Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([N:13]=[C:14](SC)SC)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([NH:13][C:14]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1
Reactant: COc1nc(C)nc2sc(N=C(SC)SC)nc12
Reactant: NC[C@]1(O)CN2CCC1CC2
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)nc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of dimethyl 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (56 mg, 0.19 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (51 mg, 0.22 mmol) and cesium carbonate (175 mg, 0.54 mmol) in DMF (0.5 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (34 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (br. s., 1H) 4.14 (s, 3H) 4.03 (d, J=9.54 Hz, 1H) 3.68 (d, J=9.54 Hz, 1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 2.74-3.07 (m, 5H) 2.68 (s, 3H) 2.04-2.28 (m, 2H) 1.70-1.86 (m, 1H) 1.44-1.67 (m, 2H). MS (LC/MS) R.T.=1.10; [M+H]+=361.32.
Reaction SMILES: [C:1]1([S:7]([C:9]2[CH:14]=[CH:13][C:12]([C:15](=[O:17])[CH3:16])=[CH:11][CH:10]=2)=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[C:33]1([CH2:39][CH2:40][S:41][CH:42]([C:46](O)=[O:47])[C:43](O)=[O:44])[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>C1COCC1>[OH:47][C:46]1[CH:16]=[C:15]([C:12]2[CH:13]=[CH:14][C:9]([S:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[O:8])=[CH:10][CH:11]=2)[O:17][C:43](=[O:44])[C:42]=1[S:41][CH2:40][CH2:39][C:33]1[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=1
Reactant: CC(=O)c1ccc(S(=O)c2ccccc2)cc1
Reactant: O=C(O)C(SCCc1ccccc1)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=c1oc(-c2ccc(S(=O)c3ccccc3)cc2)cc(O)c1SCCc1ccccc1

Procedure:
The title compound was prepared by Method A using 4'-(phenylsulfinyl)acetophenone (2.50 g, 10.24 mmol), lithium bis(trimethylsilyl)amide (2.57 g,15.36 mmol), chlorotrimethylsilane (1.94 mL,15.36 mmol), THF (100 mL), and diethyl ester of [(2-phenylethyl)thio]-propanedioic acid (1.00 g, 3.37 mmol). m.p. 171-173° C.; 1H NMR (400 MHz, DMSO-d6) δ2.76 (t, 2 H), 3.01 (t, 2 H), 6.83 (s, 1 H), 7.19 (m, 5 H), 7.54 (m, 3 H), 7.75 (d, 2 H), 7.86 (d, 2 H), 7.95 (d, 2 H), 12.05 (bs, 1 H).
Reaction SMILES: [N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([OH:19])=O)=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C1([N:26]=C=NC2CCCCC2)CCCCC1.N.ClCCl.C(=O)([O-])O.[Na+]>ClCCl>[N:1]1[C:11]2[O:10][C:9]3[CH:12]=[CH:13][C:14]([CH2:16][C:17]([NH2:26])=[O:19])=[CH:15][C:8]=3[CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)Cc1ccc2c(c1)CCc1cccnc1O2
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: NC(=O)Cc1ccc2c(c1)CCc1cccnc1O2
Yield: 37.6 %

Procedure:
A mixture of 40 mg of (5,6-dihydro benzo[b]pyrido[3,2-f]-oxepin-8-yl)-acetic acid, 60 mg of dicyclohexylcarbodimide and 2 ml of dry dichloromethane was stirred under ice cooling. To the resulting mixture was added 8 ml of a saturated liquid ammonia-dichloromethane solution, and the mixture was stirred for 3 hours. After the completion of the reaction, this was basified with a saturated sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with water and then with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a light yellow oil, which was chromatographed over 4 g of silica gel and eluted with chloroform/ethyl acetate (10/1-8/2) to obtain crystals. These were recrystallized from ethyl acetate to yield 15 mg (yield: 40%) of (5,6-dihydro benzo[b]pyrido[3,2-f]oxepin-8-yl)-acetamide as light yellow needle crystals having a melting point of 164°-165° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:26][CH2:25][N:24]([C:34]2[C:43]([F:44])=[CH:42][C:37]([C:38]([O:40]C)=[O:39])=[CH:36][C:35]=2[F:45])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1COCC1.[OH-].[Na+].Cl>CO>[C:1]([O:5][C:6]([N:8]([CH2:21][CH:22]1[CH:27]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH2:26][CH2:25][N:24]([C:34]2[C:43]([F:44])=[CH:42][C:37]([C:38]([OH:40])=[O:39])=[CH:36][C:35]=2[F:45])[CH2:23]1)[C@@H:9]([C:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:14]=[CH:13][CH:12]=1)[CH3:10])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cc(F)c(N2CCC(c3ccccc3)C(CN(C(=O)OC(C)(C)C)[C@H](C)c3cccc4ccccc34)C2)c(F)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: C[C@H](c1cccc2ccccc12)N(CC1CN(c2c(F)cc(C(=O)O)cc2F)CCC1c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
To 122 mg of methyl 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoate were added 2.0 mL of THF, 2.0 mL of methanol, and 1.0 mL of a 1 M aqueous sodium hydroxide solution, followed by stirring at room temperature overnight. It was neutralized by addition of 1.1 mL of 1 M hydrochloric acid, and then extracted with ethyl acetate, and the organic layer was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform-methanol) to obtain 115 mg of 4-[3-({(tert-butoxycarbonyl)[(1R)-1-(1-naphthyl)ethyl]amino}methyl)-4-phenylpiperidin-1-yl]-3,5-difluorobenzoic acid as a pale yellow oily substance. ESI+: 601
Reaction SMILES: [OH:1][C@H:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[H-].[Na+].Cl[C:18]1[C:19]2[CH:26]=[CH:25][N:24]([CH2:27][O:28][CH2:29][CH2:30][Si:31]([CH3:34])([CH3:33])[CH3:32])[C:20]=2[N:21]=[CH:22][N:23]=1>CS(C)=O.O>[CH3:32][Si:31]([CH3:34])([CH3:33])[CH2:30][CH2:29][O:28][CH2:27][N:24]1[C:20]2[N:21]=[CH:22][N:23]=[C:18]([O:1][C@H:2]3[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]3)[C:19]=2[CH:26]=[CH:25]1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H](O)C1
Reactant: C[Si](C)(C)CCOCn1ccc2c(Cl)ncnc21
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](Oc2ncnc3c2ccn3COCC[Si](C)(C)C)C1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 83.6 %

Procedure:
To a solution of (S)-tert-butyl 3-hydroxypiperidine-1-carboxylate (0.4 g, 2.0 mmol) in DMSO (5 mL) under nitrogen, was added NaH (60% suspension in mineral oil, 79 mg, 2.0 mmol). After the reaction was stirred for 1.5 h at rt, a solution of 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (564 mg, 2.0 mmol) in DMSO (5 mL) was added dropwise at rt and the mixture was heated at 50° C. for 2 h. The reaction mixture was cooled to rt, diluted with water (10 mL) and extracted with EtOAc (4×60 mL). The combined organic layer was washed with water (50 mL), dried over Na2SO4 and concentrated in vacuo to give the crude compound which was purified by column chromatography (silica gel, gradient EtOAc in Hexanes) to give (750 mg, 85%) of the titled intermediate.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)OC(C)C)#[N:2].[N+]([O-])(O)=O.[O:19]([CH2:23][CH2:24][CH2:25][NH2:26])[N+:20]([O-:22])=[O:21].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[N:26][CH2:25][CH2:24][CH2:23][O:19][N+:20]([O-:22])=[O:21])#[N:2]
Reactant: CC(C)OC(=NC#N)c1cccnc1
Reactant: NCCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCCO[N+](=O)[O-])c1cccnc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 38.5 %

Procedure:
Isopropyl N-cyano-3-pyridinecarboximidate (0.50 g, 2.6 mmol) was dissolved in methanol (10 ml), and 3-nitroxypropylamine nitrate (0.53 g, 2.9 mmol) and sodium methoxide (0.16 g, 2.9 mmol) were added. The mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was extracted with chloroform (30 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The concentrated residue thus obtained was subjected to chromatography on a silica gel column (WAKO GEL C-200, 30 g) eluting with chloroform-methanol (60:1). Eluted fractions were concentrated under reduced pressure and crystallized from methanol-diethyl ether to give the title compound (0.26 g, 1.0 mmol, yield: 39%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[C:3]2[S:20][C:19]([NH2:21])=[N:18][C:4]=2[N:5]=[C:6]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=2[F:17])[N:7]=1.[NH2:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:31])([CH3:30])[CH3:29]>>[NH2:21][C:19]1[S:20][C:3]2[C:2]([NH:22][CH2:23][CH2:24][NH:25][C:26](=[O:32])[O:27][C:28]([CH3:30])([CH3:29])[CH3:31])=[N:7][C:6]([S:8][CH2:9][C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=3[F:17])=[N:5][C:4]=2[N:18]=1
Reactant: Nc1nc2nc(SCc3cccc(F)c3F)nc(Cl)c2s1
Reactant: CC(C)(C)OC(=O)NCCN
Product: CC(C)(C)OC(=O)NCCNc1nc(SCc2cccc(F)c2F)nc2nc(N)sc12

Procedure:
Prepared by the method of example 2 step a), using the product of example 4, step b) and (2-aminoethyl)-carbamic acid, 1,1-dimethylethyl ester.
Reaction SMILES: [OH:1][C:2]([C:4]([F:7])([F:6])[F:5])=[O:3].C([N:15]1[CH2:24][CH2:23][C:22]2[C:17](=[N:18][C:19]([NH:41][CH:42]3[CH2:44][CH2:43]3)=[C:20]([N:25]3[CH2:30][CH2:29][CH:28]([CH:31]([C:33]4[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=4[F:40])[F:32])[CH2:27][CH2:26]3)[N:21]=2)[CH2:16]1)C1C=CC=CC=1>C1COCC1.[OH-].[OH-].[Pd+2]>[CH:42]1([NH:41][C:19]2[N:18]=[C:17]3[CH2:16][NH:15][CH2:24][CH2:23][C:22]3=[N:21][C:20]=2[N:25]2[CH2:30][CH2:29][CH:28]([CH:31]([C:33]3[CH:38]=[CH:37][C:36]([F:39])=[CH:35][C:34]=3[F:40])[F:32])[CH2:27][CH2:26]2)[CH2:43][CH2:44]1.[C:2]([OH:3])([C:4]([F:7])([F:6])[F:5])=[O:1]
Reactant: Fc1ccc(C(F)C2CCN(c3nc4c(nc3NC3CC3)CN(Cc3ccccc3)CC4)CC2)c(F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: Fc1ccc(C(F)C2CCN(c3nc4c(nc3NC3CC3)CNCC4)CC2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 6-benzyl-N-cyclopropyl-2-(4-((2,4-difluorophenyl)fluoromethyl)piperidin-1-yl)-5,6,7,8-tetrahydropyrido[3,4-b]pyrazin-3-amine TFA salt (93.5 mg, 0.150 mmol) and Pd(OH)2 (20 wt %, 10 mg, 0.014 mmol) in THF (750 μL) was stirred at room temperature under an atmosphere of hydrogen gas (balloon). After 2 h, the mixture was directly purified by HPLC Method A to give the title compound as a TFA salt (67.7 mg, 85%) as a yellow oil. 1H NMR (400 MHz, methanol-d4) δ ppm 0.51-0.57 (m, 2H), 0.75-0.81 (m, 2H), 1.43 (br d, J=13.1 Hz, 1H), 1.52-1.72 (m, 2H), 1.94-2.13 (m, 2H), 2.59-2.72 (m, 3H), 2.97 (t, J=6.3 Hz, 2H), 3.40-3.50 (m, 2H), 3.51-3.56 (m, 2H), 3.98 (s, 1H), 4.22 (s, 2H), 5.51 (dd, J=46.2, 7.3 Hz, 1H), 6.96-7.08 (m, 2H), 7.46-7.54 (m, 1H); ESI-MS m/z [M+H]+ 418.3.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]#[N:8])=[CH:5][NH:4][N:3]=1.CN(C)[CH:11]=[CH:12][C:13]([C:15]1[CH:16]=[C:17]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=1)=O>C(O)(=O)C>[C:7]([C:6]1[CH:5]=[N:4][N:3]2[C:13]([C:15]3[CH:16]=[C:17]([N:21]([CH3:25])[C:22](=[O:24])[CH3:23])[CH:18]=[CH:19][CH:20]=3)=[CH:12][CH:11]=[N:1][C:2]=12)#[N:8]
Reactant: CC(=O)N(C)c1cccc(C(=O)C=CN(C)C)c1
Reactant: N#Cc1c[nH]nc1N
Solvent: CC(=O)O
Product: CC(=O)N(C)c1cccc(-c2ccnc3c(C#N)cnn23)c1

Procedure:
A mixture of 540 mg of 3-aminopyrazole-4-carbonitrile, 1.23 g of N-[3-[3-(dimethylamino)-1-oxo-2-propenyl]phenyl]-N-methylacetamide and 50 ml of glacial acetic acid was heated at reflux for 8 hours then the solvent was removed: The residue was partitioned between saturated aqueous sodium bicarbonate and dichloromethane. The organic layer was separated, dried, passed through a pad of hydrous magnesium silicate and hexane was added to the refluxing filtrate to crystallize the product. The mixture was cooled and the solid collected, giving the desired product, mp 195°-197° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].Cl.[CH:24]1([CH2:27][NH:28][CH3:29])[CH2:26][CH2:25]1.CCN(CC)CC>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:28]([CH2:27][CH:24]2[CH2:26][CH2:25]2)[CH3:29])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNCC1CC1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN(CC1CC1)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example B5) (5.11 g 15 mmol), cyclopropylmethyl-methyl-amine hydrochloride (5.47 g, 45 mmol) and Et3N (10.5 mL, 75 mmol) in DMSO (50 mL) at 23° C. according to the general procedure C. Obtained as a yellow solid (5.73 g).
Reaction SMILES: C([Li])(C)(C)C.Br[C:7]1[CH:12]=[CH:11][C:10]([CH:13]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[CH:9][CH:8]=1.[CH2:27]=[O:28]>CCCCC.C1COCC1>[Si:20]([O:19][CH:13]([C:10]1[CH:11]=[CH:12][C:7]([CH2:27][OH:28])=[CH:8][CH:9]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]
Reactant: C=O
Reactant: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: C1CCOC1
Product: CCCCCC(O[Si](C)(C)C(C)(C)C)c1ccc(CO)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 69 %

Procedure:
tert-Butyllithium (6.6 mL of a 1.7 M solution in pentane, 11.32 mmol) was added to a solution of the aryl bromide 7 (2.0 g, 5.39 mmol) in THF (22 mL) at −78° C. After 0.5 h paraformaldehyde (323 mg, 8.09 mmol) was added. The reaction was warmed to room temperature and stirred for 16 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The organic portion was dried (MgSO4), filtered and concentrated in vacuo. FCC (silica gel, 6:1 hex/EtOAc) yielded 1.2 g (69%) of the alcohol 8 as a clear, colorless oil.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.Br[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13].[K]>CC(C)=O>[CH:6]([C:5]1[CH:8]=[CH:9][C:2]([O:1][CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:3][CH:4]=1)=[O:7]
Reactant: CCOC(=O)CBr
Reactant: O=Cc1ccc(O)cc1
Agent: [K]
Solvent: CC(C)=O
Product: CCOC(=O)COc1ccc(C=O)cc1
Temperature: 0 °C
Yield: 75.4 %

Procedure:
p-Hydroxybenzaldehyde (122 g, 1 mole), ethyl bromoacetate (167 g, 1 mole), potassium carborate (138 g, 1 mole) and acetone (500 ml) were united, stirred and refluxed for 3 hours. The reaction mixture was poured into crushed ice (2 kg). The solid that separates was removed by filtrations, washed with water, dried and recrystallized from ethanol to give 157 g of product, m.p. 41°-42° C.
Reaction SMILES: [OH:1][C:2]1([CH3:11])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][C:9]#[CH:10].[C:12](OC(=O)C)(=[O:14])[CH3:13]>>[C:12]([O:1][C:2]1([CH3:11])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]1[CH2:8][C:9]#[CH:10])(=[O:14])[CH3:13]
Reactant: CC(=O)OC(C)=O
Reactant: C#CCC1C(=O)C=CC1(C)O
Product: C#CCC1C(=O)C=CC1(C)OC(C)=O

Procedure:
Into the same flask as used in Example 1, dl-3-hydroxy-2-propargyl-3-methyl-4-cyclopentenone (30 g) and acetic anhydride (70 g) were charged, and the resultant mixture was stirred at 100°-120° C. for 3 hours. After completion of the reaction, the reaction mixture was subjected to the same work-up as in Example 1 to give 36.4 g of dl-3-acetoxy-2-propargyl-3-methyl-4-cyclopentenone. Yield, 95%. B.P., 82°-86° C./0.2-0.3 mmHg).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[F:11][C:12]([F:16])([F:15])[CH2:13][NH2:14]>CS(C)=O>[N+:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:14][CH2:13][C:12]([F:16])([F:15])[F:11])([O-:10])=[O:9]
Reactant: NCC(F)(F)F
Reactant: O=[N+]([O-])c1ccccc1F
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccccc1NCC(F)(F)F
Temperature: 120 °C

Procedure:
A mixture of 1-fluoro-2-nitro-benzene (1.55 g, 11.0 mmol), 2,2,2-trifluoro-ethylamine (3.27 g, 33.0 mmol) and DMSO (4.5 mL) was heated at 120° C. for 24 h. The resulting mixture was poured onto ice/H2O and the resultant precipitate was collected by filtration, washed with H2O and hexanes to yield (2-nitro-phenyl)-(2,2,2-trifluoro-ethyl)-amine MS 221 (M+1)+.
Reaction SMILES: [CH2:1]1[CH2:5][O:4][CH2:3][CH2:2]1.C([Li])CCC.[CH3:11][CH2:12][CH2:13][CH2:14][CH2:15]C>>[CH2:3]([O:4][C:5]#[CH:1])[C:2]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCCCCC
Reactant: C1CCOC1
Agent: [Li]CCCC
Product: C#COCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A 70 ml THF solution of the Part G dibromide (5.48 g, 13.3 mmol) under argon atmosphere was cooled to -78° C. n-Butyllithium (10.6 ml of a 2.5M solution in hexane, 26.5 mmol) was added to the dibromide solution over 10 minutes. The reaction was stirred at -78° C. for 1 hour and then quenched at -78° C. with saturated aqueous NH4Cl solution. After the reaction was warmed to room temperature, it was diluted with 60 ml of H2O, and the aqueous layer was extracted 2 times with ether. All of the organic layers were combined and dried over MgSO4. Filtration and solvent removal gave 3.8 g of title benzyloxyacetylene in the form of a yellow solid. The title benzyloxyacetylene was purified by flash chromatography eluting with 3% ether/hexane. Title acetylene was obtained in 85% yield (2.76 g) as a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8].C(O)(=O)C(O)=O.[CH3:18][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][SH:28])=[CH:24][CH:23]=1)[CH3:20].C(=O)([O-])[O-].[K+].[K+]>O.O1CCCC1>[CH3:20][N:19]([CH2:21][C:22]1[O:26][C:25]([CH2:27][S:28][CH2:2][CH2:3][NH:4][C:5]([NH:10][CH3:11])=[CH:6][N+:7]([O-:9])=[O:8])=[CH:24][CH:23]=1)[CH3:18]
Reactant: CNC(=C[N+](=O)[O-])NCCCl
Reactant: CN(C)Cc1ccc(CS)o1
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=C[N+](=O)[O-])NCCSCc1ccc(CN(C)C)o1
Temperature: 25 °C
Reaction time: 120 h
Yield: 63.9 %

Procedure:
A mixture of N-(2-chloroethyl)-N'-methyl-2-nitro-1,1-ethenediamine (0.9 g), 5-[(dimethylamino)methyl]-2-furanmethanethiol oxalate (1:1) (1.3 g) and potassium carbonate (2.7 g) in water (10 ml) and tetrahydrofuran (10 ml) was stirred under nitrogen at room temperature for 5 days. The suspension was evaporated in vacuo, the residue mixed with water (40 ml) and the suspension extracted with ether (2×30 ml). The aqueous fraction was evaporated in vacuo and the residue evaporated with ethanol (2×10 ml). Tetrahydrofuran (20 ml), MgSO4 and decolourising charcoal were added and after 1 hour the mixture was filtered. Evaporation of the filtrate gave an oil (1 g) which was chromatographed (silica/methanol: 0.88 ammonia, 79:1). The appropriate eluate was evaporated and the oily residue (0.66 g) extracted with hot isopropyl acetate. The solid which separated was filtered to give the title compound (0.4 g), m.p. 65°-68°, which was not depressed on admixture with a sample prepared according to the method of Example 15 in British Patent No. 1,565,966.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[CH:17][C:6]([CH:7]=[CH:8][C:9]2[C:10](C#N)=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:5][CH:4]=1.[OH2:19]>Cl.C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]=[CH:8][C:9]2[CH:14]=[CH:13][C:12]([C:1]([O:2][CH2:3][CH3:4])=[O:19])=[CH:11][CH:10]=2)=[CH:17][CH:18]=1
Reactant: O
Reactant: COc1ccc(C=Cc2ccccc2C#N)cc1
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1ccc(C=Cc2ccc(OC)cc2)cc1
Reaction time: 6 h

Procedure:
4'-Methoxystilbenenitrile, 72.5 g. [Neher et al., Helv. Chim. Acta 29, 449-67 (1946)] in 1 liter of 5N hydrogen chloride in ethanol was heated under reflux for eight hours. An additional 100 ml. of 10N hydrogen chloride in ethanol was added and refluxing continued for about sixteen hours. An additional 100 ml. of 10N hydrogen chloride in ethanol was then added and refluxing continued for six hours. The reaction mixture was diluted with 2 liters of water, and the solid product which separated was collected by filtration and air-dried. The product was dissolved in methylene dichloride, dried over anhydrous magnesium sulfate and the solvent removed to give 73 g. of ethyl 4-(4-methoxystyryl)benzoate, m.p. 191°-192° C. when recrystallized from ethanol.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[F:9].C([Li])CCC.[F:15][CH2:16][C:17](OCC)=[O:18]>C1COCC1>[F:15][CH2:16][C:17]([C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[F:9])=[O:18]
Reactant: CCOC(=O)CF
Reactant: Cc1cccc(Br)c1F
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)CF)c1F
Temperature: -78 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
A solution of 1-bromo-2-fluoro-3-methylbenzene (7.0 g, 37.0 mmol) in THF (60 mL) was brought to −78° C. followed by the dropwise addition of butyllithium (15.55 ml, 38.9 mmol). The resulting mixture was stirred at −78° C. for 1 h then neat ethyl 2-fluoroacetate (3.76 ml, 38.9 mmol) was added dropwise. After 30 min the reaction went to completion. The reaction was quenched at −78° C. with saturated NH4Cl, warmed to rt and transferred to a separatory funnel. The aqueous phase was extracted with EtOAc and the combined organic extracts were washed with brine, dried over Na2SO4, filtered, concentrated and chromatographed on silica gel using 0-10% EtOAc/hexanes to afford a colorless oil that turned into a white solid as 2-fluoro-1-(2-fluoro-3-methylphenyl)ethanone (5.03 g, 29.6 mmol, 80% yield). MS m/z=171 [M+H]+. Calculated for C9H8F2O: 170.05.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]([NH2:13])=[O:12])=[CH:6][CH:5]=1)N.C(O[CH:17](OCC)[CH2:18][CH2:19][CH2:20][N:21]1[C:29](=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:22]1=[O:31])C.C(OCC)(=O)C>C(O)(=O)C>[O:31]=[C:22]1[C:23]2[C:28](=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:29](=[O:30])[N:21]1[CH2:20][CH2:19][C:18]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH2:10][C:11]([NH2:13])=[O:12])[CH:8]=2)[NH:2][CH:17]=1
Reactant: CCOC(CCCN1C(=O)c2ccccc2C1=O)OCC
Reactant: NNc1ccc(CC(N)=O)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: NC(=O)Cc1ccc2[nH]cc(CCN3C(=O)c4ccccc4C3=O)c2c1

Procedure:
A mixture of the crude 2-(4-hydrazinophenyl)acetamide hydrochloride (16.19 g) (contains 0.05 mol) and 4-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)butanal diethyl acetal (14.5 g) was heated under reflux in 25% aqueous acetic acid (1 l) for 30 min. The cooled mixture was poured into ethyl acetate (750 ml) the organic phase was separated and the aqueous phase was washed with ethyl acetate (250 ml). The combined organic extracts were washed with water (500 ml), dried (Na2SO4) and evaporated under reduced pressure. Water (500 ml) was added to the oily residue which solidified on stirring. The solid was collected by filtration, washed with water and dried. Crystallisation from ethyl acetate-methanol gave the title compound as pale yellow granules (11.9 g) m.p. 191°-3° C.