Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][CH2:3][S:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)(=[O:6])=[O:5].[H-].[Na+].Br[CH2:16][C@@:17]1([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=[CH:24][CH:23]=2)[CH2:19][CH:18]1[CH2:20]Br.C(OCC)(=O)C.CCCCCC>CN(C)C=O>[C:7]1([S:4]([C:3]2([S:2][CH3:1])[CH2:20][C@H:18]3[C@:17]([C:22]4[C:31]5[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=5)[CH:25]=[CH:24][CH:23]=4)([CH2:19]3)[CH2:16]2)(=[O:5])=[O:6])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCC1C[C@@]1(CBr)c1cccc2ccccc12
Reactant: CSCS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CSC1(S(=O)(=O)c2ccccc2)C[C@@H]2C[C@]2(c2cccc3ccccc23)C1
Temperature: 40 °C
Yield: 145.4 %

Procedure:
1-((Methylthio)methylsulfonyl)benzene (6.54 g, 32.2 mmole) was dissolved in dry dimethylforamide (DMF, 40 mL). Sodium hydride (3.86 g, 80.5 mmol) was added portion wise under nitrogen atmosphere at 0° C. The reaction mass was gradually heated to 40° C. and maintained for 30 minutes at 40° C. (1S)-1,2-bis(bromomethyl)-1-(1-naphthyl)cyclopropane (5.7 g, 6.1 mmol) dissolved in DMF (15 mL) was added dropwise for 30 min at 0° C. The temperature of the reaction mass was gradually brought to room temperature and maintained for 7 hours. The reaction was monitored by TLC (ethyl acetate/hexane (10:90)). The reaction mass was quenched with water. The aqueous layer was extracted with diethyl ether (2×250 mL). The combined organic layer was dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to yield 12.0 g of crude oil that was purified by column chromatography (silica gel, ethyl acetate/hexane (4:96) to yield 3.5 g (53%) of product. 1H NMR δ(300 MHz,CDCl3): 1.93 (2H,m), 2.01 (1H,m), 2.07 (3H,s), 2.28 (2H,m), 2.44 (2H,m), 2.88 (1H, dd, J=15 Hz), 7.36 (1H,m), 7.47-7.68 (7H,m), 7.74 (1H,m), 7.91-7.97 (3H,m).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH3:41])[CH2:16][NH:17][C:18]1[N:19]([CH2:37][C:38]#[C:39][CH3:40])[C:20]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])[N:23]=[CH:22][C:21]=2[N:36]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].CI.O>CS(C)=O>[C:7]([O:11][C:12]([NH:14][C@@H:15]([CH3:41])[CH2:16][N:17]([C:18]1[N:19]([CH2:37][C:38]#[C:39][CH3:40])[C:20]2[C:25](=[O:26])[N:24]([CH2:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=3[C:34]#[N:35])[N:23]=[CH:22][C:21]=2[N:36]=1)[CH3:1])=[O:13])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)[O-]
Reactant: CC#CCn1c(NC[C@H](C)NC(=O)OC(C)(C)C)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CS(C)=O
Product: CC#CCn1c(N(C)C[C@H](C)NC(=O)OC(C)(C)C)nc2cnn(Cc3ccccc3C#N)c(=O)c21
Temperature: 25 °C

Procedure:
0.96 g potassium-tert-butoxide are added to an ice-cooled solution of 0.39 g (S)-2-[(2-tert-butyloxycarbonylamino-propyl)amino]-3-(2-butyn-1-yl)-5-(2-cyanophenylmethyl)-3,5-dihydro-imidazo[4,5-d]pyridazin-4-one in 5 ml dimethylsulphoxide. The mixture is stirred at ambient temperature, until the solution is clear. Then 53 μl methyl iodide are added, and the solution is stirred for a further 3.5 h at ambient temperature. Then water is added to the reaction solution, the precipitate formed is separated off and washed with water. The dried precipitate is purified by chromatography through silica gel (petroleum ether/ethyl acetate 1:1).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[CH:2]=[C:3]=[CH2:4].[O:9]1[CH:13]=[CH:12][CH:11]=[CH:10]1.Cl>[Cl-].[Zn+2].[Cl-].C1(C)C=CC=CC=1>[CH2:7]([O:6][C:1]([CH:2]1[C:3](=[CH2:4])[CH:10]2[O:9][CH:13]1[CH:12]=[CH:11]2)=[O:5])[CH3:8]
Reactant: c1ccoc1
Reactant: C=C=CC(=O)OCC
Agent: Cl
Agent: [Cl-]
Agent: [Zn+2]
Solvent: Cc1ccccc1
Product: C=C1C2C=CC(O2)C1C(=O)OCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
Ethyl 2,3-butadienoate (0.84 g, 7.5 mmol) and 2.52 g of furan (37 mmol) were combined in a flask under nitrogen and cooled to 0° C. Anhydrous zinc chloride (0.25 g, 1.8 mmol) was added, then the reaction mixture was warmed to room temperature and stirred overnight. NMR analysis indicated that the reaction was complete. Toluene and dilute HCl were added. A black lump of material separated. The toluene and water phases were decanted. The toluene phase was washed with water, filtered and rotovapped. Methylene chloride and aqueous HCl were added to the black solids which dissolved. The methylene chloride phase was washed with water, combined with the rotovapped toluene phase and stripped. A total of 1.18 g of a light brown liquid was obtained.
Reaction SMILES: Br[CH:2]([CH:8](Br)[C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)[C:3](OCC)=[O:4].Cl.[NH2:18][OH:19].C[O-].[Na+].Cl>CO.C(OCC)(=O)C.O>[CH3:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:19][N:18]=[C:3]([OH:4])[CH:2]=2)=[CH:10][CH:11]=1
Reactant: NO
Reactant: CCOC(=O)C(Br)C(Br)c1ccc(C)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2cc(O)no2)cc1
Reaction time: 12 h
Yield: 68.5 %

Procedure:
0.35 g of ethyl 2,3-dibromo-3-(4-methylphenyl)propanoate and 0.083 g of hydroxylamine hydrochloride was suspended in 7 mL of methanol, to which 0.19 g of a 28% solution of sodium methoxide in methanol was added at room temperature, and then this solution was stirred for 12 hours at the same temperature. The reaction mixture, to which water was added, was adjusted to pH 1 with 6M hydrochloric acid followed by addition of ethyl acetate, and the organic phase was separated therefrom. After the resultant organic phase was washed with water and a saturated sodium chloride solution successively, the washed phase was dried over anhydrous magnesium sulfate, and the solvent was distilled out therefrom under reduced pressure. The resultant residue was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=4:1] to yield 0.12 g of 5-(4-methylphenyl)-3-isoxazolol as yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][CH2:25][C:26]#[N:27])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:28][NH:29][NH2:30].[CH:31](Cl)(Cl)Cl>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@H:8]2[N:12]([S:13]([C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)(=[O:15])=[O:14])[C@@H:11]([CH2:23][CH2:24][CH2:25][C:26]3[N:30]([CH3:31])[N:29]=[CH:28][N:27]=3)[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: ClC(Cl)Cl
Reactant: Cc1ccc(S(=O)(=O)N2[C@@H](CCCC#N)CC[C@H]2c2ccc(F)cc2)cc1
Reactant: CNN
Product: Cc1ccc(S(=O)(=O)N2[C@@H](CCCc3ncnn3C)CC[C@H]2c2ccc(F)cc2)cc1

Procedure:
The title compound, colorless oil, MS: m/e=443.2 (M+H+) and [α]D20=−68.8° (c=0.3443 in chloroform), was prepared in accordance with the general method of example 26 from (2S,5S)-4-[5-(4-fluoro-phenyl)-1-(toluene-4-sulfonyl)-pyrrolidin-2-yl]-butyronitrile and methylhydrazine.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[CH:9]=[N:10][C:11]([C:14]2[C:22]3[C:17](=[N:18][CH:19]=[CH:20][CH:21]=3)[N:16]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[F:30])[N:15]=2)=[N:12][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+].I[CH:38]([CH3:40])[CH3:39].O>CC(C)=O>[F:30][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=1[CH2:23][N:16]1[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:22]2[C:14]([C:11]2[N:10]=[CH:9][C:8]([N:2]3[CH2:3][CH:4]4[CH2:7][CH:1]3[CH2:6][N:5]4[CH:38]([CH3:40])[CH3:39])=[CH:13][N:12]=2)=[N:15]1
Reactant: CC(C)I
Reactant: Fc1ccccc1Cn1nc(-c2ncc(N3CC4CC3CN4)cn2)c2cccnc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: CC(C)N1CC2CC1CN2c1cnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
50 mg (0.13 mmol) of 3-[5-(2,5-diazabicyclo[2.2.1]hept-2-yl)-2-pyrimidinyl]-1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine (example 9) are dissolved in 5 ml of absolute acetone, and 92 mg (0.87 mmol) of sodium carbonate are added. 64 mg (0.37 mmol) of 2-iodopropane are added to the suspension, and the mixture is stirred at RT overnight. The reaction solution is mixed with water and extracted with DCM. The organic phases are combined, washed with saturated aqueous sodium chloride solution, dried and filtered. The solvent is removed in vacuo, and the residue is purified by preparative HPLC with addition of small portions of aqueous hydrochloric acid. 25 mg (42% of theory) of the product are obtained.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([CH3:14])=[C:6]([CH:13]=1)[C:7]([NH:9][CH:10]1[CH2:12][CH2:11]1)=[O:8].CC1(C)C(C)(C)OB(/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])O1.CN(C=O)C.C([O-])([O-])=O.[Na+].[Na+]>O.C(O)CC>[CH:10]1([NH:9][C:7](=[O:8])[C:6]2[CH:13]=[C:2](/[CH:24]=[CH:25]/[CH2:26][O:27][CH3:28])[CH:3]=[C:4]([CH3:15])[C:5]=2[CH3:14])[CH2:12][CH2:11]1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc(Br)cc(C(=O)NC2CC2)c1C
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCO
Solvent: CN(C)C=O
Solvent: O
Product: COC/C=C/c1cc(C)c(C)c(C(=O)NC2CC2)c1
Temperature: 100 °C

Procedure:
5-Bromo-N-cyclopropyl-2,3-dimethylbenzamide (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (1.5 eq.) were combined in a 5:1 (v/v) mixture of DMF:n-PrOH (0.1 M). To this solution was then added trans-bis(triphenylphosphine) palladium(II) bromide (0.05 eq.) and the vessel was repeatedly evacuated and back-filled with nitrogen. Finally, 2 M aq. Na2CO3 (3 eq.) was added and the resulting biphasic suspension was heated at 100° C. for 18 h. The now black suspension was cooled to RT, diluted with water and extracted with ether. The combined organic extracts were then washed with water and brine, dried over Na2SO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product by way of flash chromatography (SiO2, 9:1 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([C:18]#[N:19])=[N:16]2)=[CH:11][CH:10]=1.C([OH:22])C.[Cl:23][Si](C)(C)C.Cl.CCO.C(O[Si](C)(C)C)C>>[ClH:23].[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:17]2[C:12]([CH:13]=[N:14][C:15]([C:18]([NH2:19])=[O:22])=[N:16]2)=[CH:11][CH:10]=1
Reactant: C[Si](C)(C)Cl
Reactant: COc1ccccc1-c1ccc2cnc(C#N)nn12
Reactant: CCO
Agent: CCO[Si](C)(C)C
Agent: Cl
Product: COc1ccccc1-c1ccc2cnc(C(N)=O)nn12
Reaction time: 0.33 h
Yield: 68.4 %

Procedure:
7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carbonitrile (30.0 mg, 0.120 mmol) was suspended in Ethanol (3.0 mL, 51 mmol). Separately, Chlorotrimethylsilane (6.00 mL, 47.3 mmol) was added to Ethanol (9.00 mL, 154 mmol) in a vial, which was sealed and allowed to stand 20 min. The mixture of HCl/EtOH/EtOTMS was then added to the nitrile suspension. Monitoring by 1H-NMR (0.1 mL aliquots dried in vacuo) showed conversion overnight. Conc. in vacuo gave 7-(2-Methoxy-phenyl)-pyrrolo[2,1-f][1,2,4]triazine-2-carboxylic acid amide hydrochloride (25 mg, 68%). 1H-NMR (DMSO-d6): 9.26 (s, 1H), 8.04 (s, 1H), 7.85 (s, 1H), 7.78 (d, 1H, J=7.8 Hz), 7.49 (m, 1H), 7.37 (s, 1H), 7.23 (m, 2H), 7.12 (m, 1H), 3.09 (s, 3H); LCMS (Bruker): 3.0 min, 269 (M+H).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH3:4].[CH3:13][O:14][CH:15]=[CH2:16]>>[C:6]1([C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[OH:12])[OH:5].[CH3:13][O:14][CH:15]([O:5][CH:3]([O:2][CH3:1])[CH3:4])[CH3:16]
Reactant: COC(C)Oc1ccccc1O
Reactant: C=COC
Product: COC(C)OC(C)OC
Product: Oc1ccccc1O

Procedure:
The reaction described under (a) is repeated but with twice the amount (128 parts by weight) of vinyl methyl ether. 122 parts by weight of a colorless oil is obtained having a boiling point of 99° to 105° C. at 0.5 mm.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][PH3+].[Li]CCCC.[CH3:11][O:12][C@H:13]1[C@@H:18]([CH3:19])[CH2:17][O:16][C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]1=O>O1CCCC1.C(OCC)(=O)C>[CH3:2][O:3][C@H:4]1[C@@H:18]([CH3:19])[CH2:17][O:16][C@@H:15]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:14]1=[CH:13][O:12][CH3:11]
Reactant: COC[PH3+]
Reactant: CCCCCCCCC[C@@H]1OC[C@H](C)[C@H](OC)C1=O
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCC[C@@H]1OC[C@H](C)[C@H](OC)C1=COC
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 82.6 %

Procedure:
To a stirred suspension of methoxymethylphosphonium chloride (1,130 mg) in dry tetrahydrofuran (3 ml) there was added n-BuLi (1.9 ml, 1.6M in n-hexane) at 0° C. After the mixture was stirred at 0° C. for 30 min, a solution of (2S,4S,5S)-4-methoxy-5-methyl-2-nonyltetrahydro-2H-pyran-3-one (273 mg) in dry tetrahydrofuran (3 ml) was added to the resulting deep orange solution. After 30 min, the mixture was allowed to warm to room temperature, and stirred for an additional 2 hrs. The reaction was quenched by addition of saturated aqueous ammonium chloride solution. The mixture was extracted with diethyl ether, and the combined organic extracts were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Purification of the residue by silica gel chromatography (n-hexane: ethyl acetate=10:1 as an eluent) gave (2S,4S,5S)-4-methoxy-5-methyl-3-methoxymethylene-2-nonyltetrahydro-2H-pyran (249 mg, 83% yield).
Reaction SMILES: Cl.[NH2:2][OH:3].[OH-].[Na+].[Cl:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9](Cl)=[O:10]>O>[Cl:6][CH2:7][C:8]([CH3:13])([CH3:12])[C:9]([NH:2][OH:3])=[O:10]
Reactant: NO
Reactant: CC(C)(CCl)C(=O)Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(CCl)C(=O)NO
Temperature: 25 °C
Reaction time: 16 h
Yield: 40.9 %

Procedure:
A stirred solution of 28.0 grams (0.40 mole) of hydroxylamine hydrochloride in 60 ml of water was cooled to 0° and a solution of 16.0 grams (0.40 mole) of sodium hydroxide in 40 ml of water was added dropwise while maintaining the temperature of the reaction mixture at 0°-5°. Upon completion of addition 31.0 grams (0.20 mole) of 3-chloro-2,2-dimethylpropionyl chloride was added dropwise during a 45-minute period while maintaining the temperature of the reaction mixture at -3° to -5°. Upon completion of addition the reaction mixture was maintained at 5° for one hour, then was allowed to warm to ambient temperature where it was stirred for 16 hours. A white solid precipitate was collected by filtration and air-dried. The dried solid was recrystallized from ethanol-water to give 12.4 grams of 3-chloro-N-hydroxy-2,2-dimethylpropanamide; mp 148°-151°, decomposes.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[I:13]I.S([O-])([O-])(=O)=S.[Na+].[Na+]>O.CO.ClCCl>[N:1]1([C:6]2[CH:11]=[CH:10][C:9]([OH:12])=[C:8]([I:13])[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: II
Reactant: Oc1ccc(-n2ccnc2)cc1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Oc1ccc(-n2ccnc2)cc1I
Temperature: 25 °C
Reaction time: 192 h
Yield: 13.8 %

Procedure:
4-(Imidazol-1-yl)phenol (500 mg) was dissolved in water (6 ml), methanol (18 ml), and dichloromethane (6 ml) to prepare a solution. Iodine (1.58 g) was added to the solution, and the mixture was stirred at room temperature for 8 days. An aqueous sodium thiosulfate solution and methanol were added to the reaction solution, and the mixture was stirred and was then concentrated. The concentrate was extracted with chloroform, and the chloroform layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give 4-(imidazol-1-yl)-2-iodophenol (123 mg, yield 14%).
Reaction SMILES: [NH2:1][OH:2].[CH3:3][C:4]1[CH:13]=[C:12]([CH2:14][O:15][C:16]2[CH:21]=[CH:20][C:19]([S:22]([NH:25][CH:26]3CCNC[CH:27]3[C:32](O)=[O:33])(=[O:24])=[O:23])=[CH:18][CH:17]=2)[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1.[CH:35]([OH:37])=O>>[OH:2][NH:1][C:32]([CH:27]1[CH2:3][CH2:4][N:5]([CH:35]=[O:37])[CH2:6][CH:26]1[NH:25][S:22]([C:19]1[CH:20]=[CH:21][C:16]([O:15][CH2:14][C:12]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[N:5]=[C:4]([CH3:3])[CH:13]=2)=[CH:17][CH:18]=1)(=[O:24])=[O:23])=[O:33]
Reactant: O=CO
Reactant: NO
Reactant: Cc1cc(COc2ccc(S(=O)(=O)NC3CCNCC3C(=O)O)cc2)c2ccccc2n1
Product: Cc1cc(COc2ccc(S(=O)(=O)NC3CN(C=O)CCC3C(=O)NO)cc2)c2ccccc2n1

Procedure:
According to the procedure of Example 29, Step 2, 0.4 g (0.878 mmol) of 4-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonylamino]-piperidine-3-carboxylic acid hydroxylamine and formic acid gave a mixture of cis- and trans-1-formyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-benzenesulfonyl amino]-piperidine-4-carboxylic acid hydroxyamide as an amorphous white solid (0.035 g, 8%) after reverse phase HPLC (Gilson) on a Phenomex C-18 semi-prep column, eluting with an acetonitrile:water gradient. MS: 499 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:13][CH2:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])=[C:7]([NH2:12])[CH:8]=[N:9]2)=[CH:4][CH:3]=1.[CH2:21]([O:23][CH2:24][C:25](Cl)=O)[CH3:22].C(O)C>C(#N)C.C(N(CC)CC)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[N:13]([CH2:14][CH2:15][CH2:16][O:17][CH:18]([CH3:20])[CH3:19])[C:22]([CH2:21][O:23][CH2:24][CH3:25])=[N:12][C:7]=3[CH:8]=[N:9][C:10]=2[CH:11]=1
Reactant: CCOCC(=O)Cl
Reactant: CC(C)OCCCNc1c(N)cnc2cc(Br)ccc12
Solvent: CC#N
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCOCc1nc2cnc3cc(Br)ccc3c2n1CCCOC(C)C
Reaction time: 16 h
Yield: 67.1 %

Procedure:
7-Bromo-N4-(3-isopropoxypropyl)quinoline-3,4-diamine (45 g) was dissolved in acetonitrile (1.3 L) and triethylamine (19.4 mL). Ethoxyacetyl chloride (18.0 g) was added dropwise to the solution and the reaction was stirred for 16 hours. The solvent was removed under reduced pressure to afford a tan solid. The solid was added to a solution of ethanol (1 L) and triethylamine (77.5 mL) and heated at reflux for 4 hours. The solvent was removed under reduced pressure. Water was added to the solid residue and the crude product was recovered by filtration. Recrystallization from acetonitrile yielded 36.25 g of 7-bromo-2-ethoxymethyl-1-(3-isopropoxypropyl)-1H-imidazo[4,5-c]quinoline as a tan crystalline solid.
Reaction SMILES: Cl.[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCN(CC)CC.[C:27](#[N:30])[CH:28]=[CH2:29]>CCO>[C:2]1([C:8]2([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:9][CH2:10][N:11]([CH2:29][CH2:28][C:27]#[N:30])[CH2:12][CH2:13]2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CC#N
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N#CCCN1CCC(c2ccccc2)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 82.2 %

Procedure:
To a suspension of 4,4-diphenylpiperidine hydrochloride (195 mg, 0.712 mmol, 1.0 equiv) in EtOH (1.5 mL) was added Et3N (0.25 mL, 1.8 mmol, 2.6 equiv) followed by acrylonitrile (0.13 mL, 2.01 mmol, 2.8 equiv). The resulting solution was stirred at room temperature under argon for 15 minutes and then concentrated. Water was added, and the mixture was extracted three times with EtOAc. The combined organic extracts were dried over MgSO4 and concentrated to give 170 mg (87%) of tan solid, which was characterized spectroscopically and used for the next reaction without purification.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23](O)=[O:24])[CH:18]=2)[CH2:13][CH2:12]1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH:30]2[CH2:36][C:37]([O:39][CH3:40])=[O:38].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(CC)CC)C>CN(C=O)C>[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[N:32]([C:23]([C:19]1[CH:18]=[C:17]([N:14]3[CH2:13][CH2:12][CH:11]([N:3]4[C:4]5[C:5](=[N:6][CH:7]=[CH:8][CH:9]=5)[NH:10][C:2]4=[O:1])[CH2:16][CH2:15]3)[N:22]=[CH:21][N:20]=1)=[O:24])[CH2:31][CH:30]2[CH2:36][C:37]([O:39][CH3:40])=[O:38]
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: COC(=O)CC1CNc2ccc(F)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)CC1CN(C(=O)c2cc(N3CCC(n4c(=O)[nH]c5ncccc54)CC3)ncn2)c2ccc(F)cc21

Procedure:
150 mg (0.441 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid, 105 mg (0.500 mmol) methyl (5-fluoro-2,3-dihydro-1H-indol-3-yl)-acetate, 148 mg (0.460 mmol) TBTU and 112 μL (0.80 mmol) triethylamine in 2 mL DMF were stirred for 3 h at RT. The reaction mixture was purified by preparative HPLC-MS without any further working up. The product fractions were combined and lyophilised.
Reaction SMILES: C(O[CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])C.[CH2:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([NH:17][CH:4]=[C:5]([C:8]#[N:9])[C:6]#[N:7])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: NCc1ccccc1
Reactant: CCOC=C(C#N)C#N
Product: N#CC(C#N)=CNCc1ccccc1

Procedure:
{[Benzylamino]methylene}methane-1,1-dicarbonitrile was synthesized in the same manner using (ethoxymethylene)methane-1,1-dicarbonitrile and benzylamine. The NMR data for this compound are shown below.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:21][C@@H:22]2[C@H:26]([CH2:27][CH3:28])[CH2:25][C@H:24]([NH:29][S:30]([CH:33]3[CH2:35][CH2:34]3)(=[O:32])=[O:31])[CH2:23]2)=[C:4]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:20]=[CH:19][C:17]([CH3:18])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:5]2=[N:6][CH:7]=1.Cl.[N:37]([O-])=O.[Na+]>O>[CH2:27]([C@H:26]1[C@@H:22]([N:21]2[C:3]3=[C:4]4[CH:10]=[CH:9][N:8]([S:11]([C:14]5[CH:15]=[CH:16][C:17]([CH3:18])=[CH:19][CH:20]=5)(=[O:12])=[O:13])[C:5]4=[N:6][CH:7]=[C:2]3[N:1]=[N:37]2)[CH2:23][C@@H:24]([NH:29][S:30]([CH:33]2[CH2:35][CH2:34]2)(=[O:31])=[O:32])[CH2:25]1)[CH3:28]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c(N)cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1n1nnc2cnc3c(ccn3S(=O)(=O)c3ccc(C)cc3)c21
Temperature: 0 °C
Reaction time: 3 h
Yield: 72.4 %

Procedure:
A mixture of N-((1S,3S,4R)-3-(5-amino-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)-4-ethylcyclopentyl)cyclopropanesulfonamide (0.15 g, 0.23 mmol, Example #23 Step I) and aqueous HCl (6 N, 1.0 mL, 6.00 mmol) was cooled to about 0° C. A solution of NaNO2 (0.022 g, 0.32 mmol) in water (0.2 mL) was added and the reaction was stirred at about 0° C. After about 3 h, the reaction was warmed to rt. After about 15.5 h, the reaction was filtered to collect the yellow solid by vacuum filtration, while washing with water (10 mL). The crude solid was purified by silica gel chromatograpy eluting with 0-20% EtOAc in DCM to give N-((1S,3R,4S)-3-ethyl-4-(6-tosylpyrrolo[2,3-b][1,2,3]triazolo[4,5-d]pyridin-1(6H)-yl)cyclopentyl)cyclopropanesulfonamide (0.088 g, 74%): LC/MS (Table 1, Method a) Rt=2.44 min; MS m/z: 529 (M+H)+.