Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](Cl)([CH2:10][CH:11]=[CH2:12])[C:5]([O:8][CH3:9])=[CH:6][N:7]=1.[Cl:14]C1N=CC(OC)=C(Cl)N=1.C([Mg]Br)C=C.C(C1C(=O)C(Cl)=C(Cl)C(=O)C=1C#N)#N>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([CH2:10][CH:11]=[CH2:12])[C:5]([O:8][CH3:9])=[C:6]([Cl:14])[N:7]=1
Reactant: COc1cnc(Cl)nc1Cl
Reactant: C=CCC1(Cl)NC(Cl)=NC=C1OC
Agent: C=CC[Mg]Br
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1CCOC1
Product: C=CCc1nc(Cl)nc(Cl)c1OC
Reaction time: 0.33 h
Yield: 67 %

Procedure:
2,6-Dichloro-5-methoxy-6-allyl pyrimidine may be prepared using 2,6-dichloro-5-methoxy pyrimidine, which is commercially available. 2,6-Dichloro-5-methoxy pyrimidine (3.0 g, 17 mmol) was dissolved in THF (30 mL) and treated in portions with allyl magnesium bromide (17 mL of 1M allyl magnesium bromide in diethyl ether, 17 mmol). The resulting reaction was exothermic. External cooling was used to keep the temperature of the mixture below 30° C. After 20 minutes, the mixture was subjected to HPLC and GC-MS. After 45 minutes, the mixture was cooled in ice/salt and the reaction quenched with saturated ammonium chloride (30 mL) then diluted with ethyl acetate (75 mL). The organic phase was washed with saturated sodium chloride (30 mL), dried, and evaporated. The residue was dissolved in 1,4-dioxane (50 mL), treated with DDQ (3.9 g, 17 mmol), and stirred for 20 h. GC-MS showed presence of 2,6-dichloro-5-methoxy-6-allyl pyrimidine (having molar weight of 218 g/mol). The residue was washed in water and ethyl acetate and purified by column chromatography using silica with ethyl acetate and hexane. This provided the title compound (2.5 g, 67% yield): mp 61-62° C. 1H NMR (400 MHz, CDCl3) δ 6.07-5.94 (m, 1H), 5.26-5.16 (m, 2H), 3.94-3.89 (s, 3H), 3.65-3.56 (m, 2H)); EIMS m/z 218.
Reaction SMILES: [OH:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)\[CH3:5].[CH2:21]([O:23][C@@H:24]([CH2:30][C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)[C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:22]>>[C:18]([C:15]1[CH:14]=[CH:13][C:12]([C:9]2[CH:10]=[CH:11][C:6](/[C:4](/[CH3:5])=[CH:3]/[CH2:2][O:1][C:34]3[CH:33]=[CH:32][C:31]([CH2:30][C@H:24]([O:23][CH2:21][CH3:22])[C:25]([O:27][CH2:28][CH3:29])=[O:26])=[CH:36][CH:35]=3)=[CH:7][CH:8]=2)=[CH:17][CH:16]=1)(=[O:20])[CH3:19]
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)OCC
Reactant: CC(=O)c1ccc(-c2ccc(/C(C)=C/CO)cc2)cc1
Product: CCOC(=O)[C@H](Cc1ccc(OC/C=C(\C)c2ccc(-c3ccc(C(C)=O)cc3)cc2)cc1)OCC
Yield: 75.4 %

Procedure:
The title compound (275 mg, 75%) was prepared from (E)-1-[4′-(3-hydroxy-1-methyl-propenyl)-biphenyl-4-yl]-ethanone (200 mg, 0.75 mmol) and (S)-ethyl 2-ethoxy-3-(4-hydroxyphenyl)-propionate (188 mg, 0.79 mmol) by a procedure analogous to that described in example 52c.
Reaction SMILES: [CH2:1]([N:8]=[C:9]=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:11][N:12]([C:23]1[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=1)[N:13]1[C:21]2[C:16](=[CH:17][C:18]([OH:22])=[CH:19][CH:20]=2)[CH:15]=[CH:14]1.C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[C:2]1([CH2:1][NH:8][C:9](=[O:10])[O:22][C:18]2[CH:17]=[C:16]3[C:21](=[CH:20][CH:19]=2)[N:13]([N:12]([CH3:11])[C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)[CH:14]=[CH:15]3)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1ccncc1)n1ccc2cc(O)ccc21
Reactant: O=C=NCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CN(c1ccncc1)n1ccc2cc(OC(=O)NCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 3 h
Yield: 97.7 %

Procedure:
Benzyl isocyanate (1.7 g) was added to a solution of 1-(methyl-4-pyridinylamino)-1H-indol-5-ol (2.5 g) in 75 mL tetrahydrofuran containing potassium carbonate (milled, 3 g). After stirring three hours at ambient temperature the mixture was filtered and concentrated. The residue was eluted through silica with ethyl acetate via flash column chromatography to yield 3.8 g solid. This was recrystallized from acetonitrile to yield 3.2 g crystals, m.p. 179°-181° C.
Reaction SMILES: [C:1]([CH:3]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]2[C:16]3=[N:17][CH:18]=[CH:19][C:20]([CH3:21])=[C:15]3[N:14]=[C:13]2[CH2:22][CH2:23][CH3:24])=[CH:7][CH:6]=1)#[N:2].C[Sn]([N:35]=[N+:36]=[N-:37])(C)C>C1(C)C=CC=CC=1>[CH3:21][C:20]1[CH:19]=[CH:18][N:17]=[C:16]2[N:12]([CH2:11][C:8]3[CH:7]=[CH:6][C:5]([CH2:4][CH:3]([C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[C:1]4[NH:37][N:36]=[N:35][N:2]=4)=[CH:10][CH:9]=3)[C:13]([CH2:22][CH2:23][CH3:24])=[N:14][C:15]=12
Reactant: C[Sn](C)(C)N=[N+]=[N-]
Reactant: CCCc1nc2c(C)ccnc2n1Cc1ccc(CC(C#N)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: CCCc1nc2c(C)ccnc2n1Cc1ccc(CC(c2ccccc2)c2nnn[nH]2)cc1
Yield: 37.3 %

Procedure:
To a solution of the product of the product of Step E (46 mg, 0.12 mmol) in toluene (2 mL) was added 29 mg (0.14 mmol) of trimethylstannyl azide and the reaction mixture was refluxed for 24 hours. The reaction mixture was concentrated in vacuo. The residue was dissolved in THF and treated with 12N HCl (5 drops) for 5 minutes at room temperature. The mixture was concentrated in vacuo and purified on a silica gel flash chromatography column eluted with CHCl3 /MeOH/NH4OH (80:20:2) to afford 19.6 mg (38%) of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][OH:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH:14]1[CH2:19][CH2:18][CH:17]([C:20](=O)[CH3:21])[CH2:16][CH2:15]1.Cl>C(O)C>[CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]2[C:20]([CH:17]3[CH2:18][CH2:19][NH:14][CH2:15][CH2:16]3)([CH3:21])[O:13][CH2:12][CH2:11][C:5]=2[CH:4]=1
Reactant: CC(=O)C1CCNCC1
Reactant: COc1ccc(CCO)cc1OC
Agent: Cl
Solvent: CCO
Product: COc1cc2c(cc1OC)C(C)(C1CCNCC1)OCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 78.5 %

Procedure:
A mixture of 200 g of 3,4-dimethoxybenzeneethanol and 163.7 g of 1-(4-piperidinyl)ethanone in 800 ml of ethanol saturated with anhydrous hydrochloric acid was stirred for 15 h at ambient temperature. The mixture was concentrated under vacuum, and the concentrate was diluted with 500 ml of ethanol after which the hydrochloride precipitated. After filtration the hydrochloride was dissolved in water and sodium hydroxide until the pH was 12. The base was extracted with dichloromethane, and the organic phase was washed with water, dried and evaporated to yield 251 g (86.5%) of crude 4-(3,4-dihydro-6,7-dimethoxy-1-methyl-1H-2-benzopyran-1-yl)piperidine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([O-:11])=[O:10])=[CH:5][C:4]=1[N+:12]([O-:14])=[O:13].[Na+].Cl[CH2:17][C:18]1[CH:19]=[C:20]([O:28][CH3:29])[C:21]([O:26][CH3:27])=[C:22]([O:24][CH3:25])[CH:23]=1>CN(C=O)C>[CH3:25][O:24][C:22]1[CH:23]=[C:18]([CH2:17][S:9]([C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([N+:12]([O-:14])=[O:13])[CH:5]=2)(=[O:11])=[O:10])[CH:19]=[C:20]([O:28][CH3:29])[C:21]=1[O:26][CH3:27]
Reactant: COc1ccc(S(=O)[O-])cc1[N+](=O)[O-]
Reactant: COc1cc(CCl)cc(OC)c1OC
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(S(=O)(=O)Cc2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 120 °C

Procedure:
A suspension of Example 96A (380 mg, 1.6 mmol) in DMF (10 mL) was treated slowly with a solution of 5-(chloromethyl)-1,2,3-trimethoxybenzene (344 mg, 1.6 mmol) in DMF (5 mL), heated to 120° C. for hour, cooled to room temperature, and partitioned between ethyl acetate and brine. The aqueous layer was extracted with ethyl acetate, and the combined extracts were washed with water and brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 10% ethyl acetate/dichloromethane to provide the desired product.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([O:8][CH2:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH:12]C(=O)C(F)(F)F)=[O:7])[C@@H:3]([CH3:5])[OH:4].ClCC(O)=O.[N:27]([O-])=O.[Na+]>O>[N+:1](=[C:2]([C@H:3]([OH:4])[CH3:5])[C:6]([O:8][CH2:9][CH2:10][C@@H:11]([C:19]([OH:21])=[O:20])[NH2:12])=[O:7])=[N-:27]
Reactant: C[C@@H](O)[C@H](N)C(=O)OCC[C@H](NC(=O)C(F)(F)F)C(=O)O
Reactant: O=N[O-]
Agent: O=C(O)CCl
Agent: [Na+]
Solvent: O
Product: C[C@@H](O)C(=[N+]=[N-])C(=O)OCC[C@H](N)C(=O)O
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 4.8 %

Procedure:
To a solution of O-L-threonyl-N-trifluoroacetyl-L-homoserine (800 mg) and 4M aqueous chloroacetic acid (100 μl) in water (10 ml) was added sodium nitrite (345 mg) at room temperature. After stirring for 15 minutes at room temperature, the reaction mixture was neutrized with 2M tris buffer solution to pH 7.0 to 7.3 and then Acylase I (acylase, Sigma A-7264, made by Sigma Chemicals) (100 mg) was added. The mixture was stirred for 5 hours at 35° C. and chromatographed on carbon (50 ml) eluting successively with water and a 9:1 mixture of water and acetone to give O-[2-diazo-3(R)-hydroxy-1-oxobutyl]-L-homoserine (28 mg).
Reaction SMILES: [SH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Br[CH2:11][CH3:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:11]([S:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[CH3:12]
Reactant: N#Cc1ccc(S)cc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCSc1ccc(C#N)cc1
Temperature: 25 °C
Yield: 82.8 %

Procedure:
Combine 4-mercapto-benzonitrile (0.4 g, 2.96 mmol), bromoethane (1.4 mL, 8.88 mmol) and potassium carbonate (3.3 g, 23.7 mmol) in anhydrous DMF (7 mL) and heat at 60° C. for 17 h. Cool the reaction mixture to ambient temperature and partition between brine (20 mL) and EtOAc (20 mL). Separate the organic layer, dry over anhydrous Na2SO4 and concentrate. Purify by chromatography on silica gel eluting with hexane/EtOAc (1:0, 9:1 and 4:1) to obtain the desired intermediate as a colorless oil (0.4 g, 83%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:11]2([NH:15][C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:32]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:11]2([N:15]([CH3:32])[C:14](=[O:16])[N:13]([CH2:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[C:12]2=[O:26])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: COc1ccc(CN2C(=O)NC3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CN2C(=O)N(C)C3(CCN(C(=O)OC(C)(C)C)CC3)C2=O)cc1
Reaction time: 2 h
Yield: 100.1 %

Procedure:
390 mg (1 mmol) of 3-(4-methoxybenzyl)-2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylic acid tert-butyl ester were solubilized in 5 mL of DMF under nitrogen before adding 61 mg (1.5 mmol) of sodium hydride in mineral oil 60%. The reaction mixture was agitated for 5 minutes before the addition of 70 μL (1.1 mmol) of iodomethane. After 2 hours of agitation at room temperature, the reaction mixture was quenched with 20 mL of water and then extracted with diethyl ether (2×20 mL). The organic layers were dried over sodium sulfate, filtrated and evaporated in vacuo to give quantitatively 3-(4-methoxy-benzyl)-1-methyl-2,4-dioxo-1,3,8-triaza-spiro[4.5]decane-8-carboxylic acid tert-butyl ester (404 mg) as a yellowish oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10].[CH3:19][NH:20][CH3:21].C1COCC1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClC(Cl)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:12]2[CH2:17][CH2:16][CH:15]([N:20]([CH3:21])[CH3:19])[CH2:14][CH2:13]2)[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1cc(N2CCC(=O)CC2)ccc1[N+](=O)[O-]
Reactant: CNC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cc(N2CCC(N(C)C)CC2)ccc1[N+](=O)[O-]
Reaction time: 0.75 h
Yield: 91 %

Procedure:
1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-one (300 mg, 1.20 mmol) in dichloroethane (6 mL) was treated with 2 M Dimethylamine in THF (3 mL, 6 mmol) followed by sodium triacetoxyborohydride (420 mg, 2 mmol) at rt. After 16 h the mixture was treated with saturated aqueous NaHCO3, stirred 45 minutes. The layers were then separated, and the organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure to give 305 mg (91%) of desired [1-(3-Methoxy-4-nitro-phenyl)-piperidine-4-yl]dimethyl-amine, which was used without further manipulation. LC/MS (E/I+) 280.12 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:20]=O)[CH:17]=[N:18][CH:19]=1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:20][C:16]2[CH:17]=[N:18][CH:19]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: O=Cc1cncc(Br)c1
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCOC(=O)c1ccc(N=Cc2cncc(Br)c2)cc1
Temperature: 25 °C
Yield: 101.4 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (16.5 g, 100 mmol), 5-bromo-pyridine-3-carbaldehyde (18.6 g, 100 mmol) and p-toluenesulfonic acid (380 mg, 2 mmol) in toluene (200 mL) was heated to reflux for 12 h. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-[(5-bromo-pyridin-3-ylmethylene)-amino]-benzoic acid ethyl ester (33.8 g, quant.) as a light yellow solid: LC/MS m/e calcd for C15H13BrN2O2 (M+H)+: 334.19, observed: 332.9 & 335.0.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][C:2]1=O.[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH2:15]>C1(C)C=C(C)C=C(C)C=1>[OH:1][CH2:6][CH2:5][O:4][CH2:3][C:2]1[NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[N:15]=1
Reactant: O=C1COCCO1
Reactant: Nc1ccccc1N
Solvent: Cc1cc(C)cc(C)c1
Product: OCCOCc1nc2ccccc2[nH]1

Procedure:
Using a Dean-Stark separator, 1.4-dioxan-2-one (204 g, 20 mmol) and 1.2-diaminobenzene (2.16 g, 20 mmol) were heated under reflux in mesitylene (150 ml) for 10 h. The crystals formed on cooling were then filtered off with suction (2.94 g. 77% of theory). Rf (dichloromethane:methanol 10:1)=0.45, MS (EI)=192 (M+, 20%), 148 (20%), 147 (40%), 132 (100%), 1H-NMR (DMSO-d6): 3.6 (4H, s); 4.65 (1H, s); 4.7 (2H, s); 7.1-7.2 (2H, m); 7.45 (1H, d); 7.55 (1H, d); 12.4 (1H, br s).
Reaction SMILES: [Li]CCCC.C([Mg]Br)C.Br[C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[N:15]=[CH:14]2.CN([CH:24]=[O:25])C>C1(C)C=CC=CC=1.C1COCC1>[CH3:20][N:16]1[C:17]2[C:13](=[CH:12][C:11]([CH:24]=[O:25])=[CH:19][CH:18]=2)[CH:14]=[N:15]1
Reactant: Cn1ncc2cc(Br)ccc21
Reactant: CN(C)C=O
Agent: CC[Mg]Br
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1ncc2cc(C=O)ccc21
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 80.2 %

Procedure:
A suspension of n-BuLi (7.33 mL, 11.73 mmol) and ethylmagnesium bromide (5.76 mL, 5.76 mmol) in 30 mL toluene was stirred at −30° C. for 30 min, then 5-bromo-1-methyl-1H-indazole (2.25 g, 10.66 mmol) in 5 mL THF was added. After stirring at −10° C. for 1 hour, anhydrous DMF (4.95 mL, 64.0 mmol) was added at −10° C. The reaction was allowed to warm to room temperature and stirred for 2 hours. The reaction was quenched with 1N HCl and concentrated in vacuo. The residue was diluted with water, extracted with DCM twice. The organic layers were combined, dried over Na2SO4 and concentrated. The crude product was purified by flash chromatography (hexane:EtOAc=10:1) to give the title compound as a white solid (1.37 g, 76%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 10.02 (s, 1H), 8.41 (d, 1H), 8.31 (d, 1H), 7.86 (dd, 1H), 7.78 (d, 1H), 4.09 (s, 3H). LCMS (method A): [MH]+=161, tR=4.00 min.
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][C:24]([CH:27]=O)=[CH:23][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.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CS(C)=O.C(O)(=O)C>[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:22]=[CH:23][C:24]([CH2:27][N:32]5[CH2:37][CH2:36][O:35][CH2:34][CH2:33]5)=[CH:25][CH:26]=4)[CH:19]=3)[NH:14][CH:13]=2)[CH2:10][CH2:11]1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(C=O)cc4)cc23)CC1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CC(=O)O
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4ccc(CN5CCOCC5)cc4)cc23)CC1
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a solution of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-(4-formylphenyl)-1H-indole-7-carboxamide (50 mg, 0.114 mmol) in DMSO (3 mL) and acetic acid was added morpholine (30 μL, 0.342 mmol). After 2 h, sodium triacetoxyborohydride (290 mg, 1.36 mmol) was added. Reaction mixture was stirred overnight. Compound was purified by Gilson Preparatory HPLC to afford 40.3 mg of the title compound (70%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)[Cl:16]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 4-Fluoro-3-nitro-benzoic acid (1.00 g, 5.40 mmol) dissolved in 1,2-dichloroethane (30 mL) was added SOCl2 (6.42 g, 54.0 mmol). The reaction mixture was then heated to 80° C. for 16 hrs. At this time the reaction mixture was cooled to room temperature and the solvent removed under vacuum to provide the title product.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)[CH2:7][C@H:6]1[CH3:19])=[O:4].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH2:2][C:3]([N:5]2[CH2:10][CH2:9][N:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=3)[CH2:7][C@H:6]2[CH3:19])=[O:4])=[C:23]([N+:28]([O-:30])=[O:29])[CH:22]=1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)CCN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 94.8 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R)-2-methyl-piperazin-1-yl]-ethanone (0.40 g, 1.4 mmol) in 2-butanone (14 mL) was added 4-chloro-2-nitro-phenol (0.25 g, 1.4 mmol), potassium carbonate (0.39 g, 2.8 mmol) and potassium iodide (233 mg, 1.4 mmol). The reaction was refluxed overnight, cooled and concentrated in vacuo. Chromatography on silica gel gave the title compound (0.56 g).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([NH:14]C(=O)C)[CH:5]=[CH:6][C:7]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH:18]S(O)(=O)=O.N([O-])=O.[Na+].NC(N)=O>O>[NH2:14][C:4]1[CH:5]=[CH:6][C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[C:2]([OH:18])[CH:3]=1
Reactant: O=S(=O)(O)O
Reactant: CC(=O)Nc1ccc(C2CCCCC2)c(N)c1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: Nc1ccc(C2CCCCC2)c(O)c1
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 74.2 %

Procedure:
N-(3-amino-4-cyclohexyl-phenyl)acetamide (696 mg, 3.0 mmol) was added dropwise to a mixture of conc. H2SO4 (3 mL, 56.28 mmol) and H2O (17 mL). This reaction mixture was cooled to 0° C. and a solution of NaNO2 (229 mg, 3.32 mmol) in H2O (2 mL) was added. The reaction mixture was stirred for 5 minutes at 0° C. and then 1 g of urea was added, followed by the addition of 10 mL of 1:2 H2SO4:H2O. The reaction mixture was then refluxed for 1 hour, cooled to room temperature and extracted with EtOAc. The aqueous layer was basified with solid NaOH and extracted with EtOAc. The combined organic layer was washed with brine, dried over MgSO4, filtered and concentrated to obtain 5-amino-2-cyclohexylphenol (426 mg, 74%), which was used without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=O.[CH3:10][C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1.C(OC(=O)C)(=O)C>C(O)=O>[OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)/[CH:5]=[CH:10]/[C:11]1[S:12][C:13]2[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=2[N:15]=1
Reactant: Cc1nc2ccccc2s1
Reactant: O=Cc1cccc(O)c1
Solvent: CC(=O)OC(C)=O
Solvent: O=CO
Product: Oc1cccc(/C=C/c2nc3ccccc3s2)c1
Temperature: 120 °C
Yield: 39.7 %

Procedure:
A mixture of 25 g of 3-hydroxybenzaldehyde, 36.6 g of 2-methylbenzothiazole, 38.8 ml of acetic anhydride and 7.7 ml of formic acid was heated at 120° C. for 25 hours. The low boiling materials were evaporated together with toluene under reduced pressure, and the residue was added to 150 ml of methanol and refluxed with addition of 3 g of potassium carbonate for 1 hour. After cooled to room temperature, the mixture was filtered and filtrate was concentrated. The crude product formed was washed with methanol and ethyl ether and dried under reduced pressure to obtain 20.6 g (yield 40%) of the title compound.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)(=[O:16])=[O:15].N1C=CC=CC=1>C(Cl)Cl>[CH3:13][S:14]([N:17]1[CH2:22][CH2:21][N:20]([C:2]([Cl:1])=[O:4])[CH2:19][CH2:18]1)(=[O:16])=[O:15]
Reactant: CS(=O)(=O)N1CCNCC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Temperature: 25 °C
Yield: 159.4 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (1.81 g, 6.09 mmol) in CH2Cl2 (30 ml) at 0° C., was added a solution of 1-methanesulfonyl-piperazine (2.0 g, 12.2 mmol) and pyridine (1.08 ml, 13.4 mmol) in CH2Cl2 (5 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued over night. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc) yielded 2.20 g (79%) of the title compound as white solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)C(C)C)(C)C.Cl[C:18]([O:20][CH:21]([CH3:23])[CH3:22])=[O:19]>ClCCl>[CH:21]([O:20][C:18]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:19])([CH3:23])[CH3:22]
Reactant: CC(C)OC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 12.5 °C
Reaction time: 2 h
Yield: 83.2 %

Procedure:
A magnetically stirred solution of 4-hydroxypiperidine (70.3 g, 695 mmol) and N,N-diisopropylethylamine (105 mL, 600 mmol) in dichloromethane (1.0 L) was cooled to 10° C. under N2. A solution of isopropyl chloroformate (1.0 M in toluene, 580 mL, 580 mmol) was added dropwise over 2 h, maintaining a temperature of 10-15° C. The reaction mixture was stirred for an additional 2 h and then extracted with 1 N HCl (1.2 L). The organic extract was dried over MgSO4, and the solvent was removed under reduced pressure to give the title compound (90.3 g, 83%) as a pale, straw-colored oil. Exact Mass calculated for C9H17NO3: 187.1. Found: LCMS m/z=188.2 (M+H+), 210.3 (M+Na+); 1H NMR (400 MHz, CDCl3) δ 1.24 (d, J=6.3 Hz, 6H), 1.47 (m, 2H), 1.86 (m, 2H), 3.08 (m, 2H), 3.86 (m, 3H), 4.90 (m, 1H).