Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][N:4]=1)#[CH:2].[N:12]([C:15]1[CH:16]=[CH:17][C:18]([Cl:21])=[N:19][CH:20]=1)=[N+:13]=[N-:14]>O1CCOCC1.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Cu+2]>[Cl:21][C:18]1[N:19]=[CH:20][C:15]([N:12]2[CH:2]=[C:1]([C:3]3[C:11]4[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=4)[NH:5][N:4]=3)[N:14]=[N:13]2)=[CH:16][CH:17]=1
Reactant: C#Cc1n[nH]c2ccccc12
Reactant: [N-]=[N+]=Nc1ccc(Cl)nc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Clc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cn1
Temperature: 80 °C

Procedure:
3-Ethynyl-1H-indazole (249 mg; 1.75 mmol; 1.0 eq.) and 5-azido-2-chloropyridine (270 mg; 1.75 mmol; 1.0 eq.) were dissolved in 1,4-dioxane (11 mL). D-(−)-isoascorbic acid sodium salt (69 mg; 0.35 mmol; 0.2 eq.) was added followed by copper sulfate pentahydrate (17.5 mg; 0.07 mmol; 0.04 eq.) in water (3.7 mL) and the reaction mixture was heated at 80° C. for 2 days. The precipitate obtained was filtered, washed with water and EtOAc and dried under vacuum to afford the title compound as a beige powder. m.p.=272-280° C. 1H NMR (300 Mz, DMSO-d6) δ 13.40 (s, 1H), 9.44 (s, 1H), 9.16 (d, J=2.8 Hz, 1H), 8.56 (dd, J=2.9, 8.8 Hz, 1H), 8.33 (d, J=8.1 Hz, 1H), 7.83 (d, J=8.9 Hz, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.44 (m, 1H), 7.26 (m, 1H). HPLC (Condition A): Rt 3.30 min (purity 100%).
Reaction SMILES: [C-]#N.[Na+].C(O)C.[C:7]([C:9]1[CH:10]=[C:11]([CH:14]=[CH:15][CH:16]=1)[CH:12]=[O:13])#[N:8].[CH3:17][S:18][C:19]1[CH:26]=[CH:25][C:22]([CH:23]=[O:24])=[CH:21][CH:20]=1>O>[C:7]([C:9]1[CH:10]=[C:11]([C:12](=[O:13])[CH:23]([OH:24])[C:22]2[CH:25]=[CH:26][C:19]([S:18][CH3:17])=[CH:20][CH:21]=2)[CH:14]=[CH:15][CH:16]=1)#[N:8]
Reactant: N#Cc1cccc(C=O)c1
Reactant: CSc1ccc(C=O)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(O)C(=O)c2cccc(C#N)c2)cc1
Yield: 61 %

Procedure:
Sodium cyanide (3 mmol, 0.147 g) was added to a mixture of ethanol (30 ml), water (30 ml), 3-cyanobenzaldehyde (30 mmol, 3.93 g) and 4-(methylthio)benzaldehyde (30 mmol, 4.0 ml). The reaction was stirred at reflux 30 minutes, diluted with water (20 ml) and extracted with ethyl acetate (250 ml). The organic layer was separated, dried over magnesium sulfate, concentrated, and the residue purified by silica gel chromatography (2:1 hexane:ethyl acetate), affording the title compound as a solid (5.2, 61%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:29]=[CH:28][C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:17][CH2:18][CH2:19][CH2:20][C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)=[O:16])[CH2:11][CH2:10]2)=[CH:6][CH:5]=1.C([Si]([O:47][C:48]1[CH:53]=[CH:52][C:51]([O:54][CH2:55][CH:56]2[CH2:58][O:57]2)=[CH:50][CH:49]=1)(C1C=CC=CC=1)C1C=CC=CC=1)(C)(C)C>C(Cl)(Cl)Cl.CO>[C:24]1([CH3:27])[CH:25]=[CH:26][C:21]([CH2:20][CH2:19][CH2:18][NH:17][C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:7]3[CH:28]=[CH:29][C:4]([CH2:3][CH2:2][NH:1][CH2:58][C@H:56]([OH:57])[CH2:55][O:54][C:51]4[CH:52]=[CH:53][C:48]([OH:47])=[CH:49][CH:50]=4)=[CH:5][CH:6]=3)[CH2:10][CH2:11]2)=[O:16])=[CH:22][CH:23]=1
Reactant: CC(C)(C)[Si](Oc1ccc(OCC2CO2)cc1)(c1ccccc1)c1ccccc1
Reactant: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCN)cc3)CC2)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: Cc1ccc(CCCNC(=O)N2CCC(Nc3ccc(CCNC[C@H](O)COc4ccc(O)cc4)cc3)CC2)cc1
Yield: 23 %

Procedure:
4-[4-(2-Aminoethyl)anilino]-N-[3-(4-methylphenyl)propyl]-1-piperidine-carboxamide foramte (0.44 g, 1.0 mmol) was reacted with tert-butyl-(4-oxiranylmethoxy-phenoxy)-diphenyl-silane (0.40 g, 1.0 mmol) according to Procedure G (eluant: 20:1 chloroform-methanol) to give the title compound (0.185 g, 0.23 mmol).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.CN(C)C=O.[Cl:14][C:15]1[N:20]=[N:19][C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)=[C:17]([OH:32])[CH:16]=1.Cl>O>[Br:1][C:16]1[C:17]([OH:32])=[C:18]([O:21][C:22]2[C:27]([CH3:28])=[CH:26][CH:25]=[CH:24][C:23]=2[CH:29]2[CH2:31][CH2:30]2)[N:19]=[N:20][C:15]=1[Cl:14]
Reactant: Cc1cccc(C2CC2)c1Oc1nnc(Cl)cc1O
Reactant: O=C1CCC(=O)N1Br
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(C2CC2)c1Oc1nnc(Cl)c(Br)c1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 61 %

Procedure:
108 mg (0.607 mmol) of N-bromosuccinimide was added to a N,N-dimethylformamide (2 mL) solution containing 157 mg (0.567 mmol) of 6-chloro-3-(2-cyclopropyl-6-methyl-phenoxy)-4-pyridazinol, and the resulting mixture was stirred at room temperature for 3 hours and 30 minutes. Water, and then, 4 mol/L hydrochloric acid were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed successively with water and brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off and the residue was purified by preparative thin-layer chromatography (available from MERCK CO. 1.05744, developed by hexane:ethyl acetate=2:1) to obtain 123 mg (0.346 mmol, Yield: 61.0%) of 5-bromo-6-chloro-3-(2-cyclopropyl-6-methylphenoxy)-4-pyridazinol (Compound No. 3843).
Reaction SMILES: [CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)=[N:14][CH:15]=[C:10]3[CH2:9][NH:8][C:7]2=[O:30])[CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+]>CS(C)=O>[CH:1]1([N:6]2[C:11]3=[N:12][C:13]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:28][CH2:27][CH:26]([OH:29])[CH2:25][CH2:24]5)=[CH:21][CH:22]=4)=[N:14][CH:15]=[C:10]3[CH:9]=[N:8][C:7]2=[O:30])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C1NCc2cnc(Nc3ccc(N4CCC(O)CC4)cc3)nc2N1C1CCCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=c1ncc2cnc(Nc3ccc(N4CCC(O)CC4)cc3)nc2n1C1CCCC1
Yield: 32.8 %

Procedure:
Prepared from 60 mg (0.15 mmol) of 1-cyclopentyl-7-[4-(4-hydroxypiperidin-1-yl)phenylamino]-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 66 mg (0.58 mmol) of potassium tert-butoxide in 1.5 mL of DMSO. The crude semi-solid residue is triturated in 15 mL of 2:1 diethyl ether/hexane, and the orange amorphous solid is collected and dried to leave 20 mg (30%) of the title compound: mp>185° C. (dec).
Reaction SMILES: C1C=C(Cl)C=C(C(OO)=[O:9])C=1.[CH2:12]([N:16]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[S:17]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N+:26]([O-:28])=[O:27])(=[O:19])=[O:18])[CH2:13][CH:14]=[CH2:15]>C(Cl)(Cl)Cl.O.C([O-])(O)=O.[Na+]>[N+:26]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[S:17]([N:16]([CH2:12][CH2:13][CH:14]1[CH2:15][O:9]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)(=[O:19])=[O:18])([O-:28])=[O:27]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CCCN(c1ccccc1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N(CCC1CO1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 97 %

Procedure:
mCPBA (77%, 0.0550 g, 0.246 mmol) was added to N-(but-3-enyl)-2-nitro-N-phenylbenzenesulfonamide (0.0653 g, 0.196 mmol) in 1 mL CHCl3 at 0° C. The mixture was stirred at 0° C. for 30 min, then gradually warmed up to room temperature and continued to stir for 18 hr. After TLC showed the disappearance of starting material, the reaction mixture was diluted with a 1:1 mixture of water and saturated NaHCO3 (2×10 mL) and water (10 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated to afford the crude product, which was subjected to silica gel chromatography using Hexanes/EtOAc to afford 0.0662 g colorless oil as product, yield 96.9%.
Reaction SMILES: [P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=O)[CH:15]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2].[CH2:23]([C:26]1[CH:27]=[C:28]([CH:33]=[CH:34][CH:35]=1)[C:29]([NH:31][NH2:32])=[O:30])[CH:24]=[CH2:25]>CO.C(Cl)Cl>[P:1]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][CH:21]=[N:32][NH:31][C:29](=[O:30])[C:28]2[CH:33]=[CH:34][CH:35]=[C:26]([CH2:23][CH:24]=[CH2:25])[CH:27]=2)[CH:15]=1)([S:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])([S:3][CH2:4][CH3:5])=[O:2]
Reactant: CCCCCCSP(=O)(Oc1cccc(CC=O)c1)SCC
Reactant: C=CCc1cccc(C(=O)NN)c1
Solvent: ClCCl
Solvent: CO
Product: C=CCc1cccc(C(=O)NN=CCc2cccc(OP(=O)(SCC)SCCCCCC)c2)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of S-ethyl S-hexyl O-(3-Formylmethylphenyl) dithiophosphate (0.02 mole) in methanol (50 ml) and 3-allylbenzoylhydrazine (0.02 mole) are charged into a glass reaction vessel and the mixture is stirred at room temperature for a period of about 12 hours. After this time the reaction mixture is stripped of methanol under vacuum and the residue is dissolved in methylene chloride (100 ml) and the resulting solution is washed with water (75 ml), with aqueous sodium hydroxide (75 ml; 0.1 N) and again with water (75 ml). The washed solution is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product S-ethyl S-hexyl O-{3-[2-(3-allylbenzoylhydrazono)ethyl]phenyl} dithiophosphate.
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:12].[H-].[Na+].[CH3:16][Si:17]([CH3:24])([CH3:23])[CH2:18][CH2:19][O:20][CH2:21]Cl>CN(C)C=O>[CH3:1][C:2]1([CH3:13])[C:10]2[C:5](=[C:6]([CH3:11])[CH:7]=[CH:8][CH:9]=2)[N:4]([CH2:21][O:20][CH2:19][CH2:18][Si:17]([CH3:24])([CH3:23])[CH3:16])[C:3]1=[O:12]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1cccc2c1NC(=O)C2(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc2c1N(COCC[Si](C)(C)C)C(=O)C2(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The stirred solution of 2.00 g of 3,3,7-trimethyl-1,3-dihydroindol-2-one and 10 ml of N,N-dimethylformamide is cooled to 0° C. and admixed with 0.479 g of sodium hydride dispersion (60%). The mixture is stirred at 0° C. over 1 hour and subsequently admixed with 2.33 ml of 2-(trimethylsilyl)ethoxymethyl chloride. The ice bath is removed and the reaction mixture is stirred further at room temperature over 14 hours. The reaction mixture is poured onto ice-water (100 ml) and extracted with tert-butyl methyl ether (2×100 ml). The organic phases are washed successively with water (2×100 ml) and brine (1×100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.51 (1:3 EtOAc-heptane); Rt=5.93.
Reaction SMILES: [Br:1][C:2]1[CH:13]=[C:6]2[C:7]([O:9]C(=O)[NH:11][C:5]2=[CH:4][CH:3]=1)=O.[NH2:14][CH2:15][C:16]([NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>C(#N)C>[NH2:11][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:13][C:6]=1[C:7]([NH:14][CH2:15][C:16](=[O:17])[NH:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:9]
Reactant: CC(C)(C)NC(=O)CN
Reactant: O=c1[nH]c2ccc(Br)cc2c(=O)o1
Solvent: CC#N
Product: CC(C)(C)NC(=O)CNC(=O)c1cc(Br)ccc1N
Temperature: 25 °C
Reaction time: 20 h
Yield: 64.4 %

Procedure:
A suspension of 5-bromoisatoic anhydride (1.2 g, 5.0 mmol) and 2-amino-N-tert-butylacetamide (INTERMEDIATE I.2) (0.78 g, 6.0 mmol) in acetonitrile (8 mL) was stirred at room temperature for 20 h. The white suspension was filtered, and the white precipitate washed cold EtOH to give 2-amino-5-bromo-N-(tert-butylcarbamoylmethyl)benzamide (1.06 g, 3.22 mmol, 65%).
Reaction SMILES: [CH2:1]([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][C@@H:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[OH:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CN=C1.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]>CN(C)C=O>[CH2:1]([N:8]([CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)[CH2:9][C@H:10]([O:11][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CN(CCc1ccc(Br)cc1)Cc1ccccc1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 14 h
Yield: 90.3 %

Procedure:
To a solution of (1R)-2-[benzyl[2-(4-bromophenyl)ethyl]amino]-1-(3-chlorophenyl)ethanol (18.5 g) in N,N-dimethylformamide (40 ml) were successively added imidazole (3.96 g) and tert-butyldimethylsilyl chloride (7.52 g) and the solution was stirred at room temperature for 14 hours. The reaction mixture was quenched by the addition of water (100 ml) and extracted with ethyl acetate (100 ml×1). The extract was washed with water (100 ml×2), brine (100 ml×1), and dried over magnesium sulfate. Filtration followed by evaporation gave a colorless oil, which was chromatographed on silica gel (eluent:hexane/ethyl acetate) to give (2R)-N-benzyl-N-[2-(4-bromophenyl)ethyl]-2-[[tert-butyl(dimethyl)silyl]oxy]-2-(3-chlorophenyl)ethanamine (21.0 g) as a colorless oil.
Reaction SMILES: [BH4-].[Na+].[C:3]([NH:7][C:8]1[N:13]=[C:12]2[C:14](=[O:27])[CH2:15][CH2:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:18][C:11]2=[CH:10][CH:9]=1)([CH3:6])([CH3:5])[CH3:4]>CO>[C:3]([NH:7][C:8]1[N:13]=[C:12]2[C@H:14]([OH:27])[CH2:15][CH2:16][C@@H:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[C:20]=3[F:26])[CH2:18][C:11]2=[CH:10][CH:9]=1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)Nc1ccc2c(n1)C(=O)CC[C@@H](c1cccc(F)c1F)C2
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)Nc1ccc2c(n1)[C@H](O)CC[C@@H](c1cccc(F)c1F)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
SODIUM BOROHYDRIDE (0.072 g, 1.893 mmol) was added to the MeOH (10 mL) solution of (R)-2-(tert-butylamino)-6-(2,3-difluorophenyl)-7,8-dihydro-5H-cyclohepta[b]pyridin-9(6H)-one (0.2173 g, 0.631 mmol) at rt. The reaction was stirred at room temperature for 1 hour. LCMS showed the reaction was finished. The solvent was removed via vacuum. The crude was separated via flash column eluted with ethyl acetate in hexane from 0 to 35% to 65% to give two compounds. This is the less polar compound (134.9 mg, 61%). HPLC tR=2.43 min; MS (ESI)[M+H+]=347.33; 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 7.18 (d, J=8.06 Hz, 1H) 6.99-7.11 (m, 3H) 6.28 (d, J=8.06 Hz, 1H) 4.76 (dd, J=11.33, 2.01 Hz, 1H) 4.53 (br. s., 1H) 3.03 (d, J=13.85 Hz, 1H) 2.89 (d, J=4.28 Hz, 1H) 2.64 (d, J=14.10 Hz, 1H) 2.28 (dd, J=12.59, 2.01 Hz, 1H) 2.13 (dd, J=9.82, 3.78 Hz, 2H) 1.58-1.71 (m, 1H) 1.42-1.55 (m, 9H).
Reaction SMILES: [CH2:1]([N:8]([CH3:21])[C:9](=O)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.B.O1CCCC1.CO.Cl>O1CCCC1>[CH2:1]([N:8]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([N+:17]([O-:19])=[O:18])=[CH:15][CH:16]=1)[CH3:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(Cc1ccccc1)C(=O)Cc1ccc([N+](=O)[O-])cc1
Agent: B
Agent: Cl
Solvent: C1CCOC1
Solvent: CO
Product: CN(CCc1ccc([N+](=O)[O-])cc1)Cc1ccccc1
Yield: 100.1 %

Procedure:
To a stirred solution of N-benzyl-N-methyl-4-nitrophenylacetamide (step (b), 24.9 g, 87.6 mmol) in tetrahydrofuran (270 ml) under nitrogen, was added dropwise 1.0M borane-tetrahydrofuran (245 ml, 245 mmol). The reaction was heated at reflux for 2 hours, cooled, then methanol (53 ml) was added dropwise followed by the cautious addition of aqueous 2.5N hydrochloric acid (100 ml). The resulting mixture was refluxed for 1 hour and then concentrated on a rotary evaporator to remove the organic solvents. Water was added to the residue and the mixture was basified to pH 11 with 2.5N aqueous sodium hydroxide. The product was then extracted into three portions of methylene chloride. The combined extracts were washed with water, dried over magnesium sulfate, filtered and concentrated to yield 23.7 g (100%) of N-benzyl-N-methyl[2-(4-nitrophenyl)ethyl]amine. The hydrochloride salt, prepared in methanol and recrystallized from 95% ethanol-ether, melted at 222°-4° C. (dec).
Reaction SMILES: [CH2:1]([CH:4]1[C:13]2[NH:12][C:11](=[O:14])[CH:10]=[CH:9][C:8]=2[CH2:7][C:6]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:5]1)[CH:2]=[CH2:3].I[CH3:20]>C(Cl)(Cl)Cl>[CH2:1]([CH:4]1[C:13]2[N:12]=[C:11]([O:14][CH3:20])[CH:10]=[CH:9][C:8]=2[CH2:7][C:6]2([O:18][CH2:17][CH2:16][O:15]2)[CH2:5]1)[CH:2]=[CH2:3]
Reactant: CI
Reactant: C=CCC1CC2(Cc3ccc(=O)[nH]c31)OCCO2
Solvent: ClC(Cl)Cl
Product: C=CCC1CC2(Cc3ccc(OC)nc31)OCCO2
Yield: 89.8 %

Procedure:
A mixture of Ag2CO3 (7.17 g, 26.2 mmol), pyridone 3 (5.4 g, 21.9 mmol), and iodomethane (8.0 mL, 131 mmol) in 200 mL of CHCl3 was refluxed in the dark with stirring. After cooling, filtration, and concentration, the residue was purified by flash chromatography with 25% ethyl acetate in hexanes as the eluent to afford 5.14 g (90%) of 4a: IR (neat) 2953, 1589, 1487, 830 cm-1 ; 1H NMR δ7.22 (d, 1H, J=8.2 Hz), 6.52 (d, 1H, J=8.2 Hz), 5.80 (m, 1H), 5.03 (m, 2H), 4.01 (m, 4H), 3.89 (s, 3H), 3.11 (m, 1H), 2.96 (m, 2H), 2.80 (dd, 1H, J=16.0, 2.4 Hz), 2.50 (m, 1H), 2.06 (m, 1H), 1.80 (dd, 1H, J=13.2, 10.9 Hz); 13C NMR δ162.0, 154.5, 139.7, 137.1, 121.6, 116.3, 108.1, 107.9, 64.5, 64.4, 53.1, 39.4, 38.1, 38.0, 36.6; MS m/z 261 (M+), 246, 220, 174, 148.
Reaction SMILES: CC1(C)N([Br:9])C(=O)N(Br)C1=O.[CH3:12][CH:13]([CH3:26])[CH2:14][O:15][C:16](=[O:25])[NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([F:24])[CH:19]=1.S([O-])([O-])=O.[Na+].[Na+]>O>[Br:9][C:21]1[CH:22]=[CH:23][C:18]([NH:17][C:16](=[O:25])[O:15][CH2:14][CH:13]([CH3:26])[CH3:12])=[CH:19][C:20]=1[F:24]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CC(C)COC(=O)Nc1cccc(F)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(C)COC(=O)Nc1ccc(Br)c(F)c1
Reaction time: 12 h

Procedure:
To a mixture of 3-fluoroaniline (I, 29.058 g, 261.5 mmol) in methylene chloride (116 ml) is added a mixture of potassium carbonate (27.26 g, 197.3 mmol, 0.75 eq) in water (116 ml) at 20-25°. The mixture is warmed to 32°, and isobutyl chloroformate (38.5 g, 282 mmol, 1.08 eq) is added over 13 min while maintaining 30-35° with mild cooling. The mixture is stirred at 30-35° for 2.5 hr until the reaction is complete to give 2-methylpropyl-(3-fluorophenyl)carbamate as determined by GC [GC method A, <0.1 area % 3-fluoroaniline; RT (3-fluoroaniline)=3.97 min, RT=14.2 min]. Aqueous ammonia (29.3 wt %, 4.20 ml, 65.0 mmol, 0.25 eq) is added and the mixture stirred at 30-35° for 15 min. The mixture is cooled to 20-25° and the pH adjusted from 8.7 to 1.9 with hydrochloric acid (37 wt %, 6.36 g, 64.5 mmol, 0.25 eq). The phases are separated and the aqueous washed with methylene chloride (58 ml). The combined organics are washed with water (118 ml) and the water wash back extracted with methylene chloride (58 ml). [In a prior experiment crystallization at this point from heptane at −30° gave 2-methylpropyl-(3-fluorophenyl)carbamate analytically pure in 98.1% yield.]. Dibromantin (57.37 g;, 200.6 mmol, 0.767 eq) and water (174 ml) are added to the combined organics and the mixture stirred at 40° for 12 hr until complete as measured by HPLC (<0.1 2-methylpropyl-(3-fluorophenyl)carbamate). The mixture is cooled to 20-25° and clarified on a “C” frit by vacuum filtration. The phases are separated and the organic (lower) phase added to a mixture of sodium sulfite (33.06 g, 262.3 mmol, 1.00 eq) in water (220 ml) with good agitation. The phases are separated and the organic phase washed with water (150 ml). Serial back-extracted the clarified solids and all aqueous with a single portion of methylene chloride (150 ml). Added heptane (520 ml) to the combined organic phases and concentrated under reduced pressure. Heptane (240 ml) is added, the mixture cooled to −30°, the precipitate is collected by vacuum filtration, washed with cold heptane (150 ml) and dried in a nitrogen stream to give the title compound; mp=79-82°; TLC Rf=0.41 (ethyl acetate/hexanes, 5/95); HPLC (method A) rt=6.75 min; NMR (CDCl3, 400 MHz) d 7.41, 6.96, 6.87, 3.96, 1.97 and 0.96; CMR (CDCl3, 75 MHz) d 159.2, 153.4, 139.0, 133.3, 115.1, 107.1, 102.0, 71.8, 27.9 and 19.0; MS (CI, NH3) m/Z (relative intensity) 310 (9.3), 309 (100), 308 (6.1), 307 (100), 292 (11), 291 (18), 290 (7.5) and 289 (19)
Reaction SMILES: [CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][C:13](=O)[CH2:12][C:11]1([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:21]([NH2:25])[CH2:22][CH2:23][CH3:24]>>[CH3:1][CH:2]([O:9][N:10]1[C:15]([CH3:17])([CH3:16])[CH2:14][CH:13]([NH:25][CH2:21][CH2:22][CH2:23][CH3:24])[CH2:12][C:11]1([CH3:20])[CH3:19])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCN
Reactant: CC(ON1C(C)(C)CC(=O)CC1(C)C)c1ccccc1
Product: CCCCNC1CC(C)(C)N(OC(C)c2ccccc2)C(C)(C)C1

Procedure:
The title compound, a colorless oil, is prepared from 1-alpha-methylbenzyloxy-2,2,6,6-tetramethylpiperidine-4-one and butylamine according to the procedure given in Example 35 except that acetonitrile is substituted for tetrahydrofuran and the molecular sieves are omitted.
Reaction SMILES: [CH2:1]([C:5]1[NH:9][C:8]([CH:10]=[O:11])=[C:7]([Cl:12])[N:6]=1)[CH2:2][CH2:3][CH3:4].[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32]Br)=[CH:28][CH:27]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[C:13]([O:17][C:18]([C:20]1[C:21]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][N:9]3[C:8]([CH:10]=[O:11])=[C:7]([Cl:12])[N:6]=[C:5]3[CH2:1][CH2:2][CH2:3][CH3:4])=[CH:28][CH:27]=2)=[CH:22][CH:23]=[CH:24][CH:25]=1)=[O:19])([CH3:16])([CH3:15])[CH3:14]
Reactant: CCCCc1nc(Cl)c(C=O)[nH]1
Reactant: CC(C)(C)OC(=O)c1ccccc1-c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCc1nc(Cl)c(C=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.1 %

Procedure:
2-Butyl-5-chloro-3H-imidazole-4-carbaldehyde (9.9 g, 53.3 mmol), 4′-bromomethylbiphenyl-2-carboxylic acid t-butyl ester (18.5 g, 53.3 mmol), and K2CO3 (7.4 g, 53.3 mmol) were combined in DMF (200 mL) and stirred at room temperature overnight. The reaction was quenched with water, extracted with EtOAc, washed with saturated aqueous NaCl, dried over MgSO4, filtered and concentrated. The crude mixture was purified by flash chromatography (0-40% EtOAc:hexanes) to yield 21.5 g of intermediate (4a).
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Reactant: CC(C)N=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and iso-propyl isocyanate (25 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (74 mg, 66%).
Reaction SMILES: [CH3:1][P:2]([CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])(=O)[O:3]C.S(Cl)([Cl:31])=O>>[CH3:1][P:2]([Cl:31])([CH2:6][O:7][C:8]1[CH:13]=[C:12]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[Cl:25])[CH:11]=[CH:10][C:9]=1[N+:26]([O-:28])=[O:27])=[O:3]
Reactant: O=S(Cl)Cl
Reactant: COP(C)(=O)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]
Product: CP(=O)(Cl)COc1cc(Oc2ccc(C(F)(F)F)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
Following the procedure of Example 4, methyl P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)-phenoxymethylphosphinate is reacted with thionyl chloride to give P-methyl-2-nitro-5-(2-chloro-4-trifluoromethylphenoxy)phenoxymethylphosphinic chloride.