Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=O)=[CH:5][CH:4]=1.[Br-:12].[NH2:13][NH+:14]1[CH:18]=[CH:17][N:16]([CH2:19][C:20]([C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)=[O:21])[C:15]1(CC)[CH2:30][CH3:31]>C(O)(=O)C>[Br-:12].[CH3:1][N:2]([CH3:11])[C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[N:13][N+:14]2[CH:18]=[CH:17][N:16]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)=[O:21])[C:15]=2[CH2:30][CH3:31])=[CH:5][CH:4]=1
Reactant: CN(C)c1ccc(C=O)cc1
Reactant: CCC1(CC)N(CC(=O)c2ccc(OC)cc2)C=C[NH+]1N
Agent: [Br-]
Solvent: CC(=O)O
Product: CCc1n(CC(=O)c2ccc(OC)cc2)cc[n+]1N=Cc1ccc(N(C)C)cc1
Temperature: 25 °C
Reaction time: 96 h

Procedure:
1.18 g (7.9 mmol) of p-dimethylaminobenzaldehyde are added to a solution of 2.7 g (7.9 mmol) of 1-amino-2-ethyl-3-(p-methoxyphenacyl)-2-ethylimidazolium bromide in 40 ml of glacial acetic acid. The mixture is stirred at room temperature for 4 days, the product is crystallized out by the addition of ether and filtered off. It is washed with water, dried at room temperature and recrystallized from ethanol. There is obtained 1-[[p-(dimethylamino)benzylidene]amino]-2-ethyl-3-(p-methoxyphenacyl)-imidazolium bromide of melting point 244°-246°.
Reaction SMILES: [C:1]([C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[C:1]([C:3]1[C:12]([N+:14]([O-:16])=[O:15])=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[C:5]([CH3:13])[CH:4]=1)#[N:2]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(C#N)cc1C
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C#N)cc1C
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 65 %

Procedure:
A solution of methyl 4-cyano-2-methylbenzoate (18.1 g, 0.103 mol) in concentrated sulfuric acid (130 mL) was cooled to −10° C. While maintaining this internal temperature, fuming nitric acid (15.6 mL) was slowly added over a period of 30 min. The reaction mixture was stirred an additional 2.5 h at 0° C., at which time it was poured over 1.0 L of ice and then partitioned with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over anhydrous magnesium sulfate, and then concentrated in vacuo. The residue was triturated with 10% ethyl acetate/hexanes to afford methyl 4-cyano-2-methyl-5-nitrobenzoate (14.8 g, 65%) as a white powder. The title product was isolated as the major isomer in a 9:1 regioisomeric mixture. 1H NMR (400 MHz, CDCl3), Major: 8.85 (s, 1H), 7.81 (s, 1H), 4.00 (s, 3H), 2.77 (s, 3H); Minor: 8.07 (d, 1H), 7.72 (d, 1H), 3.98 (s, 3H), 2.57 (s, 3H). MS (EI) for C10H8N2O4: 238 (M+H2O).
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13]([C:18]([NH:20][CH:21]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:22](O)=[O:23])=[O:19])=[CH:12]2>>[CH2:25]([CH:21]([NH:20][C:18]([C:13]1[NH:14][C:15]2[C:11]([CH:12]=1)=[CH:10][C:9]([Cl:8])=[CH:17][CH:16]=2)=[O:19])[C:22](=[O:23])[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1)[C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reactant: C1CCNCC1
Agent: Cl
Product: O=C(NC(Cc1ccccc1)C(=O)N1CCCCC1)c1cc2cc(Cl)ccc2[nH]1

Procedure:
Piperidine hydrochloride (0.34 mmol) and 2-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid (0.30 mmol) were coupled according to procedure A (0-25° C. reaction temperature). The crude product was chromatographed on silica gel eluted with 20%, 30%, 40%, 50%, 75% and 100% ethyl acetate in hexane giving partial separation. The pure fractions were pooled giving 31 mg (25%) of the title substance: HPLC (60/40) 9.38 minutes (94%); PBMS 410/412 (MH+, 100%);
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][CH:3]=1.[CH2:11](Br)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CCOC(C)=O>O1CCOCC1>[CH2:11]([N:7]1[CH:6]=[C:5]2[C:9]([CH:10]=[C:2]([Br:1])[CH:3]=[CH:4]2)=[N:8]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: BrCc1ccccc1
Reactant: Brc1ccc2cn[nH]c2c1
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: Brc1ccc2cn(Cc3ccccc3)nc2c1
Temperature: 120 °C
Reaction time: 8 h
Yield: 60.8 %

Procedure:
6-Bromoindazole (14.42 g, 73.2 mmol) was suspended in 50 mL of dioxane and the mixture was treated with benzyl bromide (10.5 mL, 88.8 mmol) and then heated in an oil bath to 120° C. with mechanical stirring overnight. The resulting thick suspension was allowed to cool to 80° C. (bath temp) and 200 mL of EtOAc was added. The mixture was vigorously stirred for 20 minutes and the precipitated orange-brown solid was collected by filtration, washed well with EtOAc and air-dried. The resulting brown solid was partitioned between sat aq. NaHCO3 (100 mL) and EtOAc (300 mL) with stirring until all of the solid material had dissolved. The layers were separated and the aqueous phase was extracted with 2×100 mL of EtOAc. The combined organic phases were washed with brine, dried and filtered and concentrated in vacuo to give a brown solid. Recrystallization of the solid from 200 mL of 2:1 EtOH:water gave 12.78 g (61%) of desired product as tan needles. 1H-NMR (DMSO-d6) 8.55 (s, 1H), 7.84 (s, 1H), 7.72 (d, 1H), 7.48-7.28 (m, 5H), 7.13 (d, 1H), 5.62 (s, 2H); LC-MS [M+H]+=287.3, 289.0, RT=3.53 min.
Reaction SMILES: [CH3:1][S:2]([N:5]([S:7]([NH:10][C:11](=[O:15])OCC)(=[O:9])=[O:8])[CH3:6])(=[O:4])=[O:3].[NH2:16][C:17]1[N:22]=[C:21]([O:23][CH3:24])[CH:20]=[C:19]([O:25][CH3:26])[N:18]=1>ClC1C=CC=CC=1>[CH3:1][S:2]([N:5]([S:7]([NH:10][C:11]([NH:16][C:17]1[N:18]=[C:19]([O:25][CH3:26])[CH:20]=[C:21]([O:23][CH3:24])[N:22]=1)=[O:15])(=[O:8])=[O:9])[CH3:6])(=[O:3])=[O:4]
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCOC(=O)NS(=O)(=O)N(C)S(C)(=O)=O
Solvent: Clc1ccccc1
Product: COc1cc(OC)nc(NC(=O)NS(=O)(=O)N(C)S(C)(=O)=O)n1
Temperature: 80 °C
Yield: 98.5 %

Procedure:
52.0 g of ethyl (N-methylsulfonyl-N-methylamino)sulfonylcarbamate are dissolved in 500 ml of chlorobenzene, 31.0 g of 2-amino-4,6-dimethoxypyrimidine are added at room temperature with stirring, and the mixture is heated at 80° C. for 3 hours. After cooling to 0° C., the precipitate is filtered off and washed with 100 ml of chlorobenzene. 72.7 g of the desired product of a purity of 98.5% are obtained, which corresponds to a yield of 97.2% of theory. The melting point of the product is 185°-186° C.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH3:5][C:6]1[CH:7]=[C:8]([CH2:12][CH2:13][C:14](=[O:21])[CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:9]=[CH:10][CH:11]=1>O.C(O)(=O)C>[OH:3][N:1]=[C:15]([C:14](=[O:21])[CH2:13][CH2:12][C:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH3:5])[CH:7]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CC(=O)CCc1cccc(C)c1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCOC(=O)C(=NO)C(=O)CCc1cccc(C)c1
Reaction time: 1 h

Procedure:
Sodium nitrite (32 g) in water (60 ml) was added dropwise over 1 hour to a stirred solution of the product from example 13 step (i) (99.4 g) in acetic acid (200 ml) at a rate such that the internal temperature did not rise above 30° C. The solution was allowed to stir a further 1 hour before adding water (500 ml). After stirring for a further 24 h the reaction mixture was extracted with diethyl ether (×4). The combined ether extracts were washed with saturated sodium bicarbonate solution, and finally water before collecting the organic layer and drying over magnesium sulphate. The solution was filtered and the solvent evaporated under reduced pressure to leave the subtitle product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH:6]C(OC(C)(C)C)=O.[C:38]([OH:44])([C:40]([F:43])([F:42])[F:41])=[O:39]>C(Cl)Cl>[F:41][C:40]([F:43])([F:42])[C:38]([OH:44])=[O:39].[CH3:1][O:2][C:3](=[O:37])[C@@H:4]([NH:14][C:15]([C:17]1[S:18][C:19]([C:24](=[O:36])[NH:25][CH2:26][C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[CH:29]=[N:30][NH:31]3)=[CH:20][C:21]=1[CH2:22][CH3:23])=[O:16])[CH2:5][NH2:6]
Reactant: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CNC(=O)OC(C)(C)C)C(=O)OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(C(=O)NCc2cccc3[nH]ncc23)sc1C(=O)N[C@@H](CN)C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-3-tert-Butoxycarbonylamino-2-({3-ethyl-5-[(1H-indazol-4-ylmethyl)-carbamoyl]-thiophene-2-carbonyl}-amino)-propionic acid methyl ester (0.076 g, 0.14 mmol) in DCM (5 mL) was added TFA (1 mL). The mixture was stirred at room temperature 1 h and evaporated to give crude product which was used without further purification.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([F:17])[CH:3]=1.[F:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1>>[F:17][C:4]1[CH:3]=[C:2]([C:22]2[CH:23]=[CH:24][C:19]([F:18])=[CH:20][CH:21]=2)[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=1
Reactant: O=C1NCCCn2c1cc1cc(F)cc(Br)c12
Reactant: OB(O)c1ccc(F)cc1
Product: O=C1NCCCn2c1cc1cc(F)cc(-c3ccc(F)cc3)c12

Procedure:
The title compound, light brown solid (54 mg, 69%), MS (ISP) m/z=313.2 [(M+H)+], mp 239.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-9-fluoro-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indol-1-one (intermediate 2) (74.3 mg, 0.25 mmol) and commercially available 4-fluoro-phenylboronic acid (45.5 mg, 0.325 mmol).
Reaction SMILES: [F:1][S:2]([C:5]([F:10])([F:9])[C:6](F)=[O:7])(=[O:4])=[O:3].Cl.[C:12]([O:17][CH2:18][CH2:19][NH2:20])(=[O:16])[C:13]([CH3:15])=[CH2:14].N1C=CC=CC=1.Cl>C(Cl)Cl>[C:12]([O:17][CH2:18][CH2:19][NH:20][C:6](=[O:7])[C:5]([F:10])([F:9])[S:2]([F:1])(=[O:4])=[O:3])(=[O:16])[C:13]([CH3:15])=[CH2:14]
Reactant: C=C(C)C(=O)OCCN
Reactant: O=C(F)C(F)(F)S(=O)(=O)F
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: C=C(C)C(=O)OCCNC(=O)C(F)(F)S(=O)(=O)F
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 63.5 %

Procedure:
A 500 ml flask was charged with CH2Cl2 (80 ml) under nitrogen stream and stirred for 10 min at 0° C. and then 2-(fluorosulfonyl)difluoroacetyl fluoride (29.9 g, 166.0 mmol, 1.5 equivalent (eq.)) was added. After 25 minutes, a CH2Cl2 (160 ml) solution of 2-aminoethyl methacrylate hydrochloride (18.4 g, 111.0 mmol, 1.0 eq.) and pyridine (17.5 g, 221.0 mmol, 2.0 eq.) was added drop wise to the mixture over 50 minutes. The mixture was allowed to warm to room temperature (RT) and stirred for 3 hours at RT. 1N HCl was added to the final reaction mixture and the lower layer was separated and washed with 1N HCl and Brine. The solution was dried over anhydrous MgSO4, filtrated and then CH2Cl2 was removed by an evaporator. The crude product was purified by recrystallization (hexane/CHCl3). The target compound was obtained as a white solid (20.4 g) in 64% yield. 1H-NMR (400 MHz, CDCl3); delta=1.93 (dd, J=1.1, 1.2 Hz, 3H), 3.73 (td, J=5.4, 5.2 Hz, 2H), 4.35 (dd, J=5.1, 5.0 Hz, 2H), 5.63 (dq, J=1.4, 1.5 Hz, 1H), 6.12-6.14 (m, 1H), 7.09 (brs, 1H). 19F-NMR (376 MHz, CDCl3, C6F6 as standard); delta=40.68 (t, J=5.1 Hz, 1F), −105.91 (d, J=4.8 Hz, 2F).
Reaction SMILES: [O:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][C:9]([C:12](=[O:14])[CH3:13])=[CH:8][CH:7]=2)[N:3]=[CH:2]1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18].C[O-].[Na+].Cl>C(OC)(C)(C)C>[F:15][C:16]([F:23])([F:22])[C:17](=[O:18])[CH2:13][C:12]([C:9]1[CH:8]=[CH:7][C:6]([C:4]2[N:3]=[CH:2][O:1][CH:5]=2)=[CH:11][CH:10]=1)=[O:14]
Reactant: CC(=O)c1ccc(-c2cocn2)cc1
Reactant: CCOC(=O)C(F)(F)F
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: COC(C)(C)C
Product: O=C(CC(=O)C(F)(F)F)c1ccc(-c2cocn2)cc1
Reaction time: 20 h
Yield: 99 %

Procedure:
To a stirred solution of 1-[4-(1,3-oxazol-4-yl)phenyl]-1-ethanone (256 mg, 1.37 mmol), ethyl trifluoroacetate (214 mg, 1.51 mmol) in t-butylmethylether (22 ml) was added sodium methoxide (28 wt. % solution in methanol; 0.4 ml, 1.67 mmol) over 5 minutes, and the mixture was stirred for 20 hours. The mixture was made neutral by addition of 2N HCl, and the whole was extracted with ethyl acetate. The organic layer was washed with brine, dried over MgSO4, and concentrated in vacuo. The residue was used for next reaction without further purification. (433 mg, 99% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(N(CC)C(C)C)(C)C.Cl[C:17]1[C:18]2[C:25]([C:26]3[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=3)[C:29]#[N:30])=[CH:24][NH:23][C:19]=2[N:20]=[CH:21][N:22]=1>C(O)CCC>[N:1]1([C:17]2[C:18]3[C:25]([C:26]4[CH:27]=[C:28]([CH:31]=[CH:32][CH:33]=4)[C:29]#[N:30])=[CH:24][NH:23][C:19]=3[N:20]=[CH:21][N:22]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCN1
Reactant: N#Cc1cccc(-c2c[nH]c3ncnc(Cl)c23)c1
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1cccc(-c2c[nH]c3ncnc(N4CCOCC4)c23)c1

Procedure:
Morpholine (871 mg, 10 mmol) and N,N-diisopropylethylamine (2.6 g, 20 mmol) were added to a solution of 3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzonitrile (C14) (2.5 g, 9.8 mmol) in n-butanol (100 mL), and the reaction mixture was heated at reflux for 3 hours. Solvents were removed in vacuo and the residue was purified using chromatography on silica gel (Eluent: 1:1 ethyl acetate/petroleum ether). Subsequent recrystallization from ethyl acetate and tert-butyl methyl ether afforded the product as a white solid. Yield: 770 mg, 2.52 mmol, 26%. LCMS m/z 306.0 [M+H+]. 1H NMR (400 MHz, DMSO-d6) δ 12.34 (br s, 1H), 8.41 (s, 1H), 7.99-8.02 (m, 1H), 7.89 (br d, J=8 Hz, 1H), 7.76 (br d, J=7.5 Hz, 1H), 7.71 (s, 1H), 7.68 (dd, J=7.8, 7.8 Hz, 1H), 3.44-3.50 (m, 4H), 3.11-3.17 (m, 4H).
Reaction SMILES: CC([O-])(C)C.[K+].F[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1.[Cl:17][CH2:18][CH2:19][CH2:20][OH:21]>CS(C)=O>[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=1
Reactant: OCCCCl
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=[N+]([O-])c1ccc(OCCCCl)cc1
Reaction time: 3 h
Yield: 34.6 %

Procedure:
To a cooled (5°-10° C.) suspension of KOtBu (1.34 g, 11.96 mmol) in DMSO (5 mL) was added a solution of 4-fluoronitrobenzene (1.61 g, 11.39 mmol) and 3-chloro-1-propanol (1.13 g, 11.96 mmol) in DMSO (5 mL). The cooling bath was removed and stirring was continued for 3 hours. The mixture was diluted with water (100 mL) and extracted with ether. The combined extracts were washed with brine, dried (MgSO4), and concentrated to give a brown oil. Purification by flash chromatography (10% EtOAc/hexane) gave 850 mg (35%) of product as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2[C:10](=[N:11][NH:12][C:13]=2[NH2:16])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:17][C:18](=O)[CH2:19][C:20](=O)[CH3:21].C([O-])(O)=O.[Na+]>CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:15][C:14]2=[C:13]3[N:12]([N:11]=[C:10]2[CH2:9]1)[C:20]([CH3:21])=[CH:19][C:18]([CH3:17])=[N:16]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2n[nH]c(N)c2C1
Reactant: CC(=O)CC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1cc(C)n2nc3c(c2n1)CN(C(=O)OC(C)(C)C)C3
Yield: 98.9 %

Procedure:
A solution of 3-amino-2,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-5-carboxylic acid tert-butyl ester (700 mg; 3.12 mmol; 1 eq.) and pentane-2,4-dione (0.35 mL; 3.43 mmol; 1.1 eq.) in AcOH (3.1 mL) was stirred at room temperature for 1 hour then poured into sat. aq. NaHCO3. The precipitate was filtered off and dried to afford the title compound (890 mg, 97%) as a white solid. HPLC (max plot) 98.8%; Rt 3.32 min.
Reaction SMILES: [OH:1][C:2]1[C:7]2[C:8]3[CH2:9][NH:10][CH2:11][CH2:12][C:13]=3[C:14]([CH3:17])([CH3:16])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1.Cl[CH2:22][C:23]([NH:25][CH3:26])=[O:24]>>[OH:1][C:2]1[C:7]2[C:8]3[CH2:9][N:10]([CH2:22][C:23]([NH:25][CH3:26])=[O:24])[CH2:11][CH2:12][C:13]=3[C:14]([CH3:16])([CH3:17])[O:15][C:6]=2[CH:5]=[C:4]([CH:18]([CH3:20])[CH3:19])[CH:3]=1
Reactant: CC(C)c1cc(O)c2c(c1)OC(C)(C)C1=C2CNCC1
Reactant: CNC(=O)CCl
Product: CNC(=O)CN1CCC2=C(C1)c1c(O)cc(C(C)C)cc1OC2(C)C

Procedure:
The above-titled compound was prepared by reacting 10-hydroxy-8-isopropyl-5,5-dimethyl-1,2,3,4-tetrahydro-5H-[1]benzopyrano[4,3-c]pyridine with 2-chloro-N-methylacetamide according to the method of Example 1; m.p. 178-190°.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH2:16])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[F:19])=[CH:4][CH:3]=1.[Cl:21][C:22]1[C:35]([N:36]=[C:37]=[S:38])=[C:34]([Cl:39])[CH:33]=[CH:32][C:23]=1[CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28].CN(C=O)C>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:20])[C:10]2[CH:15]=[C:14]([NH:16][C:37]([NH:36][C:35]3[C:34]([Cl:39])=[CH:33][CH:32]=[C:23]([CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:30])[CH3:29])[C:22]=3[Cl:21])=[S:38])[C:13]([NH:17][CH3:18])=[CH:12][C:11]=2[F:19])=[CH:6][CH:7]=1
Reactant: CC(C)(C)C(=O)NCc1ccc(Cl)c(N=C=S)c1Cl
Reactant: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1N
Solvent: CN(C)C=O
Solvent: O
Product: CNc1cc(F)c(C(=O)Nc2ccc(Br)cc2)cc1NC(=S)Nc1c(Cl)ccc(CNC(=O)C(C)(C)C)c1Cl
Reaction time: 72 h

Procedure:
A mixture of N-(4-bromophenyl)-2-fluoro-4-methylamino-5-amino-benzamide (220 mg, 0.543 mmol), N-(2,4-Dichloro-3-isothiocyanato-benzyl)-2,2-dimethyl-propionamide (0.172 mg, 0.543 mmol) and DMF (5 mL) is stirred for 3 d, diluted with water, and extracted with EtOAc. The organic phase is washed with water, dried with Na2SO4 and concentrated to give the crude product.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[CH:7][CH:6]=1)(=[O:4])=[O:3].P(Cl)(Cl)(Cl)(Cl)Cl.[Cl:19][S:20](O)(=[O:22])=[O:21]>ClCCl>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([S:20]([Cl:19])(=[O:22])=[O:21])[CH:6]=1)(=[O:3])=[O:4]
Reactant: COc1ccc(S(C)(=O)=O)cc1
Reactant: O=S(=O)(O)Cl
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(S(C)(=O)=O)cc1S(=O)(=O)Cl
Temperature: 25 °C

Procedure:
To a solution of crude 1-methanesulfonyl-4-methoxybenzene (8 mmol) in dry dichloromethane (20 mL), chlorosulfonic acid (1 mL) was added dropwise at 0° C. The reaction mixture was warm to room temperature followed by the addition of PCl5 (0.5 g). The resulting reaction mixture was refluxed for 1 h. After cooling to room temperature, the reaction mixture was poured into stirring ice water (50 mL). The water layer was then extracted with EtOAc (2×40 mL.) The combined organic extracts was washed with saturated sodium chloride aqueous solution (2×40 mL), dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was purified by flash column chromatography eluting with hexanes/EtOAc (3:1) to give 1.6 g of 5-methanesulfonyl-2-methoxybenzenesulfonyl chloride.
Reaction SMILES: C[O:2][C:3](=O)[CH:4]=[CH:5][C:6](=[C:11]([NH:13][CH3:14])[CH3:12])[C:7]([O:9][CH3:10])=[O:8].C[O-].[Na+].[Br:19]N1C(=O)CCC1=O>CO>[CH3:10][O:9][C:7]([C:6]1[CH:5]=[C:4]([Br:19])[C:3](=[O:2])[N:13]([CH3:14])[C:11]=1[CH3:12])=[O:8]
Reactant: O=C1CCC(=O)N1Br
Reactant: CNC(C)=C(C=CC(=O)OC)C(=O)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cc(Br)c(=O)n(C)c1C
Temperature: 25 °C
Yield: 45.6 %

Procedure:
MeOH (45 mL) was added to a flask containing 4-(1-methylamino-ethylidene)-pent-2-enedioic acid dimethyl ester (0.97 g, 4.55 mmol). NaOMe solution (1.04 mL, 4.55 mmol, 4.375 M in MeOH) and N-bromosuccinimide (0.97 g, 5.46 mmol) were added, and the resulting mixture was refluxed for 1 h. After cooling to r.t., the solvent was evaporated in vacuo. The residue was partitioned between saturated NH4Cl and CH2Cl2. The aqueous layer was extracted with additional CH2Cl2 and the organic layers were combined, dried over MgSO4, and concentrated. The crude product was chromatographed (0-50% EtOAc/hexanes) to give 540 mg of the title compound. MS: (+) m/z 260.22, 262.18 (M+Na, 79/81Br).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:20][C:19](=O)[CH2:18][C@H:12]1[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([SH:25])[CH2:23][SH:24]>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[C@H:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:18][C:19]2([S:25][CH2:22][CH2:23][S:24]2)[CH2:20]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: SCCS
Reactant: CCOC(=O)[C@@H]1CC(=O)CN1C(=O)OCc1ccccc1
Solvent: CCO
Product: CCOC(=O)[C@@H]1CC2(CN1C(=O)OCc1ccccc1)SCCS2

Procedure:
As described in Example 23, react 1-benzyloxycarbonyl-4-keto-(S)-proline, ethyl ester (prepared from the acid by esterification in ethanol) with 1,2-ethanedithiol to obtain 7-benzyloxycarbonyl-1,4-dithia-7-azaspiro [4.4]nonane-8(S)carboxylic acid, ethyl ester, a yellow oil [α]D26 -21.0° (ethanol).
Reaction SMILES: [CH2:1]([N:8]([S:18]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)(=[O:20])=[O:19])[C:9]1[CH:17]=[CH:16][C:12]([C:13](O)=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([N:8]([C:9]1[CH:17]=[CH:16][C:12]([C:13]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)=[O:14])=[CH:11][CH:10]=1)[S:18]([C:21]1[N:22]=[CH:23][N:24]([CH3:26])[CH:25]=1)(=[O:19])=[O:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cn1cnc(S(=O)(=O)N(Cc2ccccc2)c2ccc(C(=O)O)cc2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CN1CCN(C(=O)c2ccc(N(Cc3ccccc3)S(=O)(=O)c3cn(C)cn3)cc2)CC1

Procedure:
To a stirred solution of 4-[benzyl-(1-methyl-1H-imidazole-4-sulfonyl)-amino]-benzoic acid (37 mg, 0.1 mmol) in dry dimethylformamide (1 ml) was added N-methylpiperazine (20 mg, 0.2 mmol), triethylamine (28 μl, 0.2 mmol) then 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (42 mg, 0.11 mmol) and the solution was stirred at room temperature for 16 hours. The reaction mixture was concentrated in vacuo and the residue purified using preparative HPLC to afford the title compound as a clear oil (30 mg, 66% HPLC retention time 4.5 min. Mass spectrum (ES+) m/z 454 (M+H).
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]1([C:6](O)=[O:7])[CH2:5][CH2:4]1.[NH2:11][C:12]1[N:17]=[N:16][C:15]([N:18]2[CH2:23][CH2:22][N:21]([C:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[C:32]([F:35])([F:34])[F:33])=[O:25])[CH2:20][CH2:19]2)=[CH:14][CH:13]=1>>[F:35][C:32]([F:33])([F:34])[C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:24]([N:21]1[CH2:20][CH2:19][N:18]([C:15]2[N:16]=[N:17][C:12]([NH:11][C:6]([C:3]3([C:2]([F:10])([F:9])[F:1])[CH2:5][CH2:4]3)=[O:7])=[CH:13][CH:14]=2)[CH2:23][CH2:22]1)=[O:25]
Reactant: O=C(O)C1(C(F)(F)F)CC1
Reactant: Nc1ccc(N2CCN(C(=O)c3ccccc3C(F)(F)F)CC2)nn1
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(c2ccc(NC(=O)C3(C(F)(F)F)CC3)nn2)CC1

Procedure:
Following the procedure of Example 2, making variations only as required to use 1-trifluoromethylcyclopropanecarboxylic acid in place of benzyloxyacetic acid to react with [4-(6-aminopyridazin-3-yl)piperazin-1-yl](2-trifluoromethylphenyl)-methanone, the title compound was obtained as a white powder (16% yield). 1H NMR (300 MHz, CDCl3) δ 8.62, 8.18, 7.74, 7.63, 7.56, 7.34, 7.01, 4.03-3.89, 3.71-3.62, 3.60-3.58, 3.34-3.32, 1.54-1.52, 1.39-1.36. MS (ES+) m/z 487.9 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12]>CO.[Ni]>[Br:1][C:2]1[CH:7]=[C:6]([CH:5]=[CH:4][C:3]=1[CH2:11][CH3:12])[NH2:8]
Reactant: CCc1ccc([N+](=O)[O-])cc1Br
Agent: [Ni]
Solvent: CO
Product: CCc1ccc(N)cc1Br
Reaction time: 3 h
Yield: 210.4 %

Procedure:
To a solution of 2-bromo-1-ethyl-4-nitro-benzene (25 g, 0.019 mol) in MeOH (100 mL) was added Raney-Ni (2.5 g). The reaction mixture was hydrogenated under hydrogen (1 atm) at room temperature. After stirring for 3 hours, the mixture was filtered and concentrated under reduced pressure. The crude material was purified by preparative HPLC to give 3-bromo-4-ethylaniline (8.0 g, 48%). 1H NMR (400 MHz, CDCl3) δ 6.92 (d, J=8.4 Hz, 1 H), 6.83 (d, J=2.4 Hz, 1 H), 6.52 (dd, J=2.4, 8.4 Hz, 1 H), 2.57 (q, J=7.6 Hz, 2 H), 1.10 (t, J=7.6 Hz, 3 H). MS (ESI) m/e (M+H+) 200.