Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C-:1]#[N:2].[K+].[Br:4][C:5]1[CH:6]=[C:7]([C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1)[CH2:8]Cl>O>[Br:4][C:5]1[CH:6]=[C:7]([CH2:8][C:1]#[N:2])[C:10]([S:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[CH:11][CH:12]=1
Reactant: [C-]#N
Reactant: ClCc1cc(Br)ccc1Sc1ccccc1
Agent: [K+]
Solvent: O
Product: N#CCc1cc(Br)ccc1Sc1ccccc1

Procedure:
136.5 g of potassium cyanide in 183 ml of water are heated under reflux for 10 hours under a nitrogen atmosphere with 470 g of 3-bromo-6-(phenylthio)-benzyl chloride. The ethanol is distilled off under reduced pressure, the residue diluted with water and extracted with ether. The extracts are washed with water, dried over magnesium sulphate and evaporated. There is obtained 3-bromo-6-(phenylthio)-phenylacetonitrile as a brown oil.
Reaction SMILES: Cl[C:2](Cl)(Cl)[CH:3](O)[OH:4].S(O)(O)(=O)=O.[NH2:13][C:14]1[N:15]=[C:16]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[O:28][CH2:29][CH2:30][CH3:31])[NH:17][C:18](=[O:21])[C:19]=1[NH2:20]>C=O.CO>[CH2:29]([O:28][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=1[C:16]1[NH:17][C:18](=[O:21])[C:19]2[NH:20][C:3](=[O:4])[CH:2]=[N:13][C:14]=2[N:15]=1)[CH2:30][CH3:31]
Reactant: OC(O)C(Cl)(Cl)Cl
Reactant: CCCOc1ccccc1-c1nc(N)c(N)c(=O)[nH]1
Agent: C=O
Agent: O=S(=O)(O)O
Solvent: CO
Product: CCCOc1ccccc1-c1nc2ncc(=O)[nH]c2c(=O)[nH]1
Temperature: 80 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
A solution of chloral hydrate (1.74 g) in 50% aqueous methanal (10 ml) was added over 10 minutes to a stirred solution of 4,5-diamino-2-(2-propoxyphenyl)pyrimidin-6-one sulphate (1.89 g) in 50% aqueous methanol (60 ml) at 80° C. and the reaction mixture was stirred at 80° C. for 1.5 hours. The cooled reaction mixture was filtered to remove an orange brown solid which was discarded. On standing overnight the filtrate afforded a crude solid product (0.96 g) which was collected and washed with dilute aqueous potassium bicarbonate and water. The crude product together with another sample (0.20 g) similarly prepared was eluted from a silica column with chloroform. The combined fractions containing product were evaporated under reduced pressure to afford a solid (0.54 g) which was recrystallized from acetonitrile to afford the title compound, 0.39 g, m.p. 232-233.5° C.
Reaction SMILES: C([O:4][CH2:5][C@H:6]1[O:26][C@H:25]([C@@H:27]([CH2:36][O:37]C(=O)C)[O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@@H:7]1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=O)C.[O-]CC.[Na+].C(O)(=O)C>C(O)C>[C:10]1([CH2:9][O:8][C@H:7]2[C@H:16]([O:17][CH2:18][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)[C@@H:25]([C@@H:27]([CH2:36][OH:37])[O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[O:26][C@@H:6]2[CH2:5][OH:4])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(=O)OC[C@@H](OCc1ccccc1)[C@H]1O[C@H](COC(C)=O)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: OC[C@@H](OCc1ccccc1)[C@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Reaction time: 1 h
Yield: 70.6 %

Procedure:
A solution of 485 mg of 2,5-anhydro-3,4,6-tris-O-(phenylmethyl)-D-glycero-D-manno-heptitol 1,7-diacetate in 2 ml of ethanol was treated with 183 μl of an ethanolic solution of sodium ethoxide (2.4N). After 1 hour, 150 μl of glacial acetic acid was added and the mixture evaporated. The residue was taken up in ether, washed with saturated aqueous sodium bicarbonate and brine, dried and evaporated. Flash chromatography, eluting with hexane:ethyl acetate (1:1), gave 290 mg of the desired compound.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[CH:9][C:10]([O:13][CH3:14])=[N:11][CH:12]=1.[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])([O-:17])=[O:16].[K+].[Br-]>O1CCCC1.CCCCCC>[N+:15]([C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]([C:7]1[CH:12]=[N:11][C:10]([O:13][CH3:14])=[CH:9][CH:8]=1)[OH:21])([O-:17])=[O:16]
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Reactant: COc1ccc(Br)cn1
Agent: [Br-]
Agent: [K+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc(C(O)c2ccccc2[N+](=O)[O-])cn1
Temperature: -85 °C

Procedure:
n-Butyllithium (6.7 ml of a 1.6M hexane solution) was added dropwise to a stirred, cooled (-100° C.) solution of 5-bromo-2-methoxypyridine (2.0 g, Eur. J. Med. Chem. 1977, 12, 531) in anhydrous tetrahydrofuran (60 ml), under a nitrogen atmosphere. After 20 minutes a solution of 2-nitrobenzaldehyde (1.61 g) in anhydrous tetrahydrofuran (30 ml)was added dropwise and the reaction mixture was stirred whilst maintaining the temperature between -90° and -100° C. for 2 hours. The reaction mixture was warmed to -85° C. then quenched with saturated aqueous ammonium chloride solution then allowed to warm to room temperature. The organic layer was separated and the aqueous extracted with ethyl acetate (3×100 ml). The combined organics were dried (magnesium sulphate) then evaporated to give a gum which was purified by column chromatography on silica using ethyl acetate/petroleum ether (60-80) (1:4) to afford an oil which solidified to give a low melting solid on standing (1.42 g). Rf =0.30 in 33% ethyl acetate/petroleum ether (60-80) on silica plates; 1H NMR (360 MHz, CDCl3) δ 2.60 (1H, broad s), 3.91 (3H, s), 6.43 (1H, s), 6.70 (1H, d, J=9 Hz), 7.48 (1H, dd, J=1 and 8 Hz), 7.53 (1H, dd, J=3 and 9 Hz), 7.67 (1H, dd, J=1 and 8 Hz), 7.83 (1H, d, J=8 Hz), 7.96 (1H, dd, J=1 and 8 Hz), 8.11 (1H, d, J=3 Hz); MS, m/z 261 for (M+H)+ ; IR (KBr) 3300 cm-1 (v. broad).
Reaction SMILES: C[O:2][C:3](=[O:27])[C:4]1[C:9]([NH:10][CH:11]([CH2:14][CH3:15])[CH2:12][CH3:13])=[CH:8][C:7]([CH3:16])=[N:6][C:5]=1[O:17][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=1[CH3:26].[OH-].[Li+]>O1CCOCC1.O>[CH2:12]([CH:11]([NH:10][C:9]1[C:4]([C:3]([OH:27])=[O:2])=[C:5]([O:17][C:18]2[C:23]([CH3:24])=[CH:22][C:21]([CH3:25])=[CH:20][C:19]=2[CH3:26])[N:6]=[C:7]([CH3:16])[CH:8]=1)[CH2:14][CH3:15])[CH3:13]
Reactant: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)OC
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CCC(CC)Nc1cc(C)nc(Oc2c(C)cc(C)cc2C)c1C(=O)O
Temperature: 25 °C
Yield: 45.7 %

Procedure:
A mixture of 4-(1-Ethyl-propylamino)-6-methyl-2-(2,4,6-trimethyl-phenoxy)-nicotinic acid methyl ester (16 mg, 0.043 mmol) and lithium hydroxide (30 mg) in dioxane (1 ml) and water (1 ml) was stirred at rt over night. The mixture was quenched with water and adjusted to pH 7.0 and extracted with chloroform. The organic layer was dried and concentrated to give the crude material. The crude material was purified through silica gel column chromatography using 10% ethyl acetate in chloroform as eluent to give 7 mg of the title compound as white solid. 1H NMR (CDCl3) δ 9.12 (d, 1H), 6.87 (s, 2H), 6.16 (s, 1H), 3.35 (m, 1H), 2.29 (s, 3H), 2.10 (s, 3H), 2.07 (s, 6H), 1.4–1.6 (m, 4H), 0.94 (t, 6H) ppm.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19](Br)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)(C)(C)C.[CH3:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([NH2:36])=[CH:32][CH:31]=1>>[NH2:7][C:8]1[N:9]([CH3:26])[C:10](=[O:25])[C:11]([CH3:24])([CH3:23])[C@:12]([C:15]2[CH:20]=[C:19]([NH:36][C:33]3[CH:34]=[CH:35][C:30]([O:29][CH3:28])=[CH:31][CH:32]=3)[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1
Reactant: COc1ccc(N)cc1
Reactant: CN1C(=O)C(C)(C)[C@@](C)(c2cc(Br)ccc2F)N=C1NC(=O)OC(C)(C)C
Product: COc1ccc(Nc2ccc(F)c([C@@]3(C)N=C(N)N(C)C(=O)C3(C)C)c2)cc1

Procedure:
The coupling of [(S)-4-(5-bromo-2-fluoro-phenyl)-1,4,5,5-tetramethyl-6-oxo-1,4,5,6-tetrahydro-pyrimidin-2-yl]-carbamic acid tert-butyl ester (intermediate E8) and 4-methoxyphenylamine according to procedure A followed by deprotection yielded the title compound as an off white solid. MS (ESI): m/z=385.2 [M+H]+.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[CH2:16][C@@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][N:13]2[C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][CH:27]=2)=[O:23])(=O)=O)=CC=1.[C:36]1(=[O:46])[NH:40][C:39](=[O:41])[C:38]2=[CH:42][CH:43]=[CH:44][CH:45]=[C:37]12.[K]>CN(C)C=O>[N+:32]([C:29]1[CH:28]=[CH:27][C:26]([CH2:25][O:24][C:22]([N:13]2[CH2:14][C@H:15]([O:17][S:18]([CH3:21])(=[O:20])=[O:19])[CH2:16][C@H:12]2[CH2:11][N:40]2[C:36](=[O:46])[C:37]3=[CH:45][CH:44]=[CH:43][CH:42]=[C:38]3[C:39]2=[O:41])=[O:23])=[CH:31][CH:30]=1)([O-:34])=[O:33]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2C[C@@H](OS(C)(=O)=O)CN2C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CS(=O)(=O)O[C@@H]1C[C@@H](CN2C(=O)c3ccccc3C2=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Temperature: 60 °C
Reaction time: 7 h
Yield: 78.8 %

Procedure:
A mixture of (2S,4R)-1-p-nitrobenzyloxycarbonyl-4-methanesulfonyloxypyrrolidine-2-methanol p-toluenesulfonate (25 g: 47.3 mmole) and potassium phthalimide (17.52 g: 2 eq.) in dimethylformamide (250 ml) is stirred at 60° C. for 7 hours. The reaction mixture is poured into ice water and filtrated. The resulting precipitate is dissolved in ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and concentrated in vacuo. The residue is recrystallized from methanol to give (2S,4R)-1-p-nitrobenzyloxycarbonyl-2-phthalimidomethyl-4-methanesulfonyloxypyrrolidine (18.76 g). Yield: 79%. mp. 121° to 123° C. NMR δ(CDCl3) ppm: 2.03 to 2.60(m, 2H), 3.02(s, 3H), 3.50 to 4.15(m, 4H), 4.40 to 4.63(m, 1H), 5.10, 5.29(ABq, J=15 Hz, 2H), 5.10 to 5.30(m, 1H), 7.46 (d, J=9 Hz, 1H), 7.57(d, J=9 Hz, 1H), 7.63 to 7.88(m, 4H), 8.20(d, J=9 Hz, 2H) IR ν (CHCl3) cm-1 : 1773, 1715, 1605.
Reaction SMILES: [SH:1][C:2]1[N:6]2[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.BrC1C=CC2N(C(S[C:25]3[CH:26]=[CH:27][C:28]4[N:29]([CH:31]=[C:32]([NH:34][C:35]([CH:37]5[CH2:39][CH2:38]5)=[O:36])[N:33]=4)[N:30]=3)=NN=2)C=1>>[CH:37]1([C:35]([NH:34][C:32]2[N:33]=[C:28]3[CH:27]=[CH:26][C:25]([S:1][C:2]4[N:6]5[CH:7]=[C:8]([C:11]([OH:13])=[O:12])[CH:9]=[CH:10][C:5]5=[N:4][N:3]=4)=[N:30][N:29]3[CH:31]=2)=[O:36])[CH2:38][CH2:39]1
Reactant: O=C(Nc1cn2nc(Sc3nnc4ccc(Br)cn34)ccc2n1)C1CC1
Reactant: O=C(O)c1ccc2nnc(S)n2c1
Product: O=C(O)c1ccc2nnc(Sc3ccc4nc(NC(=O)C5CC5)cn4n3)n2c1

Procedure:
Compound 33 was prepared from 3-mercapto-[1,2,4]triazolo[4,3-a]pyridine-6-carboxylic acid following the procedure described in the synthesis of compound 4. 1H NMR (400 MHz, CDCl3—CD3OD 10:1) δ ppm 9.03 (bs, 1 H), 8.01 (d, J=9.1 Hz, 1 H), 7.87 (d, J=9.6 Hz, 1 H), 7.68 (d, J=9.4 Hz, 1 H), 7.36 (m, 1H), 7.09 (d, J=9.3 Hz, 1 H), 2.84 (m, 1 H), 1.72 (m, 1 H), 0.97 (m, 2 H), 0.84 (m, 2H) ESI-MS:m/z 396.1 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([CH3:43])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)ccn1
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (152 mg, 0.5 mmol) and 3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K12) (156 mg, 0.5 mmol) according to the general procedure M. Obtained as a light yellow foam (213 mg, 79%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)[CH:5]=O.[NH2:13][C:14]1[CH:23]=[CH:22][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:16][CH:15]=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:10]([O-:12])=[O:11])[CH:9]=1)/[CH:5]=[N:13]/[C:14]1[CH:15]=[CH:16][C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: O=Cc1cc(Cl)cc([N+](=O)[O-])c1
Reactant: COC(=O)c1ccc(N)cc1
Solvent: CCO
Product: COC(=O)c1ccc(/N=C/c2cc(Cl)cc([N+](=O)[O-])c2)cc1
Yield: 1085.6 %

Procedure:
To a solution of 3-chloro-5-nitrobenzaldehyde (371 mg, 0.1 mmol) in ethanol (6 mL) was added methyl 4-aminobenzoate (302 mg, 2.0 mmol). After a while, solids precipitated from the resulting clear yellow solution. The precipitated solid was filtered and 346 mg of (E)-methyl 4-(3-chloro-5-nitrobenzylideneamino)benzoate as a yellow solid was obtained. Yield=54%.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.N1C2C(=CC=CC=2)C=CC=1.[C:16]([C:18]1[C:19](O)=[N:20][CH:21]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:23]=1)#[N:17].C(=O)(O)[O-].[Na+]>O>[Cl:3][C:19]1[C:18]([C:16]#[N:17])=[CH:23][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:21][N:20]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: N#Cc1cc(C(F)(F)F)cnc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccc2ncccc2c1
Product: N#Cc1cc(C(F)(F)F)cnc1Cl
Temperature: 25 °C

Procedure:
To a mixture of phosphorous oxychloride (13.4 mL, 144 mmol) and quinoline (8.7 mL, 73 mmol) was added the product from Step C above (24.6 g, 131 mmol) and the resultant mixture was heated to reflux for 3 h. The reaction was cooled to 100° C. before water (70 mL) was slowly added. The mixture was further cooled to room temperature and neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution. The aqueous layer was extracted with three portions of ethyl acetate and the organic layers were combined, dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by flash chromatography to afford the desired compound. 1H NMR (500 MHz, CDCl3) δ 8.88 (d, J=2.0 Hz, 1H), 8.26 (d, J=2.5 Hz, 1H).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10](S(C)=O)[N:9]=[C:8]([NH2:16])[N:7]=1.[C:17]1([CH2:23][CH2:24][CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C1CCN2C(=NCCC2)CC1>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[C:11]([I:12])=[C:10]([O:26][CH2:25][CH2:24][CH2:23][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:9]=[C:8]([NH2:16])[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1I
Reactant: OCCCc1ccccc1
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: Nc1nc(OCCCc2ccccc2)c(I)c(-c2ccco2)n1

Procedure:
From 4-furan-2-yl-5-iodo-6-methanesulfinyl-pyrimidin-2-yl-amine, 3-phenylpropanol and DBU in THF. ES-MS m/e (%): 422 (M+H+, 100).
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[CH:4]1[CH2:11][CH2:10][CH2:9][CH2:8][C:5]21[CH2:7][CH2:6]2.[CH:13]1([C:16](=O)[CH2:17][C:18]([O:20]C)=[O:19])[CH2:15][CH2:14]1>>[CH:13]1([C:16]2[O:1][N:2]=[C:3]([CH:4]3[CH2:11][CH2:10][CH2:9][CH2:8][C:5]43[CH2:7][CH2:6]4)[C:17]=2[C:18]([OH:20])=[O:19])[CH2:15][CH2:14]1
Reactant: ON=C(Cl)C1CCCCC12CC2
Reactant: COC(=O)CC(=O)C1CC1
Product: O=C(O)c1c(C2CCCCC23CC3)noc1C1CC1

Procedure:
5-Cyclopropyl-3-(spiro[2.5]octan-4-yl)isoxazole-4-carboxylic acid (I-11K) was prepared from N-hydroxyspiro[2.5]octane-4-carbimidoyl chloride and methyl 3-cyclopropyl-3-oxopropanoate following the same protocol as described for I-6E. MS m/z 262.1 (M+1).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][C:3]=1[F:10].O.[CH3:12][N:13](C=O)C>[C-]#N.[Zn+2].[C-]#N>[F:10][C:3]1[CH:4]=[C:5]([CH2:6][OH:7])[CH:8]=[CH:9][C:2]=1[C:12]#[N:13]
Reactant: OCc1ccc(Br)c(F)c1
Reactant: CN(C)C=O
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: N#Cc1ccc(CO)cc1F
Temperature: 95 °C
Reaction time: 0.25 h

Procedure:
4-Bromo-3-fluorobenzyl alcohol( 20 g, 0.097 mol) was dissolved in DMF (100 mL) and then placed under high vacuum for 15 min. The solution was then purged with Ar for 15 min. While purging continued, zinc cyanide ( 8 g, 0.068 mol) and the catalyst, Pd[(PPh3)]4, (5.63 g, 0.0049 mol) were added. The reaction mixture was heated at 95° C. under Ar for 18 h, then cooled to ambient temperature and added to H2O. The mixture was extracted with EtOAc, then washed with 1 M HCl, H2O, brine, and dried (Na2SO4). Filtration and concentration to dryness gave the title compound as a white solid after chromatography (silica gel, hexane: EtOAc, 6.5:3.5).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[CH2:10]([O:12][P:13]([O:17]CC)[O:14][CH2:15][CH3:16])[CH3:11]>CCCCCC.C(OC(=O)C)C>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][P:13](=[O:17])([O:14][CH2:15][CH3:16])[O:12][CH2:10][CH3:11])=[CH:4][CH:3]=1
Reactant: CCOP(OCC)OCC
Reactant: BrCc1ccc(Br)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCOP(=O)(Cc1ccc(Br)cc1)OCC
Reaction time: 24 h
Yield: 81.4 %

Procedure:
4-bromobenzylbromide (10.0 g, 40.0 mmol) was dissolved in triethylphosphite (8.4 mL, 48.0 mmol) under a nitrogen atmosphere, and the reaction solution was refluxed and stirred for 24 hours. The reaction solution was passed through a silica gel column by using hexane-ethylacetate 7:3 as an eluant. After the solvent was removed, the residue material was dried in vacuum to thereby obtain pale yellow oil (10.0 g, yield: 81%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[NH:8][C:9]1[C:14]([NH2:15])=[CH:13][N:12]=[C:11]2[CH:16]=[CH:17][S:18][C:10]=12.[Cl:19][CH2:20][C:21](OCC)(OCC)OCC>C(O)(=O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][C@@H:2]2[N:8]1[C:9]2=[C:10]3[S:18][CH:17]=[CH:16][C:11]3=[N:12][CH:13]=[C:14]2[N:15]=[C:21]1[CH2:20][Cl:19]
Reactant: CCOC(CCl)(OCC)OCC
Reactant: Nc1cnc2ccsc2c1N[C@H]1CC2CCC1C2
Solvent: CC(=O)O
Product: ClCc1nc2cnc3ccsc3c2n1[C@H]1CC2CCC1C2
Temperature: 120 °C
Reaction time: 0.5 h

Procedure:
A mixture of N7-[(2S)-bicyclo[2.2.1]hept-2-yl]thieno[3,2-b]pyridine-6,7-diamine (0.060 g, 0.23 mmol) and 2-chloro-1,1,1-triethoxyethane (0.134 mL, 0.700 mmol) in acetic acid (0.2 mL) was stirred at 120° C. for 30 min. The solvent was removed and the resultant residue was dissolved in dichloromethane and purified on silica gel (eluting with 0-5% MeOH in dichloromethane) to give the desired product. LCMS calculated for C16H17ClN3S (M+H)+: m/z=318.1. Found: 318.0.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9]Br.[Na+].[I-].[C:13]([S-:15])#[N:14].[K+]>CN(C=O)C.O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][N:14]=[C:13]=[S:15]
Reactant: N#C[S-]
Reactant: Fc1ccc(Br)c(CBr)c1
Agent: [I-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(Br)c(CN=C=S)c1
Temperature: 80 °C

Procedure:
To a solution of 1-bromo-2-(bromomethyl)-4-fluorobenzene (12, 5.36 g, 20.0 mmol) in dry DMF (20 mL) was added NaI (1.20 g, 8.00 mmol) and KSCN (3.88 g, 40.0 mmol). The mixture was heated under N2 at 80° C. for 12 h. After cooling to RT, the mixture was diluted with water (100 mL), and extracted with EtOAc (50 mL×2). The combined extracts were washed with brine, dried over MgSO4 and concentrated to give crude product. This was purified by column chromatography on silica gel, and eluted with petroleum ether to provide 1-bromo-4-fluoro-2-(isothiocyanatomethyl)benzene (13).
Reaction SMILES: C(OC([N:8]([CH2:49][CH2:50][NH:51]C(OC(C)(C)C)=O)[C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C@H:19]([B:36]2[O:44]C3C(C)(C4CC(C3)C4(C)C)[O:37]2)[CH2:20][C:21]2[C:22](OC)=[C:23]([CH:31]=[CH:32][CH:33]=2)[C:24]([O:26]C(C)(C)C)=[O:25])=[O:17])=[CH:11][CH:10]=1)=O)(C)(C)C.B(Cl)(Cl)Cl>>[NH2:51][CH2:50][CH2:49][NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C:16]([NH:18][C@H:19]2[CH2:20][C:21]3[CH:33]=[CH:32][CH:31]=[C:23]([C:24]([OH:26])=[O:25])[C:22]=3[O:44][B:36]2[OH:37])=[O:17])=[CH:11][CH:10]=1
Reactant: COc1c(C[C@H](NC(=O)Cc2ccc(N(CCNC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)nc2)B2OC3CC4CC(C4(C)C)C3(C)O2)cccc1C(=O)OC(C)(C)C
Agent: ClB(Cl)Cl
Product: NCCNc1ccc(CC(=O)N[C@H]2Cc3cccc(C(=O)O)c3OB2O)cn1

Procedure:
Prepared from tert-butyl 3-((2R)-2-(2-(6-(tert-butoxycarbonyl(2-(tert-butoxycarbonylamino)ethyl)amino)pyridin-3-yl)acetamido)-2-(2,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo[6.1.1.02,6]dec-4-yl)ethyl)-2-methoxybenzoate and BCl3 following the procedure described in Step 2 of Example 3. The crude product was purified by reverse phase preparative HPLC and dried using lyophilization. ESI-MS m/z 385 (MH)+.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH2:13].[CH2:17]([S:23]([CH2:25][C:26](OC1C=CC([N+]([O-])=O)=CC=1)=[O:27])=[O:24])[C:18]1[O:22][CH:21]=[CH:20][CH:19]=1>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[CH:7]=[C:8]([CH:14]=[CH:15][CH:16]=1)[O:9][CH2:10][CH2:11][CH2:12][NH:13][C:26](=[O:27])[CH2:25][S:23]([CH2:17][C:18]1[O:22][CH:21]=[CH:20][CH:19]=1)=[O:24]
Reactant: O=C(CS(=O)Cc1ccco1)Oc1ccc([N+](=O)[O-])cc1
Reactant: NCCCOc1cccc(C2OCCO2)c1
Solvent: ClCCl
Product: O=C(CS(=O)Cc1ccco1)NCCCOc1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 74.1 %

Procedure:
3-[3-(1,3-dioxolan-2-yl)phenoxy]propylamine (16.3 g) was dissolved in 400 ml of methylene chloride, and p-nitrophenyl 2-(furfurylsulfinyl)acetate (22.58 g) was added little by little. The mixture was stirred at room temperature for 18 hours. The organic layer was washed successively with a 1N aqueous NaOH solution and water and dried over anhydrous magnesium sulfate. The solvent was evaporated to give 21.29 g (yield 74%) of N-{3-[3-(1,3-dioxolan-2-yl)phenoxy]propyl}-2-(furfurylsulfinyl)acetamide.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][C@H:10]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:9]1)(OC(C)(C)C)=O.C(=O)([O-])[O-].[K+].[K+].I[CH2:30][CH3:31].C1(S)C=CC=CC=1.C(=O)([O-])[O-].C(N(C(C)C)CC)(C)C>CC(C)=O>[Cl:22][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[O:21][CH2:30][CH3:31])[CH2:14][C@H:10]1[O:11][CH2:12][CH2:13][NH:8][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCO[C@H](Cc2ccc(O)c(Cl)c2)C1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: Sc1ccccc1
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOc1ccc(C[C@@H]2CNCCO2)cc1Cl
Temperature: 55 °C
Reaction time: 16 h

Procedure:
N-BOC-(R)-2-(3-chloro-4-hydroxybenzyl)morpholine, example 7, intermediate (a) (52 mg, 0.16 mmol), was dissolved in acetone (1.5 mL) with potassium carbonate (44 mg, 0.32 mmol) and iodoethane (38 uL, 0.47 mmol) added in one portion. The reaction was then heated to 55° C. and shaken at that temperature for 16 hrs. The reaction mixture was filtered, washing with acetone (1 mL×2) and the liquor evaporated under a high flow of nitrogen. The residue was dissolved in tetrahydrofuran: ethanol (1:1, 4 mL) and polymer supported thiophenol (0.43 g, 0.64 mmol), MP-carbonate (0.24 g, 0.64 mmol) and diisopropylethylamine (119 uL, 0.68 mmol) added. The reaction was shaken for 24 hrs, then filtered and concentrated under a high flow of nitrogen. The crude residue was dissolved in TFA (20% v/v solution in dichloromethane, 2.0 mL) and shaken for 3 hrs at room temperature. The reaction mixture was added directly to an SCX-2 column (2 g) and washed with dichloromethane (2 mL×2) and methanol (2 mL×2). The SCX-2 column was then washed with ammonia (2N in methanol, 3×2 mL). Combined ammonia washes were concentrated in vacuo. The residue was then purified by preparative HPLC to yield the desired morpholine example 28 as a colorless oil (17 mg).