Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][C:7]([O:10][C:11]3[CH:12]=[C:13]([NH:17][C:18](=[O:30])[C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]5([C:28]#[N:29])[CH2:27][CH2:26]5)[CH:20]=4)[CH:14]=[CH:15][CH:16]=3)=[N:6][N:5]2[CH:31]=1.[F:32][C:33]([F:44])([F:43])[C:34]1[CH:42]=[CH:41][C:37]([C:38](O)=[O:39])=[CH:36][N:35]=1.C(Cl)(=O)C(Cl)=O.O1CCCC1>CN(C)C=O.CN(C)C(=O)C>[C:28]([C:25]1([C:21]2[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=2)[C:18]([NH:17][C:13]2[CH:12]=[C:11]([CH:16]=[CH:15][CH:14]=2)[O:10][C:7]2[CH:8]=[CH:9][C:4]3[N:5]([CH:31]=[C:2]([NH:1][C:38](=[O:39])[C:37]4[CH:41]=[CH:42][C:34]([C:33]([F:44])([F:32])[F:43])=[N:35][CH:36]=4)[N:3]=3)[N:6]=2)=[O:30])[CH2:27][CH2:26]1)#[N:29]
Reactant: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(N)cn5n4)c3)c2)CC1
Reactant: O=C(O)c1ccc(C(F)(F)F)nc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CC(=O)N(C)C
Solvent: C1CCOC1
Product: N#CC1(c2cccc(C(=O)Nc3cccc(Oc4ccc5nc(NC(=O)c6ccc(C(F)(F)F)nc6)cn5n4)c3)c2)CC1
Yield: 26.8 %

Procedure:
Using N-{3-[(2-aminoimidazo[1,2-b]pyridazin-6-yl)oxy]phenyl}-3-(1-cyanocyclopropyl)benzamide (150 mg, 0.365 mmol), 6-(trifluoromethyl)nicotinic acid (83 mg, 0.438 mmol), oxalyl chloride (64 μL, 0.730 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3 mL) and N,N-dimethylacetamide (3 mL) as starting materials and in the same manner as in Example 412, the title compound (57 mg, 27%) was obtained as a pale-yellow powder.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1.[N+:28]([CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32])#[C-:29].CC(C)([O-])C.[K+]>C1COCC1>[CH2:34]([O:33][C:31]([CH:30]([N+:28]#[C-:29])[CH2:2][C:3]1[N:4]=[C:5]([F:27])[N:6]([C:8]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1)=[O:32])[CH3:35]
Reactant: [C-]#[N+]CC(=O)OCC
Reactant: Fc1nc(CCl)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: [C-]#[N+]C(Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(F)n1)C(=O)OCC

Procedure:
Reaction of 4-chloromethyl-2-fluoro-1-triphenylmethylimidazole with ethyl isocyanoacetate/potassium t-butoxide in THF followed by chromatography on silica gel gave 4-(2-ethoxycarbonyl-2-isocyanoethyl)-2-fluoro-1-triphenylmethylimidazole having the following n.m.r. in CDCl3 : 1.24 (t, 2H); 2.7-3.17 (d, 2H); 4.18 (q, 1H); 4.5 (dd, 1H); 6.4 (s, 1H); 7.0-7.4 (m, 15H).
Reaction SMILES: [CH3:1][N:2]([CH3:16])[C:3](=[O:15])[C@@H:4]([CH:12]([CH3:14])[CH3:13])[NH:5][C:6]1[CH2:10][S:9][C:8](=[O:11])[N:7]=1.[F:17][C:18]([F:39])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25]([CH:28]=O)[CH2:24][CH2:23]1.C([O-])(=O)C.[NH2+]1CCCCC1>CC(O)C>[F:39][C:18]([F:17])([F:38])[C:19]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:20]=1[CH2:21][N:22]1[CH2:27][CH2:26][CH:25](/[CH:28]=[C:10]2/[C:6]([NH:5][C@@H:4]([C:3]([N:2]([CH3:1])[CH3:16])=[O:15])[CH:12]([CH3:14])[CH3:13])=[N:7][C:8](=[O:11])[S:9]/2)[CH2:24][CH2:23]1
Reactant: CC(C)[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Reactant: O=CC1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1
Agent: C1CC[NH2+]CC1
Agent: CC(=O)[O-]
Solvent: CC(C)O
Product: CC(C)[C@@H](NC1=NC(=O)S/C1=C\C1CCN(Cc2ccc(C(F)(F)F)cc2C(F)(F)F)CC1)C(=O)N(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 62 %

Procedure:
To a solution of N,N-dimethyl-N2-(2-oxo-2,5-dihydro-1,3-thiazol-4-yl)-D-valinamide (0.730 g) and 1-[2,4-bis(trifluoromethyl)benzyl]piperidine-4-carbaldehyde (1.018 g) in 2-propanol (10 mL) was added piperidinium acetate (0.436 g) under ice-cooling. The reaction mixture was stirred at 60° C. overnight, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (NH, ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (1.050 g).
Reaction SMILES: Cl[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=1)=[O:4].Cl.[F:18][C:19]1[CH:31]=[CH:30][C:22]([CH2:23][CH:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[CH:21][CH:20]=1>CCCCCC>[F:18][C:19]1[CH:20]=[CH:21][C:22]([CH2:23][CH:24]2[CH2:25][CH2:26][N:27]([CH2:2][C:3]([NH:5][C:6]3[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][CH:7]=3)=[O:4])[CH2:28][CH2:29]2)=[CH:30][CH:31]=1
Reactant: CS(=O)(=O)Nc1ccc(NC(=O)CCl)cc1
Reactant: Fc1ccc(CC2CCNCC2)cc1
Agent: Cl
Solvent: CCCCCC
Product: CS(=O)(=O)Nc1ccc(NC(=O)CN2CCC(Cc3ccc(F)cc3)CC2)cc1

Procedure:
The title compound is prepared from 2-chloro-N-(4-methanesulfonylamino-phenyl)-acetamide (Example 180a) and 4-(4-fluoro-benzyl)-piperidine hydrochloride according to the method described in Example 142b. Melting Point: 169-171° C. (hexane)
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([NH:17][CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])(=[O:16])=[O:15].[H-].[Na+].Br[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1>CN(C=O)C>[CH3:2][N:3]([CH3:24])[C:4](=[O:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][CH:8]=[CH:7][C:6]=1[S:14]([N:17]([CH2:18][CH2:19][N:20]([CH3:22])[CH3:21])[CH2:28][CH2:29][O:30][CH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][O:32]1)(=[O:15])=[O:16]
Reactant: BrCCOC1CCCCO1
Reactant: CN(C)CCNS(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(C)CCN(CCOC1CCCCO1)S(=O)(=O)c1cccc([N+](=O)[O-])c1C(=O)N(C)C
Reaction time: 20 h

Procedure:
To a suspension of N,N-dimethyl-2-[N-(2-dimethylaminoethyl)aminosulfonyl]-6-nitrobenzamide hydrochloride (347 mg, 0.91 mmol) in DMF (5 ml) under N2 was added 50% NaH (87 mg, 1.82 mmol). After stirring at 20-25° for 15 minutes until all of the NaH had reacted, a solution of 2-(2-bromoethoxy)tetrahydro-2H-pyran in DMF (2 ml) was added. The solution was stirred at 20-25° under N2 for 20 hours and then concentrated under reduced pressure to remove most of the DMF. The residue was partitioned between EtOAc and a saturated aqueous solution of NaCl. After drying (Na2SO4) the EtOAc extract, filtering and concentrating, the residue was chromatographed over silica gel. Elution with 7% MeOH-93% CHCl3 gave 100 mg of product.
Reaction SMILES: NCC1C=C(C2C=CC=C3C=2CCCN3C(=O)CCCOC2C=CC=C(C)C=2C)C=CC=1.CC1C(C)=CC=CC=1OCCCC(N1C2C(=C(C3C=C(C=CC=3)CNC(=O)OC(C)(C)C)C=CC=2)CCC1)=O.[CH3:72][C:73]1[C:118]([CH3:119])=[CH:117][CH:116]=[CH:115][C:74]=1[O:75][CH2:76][CH2:77][CH2:78][C:79]([N:81]1[C:90]2[C:85](=[C:86]([C:91]3[CH:92]=[N:93][N:94]([CH2:96][C:97]4[CH:98]=[C:99]([CH:112]=[CH:113][CH:114]=4)[O:100][CH2:101][CH2:102][CH2:103][NH:104]C(=O)OC(C)(C)C)[CH:95]=3)[CH:87]=[CH:88][CH:89]=2)[CH2:84][CH2:83][CH2:82]1)=[O:80]>>[NH2:104][CH2:103][CH2:102][CH2:101][O:100][C:99]1[CH:98]=[C:97]([CH:114]=[CH:113][CH:112]=1)[CH2:96][N:94]1[CH:95]=[C:91]([C:86]2[CH:87]=[CH:88][CH:89]=[C:90]3[C:85]=2[CH2:84][CH2:83][CH2:82][N:81]3[C:79](=[O:80])[CH2:78][CH2:77][CH2:76][O:75][C:74]2[CH:115]=[CH:116][CH:117]=[C:118]([CH3:119])[C:73]=2[CH3:72])[CH:92]=[N:93]1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCCNC(=O)OC(C)(C)C)c5)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CN)c4)cccc32)c1C
Agent: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cnn(Cc5cccc(OCCCN)c5)c4)cccc32)c1C

Procedure:
The title compound was prepared using a procedure analogous to 1-(5-(3-(aminomethyl)phenyl)-3,4-dihydroquinolin-1(2H)-yl)-4-(2,3-dimethylphenoxy)butan-1-one except that tert-butyl 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzylcarbamate was replaced with tert-butyl 3-(3-((4-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)methyl)phenoxy)propylcarbamate. LCMS, [M+H]+=553.3.
Reaction SMILES: [Cl:1][C:2]([F:16])([F:15])[CH:3]=[CH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Br.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=1.C1CCN2C(=NCCC2)CC1.[Br-]>O.CCCCCCC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:24][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH:4]=[CH:3][C:2]([Cl:1])([F:16])[F:15])=[CH:20][CH:19]=1
Reactant: Oc1ccc(Cl)cc1
Reactant: FC(F)(Cl)C=CCCCCCCCCCBr
Agent: [Br-]
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCCCCCC
Product: FC(F)(Cl)C=CCCCCCCCCCOc1ccc(Cl)cc1
Yield: 30.7 %

Procedure:
A mixture of 1.6 grams (0.005 mole) of 12-chloro-12,12-difluoro-10-dodecenyl bromide and 0.65 gram (0.005 mole) of 4-chlorophenol was stirred, and 0.75 ml (0.005 mole) of DBU was added dropwise. Upon completion of addition, the reaction mixture was stirred at ambient temperature for 18 hours. Gas chromatographic analysis of the reaction mixture indicated the presence of the bromide starting material. An additional 0.5 ml of DBU was added, and the reaction mixture was stirred for 18 hours more. After this time the reaction mixture was shaken with heptane and water. The heptane layer was washed with several portions of water and then with two portions of an aqueous solution saturated with sodium chloride. The organic layer was dried with sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to a residual oil. The oil was subjected to column chromatography on silica gel. Elution was accomplished using in succession heptane, 20% ethyl acetate in heptane, and 5% ethanol in heptane. The appropriate fractions were combined and concentrated under reduced pressure yielding 0.56 gram of 12-chloro-12,12-difluoro-10-dodecenyl 4-chlorophenyl ether. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C:29](=[N:30][OH:31])[C:28](=[O:32])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])(=[O:3])[CH3:2].[N+](=[CH2:35])=[N-]>CCOCC>[C:1]([O:4][CH2:5][C:6]1[CH2:7][S:8][C@@H:9]2[C:29](=[N:30][O:31][CH3:35])[C:28](=[O:32])[N:10]2[C:11]=1[C:12]([O:14][CH:15]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:13])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: CC(=O)OCC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(=NO)[C@H]2SC1
Solvent: CCOCC
Product: CON=C1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(COC(C)=O)CS[C@H]12
Temperature: 25 °C
Yield: 20.9 %

Procedure:
In ether (6 ml) is dissolved diphenylmethyl 3-acetoxymethyl-7-hydroxyimino-3-cephem-4-carboxylate (349 mg), and under ice-cooling, an ethereal solution of diazomethane (1 ml, 0.77 mmol) is added. While the temperature raised gradually to room temperature, the mixture is stirred for an hour. The reaction mixture is then concentrated under reduced pressure and the residue is purified by thin-layer chromatography (developer: ethyl acetate-hexane=1:1) to give diphenylmethyl 3-acetoxymethyl-7-methoxyimino-3-cephem-4-carboxylate (75 mg).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[OH-].[Na+].I[CH2:31][CH:32]([OH:35])[CH2:33][OH:34].O>CN(C)P(N(C)C)(N(C)C)=O.CCOCC>[F:1][C:2]1[CH:10]=[C:9]([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH:8]=[CH:7][C:3]=1[C:4]([O:6][CH2:31][CH:32]([OH:35])[CH2:33][OH:34])=[O:5]
Reactant: OCC(O)CI
Reactant: CCCCCCCCCCCCCCCCNc1ccc(C(=O)O)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: O
Product: CCCCCCCCCCCCCCCCNc1ccc(C(=O)OCC(O)CO)c(F)c1
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A solution of 7.34 g. of 2-fluoro-4-(hexadecylamino)-benzoic acid, 4.80 g. of 25% aqueous sodium hydroxide, and 12.6 g. of 3-iodo-1,2-propanediol in 50 ml of hexamethylphosphoramide is stirred for 24 hours at ambient temperature, diluted with 100 ml of ether and stirred for 5 days at ambient temperature. The mixture is treated with water and extracted with ether. The dried extracts are evaporated to yield 2,3-dihydroxypropyl 2-fluoro-4-(hexadecylamino)benzoate.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([OH:22])=[O:21])([CH2:16][CH2:17]1)[CH2:14][CH2:13]2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2[N:37]=[N:36]1.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH2:1]([O:8][C:9]([N:11]([CH2:23][C:24]([N:26]1[CH2:30][C@@H:29]([F:31])[CH2:28][C@H:27]1[C:32]#[N:33])=[O:25])[C:12]12[CH2:19][CH2:18][C:15]([C:20]([O:22][N:35]3[C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=4[N:37]=[N:36]3)=[O:21])([CH2:14][CH2:13]1)[CH2:16][CH2:17]2)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)O)(CC1)CC2
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: N#C[C@@H]1C[C@H](F)CN1C(=O)CN(C(=O)OCc1ccccc1)C12CCC(C(=O)On3nnc4ccccc43)(CC1)CC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 80.1 %

Procedure:
(2S,4S)-1-[[N-Benzyloxycarbonyl-N-(4-carboxybicyclo[2.2.2]oct-1-yl)amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (91.5 mg) and 1-hydroxybenzotriazole (45.9 mg) were dissolved in N,N-dimethylformamide (2.0 mL). While the solution was chilled in an ice bath, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (95.9 mg) was added and the mixture was allowed to warm to room temperature and was stirred for 15 hours. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (eluant:ethyl acetate) to give (2S,4S)-1-[[N-benzyloxycarbonyl-N-[4-(benzotriazol-1-yl)oxycarbonylbicyclo[2.2.2]oct-1-yl]amino]acetyl]-4-fluoropyrrolidine-2-carbonitrile (92.0 mg).
Reaction SMILES: C1C2C(COC([CH2:18][C:19]([N:21]3[CH2:25][C@H:24]([F:26])[CH2:23][C@@H:22]3[C:27]([O:29]C)=O)=[O:20])=O)C3C(=CC=CC=3)C=2C=CC=1.[NH:31]1CCCCC1>CO>[F:26][C@H:24]1[CH2:25][N:21]2[C:19](=[O:20])[CH2:18][NH:31][C:27](=[O:29])[CH:22]2[CH2:23]1
Reactant: C1CCNCC1
Reactant: COC(=O)[C@H]1C[C@@H](F)CN1C(=O)CC(=O)OCC1c2ccccc2-c2ccccc21
Solvent: CO
Product: O=C1NCC(=O)N2C[C@H](F)CC12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A scintillation vial was charged with (2S,4R), (2R,4R)-methyl 1-(2-(((9H-fluoren-9-yl)methoxy)carbonyl)acetyl)-4-fluoropyrrolidine-2-carboxylate (815 mg, 1911 μmol), 19 mL MeOH and piperidine (946 μl, 9556 μmol). The mixture was stirred at RT overnight The mixture was concentrated, dissolved in DCM/MeOH and purified by silica gel chromatography, 50-100% 90/10/1 DCM/MeOH/NH4OH in DCM. (7R)-7-fluoro-hexahydropyrrolo[1,2-a]pyrazine-1,4-dione was isolated as a white solid, and confirmed by 1H-NMR.
Reaction SMILES: C([O:3][C:4](=[O:22])[CH2:5][O:6][C:7]1[C:19]([Cl:20])=[C:18]([Cl:21])[C:10]2[S:11][C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])=[CH:13][C:9]=2[CH:8]=1)C.[OH-].[Na+].Cl>C(O)C.O.C(OCC)C>[Cl:20][C:19]1[C:7]([O:6][CH2:5][C:4]([OH:22])=[O:3])=[CH:8][C:9]2[CH:13]=[C:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[S:11][C:10]=2[C:18]=1[Cl:21]
Reactant: CCOC(=O)COc1cc2cc(CC(C)C)sc2c(Cl)c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)Cc1cc2cc(OCC(=O)O)c(Cl)c(Cl)c2s1
Yield: 93.7 %

Procedure:
To 9.6 g of ethyl[(6,7-dichloro-2-isobutylbenzo[b]thien-5-yl)oxy]acetate in 75 ml of 95% ethanol is added 175 ml of a 6N sodium hydroxide solution and the mixture is refluxed at 100° for 30 mins. The cooled mixture is concentrated in vacuo to give a slurry which is diluted with 500 ml of water and 500 ml of diethyl ether. With stirring and cooling, the mixture is acidified with 6N hydrochloric acid. The acidic mixture is extracted with diethyl ether. The ether extracts are washed, dried over anhydrous magnesium sulfate, filtered and the solvent is removed. Recrystallization of the solid from diethyl ether and hexane gives 8.3 g of [(6,7-dichloro-2-isobutylbenzo[b]thien-5-yl)oxy]acetic acid, mp 164°-165°.
Reaction SMILES: Br.C[O:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8]([C:11](=[O:13])[CH3:12])=[N:9][O:10][C:6]=2[CH:5]=1>C(O)(=O)C>[OH:3][C:4]1[CH:15]=[CH:14][C:7]2[C:8]([C:11](=[O:13])[CH3:12])=[N:9][O:10][C:6]=2[CH:5]=1
Reactant: COc1ccc2c(C(C)=O)noc2c1
Agent: Br
Solvent: CC(=O)O
Product: CC(=O)c1noc2cc(O)ccc12
Temperature: 0 °C

Procedure:
350 ml of a 48% solution of hydrobromic acid are added to 34.2 g of 1-(6-methoxy-1,2-benzisoxazol-3-yl)ethanone in 350 ml of acetic acid. The reaction mixture is refluxed for 6.5 h, cooled, and then poured onto a mixture of ice/water. The precipitated crude product is isolated by filtration and washed with water. This crude product is purified by chromatography over silica gel with ethyl acetate/hexane (1:3), giving 1-(6-hydroxy-1,2-benzisoxazol-3-yl)ethanone having a melting point of 159°-161° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl[CH:13]([CH2:19]Cl)[CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:19]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[F:1])[CH2:13][CH2:14][Si:15]([Cl:18])([Cl:17])[Cl:16]
Reactant: ClCC(Cl)C[Si](Cl)(Cl)Cl
Reactant: Fc1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Product: Fc1ccccc1C(CC[Si](Cl)(Cl)Cl)c1ccccc1F
Reaction time: 1 h
Yield: 40.7 %

Procedure:
In the same apparatus and procedures as EXAMPLE 2 above, 18.8 ml (200 mmol) of fluorobenzene and 0.31 g (2.3 mmol) of aluminum chloride were alkylated with 5.61 g (22.8 mmol) of (2,3-dichloropropyl)trichlorosilane for 10 min at 70° C. The aluminum chloride catalyst was quenched with POCl3 and then stirred for another 1 hour to complete the deactivation. Freshly distilled hexane (50 ml) was added to the reaction mixture and insoluble solids in hexane were filtered from the organic soultion. After hexane and fluorobenzene were distilled, the reaction products were vacuum distilled to give 3.39 g of [3,3-bis(fluorophenyl)propyl]trichlorosilane (bp; 121-122° C./0.5 torr, yield; 41%) as a mixutre of isomers.
Reaction SMILES: [CH2:1]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].Cl.CO.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]=O)[CH:27]=1.C([BH3-])#N.[Na+].[OH-].[K+]>O.CO>[CH2:1]([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:32][C:28]2[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=2)=[CH:18][CH:17]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: CCCCCCCCCCCCCCOc1ccc(N)cc1
Reactant: O=Cc1cccnc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [K+]
Solvent: CO
Solvent: O
Product: CCCCCCCCCCCCCCOc1ccc(NCc2cccnc2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 76.4 %

Procedure:
To a room temperature slurry of 7.26 g of product from Example 82, 60 ml of methyl alcohol and 9.5 ml of 5N hydrochloric acid/methanol is added, dropwise, 2.55 g of 3-pyridinecarboxaldehyde. After 10 minutes, a total of 1.64 g of sodium cyanoborohydride is very carefully added in 3 separate portions over 1.5 hours. The initial reaction is vigorous. The reaction mixture is stirred at room temperature for 68 hours, diluted with water, made basic with potassium hydroxide and extracted with methylene chloride. The methylene chloride extract is washed with saturated sodium chloride, dried and concentrated in vacuo. The residue is purified by column chromatography (silica gel: 90% ethyl acetate/hexane) to give 7.2 g of the desired product as colorless crystals.
Reaction SMILES: O.[P:2](=[O:6])([OH:5])([OH:4])[OH:3].[O-2].[Nb+5:8].[O-2].[O-2].[O-2].[O-2].[Nb+5]>>[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Nb+5:8].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[P:2]([O-:6])([O-:5])([O-:4])=[O:3].[Nb+5:8].[Nb+5:8]
Reactant: O=P(O)(O)O
Agent: [Nb+5]
Agent: [O-2]
Solvent: O
Product: O=P([O-])([O-])[O-]
Temperature: 25 °C

Procedure:
Niobic acid, Nb2O5 ×H2O (60.33 g; 0.211 mole) is stirred in 85 percent phosphoric acid (602.20 g; 5.22 moles) at 150° C. The niobium oxide dissolves to form a pink solution, and upon further heating a precipitate forms. The precipitate is boiled in the phosphoric acid solution for about 2 hours with stirring. The mixture is cooled to room temperature, and the liquid is decanted from the precipitate. Water (500 ml) is added to the precipitate with stirring, and the precipitate is filtered. The washing and filtering cycle is repeated five times. The filtered solid is dried at 110° C. under air for 21/2 days to yield a niobium phosphate catalyst. The elemental analysis of the catalyst is consistent with the composition NbOPO4.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH:3]([OH:6])[CH2:2]1.CCN(C(C)C)C(C)C.[Cl:16][C:17](Cl)([O:19]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1>[OH:6][CH:3]1[CH2:4][CH2:5][N:1]([C:17]([Cl:16])=[O:19])[CH2:2]1
Reactant: OC1CCNC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Cl)N1CCC(O)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of pyrrolidin-3-ol (0.083 g, 0.955 mmol) in dry THF (5 mL) was added DIPEA (0.3 mL, 1.91 mmol) and cooled 0° C. To the resulting mixture was added triphosgene (0.127 g, 0.429 mmol) and the mixture was stirred for 2 h at an ambient temperature.
Reaction SMILES: Br[CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][C:6]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:8]=2)[C:3]1=[O:15].[CH3:16][NH:17][C:18]([NH:20][CH3:21])=[S:19]>CC(C)=O>[CH3:14][S:11]([C:6]1[CH:7]=[CH:8][C:9]2[CH2:10][CH:2]3[S:19][C:18](=[N:17][CH3:16])[N:20]([CH3:21])[C:3]3([OH:15])[C:4]=2[CH:5]=1)(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc2c(c1)C(=O)C(Br)C2
Reactant: CNC(=S)NC
Solvent: CC(C)=O
Product: CN=C1SC2Cc3ccc(S(C)(=O)=O)cc3C2(O)N1C
Reaction time: 0.17 h

Procedure:
1.45 g of 2-bromo-6-methanesulfonyl-1-indanone are dissolved in 15 ml of acetone and, while stirring, 0.65 g of N,N′-dimethylthiourea in 10 ml of acetone is added. The solution is initially clear but, after about 10 min, the hydrobromide of 5-methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol crystallizes out. Stirring, at room temperature for 1 h is followed by filtration with suction and washing with a little acetone. 2.1 g of hydrobromide (melting point 265° C.) are suspended in 10 ml of methanol, and 1 ml of triethylamine is added. After 15 min, 150 ml of water is added, and the mixture is stirred while cooling in ice for 1 h. The product which is formed is filtered off with suction and washed with a little cold water. 5-Methanesulfonyl-3-methyl-2-methylimino-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of 158° C.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH:11]C(NC2C(C)=CSC=2)=N)[O:4][CH2:3][CH2:2]1.ClN1C(=O)CCC1=O>C(O)(=O)C>[O:1]1[C:5]2([CH2:10][CH2:9][CH2:8][CH2:7][CH:6]2[NH2:11])[O:4][CH2:3][CH2:2]1
Reactant: Cc1cscc1NC(=N)NC1CCCCC12OCCO2
Agent: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: NC1CCCCC12OCCO2
Yield: 92 %

Procedure:
N-(1,4-Dioxaspiro[4.5]dec-6-yl)-N′-(4-methylthiophen-3-yl)guanidine (49 mg) was dissolved in glacial acetic acid (3 ml), and a solution of N-chlorosuccinimide (20.3 mg) in glacial acetic acid (5 ml) was added slowly. The mixture was stirred for a number of hours and then allowed to stand at room temperature over the weekend, after which the glacial acetic acid was removed under reduced pressure, the residue was taken up in water and the mixture was adjusted to pH 10 using 2N sodium hydroxide solution. The basic phase was extracted three times with ethyl acetate and the combined organic phases were dried over magnesium sulfate, filtered and concentrated. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4) and filtered. Removal of the solvent under reduced pressure gave 24 mg of the desired product which was used directly for the next step.