Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4](S(C)=O)[N:3]=1.[NH:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1>C(O)CC(C)C>[NH2:1][C:2]1[C:11]2[CH2:10][CH:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:18])[CH2:8][CH2:7][C:6]=2[N:5]=[C:4]([N:22]2[CH2:26][CH2:25][CH2:24][CH2:23]2)[N:3]=1
Reactant: C1CCNC1
Reactant: CS(=O)c1nc(N)c2c(n1)CCC(c1ccccc1Cl)C2
Solvent: CC(C)CCO
Product: Nc1nc(N2CCCC2)nc2c1CC(c1ccccc1Cl)CC2
Temperature: 200 °C

Procedure:
This compound is prepared in a manner analogous to that of Example 18, using 1.60 grams (0.005 mole) of 4-amino-2-methylsulfinyl-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (prepared as in Example 17) and 0.71 gram (0.010 mole) of pyrrolidine in 50 mL of isoamyl alcohol. The sealed tube is heated at about 200° C. for 7 hours. The reaction mixture is subjected to column chromatography on silica gel, yielding 4-amino-2-(pyrrolidin-1-yl)-6-(2-chlorophenyl)-5,6,7,8-tetrahydroquinazoline.
Reaction SMILES: [F:1][C:2]([F:6])([S:4]Cl)[CH3:3].[P:7]([O:16]CC)([O:13][CH2:14][CH3:15])[S:8][CH:9]([CH2:11][CH3:12])[CH3:10]>ClCCl>[P:7]([S:4][C:2]([F:6])([F:1])[CH3:3])([O:13][CH2:14][CH3:15])([S:8][CH:9]([CH2:11][CH3:12])[CH3:10])=[O:16]
Reactant: CCOP(OCC)SC(C)CC
Reactant: CC(F)(F)SCl
Solvent: ClCCl
Product: CCOP(=O)(SC(C)CC)SC(C)(F)F

Procedure:
The compounds of the general formula (I) obtainable according to the invention are useful precursors and intermediates for organic syntheses, for example for the preparation of insecticidal phosphoric acid esters (compare DE-A 3,903,409). Thus, for example, the 1,1-difluoroethanesulphenyl chloride obtainable according to the invention can be reacted with S-s-butyl O,O-diethyl thiophosphite in dichloromethane as a solvent to give the insecticidally active O-ethyl S-s-butyl S-(1,1-difluoroethyl) dithiophosphate (b.p. 75° C./1.3 mbar). This phosphoric acid ester can be formulated in a customary manner to give a plant protection agent which can be employed as an insecticide in a customary manner.
Reaction SMILES: [CH2:1](N(CC)CC)[CH3:2].Cl.[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:28])=[C:18]([N:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[C:19]=2[F:21])[C:14](=[O:29])[C:13]([C:30]([OH:32])=[O:31])=[CH:12]1)[CH3:10].C(I)C>CN(C=O)C>[CH2:9]([N:11]1[C:20]2[C:15](=[CH:16][C:17]([F:28])=[C:18]([N:22]3[CH2:23][CH2:24][N:25]([CH2:1][CH3:2])[CH2:26][CH2:27]3)[C:19]=2[F:21])[C:14](=[O:29])[C:13]([C:30]([OH:32])=[O:31])=[CH:12]1)[CH3:10]
Reactant: CCN(CC)CC
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNCC3)c(F)c21
Agent: Cl
Solvent: CCI
Solvent: CN(C)C=O
Product: CCN1CCN(c2c(F)cc3c(=O)c(C(=O)O)cn(CC)c3c2F)CC1
Temperature: 90 °C
Reaction time: 3 h
Yield: 20.5 %

Procedure:
Triethylamine (0.2 g), 1-ethyl-6,8-difluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)quinoline-3-carboxylic acid hydrochloride (0.3 g), ethyl iodide (0.19 g), and DMF (5 ml) were mixed, heated with stirring at 90° C. for 3 hours, and the solvent was evaporated. The residue was dissolved in 2N sodium hydroxide solution. The alkaline solution was neutralized with aqueous acetic acid and extracted with dichloromethane. The dichloromethane layer was washed with water, dried over anhydrous sodium sulfate, and evaporated. The residue was recrystallized from a mixture of DMF and ethanol to give 1-ethyl-7-(4-ethyl-1-piperazinyl)-6,8-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (0.06 g), mp 236°-239° C.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].[NH2:8][C@@H:9]([CH3:29])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=2)[C:15]([C:18]#[N:19])=[N:16][CH:17]=1.OO.[OH-:32].[Na+]>CS(C)=O>[OH:3][C:2]([C:4]([F:7])([F:6])[F:5])=[O:1].[NH2:8][C@@H:9]([CH3:29])[CH2:10][NH:11][C:12]1[CH:13]=[C:14]([NH:20][C:21]2[CH:26]=[C:25]([CH3:27])[CH:24]=[C:23]([CH3:28])[N:22]=2)[C:15]([C:18]([NH2:19])=[O:32])=[N:16][CH:17]=1
Reactant: [OH-]
Reactant: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C#N)c1
Agent: OO
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CS(C)=O
Product: Cc1cc(C)nc(Nc2cc(NC[C@H](C)N)cnc2C(N)=O)c1
Reaction time: 16 h

Procedure:
To a solution of 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carbonitrile TFA salt (166 mg, 0.404 mmol) in DMSO (3 ml) were added hydrogen peroxide (35% aqueous solution, 0.053 ml, 0.61 mmol) and sodium hydroxide (4.0 M aqueous solution, 0.32 mL, 1.3 mmol) at 20° C. After 16 hour, the reaction mixture was purified directly by reverse phase HPLC (acetonitrile/water with 0.1% TFA) to give 5-{[(2S)-2-aminopropyl]amino}-3-[(4,6-dimethylpyridin-2-yl)amino]pyridine-2-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 7.81 (s, 1H), 7.59 (s, 1H), 7.10 (s, 1H), 6.90 (s, 1H), 3.72-3.49 (m, 1H), 3.52-3.33 (m, 2H), 2.53 (s, 3H), 2.40 (s, 3H), 1.39 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH:1]([C:3]1[CH:7]=[CH:6][N:5]([C:8]2[N:18]=[CH:17][CH:16]=[CH:15][C:9]=2[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=1)=O.[NH:19]1[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1.C(O)(=O)C>C(#N)C>[O:22]1[CH2:23][CH2:24][N:19]([CH2:1][C:3]2[CH:7]=[CH:6][N:5]([C:8]3[N:18]=[CH:17][CH:16]=[CH:15][C:9]=3[C:10]([O:12][CH2:13][CH3:14])=[O:11])[N:4]=2)[CH2:20][CH2:21]1
Reactant: C1COCCN1
Reactant: CCOC(=O)c1cccnc1-n1ccc(C=O)n1
Solvent: CC(=O)O
Solvent: CC#N
Product: CCOC(=O)c1cccnc1-n1ccc(CN2CCOCC2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a solution of ethyl 2-(3-formyl-1H-pyrazol-1-yl)nicotinate (400 mg, 1.631 mmol) and morpholine (220 μl, 2.53 mmol) in acetonitrile (25 mL) NaCNBH4 (130 mg, 2.069 mmol) was added, and the pH adjusted to 5-6 by adding glacial acetic acid (110 μL, 1.922 mmol). The mixture was stirred at room temperature for 1 h, another portion of NaCNBH4 (30 mg, 0.477 mmol) added and stirred for 2 hrs. For work up the mixture was concentrated, dissolved in 100 mL of dichloromethane, washed subsequently with water and brine, dried (MgSO4), filtered off and concentrated to give 710 mg of the crude title product. Purification by chromatography over silica gel (CH2Cl2/3%-5% methanol) and concentration yielded 518 mg of the title compound as clear oil; ESI-MS [M+H]+: 317.20.
Reaction SMILES: [C:1]([O:4][C:5](=[O:7])[CH3:6])(=O)[CH3:2].[NH2:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12](CCO)=[C:11]([N+:22]([O-:24])=[O:23])[CH:10]=1>N1C=CC=CC=1.CCOC(C)=O>[C:5]([O:4][CH2:1][CH2:2][C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:9]([NH2:8])=[CH:10][C:11]=1[N+:22]([O-:24])=[O:23])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: Nc1cc([N+](=O)[O-])c(CCO)c2ccccc12
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: CC(=O)OCCc1c([N+](=O)[O-])cc(N)c2ccccc12
Reaction time: 2 h
Yield: 25.7 %

Procedure:
Acetic anhydride (4.0 mL, 42.39 mmol) was added to a solution of 2-[4-amino-2-nitronaphthalen-1-yl]ethanol (3.3 g, 14.21 mmol) in dry pyridine (33 mL) at room temperature and stirred for 2 hr. The mixture was diluted with AcOEt (100 mL). The organic layer was washed with H2O (30 mL), saturated aqueous NaHCO3 (30 mL), saturated aqueous NaCl (30 mL), and then the organic layer was dried (Na2SO4) and concentrated under reduced pressure. Flash chromatography (33% AcOEt-Petroleum ether) afforded 2-[4-amino-2-nitronaphthalen-1-yl]ethyl acetate (1.0 g, 26%) as an orange solid.; mp 108-110 ° C.; 1H NMR (CDCl3, 500 MHz) δ 8.33 (d, 8.5, 1H), 7.84 (dd, 8.0, 0.5, 1H), 7.70 (dt, 7.5, 0.5, 1H), 7.64 (dt, 8.5, 1.5, 1H), 7.11 (s, 1H), 4.44 (t, 8.0, 2H), 4.38 (brs, 2H), 3.49 (t, 8.0, 2H), 2.06 (d, 0.5, 3H); FABMS (NBA) m/z 274 (M+), IR (neat) 3381, 1728, 1636, 1589, 1516, 1469, 1437, 1342, 1241, 1041, 754 cm−1.
Reaction SMILES: [CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[CH3:1][CH:2]([CH2:6][CH3:7])[C:3]([O:5][CH2:8][S:9][CH3:10])=[O:4]
Reactant: CSCCl
Reactant: CCC(C)C(=O)O
Solvent: CCN(CC)CC
Product: CCC(C)C(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting 2-methylbutyric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 75°-77° C./12 mm Hg, nD20 1.4505.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[N:35]=[CH:34][CH:33]=[CH:32][N:31]=1>>[N:31]1[CH:32]=[CH:33][CH:34]=[N:35][C:30]=1[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:26])([F:25])[F:27])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5]
Reactant: Brc1ncccn1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: O=C(c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1)c1ncccn1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromo-pyrimidine
Reaction SMILES: [C:1]([O:5][C:6]([N:8]=[C:9](C1C(C)=NNC=1C)[NH2:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH2:19][CH2:20][CH2:21][NH2:22]>>[NH2:18][CH2:19][CH2:20][CH2:21][NH:22][C:9]([NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])=[NH:10]
Reactant: NCCCN
Reactant: Cc1n[nH]c(C)c1C(N)=NC(=O)OC(C)(C)C
Product: CC(C)(C)OC(=O)NC(=N)NCCCN
Temperature: 25 °C
Reaction time: 17 h
Yield: 46.2 %

Procedure:
A mixture of tert-butoxycarbonyl-1-(3,5-dimethylpyrazolyl)-formamidine (0.38 g, 1.5 mmol) and 1,3-diaminopropane (0.56 g, 7.5 mmol) was stirred at room temperature for 17 h. The crystalline product was collected by filtration, washed with toluene (2×0.7) mL), and vacuum dried (35° C., 1.5 h) to afford 0.15 g (47%) of white crystals of N-(3-aminopropyl)-N'-tert-butoxycarbonyl guanidine (IIIg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[CH:9]#[C:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH3:18].[Li].N>>[CH2:7]([OH:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][C:9]#[C:10][CH2:11][CH2:12]/[CH:13]=[CH:14]/[CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: OCCCCCCBr
Reactant: C#CCC/C=C/CCCC
Agent: N
Agent: [Li]
Product: CCCC/C=C/CCC#CCCCCCCO

Procedure:
The use of a protected derivative of 6-bromohexanol can be avoided. Thus, an excess of lithium (E)-5-decen-1-yne in liquid ammonia is used and allowed to react directly with 6-bromohexanol to give (E)-11-hexadecen-7-yne-1-ol, bp 134°-136°/1 mm, nD21 1,4755. Acetylation converts the alcohol to the above acetate.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[C:5]1([C:11]2[C:12]3[CH:25]=[CH:24][CH:23]=[CH:22][C:13]=3[S:14][C:15]=2[CH2:16]OS(C)(=O)=O)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>CN(C=O)C.O>[N:1]([CH2:16][C:15]1[S:14][C:13]2[CH:22]=[CH:23][CH:24]=[CH:25][C:12]=2[C:11]=1[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCc1sc2ccccc2c1-c1ccccc1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1sc2ccccc2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 50 %

Procedure:
Sodium azide (179 mg, 2.76 mmol) was added to a solution of methanesulfonic acid 3-phenylbenzo[b]thiophen-2-ylmethyl ester (828 mg, 1.84 mmol) in DMF (10 mL) and the mixture stirred at RT for 18 h. The reaction mixture was diluted with water and extracted with EtOAc. The organic fraction was washed with brine, dried (Na2SO4) and concentrated in vacuo and the resulting residue purified by column chromatography (Si—PCC, gradient 0-35% DCM in cyclohexane) affording the title compound as a clear oil (244 mg, 50%). LCMS (Method C): RT 4.46 min [M+H-N2]+ 237.8
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH:13](=O)[CH2:14][CH2:15][CH3:16].[OH-].[K+].Cl>C(O)C.O>[CH:13](=[C:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH2:14][CH2:15][CH3:16]
Reactant: CCCC=O
Reactant: COc1ccc2c(c1)C(=O)CC2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCC=C1Cc2ccc(OC)cc2C1=O
Reaction time: 1 h

Procedure:
To a 0° C. mixture of 9.66 g (59.6 mmol) of 6-methoxy-1-indanone and 4.29 g (59.6 mmol) of butyr-aldehyde in 10 ml ethanol is added 9.66 ml of a 4% KOH in ethanol solution. The reaction is stirred 1 hour and then added to 300 ml water and the pH of the quench adjusted to 2 with 1N hydrochloric acid. The resultant mixture is extracted with 3×300 ml ether, and the extracts combined, dried over MgSO4, evaporated and the residue triturated with ether to yield present title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16].[H-].[Na+].Cl.Cl[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH:32]=[CH:31][N:30]=[CH:29]2)=[CH:24][CH:23]=1.O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:26][CH:27]=1)[C:6]([CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[C:5]2[CH3:16]
Reactant: Cc1c(CCC(=O)O)[nH]c2ccc(F)cc12
Reactant: ClCc1ccc(-n2ccnc2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(CCC(=O)O)n(Cc2ccc(-n3ccnc3)cc2)c2ccc(F)cc12
Temperature: 0 °C
Reaction time: 1 h
Yield: 10.4 %

Procedure:
A solution of 198 mg of 5-fluoro-3-methyl-1H-indole-2-propanoic acid in 20 ml of dry DMF is cooled at 0° C., and treated with 155 mg of 55% NaH. The reaction mixture is stirred for 60 minutes at 0° C., then 307 mg of 1-[4-(chloro-methyl)phenyl]-1H-imidazole hydrochloride are added portionwise under nitrogen at 0° C. After stirring at room temperature for 16 hours the mixture is poured into water and washed with methylene chloride. The aqueous solution is neutralized with diluted HCl and extracted with methylene chloride. The organic layer is dried over sodium sulfate and evaporated to dryness. The residue, taken up with acetone, filtered and dried, yields 35 mg of the title compound (m.p. 222° C.)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4](I)[C:3]=1[C:9]1[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:12]([CH3:19])[O:11][N:10]=1.C[CH2:21][N:22](CC)CC.[Si](C#N)(C)(C)C>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:17]([O:16][C:14]([C:13]1[C:9]([C:3]2[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=2[C:21]#[N:22])=[N:10][O:11][C:12]=1[CH3:19])=[O:15])[CH3:18]
Reactant: CCOC(=O)c1c(-c2c(F)cccc2I)noc1C
Reactant: CCN(CC)CC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C[Si](C)(C)C#N
Solvent: O
Product: CCOC(=O)c1c(-c2c(F)cccc2C#N)noc1C
Temperature: 25 °C
Yield: 82 %

Procedure:
To a mixture of ethyl 3-(2-Fluoro-6-iodo-phenyl)-5-methyl-isoxazole-4-carboxylate (0.25 g, 0.67 mmol), tetrakis(triphenylphosphine)palladium (0.08 g, 0.067 mmol), and Et3N (5 mL) under N2 was added TMSCN and heated at reflux overnight. The reaction was cooled to room temperature, diluted with H2O, and extracted with EtOAc (2×). The combined extracts were washed (H2O then brine), dried (MgSO4), filtered, and concentrated. Flash chromatography (silica gel, EtOAc/hexanes gradient) gave the title compound (0.15 g, 82%). Mass Spectrum (ES+) (m/z) 275.0 [M+1].
Reaction SMILES: [C:1]1([CH2:7][C:8]#[N:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH:15]=[CH2:16].[Cl-].[Na+]>CN(C=O)C.C(OCC)(=O)C>[CH2:13]([C:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)([CH2:3][CH2:2][CH:1]=[CH2:6])[C:8]#[N:9])[CH2:14][CH2:15][CH3:16]
Reactant: N#CCc1ccccc1
Reactant: C=CCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CCCC(C#N)(CCCC)c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-phenylacetonitrile (1 mL) in DMF (1.0 mL) at 0° C. was added sodium hydride (95% oil dispersion, 547 mg) and the resulting suspension was stirred at 0° C. for 10 min. 4-Bromobut-1-ene (2.2 mL) was added, and the reaction mixture was stirred at room temperature for 2 h. Saturated sodium chloride was added followed by ethyl acetate, the aqueous layer was extracted with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and filtered, and the filtrate was evaporated in vacuo. The residue was purified by silica gel flash chromatography eluting with 10% ethyl acetate/90% hexanes to give the title compound as an oil (773 mg). 1H NMR (400 MHz, CDCl3) δ 1.8-2.3 (8H, m), 4.95 (4H, m), 5.73 (2H, m), and 7.31 (5H, m).
Reaction SMILES: [N:1]([C:4]1[CH:11]=[CH:10][C:9]([Cl:12])=[CH:8][C:5]=1[C:6]#[N:7])=[C:2]=[O:3].[OH:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([NH:20][NH2:21])=O)=[CH:16][CH:15]=1.C(N(CC)CC)C>CS(O)(=O)=O.C(O)C>[Cl:12][C:9]1[CH:10]=[CH:11][C:4]2[NH:1][C:2](=[O:3])[N:21]3[N:20]=[C:18]([C:17]4[CH:22]=[CH:23][C:14]([OH:13])=[CH:15][CH:16]=4)[N:7]=[C:6]3[C:5]=2[CH:8]=1
Reactant: NNC(=O)c1ccc(O)cc1
Reactant: N#Cc1cc(Cl)ccc1N=C=O
Agent: CS(=O)(=O)O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(Cl)cc2c2nc(-c3ccc(O)cc3)nn12
Yield: 53 %

Procedure:
The intermediate prepared from 2-isocyanato-5-chlorobenzonitrile (6.1 g) and 4-hydroxybenzoylhydrazine (7.0 g) in 53% yield as described in Example 23 is added to a mixture of triethylamine (31 ml), methanesulphonic acid (25 drops) and ethanol (300 ml) and stirred at reflux under nitrogen for two hours. The reaction mixture is concentrated to dryness at reduced pressure, redissolved in ethanol and treated with water. The solid is collected, washed with water and dried under high vacuum to afford pure 9-chloro-2-(4-hydroxy-phenyl)-[1,2,4]triazolo[1,5-c]quinazolin-5(6H)one, mp>350°
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Cl[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:21][C:20]=1[CH3:35].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C.O>[CH3:1][O:2][C:3](=[O:16])[CH2:4][CH2:5][NH:6][C:7](=[O:15])[C:8]1[CH:9]=[CH:10][C:11]([O:14][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]([F:32])([F:33])[F:34])=[CH:27][CH:26]=3)=[CH:21][C:20]=2[CH3:35])=[CH:12][CH:13]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)ccc1CCl
Reactant: COC(=O)CCNC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC#N
Product: COC(=O)CCNC(=O)c1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)cc2C)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 56.9 %

Procedure:
To a solution of 3-(4-hydroxy-benzoylamino)-propionic acid methyl ester (0.11 g, 0.49 mmol) and 4-chloromethyl-3-methyl-4′-trifluoromethyl-biphenyl (0.12 g, 0.41 mmol) in acetonitrile (4 mL) is added Cs2CO3 (0.20 g, 0.61 mmol). The mixture is stirred at RT for 12 h. The mixture is diluted with water and extracted with EtOAc. The organics are dried with MgSO4, and the crude material is purified by flash chromatography to yield 0.11 g (58%) of the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].C(N(C(C)C)CC)(C)C.[S:21](Cl)([CH3:24])(=[O:23])=[O:22]>ClCCl>[CH3:24][S:21]([O:1][CH2:2][CH2:3][NH:4][C:5](=[O:11])[O:6][C:7]([CH3:8])([CH3:10])[CH3:9])(=[O:23])=[O:22]
Reactant: CS(=O)(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOS(C)(=O)=O
Temperature: 23 °C
Reaction time: 18 h
Yield: 96.7 %

Procedure:
A solution of tert-butyl 2-hydroxyethylcarbamate (25 mL, 161.6 mmol) in dichloromethane (60 mL) was cooled to 0° C. and stirred while first diisopropylethylamine (33.8 mL, 193.9 mmol) was added and then mesyl chloride (13.7 mL, 177.8 mmol) then was added dropwise. The mixture was allowed to warm to 23° C., stirred for 18 hours, poured into dichloromethane (200 mL) and washed with aqueous hydrochloric acid (3M, 3×25 mL) and saturated aqueous sodium hydrogencarbonate (2×25 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo to provide tert-butyl 2-methylsulfonyloxyethylcarbamate (37.39 g, 97% yield) as a brown oil; MS (PB-PCI) C8H17NO5S m/e calc 239.08; found 240 (MH+).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-])=O)=[C:8]([OH:13])[C:7]([C:14]([CH3:17])([CH3:16])[CH3:15])=[CH:6][C:5]=1[CH3:18])([O-])=O.[H][H]>C(O)C.[C].[Pd]>[NH2:1][C:4]1[C:9]([NH2:10])=[C:8]([OH:13])[C:7]([C:14]([CH3:16])([CH3:15])[CH3:17])=[CH:6][C:5]=1[CH3:18]
Reactant: Cc1cc(C(C)(C)C)c(O)c([N+](=O)[O-])c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C(C)(C)C)c(O)c(N)c1N

Procedure:
A solution of 2,3-dinitro-4-hydroxy-5-tert-butyltoluene (Description 10) (7.5 g) in ethanol (350 ml) was hydrogenated at room temperature and atmospheric pressure over 10% palladium-carbon (2.5 g) until uptake of hydrogen ceased. The solution was filtered under nitrogen and evaporated to dryness in vacuo to afford the unstable title compound, m.p. 129°-136° C., which was used immediately for the next reaction.
Reaction SMILES: [Cl:1][Si:2](Cl)([CH3:4])[CH3:3].[CH:6]1([NH-:12])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1.[Li+].CCCCCC>C1COCC1>[Cl:1][Si:2]([CH3:4])([CH3:3])[NH:12][CH:6]1[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: [NH-]C1CCCCC1
Reactant: C[Si](C)(Cl)Cl
Agent: [Li+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: C[Si](C)(Cl)NC1CCCCC1
Reaction time: 8 h
Yield: 84 %

Procedure:
In the drybox in a 250 mL flask 60.0 mL (490.89 mmol) of dichlorodimethylsilane was stirred in about 80 mL of THF. To this stirring solution 6.00 g (57.08 mmol) of lithium cyclohexylamide was added as a solid slowly and stirred overnight. The THF was removed under vacuum leaving a cloudy solution. Hexane was added to this mixture and the solids were filtered off and washed with hexane. The hexane was then removed from the filtrate under vacuum leaving a clear light yellow product weighing 9.18 g. Yield 84 percent.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]2[N:5]([C:9]([C:12]3[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:30])([F:29])[F:28])=[O:24])[CH:15]=[C:16]([O:18][CH:19]([CH3:21])[CH3:20])[CH:17]=3)=[CH:10][N:11]=2)[CH:6]=[CH:7][CH:8]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:64](O)(=[O:67])[C:65]#[CH:66]>C(Cl)Cl>[CH:19]([O:18][C:16]1[CH:17]=[C:12]([C:9]2[N:5]3[CH:6]=[CH:7][CH:8]=[C:3]([CH2:2][NH:1][C:64](=[O:67])[C:65]#[CH:66])[C:4]3=[N:11][CH:10]=2)[CH:13]=[C:14]([NH:22][C:23]([NH:25][CH2:26][C:27]([F:29])([F:30])[F:28])=[O:24])[CH:15]=1)([CH3:21])[CH3:20]
Reactant: CC(C)Oc1cc(NC(=O)NCC(F)(F)F)cc(-c2cnc3c(CN)cccn23)c1
Reactant: C#CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CC(=O)NCc1cccn2c(-c3cc(NC(=O)NCC(F)(F)F)cc(OC(C)C)c3)cnc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64.5 %

Procedure:
To a solution of 1-(3-(8-(aminomethyl)imidazo[1,2-a]pyridin-3-yl)-5-isopropoxyphenyl)-3-(2,2,2-trifluoroethyl)urea (26 mg, 0.062 mmol) in DCM (3 ml) was added DIEA (0.075 ml, 0.432 mmol) and HATU (35.2 mg, 0.093 mmol) and finally propiolic acid (4.95 μl, 0.080 mmol). Reaction was stirred for 30 minutes at room temperature. Reaction was loaded directly onto silica column and purified by flash chromatography (0-10% CH2Cl2/MeOH) to give the title compound (19 mg, 0.040 mmol, 65.0% yield) as an off white solid. MS (ES+) C23H22F3N5O3 requires: 473. Found: 474 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 9.34 (s, 1H), 8.92 (s, 1H), 8.47 (d, J=6.8 Hz, 1H), 7.74 (s, 1H), 7.17 (d, J=1.9 Hz, 2H), 7.10 (s, 1H), 6.98 (s, 1H), 6.82 (s, 1H), 6.74 (s, 1H), 4.69-4.58 (m, 2H), 3.93 (dd, J=9.7, 6.4 Hz, 2H), 2.72-2.64 (m, 1H), 1.30-1.19 (m, 6H).