Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][CH2:19][CH2:20][OH:21])(=[O:12])=[O:11])#[N:2].C(N(CC)C(C)C)(C)C.CS(C)=O>ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[S:10]([O:13][C:14]1[CH:15]=[C:16]([CH:22]=[C:23]([CH3:25])[CH:24]=1)[O:17][CH2:18][CH2:19][CH:20]=[O:21])(=[O:12])=[O:11])#[N:2]
Reactant: Cc1cc(OCCCO)cc(OS(=O)(=O)c2cc(C)ccc2C#N)c1
Solvent: ClCCl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCCC=O)cc(OS(=O)(=O)c2cc(C)ccc2C#N)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.3 %

Procedure:
Sulfur trioxide pyridine complex (1.0 g, 6.5 mmol) was added to a solution of 3-[3-(2-cyano-5-methylphenylsulfonyloxy)-5-methylphenoxy]-propanol (720 mg, 2.0 mmol), as prepared in the preceding step, N,N-diisopropylethylamine (0.7 mL, 5.5 mmol) and anhydrous dimethyl sulfoxide (0.4 mL, 5.6 mmol) in anhydrous dichloromethane (20 mL). The reaction mixture was stirred at ambient temperature for 1 hour and then quenched with 10% aqueous citric acid (60 mL). The mixture was extracted into dichloromethane (3×50 mL), and the dichloromethane solution was washed with 10% aqueous citric acid (40 mL) and dried over Na2SO4. After removing the solvent in vacuo, the residue was purified by flash column chromatography (dichloromethane) to give the title compound as a colorless oil (520 mg, 72%). 1H-NMR (300 MHz, CDCl3) δ 9.81 (s, 1H), 7.89 (s, 1H), 7.79 (d, J=7.8 Hz, 1H), 7.55 (d, J=7.9 Hz, 1H), 6.62 (s, 1H), 6.60 (s, 1H), 6.56 (s, 1H), 4.22 (t, J=6.0 Hz, 2H), 2.85 (t, J=6.0 Hz, 2H), 2.49 (s, 3H), 2.25 (s, 3H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:11]2[O:10][C:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.[H-].[Na+].Cl.[Cl:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1>CS(C)=O.O>[ClH:21].[N:24]1([CH2:23][CH2:22][O:1][CH2:2][C:3]2[C:11]3[O:10][C:9]([C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:8][C:7]=3[CH:6]=[CH:5][CH:4]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: OCc1cccc2cc(-c3ccccc3)oc12
Reactant: ClCCN1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: c1ccc(-c2cc3cccc(COCCN4CCCCC4)c3o2)cc1
Reaction time: 0.17 h
Yield: 50.7 %

Procedure:
7-Hydroxymethyl-2-phenylbenzofuran (1.57 g) is dissolved in dimethylsulfoxide (10 ml), and sodium hydride (60% oil dispersion) (0.57 g) is added thereto. After the mixture is stirred for 10 minutes, N-(2-chloroethyl)piperidine hydrochloride (1.35 g) is added to the mixture and the mixture is stirred at room temperature for 4 hours. The mixture is diluted with water and extracted with ethyl acetate. The extract is washed with water, dried and concentrated under reduced pressure to remove solvent. The residue is converted to its hydrochloride and recrystallized from ethyl acetate, whereby 7-[(2-piperidinoethoxy)methyl]-2-phenylbenzofuran hydrochloride (1.32 g) is obtained. Yield: 51%.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.Cl.[CH3:12][NH:13][O:14][CH3:15].C(N(C(C)C)C(C)C)C.C(Cl)CCl>CN(C=O)C.O>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:13]([O:14][CH3:15])[CH3:12])=[O:8])=[CH:9][CH:10]=1
Reactant: CNOC
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CON(C)C(=O)c1ccc(O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 4-hydroxybenzoic acid (20.29 g, 147 mmol), N,O-dimethylhydroxylamine hydrochloride (21.49 g, 220 mmol), N-ethyl-N-isopropylpropan-2-amine (77 mL, 441 mmol), hobt (22.50 g, 147 mmol), and EDC (33.8 g, 176 mmol) in DMF (100 mL) was stirred at RT in 24 h. H2O was added, extracted with ether (3×), dried over MgSO4, concentrated, and purified by ISCO (40% EtOAc/Hexanes) to give the titled compound. MS [M+1]: 182.1.
Reaction SMILES: [C:1]([OH:10])(=[O:9])[CH:2]([CH:4]([C:6]([OH:8])=[O:7])[OH:5])[OH:3].C([O-])(=O)C.[Na+:15]>C(O)(=O)C>[C:6]([CH:4]([CH:2]([C:1]([O-:10])=[O:9])[OH:3])[OH:5])([OH:8])=[O:7].[Na+:15]
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C([O-])C(O)C(O)C(=O)O

Procedure:
In reaction ii, sodium bisulfate is reacted with sodium acetate to produce sodium sulfate and solid acetic acid. In reaction iii., malic acid is reacted with sodium acetate to produce sodium hydrogen diglycolate and solid acetic acid. In reaction iv., fumaric acid is reacted with sodium acetate to produce sodium hydrogen fumarate and solid acetic acid. In reaction v., tartaric acid is reacted with sodium acetate to produce sodium hydrogen tartrate and solid acetic acid. In reaction vi., adipic acid is reacted with sodium acetate to produce sodium hydrogen adipate and solid acetic acid. In reaction vii, sulfamic acid is reacted with sodium acetate to produce sulpher sodium nitrate and solid acetic acid.
Reaction SMILES: C(O)(=O)C.[CH2:5]([C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8].[BH4-].[Na+]>CS(C)=O>[CH2:5]([C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][N+:17]([O-:19])=[O:18])=[CH:11][CH:10]=1)[CH2:6][CH2:7][CH3:8]
Reactant: CCCCc1ccc(/C=C/[N+](=O)[O-])cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCCCc1ccc(CC[N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 25.7 %

Procedure:
To an acetic acid (5.7 mL) and dimethyl sulfoxide (95 mL) solution of 1-butyl-4-((E)-2-nitro-vinyl)-benzene (5.7 g, 27.8 mmol) described in Manufacturing Example 70-1-1 was added sodium borohydride (1.68 g, 44.5 mmol) at room temperature while cooling appropriately. This mixture was stirred for 3 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure, and the residue was purified by silica gel column chromatography (heptane:ethyl acetate=4:1-2:1) to obtain the title compound (1.48 g, 26%).
Reaction SMILES: [F:1][C:2]1[C:10]([O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18]OS(C)(=O)=O)[CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:24])[NH:6]2.[CH3:25][NH2:26].C1COCC1>C(Cl)Cl.O.CCOC(C)=O>[F:1][C:2]1[C:10]([O:11][C:12]2[N:17]=[CH:16][N:15]=[C:14]([CH2:18][NH:26][CH3:25])[CH:13]=2)=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:24])[NH:6]2
Reactant: CN
Reactant: Cc1cc2c(F)c(Oc3cc(COS(C)(=O)=O)ncn3)ccc2[nH]1
Solvent: O
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CNCc1cc(Oc2ccc3[nH]c(C)cc3c2F)ncn1

Procedure:
Methanesulfonic acid 6-(4-fluoro-2-methyl-1H-indol-5-yloxy)-pyrimidin-4-ylmethyl ester (2.5 g, 8.78 mmol) is stirred in DCM (40.0 mL) with 1 M methylamine in THF (4.39 mL, 8.78 mmol) at rt for 24 h. The reaction is diluted with H2O and EtOAc. The organic layer is washed with brine, dried over Na2SO4, filtered, and purified by FCC eluting with first 10-100% EtOAc in heptanes, then washing with 0-25% MeOH with NH3 in EtOAc to provide the title compound. MS (ESI) m/z 287.2 (M+1); 1H NMR (400 MHz, MeOD) δ ppm 8.63 (d, J=1.01 Hz, 1 H) 7.11 (d, J=8.59 Hz, 1 H) 7.02 (s, 1 H) 6.85 (dd, J=8.59, 7.33 Hz, 1 H) 6.23 (s, 1 H) 3.81 (s, 2 H) 2.41 (s, 3 H) 2.44 (s, 3 H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH:15][CH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([N:19]2[CH2:20][CH2:21][CH:16]([OH:15])[CH2:17][CH2:18]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Reactant: OC1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCC(N2CCC(O)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 1-tert-butoxycarbonyl-4-piperidone (200 g, 1.01 mol) in tetrahydrofuran (THF) (1500 ml) was added 4-hydroxypiperidine (78.1 g, 0.77 mol). The resultant slurry was stirred for 30 minutes before cooling the reaction mixture with ice/water, acetic acid (47 ml) is then added (exotherm) which caused precipitation. The slurry was allowed to warm to room temperature before the addition of sodium triacetoxyborohydride (236 g, 1.12 mol) which was washed in with THF (500 ml). The resultant slurry was stirred overnight at room temperature. To the reaction mixture was added water (2000 ml) to give a solution. The solution was then extracted with diethyl ether (3×1800 ml). The aqueous phase was basified with 10% aq NaOH (950 ml) and extracted with dichloromethane (DCM) (3×1500 ml). The combined DCM layers are dried (MgSO4), filtered and the solvent removed to give the sub-titled compound as a yellow viscous oil, (177 g, 81%; MS: (M+H) 285).
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[N:52](C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:7]([C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH2:20][CH2:21][CH:22]([CH3:34])[C@@H:23]([O:30][N+:31]([O-:33])=[O:32])[C@H:24]([O:26][N+:27]([O-:29])=[O:28])[CH3:25])=[O:18])[CH3:15])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4].CO>C(Cl)Cl>[CH2:1]([C:5]1[N:6]([CH2:35][C:36]2[CH:41]=[CH:40][C:39]([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][C:43]=3[C:48]3[NH:52][N:51]=[N:50][N:49]=3)=[CH:38][CH:37]=2)[C:7]([C:11]([O:13][CH:14]([O:16][C:17]([O:19][CH2:20][CH2:21][CH:22]([CH3:34])[C@@H:23]([O:30][N+:31]([O-:33])=[O:32])[C@H:24]([O:26][N+:27]([O-:29])=[O:28])[CH3:25])=[O:18])[CH3:15])=[O:12])=[C:8]([Cl:10])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CO
Product: CCCCc1nc(Cl)c(C(=O)OC(C)OC(=O)OCCC(C)[C@@H](O[N+](=O)[O-])[C@@H](C)O[N+](=O)[O-])n1Cc1ccc(-c2ccccc2-c2nnn[nH]2)cc1
Temperature: 70 °C

Procedure:
1-[({[(4R,5R)-3-methyl-4,5-bis(nitrooxy)hexyl]oxy}carbonyl)oxy]ethyl 2-butyl-4-chloro-1-{[2′-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl}-1H-imidazole-5-carboxylate (1.08 g, 1.09 mmol) was dissolved in CH2Cl2 (3 mL) and MeOH was added (17 mL). The solution was heated in a microwave apparatus (70° C., 40 minutes). The solution was then concentrated and the residue was purified by flash chromatography (Biotage SP1, SNAP 100 g column, CH2Cl2/MeOH 98:2) affording the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[F:15][C:16]([F:33])([O:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH:31]=[N:30][NH:29][C:28]2=[O:32])=[CH:23][CH:22]=1)[CH:17]([F:19])[F:18]>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([O:10][CH2:11]1)[C@H:12]([N:29]1[C:28](=[O:32])[N:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][C:16]([F:15])([F:33])[CH:17]([F:18])[F:19])=[CH:26][CH:25]=2)[CH:31]=[N:30]1)[CH3:13]
Reactant: O=c1[nH]ncn1-c1ccc(OC(F)(F)C(F)F)cc1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1ncn(-c2ccc(OC(F)(F)C(F)F)cc2)c1=O)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 53.8 %

Procedure:
In the same manner as in Reference Example 5, starting from 1.0 g of (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol and 1.11 g of 4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone, 2-[(1R,2S)-2-(2,4-difluorophenyl)-2,3-epoxy-1-methylpropyl]-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]-3(2H,4H)-1,2,4-triazolone (0.99 g) was obtained as a colorless oil.
Reaction SMILES: [CH2:1]([C:9]1[C:10]([C:22]([F:25])([F:24])[F:23])=[C:11]2[C:15]3=[C:16]([CH2:18][NH:19][CH2:20][CH2:21][N:14]3[CH:13]=[CH:12]2)[CH:17]=1)[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30](O)=[O:31].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C1COCC1>[F:26][C:27]([F:35])([F:34])[CH:28]([CH3:33])[CH2:29][C:30]([CH:20]1[NH:19][CH2:18][C:16]2=[C:15]3[C:11](=[C:10]([C:22]([F:25])([F:24])[F:23])[C:9]([CH2:1][CH2:2][C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=4)=[CH:17]2)[CH:12]=[CH:13][N:14]3[CH2:21]1)=[O:31]
Reactant: CC(CC(=O)O)C(F)(F)F
Reactant: FC(F)(F)c1c(CCc2ccccc2)cc2c3c1ccn3CCNC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(CC(=O)C1Cn2ccc3c(C(F)(F)F)c(CCc4ccccc4)cc(c32)CN1)C(F)(F)F
Reaction time: 8 h
Yield: 95.1 %

Procedure:
A mixture of 6-phenethyl-7-(trifluoromethyl)-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole (prepared as described in Example 2 above, 64 mg, 0.17 mmol), 3-(trifluoromethyl)butanoic acid (27 mg, 0.18 mmol), HATU (73 mg, 0.2 mmol) and triethylamine (85 mg, 0.84 mmol) in THF (7 mL) was stirred overnight. The resulting mixture was partitioned between ethyl acetate and water, and the organic layer was washed sequentially with NaHCO3 (sat'd) and brine, then dried and concentrated. The residue was purified by reverse-phase chromatography (CH3CN-water/TFA) to yield 4,4,4-trifluoro-3-methyl-1-(6-phenethyl-7-(trifluoromethyl)-3,4-dihydro-[1,4]diazepino[6,7,1-hi]indol-2(1H)-yl)butan-1-one (78 mg).
Reaction SMILES: Cl.[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([C:21]([O:23]C)=[O:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:11]=[CH:10][C:8]([CH3:9])=[CH:7][CH:6]=1)(=[O:4])=[O:3]>O1CCOCC1>[S:2]([N:12]1[C:16]2=[N:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=[C:15]2[CH:14]=[CH:13]1)([C:5]1[CH:6]=[CH:7][C:8]([CH3:9])=[CH:10][CH:11]=1)(=[O:4])=[O:3]
Reactant: COC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)n1
Agent: Cl
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)n2ccc3nc(C(=O)O)cnc32)cc1
Temperature: 60 °C
Yield: 84.7 %

Procedure:
HCl (6 N aqueous, 714 mL) was added to a yellow solution of methyl 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylate (17.8 g, 53.6 mmol) in 1,4-dioxane (715 mL) within a 2 L round bottom flask, and the mixture was heated at about 60° C. for about 16 h. The reaction mixture was cooled to ambient temperature. The organic solvent was removed under reduced pressure and the precipitate was collected, washed with water, and dried to yield 5-tosyl-5H-pyrrolo[2,3-b]pyrazine-2-carboxylic acid (14.4 g, 85%) as a yellow solid: LC/MS (Table 1, Method a) Rt=1.63 min; MS m/z 316 (M−H)−.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.[CH3:12][O-:13].[Na+].Cl>CO>[Cl:11][C:9]1[CH:8]=[C:7]([O:13][CH3:12])[C:3]([C:4]#[N:6])=[CH:2][N:10]=1
Reactant: C[O-]
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ncc1C#N
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a solution of 4,6-dichloro-nicotinonitrile (1) (200 mg, 1.06 mmol) in methanol (anhydrous, 10 mL) was added sodium methoxide solution (0.5 M/MeOH, 2.12 mL, 1.06 mmol). The reaction was heated at 60° C. overnight. After cooling the reaction solution to room temperature, HCl (1M, 8 mL) was added. The volatile components were evaporated in vacuo. Purification was accomplished by Biotage (10%-50% EtOAc/hexanes gradient mobile phase) to afford 150 mg (77% yield) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1H), 6.98 (s, 1H), 4.03 (s, 3H)
Reaction SMILES: [CH:1]1([C:6]2([OH:11])[CH2:10][CH2:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C([Li])CCC.[C:17](Cl)(=[O:21])[C:18]([CH3:20])=[CH2:19].C(=O)(O)[O-].[Na+]>O1CCCC1.C(OCC)C>[C:17]([O:11][C:6]1([CH:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:7][CH2:8][CH2:9][CH2:10]1)(=[O:21])[C:18]([CH3:20])=[CH2:19]
Reactant: OC1(C2CCCC2)CCCC1
Reactant: C=C(C)C(=O)Cl
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=C(C)C(=O)OC1(C2CCCC2)CCCC1
Temperature: 25 °C
Yield: 91 %

Procedure:
To a 1-L 3-necked round bottom flask equipped with a 250-mL pressure equalizing addition funnel, a nitrogen inlet with thermocouple and an overhead stirrer was added 56 g (0.364 mol) of 1-cyclopentyl-1-cyclopentanol and 400 mL of anhydrous tetrahydrofuran. The addition funnel was charged with 250 mL (0.4 mol) of n-butyllithium (1.6M in hexane) which was then added to the cooled alcohol over 2 hours. The addition funnel was then charged with a solution of 41 g (0.39 mol) of freshly distilled methacryloyl chloride in 100 mL of dry tetrahydrofuran which was then added slowly with cooling over 1.5 hours. The reaction mixture was allowed to warm to room temperature with stirring overnight after which 100 mL of saturated sodium bicarbonate was carefully added with stirring. The mixture was stirred for 1 hour at which time it was diluted with 1 L of diethyl ether and the organics washed with water, brine and dried for 1 hour over anhydrous magnesium sulfate. Filtration and removal of the solvent at reduced pressure resulted in a light-colored oil which was eluted with hexane through a column of 600 g of silica gel. The UV active fractions were collected and the solvent removed at reduced pressure to yield 74 g (91%) of the title compound as a clear, colorless oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[C:5]([CH3:17])=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:24][CH2:23][N:22]([CH2:25][C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1>C(Cl)Cl.CO>[Cl:16][C:11]1[CH:10]=[C:9]([NH:8][C:6]2[C:5]([CH3:17])=[CH:4][N:3]=[C:2]([NH:30][C:29]3[CH:28]=[CH:27][C:26]([CH2:25][N:22]4[CH2:21][CH2:20][N:19]([CH3:18])[CH2:24][CH2:23]4)=[CH:32][CH:31]=3)[N:7]=2)[CH:14]=[CH:13][C:12]=1[F:15]
Reactant: CN1CCN(Cc2ccc(N)cc2)CC1
Reactant: Cc1cnc(Cl)nc1Nc1ccc(F)c(Cl)c1
Solvent: CO
Solvent: ClCCl
Product: Cc1cnc(Nc2ccc(CN3CCN(C)CC3)cc2)nc1Nc1ccc(F)c(Cl)c1
Yield: 78 %

Procedure:
The title compound was prepared according to synthesis procedure B described above from 2-chloro-N-(3-chloro-4-fluorophenyl)-5-methylpyrimidin-4-amine and 4-((4-methylpiperazin-1-yl)methyl)aniline in 78% yield (yellow solid) after flash chromatography (CH2Cl2/CH3OH 99:1 gradually increasing to 95:5). MS (ESI): 440.4 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:22])=[O:21])=[C:16]([F:26])[C:15]=2[F:27])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:28]>O1CCOCC1>[ClH:28].[F:27][C:15]1[C:16]([F:26])=[C:17]([S:20]([CH:23]([CH3:25])[CH3:24])(=[O:21])=[O:22])[CH:18]=[CH:19][C:14]=1[N:11]1[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1
Reactant: CC(C)S(=O)(=O)c1ccc(N2CCN(C(=O)OC(C)(C)C)CC2)c(F)c1F
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)S(=O)(=O)c1ccc(N2CCNCC2)c(F)c1F
Temperature: 80 °C

Procedure:
To 7.5 mmol 4-[2,3-difluoro-4-(propane-2-sulfonyl)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester in 100 ml dioxane was added 30.2 mmol HCl (as a 4 M solution in dioxane), and the mixture was heated at 80° C. for 1 h. The mixture was then cooled to room temperature, and the ensuing white crystals were collected by filtration, washing twice with ether, to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>O1CCCC1>[F:1][C:2]1[CH:9]=[C:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(F)cc1F
Reactant: C1COCCN1
Solvent: C1CCOC1
Product: N#Cc1ccc(N2CCOCC2)cc1F
Yield: 65 %

Procedure:
A solution of 2,4-difluorobenzonitrile (6.03 g, 43.35 mmol) and morpholine (8.3 ml, 95.17 mmol) in tetrahydrofuran (27 ml) was stirred at room temperature for 24 hr. The mixture was evaporated and the white solid purified by Biotage™ column (90 g, silica) eluting with cyclohexane:ethyl acetate: (4:1) to give 2-fluoro-4-(morpholino)-benzonitrile as a white solid (5.81 g, 65%).
Reaction SMILES: [CH2:1]([O:19][CH2:20][CH:21]([CH2:41][OH:42])[O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:43][N:44]([CH3:52])[CH2:45][CH2:46][NH:47][S:48](Cl)(=[O:50])=[O:49]>C(Cl)Cl.N1C=CC=CC=1.C(Cl)Cl>[CH3:43][N:44]([CH3:52])[CH2:45][CH2:46][NH:47][S:48]([O:42][CH2:41][CH:21]([O:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]/[CH:31]=[CH:32]\[CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40])[CH2:20][O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8]/[CH:9]=[CH:10]\[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])(=[O:50])=[O:49]
Reactant: CCCCCCCC/C=C\CCCCCCCCOCC(CO)OCCCCCCCC/C=C\CCCCCCCC
Reactant: CN(C)CCNS(=O)(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCCCCCCC/C=C\CCCCCCCCOCC(COS(=O)(=O)NCCN(C)C)OCCCCCCCC/C=C\CCCCCCCC
Reaction time: 2 h
Yield: 18.3 %

Procedure:
In 4 ml of methylene chloride-pyridine (2:1) was dissolved 150 mg (0.25 mmol) of 1,2-O-dioleylglycerol. Then, 1 ml of a solution of 150 mg (0.75 mmol) (2-dimethylaminoethyl)sulfamoyl chloride in methylene chloride was added and the reaction was carried out at ambient temperature for 2 hours. After completion of the reaction, the solvent was distilled off under reduced pressure and the residue was treated with methylene chloride-saturated aqueous sodium hydrogen carbonate solution. The methylene chloride layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel/methylene chloride-methanol) to provide 34 mg (18%) of the title compound. 1H-NMR (200 MHz, CDCl3) δ:0.88 (6H, t, J=6 Hz), 1.20-1.40 (44H, m), 1.45-1.65 (4H, m), 1.90-2.10 (8H, m), 2.24 (6H, s), 2.48 (2H, t, J=6 Hz), 3.18 (2H, t, J=6 Hz), 3.40-3.60 (6H, m), 3.60-3.75 (1H, m), 4.08-4.30 (2H, m), 5.30-5.40 (4H, m) MS (FAB): 743 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:9]([C:12]1[S:13][CH:14]=[C:15]([C:17](OCC)=[O:18])[N:16]=1)[CH2:10][CH3:11])[CH3:8].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.C1COCC1>[CH2:7]([N:9]([C:12]1[S:13][CH:14]=[C:15]([CH2:17][OH:18])[N:16]=1)[CH2:10][CH3:11])[CH3:8]
Reactant: CCOC(=O)c1csc(N(CC)CC)n1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCN(CC)c1nc(CO)cs1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.9 %

Procedure:
A solution of 3.14 ml of lithium aluminum hydride in toluene was diluted in a dry flask under N2 atmosphere with 30 ml of THF. The resulting mixture was cooled to 0° C. and treated dropwise with a solution of 1.43 g (6.28 mmol) of ethyl 2-(N,N-diethylamino)thiazole-4-carboxylate in 5 ml of THF. After addition, the solution was allowed to warm slowly to ambient temperature, stirred for 1 h, recooled to 0° C., and treated with a small amount of aqueous Rochelle's salt followed by ethyl acetate. After stirring, the slurry was filtered, washed with additional ethyl acetate, and the combined filtrates were concentrated in vacuo. The residue was purified by silica gel chromatography using methanol in chloroform to provide 0.864 g (73%) of the desired compound, Rf 0.17 (4% methanol in chloroform). Mass spectrum: (M+H)+ =187.
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[C:3]([OH:5])=[O:4].[CH3:20]O>>[CH3:20][O:4][C:3](=[O:5])[CH:2]([OH:1])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCCCCCCCCCCC(O)C(=O)O
Reactant: CO
Product: CCCCCCCCCCCCCCC(O)C(=O)OC
Yield: 85 %

Procedure:
2-hydroxyhexadecanoic acid (10.0 g, 0.0367 moles) and 8.40 g acidic resin were refluxed in 250 mls methanol for 20 hours. The solution was decolorized, filtered and concentrated giving a white solid (yield=85%)
Reaction SMILES: [F:1][CH:2]([F:12])[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)[CH3:4]>C(O)(C)C.[Rh]>[F:1][CH:2]([F:12])[CH:3]([CH:5]1[CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]1)[CH3:4]
Reactant: CC(c1ccc(O)cc1)C(F)F
Agent: [Rh]
Solvent: CC(C)O
Product: CC(C(F)F)C1CCC(O)CC1

Procedure:
At 50° C. and 150 bar, 19.7 g of 4-(2,2-difluoro-1-methylethyl)phenol in 150 ml of isopropanol were hydrogenated in the presence of rhodium on carbon as catalyst for 20 h. The catalyst was filtered off and the reaction solution was concentrated, giving 16.9 g (83% of theory) of product as a colourless oil which was reacted further without any purification.