Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].S(Cl)([Cl:16])(=O)=O>ClCCCl>[Cl:16][C:8]1[C:7]2[C:11](=[CH:12][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[NH:10][N:9]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc2c(Cl)n[nH]c2c1
Temperature: 80 °C

Procedure:
To a solution of 6-nitroindazole (2 mmol) in DCE (5 mL), sulfuryl chloride (10 mmol) was added and the resulting mixture was heated 80° C. for 3-5 h. The reaction mixture was concentrated, added with 5% aqueous Na2CO3 solution (20 mL) and extracted with EtOAc (2×15 mL). The combined organics were then washed with water (20 mL) and brine (20 mL) and dried over anhydrous Na2SO4. Removal of volatiles afforded 3-chloro-6-nitro-1H-indazole as a yellow solid.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=1[S:12]([NH:15][C:16]1[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]2[C:19]([CH:20]3[CH2:30][CH:21]3[CH2:22][O:23]2)=[CH:18][CH:17]=1)(=[O:14])=[O:13])(O)=[O:2].CCN=C=[N:35][CH2:36][CH2:37][CH2:38][N:39]([CH3:41])[CH3:40].[CH2:42](N(CC)CC)C>C(Cl)Cl>[CH2:41]([N:39]1[CH2:38][CH2:37][C@H:36]([NH:35][C:1]([CH2:4][C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[S:12]([NH:15][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([CH:20]4[CH2:30][CH:21]4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:13])=[O:14])=[O:2])[CH2:40]1)[CH3:42]
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2CC(=O)O)ccc2c1OCC1CC21
Reactant: CCN(CC)CC
Reactant: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCN1CC[C@H](NC(=O)Cc2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Reaction time: 144 h
Yield: 81 %

Procedure:
A solution of methyl (1aRS,7bSR)-5-(2-carboxymethyl-4-fluorobenzenesulfonylamino)-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 83, 0.180 g), (S)-1-ethylpyrrolidin-3-ylamine ditrifluoroacetic acid salt (Intermediate 81, 0.171 g), EDAC (0.144 g) and triethylamine (0.202 g) in DCM (5 mL) was allowed to stand at room temperature for 6 days then washed with water and filtered through a phase separator. The filtrate was directly purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-20% to give methyl (1aRS,7bSR)-5-{2-[((S)-1-ethylpyrrolidin-3-ylcarbamoyl)methyl]-4-fluorobenzenesulfonylamino}-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (0.178 g) as an off-white foam.
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[CH:3]=1.[N+:12]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][CH:22]=1)[CH:18]=O)([O-:14])=[O:13].[C:23]([O:29][CH3:30])(=[O:28])[CH2:24][C:25]([CH3:27])=O>C(O)(=O)C>[CH3:8][N:7]1[C:2]2[NH:1][C:25]([CH3:27])=[C:24]([C:23]([O:29][CH3:30])=[O:28])[CH:18]([C:17]3[CH:20]=[CH:21][CH:22]=[C:15]([N+:12]([O-:14])=[O:13])[CH:16]=3)[C:3]=2[C:4](=[O:11])[N:5]([CH3:10])[C:6]1=[O:9]
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Reactant: COC(=O)CC(C)=O
Reactant: Cn1c(N)cc(=O)n(C)c1=O
Solvent: CC(=O)O
Product: COC(=O)C1=C(C)Nc2c(c(=O)n(C)c(=O)n2C)C1c1cccc([N+](=O)[O-])c1
Yield: 13.6 %

Procedure:
A mixture of 6-amino-N,N'-dimethyluracil (3.1 g,20 mM),3-nitrobenzaldehyde (3 g,20 mM), and methyl acetoacetate (2.3 g, 1.4 ml, 20 mM) in glacial acetic acid (10 ml) was stirred under N2 at reflux for 3 hours, cooled to ambient, light yellow solid which was filtered and rinsed with acetone to give the title compound (1.04 g,13.5%),mp >230° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][CH3:25])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].[CH3:32][C:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>ClCCl.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([N:24]([CH3:25])[C:39]([C:33]2([CH3:32])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)=[O:40])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)[CH2:11][CH2:10]1
Reactant: CC1(C(=O)Cl)CCCCC1
Reactant: CN[C@H](Cc1ccccn1)CN1CCN(c2ccccc2OC)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccccn2)N(C)C(=O)C2(C)CCCCC2)CC1
Temperature: 25 °C
Yield: 56.3 %

Procedure:
To a solution of (2R)-1-[4-(2-methoxyphenyl)piperazin-1-yl]-N-methyl-3-pyridin-2-ylpropan-2-amine (90 mg.; 0.26 mmol, from Example 17) in dichloromethane (3 mL) at 0° C. was added a solution of potassium carbonate (180 mg.; 1.3 mmol) in water (0.5 mL), followed by a solution of 1-methyl-1-cyclohexanecarbonyl chloride (41 mg.; 0.26 mmol) in dichloromethane (0.5 mL). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour, diluted with dichloromethane (5 mL), and the layers allowed to separate. The organic layer was dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (10% methanol/ethyl acetate) to yield the free base of the title compound as a clear oil (68 mg.; 56%). Treatment with an equimolar amount of fumaric acid in acetonitrile afforded the fumarate salt as a white crystalline solid, m.p. 145–146° C.; MS (+) ESI [M+H]+ @ m/z 465; 1H NMR, 400 MHz, DMSO-d6. Analysis for C28H40N4O2.C4H4O4 Calculated: C, 66.18; H, 7.64; N, 9.65 Found: C, 65.95; H, 7.41; N, 9.54
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[C:9](OC(=O)C)(=[O:11])[CH3:10]>>[C:9]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1)(=[O:11])[CH3:10]
Reactant: Nc1cccc(Br)n1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nc1cccc(Br)n1
Yield: 68 %

Procedure:
20 g (0.116 mole) of 2-amino-6-bromopyridine was dissolved in 140 ml. acetic anhydride and heated at 70° C. for 45 minutes. 2-Acetamido-6-bromopyridine was isolated by filtration as white flakes, m.p=159.2°-160.0° C., in 68% yield. The excess acetic anhydride present in the reaction mixture was hydrolyzed by the addition of 300 ml. water to the filtrate; the reaction mixture was agitated and an additional 27% yield of 2-acetamido-6-bromopyridine was collected by filtration, giving a 95% yield of reaction product, 2-acetamido-6-bromopyridine which was recrystallized from benzene. Elemental Analysis:
Reaction SMILES: C(O[C:4](=[O:11])[CH2:5][N:6]1[N:10]=[CH:9][CH:8]=[N:7]1)C.O.[NH2:13][NH2:14]>C(O)C>[N:10]1[N:6]([CH2:5][C:4]([NH:13][NH2:14])=[O:11])[N:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)Cn1nccn1
Reactant: NN
Solvent: CCO
Solvent: O
Product: NNC(=O)Cn1nccn1
Temperature: 25 °C
Yield: 68 %

Procedure:
As described for example 112a, [1,2,3]triazol-2-yl-acetic acid ethyl ester in ethanol was reacted with hydrazine hydrate (2 equivalents) and the resulting mixture heated under reflux for 3 h. The mixture was cooled to rt and the precipitated product was filtered off and dried to afford the title compound as a white solid (yield: 68%). MS: m/e=141.1 [M]+.
Reaction SMILES: [CH:1]1[C:10]2[CH:9]=[CH:8][CH:7]=[C:6]([NH2:11])[C:5]=2[CH:4]=[CH:3][N:2]=1.CCN(C(C)C)C(C)C.[N:21]([CH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[C:22]=[O:23]>C(Cl)Cl>[CH:24]1([NH:21][C:22]([NH:11][C:6]2[CH:7]=[CH:8][CH:9]=[C:10]3[C:5]=2[CH:4]=[CH:3][N:2]=[CH:1]3)=[O:23])[CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Nc1cccc2cnccc12
Reactant: O=C=NC1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1cccc2cnccc12)NC1CCCC1
Reaction time: 24 h

Procedure:
To isoquinolin-5-amine (0.23 g, 1.595 mmol) in DCM (5 mL) was added DIEA (0.557 mL, 3.19 mmol) and isocyanatocyclopentane (0.180 mL, 1.595 mmol). After 24 h, the reaction was quenched with H2O (15 mL) and extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine (10 mL) and dried (MgSO4). The impure yellow solid was collected and was carried onto the next step. MS (ESI) m/z: 256 (M+H)+.
Reaction SMILES: Cl.[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)#[N:3].C(=O)([O-])[O-].[NH4+:38].[NH4+]>C(O)C>[C:2]([C:4]1[CH:5]=[C:6]([N:10]([CH:27]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]2)[C:11]([NH:13][CH:14]2[CH2:19][CH2:18][N:17]([CH2:20][C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH2:16][CH2:15]2)=[O:12])[CH:7]=[CH:8][CH:9]=1)(=[NH:38])[NH2:3]
Reactant: [NH4+]
Reactant: N#Cc1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: N=C(N)c1cccc(N(C(=O)NC2CCN(Cc3ccccc3)CC2)C2CCCCCC2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Dry hydrogen chloride gas was bubbled through an ice cooled solution of N-(3-cyanophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea (0.03 g, 0.077 mmol) in anhydrous ethanol (10 ml) under a nitrogen atmosphere for 15 min. The reaction was stoppered, allowed to warm to ambient temperature and stirred for 24 h. The reaction was concentrated to a solid and dissolved in anhydrous ethanol (5 ml) and ammonium carbonate (0.023 g, 0.23 mmol) was added. The reaction mixture was stirred at ambient temperature overnight then was concentrated in vacuo. N-(3-Amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea was purified by HPLC on a Vydec® C-18 column eluting with solvent mixture A (acetonitrile:water:TFA 80:20:0.3) and solvent mixture B (water:TFA 99.7:0.3) using a gradient starting with A:B at 3:97 and changing to A:B at 70:30 over 15 min. The major fraction eluting at 15 minutes was concentrated to give N-(3-amidinophenyl)-N'-(1-benzylpiperidin-4-yl)cycloheptylurea as an amorphous solid; LRMS (M+H)+ m/z 406, (M+2H)+2 m/z 203.8; 1H NMR (DMSO-d6): 9.52(broad s, 1H), 9.27(s, 2H), 9.02(s, 2H), 7.5(m, 9H), 4.3(m,m, 2H), 3.95(m, 1H), 3.67(m, 2H), 3.42(m, 2H), 3.2(m, 2H), 3.1(m, 2H), 2.05-1.6(m, 8H).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:34])[C:25](=[O:33])/[CH:26]=[CH:27]/[C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:35])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:3][CH2:2]1.[C:36](OCC)(=O)C.C[I:43]>CO>[I-:43].[CH:1]1([CH2:4][N+:5]2([CH3:36])[CH2:23][CH2:22][C@:12]34[C:13]5[C:14]6[O:21][C@H:11]3[C@H:10]([N:24]([CH3:34])[C:25](=[O:33])/[CH:26]=[CH:27]/[C:28]3[CH:32]=[CH:31][O:30][CH:29]=3)[CH2:9][CH2:8][C@@:7]4([OH:35])[C@H:6]2[CH2:19][C:18]=5[CH:17]=[CH:16][C:15]=6[OH:20])[CH2:2][CH2:3]1
Reactant: CN(C(=O)/C=C/c1ccoc1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3CC2CC2)[C@H]1O5
Reactant: CI
Reactant: CCOC(C)=O
Solvent: CO
Product: CN(C(=O)/C=C/c1ccoc1)[C@@H]1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CC[N+]3(C)CC2CC2)[C@H]1O5
Product: [I-]
Temperature: 100 °C
Reaction time: 96 h

Procedure:
17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-(N-methyl-trans-3-(3-furyl)acrylamido)morphinan 2.0699 g (4.3 mmol), ethyl acetate 60 ml, methanol 6 ml, and methyl iodide 1.3 ml were placed together in a container to be sealed, and, while being sealed, was stirred at 100° C. for four days. To the reaction solution was added methanol 60 ml; the precipitated solid was dissolved and concentrated; and to the resulting residue was added distilled water 400 ml. This aqueous solution was washed with chloroform (100 ml×7); the water phase was concentrated; the resulting residue was recrystallized from ethyl acetate-methanol; and the resulting crystal was dissolved in distilled water 500 ml. This aqueous solution was washed with chloroform (100 ml×3); the water phase was concentrated; the resulting residue was recrystallized three times from methanol; and the compound in the title 102 mg was obtained.
Reaction SMILES: CO.NN.[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10](Cl)(=[O:12])=[O:11].[Br:14]Br>C(Cl)(Cl)Cl.O>[S:5]1[CH:9]=[CH:8][CH:7]=[C:6]1[S:10]([Br:14])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: BrBr
Agent: NN
Solvent: O
Solvent: CO
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Br)c1cccs1
Temperature: 7 °C
Yield: 67.5 %

Procedure:
In a 500 ml Erlenmeyer flask equipped with a magnetic stirrer and a thermometer were placed 200 ml of methanol and 6.80 g (0.20 mol) of 95% hydrazine. This solution wa cooled to 7° C. and 18.26 g (0.10 mol) of 2-thiophenesulfonyl chloride was added portion-wise in such a manner that the temperature did not exceed 15° C. After the addition was complete, the reaction mixture was allowed to warm to room temperature. The methanol was removed in vacuo leaving a mixture of a heavy oil and a fluffy solid. The mixture was treated with water, and the solid dissolved and oil separated. The mixture of oil and water (which contained the hydrazine hydrochloride from the first reaction) was placed in a flask containing 300 ml of chloroform and a magnetic stirrer. Crushed ice was added and to the resulting slurry 64.0 g of bromine was added at such a rate that the reaction temperature remained below 10° C. After the addition was complete and the bromine color had dissipated, the layers were separated. The chloroform layer was dried over anhydrous magnesium sulfate, and the chloroform removed in vacuo leaving a yellow oil which crystallized on addition of hexane. The solid was filtered and dried to give 15.33 g of the title compound as slightly yellow crystals, mp 49°-51° C.
Reaction SMILES: [C:1]1([CH2:7][C:8](Cl)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[S-:11][C:12]#[N:13].[K+].[NH2:15][C:16]1[CH:36]=[CH:35][C:19]([O:20][C:21]2[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[O:29])[CH:22]=2)=[C:18]([CH3:37])[CH:17]=1>C(#N)C.C(OCC)C>[CH3:37][C:18]1[CH:17]=[C:16]([NH:15][C:12]([NH:13][C:8](=[O:9])[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[S:11])[CH:36]=[CH:35][C:19]=1[O:20][C:21]1[CH:26]=[CH:25][N:24]=[C:23]([NH:27][C:28]([N:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)=[O:29])[CH:22]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cc(N)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Reactant: N#C[S-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC#N
Product: Cc1cc(NC(=S)NC(=O)Cc2ccccc2)ccc1Oc1ccnc(NC(=O)N2CCCC2)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 41 %

Procedure:
To a solution of 2-phenylacetyl chloride (0.0549 ml) in acetonitrile (5.0 ml) was added potassium thiocyanate (37.3 mg, 0.384 mmol), followed by stirring under a nitrogen atmosphere at 50° C. for 1 hr. The reaction mixture was cooled down to room temperature, and then pyrrolidine-1-carboxylic acid [4-(4-amino-2-methylphenoxy)pyridin-2-yl]amide (80 mg) was added thereto, followed by stirring under a nitrogen atmosphere for 21 hrs. The reaction mixture was partitioned between ethyl acetate (100 ml) and water (40 ml). The organic layer was washed with brine, and dried over anhydrous sodium sulfate. The solvent was evaporated to give a residue, which was then purified by silica gel column chromatography (eluent; ethyl acetate). Fractions containing the target compound were concentrated to give a solid, which was suspended in diethyl ether (4 ml). The solid was filtered off, and dried under aeration to provide the titled compound (51 mg, 41%) as colorless powder.
Reaction SMILES: [CH3:1][C@@H:2]1[N:7]([C:8]2[C:9]3[CH2:24][CH2:23][N:22]([C:25]4[N:30]=[CH:29][CH:28]=[CH:27][N:26]=4)[CH2:21][C:10]=3[N:11]=[C:12]([C:14]3[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=3)[N:13]=2)[CH2:6][CH2:5][O:4][CH2:3]1.[O:31]1CCN(C2C3CNC(C4N=CC=CN=4)CC=3N=C(C3C=CC(N)=CC=3)N=2)C[CH2:32]1.[NH2:60][C:61]1[N:65]([CH3:66])[N:64]=[CH:63][CH:62]=1.C1(CN)CC1>>[CH3:66][N:65]1[C:61]([NH:60][C:32]([NH:18][C:17]2[CH:19]=[CH:20][C:14]([C:12]3[N:13]=[C:8]([N:7]4[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]4[CH3:1])[C:9]4[CH2:24][CH2:23][N:22]([C:25]5[N:26]=[CH:27][CH:28]=[CH:29][N:30]=5)[CH2:21][C:10]=4[N:11]=3)=[CH:15][CH:16]=2)=[O:31])=[CH:62][CH:63]=[N:64]1
Reactant: Cn1nccc1N
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(N)cc2)nc2c1CCN(c1ncccn1)C2
Reactant: Nc1ccc(-c2nc3c(c(N4CCOCC4)n2)CNC(c2ncccn2)C3)cc1
Agent: NCC1CC1
Product: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)Nc3ccnn3C)cc2)nc2c1CCN(c1ncccn1)C2

Procedure:
The title compound was prepared by the general procedure of Example 30 substituting (S)-4-(4-(3-methylmorpholino)-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)aniline (ld) for 4-(4-morpholino-7-(pyrimidin-2-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-2-yl)aniline and 5-amino-1-methyl-1H-pyrazole for cyclopropylmethylamine. LC-MS: m/z=+527 (M+H)+.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10].[NH2:20][OH:21].[OH-].[K+].CO>C1COCC1>[OH:21][NH:20][C:3](=[O:2])[CH:4]=[CH:5][CH:6]=[CH:7][CH2:8][S:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=1)=[O:10]
Reactant: COC(=O)C=CC=CCS(=O)c1ccc(OC)cc1
Reactant: NO
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc(S(=O)CC=CC=CC(=O)NO)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a solution of 6-(4-methoxybenzenesulfinyl)-hexa-2,4-dienoic acid methyl ester (0.32 g, 1.14 mmol) in distilled THF (6 mL) containing an aqueous solution of hydroxylamine (50%, 0.7 ml, 10.6 mmol) was added at 0° C. a solution of potassium hydroxide in methanol (1M, 1.8 ml, 1.8 mmol) over a period of 30 minutes. After stirring at 0° C. for 1 hour, distilled water (6 mL) was added and the mixture was made neutral by dropwise addition of concentrated hydrochloric acid (10 M) at 0° C. The aqueous solution was extracted with ethyl acetate (3×20 mL) and the combined extracts were dried over anhydrous MgSO4, and evaporated to dryness. The residue was recrystallised from acetone to give the title compound (0.11 g, 34%) as a pale brown powder, mp 145-147° C. (decomp).
Reaction SMILES: Br[CH:2]([C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([Br:12])[CH:7]=1)[C:3]([OH:5])=O.C(Cl)(=O)C(Cl)=O.[C:19]1([C@H:25]([NH:27][CH2:28][CH2:29][CH2:30][OH:31])[CH3:26])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[OH-].[K+]>ClCCl.CN(C)C=O>[Br:12][C:8]1[CH:7]=[C:6]([CH:2]2[C:3](=[O:5])[N:27]([C@@H:25]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH3:26])[CH2:28][CH2:29][CH2:30][O:31]2)[CH:11]=[CH:10][CH:9]=1
Reactant: O=C(O)C(Br)c1cccc(Br)c1
Reactant: C[C@@H](NCCCO)c1ccccc1
Agent: O=C(Cl)C(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C[C@H](c1ccccc1)N1CCCOC(c2cccc(Br)c2)C1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 27.4 %

Procedure:
To a solution of bromo-(3-bromo-phenyl)-acetic acid (27.8 g, 94.6 mmol) in dichloromethane (200 ml) was added oxalylchloride (19.8 g, 156 mmol) and a few drops of N,N-dimethylformamide at room temperature. After the mixture was stirred at 40° C. for one hour, the solvent was removed under reduced pressure. The residue was dissolved in dichloromethane (30 ml) and the solution was added to a solution of (R)-3-(1-phenylethyl amino)propan-1-ol (18.6 g, 104 mmol) and triethylamine (11.6 g, 114 mmol) in dichloromethane (312 ml) at 0° C. The mixture was stirred for 1.5 hours at 0° C. and partitioned between 0.5 N hydrochloric acid and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was dissolved into 2-propanol (312 ml) and then potassium hydroxide (11.7 g, 208 mmol) was added at 0° C. The mixture was stirred at 0° C. for 3 hours and partitioned between saturated ammonium chloride solution and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate and concentrated in vacuo. The crude mixture was triturated with ether. The resulting solid materials were collected by filtration and dried under reduced pressure to afford diastereomerically pure 2-(3-bromo-phenyl)-4-((R)-1-phenyl-ethyl)-[1,4]oxazepan-3-one (diastereomer 1) as white solid (9.71 g, 25%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4](O)=[O:5].C[N:15](C)C=O.S(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][C:3]=1[C:4]([NH2:15])=[O:5]
Reactant: O=C(O)c1cc([N+](=O)[O-])ccc1Cl
Reactant: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: NC(=O)c1cc([N+](=O)[O-])ccc1Cl
Temperature: 25 °C

Procedure:
2-Chloro-5-nitrobenzoic acid (500 g) was added to a mixed solvent of dimethylformamide (500 ml) and toluene (1.5 Liters). Thionyl chloride (217 ml) was added thereto at room temperature with stirring and the mixture was stirred at a refluxing temperature for 3 h. The reaction mixture was then ice-cooled and added dropwise to 28% aqueous amonia (750 ml). The mixture was stirred further for 1 h. The precipitated crystals were collected by filtration, and the crystals were recrystallized from hydrous ethanol to give 2-chloro-5-nitrobenzamide (346 g), melting point: 177–179° C.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:13]=1[OH:14])[C:8]([OH:10])=O)([CH3:4])([CH3:3])[CH3:2].C1(N=C=NC2CCCCC2)CCCCC1.C(N(CC)CC)C.[C:41]1([NH2:48])[CH:46]=[CH:45][CH:44]=[CH:43][C:42]=1[NH2:47]>C(Cl)Cl.CN(C)C1C=CN=CC=1>[NH2:47][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=1[NH:48][C:8](=[O:10])[C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:13]([OH:14])=[C:12]([C:15]([CH3:17])([CH3:16])[CH3:18])[CH:11]=1
Reactant: Nc1ccccc1N
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)c1cc(C(=O)Nc2ccccc2N)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 32.4 %

Procedure:
To a solution of 3,5-di-t-butyl-4-hydroxybenzoic acid (5.0 g) in methylene chloride (20 ml) was added dicyclohexylcarbodiimide (2.17 g) and the mixture was stirred overnight at room temperature. Subsequently, triethylamine (2.1 ml), 4-dimethylaminopyridine (0.37 g) and o-phenylenediamine (1.08 g) were added and the mixture was stirred overnight at room temperature. The insolubles was filtered off and the filtrate was concentrated to dryness. The residue was purified by a silica gel column chromatography (chloroform:ethyl acetate=20:1) and crystallized from diisopropyl ether to give N-(2-aminophenyl)-3,5-di-t-butyl-4-hydroxybenzamide (1.10 g, 32%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9].[CH2:17]([OH:19])C.[C:20]1([CH3:26])C=CC=CC=1.Cl>>[C:2]1([NH:1][C:17](=[O:19])[O:9][CH2:20][CH3:26])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:8][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[N+:8]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O-:10])=[O:9]
Reactant: Cc1ccccc1
Reactant: CCO
Agent: Cl
Solvent: Nc1ccccc1
Solvent: O=[N+]([O-])c1ccccc1
Product: CCOC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
Into a 100 ml capacity SUS 316 stainless autoclave were fed the above catalyst (61.9 mg) (0.020 mmol in terms of Pd), aniline (0.931 g, 0.010 mol), nitrobenzene (1.23 g, 0.010 mol), ethanol (4.61 g, 0.10 mol), toluene (10.6 g, 0.11 mol) and 35% hydrochloric acid aqueous solution (0.071 g, HCl=0.68 mmol, H2O=0.067 mmol), followed by introducing CO gas up to 28 Kg/cm2 at room temperature without purging the air inside the system, reacting them at a reaction temperature of 190° C. for 3 hours, cooling the reaction mixture down to room temperature after the reaction, returning the pressure inside the system to the atmospheric pressure and analyzing the reaction product according to gas chromatography. As a result, ethyl N-phenylcarbamate (NPU) (2.97 g) was formed (NPU yield: 90%), and aniline (0.093 g, 0.001 mol) and nitrobenzene (0.123 g, 0.001 mol) remained unreacted.