Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([C:10]2[N:14]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=3)[CH:13]=[N:12][CH:11]=2)=O)=[C:6]([Cl:23])[N:5]=[CH:4][N:3]=1.[CH3:24][NH:25][NH2:26].N1C=CC=CC=1>C(#N)C>[Cl:23][C:6]1[N:5]=[CH:4][N:3]=[C:2]2[N:25]([CH3:24])[N:26]=[C:8]([C:10]3[N:14]([C:15]4[CH:20]=[CH:19][C:18]([CH2:21][CH3:22])=[CH:17][CH:16]=4)[CH:13]=[N:12][CH:11]=3)[C:7]=12
Reactant: CCc1ccc(-n2cncc2C(=O)c2c(Cl)ncnc2Cl)cc1
Reactant: CNN
Solvent: c1ccncc1
Solvent: CC#N
Product: CCc1ccc(-n2cncc2-c2nn(C)c3ncnc(Cl)c23)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of (4,6-dichloropyrimidin-5-yl)[1-(4-ethylphenyl)-1H-imidazol-5-yl]methanone (C21) (136 mg, 0.392 mmol) in acetonitrile (3 mL) was added to a solution of methylhydrazine (18.1 mg, 0.393 mmol) in acetonitrile (3 mL). After addition of pyridine (41 mg, 0.52 mmol), the reaction mixture was stirred at room temperature for 1 hour and then concentrated in vacuo. Purification via silica gel chromatography (Gradient: 0% to 20% ethyl acetate in heptane) afforded the product, along with recovered starting material (35 mg, 0.10 mmol). Yield: 81 mg, 0.24 mmol, 61% (82% based on recovered starting material). LCMS m/z 339.0 (M+1). 1H NMR (500 MHz, CDCl3) δ 1.21 (t, J=7.6 Hz, 3H), 2.62 (q, J=7.6 Hz, 2H), 4.11 (s, 3H), 7.11-7.15 (m, 4H), 7.52 (d, J=0.8 Hz, 1H), 7.85 (d, J=1.0 Hz, 1H), 8.73 (s, 1H).
Reaction SMILES: [OH:1][C@H:2]([CH2:6][OH:7])[CH2:3][C:4]#[N:5].[S:8](Cl)([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9].Cl>N1C=CC=CC=1>[OH:1][C@H:2]([CH2:6][O:7][S:8]([C:11]1[CH:17]=[CH:16][C:14]([CH3:15])=[CH:13][CH:12]=1)(=[O:10])=[O:9])[CH2:3][C:4]#[N:5]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: N#CC[C@H](O)CO
Agent: Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CC#N)cc1
Yield: 79.8 %

Procedure:
(3S)-3,4-Dihydroxybutyronitrile (43.1 g, 426 mmol), pyridine (240 ml) and tosyl chloride (119.5 g) were mixed at 0° C. for 4 hours. The mixture was poured in ice-cooled 1N hydrochloric acid and stirred, followed by extraction with ethyl acetate. After the organic layer was dried over anhydrous sodium sulfate, the solvent was evaporated off with an evaporator. The residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) to obtain (3S)-3-hydroxy-4-p-toluenesulfonyloxybutyronitrile (87.0 g, 340 mmol). Yield, 80 %.
Reaction SMILES: [C:1]1([C:7]2[C:8](=[O:16])O[C:10](C)(C)[O:11][C:12]=2[CH3:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=[N:18][C:19]([CH3:28])([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[CH3:28][C:19]([N:18]1[C:8](=[O:16])[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[C:12]([CH3:13])[O:11][CH2:10]1)([CH3:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CC1=C(c2ccccc2)C(=O)OC(C)(C)O1
Reactant: C=NC(C)(C)Cc1ccccc1
Product: CC1=C(c2ccccc2)C(=O)N(C(C)(C)Cc2ccccc2)CO1
Yield: 77.3 %

Procedure:
5-phenyl-2,2,6-trimethyl-2H,4H-1,3-dioxin-4-one (0.65 g) and N-methylene-1,1-dimethyl-2-phenylethylamine (0.63 g) were reacted at 140° for 30 minutes. The reaction mixture was purified by silica gel chromatography to obtain the captioned compound (0.74 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][NH:11]1)([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.[C:31]([S:34][CH2:35][CH:36]([CH3:40])[C:37](Cl)=[O:38])(=[O:33])[CH3:32]>ClCCl>[C:1]([O:5][C:6](=[O:23])[C@H:7]([CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[NH:8][C:9](=[O:15])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:37](=[O:38])[CH:36]([CH3:40])[CH2:35][S:34][C:31](=[O:33])[CH3:32])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(=O)SCC(C)C(=O)Cl
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H]1CCCN1
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CC(=O)SCC(C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a stirred solution of L-prolyl-L-phenylalanine tert-butyl ester (1.0 g) [prepared by the method described in Ann. Chem. 680, 132-141 (1964)] in dichloromethane at about -30° C. were added N-methylmorpholine (0.32 g) and then dropwise 3-acetylthio-2-methylpropanoyl chloride (0.57 g). The mixture was stirred at the same temperature for 30 minutes and then at room temperature for one hour. The reaction mixture was washed successively with 4% sodium bicarbonate, water, 10% citric acid, and water, dried over sodium sulfate, and concentrated under reduced pressure. The residue was chromatographed on silica gel with chloroform to give 1-(3-acetylthio-2-methylpropanoyl)-L-prolyl-L-phenylalanine tert-butyl ester.
Reaction SMILES: Cl[C:2]1[NH:11][C:10](=[O:12])[C:9]2[C:4](=[CH:5][C:6]([O:15][CH3:16])=[C:7]([O:13][CH3:14])[CH:8]=2)[N:3]=1.[N:17]1([C:23]2[C:24]3[CH2:32][CH2:31][NH:30][CH2:29][C:25]=3[N:26]=[CH:27][N:28]=2)[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>COC(O)C>[CH3:14][O:13][C:7]1[CH:8]=[C:9]2[C:4](=[CH:5][C:6]=1[O:15][CH3:16])[N:3]=[C:2]([N:30]1[CH2:31][CH2:32][C:24]3[C:23]([N:17]4[CH2:18][CH2:19][O:20][CH2:21][CH2:22]4)=[N:28][CH:27]=[N:26][C:25]=3[CH2:29]1)[NH:11][C:10]2=[O:12]
Reactant: COc1cc2nc(Cl)[nH]c(=O)c2cc1OC
Reactant: c1nc2c(c(N3CCOCC3)n1)CCNC2
Agent: COC(C)O
Product: COc1cc2nc(N3CCc4c(ncnc4N4CCOCC4)C3)[nH]c(=O)c2cc1OC
Temperature: 100 °C
Reaction time: 18 h
Yield: 61.9 %

Procedure:
A mixture of 2-chloro-6,7-dimethoxy-3H-quinazolin-4-one 1b (0.28 g, 1.18 mmol) and 4-morpholin-4-yl-5,6,7,8-tetrahydro-pyrido[3,4-d]pyrimidine 6a (0.26 g, 1.20 mmol) in methoxyethanol (10 mL) was heated to 100° C. with stirring for 18 h. After cooling to room temperature, the precipitated solid was separated by filtration, washed with methoxyethanol and dried to give 0.31 g of 6,7-dimethoxy-2-(4-morpholin-4-yl-5,8-dihydro-6H-pyrido[3,4-d]pyrimidin-7-yl)-3H-quinazolin-4-one 201, mp. 287.7–290.4° C.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([NH:7][CH:8]2[CH2:11][CH:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:9]2)=[N:5][N:6]=1.[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH:32]([C:38](=O)[CH2:39][CH2:40][CH3:41])[C:33](OCC)=[O:34])=[C:27]([F:43])[CH:26]=1)#[N:18].N12CCCN=C1CCCCC2>C(N(CC)C1C=CC=CC=1)C.C(OCC)(=O)C>[C:17]([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]2[C:33](=[O:34])[N:7]([C@@H:8]3[CH2:9][C@H:10]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:11]3)[C:4]3[N:5]([N:6]=[C:2]([CH3:1])[N:3]=3)[C:38]=2[CH2:39][CH2:40][CH3:41])=[C:27]([F:43])[CH:26]=1)#[N:18]
Reactant: CCOC(=O)C1CC(Nc2nnc(C)[nH]2)C1
Reactant: CCCC(=O)C(Cc1ccc(-c2ccccc2C#N)cc1F)C(=O)OCC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: CCN(CC)c1ccccc1
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2F)c(=O)n([C@H]2C[C@@H](C(=O)OCC)C2)c2nc(C)nn12

Procedure:
A solution of ethyl 3-[(5-methyl-4H-1,2,4-triazol-3-yl)amino]cyclobutanecarboxylate (7.85 g), ethyl 2-[(2′-cyano-3-fluorobiphenyl-4-yl)methyl]-3-oxohexanoate (23.15 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (2.62 mL) in N,N-diethylaniline (70 mL) was stirred at 180° C. for 20 hr. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with 1 N hydrochloric acid and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography [eluent: hexane/ethyl acetate=85/15→65/35 (volume ratio)] to give the title compound as a pale-yellow amorphous compound (3.91 g, 21%).
Reaction SMILES: C(O/[CH:4]=[CH:5]\[C:6]1[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=1)C.BrN1C(=O)CCC1=O.[CH2:24]([C:26]1[C:27]([NH2:32])=[N:28][CH:29]=[CH:30][CH:31]=1)[CH3:25].C(=O)([O-])O.[Na+]>O1CCOCC1.O>[CH2:24]([C:26]1[C:27]2[N:28]([C:5]([C:6]3[C:11]([C:12]#[N:13])=[CH:10][N:9]=[C:8]([S:14][CH3:15])[N:7]=3)=[CH:4][N:32]=2)[CH:29]=[CH:30][CH:31]=1)[CH3:25]
Reactant: CCO/C=C\c1nc(SC)ncc1C#N
Reactant: CCc1cccnc1N
Agent: O=C([O-])O
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1cccn2c(-c3nc(SC)ncc3C#N)cnc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
4.89 g of 4-[(Z)-2-ethoxyvinyl]-2-(methylthio)-5-pyrimidinecarbonitrile (synthesized according to the method disclosed in International Publication WO2006/025567, page 90 to 91) was dissolved in a mixed solvent of 50 mL of 1,4-dioxane and 5 mL of water, then 3.93 g of N-bromosuccinimide was added under an ice-cold condition, and the mixture was stirred for 1 hour at room temperature. To the reaction solution was added 2.7 g of 3-ethylpyridine-2-amine (synthesized according to the method disclosed in International Publication WO2006/025567, page 142), and the solution was stirred overnight at room temperature. To the reaction solution was added a saturated aqueous solution of sodium hydrogen carbonate, the solution was extracted with chloroform, and the resulting organic layer was dried over anhydrous sodium sulfate. The insolubles were filtered, and the filtrate was concentrated under reduced pressure. Diethylether was added to the resulting residue, and the resultant solution was stirred for 3 hours. Thus produced solid was taken by filtration and dried under reduced pressure to obtain 4.46 g of 4-(8-ethylimidazo[1,2-a]pyridin-3-yl)-2-(methylthio)pyrimidine-5-carbonitrile [5-6] (hereinafter, referred to as the compound [5-6]) as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[C:5]([NH2:15])=[C:6]([NH2:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-:3])=[O:2].[C:16](O)(=[O:20])[C:17](O)=[O:18]>Cl>[N+:1]([C:4]1[CH:9]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:7]=[C:6]2[C:5]=1[NH:15][C:16](=[O:20])[C:17](=[O:18])[NH:14]2)([O-:3])=[O:2]
Reactant: Nc1cc(C(F)(F)F)cc([N+](=O)[O-])c1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2cc(C(F)(F)F)cc([N+](=O)[O-])c2[nH]c1=O
Temperature: 25 °C

Procedure:
A suspension of 3-nitro-5-trifluoromethyl-1,2-phenylenediamine (0.560 g, 2.53 mmol) and oxalic acid (0.325 g, 2.58 mmol) in 2N HCl (8.5 mL) was refluxed for 6 h. The suspension was then cooled to r.t. and the solid filtered, washed with water (5.0 mL) and dried under vacuum to yield 0.502 (72%) of pure title compound as a yellow brown powder, m.p. 329°-332° C.; 1H NMR (DMSO-d6): 7.640 (s, 1H), 8.111 (s, 1H), 11.414 (s, 1H), 2.432 (1H).
Reaction SMILES: [C:1]([SH:3])#[N:2].N.[C:5](Cl)(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[CH:18][C:17]=1[NH2:28]>CC(C)=O>[C:5]([NH:2][C:1]([NH:28][C:17]1[CH:18]=[C:19]([CH:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:20]=[CH:21][C:16]=1[O:15][CH3:14])=[S:3])(=[O:12])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1ccc(C2CCOCC2)cc1N
Reactant: N#CS
Agent: N
Solvent: CC(C)=O
Product: COc1ccc(C2CCOCC2)cc1NC(=S)NC(=O)c1ccccc1
Temperature: 25 °C
Yield: 66 %

Procedure:
To a stirred solution of 1.11 g (14.6 mmol) ammonium rhodanide in 60 ml acetone was added dropwise 1.54 ml (13.3 mmol) benzoyl chloride and the mixture heated at reflux for 10 minutes. A solution of 2.75 g (13.3 mmol) 2-methoxy-5-(tetrahydro-pyran-4-yl)-phenylamine in 30 ml acetone was then added dropwise and the reaction mixture heated at reflux for a further 10 minutes. The mixture was then cooled to room temperature, poured onto sodium bicarbonate solution, and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and concentrated in vacuo. Flash chromatography (1/1 ethyl acetate/hexane) followed by trituration in ether afforded 3.25 g (66%) 1-benzoyl-3-[2-methoxy-5-(tetrahydro-pyran-4-yl)-phenyl]-thiourea as a white solid. ES-MS m/e (%): 371 (M+H+, 100).
Reaction SMILES: COCN[C:5]([C:7]1[C:8]([NH2:16])=[N:9][C:10]([S:13][CH2:14][CH3:15])=[N:11][CH:12]=1)=[O:6].Br[C:18]1[CH:23]=[C:22]([F:24])[C:21]([F:25])=[CH:20][C:19]=1[O:26][CH3:27]>>[NH2:16][C:8]1[C:7]([C:5]([C:20]2[C:19]([O:26][CH3:27])=[CH:18][CH:23]=[C:22]([F:24])[C:21]=2[F:25])=[O:6])=[CH:12][N:11]=[C:10]([S:13][CH2:14][CH3:15])[N:9]=1
Reactant: COc1cc(F)c(F)cc1Br
Reactant: CCSc1ncc(C(=O)NCOC)c(N)n1
Product: CCSc1ncc(C(=O)c2c(OC)ccc(F)c2F)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanylpyrimidine-5-carboxylic acid methoxymethylamide, Example 1, and 2-bromo4,5-difluoro-anisole (Astatech), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(2,3-difluoro-6-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 326.
Reaction SMILES: [ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=S.Cl.C(O)(=[O:35])C>C(OCC)(=O)C.C(OCC)C>[ClH:1].[CH3:2][CH:3]([CH3:31])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[CH:22]=[CH:21][C:20]2[S:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH:23]([CH3:30])[CH2:24][N:25]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[C:11]=2[CH:10]=1)=[O:35]
Reactant: CC(C)CCNC(=S)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2
Reactant: CC(=O)O
Agent: Cl
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: CC(C)CCNC(=O)c1ccc2c(c1)N(C(C)CN1CCCC1)c1ccccc1S2

Procedure:
Mercuric acetate (0.668 g) is added with stirring to a suspension of N-(3-methylbutyl)-10-[(2RS)-1-(1-pyrolidinyl)-2-propyl]-2-phenothiazinecarbothioamide hydrochloride (1 g) in acetic acid (20 cc), and the mixture is left to react for 5 hours 30 minutes at a temperature in the region of 20° C. The reaction mixture is diluted with ethyl acetate (150 cc) and distilled water (50 cc) and then treated with caustic soda (d=1.33) to pH 13. The organic phase is separated and the aqueous phase is extracted again with ethyl acetate (2×50 cc). The combined organic phases are washed with saturated aqueous sodium hydrogen carbonate solution (100 cc) and then with saturated aqueous sodium chloride solution (100 cc), dried over magnesium sulphate, filtered and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The residual yellow oil (0.53 g) is purified by chromatography on a column (height: 30 cm; diameter: 2.5 cm) of silica gel (0.04-0.063 mm) under a slight excess pressure of nitrogen (40 kPa), eluting successively with a mixture (97.5:2.5 by volume) (100 cc) of methylene chloride and methanol and then with a mixture (95:5 by volume) (200 cc) of methylene chloride and methanol and collecting 15-cc fractions. Fractions 12 to 34 are combined and concentrated to dryness under reduced pressure (30 mm Hg; 4 kPa) at 40° C. The oil obtained is dissolved in ethyl acetate (10 cc) and a 3N solution (0.5 cc) of hydrochloric acid in ethyl ether is added. The solid formed is drained, washed with ethyl ether (2×2 cc) and dried under reduced pressure (5 mm Hg; 0.7 kPa) at 40° C. N-(3-Methylbutyl)-10-[(2RS)-1-(1-pyrrolidinyl)-2-propyl]-2-phenothiazinecarboxamide hydrochloride (0.37 g) is thereby obtained in the form of a pale yellow solid, m.p. about 100° C. (melts forming a paste), the NMR spectrum of which is identical to that of the product described below in Example 26.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:12]=2[CH2:13]O)=[CH:8][CH:7]=1.N1C=CC=CC=1.C1C=CC=CC=1>O>[Cl:3][CH2:13][C:12]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:11]=1[O:10][C:9]1[CH:20]=[CH:21][C:6]([CH3:5])=[CH:7][CH:8]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1ccc(Oc2ccc(C)cc2CO)cc1
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: Cc1ccc(Oc2ccc(C)cc2CCl)cc1

Procedure:
36.5 Ml. of thionyl chloride are added dropwise at 10°-15° C. with stirring and cooling with ice to a solution of 110 g. of 2-(4-methyl-phenoxy)-5-methyl-benzyl alcohol in 78 ml. of pyridine. The mixture is stirred for an additional 1 hour at 10° C. and then diluted with 200 ml. of benzene. Then, 200 ml. of water are carefully added dropwise with ice-cooling. The aqueous phase is separated and the organic phase washed successively with dilute hydrochloric acid, water and saturated sodium bicarbonate solution. The aqueous phases are each extracted once more with benzene. The combined benzene extracts are dried over sodium sulfate and evaporated to dryness in vacuo and there is obtained 3-chloromethyl-4-(4-methyl-phenoxy)-toluene as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:10]=[C:4]2[C:3]=1[O:20][CH2:21]OCC[Si](C)(C)C.C(=O)([O-])[O-].[Cs+].[Cs+].IC.CCOC(C)=O>O>[Br:1][C:2]1[CH:7]=[CH:6][N:5]2[C:8](=[O:19])[N:9]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:16])([CH3:17])[CH3:18])[N:10]=[C:4]2[C:3]=1[O:20][CH3:21]
Reactant: C[Si](C)(C)CCOCOc1c(Br)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CCOC(C)=O
Product: COc1c(Br)ccn2c(=O)n(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 192 h
Yield: 51 %

Procedure:
To a stirred suspension of the mixture of 7-bromo-8-methoxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one and 7-bromo-8-hydroxy-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one (from step 4) in DCM (120 mL) at 0° C. was added DIPEA (35 mL, 0.2 mol). After 5 min, (2-chloromethoxy-ethyl)-trimethylsilane (11.9 mL, 67.2 mmol) was added. The mixture was stirred at 0° C. for 1 hour and at RT for a further 2 hours. The resulting mixture was diluted with DCM (200 mL) and washed successively with 0.5 M HCl (aq) (400 mL) and water, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% ethyl acetate in cyclohexane) to afford the title compound (1.30 g, 20%) as a yellow solid. Fractions containing 7-bromo-8-(2-trimethylsilanyl-ethoxymethoxy)-2-(2-trimethylsilanyl-ethoxymethyl)-2H-[1,2,4]triazolo[4,3-a]pyridin-3-one were evaporated and the resultant residue was dissolved in MeOH (120 mL). The solution was stirred for 8 days at RT before evaporating to dryness. The resultant residue was dissolved in DMF (25 mL), cooled to 0° C., and cesium carbonate (13 g, 40 mmol) and iodomethane (3.11 mL, 50 mmol) were added. The reaction mixture was stirred at RT for 16 hours. EtOAc and water were added, the aqueous phase was isolated and extracted twice with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered, and concentrated in vacuo. The resultant residue was subjected to flash chromatography (SiO2, gradient 15 to 30% EtOAc in cyclohexane) to afford a further quantity of the title compound (3.26 g, 51%) as a yellow solid. LCMS (Method A): RT=4.70 min, [M+H]+=396/398.
Reaction SMILES: C(OC([N:8]1[CH2:11][CH:10]([NH:12][C:13]([C:15]2[C:16]3[CH2:17][C@H:18]4[CH2:31][C@H:19]4[C:20]=3[N:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:22]=2)=[O:14])[CH2:9]1)=O)(C)(C)C>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH:8]1[CH2:11][CH:10]([NH:12][C:13]([C:15]2[C:16]3[CH2:17][C@H:18]4[CH2:31][C@H:19]4[C:20]=3[N:21]([C:23]3[CH:28]=[CH:27][C:26]([F:29])=[CH:25][C:24]=3[F:30])[N:22]=2)=[O:14])[CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CC(NC(=O)c2nn(-c3ccc(F)cc3F)c3c2C[C@H]2C[C@@H]32)C1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(NC1CNC1)c1nn(-c2ccc(F)cc2F)c2c1C[C@H]1C[C@@H]21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
3-{[(1aR,5aR)-2-(2,4-Difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carbonyl]-amino}-azetidine-1-carboxylic acid tert-butyl ester was dissolved in 20% TFA/DCM. The reaction mixture was stirred at room temperature for 1 h. The solvent was evaporated, and the residue was purified by cation exchange resin to give (1aR,5aR)-2-(2,4-difluoro-phenyl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (azetidin-3-yl)-amide. This material was mixed with 3-bromo-1,1,1-trifluoropropane and Et3N in IPA. The reaction was heated under microwave irradiation for 1 h at 150° C. The mixture was purified by preparative HPLC to provide the title compound. LCMS m/z=427.3 [M+H]+.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[NH2:4][CH:5]([C:10]([OH:12])=O)[CH2:6][CH2:7][S:8][CH3:9].N1C=CC=CC=1.N[CH2:20][CH2:21][C:22]([OH:24])=[O:23]>CO>[C:22]([CH2:21][CH2:20][N:1]1[C:10](=[O:12])[CH:5]([CH2:6][CH2:7][S:8][CH3:9])[NH:4][C:2]1=[O:3])([OH:24])=[O:23]
Reactant: NCCC(=O)O
Reactant: CSCCC(N)C(=O)O
Reactant: [N-]=C=O
Solvent: c1ccncc1
Solvent: CO
Product: CSCCC1NC(=O)N(CCC(=O)O)C1=O

Procedure:
189 g (1 mole) of the isocyanate derivative of the methyl ester of dl-methionine are poured slowly into a pyridine solution of β-alanine (89 g, 1 mole). The reaction takes place spontaneously, accompanied by the elimination of methanol. The reaction medium is then concentrated to dryness under reduced pressure. The residue is purified by recrystallisation from dichlorethane.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2.[CH3:13][CH:14]1[CH2:16][O:15]1.O>O1CCCC1.CCOCC>[CH3:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH:14]([OH:15])[CH3:16])[CH:8]=[CH:7]2
Reactant: Cc1ccc2[nH]ccc2c1
Reactant: CC1CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: Cc1ccc2c(ccn2CC(C)O)c1
Reaction time: 1 h
Yield: 62.7 %

Procedure:
A suspension of 0.26 g of sodium hydride dispersion in 35 ml of tetrahydrofuran was treated with 0.95 g of 5-methylindole at 0° and stirred at this temperature for 1 hour. After the addition of 1 ml of (RS)-methyloxirane the reaction mixture was stirred at room temperature for 48 hours and subsequently treated with water. The mixture was diluted with ether, washed with water and with saturated sodium chloride solution and the organic phase was dried over sodium sulfate. After removal of the solvent the residue was chromatographed over 30 g of silica gel with toluene-ethyl acetate (19:1). There was obtained 0.86 g (62.7%) of (RS)-1-(5-methyl-indol-1-yl)-propan-2-ol as a yellow oil.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1(C)C=CC=CC=1.CO>C(O)C.[Ni]>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C@H:14]2[CH2:19][CH2:18][C@H:17]([OH:20])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCc1ccc(-c2ccc(O)cc2)cc1
Agent: [Ni]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: CCO
Product: CCCCCCCc1ccc([C@H]2CC[C@H](O)CC2)cc1
Temperature: 110 °C
Reaction time: 1 h

Procedure:
4-(4'-Heptylphenyl)phenol (200 g) was dissolved in ethanol (0.5 l) and a commercially available Raney nickel catalyst (20 g) was added, followed by hydrogenation at 80°~120° C. under hydrogen pressures of 30~40 Kg/cm2G for 6 hours in an autoclave. The reaction was traced by gas chromatography (column: SIDC-560-10%, 2 m, 280° C.), and when the raw material was extinct, the reaction was stopped. The catalyst was filtered off from the hydrogenation product, and after ethanol was distilled off under reduced pressure, the product was dissolved in toluene (200 ml). On the other hand, metallic sodium (18.4 g) was added to toluene (400 ml), followed by heating to 110° C. and then quenching down to room temperature under high speed agitation to prepare a sodium dispersion. To this dispersion was added the above toluene solution of the hydrogenation product, followed by stirring at room temperature for one hour. The mixture was further agitated at 100° C. for 4 hours, followed by cooling and then gradually adding methanol (200 ml). The whole mixture was transferred into a separating funnel and washed twice with 10% hydrochloric acid (200 ml) and once with a saturated aqueous solution of sodium hydrogen carbonate (200 ml), followed by repeated washings with water until the water layer became neutral. The toluene layer was dried over anhydrous sodium sulfate and toluene was distilled off under reduced pressure, followed by adding n-hexane (200 ml) and standing still overnight obtain crystals of trans-4-(4'-heptylphenyl)cyclohexanol. Yield: 41.6 g, 20.4%, m.p.: 80.2°~82.5° C.