Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:6])([F:5])[CH2:3][OH:4].[H-].[Na+].Cl[C:10]1[C:15]([Br:16])=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=1.O>O1CCCC1>[Br:16][C:15]1[C:10]([O:4][CH2:3][C:2]([F:6])([F:5])[F:1])=[N:11][CH:12]=[C:13]([C:17]([F:19])([F:18])[F:20])[CH:14]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Br)c1
Reactant: OCC(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: FC(F)(F)COc1ncc(C(F)(F)F)cc1Br
Temperature: 22 °C
Reaction time: 0.33 h
Yield: 62.4 %

Procedure:
To 2,2,2-trifluoroethanol (1.4 ml 19.2 mmol) in tetrahydrofuran (3 ml) was added sodium hydride (760 mg, 60% suspension in oil, 19.0 mmol) and the suspension was stirred at 22° C. for 20 mins. 2-Chloro-3-bromo-5-trifluoromethylpyridine (1.0 g, 3.84 mmol) in tetrahydrofuran (2 ml) was then added and the mixture stirred for 16 hrs at 22° C., before being poured into water (100 ml) and extracted with ethyl acetate (2×100 ml). The extracts were dried (MgSO4) and concentrated to give the product as an oil (776 mg, 62% yield).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH3:23])[N:20]=4)[N:15]=[CH:14][C:13]=3[F:24])[CH2:8][CH2:7]2)[CH2:4][C@H:3]1[OH:25].[O-]S([O-])(=O)=O.[Na+].[Na+].[O:33]=[C:34]1[CH2:39][S:38][C:37]2[CH:40]=[CH:41][C:42]([CH:44]=O)=[N:43][C:36]=2[NH:35]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl.CCO>[F:24][C:13]1[CH:14]=[N:15][C:16]2[C:21]([C:12]=1[N:9]1[CH2:10][CH2:11][C:5]3([CH2:6][C@H:2]([NH:1][CH2:44][C:42]4[CH:41]=[CH:40][C:37]5[S:38][CH2:39][C:34](=[O:33])[NH:35][C:36]=5[N:43]=4)[C@H:3]([OH:25])[CH2:4]3)[CH2:7][CH2:8]1)=[N:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2
Reactant: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](N)C4)c2n1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Product: COc1ccc2ncc(F)c(N3CCC4(CC3)C[C@@H](O)[C@@H](NCc3ccc5c(n3)NC(=O)CS5)C4)c2n1
Reaction time: 12 h
Yield: 83.8 %

Procedure:
To a solution of (2R,3S)-3-amino-8-[3-fluoro-6-(methyloxy)-1,5-naphthyridin-4-yl]-8-azaspiro[4.5]decan-2-ol (0.26 mg, 75.1 μmol) in DCM-EtOH (1 mL, 1:1) were added Na2SO4 (16 mg, 0.112 mmol) and 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (15 mg, 75.1 μmol). After 12 h at 25° C., the imine was quenched by addition of NaBH(OAc)3 (32 mg, 0.150 mmol) in one portion. After an additional 1 h, the solution was partitioned between NaHCO3-DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried (Na2SO4), concentrated and purified by column chromatography (silica, 1% MeOH in DCM (1% NH4OH)) affording the title compound (33 mg, 84%) as a light yellow oil: LCMS (ES) m/e 525 (M+H)+; 1H NMR (400 MHz, CDCl3) δ 8.45 (d, J=5.5 Hz, 1H), 8.11 (d, J=9.0 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.95 (d, J=7.8 Hz, 1H), 4.12-4.19 (m, 1H), 4.03 (s, 3H), 3.92 (AB quart., 2H), 3.52-3.67 (m, 4H), 3.46 (s, 2H), 3.00-3.21 (m, 1H), 1.94-1.96 (m, 1H), 1.79-1.91 (m, 1H), 1.65-1.71 (m, 4H).
Reaction SMILES: [C:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH2:20]C)=[O:18])=[C:15]([OH:22])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[C:29]1C(OC)=C(C(CS(C2CCCCC2)(=O)=O)=CC=1)C(OC)=O>>[CH:1]1([S:7]([CH2:10][C:11]2[C:16]([C:17]([O:19][CH3:20])=[O:18])=[C:15]([O:22][CH3:29])[C:14]([C:23]3[CH:27]=[CH:26][O:25][CH:24]=3)=[CH:13][CH:12]=2)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COC(=O)c1c(CS(=O)(=O)C2CCCCC2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccoc2)c1O
Product: COC(=O)c1c(CS(=O)(=O)C2CCCCC2)ccc(-c2ccoc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 36, starting from methyl 3-bromo-6-(cyclohexanesulphonylmethyl)-2-methoxybenzoate (Intermediate 157).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[Cl:4][CH:5]=[CH:6][CH2:7]Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([C:32]#[CH:33])([CH3:31])([CH3:30])[CH3:29]>[Cu]I.[Pd](Cl)Cl>[ClH:4].[CH3:29][C:28]([CH3:31])([CH3:30])[C:32]#[C:33]/[CH:5]=[CH:6]/[CH2:7][NH:3][CH2:1][CH3:2]
Reactant: C#CC(C)(C)C
Reactant: ClC=CCCl
Reactant: CCN
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: CCNC/C=C/C#CC(C)(C)C
Product: Cl
Yield: 74 %

Procedure:
By using 145 ml (1.79 mol) of 70% ethylamine aqueous solution instead of n-propylamine, 255 ml of tetahydrofuran, 27.3 ml (0.296 mol) of 1,3-dichloropropene (E/Z =9/1), 2.85 g (15 mmol) of copper (I) iodide, 1.07 g (6.0 mmol) of palladium chloride, 3.15 g (12 mmol) of triphenylphosphine and 45.0 ml (0.365 mol) of tert-butylacetyiene, the treatment was conducted in the same manner as in Example 1 to obtain 44.4 g (yield: 74%) of the above identified compound as slightly yellowish brown crystalline powder.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]3[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=3[S:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:19]([C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][CH:27]=1)[NH2:24])#[CH:20]>>[C:19]([C:21]1[CH:22]=[C:23]([NH:24][C:2]2[C:3]3[C:10]4[CH2:11][N:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[CH2:13][C:9]=4[S:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH:25]=[CH:26][CH:27]=1)#[CH:20]
Reactant: C#Cc1cccc(N)c1
Reactant: CCOC(=O)N1Cc2sc3ncnc(Cl)c3c2C1
Product: C#Cc1cccc(Nc2ncnc3sc4c(c23)CN(C(=O)OCC)C4)c1

Procedure:
In analogy to Example 22A, ethyl 4-chloro-5,7-dihydro-6H-pyrrolo[3′,4′:4,5]thieno[2,3-d]pyrimidine-6-carboxylate from Example 21A (235 mg, 0.83 mmol) and 3-ethynylaniline (102 mg, 0.87 mmol) were reacted to the title compound to yield 211 mg (67%).
Reaction SMILES: C([O:4][C@@H:5]1[C@@H:18]([O:19]C(=O)C)[C@H:17]([O:23]C(=O)C)[CH2:16][S:15][C@H:6]1[O:7][C:8]1[CH:9]=[N:10][C:11](Br)=[CH:12][CH:13]=1)(=O)C.[CH3:27][O:28][C:29]1[CH:34]=[CH:33][N:32]=[CH:31][C:30]=1B(O)O>>[O:7]([C:8]1[CH:9]=[N:10][C:11]([C:30]2[CH:31]=[N:32][CH:33]=[CH:34][C:29]=2[O:28][CH3:27])=[CH:12][CH:13]=1)[C@@H:6]1[S:15][CH2:16][C@@H:17]([OH:23])[C@H:18]([OH:19])[C@H:5]1[OH:4]
Reactant: COc1ccncc1B(O)O
Reactant: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@H](OC(C)=O)CS[C@H]1Oc1ccc(Br)nc1
Product: COc1ccncc1-c1ccc(O[C@@H]2SC[C@@H](O)[C@H](O)[C@H]2O)cn1

Procedure:
By carrying out the operation analogously to example 239, starting from 6-bromo-3-pyridinyl 2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoside, obtained according to preparation IV, and 4-methoxy-3-pyridineboronic acid, the desired product is obtained in the form of a white solid (yield=37%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([NH:11][C:12]([C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[NH:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.C(=O)(O)[O-].[Na+].Br[CH2:27][C:28](=O)[C:29]([O:31][CH2:32][CH3:33])=[O:30]>O1CCOCC1>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH:27]=[C:28]([C:29]([O:31][CH2:32][CH3:33])=[O:30])[N:13]=[C:12]3[C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: N=C(Nc1ccc2c(c1)OCCO2)c1ccc(F)cc1
Reactant: CCOC(=O)C(=O)CBr
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(-c2ccc3c(c2)OCCO3)c(-c2ccc(F)cc2)n1
Temperature: 25 °C

Procedure:
To a mixture of the compound from Step A and 4.0 g (48 mmol) of sodium bicarbonate in 50 mL of 1,4-dioxane was added 3.0 mL (24 mmol) of ethyl bromopyruvate. The reaction mixture was refluxed overnight. After cooling to room temperature, the solid was filtered off and the filtrate was concentrated in vacuo. Flash chromatography on a Biotage Horizon® system (silica gel, 0 to 50% ethyl acetate in hexanes gradient) gave the title compound as yellow solid. LC/MS 369.1 (M+1).
Reaction SMILES: [C:1]1([CH3:11])C=CC(S(O)(=O)=O)=CC=1.[F:12][CH:13]([F:31])[O:14][C:15]1[CH:16]=[C:17]([S:21][C:22]2[CH:23]=[C:24]([CH3:30])[C:25](=[CH:27][C:28]=2[CH3:29])[NH2:26])[CH:18]=[CH:19][CH:20]=1.CCCCCC.C(OCC)(=O)C.[CH2:44]([NH:46][CH3:47])C>C(Cl)Cl>[CH2:1]([N:46]([CH3:47])[CH:44]=[N:26][C:25]1[CH:27]=[C:28]([CH3:29])[C:22]([S:21][C:17]2[CH:18]=[CH:19][CH:20]=[C:15]([O:14][CH:13]([F:12])[F:31])[CH:16]=2)=[CH:23][C:24]=1[CH3:30])[CH3:11]
Reactant: Cc1cc(Sc2cccc(OC(F)F)c2)c(C)cc1N
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCNC
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCN(C)C=Nc1cc(C)c(Sc2cccc(OC(F)F)c2)cc1C
Reaction time: 3 h

Procedure:
Catalytic p-toluenesulfonic acid is added to a mixture of 25 g of 4-(3-difluoromethoxyphenylthio)-2,5-xylidine (0.085 moles) and 141 ml of triethylorthoformiate (0.85 moles). The temperature is brought to reflux and the mixture is kept under stirring for 3 hours. The reaction trend is controlled with TLC (eluent hexane/ethyl acetate 8:2). When the reaction is completed, the mixture is concentrated at reduced pressure and the raw product obtained dissolved in methylene chloride (234 ml); 14.3 ml of N-ethylmethylamine (0.17 moles) are added dropwise. The mixture is kept under stirring for 3 hours at 40° C. and, after TLC control (eluent hexane/ethyl acetate 8:2), is concentrated at reduced pressure. 20 g of the desired product are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl[C:24](Cl)([O:26][C:27](=[O:33])OC(Cl)(Cl)Cl)Cl.[CH:35]1(O)[CH2:40][CH2:39]C[CH2:37][CH2:36]1.C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][C:27](=[O:33])[O:26][CH:24]2[CH2:39][CH2:40][CH2:35][CH2:36][CH2:37]2)=[CH:18][CH:17]=1
Reactant: COc1cc2ncnc(Oc3ccc(N)cc3)c2cc1OC
Reactant: OC1CCCCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: COc1cc2ncnc(Oc3ccc(NC(=O)OC4CCCCC4)cc3)c2cc1OC
Yield: 84.3 %

Procedure:
4-[(6,7-Dimethoxy-4-quinazolinyl)oxy]aniline (50 mg) was added to toluene (5 ml), and triethylamine (0.5 ml), and the mixture was heated under reflux to prepare a solution. A solution of triphosgene (77 mg) in methylene chloride was then added thereto, and the mixture was heated under reflux for 10 min. Next, 1-cyclohexanol (26 mg) was added thereto, and the mixture was further stirred with heating under reflux for 3 hr. A saturated aqueous sodium bicarbonate solution was added to stop the reaction, and the reaction solution was then extracted with chloroform, followed by washing with a 1 N aqueous hydrochloric acid solution, water, and saturated brine in that order. The extract was dried over sodium sulfate and was then concentrated. The residue was purified on a column using chloroform/methanol to give the title compound (60 mg, yield 71%).
Reaction SMILES: Cl.[NH:2]1[C:6]2([CH2:10][CH2:9][NH:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3]1.[C:12]([O:16][C:17](OC([O-])=O)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N(CC)CC)C>ClCCl.O>[C:12]([O:16][C:17]([N:2]1[C:6]2([CH2:10][CH2:9][NH:8][C:7]2=[O:11])[CH2:5][CH2:4][CH2:3]1)=[O:18])([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)OC(=O)[O-]
Reactant: O=C1NCCC12CCCN2
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCCC12CCNC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.2 %

Procedure:
To a solution of 1,7-diazaspiro[4,4]nonan-6-one hydrochloride (0.98 g, 5.4 mmol) in dichloromethane were added tert-butyldicarbonate (1.41 g, 6.48 mmol) and triethylamine (1.3 g, 13.5 mmol). The resulting solution was stirred overnight at room temperature. The solution was diluted with water and extracted with dichloromethane. The organic phase was separated, dried, filtered and concentrated to afford 6-oxo-1,7-diaza-spiro[4,4]nonan-1-carboxylic acid tert-butyl ester product as white powder (1.3 g) in 100% yield and used directly without further purification. 1H NMR (400 MHz, CD2Cl2) δ 6.13-5.74 (br, 1H), 3.59-3.20 (m, 4H), 2.75-2.49 (m, 1H), 2.16-1.76 (m, 5H), 1.43 (s, 3H), 1.42 (s, 6H). MS m/z 241.2 (M+H)+
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[OH:11])[CH2:8]2.[Cl:12][C:13]([O:16]C(=O)OC(Cl)(Cl)Cl)(Cl)Cl.N1C=CC=CC=1>ClCCl>[Cl:12][C:13]([O:11][CH:2]1[CH:3]2[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]1[CH2:8]3)[CH2:4]2)=[O:16]
Reactant: OC1C2CC3CC(C2)CC1C3
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: O=C(Cl)OC1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 251.2 %

Procedure:
A solution of 2-adamantanol (10.1 g, 66.5 mmol) in dichloromethane (200 mL) was cooled in an ice bath. Bis(trichloromethyl)carbonate (triphosgene) (7.55 g, 25.4 mmol) was added followed by dropwise addition of pyridine (6.2 mL, 77 mmol) at such a rate that the temperature remained below 20° C. After a further 10 minutes the mixture was warmed to room temperature and stirred for a further 2.5 hours. The dichloromethane was removed in vacuo without heating and the residue slurried with ethyl acetate (50 mL). The pyridinium hydrochloride was filtered off and the filtrate evaporated to dryness without heating to yield 2-adamantylchloroformate (76) (13.7 g, 96%); δ H (300M Hz, CDCl3, 1.48-2.32 (14H, m, adamantyl), 5.01 (1H, t, J 3 Hz, adamantyl 2-H); (lit. ,2 δ H (CCl4) 1.3-2.4 (14H, m), 4.95 (1H, s).
Reaction SMILES: [C:1]([O:14][CH2:15][C@@H:16]([O:62][C:63](=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:17][S:18][CH2:19][C@H:20]([NH:44]C(OCC1C2C=CC=CC=2C2C1=CC=CC=2)=O)[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])=[CH:28][CH:27]=1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].N1CCCCC1.C1(C)C=CC=CC=1>C(#N)C>[C:1]([O:14][CH2:15][C@@H:16]([O:62][C:63](=[O:75])[CH2:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH3:74])[CH2:17][S:18][CH2:19][C@H:20]([NH2:44])[C:21]([NH:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][C:29]([O:32][CH2:33][CH2:34][CH2:35][P:36]([O:41][CH2:42][CH3:43])([O:38][CH2:39][CH3:40])=[O:37])=[CH:28][CH:27]=1)=[O:22])(=[O:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Solvent: Cc1ccccc1
Solvent: CC#N
Solvent: C1CCNCC1
Product: CCCCCCCCCCCC(=O)OC[C@H](CSC[C@H](N)C(=O)NCCc1ccc(OCCCP(=O)(OCC)OCC)cc1)OC(=O)CCCCCCCCCCC
Temperature: 25 °C

Procedure:
To a solution of (R)-3-((R)-2-(((9H-fluoren-9-yl)methoxy)carbonylamino)-3-(4-(3-(diethoxyphosphoryl)propoxy)phenethylamino)-3-oxopropylthio)propane-1,2-diyl didodecanoate (1 eq) was added 20% piperidine (50 eq) in acetonitrile. The resulting mixture was stirred at 25° C. until the starting material disappeared. To the mixture was added toluene and then concentrated en vaccuo. The crude mixture was purified by flash chromatography on a COMBIFLASH® system (ISCO) using 100% EtOAc then 0-10% MeOH/DCM to give the product as a colorless oil.
Reaction SMILES: [C:1]([NH:4][NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)=[CH:8][CH:7]=1)(=[O:3])[CH3:2].[C:22]1([N:28]=[C:29]=[S:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>C(O)C.O>[C:1]([NH:4][NH:5][C:6]1[CH:7]=[CH:8][C:9]([N:12]([CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[C:29]([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[S:30])=[CH:10][CH:11]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(CNc2ccc(NNC(C)=O)cc2)cc1
Reactant: S=C=Nc1ccccc1
Solvent: CCO
Solvent: O
Product: COc1ccc(CN(C(=S)Nc2ccccc2)c2ccc(NNC(C)=O)cc2)cc1

Procedure:
1-Acetyl-2-[4-(4-methoxybenzyl)aminophenyl]hydrazine (3.1 g, 0.011 mole) and phenylisothiocyanate (1.35 g, 0.01 mole) were mixed in ethanol (25 ml) and the resulting mixture was refluxed for 10 minutes. The mixture was chilled in ice and diluted with water. The product oiled out of solution, but upon standing and scratching the substance solidified. The solid material was filtered off, washed with water and allowed to dry. The material was stirred twice in a large volume of ether, then was filtered and washed with fresh ether. The product was a white powder. Yield 2.75 g (66%), m.p. 126°-128° C.
Reaction SMILES: F[B-](F)(F)F.[C:6]1([CH2:12][CH2:13][C:14]([OH:16])=O)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[FH:17].F.F.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>ClCCl>[C:6]1([CH2:12][CH2:13][C:14]([F:17])=[O:16])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: F
Agent: F[B-](F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(F)CCc1ccccc1
Reaction time: 24 h
Yield: 69 %

Procedure:
To a suspension of diethylaminosulfinium tetrafluoroborate (750 mg, 3.3 mmol) in dichloromethane (10 mL) at room temperature was added 3-phenylpropanoic acid (245 mg, 1.6 mmol) and triethylamine trihydrofluoride (266 μl, 1.6 mmol). The reaction mixture was stirred for 24 hours, then an aqueous solution of sodium bicarbonate (5%) was added and stirring was continued for 30 minutes. The organic phase was isolated and dried with magnesium sulphate. The solution was diluted with pentane (10 mL) and the solution was passed through a pad of silica gel with pentane elution. Solvent were evaporated in vacuum to provide 3-phenylpropanoyl fluoride (168 mg, 68%) as a clear liquid. 1H NMR (CDCl3, 300 MHz) δ 7.30-7.17 (m, 5H), 2.96 (t, J=7.6 Hz, 2H), 2.79 (t, J=7.6 Hz, 2H); 19F NMR (CDCl3, 282 MHz) δ 44.8 (s, 1F); 13C NMR (CDCl3, 75 MHz) δ 163.0 (d, 1JC-F=180.2 Hz), 139.1, 128.9, 128.5, 127.0, 34.7 (d, =50.7 Hz), 30.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9](O)=[N:8][C:7]([C:12]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)=[N:6]2.F[P-](F)(F)(F)(F)F.[N:30]1(O[P+](N(C)C)(N(C)C)N(C)C)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2[N:32]=N1.C1CCN2C(=NCCC2)CC1.N1C=CC=CC=1CN>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([NH:32][CH2:33][C:38]1[CH:37]=[CH:36][CH:35]=[CH:34][N:30]=1)=[N:8][C:7]([C:12]1([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]1)=[N:6]2
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: CC(C)(C)OC(=O)NC1(c2nc(O)c3c(Cl)ccn3n2)CC1
Agent: F[P-](F)(F)(F)(F)F
Agent: NCc1ccccn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC(C)(C)OC(=O)NC1(c2nc(NCc3ccccn3)c3c(Cl)ccn3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.1 %

Procedure:
To a stirred solution of tert-butyl (1-(5-chloro-4-hydroxypyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (500 mg, 1.54 mmol) in acetonitrile (50 mL) was added BOP (1.02 g, 2.31 mmol), DBU (0.464 mL, 3.08 mmol) and the reaction mixture was stirred at RT for 1 h. Pyridin-2-ylmethanamine (166 mg, 1.54 mmol) was added to the reaction mixture and stirred for 12 h. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed water (2×30 mL). The organic layer was separated, dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by CombiFlash ISCO (REDISEP®, SiO2, 12 g, 10% MeOH/CHCl3) to give tert-butyl (1-(5-chloro-4-((pyridin-2-ylmethyl)amino)pyrrolo[2,1-f][1,2,4]triazin-2-yl)cyclopropyl)carbamate (320 mg, 50.1%) as a pale yellow solid. LCMS Condition B-16: retention time 1.06 min, [M+1]=415.2. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.89-0.92 (m, 2H), 1.15-1.17 (m, 2H), 1.38 (s, 9H), 4.75 (d, J=5.7 Hz, 2H), 6.69 (d, J=2.7 Hz, 1H), 7.25-7.33 (m, 3H), 7.52-7.56 (m, 1H), 7.73-7.76 (m, 1H), 7.96-7.98 (m, 1H), 8.53 (d, J=5.2 Hz, 1H).
Reaction SMILES: CS[C:3]1[S:4]/[C:5](=[CH:9]\[C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)/[C:6](=[O:8])[N:7]=1.[Br:20][C:21]1[CH:26]=[CH:25][C:24]([CH:27]([NH2:30])[CH2:28][OH:29])=[CH:23][CH:22]=1.CCN(C(C)C)C(C)C>>[Br:20][C:21]1[CH:22]=[CH:23][C:24]([CH:27]([NH:30][C:3]2[S:4]/[C:5](=[CH:9]\[C:10]3[CH:11]=[C:12]4[C:17](=[CH:18][CH:19]=3)[N:16]=[CH:15][CH:14]=[CH:13]4)/[C:6](=[O:8])[N:7]=2)[CH2:28][OH:29])=[CH:25][CH:26]=1
Reactant: NC(CO)c1ccc(Br)cc1
Reactant: CSC1=NC(=O)/C(=C/c2ccc3ncccc3c2)S1
Solvent: CCN(C(C)C)C(C)C
Product: O=C1N=C(NC(CO)c2ccc(Br)cc2)S/C1=C\c1ccc2ncccc2c1

Procedure:
Similar procedure as described in example 1b was used, starting from 2-methylsulfanyl-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one, 1-(4-bromo-phenyl)-2-hydroxy-ethylamine and DIEA to give 2-[1-(4-bromo-phenyl)-2-hydroxy-ethylamino]-5-[1-quinolin-6-yl-meth-(Z)-ylidene]-thiazol-4-one. LC-MS m/e 455 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][CH3:11])=[N:7][C:6]=2[CH:12]=1.[C:13]1([CH3:24])[CH:18]=[CH:17][C:16]([S:19]([O:22]C)(=[O:21])=[O:20])=[CH:15][CH:14]=1>CC(C)=O>[C:13]1([CH3:24])[CH:14]=[CH:15][C:16]([S:19]([O-:22])(=[O:20])=[O:21])=[CH:17][CH:18]=1.[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([S:10][CH3:11])=[N+:7]([CH3:13])[C:6]=2[CH:12]=1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CSc1nc2cc(Cl)ccc2o1
Solvent: CC(C)=O
Product: CSc1oc2ccc(Cl)cc2[n+]1C
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 60 °C
Reaction time: 8 h

Procedure:
5-Chloro-2-(methylthio)-benzoxazole (Int-I) (19.9 g, 01 mol) and 18.7 g methyl p-toluenesulfonate were heated to 140°-150° C. for 2.5 hrs. Upon cooling to 60° C., acetone was added to cover and slurry. The product was collected by filtration, crushed, and slurried overnight in acetone. Filtration and drying yielded 21.37 g (56%), mp 145°-164° C.
Reaction SMILES: C(OP([CH2:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:14]=1)(=O)OCC)C.CC([O-])(C)C.[K+].[C:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)(=O)[CH:41]([CH3:43])[CH3:42]>C1COCC1>[CH3:42][CH:41]([CH3:43])[C:40]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[CH:9][C:10]1[N:11]=[CH:12][N:13]([C:15]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:14]=1
Reactant: CCOP(=O)(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)OCC
Reactant: CC(C)C(=O)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)C(=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred suspension of (1-trityl-1H-imidazol-4-ylmethyl)-phosphonic acid diethyl ester (921 mg; CAS 473659-21-1) at r.t. in THF (20 ml) under an argon atmosphere was added potassium tert-butylate (241 mg). The mixture was then stirred at r.t. for 15 minutes, and isobutyrophenone (0.25 ml) was added in one portion. The mixture (clear brown orange solution) was heated to 80° C. for 21 hours. The reaction mixture was filtered and the cake was washed with EtOAc. The filtrate was concentrated. The crude product was purified by column chromatography (silica gel; gradient: cyclohexane→cyclohexane/EtOAc 1:1) to give 4-(3-methyl-2-phenyl-but-1-enyl)-1-trityl-1H-imidazole (91 mg; not completely pure) as orange sticky solid. MS (ISP): 243.2 ([Trt]+)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[CH:13]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: c1ccsc1
Reactant: O=C(O)Cc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O
Product: O=C(Cc1ccc(Cl)cc1)c1cccs1

Procedure:
A mixture of 85.3 g of p-chlorophenylacetic acid and 200 ml of thiophene was stirred at 40° C. as 105 g of trifluoroacetic anhydride was added. The mixture was then refluxed for 4 hrs. It was poured into ice and water and made basic with sodium carbonate. The mixture was extracted with dichloromethane, dried over potassium carbonate and concentrated. The crude yield was 126.4 g. This was recrystallized from 300 ml of methanol to give 103 g, m.p. 98°-99° C.