Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[C:3]1([C:9]2[O:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)[CH:8]=[CH:7]C=[CH:5][CH:4]=1.C(O)(=O)C1C=C[N:24]=CC=1>>[ClH:1].[ClH:1].[N:24]1[CH:7]=[CH:8][C:3]([C:9]2[O:13][N:12]=[C:11]([N:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[N:10]=2)=[CH:4][CH:5]=1
Reactant: O=C(O)c1ccncc1
Reactant: c1ccc(-c2nc(N3CCNCC3)no2)cc1
Agent: Cl
Product: c1cc(-c2nc(N3CCNCC3)no2)ccn1

Procedure:
The title product was prepared following the procedure of Intermediate 11 (step a to d) but using isonicotinic acid in step c). The title compound was obtained as a solid. TLC-Chloroform/methanol (8/2): Rf=0.2. HPLC purity: 97%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:8]([O:12][CH3:13])(=[O:11])[CH:9]=[CH2:10].C(O)(=O)C>CCCCCC>[C:2]1([NH:1][CH2:10][CH2:9][C:8]([O:12][CH3:13])=[O:11])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: C=CC(=O)OC
Solvent: CCCCCC
Solvent: CC(=O)O
Product: COC(=O)CCNc1ccccc1

Procedure:
A mixture of 20 ml of aniline, 22 ml of methyl acrylate and 2 ml of acetic acid is refluxed for 8 hours. After concentrating the reaction mixture under vacuum, the resulting oil is distilled off under reduced pressure (b.p.=132° C. at 333.3 Pa and then b.p.=110° C. at 6.66 Pa). The product obtained is taken up in hexane and the precipitate formed is filtered off by suction. 25 g of the expected product are obtained.
Reaction SMILES: [CH2:1]([NH:3][C:4]([CH:6]1[CH2:10][CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[C:14]=3[N:13]=[N:12]2)[CH:8]([OH:34])[CH:7]1[OH:35])=[O:5])[CH3:2].[NH2:36][CH2:37][C:38]1[CH:43]=[CH:42]C=CN=1>>[OH:35][CH:7]1[CH:8]([OH:34])[CH:9]([N:11]2[C:15]3[N:16]=[C:17]([S:30][CH2:31][CH2:32][CH3:33])[N:18]=[C:19]([NH:20][CH:21]4[CH2:23][CH:22]4[C:24]4[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=4)[C:14]=3[N:13]=[N:12]2)[CH2:10][CH:6]1[C:4]([NH:3][CH2:1][C:2]1[CH:42]=[CH:43][CH:38]=[CH:37][N:36]=1)=[O:5]
Reactant: NCc1ccccn1
Reactant: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCC)C(O)C3O)c2n1
Product: CCCSc1nc(NC2CC2c2ccccc2)c2nnn(C3CC(C(=O)NCc4ccccn4)C(O)C3O)c2n1

Procedure:
The subtitle compound was prepared according to the method of example 39, step a) using the product of example 1, step c) and 2-(aminomethyl)pyridine.
Reaction SMILES: [CH3:1][N:2]([CH:4]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH2:5][CH2:6][CH:7]=[CH2:8])[CH3:3].S(=O)(O)[O-:22].[Na+].[OH2:26]>N1C=CC=CC=1.[Os](=O)(=O)(=O)=O>[Cl:20][C:15]1[CH:14]=[C:13]([C:9]2([CH:4]([N:2]([CH3:3])[CH3:1])[CH2:5][CH2:6][CH:7]([OH:22])[CH2:8][OH:26])[CH2:12][CH2:11][CH2:10]2)[CH:18]=[CH:17][C:16]=1[Cl:19]
Reactant: O
Reactant: O=S([O-])O
Reactant: C=CCCC(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Solvent: c1ccncc1
Product: CN(C)C(CCC(O)CO)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
A solution of osmium tetroxide (2 g) in pyridine (10 ml) was added with stirring to a solution of N,N-dimethyl-1-[1(3,4-dichlorophenyl)cyclobutyl]pent-4-enylamine (2.43 g) in pyridine (20 ml). The mixture was allowed to stand for one and three quarter hours and was then added to a mixture of pyridine (40 ml) and a solution of sodium bisulphite (3.6 g) in water (60 ml). The resulting aqueous layer was extracted with dichloromethane and the extracts washed, dried and evaporated in vacuo to give a residue which was purified by flash chromatography using ether as eluant to give 5-[1-(3,4-dichlorophenyl)cyclobutyl]-5-dimethylaminopentane-1,2-diol the boiling point of which was not determined.
Reaction SMILES: [CH2:1]([O:3][C:4]([NH:6][C@H:7]([C:11]([OH:13])=O)[CH:8]([CH3:10])[CH3:9])=[O:5])[CH3:2].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[S:28]1[C:32]([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([NH2:64])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:35][CH:34]=2)=[CH:31][N:30]=[CH:29]1>CN(C=O)C>[S:28]1[C:32]([C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([NH:64][C:11](=[O:13])[C@H:7]([CH:8]([CH3:9])[CH3:10])[NH:6][C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:41][C@H:42]([OH:63])[C@@H:43]([NH:51][C:52](=[O:62])[C@H:53]([CH:59]([CH3:61])[CH3:60])[NH:54][C:55]([O:57][CH3:58])=[O:56])[CH2:44][C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)=[CH:37][CH:38]=2)=[CH:31][N:30]=[CH:29]1
Reactant: CCOC(=O)N[C@H](C(=O)O)C(C)C
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2cncs2)cc1)C(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N[C@H](C(=O)NN(Cc1ccc(-c2cncs2)cc1)C[C@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](NC(=O)OC)C(C)C)C(C)C

Procedure:
Analogously to Example 7, 213 mg (1.13 mmol) of N-ethoxycarbonyl-(L)-valine, 431 mg (2.25 mmol) of EDC and 304 mg (2.25 mmol) of HOBT in 18 ml of DMF and 627 μl (4.5 mmol) of TEA are reacted with 0.75 mmol of 1-[4-(thiazol-5-yl)-phenyl]-4(S)-hydroxy-2-amino-5(S)-N-(N-methoxycarbonyl-(L)-valyl)amino-6-phenyl-2-azahexane (Example 7b) to form the title compound: m.p: 243-244° C.; HPLC20-100 : tRet =14.0; FAB MS (M+H)+ =697.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][C@@H:7]2[CH2:10][C@H:9]([NH:11][S:12]([CH3:15])(=[O:14])=[O:13])[CH2:8]2)=[CH:4][C:3]=1[CH3:19].[H-].[Na+].I[CH3:23]>CN(C)C(=O)C>[Br:1][C:2]1[C:17]([CH3:18])=[CH:16][C:5]([O:6][C@@H:7]2[CH2:8][C@H:9]([N:11]([CH3:23])[S:12]([CH3:15])(=[O:14])=[O:13])[CH2:10]2)=[CH:4][C:3]=1[CH3:19]
Reactant: Cc1cc(O[C@H]2C[C@@H](NS(C)(=O)=O)C2)cc(C)c1Br
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Cc1cc(O[C@H]2C[C@@H](N(C)S(C)(=O)=O)C2)cc(C)c1Br
Temperature: 25 °C
Reaction time: 8 h

Procedure:
N-(cis-3-(4-bromo-3,5-dimethylphenoxy)cyclobutyl)methanesulfonamide (130 mg) and sodium hydride (16 mg) are stirred in N,N-dimethylacetamide (2 mL) for 10 minutes. Iodomethane (0.1 mL) is added and the mixture is stirred at ambient temperature overnight. After cooling to ambient temperature, the mixture is concentrated, partitioned between ethyl acetate and water. The organic phase is dried (MgSO4) and concentrated. The residue is chromatographed on silica gel (cyclohexane/ethyl acetate gradient of increasing polarity) to give the title compound. Yield: 110 mg.
Reaction SMILES: [CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2=[O:19].[CH3:20][Mg]Br.CCOCC.O>C1COCC1>[CH3:1][CH:2]1[S:7][C:6](=[O:8])[NH:5][N:4]=[C:3]1[C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[C:12]2([OH:19])[CH3:20]
Reactant: CC1SC(=O)NN=C1c1ccc2c(c1)C(=O)C(=O)N2
Reactant: C[Mg]Br
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CC1SC(=O)NN=C1c1ccc2c(c1)C(C)(O)C(=O)N2
Reaction time: 8 h
Yield: 28 %

Procedure:
1 g (3,6 mmol) 5-(3,6-dihydro-6-methyl-2-oxo-2H-1,3,4-thiadiazin-5-yl)-1H-indole-2,3 dione (Example 12) were dissolved under argon in 25 ml dry THF in a flame dried flask. 12 ml 3M methyl magnesium bromide in ether (10 eq) were added dropwise at 0°-5° C. The mixture was stirred overnight. 50 ml water were added, and extracted with ethyl acetate. The organic layers were washed with water and dried over magnesium sulfate. Purification by chromatography on silica (eluent:methylene chloride/ethyl acetate: 2/1), yielded 300 mg (28%) of the desired compound.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])[CH2:8]2)([CH3:4])([CH3:3])[CH3:2].[CH:17](OC)(OC)[O:18][CH3:19]>C(O)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[C:11](=[O:15])[NH:10][C:9](=[O:16])/[C:8]/2=[CH:17]/[O:18][CH3:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(OC)OC
Reactant: CC(C)(C)c1ccc2c(c1)CC(=O)NC2=O
Solvent: CC(=O)O
Product: CO/C=C1/C(=O)NC(=O)c2ccc(C(C)(C)C)cc21
Temperature: 90 °C
Yield: 79 %

Procedure:
An amount 200 mg (0.92 mmol) of 6-tert-butylisoquinoline-1,3(2H,4H)-dione is dissolved in acetic acid 1.0 mL followed by addition of trimethyl orthoformate (25 uL, 2.3 mmol). After, the mixture is heated at 90° C. for 1 h, and cooled to room temperature. The yellow solution evaporated to dryness. Small amounts of anhydrous ether is added and hexane. The yellow solid is collected with hexane to give 188 mg (79% yield) MS (ESI) m/z 260.2 (M+1). 1H NMR (300 MHz, DMSO-d6) 1.346 (S, 9H), 4.178 (S, 3H), 7.472-7.505 (dd, J=1.8 Hz, J=1.8 Hz 1H), 8.007 (d, J=8.52 Hz 2H), 8.31 (d, J=1.71 Hz 1H).
Reaction SMILES: [Cl:1][CH:2]([Cl:6])[C:3](Cl)=[O:4].[OH:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11].CCO>C(Cl)Cl>[Cl:1][CH:2]([Cl:6])[C:3]([O:7][N:8]=[C:9]([C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=1)[C:10]([OH:12])=[O:11])=[O:4]
Reactant: O=C(O)C(=NO)c1ccc(Cl)cc1
Reactant: O=C(Cl)C(Cl)Cl
Solvent: CCO
Solvent: ClCCl
Product: O=C(O)C(=NOC(=O)C(Cl)Cl)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of dichloroacetyl chloride (1.8 ml.) in methylene chloride (15 ml.) was added 2-hydroxyimino-(4-chlorophenyl)acetic acid (anti-isomer) (1.5 g.) and the suspension stirred for two hours at room temperature. During this time most of the material dissolved. The solid was removed, washed with petroleum (b.p. 40°-60°) and the washings and filtrate were combined, kept at 5° overnight and the resulting solid was collected and dried to give the title acid (2.0 g; 85%), m.p. 80°, λmax. (EtOH) 258 nm (ε 12,280), νmax. (Nujol) 1774 (ester), 1750 and 1722 cm.-1 (CO2H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][CH2:6][C:7]2=[O:12].Br[CH2:14][CH:15]1[CH2:17][CH2:16]1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC.CCOC(C)=O>[CH:15]1([CH2:14][O:1][C:2]2[CH:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH2:4][CH2:5][CH2:6][C:7]3=[O:12])[CH2:17][CH2:16]1
Reactant: O=C1CCCc2c(O)cccc21
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: O=C1CCCc2c(OCC3CC3)cccc21
Temperature: 80 °C
Yield: 79.9 %

Procedure:
To a solution of 5-hydroxy-1-tetralone (1.8 g, 11.0 mmol) in butanone was added (bromomethyl)cyclopropane (1.8 g, 13.2 mmol) and K2CO3 (3.0 g, 22.0 mmol) at rt. The mixture was heated at 80° C. overnight. After the reaction was cooled to rt, it was diluted with EtOAc, filtered, and concentrated. The residue was purified by silica gel chromatography (20:1 PE/EtOAc) to give 1.9 g (78%) of the title compound as a tan oil. 1H NMR (300 MHz, CDCl3): δ 0.35-0.40 (2H, m), 0.62-0.68 (2H, m), 1.27-1.32 (1H, m), 2.05-2.17 (2H, m), 2.64 (2H, t, J=6.6 Hz), 2.96 (2H, t, J=6.0 Hz), 3.86 (2H, d, J=6.9 Hz), 6.98 (1H, d, J=8.1 Hz), 7.24 (1H, t, J=8.7 Hz), 7.65 (1H, d, J=8.1 Hz).
Reaction SMILES: C(O[C:4]([C:6]1[N:11]=[CH:10][C:9]2[N:12]=[C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)[S:14][C:8]=2[C:7]=1[OH:21])=[O:5])C.[NH2:22][CH2:23][C:24]([OH:26])=[O:25]>C[O-].[Na+].CO>[OH:21][C:7]1[C:8]2[S:14][C:13]([C:15]3[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=3)=[N:12][C:9]=2[CH:10]=[N:11][C:6]=1[C:4]([NH:22][CH2:23][C:24]([OH:26])=[O:25])=[O:5]
Reactant: NCC(=O)O
Reactant: CCOC(=O)c1ncc2nc(-c3cccnc3)sc2c1O
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: O=C(O)CNC(=O)c1ncc2nc(-c3cccnc3)sc2c1O
Temperature: 25 °C
Yield: 57.2 %

Procedure:
A mixture of 7-hydroxy-2-pyridin-3-yl-thiazolo[4,5-c]pyridine-6-carboxylic acid ethyl ester (27 mg, 0.09 mmol) and glycine (169 mg, 1.80 mmol) in 0.5 M sodium methoxide/methanol (4.5 mL) was refluxed for 3 days before it was cooled to room temperature and concentrated in vacuo. It was dissolved in water (15 mL) and extracted twice with methyl t-butyl ether. The remaining aqueous layer was acidified to pH=3 with 1N HCl (3.3 mL). The solid precipitate was filtered, washed with water and dried in vacuo to give the title compound as a yellow solid (17 mg): 1H NMR (DMSO-d6, 200 MHz): δ=9.56 (br s, 1H), 9.34 (s, 1H), 8.94 (s, 1H), 8.80 (d, 1H), 8.53 (m, 1H), 7.66 (m, 1H), 4.03 (d, J=5.8 Hz, 2H); MS: (+) m/z 331.00 (M+1).
Reaction SMILES: Cl[C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=2)=[CH:6][CH:7]=1.[C:18]([NH:22][NH2:23])(=O)[CH2:19][CH3:20].C(O)CCC>C(Cl)(Cl)Cl.CCCCCC>[CH2:19]([C:18]1[N:3]2[N:4]=[C:5]([C:8]3[CH:9]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][CH:13]=3)[CH:6]=[CH:7][C:2]2=[N:23][N:22]=1)[CH3:20]
Reactant: FC(F)(F)c1cccc(-c2ccc(Cl)nn2)c1
Reactant: CCC(=O)NN
Solvent: ClC(Cl)Cl
Solvent: CCCCCC
Solvent: CCCCO
Product: CCc1nnc2ccc(-c3cccc(C(F)(F)F)c3)nn12

Procedure:
A mixture of 5.0 g. of 3-chloro-6-(α,α,α-trifluoro-m-tolyl)pyridazine, 3.40 g. of propionic acid hydrazide and 100 ml. of n-butanol is refluxed for 48 hr. The solvent is removed under vacuum and the residue dissolved in chloroform. The solution is passed through a column of hydrous magnesium silicate and the eluent concentrated to give 3.0 g. of crystals (from CHCl3 -hexane), m.p. 183°-185° C.
Reaction SMILES: [C:1]([N:8]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10][CH:9]1S(C)(=O)=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C-:20]#[N:21].[K+].C1OCCOCCOCCOCCOCCOC1>CN(C=O)C>[C:1]([N:8]1[CH:13]=[C:12]([CH2:14][NH2:15])[CH:11]=[N:10][CH:9]1[C:20]#[N:21])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: [C-]#N
Reactant: CC(C)(C)OC(=O)N1C=C(CN)C=NC1S(C)(=O)=O
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C=C(CN)C=NC1C#N
Temperature: 60 °C
Reaction time: 4 h
Yield: 46 %

Procedure:
1 Eq. of N-Boc-5-aminomethyl-2-methylsulfonylpyrimidine was dissolved in DMF and introduced into a reflux apparatus. After addition of 2 eq. of KCN and catalytic amounts of 18-crown-6, the reaction mixture was stirred at 60° C. for 4 h. The suspension was then concentrated and poured into 200 ml of water. The precipitated solid was filtered off with suction and dissolved in ethyl acetate. The solution was washed with water and saturated NaCl solution, dried and evaporated in a rotary evaporator. N-Boc-5-aminomethyl-2-cyanopyrimidine was used as crude product without further purification in the next reaction. Yield: 46%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13]3[N:14]=[CH:15][NH:16][C:17](=O)[C:18]=3[N:19]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].P(Cl)(Cl)([Cl:23])=O.N1C(C)=CC=CC=1C>C1(C)C=CC=CC=1>[Cl:23][C:17]1[C:18]2[N:19]=[C:10]([C:4]3[CH:5]=[CH:6][C:7]([O:8][CH3:9])=[C:2]([CH3:1])[CH:3]=3)[CH:11]=[CH:12][C:13]=2[N:14]=[CH:15][N:16]=1
Reactant: COc1ccc(-c2ccc3nc[nH]c(=O)c3n2)cc1C
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1cccc(C)n1
Solvent: Cc1ccccc1
Product: COc1ccc(-c2ccc3ncnc(Cl)c3n2)cc1C
Yield: 74.5 %

Procedure:
To a suspension of 6-(3-methyl-4-methoxyphenyl)-pyrido[3,2-d]pyrimidin-4(3H)one (1.41 mmole) in toluene (80 ml) was added phosphorus oxychloride (4.23 mmole) and 2,6-lutidine (4.23 mmole). The reaction mixture was refluxed for 16 hours until a black solution was obtained. After evaporation to dryness, the residue was redissolved in ethyl acetate and extracted with a saturated sodium bicarbonate solution. The combined organic layers were evaporated in vacuo. The residue was purified by silica gel column chromatography (the mobile phase being a ethylacetate/hexane mixture in a ratio gradually ranging from 2:8 to 3:7), resulting in the pure title compound (300 mg, yield 74%) which was characterized by its mass spectrum as follows: MS (m/z): 287 ([M+H]+, 100).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][C:4]([CH2:8]O)=[N:3]1.S(Cl)([Cl:12])=O>C(Cl)Cl>[ClH:12].[Cl:12][CH2:8][C:4]1[CH:5]=[C:6]([CH3:7])[N:2]([CH3:1])[N:3]=1
Reactant: O=S(Cl)Cl
Reactant: Cc1cc(CO)nn1C
Solvent: ClCCl
Product: Cc1cc(CCl)nn1C
Product: Cl
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.8 %

Procedure:
To (1,5-dimethyl-1H-pyrazol-3-yl)methanol (5.01 g, 39.71 mmol) in DCM (80 mL) at 0° C. was cautiously added thionyl chloride (25 mL, 343.6 mmol). The cold bath was removed and the reaction mixture was stirred at ambient temperature for 3 hours. The reaction mixture was concentrated under reduced pressure to give crude product (7.32 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(N)=S)=[CH:4][N:3]=1.[C:12]([O:16][C:17](=[O:20])[CH2:18][NH2:19])([CH3:15])([CH3:14])[CH3:13].[CH:21]1([N:27]=C=NC2CCCCC2)CCCCC1>C(OCC)(=O)C.ClCCl>[Cl:1][C:2]1[C:7]([C:21](=[NH:27])[NH:19][CH2:18][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:20])=[CH:6][C:5]([NH2:8])=[CH:4][N:3]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CC(C)(C)OC(=O)CN
Reactant: NC(=S)Nc1ccc(Cl)nc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)CNC(=N)c1cc(N)cnc1Cl
Yield: 35.7 %

Procedure:
A solution of 1.2 g (6.4 mmol) of 2-chloro-5pyridylthiourea, 1 g (7.68 mmol) of glycine tert-butyl ester and 1.45 g (7.04 mmol) of dicyclohexylcarbodiimide in 30 ml of ethyl acetate is heated for 2.5 hr at 60° C. The dicyclohexylthiourea precipitate formed is eliminated by filtration. The filtrate is concentrated to dryness The product obtained is taken up in 20 ml of dichloromethane and then extracted with a 0.25 N aqueous hydrochloric acid solution (4 × 30 ml). The acid solution is then neutralized with a 1 N sodium hydroxide solution, and thereafter is extracted with dichloromethane (3× 20 ml), thus permitting 0.65 g (yield 36%) of tert-butyl N-[2-chloro-5-aminopyridyl(imino)methyl]-2-aminoethanoate to be obtained in the form of an oil.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[N+:17]([O-])=O)=[CH:8][CH:7]=1.[Cl-:26].[NH4+]>C(O)C.O.[Fe]>[ClH:26].[F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([O:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[NH2:17])=[CH:8][CH:7]=1
Reactant: [Cl-]
Reactant: O=[N+]([O-])c1ccccc1Oc1ccc(OCc2ccccc2F)cc1
Agent: [Fe]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Cl
Product: Nc1ccccc1Oc1ccc(OCc2ccccc2F)cc1
Reaction time: 0.5 h
Yield: 163 %

Procedure:
To a solution of 1-[4-(2-fluorobenzyloxy)phenoxy]-2-nitrobenzene (0.65 g, 1.9 mmol) in ethanol (50 ml) were added an iron powder (0.53 g, 9.5 mg-atom) and a solution of ammonium chloride (0.06 g, 1.1 mmol) in water (10 ml), followed by reflux for 3 hours. The insoluble matter was removed by filtration, the solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. After drying, the solvent was again evaporated under reduced pressure, the residue was dissolved in a small amount of ethyl acetate, and 4 N hydrogen chloride-ethyl acetate solution (2 ml) was added, followed by stirring for 30 minutes. The solvent was evaporated under reduced pressure, and crystallization from diethyl ether gave the title compound (0.62 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8](O)[CH3:9])=[CH:4][C:3]=1[S:11]([CH3:14])(=[O:13])=[O:12].C1(P([N:29]=[N+:30]=[N-:31])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[N:29]([CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:4]=1)[CH3:9])=[N+:30]=[N-:31]
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: CC(O)c1ccc(Cl)c(S(C)(=O)=O)c1
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(N=[N+]=[N-])c1ccc(Cl)c(S(C)(=O)=O)c1
Temperature: 25 °C
Yield: 28.5 %

Procedure:
A round bottom flask was charged with 1-(4-chloro-3-(methylsulfonyl)phenyl)ethanol (8.5 g, 32.44 mmol) and toluene (100 mL). Diphenyl phosphoryl azide (8.4 mL, 38.93 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (5.8 mL, 38.93 mmol) were added at 0° C. and the mixture was stirred over night at room temperature. The volatiles were removed under reduced pressure and the residue was diluted with water and extracted with EtOAc. The combined organic layers were concentrated under reduced pressure and the residue was purified by column chromatography to get the product (2.4 g, 28% yield).
Reaction SMILES: Cl[C:2]1[C:3](=[O:17])[N:4]([CH2:15][CH3:16])[S:5](=[O:14])(=[O:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[NH:18]1[CH:22]=[C:21]([CH2:23][CH2:24][NH2:25])[N:20]=[CH:19]1>>[CH2:15]([N:4]1[C:3](=[O:17])[C:2]([NH:25][CH2:24][CH2:23][C:21]2[N:20]=[CH:19][NH:18][CH:22]=2)=[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[S:5]1(=[O:14])=[O:13])[CH3:16]
Reactant: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Reactant: NCCc1c[nH]cn1
Product: CCN1C(=O)C(NCCc2c[nH]cn2)=C(c2ccccc2)S1(=O)=O

Procedure:
The title compound was prepared from 4-chloro-2-ethyl-5-phenylisothiazol-3(2H)-one 1,1-dioxide and 2-(1H-imidazol-4-yl)ethanamine in a similar manner as described for Example 1.
Reaction SMILES: C.Cl[C:3]1[CH:8]=[C:7]([NH:9][CH2:10][CH:11]([OH:13])[CH3:12])[C:6]([N+:14]([O-:16])=[O:15])=[C:5]([NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[CH:4]=1.C(O)C.C(N(CC)CC)C>[Pd].C(O)=O>[OH:13][CH:11]([CH3:12])[CH2:10][NH:9][C:7]1[CH:8]=[CH:3][CH:4]=[C:5]([NH:17][CH2:18][CH:19]([OH:21])[CH3:20])[C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(O)CNc1cc(Cl)cc(NCC(C)O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(O)CNc1cccc(NCC(C)O)c1[N+](=O)[O-]

Procedure:
340 mg of palladium at a concentration of 10% on active charcoal are added to 0.07 mole (21.3 g) of 4-chloro-2-(β-hydroxypropyl)amino-6-(β-hydroxypropyl)aminonitrobenzene in 30 ml of 96° ethanol and 29.2 ml of triethylamine, after which 5.8 ml of formic acid are run in dropwise.
Reaction SMILES: [BrH:1].[CH2:2]([O:7][CH2:8][CH2:9][C:10]([CH3:14])(O)[CH:11]=[CH2:12])[CH2:3][CH:4]([CH3:6])[CH3:5]>>[Br:1][CH2:12][CH:11]=[C:10]([CH3:14])[CH2:9][CH2:8][O:7][CH2:2][CH2:3][CH:4]([CH3:6])[CH3:5]
Reactant: C=CC(C)(O)CCOCCC(C)C
Reactant: Br
Product: CC(=CCBr)CCOCCC(C)C

Procedure:
To 40 mls of a 48% solution of hydrobromic acid are added dropwise with stirring at 5° during a period of 15 minutes 18.6 g (0.1 moles) of 5-isopentyloxy-3-methyl-1-penten-3-ol. After 30 minutes at 0°-5° the mixture is extracted with ether and the ethereal extract is washed with 10% sodium carbonate solution and then with saturated sodium chloride solution, dried with anhydrous sodium sulphate and evaporated.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14].O.[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1B(O)O)[CH3:17].C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[CH2:12][O:13][CH3:14])[CH3:17]
Reactant: CCc1ccccc1B(O)O
Reactant: COCc1cc(C(=O)OC)ccc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1ccccc1-c1ccc(C(=O)OC)cc1COC
Reaction time: 12 h
Yield: 83 %

Procedure:
To a solution of methyl 4-bromo-3-(methoxymethyl)benzoate, (Intermediate 28, step 2) (12 g, 0.0463 mol) in toluene (150 mL) and water (35 mL) under N2, was added 2-ethyl benzene boronic acid (9.02 g, 0.0601 mol) followed by potassium carbonate (19 g, 0.1389 mol) and Pd(PPh3)4 (2.67 g, 0.0023 mol). The reaction mixture was degassed with N2 for 10 min before heating. After 12 hours at 100° C., the reaction mixture was diluted with EtOAc. The organic layer was washed with sodium bicarbonate sat. solution (1×100 mL), water (2×100 mL) and finally with brine (1×100 mL). It was then dried over sodium sulphate and concentrated under reduced pressure. The residue was purified by chromatography (silica gel, 60-120 mesh, eluting with pet ether/EtOAc) to afford the title compound as a pale yellow liquid (12 g, 83%). 1H NMR (CDCl3, 400 MHz) δ 8.24-8.26 (1H, s), 7.99-8.01 (1H, d), 7.32-7.38 (2H, m), 7.22-7.27 (2H, m), 7.07-7.09 (1H, d), 4.12-4.21 (2H, d), 3.93-3.95 (3H, s), 3.28-3.30 (3H, s), 2.28-2.43 (2H, m), 1.01-1.05 (3H, t).