Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:8])=[CH:5][CH:4]=1)=O.C1(P(=[CH:45][C:46]([O:48][CH3:49])=[O:47])(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:50]1(C)C=CC=CC=1>>[C:19]([O:18][C:17]([NH:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7]([C:6]1[CH:24]=[CH:25][C:3]([CH:50]=[CH:45][C:46]([O:48][CH3:49])=[O:47])=[CH:4][CH:5]=1)=[O:8])=[O:23])([CH3:20])([CH3:22])[CH3:21]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C=O)cc1
Reactant: Cc1ccccc1
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Product: COC(=O)C=Cc1ccc(C(=O)Nc2ccccc2NC(=O)OC(C)(C)C)cc1
Temperature: 90 °C
Reaction time: 48 h
Yield: 97 %

Procedure:
A stirred suspension of compound XI (500 mg, 1.47 mmol), methyl (triphenyl-phosphoranylidene)acetate (590 mg, 1.76 mmol) in anhydrous toluene (20 ml) was heated at 90° C. under nitrogen. After 2 days, the reaction mixture was concentrated and directly purified by flash chromatography on silica gel (AcOEt/hexane:30/70→40/60) to afford the title compound XII (568 mg, 1.43 mmol, 97% yield) as a pale yellow foam. 1H NMR (300 MHz, CDCl3) δ(ppm): 9.32 (bs, 1H), AB system (δA=7.99, δB=7.62, J=8.4 Hz, 4H), 7.87 (d, J=7.9 Hz, 1H), 7.73 (s, J=15.8 Hz, 1H), 7.32–7.13 (m, 3H), 6.69 (bs, 1H), 6.53 (d, J=16.3 Hz, 1H), 3.83 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]=[CH:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C(Cl)=O.[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][CH2:35][CH2:36][NH2:37])[CH:25]=[CH:26][CH:27]=2>>[O:18]=[C:19]1[C:28]2[C:23]3[C:24](=[CH:29][CH:30]=[CH:31][C:22]=3[C:21](=[O:32])[N:20]1[CH2:33][CH2:34][CH2:35][CH2:36][NH:37][C:9](=[O:11])[CH:8]=[CH:7][C:3]1[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=1)[CH:25]=[CH:26][CH:27]=2
Reactant: NCCCCN1C(=O)c2cccc3cccc(c23)C1=O
Reactant: O=C(O)C=Cc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: O=C(C=Cc1cccnc1)NCCCCN1C(=O)c2cccc3cccc(c23)C1=O

Procedure:
Batch size: 6.1 g (41.0 mmol) 3-(3-pyridyl)-acrylic acid, 14.2 g (111.8 mmol) oxalyl chloride and 10.0 g (37.3 mmol) 4-(1,3-dioxo-1H,3H-benzo[de]isoquinolin-2-yl)-butylamine.
Reaction SMILES: [N:1](C1C=C(N=C=O)C=CC=1C)=[C:2]=[O:3].[N:14](C1C=CC=C(N=C=O)C=1C)=[C:15]=[O:16].[C:27]1([CH3:33])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>>[CH:30]1[CH:31]=[CH:32][C:27]([CH:33]([N:14]=[C:15]=[O:16])[N:1]=[C:2]=[O:3])=[CH:28][CH:29]=1
Reactant: Cc1ccc(N=C=O)cc1N=C=O
Reactant: Cc1c(N=C=O)cccc1N=C=O
Reactant: Cc1ccccc1
Product: O=C=NC(N=C=O)c1ccccc1

Procedure:
The partially capped toluylene diisocyanate was prepared by reacting a technical grade mixture of 1.05 kg of 2,4-diisocyanatotoluene (6 mol) and 260 g of 2,6-diisocyanatotoluene (1.5 mol) with 1.03 kg of dibutylanine (8 mol) at 50° C. in 600 g of toluene
Reaction SMILES: [Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]([N+:9]([O-])=O)[C:5]([NH2:8])=[N:6][CH:7]=1.CCO.[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:42]=[CH:41][C:38]([CH:39]=O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.[O-]S(S([O-])=O)=O.[Na+].[Na+]>C(Cl)Cl.N.CN(C=O)C>[Br:1][C:2]1[C:3]([N:12]2[CH2:17][CH2:16][N:15]([CH2:18][C:19]3[N:23]([CH3:24])[CH:22]=[N:21][CH:20]=3)[CH2:14][CH2:13]2)=[C:4]2[N:9]=[C:39]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:42][CH:41]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: Cn1cncc1CN1CCN(c2c(Br)cnc(N)c2[N+](=O)[O-])CC1
Reactant: O=Cc1ccc(CN2CCOCC2)cc1
Agent: N
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCO
Product: Cn1cncc1CN1CCN(c2c(Br)cnc3[nH]c(-c4ccc(CN5CCOCC5)cc4)nc23)CC1
Temperature: 85 °C

Procedure:
To a mixture of 5-bromo-4-(4-((1-methyl-1H-imidazol-5-yl)methyl)piperazin-1-yl)-3-nitropyridin-2-amine (0.030 g, 0.076 mmol, 1 eq), EtOH (1.95 mL) and DMF (0.29 mL), 4-(morpholinomethyl)-benzaldehyde (0.017 g, 0.083 mmol, 1.1 eq) was added followed by a freshly prepared aqueous solution of Na2S2O4 (1M; 0.23 mL, 0.23 mmol). The reaction mixture was heated at 85° C. for 24 h, then allowed to cool to room temperature and diluted with DCM and a few drops of aqueous NH3 until complete dissolution was observed. This solution was deposited on two preparative silica TLC plates and eluted with DCM/MeOH (v/v; 94:6). The title compound was obtained after trituration with diethyl ether as a yellow solid (0.005 g, 14.7%); 1H-NMR (500 Mz, DMSO-d6): δ 2.35-2.41 (m, 4H), 2.55-2.62 (m, 4H), 3.52-3.55 (2 s, 4H, 2NCH2), 3.59 (t, J=4.5 Hz, 4H), 3.62-3.67 (m, 4H), 3.68 (m, 3H, imidazole Me), 6.80 (s, 1H, imidazole 4-H), 7.46 (d, J=8.0 Hz, 2H, ArH, C6H4), 7.57 (s, 1H, imidazole 2-H), 8.13 (d, J=8.0 Hz, 2H, ArH, C6H4), 8.23 (s, 1H, imidazo[4,5-b]pyridine 5-H), 13.47 (br s, 1H, imidazo[4,5-b]pyridine N—H); LC (Method B)-MS (ESI, m/z): R=1.79 min—551/553 [(M+H+), Br isotopic pattern, 100%]; ESI-HRMS: Found: 551.1882, calculated for C26H32N8OBr (M+H)+: 551.1882.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1.CN[C:18]1[CH:23]=[CH:22][C:21]([CH:24]=[CH2:25])=[CH:20][N:19]=1.[OH-].[K+].[CH3:28][N:29]1C(=O)CCC1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([CH2:25][CH2:24][C:21]3[C:20]([NH:29][CH3:28])=[N:19][CH:18]=[CH:23][CH:22]=3)[C:6]3[CH2:11][CH2:12][N:13]([CH3:15])[CH2:14][C:5]=3[C:4]=2[CH:3]=1
Reactant: C=Cc1ccc(NC)nc1
Reactant: CN1CCc2[nH]c3ccc(Cl)cc3c2C1
Reactant: CN1CCCC1=O
Agent: [K+]
Agent: [OH-]
Product: CNc1ncccc1CCn1c2c(c3cc(Cl)ccc31)CN(C)CC2

Procedure:
The title compound is prepared from a mixture of 8-chloro-2,3,4,5-tetrahydro-2-methyl-1H-pyrido[4,3-b]indole, N-methyl-5-vinylpyridin-2-amine and KOH (5-7 equiv) in NMP at a temperature ranging between 25 deg C. to 100 deg C. The product obtained is isolated by preparative HPLC.
Reaction SMILES: CC(C)([O-])C.[K+].Cl[CH2:8][C:9]#[N:10].[C:11]1(=[O:16])[CH2:15][CH2:14][CH2:13][CH2:12]1>C(O)(C)(C)C>[O:16]1[C:11]2([CH2:15][CH2:14][CH2:13][CH2:12]2)[CH:8]1[C:9]#[N:10]
Reactant: N#CCCl
Reactant: O=C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: N#CC1OC12CCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 68.3 %

Procedure:
A 1 M solution of potassium tert-butoxide in tert-butyl alcohol (184.4 mL, 184.4 mmol) is added slowly to a solution of chloroacetonitrile (10.8 mL, 167.6 mmol) and cyclopentanone (15.0 mL, 167.6 mmol) in anhydrous t-butyl alcohol (33 mL). The reaction is stirred at room temperature for 16 h. The mixture is filtered through diatomaceous earth, the solvent is removed, and the residue is diluted with water. The mixture is neutralized with 30% aq.sodium dihydrogen phosphate solution and extracted with diethyl ether. The organic layers are combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed. The residue is purified by flash chromatography over silica gel to obtain 14.1 g of the title compound as a colourless oil. 1H NMR (CDCl3) δ (ppm): 3.46 (s, 1H), 1.65-2.20 (m, 8H).
Reaction SMILES: O.[CH:2]([C:4]1[CH:13]=[N+:12]([O-:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:15])=[O:3].[N+:16]([CH3:19])([O-:18])=[O:17]>CO.C(N(CC)CC)C>[OH:3][CH:2]([C:4]1[CH:13]=[N+:12]([O-:14])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N+:5]=1[O-:15])[CH2:19][N+:16]([O-:18])=[O:17]
Reactant: C[N+](=O)[O-]
Reactant: O=Cc1c[n+]([O-])c2ccccc2[n+]1[O-]
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: O=[N+]([O-])CC(O)c1c[n+]([O-])c2ccccc2[n+]1[O-]
Temperature: 25 °C

Procedure:
2-Formylquinoxaline-1,4-dioxide hydrate 2 g (0.01 mole) was dissolved in 100 ml of warm methanol. Ten drops of triethylamine were added with stirring and 1.3 g of nitromethane was added incrementally. The heat source was removed and the reaction mixture was allowed to cool to room temperature. The methanol was removed by evaporation and the residue was recrystallized from water, 1 g/75 ml. There was obtained 2-(1-hydroxy-2-nitroethyl)quinoxaline-1,4-dioxide, m.p. 202°-204° C. with decomposition. This compound was dissolved in an excess of warm acetyl chloride. The mixture was heated to boiling for about 30 minutes, then allowed to cool. The solids which separated were isolated by filtration, rinsed with ether and dried. A sample was purified by recrystallization from a mixture of dimethylsulfoxide and methanol (1 g/5 ml/45 ml respectively). There was obtained 2-(1-acetoxy-2-nitroethyl)quinoxaline-1,4-dioxide, m.p. 201°-204° C. It analyzed as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:12][C:13]#[N:14])[CH:9]=[CH:10][CH:11]=1.[N-:20]=[N+:21]=[N-:22].[Na+].[Cl-].[NH4+].C(OCC)(=O)C>CN(C)C=O.CCCCCC>[CH3:1][C:2]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:3]=1[CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:9]=[CH:10][CH:11]=1)[CH2:12][C:13]1[NH:22][N:21]=[N:20][N:14]=1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cccc(C)c1COc1cccc(CC#N)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: Cc1cccc(C)c1COc1cccc(Cc2nnn[nH]2)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(3-(2,6-Dimethylbenzyloxy)phenyl)acetonitrile (Step B, 3.2 g, 12.7 mmol), sodium azide (1.28 g, 16.7 mmol) and ammonium chloride (1.08 g, 20.2 mmol) in dry dimethylformamide (30 ml) was heated under argon at 90° C. for 9 hours or until all the starting material is consumed and the reaction mixture was concentrated under reduced pressure. The reaction mixture was taken in ethyl acetate and washed with water (2×), dried over Na2SO4, filtered, concentrated and purified by flash chromatography on a silica gel column (methylene chloride:methanol 9:1) to give the oily product. The oil was stirred with 1:2 ethyl acetate:hexane for 10 minutes, and solid was filtered to give product as a white solid.
Reaction SMILES: [OH:1][CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][N:12]=1)[CH3:10])=[O:7].[C:23]1(O)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>O1CCCC1.O>[O:1]([CH2:2][C@H:3]1[CH2:5][C@@H:4]1[C:6]([NH:8][C@@H:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:20])[F:21])=[CH:13][N:12]=1)[CH3:10])=[O:7])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Oc1ccccc1
Reactant: C[C@@H](NC(=O)[C@H]1C[C@@H]1CO)c1ccc(OCC(F)(F)F)cn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](NC(=O)[C@H]1C[C@@H]1COc1ccccc1)c1ccc(OCC(F)(F)F)cn1
Temperature: 25 °C
Reaction time: 24 h
Yield: 32.6 %

Procedure:
To a mixture of (1S*,2S*)-2-(hydroxymethyl)-N-((R)-1-(5-(2,2,2-trifluoroethoxy)pyridin-2-yl)ethyl)cy clopropanecarboxamide (30 mg, 0.094 mmol) and phenol (16.0 mg, 0.17 mmol) in tetrahydrofuran (1 mL), triphenylphosphine (45 mg, 0.17 mmol) and di-tert-butyl azodicarboxylate (28.2 mg, 0.12 mmol) were added successively. After stirring at room temperature for 1 day, the mixture was poured into water, and the aqueous layer was extracted with dichloromethane three times. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The residue was purified by preparative LC-MS to give 12.1 mg (33% yield) of the title compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10]C)=O)[CH:3]=1.Cl.[CH:13]([C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][C:17]=1[CH3:23])([CH3:15])[CH3:14].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([NH:22][C:19]2[CH:20]=[CH:21][C:16]([CH:13]([CH3:14])[CH3:15])=[C:17]([CH3:23])[CH:18]=2)=[O:10])[CH:3]=1
Reactant: COC(=O)c1cc(Br)ccn1
Reactant: Cc1cc(N)ccc1C(C)C
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(NC(=O)c2cc(Br)ccn2)ccc1C(C)C
Temperature: 25 °C
Yield: 79.2 %

Procedure:
To a solution of methyl 4-bromopicolinate (1.0 g, 5.0 mmol) in DCM (500 mL) and DMF (20 mL) was added 4-isopropyl-3-methylbenzenamine hydrochloride (1.08 g, 5.90 mmol), HATU (3.8 g, 10 mmol), DIPEA (4.9 mL, 30 mmol) and the mixture was stirred at reflux overnight. After cooling to room temperature and evaporation of the solvent, the residue was purified by combi-flash (ISCO, 40g silica, UV254, 3:1 pet ether/ethyl acetate) to afford 4-bromo-N-(4-isopropyl-3-methylphenyl)picolinamide (1.32 g, 80% yield) as a yellow oil: MS (ES) m/z 333 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:3]=1[NH2:4].[N+]([C:13]1[CH:14]=C(S(O)(=O)=O)C=[CH:17][CH:18]=1)([O-])=O.P(=O)(O)(O)O.C(=O)/C=C/C.O.N>O>[Br:1][C:2]1[CH:8]=[CH:7][C:6]([F:9])=[C:5]2[C:3]=1[N:4]=[C:18]([CH3:17])[CH:13]=[CH:14]2
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)O)c1
Reactant: Nc1cc(F)ccc1Br
Agent: C/C=C/C=O
Agent: N
Agent: O=P(O)(O)O
Solvent: O
Product: Cc1ccc2c(F)ccc(Br)c2n1
Temperature: 80 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
2-Bromo-5-fluoro-aniline (5.00 g, 95 mass % article, 25.0 mmol), m-nitrobenzenesulfonic acid (2.65 g, 13.0 mmol), 20.0 mL of 85 wt % aqueous phosphoric acid solution and ferrous sulfate heptahydrate (65.5 mg, 0.250 mmol) were placed in a 100 mL three-neck flask equipped with a magnetic stirrer, a reflux condenser, a thermometer and a dropping funnel and the mixture was heated to 80° C. in an oil bath. Subsequently, crotonaldehyde (4.64 g, 98 mass % article, 65.0 mmol) was added dropwise thereto through the dropping funnel for 1 hour. After completion of the dropwise addition, the mixture was heated and stirred at 100° C. for 2 hours. Then, the reaction mixture was poured into water and neutralized to pH 7 by ammonia water. The neutralized liquid was extracted with dichloromethane, and then dichloromethane was removed under reduced pressure. The resulting crude reaction product was purified by column chromatography (Hexane/AcOEt=100/0→1/1) using silica gel, followed by drying under reduced pressure to give 1.31 g of 8-bromo-5-fluoro-2-methyl-quinoline as a yellowish white solid (yield: 21.8%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[C:10]#[C:11][CH2:12][OH:13].[OH-].[Na+].[CH2:16]([SH:28])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>CN1CCCC1=O.C(OCC)(=O)C.O>[CH2:16]([S:28][CH:12]([OH:13])[CH:11]=[CH:10][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([Cl:8])=[CH:5][C:4]=1[Cl:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCCCCCCCCCS
Reactant: OCC#Cc1c(Cl)cc(Cl)cc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: CCCCCCCCCCCCSC(O)C=Cc1c(Cl)cc(Cl)cc1Cl
Temperature: 22 °C
Reaction time: 0.5 h
Yield: 32.6 %

Procedure:
To a solution of 3-(2,4,6-trichloro-phenyl)-prop-2-yn-1-ol (1.0 g; 4.2 mmol) in N-methyl-2-pyrrolidone (10 ml) and ethyl acetate (2 ml) at 2° C. was added sodium hydroxide (grind to powder) (0.19 g; 4.7 mmol). At 5° C. was added dropwise dodecanethiol (1.4 ml; 6.0 mmol). The reaction mixture was allowed to warm at 22° C. and was stirred for 30 min. The mixture was poured in water and ethyl acetate was added. Organic layer was washed three times with brine, dried over sodium sulfate and evaporated. The crude oil obtained was subject to flash chromatography (eluant: c-hexane/ethyl acetate 99:1 to 80:20) to afford 0.60 g (32% of theory) of dodecylsulfanyl-3-(2,4,6-trichloro-phenyl)-prop-2-en-1-ol as a yellow oil.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][O:8][C:7]([CH3:11])([CH3:10])[N:6]1[C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=O.[BH4-].[Li+]>CCOCC>[CH3:11][C:7]1([CH3:10])[N:6]([C:12](=[O:19])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[C@H:5]([CH2:3][OH:2])[CH2:9][O:8]1
Reactant: CCCCCCC(=O)N1[C@H](C(=O)OC)COC1(C)C
Agent: [BH4-]
Agent: [Li+]
Solvent: CCOCC
Product: CCCCCCC(=O)N1[C@H](CO)COC1(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 8a (296 mg, 1.09 mmol) in dry ether (1 mL) is treated with lithium borohydride (2M solution in THF, 0.55 mL, 1.09 meg) under an argon atmosphere. The mixture is stirred for 3 h at reflux and 18 h at room temperature. The resulting mixture is diluted with ether and quenched with methanol. The volatiles are removed and the residue is taken up in EtOAc/H2O. Workup provides the crude alcohol which is purified by chromatography (2:1 hexane/EtOAc): NMR δ 0.88 (m, 3H), 1.30 (m, 6H), 1.54 (s, 3H), 1.62 (s, 3H), 2.35 (m, 2H), 3.30-4.40 (complex m, 6H); MS (HR-E1) m/z 243.1837 (M calcd. for C13H25NO3 243.1840); [α]D26 =-5±1 (CHCl3).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]3[CH:25]=[CH:24][C:14]([O:15][C:16]4[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=4)=[CH:13][CH:12]=3)=[CH:9][N:8]([CH:26]3[CH2:30][CH2:29][O:28][CH2:27]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[NH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[O:34]1[CH2:35][CH2:36][N:31]([CH2:20][C:19]2[CH:22]=[CH:23][C:16]([O:15][C:14]3[CH:13]=[CH:12][C:11]([C:10]4[C:3]5[C:2]([NH2:1])=[N:7][CH:6]=[N:5][C:4]=5[N:8]([CH:26]5[CH2:30][CH2:29][O:28][CH2:27]5)[CH:9]=4)=[CH:25][CH:24]=3)=[CH:17][CH:18]=2)[CH2:32][CH2:33]1
Reactant: C1COCCN1
Reactant: Nc1ncnc2c1c(-c1ccc(Oc3ccc(C=O)cc3)cc1)cn2C1CCOC1
Product: Nc1ncnc2c1c(-c1ccc(Oc3ccc(CN4CCOCC4)cc3)cc1)cn2C1CCOC1

Procedure:
In a similar manner to Example 10 a mixture of 4-[4-(4-amino-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)phenoxy]benzaldehyde (336 mg), and morpholine (146 mg) were reacted to give 5-[4-(4-morpholinomethylphenoxy)-phenyl]-7-(3-tetrahydrofuryl)-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine, m.p 142-144° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](F)=[C:6]([CH:9]=1)[C:7]#[N:8].[F:11][C@H:12]1[CH2:16][CH2:15][NH:14][CH2:13]1>CC#N>[Br:1][C:2]1[CH:3]=[N:4][C:5]([N:14]2[CH2:15][CH2:16][C@H:12]([F:11])[CH2:13]2)=[C:6]([CH:9]=1)[C:7]#[N:8]
Reactant: F[C@H]1CCNC1
Reactant: N#Cc1cc(Br)cnc1F
Solvent: CC#N
Product: N#Cc1cc(Br)cnc1N1CC[C@H](F)C1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
5-Bromo-2-fluoro-nicotinonitrile (4) (5.0 g, 24.9 mmol) and (S)-(+)-3-fluoropyrrolidine (3.3 g, 25.9 mmol) were dissolved in dry MeCN (100 mL). TEA (8.0 mL, 57.4 mol) was added and the mixture stirred at rt for 2 hours. The solvent was evaporated in vacuo and the residue partitioned between H2O (100 mL) and EtOAc (100 mL). The organic phase was washed with saturated brine solution (100 mL), then dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue was dissolved in DCM (100 mL) and the solvent evaporated in vacuo. The title compound was obtained as an off-white solid (6.3 g, 94%); LCMS, Rt=2.86 min (MeOH-FA method), m/z 270, 272 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:11]2[CH:10]3[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]3[C:8]([CH3:18])([CH3:17])[O:7][C:6]=2[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=1.[BrH:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34](O)=[O:35])[CH2:27][CH2:26]1.C1(N=C=NC2CCCCC2)CCCCC1.C(Cl)Cl>CO.C(Cl)(Cl)Cl>[BrH:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33][C:34]([O:1][C:2]2[C:11]3[CH:10]4[CH:12]=[C:13]([CH3:16])[CH2:14][CH2:15][CH:9]4[C:8]([CH3:17])([CH3:18])[O:7][C:6]=3[CH:5]=[C:4]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:3]=2)=[O:35])[CH2:27][CH2:26]1
Reactant: CCCCCc1cc(O)c2c(c1)OC(C)(C)C1CCC(C)=CC21
Reactant: O=C(O)CCCN1CCOCC1
Agent: Br
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CO
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CCCCCc1cc(OC(=O)CCCN2CCOCC2)c2c(c1)OC(C)(C)C1CCC(C)=CC21

Procedure:
3.54 g. (11.27 mmole) of 1-Hydroxy-3-n-pentyl-6,6,9-trimethyl-10a,6a,7,8-tetrahydrodibenzo[b,d]pyran, 2.86 g. (11.27 mmole) of γ-morpholinobutyric acid hydrobromide and 2.50 g. (12.12 mole) of dicyclohexylcarbodiimide were combined in 200 ml. of methylene chloride and stirred at room temperature for 24 hours. The reaction mixture was cooled and the by-product of dicyclohexylurea was removed by filtration. The volume of methylene chloride was reduced and 25 ml. of cyclohexane was added. The mixture was cooled and the small amount of solid which formed was removed by filtration. All solvents were removed on a rotary evaporator and the residue was dried in vacuo. The resulting foamy material was dissolved in a mixture of benzene and ether and placed in cold storage to yield 3.0 g. (50%) of product as colorless crystals, m.p. 103°-105°. The compound gave a Rf 0.5 in 5% MeOH/CHCl3. The infrared and nmr spectra are consistent with the proposed structure.
Reaction SMILES: [C:1]([O:5][OH:6])([CH3:4])([CH3:3])[CH3:2].[C:7](Cl)(=[O:11])[C:8]([Cl:10])=[O:9]>>[C:1]([O:5][O:6][C:7](=[O:11])[C:8]([Cl:10])=[O:9])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC(C)(C)OO
Product: CC(C)(C)OOC(=O)C(=O)Cl
Temperature: 0 °C
Reaction time: 3 h

Procedure:
A solution of tert-butyl hydroperoxide (9.0 g; 0.1 mole) in petroleum spirit (80 ml) was added dropwise over a period of 1 hour to a stirred solution of oxalyl chloride (25.4 g; 0.2 mole) in petroleum spirit (80 ml) at a temperature of 0° C. On completion of the addition the reaction mixture was stirred for a further 3 hours at a temperature of 0° C. The solvent and excess oxalyl chloride were evaporated under reduced pressure at ice bath temperature to give tert-butylperoxyoxalyl chloride as a colourless oil (16.6 g; 92%) suitable for use in further preparations.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH:17][C:16](=[O:24])[N:15]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:14]2=[O:30])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:7][CH2:8][CH2:9][NH:10][C:11]1[CH:12]=[C:13]2[C:18](=[CH:19][C:20]=1[N+:21]([O-:23])=[O:22])[NH:17][C:16](=[O:24])[N:15]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:14]2=[O:30]
Reactant: CC(C)(C)OC(=O)NCCNc1cc2c(=O)n(NS(C)(=O)=O)c(=O)[nH]c2cc1[N+](=O)[O-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Nn1c(=O)[nH]c2cc([N+](=O)[O-])c(NCCN)cc2c1=O
Temperature: 0 °C
Reaction time: 3 h
Yield: 114.2 %

Procedure:
To an ice-cooled solution of [2-(3-Methanesulfonylamino-7-nitro-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-6-ylamino)-ethyl]-carbamic acid tert-butyl ester (10 mg, 0.022 mmol) in dichloro-methane (0.5 ml) is added trifluoroacetic acid (0.25 ml). The reaction mixture is stirred at 0° C. for 3 h. The mixture is filtered and the resulting red solid dried under vacuum to afford 9 mg (87%) of a red powder. Rt=2.13 min.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=O.[O:8]([C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][NH:23][CH2:24][C:25]2[CH:30]=[CH:29][C:28]([CH:31]3[S:35](=[O:37])(=[O:36])[NH:34][C:33](=[O:38])[CH2:32]3)=[CH:27][CH:26]=2)=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(OC(=O)C)(=O)C.C[N:47]1[CH2:51][CH2:50][CH2:49][C:48]1=O>C(N(CC)C(C)C)(C)C>[O:36]=[S:35]1(=[O:37])[CH:31]([C:28]2[CH:29]=[CH:30][C:25]([CH2:24][N:23]([CH2:22][CH2:21][C:18]3[CH:17]=[CH:16][C:15]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)=[CH:20][CH:19]=3)[C:3](=[O:5])[C:2]3[CH:50]=[CH:51][N:47]=[CH:48][CH:49]=3)=[CH:26][CH:27]=2)[CH2:32][C:33](=[O:38])[NH:34]1
Reactant: CN1CCCC1=O
Reactant: O=C(O)C(F)(F)F
Reactant: O=C1CC(c2ccc(CNCCc3ccc(Oc4ccccc4)cc3)cc2)S(=O)(=O)N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(=O)OC(C)=O
Product: O=C1CC(c2ccc(CN(CCc3ccc(Oc4ccccc4)cc3)C(=O)c3ccncc3)cc2)S(=O)(=O)N1
Reaction time: 1 h

Procedure:
5-[4-([2-(4-phenoxyphenyl)ethyl]aminomethyl)phenyl]isothiazolidin-3-one 1,1-dioxide trifluoroacetate of (6.5 mg, 0.012 mmol) was dissolved in N-methyl-pyrrolidinone (100 μL) with N,N-diisopropylethylamine (10 μL). A solution of acetic anhydride in N-methyl-pyrrolidinone (100 mL) was added and the mixture stirred for 1 h. The mixture was purified by preparative LCMS to give the desired product. White solid, (5.0 mg, 87%). LCMS found for C26H27N2O5S (M+H)+: m/z=479.