12]12[CH2:21][CH:16]3[CH2:17][CH:18]([CH2:20][C:14]([OH:22])([CH2:15]3)[CH2:13]1)[CH2:19]2)[C:9](O)=[O:10])=[O:6])[CH3:3].CS(Cl)(=O)=O.C(N(C(C)C)CC)(C)C.Cl.[C@H:39]12[CH2:44][C@H:43]1[CH2:42][C@@H:41]([C:45]([NH2:47])=O)[NH:40]2.OC1C2N=NNC=2C=CC=1>C1COCC1>[C:45]([C@@H:41]1[CH2:42][C@H:43]2[C@H:39]([CH2:44]2)[N:40]1[C:9](=[O:10])[C@H:8]([C:12]12[CH2:19][CH:18]3[CH2:17][CH:16]([CH2:15][C:14]([OH:22])([CH2:20]3)[CH2:13]1)[CH2:21]2)[NH:7][C:5]([O:4][C:2]([CH3:23])([CH3:1])[CH3:3])=[O:6])#[N:47]
Reactant: NC(=O)[C@@H]1C[C@@H]2C[C@@H]2N1
Reactant: CC(C)(C)OC(=O)N[C@H](C(=O)O)C12CC3CC(CC(O)(C3)C1)C2
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21)C12CC3CC(CC(O)(C3)C1)C2
Temperature: -6 °C
Reaction time: 8 h

Procedure:
A 2 L three-necked flask equipped with a thermometer, a mechanical stirrer and a gas inlet was charged with (αS)-α[[(1,1-dimethylethoxy)carbonyl]amino]-3-hydroxytricyclo[3.3.1.13,7]decane-1-acetic acid (Formula 3) (50 grams, 153.8 mmol). THF (200 ml) was added and stirred to produce a clear solution. The solution was cooled to −6° C. in an acetone-dry ice-water bath. Methanesulfonyl chloride (Mes-C1) (13.1 ml, 169 mmol, 1.1 equivalents) was then added as a single portion followed by diisopropylethylamine (94 ml, 539 mmol, 1.1 equivalents). The diisopropylethylamine was added slowly over a period of about 4 minutes to keep the internal temperature below 8° C. The reaction mixture was stirred at 0° C. until all acid was converted to mixed anhydride. (1S,3S,5S)-2-azabicyclo[3.1.0]hexane-3-carboxamide hydrochloride salt (32.5 grams, 200 mmol, 1.1 equivalents) and hydroxybenzotriazole (HOBT) (1.04 grams, 7.6 mmol, 0.05 equivalents) were then added in a single portion and the flask was removed from the cooling bath. The reaction mixture was stirred at room temperature for 2 hours and then left overnight at room temperature.
Reaction SMILES: S(=O)(=O)(O)O.[Cl:6][C:7]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[CH3:18]O>>[Cl:6][C:7]1[C:15]([CH3:16])=[C:14]([Cl:17])[CH:13]=[CH:12][C:8]=1[C:9]([O:11][CH3:18])=[O:10]
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccc(Cl)c(C)c1Cl

Procedure:
60 ml of concentrated sulfuric acid were added dropwise to a solution of 424.0 g (2 mol) of 2,4-dichloro-3-methylbenzoic acid and 1500 ml of methanol. After heating for 5 hours under reflux, the reaction mixture was cooled, concentrated under reduced pressure and then taken up in 1000 ml of methylene chloride. The organic phase was washed with water, then with 5% strength of sodium hydrogen carbonate solution and then again with water, dried and concentrated under reduced pressure. 401.0 g of methyl 2,4-dichloro-3-methylbenzoate were obtained.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:11])[CH2:5][CH:6](Br)[CH2:7][CH2:8][CH3:9])[CH3:2].[Na].[OH:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1>O1CCCC1>[CH2:1]([O:3][C:4](=[O:11])[CH:5]([O:13][C:14]1[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=1)[CH2:6][CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(Br)CC(=O)OCC
Reactant: Oc1cccnc1
Agent: [Na]
Solvent: C1CCOC1
Product: CCCCC(Oc1cccnc1)C(=O)OCC
Yield: 34 %

Procedure:
To a solution of ethyl-3-bromohexanoate, 5.0 g (22.4 mmol) in 200 mL of tetrahydrofuran was added 4.6 g (26.9 mmol) of 3-hydroxypyridine sodium salt. The mixture was refluxed for four hours and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The organics were washed with saturated aqueous sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness. The residue was purified by column chromatography using a methanol/chloroform gradient as eluent and concentrated to dryness to yield 1.82 g (34%) of the desired mixture of isomers as a brown liquid. MS (ion spray) 238.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].O.[O:18]=[C:19](Cl)OC(Cl)(Cl)Cl>O1CCOCC1>[N:11]1([C:8]2[CH:7]=[C:3]3[C:4]([O:6][C:19](=[O:18])[NH:1][C:2]3=[CH:10][CH:9]=2)=[O:5])[CH2:12][CH2:13][O:14][CH2:15][CH2:16]1
Reactant: Nc1ccc(N2CCOCC2)cc1C(=O)O
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c2ccc(N3CCOCC3)cc2c(=O)o1

Procedure:
To the mixture of 8.9 g of 2-amino-5-(morpholin-4-yl)benzoic acid in 60 mL of dioxane, under stirring and external cold water cooling 10 mL of diphosgene is added dropwise. The mixture is heated under reflux conditions for 4 hours. From the cold reaction mixture the solid material is filtered off, washed with 50 mL of ether. The product is stirred for 5 minutes in the mixture of 50 mL of methanol and 5 mL of triethylamine, it is filtered off and washed with 30 mL of methanol. After drying 7 g of the title product is obtained, m.p.: 235° C.
Reaction SMILES: F[C:2]1[CH:9]=[C:8]([N:10]2[C@H:14]([CH3:15])[CH2:13][C@@:12]([OH:17])([CH3:16])[C@@H:11]2[CH3:18])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[CH3:19][O-:20].[Na+].O>CS(C)=O>[OH:17][C@@:12]1([CH3:16])[CH2:13][C@@H:14]([CH3:15])[N:10]([C:8]2[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([O:20][CH3:19])[CH:9]=2)[C@H:11]1[CH3:18]
Reactant: C[O-]
Reactant: C[C@@H]1C[C@](C)(O)[C@H](C)N1c1ccc(C#N)c(F)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc(N2[C@H](C)C[C@](C)(O)[C@@H]2C)ccc1C#N
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 50.3 %

Procedure:
To a solution (5 mL) of 2-fluoro-4-[(2S,3S,5R)-3-hydroxy-2,3,5-trimethylpyrrolidin-1-yl]benzonitrile (47.6 mg) in DMSO was added sodium methoxide (35 mg) and the mixture was stirred at 100° C. for 3.5 hr. Sodium methoxide (130 mg) was added, and the mixture was stirred at 100° C. for 4.5 hr. The reaction mixture was added to water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=50/1→2/3) to give the title compound as a colorless solid (yield: 25.1 mg, yield: 50%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]([CH:14]([F:16])[F:15])=[C:7]([CH:13]=1)[C:8]([N:10]=[C:11]=[O:12])=O)#[N:2].[F:17][C:18]([F:35])([F:34])[C:19]1[CH:24]=[CH:23][C:22]([NH:25][NH:26]C(OC(C)(C)C)=O)=[CH:21][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:15][CH:14]([F:16])[C:6]1[C:7]([C:8]2[NH:10][C:11](=[O:12])[N:25]([C:22]3[CH:23]=[CH:24][C:19]([C:18]([F:17])([F:35])[F:34])=[CH:20][CH:21]=3)[N:26]=2)=[CH:13][C:3]([C:1]#[N:2])=[CH:4][N:5]=1
Reactant: N#Cc1cnc(C(F)F)c(C(=O)N=C=O)c1
Reactant: CC(C)(C)OC(=O)NNc1ccc(C(F)(F)F)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1cnc(C(F)F)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Yield: 22.8 %

Procedure:
The title compound was prepared by following the procedure as described in Example-83 by using 5-cyano-2-(difluoromethyl)nicotinoyl isocyanate (Intermediate-145, 0.900 g, 4.03 mmol), tert-butyl 2-(4-(trifluoromethyl)phenyl)hydrazinecarboxylate (Intermediate-53, 1.0 g, 163 mmol), TFA (10 mL), DCM (40 mL) to afford 0.350 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.45-7.56 (t, J=53.4 Hz, 1H), 7.90 (d, J=9.3 Hz, 2H), 8.20 (d, J=8.7 Hz, 2H), 8.77 (s, 1H), 9.32 (s, 1H), 13.01 (s, 1H); MS (m/z): 382.15 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:10]=[C:11]([C:14]([NH:16][NH2:17])=[O:15])[NH:12][N:13]=1.[OH:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=O>C(O)C>[OH:18][C:19]1[CH:26]=[C:25]([OH:27])[CH:24]=[CH:23][C:20]=1[CH:21]=[N:17][NH:16][C:14]([C:11]1[NH:12][N:13]=[C:9]([C:3]2[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH:10]=1)=[O:15]
Reactant: O=Cc1ccc(O)cc1O
Reactant: NNC(=O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Solvent: CCO
Product: O=C(NN=Cc1ccc(O)cc1O)c1cc(-c2ccc(Cl)cc2Cl)n[nH]1
Yield: 66 %

Procedure:
In ethanol (30 ml), 5-(2,4-dichlorophenyl)-2H-pyrazole-3-carboxylic acid hydrazide (136 mg) prepared in the Step 21-1-1 and 2,4-dihydroxybenzaldehyde (69 mg) was heated under reflux for 29 hours. Crystal appeared as the mixture was concentrated under a reduced pressure, the resulting crystal was separated by filtration, washed with ethanol, washed with ethyl acetate, and dried to give the title compound (129 mg, 66%).
Reaction SMILES: [CH3:1][C:2]([CH3:6])(O)[C:3]#[N:4].[OH2:7]>>[CH3:1][C:2]1([CH3:6])[NH:4][CH2:3][C:2]([CH3:6])([CH3:1])[NH:4][C:3]1=[O:7]
Reactant: O
Reactant: CC(C)(O)C#N
Product: CC1(C)CNC(C)(C)C(=O)N1

Procedure:
In a manner analogous to that described in example 3A above, 2,methyl-1,2-diaminopropane, water and acetone cyanohydrin are reacted, and the reaction product recovered. When dissolved in acetone and recrystallized it is identified as 3,3,6,6-tetramethyl-2-piperazinone.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1C(=O)C2=CC=CC=C2C1=O.[Cl:16][C:17]1[CH:35]=[CH:34][C:20]([CH:21]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[NH2:5][CH2:4][CH2:3][CH2:2][N:31]1[CH2:30][CH2:29][N:28]([CH:21]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:20]2[CH:19]=[CH:18][C:17]([Cl:16])=[CH:35][CH:34]=2)[CH2:33][CH2:32]1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: Clc1ccc(C(c2ccccc2)N2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NCCCN1CCN(C(c2ccccc2)c2ccc(Cl)cc2)CC1
Temperature: 70 °C
Reaction time: 2.5 h
Yield: 102.1 %

Procedure:
A mixture of N-(3-bromopropyl)phthalimide (26.8 g), 1-(4-chlorobenzhydryl)piperazine (28.6 g) and anhydrous potassium carbonate (13.8 g) in dimethylformamide (150 ml) was stirred at 70° C. for 2.5 hours. After being cooled to ambient temperature, the reaction mixture was poured into ice-water. The crystalline precipitate was collected by filtration, dried and dissolved in ethanol (800 ml). To the solution was added hydrazine hydrate (11.0 g) and the mixture was refluxed for 20 hours. The reaction mixture was hot-filtered and stood to cool. The obtained crystal was suspended in 10% hydrochloric acid (500 ml). The suspension was filtered and the filtrate was concentrated. The resultant residue was neutralized with aqueous sodium carbonate and extracted with chloroform. The extract was washed with water, dried and evaporated in vacuo to give 1-(3-aminopropyl)-4-(4-chlorobenzhydryl)piperazine (35.0 g) as an oil.
Reaction SMILES: Cl[NH:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][CH:4]=1.[CH3:10][CH2:11][C:12](=S)C>>[Cl:9][C:6]1[CH:5]=[C:4]2[C:3](=[CH:8][CH:7]=1)[NH:2][C:11]([CH3:12])=[CH:10]2
Reactant: ClNc1ccc(Cl)cc1
Reactant: CCC(C)=S
Product: Cc1cc2cc(Cl)ccc2[nH]1
Yield: 72 %

Procedure:
This compound was prepared from N-chloro-4-chloroaniline and methylthioacetone following Method A, which gave 6.68 g (0.032 mol, 72%) of the sub-titled product: mp. 64°-64.5° (recr. from cyclohexane ir (KBr) 3350 cm-1 (NH); pmr (CCl4), 2.42 (1H,s,NH), 2.52 and 3.15 (1 resp. 2H,m,aromatic H), 7.72 and 7.90 (3H, s, CH3 and SCH3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9]O)=[C:6]([F:8])[CH:7]=1.[BrH:12].O>C(O)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([F:11])[C:5]([CH2:9][Br:12])=[C:6]([F:8])[CH:7]=1
Reactant: Br
Reactant: OCc1c(F)cc(Br)cc1F
Solvent: CC(=O)O
Solvent: O
Product: Fc1cc(Br)cc(F)c1CBr
Yield: 98 %

Procedure:
A solution of 5-Bromo-2-hydroxymethyl-1,3-difluoro-benzene (0.89 g, 4.0 mmol) and 30 wt % of hydrogen bromide in acetic acid was stirred at room temperature for 90 minutes before it was poured into 80 ml of water. The mixture was extracted with pentane (3×50 ml) and the combined organic layers were washed with water (3×20 ml), dried over MgSO4 and concentrated at low pressure to afford the desired product (10.0 g, 98% yield). 1H NMR (CDCl3) δ: 4.47 (s, 2H), 7.09-7.10 (m, 1H), 7.12-7.13 (m, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1([C:9]2[N:20]=[C:12]3[C:13]([O:18][CH3:19])=[CH:14][CH:15]=[C:16]([I:17])[N:11]3[N:10]=2)[CH2:8][CH2:7]1)=[O:5])C.[Li+].[OH-]>O1CCOCC1.O>[I:17][C:16]1[N:11]2[N:10]=[C:9]([C:6]3([C:4]([OH:5])=[O:3])[CH2:8][CH2:7]3)[N:20]=[C:12]2[C:13]([O:18][CH3:19])=[CH:14][CH:15]=1
Reactant: CCOC(=O)C1(c2nc3c(OC)ccc(I)n3n2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(I)n2nc(C3(C(=O)O)CC3)nc12
Reaction time: 15 h

Procedure:
1-(5-Iodo-8-methoxy-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-cyclopropanecarboxylic acid ethyl ester (compound 305) (0.06 g, 0.16 mmol) was suspended in 1,4-dioxan (1.4 mL) and LiOH (0.01 g, 0.23 mmol) in H2O (0.23 mL) was added. The suspension was stirred for 15 h. The mixture was concentrated in vacuo. H2O and 4N HCL (0.085 mL) was added. Brine was added and the aqueous phase was extracted with DCM (×3). The combined organic phases were dried over Na2SO4, filtered and concentrated in vacuo. The title compound was obtained as a slightly coloured solid.
Reaction SMILES: C([Li])CCC.[C:6]1([C:12]([N:21]([CH3:30])[C@@H:22](C2C=CC=CC=2)C)([C:15]2C=CC=CC=2)[PH2]=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]3[C:47]([CH3:70])=[N:48][N:49]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:50]=3)=[CH:44][CH:45]=2)=O)=[CH:34][CH:33]=1>O1CCCC1>[Cl:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]([C:40]2[CH:41]=[N:42][C:43]([C:46]3[C:47]([CH3:70])=[N:48][N:49]([C:51]([C:64]4[CH:69]=[CH:68][CH:67]=[CH:66][CH:65]=4)([C:58]4[CH:63]=[CH:62][CH:61]=[CH:60][CH:59]=4)[C:52]4[CH:57]=[CH:56][CH:55]=[CH:54][CH:53]=4)[CH:50]=3)=[CH:44][CH:45]=2)=[CH:30][N:21]([CH3:22])[CH:12]([C:6]2[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=2)[CH3:15])=[CH:34][CH:33]=1
Reactant: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=O)c2ccc(Cl)cc2)cn1
Reactant: C[C@H](c1ccccc1)N(C)C([PH2]=O)(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1nn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1-c1ccc(C(=CN(C)C(C)c2ccccc2)c2ccc(Cl)cc2)cn1
Temperature: -15 °C
Reaction time: 0.5 h

Procedure:
n-Butyllithium (0.47 ml, 0.76 mmol, 1.6M in Hexanes) was added dropwise to a solution of (R)(Diphenyl-phosphinoylmethyl)-methyl-(1-phenyl-ethyl)-amine* (0.18 g, 0.51 mmol) in dry tetrahydrofuran (9 ml) at −15° C. After 15 minutes a solution of (4-Chloro-phenyl)-[6-(3-methyl-1-trityl-1H-pyrazol-4-yl)-pyridin-3-yl]-methanone (0.14 g, 0.25 mmol) in tetrahydrofuran (0.9 ml) was added and the reaction mixture was stirred for a further 30 minutes at −15° C. before warming to room temperature over 1 hour. The reaction mixture was quenched with water, extracted with diethyl ether, organic extracts were combined, dried (MgSO4) and concentrated to afford the title compound, which was used in the next step without further purification.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1)=O.Cl.[NH2:28][OH:29].C(N(CC)CC)C.CC1C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[OH:29][N:28]=[CH:1][C:3]1[CH:8]=[CH:7][N:6]2[C:9]([C:12]3[CH:13]=[C:14]([NH:18][C:19]([NH:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[O:20])[CH:15]=[CH:16][CH:17]=3)=[CH:10][N:11]=[C:5]2[CH:4]=1
Reactant: O=Cc1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(C=NO)ccn23)c1
Reaction time: 18 h
Yield: 43.5 %

Procedure:
To a suspension of 1-[3-(7-Formyl-imidazo[1,2-a]pyridin-3-yl)-phenyl]-3-(2,2,2-trifluoro-ethyl)-urea (50 mg, 0.14 mmol) in toluene (5 ml) was added hydroxylamine hydrochloride (11 mg, 0.15 mmol) and triethylamine (21 μl, 0.15 mmol). The reaction mixture was stirred for 10 min before tosic acid (3 mg, 0.014 mmol) was added and then stirred for a further 18 h. The resulting precipitate was filtered off and washed with Et2O to give the product (23 mg). MS: [M+H]+ 378.
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[CH:10]=[CH:9]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>ClCCl>[CH:1]1([C:10]2[C:11]3[C:16](=[CH:15][C:14]([C:17]([O:19][CH3:20])=[O:18])=[CH:13][CH:12]=3)[NH:8][CH:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2cc[nH]c2c1
Reactant: O=C1CCCCC1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c[nH]c2c1
Temperature: 10 °C
Reaction time: 12 h
Yield: 85.5 %

Procedure:
Cyclohexanone (42.46 mL, 0.40 mol) was added in a single portion to a stirred solution of methyl indole-6-carboxylate (47.8 g, 0.27 m) in dry dichloromethane (500 mL). The reaction mixture was then cooled to 10° C. and trifluoroacetic acid (63.13 mL, 0.8 m) was added dropwise followed by triethyl silane (174.5 mL, 1.09 m). Upon addition, the temperature was allowed to rise to rt, after which it was stirred for a further 12 h. Dichloromethane (200 mL) was then added and the reaction mixture was washed successively with 10% sodium bicarbonate solution and brine. The organic layer dried over sodium sulfate, filtered and concentrated under vacuum. The resultant residuce was purified by flash chromatography on silica (60-120) using hexane—ethyl acetate (9.5:0.5) mixture as eluant. Homogeneous fractions were combined and evaporated to give 60 g of the desired product (85%). Analytical data on this material was consistant with that observed with a sample prepared by the alternative route described above.
Reaction SMILES: [Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([NH:14][CH:15]3[CH2:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([N:31]([CH:41]2[CH2:43][CH2:42]2)CC2C=CC(OC)=CC=2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1.IC.[C:51](=O)([O-])[O-].[Cs+].[Cs+]>O1CCCC1>[Cl:1][C:2]1[C:7]([N:8]2[CH2:13][CH2:12][CH:11]([N:14]([CH3:51])[CH:15]3[CH2:19][C:18](=[O:20])[N:17]([CH3:21])[CH2:16]3)[CH2:10][CH2:9]2)=[CH:6][C:5]([C:22]#[N:23])=[CH:4][C:3]=1[NH:24][C:25]1[N:30]=[C:29]([NH:31][CH:41]2[CH2:42][CH2:43]2)[C:28]2=[N:44][CH:45]=[C:46]([C:47]#[N:48])[N:27]2[N:26]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CN(c2nc(Nc3cc(C#N)cc(N4CCC(NC5CC(=O)N(C)C5)CC4)c3Cl)nn3c(C#N)cnc23)C2CC2)cc1
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1CC(N(C)C2CCN(c3cc(C#N)cc(Nc4nc(NC5CC5)c5ncc(C#N)n5n4)c3Cl)CC2)CC1=O
Temperature: 25 °C
Reaction time: 5 h

Procedure:
A vial was charged with 2-((2-chloro-5-cyano-3-(4-((1-methyl-5-oxopyrrolidin-3-yl)amino)piperidin-1-yl)phenyl)amino)-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazine-7-carbonitrile (35 mg, 0.053 mmol) and iodomethane (3.94 μl, 0.063 mmol) in tetrahydrofuran (263 μl). Cesium carbonate (34.2 mg, 0.105 mmol) was added and the reaction mixture was stirred at room temperature 5 h. The reaction mixture was quenched with water and ethyl acetate. The aqueous layer was extracted with ethyl acetate (2×). The combined organics were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude material was used as is in the final deprotection.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7].[N-:11]=[N+:12]=[N-:13].[Na+]>CN(C)C=O.O>[N:11]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([O:8][CH2:9][CH3:10])=[O:7])=[N+:12]=[N-:13]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)CCCCBr
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCCCN=[N+]=[N-]
Yield: 95 %

Procedure:
Ethyl 5-bromovalerate (2.1 g; 10 mmol; Aldrich) was added to a stirred suspension of sodium azide (1.3 g, 20 mmol; Fisher) in 5 ml dimethylformamide and 5 ml water, and the reaction mixture was heated 12 h at 80° Cs. The reaction was partitioned between diethyl ether (100 ml) and water (100 ml), and the resulting organic layer was washed with water (100 ml) and brine (100 ml), dried over sodium sulfate, and dried in vacuo. Yield: 1.6 g (9.3 mmol, 95% yield).
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH2:20]>>[CH3:16][O:17][CH:18]([O:21][CH3:22])[CH2:19][NH:20][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9]
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Reactant: COC(CN)OC
Product: COC(CNC(c1ccccc1)C(O)c1ccccc1)OC
Temperature: 140 °C
Reaction time: 16 h
Yield: 71.3 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mol) and 2,2-dimethoxyethylamine (3.15 g, 0.030 mol) was heated in an oil bath at 140° C. for 5 hours. After standing at ambient temperature for 16 hours, the solid reaction mixture was triturated with isooctane and the white solid that remained was collected by filtration to obtain 2.15 g (71%) of the product. The product was recrystallized from toluene-isooctane; mp 147°-149° C.