Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](=[NH:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:16][CH2:17][C:18]#N>ClCCl>[C:1](=[N:14][CH2:18][C:17]#[N:16])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(c1ccccc1)c1ccccc1
Reactant: N#CCN
Agent: Cl
Solvent: ClCCl
Product: N#CCN=C(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 120 h
Yield: 157.5 %

Procedure:
A mixture of benzophenone imine (25 g, 0.138 mol, Aldrich) and aminoacetonitrile hydrochloride (25 g, 0.270 mol, Lancaster) in dichloromethane (1000 mL) was stirred in a 2 L Erlenmeyer flask under nitrogen at room temperature for 5 days. The reaction mixture was filtered to remove the precipitated ammonium chloride and the filtrate was evaporated to dryness in vacuo. The resulting residue was dissolved in ether (400 mL) washed with water (200 mL) and brine. After drying over magnesium sulfate the solution was evaporated to give (benzhydrylideneamino)-acetonitrile (47.89 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:34][C:35]2[CH:36]=[N:37][CH:38]=[CH:39][C:40]=2[CH3:41])[CH:10]2[CH2:15][CH2:14][N:13]([C@H:16]([CH3:33])[CH2:17][CH2:18][NH:19][C:20](=[O:32])[C:21]3[C:29]([CH3:30])=[CH:28][C:24]([C:25](O)=[O:26])=[CH:23][C:22]=3[CH3:31])[CH2:12][CH2:11]2)=[CH:5][CH:4]=1.CCN=C=NCCCN(C)C.C1C=C[C:56]2N(O)N=[N:59][C:57]=2[CH:58]=1.C(N)(C)C.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:57]([NH:59][C:25](=[O:26])[C:24]1[CH:28]=[C:29]([CH3:30])[C:21]([C:20]([NH:19][CH2:18][CH2:17][C@H:16]([N:13]2[CH2:12][CH2:11][CH:10]([N:9]([C:6]3[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)[CH2:34][C:35]3[CH:36]=[N:37][CH:38]=[CH:39][C:40]=3[CH3:41])[CH2:15][CH2:14]2)[CH3:33])=[O:32])=[C:22]([CH3:31])[CH:23]=1)([CH3:58])[CH3:56]
Reactant: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)O)cc3C)CC2)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CC(C)N
Product: COc1ccc(N(Cc2cnccc2C)C2CCN([C@H](C)CCNC(=O)c3c(C)cc(C(=O)NC(C)C)cc3C)CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.2 %

Procedure:
N-((R)-3-{4-[(4-Methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-3,5-dimethyl-terephthalamic acid (0.050 g, 0.09 mmol), EDCI (0.019 g, 0.10 mmol) and HOBT (0.013 g, 0.10 mmol) were combined in DMF (5 mL) to give a pale yellow solution. To this solution was added isopropylamine (8 μL, 0.10 mmol) followed by DIPEA (19 μL, 0.11 mmol) and the resulting mixture was stirred at 25° C. for 16 h. Standard workup according to General Procedure C gave the crude product as a tan oil. Purification by column chromatography on silica gel (CH2Cl2:MeOH:NH4OH, 93:5:2, v/v/v) afforded N′-isopropyl-N-((R)-3-{4-[(4-methoxy-phenyl)-(4-methyl-pyridin-3-ylmethyl)-amino]-piperidin-1-yl}-butyl)-2,6-dimethyl-terephthalamide (0.046 g, 86%) as a white foam. 1H NMR (CDCl3) δ 0.97 (d+m, 4H), 1.18 (d+m, 7H), 1.55 (m, 1H), 1.72 (m, 3H), 2.08 (br t, 1H), 2.26 (s, 6H), 2.30 (s, 3H), 2.42 (br t, 1H), 2.67-2.81 (m, 3H), 3.14 (m, 1H), 3.31 (m, 1H), 3.72 (s, 3H), 3.78 (m, 1H), 3.99 (s, 2H), 4.23 (m, 1H), 6.57 (d, 1H, J=6.0 Hz), 6.68 (d, 2H, J=9.0 Hz), 6.73 (d, 2H, J=9.0 Hz), 7.00 (d, 1H, J=3.0 Hz), 7.45 (s, 2H), 7.83 (s, 1H), 8.29 (s, 1H), 8.31 (d, 1H, J=6.0 Hz). 13C NMR (CDCl3) δ 13.7, 19.0, 19.6, 23.1, 29.7, 30.4, 31.3, 39.6, 42.2, 44.2, 47.7, 49.2, 51.9, 55.9, 59.6, 60.0, 114.8, 118.2, 121.4, 125.3, 126.5, 134.0, 134.8, 135.1, 141.2, 143.3, 145.2, 148.1, 149.4, 154.5, 166.5, 169.8. ES-MS m/z 600 (M+H). Anal. Calcd. for C36H49N5O3.0.1 CH2Cl2: C, 71.28; H, 8.15; N, 11.51. Found: C, 71.26; H, 8.18; N, 11.41.
Reaction SMILES: Br[C:2]1[C:16]([CH3:17])=[CH:15][C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[C:4]([O:18][CH3:19])[CH:3]=1.C([Li])CCC.[B:25](OC)([O:28]C)[O:26]C>C1COCC1>[CH3:19][O:18][C:4]1[C:5]([O:6][CH2:7][O:8][CH2:9][CH2:10][Si:11]([CH3:14])([CH3:13])[CH3:12])=[CH:15][C:16]([CH3:17])=[C:2]([B:25]([OH:28])[OH:26])[CH:3]=1
Reactant: COB(OC)OC
Reactant: COc1cc(Br)c(C)cc1OCOCC[Si](C)(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cc(B(O)O)c(C)cc1OCOCC[Si](C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 47.4 %

Procedure:
[2-(4-Bromo-2-methoxy-5-methyl-phenoxymethoxy)-ethyl]-trimethyl-silane (2.6 g, 7.5 mmol) was stirred in dry THF (10 mL) at −78° C. under argon. n-Butyllithium (3.75 mL, 2.5 M in hexanes, 9.36 mmol) was added dropwise, and the reaction stirred for 30 min before it was transferred via cannula to a flask of trimethyl borate (8.4 mL, 75 mmol) in THF (15 mL), which was also stirring at −78° C. under argon. After addition was complete, the reaction stirred 30 min at −78° C. and then 30 min while warming to 0° C. It was then quenched with H2O (20 mL), acidified with 0.1 N HCl, and extracted with ethyl acetate (2×25 mL). Organics were washed with brine (20 mL), dried (Na2SO4), and concentrated in vacuo. Purification by silica gel chromatography (20% to 50% ethyl acetate/hexanes) gave 1.11 g (47%) of 5-methoxy-2-methyl-4-[2-(trimethyl-silanyl)-ethoxymethoxy]-phenyl-boronic acid as a white solid. 1H NMR (300 MHz, CDCl3) δ 7.78 (s, 1H), 7.10 (s, 1H), 5.36 (s, 2H), 3.93 (s, 3H), 3.83 (t, 2H, J=8.4 Hz), 2.79 (s, 3H), 0.98 (t, 2H, J=8.4 Hz), 0.01 (s, 9H). Anal. (C14H25BO5Si—H2O) C, H. Calculated: C, 57.15; H, 7.88. Found: C, 56.89; H, 7.87.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12]2[C:13](O)=[N:14][C:15]([NH2:19])=[N:16][C:17]=2[CH3:18])[CH:6]=1)[CH3:2].P(Cl)(Cl)([Cl:24])=O>>[CH2:1]([O:3][C:4](=[O:21])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH2:11][C:12]2[C:13]([Cl:24])=[N:14][C:15]([NH2:19])=[N:16][C:17]=2[CH3:18])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2O)c1
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cccc(Cc2c(C)nc(N)nc2Cl)c1
Temperature: 100 °C

Procedure:
The product from step (i) (1.9 g) was added to phosphorous oxychloride (30 mL) and the mixture was heated at 100° C. for 15 h. The mixture was allowed to cool and the phosphorous oxychloride evaporated under reduced pressure. The residue was diluted with water (10 mL) and the pH of the mixture was adjusted to pH ˜7 using sodium bicarbonate. The mixture was then heated at 50° C. for 2 h and the aqueous was extracted with EtOAc. The combined organic phase was dried and evaporated under reduced pressure to give the subtitle compound as a pale yellow solid 1.65 g that was used without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([CH3:17])(=[O:16])=[O:15])=[CH:6][CH:5]=1)#[N:2].[CH2:18](N)[CH2:19][NH2:20]>C(=S)=S>[NH:2]1[CH2:18][CH2:19][N:20]=[C:1]1[CH2:3][C:4]1[C:9]2[CH:10]=[CH:11][O:12][C:8]=2[C:7]([NH:13][S:14]([CH3:17])(=[O:15])=[O:16])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Nc1ccc(CC#N)c2ccoc12
Reactant: NCCN
Solvent: S=C=S
Product: CS(=O)(=O)Nc1ccc(CC2=NCCN2)c2ccoc12
Yield: 93.7 %

Procedure:
A mixture of N-(4-cyanomethyl-benzofuran-7-yl)-methanesulfonamide (1.0 g, 4.0 mmole), ethylene diamine (8 mL, 119.7 mmoles), and carbon disulfide (one drop) was microwaved at 140° C. for 30 minutes in a Smith creators. The reaction mixture was transferred into a large beaker (1 L) and the reaction vessel was rinsed with methanol (5 mL). Ether (600 mL) was added to the reaction mixture and insoluble material settled at the bottom of the container. The ether solution was removed by decantation. The residue was purified by flash column chromratography over silica gel eluting with 8% methanol in dichloromethane with 0.1% concentrated ammonium hydroxide to give N-[4-(4,5-dihydro-1H-imidazol-2-ylmethyl)-benzofuran-7-yl]-methanesulfonamide as a solid (1.1 g, 85%).
Reaction SMILES: N[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[C:4]([CH3:10])[N:3]=1.N([O-])=O.[Na+].[ClH:15]>>[Br:9][C:5]1[C:4]([CH3:10])=[N:3][C:2]([Cl:15])=[CH:7][C:6]=1[CH3:8]
Reactant: Cl
Reactant: Cc1cc(N)nc(C)c1Br
Agent: O=N[O-]
Agent: [Na+]
Product: Cc1cc(Cl)nc(C)c1Br
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
A stirred solution of 2-amino-5-bromo-4,6-dimethylpyridine (65 g, 323 mmol) in 37% hydrochloric acid (780 ml) was cooled to −10° C. Sodium nitrite (66.9 g, 970 mmol) was added in small portions over 10 min. The reaction was stirred for 15 min at −10° C. and then warmed to room temperature. After stirring for 1 hour at r.t., the reaction was quenched by pouring into ice/water (4 L). The mixture was stirred for 5 minutes and then extracted with EtOAc (4 L). The organic extract was washed with water (4 L) and brine (2 L). The organic layer was dried over Na2SO4, filtered, and concentrated. The resulting white solid was dissolved in CH2Cl2 (200 mL) and heptanes (700 mL) were added. The solution was stirred for 20 minutes and then filtered to remove solids. The filtrate was concentrated and the residue was purified by flash chromatography on silica gel with 0 to 15% EtOAc/heptanes to afford 3-bromo-6-chloro-2,4-dimethylpyridine. LCMS=219.9 and 221.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.05 (s, 1H), 2.65 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[NH:6][N:5]=[N:4][N:3]=1.F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][C:2]1[N:3]=[N:4][N:5]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[N:6]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: Cc1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nnn(-c2ccc([N+](=O)[O-])cc2)n1
Temperature: 110 °C

Procedure:
5-methyl-1H-tetrazole (715 mg, 8.5 mmol) was dissolved in DMF (7 mL) in a 40 mL biotage microwave tube. 4-fluoro-nitrobenzene (1 g, 7.09 mmol) was added, followed by addition of potassium carbonate (1.175 g, 8.5 mmol). The tube was crimp sealed and heated at 110° C. for 4 hours (caution: build-up of pressure possible; use a safety shield). TLC indicated complete consumption of starting materials. Most DMF was removed under vacuum. Water (50 mL) was added. Large amount of brown solid formed (1 gram) and was collected by filtration. The solid was further purified by column through a 80 gram biotage silica gel cartridge using 30-75% ethyl acetate/hexanes to give clean fraction of 5-methyl-2-(4-nitrophenyl)-2H-tetrazole, LRMS calc: 205.1; obs: 206.3 (W+1).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(O[C:13]([N:15](C)[C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1)=O)(C)(C)C>C(Cl)Cl>[CH3:13][NH:15][C@H:16]1[C:24]2[C:19](=[CH:20][CH:21]=[C:22]([C:25]([O:27][CH3:28])=[O:26])[CH:23]=2)[CH2:18][CH2:17]1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N(C)C(=O)OC(C)(C)C)CC2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN[C@@H]1CCc2ccc(C(=O)OC)cc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
TFA (2 ml) was added dropwise to a solution of (R)-methyl 3-(tert-butoxycarbonyl(methyl)-amino)-2,3-dihydro-1H-indene-5-carboxylate (760 mg, 2.49 mmol, 1.0 eq.) in methylene chloride (10 ml) at 0° C. The reaction mixture was then stirred at RT for 2 h. After completion of the reaction, the reaction mixture was concentrated to afford the desired product which was used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH2:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=1.[ClH:34].[NH:35](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[C@H:36]([C:43]([OH:45])=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[NH2:35][C@H:36]([C:43]([OH:45])=[O:44])[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH2:15])[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:6][CH:7]=1.[CH2:16]=[CH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[CH2:24]=[CH:25][C:26]1[CH:31]=[CH:30][C:29]([CH:32]=[CH2:33])=[CH:28][CH:27]=1.[ClH:34]
Reactant: O=C(N[C@H](C(=O)O)c1ccccc1)OCC1c2ccccc2-c2ccccc21
Agent: C=Cc1ccc(C=C)cc1
Agent: Cc1ccc(C(N)c2ccccc2)cc1
Agent: Cl
Solvent: C=Cc1ccccc1
Product: N[C@H](C(=O)O)c1ccccc1

Procedure:
The commercially available MBHA resin (2.6 g, 1.12 mmol/g, 2.91 mmol) was transferred to a 250 mL fritted solid phase reaction vessel equipped with a nitrogen inlet. It was then washed thoroughly with 30 ml portions of dichloromethane, methanol, dimethylformamide and dichloromethane and coupled over 18 hours to the commercially available Fmoc-Phg-OH (2.17 g, 5.82 mmol) according Procedure A with 99.82% efficiency. The resin was then subjected to Fmoc deprotection according to procedure B. A qualitative ninhydrin assay on a small aliquot gave dark blue resin and solution, indicating a successful reaction.
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([O:22]CC)=[O:21])=[C:15]([F:25])[CH:14]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2].C(O)(=O)C.Cl.ClCCl>CO>[CH2:1]([O:3][C:4]1[C:12]2[CH2:11][N:10]([C:13]3[CH:18]=[CH:17][C:16]([CH2:19][C:20]([OH:22])=[O:21])=[C:15]([F:25])[CH:14]=3)[C:9](=[O:26])[C:8]=2[C:7]([O:27][CH2:28][CH3:29])=[C:6]2[CH:30]=[CH:31][CH:32]=[CH:33][C:5]=12)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(N2Cc3c(c(OCC)c4ccccc4c3OCC)C2=O)cc1F
Agent: Cl
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: CCOc1c2c(c(OCC)c3ccccc13)C(=O)N(c1ccc(CC(=O)O)c(F)c1)C2
Temperature: 0 °C
Yield: 87.1 %

Procedure:
A suspension of ethyl {-4-[4,9-bis(ethyloxy)-1-oxo-1,3-dihydro-2H-benzo[f]isoindol-2-yl]-2-fluorophenyl}acetate (200.0 g, 443 mmol) in a mixture of glacial acetic acid (2080 mL) and hydrochloric acid (2 M, 700 mL) was heated to reflux under a nitrogen atmosphere, with the reaction progress monitored by TLC analysis (silica, dichloromethane:methanol, 99:1). After 60 minutes the reaction mixture was cooled to 0° C. The precipitated solid was isolated by filtration, washed with water (1400 mL), and freeze-dried to give the desired product as an off-white solid (163.4 g, 87% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].[ClH:12]>>[Cl-:12].[C:2]1([N+:1]#[N:8])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: Cl
Reactant: O=N[O-]
Agent: [Na+]
Product: N#[N+]c1ccccc1
Product: [Cl-]

Procedure:
In a method for preparing the compound: ##STR3## wherein aniline is diazotized in aqueous hydrochloric acid employing sodium nitrite as the diazotizing agent to form benzenediazonium chloride, the benzenediazonium chloride is coupled into aniline to form aminoazobenzene, and the aminoazobenzene is diazotized and coupled into phenol; the improvement comprising: diazotizing the aniline employing an excess of sodium nitrite of up to about 10% of the amount stoichiometrically required to diazotize one-half of the aniline on a molar basis; coupling the resultant benzenediazonium chloride with the remaining aniline to form a mixture of aminoazobenzene and excess benzenediazonium chloride in aqueous hydrochloric acid; heating said mixture to about 40° C. and allowing said excess benzenediazonium chloride to decompose and, subsequently, without isolation, diazotizing said aminoazobenzene and coupling it into phenol.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[CH3:12][O:5][C:4](=[O:6])[C:3]1[C:7]([CH3:11])=[CH:8][CH:9]=[CH:10][C:2]=1[Br:1]
Reactant: O=C([O-])[O-]
Reactant: Cc1cccc(Br)c1C(=O)O
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Product: COC(=O)c1c(C)cccc1Br

Procedure:
2-Bromo-6-methyl-benzoic acid (4.95 g) and K2CO3 (16.26 g) were suspended in acetone (150 mL). MeI (7.5 mL) was added and the mixture was heated at reflux for 3.5 h. The solid was removed by filtration and the filtrate was concentrated. The residue was taken into EtOAc and washed with saturated NH4Cl, H2O and saturated NaCl. The organic phase was dried over MgSO4, filtered, and concentrated to yield 2-bromo-6-methyl-benzoic acid methyl ester as an orange oil.
Reaction SMILES: [C:1]([O-])([O-])=O.[K+].[K+].[F:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][N:9]=1.CI>CN(C)C=O>[CH3:1][O:13][C:12](=[O:14])[C:11]1[CH:15]=[CH:16][C:8]([F:7])=[N:9][CH:10]=1
Reactant: O=C(O)c1ccc(F)nc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)c1ccc(F)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 84 %

Procedure:
A round bottom flask was charged with K2CO3 (191 g, 1380 mmol), 6-fluoronicotinic acid (77.8 g, 551 mmol) and dimethylformamide (551 mL). Methyl iodide (51.5 mL, 827 mmol) was then added in one portion at room temperature and mixture stirred overnight at room temperature. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed three times with water and once with brine, and then dried over Na2SO4. Purification by silica gel flash chromatography (ethyl acetate/dichloromethane) gave 6-fluoro-nicotinic acid methyl ester (71.8 g, 84%) as a white solid. 1H NMR (400 MHz, CDCl3, δ): 3.96 (s, 3H) 7.01 (dd, J=8.58, 2.93 Hz, 1H) 8.41 (ddd, J=8.49, 7.61, 2.44 Hz, 1H) 8.89 (d, J=2.34 Hz, 1H); MS (M+1): 156.1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1.C(N(CC)CC)C.[CH3:28][S:29](Cl)(=[O:31])=[O:30].[Cl-].[NH4+]>ClCCl>[CH3:28][S:29]([O:1][C@@H:2]1[CH2:11][CH2:10][C@@H:9]2[C@H:4]([CH2:5][C@@H:6]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:7]([C:12]([O:14][CH3:15])=[O:13])[CH2:8]2)[CH2:3]1)(=[O:31])=[O:30]
Reactant: CCOC(=O)[C@@H]1C[C@@H]2C[C@H](O)CC[C@H]2CN1C(=O)OC
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)[C@@H]1C[C@@H]2C[C@H](OS(C)(=O)=O)CC[C@H]2CN1C(=O)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 99.8 %

Procedure:
To an ice-cooled solution of ethyl (3S, 4aR, 6R, 8aR) 6-hydroxy-2-methoxycarbonyl-1,2,3,4,4a, 5,6,7,8,8a-decahydroisoquinoline-3-carboxylate (760 mg, 2.66 mmol) in dry dichloromethane (10 mL) under nitrogen, triethylamine (0.60 mL, 4.3 mmol) and methanesulfonyl chloride (0.33 mL, 4.3 mmol) were added. The resulting mixture was stirred overnight at room temperature and a saturated solution of ammonium chloride was added (10 mL). The layers were separated and the aqueous layer extracted with dichloromethane (10 mL×2). The combined organic phases were washed with 1 N hydrochloric acid (10 mL), dried over sodium sulfate and concentrated in vacuo to give the title compound as an oil (0.965 g, 100%).
Reaction SMILES: [Si]([O:8][CH2:9][C:10]1([CH2:23][CH2:24][CH:25]([C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[C:34]([O:37][CH3:38])[CH:35]=3)[N:30]=[CH:29][C:28]=2[Cl:39])[OH:26])[CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12][CH2:11]1)(C(C)(C)C)(C)C.C(OCC)C>Cl.O1CCOCC1>[ClH:39].[ClH:39].[Cl:39][C:28]1[CH:29]=[N:30][C:31]2[C:36]([C:27]=1[CH:25]([OH:26])[CH2:24][CH2:23][C:10]1([CH2:9][OH:8])[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2
Reactant: COc1ccc2ncc(Cl)c(C(O)CCC3(CO[Si](C)(C)C(C)(C)C)CCN(C(=O)OC(C)(C)C)CC3)c2c1
Agent: Cl
Solvent: CCOCC
Solvent: C1COCCO1
Product: COc1ccc2ncc(Cl)c(C(O)CCC3(CO)CCNCC3)c2c1
Yield: 328.1 %

Procedure:
A mixture of 1.5 g of tert-butyl 4-(tert-butyldimethylsilanyloxymethyl)-4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidine-1-carboxylate in 6.5 cm3 of 5N hydrochloric acid dissolved in dioxane and 30 cm3 of dioxane was stirred at a temperature in the region of 20° C. for 17 hours. 100 cm3 of diethyl ether were added to the reaction mixture. The precipitate formed was filtered off to give 1.24 g of {4-[3-(3-chloro-6-methoxyquinolin-4-yl)-3-(R,S)-hydroxypropyl]piperidin-4-yl}methanol dihydrochloride in the form of a pale yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][OH:5].[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:16]4[C:30](=O)[O:29][C:28](=[O:32])[C:17]=4[CH:18]=[C:19]4[C:27]=3[C:23]3[O:24][CH2:25][O:26][C:22]=3[CH:21]=[CH:20]4)=[CH:14][C:9]=2[O:8][CH2:7]1.O>C1(C)C=CC=CC=1>[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([C:15]3[C:27]4[C:19](=[CH:20][CH:21]=[C:22]5[O:26][CH2:25][O:24][C:23]5=4)[CH:18]=[C:17]4[C:28](=[O:32])[N:1]([CH2:2][CH2:3][CH2:4][OH:5])[C:30](=[O:29])[C:16]=34)=[CH:14][C:9]=2[O:8][CH2:7]1
Reactant: NCCCO
Reactant: O=C1OC(=O)c2c1cc1ccc3c(c1c2-c1ccc2c(c1)OCO2)OCO3
Solvent: Cc1ccccc1
Solvent: O
Product: O=C1c2cc3ccc4c(c3c(-c3ccc5c(c3)OCO5)c2C(=O)N1CCCO)OCO4
Temperature: 25 °C
Reaction time: 1 h
Yield: 7.9 %

Procedure:
3-Amino-1-propanol (27 mg, 0.36 mmol) in toluene (5 mL) at 0° C. was added dropwise to a stirred solution of anhydride 1 (109 mg, 0.3 mmol) in toluene (40 mL). The mixture was stirred at room temperature for 1 h and then heated under Dean-Stark trap for 3 h. After water ceased to distill, the reaction mixture was cooled, washed successively with water (2×50 mL), 5% aqueous NaHCO3 solution (2×50 mL), and water (2×50 mL), and then dried over MgSO4. The solvent was removed in vacuo, and the resulting product was purified by column chromatography on silica gel using CH2Cl2/acetone (3:1 to 1:1, v/v) to provide 29 (10 mg, 11%) as a pale yellow powder. mp 150-152° C.; 1H NMR (CDCl3) δ 8.27 (s, 1H, H4), 7.56 (d, 1H, H5, J=8.4 Hz), 7.26 (d, 1H, H6, J=8.4 Hz), 6.86-6.91 (m, 3H, H2′+H5′+H6′), 6.04 (s, 2H, 3′,4′-OCH2O—), 5.97 (s, 2H, 7,8-OCH2O—), 3.69-3.76 (m, 4H, NCH2CH2CH2OH), 1.83 (m, 2H, NCH2CH2CH2OH).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N+:9]([O-])=O)=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(O)C.[H][H]>[Pd]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: [H][H]
Reactant: COc1ccc([N+](=O)[O-])cc1N1CCOCC1
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N)cc1N1CCOCC1
Yield: 87.7 %

Procedure:
4-(2-Methoxy-5-nitro-phenyl)-morpholine (0.600 g, 2.52 mmol) was dissolved in Ethanol (35.0 mL, 599 mmol) and the solution was carefully poured over 10% Palladium on Carbon (0.300 g, 22.5 mmol) under nitrogen. The mixture was then placed on a Parr hydrogenation apparatus and was allowed to shake at 55 psi until uptake of hydrogen ceased. The catalyst was then filtered to afford 460 mg of 4-Methoxy-3-morpholin-4-yl-phenylamine without further purification. (M+H)=209.2. 1H NMR (400 MHz, DMSO, d6) δ 6.62 (d, 1H, J=8.36 Hz), 6.15 (m, 1H), 6.13 (m, 1H), 4.56 (s, 2H), 3.69 (m, 4H), 3.65 (s, 3H), 2.89 (m, 4H).
Reaction SMILES: C(OC=CC[S:8]C)(=O)C.CO.[C]=O.[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=O)(=[O:16])[CH3:15]>O1CCCC1.[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[C-]#[O+].[Mn].[Mn].C1(C)C=CC=CC=1>[C:14]([O:17][CH:18]([CH2:23][CH2:24][S:25][CH3:26])[C:19]([O:21][CH3:22])=[S:8])(=[O:16])[CH3:15]
Reactant: COC(=O)C(CCSC)OC(C)=O
Reactant: CSCC=COC(C)=O
Agent: [Mn]
Agent: [C-]#[O+]
Agent: [C]=O
Solvent: CO
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=S)C(CCSC)OC(C)=O
Temperature: 120 °C

Procedure:
0.5 mmoles 1-acetoxy-3-methylthiopropene (Z-:E ratio 43:57) and 0.5 mmoles methanol were charged into a 71 cc stainless steel bomb equipped with a glass liner and a Teflon coated stir bar. One mole percent, based on 1-acetoxy-3-methylthiopropene, of a catalyst comprising Mn2 (CO)10 was added. Toluene was included as an internal standard. Five milliliters of tetrahydrofuran as a solvent were also included in the reaction system. The reaction mixture was charged under argon. The bomb was sealed and carbon monoxide at a pressure of 1000 psi (at room temperature) was charged to the bomb, and the bomb was heated to 120° C. and allowed to react for 44 hours with stirring. At the termination of the reaction, the reaction products were analyzed by gas chromatography and it was found that no 2-acetoxy-4-(methylthio)butanoic acid, methyl ester was produced and that no 2-acetoxy-4-(methylthio)thiobutanoic acid, methyl ester was produced.