Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[C:14]([C:26](O)=[O:27])=[N:15][N:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:17]=2)=[O:11])=[CH:4][CH:3]=1.[NH4+:29].[OH-]>O1CCCC1.C(Cl)(=O)C(Cl)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][CH2:9][C:10]([NH:12][C:13]2[C:14]([C:26]([NH2:29])=[O:27])=[N:15][N:16]([CH2:18][CH2:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(CSc1ccc(Br)cc1)Nc1cn(CCc2ccccc2)nc1C(=O)O
Reactant: [NH4+]
Agent: O=C(Cl)C(=O)Cl
Agent: [OH-]
Solvent: C1CCOC1
Product: NC(=O)c1nn(CCc2ccccc2)cc1NC(=O)CSc1ccc(Br)cc1
Reaction time: 0.5 h
Yield: 19 %

Procedure:
113 mg (0.3 mM) of the compound obtained in Example 23 was dissolved in 1 ml of tetrahydrofuran to which 60 μl (0.7 mM) of oxalyl chloride was added dropwise, and the resulting mixture was stirred under a nitrogen atmosphere for 30 minutes. Subsequently, 70 μl of NH4OH was added thereto, and the resulting mixture was stirred under a nitrogen atmosphere for 1 hour. The solvent was distilled off under reduced pressure, and the resultant was extracted with ethyl acetate and brine. The organic solvent layer was dried over anhydrous sodium sulfate, filtered, and then distilled under reduced pressure. The resulting impure compound was purified by column chromatography (hexane:ethyl acetate=2:1), to obtain 21 mg (19%) of the title compound.
Reaction SMILES: O[C:2]1[CH:11]=[CH:10][C:9]2[CH2:12][CH2:13][CH2:14]C[N:7]3[C:8]=2[C:3]=1[C:4](=[O:16])[CH2:5][CH2:6]3.C[O:18][C:19]1C=CC=C2[C:20]=1[CH:21]=[CH:22]C(N)=C2>>[OH:18][C:19]1[C:11]2[C:2](=[C:3]3[C:8]4=[C:9]([CH2:12][CH2:13][CH2:14][N:7]4[CH2:6][CH2:5][C:4]3=[O:16])[CH:10]=2)[CH:22]=[CH:21][CH:20]=1
Reactant: O=C1CCN2CCCCc3ccc(O)c1c32
Reactant: COc1cccc2cc(N)ccc12
Product: O=C1CCN2CCCc3cc4c(O)cccc4c1c32

Procedure:
The title compound was synthesized in a similar manner as 11-hydroxy-2,3,5,6,7,8-hexahydro-1H-azepino[3,2,1-ij]quinolone starting from 5-methoxy-2-aminonaphthalene: 1H NMR (DMSO-d6) δ 9.55 (s, 1H), 7.55 (s, 1H); 7.08-7.00 (m, 2H), 6.48 (dd, 1H), 3.14 (q, 4H), 2.86 (q, 2H), 2.02-1.86 (m, 4H); MS expected 240 (C16H18NO, M+1), found 240.
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:30])[NH:9][CH:10]([C:23](=[O:29])[NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:11][S:12][CH2:13][C:14]([C:16]([O:18][CH2:19][CH2:20]CC)=[O:17])=O)[C:3]([OH:5])=[O:4].Cl.[NH2:32][OH:33]>>[NH2:1][CH:2]([CH2:6][CH2:7][C:8](=[O:30])[NH:9][CH:10]([C:23](=[O:29])[NH:24][CH2:25][C:26]([OH:28])=[O:27])[CH2:11][S:12][CH2:13][C:14]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:32][OH:33])[C:3]([OH:5])=[O:4]
Reactant: CCCCOC(=O)C(=O)CSCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O
Reactant: NO
Agent: Cl
Product: CCOC(=O)C(CSCC(NC(=O)CCC(N)C(=O)O)C(=O)NCC(=O)O)=NO

Procedure:
Similarly, by following the procedure of Example 30A and substituting 2-amino-4-[1-(carboxymethyl-carbamoyl)-2-(2-ethoxycarbonyl-2-oxo-ethylsulfanyl)-ethylcarbamoyl]-butyric acid with 2-amino-4-[2-(2-butoxycarbonyl-2-oxo-ethylsulfanyl)-1-(carboxymethyl-carbamoyl)-ethylcarbamoyl]-butyric acid and hydroxylamine HCl with another substituted hydroxylamine there are obtained the following compounds:
Reaction SMILES: [CH3:1][C:2]1[N:6]2[N:7]=[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([CH:20]4[CH2:22][CH2:21]4)=[O:19])[CH:14]=[CH:15][CH:16]=3)[CH:9]=[CH:10][C:5]2=[N:4][N:3]=1.[H-].[Na+].CN(C)C=O.[CH2:30](I)[CH3:31]>O>[CH2:30]([N:17]([C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([C:8]2[CH:9]=[CH:10][C:5]3[N:6]([C:2]([CH3:1])=[N:3][N:4]=3)[N:7]=2)[CH:12]=1)[C:18]([CH:20]1[CH2:22][CH2:21]1)=[O:19])[CH3:31]
Reactant: CCI
Reactant: Cc1nnc2ccc(-c3cccc(NC(=O)C4CC4)c3)nn12
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCN(C(=O)C1CC1)c1cccc(-c2ccc3nnc(C)n3n2)c1
Reaction time: 8 h

Procedure:
A mixture 1.57 g of N-[3-(3-methyl-1,2,4-triazolo[4,3-b]pyridazin-6-yl)phenyl]cyclopropanecarboxamide, 0.36 g of sodium hydride (50% in oil) and 200 ml of dry dimethylformamide under argon was stirred at room temperature for 1 hour and then 0.60 ml of ethyl iodide was added. After stirring overnight, the mixture was poured into 200 ml of water and extracted with dichloromethane. The combined extracts were dried, the solvent removed and the residue chromatographed on a silica gel column with dichlormethane-methanol (97:3) as solvent. The fractions containing product were combined, the solvent removed and the solid recrystallized from dichloromethane-hexane to give 0.80 g of pale yellow crystals, mp 149°-151° C.
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[C:12]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6].[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:30]=1O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C(Cl)Cl>[Cl:28][C:29]1[CH:34]=[C:33]([Cl:35])[C:32]([Cl:36])=[CH:31][C:30]=1[O:1][CH2:2][CH2:3][CH2:4][C:5]([N:7]1[C:16]2[C:11](=[C:12]([C:17]3[CH:18]=[N:19][N:20]([CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])[CH:21]=3)[CH:13]=[CH:14][CH:15]=2)[CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: Oc1cc(Cl)c(Cl)cc1Cl
Reactant: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCO)cn1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCOC(=O)Cn1cc(-c2cccc3c2CCCN3C(=O)CCCOc2cc(Cl)c(Cl)cc2Cl)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 31.8 %

Procedure:
In an oven dried 1-dram vial was a mixture of ethyl 2-(4-(1-(4-hydroxybutanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)-1H-pyrazol-1-yl)acetate (40 mg, 0.108 mmol), 2,4,5-trichlorophenol (34.0 mg, 0.172 mmol), triphenylphosphine (45.2 mg, 0.172 mmol) in CH2Cl2 (35.9 mL). DIAD (29.2 μL, 0.172 mmol) was added, and the reaction mixture was stirred at room temperature overnight. At the conclusion of this period, the reaction mixture was concentrated and purified by preparative HPLC (PHENOMENEX® Axia Luna column, 5μ, C18, 21.2×250 mm; 25 min gradient from 40% A:60% B to 0% A:100% B and 3 min 100% B (A=90% H2O/10% MeOH+0.1% TFA); (B=90% MeOH/10% H2O+0.1% TFA); detection at 220 nm) to afford the title compound (18.9 mg, 32% yield) as a colorless oil. LCMS, [M+H]+=550.1. 1H NMR (400 MHz, MeOD) δ 7.76 (s, 1H), 7.61 (s, 1H), 7.48 (s, 1H), 7.28-7.16 (m, 4H), 5.06 (s, 2H), 4.25 (q, J=7.1 Hz, 2H), 4.04 (br. s, 2H), 3.77 (t, J=6.8 Hz, 2H), 2.79 (t, J=7.0 Hz, 2H), 2.66 (br. s, 2H), 2.13 (dt, J=12.7, 6.4 Hz, 2H), 1.92-1.80 (m, 2H), 1.29 (t, J=7.1 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25](O)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1.Cl.[NH:36]1[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]1>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH:17]([CH3:18])[CH2:16][C:15]3[C:10](=[CH:11][C:12]([C:19]4[CH:20]=[CH:21][C:22]([C:25]([N:36]5[CH2:39][CH:38]([C:40]#[N:41])[CH2:37]5)=[O:26])=[N:23][CH:24]=4)=[CH:13][CH:14]=3)[CH2:9]2)[CH:5]=[C:4]([N:28]2[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]2)[N:3]=1
Reactant: N#CC1CNC1
Reactant: CC1Cc2ccc(-c3ccc(C(=O)O)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1
Agent: Cl
Product: CC1Cc2ccc(-c3ccc(C(=O)N4CC(C#N)C4)nc3)cc2CN1c1cc(N2CCN(C)CC2)nc(N)n1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 50A starting from 5-{2-[2-amino-6-(4-methylpiperazin-1-yl)pyrimidin-4-yl]-3-methyl-1,2,3,4-tetrahydroisoquinolin-7-yl}pyridine-2-carboxylic acid (Example 50A, Step 1) and azetidine-3-carbonitrile hydrochloride (Astatech, Cat. No. 52028). LCMS (M+H)+: m/z=524.3.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4]/[C:3](=[CH:7]/[C:8]([O:10][CH2:11][CH3:12])=[O:9])/[CH2:2]1.[NH3:13]>O1CCOCC1.CO>[NH2:13][C:3]1([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:4][CH2:5][CH2:6][O:1][CH2:2]1
Reactant: CCOC(=O)/C=C1/CCCOC1
Reactant: N
Solvent: C1COCCO1
Solvent: CO
Product: CCOC(=O)CC1(N)CCCOC1
Temperature: 150 °C

Procedure:
Ethyl (2Z)-dihydro-2H-pyran-3(4H)-ylideneacetate (Preparation 37, 1.21 g, 7.11 mmol) was stirred in 1,4-dioxane (7 mL) in a microwave vial. A solution of 7M ammonia in methanol (5 mL) was added and the reaction heated for 3 hours at 150° C. in a Biotage Initiator™ microwave. A further solution of 7M ammonia in methanol (2 mL) was added and the reaction heated again for 2 hours at 150° C. in the microwave. The reaction was concentrated in vacuo and the residue dissolved in a further portion of 7M ammonia in methanol (10 mL) and heated for a further 5 hours at 150° C. in the microwave. The reaction was concentrated in vacuo to afford the title compound along with the methyl ester where trans-esterification had occurred. The material was used without further purification in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:16][CH2:17][CH2:18][CH2:19][Cl:20])=[CH:5][C:6]([N+:13]([O-])=O)=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:12]=[C:7]([C:8]([O:10][CH3:11])=[O:9])[C:6]([NH2:13])=[CH:5][C:4]=1[O:16][CH2:17][CH2:18][CH2:19][Cl:20]
Reactant: [H][H]
Reactant: COC(=O)c1cc(OC)c(OCCCCl)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cc(OC)c(OCCCCl)cc1N
Yield: 94.4 %

Procedure:
In a 50 mL volume glass flask equipped with a stirrer, a thermometer, a reflux condenser and a gas inlet were placed 1.01 g (3.29 mmol) of methyl 5-methoxy-4-(3-chloropropoxy)-2-nitrobenzoate (purity: 99%) obtained in Reference Example III-4, 0.46 g of 10 wt. % palladium/carbon and 16 mL of methanol. The resulting mixture was heated to 30° C. for 2 hours, while hydrogen was introduced to the mixture under atmospheric pressure at a rate of 50 mL/min. After the reaction was complete, the reaction mixture was filtered. The filtrate was analyzed by high performance liquid chromatography (absolute quantitative analysis). There was produced 0.85 g (reaction yield: 95.2%) of methyl 5-methoxy-4-(3-chloropropoxy)anthranilate.
Reaction SMILES: [C:1]([N:4]([CH2:6][C:7]([OH:9])=[O:8])[CH3:5])(=O)C.C=O.[OH:12][PH:13]([OH:15])=[O:14].P(Cl)(Cl)Cl>>[P:13]([CH2:1][N:4]([CH3:5])[CH2:6][C:7]([OH:9])=[O:8])([OH:15])([OH:14])=[O:12]
Reactant: O=[PH](O)O
Reactant: CC(=O)N(C)CC(=O)O
Agent: C=O
Solvent: ClP(Cl)Cl
Product: CN(CC(=O)O)CP(=O)(O)O

Procedure:
As depicted, the carboxymethylation step of Reaction Scheme 12 is the same as the carboxymethylation step of Reaction Schemes 10 and 11. In Reaction Scheme 12, however, N-acetylsarcosine XX is reacted with formaldehyde and H3PO3, PCl3 or other H3PO3 source to produce N-(phosphonomethyl)-N-methyl-glycine XXI which is oxidized in the presence of a platinum catalyst and oxygen to Glyphosate I and acetic acid. The acetic acid is then reacted with methylamine to yield the N-methylacetamide starting material.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([NH:12][C:13]3[C:21]([CH3:22])=[CH:20][CH:19]=[CH:18][C:14]=3[C:15](O)=[O:16])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.[NH2:23][CH:24]1[CH2:29][CH2:28][N:27]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:26][CH2:25]1>>[CH2:30]([N:27]1[CH2:28][CH2:29][CH:24]([NH:23][C:15](=[O:16])[C:14]2[CH:18]=[CH:19][CH:20]=[C:21]([CH3:22])[C:13]=2[NH:12][C:6]2[C:5]3[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=3)[N:9]=[CH:8][CH:7]=2)[CH2:25][CH2:26]1)[CH2:31][CH2:32][CH3:33]
Reactant: Cc1cccc(C(=O)O)c1Nc1ccnc2cc(Cl)ccc12
Reactant: CCCCN1CCC(N)CC1
Product: CCCCN1CCC(NC(=O)c2cccc(C)c2Nc2ccnc3cc(Cl)ccc23)CC1

Procedure:
2-(7-Chloro-4-quinolylamino)-3-methyl benzoic acid is converted to the acid chloride which is reacted with 4-amino-1-n-butyl piperidine as in Example 1 to give the title compound.
Reaction SMILES: [Na+].C([S:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([O-:16])=[O:15])=[O:9])(=O)C.[OH-].[Na+].Cl>O>[SH:5][CH2:6][CH:7]([CH2:20][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[CH:25][CH:26]=1)[C:8]([NH:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:9]
Reactant: CC(=O)SCC(Cc1ccc(F)cc1)C(=O)Nc1cccc(C(=O)[O-])c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1cccc(NC(=O)C(CS)Cc2ccc(F)cc2)c1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
3-[[2-Acetylthiomethyl-3-(4-fluorophenyl)-propionyl]amino]benzoic acid sodium salt (compound of Example 40) (1.2 g) is dissolved in water (20 ml), and the mixture is adjusted to pH 12.0 with 10% aqueous sodium hydroxide solution under nitrogen. After reacting at room temperature for one hour, the reaction mixture is adjusted to pH 2.5 with 10% hydrochloric acid. The mixture is extracted with ethyl acetate (50 ml). The extract is washed with water and ethyl acetate is distilled off. The residue is purified by a medium pressure column chromatography with CHP-20P (eluant, water-dioxane). The fractions containing the desired compound are collected and lyophilized to give the title compound (0.6 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[F:9].[N:10]1[CH:15]=[CH:14][CH:13]=[C:12]2[CH2:16][C:17](=[O:21])[CH2:18][CH2:19][CH2:20][C:11]=12>C1COCC1>[F:9][C:3]1[C:4]([F:8])=[CH:5][CH:6]=[CH:7][C:2]=1[C:17]1([OH:21])[CH2:18][CH2:19][CH2:20][C:11]2=[N:10][CH:15]=[CH:14][CH:13]=[C:12]2[CH2:16]1
Reactant: O=C1CCCc2ncccc2C1
Reactant: Fc1cccc(Br)c1F
Solvent: C1CCOC1
Product: OC1(c2cccc(F)c2F)CCCc2ncccc2C1
Temperature: -78 °C
Reaction time: 0.33 h

Procedure:
In an oven-dried 500 mL round-bottomed flask was BuLi (17.19 mL, 43.0 mmol) in THF (100 mL) to give a colorless solution at −78° C. under nitrogen. 1-Bromo-2,3-difluorobenzene (4.81 mL, 43.0 mmol) was added dropwise via syringe. The mixture was stirred at −78° C. for 20 min, and 8,9-dihydro-5H-cyclohepta[b]pyridin-6(7H)-one (4.947 g, 30.7 mmol) (azeotroped with dry benzene and dried under high vac) dissolved in 10 ml THF was added dropwise via canuula (plus 10 ml THF rinse). The mixture was warmed up to rt in 1 h. TLC showed some conversion to a slightly more polar spot. After quenched with saturated NH4Cl solution, THF was stripped off. The remaining mixture was partitioned between water and EtOAc. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, and concentrated to a dark oil. The residue was purified by FCC up to 10% MeOH/CH2Cl2 (very difficult separation). The impure fractions were pooled and purified by FCC with EtOAc/CH2Cl2 up to pure EtOAc. The recovered SM: 1.88 g (38%). The product fractions were pooled and concentrated to a tan solid, which were washed repeatedly with Et2O to a tan solid (1.79 g, 21%). 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.27 (dd, J=4.91, 1.38 Hz, 1H) 7.38-7.47 (m, 1H) 7.30-7.35 (m, 1H) 6.97-7.12 (m, 3H) 3.93 (dd, J=14.60, 2.52 Hz, 1H) 3.06-3.20 (m, 2H) 2.86 (dd, J=14.60, 1.76 Hz, 1H) 2.37-2.68 (m, 2H) 1.68-1.94 (m, 2H) 1.17 (t, J=7.05 Hz, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5]([NH:8][CH2:9][CH:10]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:11][S: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][CH2:27][CH3:28])(=[O:7])=[O:6].C(SCC(OC)CNS(CCC[I:60])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:13]([S:12][CH2:11][CH:10]([CH2:29][C:30](=[O:32])[CH3:31])[CH2:9][NH:8][S:5]([CH2:4][CH2:3][CH2:2][I:60])(=[O:7])=[O:6])[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][CH2:27][CH3:28]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCCl)CC(C)=O
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Product: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)CC(C)=O

Procedure:
1-(3-Chloropropylsulfonylamino)-3-hexadecylthio-2-(2-oxopropan-1-yl)propane IIIm2 is allowed to react by the same procedure as described in (5). The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: [N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:16])([CH3:15])[C:12](=[O:17])[CH:11]=3)[CH:7]=[CH:6][C:5]=12.C1C(=O)N([Br:25])C(=O)C1>C(Cl)(Cl)Cl.C(Cl)Cl>[N:1]1[O:2][N:3]=[C:4]2[CH:9]=[C:8]([C:10]3[O:14][C:13]([CH3:15])([CH3:16])[C:12](=[O:17])[C:11]=3[Br:25])[CH:7]=[CH:6][C:5]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: CC1(C)OC(c2ccc3nonc3c2)=CC1=O
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC1(C)OC(c2ccc3nonc3c2)=C(Br)C1=O
Reaction time: 3 h
Yield: 59.6 %

Procedure:
To a stirred solution of 5-(benzo[c][1,2,5]oxadiazol-5-yl)-2,2-dimethylfuran-3(2H)-one (0.25 g, 1.086 mmol) in CHCl3 (15 mL), NBS (0.29 g, 1.630 mmol) was added portionwise at RT. The reaction mixture was then stirred for 3 h and diluted with DCM (10 mL). The organic layer was then washed with water (5 mL) and brine (10 mL), dried over Na2SO4, filtered, and then concentrated in vacuo to obtain the crude product. The crude material was purified via silica gel column chromatography to afford 5-(benzo[c][1,2,5]oxadiazol-5-yl)-4-bromo-2,2-dimethylfuran-3(2H)-one (0.2 g, 60%) as a yellow solid.
Reaction SMILES: [CH3:1][S:2]([NH:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]2)(=[O:4])=[O:3].C([O-])([O-])=O.[K+].[K+].Cl.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>CC#N>[O:33]1[CH2:34][CH2:35][N:30]([CH2:29][CH2:28][N:5]([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[N:11]([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH:10]=[CH:9]3)[S:2]([CH3:1])(=[O:3])=[O:4])[CH2:31][CH2:32]1
Reactant: COC(=O)Cn1ccc2cc(NS(C)(=O)=O)ccc21
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)Cn1ccc2cc(N(CCN3CCOCC3)S(C)(=O)=O)ccc21
Yield: 59.4 %

Procedure:
To a solution of methyl 2-(5-(methylsulfonamido)-1H-indol-1-yl)acetate (1.8 g, 6.38 mmol) (prepared in an analogous manner as described in, Example 14, Scheme 14, Steps 1, 2, 3) in CH3CN (30 ml), K2CO3 (1.762 g, 12.75 mmol) and 4-(2-chloroethyl)morpholine hydrochloride (1.186 g, 6.38 mmol) were added, and the mixture heated to reflux for 3 hours. The solvent was removed and the residue was purified by flash chromatography on silica gel (DCM/MeOH 99:1 to 97:3) recovering methyl 2-(5-(N-(2-morpholinoethyl)methylsulfonamido)-1H-indol-1-yl)acetate (1.5 g, 3.79 mmol, 59.5% yield, UPLC-MS purity: 96%, MS/ESI+ 396.2 [MH]+).
Reaction SMILES: Cl[C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1.[CH2:17]([SH:20])[CH2:18][CH3:19].[H-].[Na+]>>[CH2:17]([S:20][C:2]1[C:7]([CH:8]=[CH:9][C:10]([OH:12])=[O:11])=[CH:6][CH:5]=[C:4]([C:13]([F:16])([F:15])[F:14])[N:3]=1)[CH2:18][CH3:19]
Reactant: CCCS
Reactant: O=C(O)C=Cc1ccc(C(F)(F)F)nc1Cl
Agent: [H-]
Agent: [Na+]
Product: CCCSc1nc(C(F)(F)F)ccc1C=CC(=O)O
Yield: 40.9 %

Procedure:
3-(2-Chloro-6-trifluoromethyl-pyridin-3-yl)-acrylic acid (243 mg, 0.966 mmol) was reacted with propanthiol (229 mg, 3.01 mmol) and sodium hydride (145 mg, 3.62 mmol) to afford title compound (115 mg) after purification by column chromatography (Hex EtOAc=2/3).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5](Cl)[N:6]=1.[I-:11].[Na+].O>CC(C)=O>[Cl:1][C:2]1[S:3][C:4]([N+:8]([O-:10])=[O:9])=[C:5]([I:11])[N:6]=1
Reactant: O=[N+]([O-])c1sc(Cl)nc1Cl
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: O=[N+]([O-])c1sc(Cl)nc1I
Temperature: 25 °C
Reaction time: 144 h
Yield: 25.8 %

Procedure:
39.8 g (0.2 mol) of 2,4-dichloro-5-nitrothiazole are dissolved in 500 ml of acetone and, after addition of 90 g (0.6 mol) of sodium iodide, the mixture is stirred at room temperature for about 6 days, the progress of the reaction being monitored by gas chromatography The solvent is then stripped off in vacuo and the residue is stirred into water, filtered off, washed with water and dried. A substance mixture which, according to analysis by gas chromatography, contains 71.5% of 2-iodo-4-chloro-5-nitrothiazole and 25.8% of 2-chloro-4-iodo-5-nitrothiazole is obtained. HPLC (=high pressure liquid chromatography) chromatographic separation gave the pure substances with the following melting points:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N+:7]([O-])=O)[CH:4]=[C:3]1[C:10]([OH:12])=O.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>>[NH2:7][C:5]1[CH:4]=[C:3]([C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)=[O:12])[N:2]([CH3:1])[CH:6]=1
Reactant: Cn1cc([N+](=O)[O-])cc1C(=O)O
Reactant: C1COCCN1
Product: Cn1cc(N)cc1C(=O)N1CCOCC1

Procedure:
(4-amino-1-methyl-1H-pyrrol-2-yl)(morpholino)methanone was prepared as in Example 239 (Steps i-ii) using 1-methyl-4-nitro-1H-pyrrole-2-carboxylic acid and morpholine:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[CH3:10][C:11]([CH3:13])=O.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>C(Cl)Cl>[CH3:10][C:11]1([CH3:13])[O:1][C:2]2[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=2[O:9]1
Reactant: CC(C)=O
Reactant: Oc1ccc(F)cc1O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: ClCCl
Product: CC1(C)Oc2ccc(F)cc2O1
Yield: 56.2 %

Procedure:
In a flask were placed 40 g (0.31 mole) of 1,2-dihydroxy-4-fluorobenzene, 36.25 g (0.625 mole) of acetone, and 400 mL of methylene chloride. To this solution was added 133 g (0.937 mole) of phosphorus pentoxide in portions during a five minute period. This mixture was stirred at ambient temperature for approximately 16 hours after which the methylene chloride was decanted from the solid material in the flask. Ice was added to the flask, and the solid residue was dissolved in water and extracted with methylene chloride. The phases were separated, and the organic phase was combined with the methylene chloride solution that had been decanted from the reaction mixture. This solution was washed in succession with a 5% aqueous solution of sodium hydroxide and then with water. After being dried over anhydrous magnesium sulfate and filtered, the organic solution was evaporated under reduced pressure, leaving 29.3 g of 2,2-dimethyl-5-fluoro-1,3-benzodioxole as a residue. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: C(O)(=O)C.C(O)(=O)C.O[CH2:10][C:11]1[CH:12]2[CH:20]=[CH:19][C:15]([CH3:21])([C:16]=1[CH2:17]O)[C:14](=[O:22])[C:13]2([CH3:24])[CH3:23]>[Pd].C(O)(C)C>[CH3:21][C:15]12[CH2:19][CH2:20][CH:12]([C:11]([CH3:10])=[C:16]1[CH3:17])[C:13]([CH3:24])([CH3:23])[C:14]2=[O:22]
Reactant: CC12C=CC(C(CO)=C1CO)C(C)(C)C2=O
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CC(C)O
Product: CC1=C(C)C2(C)CCC1C(C)(C)C2=O
Temperature: 80 °C
Reaction time: 0.07 h
Yield: 119.9 %

Procedure:
To a 450 ml Parr mini-pressure reactor is charged 15 grams of 5,6-bis(hydroxymethyl)-1,3,3-trimethylbicyclo[2.2.2]-octa-5,7-dien-2-one diacetate produced according to Example IV, 60 ml of isopropyl alcohol and 0.3 grams of 10% palladium on charcoal. After flushing with nitrogen and hydrogen, the hydrogen is charged to a pressure of 195 psig while maintaining the reaction mass temperature at 22°-27° C. Within four minutes, the pressure drops to 140 psig and holds steady for six minutes. Hydrogen is again charged to 195 psig and the temperature is gradually raised to 80° C. At 80° C. the pressure begins to drop. The temperature is raised to 85° C. and maintained at 85° C. until the pressure holds constant at 102 psig (1.7 hours). After cooling to room temperature, the reaction mass is filtered and the toluene is removed in vacuo to yield 10.1 grams of 1,3,3,5,6-pentamethyl-bicyclo[2.2.2]octa-5-en-2-one. This material is identical to that prepared from 2,6,6-trimethylcyclohexa-2,4-dien-1-one and 2-butyne according to Examples I and II, supra.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][NH:18][C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[F:21][CH:22]([F:34])[O:23][C:24]1[CH:25]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:27]=[CH:28][CH:29]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:11][CH:10]([C:12]2[CH:13]=[C:14]3[CH:20]=[CH:19][N:18]([S:30]([C:26]4[CH:27]=[CH:28][CH:29]=[C:24]([O:23][CH:22]([F:21])[F:34])[CH:25]=4)(=[O:32])=[O:31])[C:15]3=[N:16][CH:17]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CC(c2cnc3[nH]ccc3c2)C1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)F)c1
Product: CC(C)(C)OC(=O)N1CC(c2cnc3c(ccn3S(=O)(=O)c3cccc(OC(F)F)c3)c2)C1

Procedure:
This compound was prepared from 3-(1H-pyrrolo[2,3-b]pyridine-5-yl)-azetidine-1-carboxylic acid tert-butyl ester and 3-Difluoromethoxy-benzenesulfonyl chloride by the method outlined under Example 46.b.