Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[C:9](Cl)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([O:14]CC)=[O:13])([O-:3])=[O:2].[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C(=O)([O-])[O-].[K+].[K+]>>[N+:1]([C:4]1[C:9]([O:24][C:21]2[CH:22]=[CH:23][C:18]([Cl:17])=[CH:19][CH:20]=2)=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11][C:12]([OH:14])=[O:13])([O-:3])=[O:2]
Reactant: Oc1ccc(Cl)cc1
Reactant: CCOC(=O)Cc1cccc(Cl)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Product: O=C(O)Cc1cccc(Oc2ccc(Cl)cc2)c1[N+](=O)[O-]
Yield: 54.6 %

Procedure:
A mixture of ethyl 2-(2-nitro-3-chlorophenyl)acetate (10 g.), 4-chlorophenol (7.8 g.), anhydrous potassium carbonate (8.5 g.) and cupric oxide (3 g.) was treated in a similar manner to the above Preparations to give 2-[2-nitro-3-(4-chlorophenoxy)phenyl]acetic acid (6.9 g.). mp 167° to 170° C.
Reaction SMILES: [OH:1][N:2]=[C:3]([C:5]1[CH:13]=[CH:12][C:8]2NC=N[C:7]=2[CH:6]=1)[NH2:4].C(C1C=C2C([CH2:20][CH2:21][N:22]([CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23]2)=CC=1)#N>>[NH2:4][C:3](=[N:2][OH:1])[C:5]1[CH:6]=[C:7]2[C:8]([CH2:20][CH2:21][N:22]([CH2:26][C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[CH2:23]2)=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)CN1CCc2ccc(C#N)cc2C1
Reactant: NC(=NO)c1ccc2[nH]cnc2c1
Product: CC(C)(C)OC(=O)CN1CCc2ccc(C(N)=NO)cc2C1

Procedure:
The title compound was prepared following procedure described for Intermediate 1, step 2, but starting from tert-butyl (7-cyano-3,4-dihydroisoquinolin-2(1H)-yl)acetate obtained in step 1 (3.32 g; 12.19 mmol) as a pale yellow powder (3.69 g; 99%). 1H NMR (DMSO-d6) δ 9.50 (s, 1H), 7.43-7.40 (m, 1H), 7.33 (m, 1H), 7.08 (d, J=8 Hz, 1H), 5.71 (bs, 2H), 3.68 (s, 2H), 3.30 (s, 2H), 2.78 (s, 4H), 1.43 (s, 9H). HPLC (Method A), Rt 1.82 min (Purity: 91.1%). LC/MS (Method B): 306.2 (M+H)+.
Reaction SMILES: [OH:1][CH:2]1[CH2:5][O:4][CH2:3]1.[H-].[Na+].[H][H].[Br:10][C:11]1[C:12](Cl)=[N:13][C:14]([Cl:20])=[N:15][C:16]=1[CH2:17][O:18][CH3:19]>C1COCC1>[Br:10][C:11]1[C:16]([CH2:17][O:18][CH3:19])=[N:15][C:14]([Cl:20])=[N:13][C:12]=1[O:1][CH:2]1[CH2:5][O:4][CH2:3]1
Reactant: OC1COC1
Reactant: COCc1nc(Cl)nc(Cl)c1Br
Reactant: [H][H]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCc1nc(Cl)nc(OC2COC2)c1Br
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71.9 %

Procedure:
To a solution of 3-hydroxyoxetane (76 mg, 1.02 mmol) in anhydrous THF (8 mL) at r.t. was added NaH (60% in mineral oil, 39 mg, 0.97 mmol). The mixture was stirred at r.t. for 5 min until there was no hydrogen bubbles generated. 5-bromo-2,4-dichloro-6-(methoxymethyl)pyrimidine (3) (250 mg, 0.93 mmol) was added and the resulting reaction mixture was stirred at r.t. overnight. The reaction was quenched with aqueous NH4Cl and extracted with EtOAc. The organic layer was separated, washed with aqueous NaHCO3, dried (Na2SO4) and concentrated in vacuo. The residue was purified using ISCO chromatography (24 g silica gel, 0-20% EtOAc in hexanes in 40 min) to give the title compound (207 mg, 73%) as a white solid. 1H NMR (DMSO, 500 MHz) δ 5.57-5.52 (m, 1H), 4.91-4.86 (m, 2H), 4.68 (s, 2H), 4.61-4.57 (m, 2H), 3.98 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH3:14])=[N:11]2)=[CH:6][C:5]=1[F:15])[CH3:2].[Se](=O)=[O:17].C(Cl)Cl.[O-]S([O-])(=O)=O.[Mg+2]>O1CCOCC1.O>[CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][C:10]([CH:14]=[O:17])=[N:11]2)=[CH:6][C:5]=1[F:15])[CH3:2]
Reactant: O=[Se]=O
Reactant: CCOc1cc2nc(C)ccc2cc1F
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Solvent: ClCCl
Solvent: C1COCCO1
Product: CCOc1cc2nc(C=O)ccc2cc1F

Procedure:
To 7-ethoxy-6-fluoro-2-methylquinoline (180 mg, 0.877 mmol) in dioxane/water (5 mL/0.05 mL) was added selenium dioxide (136 mg, 1.23 mmol) and the reaction was heated to reflux for 2 hours. After cooling, DCM was added followed by MgSO4. After concentration, the residue was used in the next step without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[NH:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.I[CH3:24].C>CN(C)C=O.C(O)C.C(OCC)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:17](=[O:18])[C:16]3[C@@H:15]4[C:19]([CH3:21])([CH3:20])[C@@:12]([CH3:22])([CH2:13][CH2:14]4)[C:11]=3[N:10]2[CH3:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CI
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)c1[nH]n(-c3cc(Cl)cc(Cl)c3)c(=O)c12
Solvent: CN(C)C=O
Solvent: CCO
Solvent: CCOCC
Product: Cn1c2c(c(=O)n1-c1cc(Cl)cc(Cl)c1)[C@H]1CC[C@]2(C)C1(C)C
Temperature: 95 °C
Reaction time: 8 h
Yield: 18.8 %

Procedure:
A mixture of (4S,7R)-2-(3,5-dichloro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 45; 200 mg, 0.59 mmol) and iodomethane (180 μL, 2.9 mmol) in dimethylformamide (3 mL) was heated at 95° C. for 7 h and then stirred overnight at room temperature. The solvent was evaporated, dichloromethane (50 mL) was added and the solution was washed with water (3×25 mL), saturated aqueous sodium thiosulfate (25 mL), and brine (25 mL). The solution was dried (magnesium sulfate), filtered, evaporated, and purified by column chromatography, eluting with 20% ethyl acetate/petroleum ether, and dried under high vacuum overnight to give a pale orange solid. This was dissolved in ethanol and the solution was treated with charcoal, then filtered through Celite (washing the Celite well with ethanol) and evaporated to give a brown solid. The brown solid was dissolved in ethyl ether and the solution was cooled in a freezer for 1 h. The solid was filtered off and washed with ether to give (4S,7R)-2-(3,5-dichloro-phenyl)-1,7,8,8-tetramethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (39 mg, 19%). ES(+)-MS (M+H) 351.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][C:7]([CH2:11][C:12]3[N:16]4[N:17]=[C:18]([C:21](=O)[CH3:22])[CH:19]=[CH:20][C:15]4=[N:14][N:13]=3)=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[CH3:24][N:25]([C:27]([NH2:29])=[O:28])[NH2:26].N1C2C(=CC(CC3N4N=C(/C(=N/NC(N)=O)/C)C=CC4=NN=3)=CC=2)C=CC=1>>[CH3:24][N:25]([C:27]([NH2:29])=[O:28])/[N:26]=[C:21](/[C:18]1[CH:19]=[CH:20][C:15]2[N:16]([C:12]([CH2:11][C:7]3[CH:6]=[C:5]4[C:10](=[CH:9][CH:8]=3)[N:1]=[CH:2][CH:3]=[CH:4]4)=[N:13][N:14]=2)[N:17]=1)\[CH3:22]
Reactant: CC(=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Reactant: CN(N)C(N)=O
Agent: C/C(=N\NC(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Product: C/C(=N\N(C)C(N)=O)c1ccc2nnc(Cc3ccc4ncccc4c3)n2n1
Yield: 54.6 %

Procedure:
The title compound (27 mg, 55%) was synthesized from 1-(3-(quinolin-6-ylmethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)ethanone (40 mg, 0.132 mmol) and 1-methylhydrazine-carboxamide (23.5 mg, 0.264 mmol) using the same procedure as described in the synthesis of 37. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.06 (d, 1H), 8.73 (d, 1H), 8.17 (m, 4H), 8.00 (d, 1H), 7.79 (m, 1H), 6.69 (s, 2H), 4.82 (s, 2H), 3.27 (s, 3H), 2.32 (s, 3H). LCMS (method A): [MH]+=375.0, tR=3.79 min.
Reaction SMILES: [C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14](Cl)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[NH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[C:1]12([NH:11][C:12]3[N:17]=[C:16]([NH:18][C:19]45[CH2:28][CH:23]6[CH2:24][CH:25]([CH2:27][CH:21]([CH2:22]6)[CH2:20]4)[CH2:26]5)[CH:15]=[C:14]([N:30]4[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[N:13]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2
Reactant: C1CNCCN1
Reactant: Clc1cc(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)n1
Product: c1c(NC23CC4CC(CC(C4)C2)C3)nc(NC23CC4CC(CC(C4)C2)C3)nc1N1CCNCC1
Yield: 83.36 %

Procedure:
The reaction of 2,4-bis(1-adamantylamino)-6-chloropyrimidine with piperazine as described in Example 4 gives the title compound in a yield of 83.36%, m.p.: 168°-175° C.
Reaction SMILES: [F:1][C:2]([Si](C)(C)C)([F:4])[F:3].O.O.O.[F-].C([N+:17]([CH2:26][CH2:27][CH2:28][CH3:29])([CH2:22][CH2:23]CC)CCCC)CCC.Cl.C(=O)(O)[O-:32].[Na+]>O1CCCC1>[F:1][C:2]([F:4])([F:3])[CH:29]([C:28]1[CH:23]=[CH:22][N:17]=[CH:26][CH:27]=1)[OH:32]
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: O=C([O-])O
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: OC(c1ccncc1)C(F)(F)F
Reaction time: 1 h

Procedure:
To 60 ml of tetrahydrofuran were added 4.98 ml of trifluoromethyltrimethylsilane and 3 g of isonicotinealdehyde, and 0.09 g of tetrabutylammonium fluoride trihydrate was added at 0° C., and the mixture was stirred for 1 hour. Thereafter, 10% hydrochloric acid was added at 0° C., and the mixture was stirred for 3 hours, and poured into an aqueous saturated sodium bicarbonate solution. After extraction with ethyl acetate three times, the organic layers were combined, washed with an aqueous saturated sodium chloride solution, dried with anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 4.7 g of 2,2,2-trifluoro-1-pyridin-4-yl-ethanol.
Reaction SMILES: C([O:5][C:6](=[O:29])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([CH:18]2[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[S:20](=[O:28])(=[O:27])[NH:19]2)=[CH:9]1)(C)(C)C.Br[CH:31]([CH3:34])[C:32]#[N:33]>>[C:32]([CH:31]([CH3:34])[N:19]1[CH:18]([C:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([CH3:17])[CH:12]=3)[N:8]([CH2:7][C:6]([OH:5])=[O:29])[CH:9]=2)[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[S:20]1(=[O:28])=[O:27])#[N:33]
Reactant: CC(Br)C#N
Reactant: Cc1ccc2c(c1)c(C1NS(=O)(=O)c3ccccc31)cn2CC(=O)OC(C)(C)C
Product: Cc1ccc2c(c1)c(C1c3ccccc3S(=O)(=O)N1C(C)C#N)cn2CC(=O)O

Procedure:
The title compound was prepared by the method described for example 14 using the product from example 2, step c) and 2-bromo-propionitrile. MS: ESI (negative): 408 (M−H).
Reaction SMILES: O1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2]1.[SH:27][CH2:28][CH2:29][OH:30].B(F)(F)F>>[O:30]1[C:3]2([CH2:8][CH2:7][N:6]([C:9]3[CH:14]=[CH:13][C:12]([N:15]4[CH2:19][C@H:18]([CH2:20][NH:21][C:22](=[O:24])[CH3:23])[O:17][C:16]4=[O:25])=[CH:11][C:10]=3[F:26])[CH2:5][CH2:4]2)[CH2:2][S:27][CH2:28][CH2:29]1
Reactant: OCCS
Reactant: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CO4)c(F)c2)C(=O)O1
Agent: FB(F)F
Product: CC(=O)NC[C@H]1CN(c2ccc(N3CCC4(CC3)CSCCO4)c(F)c2)C(=O)O1

Procedure:
The title compound was prepared by reacting (S)-N-{3-[4-(1-oxa-6-aza-spiro[2.5]oct-6-yl)-3-fluorophenyl]-2-oxo-oxazolidin-5-ylmethyl}-acetamide (1.0 mmol) with 2-mercaptoethanol (1.2 mmol), BF3.etherate (catalytic) in tetrahydrofuran (10 ml) at 70-80° C. for 14 hours followed by silica gel column chromatographic purification to provide title compound in 52% yield.
Reaction SMILES: [N+:1]([C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9](=[O:22])[C:10](=[CH:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:6]=2[CH:5]=1)([O-])=O.O.NN>[Ni].C(O)C>[NH2:1][C:4]1[CH:24]=[CH:23][C:7]2[NH:8][C:9](=[O:22])[C:10](=[CH:12][C:13]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[NH:15][CH:14]=3)[S:11][C:6]=2[CH:5]=1
Reactant: O=C1Nc2ccc([N+](=O)[O-])cc2SC1=Cc1c[nH]c2ccccc12
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(c1)SC(=Cc1c[nH]c3ccccc13)C(=O)N2
Yield: 47.7 %

Procedure:
A catalytic amount of Raney nickel was added portionwise with stirring to a mixture of 7-nitro-2-[(indol-3-yl)methylene]-2H-1,4-benzothiazin-3(4H)-one (see Example 31) (0.39 g, 1.16 mmol) and hydrazine hydrate (98%) (0.60 ml) in ethanol (15 ml). The reaction mixture was refluxed for 5 h, then filtered hot. The solid residue was boiled with ethanol (100 ml) and filtered hot. The combined filtrates were brought to dryness in vacuo and chromatographed on silica gel using a gradient of (9:1) to (8:2) dichloromethane:ethanol as the mobile phase to afford 0.17 g (35%) product.
Reaction SMILES: C(O[C:4](=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[N:7][CH:6]=1)C.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]#[N:21]>>[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:4]([C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1)=[O:11].[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][CH:20]([NH2:21])[C:5]1[CH:6]=[N:7][CH:8]=[CH:9][CH:10]=1
Reactant: N#CCc1ccccc1F
Reactant: CCOC(=O)c1cccnc1
Product: NC(Cc1ccccc1F)c1cccnc1
Product: O=C(Cc1ccccc1F)c1cccnc1

Procedure:
The title compound was generated from commercially available nicotinic acid ethyl ester and (2-fluoro-phenyl)-acetonitrile according to the general procedure D described above. The intermediates 2-(2-fluoro-phenyl)-1-pyridin-3-yl-ethanone and 2-(2-fluoro-phenyl)-1-pyridin-3-yl-ethylamine were isolated and characterized.
Reaction SMILES: [F:1][C:2]([F:4])=[CH2:3].[Li]C(CC)C.[O:10]1[C:14]2([CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.[Cl-].[NH4+].CCN(S(F)(F)[F:28])CC>C(Cl)Cl.C(OCC)C.O1CCCC1>[F:1][C:2]([F:28])([F:4])[CH:3]=[C:17]1[CH2:18][CH2:19][C:14]2([O:13][CH2:12][CH2:11][O:10]2)[CH2:15][CH2:16]1
Reactant: C1CCC2(CC1)OCCO2
Reactant: C=C(F)F
Reactant: CCN(CC)S(F)(F)F
Agent: [Cl-]
Agent: [Li]C(C)CC
Agent: [NH4+]
Solvent: CCOCC
Solvent: ClCCl
Solvent: C1CCOC1
Product: FC(F)(F)C=C1CCC2(CC1)OCCO2
Temperature: -100 °C
Reaction time: 0.33 h

Procedure:
At −100° C., 22 g of 1,1-difluoroethylene were condensed into a solvent mixture of 400 ml of tetrahydrofuran and 100 ml of diethyl ether. Subsequently, 153 ml of a 1.3 molar solution of sec-BuLi were added dropwise to the reaction solution at a temperature between −90° C. and −100° C. Finally, 31.2 g of 1,4-dioxaspiro[4.5]decane were added, the solution was stirred at −100° C. for another 20 minutes and subsequently warmed to 0° C. with stirring. The reaction solution was poured into an aqueous ammonium chloride and extracted with methylene chloride and the combined organic phases were dried over magnesium sulfate and concentrated. The residue was taken up in 400 ml of methylene chloride and, at −70° C., reacted with 32 g (0.2 mol) of DAST, dissolved in 100 ml of methylene chloride. The mixture was then slowly warmed to 0° C. with stirring, and the reaction solution was subsequently poured into an aqueous ammonium chloride. The product was extracted with diethyl ether and the combined organic phases were dried over MgSO4 and concentrated. The residue was chromatographed over silica gel (petroleum ether/ethyl acetate 4:1), to give the title product as a colourless oil.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1.[OH-:11].[K+].O.[CH3:14]O>>[CH3:14][O:11][C:2]1[C:3]2[CH:10]=[CH:9][NH:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CO
Reactant: Clc1ncnc2[nH]ccc12
Reactant: [OH-]
Agent: [K+]
Solvent: O
Product: COc1ncnc2[nH]ccc12
Temperature: 60 °C
Reaction time: 8 h

Procedure:
To 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 3.5 g, 23.0 mmol) in 70 mL of methanol, potassium hydroxide (2.3 g, 41.0 mmol) was added and the reaction stirred at 60° C. overnight, then poured into water and extracted with ethyl acetate. The organic layer was separated and dried over sodium sulfate, filtered and the filtrate concentrated under vacuum to provide the desired compound (3, 3.20 g).
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1.CN([CH:22]=[O:23])C.Cl>CCCCCC.C1COCC1>[CH:22]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][CH3:18])[CH:13]=2)[CH:8]=1)=[O:23]
Reactant: COc1ccc2cc(Br)ccc2c1
Reactant: CN(C)C=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COc1ccc2cc(C=O)ccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
n-BuLi in hexane (1.59M, 125 ml) was added dropwise to a solution of 2-bromo-6-methoxynaphthalene (42.27 g) in THF (600 ml) at −78° C. and was stirred at −78+ C. for 30 minutes. To the mixture was added DMF (28 ml), and the whole was allowed to warm to room temperature. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The extract was dried and concentrated to give the titled compound (32.31 g) as a colorless solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]2[CH:7]=[C:8]([Cl:11])[CH:9]=[CH:10][C:4]=2[C:3]=1[C:12]#[N:13].F[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[N+:21]([O-:23])=[O:22]>>[Cl:11][C:8]1[CH:9]=[CH:10][C:4]2[C:3]([C:12]#[N:13])=[C:2]([NH:1][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[N+:21]([O-:23])=[O:22])[S:6][C:5]=2[CH:7]=1
Reactant: N#Cc1c(N)sc2cc(Cl)ccc12
Reactant: O=[N+]([O-])c1ccccc1F
Product: N#Cc1c(Nc2ccccc2[N+](=O)[O-])sc2cc(Cl)ccc12

Procedure:
In the same manner as in Starting Material Synthesis Example 51 and using 2-amino-6-chlorobenzo[b]thiophene-3-carbonitrile and 2-fluoronitrobenzene, 6-chloro-2-(2-nitroanilino)benzo[b]thiophene-3-carbonitrile is obtained.
Reaction SMILES: [C:1]1([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[NH2:14])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:31])[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=1>ClCCl>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([C:22]([NH:14][C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: Nc1ccccc1Nc1ccccc1
Reactant: COc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2ccccc2Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62.2 %

Procedure:
A vigorously stirring solution of N-phenyl-1,2-phenylenediamine (20.15 g) in dichloromethane (325 ml) and triethylamine (11.07 g) was cooled in an ice/acetone bath under nitrogen. p-Anisoyl chloride (18.66 g) dissolved in dichloromethane (100 ml) was added dropwise over a 20 minute period while maintaining a temperature of <5° C. The reaction mixture was allowed to warm to ambient temperature and stirred for two hours. The organic solution was washed successively with water (200 ml), 2N aqueous HCl (80 ml), and saturated brine solution (160 ml), then dried over sodium sulfate and passed through a pad of silica (150 g). The silica was eluted with ethyl acetate (1 L) and the eluent was evaporated in vacuo to a pink solid. The solid was triturated overnight with ethyl ether (350 ml), cooled in an ice bath, filtered, and dried in vacuo to give the title compound as a light pink solid (21.67 g). 1H (300 MHz, CDCl3): d 3.82 (s, 3H), 5.75 (br s, 1H), 6.80-6.91(m, 5H), 7.12-7.29 (m, 5H), 7.62 (d, J=8.8 Hz, 2H), 8.15 (dd, J=1.7, 7.8 Hz, 1H), 8.36 (s, 1H); TLC (EtOAc/Hex, 1:4): Rf =0.24; m.p.: 148°-150° C.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:13]([CH:14]=S)=[CH:12][N:11]=[C:10](C)[N:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:19]=1[NH2:20].C1(C)C=C[C:29]([S:32](O)(=O)=O)=CC=1.[BH4-].[Na+]>C1(C)C=CC=CC=1.CO.O>[Cl:17][C:18]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:19]=1[NH:20][CH2:14][C:13]1[C:8]([NH:7][C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[N:9][C:10]([S:32][CH3:29])=[N:11][CH:12]=1
Reactant: Cc1ncc(C=S)c(Nc2ccccc2)n1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: Nc1c(Cl)cccc1Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2ccccc2)n1
Reaction time: 0.5 h
Yield: 209.5 %

Procedure:
A mixture of 700 mg (2.9 mmol) of 4-phenylamino-2-methylthiopyrimidine-5-carboxaldehyde, 490 mg (3.0 mmol) of 2,6-dichloroaniline and 100 mg (0.5 mmol) of 4-toluenesulfonic acid in 50 ml of toluene was heated at reflux with the azeotropic removal of water for 18 hours. The mixture was cooled and evaporated. 50 ml of methanol and 400 mg (11.7 mmol) of sodium borohydride were added and the mixture was heated at reflux for 20 minutes, cooled and then evaporated. The residue was stirred in a mixture of 50 ml of 2M aqueous sodium hydroxide and 50 ml of ethyl acetate for 30 minutes and then the phases were separated. The organic phase was dried over magnesium sulfate, filtered and evaporated. Flash chromatography of the residue on silica gel using diethyl ether/hexane (2:3) for the elution gave 410 mg (36%) of 5-(2,6-dichlorophenyl)aminomethyl-4-phenylamino-2-methylthiopyrimidine as a white solid.
Reaction SMILES: [H-].[Na+].CO[C:5]1C=C[C:8]([SH:11])=[CH:7][CH:6]=1.Cl[CH2:13][C:14](=[O:16])[CH3:15].[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1>>[CH2:13]([S:11][CH2:8][C:7]1[CH:18]=[CH:17][C:21]([O:20][CH3:19])=[CH:5][CH:6]=1)[C:14]([CH3:15])=[O:16]
Reactant: C1CCOC1
Reactant: COc1ccc(S)cc1
Reactant: CC(=O)CCl
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(CSCC(C)=O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.165 Mol sodium hydride is added portionwise at 0° to a solution of 4-methoxy-thiophenol (0.15 mol) in 300 ml THF. After 1 hour chloracetone (0.165 mol) is added. The mixture is stirred overnight at room temperature. Thereafter the solvent is evaporated and the mixture is dissolved in CH2Cl2 and washed with 2 N Na2CO3. The organic phase is dried and the solvent is evaporated to yield the title a) compound which is used without further purification.
Reaction SMILES: [NH:1]1[CH2:8][CH2:7][CH2:6][C@H:2]1C(O)=O.[C:9]([O:13][CH2:14][CH3:15])(=[O:12])[CH:10]=[CH2:11].[CH2:16]=O>C1(C)C=CC=CC=1>[CH2:14]([O:13][C:9]([CH:10]1[CH:8]2[N:1]([CH2:2][CH2:6][CH2:7]2)[CH2:16][CH2:11]1)=[O:12])[CH3:15]
Reactant: C=O
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: C=CC(=O)OCC
Solvent: Cc1ccccc1
Product: CCOC(=O)C1CCN2CCCC12

Procedure:
A mixture of rac-proline (1.15 g), ethyl acrylate (1.20 g), toluene (80 ml) and paraformaldehyde (3.6 g) was heated to reflux for 3 hours. The mixture was concentrated and the residue was filtered through silica gel. The product with the molecular weight of 183.25 (C10H17NO2); MS (ESI): 184 (M+H+) was obtained in this way.
Reaction SMILES: [Br-].[Br:2][C:3]1[CH:28]=[CH:27][C:6]([CH2:7][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=[CH:5][CH:4]=1.[H-].[Na+].[Cl:31][C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1.O>CN(C=O)C.CCOCC>[Br:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:36][C:35]2[CH:38]=[CH:39][C:32]([Cl:31])=[CH:33][CH:34]=2)=[CH:27][CH:28]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: Brc1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Clc1ccc(C=Cc2ccc(Br)cc2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 73.4 %

Procedure:
To a solution of (4-bromobenzyl)triphenylphosphonium bromide (396 g; 0.77 mol) in 2.5 L of DMF at 0° C., was added 37 g (0.92 mol) of NaH (60% in oil) in four portions. The solution was stirred 1 hr at 0° C. followed by the addition of 109 g (0.77 mol) of 4-chlorobenzaldehyde in two portions. This mixture was warmed up to room temperature, stirred 1 hr and quench by pouring the reaction into a 5° C. mixture of 10 L of water and 2.5 L of Et2O. Aqueous layer was extracted with Et2O, combined organic layers were washed with brine and dried over Na2SO4. Volatiles were removed under reduced pressure and the residue was dissolved in 1.5 L of cyclohexane and filtered through a pad of silica gel (wash with cyclohexane). 16 g of one isomer cristallized out of the solution as a white solid and after evaporation of the volatiles, 166 g of the other isomer 1-bromo-4-[2-(4-chlorophenyl)vinyl]benzene was isolated.