Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:6]1)(=[O:4])=[O:3].[N:19]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][CH:23]=1)=[C:20]=[O:21]>ClCCl>[CH3:1][S:2]([N:5]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:7]2([CH2:8][CH2:9][N:10]([C:20]([NH:19][C:22]3[CH:23]=[CH:24][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:31][CH:32]=3)=[O:21])[CH2:11][CH2:12]2)[CH2:6]1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)N1CC2(CCNCC2)c2ccccc21
Reactant: CCOC(=O)c1ccc(N=C=O)cc1
Solvent: ClCCl
Product: CCOC(=O)c1ccc(NC(=O)N2CCC3(CC2)CN(S(C)(=O)=O)c2ccccc23)cc1
Reaction time: 4 h
Yield: 99.7 %

Procedure:
To a stirred solution of 1-methylsulfonyl-spiro[indoline-3,4′-piperidine] (2.66 g, 10 mmol) in dichloromethane (50 mL), was added ethyl 4-isocyanatobenzoate (1.91 g, 10 mmol) at room temperature. The resulting solution was stirred for four hours during which time precipitation occurred. The mixture was evaporated to remove dichloromethane, and then was suspended in methanol (20 mL), filtration followed by washing with cold methanol gave 1500 as a white solid (4.56 g, 100%)
Reaction SMILES: [OH:1][CH2:2][C:3]1[S:11][C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[Cl:12])[CH:4]=1.Cl.Cl[CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.[OH-].[Na+].C(=O)(O)[O-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>[Br-].C([N+](CC)(CC)CC)C1C=CC=CC=1.C1(C)C=CC=CC=1.[Cl-].[Na+].O.C(OCC)(=O)C>[Cl:12][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[CH:4]=[C:3]([CH2:2][O:1][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)[S:11][C:10]=12
Reactant: OCc1cc2nccc(Cl)c2s1
Reactant: ClCCN1CCCC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Solvent: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: Clc1ccnc2cc(COCCN3CCCC3)sc12
Yield: 71.1 %

Procedure:
A mixture of 2-(hydroxymethyl)-7-chlorothieno[3,2-b]pyridine 114a (0.35 g, 1.8 mmole), 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (31 g, 18 mmole), benzyltriethylammonium bromide (0.2 g, 0.7 mmole) and 19 M sodium hydroxide (10 mL) in toluene was refluxed for three hours. The reaction mixture was buffered with 50% saturated sodium bicarbonate and the workup was performed with ethyl acetate, brine and magnesium sulfate. The crude product was purified over silica gel (100 g) using 2-7% methanol-chloroform with 0.1% ammonium hydroxide, which provided the title compound as an amber oil (0.38 g, 62%): 1H-NMR (DMSO-d6, 400 MHz)68.62 (1H, d, J=5.0 Hz)., 7.58 (1H, s), 7.54 (1H, d, J=5.1 Hz), 4.86 (2H, s), 3.62 (2H, t, J=6.0 Hz), 2.64 (2H, t, J=5.8 Hz), 2.49-2.47 (4H, m), 1.67-1.63 (4H, m); MS m/z 297 (M+H)+.
Reaction SMILES: [Na].[Cl:2][C:3]1[CH:8]=[C:7]([S:9][CH2:10][C:11]([F:14])([F:13])[F:12])[CH:6]=[C:5]([Cl:15])[C:4]=1[OH:16].[CH2:17](Br)[CH2:18][Br:19]>C(O)C>[Cl:15][C:5]1[CH:6]=[C:7]([S:9][CH2:10][C:11]([F:13])([F:14])[F:12])[CH:8]=[C:3]([Cl:2])[C:4]=1[O:16][CH2:17][CH2:18][Br:19]
Reactant: Oc1c(Cl)cc(SCC(F)(F)F)cc1Cl
Reactant: BrCCBr
Agent: [Na]
Solvent: CCO
Product: FC(F)(F)CSc1cc(Cl)c(OCCBr)c(Cl)c1
Temperature: 40 °C
Reaction time: 2 h
Yield: 58.4 %

Procedure:
To an ethanol solution of sodium ethylate obtained by dissolving 0.7 g of metallic sodium in 50 ml of ethanol were added 8.9 g of 2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenol and 20 g of ethylene bromide. The mixture was stirred at 40° C. for 2 hours and under reflux for 4 hours. Ethanol and the excess of ethylene bromide were evaporated. The residue was taken into 150 ml of toluene, washed with a 5% aqueous solution of potassium hydroxide and water in this sequence, and dried over anhydrous sodium sulfate. Toluene was evaporated, and the residue was distilled under reduced pressure to give 7.2 g of 2-[2,6-dichloro-4-(2,2,2-trifluoroethylthio)-phenoxy]-ethyl bromide with the b.p.=124°-126° C./0.8 mmHg.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:25]([O:28][CH2:29][C:30]1[C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][CH:33]=[CH:32][C:31]=1[N:45]1[CH2:57][CH2:56][N:48]2[C:49]3[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=3[CH:55]=[C:47]2[C:46]1=[O:58])(=[O:27])[CH3:26]>>[C:25]([O:28][CH2:29][C:30]1[C:31]([N:45]2[CH2:57][CH2:56][N:48]3[C:49]4[CH2:50][CH2:51][CH2:52][CH2:53][C:54]=4[CH:55]=[C:47]3[C:46]2=[O:58])=[CH:32][CH:33]=[CH:34][C:35]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[O:18])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:27])[CH3:26]
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Reactant: Cn1cc(Br)cc(Nc2ccc(C(=O)N3CCOCC3)cn2)c1=O
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(C(=O)N4CCOCC4)cn3)c(=O)n(C)c2)cccc1N1CCn2c(cc3c2CCCC3)C1=O
Yield: 27 %

Procedure:
Following Example 136d, 5-bromo-1-methyl-3-(5-(morpholine-4-carbonyl)pyridin-2-ylamino)pyridin-2(1H)-one 170a and 2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate 114a were reacted to give 171a in 27% yield. LCMS: (M+H)+ 651
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[N+:12]([O-:14])=[O:13].C(N(CC)CC)C.[NH2:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27].O>ClCCl>[N+:12]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:2]=1[NH:22][CH2:23][CH2:24][CH2:25][CH2:26][OH:27])=[CH:10][CH:9]=[CH:8][CH:7]=2)([O-:14])=[O:13]
Reactant: O=[N+]([O-])c1cnc2ccccc2c1Cl
Reactant: NCCCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1cnc2ccccc2c1NCCCCO
Reaction time: 8 h
Yield: 90.3 %

Procedure:
To a stirred mixture of 4-chloro-3-nitroquinoline (100.0 g, 479 mmol) and triethylamine (72.8 g, 719 mmol) in dichloromethane (700 mL) was added dropwise 4-amino-1-butanol (42.7 g, 479 mmol). After the addition was complete, water (500 mL) was added to the reaction mixture to cause the product to precipitate. More water (2 L) was added, and the mixture was stirred overnight and then filtered. The organic solution was dried over sodium sulfate, concentrated under reduced pressure, and combined with the product isolated by filtration to provide 4-(3-nitroquinolin-4-ylamino)butan-1-ol (113 g) as a bright yellow solid.
Reaction SMILES: [Cu][C:2]#[N:3].Br[C:5]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:8]=[CH:7][C:6]=1[NH2:15]>CN1CCCC1=O.C(OCC)(=O)C>[NH2:15][C:6]1[CH:5]=[CH:10][C:9]([C:11]([F:12])([F:13])[F:14])=[CH:8][C:7]=1[C:2]#[N:3]
Reactant: N#C[Cu]
Reactant: Nc1ccc(C(F)(F)F)cc1Br
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: N#Cc1cc(C(F)(F)F)ccc1N
Yield: 47 %

Procedure:
Heat a mixture of copper (I) cyanide (2.24 g, 25.00 mmol) and 2-bromo-4-trifluoromethyl-phenylamine (5.0 g, 20.83 mmol from Avocado) in 1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute the reaction mixture with 100 ml of ethyl acetate and wash the dark solution twice with 28% aqueous ammonium hydroxide, twice with saturated aqueous sodium chloride (brine) and twice with water. Collect the organic layer, dry over sodium sulfate and remove the solvent under reduced pressure. Purify the residue via flash chromatography eluting with a step gradient starting with hexanes and going to 70% hexanes with 30% ethyl acetate to obtain 1.821 g (9.78 mmol, 47% yield) the title compound as a green amorphous solid: Mass Spectrum (m/e): 187(M+1).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH:9]([S:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH:10]=O)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>O1CCCC1>[C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH:9]([S:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:10][N:21]1[CH2:26][CH2:25][S:24][CH2:23][CH2:22]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C1CSCCN1
Reactant: CC(C)(C)OC(=O)NCC(C=O)SCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCC(CN1CCSCC1)SCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
To a solution of tert-butyl[2-(benzylthio)-3-oxopropyl]carbamate (820 mg) in tetrahydrofuran (30 mL) was added thiomorpholine (0.42 mL), and the mixture was stirred at room temperature for 1 hr. Sodium triacetoxyborohydride (1.76 g) was added to the reaction mixture under ice-cooling, and the mixture was stirred overnight at room temperature. Saturated aqueous sodium hydrogencarbonate solution was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel chromatography to give the title compound (936 mg, yield 91%) as a colorless oil from a fraction eluted with is ethyl acetate-hexane (3:7).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[N:16]=[C:17]([CH3:26])[O:18][C:19]=2[C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[CH:11][CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.[OH-].[OH-].[Pd+2]>[CH3:26][C:17]1[O:18][C:19]([C:20]2[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=2)=[C:15]([C:12]2[CH:11]=[CH:10][C:9]([OH:8])=[CH:14][CH:13]=2)[N:16]=1
Reactant: Cc1nc(-c2ccc(OCc3ccccc3)cc2)c(-c2ccncc2)o1
Agent: [Pd+2]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: Cc1nc(-c2ccc(O)cc2)c(-c2ccncc2)o1
Yield: 86 %

Procedure:
4-(4-(4-(Benzyloxy)phenyl)-2-methyloxazol-5-yl)pyridine was hydrogenated in the presence of ammonium formate and Pd(OH)2 in methanol for 1 h at 50° C. The catalyst was removed via filtration and the filtrate was concentrated. The resultant residue was dissolved in methylene chloride and dried with Na2SO4. Evaporation of the solvent gave 69 mg (86%) of the title compound as a brown solid. MS m/z: 253.
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=O)[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1COCC1>[CH2:17]([N:24]1[CH2:29][CH2:28][C:27](=[CH:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:26][CH2:25]1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: O=C1CCN(Cc2ccccc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C=C1CCN(Cc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 87.5 %

Procedure:
To a suspension of NaH (318 mg, 7.94 mmol) in THF (20 mL) was added a solution of ethyl 2-(diethoxyphosphoryl)acetate (1.78 g, 7.94 mmol) in THF (5 mL) dropwise over 30 min at 0° C. After stirring for 10 min, a solution of 1-benzylpiperidin-4-one (1.0 g, 5.29 mmol) in THF (5 mL) was added dropwise at 0° C. over 20 min. The mixture was allowed to stir for 60 min. Then, the reaction was quenched with water (10 mL). The mixture was extracted with EA (10 mL×3). The combined organic layers were dried over Na2SO4, concentrated and purified by chromatography column on silica gel using 25% of EA in PE as eluant to give the product (1.2 g, 87.3%) as a yellow oil. MS (ESI, m/e) [M+1]+ 260.0.
Reaction SMILES: ClC1(Cl)C(=O)[CH2:8][CH:7]2[CH:3]1[CH2:4][CH2:5][CH:6]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][O:16][Si](C(C)(C)C)(C)C.CC[O:27][CH2:28][CH3:29]>C(O)(=O)C.[Zn]>[OH:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:6]12[CH2:29][C:28](=[O:27])[CH2:8][CH:7]1[CH2:3][CH2:4][CH2:5]2
Reactant: CC(C)(C)[Si](C)(C)OCCCCCC1CCC2C1CC(=O)C2(Cl)Cl
Reactant: CCOCC
Agent: [Zn]
Solvent: CC(=O)O
Product: O=C1CC2CCCC2(CCCCCO)C1
Temperature: 70 °C

Procedure:
The starting material, 6,6-dichloro-2-(5-[(1,1-dimethylethyl)dimethylsiloxy]pent-1-yl)bicyclo[3.3.0]octan-7-one {1,1-dichloro-4-[5-[[(1,1-dimethylethyl)dimethylsilyl]oxy]pentyl]hexahydro-2(1H)-pentalenone} (12.1 g, 0.30 moles) is dissolved in glacial acetic acid (85 ml) and the solution is stirred while zinc (25 g) is slowly added. The reaction is heated at 70° C. for 1 hour, after which time ether (100 ml) is added and the solution filtered. The filtrate is washed with brine and then neutralized with saturated sodium bicarbonate. The ether layer is separated and dried over anhydrous sodium sulfate. The solvent is removed under vacuum leaving a clear yellow oil. The crude product is chromatographed on silica gel and subsequently kugelrohred under vacuum leaving a clear, colorless oil (0.72 g, 3.4 mmoles).
Reaction SMILES: O[C:2]1([C:17]#[C:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:6][C:5]2([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]2)[O:4][CH2:3]1.S(Cl)(Cl)=O.O.Cl>N1C=CC=CC=1>[C:19]1([C:18]#[C:17][C:2]2[CH2:3][O:4][C:5]3([CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:8][CH2:7]3)[CH:6]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: CCOC(=O)N1CCC2(CC1)CC(O)(C#Cc1ccccc1)CO2
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)N1CCC2(C=C(C#Cc3ccccc3)CO2)CC1
Reaction time: 2 h
Yield: 20.5 %

Procedure:
To a solution of Compound 26a (93 mg, 0.282 mmol) stirred in pyridine (4 mL) at 0° C. was added thionyl chloride (0.103 mL, 1.141 mmol) and the reaction mixture was stirred at 0° C. to r.t. for 2 h. Afterwards, it was poured into water, acidified with 1M HCl and extracted with chloroform. The organic layers were combined, washed with brine, dried over sodium sulphate and evaporated to dryness to afford a crude, which was purified by automated flash chromatography (SP1®TM-Biotage; gradient Petroleum Ether-EtOAc from 92:8 to 75:25) to give 18 mg of the title compound.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]2)[CH:5]=[C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:3]=1.[NH2:21][C:22]1[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=1>>[OH:14][CH:11]1[CH2:12][CH2:13][N:8]([C:6]2[CH:5]=[C:4]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[N:3]=[C:2]([NH:21][C:22]3[CH:27]=[CH:26][C:25]([S:28]([NH:31][CH3:32])(=[O:30])=[O:29])=[CH:24][CH:23]=3)[N:7]=2)[CH2:9][CH2:10]1
Reactant: OC1CCN(c2cc(-c3ccccc3)nc(Cl)n2)CC1
Reactant: CNS(=O)(=O)c1ccc(N)cc1
Product: CNS(=O)(=O)c1ccc(Nc2nc(-c3ccccc3)cc(N3CCC(O)CC3)n2)cc1

Procedure:
A sample of 4-[4-(4-hydroxy-piperidin-1-yl)-6-phenyl-pyrimidin-2-ylamino]-N-methyl-benzenesulfonamide was prepared from compound 1-(2-chloro-6-phenyl-pyrimidin-4-yl)-piperidin-4-ol (0.5 g, 1.74 mmol) and 4-amino-N-methyl-benzenesulfonamide (0.39 g, 1.74 mmol) according to a procedure analogous to that described above in Example 48.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31].Cl.[O:33]1[CH2:37][CH2:36][CH:35]([NH2:38])[CH2:34]1.C(N(CC)CC)C>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([NH:38][CH:35]3[CH2:36][CH2:37][O:33][CH2:34]3)[N:17]=[C:18]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=3[CH3:26])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:31]
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: NC1CCOC1
Agent: Cl
Solvent: CCN(CC)CC
Product: Cc1cc(F)ccc1-c1nc(NC2CCOC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Yield: 30 %

Procedure:
Following the general procedure outlined in Example 195, the product of Example 48 (125 mg, 0.28 mmol), the crude tetrahydro-furan-3-ylamine hydrochloride (240 mg) and triethylamine (0.27 mL, 1.9 mmol) were reacted to give the crude material. Purification by flash chromatography, eluting with EtOAc/hexane/triethylamine (50/50/2, v/v/v), gave the desired product (38 mg, 30%). LC-MS: 453.2 (MH+, m/z), 2.20 (Rt, min).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[CH:9]=[N:10][C:11](=O)[NH:12][N:13]=1.C(Cl)(Cl)[Cl:16].P(Cl)(Cl)(Cl)=O.CN(C)C=O>CCCCCC>[Cl:16][C:11]1[N:12]=[N:13][C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])=[CH:9][N:10]=1
Reactant: ClC(Cl)Cl
Reactant: O=c1ncc(-c2ccccc2F)n[nH]1
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CCCCCC
Product: Fc1ccccc1-c1cnc(Cl)nn1

Procedure:
A suspension of 42.4 g. of 6-(o-fluorophenyl)-1,2,4-triazin-3(2H)-one in 350 ml. of chloroform is refluxed overnight, cooled in an ice bath, and 350 ml. of phosphorus oxychloride followed by 2.6 g. of N,N-dimethylformamide are added. The mixture is refluxed for 4.5 hours, cooled and concentrated to a brown oil. This oil is dissolved in methylene chloride, poured onto ice and made basic, giving a brown solid. The mixture is filtered and the filtrate is passed through a silica gel column giving a crystalline solid. This solid is heated with hexane and filtered giving crystals. Recrystallization from hexane gives a tan solid which sublimes on heating giving 3-chloro-6-(o-fluorophenyl)-1,2,4-triazine as tan crystals.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH3:9][OH:10].[ClH:11]>C1(C)C=CC=CC=1>[ClH:11].[CH3:9][O:10][C:3]([C@H:4]1[CH2:7][C@@H:1]([NH2:2])[CH:6]=[CH:5]1)=[O:8]
Reactant: CO
Reactant: O=C1NC2C=CC1C2
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1C=C[C@H](N)C1
Reaction time: 1 h
Yield: 94.5 %

Procedure:
20.0 g (183.3 mmol) of 2-azabicyclo[2.2.1]hept-5-en-3-one, 8.8 g (274.7 mmol) of methanol, and 150 mL of toluene were put into a four-necked flask (300 mL volume) equipped with a hydrogen chloride introducing tube, a thermometer, and an exhaust tube. 6.7 g (183.8 mmol) of hydrogen chloride was introduced into the obtained mixture over a period of 2 hours through the hydrogen chloride introducing tube at room temperature. Following 1 hour of stirring, the precipitated crystals were filtered off with a glass filter. The obtained crystals were dried under reduced pressure to give 30.8 g (173.2 mmol) of cis-4-amino-2-cyclopentene-1-carboxylic acid methyl ester hydrochloride (that is, (1S*, 4R*)-4-amino-1-methoxycarbonyl-2-cyclopentene hydrochloride). The yield was 94.4%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[N:18]=[C:19]([O:44][C:45]2([CH3:49])[CH2:48][CH2:47][CH2:46]2)[C:20]2[C:25]([C:26]3[CH:35]=[CH:34][C:29]4[N:30]=[C:31]([CH3:33])[O:32][C:28]=4[CH:27]=3)=[CH:24][N:23](COCC[Si](C)(C)C)[C:21]=2[N:22]=1)[C:6]([NH:8][CH:9]1[CH2:12][O:11][CH2:10]1)=[O:7].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][C:15]=1[NH:16][C:17]1[N:18]=[C:19]([O:44][C:45]2([CH3:49])[CH2:48][CH2:47][CH2:46]2)[C:20]2[C:25]([C:26]3[CH:35]=[CH:34][C:29]4[N:30]=[C:31]([CH3:33])[O:32][C:28]=4[CH:27]=3)=[CH:24][NH:23][C:21]=2[N:22]=1)[C:6]([NH:8][CH:9]1[CH2:10][O:11][CH2:12]1)=[O:7]
Reactant: COc1cc(C(=O)NC2COC2)ccc1Nc1nc(OC2(C)CCC2)c2c(-c3ccc4nc(C)oc4c3)cn(COCC[Si](C)(C)C)c2n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1cc(C(=O)NC2COC2)ccc1Nc1nc(OC2(C)CCC2)c2c(-c3ccc4nc(C)oc4c3)c[nH]c2n1
Temperature: 90 °C
Yield: 17 %

Procedure:
A mixture of 3-methoxy-4-((5-(2-methylbenzo[d]oxazol-6-yl)-4-(1-methylcyclobutoxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)-N-(oxetan-3-yl)benzamide (1 equiv) in THF (0.1 M) in a sealed tube was added a solution of tetrabutylammonium fluoride in THF (1 M, 10 equiv). The resulting mixture was heated at 90° C. for 16 h. The reaction mixture was cooled to room temperature and concentrated. The residue was purified to afford the title compound (17% yield over two steps). 1H NMR (400 MHz, DMSO-d6) δ ppm 11.82 (s, 1H), 8.97 (d, J=6.4 Hz, 1H), 8.58 (d, J=8.0 Hz, 1H), 7.97 (d, J=0.8 Hz, 1H), 7.68-7.54 (m, 5H), 7.38 (d, J=2.4 Hz, 1H), 5.06-5.00 (m, 1H), 4.79 (t, J=7.0 Hz, 2H), 4.62 (t, J=6.4 Hz, 2H), 3.98 (s, 3H), 2.62 (s, 3H), 2.49-2.43 (m, 2H), 2.32-2.27 (m, 2H), 1.87-1.78 (m, 2H), 1.75 (s, 3H). MS (ESI) m/z 555.3 [M+H]+.
Reaction SMILES: CO.C[O-].[Na+].CO.[Br:8][CH2:9][CH2:10]Br.[F:12][C:13]1[CH:14]=[C:15]([SH:19])[CH:16]=[CH:17][CH:18]=1>O.C(OCC)(=O)C>[F:12][C:13]1[CH:14]=[C:15]([S:19][CH2:10][CH2:9][Br:8])[CH:16]=[CH:17][CH:18]=1
Reactant: Fc1cccc(S)c1
Reactant: BrCCBr
Agent: C[O-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1cccc(SCCBr)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 2 mL of a methanol solution containing 0.83 g of 28% sodium methoxide/methanol, 1.0 mL of 1,2-dibromoethane and 0.50 g of 3-fluorobenzenethiol were added under cooling with ice, the mixture was stirred at the same temperature for 1 hour, at room temperature for 2 hours, and at 50° C. for 1 hour, and then the reaction mixture was refluxed by heating for 5 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and water were added thereto. The organic layer was separated, washed with an aqueous saturated sodium chloride solution and dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane] to obtain 0.62 g of a pale yellow oily substance, 1-(3-fluorophenyl)thio-2-bromoethane.
Reaction SMILES: [CH2:1]([C:3]1[S:7][C:6]([N:8]=[C:9]=[S:10])=[C:5]([C:11]([O:13]C)=O)[CH:4]=1)[CH3:2].[CH3:15][C:16]1[N:20]([CH2:21][CH2:22][CH2:23][NH2:24])[CH:19]=[N:18][CH:17]=1>>[CH2:1]([C:3]1[S:7][C:6]2[NH:8][C:9](=[S:10])[N:24]([CH2:23][CH2:22][CH2:21][N:20]3[C:16]([CH3:15])=[CH:17][N:18]=[CH:19]3)[C:11](=[O:13])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: Cc1cncn1CCCN
Reactant: CCc1cc(C(=O)OC)c(N=C=S)s1
Product: CCc1cc2c(=O)n(CCCn3cncc3C)c(=S)[nH]c2s1

Procedure:
The compound was synthesized starting from methyl 5-ethyl-2-isothiocyanatothiophene-3-carboxylate (0.1 g, 0.44 mmol) and 3-(5-methyl-1H-imidazol-1-yl)propan-1-amine (5) (0.06 g, 0.44 mmol) as described above.
Reaction SMILES: [H-].[Na+].Br[CH2:4][C:5]1[CH:6]=[C:7]([B:13]2[O:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=[C:9]([CH2:11][Br:12])[CH:10]=1.[CH2:19]([OH:23])[CH2:20][CH2:21][OH:22]>C(#N)C>[Br:12][CH2:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([B:13]2[O:18][CH2:17][CH2:16][CH2:15][O:14]2)[CH:8]=1)[CH2:4][O:22][CH2:21][CH2:20][CH2:19][OH:23]
Reactant: BrCc1cc(CBr)cc(B2OCCCO2)c1
Reactant: OCCCO
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: OCCCOCc1cc(CBr)cc(B2OCCCO2)c1
Temperature: 25 °C

Procedure:
An oven-dried, 250-mL round bottom flask equipped with a magnetic stirring bar and reflux condenser was cooled under argon and charged with NaH (0.800 g of 60% in mineral oil, 20 mmols). The powder was washed with pentane (3×100 mL) and dried in vacuum. Acetonitrile (50 mL) was added by syringe and the mixture stirred at room temperature. 1,3-Propane diol (10 mL) was added dropwise over ten min. to form a white insoluble precipitate. The suspension was vigorously stirred for one hour at which time 20 mL was taken up by syringe and added dropwide to a 250-mL round bottom flask charged with 2-(3,5-Bis-bromomethyl-phenyl)-(1,3,2)dioxaborinane (2.865 g, 8.2 mmols) and acetonitrile (50 mL). The mixture was stirred for 12 hr at room temperature. A reflux condenser was attached along with a vacuum adapter and the reaction mixture was heated to reflux under argon for two hours. The acetonitrile was removed in vacuo and the residue purified by flash chromatography (EtOAc:hexane, 2:1). Removal of solvents gave a suspension of white solids in a yellow oil, which when analyzed by thin layer chromatography showed no starting material. The crude mixture containing 1,3-propane diol was used without further purification.