Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[C:3]1[NH:4][C:5]2[C:6]([N:27]=1)=[C:7]1[C:12](=[CH:13][CH:14]=2)[CH2:11][CH2:10][CH:9]([CH2:15]OS(C2C=CC(C)=CC=2)(=O)=O)[O:8]1.[CH2:30]([NH2:37])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1.O>CS(C)=O>[CH2:30]([NH:37][CH2:15][CH:9]1[O:8][C:7]2[C:12](=[CH:13][CH:14]=[C:5]3[N:4]=[C:3]([C:2]([F:29])([F:28])[F:1])[NH:27][C:6]3=2)[CH2:11][CH2:10]1)[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2CCc3ccc4[nH]c(C(F)(F)F)nc4c3O2)cc1
Reactant: NCc1ccccc1
Solvent: CS(C)=O
Solvent: O
Product: FC(F)(F)c1nc2ccc3c(c2[nH]1)OC(CNCc1ccccc1)CC3
Temperature: 80 °C
Reaction time: 6 h
Yield: 173.8 %

Procedure:
To a solution of toluene-4-sulfonic acid 2-trifluoromethyl-3,6,7,8-tetrahydro-9-oxa-1,3-diaza-cyclopenta[a]naphthalen-8-ylmethyl ester (213 mg, 0.5 mmol) in dimethyl sulfoxide (20 mL) was added benzylamine (268 mg, 2.5 mmol). The reaction mixture was stirred at 80° C. for 6 h, cooled to room temperature and then poured into water (20 mL), extracted with chloroform (3×30 mL) dried over anhydrous Na2SO4. Purification by chromatography (ethyl acetate) provided 314 mg (87%) of the title compound which was converted to its oxalate salt: mp 244° C.; 1H NMR (400 MHz, CDCl3): δ1.81 (m, 1H), 2.13 (m, 1H), 2.84 (m, 2H), 3.28 (m, 2H), 4.25 (d, J=13.4 Hz, 1H), 4.31 (d, J=13.4 Hz, 1H), 4.50 (m, 1H), 7.08 (d, J=8.4 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 7.42 (m, 3H), 7.58 (m, 2H), 13.85 (bs, 1H); IR: 3450, 3080, 2980, 1725, 1640, 1600, 1550,1080 cm−1; MS 362 [M+H]+.
Reaction SMILES: [OH:1][NH2:2].[O:3]([C@H:10]1[CH2:15][C@H:14]([C:16](OC)=[O:17])[C@@H:13]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:24][CH2:23]2)=[O:21])[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>CO>[OH:1][NH:2][C:16]([C@H:14]1[CH2:15][C@H:10]([O:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:11][CH2:12][C@@H:13]1[C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:24][CH2:23]1)=[O:21])=[O:17]
Reactant: NO
Reactant: COC(=O)[C@H]1C[C@H](Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: O=C(NO)[C@H]1C[C@H](Oc2ccccc2)CC[C@@H]1C(=O)N1CCN(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of hydroxyamine in MeOH (1.5 M, 0.75 ml) was added to methyl (1S,2S,5R)-5-phenoxy-2-[(4-phenylpiperazin-1-yl)carbonyl]cyclohexane-carboxylate (0.29 mmol, 0.00029 mol) in MeOH (0.5 mL) at RT. The resulting mixture was stirred at RT for 2 hrs, and was adjusted to PH=2.0 with TFA, and then was purified by Prep-HPLC to give the desired product. LCMS: (M+H)+=424.2.
Reaction SMILES: [CH2:1]([S:3]([N:6]1[CH2:11][CH2:10][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH:27]=O)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:8][CH2:7]1)(=[O:5])=[O:4])[CH3:2].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[CH2:1]([S:3]([N:6]1[CH2:7][CH2:8][CH:9]([C:12]2[C:20]3[C:15](=[C:16]([C:29]([NH2:31])=[O:30])[CH:17]=[C:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)[CH:22]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(C=O)c4)cc23)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CN5CCOCC5)c4)cc23)CC1
Yield: 43.2 %

Procedure:
Following the general procedure of example 1, 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(3-formylphenyl)-1H-indole-7-carboxamide (15.0 mg, 0.034 mmol), morpholine (3.5 ul, 0.04 mmol) and NaBH(OAc)3 (23.0 mg, 0.102 mmol) were reacted to give the title compound (7.5 mg, 43%).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([N:10]2[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].[NH2:16][C:17]1[N:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[N:18]=1.[O-]C1C=CC=CC=1.[Na+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.O>[CH3:24][C:19]1[CH:20]=[C:21]([CH3:23])[N:22]=[C:17]([NH:16][C:2]2[CH:3]=[CH:4][C:5]([N:10]3[CH:14]=[C:13]([CH3:15])[N:12]=[CH:11]3)=[C:6]([CH:9]=2)[C:7]#[N:8])[N:18]=1
Reactant: Cc1cn(-c2ccc(Br)cc2C#N)cn1
Reactant: Cc1cc(C)nc(N)n1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Agent: [O-]c1ccccc1
Solvent: C1COCCO1
Solvent: O
Product: Cc1cn(-c2ccc(Nc3nc(C)cc(C)n3)cc2C#N)cn1
Temperature: 80 °C

Procedure:
A mixture of 5-bromo-2-(4-methyl-imidazol-1-yl)-benzonitrile (200 mg, 0.76 mmol), 2-amino-4,6-dimethyl-pyrimidine (141 mg, 1.14 mmol), sodium phenoxide (266 mg, 2.29 mmol), tris(dibenzylideneacetone)dipalladium chloroform complex (21 mg, 0.02 mmol) and 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene=xanthphos (26 mg, 0.04 mmol) in 5 mL of dioxane was heated to 80° C. under argon for 2 hours. The mixture was diluted with water, extracted with ethyl acetate and the product purified by by chromatography on silica gel using dichloromethane/methanol 9:1 v/v as an eluent. The title compound was obtained as a colorless solid (144 mg, 62%). MS ISP (m/e): 305.1 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): 8 (ppm)=10.08 (s, 1H), 8.44 (s, 1H), 8.15 (d, 1H), 7.89 (s, 1H), 7.55 (d, 1H), 7.25 (s, 1H), 6.76 (s, 1H), 2.36 (s, 6H), 2.18 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[NH:12][N:11]=[N:10]1.[CH3:15]N(C)C=O.[H-].[Na+].CI>O>[CH3:1][C:2]1[C:7]([Br:8])=[CH:6][CH:5]=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[N:12]([CH3:15])[N:11]=[N:10]1
Reactant: CN(C)C=O
Reactant: Cc1c(Br)cccc1-n1nn[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: Cc1c(Br)cccc1-n1nnn(C)c1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of the above-mentioned 1-(2-methyl-3-bromophenyl)-1,4-dihydrotetrazole-5-one 31.40 g and N,N-dimethylformamide 250 mL was added 60% sodium hydride 5.90 g under ice-cooling. The mixtures were raised to room temperature and were stirred for one hour. To the reaction mixtures was added methyl iodide 8.4 mL under ice-cooling. The mixtures were raised to room temperature and were stirred for fourteen hours. To the reaction mixtures was added water and the mixtures were extracted with ethyl acetate. The organic layers were washed with 10% hydrochloric acid, water and saturated saline, and were dried over anhydrous magnesium sulfate and were then concentrated under reduced pressure. The resulting residues were subjected to a silica gel column chromatography to give 1-(2-methyl-3-bromophenyl)-4-methyl-1,4-dihydrotetrazole-5-one (hereinafter, referred to as “Intermediate (PRB-P)”) 8.47 g.
Reaction SMILES: C(OC([NH:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:44][CH:45]=[C:39]([CH:40]=[CH:41]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:48])[CH3:47])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([O:19]C(C)(C)C)=[O:18])=[CH:11][CH:10]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[NH2:8][C:9]1[N:14]=[CH:13][C:12]([CH2:15][C@H:16]([NH:24][C:25]([NH:27][C@@H:28]2[CH2:43][C:42]3=[CH:41][CH:40]=[C:39]([CH:45]=[CH:44]3)[O:38][CH2:37][CH2:36][CH2:35][CH2:34][O:33][CH2:32][C@H:31]([CH:46]([CH3:47])[CH3:48])[NH:30][C:29]2=[O:49])=[O:26])[C:17]([OH:19])=[O:18])=[CH:11][CH:10]=1
Reactant: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(NC(=O)OC(C)(C)C)nc2)C(=O)OC(C)(C)C)C(=O)N1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)[C@H]1COCCCCOc2ccc(cc2)C[C@@H](NC(=O)N[C@@H](Cc2ccc(N)nc2)C(=O)O)C(=O)N1
Temperature: 25 °C
Reaction time: 5 h
Yield: 89 %

Procedure:
160 mg (0.23 mmol) of tert-butyl (S)-3-(6-tert-butoxycarbonylaminopyridin-3-yl)-2-[3-((9S,12R)-9-isopropyl-11-oxo-2,7-dioxa-10-azabicyclo[12.2.2]octadeca-1(17),14(18),15-trien-12-yl)ureido]propionate were dissolved in 6 ml of dichloromethane and, after addition of the same volume of TFA, stirred at RT. After 5 h, the mixture was concentrated and purified by preparative HPLC. The required fractions were combined, freed of acetonitrile, mixed with 1N hydrochloric acid, concentrated further and finally freeze dried. 108 mg of the title compound were obtained as hydrochloride.
Reaction SMILES: ClC1C=CC=CC=1CC(O)=O.[Br:12]C1C=CC2C3SC(C(OC)=O)=CC=3CCOC=2C=1.[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[C:41]3[S:42][C:43]([C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])=[CH:44][C:40]=3[CH2:39][CH2:38][O:37][C:36]=2[CH:55]=1.C(O)(=O)C>C(OCC)(=O)C.[Cu](Br)Br>[Br:31][C:32]1[CH:33]=[CH:34][C:35]2[C:41]3[S:42][C:43]([C:45](=[O:54])[CH2:46][C:47]4[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=4[Cl:53])=[CH:44][C:40]=3[CH2:39][CH2:38][O:37][C:36]=2[CH:55]=1.[Br:12][CH:46]([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][C:48]=1[Cl:53])[C:45]([C:43]1[S:42][C:41]2[C:35]3[CH:34]=[CH:33][C:32]([Br:31])=[CH:55][C:36]=3[O:37][CH2:38][CH2:39][C:40]=2[CH:44]=1)=[O:54]
Reactant: COC(=O)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: Br[Cu]Br
Agent: O=C(Cc1ccccc1Cl)c1cc2c(s1)-c1ccc(Br)cc1OCC2
Agent: O=C(O)Cc1ccccc1Cl
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: O=C(c1cc2c(s1)-c1ccc(Br)cc1OCC2)C(Br)c1ccccc1Cl
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1-(8-Bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone (1.0 g, 2.3 mmol) was prepared by reaction of 2-chlorophenylacetic acid with methyl 8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepine-2-carboxylate. A solution of 1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone in ethyl acetate (60 mL) was treated with copper(II) bromide (1.3 g, 5.8 mmol) in one portion in 100 mL rb flask. Acetic acid (2 mL) was added, and the flask sealed and heated at 85° C. After 8 hr, the reaction was removed from heat and allowed to stand overnight. The reaction mixture was concentrated to dryness, diluted with 100 mL diethyl ether and filtered through celite (ether wash). The eluent was re-filtered through the same celite pad, and concentration gave 2-bromo-1-(8-bromo-4,5-dihydrobenzo[b]thieno[2,3-d]oxepin-2-yl)-2-(2-chlorophenyl)ethanone as a crude solid used without purification.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([NH:11]C=O)[N:8]=[C:7]2[C:3]=1[N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20].[NH3:27]>C(O)C>[NH2:11][C:9]1[N:8]=[C:7]2[C:3]([N:4]=[CH:5][N:6]2[O:14][CH2:15][CH2:16][O:17][CH2:18][P:19]([O:24][CH2:25][CH3:26])([O:21][CH2:22][CH3:23])=[O:20])=[C:2]([NH2:27])[N:10]=1
Reactant: N
Reactant: CCOP(=O)(COCCOn1cnc2c(Cl)nc(NC=O)nc21)OCC
Solvent: CCO
Product: CCOP(=O)(COCCOn1cnc2c(N)nc(N)nc21)OCC
Temperature: 25 °C
Yield: 35 %

Procedure:
A solution of 6-chloro-9-[2-(diethoxyphosphorylmethoxy)ethoxy]-2-formamidopurine (0.80 g, 1.96 mmol) in ethanol (10 ml) saturated with ammonia gas was heated in a sealed steel vessel at 110° C. for 51/2 hours. The reaction mixture was cooled to ambient temperature, evaporated to dryness and the residue chromatographed on silica gel (eluted with dichloromethane:methanol 90:10) to give the title compound (0.25 g, 35%), m.p. 139°-141° (acetonitrile). UV: νmax (EtOH) 256 (ε8,200), 280 (ε10,200)nm:
Reaction SMILES: [CH2:1](Cl)[CH2:2][OH:3].[F:5][C:6]([F:14])([F:13])[C:7]([C:9]([F:12])([F:11])[F:10])=[O:8].COC(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[F:5][C:6]([F:14])([F:13])[C:7]1([C:9]([F:12])([F:11])[F:10])[O:3][CH2:2][CH2:1][O:8]1
Reactant: OCCCl
Reactant: O=C(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COC(C)(C)C
Product: FC(F)(F)C1(C(F)(F)F)OCCO1
Reaction time: 0.25 h
Yield: 62.7 %

Procedure:
Into a 300 mL three-necked flask equipped with a gas-inlet tube, a reflux condenser, and a thermometer was charged 10.0 g (0.12 mol) of ethylene chlorohydrin beforehand, followed by cooling with ice. Then, 20.0 g (0.12 mol) of hexafluoroacetone was added through the gas-inlet tube. After completion of the addition, the whole was stirred for 15 minutes as it was and then 100 mL of t-butyl methyl ether was added. Then, 16.6 g (0.12 mol) of potassium carbonate was added portionwise over a period of 1 hour and, after completion of the addition, the whole was stirred as it was. The resulting mixture was poured into 100 mL of water and an organic layer was separated by two-layer separation in a separating funnel. The resulting organic layer was subjected to distillation under normal pressure to collect a fraction of 106° C. to 107° C. to obtain 15.8 g (purity 99%, yield 62.0%) of 2,2-bis(trifluoromethyl)-1,3-dioxolane (fluorinated acetal (E)).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][C:4](=[O:7])[CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19])[CH:13]=O>CCO.Cl>[CH3:8][O:9][C:10]1[CH:11]=[C:12]([CH:13]=[C:3]2[C:4](=[O:7])[C:5](=[CH:13][C:12]3[CH:15]=[C:16]([O:20][CH3:21])[C:17]([O:18][CH3:19])=[C:10]([O:9][CH3:8])[CH:11]=3)[CH2:6][O:1][CH2:2]2)[CH:15]=[C:16]([O:20][CH3:21])[C:17]=1[O:18][CH3:19]
Reactant: COc1cc(C=O)cc(OC)c1OC
Reactant: O=C1CCOCC1
Agent: Cl
Solvent: CCO
Product: COc1cc(C=C2COCC(=Cc3cc(OC)c(OC)c(OC)c3)C2=O)cc(OC)c1OC

Procedure:
A solution of 6.0 g (0.06 mole) of tetrahydro-4H-pyran-4-one and 25 g (0.127 mole) of 3,4,5-trimethoxybenzaldehyde in 75 ml of EtOH and 10 ml of concentrated HCl is stirred and heated at reflux for 3 hours. The product gradually precipitates from the cooled solution. The yield of yellow crystals is 12.0 g (44%), m.p. 187°-189°.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:25]([O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:26]>ClCCl.C(N(C(C)C)C(C)C)C>[CH2:28]([O:27][C:25](=[O:26])[N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:21])[C:12]([NH:22][CH3:23])=[CH:11][N:10]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CNc1cnc(NCc2ccccc2)cc1-c1ccccc1C
Reactant: O=C(Cl)OCc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNc1cnc(N(Cc2ccccc2)C(=O)OCc2ccccc2)cc1-c1ccccc1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 80.5 %

Procedure:
To a solution of 2.03 g (6.7 mmol) N2-benzyl-N5-methyl-4-o-tolyl-pyridine-2,5-diamine in 100 ml dichloromethane and 40 ml N-ethyldiisopropylamine a solution of 2.1 ml (14.09 mmol) benzyl chloroformate in 50 ml dichloromethane was added dropwise at 0° C. After stirring for 2 h at room temperature the reaction mixture was washed with water (2×50 ml), brine (50 ml), dried (magnesium sulfate) and evaporated. Chromatography of the residue afforded 2.36 g (80%) of the title compound as light brown crystals. M.p. 110-112° C.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][C:14]([OH:16])=O.[CH3:17][N:18]([CH3:24])S(=O)N(C)C>C(Cl)(Cl)Cl>[CH3:17][N:18]([CH3:24])[C:14](=[O:16])[CH2:13][C:3]1[N:4]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:6][C:2]=1[Cl:1]
Reactant: CN(C)S(=O)N(C)C
Reactant: O=C(O)Cc1nc(-c2ccccc2)sc1Cl
Solvent: ClC(Cl)Cl
Product: CN(C)C(=O)Cc1nc(-c2ccccc2)sc1Cl

Procedure:
A mixture of 5-chloro-2-phenylthiazol-4-yl-acetic acid (1.98 g, 7.8 mmol), tetramethylsulphurous diamide (1.01 g, 9 mmol) and chloroform (dry, 30 ml) were heated under reflux for 4 hours. The reaction mixture was cooled and was concentrated under reduced pressure. The residue was taken up into chloroform (100 ml) and H2O (50 nl) and an excess of sodium bicarbonate added. After filtration the chloroform layer was washed with dilute HCl, water, dried (MgSO4), filtered and was concentrated under reduced pressure. The product was purified from hot petroleum ether (100°-126° C.) (0.47 g) m.p. 77°-79° C.
Reaction SMILES: [I:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12](O)=[O:13].ON1C(=O)CCC1=O.C1CCC(N=C=NC2CCCCC2)CC1.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51]>CO>[O:13]=[C:12]([NH:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH2:49][C:50]([OH:52])=[O:51])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:1]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: O=C(O)CCCCCCCCCCI
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1CCC(=O)N1O
Solvent: CO
Product: O=C(O)CCCCCCCCCCCNC(=O)CCCCCCCCCCI
Yield: 82.1 %

Procedure:
Similar to example 2, reaction of 07.90 g (25.3 mmol) 11-iodoundecanoic acid with 2.90 g (25.3 mmol) N-hydroxysuccinimide and 5.22 g (25.3 mmol) DCC gave 10.0 g (96%) of the succiminidylester, which was reacted with 5.40 g (25.1 mmol) 12-aminododecanoic acid to yield 10.5 g (84%) of colourless crystals, m.p. 107°-110° C. (methanol).
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([CH2:6][N:7]2[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]2=[O:15])[N:3]=[CH:2]1.[Cl:16]N1C(=O)CCC1=O>CC#N.C1COCC1>[Cl:16][C:5]1[N:1]=[CH:2][NH:3][C:4]=1[CH2:6][N:7]1[CH2:11][CH:10]([CH2:12][CH2:13][CH3:14])[CH2:9][C:8]1=[O:15]
Reactant: CCCC1CC(=O)N(Cc2c[nH]cn2)C1
Reactant: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CC#N
Product: CCCC1CC(=O)N(Cc2[nH]cnc2Cl)C1
Temperature: 0 °C
Reaction time: 18 h
Yield: 75.8 %

Procedure:
In a 100 ml, three-necked flask fitted with a magnetic stirrer and under inert atmosphere, 1-(1H-imidazol-4-ylmethyl)-4-propylpyrrolidin-2-one 110 (500 mg, 2.4 mmol) is dissolved in a 1/1 mixture of CH3CN/THF (40 ml) and the solution is cooled to 0° C. N-chlorosuccinimide (410 mg, 3.1 mmol) is added by portions while the temperature is maintained at 0° C. The mixture is stirred for 18 h at this temperature. Most of the solvents are removed under vacuum and the residue is dissolved in 1N HCl and diluted with CH2Cl2. The first organic phase is removed and pH of the aqueous phase is adjusted to 9 by addition of solid Na2CO3. Then CH2Cl2 is added and the second organic phase is separated, dried over MgSO4 and concentrated to dryness. Purification by preparative chromatography on silicagel (eluent: CH2Cl2/MeOH/NH4OH: 95/05/0.5 (v/v/v)) affords 440 mg of 1-[(4-chloro-1H-imidazol-5-yl)methyl]-4-propylpyrrolidin-2-one 126.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=C.[O:10]=[O+][O-]>CO.C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH:8]=[O:10]
Reactant: C=CCCCCCCBr
Reactant: O=[O+][O-]
Solvent: CO
Solvent: ClCCl
Product: O=CCCCCCCBr
Temperature: -55 °C
Reaction time: 1 h

Procedure:
A solution of 8-bromo-1-octene (5.0 g, 0.026 mol) in 25 mL of MeOH and 5 mL of CH2Cl2 was cooled to -40° C. and treated with O3 while the mixture was cooled to -50 to -60° C. After 30 min the mixture turned bluish and after another 10 min of O3 treatment the mixture was purged with a stream of N2 for 5 min. With the mixture still at -50° C. and covered with a blanket of N2, 2.5 mL of dimethylsulfide was added. This mixture was stirred for 1 h at -40° C., 1 h at -20° C. and then allowed to warm to -10° C. over 1 h. A vacuum from the water aspiration was applied to remove some of the excess dimethylsulfide, and the residue concentrated further on a rotary evaporator (house vacuum). The residue was treated with 10 mL of water and this mixture was extracted with hexane; the organic extracts were washed with water, then brine, dried (MgSO4) and concentrated. A portion of the crude product (0.7 g) was chromatographed under pressure to give 7-bromoheptaldehyde: NMR (CDCl3) δ1.41 (m, 4H), 1.63 (m, 2H), 1.87 (m, 2H), 2.45 (m, 2H), 3.41 (m, 2H), 9.78 (s, 1H).
Reaction SMILES: [C:1]([NH:8][C@H:9]([CH:14]=[O:15])[CH2:10][CH:11]([CH3:13])[CH3:12])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[CH:16]([Mg]Br)=[CH2:17]>O1CCCC1>[C:4]([O:3][C:1]([NH:8][C@@H:9]([CH2:10][CH:11]([CH3:12])[CH3:13])[CH:14]([OH:15])[CH:16]=[CH2:17])=[O:2])([CH3:6])([CH3:5])[CH3:7]
Reactant: C=C[Mg]Br
Reactant: CC(C)C[C@@H](C=O)NC(=O)OC(C)(C)C
Solvent: C1CCOC1
Product: C=CC(O)[C@H](CC(C)C)NC(=O)OC(C)(C)C
Reaction time: 5 h
Yield: 65 %

Procedure:
To a stirred 0° C. solution of Boc-leucinal (3.00 g, 13.9 mmol) in dry tetrahydrofuran (THF) (70 ml) was added vinyl magnesium bromide (35 ml of a 1.0M solution in THF). After 5 hours, the mixture was quenched with 1.0M NH4Cl (50 ml). Most of the THF was evaporated in vacuo and the residue was extracted with ether several times. The combined extracts were washed (brine), dried (Na2SO4), filtered, and evaporated to give the desired product as a 3:2 mixture of hydroxy diastereomers in 65% yield.
Reaction SMILES: F[C:2]1[C:20]([C:21]2[CH:22]=[C:23]3[C:28](=[CH:29][CH:30]=2)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]3)=[C:19]([CH3:33])[CH:18]=[CH:17][C:3]=1[C:4](=S)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1.O.[NH2:35][NH2:36]>C(O)CCC>[CH:13]([O:12][C:8]1[CH:7]=[C:6]([NH:5][C:4]2[C:3]3[C:2](=[C:20]([C:21]4[CH:22]=[C:23]5[C:28](=[CH:29][CH:30]=4)[N:27]=[C:26]([NH:31][CH3:32])[N:25]=[CH:24]5)[C:19]([CH3:33])=[CH:18][CH:17]=3)[NH:36][N:35]=2)[CH:11]=[CH:10][CH:9]=1)([CH3:15])[CH3:14]
Reactant: CNc1ncc2cc(-c3c(C)ccc(C(=S)Nc4cccc(OC(C)C)c4)c3F)ccc2n1
Reactant: NN
Solvent: CCCCO
Solvent: O
Product: CNc1ncc2cc(-c3c(C)ccc4c(Nc5cccc(OC(C)C)c5)n[nH]c34)ccc2n1
Temperature: 150 °C

Procedure:
A mixture of 2-fluoro-N-(3-isopropoxyphenyl)-4-methyl-3-(2-(methylamino)quinazolin-6-yl)benzothioamide (54 mg, 117 μmol) and hydrazine hydrate (11 μL, 234 μmol) in n-butanol (6 mL) was heated in a microwave reactor at 150° C. for 33 min. Solvent was removed and the residue was purified by preparative TLC (50% EtOAc/hexane) to give the title compound. MS (M+H)+ 439.
Reaction SMILES: [CH3:1][C:2]([CH3:21])([CH3:20])[CH2:3][N:4]1[C:12]2[C:7](=[N:8][C:9]([C@H:13]([CH2:15][CH2:16]O)[CH3:14])=[CH:10][CH:11]=2)[N:6]([CH3:18])[C:5]1=[O:19].C(N(CC)CC)C.CS(Cl)(=O)=O.[N-:34]=[N+:35]=[N-:36].[Na+]>ClCCl>[N:34]([CH2:16][CH2:15][C@@H:13]([C:9]1[N:8]=[C:7]2[N:6]([CH3:18])[C:5](=[O:19])[N:4]([CH2:3][C:2]([CH3:21])([CH3:20])[CH3:1])[C:12]2=[CH:11][CH:10]=1)[CH3:14])=[N+:35]=[N-:36]
Reactant: [N-]=[N+]=[N-]
Reactant: C[C@@H](CCO)c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Agent: CS(=O)(=O)Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](CCN=[N+]=[N-])c1ccc2c(n1)n(C)c(=O)n2CC(C)(C)C
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a stirred solution of 36-2 (0.15 g, 0.52 mmol) in dichloromethane (2 mL) was added triethylamine (0.15 mL, 1.08 mmol) and methanesulfonyl chloride (0.05 mL, 0.62 mmol). The resulting mixture was stirred at room temperature for 10 minutes and concentrated. The residue was dissolved in DMF (2 mL). To this solution was added sodium azide (0.20 g, 3.08 mmol) and the mixture was heated to 90° C. for 3 days. The reaction was allowed to cool and partitioned between ethyl acetate and water. The organic phase was concentrated to give 36-3. (0.13 g, 83%). LRMS (ES) (M+H)+: observed=317.1, calculated=317.4.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[CH:16][C:3]=1[CH2:4][C:5]1[NH:13][C:12]2[C:7](=[N:8][C:9]([F:15])=[N:10][C:11]=2[NH2:14])[N:6]=1.C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:34][CH2:35][CH2:36][C:37]#[CH:38])(=O)=O>CN(C=O)C>[F:15][C:9]1[N:8]=[C:7]2[C:12]([N:13]=[C:5]([CH2:4][C:3]3[CH:16]=[C:17]([O:22][CH3:23])[C:18]([O:20][CH3:21])=[CH:19][C:2]=3[Br:1])[N:6]2[CH2:38][CH2:37][CH2:36][C:35]#[CH:34])=[C:11]([NH2:14])[N:10]=1
Reactant: COc1cc(Br)c(Cc2nc3nc(F)nc(N)c3[nH]2)cc1OC
Reactant: C#CCCCOS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: C#CCCCn1c(Cc2cc(OC)c(OC)cc2Br)nc2c(N)nc(F)nc21

Procedure:
A solution of 8-(2-bromo-4,5-dimethoxy-benzyl)-2-fluoroadenine (13 mg, 0.034 mmol), Cs2CO3 (11 mg, 0.034 mmol), pent-4-ynyl tosylate (10 mg, 9 L, 0.044 mmol) in anhydrous DMF (80 L) was stirred at 60° C. for 30 min. Following solvent removal, the product (8.2 mg, 53.6%) was collected through silica gel column purification (CHCl3:EtOAc:hexanes:i-PrOH at 20:10:20:1). 1H NMR (400 MHz, CDCl3) 7.06 (s, 1H), 6.67 (s, 1H), 5.92 (bs, 2H), 4.31 (s, 2H), 4.14 (t, J=7.4 Hz, 2H), 3.88 (s, 3H), 3.75 (s, 3H), 2.25-2.20 (m, 2H), 1.99 (t, J=2.6 Hz, 1H), 1.96-1.89 (m, 2H); 13C NMR (100 MHz, CDCl3) 160.0, 158.3, 156.7, 153.4, 151.3, 149.4, 127.2, 117.3, 115.9, 114.5, 113.2, 82.7, 70.2, 56.62, 56.56, 42.7, 34.3, 30.1, 28.5, 16.3; MS ink 447.9 (M+H)+. HPLC: (a) 99.0% (60% water-40% acetonitrile); (b) 98.8% (35% to 55% acetonitrile).