Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH2:16])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH:21](OCC)=[O:22]>>[F:1][C:2]([C:13]1[CH:20]=[CH:19][CH:18]=[CH:17][C:14]=1[CH2:15][NH:16][CH:21]=[O:22])([F:12])[C:3]([F:11])([F:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: NCc1ccccc1C(F)(F)C(F)(F)c1ccccc1
Reactant: CCOC=O
Product: O=CNCc1ccccc1C(F)(F)C(F)(F)c1ccccc1

Procedure:
2-(α, α, β, β-Tetrafluorophenethyl)benzylamine, 1.4 g. (0.005 mole), in 100 ml. of ethyl formate, is stirred and heated to refluxing for about 20 hours. Evaporation of the solution to dryness and trituration of the residual solid with petroleum ether gives N-[2-(α, α, β, β-tetrafluorophenethyl)benzyl]formamide, m.p. 61°-75° C.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](O)=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].S(Cl)([Cl:16])=O>CN(C)C=O.C1C=CC=CC=1>[C:1]([O:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([Cl:16])=[O:10])=[CH:7][CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: CC(=O)Oc1ccc(C(=O)Cl)cc1

Procedure:
In a 20 ml-round-bottomed flask, 2.90 g (16.1 mM) of 4-acetoxybenzoic acid and 3.7 ml of thionyl chloride were placed. To the mixture, two drops of N,N-dimethylformamide was added at room temperature under stirring, followed by heat-refluxing for 20 minutes under stirring. After the reaction, dry benzene was added to the reaction mixture, followed by distilling-off of excessive thionyl chloride together with benzene. The above operation was repeated two times to obtain 4-acetoxybenzoic acid chloride. Then, in a 100 ml-round-bottomed flask, the above-prepared 4-acetoxybenzoic acid chloride, 3.10 g (15.1 mM) of 2-amino-4-octylphenol and 40 ml of dioxane were placed and heated. To the mixture, 5.5 ml of pyridine was added dropwise at 80°-84° C. under stirring, followed by further stirring for 20 minutes at 85°-88.5° C. After the reaction, the reaction mixture was cooled on an ice bath and poured into about 200 ml of ice water to precipitate a crystal. The crystal was recovered by filtration and washed with water, followed by recrystallization from methanol to obtain 4.10 g of 2-(4-acetoxybenzoylamino)-4-octylphenol (Yield: 70.8%).
Reaction SMILES: C([C:5]1[CH:6]=[C:7](C2OC=C(CCO)N=2)[CH:8]=[C:9](C(C)(C)C)[C:10]=1[OH:11])(C)(C)C.C(NCC[C:31]1[CH:36]=[CH:35][C:34](O)=[CH:33][CH:32]=1)(=O)CC.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[C:31]1([O:11][C:10]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: CC(C)(C)c1cc(-c2nc(CCO)co2)cc(C(C)(C)C)c1O
Reactant: CCC(=O)NCCc1ccc(O)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Temperature: 0 °C
Reaction time: 22 h
Yield: 109.7 %

Procedure:
To a stirred solution of 2-(3,5-di-t-butyl-4-hydroxyphenyl)-4-(2-hydroxyethyl)oxazole (5.51 g, 17.38 mmole) in tetrahydrofuran (47 ml) was added N-ethyl, N-propionyl tyramine (3.5 g, 15.8 mmole) and triphenylphosphine (4.55 g, 17.38 mmole). After cooling to 0° C., a solution of diethylazodicarboxylate (2.73 ml, 17.38 mmole) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. The reaction was allowed to warm to room temperature and stir for 22 hours, evaporated, and triturated with methylene chloride (50 ml) and filtered. The filtrate was chromatographed on silica gel twice using methylene chloride-ethyl acetate and hexane-acetone gradients to give the intermediate phenyl ether (2.95 g, 36%):
Reaction SMILES: [CH3:1][C:2]1[NH:16][CH2:15][CH2:14][C:4]2=[C:5]3[C:10](=[N:11][C:3]=12)[CH:9]=[CH:8][C:7]([O:12][CH3:13])=[CH:6]3.C(N(CC)CC)C.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>ClCCl>[CH2:1]=[C:2]1[C:3]2[NH:11][C:10]3[C:5](=[CH:6][C:7]([O:12][CH3:13])=[CH:8][CH:9]=3)[C:4]=2[CH2:14][CH2:15][N:16]1[C:25]([O:27][CH2:28][CH3:29])=[O:26]
Reactant: COc1ccc2c(c1)=C1CCNC(C)=C1N=2
Reactant: CCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=C1c2[nH]c3ccc(OC)cc3c2CCN1C(=O)OCC
Temperature: 0 °C

Procedure:
To a solution of 10-methoxyharmalan in dichloro-methane is added triethylamine (1.5 eq) and the mixture is cooled to 0° C. A solution (1/5 v/v) of ethyl chloro-formate in dichloromethane is then added dropwise. The mixture is stirred at 0° C. until the starting material disappears (2 h). After evaporation of the solvent, the crude product is separated out on a chromatography plate (eluent: EtOAc/pet. ether; 50/50).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([O:8][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: Oc1cccc(Br)c1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Product: CCOC(=O)COc1cccc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
3-Bromophenol (2.84 g, 16.4 mmol) was dissolved in dimethylformamide (50 ml) in a dry 100 ml flask under nitrogen. Sodium hydride (0.7 g of a 60% suspension in mineral oil, washed with hexane, 16.7 mmol) was added in portions and the mixture was stirred for one hour at room temperature. Ethyl bromoacetate (1.85 ml, 16.7 mmol) was added drop-wise and the reaction was stirred overnight at room temperature. Approximately two-thirds of the solvent was removed under reduced pressure and the residue was mixed with water (150 ml) and extracted with methylene chloride (3×20 ml). The extracts were combined, washed with water (50 ml), saturated sodium chloride solution (50 ml), then dried (MgSO4). The solution was filtered and concentrated which gave 4.18 g (98%) of ethyl 3-bromophenyloxyacetate.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH2:26])=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1.[C:29]([C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1)([CH3:32])([CH3:31])[CH3:30].C(OC)(OC)OC.[BH4-].[Na+]>CO>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][N:7]([CH2:14][C:15]1[CH:28]=[CH:27][C:18]([C:19]([NH:21][CH2:22][CH2:23][CH2:24][CH2:25][NH:26][CH2:37][C:36]2[CH:39]=[CH:40][C:33]([C:29]([CH3:32])([CH3:31])[CH3:30])=[CH:34][CH:35]=2)=[O:20])=[CH:17][CH:16]=1)[CH2:8][C:9]1[NH:13][CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)c1ccc(C=O)cc1
Reactant: NCCCCNC(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2ncc[nH]2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: COC(OC)OC
Product: CC(C)(C)c1ccc(CNCCCCNC(=O)c2ccc(CN(Cc3ncc[nH]3)Cc3ncc[nH]3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The compound (50.6 mg) obtained in Example 3-2 was dissolved in anhydrous methanol (2.0 ml) and added with 4-t-butyl-benzaldehyde (manufactured by Tokyo Kasei Kogyo Co., Ltd.) (0.0330 ml) and trimethyl orthoformate (0.0430 ml), followed by stirring at room temperature for 30 minutes. Then, the solution was added with sodium borohydride (14.8 mg), followed by stirring at room temperature for 15 minutes. After completion of the reaction, the solvent was distilled off. The residue was dissolved in chloroform and washed with a 1 mol/l sodium hydroxide aqueous solution and saturated saline solution, followed by drying with anhydrous magnesium sulfate. The solvent was distilled off and the residue was then treated with hydrochloric acid. Subsequently, the residue was purified through silica gel column chromatography (chloroform/methanol/water), thereby obtaining hydrochloride (42.0 mg) of the subject compound as a white solid.
Reaction SMILES: C(N(CC)CC)C.[C:8]([N:27]1[CH:31]=[C:30]([CH2:32][OH:33])[N:29]=[CH:28]1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Si:34]([O:41][CH:42]([C:46]1[CH:51]=[CH:50][C:49]([C:52]#[N:53])=[CH:48][CH:47]=1)[C:43](O)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]>ClCCl>[Si:34]([O:41][CH:42]([C:46]1[CH:47]=[CH:48][C:49]([C:52]#[N:53])=[CH:50][CH:51]=1)[C:43]([O:33][CH2:32][C:30]1[N:29]=[CH:28][N:27]([C:8]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:31]=1)=[O:44])([C:37]([CH3:40])([CH3:39])[CH3:38])([CH3:36])[CH3:35]
Reactant: CC(C)(C)[Si](C)(C)OC(C(=O)O)c1ccc(C#N)cc1
Reactant: OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OC(C(=O)OCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 mmol of triethylamine and 1.0 mmol propanephosphonic acid cyclic anhydride [68957-94-8](50% in ethyl acetate) are added to a solution of 1.0 mmol of (1-trityl-1H-imidazol-4-yl)methanol [33769-07-2] and 1.0 mmol of (tert-butyldimethylsilanyloxy)(4-cyanophenyl)acetic acid in 20 ml of dichloromethane. The reaction mixture is stirred at room temperature for 3 hours and diluted with dichloromethane. The phases are separated and the organic phase is washed with 1M HCl and brine, dried with sodium sulphate and evaporated. The title compound is identified from the residue on the basis of the Rf by flash chromatography (SiO2 60F).
Reaction SMILES: CC1(C)[O:10][C@H:9]2[C@H:4]([C@@H:5]([CH2:16][OH:17])[O:6][C@@H:7]3[O:13]C(C)(C)[O:11][C@@H:8]32)[O:3]1.[C:19](O)(=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41].C(N=C=NCCCN(C)C)C>C(Cl)Cl>[C:19]([O:17][CH2:16][CH:5]1[CH:4]([OH:3])[CH:9]([OH:10])[CH:8]([OH:11])[CH:7]([OH:13])[O:6]1)(=[O:42])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]#[C:29][C:30]#[C:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH3:41]
Reactant: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)O
Reactant: CC1(C)O[C@H]2[C@@H](O1)[C@@H](CO)O[C@@H]1OC(C)(C)O[C@@H]12
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CCCCCCCCCCC#CC#CCCCCCCCCC(=O)OCC1OC(O)C(O)C(O)C1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1,2,3,4-di-O-isopropylidene-D-galactopyranose (2.6 g, 10 mmol) and 10,12-tricosadiynoic acid (3.5 g, 10 mmol) were dissolved in 25 ml methylene chloride. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (2 g, >10 mmol) was added neat. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted to 100 ml, extracted with water (2×25 ml), dried over MgSO4 and the solvent was remove din vacuo. The crude product was treated with trifluoroacetic acid (10 ml) at room temperature for 30 minutes, evaporated in vacuo, and purified by straight phase chromatography on a CHROMATOTRON, eluted with methanol/chloroform (5:95). The product was characterised by NMR.
Reaction SMILES: Br[C:2]1[C:3]2[CH:13]=[CH:12][CH:11]=[CH:10][C:4]=2[S:5][C:6]=1[N+:7]([O-:9])=[O:8].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CN(C=O)C>[N+:7]([C:6]1[S:5][C:4]2[CH:10]=[CH:11][CH:12]=[CH:13][C:3]=2[C:2]=1[NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([O-:9])=[O:8]
Reactant: Nc1ccccc1
Reactant: O=[N+]([O-])c1sc2ccccc2c1Br
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1sc2ccccc2c1Nc1ccccc1
Yield: 95.9 %

Procedure:
A mixture solution of 3-bromo-2-nitrobenzo[b]thiophene (14 g, 54 mmol), aniline (14 ml, 154 mmol) and triethylamine (11 ml, 79 mmol) in DMF (150 ml) was heated at 120° C. for 30 min before quenching with water. The solid was isolated by filtration, washed with water and recrystallized from DCM/hexane to yield 2-nitro-N-phenylbenzo[b]thiophen-3-amine (14 g, 96%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:30]([CH3:31])=[CH:29][C:15]2[N:16]=[C:17]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[NH:24][N:23]=[C:22]4[CH3:28])[S:18][C:14]=2[C:13]=1[C:32]1[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[CH2:45](Br)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1>C(#N)C>[CH2:45]([N:24]1[C:25]2[C:21](=[CH:20][C:19]([C:17]3[S:18][C:14]4[C:13]([C:32]5[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=5)=[C:12]([C@H:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:30]([CH3:31])=[CH:29][C:15]=4[N:16]=3)=[CH:27][CH:26]=2)[C:22]([CH3:28])=[N:23]1)[C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1
Reactant: BrCc1ccccc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4[nH]nc(C)c4c3)sc2c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4c(c3)c(C)nn4Cc3ccccc3)sc2c1-c1ccc(Cl)cc1
Temperature: 75 °C

Procedure:
To a stirring solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(3-methyl-1H-indazol-5-yl)benzo[d]thiazol-6-yl)acetate (219 mg, 0.4 mmol) in ACN (5 mL) was added K2CO3 (166 mg, 1.2 mmol) and benzyl bromide (71 μL, 0.6 mmol). The reaction was then heated to 75° C. for 27 hours. After cooling to room temperature, the solids were filtered off, the crude reaction was concentrated and purified by column chromatography (gradient 0 to 20% EtOAc in hexanes) to give (S)-ethyl 2-(2-(1-benzyl-3-methyl-1H-indazol-5-yl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate. 1H NMR (400 MHz, CDCl3) δ 8.40 (s, 1H), 8.05 (d, J=8.9 Hz, 1H), 7.92 (s, 1H), 7.60-7.45 (m, 4H), 7.35-7.27 (m, 4H), 7.22-7.18 (m, 2H), 5.54 (s, 2H), 5.16 (s, 1H), 4.21 (dtt, J=10.9, 7.4, 3.7 Hz, 2H), 2.63 (s, 3H), 2.60 (s, 3H), 1.26 (t, J=7.1 Hz, 3H), 0.98 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]2.CO[CH:20]1[CH2:24][CH2:23][CH:22](OC)O1>>[N:1]1([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][C:11]=2[C:12]([F:15])([F:14])[F:13])[NH:8][C:7](=[O:16])[C:6](=[O:17])[NH:5]3)[CH:20]=[CH:24][CH:23]=[CH:22]1
Reactant: COC1CCC(OC)O1
Reactant: Nc1cc2[nH]c(=O)c(=O)[nH]c2cc1C(F)(F)F
Product: O=c1[nH]c2cc(-n3cccc3)c(C(F)(F)F)cc2[nH]c1=O

Procedure:
12.2mmol of 6-amino-7-trifluoromethyl-2,3(1H,4H)-quinoxalinedione were reacted with 12.2 mmol of 2,5-dimethoxytetrahydrofuran by the method of Example 5d.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH:12]=[C:10]([CH3:11])[C:8](=[O:9])[NH:7][C:5]1=[O:6].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH2:19].O>CS(C)=O>[CH2:19]([N:7]1[C:8](=[O:9])[C:10]([CH3:11])=[CH:12][N:4]([CH3:3])[C:5]1=[O:6])[CH2:18][CH2:17][CH2:16][CH:15]=[CH2:14]
Reactant: C=CCCCCBr
Reactant: Cc1cn(C)c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: C=CCCCCn1c(=O)c(C)cn(C)c1=O
Reaction time: 0.25 h
Yield: 90 %

Procedure:
3-(5,6-Oxidohexyl)-1-methylthymine was synthesized as follows: A mixture of sodium hydride (343 mg, 14 mmol) and 1-methylthymine (2.00 g, 14 mmol) in dimethylsulfoxide (30 ml) was stirred for 15 minutes, and then 6-bromo-1-hexene (2.30 g, 14 mmol) was added. After stirring for 69 hours, the reaction mixture was poured into water (100 ml) and extracted with dichloromethane (4×50 ml). The combined organic layers were washed with saturated aqueous sodium chloride solution (40 ml), dried over sodium sulfate, and then the solvent was evaporated under vacuum to give a residue which was recrystallized (dichloromethane-ethyl ether) to give 3-(5-hexenyl)-1-methylthymine (2.80 g, 88% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:13][C:12]=3[CH:25]=2)=[CH:4][C:3]=1[N+:26]([O-])=O.C(OCC)(=O)C>C(O)(=O)C.[Pd]>[NH2:26][C:3]1[CH:4]=[C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:17][CH2:16][CH2:15][N:14]([C:18]([O:20][C:21]([CH3:23])([CH3:22])[CH3:24])=[O:19])[CH2:13][C:12]=3[CH:25]=2)[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c([N+](=O)[O-])c3)cc2C1
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCOc2ccc(-c3ccc(N)c(N)c3)cc2C1
Yield: 93.8 %

Procedure:
A solution of 1,1-dimethylethyl 7-(4-amino-3-nitrophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (example 8, step 1) (2.3 g, 6.0 mmol), in acetic acid (20 mL) and ethyl acetate (20 mL) was hydrogenated at 45 psi over 10% Pd—C (1.0 g) for 1 h using a Parr apparatus. The catalyst was filtered off and the filtrate was concentrated to give 1,1-dimethylethyl 7-(3,4-diaminophenyl)-2,3-dihydro-1,4-benzoxazepine-4(5H)-carboxylate (2.0 g, 94% yield) as a light yellow oil. MS (EI) for C20H25N3O3: 356 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([NH:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:3]=1.[C:16]([O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26](=[O:29])[CH2:27]Br)(=[O:18])[CH3:17]>>[C:16]([O:19][CH2:20][C:21]1[CH:25]=[CH:24][O:23][C:22]=1[C:26]([C:27]1[N:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]2[C:5]([C:6]=1[NH2:7])=[CH:8][CH:9]=[C:2]([Cl:1])[CH:3]=2)=[O:29])(=[O:18])[CH3:17]
Reactant: CC(=O)OCc1ccoc1C(=O)CBr
Reactant: CCOC(=O)Nc1cc(Cl)ccc1C#N
Product: CCOC(=O)n1c(C(=O)c2occc2COC(C)=O)c(N)c2ccc(Cl)cc21

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 1 from 4-chloro-2-[(ethoxycarbonyl)amino]benzonitrile (Example 1, step 1) and 3-acetoxymethyl-2-(bromoacetyl)furan (Step 1).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](Cl)=[O:5].[H-].[Na+].[Br:15][C:16]1[CH:21]=[C:20]([NH2:22])[CH:19]=[CH:18][N:17]=1>CN(C=O)C.C(OCC)(=O)C>[Br:15][C:16]1[CH:21]=[C:20]([NH:22][C:4](=[O:5])[C:3]2[C:2]([Cl:1])=[CH:10][C:9]([I:11])=[CH:8][C:7]=2[Cl:12])[CH:19]=[CH:18][N:17]=1
Reactant: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Reactant: Nc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(Nc1ccnc(Br)c1)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 40.4 %

Procedure:
To a cooled (0° C.) solution of 2,6-dichloro-4-iodobenzoyl chloride (70 mg, 0.21 mmol) in DMF (2 mL) was added NaH (17 mg, 0.42 mmol). The mixture was stirred for 10 minutes and then 2-bromopyridin-4-amine (40 mg, 0.23 mmol) was added. The resulting mixture was slowly warmed to 25° C., diluted with ethyl acetate (10 mL), quenched with water (1 mL), washed with saturated Na2CO3 and water, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by silica-gel chromatography (Pet Ether/EtOAc=20:1 to 3:1) to afford N-(2-bromopyridin-4-yl)-2,6-dichloro-4-iodobenzamide (40 mg, 40% yield). LCMS (ESI) m/z: 470.9 [M+H+].
Reaction SMILES: [N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([OH:26])=O)[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:4][CH2:3][CH2:2]1.[F:28][C:29]([F:34])([F:33])[CH2:30][CH2:31][NH2:32].C(N(C(C)C)C(C)C)C.CCCP1(OP(CCC)(=O)OP(CCC)(=O)O1)=O.C(=O)(O)[O-].[Na+]>O1CCCC1>[N:1]1([C:5]([C:7]2[CH:8]=[N:9][N:10]([CH3:27])[C:11]=2[C:12]([NH:14][C:15]2[CH:20]=[CH:19][N:18]3[N:21]=[C:22]([C:24]([NH:32][CH2:31][CH2:30][C:29]([F:34])([F:33])[F:28])=[O:26])[N:23]=[C:17]3[CH:16]=2)=[O:13])=[O:6])[CH2:2][CH2:3][CH2:4]1
Reactant: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)O)nc2c1
Reactant: NCCC(F)(F)F
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cn1ncc(C(=O)N2CCC2)c1C(=O)Nc1ccn2nc(C(=O)NCCC(F)(F)F)nc2c1
Reaction time: 10 h
Yield: 17.6 %

Procedure:
A mixture of 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxylic acid (140 mg, 0.379 mmole), 3,3,3-trifluoropropan-1-amine (214 mg, 1.9 mmole), N-ethyldiisopropylamine (265 ul, 1.52 mmole) and 1-propanephosphonic acid cyclic anhydride (50% in ethyl acetate, 569 ul, 0.948 mmole) in tetrahydrofurane (7 ml) is stirred for 10 h at roomtemperature. The reaction mixture is poured on sat. aqueous sodium bicarbonate solution (60 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layer is washed once with water, once with brine, dried with magnesium sulfate and the solvent is removed in vacuo. Purification of the residue by chromatography on a 12 g silica cartridge (eluent dichloromethane+2% methanol) affords 7-(4-(azetidine-1-carbonyl)-1-methyl-1H-pyrazole-5-carboxamido)-N-(3,3,3-trifluoropropyl)-[1,2,4]triazolo[1,5-a]pyridine-2-carboxamide (31 mg, 17.6%) as a white foam. MS: m/z=465.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([OH:25])=O)[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C([Si](C)(C)[O:31][C@H:32]1[C@@H:37]([O:38][Si](C(C)(C)C)(C)C)[CH2:36][CH2:35][NH:34][CH2:33]1)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4](/[CH:9]=[CH:10]/[C:11]([N:13]2[CH2:19][CH2:18][C:17](=[O:20])[N:16]([CH2:21][CH2:22][C:23]([N:34]3[CH2:35][CH2:36][CH:37]([OH:38])[CH:32]([OH:31])[CH2:33]3)=[O:25])[CH2:15][CH2:14]2)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCNC[C@H]1O[Si](C)(C)C(C)(C)C
Reactant: O=C(O)CCN1CCN(C(=O)/C=C/c2ccc(Cl)c(Cl)c2)CCC1=O
Product: O=C(/C=C/c1ccc(Cl)c(Cl)c1)N1CCC(=O)N(CCC(=O)N2CCC(O)C(O)C2)CC1
Yield: 95 %

Procedure:
In analogy to the procedure described in Example 1,3-{4-[(E)-3-(3,4-dichloro-phenyl)-acryloyl]-7-oxo-[1,4]diazepan-1-yl}-propionic acid (intermediate 5) and (cis)-(rac)-3,4-bis-(tert-butyl-dimethyl-silanyloxy)-piperidine (intermediate 9) gave the titled compound in 95% yield as a white solid. MS: 712.5 (MH+, 2Cl).
Reaction SMILES: [Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[NH:11][C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[N:8]=2)=[CH:4][CH:3]=1.[H-].[Na+].Cl[CH2:21][C:22](=[O:24])[CH3:23]>CN(C=O)C.CCOC(C)=O>[Br:1][C:2]1[CH:17]=[CH:16][C:5]([O:6][C:7]2[N:8]([CH2:21][C:22](=[O:24])[CH3:23])[C:9]3[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=3[N:11]=2)=[CH:4][CH:3]=1
Reactant: CC(=O)CCl
Reactant: Brc1ccc(Oc2nc3ccccc3[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)Cn1c(Oc2ccc(Br)cc2)nc2ccccc21
Reaction time: 0.08 h

Procedure:
To a solution of 2-(4-bromophenoxy)-1H-benzo[d]imidazole (5.72 g) in DMF (60 mL) was added NaH (60% in oil, 950 mg) at 0° C. After stirring for 5 min, chloroacetone (2.36 mL) was added to the mixture at 0° C. The mixture was stirred at room temperature for 5 h. The mixture was diluted with AcOEt and washed with water. The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt in hexane) and recrystallized from THF/Et2O to give the title compound (3.47 g).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH2:8]Br)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(N(CC)CC)C.[NH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>C(Cl)Cl>[N:19]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=2)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: C1CCNCC1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(CN2CCCCC2)cc1

Procedure:
40.0 g of 4-nitrobenzyl bromide are dissolved in 500 ml of methylene chloride, 51.5 ml of triethylamine are added and 18.3 ml of piperidine are carefully added dropwise. After the end of the exothermic reaction the mixture is refluxed for another 30 minutes. After cooling it is washed with water and the organic phase is dried over sodium sulphate. Finally, the organic phase is evaporated down.
Reaction SMILES: [N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.O.[Cl:18][S:19](O)(=[O:21])=[O:20]>P(Cl)(Cl)(Cl)(Cl)Cl>[N:1]1([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([S:19]([Cl:18])(=[O:21])=[O:20])[CH:15]=3)[N:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(O)Cl
Reactant: c1ccc2c(N3CCCCC3)ncnc2c1
Agent: ClP(Cl)(Cl)(Cl)Cl
Solvent: O
Product: O=S(=O)(Cl)c1ccc2ncnc(N3CCCCC3)c2c1
Temperature: 150 °C

Procedure:
In a mixture of 18.1 ml of chlorosulfonic acid and 5.4 g of phosphorus pentachloride was gradually added 8.6 g of 4-piperidinoquinazoline, and the mixture was heated at 150° C. for 20 hours. The reaction solution was poured into 200 g of a mixture of ice and water and extracted with chloroform. The chloroform layer was washed with water, then with a saturated sodium bicarbonate solution, and dried with Glauber's salt. The chloroform layer thus obtained was condensed under reduced pressure to give 6.0 g of 4-piperidino-6-quinazolinesulfonyl chloride as an oily substance.