Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:12]2[C:13]([C:19](=[O:29])[C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[N+:26]([O-])=O)=[N:14][CH:15]=[C:16]([Cl:18])[CH:17]=2)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:30]([F:33])([F:32])[F:31]>C(O)(=O)C.CCOC(C)=O.[Fe]>[NH2:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:19]([C:13]1[C:12]([NH:11][S:8]([C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:30]([F:33])([F:32])[F:31])[CH:4]=2)(=[O:10])=[O:9])=[CH:17][C:16]([Cl:18])=[CH:15][N:14]=1)=[O:29]
Reactant: O=C(c1ccccc1[N+](=O)[O-])c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: [Fe]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Nc1ccccc1C(=O)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred suspension of Fe (176 mg, 3.15 mmol) in glacial acetic acid (5 mL) was added a solution 4-chloro-N-[5-chloro-2-(2-nitro-benzoyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (410 mg, 0.788 mmol) in AcOH (5 mL) at 80° C. for 15 minutes. After complete addition the mixture was stirred at the same temperature for 30 minutes and the progress of the reaction was followed by LCMS. The reaction mixture was then cooled to room temperature and it was then diluted with EtOAc and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure and residue was portioned between NaHCO3 and EtOAc. The organic portion was separated and the aqueous portion was extracted with EtOAc. The combined extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to provide N-[2-(2-amino-benzoyl)-5-chloro-pyridin-3-yl]-4-chloro-3-trifluoromethyl-benzenesulfonamide. 1H NMR (400 MHz, CDCl3) δ 8.98 (s, 1 H), 8.42 (d, J=2.4 Hz, 1 H), 8.12 (d, J=2.0 Hz, 1 H), 7.93 (d, J=2.4 Hz, 1 H), 7.64-7.61 (m, 1 H), 7.30-7.26 (m, 2 H), 7.03-7.00 (m, 1 H), 6.64 (d, J=8.4 Hz, 1 H), 6.47-6.43 (m, 1 H), 6.26 (s, 2 H); Mass spectrum m/z: 490.0 (M+H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([N:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:11]=[C:10]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[C:26]#[N:27])[C:9]2=[O:28])[CH:5]=[CH:6][CH:7]=1.[S-:29][C:30]#[N:31].[NH4+:32].BrBr.C(=O)([O-])[O-].[K+].[K+]>O.C(OCC)(=O)C.C(O)(=O)C>[NH2:31][C:30]1[S:29][C:2]2[CH:3]=[C:4]([N:8]3[CH:13]=[C:12]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=4)[CH:11]=[C:10]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[C:26]#[N:27])[C:9]3=[O:28])[CH:5]=[CH:6][C:7]=2[N:32]=1
Reactant: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2cccc(N)c2)c1=O
Reactant: [NH4+]
Reactant: N#C[S-]
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccccc1-c1cc(-c2ccccn2)cn(-c2ccc3nc(N)sc3c2)c1=O
Reaction time: 1 h
Yield: 33.4 %

Procedure:
150 mg of 1-(3-aminophenyl)-3-(2-cyanophenyl)-5-(2-pyridyl)-1,2-dihydropyridin-2-one and 63 mg of ammonium thiocyanate were added to 2 ml of acetic acid. The mixture was stirred at room temperature for 1 hour, to which 0.022 ml of bromine was added, and further stirred for 1 hour. The reaction mixture was distributed into the ethyl acetate and water layers, and neutralized with 20% aqueous solution of potassium carbonate. The organic layer was washed with water, dried and concentrated, and the residue was refined by silica gel chromatography (ethyl acetate/hexane-based solvent), to obtain 58 mg of the subject compound.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:16]1([C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)=[O:23])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[N:16]1([C:22]([N:24]2[CH2:25][CH2:26][N:27]([C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)[CH2:28][CH2:29]2)=[O:23])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]1
Reactant: O=C(N1CCCCC1)N1CCNCC1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Product: COc1cc2ncnc(N3CCN(C(=O)N4CCCCC4)CC3)c2cc1OC

Procedure:
In like manner, 1-chloro-6,7-diethoxyisoquinoline and 1-(piperidinocarbonyl)piperazine react to afford 1-(4-piperidinocarbonyl-1-piperazinyl)-6,7-diethoxyisoquinoline, while 4-chloro-6,7-dimethoxyquinazoline and 1-(piperidinocarbonyl)piperazine react to afford 4-(4-piperidinocarbonyl-1-piperazinyl)-6,7-dimethoxyquinazoline respectively. The latter compound is, of course, identical in every respect with the product of Example V.
Reaction SMILES: C[O:2][C:3](=[O:9])[CH2:4][C:5]([CH2:7]Br)=O.[CH3:10][C:11]([NH:16][C:17]([NH2:19])=[O:18])([CH3:15])[CH2:12][CH2:13][CH3:14].O>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:10][C:11]([NH:16][C:17]([NH:19][C:5]1[CH2:7][O:2][C:3](=[O:9])[CH:4]=1)=[O:18])([CH3:15])[CH2:12][CH2:13][CH3:14]
Reactant: COC(=O)CC(=O)CBr
Reactant: CCCC(C)(C)NC(N)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CCCC(C)(C)NC(=O)NC1=CC(=O)OC1
Yield: 8 %

Procedure:
To a solution of 22 g of methyl-4-bromoacetoacetate in 200 ml benzene is added 14.4 g of 1,1-dimethylbutylurea and 100 mg of p-toluene sulfonic acid. The solution is heated at reflux under nitrogen for four hours with water removal. At the end of this period the solution is cooled and concentrated. The residual material is chromatographed on 400 g of silicic acid. Elution with a solution of benzene (60%), ethyl acetate (30%) and methanol (10%) gives crystalline material. Recrystallization of this material from ethyl acetate gives 1.8 g of 1-(1,1-dimethylbutyl)-3-(2,5-dihydro-5-oxo-3-furyl)urea, m.p. 130°-132° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2(O)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[Cl-].[Al+3].[Cl-].[Cl-].Cl>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:15]2([C:12]3[CH:13]=[CH:14][C:9]([F:8])=[CH:10][CH:11]=3)[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]2)=[CH:4][CH:3]=1
Reactant: Fc1ccccc1
Reactant: O=C1CCC(O)(c2ccc(F)cc2)CC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Product: O=C1CCC(c2ccc(F)cc2)(c2ccc(F)cc2)CC1
Reaction time: 2 h
Yield: 75.9 %

Procedure:
To a stirred and cooled (ice-bath) mixture of 50 parts of fluorobenzene and 4.1 parts of 4-(4-fluorophenyl)-4-hydroxycyclohexanone were added portionwise 11 parts of aluminium chloride. Upon completion, stirring was continued for 2 hours while still cooling. The reaction mixture was decomposed by pouring onto a mixture of crushed ice and a hydrochloric acid solution. The product was extracted with methylbenzene. The extract was washed with water till neutralization, dried, filtered and evaporated. The residue was purified by column-chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated, yielding 4.3 parts (75.9%) of 4,4-bis(4-fluorophenyl)-1-cyclohexanone as a residue (intermediate 19).
Reaction SMILES: [CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)=[O:2].[CH3:12][N:13]=[C:14]=[S:15].O>C(O)C>[CH:1]([NH:3][NH:4][C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:14]([NH:13][CH3:12])=[S:15])=[CH:7][CH:6]=1)=[O:2]
Reactant: CN=C=S
Reactant: Nc1ccc(NNC=O)cc1
Solvent: CCO
Solvent: O
Product: CNC(=S)Nc1ccc(NNC=O)cc1

Procedure:
1-Formyl-2-(4-aminophenyl)hydrazine (1.51 g, 0.01 mole) and methyl isothiocyanate (0.73 g, 0.01 mole) were mixed in ethanol (20 ml) and the mixture was refluxed for 30 minutes. The mixture was chilled in ice, and water was added to precipitate the product. The product came out of solution in an oily form, but solidifed upon scratching and standing. The solid material was filtered off and washed thoroughly with ether. The product was dried to give a white crystalline powder. Yield 1.3 g (58%), m.p. 176°-178° C.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:12](=[O:13])[C:11]2[C:6](=[CH:7][C:8]([Cl:14])=[CH:9][CH:10]=2)[N:5]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:4]=1.[N:21]1([C:26]2[CH:27]=[C:28]([CH:32]=[CH:33][N:34]=2)[C:29](O)=[O:30])[CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:14][C:8]1[CH:7]=[C:6]2[C:11]([C:12](=[O:13])[C:3]([CH2:2][NH:1][C:29](=[O:30])[C:28]3[CH:32]=[CH:33][N:34]=[C:26]([N:21]4[CH2:22][CH2:23][CH2:24][CH2:25]4)[CH:27]=3)=[CH:4][N:5]2[C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)=[CH:10][CH:9]=1
Reactant: NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O
Reactant: O=C(O)c1ccnc(N2CCCC2)c1
Product: O=C(NCc1cn(-c2ccccc2)c2cc(Cl)ccc2c1=O)c1ccnc(N2CCCC2)c1

Procedure:
N-(7-Chloro-4-oxo-1-phenyl-1,4-dihydro-quinolin-3-ylmethyl)-2-pyrrolidin-1-yl-iso-nicotinamide was prepared starting from intermediate D and 2-(pyrrolidin-1-yl)isonicotinic acid. MS calcd. for C26H24ClN4O2 [(M+H)+] 459.2, obsd. 459.0.
Reaction SMILES: [OH:1][C:2]1([C:21]2[S:25][C:24]([CH:26]([CH3:28])[CH3:27])=[N:23][CH:22]=2)[CH2:7][CH2:6][CH:5]([N:8]2[CH2:12][CH2:11][C@@H:10]([NH:13]C(=O)OC(C)(C)C)[CH2:9]2)[CH2:4][CH2:3]1>Cl.O1CCOCC1>[NH2:13][C@@H:10]1[CH2:11][CH2:12][N:8]([CH:5]2[CH2:4][CH2:3][C:2]([C:21]3[S:25][C:24]([CH:26]([CH3:28])[CH3:27])=[N:23][CH:22]=3)([OH:1])[CH2:7][CH2:6]2)[CH2:9]1
Reactant: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](NC(=O)OC(C)(C)C)C3)CC2)s1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)c1ncc(C2(O)CCC(N3CC[C@@H](N)C3)CC2)s1
Temperature: 25 °C
Reaction time: 1 h
Yield: 105.2 %

Procedure:
The mixture of tert-butyl {(3R)-1-[4-hydroxy-4-(2-isopropyl-1,3-thiazol-5-yl)cyclohexyl]pyrrolidin-3-yl}carbamate (0.50 g, 1.22 mmol) in 4 N HCl/dioxane (10 mL) was stirred at room temperature for 1 hour. The solution was concentrated to give 0.397 g of the title compound as 2 HCl salt. MS (EI) calcd: (M+1)+=309.2; found: 310.2.
Reaction SMILES: Cl.[C:2](=N)([NH2:4])[CH3:3].[NH:6]([C:8]([C:10]1[C:14]([CH3:15])=[CH:13][S:12][C:11]=1[NH:16][C:17](=[O:30])[CH2:18][N:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:22][CH2:21][C:20]1=[O:29])=O)[NH2:7]>>[CH3:15][C:14]1[C:10]([C:8]2[NH:6][N:7]=[C:2]([CH3:3])[N:4]=2)=[C:11]([NH:16][C:17](=[O:30])[CH2:18][N:19]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21][C:20]2=[O:29])[S:12][CH:13]=1
Reactant: Cc1csc(NC(=O)CN2C(=O)CCc3ccccc32)c1C(=O)NN
Reactant: CC(=N)N
Agent: Cl
Product: Cc1n[nH]c(-c2c(C)csc2NC(=O)CN2C(=O)CCc3ccccc32)n1

Procedure:
The title compound was prepared from acetimidamide hydrochloride (55 mg, 0.590 mmol) and N-(3-(hydrazinecarbonyl)-4-methylthiophen-2-yl)-2-(2-oxo-3,4-dihydroquinolin-1(2H)-yl)acetamide (141 mg, 0.393 mmol) according to the procedure of Example 1.11.2, above. Retention time (min)=4.106, method [7], MS (ESI) 382.1 (M+H); 1H NMR (300 MHz, CDCl3) δ 12.07 (s, 1H), 7.23-7.31 (m, 2H), 7.05-7.23 (m, 2H), 6.57 (s, 1H), 4.86 (s, 2H), 3.02-3.07 (m, 2H), 2.84-2.87 (m, 2H), 2.41 (s, 3H), 2.39 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12](O)=[O:13])[CH:7]=1.C[N:25](C)CCCN=C=NCC.N1C2C(=NC=CC=2)N(O)N=1.C(NC(C)C)(C)C.[Cl-].[NH4+]>O1CCCC1>[CH3:1][O:2][C:3]1[CH:18]=[C:17]([NH:19][CH3:20])[C:16]([N+:21]([O-:23])=[O:22])=[CH:15][C:4]=1[O:5][C:6]1[CH:11]=[CH:10][N:9]=[C:8]([C:12]([NH2:25])=[O:13])[CH:7]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CNc1cc(OC)c(Oc2ccnc(C(=O)O)c2)cc1[N+](=O)[O-]
Agent: On1nnc2cccnc21
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CNc1cc(OC)c(Oc2ccnc(C(N)=O)c2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The mixture containing 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxylic acid (1 eq), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (2 eq), 3H-1,2,3-triazolo[4,5-b]pyridine-3-ol (1.5 eq), and diisopropylamine (5 eq) in tetrahydrofuran was stirred at room temperature for 1 hour. To this was then added ammonium chloride (2 eq) and the resulting mixture was stirred together for 48 hours. Reaction concentrated. Purification on silica gel, 50% acetone in hexanes to yield 4-(2-methoxy-4-(methylamino)-5-nitrophenoxy)pyridine-2-carboxamide as a bright yellow solid. HPLC=3.70 min; MS: MH+=319.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2)([O-])=O>[Pt]>[NH2:1][C:4]1[CH:5]=[N:6][C:7]2[C:12]([C:13]=1[NH:14][CH2:15][C:16]1([C:20]([O:22][CH2:23][CH3:24])=[O:21])[CH2:19][CH2:18][CH2:17]1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: CCOC(=O)C1(CNc2c([N+](=O)[O-])cnc3ccccc23)CCC1
Agent: [Pt]
Product: CCOC(=O)C1(CNc2c(N)cnc3ccccc23)CCC1

Procedure:
The method described in Part D of Example 64 was used to hydrogenate (35 psi, 2.4×105 Pa) ethyl 1-{[(3-nitroquinolin-4-yl)amino]methyl}cyclobutanecarboxylate (10.0 g, 30.4 mmol) in the presence of 5% platinum on carbon (1.0 g) to provide ethyl 1-{[(3-aminoquinolin-4-yl)amino]methyl}cyclobutanecarboxylate as a yellow solid.
Reaction SMILES: [Cl:1][S:2]([N:5]=[C:6]=[O:7])(=[O:4])=[O:3].[CH3:8][C:9](=[C:11]([CH3:13])[CH3:12])[CH3:10]>CCOCC>[Cl:1][S:2]([N:5]1[C:11]([CH3:13])([CH3:12])[C:9]([CH3:10])([CH3:8])[C:6]1=[O:7])(=[O:4])=[O:3]
Reactant: O=C=NS(=O)(=O)Cl
Reactant: CC(C)=C(C)C
Solvent: CCOCC
Product: CC1(C)C(=O)N(S(=O)(=O)Cl)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 0.06 mol CSI (chlorosulfonyl isocyanate) in dry ether under nitrogen, 0.06 mol of 2,3-dimethyl-but-2-ene was added dropwise at a temperature of 30° to 35° C. The reaction mixture was stirred for a further 1 hour while it was cooled to room temperature. The solution was then cooled in a salt-ice bath and the product which crystallized out as white solid was filtered off and carried through to the next step.
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34](Cl)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2].[CH3:38][N:39]([CH3:49])[C:40]1[CH:41]=[C:42](B(O)O)[CH:43]=[CH:44][CH:45]=1>>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH2:31][C:32]2[S:33][C:34]([C:44]3[CH:43]=[CH:42][CH:41]=[C:40]([N:39]([CH3:49])[CH3:38])[CH:45]=3)=[CH:35][CH:36]=2)[CH:25]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(Cl)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: CN(C)c1cccc(B(O)O)c1
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(C)c(Cc3ccc(-c4cccc(N(C)C)c4)s3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-chloro-2-thienylmethyl)-4-methylbenzene 57 obtained in Example 120 (1) and 3-dimethylaminophenylboronic acid were used and treated in a manner similar to Example 120-(2) to give 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene. APCI-Mass m/Z 638 (M+H). (2) the above 1-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)-3-(5-(3-dimethylaminophenyl)-2-thienylmethyl)-4-methylbenzene was treated in a manner similar to Example 106-(3) to give the target compound. APCI-Mass m/Z 470 (M+H).
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[NH:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1>O.CC(O)=O>[N:1]([N:5]1[C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:3]
Reactant: O=N[O-]
Reactant: c1ccc2c(c1)CCCCN2
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=NN1CCCCc2ccccc21
Temperature: 5 °C
Reaction time: 1 h
Yield: 90.5 %

Procedure:
A solution of sodium nitrite (1.35 g, 19.6 mmol) in water (4.0 mL) was added dropwise to a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (2.40 g, 16.3 mmol) in AcOH (10 mL) at 0–10° C. The mixture was stirred at 5° C. for 10 min, room temperature for 1 h and extracted with CH2Cl2 (3×20 mL). The organic layer was dried (MgSO4), concentrated in vacuo and flash column chromatography (EtOAc:hexane/1:9) gave 1-nitroso-2,3,4,5-tetrahydro-1H-1-benzazepine (2.60 g, 91%) as a brown liquid. 1H NMR (CDCl3, 300 MHz) δ 1.70–1.85 (m, 4H), 2.70–2.82 (m, 2H), 3.92 (br, 2H), 7.25–7.32 (m, 1H), 7.32–7.40 (m, 2H), 7.40–7.48 (m, 1H) ppm.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[CH3:13][Si:14]([CH2:17][CH2:18][O:19][CH2:20]Cl)([CH3:16])[CH3:15]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]2[CH:10]=[CH:9][N:8]([CH2:20][O:19][CH2:18][CH2:17][Si:14]([CH3:16])([CH3:15])[CH3:13])[C:5]2=[N:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccc2cc(Br)cnc21
Temperature: -40 °C
Reaction time: 1 h
Yield: 87.1 %

Procedure:
To a 250 ml 3-neck flask, 5-bromo-1H-pyrrolo[2,3-b]pyridine (10 g, 50.5 mmol) and DMF (80 ml) were added. The solution was cool to −40° C. under nitrogen, sodium hydride (1.5 g, 60.6 mmol) was added in 2 batches. The mixture was stirred at −40° C. for 1 hour. Then SEM-Cl (10.7 ml, 60.6 mmol) in DMF (20 ml) was added dropwise and the resulting mixture was allowed to stir at −40° C. for another 2 hours. The reaction was quenched with saturated NH4Cl (40 ml) and worked up with ethyl acetate, brine, dried with Na2SO4. Silica chromatography of the crude using a gradient of ethyl acetate and hexane afforded 5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrrolo[2,3-b]pyridine (14.4 g, 87% yield). 1H NMR (500 MHz, DMSO-d6) δ 0.02 (s, 9H), 0.92 (m, 2H), 3.59 (m, 2H), 5.72 (s, 2H), 6.65 (s, 1H), 7.84 (s, 1H), 8.37 (2, 1H), 8.45 (s, 1H). MS: m/z 327.0 (M+H+).
Reaction SMILES: [CH3:1][N:2]1[C:6](Cl)=[N:5][N:4]=[N:3]1.[CH:8]1([C:14]([CH2:16][CH2:17][CH2:18][SH:19])=[O:15])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[OH-].[K+]>CO>[CH3:1][N:2]1[C:6]([S:19][CH2:18][CH2:17][CH2:16][C:14]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]2)=[O:15])=[N:5][N:4]=[N:3]1
Reactant: O=C(CCCS)C1CCCCC1
Reactant: Cn1nnnc1Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Cn1nnnc1SCCCC(=O)C1CCCCC1
Yield: 21.9 %

Procedure:
1-Methyl-5-chloro-1,2,3,4-tetrazole (1.4 g) and 3-mercaptopropyl cyclohexyl ketone (1.9 g) are dissolved in methanol (50 ml) and potassium hydroxide (0.8 g) is added to the solution. The mixture is refluxed for 5 hours. Methanol is distilled off and water is added to the residue. The mixture is extracted with chloroform. The chloroform solution is washed with dil. aqueous sodium hydroxide, water and saturated aqueous sodium chloride and dried over sodium sulfate. Chloroform is distilled off and the residue is purified by column chromatography (Wakogel C-200, eluant: chloroform) to obtain 1-methyl-5-(3-cyclohexylcarbonylpropyl)thio-1,2,3,4-tetrazole (0.6 g) as colorless liquid, nD12 =1.5267.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:14][CH:15]([CH2:19][CH:20]([CH3:22])[CH3:21])[C:16]([OH:18])=O)([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])=[O:5])[CH3:2].[CH3:23][NH:24][C:25](=[O:32])[C@H:26]([CH2:28][CH:29]([CH3:31])[CH3:30])[NH2:27]>ClCCl.O1CCCC1>[CH2:1]([O:3][P:4]([CH2:6][N:7]1[C:11](=[O:12])[CH2:10][NH:9][C:8]1=[O:13])([CH2:14][CH:15]([C:16](=[O:18])[NH:27][C@H:26]([C:25](=[O:32])[NH:24][CH3:23])[CH2:28][CH:29]([CH3:31])[CH3:30])[CH2:19][CH:20]([CH3:22])[CH3:21])=[O:5])[CH3:2]
Reactant: CNC(=O)[C@@H](N)CC(C)C
Reactant: CCOP(=O)(CC(CC(C)C)C(=O)O)CN1C(=O)CNC1=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: CCOP(=O)(CC(CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NC)CN1C(=O)CNC1=O
Temperature: 25 °C
Reaction time: 24 h
Yield: 27.1 %

Procedure:
0.22 g (0.64 mmol) of 2(RS)-[[(RS)-(ethoxy)[(2,5-dioxo-1-imidazolidinyl)methyl]phosphinyl]methyl]-4-methylvaleric acid and 0.116 g (0.81 mmol) of L-leucine methylamide were taken up in 5 ml of dichloromethane and 2.5 ml of tetrahydrofuran. The solution was treated at -8° C. with 0.3 g (1.2 mmol) of N-ethoxycarbonyl-2-ethoxy-1,2-dihydroxyquinoline. The mixture was stirred at room temperature for 24 hours and was then left to stand at 0° C. for 48 hours. The solvent was removed by evaporation. The residue was taken up in 50 ml of chloroform. The solution was washed in sequence with 5% citric acid solution, 5% sodium hydrogen carbonate solution and sodium chloride solution, dried over anhydrous sodium sulfate and evaporated to give a gum. This gum was chromatographed on silica gel using chloroform/methanol (19:1) for the elution to give 0.08 g of [(2,5-dioxo-1-imidazolidinyl)methyl][(RS)-4-methyl-2-[[(S)-3-methyl-1-(methylcarbamoyl)butyl]carbamoyl]pentyl]phosphinic acid ethyl ester as a gum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1F)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6].[NH:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1.Cl>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[N:23]1[CH2:27][CH2:26][C@@H:25]([OH:28])[CH2:24]1)[C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([Cl:18])([F:17])[F:16])=[CH:10][CH:9]=1)=[O:6]
Reactant: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(F)c(Br)c1
Reactant: O[C@@H]1CCNC1
Agent: Cl
Solvent: CS(C)=O
Product: O=C(Nc1ccc(OC(F)(F)Cl)cc1)c1ccc(N2CC[C@@H](O)C2)c(Br)c1
Temperature: 90 °C
Reaction time: 20 h

Procedure:
A mixture of 3-bromo-N-(4-(chlorodifluoromethoxy)phenyl)-4-fluorobenzamide (1 g, 2.53 mmol), (R)-pyrrolidin-3-ol (0.331 g, 3.80 mmol), TEA (0.706 mL, 5.07 mmol) and DMSO (2.53 mL) was stirred at 90° C. for 20 h. The RM was treated with 0.5 M HCl (50 mL) and extracted with EtOAc. The combined extracts were washed with 0.5 M HCl, sat. aq. NaHCO3 and brine, dried over Na2SO4 and the solvent was evaporated off under reduced pressure to give the crude product which was purified by flash chromatography (RediSep® Silica gel column, 40 g, cyclohexane/EtOAc, from 1% to 4.5% EtOAc). The fractions containing the pure product were combined and the solvent was evaporated off under reduced pressure to give a residue which was triturated under cyclohexane to yield the title product as a white amorphous solid. UPLC-MS (Condition 3) tR=1.15 min, m/z=462.9 [M+H]+, m/z=460.9 [M−H]−; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.81-1.90 (m, 1H) 1.92-2.03 (m, 1H) 3.27 (dd, J=10.39, 1.10 Hz, 1H) 3.36-3.44 (m, 1H) 3.62-3.71 (m, 1H) 3.81 (dd, J=10.45, 4.71 Hz, 1H) 4.32-4.40 (m, 1H) 4.99 (d, J=3.42 Hz, 1H) 6.93 (d, J=8.80 Hz, 1H) 7.33 (d, J=9.05 Hz, 2H) 7.82-7.91 (m, 3H) 8.14 (d, J=2.20 Hz, 1H) 10.21 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([NH:13][CH3:14])=O)=[CH:4][CH:3]=1.[BH4-].[Na+].II.CO>C1COCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:13][CH3:14])=[CH:6][CH:7]=1
Reactant: CNC(=O)CCCc1ccc(F)cc1
Agent: II
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CNCCCCc1ccc(F)cc1
Temperature: 70 °C
Yield: 14.8 %

Procedure:
At 0° C., a solution of 4-(4-fluorophenyl)-N-methylbutyramide (1.30 g, 6.70 mmol) in THF (15 ml) was added dropwise to a suspension of sodium borohydride (604 mg, 16.0 mmol) in THF (15 ml). Successively, a solution of iodine (1.70 g, 6.70 mmol) in THF (20 ml) was added dropwise. The reaction mixture was heated to 70° C. for 16 hours. It was cooled to 0° C. Methanol (50 ml) was added carefully. The solvents were removed in vacuo. The residue was dissolved in a mixture of a 32% aqueous solution of sodium hydroxide (100 ml), water (50 ml), and tert-butyl methyl ether (200 ml). The phases were separated. The aqueous phase was extracted with tert-butyl methyl ether (2×100 ml). The combined organic layers were dried over magnesium sulphate. The solvent was removed in vacuo. The crude product was purified by flash chromatography on silica (80 g), using a mixture of DCM/methanol/25% aqueous ammonia (first 100:10:1, then 100:20:2) as eluent, to give 180 mg of N-[4-(4-fluorophenyl)butyl]-N-methylamine.