Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([S:26][CH3:27])[C:4]=1[C:5]([NH:7][CH:8]1[CH2:17][O:16][CH2:15][CH2:14][C:9]21OCC[O:10]2)=[O:6].Cl>O1CCCC1.O1CCOCC1.O.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:23])[F:24])[CH:19]=[C:18]([S:26][CH3:27])[C:4]=1[C:5]([NH:7][CH:8]1[C:9](=[O:10])[CH2:14][CH2:15][O:16][CH2:17]1)=[O:6]
Reactant: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC12OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: COc1cc(C(F)(F)F)cc(SC)c1C(=O)NC1COCCC1=O

Procedure:
2-Methoxy-6-methylsulfanyl-4-trifluoromethyl-N-(1,4,8-trioxa-spiro[4.5]dec-6-yl)-benzamide (intermediate B, 200 mg, 0.49 mmol) was dissolved in 1 mL tetrahydrofuran and 1 mL 4N HCl in dioxane was added. The reaction mixture was refluxed for 2 h. The mixture was diluted with water, ethyl acetate and neutralized with saturated sodium bicarbonate solution. The mixture was extracted two times with ethyl acetate. The combined organic layers were dried with sodium sulfate, filtered and evaporated. The crude product was used for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([Cl:29])[C:5]2[C:10]([C:11]#[C:12][C@:13]([CH3:17])([OH:16])[CH2:14][OH:15])=[CH:9][N:8]([CH2:18][C:19]3[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=3)[C:6]=2[N:7]=1.[CH3:30][O:31][C@@:32]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)([C:36]([F:39])([F:38])[F:37])[C:33](Cl)=[O:34].CCN(CC)CC.CCOC(C)=O.C(Cl)Cl>C1COCC1>[F:37][C:36]([F:38])([F:39])[C@@:32]([O:31][CH3:30])([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[C:33]([O:15][CH2:14][C@:13]([OH:16])([CH3:17])[C:12]#[C:11][C:10]1[C:5]2[C:4]([Cl:29])=[N:3][C:2]([NH2:1])=[N:7][C:6]=2[N:8]([CH2:18][C:19]2[C:24]([CH3:25])=[C:23]([O:26][CH3:27])[C:22]([CH3:28])=[CH:21][N:20]=2)[CH:9]=1)=[O:34]
Reactant: COc1c(C)cnc(Cn2cc(C#C[C@](C)(O)CO)c3c(Cl)nc(N)nc32)c1C
Reactant: CO[C@@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1c(C)cnc(Cn2cc(C#C[C@](C)(O)COC(=O)[C@](OC)(c3ccccc3)C(F)(F)F)c3c(Cl)nc(N)nc32)c1C
Temperature: 70 °C

Procedure:
A mixture of (S)-4-(2-amino-4-chloro-7-((4-methoxy-3,5-dimethylpyridin-2-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-2-methylbut-3-yne-1,2-diol (see example 52) (18 mg), (S)-(+)-α-methoxy-alpha-(trifluoromethyl)phenylacetyl chloride (45 μL), and Et3N (50 μL) in THF (3.0 mL) was heated to 70° C. for 2 h, and then to 40° C. overnight. Preparative TLC (EtOAc/DCM 25:65) gave the title compound, as a solid. HPLC Rt=6.45 min.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[Cl:28][C:29]1[CH:30]=[C:31]([CH2:35][CH2:36][C:37](OCC)=[O:38])[CH:32]=[N:33][CH:34]=1.C(OCC)(=O)C>C1COCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH2:17][C:37](=[O:38])[CH2:36][CH2:35][C:31]3[CH:32]=[N:33][CH:34]=[C:29]([Cl:28])[CH:30]=3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)CCc1cncc(Cl)c1
Reactant: CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C(CCc1cncc(Cl)c1)CS(=O)(=O)N1CCN(c2ccc(Cl)cc2)CC1
Reaction time: 0.67 h
Yield: 61.2 %

Procedure:
To a stirred solution of 1-(4-chlorophenyl)-4-(methylsulfonyl)piperazine (235 mg, 0.85 mmol) in dry THF (7.5 mL) at −10° C. under an argon atmosphere was added dropwise over 4 minutes a solution of LiHMDS (1.71 mL of a 1.0 M solution in THF, 1.71 mmol). The solution was then stirred at this temperature for 40 minutes. A solution of ethyl 3-(5-chloropyridin-3-yl)propanoate (201 mg, 0.94 mmol) in THF (1 mL) was then added dropwise via cannula over a period of 5 minutes. The reaction was stirred at −10° C. for an additional 30 minutes before being quenched with saturated aqueous ammonium chloride solution (5 mL). Volatiles were removed in vacuo, and the residue was extracted with CH2Cl2 (3×5 mL). The combined organic extracts were washed with water (10 mL) and brine (10 mL) before being dried, (MgSO4), filtered and concentrated in vacuo. Flash chromatography (silica gel, 50% ethyl acetate in hexane) gave the title compound (228 mg, 0.52 mmol) and recovered ethyl 3-(5-chloropyridin-3-yl)propanoate (74 mg, 0.35 mmol).
Reaction SMILES: N(C(C)C)C(C)C.[Li]CCCC.CCCCCC.[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[CH2:27][C:28]([O:30][CH3:31])=[O:29].I[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]>C1COCC1>[CH3:31][O:30][C:28](=[O:29])[CH:27]([C:21]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:20]=1[Cl:19])[CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Reactant: CCOC(=O)CCCI
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CC(C)NC(C)C
Product: CCOC(=O)CCCC(C(=O)OC)c1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To a solution of i-Pr2NH (0.921 mL, 1.2 eq) in anh. THF (22 mL), at 0° C., under N2, was added a 1.6 M solution of BuLi in hexane (3.42 mL, 1 eq) and the mixture was stirred at 0° C. for 10 min. It was then cooled to −78° C. and a solution of methyl 2,4-dichlorophenylacetate (1.2 g, 5.478 mmol) in anh. THF (3.3 mL) was added dropwise. The mixture was stirred at −78° C. for 45 min before the addition of a solution of ethyl 4-iodobutyrate (1.72 g, 1.3 eq) in anh. THF (2 mL). The cooling bath was then removed and the mixture was stirred at r.t. for 4 hr. The solvents were evaporated under reduced pressure. The residue was dissolved in CH2Cl2, washed with water (2×25 mL) and brine (1×25 mL) and dried over anh. Na2SO4. The solids were filtered and the solvent evaporated. The crude product was purified by flash chromatography (silica gel, cHex/EtOAc 9:1). Mixed fractions were repurified with the same eluent. The title compound was obtained as a pale yellow oil (1.36 g, 4.088 mmol, 75%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:22][CH2:23][CH2:24][NH:25][CH3:26])[C:9]2=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>CC(C)=O>[CH2:34]([N:25]([CH2:24][CH2:23][CH2:22][N:10]1[C:9](=[O:27])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:13][C:12]2[CH:14]=[CH:15][C:16]3[C:21]([C:11]1=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:35]=[CH2:36]
Reactant: C=CCBr
Reactant: CNCCCN1C(=O)C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)CCCN1C(=O)C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-1-[3-(methylamino)propyl]-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (1.79 g), potassium carbonate (2.18 g) and acetone (50 ml) is added allyl bromide (0.65 g) under ice cooling, and the mixture is stirred at room temperature overnight. The insoluble materials are filtered off and acetone is distilled off, and the oily residue is purified by silica gel column chromatography (eluent, chloroform:methanol=20:1) to give 1-[3-(N-allyl-N-methylamino)propyl]-3-(4-chlorophenyl)-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one as oil.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:8]1[CH:12]=[CH:11][CH2:10][CH2:9]1.C([O-])(=O)C.[K+].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[N+](CCCC)(CCCC)(CCCC)CCCC.[Cl-].C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.CN(C=O)C>[C:2]1([CH:12]2[CH2:11][CH:10]=[CH:9][O:8]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Ic1ccccc1
Reactant: C1=COCC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: O
Solvent: CN(C)C=O
Product: C1=COC(c2ccccc2)C1
Yield: 58 %

Procedure:
Table 1, Entry 5. In the reaction tube were mixed iodobenzene (0.102 g, 0.5 mmol), dihydrofuran (0.350 g, 5.0 mmol), palladium acetate (0.00281 g, 0.0125 mmol), potassium acetate (0.147 g,1.5 mmol), n-Bu4NCl (0.139 g, 0.5 mmol), triphenylphosphine (0.00328 g, 0.0125 mmol) and 1.0 ml DMF.under nitrogen. The contents of the flask were irradiated for 6.00 min with an effect of 60 W. After cooling, the product mixture was poured into 25 ml water and was extracted three times with 25 ml DCM. The combined extracts were washed with 25 ml water and concentrated to an oil. The crude product was purified by column chromatography on silica gel using pentaneldiethyl ether (19/1) as the eluent. The yield was 58% (yellow oil).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[CH:3]=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([O:27][CH3:28])=[C:22](B(O)O)[CH:23]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(COC)OC>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([O:27][CH3:28])=[C:20]([C:2]2[N:7]=[C:6]([NH2:8])[N:5]=[C:4]([NH:9][C:10]3[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=3)[CH:3]=2)[CH:19]=1
Reactant: Cc1ccc(Nc2cc(Cl)nc(N)n2)cc1
Reactant: COc1ccc(Cl)cc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: COCCOC
Product: COc1ccc(Cl)cc1-c1cc(Nc2ccc(C)cc2)nc(N)n1
Temperature: 92.5 °C
Reaction time: 18 h
Yield: 85.8 %

Procedure:
To a mixture of 6-chloro-N*4*-p-tolyl-pyrimidine-2,4-diamine (2.8 g, 11.9 mmol), 5-chloro-2-methoxy-phenyl boronic acid (3.96 g, 21.5 mmol), palladium (II) acetate (0.2 g, 0.9 mmol) and triphenylphosphine (0.47 g, 1.8 mmol) was added a solution of sodium carbonate (6.36 g, 60 mmol) in water (20 ml) followed by glyme (100 ml). The mixture was stirred under an argon atmosphere at 90-95° C. for 18 hours. Filtration and concentration of the filtrate yielded a residue which was purified by flash chromatography on silica gel eluting with ethyl acetate-hexane (1:3) to provide the title compound (3.48 g, 86% yield) as a white powder. 1H NMR (DMSO-d6) δ 2.27 (s, 3H, CH3), 3.88 (s, 3H, CH3), 6.27 (s, 2H, NH2), 6.72 (s, 1H, Ar), 7.10 (d, 2H, J=8.3 Hz, Ar), 7.16 (d, 1H, J=8.9 Hz, Ar), 7.44 (dd, 1H, J=8.9 Hz, J=2.8 Hz, Ar), 7.63 (d, 2H, J-8.3 Hz, Ar), 7.92 (d, 1H, J=2.8 Hz, Ar), 9.10 (s, 1H, NH).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([NH2:10])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.Cl.[CH2:12]([N:19]([CH2:23][CH2:24]Cl)[CH2:20][CH2:21]Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(C(C)C)CC)(C)C>ClC1C=CC=CC=1>[CH2:12]([N:19]1[CH2:23][CH2:24][N:10]([C:5]2[CH:6]=[CH:7][CH:8]=[C:9]3[C:4]=2[CH:3]=[CH:2][NH:1]3)[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Nc1cccc2[nH]ccc12
Reactant: ClCCN(CCCl)Cc1ccccc1
Agent: Cl
Solvent: Clc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: c1ccc(CN2CCN(c3cccc4[nH]ccc34)CC2)cc1
Temperature: 130 °C
Yield: 24.9 %

Procedure:
A mixture of 500 mg (3.78 mmole) 1H-indol-4-yl-amine, 993 mg (3.78 mmole) N-benzyl-bis(2-chloroethyl)amine hydrochloride, and 1.32 mL (7.6 mmole) diisopropylethylamine in 10 mL chlorobenzene was heated at 130° C. for 24 hours. Another 0.66 mL (3.8 mmole) diisopropylethylamine was added and the mixture was heated at 130° C. for an additional 5 hours. The mixture was partitioned between 25 mL ethyl acetate and 10 mL 5% sodium hydroxide. The organic phase was extracted with 10 mL 3 N hydrochloric acid. The aqueous phase was washed with 15 mL ethyl ether, then made basic with 50% sodium hydroxide. The product was extracted with 25 mL dichloromethane, the organic phase was washed with 10 mL water, dried (magnesium sulfate) and concentrated under reduced pressure. 4-(4-benzyl-piperazin-1-yl)-1H-indole (274 mg) was isolated as the hydrochloride salt from ethyl ether.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH3:9])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])[O-].[Na+].[Na+].[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26](OB(O)O)=[CH:25][CH:24]=1.[Cl-].[Na+]>C(O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:2]2[CH:3]=[C:4]([CH:8]([NH:10][C:11](=[O:14])[O:12][CH3:13])[CH3:9])[CH:5]=[CH:6][CH:7]=2)=[CH:25][CH:24]=1
Reactant: COC(=O)NC(C)c1cccc(Br)c1
Reactant: COc1ccc(OB(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)NC(C)c1cccc(-c2ccc(OC)cc2)c1
Temperature: 25 °C
Yield: 144.7 %

Procedure:
1.00 g of methyl N-[1-(3-bromophenyl)ethyl]carbamate, 0.41 g of sodium carbonate in aqueous solution (20 ml) and 0.09 g of tetrakis(triphenylphosphine)palladium (0) were added to toluene (40 ml) under a nitrogen atmosphere. The resulting solution was mixed with 0.59 g of 4-methoxyphenylboric acid in ethanol (20 ml) at room temperature with stirring and refluxed under heating for 2 hours. After the reaction, the reaction solution was cooled to room temperature, poured into saturated aqueous sodium chloride and extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate and evaporated under reduced pressure for removal of the solvent. The residue was purified by silica gel column chromatography to give 1.45 g of methyl N-{1-[3-(4-methoxyphenyl)phenyl]ethyl}carbamate as pale yellow crystals. m.p. 117-119° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:22])[C@H:9]1[CH2:14][CH2:13][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19]([OH:21])=O)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:25][CH2:26][CH3:27])[CH3:24].CN1CCOCC1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([C@H:9]1[CH2:10][CH2:11][C@H:12]([CH2:15][CH2:16][CH2:17][CH2:18][C:19](=[O:21])[N:25]([CH2:26][CH3:27])[CH2:23][CH3:24])[CH2:13][CH2:14]1)[CH3:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCNCC
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CC[C@H](CCCCC(=O)O)CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCN(CC)C(=O)CCCC[C@H]1CC[C@H](N(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C

Procedure:
To 1 g (3.19 mmol) trans-5-[4-(tert-Butoxycarbonyl-methyl-amino)-cyclohexyl]-pentanoic acid in 37 ml CH2Cl2 was added 0.5 ml (4.8 mmol, 1.5 eq) diethylamine and 0.53 ml (4.79 mmol, 1.5 eq) NMM. The solution was cooled to 0° C. and 795 mg (4.15 mmol, 1.3 eq) EDCI and 98 mg (6.4 mmol) HOBT were added. The mixture was stirred at RT over night, partitioned between CH2Cl2 and a saturated aqueous solution of NaHCO3. The organic phase was washed with KHSO4 and brine, dried over Na2SO4 and evaporated. Column chromatography with EtOAc/hexane 1:1 gave 1.05 g (86%) trans-[4-(4-Diethylcarbamoyl-butyl)-cyclohexyl]-methyl-carbamic acid tert-butyl ester as colorless liquid MS: 369 (MH+).
Reaction SMILES: [NH2:1][S:2]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3].CCC(N=[C:23]=[O:24])C.N12CCN(CC1)CC2.C(Cl)(Cl)=O.[N-]=C=O>C1(C)C(C)=CC=CC=1>[N:1]([S:2]([C:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[S:7][C:6]=1[C:14]([O:16][CH3:17])=[O:15])(=[O:4])=[O:3])=[C:23]=[O:24]
Reactant: COC(=O)c1sc2ccccc2c1S(N)(=O)=O
Reactant: CCC(C)N=C=O
Agent: C1CN2CCN1CC2
Agent: O=C(Cl)Cl
Agent: [N-]=C=O
Solvent: Cc1ccccc1C
Product: COC(=O)c1sc2ccccc2c1S(=O)(=O)N=C=O

Procedure:
Methyl 3-aminosulfonylbenzothiophene-2-carboxylate (10 grams), 75 ml of xylene, 3.5 g. of 3-butyl isocyanate and 0.2 g. of 1,4-diazabicyclo[2,2,2]octane in admixture were heated to reflux under a dry ice cooled reflux condenser for 10 minutes. Phosgene gas was passed into the system until the reflux temperature dropped to 120°. The addition was discontinued until the temperature rose to 130° and then additional phosgene was added to cause the temperature to drop to 120°. The cycle was repeated until the reflux temperature remained at 120° for one half hour with no further addition of phosgene. The mixture was then cooled, filtered and the filtrate was concentrated to remove the xylene and recovered butyl isocyanate. The residue thus obtained showed absorption peaks by infrared at 2200 and 1700 cm-1 consistent for the isocyanate and carboxylate groups. This product was used for the synthesis of the herbicides of this invention without further purification. The isocyanate derivatives of Tables I-Ic can be prepared from the appropriately substituted sulfonamides by the method set forth in Examples 1 and 2.
Reaction SMILES: [F:1][C:2]1([F:8])[CH2:5][CH:4]([CH2:6][OH:7])[CH2:3]1.[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>C(Cl)Cl>[Br:9][C:10]1[CH:15]=[CH:14][C:13]([S:16]([O:7][CH2:6][CH:4]2[CH2:5][C:2]([F:8])([F:1])[CH2:3]2)(=[O:18])=[O:17])=[CH:12][CH:11]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Reactant: OCC1CC(F)(F)C1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(OCC1CC(F)(F)C1)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
A round bottom flask was charged with (3,3-difluorocylobutyl)methanol (1.0 g, 8.2 mmol, 1.0 equiv), 4-bromobenzenesulphonyl chloride (2.2 g, 8.6 mmol, 1.05 equiv) and CH2Cl2 (50 mL). The mixture was cooled to 0° C. and triethylamine (2.07 g, 2.89 mL, 20.5 mmol, 2.5 equiv) was added via syringe. The mixture stirred for 12 h with warming to rt. After this time 1.0 M aq HCl (50 mL) was added. The layers were separated, the organic layer was extracted with CH2Cl2 (50 mL) and the combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated. The compound was purified by flash chromatography on silica, eluting with 0-30% EtOAc in hexanes. This afforded (3,3-difluorocyclobutyl)methyl 4-bromobenzenesulfonate (2.7 g, 95%) as an off white solid.
Reaction SMILES: N[C:2]1[N:3]=[C:4]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:8]([Br:20])[C:6]=2[N:7]=1.N1C=CC=CC=1.[FH:35].N(OC(C)(C)C)=O.C([O-])(O)=O.[Na+].C([O-])([O-])=O.[Na+].[Na+]>N1C=CC=CC=1>[CH2:22]([O:21][C:4]1[C:5]2[N:10]([CH2:11][O:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH:9]=[C:8]([Br:20])[C:6]=2[N:7]=[C:2]([F:35])[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Nc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Reactant: F
Agent: CC(C)(C)ON=O
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Product: Fc1nc(OCc2ccccc2)c2c(n1)c(Br)cn2COCc1ccccc1
Temperature: 0 °C

Procedure:
A solution of the product from Example 11.2 (0.9 g) in dry pyridine (40 mL) was cooled in an ice bath while hydrogen fluoride-pyridine (˜65%) (15 mL) was added slowly keeping the temperature ≦10° C. The resulting solution was cooled to 0° C., tert-butyl nitrite (3 mL) was added, and the solution was stirred in the ice bath for 3 h and then poured carefully onto saturated aq NaHCO3 (500 mL) adding Na2CO3 as required to keep the solution basic. The mixture was extracted (×2) with chloroform which was dried and concentrated to dryness. Chromatography gave 4-benzyloxy-5-N-benzyloxymethyl-7-bromo-2-fluoropyrrolo[3,2-d]pyrimidine (0.63 g) as a solid. 13C NMR (CDCl3) δ 158.5 (JC,F=17 Hz), 157.5 (JC,F=213 Hz), 150.6 (JC,F=16 Hz), 136.8, 135.5, 133.9, 129.1, 128.9, 128.9, 128.5, 127.9, 114.1, 91.9, 77.9, 71.1, 70.0.
Reaction SMILES: [CH:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9]/[C:10](/[C:13]([CH3:15])=O)=[N:11]\[OH:12].Cl.[OH-].[Na+]>C(O)(=O)C>[CH3:9][C:10]1[N+:11]([O-:12])=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[O:8][C:13]=1[CH3:15]
Reactant: O=Cc1ccccc1
Reactant: CC(=O)/C(C)=N/O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: Cc1oc(-c2ccccc2)[n+]([O-])c1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.4 %

Procedure:
500 g of benzaldehyde and 476 g of diacetylmonoxime were suspended in 1 L of acetic acid and cooled in an ice bath. At internal temperature of 7° C., hydrochloride gas is slowly blown in to be saturated. At room temperature, the mixture was stirred overnight. The reaction mixture was poured into 1.5 kg of ice, and neutralized with 25% sodium hydroxide solution. The crystalline precipitate was isolated by filtration and washed with 1 L of water and 1 L of diisopropylether. The obtained crystals were dissolved in 3 L of chloroform and insoluble matter was filtered off. The filtrate was dried with 200 g of anhydrous sodium sulfate, filtered, and the filtrate was concentrated in vacuo. 3 L of IPE was added to the residue to be crystallized, the crystal was isolated by filtration, dried under reduced pressure at 50° C. for 1 hour, and 440 g of the subject compound was prepared.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([Br:7])[S:4][C:3]=1[C:8]([NH2:10])=[O:9].C(N(CC)CC)C.[O:18]1[CH2:22][CH2:21][CH2:20][CH:19]1[C:23](Cl)=O>O1CCCC1>[Br:7][C:5]1[S:4][C:3]2[C:8](=[O:9])[NH:10][C:23]([CH:19]3[CH2:20][CH2:21][CH2:22][O:18]3)=[N:1][C:2]=2[CH:6]=1
Reactant: O=C(Cl)C1CCCO1
Reactant: NC(=O)c1sc(Br)cc1N
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=c1[nH]c(C2CCCO2)nc2cc(Br)sc12
Temperature: 25 °C
Yield: 97.9 %

Procedure:
To a mixture of 3-amino-5-bromothiophene-2-carboxamide (120 mg) produced in Example 1, step D, triethylamine (0.083 mL) and tetrahydrofuran (3.0 mL) was added tetrahydrofuran-2-carbonylchloride (80 mg) with stirring at room temperature. The reaction mixture was stirred for 10 min, and the reaction system was concentrated under reduced pressure. 2M Aqueous sodium hydroxide solution (1.0 mL) was added to the residue, and the mixture was stirred with heating at 120° C. for 2 hr. The mixture was extracted with ethyl acetate, washed with brine and dried over anhydrous sodium sulfate. Insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (160 mg) as a pale-yellow solid.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5]([CH:10]=[CH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[OH:20])=[O:13])[CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1>CO>[OH:20][C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[C:12](=[O:13])[CH2:11][CH2:10][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[CH:3]=[CH:2][NH:1]2
Reactant: O=C(C=Cc1cccc2[nH]ccc12)c1ccccc1O
Solvent: CO
Product: O=C(CCc1cccc2[nH]ccc12)c1ccccc1O
Yield: 71 %

Procedure:
A mixture of 200 mg of the product of Step A in 10 ml of methanol was hydrogenated in the presence of palladized carbon until absorption ceased and was then filtered. Chromatography over silica and elution with a 6-3-1 cyclohexane-dichloromethane-triethylamine mixture yielded 143 mg of 1-[2-hydroxy-phenyl]-3-[1H-indol-4-yl]-1-propanone melting at 143° C.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH:20]=[CH:21][CH:22]=1)[CH:12]([OH:19])[CH2:13][NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])C1C=CC=CC=1.[CH2:23]=O>>[OH:8][C:9]1[CH:10]=[C:11]([CH:12]2[O:19][CH2:23][N:14]([C:15]([CH3:16])([CH3:17])[CH3:18])[CH2:13]2)[CH:20]=[CH:21][CH:22]=1
Reactant: C=O
Reactant: CC(C)(C)NCC(O)c1cccc(OCc2ccccc2)c1
Product: CC(C)(C)N1COC(c2cccc(O)c2)C1

Procedure:
In the manner described in Example 32, m-(benzyloxy)-α-[(tert-butylamino)methyl]benzyl alcohol is reacted with formaldehyde to afford the oxazolidine derivative, which is debenzylated by the procedure of Example 28 to give the title compound.
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[C:3]=1[CH3:11].N([O-])=O.[Na+].S(=O)=O.N.COC1C(C)=C([S:28]([NH2:31])(=[O:30])=[O:29])C=CC=1>S(=O)(=O)(O)O.O.C(O)(=O)C.[Cu](Cl)Cl>[CH3:11][C:3]1[C:4]([N+:8]([O-:10])=[O:9])=[CH:5][CH:6]=[CH:7][C:2]=1[S:28]([NH2:31])(=[O:30])=[O:29]
Reactant: COc1cccc(S(N)(=O)=O)c1C
Reactant: Cc1c(N)cccc1[N+](=O)[O-]
Agent: Cl[Cu]Cl
Agent: N
Agent: O=N[O-]
Solvent: CC(=O)O
Solvent: O
Product: Cc1c([N+](=O)[O-])cccc1S(N)(=O)=O

Procedure:
7.5 gm (49 mmols) of 2-amino-6-nitro-toluene were dissolved in a mixture of 27.5 gm of concentrated sulfuric acid and 250 ml of water, and the solution was diazotized with a solution of 3.75 gm (54 mmols) of sodium nitrite in 7.5 ml of water at 0° to 5° C. After 2 hours the reaction mixture was added in portions to a previously prepared mixture of 90 ml of a sulfur dioxide solution in glacial acetic acid and a solution of 1.5 gm of copper(II)chloride in 4 ml of water at 20° C. The further treatment and the reaction with ammonia was carried out analogous to the method described for the preparation of 3-methoxy-2-methylbenzene sulfonamide (Example 8).