Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl-].[NH2:2][N+:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=1)#[N:10].[OH-].[Na+]>C(O)C.O>[N:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[C:9]1[N:10]=[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]2[N:2]=1
Reactant: N#Cc1ccccn1
Reactant: N[n+]1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc(-c2nc3ccccn3n2)nc1
Reaction time: 72 h
Yield: 36.5 %

Procedure:
To a stirred and cooled solution of N-amino-pyridinium chloride (26.1 g) and 2-cyanopyridine (31.2 g) in ethanol (100 ml) was added a solution of sodium hydroxide (8.0 g) in water (50 ml) over a period of one hour. The mixture was then left at room temperature for 72 hours, after which time the ethanol was removed in vacuo and the residue extracted with chloroform. The chloroform extract was dried and evaporated. The residue, on recrystallisation from acetone, yielded 14.3 g of 2-(2-pyridyl)-s-triazolo[1,5-a]pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.C(Cl)(=O)C(Cl)=O.[Cl:28][C:29]1[CH:35]=[C:34]([Br:36])[CH:33]=[CH:32][C:30]=1[NH2:31]>C(OCC)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:15])[NH:31][C:30]1[CH:32]=[CH:33][C:34]([Br:36])=[CH:35][C:29]=1[Cl:28])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1ccc(Br)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CCCC1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: c1ccncc1
Product: CC(C)(C)OC(=O)N1CCCC1C(=O)Nc1ccc(Br)cc1Cl
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester (2.2 g, 10 mmol) was dissolved in 150 mL dry diethyl ether under Ar, cooled in an ice water bath, added dry pyridine (2.8 mL, 34 mmol) followed by the dropwise addition of oxalyl chloride (1.5 mL, 17 mmol). A precipitate forms immediately. The reaction was stirred vigorously at 0° C. for 1 hours, then at ambient temperature for two hours. Added 100 mL diethyl ether, filtered off solids washing with diethyl ether. Concentrated the filtrates to an off-white oil. Redissolved oil in 100 mL dry DCM under Ar, cooled to 0° C., added 3 mL pyridine followed by 2-chloro-4-bromoaniline (1.8 g, 8.5 mmol). The reaction was allowed to warm to ambient temperature and stirred over the weekend. Concentrated reaction, redissolved in 250 mL EtOAc, washed with 10% citric acid (3×100 mL), water, (2×100 mL), brine (100 mL), dried with MgSO4, filtered and concentrated. Purified on a silica gel column eluted with an automated system with gradient of 0-60% EtOAc in hexanes. Combined and concentrated pure fractions to yield title compound as a yellow solid. (2.7 g, 79%) APCI (AP−): 401.0, 403.0, 405.0 (M−H)−.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]=[O:10].[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC=CC=1>C1(C)C=CC(S(O)(=O)=O)=CC=1.O>[CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[CH2:3][CH:2]2[CH2:8][CH:9]1[O:13][CH2:12][CH2:11][O:10]1
Reactant: OCCO
Reactant: O=CCC1CC2C=CC1C2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: C1=CC2CC1CC2CC1OCCO1
Yield: 95 %

Procedure:
40.0 g of (5-norbornen-2-yl)acetoaldehyde, 23.0 g of ethylene glycol, 120 ml of toluene and 200 mg of p-toluenesulfonic acid were mixed and heated under reflux for one hour while the water formed was removed through an H tube. The reaction mixture was allowed to cool down and poured into 50 ml of saturated sodium bicarbonate water. The resulting mixture separated into two layers. The organic layer was washed with water and saturated sodium chloride water, dried over anhydrous sodium sulfate, and concentrated in vacuum. It was further purified by vacuum distillation, obtaining 50.3 g of 2-(5-norbornen-2-yl)methyl-1,3-dioxolane (boiling point 63° C./200 Pa, yield 95%).
Reaction SMILES: [NH2:1][C:2]1[CH:36]=[CH:35][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]3[CH:13]=[C:14]([C:16]4[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=4)[S:15][C:8]=23)=[C:4]([F:37])[CH:3]=1.ClC(Cl)(O[C:42](=[O:48])OC(Cl)(Cl)Cl)Cl.CC[N:52]([CH:56]([CH3:58])[CH3:57])C(C)C.C1(N)CC1>O1CCCC1>[CH:56]1([NH:52][C:42](=[O:48])[NH:1][C:2]2[CH:36]=[CH:35][C:5]([O:6][C:7]3[CH:12]=[CH:11][N:10]=[C:9]4[CH:13]=[C:14]([C:16]5[N:21]=[CH:20][C:19]([CH2:22][N:23]([CH2:31][CH2:32][O:33][CH3:34])[C:24](=[O:30])[O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[CH:18][CH:17]=5)[S:15][C:8]=34)=[C:4]([F:37])[CH:3]=2)[CH2:58][CH2:57]1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CCN(C(C)C)C(C)C
Reactant: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Agent: NC1CC1
Solvent: C1CCOC1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)NC5CC5)cc4F)c3s2)nc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h
Yield: 173.7 %

Procedure:
To amine 126 (0.24 g, 0.46 mmol) in tetrahydrofuran (60 mL) at 0° C. was added triphosgene (0.054 g, 0.18 mmol) and the resulting solution was stirred for 1 h at 0° C. DIPEA (0.40 mL, 0.30 g, 2.3 mmol) and cyclopropylamine (0.26 g, 4.6 mmol) were sequentially added and the mixture was warmed to room temperature and stirred for 3 h, then concentrated under reduced pressure. The residue was partitioned between dichloromethane and water, the organic phase was collected, washed with sat. NH4Cl(aq) and brine, dried over MgSO4, filtered and concentrated. The residue was purified by flash chromatography on silica gel (ethyl acetate to 5% methanol/ethyl acetate), yielding 338 (0.19 g, 67% yield). MS (m/z): 608.4 (M+H).
Reaction SMILES: [Na].[Cl:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH2:12][C:13]#[N:14])[CH:4]=1.[F:15][C:16]([F:23])([F:22])[C:17](OCC)=[O:18]>C(O)C>[Cl:2][C:3]1[C:8]2[O:9][CH2:10][O:11][C:7]=2[CH:6]=[C:5]([CH:12]([C:17](=[O:18])[C:16]([F:23])([F:22])[F:15])[C:13]#[N:14])[CH:4]=1
Reactant: N#CCc1cc(Cl)c2c(c1)OCO2
Reactant: CCOC(=O)C(F)(F)F
Agent: [Na]
Solvent: CCO
Product: N#CC(C(=O)C(F)(F)F)c1cc(Cl)c2c(c1)OCO2
Yield: 112.6 %

Procedure:
Under reflux, 1.7 g of sodium (72.8 mmol) was dissolved in 50 ml of ethanol. At 50° C., a solution of 14.2 g (72.8 mmol) of 2-(7-chloro-1,3-benzodioxol-5-yl)acetonitrile and 10.3 g (72.8 mmol) of ethyl trifluoroacetate in 50 ml of ethanol was added dropwise, and the reaction mixture was then stirred under reflux for 12 hours. After cooling, the reaction mixture was concentrated on a rotary evaporator, dissolved in ethyl acetate and washed twice with 100 ml of 1N hydrochloric acid and once with water. The organic phase was separated off, dried over sodium sulphate, filtered and concentrated to give the title compound (23.9 g; 100%) and used for the next step directly.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]#[N:8])[CH2:3][CH2:2]1.N1CCCC1.CC(O[C:19]([NH:21][C@@H:22]([C:26]([OH:28])=O)[CH:23]1[CH2:25][CH2:24]1)=[O:20])(C)C.C(N[C@@H](C(O)=O)C(C)(C)C)(OC(C)(C)C)=O.[CH2:45]([N:47]1[CH:51]=[C:50]([C:52]2[N:57]=[C:56]3[C:58](C(O)=O)=[CH:59][N:60](COCC[Si](C)(C)C)[C:55]3=[N:54][CH:53]=2)[CH:49]=[N:48]1)[CH3:46].C1(C2N=C3C(C(O)=O)=CN(COCC[Si](C)(C)C)C3=NC=2)CC1.FC(F)(F)C(O)=O>>[C:7]([CH:4]1[CH2:5][CH2:6][N:1]([C:26](=[O:28])[C@H:22]([NH:21][C:19]([C:58]2[C:56]3[C:55](=[N:54][CH:53]=[C:52]([C:50]4[CH:49]=[N:48][N:47]([CH2:45][CH3:46])[CH:51]=4)[N:57]=3)[NH:60][CH:59]=2)=[O:20])[CH:23]2[CH2:24][CH2:25]2)[CH2:2][CH2:3]1)#[N:8]
Reactant: N#CC1CCNCC1
Reactant: CCn1cc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)cn1
Reactant: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C1CC1
Agent: CC(C)(C)OC(=O)N[C@@H](C(=O)O)C(C)(C)C
Agent: C[Si](C)(C)CCOCn1cc(C(=O)O)c2nc(C3CC3)cnc21
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCNC1
Product: CCn1cc(-c2cnc3[nH]cc(C(=O)N[C@@H](C(=O)N4CCC(C#N)CC4)C4CC4)c3n2)cn1

Procedure:
Prepared according to the procedure outlined in Example 1 substituting piperidine-4-carbonitrile for pyrrolidine, Boc-D-cyclopropyl glycine for Boc-D-tert-leucine, and 2-(1-ethyl-1H-pyrazol-4-yl)-5-((2-(trimethylsilyl)ethoxy)methyl)-5H-pyrrolo[3,2-b]pyrazine-7-carboxylic acid for 2-cyclopropyl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid. Trifluoroacetic acid was used in place of hydrochloric acid for all N-Boc deprotection steps. MS: (M+H)+=447.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1([CH2:9][OH:10])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.CC(C)([O-])C.[K+].[Cl:19][C:20]1[C:21](F)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26].Cl>CS(C)=O>[Cl:19][C:20]1[C:21]([O:10][CH2:9][C:3]2([C:2]([F:11])([F:12])[F:1])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)=[CH:22][C:23]([F:29])=[C:24]([CH:28]=1)[C:25]([OH:27])=[O:26]
Reactant: O=C(O)c1cc(Cl)c(F)cc1F
Reactant: OCC1(C(F)(F)F)CCCCC1
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(O)c1cc(Cl)c(OCC2(C(F)(F)F)CCCCC2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.5 %

Procedure:
To a solution of (1-(trifluoromethyl)cyclohexyl)methanol (3.20 g, 17.57 mmol) in anhydrous dimethylsulfoxide (50 ml) was added potassium tert-butoxide (4.90 g, 43.66 mmol) and the reaction mixture was stirred at ambient temperature for 30 minutes. 5-chloro-2,4-difluorobenzoic acid (3.38 g, 17.55 mmol) was added to the reaction mixture, and stirring was continued for 2 hours. The reaction mixture was acidified to pH=1 with 5% aqueous hydrochloric acid solution and extracted with ethyl acetate, the combined organic extracts was washed with brine; dried over anhydrous sodium sulfate and concentrated in vacuo. Purification of the residue by column chromatography (30% ethyl acetate in hexanes) afforded the title compound (5.20 g, 83%) containing o-substituted regioisomer, which was used for next step without further purification: MS (ES−) m/z 355.2, 353.2 (M−1).
Reaction SMILES: ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl.C1(C[O:26][C@@H:27]2[C@@:31]3([CH2:38][O:39][C@H:28]2[C@:29]([SiH:48]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=2)[C:49]2[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=2)([N:40]2[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]2=[O:42])[O:30]3)[CH2:32][O:33][C:34]([CH3:37])([CH3:36])[CH3:35])C2C(=CC=CC=2)C=CC=1>C(Cl)Cl.O>[C:34]([O:33][CH2:32][C@@:31]12[CH2:38][O:39][C@@H:28]([C@:29]([SiH:48]([C:55]3[CH:56]=[CH:57][CH:58]=[CH:59][CH:60]=3)[C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=3)([N:40]3[CH:47]=[CH:46][C:44](=[O:45])[NH:43][C:41]3=[O:42])[O:30]1)[C@@H:27]2[OH:26])([CH3:37])([CH3:35])[CH3:36]
Reactant: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1OCc1cccc3ccccc13)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC[C@]12CO[C@H]([C@@H]1O)[C@@](n1ccc(=O)[nH]c1=O)([SiH](c1ccccc1)c1ccccc1)O2
Temperature: 25 °C
Reaction time: 7 h
Yield: 97.5 %

Procedure:
2,3-Dichloro-5,6-dicyano-1,4-benzoquinone (15.9 g, 70.0 mmol) was added to a mixture of compound 11 (19.7 g, 31.1 mmol) in CH2Cl2 (200 mL) and H2O (40 mL). After 7 hours of vigorous stirring at room temperature, the mixture was poured into CH2Cl2 (1 L). The resulting solution was washed with 2% (w/v) aqueous sodium bisulfite, followed by saturated aqueous NaHCO3, then dried over anhydrous Na2SO4, filtered, then evaporated to a light-brown foam. Purification by silica gel chromatography (2.5 vol. % methanol in CH2Cl2) yielded 15.0 g (97%) of 12 as an off-white foam.
Reaction SMILES: [O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([OH:20])=O)=[CH:3]1.ON1C2C=CC=CC=2N=N1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:46][N:47]1[CH2:51][CH2:50][NH:49][C:48]1=[O:52]>CN(C)C=O>[O:1]=[C:2]1[C:7]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][NH:5][C:4]([CH:16]=[CH:17][C:18]([NH:46][N:47]2[CH2:51][CH2:50][NH:49][C:48]2=[O:52])=[O:20])=[CH:3]1
Reactant: O=C(O)C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1
Reactant: NN1CCNC1=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: O=C(C=Cc1cc(=O)c(OCc2ccccc2)c[nH]1)NN1CCNC1=O
Temperature: 0 °C
Reaction time: 10 h
Yield: 87.7 %

Procedure:
3-[1,4-Dihydro-4-oxo-5-(phenylmethoxy)-2pyridinyl-]-2-propenoic acid (10.85 g), 1 g of N-hydroxybenzotriazole, 0.01 g of N,N-dimethylaminopyridine and 8.24 g of dicyclohexylcarbodiimide were stirred for 30 minutes in 100 ml of dimethylformamide. After cooling to 0° C., 4 g of N-aminoimidazolidinone was added and stirring continued for 1 hour at 0° C. and 10 hours at room temperature. The resulting suspension was then heated to 60° C. and filtered. It was again suspended in 50 ml of dimethylformamide and heated to 60° C. and filtered again. The combined filtrates were evaporated at 40° C. (oil vacuo). The oily residue was stirred with 50 ml of water containing 2 g of sodium bicarbonate. After the filtration, the solid was washed with water, acetone and ether. 12.3 g of solid was obtained after drying. It was stirred together with 8 g of p-toluenesulfonic acid in 100 ml of dichloromethane for 1 hour. Filtration yielded 12.98 g of a white solid. This material was suspended in water. Recrystallization from water/dimethylformamide yielded 8.49 g of the title compound, melting point 271° C.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[CH3:12][OH:13].C[O-].[Na+]>C(=O)=O.C(O)(C)C>[CH3:12][O:13][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CO
Agent: C[O-]
Agent: O=C=O
Agent: [Na+]
Solvent: CC(C)O
Product: COc1ncc([N+](=O)[O-])cc1C
Temperature: 0 °C
Yield: 97 %

Procedure:
2-Chloro-3-methyl-5-nitropyridine (139 g, 0.806 mol) from the above procedure was divided into two portions and placed in two 2-L round bottom flasks with methanol (500 mL). The solutions were cooled in dry ice/isopropanol baths as solid sodium methoxide (26.5 g, 0.467 mol) was added portion-wise to each flask so that the temperature was remained below 20° C. When the additions were complete, the resulting mixtures were heated to reflux for 1 h. The mixtures were cooled and diluted with ice water (500 mL) to give white precipitates, which were collected by filtration. The combined filtrates were washed with water and air dried to give 2-methoxy-3-methyl-5-nitropyridine (127 g, 97% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 8.91 (d, J=2.0 Hz, 1H), 8.16 (s, 1H), 4.06 (s, 3H), 2.25 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 165.83, 141.91, 139.37, 132.92, 121.77, 54.83, 15.84. An analytical sample was recrystallized from hexane to give white needles, mp 95-96.5° C. Anal. calcd. for C7H8N2O3: C, 50.00; H, 4.79; N, 16.66. Found: C, 49.73; H, 5.02; N, 16.48.
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[C:11]([CH3:12])=[CH:10][CH:9]=[CH:8][C:7]=1[CH3:13])=[O:4].Br.[CH3:15][S:16](=[S:22])([O:18]CCN)=[O:17].[CH:23]([N:26](C(C)C)CC)(C)[CH3:24]>CN(C=O)C>[CH3:13][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]([CH3:12])[C:6]=1[NH:5][C:3](=[O:4])[CH2:2][NH:26][CH2:23][CH2:24][S:18][S:16](=[O:17])(=[O:22])[CH3:15]
Reactant: CCN(C(C)C)C(C)C
Reactant: CS(=O)(=S)OCCN
Reactant: Cc1cccc(C)c1NC(=O)CBr
Agent: Br
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1NC(=O)CNCCSS(C)(=O)=O
Yield: 63.5 %

Procedure:
A solution of 2-bromo-N-(2,6-dimethylphenyl)acetamide (2 g; 8.26 mmol), aminoethyl methanethiosulfonate hydrobromide (2.8 g; 11.86 mmol), and diisopropylethylamine (4 mL; 23 mmol) in dry DMF (70 mL) was stirred at room temperature for 3.5 hours. The solution was evaporated and the residue purified by column chromatography on SiO2. The column was eluted with CH2Cl2/MeOH/NH4OH 95:5:0.2 and evaporation of the fractions containing the desired product afforded a pale yellow oil (1.66 g) which crystallized upon standing in the freezer. This was disolved in methanol/ether (1:1; 50 mL). A saturated solution of HCl in ether (4 mL) was added. The precipitated hydrochloride salt was filtered and dried to yield a light brown solid (1.15 g; 39% yield) with a melting point of 158-162° C. 1H NMR (500 MHz,(CD3)2SO) δ 9.93 (s, 1H), 9.32 (s, br, 2H), 7.10-7.07 (m, 3H); 4.08 (s, 2H), 3.61 (s, 3H), 3.54 (t, J=7.2 Hz, 2H), 3.40 (t, J7.2 Hz, 2H), 2.16 (s, 6H).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:19]=[CH:18][C:6]([C:7]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[O:16][CH3:17])=[O:8])=[CH:5][CH:4]=1.[CH3:20][NH2:21]>O1CCOCC1>[CH3:17][O:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:7](=[O:8])[C:6]1[CH:18]=[CH:19][C:3]([CH2:2][NH:21][CH3:20])=[CH:4][CH:5]=1
Reactant: CN
Reactant: COc1ccccc1NC(=O)c1ccc(CCl)cc1
Solvent: C1COCCO1
Product: CNCc1ccc(C(=O)Nc2ccccc2OC)cc1
Yield: 100 %

Procedure:
4-Chloromethyl-N-(2-methoxyphenyl)benzamide (400 mg, 1.45 mmol) was dissolved in dioxane (4 ml) and then mixed with 50% methylamine aqueous solution (4 ml) at room temperature. After 1 hour of stirring at the same temperature, dioxane was removed by evaporation, and the resulting residue was diluted with methylene chloride (10 ml). After drying on anhydrous sodium carbonate, the solvent was removed by evaporation to obtain 500 mg (100%) of the title compound in the form of colorless oil.
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7](=[O:9])[CH3:8])[N:6]=1.[BrH:11].BrBr>C(O)(=O)C>[CH3:1][C:2]1[O:3][C:4]([CH3:10])=[C:5]([C:7](=[O:9])[CH2:8][Br:11])[N:6]=1
Reactant: CC(=O)c1nc(C)oc1C
Reactant: Br
Agent: BrBr
Solvent: CC(=O)O
Product: Cc1nc(C(=O)CBr)c(C)o1
Temperature: 100 °C

Procedure:
2.8 g (0.02 mol) of 2,5-Dimethyl-4-acetyl-oxazole are dissolved in 30 ml of glacial acetic acid, and 3 ml of a 35% strength solution of hydrogen bromide in glacial acetic acid are added. The mixture is heated to 100° C. and, over the course of 1 hour, a solution of 3.2 g (0.02 mol) of bromine in 10 ml of glacial acetic acid is added. After a further 2 hours the solvent is removed, and the residue is triturated with 50 ml of ether and filtered off with suction.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:16][S:17](Cl)(=[O:19])=[O:18].CO.O>N1C=CC=CC=1>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([O:15][S:17]([CH3:16])(=[O:19])=[O:18])[CH2:13][CH2:14]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](OS(C)(=O)=O)CC1
Reaction time: 0.25 h

Procedure:
A solution of Intermediate 35 (90.3 g) in pyridine (415 ml) was added dropwise with methanesulfonyl chloride (42.4 ml) with stirring and ice cooling over 15 minutes and stirred with ice cooling for 30 minutes and at room temperature for 20 minutes. The reaction mixture was added with methanol (54.2 ml) to terminate the reaction, stirred at room temperature for 2.5 hours, further added with water (540 ml) and stirred at room temperature for 1 hour and with ice cooling for 1 hour. The deposited precipitates were collected by filtration, washed with water and then dried at 40° C. under reduced pressure to obtain the title compound (105 g).
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:8](CC)(CC)CC.[C:15]1(=[O:25])[O:20][C:18](=O)[C:17]2=[CH:21][CH:22]=[CH:23][CH:24]=[C:16]12>O>[C@@H:1]1([N:8]2[C:15](=[O:25])[C:16]3[C:17](=[CH:21][CH:22]=[CH:23][CH:24]=3)[C:18]2=[O:20])[CH2:6][CH2:5][CH:4]=[CH:3][CH2:2]1
Reactant: CCN(CC)CC
Reactant: Cc1ccccc1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H]1CC=CCC1

Procedure:
1 g of Cyclohex-3-enyl-1(R)-amine hydrochloride (Example 3 Step A2) and 40 ml of toluene was charged to a flask at RT and the mixture obtained was stirred. To the mixture obtained 1.9 ml of (C2H5)3N was added dropwise, the mixture obtained was stirred for 10 min followed by 1.12 g of phthalic anhydride and the mixture obtained was heated to reflux, with H2O removed under Dean-Stark conditions, until reaction completion (determined by HPLC). The mixture obtained was washed with 0.1 M HCl followed by 5% NaHCO3 and H2O, dried over Na2SO4 and concentrated to dryness. 1.20 g of 2-(cyclohex-3-en-1(R)-yl)-isoindole-1,3-dione in the form of a pale white crystalline solid was obtained.
Reaction SMILES: Cl.O1CCO[CH2:4][CH2:3]1.[CH3:8][N:9]1[CH2:14][CH2:13][CH:12]([C:15]([OH:17])=[O:16])[CH2:11][CH2:10]1>>[CH2:3]([O:16][C:15]([CH:12]1[CH2:13][CH2:14][N:9]([CH3:8])[CH2:10][CH2:11]1)=[O:17])[CH3:4]
Reactant: C1COCCO1
Reactant: CN1CCC(C(=O)O)CC1
Agent: Cl
Product: CCOC(=O)C1CCN(C)CC1
Yield: 499.5 %

Procedure:
A solution of 2N hydrochloric acid in dioxane (2.8 ml, 11.13 mmol) was added to 1-methyl-4-piperdine carboxylic acid (20 g, 111.33 mmol) and the mixture heated at reflux for 18 hours. The reaction was concentrated to dryness and the resultant solid dissolved in dichloromethane and washed with a saturated solution of sodium bicarbonate, dried (magnesium sulphate) and concentrated to afford 1-methyl-4-piperdine carboxylic acid ethyl ester as a white solid (9.52 g, 50% yield).
Reaction SMILES: [C:1]([C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][S:6][N:5]=1)(=O)[CH3:2].[F:12][C:13]1[CH:14]=[C:15]([NH:19][C:20]([NH:22][NH2:23])=[NH:21])[CH:16]=[CH:17][CH:18]=1>>[CH3:2][C:1]([C:4]1[C:8]([C:9]([OH:11])=[O:10])=[CH:7][S:6][N:5]=1)=[N:23][NH:22][C:20](=[NH:21])[NH:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([F:12])[CH:14]=1
Reactant: N=C(NN)Nc1cccc(F)c1
Reactant: CC(=O)c1nscc1C(=O)O
Product: CC(=NNC(=N)Nc1cccc(F)c1)c1nscc1C(=O)O

Procedure:
Following the procedure of Example 7, 3-acetyl-4-isothiazole carboxylic acid (2.05 g, 12.0 mmol) and N-(3-fluorophenyl)hydrazinecarboximidamide (3.55 g, 12.0 mmol) are reacted together to give 2-[methyl(4-carboxy-3-isothiazolyl)methylene]-N-(3-fluorophenyl)hydrazinecarboximidamide, (compound 17).
Reaction SMILES: [C:1](C(C(C(O)=O)O)O)(O)=O.[NH2:11][C@@H:12]([C:19]([OH:21])=[O:20])[CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1.[ClH:22]>CO>[ClH:22].[ClH:22].[CH3:1][O:20][C:19](=[O:21])[C@@H:12]([CH2:13][C:14]1[N:18]=[CH:17][NH:16][CH:15]=1)[NH2:11]
Reactant: N[C@H](Cc1c[nH]cn1)C(=O)O
Reactant: O=C(O)C(O)C(O)C(=O)O
Agent: Cl
Solvent: CO
Product: COC(=O)[C@H](N)Cc1c[nH]cn1

Procedure:
A process according to claim 1, further comprising the step of reacting the crude D-histidine tartrate with hydrochloric acid and methanol at reflux temperature to produce D-histidine methylester dihydrochloride.
Reaction SMILES: [N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22](Br)=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.BrC1C=CC2OCCN3C(CN4C=CN=C4C)=C(C(N)=O)N=C3C=2C=1.N1C2C=CC=CC=2NC=1.[CH3:63][C:64]([OH:68])([C:66]#[CH:67])[CH3:65]>>[N:1]1([CH2:10][C:11]2[N:15]3[CH2:16][CH2:17][O:18][C:19]4[CH:24]=[CH:23][C:22]([C:67]#[C:66][C:64]([OH:68])([CH3:65])[CH3:63])=[CH:21][C:20]=4[C:14]3=[N:13][C:12]=2[C:26]([NH2:28])=[O:27])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1nc2n(c1Cn1cnc3ccccc31)CCOc1ccc(Br)cc1-2
Agent: Cc1nccn1Cc1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Agent: c1ccc2[nH]cnc2c1
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)c(Cn3cnc4ccccc43)n1CCO2
Yield: 35 %

Procedure:
Similar to as described in General Procedure G, 3-((1H-benzo[d]imidazol-1-yl)methyl)-10-bromo-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide (prepared similarly as described in the synthesis of 10-bromo-3((2-methyl-1H-imidazol-1-yl)methyl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide replacing 2-methylimidazole with benzimidazole) was reacted with 2-methylbut-3-yn-2-ol to give the titled compound as an off-white solid (28 mg, 35%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[O:5][C:4](=[O:9])[CH:3]=1.CO[CH:12](OC)[N:13]([CH3:15])[CH3:14]>C1(C)C=CC=CC=1>[CH3:12][N:13]([CH:15]=[C:3]1[C:2](=[O:1])[CH:7]=[C:6]([CH3:8])[O:5][C:4]1=[O:9])[CH3:14]
Reactant: Cc1cc(O)cc(=O)o1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CC1=CC(=O)C(=CN(C)C)C(=O)O1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 4-hydroxy-6-methyl-2-pyrone (11.50 g, 91.2 mmol) in toluene (30 mL) is added N,N-dimethylformamide dimethyl acetal (13.00 mL, 97.9 mmol). After stirring for 2 h at room temperature, the reaction mixture is evaporated under reduced pressure and co-evaporated with toluene several times. Yield: 18.5 g; ESI mass spectrum: [M+H]+=182; Retention time HPLC: 0.72 min (Z002_007).