Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH2:12])[CH:5]=1.[CH3:14][S:15](Cl)(=[O:17])=[O:16].C(N(CC)CC)C>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][CH2:11][NH:12][S:15]([CH3:14])(=[O:17])=[O:16])[CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cccc(CCN)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(CCNS(C)(=O)=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.6 %

Procedure:
To a solution of 3-(2-amino-ethyl)-benzoic acid methyl ester (500 mg) in CH2Cl2 (35 mL) at 0° C. was added methanesulfonyl chloride (292 mg, 2.55 mmol) and triethylamine (1.6 mL, 11.5 mmol). The reaction was stirred at room temperature for 18 h and was washed consecutively with 5.5% HCl, water, saturated NaHCO3, and brine. The organic solution was dried over MgSO4, filtered, and concentrated to yield the title compound (522 mg) as a white solid. MS 275 (M+18).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:16])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][CH:10]=1.[N:17]1([C:23](Cl)=[O:24])[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:16][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]1[CH:10]=[CH:11][C:12]([O:15][C:23]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[O:24])=[CH:13][CH:14]=1
Reactant: Oc1ccc(Oc2c(Cl)cncc2Cl)cc1
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Oc1ccc(Oc2c(Cl)cncc2Cl)cc1)N1CCOCC1

Procedure:
The title compound was prepared from 4-(3,5-dichloro-pyridin-4-yloxy)-phenol and morpholine-4-carbonyl chloride. The crude product was purified by preparative HPLC (66%, white crystals. HPLC-MS m/z=368.9 (M+1), Rt: 4.0 min.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1.[C-:15]#[N:16].[Na+]>CS(C)=O>[C:15]([CH2:2][C:3]1[C:11]([CH:12]([CH3:14])[CH3:13])=[CH:10][C:6]2[O:7][CH2:8][O:9][C:5]=2[CH:4]=1)#[N:16]
Reactant: [C-]#N
Reactant: CC(C)c1cc2c(cc1CCl)OCO2
Agent: [Na+]
Solvent: CS(C)=O
Product: CC(C)c1cc2c(cc1CC#N)OCO2
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.9 %

Procedure:
6.9 g of 5-chloromethyl-6-isopropyl-1,3-benzodioxole was dissolved in 100 ml of dimethyl sulfoxide, followed by the addition of 3.12 g of sodium cyanide. The obtained mixture was stirred at a room temperature for 3 hours and distilled to remove the solvent. Ethyl acetate was added to the residue and the obtained mixture was washed with water and a saturated aqueous solution of common salt successively, dried over anhydrous magnesium sulfate and filtered. The filtrate was concentrated to obtain 6.26 g of the title compound as a crude oil.
Reaction SMILES: [CH2:1]([C:5]1[C:9](/[CH:10]=[CH:11]/[C:12]2[S:13][C:14]([C:18]([OH:20])=O)=[C:15]([CH3:17])[N:16]=2)=[C:8]([CH3:21])[O:7][N:6]=1)[CH2:2][CH2:3][CH3:4].[NH2:22][C:23]([CH3:27])([CH3:26])[CH2:24][OH:25]>>[OH:25][CH2:24][C:23]([NH:22][C:18]([C:14]1[S:13][C:12](/[CH:11]=[CH:10]/[C:9]2[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[N:6][O:7][C:8]=2[CH3:21])=[N:16][C:15]=1[CH3:17])=[O:20])([CH3:27])[CH3:26]
Reactant: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)O)s1
Reactant: CC(C)(N)CO
Product: CCCCc1noc(C)c1/C=C/c1nc(C)c(C(=O)NC(C)(C)CO)s1
Yield: 46 %

Procedure:
As described for example 104, 2-[(E)-2-(3-butyl-5-methyl-isoxazol-4-yl)-vinyl]-4-methyl-thiazole-5-carboxylic acid (153 mg, 0.5 mmol) was converted, using 2-amino-2-methyl-1-propanol instead of rac-2-amino-1-butanol, to the title compound (87 mg, 46%) which was obtained as a colourless gum after purification by chromatography (silica, 0 to 100% ethyl acetate in heptane). MS: m/e=378.3 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]([CH2:5]Br)=[O:4].[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[C:10](O)=[O:11].[F-].[K+]>CN(C)C=O>[Cl:7][C:8]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[C:9]=1[CH2:10][O:11][CH2:2][C:3]([CH2:5][O:11][CH2:10][C:9]1[C:8]([Cl:7])=[CH:16][CH:15]=[CH:14][C:13]=1[Cl:17])=[O:4]
Reactant: O=C(CBr)CBr
Reactant: O=C(O)c1c(Cl)cccc1Cl
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C(COCc1c(Cl)cccc1Cl)COCc1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The bromomethylketone derivative (4.36 g) and 2,6-dichlorobenzoic acid (2.28 g, 1.1 eq) were dissolved in dimethylformamide (18 mL), KF (1.58 g, 2.5 eq) was added thereto, and the mixture was stirred for 2 h at room temperature. The residue obtained by concentration under reduced pressure was extracted with ethyl acetate, washed with water, twice with saturated aqueous sodium hydrogen carbonate solution, and aqueous sodium chloride solution, dried (anhydrous Na2SO4), and concentrated under reduced pressure to give the 2,6-dichlorobenzoxymethylketone derivative. This compound was dissolved in methanol (20 mL), and reacted by adding NaBH4 (412 mg)-methanol solution (40 mL). The reaction mixture was slowly warmed to room temperature for 2 h. The reaction was stopped by acetic acid. The reaction mixture was distilled under reduced pressure to remove methanol, extracted with ethyl acetate (50 mL×2), washed with water and aqueous sodium chloride solution, dried (anhydrous Na2SO4), concentrated under reduced pressure, and separated by column chromatography (ethyl acetate-hexane, 1:5) to give 4.80 g (86%) of the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[S:10]([O:13][C:14]1[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27]Cl)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=[C:16]([NH2:32])[N:15]=1)(=[O:12])=[O:11].[NH:33]1[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][N:35]=[CH:34]1>>[NH2:32][C:16]1[N:15]=[C:14]([O:13][S:10]([C:3]2[C:2]([CH3:1])=[CH:7][C:6]([CH3:8])=[CH:5][C:4]=2[CH3:9])(=[O:12])=[O:11])[C:19]([CH2:20][C:21]2[CH:26]=[CH:25][C:24]([CH2:27][N:33]3[C:37]([C:38]([O:40][CH3:41])=[O:39])=[CH:36][N:35]=[CH:34]3)=[CH:23][C:22]=2[O:29][CH3:30])=[C:18]([CH3:31])[N:17]=1
Reactant: COc1cc(CCl)ccc1Cc1c(C)nc(N)nc1OS(=O)(=O)c1c(C)cc(C)cc1C
Reactant: COC(=O)c1cnc[nH]1
Product: COC(=O)c1cncn1Cc1ccc(Cc2c(C)nc(N)nc2OS(=O)(=O)c2c(C)cc(C)cc2C)c(OC)c1
Yield: 15.1 %

Procedure:
The sub-title compound was synthesized by the method of example 1 step (vii) from the product of example 1 step (v) (500 mg) and Methyl 1H-imidazole-5-carboxylate (199 mg). The sub-title compound (90 mg) was obtained as a white solid; 1H NMR (300 MHz, CDCl3); 7.73 (1H, s), 7.61 (1H, s), 6.89 (2H, s), 6.83 (1H, d), 6.61 (1H, s), 6.55 (1H, d), 5.42 (2H, s), 3.78 (3H, s), 3.68 (5H, s), 2.46 (3H, s), 2.42 (6H, s), 2.26 (3H, s); LC-MS: m/z 566.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([CH:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1.Cl[C:24]([O:26][CH2:27][CH3:28])=[O:25]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:15]([CH:16]3[CH2:17][CH2:18][N:19]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:20][CH2:21]3)[C:10]3=[N:11][CH:12]=[CH:13][CH:14]=[C:9]3[CH2:8][CH2:7][C:6]=2[CH:22]=1
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)CCc1cccnc1C2C1CCNCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)N1CCC(C2c3ccc(Cl)cc3CCc3cccnc32)CC1

Procedure:
8-Chloro-6,11-dihydro-11-(4-piperidinyl)-5H-benzo[5,6]cyclohepta-[1,2-b]pyridine (product from Preparative Example 2) (4.18 g, 13 mmol) was dissolved in toluene (175 mL). Ethyl chloroformate(11.6 g, 110 mmol, 10.2 mL) was then added and the reaction mixture was heated to ~120° C. overnight. All volatiles were stripped off and the crude product was purified on silica gel column eluting with 50% ethyl acetate- hexanes to give the title compound as a white solid(MH+ 385).
Reaction SMILES: C(OC(=O)[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)(C)(C)C.I[C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:27][CH:26]=1>>[NH2:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[CH:9]([C:25]1[CH:37]=[CH:36][C:28]([O:29][CH:30]2[CH2:31][CH2:32][O:33][CH2:34][CH2:35]2)=[CH:27][CH:26]=1)[OH:14]
Reactant: Ic1ccc(OC2CCOCC2)cc1
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Product: NC(c1ccc(Cl)c(Cl)c1)C(O)c1ccc(OC2CCOCC2)cc1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 4-(4-iodophenoxy)tetrahydropyran in analogy to Example 1a): MS (ISP): 480.2 and 482.1 (M+H)+, 424.1 and 426.0 ((M-isobutene)+H)+ (100%), 380.1 and 382.0 ((M-Boc)+H)+ (94%).
Reaction SMILES: [N:1]([CH2:4][CH2:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:11][C:12]([C:16]#[N:17])=[N:13]2)=[CH:8][CH:7]=1)=[N+:2]=[N-:3].[CH2:24]([C:26]([OH:31])([CH2:29][CH3:30])[C:27]#[CH:28])[CH3:25].C(N(C(C)C)CC)(C)C>C1COCC1.[Cu](I)I>[CH2:27]([C:26]([C:24]1[N:3]=[N:2][N:1]([CH2:4][CH2:5][C:6]2[CH:15]=[C:14]3[C:9]([C:10]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:11][C:12]([C:16]#[N:17])=[N:13]3)=[CH:8][CH:7]=2)[CH:25]=1)([OH:31])[CH2:29][CH3:30])[CH3:28]
Reactant: N#Cc1cc(-c2ccccc2)c2ccc(CCN=[N+]=[N-])cc2n1
Reactant: C#CC(O)(CC)CC
Agent: I[Cu]I
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(O)(CC)c1cn(CCc2ccc3c(-c4ccccc4)cc(C#N)nc3c2)nn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A mixture of 7-(2-azidoethyl)-4-phenylquinoline-2-carbonitrile (128 mg, 0.43 mmol), 3-ethylpent-1-yn-3-ol (63 mg, 0.56 mmol), copper iodide (58 mg, 0.65 mmol) and diisopropylethylamine (375 μL, 2.2 mmol) in THF (5 mL) was stirred at rt for 6 h. The reaction was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification on silica gel (eluting with acetone/dichloromethane, 2:8) gave the title compound. MS (+ESI): 394 (M+H)+.
Reaction SMILES: [C:1]1([NH2:8])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[NH2:7].Cl.C(O[C:13](=N)[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C>C(O)C>[N:7]1[C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=2[NH:8][C:13]=1[CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: Nc1ccccc1N
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Solvent: CCO
Product: CCOC(=O)Cc1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A solution of 1,2-phenylenediamine (1.0 eq) and ethyl 3-ethoxy-3-iminopropanoate hydrochloride (1.3 eq) in ethanol was stirred at 90° C. overnight. The reaction was cooled to room temperature and the solvent was removed in vacuo. Water and CH2Cl2 were added to the residue. The organic layer was separated, dried over Na2SO4 and the solvent removed. The solid recovered was used without purification. LC/MS m/z 205.2 (MH+), Rt 1.44 minutes.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][OH:24])=[C:9]2[CH3:25])=[CH:4][CH:3]=1.CCOC(/N=N/C(OCC)=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:57][C:58]1[CH:63]=[CH:62][C:61](O)=[CH:60][CH:59]=1>C1COCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:15][CH:14]=3)=[CH:11][C:10]([CH2:23][O:24][C:61]3[CH:62]=[CH:63][C:58]([I:57])=[CH:59][CH:60]=3)=[C:9]2[CH3:25])=[CH:6][CH:7]=1
Reactant: Cc1c(CO)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1
Reactant: Oc1ccc(I)cc1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: Cc1c(COc2ccc(I)cc2)cc(-c2ccc(S(C)(=O)=O)cc2)n1-c1ccc(F)cc1

Procedure:
Compound 6 (from Example A) (1 mmol) is added to a solution of diethylazodicarboxylate (1 mmol), triphenylphosphine (1 mmol) and 4-iodophenol (1 mmol) in dry THF (25 mL). The progress of the reaction is monitored by tlc. When the reaction is complete, water is added and the crude product is extracted in ethyl acetate. The extract is dried and evaporated and the title compound 25 is purified by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:31])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26](Br)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)([CH3:7])[CH3:6])[CH3:2].B(O)(O)[C:33]1[C:42]2[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:36]=[CH:35][CH:34]=1.C(O)C.C([O-])([O-])=O.[Na+].[Na+]>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>[CH2:1]([O:3][C:4](=[O:31])[C:5]([CH3:7])([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:41]4[C:42]5[C:37](=[CH:36][CH:35]=[CH:34][CH:33]=5)[CH:38]=[CH:39][CH:40]=4)[CH:25]=3)[O:21][C:22]=2[CH3:23])=[CH:11][CH:10]=1)[CH3:6])[CH3:2]
Reactant: OB(O)c1cccc2ccccc12
Reactant: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(Br)c3)oc2C)cc1
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: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C)(C)Oc1ccc(OCCc2nc(-c3cccc(-c4cccc5ccccc45)c3)oc2C)cc1
Temperature: 25 °C

Procedure:
A solution of 2-(4-{2-[2-(3-bromophenyl)-5-methyloxazol-4-yl]ethoxy}phenoxy)-2-methylpropionic acid ethyl ester (433 mg, 0.907 mmol) (see Ex. 3, part F) and 1-naphthyleneboronic acid (0.998 mmol) in toluene:ethanol (18.2 mL of a 1:1 solution) was treated with Na2CO3(aq) (0.906 mL of a 2M solution). A nitrogen atmosphere was applied, Pd(PPh3)4 (52.5 mg) was added, and the orange mixture was heated at reflux for 2 h. After cooling to room temperature, the mixture was partitioned between ethyl acetate (20 mL) and H2O (30 mL). The layers were separated, and the aqueous phase was back-extracted with ethyl acetate (2×10 mL). Combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated. The product was purified by silica gel chromatography (20 g SiO2, 3:7 ethyl acetate:hexanes). Rf=0.16 in 1:9 ethyl acetate:hexanes; 1H NMR (400 MHz, CDCl3) δ 8.11-8.05 (m, 2H), 7.90-7.82 (m, 3H), 7.56-7.39 (m, 6H), 6.80-6.72 (m, 4H), 4.22-4.19 (m, 4H), 2.98 (t, 2H), 2.35 (s, 3H) 1.47 (s, 3H), 1.22 (t, 6H); MS (EI) 436.5 (M+H)+.
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[O:9]=[C:10]1[NH:19][CH:18]([C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][CH:21]=2)[C:17]2[C:16](=[O:28])[CH2:15][CH2:14][CH2:13][C:12]=2[N:11]1[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([C:35]([F:38])([F:37])[F:36])[CH:30]=1.Br.Br[CH2:41][CH2:42][CH2:43][N:44]1[CH2:48][CH2:47][CH2:46][CH2:45]1.O>CN(C)C=O>[F:37][C:35]([F:38])([F:36])[C:31]1[CH:30]=[C:29]([N:11]2[C:12]3[CH2:13][CH2:14][CH2:15][C:16](=[O:28])[C:17]=3[CH:18]([C:20]3[CH:21]=[CH:22][C:23]([C:24]#[N:25])=[CH:26][CH:27]=3)[N:19]([CH2:41][CH2:42][CH2:43][N:44]3[CH2:48][CH2:47][CH2:46][CH2:45]3)[C:10]2=[O:9])[CH:34]=[CH:33][CH:32]=1
Reactant: N#Cc1ccc(C2NC(=O)N(c3cccc(C(F)(F)F)c3)C3=C2C(=O)CCC3)cc1
Reactant: BrCCCN1CCCC1
Agent: Br
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1ccc(C2C3=C(CCCC3=O)N(c3cccc(C(F)(F)F)c3)C(=O)N2CCCN2CCCC2)cc1
Temperature: 25 °C

Procedure:
In a first flask, lithium diisopropylamide (2.0 M in tetrahydrofuran, 135 μL, 0.27 mmol) is added at 0° C. to a solution of 4-(2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-1,2,3,4,5,6,7,8-octahydroquinazolin-4-yl)-benzonitrile (example 1, 100 mg, 0.243 mmol) in N,N-dimethyl-formamide (3 mL, solution A). In another flask, lithium diisopropylamide (2.0 M in tetrahydrofuran, 135 μL, 0.27 mmol) is added to a solution of 1-(3-bromopropyl)pyrrolidine hydrobromide (70 mg, 0.256 mmol) in N,N-dimethylformamide (2 mL, solution B). This solution is then added to solution A and the resulting mixture is stirred at room temperature over night. Water is added, and the mixture is extracted twice with dichloromethane. The combined organic layers are dried over Na2SO4 and concentrated under reduced pressure. The residue is purified by reversed phase HPLC (Waters Xbridge-C18, gradient of methanol in water, 0.1% TFA). Yield: 15 mg; ESI mass spectrum [M+H]+=523; Retention time HPLC: 1.15 min (V001—006).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[C:21]([C:22]2[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=2)=[C:8]2[NH:9][C:10](=O)[CH:11]=[C:12]([C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[N:7]2[N:6]=1)[CH3:2].N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:37]>>[Cl:37][C:10]1[CH:11]=[C:12]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:7]2[N:6]=[C:5]([CH2:4][O:3][CH2:1][CH3:2])[C:21]([C:22]3[CH:27]=[CH:26][C:25]([CH3:28])=[CH:24][CH:23]=3)=[C:8]2[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOCc1nn2c(-c3ccc(F)cc3)cc(=O)[nH]c2c1-c1ccc(C)cc1
Solvent: c1ccncc1
Product: CCOCc1nn2c(-c3ccc(F)cc3)cc(Cl)nc2c1-c1ccc(C)cc1
Temperature: 25 °C

Procedure:
2-(Ethoxymethyl)-7-(4-fluorophenyl)-3-(4-methylphenyl)pyrazolo[1,5-a]pyrimidin-5(4H)-one (132 mg) is dissolved in POCl3 (15 mL) and pyridine (0.2 mL) and stirred overnight while heating. After cooling to room temperature, the reaction solvent is removed by distillation under reduced pressure. The remainder is extracted with ethyl acetate and water. The extracted organic layer is washed with 1 M NaHCO3 aqueous solution and brine and dehydrated with anhydrous MgSO4. The dehydrated organic layer is distilled under reduced pressure and purified by column chromatography to yield the target compound (381 mg). 1H NMR (CDCl3, 300 MHz): δ 8.11 (m, 2H), 7.73 (d, J=0.8.1 Hz, 2H), 7.26 (m, 4H), 6.87 (s, 1H), 4.70 (s, 2H), 6.66 (m, 2H), 2.41 (s, 3H), 1.26 (3H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([O:10]CC)=[O:9])[CH2:3][CH2:2]1>Cl>[O:1]1[CH2:6][CH2:5][N:4]([CH2:7][C:8]([OH:10])=[O:9])[CH2:3][CH2:2]1
Reactant: CCOC(=O)CN1CCOCC1
Agent: Cl
Product: O=C(O)CN1CCOCC1
Yield: 60 %

Procedure:
The solution of ethyl 2-morpholinoacetate (0.73 g, 4.24 mmol, 1.0 eq) in 8 N HCl was stirred at 95° C. for 16 h. The mixture was concentrated on vacuum pump and quenched and extracted as in Intermediate Example 15(b). The solvent was distilled off to afford the product in 60% yield (0.37 g). LC-MS (ESI): Calculated mass: 145.1; Observed mass 146.3 [M+H]+ (rt: 0.28 min).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([NH:16][C:17](=[O:32])/[CH:18]=[CH:19]/[C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:23]=[N:22][CH:21]=2)=[CH:12][CH:11]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]>[C].[Pd].C(O)C>[CH2:1]([O:3][P:4]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([NH:16][C:17](=[O:32])[CH2:18][CH2:19][C:20]2[N:24]([C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH:23]=[N:22][CH:21]=2)=[CH:14][CH:15]=1)([O:6][CH2:7][CH3:8])=[O:5])[CH3:2]
Reactant: CCOP(=O)(Cc1ccc(NC(=O)/C=C/c2cncn2-c2ccc(F)cc2)cc1)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOP(=O)(Cc1ccc(NC(=O)CCc2cncn2-c2ccc(F)cc2)cc1)OCC
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
A mixture of (2E)-N-[4-(diethylphosphonomethyl)phenyl]-3-[1-(4-fluorophenyl)-1H-imidazol-5-yl]acrylamide (92 mg), 5% palladium-carbon (100 mg) and ethanol (10 ml) was stirred at room temperature under a hydrogen atmosphere at atmospheric pressure for 3 hrs. The reaction mixture was filtered, and the organic layer was concentrated to give N-[4-(diethylphosphonomethyl)phenyl]-3-[1-(4-fluorophenyl)-1H-imidazol-5-yl]propionamide (60 mg, 65%) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([CH3:13])[CH:10]=[CH:9][C:4]=1[C:5]([O:7][CH3:8])=[O:6].[I:14]Cl>CO>[I:14][C:10]1[C:11]([CH3:13])=[CH:12][C:3]([O:2][CH3:1])=[C:4]([CH:9]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COC(=O)c1ccc(C)cc1OC
Reactant: ClI
Solvent: CO
Product: COC(=O)c1cc(I)c(C)cc1OC
Temperature: 50 °C

Procedure:
Methyl 2-methoxy-4-methylbenzoate (1.5 g, 8.32 mmol, 1 eq) was dissolved in methanol. To this solution was added dropwise iodine monochloride (6.75 g, 41.6 mmol, 5 eq) in methanol at room temperature. The reaction mixture was heated at 50° C. for 15 h. Finally, methanol was concentrated, diluted with water and extracted with ethyl acetate. The organic layer was washed with 0.1 N HCl (50 ml), water (100 ml) and brine solution (100 ml). The product was purified by column chromatography using 60-120 silica gel and using 5% ethyl acetate/hexane as eluent. Yield: 1.7 g (80%). 1HNMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 3.86 (s, 3H), 3.88 (s, 3H), 6.86 (s, 1H), 8.20 (s, 1H). LCMS: (ES+) m/z=307.0 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([N:9](S(C)(=O)=O)[S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=1.O1CCCC1.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:18]([O-:20])=[O:19])=[C:7]([NH:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH:8]=1
Reactant: COc1ccc([N+](=O)[O-])c(N(S(C)(=O)=O)S(C)(=O)=O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COc1ccc([N+](=O)[O-])c(NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a solution of N-(5-Methoxy-2-nitro-phenyl)-N-(methylsulfonyl) methanesulfonamide (7.70 g) in Tetrahydrofuran (200 mL, 2 mol) was added 1 M of Sodium hydroxide in Water (50 mL). The mixture was stirred for 18 hours. The mixture was poured into a separatory funnel and the aqueous layer (bottom layer) was separated. The aqueous layer was washed with Ethyl Acetate (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered and evaporated. N-(5-Methoxy-2-nitro-phenyl)-methanesulfonamide isolated as an orange solid (5.59 g, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:29][C:30]([OH:32])=[O:31])=[C:13]([O:27][CH3:28])[CH:14]=[C:15]([CH2:25][NH2:26])[C:16]=1[N:17]2[CH3:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33](O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>C(Cl)Cl>[C:1]([O:5][C:6]([C:8]1[C:21]([O:22][CH3:23])=[CH:20][CH:19]=[C:18]2[C:9]=1[S:10][C:11]1[C:12]([CH2:29][C:30]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)=[O:31])=[C:13]([O:27][CH3:28])[CH:14]=[C:15]([CH2:25][NH2:26])[C:16]=1[N:17]2[CH3:24])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: OCc1ccccc1
Reactant: COc1cc(CN)c2c(c1CC(=O)O)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C
Solvent: ClCCl
Product: COc1cc(CN)c2c(c1CC(=O)OCc1ccccc1)Sc1c(ccc(OC)c1C(=O)OC(C)(C)C)N2C
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.2 %

Procedure:
A solution of 158 mg (0.77 mmol) of N,N-dicyclohexylcarbodiimide in methylene chloride was added dropwise to an ice-cooled solution of 3.20 mg (0.695 mmol) of (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-10-methyl-phenothiazin-4-yl)-acetic acid, 90.2 mg (0.84 mmol) of benzyl alcohol and 20 mg of N,N-dimethylaminopyridine in 2.5 ml of methylene chloride. The reaction mixture was stirred at room temperature overnight and filtered. The filter residue was washed with methylene chloride. The combined filtrates were washed with saturated sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The residue was chromatographed on silica gel with ethyl acetate/hexane (1:4), whereupon, after recrystallization from ethanol and drying, 280 mg (73.3%) of benzyl (6-tert.-butoxycarbonyl-aminomethyl-3,7-dimethoxy-10-methyl-phenothiazin-4-yl)-acetate were obtained as white crystals of m.p. 131°-132°.
Reaction SMILES: [N+:1]([C:4]1[CH:14]=[CH:13][C:7]2[NH:8][S:9](=[O:12])(=[O:11])[O:10][C:6]=2[CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:14]=[CH:13][C:7]2[NH:8][S:9](=[O:12])(=[O:11])[O:10][C:6]=2[CH:5]=1
Reactant: O=[N+]([O-])c1ccc2c(c1)OS(=O)(=O)N2
Agent: [Pd]
Solvent: CO
Product: Nc1ccc2c(c1)OS(=O)(=O)N2

Procedure:
A solution of 6-nitro-3H-benzo[1,2,3]oxathiazole 2,2-dioxide (example 5) (8.1 g, 37 mmol) in methanol (250 ml) is hydrogenated at atmospheric pressure in the presence of Pd-C. The catalyst is then filtered off, the clear solution is treated with methanolic HCl (1 N) and the solvent is distilled off under reduced pressure. The residue is dissolved in ethanol and the product crystallizes after addition of diethyl ether.