Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][C:6](=O)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.[NH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH3:1][C:2]1([CH3:11])[CH:7]=[C:6]([N:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1
Reactant: C1CCNCC1
Reactant: CC1(C)CC(=O)CC(C)(C)N1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O
Product: CC1(C)C=C(N2CCCCC2)CC(C)(C)N1
Yield: 21 %

Procedure:
154.7 g of 2,2,6,6-tetramethyl-4-piperidone, 160 g of piperidine and 10.0 g of p-toluenesulphonic acid monohydrate were dissolved in 200 ml of benzene. The solution was refluxed by heating for 8.5 hours, whilst the water formed in situ was removed with a Dean-Stark separator. The reaction mixture was then poured into a mixture comprising 700 ml of water, 200 ml of concentrated aqueous ammonia and 100 g of ice. The organic layer was separated, washed three times with water and then dried over anhydrous magnesium sulphate. After removing the solvent, the residue was distilled under reduced pressure, giving 46.6 g of 1,2,5,6-tetrahydro-2,2,6,6-tetramethyl-4-piperidinopyridine (bp 80° - 82° C/1 mmHg).
Reaction SMILES: Br[C:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[S:5][CH:6]=1.S1C=CC2C=CC=CC1=2.C([Li])CCC.[Br:25]Br>Cl[Ni]1(Cl)[P](C2C=CC=CC=2)(C2C=CC=CC=2)CCC[P]1(C1C=CC=CC=1)C1C=CC=CC=1>[Br:25][C:6]1[S:5][C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[CH:2]=1
Reactant: BrBr
Reactant: Brc1csc2ccccc12
Agent: Cl[Ni]1(Cl)[P](c2ccccc2)(c2ccccc2)CCC[P]1(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Agent: c1ccc2sccc2c1
Product: Brc1cc2ccccc2s1

Procedure:
Starting from the commercially available 3-bromobenzo[b]thiophene (5), a synthetic route to poly(2,2′-bisbenzo[b]thiophene) (4) is outlined below in Scheme 1. 3-bromobenzo[b]thiophene (5) is alkylated to (6) using an alkyl grignard and Ni(dppp)Cl2. Benzo[b]thiophene (6) is brominated at the 2-position using n-butyllithium followed by bromine to yield (7). 2-Bromobenzo[b]thiophene (7) is homo-coupled using a liganded nickel complex reducing agent (generated from NaH, t-AmONa, Ni(OAc)2 and bipyridine) to yield 2,2′-bisbenzo[b]thiophene (2). Bromination of 2,2′-bisbenzo[b]thiophene (2) with N-bromosuccinimide or bromine water yields 5-5′-dibromo 2,2′-bisbenzo[b]thiophene (8).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[NH:10][N:9]=2)=[CH:4][CH:3]=1.C1C(=O)N([I:23])C(=O)C1>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:12]([I:23])=[C:11]([CH2:13][CH2:14][OH:15])[NH:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1I
Reactant: OCCc1cc(-c2ccc(F)cc2)n[nH]1
Solvent: CN(C)C=O
Product: OCCc1[nH]nc(-c2ccc(F)cc2)c1I
Yield: 89 %

Procedure:
Analogously to Process step [11], 2-[3-(4-fluorophenyl)-1H-pyrazol-5-yl]ethanol can be reacted with 1.1 eq. of NIS in DMF. In a yield of 89%, the desired product is obtained as a mixture of isomers: log P(HCOOH): 1.99; 1H-NMR (DMSO-d6): 13.29 & 13.19 (s, 1H) 7.78 & 7.69 (dd, 2H), 7.38 & 7.28 (dd, 2H), 4.92 & 4.72 (t, 1H), 3.62 (m, 2H), 2.79 & 2.73 (t, 2H).
Reaction SMILES: [CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([O:20]C)=O)[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:7])=[O:6])[CH2:2][CH2:3][CH3:4].[K].[NH2:23][OH:24].C(O)(=O)C>CO>[CH2:1]([S:5]([N:8]1[CH2:17][CH2:16][C:15]2[N:14]=[C:13]([C:18]([NH:23][OH:24])=[O:20])[CH:12]=[CH:11][C:10]=2[CH2:9]1)(=[O:6])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: NO
Reactant: CCCCS(=O)(=O)N1CCc2nc(C(=O)OC)ccc2C1
Agent: [K]
Solvent: CC(=O)O
Solvent: CO
Product: CCCCS(=O)(=O)N1CCc2nc(C(=O)NO)ccc2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 28.3 %

Procedure:
To a microwave vial containing methyl 6-(butylsulfonyl)-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxylate was added MeOH (1 mL) and hydroxylamine potassium salt (1 mL, 1.76 mmol, 1.76 M in MeOH). The solution was shaken at rt for 1 h, then acetic acid (0.102 mL, 1.8 mmol) was added to quench excess base. The solvent was then concentrated. To the resulting residue was added DMSO (1.2 mL) and after filtration, the solution underwent purification via prep-HPLC to give 6-(butylsulfonyl)-N-hydroxy-5,6,7,8-tetrahydro-1,6-naphthyridine-2-carboxamide (13.3 mg, 28.3%). LC-MS: (FA) ES+ 314; 1H NMR (Methanol-d4, 300 MHz) δ 7.97 (d, J=8.1 Hz, 1H), 7.76 (d, J=7.9 Hz, 1 H), 4.59 (s, 2H), 3.70 (t, J=6.0 Hz, 2H), 3.13 (m, 4H), 1.77 (m, 2H), 1.47 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[CH:5]=[N:4][N:3]=1.Cl.[NH:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH3:30])[C:24](=[O:29])[C:25]([F:28])([F:27])[F:26])[CH2:19][CH2:18]1.C(N(CC)CC)C>C(O)CC(C)C>[CH3:15][O:14][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][C:9]=1[O:12][CH3:13])[C:2]([N:17]1[CH2:22][CH2:21][CH:20]([N:23]([CH3:30])[C:24](=[O:29])[C:25]([F:27])([F:26])[F:28])[CH2:19][CH2:18]1)=[N:3][N:4]=[CH:5]2
Reactant: COc1cc2cnnc(Cl)c2cc1OC
Reactant: CN(C(=O)C(F)(F)F)C1CCNCC1
Agent: Cl
Solvent: CC(C)CCO
Solvent: CCN(CC)CC
Product: COc1cc2cnnc(N3CCC(N(C)C(=O)C(F)(F)F)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h
Yield: 36.3 %

Procedure:
1-Chloro-6,7-dimethoxyphthalazine (4.5 g), N-(piperid-4-yl)-N-methyltrifluoracetamide hydrochloride (9.9 g) and triethylamine (5.5 ml) were heated together for 5 hours at 100° in iso-amylalcohol (100 ml). The solution was cooled to room temperature and the excess iso-amylalcohol was removed by distillation in vacuo. The residue was dissolved in dilute hydrochloric acid to pH 2, extracted with chloroform (2×100 ml), the chloroform extract shaken with dilute sodium hydroxide, and then quickly separated. The organic phase was washed with water (150 ml), dried over magnesium sulphate, and taken to dryness in vacuo. The resultant brown oil was triturated with ether, filtered, and the filtrate was left standing at room temperature for two hours, during which time a yellow solid precipitated from solution. This solid was collected and crystallized from iso-propylalcohol, yielding 6,7-dimethoxy-1-[4-(N-methyltrifluoracetamido)piperidino]phthalazine (2.9 g), m.p. 150°-152°.
Reaction SMILES: [NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19](O)=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH2:32][C@H:33]([C:37]([CH2:39][Cl:40])=[O:38])[CH:34]([CH3:36])[CH3:35].Cl.N(C(OCC1C=CC=CC=1)=O)[C@H](C(NCC(N[C@H](C(N[C@H](C(CCl)=O)CC(C)C)=O)CC(C)C)=O)=O)CC1C=CC=CC=1>>[NH:1]([C:22]([O:24][CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)=[O:23])[C@H:2]([C:10]([NH:12][CH2:13][C:14]([NH:16][C@H:17]([C:19]([NH:32][C@H:33]([C:37]([CH2:39][Cl:40])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:20])[CH3:18])=[O:15])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(C)[C@H](N)C(=O)CCl
Reactant: C[C@H](NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl
Agent: Cl
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)CNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)CCl

Procedure:
Z-Phe-Gly-Ala-OH (1.60 g, 3.73 mmol) was then coupled to H-ValCH2Cl.HCl by a procedure substantially similar to that described for the preparation of Z-Phe-Gly-Leu-LeuCH2Cl, above. The resulting product was crystallized from ethyl acetate:ether to yield 1.29 g of Z-Phe-Gly-Ala-ValCH2Cl (m.p. 143°-144°).
Reaction SMILES: [H-].[Na+].[NH:3]1[C:7]2=[N:8][CH:9]=[CH:10][CH:11]=[C:6]2[CH:5]=[C:4]1[CH:12]=[O:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>CN(C)C=O.C(Cl)Cl>[CH:16]1([CH2:15][N:3]2[C:7]3=[N:8][CH:9]=[CH:10][CH:11]=[C:6]3[CH:5]=[C:4]2[CH:12]=[O:13])[CH2:18][CH2:17]1
Reactant: O=Cc1cc2cccnc2[nH]1
Reactant: BrCC1CC1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=Cc1cc2cccnc2n1CC1CC1
Temperature: 0 °C
Reaction time: 21 h
Yield: 73.3 %

Procedure:
A solution of sodium hydride (60.2 mg, 1.51 mmol) in N,N-dimethylformamide (20 mL) was stirred at 0° C. for 10 min. 1H-Pyrrolo[2,3-b]pyridine-2-carbaldehyde (200 mg, 1.37 mmol) was added and the mixture was stirred at 0° C. for 30 min and at it for 30 min. (Bromomethyl)cyclopropane (0.16 mL, 1.64 mmol available, for example, from Alfa Aesar) was added and the resulting mixture was stirred at 0° C. for 30 min and at it for 21 h. Reaction mixture was quenched by the addition of water (50 mL). After addition of Et2O (50 mL), the layers were separated. The aqueous layer was further extracted with Et2O (2×50 mL) and the combined organic layers were washed with H2O (2×35 mL). The organic phase was dried through a hydrophobic frit and concentrated under reduced pressure to give a brown oil which was loaded in DCM on a 50 g SNAP silica cartridge and purified by SP4, eluting with a gradient of 0-20% ethyl acetate/cyclohexane (15CV). The appropriate fractions were combined and evaporated under reduced pressure to give the required product 1-(cyclopropylmethyl)-1H-pyrrolo[2,3-b]pyridine-2-carbaldehyde (201 mg, 73.4%) as a colourless oil.
Reaction SMILES: [CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH2:2][CH3:3].O.[N-:12]=[C:13]=[O:14].[Na+]>C(O)(=O)C>[CH2:1]([C:4]1[CH:10]=[CH:9][C:7]([NH:8][C:13]([NH2:12])=[O:14])=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: [N-]=C=O
Reactant: CCCc1ccc(N)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: CCCc1ccc(NC(N)=O)cc1
Reaction time: 0.5 h
Yield: 93.9 %

Procedure:
A solution of 31.4 g of p-n-propylaniline dissolved in 116 ml of acetic acid and 232 ml of water was added dropwise into 200 ml of a mixed solution comprising 130 g of sodium isocyanate and 900 ml of water, and then stirred in an ice-bath for 30 minutes. The crystals precipitated were filtered, washed with water and dried to give 38.88 g of 4-n-propylphenylurea. After the 4-n-propylphenylurea was added in portions into 107.6 ml of 20% fuming sulfuric acid, the reaction was carried out at 60° C. for 2 hours. Under cooling in an ice-bath, about 400 ml of ice was added into the reaction mixture, followed by heating under reflux for 4 hours. The crystals precipitated by cooling were filtered, washed with water and then dried to give 30.09 g of the above title product (yield: 64.1%). Melting point: 30 261.7°-262.3° C.
Reaction SMILES: CO.[CH3:3][C:4]1[N:8]([C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][CH:10]=2)[N:7]=[C:6]([SH:18])[N:5]=1.[OH-].[Na+].S(OC)(O[CH3:25])(=O)=O>O>[CH3:3][C:4]1[N:8]([C:9]2[CH:10]=[CH:11][C:12]([N+:15]([O-:17])=[O:16])=[CH:13][CH:14]=2)[N:7]=[C:6]([S:18][CH3:25])[N:5]=1
Reactant: COS(=O)(=O)OC
Reactant: Cc1nc(S)nn1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CSc1nc(C)n(-c2ccc([N+](=O)[O-])cc2)n1
Reaction time: 1 h
Yield: 66 %

Procedure:
To 80 parts of methanol are added 4.7 parts of 5-methyl-1-(4-nitrophenyl)-1H-1,2,4-triazole-3-thiol and 1.2 parts of sodium hydroxide and the whole is stirred till all solid enters solution. Then there are added 2.66 parts of dimethyl sulfate and stirring is continued for 1 hour at room temperature. 100 Parts of water are added. The precipitated product is filtered off, washed with water, dried, and crystallized from 2,2'-oxybispropane, yielding 3.3 parts (66%) of 5-methyl-3-(methylthio)-1-(4-nitrophenyl)-1H-1,2,4-triazole; mp. 121°-125° C.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1.N1C=CC=CC=1.O.[NH2:23][NH2:24]>O>[Br:1][C:2]1[C:3]([NH:23][NH2:24])=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1
Reactant: Clc1ccc(-c2ccnc(Cl)c2Br)cc1
Reactant: NN
Solvent: c1ccncc1
Solvent: O
Product: NNc1nccc(-c2ccc(Cl)cc2)c1Br
Temperature: 120 °C

Procedure:
A mixture of 3-bromo-2-chloro-4-(4-chlorophenyl)pyridine (10 g, 33 mmol), pyridine (50 mL) and hydrazine monohydrate (4.8 g, 96 mmol) was heated to 120° C. for 16 h. After cooling to room temperature, water (300 mL) was added, which caused solid desired product to precipitate. This was filtered, washed with water (2×50 mL), and dried to obtain the title compound as a pale yellow solid (6 g), which was used without further purification.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:11][CH2:10][CH2:9][C@H:8]2[NH2:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:1]1([CH:7]2[CH2:11][CH2:10][CH2:9][CH:8]2[NH:12][C:20](=[O:22])[CH3:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N[C@@H]1CCC[C@H]1c1ccccc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CC(=O)NC1CCCC1c1ccccc1
Reaction time: 1 h

Procedure:
4.45 g of trans-2-phenyl-cyclopentylamine and 4.2 ml of triethylamine were dissolved in 50 ml of ethyl acetate. 2.86 ml of acetic anhydride was added slowly and the mixture stirred for 1 hour and washed with 40 ml of water. After drying the organic layer with sodium sulfate, filtration and evaporation 4.7 g of a crude solid was obtained that was used without further purification.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1.C([O-])([O-])=O.[K+].[K+].[CH3:25][CH:26]([CH3:29])[CH2:27]Br>CN(C=O)C>[CH3:25][CH:26]([CH3:29])[CH2:27][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1
Reactant: Clc1ccc(OCc2nc3ccccc3[nH]2)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(COc2ccc(Cl)cc2)nc2ccccc21
Temperature: 25 °C
Reaction time: 48 h
Yield: 95.3 %

Procedure:
To a solution of 52 (5.17 g, 0.02 mol) in DMF (50 mL) was added K2CO3 (5.53 g, 0.04 mol) followed by addition of 2-methylpropyl bromide (5.2 g, 0.038 mol) under Ar. The resulting mixture was stirred at rt for 48 hr. HPLC analysis showed that the reaction was not complete. The reaction mixture was further heated at 90° C. for 8 hr, at which point HPLC analysis showed the reaction was complete. The reaction mixture was cooled to rt and filtered. The filter cake was washed with EtOAc (100 mL). The filtrate was washed with H2O (2×75 mL) and brine (100 mL), filtered through phase separation filter paper, and concentrated in vacuo to give an oil (6 g) which solidified. The solid was triturated with hexanes (50 mL), filtered, washed with hexanes (25 mL), and dried to give 4.25 g (80%) of Compound #4. HPLC analysis showed a purity of 100%. 1H NMR (300 MHz, CDCl3): δ 7.85 (m, 1H), 7.45-7.25 (m, 5H), 7.05 (m. 2H), 5.4 (s, 2H), 4.1 (d, 2H), 2.35 (m, 1H), 1.0 (d, 6H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][C:3]=1[Cl:11].[C:12]1(O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH3:9])=[CH:4][C:3]=1[Cl:11]
Reactant: Oc1ccccc1
Reactant: CC(O)c1ccc(Br)c(Cl)c1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(Oc1ccccc1)c1ccc(Br)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 1-(4-bromo-3-chlorophenyl)ethanol (1.32 g, 5.6 mmol), phenol (525 mg, 5.6 mmol) and triphenylphosphine (2198 mg, 8.4 mmol) in tetrahydrofuran (30 mL) was stirred at room temperature for 0.5 hour. Diisopropyl azodicarboxylate (1695 mg, 8.4 mmol) was dropwise to the reaction mixture and was stirred at room temperature for 12 hours. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=5:1) to give 1-bromo-2-chloro-4-(1-phenoxyethyl)benzene as a colorless oil (882 mg 54%). 1H NMR (300 MHz, CDCl3): 7.37 (d, J=8.1, 1H), 7.27-7.20 (m, 4H), 6.92-6.82 (m, 3H), 5.30 (q, J=6.6, 1H), 1.62 (d, J=6.6, 3H).
Reaction SMILES: FC(F)(F)COP([CH2:13][C:14]([O:16][CH3:17])=[O:15])(=O)OCC(F)(F)F.C1OCCOCCOCCOCCOCCOC1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:55]1([CH2:60][C:61]([C:63]2[CH:64]=[C:65]([CH:68]=[CH:69][CH:70]=2)[C:66]#[N:67])=O)[CH:59]=[CH:58][CH:57]=[N:56]1>O1CCCC1>[C:66]([C:65]1[CH:64]=[C:63](/[C:61](/[CH2:60][N:55]2[CH:59]=[CH:58][CH:57]=[N:56]2)=[CH:13]\[C:14]([O:16][CH3:17])=[O:15])[CH:70]=[CH:69][CH:68]=1)#[N:67]
Reactant: N#Cc1cccc(C(=O)Cn2cccn2)c1
Reactant: COC(=O)CP(=O)(OCC(F)(F)F)OCC(F)(F)F
Agent: C1COCCOCCOCCOCCOCCO1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C(/Cn1cccn1)c1cccc(C#N)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 32.4 %

Procedure:
To a solution of bis(2,2,2-trifluoroethyl)(methoxycarbonylmethyl)phosphonate (0.39 ml, 1.87 mmol) in 5 ml anhydrous tetrahydrofuran was added a solution of 18-crown-6 (2 g, 7.8 mmol) in 5 ml anhydrous tetrahydrofuran. Reaction was cooled to −78° C. to which a 0.5M solution of potassium bis(trimethylsilyl)amide in toluene (0.93 ml, 1.87 mmol) was added all at once. The reaction mixture was stirred at −78° C. for 20 minutes after which a solution of 3-[2-(1H-1-pyrazolyl)acetyl]-benzonitrile (330 mg, 1.56 mmol) in 5 ml anhydrous tetrahydrofuran was added dropwise over several minutes. Reaction was gradually allowed to warm to room temperature and stirred for 5 hours. Reaction was then quenched with a saturated ammonium chloride solution (10 ml) and extracted with 2×25 ml diethyl ether. Combined organic layers were washed with 2×25 ml water, 2×25 ml saturated brine solution, dried over magnesium sulfate, filtered and concentrated to a brown residue. Crude residue was chromatographed on silica gel using a gradient of 5% EtOAc in hexane containing 0.1% triethylamine to 20% EtOAc in hexane containing 0.1% triethylamine to give methyl (E)-3-(3-cyanophenyl)-4-(1H-1-pyrazolyl)-2-butenoate (135 mg, 32%) as a clear oil after drying. H1NMR (CDCl3) 3.521 (s, #H); 4.98 (s, 2H); 5.694 (s, H); 6.237-6.247 (t, H); 7.296-7.593 (m, 6H). NOE experiment confirmed the stereochemical configuration.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][C:6]([C:8]1[NH:9][C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4].[C:17]1([CH3:27])[CH:22]=[CH:21][C:20]([S:23](Cl)(=[O:25])=[O:24])=[CH:19][CH:18]=1>C1COCC1>[CH2:3]([O:5][C:6]([C:8]1[N:9]([S:23]([C:20]2[CH:21]=[CH:22][C:17]([CH3:27])=[CH:18][CH:19]=2)(=[O:25])=[O:24])[C:10]2[C:15]([CH:16]=1)=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:7])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2ccccc2n1S(=O)(=O)c1ccc(C)cc1
Temperature: 30 °C

Procedure:
To a stirred suspension of sodium hydride (3.7 g, 120 mmol, 80% in paraffin oil) in dry THF (75 mL), a solution of indol-2-carboxylic acid ethyl ester (18.9 g, 100 mmol) in dry THF (75 mL) was added in 1 hour with stirring while the inner temperature was maintained under 30° C. The reaction mixture was stirred for 30 minutes and then a solution of p-toluenesulphonyl chloride (22.9 g, 120 mmol) in dry THF (75 mL) was added dropwise to the stirring reactant. After 2 hours stirring at room temperature and 1 hour at 45° C. the solvent was evaporated in vacuo and the residue partitioned between water and ethyl ether. The organic phase was dried over MgSO4 and the solvent evaporated to leave a solid which was recrystallized from diisopropyl ether (26.8 g, 78%), mp 92°-950° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3]1.[H-].[Na+].[CH2:13]([O:20][C@H:21]([C@H:23]([N:31]1[CH:35]=[C:34]([C:36]([NH2:38])=[O:37])[N:33]=[CH:32]1)[CH2:24][CH2:25]OS(C)(=O)=O)[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.O>CN(C=O)C>[CH2:13]([O:20][C@H:21]([C@H:23]([N:31]1[CH:35]=[C:34]([C:36]([NH2:38])=[O:37])[N:33]=[CH:32]1)[CH2:24][CH2:25][N:6]1[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[S:3][C:2]1=[O:1])[CH3:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=c1[nH]c2ccccc2s1
Reactant: C[C@H](OCc1ccccc1)[C@@H](CCOS(C)(=O)=O)n1cnc(C(N)=O)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](OCc1ccccc1)[C@@H](CCn1c(=O)sc2ccccc21)n1cnc(C(N)=O)c1
Temperature: 65 °C
Reaction time: 0.17 h
Yield: 52.7 %

Procedure:
To a stirred solution of 2-oxobenzothiazole (83 mg, 0.549 mmol) in DMF (3 ml) was added NaH (60% in mineral oil, 22 mg, 0.549 mmol) at room temperature. After 10 minutes, 1-[(2S,3R)-2-benzyloxy-5-methanesulfonyloxy-3-pentyl]imidazole-4-carboxamide in DMF (3 ml) was added and the resulting mixture was stirred for 6 hours at 60 to 70° C. The reaction mixture was poured into water (30 ml) and extracted with ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate), and concentrated in vacuo. The residue was purified by silica gel (8 g) column chromatography eluting with chloroform/methanol (100:1 to 30:1) to give 1-[(2S,3R)-2-benzyloxy-5-(2-oxobenzothiazol-3-yl)-3-pentyl]imidazole-4-carboxamide (63 mg, 52.7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[CH:8][CH:7]=2.[H][H]>FC(F)(F)C(O)=O.[Pd]>[CH3:1][O:2][C:3]1[C:4]([CH3:13])=[N:5][C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1
Reactant: COc1cc2ccccc2nc1C
Reactant: [H][H]
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: COc1cc2c(nc1C)CCCC2
Yield: 99.6 %

Procedure:
A mixture of 3-methoxy-2-methylquinoline (0.081 mol) in trifluoro-acetic acid (150 ml) was hydrogenated at room temperature under a 34 bar pressure for 48 hours with palladium on activated carbon (2 g) as a catalyst. After uptake of hydrogen (2 equiv.), the catalyst was filtered through celite and washed with H2O. The filtrate was basified with a concentrated NH4 OH solution and extracted with CH2Cl2. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated, yielding 14.3 g (quant.) of 5,6,7,8-tetrahydro-3-methoxy-2-methylquinoline (interm. 13).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][OH:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1>C(Cl)Cl.CCCCCC>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH:12]=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: OCCCCCCc1ccccc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCCCCC
Solvent: ClCCl
Product: O=CCCCCCc1ccccc1
Reaction time: 3.5 h

Procedure:
A solution of 6-phenylhexanol (5.00 g, 28.0 mmol, 1 equiv) in CH2Cl2 (10 ml) was added to a solution of pyridinium chlorochromate (9.07 g, 42.1 mmol, 1.5 equiv) in CH2Cl2 (100 ml) at rt, and the mixture was stirred for 3.5 h. The reaction mixture was diluted with hexane and filtered through silica gel (20 g). The silica gel was eluted with a mixture of hexane and EtOAc (1:1). The combined filtrate was concentrated under vacuum to give 6-phenyl-1-hexional as a colorless oil, which was used as such for the next step. 1H NMR (CDCl3) δ 9.75 (t, 1H), 7.28–7.14 (m, 5H), 2.61 (T, 2H), 2.44–2.38 (m, 2H), 1.71–1.58 (m, 5H), 1.42–1.30 (m, 2H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH3:9])[CH:5]=[CH:6][C:7]=1[OH:8].C(N(CC)CC)C.[P:17](Cl)(Cl)([O:19][CH3:20])=[O:18]>CCOCC>[CH3:20][O:19][P:17]1(=[O:18])[O:8][C:7]2[CH:6]=[CH:5][C:4]([CH3:9])=[CH:3][C:2]=2[O:1]1
Reactant: COP(=O)(Cl)Cl
Reactant: Cc1ccc(O)c(O)c1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COP1(=O)Oc2ccc(C)cc2O1
Yield: 88319 %

Procedure:
3,4-Dihydroxytoluene (1.686 g, 13.58 mM) was dissolved in 40 ml of ether and, using 2.748 g of triethylamine and 2.022 g of methyl dichlorophosphate, the reaction mixture was treated in the same manner as in Reference Example 5. There was obtained 2,400 g (88.4% yield) of 2-methoxy-5-methyl-2-oxo-1,3,2-benzodioxaphosphole as a viscous oil.