Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[C:16]([C:17]#[N:18])=[CH:15][N:14]=[C:13](S(C)(=O)=O)[N:12]=3)=[CH:9][N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[C:5]2=[N:6][CH:7]=1.[NH2:33][CH:34]([CH:37]([CH3:39])[CH3:38])[CH2:35][OH:36].C(N(C(C)C)CC)(C)C>C1COCC1>[OH:36][CH2:35][C@H:34]([NH:33][C:13]1[N:12]=[C:11]([C:10]2[C:4]3[C:5](=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=3)[N:8]([S:23]([C:26]3[CH:32]=[CH:31][C:29]([CH3:30])=[CH:28][CH:27]=3)(=[O:25])=[O:24])[CH:9]=2)[C:16]([C:17]#[N:18])=[CH:15][N:14]=1)[CH:37]([CH3:39])[CH3:38]
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3nc(S(C)(=O)=O)ncc3C#N)c3cc(C)cnc32)cc1
Reactant: CC(C)C(N)CO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3nc(N[C@@H](CO)C(C)C)ncc3C#N)c3cc(C)cnc32)cc1
Yield: 76.9 %

Procedure:
A mixture of 4-(5-methyl-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-(methylsulfonyl)pyrimidine-5-carbonitrile (120 mg, 0.257 mmol), (R)-(+2-amino-3-methyl-1-butanol (57 l, 0.515 mmol) and diisopropylethylamine (90 l, 0.515 mmol) in THF (4 mL) was heated at reflux for 1 hour. The reaction mixture was concentrated in vacuo and the residue was purified on silica gel by flash column chromatography to give the title compound as a colourless glassy solid (97 mg, 77% yield).
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17](Cl)=[O:18])=[CH:13][CH:12]=1>C1(C)C=CC=CC=1>[C:11]1([CH3:20])[CH:16]=[CH:15][C:14]([C:17]([NH:1][C:2]2[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=2)=[O:18])=[CH:13][CH:12]=1
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: Cc1ccc(C(=O)Cl)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)Nc2nc(C(Cl)(Cl)Cl)ns2)cc1

Procedure:
A solution of 11.0 g (0.05 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 8.0 g (0.05 mole) 4-toluoyl chloride in 250 ml toluene was heated at reflux for 20 hours. Unreacted amino compound was removed by cooling the reaction mixture and filtering the precipitate. Concentration of the filtrate in vacuo gave the crude product, which was purified by recrystallization from cyclohexane. Yield was 9.1 g (27%); m.p. 127° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[OH:17])[CH:12]=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:26][CH2:27][CH3:28]>CN(C=O)C.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:14]=[C:15]([I:18])[C:16]=1[O:17][CH2:26][CH2:27][CH3:28])[CH:12]=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCBr
Reactant: O=Cc1cc(I)c(O)c(OCc2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCOc1c(I)cc(C=O)cc1OCc1ccccc1
Temperature: 77.5 °C
Reaction time: 12 h
Yield: 83.1 %

Procedure:
To a mixture of 3-benzyloxy-4-hydroxy-5-iodo benzaldehyde (23.1 g, 0.065 mol) and potassium carbonate (11.70 g, 0.084 mol) in DMF (55 ml) was added 1-bromo propane (12.03 g, 0.09 mol). The reaction mixture was stirred at 75-80° C. for 12 h. The reaction mixture was cooled to room temperature, diluted with water and extracted with ether (480 ml). The ether layer was dried Na2SO4), filtered and concentrated. The crude product was purified on silica gel column using (1:18) EtOAc: light petroleum as eluent to give the 3-benzyloxy-4-propoxy-5-Iodo benzaldehyde (21.4 g, 83%). TLC: Ethyl acetate:light petroleum (1:9), Rf=0.5; 1H NMR (CDCl3, 200 MHz): δ 1.03 (t, J=7.21 Hz, 3H), 1.75 (m, 2H), 4.05 (t, J=6.66 Hz, 2H), 5.15 (s, 2H), 7.3-7.45 (m, 6H), 7.83 (d, J=1.54 Hz, 1H), 9.79 (s, 1H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]=[O:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[C:27]1([Mg]Br)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C1COCC1>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:25][CH3:26])=[CH:20][C:21]([CH:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[OH:24])=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C=O)cc(OC)c21
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3)cc(OC)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 220.3 %

Procedure:
A solution of 150 mg (0.426 mmol) 2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazole-5-carbaldehyde in 2 ml THF is treated with excess phenylmagnesiumbromide (prepared from 112 μl bromobenzene and 26 mg magnesium in 5 ml diethyl ether). The resulting mixture is stirred at room temperature for 1 h. The reaction mixture is poured on water and extracted (3×) with ethyl acetate. The combined organic layers are washed with water (2×) and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by flash-chromatography on silica gel (hexane:EtOAc=1:2) to afford 136 mg of the title compound as a white solid.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][NH:19][CH:18]([CH3:22])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1.[ClH:28].[CH:29](O)=O>C=O>[ClH:28].[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:23])=[C:11]([N:16]4[CH2:21][CH2:20][N:19]([CH3:29])[CH:18]([CH3:22])[CH2:17]4)[C:12]=3[O:14][CH3:15])[C:7](=[O:24])[C:6]([C:25]([OH:27])=[O:26])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: COc1c(N2CCNC(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: O=CO
Agent: C=O
Agent: Cl
Product: COc1c(N2CCN(C)C(C)C2)c(F)cc2c(=O)c(C(=O)O)cn(C3CC3)c12

Procedure:
A solution of 1.5 g (0.004 mole) of 1-cyclopropyl-6-fluoro-8-methoxy-7-(3-methyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (free form) (prepared as described in Example 22, but omitting the final reaction with hydrochloric acid) in a mixture of 75 ml of 90% aqueous formic acid and 45 ml of 37% aqueous formaldehyde was heated under reflux for 15 hours. 8 ml of concentrated hydrochloric acid were then added to the reaction mixture, and the solvent (formic acid, formalin and water) was then removed by evaporation under reduced pressure. Methanol was then added to the residue, and the resulting solution was filtered to remove insoluble material. The filtrate was evaporated to dryness under reduced pressure, and the residue was washed with ethanol to afford 1.35 g of 1-cyclopropyl-6-fluoro-8-methoxy-7-(3,4-dimethyl-1-piperazinyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid hydrochloride as a colorless powder melting at 218°-221° C. (with decomposition).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(Cl)Cl>[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH2:30][N:7]1[CH2:6][CH:5]2[CH2:1][N:2]([C:9]3[N:14]=[CH:13][C:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:11][N:10]=3)[CH2:3][CH:4]2[CH2:8]1
Reactant: O=Cc1ccc2ccccc2c1
Reactant: CCOC(=O)c1cnc(N2CC3CNCC3C2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCOC(=O)c1cnc(N2CC3CN(Cc4ccc5ccccc5c4)CC3C2)nc1
Reaction time: 3 h
Yield: 93.1 %

Procedure:
To a solution of ethyl 2-hexahydropyrrolo[3,4-c]pyrrol-2(1H)-ylpyrimidine-5-carboxylate (0.187 g, 0.71 mmol) in DCE (2 ml) was added 2-naphthaldehyde (0.205 g, 1.31 mmol) and sodium triacetoxyborohydride (0.274 g, 1.25 mmol). The mixture was stirred for 3 h, then poured into DCM (100 ml). Sat. NaHCO3 (100 ml) was added, and extracted with further DCM (100 ml). The combined organic extracts were dried (MgSO4), concentrated and purified by flash column chromatography to yield the title compound (0.266 g, 99%). 1H NMR (300 MHz, CDCl3) δ: 1.39 (3H, t, J=6.9 Hz), 2.59 (2H, d, J=6.9 Hz), 2.73-2.90 (2H, m), 2.94-3.10 (2H, m), 3.67 (2H, d, J=11.7 Hz), 3.82 (2H, s), 3.90 (2H, dd, J=8.1, 12 Hz), 4.37 (2H, q, J=7.2 Hz), 7.41-7.43 (3H, m), 7.74 (1H, s), 7.76-7.89 (3H, m), 8.88 (2H, s).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][C:5]([CH:6]=O)=[C:4]([O:12][CH3:13])[CH:3]=1.[NH:14]1[CH2:18][CH2:17][CH2:16][CH2:15]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].OS([O-])(=O)=O.[Na+]>C(Cl)Cl.O>[CH3:11][O:10][C:9]1[CH:8]=[C:5]([CH2:6][N:14]2[CH2:18][CH2:17][CH2:16][CH2:15]2)[C:4]([O:12][CH3:13])=[CH:3][C:2]=1[OH:1]
Reactant: COc1cc(C=O)c(OC)cc1O
Reactant: C1CCNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: COc1cc(CN2CCCC2)c(OC)cc1O
Yield: 57.5 %

Procedure:
Intermediate 58, 4-Hydroxy-2,5-dimethoxybenzaldehyde (1.2 g, 6.6 mmol) was added in portions for 30 min to a mixture of pyrrolidine (0.7 mL, 8.2 mmol) and NaB(OAc)3H (1.75 g, 8.2 mmol) in CH2Cl2 (20 mL) under vigorous stirring and cooling with an ice bath in an atmosphere of argon. The mixture was stirred for 12 h and cooled with an ice bath. Water (30 mL) and a 5 N solution of NaHSO4 were added to pH 1. The organic layer was separated and discarded. The aqueous one was alkalized with a saturated solution of K2CO3 to pH 6 and subjected to extraction with chloroform (2×50 mL). The combined extracts were dried with Na2SO4 and evaporated to give the title compound (0.9 g, 58%) as a yellow oil. LCMS data: 238.1 (M+H)+ and 168.0, 167.0 (M-pyrrolidine+H) (calculated for C15H23NO 237.3). 1H NMR data (DMSO-d6): 8.88 (br. s, 1H ArOH), 6.84 (s, 1H, Ar—H), 6.45 (s, 1H, Ar—H); 3.69 (s, 3H, —OCH3), 3.659 (s, 3H, —OCH3), 3.47 (s, 2H, —CH2—), 2.37-2.49 (m, 4H, pyrrolidine (CH2)2N), 1.60-1.73 (m, 4H, CH2CH2CH2CH2).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:19]=[C:18]([C:20]4[CH:21]=[N:22][NH:23][CH:24]=4)[N:17]4[CH:25]=[CH:26][N:27]=[C:16]4[CH:15]=3)=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.[CH:28]1([CH:33]=[CH:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1.N1CCCN2CCCCCC=12>CN(C=O)C>[CH:28]1([CH:33]([N:23]2[CH:24]=[C:20]([C:18]3[N:17]4[CH:25]=[CH:26][N:27]=[C:16]4[CH:15]=[C:14]([C:11]4[CH:12]=[CH:13][C:8]([CH:5]5[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]5)=[CH:9][CH:10]=4)[N:19]=3)[CH:21]=[N:22]2)[CH2:34][C:35]#[N:36])[CH2:32][CH2:31][CH2:30][CH2:29]1
Reactant: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cn[nH]c4)n3)cc2)CC1
Reactant: N#CC=CC1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 66 h
Yield: 55.1 %

Procedure:
7-(4-(1-Methylpiperidin-4-yl)phenyl)-5-(1H-pyrazol-4-yl)imidazo[1,2-c]pyrimidine (0.130 g, 0.363 mmol) and 3-cyclopentylacrylonitrile (Table 1, compound g; 0.220 g, 1.81 mmol) were suspended in DMF (10 mL) and 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine (0.2169 mL, 1.451 mmol) added in one portion. The reaction mixture was stirred at ambient temperature for 66 hours. The reaction mixture was partitioned between saturated aqueous 1 N NaOH and EtOAc. The organics were washed with brine, dried over MgSO4 and concentrated under reduced pressure to afford the crude material, which was purified by flash column chromatography (eluant: 2-6% (9:1, MeOH:NH4OH)/DCM) to furnish 3-cyclopentyl-3-(4-(7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (0.096 g, 0.200 mmol, 55.19% yield). MS (apci) m/z=480.3 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1Cl)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2.[NH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1.CN1C(=O)CCC1>O>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[C:10]([C:11]=1[N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:9][C:8]([C:13]([O:15][CH3:16])=[O:14])=[CH:7][CH:6]=2
Reactant: COC(=O)c1ccc2ncc(Cl)c(Cl)c2c1
Reactant: C1CCNC1
Solvent: CN1CCCC1=O
Solvent: O
Product: COC(=O)c1ccc2ncc(Cl)c(N3CCCC3)c2c1
Temperature: 180 °C
Reaction time: 0.17 h
Yield: 35.2 %

Procedure:
A mixture of methyl 3,4-dichloroquinoline-6-carboxylate (100 mg), pyrrolidine (33 mg), and NMP (2 mL) was heated under stirring at 180° C. for 10 minutes under microwave irradiation. The reaction mixture was diluted with water, and extracted with ethyl acetate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified under silica gel column chromatography (hexane/ethyl acetate) to obtain methyl 3-chloro-4-(pyrrolidin-1-yl)quinoline-6-carboxylate (40 mg).
Reaction SMILES: [S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH2:20][CH3:21])=[O:18])[CH:12]=2)[C:7]([OH:9])=[O:8])[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2.C1C=CC2N(O)N=NC=2C=1.C1CCC(N=C=NC2CCCCC2)CC1.[N:51]12[CH2:58][CH2:57][CH:54]([CH2:55][CH2:56]1)[C@@H:53](O)[CH2:52]2>C1COCC1>[S:1]1[CH:5]=[C:4]([CH:6]([NH:10][C:11]2[CH:12]=[C:13]([CH:14]=[CH:15][CH:16]=2)[C:17]([O:19][CH2:20][CH3:21])=[O:18])[C:7](=[O:9])[O:8][C@@H:53]2[CH:54]3[CH2:57][CH2:58][N:51]([CH2:56][CH2:55]3)[CH2:52]2)[C:3]2[CH:22]=[CH:23][CH:24]=[CH:25][C:2]1=2
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CCOC(=O)c1cccc(NC(C(=O)O)c2csc3ccccc23)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(C(=O)O[C@H]2CN3CCC2CC3)c2csc3ccccc23)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17 %

Procedure:
2-(Benzo[b]thiophen-3-yl)-2-(3-(ethoxycarbonyl)phenylamino)acetic acid (I49) (998 mg, 2.81 mmol), HOBT (430 mg, 2.81 mmol), and DCC (1159 mg, 5.62 mmol) were dissolved in THF (28 ml). The mixture was stirred at r.t. for 30 minutes, and then (R)-quinuclidin-3-ol (714 mg, 5.62 mmol) was added. The resulting reaction mixture was stirred at r.t. overnight. The solvent was evaporated, and the crude product was partitioned between EtOAc and sat. Na2CO3. The organic phase was dried over sodium sulfate, filtered and evaporated to dryness. The crude product was purified by flash chromatography (DCM/MeOH=95/5) to collect ethyl 3-(1-(benzo[b]thiophen-3-yl)-2-oxo-2-((R)-quinuclidin-3-yloxy)ethylamino)benzoate (222 mg, 17.0% yield over two steps).
Reaction SMILES: Cl[C:2]1[N:13]=[CH:12][CH:11]=[CH:10][C:3]=1[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5].[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(O)CO>[C:15]1([NH:14][C:2]2[N:13]=[CH:12][CH:11]=[CH:10][C:3]=2[C:4]([NH:6][CH2:7][C:8]#[CH:9])=[O:5])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: C#CCNC(=O)c1cccnc1Cl
Solvent: OCCO
Product: C#CCNC(=O)c1cccnc1Nc1ccccc1
Temperature: 140 °C

Procedure:
Compound 8 (194 mg, 1 mmol) and aniline (9a, 93 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide 10a as pure product. To a solution of 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide (10a, 150 mg, 0.59 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 147 mg, 0.65 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product as solid (210 mg, 74%); mp: 124-126° C.; 1H NMR (300 MHz, CDCl3) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.66-7.60 (m, 3H), 7.33-7.25 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 7.00-6.90 (m, 7H), 6.61-6.59 (m, 1H), 5.45 (s, 2H), 4.62 ppm (d, J=5.2 Hz, 2H); MS (ESI m/z): 477 [M+H]+. Yield: 74%
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH2:13][P:14]([O:19]CC)([O:16]CC)=[O:15])[C:5]=2[N:6]=1.C[Si](Br)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([Br:11])[CH:8]=[C:7]([O:12][CH2:13][P:14]([OH:19])([OH:16])=[O:15])[C:5]=2[N:6]=1
Reactant: CCOP(=O)(COc1cc(Br)cc2sc(N)nc12)OCC
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Product: Nc1nc2c(OCP(=O)(O)O)cc(Br)cc2s1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-amino-4-diethylphosphonomethyloxy-6-bromobenzothiazole (1 mmole) in CH2Cl2 (4 mL) was treated with TMSBr (10 mmole) at 0° C. After stirred for 8 h at room temperature the reaction was evaporated to dryness and the residue was taken into water (5 mL). The resulting precipitate was collected via filtration and washed with water to give 2-amino-4-phosphonomethyloxy-6-bromobenzothiazole (27.1) as white solid. mp>220° C. (dec.). Anal. calcd. for C8H8N2O4PSBr: C: 28.34; H: 2.38; N: 8.26. Found: C: 28.32; H: 2.24; N: 8.06.
Reaction SMILES: N[C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([Cl:11])=[C:7]([Cl:12])[C:5]=2[N:6]=1.Cl.N([O-])=[O:15].[Na+]>O>[Cl:12][C:7]1[C:5]2[NH:6][C:2](=[O:15])[S:3][C:4]=2[CH:10]=[CH:9][C:8]=1[Cl:11]
Reactant: O=N[O-]
Reactant: Nc1nc2c(Cl)c(Cl)ccc2s1
Agent: Cl
Agent: [Na+]
Solvent: O
Product: O=c1[nH]c2c(Cl)c(Cl)ccc2s1
Temperature: 50 °C
Reaction time: 0.5 h
Yield: 81.8 %

Procedure:
33 g of 2-amino-4,5-dichlorobenzothiazole, 241 g of 30% hydrochloric acid and 33.9 g of water are introduced into a 750 ml pressure vessel at room temperature and subsequently heated to 50° C. After the mixture has been stirred for 30 minutes, 58.3 g of aqueous, 40% sodium nitrite solution are metered in at a uniform rate in the course of 3 hours at 50° C., with vigorous stirring. After metering in has ended, stirring is continued for 4 hours at 50° C. Excess nitrite is then removed by adding approximately 15 g of 18% aqueous urea solution. The reaction vessel is subsequently sealed, and the reaction mixture is heated for 4 hours at 140°-150° C. (pressure approximately 6 bar). After the mixture has cooled to 20° C., the crystalline product is filtered off with suction, washed with water and dried at 60° C. to constant weight. 27.9 g of 4,5-dichlorobenzothiazol-2-one with a pure substance content of 97.2% are obtained (corresponding to 81.8% yield) with a DSC melting point of 229.1° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1)[CH3:9].Cl.O>N1C=CC=CC=1>[CH2:8]([O:10][C:11](=[O:23])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19](=[O:20])(=[O:21])[NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=2)=[CH:15][CH:14]=1)[CH3:9]
Reactant: Nc1ccccn1
Reactant: CCOC(=O)Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: CCOC(=O)Cc1ccc(S(=O)(=O)Nc2ccccn2)cc1
Temperature: 25 °C
Yield: 27 %

Procedure:
A stirred solution of 2-aminopyridine (282 mg, 3.0 mmol) in dry pyridine (5.0 mL) was treated with (4-chlorosulfonyl-phenyl)-acetic acid ethyl ester (prepared according to the procedure of Kawashima et. al, as described in Chem. Pharm. Bull. 1995, 43(7), 1132) dropwise at 0–5° C. under argon. Upon completion of addition, the reaction was slowly warmed to 25° C. The reaction was stirred at 25° C. until no starting materials remained. At this time, the reaction was cooled to 0° C. and was acidified to pH=5 with a 1.0M aqueous hydrochloric acid solution. The reaction mixture was poured into water and was extracted with ethyl acetate. The combined organic extracts were washed with water and a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 3/97 methanol/methylene chloride) afforded [4-(pyridin-2-ylsulfamoyl)-phenyl]-acetic acid ethyl ester (0.26 g, 27%) as a colorless solid; 1H NMR (CDCl3, 300 MHz) δH 13.67 (broad s, 1H), 8.30 (dd, J=5.9, 1.1 Hz, 1H), 7.86 (d, J=8.4 Hz, 2H), 7.65 (tt, J=8.1, 1.7 Hz, 1H), 7.50–7.30 (m, 3H), 6.77 (t, J=6.3 Hz, 1H), 4.12 (q, J=7.0 Hz, 2H), 3.63 (s, 2H), 1.22 (t, J=7.0 Hz, 3H); LRMS for C15H16N2O4S (M+H)+ at m/z=321.
Reaction SMILES: [OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[C:11]([C:14]#[N:15])[C:12]#[N:13])[CH:6]=1)([CH3:4])[CH3:3].C[Mg]Br.Cl>O1CCOCC1.O1CCCC1.[Cu]I>[OH:1][C:2]([C:5]1[O:9][N:8]=[C:7]([CH2:10][CH:11]([C:12]#[N:13])[C:14]#[N:15])[CH:6]=1)([CH3:4])[CH3:3]
Reactant: CC(C)(O)c1cc(C=C(C#N)C#N)no1
Agent: [Cu]I
Agent: C[Mg]Br
Agent: Cl
Solvent: C1CCOC1
Solvent: C1COCCO1
Product: CC(C)(O)c1cc(CC(C#N)C#N)no1
Reaction time: 1 h
Yield: 51.5 %

Procedure:
1.02 g of {[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methylidene}malononitrile was dissolved in 50 ml of 1,4-dioxane. Thereto, 0.05 g of copper(I) iodide was added and 9 ml of a 1.4 M solution of methylmagnesium bromide in tetrahydrofuran was then added under ice-cooling. The mixture was stirred for 1 hour under ice-cooling. The reaction mixture was added to 0.1 M hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.53 g of {1-[5-(1-hydroxy-1-methylethyl)-isoxazol-3-yl]methyl}malononitrile.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]=[C:4]([CH:9]([CH:13]2[CH2:15][CH2:14]2)[C:10]([NH2:12])=[O:11])[C:3]=1[O:16][CH3:17].Cl[C:19](Cl)([O:21]C(=O)OC(Cl)(Cl)Cl)Cl>>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][N:5]2[C:19](=[O:21])[NH:12][C:10](=[O:11])[C:9]([CH:13]3[CH2:14][CH2:15]3)=[C:4]2[C:3]=1[O:16][CH3:17]
Reactant: COc1c(C(C(N)=O)C2CC2)ncc(F)c1Cl
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Product: COc1c(Cl)c(F)cn2c(=O)[nH]c(=O)c(C3CC3)c12
Yield: 15.5 %

Procedure:
The title compound (0.15 g) was prepared from (4-chloro-5-fluoro-3-methoxypyridin-2-yl)cyclopropylacetamide (0.88 g, 3.40 mmol [Example 10]) and triphosgene (2.10 g, 7.20 mmol) using a similar procedure to that of Example 2. 1H NMR (400 MHz, CDCl3) δ 9.12 (bs, 1H), 8.13 (d, 1H), 3.82 (s, 3H), 1.33-1.24 (m, 1H), 1.05-0.98 (m, 2H), 0.71-0.60 (m, 2H). MSCI: m/z 285 (MH+).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([O:7][C:8]2[N:16]=[CH:15][CH:14]=[CH:13][C:9]=2[C:10]([OH:12])=O)[CH:2]=1.S(Cl)(Cl)=O.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH2:28])=[CH:23][CH:22]=1>>[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][NH:28][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[N:16][C:8]=2[O:7][C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:23][CH:22]=1
Reactant: O=C(O)c1cccnc1Oc1cccnc1
Reactant: NCc1ccncc1
Solvent: O=S(Cl)Cl
Product: O=C(NCc1ccncc1)c1cccnc1Oc1cccnc1
Temperature: 25 °C

Procedure:
A solution of 2-(Pyridin-3-yloxy)-nicotinic acid (0.0664 grams, 0.31 mmole) in thionyl chloride (1.12 ml, 15.4 mmole) was heated to 50° C. After 1.5 hours the reaction mixture was cooled to room temperature and concentrated under reduced pressure. Pyridine (2.5 ml) was added followed by C-Pyridin-4-yl-methylamine (47 μl, 0.47 mmole) at room temperature. After 2 hours the mixture was concentrated to remove pyridine. The crude product was purified by chromatography on silica gel eluting with 9/1 ethyl acetate/methanol to give a solid. (0.0331 g). M.P. 142-144° C.; Anal. calcd. for C17H14N4O2: C, 66.66; H, 4.61; N, 18.29. Found: C, 66.40; H, 4.56; N, 17.94.