Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[C:12]([Cl:20])[CH:11]=1>N1C=CC=CC=1>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([NH:8][C:4]2[CH:5]=[N:6][CH:7]=[C:2]([Br:1])[CH:3]=2)(=[O:17])=[O:18])=[C:12]([Cl:20])[CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1Cl
Reactant: Nc1cncc(Br)c1
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cncc(Br)c1)c1ccc(Br)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 71.8 %

Procedure:
To a solution of 5-bromopyridin-3-amine (0.300 g, 1.73 mmol) in pyridine (8.67 ml) was slowly added 4-bromo-2-chlorobenzene-1-sulfonyl chloride (0.600 g, 2.08 mmol) at 0° C. The reaction mixture was stirred for 2 hours at room temperature. The reaction mixture was quenched with 1 N aq. HCl, and then extracted with DCM (2×50 mL). The combined organic layers were washed brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting residue was recrystallized from EtOAc-hexanes to give 4-bromo-N-(5-bromopyridin-3-yl)-2-chlorobenzenesulfonamide (0.530 g, 72%) as a red solid. 1H-NMR (CDCl3, Varian 400 MHz) δ 7.53-7.55 (1H, m), 7.71 (1H, d, J=1.6 Hz), 7.78 (1H, t, J=2.2 Hz), 7.89 (1H, d, J=8.4 Hz), 8.26 (1H, d, J=2.0 Hz). 8.44 (1H, d, J=2.4 Hz).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([O:9]C)=[C:4]([Cl:11])[N:3]=1.B(Br)(Br)Br>C(Cl)Cl.CO.O>[Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:11])[N:3]=1
Reactant: COc1c(Cl)nc(Cl)nc1Cl
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Solvent: CO
Product: Oc1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 68.4 %

Procedure:
Under an atmosphere of nitrogen a solution of 2,4,6-trichloro-5-methoxy-pyrimidine (4.0 g, 18.7 mmol) in DCM (200 mL) was cooled to 0° C. and treated with boron tribromide (6.6 mL, 65 mmol) dropwise. After stirring for 18 hours at RT the reaction mixture was cooled and diluted with methanol (25 mL, CARE, EXOTHERM!) and the reaction mixture diluted with water (200 mL). The aqueous layer was extracted with DCM and the combined organic extracts dried (Na2SO4) and concentrated in vacuo to give 2,4,6-Trichloro-5-hydroxy-pyrimidine as a pale tan solid (2.55 g, 71%). 13C NMR (DMSO-d6): 149.23 (C), 145.25 (C), 145.08 (C). LCMS (Method C): RT=2.65/2.77. [M−H]+ 197/199.
Reaction SMILES: C(O[C:6]([N:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH:29]4[CH2:30][CH2:31][N:26]([CH2:27][CH2:28]4)[CH2:25]3)=[CH:19][CH:18]=2)=[CH:12][CH:11]=1)N)=O)(C)(C)C.[C:32]1([C:38](=O)CC)[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.[CH3:43]CO>>[CH3:43][C:6]1[NH:8][C:10]2[C:11]([C:38]=1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[CH:12][C:13]([O:16][C:17]1[CH:22]=[CH:21][C:20]([O:23][CH:24]3[CH:29]4[CH2:28][CH2:27][N:26]([CH2:31][CH2:30]4)[CH2:25]3)=[CH:19][CH:18]=1)=[CH:14][CH:15]=2
Reactant: CCO
Reactant: CC(C)(C)OC(=O)N(N)c1ccc(Oc2ccc(OC3CN4CCC3CC4)cc2)cc1
Reactant: CCC(=O)c1ccccc1
Agent: Cl
Product: Cc1[nH]c2ccc(Oc3ccc(OC4CN5CCC4CC5)cc3)cc2c1-c1ccccc1

Procedure:
The product of Example 39A (105 mg, 0.25 mmol) was treated with 1-phenyl-propan-1-one (Aldrich, 67 mg, 0.5 mmol) and HCl (Aldrich, 4 M in dioxane, 0.5 mL, 2 mmol) in EtOH (3.0 mL) at 80° C. for 10 h. The mixture was concentrated and the title compound was was purified by preparative HPLC (Xterra™, column, Xterra RP-18 5 μm, 30×100 mm. Eluting Solvent, MeCN/H2O (NH4HCO3, 0.1 M, pH=10) (v. 40/60 to 70/30 over 20 min.) Flow rate, 75 mL/min., uv, 250 nm) as solid (60 mg, yield, 57%). 1H NMR (300 MHz, CD3OD) δ 1.45–1.80 (m, 4H), 2.09–2.19 (m, 1H), 2.37 (s, 3H), 2.62–2.97 (m, 4H), 3.19–3.44 (m, 1H), 4.34–4.53 (m, 1H), 6.81 (dd, J=8.6, 2.2 Hz, 1H), 6.85–7.04 (m, 4H), 7.09 (d, J=2.4 Hz, 1H), 7.27–7.38 (m, 2H), 7.46 (t, J=7.6 Hz, 2H), 7.63 (d, J=7.1 Hz, 2H) ppm; MS (DCl/NH3) m/z 425 (M+H)+.
Reaction SMILES: C[N:2]([CH3:6])[CH2:3][CH2:4][OH:5].[NH2:7]C1CC(C)(C)CC([CH2:17][NH2:18])(C)C1.NCCNCCN.[OH2:26]>>[NH2:7][C:6]([NH2:2])=[O:26].[NH2:18][C:17]([O:5][CH2:4][CH3:3])=[O:26]
Reactant: O
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Reactant: CN(C)CCO
Agent: NCCNCCN
Product: CCOC(N)=O
Product: NC(N)=O

Procedure:
One-thousand-two-hundred-sixty-eight parts of the prepolymer is charged to a reaction vessel and agitated. A mixture of 56 parts N,N-dimethylethanolamine and 1,385 parts water is then gradually added to the agitating prepolymer over a ten minute period, and the temperature is maintained between 30° to 33° C. Within one to two minutes after the completion of the addition of the N,N-dimethylethanolamine and water, a mixture of 20 parts 1-amino-3-aminomethyl-3,5,5-trimethylcyclohexane and 8 parts diethylenetriamine and 163 parts water is gradually added to the prepolymer dispersion over a four to five minute period, and the temperature is maintained between 33° to 36° C. to form a colloidally dispersed urea-urethane polymer. The acetone and methyl ethyl ketone are then distilled from the dispersion to yield a very stable, essentially organic solvent-free, aqueous colloidal polyurea-urethane ionomer dispersion with the following analysis: nonvolatile content of 32 percent by weight, pH of 9.1, and a viscosity of about 214 Stokes. The colloidal dispersion has an almost perfectly clear appearance and is infinitely dilutable with water. Films from this product can be cured under ambient conditions to yield very high gloss films, and optimum physical properties are attained when the films are cured at elevated temperatures. Twenty-five mil dry films cured at 70° C. overnight attain a Shore hardness of D 70 and exhibit an ultimate tensile strength of about 5,000 psi and elongation at break of about 360 percent. A 3 mil wet film attains its maximum physical properties when cured at 90° C. for less than one-half hour. The heat cured films have very good resistance to water spotting.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH2:11])[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.[F:19][C:20]([F:33])([F:32])[C:21]([N:23]1[CH2:28][CH2:27][CH:26]([C:29](Cl)=[O:30])[CH2:25][CH2:24]1)=[O:22]>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:9][CH2:10][NH:11][C:29]([CH:26]2[CH2:25][CH2:24][N:23]([C:21](=[O:22])[C:20]([F:33])([F:19])[F:32])[CH2:28][CH2:27]2)=[O:30])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C(Cl)C1CCN(C(=O)C(F)(F)F)CC1
Reactant: COc1cccc(CCN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cccc(CCNC(=O)C2CCN(C(=O)C(F)(F)F)CC2)c1
Temperature: 25 °C
Yield: 84.9 %

Procedure:
To a stirred solution of 3-methoxy phenylethylamine (9.3 g, 61.6 mmol) and triethylamine (8.1 g, 11.2 ml, 80.1 mmol) in CH2Cl2 (50 ml) at 0° C. under an atmosphere of N2 was added 1-trifluoroacetyl-piperidine-4-carbonyl chloride (15.0 g, 61.6 mmol) as a solution in CH2Cl2 (50 ml) in a dropwise manner. The reaction was allowed to warm to RT overnight. The reaction was quenched with water (50 ml), the layers were separated, and the organic layer was washed with water (1×50 ml). The combined aqueous layers were back extracted with CH2Cl2 (1×75 ml). The combined organic layers were washed with brine (1×75 ml). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The resulting solid was triturated with Et2O and filtered to give the desired product (18.8 g, 52.3 mmol, 85% yield).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][SH:6])C.[Cl:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[Cl:10][C:11]1[CH:16]=[CH:4][C:5]2[S:6][CH:15]=[CH:14][C:13]=2[CH:12]=1
Reactant: Clc1ccccc1
Reactant: CCOC(CS)OCC
Product: Clc1ccc2sccc2c1
Temperature: 0 °C
Yield: 90 %

Procedure:
In a 250 mL 2-neck round flask, 4-chlorophenyl) (2,2-diethoxyethyl)sulfane (5 g, 19 mmol) and chlorobenzene (4 mL) were poured, and then the reaction mixture was added to a polyacrylic acid (PAA) reaction solution (5 g) obtained after boiling in chlorobenzen (5 mL). After the reaction, ice water (25 mL) was added to the mixture, and the mixture was washed with brine (50 mL) and dried over Na2SO4. The mixture was subjected to column chromatography using petroleum ether to give 2.9 g of white solid (90% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8](F)[CH:9]=1)[C:5]#[N:6].[F:11][C:12]([F:16])([F:15])[CH2:13][OH:14].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:14][CH2:13][C:12]([F:16])([F:15])[F:11])[CH:9]=1)[C:5]#[N:6]
Reactant: OCC(F)(F)F
Reactant: N#Cc1cc(F)cc(Br)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Product: N#Cc1cc(Br)cc(OCC(F)(F)F)c1
Yield: 77 %

Procedure:
In analogy to the procedure described in WO2007060448, the reaction of 3-bromo-5-fluorobenzonitrile with 2,2,2-trifluoro-ethanol using sodium bis(trimethylsilyl)amide as the base yielded the title compound as a white solid (yield: 77% of theory).
Reaction SMILES: [ClH:1].Cl.C1(C[N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][N:17]3[CH2:25][C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[CH2:18]3)[CH2:12][CH2:11]2)C=CC=CC=1.C(O)C.C>O>[ClH:1].[ClH:1].[NH:10]1[CH2:11][CH2:12][CH:13]([CH2:16][N:17]2[CH2:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH2:18]2)[CH2:14][CH2:15]1
Reactant: c1ccc(CN2CCC(CN3Cc4ccccc4C3)CC2)cc1
Agent: Cl
Solvent: CCO
Solvent: O
Product: c1ccc2c(c1)CN(CC1CCNCC1)C2
Reaction time: 9 h

Procedure:
56.6 g (149 mmol) of 2-{[1-(phenylmethyl)-4-piperidyl]methyl}-2,3-dihydro-1H-isoindole dihydrochloride, 300 ml of ethanol, 50 ml of water and 5 g of palladinized charcoal (10% palladium) are introduced into a Parr apparatus and a hydrogenolysis is performed under approximately 0.41 MPa for 9 h.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:13][CH2:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[C:2]1C(O)=O.[O:17]1[C:29]2[C:21]([CH2:22][C:23]3[CH2:24][CH2:25][NH:26][C:27]=3[CH:28]=2)=[CH:20][CH:19]=[C:18]1C(O)=O.O1C2C3C=CNC=3CCC=2C=CC1C(O)=O>>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[O:13][CH2:12][CH2:11][CH2:10][C:8]3=2)[CH:3]=[CH:2]1.[O:17]1[C:29]2[C:28]3[CH:24]=[CH:25][NH:26][C:27]=3[CH2:23][CH2:22][C:21]=2[CH:20]=[CH:19][CH2:18]1
Reactant: O=C(O)c1cc2ccc3c(c2[nH]1)CCCO3
Reactant: O=C(O)C1=CC=C2CC3=C(C=C2O1)NCC3
Agent: O=C(O)C1C=CC2=C(O1)c1cc[nH]c1CC2
Product: C1=CC2=C(OC1)c1cc[nH]c1CC2
Product: c1cc2ccc3c(c2[nH]1)CCCO3

Procedure:
7,8-Dihydro-9H-pyrano[2,3-g]indole, 6,7-dihydro-5H-pyrano[3,2-g]indole and 5,6-dihydro-7H-pyrano[2,3-e]indole were prepared according to the procedure described in Example 3, using a mixture [(2,3-g):(3,2-f):(2,3-e)—11:1:4] of 7,8-dihydro-9H-pyrano[2,3-g]indole-2-carboxylic acid, 6,7-dihydro-5H-pyrano[3,2-f]indole-2-carboxylic acid and 5,6-dihydro-7H-pyrano[2,3-e]indole-2-carboxylic acid (3.12 g, 14.4 mmol) to produce, after flash column chromatography (and without further separation on a second column) a mixture [(2,3-g):(2,3-e)—72:28] of products (2.01 g, 80%) as a white, crystalline solid [Rf 0.46 (SiO2; dichloromethane)] which was used without further purification. Also collected was 6,7-dihydro-5H-pyrano[3,2-f] indole (250 mg, 10%) as an off-white solid [Rf 0.33 (SiO2; dichloromethane)].
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[C:9]([C:11]([N:13]3[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]3)=[O:12])[S:10][C:3]=12.[CH:19]1([NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([OH:34])=[CH:31][CH:32]=3)[N:27]([CH3:35])[C:26]=2[CH3:36])=[O:24])[CH2:21][CH2:20]1.C([O-])([O-])=O.[Cs+].[Cs+]>>[CH:19]1([NH:22][C:23]([C:25]2[C:33]3[C:28](=[CH:29][C:30]([O:34][C:2]4[CH:7]=[CH:6][N:5]=[C:4]5[CH:8]=[C:9]([C:11]([N:13]6[CH2:17][CH2:16][C@@H:15]([OH:18])[CH2:14]6)=[O:12])[S:10][C:3]=45)=[CH:31][CH:32]=3)[N:27]([CH3:35])[C:26]=2[CH3:36])=[O:24])[CH2:20][CH2:21]1
Reactant: Cc1c(C(=O)NC2CC2)c2ccc(O)cc2n1C
Reactant: O=C(c1cc2nccc(Cl)c2s1)N1CC[C@@H](O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: Cc1c(C(=O)NC2CC2)c2ccc(Oc3ccnc4cc(C(=O)N5CC[C@@H](O)C5)sc34)cc2n1C

Procedure:
This material was prepared by the reaction of (7-chloro-thieno [3,2-b]pyridin-2-yl)-((R)-3-hydroxy-pyrrolidin-1-yl)-methanone 4a with 6-hydroxy-1,2-dimethyl-1H-indole-3-carboxylic acid cyclopropylamide 20b and Cs2CO3 in a manner as previously described for example 1. 1H NMR (300 MHz, CD3OD) δ8.50 (1H, d, J=5.5 Hz), 7.93 (1H, d, J=17.33 Hz), 7.80 (1H, d, J=8.6 Hz), 7.39 (1H, d, J=2.1 Hz), 7.05 (1H, dd, J=2.1, 8.6 Hz), 6.71 (1H, d, J=5.5 Hz), 4.54 (1H, bs), 4.11-4.00 (2H, m), 3.85-3.72 (6H, m), 2.93-2.86 (1H, m), 2.66 (3H, s), 2.19-2.07 (2H, m), 0.90-0.84 (2H, m), 0.76-0.68 (2H, m). LCMS (ESI+) [M+H]/z Calc'd 491, found 491.
Reaction SMILES: [CH3:1][N:2]1[C@@H:11]2[CH2:12][C:13]3[C:18]([C:9]4=[C:10]2[C:5](=[CH:6][C:7]([O:25][CH3:26])=[C:8]4[O:23][CH3:24])[CH2:4][CH2:3]1)=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3.[I-:27].[K+]>Cl>[CH3:1][N:2]1[C@H:11]2[CH2:12][C:13]3[C:18](=[CH:17][C:16]([O:19][CH3:20])=[C:15]([O:21][CH3:22])[CH:14]=3)[C:9]3[C:10]2=[C:5]([CH:6]=[C:7]([O:25][CH3:26])[C:8]=3[O:23][CH3:24])[CH2:4][CH2:3]1.[IH:27]
Reactant: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1[C@@H](C2)N(C)CC3
Reactant: [I-]
Agent: Cl
Agent: [K+]
Product: COc1cc2c(cc1OC)-c1c(OC)c(OC)cc3c1[C@H](C2)N(C)CC3
Product: I

Procedure:
For making l-glaucine hydroiodide, a quantity of l-glaucine was dissolved in 2 n hydrochloric acid and the solution reacted with saturated potassium iodide solution. The resulting crystalline precipitate was recrystallized from a mixture of methyl alcohol and ether. This gave a crystalline, yellowish glaucine hydroiodide with a melting point of 238° C.
Reaction SMILES: [CH:1]1([C:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.[NH4+].C([BH3-])#[N:31].[Na+]>CO>[CH:1]1([CH:7]([C:9]2[CH:10]=[N:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)=[N:13][CH:14]=2)[NH2:31])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC(c1cnc(-c2ccc(C(F)(F)F)cc2)nc1)C1CCCCC1
Reaction time: 0.5 h

Procedure:
To a solution of crude cyclohexyl{2-[4-(trifluoromethyl)phenyl]pyrimidin-5-yl}methanone (505 mg, 1.51 mmol), and ammonium acetate (1.19 g, 15.1 mmol) in methanol (7.6 ml) was added sodium cyanoborohydride (0.150 g, 2.26 mmol). The flask was fitted with a reflux condenser and heated to reflux for 12 hours. The reaction was concentrated in vacuo, then diluted with dichloromethane and aqueous 1.0M sodium hydroxide. The mixture was stirred for 30 minutes, whereupon the aqueous layer was extracted with dichloromethane (3×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The crude material was diluted in dichloromethane, passed through a plug of SiO2 with 20% methanol in dichloromethane and was concentrated in vacuo. The crude product was used without further purification.
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][C:13](=[O:20])OCC(Cl)(Cl)Cl)=[CH:8][CH:7]=1)(=[O:4])[CH2:2][CH3:3].[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(C(C)C)CC)(C)C.CS(C)=O>O>[C:21]1([C:27]2[N:28]=[C:29]([N:32]3[CH2:37][CH2:36][N:35]([C:13]([NH:12][C:9]4[CH:8]=[CH:7][C:6]([NH:5][C:1](=[O:4])[CH2:2][CH3:3])=[CH:11][CH:10]=4)=[O:20])[CH2:34][CH2:33]3)[S:30][CH:31]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: c1ccc(-c2csc(N3CCNCC3)n2)cc1
Reactant: CCC(=O)Nc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: CCC(=O)Nc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)cs3)CC2)cc1
Yield: 44 %

Procedure:
A solution of 2,2,2-trichloroethyl [4-(propionylamino)phenyl]carbamate (200 mg, 0.589 mmol), 1-(4-phenyl-1,3-thiazol-2-yl)piperazine (145 mg, 0.589 mmol), diisopropylethylamine (0.206 ml, 1.18 mmol) and dimethyl sulfoxide (4 ml) was stirred at 70° C. for 24 hours, and the reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was recrystallized from ethyl acetate to give 113 mg (44.0%) of the desired product as a solid.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([C:14]([O:16]C)=[O:15])=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)C>[CH3:1][C:2]1[C:10]2[N:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:6]=2[C:5]([C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c2c1ccn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1ccc(C(=O)O)c2ccn(C(C)C)c12
Yield: 80.9 %

Procedure:
To a solution of methyl 7-methyl-1-(1-methylethyl)-1H-indole-4-carboxylate (137 mg, 0.592 mmol) in ethanol (30 mL) was added 1 N sodium hydroxide (2.369 mL, 2.369 mmol). The mixture was heated at reflux for 2 h, at which time it was concentrated. The residue was dissolved in water (20 mL) and acidified by addition of 1 N HCl. The mixture was extracted with DCM (4×30 mL) and the combined extracts and washed with water and brine, dried over MgSO4, filtered and concentrated to give 104 mg of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.55 (d, 6H), 2.82 (s, 3H), 5.11-5.28 (m, 1H), 7.00 (d, J=7.83 Hz, 1H), 7.31 (d, J=3.54 Hz, 1H), 7.44 (d, J=3.28 Hz, 1H), 7.89 (d, J=7.58 Hz, 1H). MS(ES) [M+H]+218.3.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][OH:8].[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>C(Cl)Cl.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:10])([CH3:9])[CH2:7][O:8][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][O:11]1
Reactant: CC(C)(CO)CCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: ClCCl
Product: CC(C)(CCCCBr)COC1CCCCO1
Yield: 82.6 %

Procedure:
According to the procedure for the preparation of 207d, (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818) 206c (521.0 g, 2.49 mol) was reacted with 3,4-dihydro-2H-pyran (278.0 g, 3.30 mol) and p-toluenesulfonic acid hydrate (3.13 g, 16 mmol) in CH2Cl2 (2.2 L) to yield 207c (603.0 g, 83%) as a pale-yellow oil, which was used without further purification. 1H NMR (CDCl3): δ 4.55 (t, 1H, J=3.3), 3.84 (m, 1H), 3.50 (m, 1H), 3.47 (d, 1 H , J=9.0), 3.42 (t, 2H, J=6.7), 2.99 (d, 1H, J=9.0), 1.88 (m, 2H), 1.75-1.33 (m, 10H), 0.91 (s, 3H), 0.90 (s, 3H). 13C NMR (CDCl3): δ 99.37, 76.58, 62.17, 38.56, 34.43, 34.19, 33.90, 30.88, 25.79, 24.80, 24.71, 22.89, 19.67. HRMS (LSIMS, nba): Calcd for C13H25BrO2 (MH+): 293.1116, found: 293.1128.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](O)=[N:5][C:6]([S:9][CH3:10])=[N:7][CH:8]=1.P(Cl)(Cl)([Cl:14])=O.C(N(CC)C1C=CC=CC=1)C>C(#N)C>[Cl:14][C:4]1[C:3]([O:2][CH3:1])=[CH:8][N:7]=[C:6]([S:9][CH3:10])[N:5]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1cnc(SC)nc1O
Solvent: CC#N
Solvent: CCN(CC)c1ccccc1
Product: COc1cnc(SC)nc1Cl

Procedure:
5-Methoxy-2-methylsulfanyl-pyrimidin-4-ol (250 mg) is dissolved in acetonitrile (7 ml) and thereto are added phosphorus oxychloride (0.7 ml) and N,N-diethyl aniline (460 μl) and the mixture is heated under reflux for 5.5 hours. The reaction solution is evaporated azeotropically with toluene three times, and to the residue are added aqueous citric acid solution and chloroform, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=19:1→17:3) to give 4-chloro-5-methoxy-2-methylsulfanyl-pyrimidine (260 mg). MS (m/z): 191/193 [M+H]+
Reaction SMILES: [Si]([O:8][CH:9]([CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:37])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])(C(C)(C)C)(C)C>CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1.O>[OH:8][CH:9]([CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:20]/[CH:21]=[CH:22]\[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[O:18])[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39]/[CH:40]=[CH:41]\[CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH3:47])=[O:37]
Reactant: CCCCCC/C=C\COC(=O)CCCCCCCC(CCCCCCCC(=O)OC/C=C\CCCCCC)O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: CCCCCC/C=C\COC(=O)CCCCCCCC(O)CCCCCCCC(=O)OC/C=C\CCCCCC
Reaction time: 48 h
Yield: 39 %

Procedure:
The silyl protected diester 8 (0.3 g, 0.44 mmol) was dissolved in 1 M solution of TBAF in THF (6 mL) and the solution was kept at 40° C. for two days. The reaction mixture was diluted with water (60 mL) and extracted with ether (2×50 mL). The combined organic layers were concentrated and the thus obtained crude product was purified by column to isolate the pure product (0.097 g, 39%). 1H NMR (400 MHz, CDCl3) δ 5.64 (dt, J=10.9, 7.4 Hz, 2H), 5.52 (dt, J=11.0, 6.8 Hz, 2H), 4.61 (d, J=6.8 Hz, 4H), 3.57 (s, 1H), 2.30 (t, J=7.5 Hz, 4H), 2.09 (q, J=7.1 Hz, 4H), 1.75-1.53 (m, 4H), 1.53-1.06 (m, 36H), 0.88 (t, J=6.8 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 173.98, 135.64, 123.57, 77.54, 77.22, 76.91, 72.14, 60.41, 37.69, 34.54, 31.89, 29.70, 29.60, 29.44, 29.29, 29.07, 27.76, 25.80, 25.15, 22.82, 14.29.
Reaction SMILES: F[C:2]1[C:7](S(C)(=O)=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][CH2:19][CH3:20])[CH2:14][CH2:13]1.[C-:21]#[N:22].[Na+].C1OCCOCCOCCOCCOCCOC1.C(=O)([O-])[O-].[Na+].[Na+].C[N:49]([CH3:52])C=O>>[CH2:18]([N:15]1[CH2:16][CH2:17][CH:12]([C:3]2[CH:4]=[CH:5][CH:6]=[C:7]([C:21]#[N:22])[C:2]=2[C:52]#[N:49])[CH2:13][CH2:14]1)[CH2:19][CH3:20]
Reactant: CN(C)C=O
Reactant: [C-]#N
Reactant: CCCN1CCC(c2cccc(S(C)(=O)=O)c2F)CC1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CCCN1CCC(c2cccc(C#N)c2C#N)CC1

Procedure:
To a solution of 4-[2-fluoro-3-(methylsulfonyl)phenyl]-1-propylpiperidine (0.2 g, 0.67 mmol) in N,N-dimethylformamide (30 ml) was added sodium cyanide (0.82 g, 1.67 mmol) and 18-crown-6-ether (5 mg). The mixture was heated at reflux for 15 h and then brought to ambient temperature. Aqueous sodium carbonate (10%, 50 ml) was added and the phases were separated. The aqueous phase was extracted with ethylacetate (2×50 ml) and the combined organic phases was dried (MgSO4) and evaporated under reduced pressure to give an oil. Purification by flash column chromatography (ethylacetate/methanol, 1:1) gave the title compound: 0.07 g (41%). MS m/z (relative intensity, 70 eV) 253 (M+, 3), 225 (17), 224 (bp), 154 (6), 70 (12).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[C:9]([O:11][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:7]([O:12][CH2:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:6]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)Cc1cc(O)cc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)Cc1cc(OCc2ccccc2)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 177.3 %

Procedure:
A mixture of (3,5-dihydroxy-phenyl)-acetic acid methyl ester (from Aldrich, 70 g, 0.385 mol), benzylbromide (137 mL, 1.16 mol), potassium carbonate (160 g, 1.16 mol) and DMF (1.5 L) under N2 was mechanically stirred at room temperature overnight. The resulting reaction mixture was poured into a mixture of 1.5 L of ice-water with stirring. The precipitate was obtained by filtration and washed with heptane successively to remove benzyl bromide to give the title compounds (123.7 g) as a brown solid which was air dried for the next reaction. 1H-NMR(CDCl3): δ 3.60 (s, 2H), 3.71(s,3H), 5.05 (s, 4H), 6.60 (s, 3H), 7.35-7.50 (m, 10H); Calcd for C23H22O4 (M+H) 363.15, Found 363.