Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH3:1].O.C[O:4][C:5]([C:7]1[C:12]([CH3:13])=[C:11]([N+:14]([O-:16])=[O:15])[CH:10]=[CH:9][C:8]=1[S:17](Cl)(=[O:19])=[O:18])=O>O1CCCC1>[CH3:13][C:12]1[C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=[C:8]2[C:7]=1[C:5](=[O:4])[NH:1][S:17]2(=[O:19])=[O:18]
Reactant: N
Reactant: COC(=O)c1c(S(=O)(=O)Cl)ccc([N+](=O)[O-])c1C
Solvent: C1CCOC1
Solvent: O
Product: Cc1c([N+](=O)[O-])ccc2c1C(=O)NS2(=O)=O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
104 ml of 25 percent ammonia solution are initially taken, 100 ml of water are added and a solution of 48.7 g (0.166 mol) of 2-methoxycarbonyl-3-methyl-4-nitrobenzenesulfonyl chloride in 70 ml of tetrahydrofuran is then added dropwise at 10° C. After stirring at 25° C. for three hours, water and THF are removed by concentration on a rotary evaporator, and the residue which remains is stirred with ethyl acetate, filtered off with suction and washed with ethyl acetate. After drying under reduced pressure, 34 g (0.131 mol)=79% of theory of a white solid of m.p.: 312° C. (dec.) are obtained.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[CH2:3][CH2:4][C:5]([CH:7]([C:11]([OH:13])=[O:12])C(O)=O)=[O:6].[C:16]1(C)C=CC(S(O)(=O)=O)=C[CH:17]=1.C(=O)([O-])O.[Na+]>O>[F:15][C:2]([F:1])([F:14])[CH2:3][CH2:4][C:5]([CH2:7][C:11]([O:13][CH2:16][CH3:17])=[O:12])=[O:6]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)C(C(=O)O)C(=O)CCC(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CC(=O)CCC(F)(F)F
Reaction time: 6 h
Yield: 24903.6 %

Procedure:
A mixture of 179 g of the 4,4,4-trifluorobutyrylmalonic acid ditheyl ester thus obtained, 260 ml of water and 322 mg of p-toluenesulfonic acid was refluxed with vigorous stirring for 6 hours. The reaction solution was then poured into saturated aqueous sodium hydrogencarbonate solution and extracted three times with diethyl ether. The ether layers were combined and the combined layer was washed with brine, dried over anhydrous magnesium sulfate. After the drying agent was removed, the solvent was removed under reduced pressure. The obtained residue was distilled inder reduced pressure to yield 98.8 g of the desired ethyl 4,4,4-trifluorobutyrylacetate in a yield of 74%. (b.p. 93°-97° C., 15 mmHg)
Reaction SMILES: C(OC1C=CN(CC(C2C=CC(C[Br:25])=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1.[F:28][C:29]1[CH:30]=[CH:31][C:32]([CH2:35][O:36][C:37]2[CH:42]=[CH:41][N:40]([CH2:43][C:44]([C:46]3[CH:51]=[CH:50][C:49]([CH2:52]O)=[CH:48][C:47]=3[CH3:54])=[O:45])[C:39](=[O:55])[CH:38]=2)=[N:33][CH:34]=1.C(OC1C=CN(CC(C2C=CC(CO)=CC=2C)=O)C(=O)C=1)C1C=CC=CC=1>>[Br:25][CH2:52][C:49]1[CH:50]=[CH:51][C:46]([C:44](=[O:45])[CH2:43][N:40]2[CH:41]=[CH:42][C:37]([O:36][CH2:35][C:32]3[CH:31]=[CH:30][C:29]([F:28])=[CH:34][N:33]=3)=[CH:38][C:39]2=[O:55])=[C:47]([CH3:54])[CH:48]=1
Reactant: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Reactant: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Agent: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Product: Cc1cc(CBr)ccc1C(=O)Cn1ccc(OCc2ccc(F)cn2)cc1=O
Yield: 93 %

Procedure:
1-[2-(4-Bromomethyl-2-methyl-phenyl)-2-oxo-ethyl]-4-(5-fluoro-pyridin-2-ylmethoxy)-1H-pyridin-2-one is prepared following preparation 1d employing 4-(5-fluoro-pyridin-2-ylmethoxy)-1-[2-(4-hydroxymethyl-2-methyl-phenyl)-2-oxo-ethyl]-1H-pyridin-2-one (preparation 2a) instead of preparation 1c.
Reaction SMILES: [CH3:1][NH:2][CH3:3].ClC[CH2:6][C:7]1[CH:8]=[C:9]([C:18]([O:20][CH3:21])=[O:19])[C:10]([C:14]([O:16][CH3:17])=[O:15])=[N:11][C:12]=1Cl>CO>[CH3:1][N:2]1[C:12]2=[N:11][C:10]([C:14]([O:16][CH3:17])=[O:15])=[C:9]([C:18]([O:20][CH3:21])=[O:19])[CH:8]=[C:7]2[CH2:6][CH2:3]1
Reactant: CNC
Reactant: COC(=O)c1cc(CCCl)c(Cl)nc1C(=O)OC
Solvent: CO
Product: COC(=O)c1cc2c(nc1C(=O)OC)N(C)CC2
Temperature: 25 °C
Reaction time: 64 h
Yield: 14 %

Procedure:
Dimethylamine (7.5 g, 166.6 mol) is bubbled into a solution of dimethyl 5-(2-chloroethyl)-6-chloro-2,3-pyridinedicarboxylate (20.0 g, 66mmol) in methanol (400 mL) over three hours. The resulting solution is stirred for 64 hours at room temperature and then four and one-half hours at reflux. After cooling the mixture is concentrated under vacuum and the crude product chromatographed on 250 g silica using 2:1 hexanes:ethyl acetate and then 1:1 hexanes:ethyl acetate as eluant, affording 2.32 g (14%) of dimethyl 1-methyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine-5,6-dicarboxylate, which is recrystallized from methylene chloride/hexanes, having a melting point 132°-133° C.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[OH:6][CH2:7][C:8]1[CH:9]=[C:10]([C:14](=[O:35])/[CH:15]=[CH:16]/[C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[CH:24]/[C:25]([NH:27][O:28][CH:29]3[CH2:34][CH2:33][CH2:32][CH2:31][O:30]3)=[O:26])=[CH:19][CH:18]=2)[CH:11]=[CH:12][CH:13]=1.C([O-])(O)=O.[Na+]>C(Cl)Cl.CN(C=O)C>[O:30]1[CH2:31][CH2:32][CH2:33][CH2:34][CH:29]1[O:28][NH:27][C:25](/[CH:24]=[CH:23]/[C:20]1[CH:21]=[CH:22][C:17](/[CH:16]=[CH:15]/[C:14]([C:10]2[CH:9]=[C:8]([CH:13]=[CH:12][CH:11]=2)[CH2:7][O:6][S:2]([CH3:1])(=[O:4])=[O:3])=[O:35])=[CH:18][CH:19]=1)=[O:26]
Reactant: O=C(/C=C/c1ccc(/C=C/C(=O)c2cccc(CO)c2)cc1)NOC1CCCCO1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)OCc1cccc(C(=O)/C=C/c2ccc(/C=C/C(=O)NOC3CCCCO3)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 46.1 %

Procedure:
Methanesulfonyl chloride (0.41 ml, 5.3 mmol) was added to a stirred solution of (E)-3-{4-[(E)-3-(3-hydroxymethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide (1.08 g, 2.68 mmol) and TEA (1.47 ml, 10.6 mmol) in DCM (18 ml) and DMF (12 ml). The mixture was stirred at room temperature for 30 min and then brought to basic conditions with 5% NaHCO3. The resulting slurry was extracted with Et2O and the organic phase was washed with water, dried over Na2SO4 and evaporated in vacuo. The crude reaction mixture was purified by column chromatography (eluent: petroleum ether/AcOEt 1:1) to give 600 mg of a mixture of the title compound and (E)-3-{4-[(E)-3-(3-chloromethyl-phenyl)-3-oxo-propenyl]-phenyl}-N-(tetrahydro-pyran-2-yloxy)-acrylamide as the main product.
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:6])[C:4]#[CH:5].Br[CH2:8][C:9]([O:11][CH3:12])=[O:10].Cl>O1CCCC1>[CH2:3]([O:6][CH2:8][C:9]([O:11][CH3:12])=[O:10])[C:4]#[CH:5]
Reactant: COC(=O)CBr
Reactant: C#CCO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C#CCOCC(=O)OC
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A mechanically stirred suspension of sodium hydride (60 5% dispersion in mineral oil) (50 g, 1.25 mol) in tetrahydrofuran (800 mL) at 0° C. under nitrogen was treated dropwise with a solution of propargyl alcohol (84 g, 1.5 mol) in tetrahydrofuran (175 mL), stirred at 0° C. for 1 hour, treated with a solution of methyl bromoacetate in tetrahydrofuran (250 mL) over 15 minutes, stirred at 0° C. for 30 minutes, stirred at ambient temperature for 2 hours, and treated with 2M HCl (800 mL). The organic layer was isolated and the aqueous layer was extracted with ethyl acetate (2×, 500 mL). The combined organic layers were washed with brine (200 mL), dreid (MgSO4), filtered, concentrated and distilled (bp 75-85° C. at 20 torr) to provide the title compound (83 g).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.B.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]=[O:27])[CH:17]=[CH:18][CH:19]=1>O1CCCC1>[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([C:2]2[O:1][CH:5]=[CH:4][N:3]=2)[OH:27])[CH:17]=[CH:18][CH:19]=1
Reactant: c1cocn1
Reactant: COc1cccc(CCCCCCC=O)c1
Agent: B
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1cccc(CCCCCCC(O)c2ncco2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.4 %

Procedure:
Under an atmosphere of argon, oxazole (0.0567 g, 0.822 mmol) was taken in dry tetrahydrofuran then treated with a 1 M borane-tetrahydrofuran complex solution (0.896 mL, 0.896 mmol) and allowed to stir for 1 hour at ambient temperature. This clear solution was then cooled to −78° C. and a 2.6 M n-butyllithium solution in hexanes (0.411 mL, 1.07 mmol) was added. Upon addition of the n-butyllithium, the reaction solution changed from a clear solution to a clear yellow or dark green solution indicating lithiation of the borane-complexed oxazole. Stirring continued for 40 minutes before the addition of 7-(3-Methoxyphenyl)heptanal (0.181 g, 0.822 mmol, dissolved in 5 mL tetrahydrofuran). After 2 hours, the reaction solution was allowed to warm to ambient temperature and the reaction was quenched with a 5% solution of acetic acid in ethanol (excess) and stirred for 16 hours. The solvent was removed under reduced pressure and the residue re-dissolved in ethyl acetate. The organic phase was washed with water, saturated sodium bicarbonate, then brine and then dried over sodium sulfate. The solvent was removed under reduced pressure and flash column chromatography with silica gel (20%-50% ethyl acetate:hexanes gradient elution) gave the title compound as a light yellow oil (69%, 0.165 g): 1H NMR (600 MHz, CDCl3) δ 7.57 (s, 1H), 7.18 (t, 1H), 7.02 (s, 1H), 6.75 (d, J=7.8 Hz, 1H), 6.71 (m, 2H), 4.78 (t, 1H), 4.75 (bs, 1H), 3.78 (s, 3H), 2.57 (t, 2H), 1.89-1.91 (m, 2H), 1.57-1.62 (m, 2H), 1.42-1.45 (m, 1H), 1.30-1.40 (m, 5H); 13C NMR (150 MHz, CDCl3) δ 166.21, 159.36, 144.21, 138.49, 128.97, 126.26, 120.65, 113.98, 110.65, 67.11, 54.88, 35.77, 35.17, 31.07, 28.97, 28.94, 24.82.
Reaction SMILES: [C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[C:21](=[CH:22][CH:23]=[C:24](F)[CH:25]=4)[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].IC1C(=O)C2C=CC3C(=[N:54][N:55]([CH:57]([CH3:59])[CH3:58])[CH:56]=3)C=2OC=1C1C=CC=CC=1>>[C:1]([O:5][C:6](=[O:36])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:27](=[O:28])[C:26]4[CH:25]=[CH:24][C:23]5[C:22](=[N:54][N:55]([CH:57]([CH3:59])[CH3:58])[CH:56]=5)[C:21]=4[O:20][C:19]=3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1cc2ccc3c(=O)c(I)c(-c4ccccc4)oc3c2n1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(-c4ccccc4)oc4ccc(F)cc4c3=O)cc2)CCC1
Product: CC(C)n1cc2ccc3c(=O)c(-c4ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc4)c(-c4ccccc4)oc3c2n1
Yield: 85 %

Procedure:
Following the procedure used to prepare {1-[4-(6-fluoro-4-oxo-2-phenyl-4H-chromen-3-yl)-phenyl]-cyclobutyl}-carbamic acid tert-butyl ester, 7-iodo-2-isopropyl-8-phenyl-2H-9-oxa-1,2-diaza-cyclopenta[a]naphthalen-6-one was reacted to give the title compound as a colourless gum (48.3 mg, 85%). LCMS (Method H): RT=4.42 min, [M+H]+=550.
Reaction SMILES: C1(C(C2[C:14]([CH2:15][O:16][CH2:17][C:18]3[C:23](C4C(=CC=C(O)C=4)O)=[CH:22][CH:21]=[CH:20][CH:19]=3)=[CH:13][CH:12]=[CH:11][CH:10]=2)=CC(=CC=1)O)O.[OH-:32].[Na+].Cl[CH:35]([F:37])[F:36]>O.O1CCOCC1>[CH2:17]([O:16][C:15]1[CH:10]=[CH:11][C:12]([O:32][CH:35]([F:37])[F:36])=[CH:13][CH:14]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: FC(F)Cl
Reactant: [OH-]
Reactant: Oc1ccc(O)c(-c2ccccc2COCc2ccccc2-c2cc(O)ccc2O)c1
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)Oc1ccc(OCc2ccccc2)cc1
Temperature: 70 °C

Procedure:
A mixture of 40.0 g of hydroquinone monobenzyl ether, 40 g of NaOH, 200 ml of water and 300 ml of dioxane are heated to 70° C. with stirring. 35.5 g of chlorodifluoromethane are passed into the cooled mixture with vigorous stirring. The reaction mixture is poured into water, and the product is extracted with petroleum ether. The organic phase is dried over Na2SO4, evaporated, and the residue is chromatographed through a short silica gel column, using petroleum ether/ethyl acetate 8:2 as eluent. A colourless liquid is obtained.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.Cl[C:8]1[N:9]=[C:10]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]3[O:26][CH2:27][CH2:28][O:29][C:22]=3[CH:21]=2)[C:11]2[CH:16]=[C:15]([CH3:17])[S:14][C:12]=2[N:13]=1>>[CH3:1][C:2]1[N:3]([C:8]2[N:9]=[C:10]([NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]4[O:26][CH2:27][CH2:28][O:29][C:22]=4[CH:21]=3)[C:11]3[CH:16]=[C:15]([CH3:17])[S:14][C:12]=3[N:13]=2)[CH:4]=[CH:5][N:6]=1
Reactant: Cc1ncc[nH]1
Reactant: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(Cl)nc2s1
Product: Cc1cc2c(NCc3ccc4c(c3)OCCO4)nc(-n3ccnc3C)nc2s1

Procedure:
Following the procedure of Example 97, the reaction of 2-methylimidazole with 2-chloro-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine gives 2-(2-methylimidazol-1-yl)-6-methyl-4-(3,4-ethylendioxybenzylamino)-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[NH2:16][C@@H:17]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[N:30]=2)=[CH:24][CH:23]=1)[C:18]([OH:20])=[O:19]>CS(C)=O>[C:18]([C@@H:17]([NH:16][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:28][C:29]2[CH:38]=[CH:37][C:36]3[C:31](=[CH:32][CH:33]=[C:34]([Cl:39])[CH:35]=3)[N:30]=2)=[CH:26][CH:27]=1)([OH:20])=[O:19]
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Reactant: N[C@@H](Cc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)O
Solvent: CS(C)=O
Product: O=C(O)c1cc2cc(Cl)ccc2nc1N[C@@H](Cc1ccc(Oc2ccc3cc(Cl)ccc3n2)cc1)C(=O)O

Procedure:
In close analogy to the procedure described in Example 109c, 2,6-dichloroquinoline-3-carboxylic acid is reacted with (S)-2-amino-3-[4-(6-chloro-quinolin-2-yloxy)-phenyl]-propionic acid (prepared by analogy to Example 109a,b) in DMSO to provide the title compound in good yield.
Reaction SMILES: [Cl:1][CH:2]1[N:11]=[C:10]([NH:12][C:13]2[NH:14][N:15]=[C:16]([CH:18]3[CH2:20][CH2:19]3)[CH:17]=2)[C:9]2[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=2[NH:3]1.[C:21](OC)(=[O:29])[C:22]1[C:23](=[CH:25][CH:26]=[CH:27][CH:28]=1)[NH2:24].C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>CO.ClCCl.Cl.CO>[ClH:1].[CH:18]1([C:16]2[CH:17]=[C:13]([NH:12][C:10]3[C:9]4[CH2:8][CH2:7][CH2:6][CH2:5][C:4]=4[N:3]4[C:21](=[O:29])[C:22]5[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=5[N:24]=[C:2]4[N:11]=3)[NH:14][N:15]=2)[CH2:20][CH2:19]1
Reactant: COC(=O)c1ccccc1N
Reactant: ClC1N=C(Nc2cc(C3CC3)n[nH]2)C2=C(CCCC2)N1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=c1c2ccccc2nc2nc(Nc3cc(C4CC4)n[nH]3)c3c(n12)CCCC3
Yield: 7.1 %

Procedure:
(2-Chloro-1,2,5,6,7,8-hexahydro-quinazolin-4-yl)-(5-cyclopropyl-2H-pyrazol-3-yl)-amine (150 mg, 0.518 mmol), in methyl anthranilate (0.1 ml, 0.777 mmol) was heated to 135° C. for 4 hours to give a brown gum. This was dissolved in methanol/dichloromethane and added to a mixture of ethyl acetate and aqueous sodium bicarbonate. The mixture was extracted with ethyl acetate and the extracts dried over magnesium sulphate and concentrated. Purification by flash chromatography on silica gel eluting with 4% methanol/dichloromethane gave a pale yellow gum. This was dissolved in 0.5M HCl in methanol and crystallised by the dropwise addition of diethyl ether to give cream coloured crystals of 5-(5-cyclopropyl-2H-pyrazol-3-ylamino)-1,2,3,4-tetrahydro-quinazolino[3,2-a]quinazolin-12-one hydrochloride (15 mg, 7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]([NH2:30])=O)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1.[Si]([N:35]=[N+:36]=[N-:37])(C)(C)C>COCCOC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]3[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:10]=3[C:9]=2[O:19][C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[C:28]3[NH:30][N:37]=[N:36][N:35]=3)=[CH:22][CH:21]=2)=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: COc1ccc2c(Oc3ccc(/C=C/C(N)=O)cc3)c(-c3ccc(F)cc3)sc2c1
Solvent: COCCOC
Product: COc1ccc2c(Oc3ccc(/C=C/c4nnn[nH]4)cc3)c(-c3ccc(F)cc3)sc2c1
Temperature: 180 °C
Yield: 71.4 %

Procedure:
To a microwave vial, (E)-3-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenyl)acrylamide (41 mg, 0.098 mmol) and Bu2SnO (2.433 mg, 9.77 μmol) were suspended in DME (3 mL). The vial was charged with TMSN3 (0.013 mL, 0.098 mmol) and the reaction was heated for 60 min at 180° C. under microwave radiation. The reaction mixture was filtered to remove solids and concentrated onto silica gel. The crude material was purified by column chromatography (SiO2, 1-20% DCM/MeOH) to afford (E)-5-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)styryl)-1H-tetrazole (31 mg, 0.070 mmol, 71.4% yield) as an orange solid. 1H NMR (400 MHz, CD3OD) δ ppm=3.78 (s, 3 H) 6.80-6.91 (m, 3 H) 6.96-7.07 (m, 3 H) 7.19 (d, J=8.59 Hz, 1 H) 7.34 (d, J=2.53 Hz, 1 H) 7.35-7.52 (m, 3 H) 7.58-7.74 (m, 2 H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:23])([CH3:22])[O:21][C:17]=3[C:16]([C:24]([OH:26])=O)=[CH:15][C:13]=2[N:14]=1.S(Cl)(Cl)=O.[F:31][C:32]([C:35]1[CH:36]=[C:37]([CH:39]=[CH:40][CH:41]=1)[NH2:38])([F:34])[CH3:33].CCN(C(C)C)C(C)C>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[NH:9][C:10]1[NH:11][C:12]2[C:18]3[CH2:19][C:20]([CH3:22])([CH3:23])[O:21][C:17]=3[C:16]([C:24]([NH:38][C:37]3[CH:39]=[CH:40][CH:41]=[C:35]([C:32]([F:31])([F:34])[CH3:33])[CH:36]=3)=[O:26])=[CH:15][C:13]=2[N:14]=1
Reactant: CC1(C)Cc2c(c(C(=O)O)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Reactant: CC(F)(F)c1cccc(N)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(C)Cc2c(c(C(=O)Nc3cccc(C(C)(F)F)c3)cc3nc(Nc4c(F)cccc4Cl)[nH]c23)O1
Yield: 6.6 %

Procedure:
The title compound was prepared by following the procedure described for Example-108 using 2-[(2-chloro-6-fluorophenyl)amino]-7,7-dimethyl-7,8-dihydro-1H-furo[3,2-e]benzimidazole-5-carboxylic acid (Intermediate-15, 0.273 g, 0.736 mmol), thionyl chloride (2.0 mL), 3-(1,1-difluoroethyl)aniline (Intermediate-39, 0.120 g, 0.736 mmol), THF (5.0 mL) and DIPEA (3 mL). The obtained crude product was purified by column chromatography on basic alumina eluting with 0.7-1.0% MeOH:DCM to afford 0.025 g of the desired product. 1HNMR (DMSO d6): δ 1.57 (s, 6H), 1.97 (t, J=19.2 Hz, 3H), 3.10 (s, 2H), 7.26-7.32 (m, 3H), 7.35-7.48 (m, 3H), 7.62 (d, J=8.4 Hz, 1H), 8.07 (s, 1H), 9.85 (s, 1H), 11.00 (s, 2H); MS [M−H]−: 513.14.
Reaction SMILES: [Cl:1][C:2]1[C:11](F)=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[C:13]([O:17][C:18](=[O:27])[NH:19][C@H:20]1[CH2:25][CH2:24][C@@H:23]([OH:26])[CH2:22][CH2:21]1)([CH3:16])([CH3:15])[CH3:14]>>[C:13]([O:17][C:18](=[O:27])[NH:19][C@H:20]1[CH2:21][CH2:22][C@@H:23]([O:26][C:11]2[C:2]([Cl:1])=[C:3]3[C:8](=[CH:9][CH:10]=2)[CH:7]=[N:6][CH:5]=[CH:4]3)[CH2:24][CH2:25]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: Fc1ccc2cnccc2c1Cl
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](O)CC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@@H](Oc2ccc3cnccc3c2Cl)CC1

Procedure:
Starting from 5-chloro-6-fluoro-isoquinoline (8) and cis-(4-hydroxy-cyclohexyl)-carbamic acid tert-butyl ester the title compound was prepared by the method described for trans-[4-(5-chloro-isoquinolin-6-yloxy)-cyclohexyl]carbamic acid tert-butyl ester (10), whereas DMF was used as solvent. Rt=1.14 min (Method #4). Detected mass: 377.2/379.2 (M+H+).
Reaction SMILES: [C:1]([N:6]([CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1)[C:7](=[N:10][N+:11]([O-:13])=[O:12])SC)(=[O:5])[CH:2]([CH3:4])[CH3:3].[CH3:21][NH2:22].CO.Cl>ClCCl>[C:1]([N:6]([CH2:14][C:15]1[S:19][C:18]([Cl:20])=[N:17][CH:16]=1)[C:7]([NH:22][CH3:21])=[N:10][N+:11]([O-:13])=[O:12])(=[O:5])[CH:2]([CH3:4])[CH3:3]
Reactant: CSC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)C(C)C
Reactant: CN
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CNC(=N[N+](=O)[O-])N(Cc1cnc(Cl)s1)C(=O)C(C)C
Reaction time: 1 h
Yield: 35.7 %

Procedure:
To a solution of N-iso-butyroyl-N-(2-chloro-5- thiazolylmethyl)-S-methyl-N'-nitroisothiourea (560 mg) in dichloromethane (5 ml) was added 40% methylamine-methanol solution (129 mg) dropwise below -11° C. and the mixture was stirred at the same temperature for 1 hour. To the mixture was added 40% methylamine-methanol solution (64 mg) dropwise below -11° C. and the mixture was stirred at the same temperature for 5.5 hours. After addition of 2N hydrochloric acid (10 ml) under ice-cooling, the mixture was extracted with toluene (5 ml). The organic layer was washed with an aqueous saturated sodium bicarbonate solution, dried over MgSO4 and concentrated in vacuo. The residue was dissolved in toluene. Crystallization by addition of n-hexane gave 190 mg of 1-iso-butyroyl-1-(2-chloro-5-thiazolylmethyl)-3-methyl-2-nitroguanidine (Compound No. 34) as a white crystal, m.p. 101°-104° C.
Reaction SMILES: [CH2:1]([C:8]1[N:9]=[C:10](Cl)[C:11]2[CH2:17][CH2:16][N:15]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:14][CH2:13][C:12]=2[N:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:32][N:33]1[CH:37]=[C:36]([CH2:38][NH2:39])[CH:35]=[N:34]1>CN(C)C(=O)C>[CH2:21]([O:20][C:18]([N:15]1[CH2:16][CH2:17][C:11]2[C:10]([NH:39][CH2:38][C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)=[N:9][C:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[N:23][C:12]=2[CH2:13][CH2:14]1)=[O:19])[CH3:22]
Reactant: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(Cl)c2CC1
Reactant: Cn1cc(CN)cn1
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: CCOC(=O)N1CCc2nc(Cc3ccccc3)nc(NCc3cnn(C)c3)c2CC1

Procedure:
A solution of ethyl 2-benzyl-4-chloro-5,6,8,9-tetrahydro-pyrimido[4,5-d]azepine-7-carboxylate of Step B (50 mg, 0.14 mmol), triethylamine (0.10 ml, 0.72 mmol) and C-(1-Methyl-1H-pyrazol-4-yl)-methylamine (50 mg, 0.45 mmol) in N,N-dimethylacetamide (2.0 ml) was stirred for 18 h at 60° C. The solvent was removed in vacuo and the crude product was deprotected without further purification. LRMS APCI m/z 421 [MH]+.
Reaction SMILES: Cl[C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[C:5]([N+:11]([O-:13])=[O:12])=[CH:4][CH:3]=1.[SH:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].N1C=CC=CC=1>C(O)C.O>[N+:11]([C:5]1[C:6]2=[N:7][O:8][N:9]=[C:10]2[C:2]([S:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:3][CH:4]=1)([O-:13])=[O:12]
Reactant: O=C(O)CCS
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Solvent: O
Solvent: c1ccncc1
Solvent: CCO
Product: O=C(O)CCSc1ccc([N+](=O)[O-])c2nonc12

Procedure:
A solution of 4-chloro-7-nitro-2,1,3-benzoxadiazole (1 mmole) and 3-mercaptopropionic acid (Sigma-Aldrich, Fine Chemicals) (1 mmole) was made to react in 6 ml of ethyl alcohol: water 0.3:1 containing 2.5 mmoles of pyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:10](=[O:12])[CH:11]=1)=O)C.O.[NH2:22][NH2:23]>C(O)C>[O:12]=[C:10]1[N:9]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[N:8]=[CH:7][C:6]([C:4]([NH:22][NH2:23])=[O:3])=[CH:11]1
Reactant: NN
Reactant: CCOC(=O)c1cnn(COCC[Si](C)(C)C)c(=O)c1
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1ncc(C(=O)NN)cc1=O
Temperature: 50 °C
Reaction time: 1 h

Procedure:
The title compound from Example 19.2 (0.85 g, 2.8 mmol) was stirred in ethanol. Hydrazine hydrate (0.720 g, 14.2 mmol) was added to the solution and the reaction was stirred at 50° C. for 1 hour. The reaction was concentrated and triturated with methanol and diethyl ether to produce a precipitate which was collected by vacuum filtration as the title compound (0.56 g, 57%).
Reaction SMILES: Br[C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6].[CH2:12](O)[CH3:13]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[CH:12]([C:2]1[C:3]([CH3:11])=[C:4]([C:7]([F:10])=[CH:8][CH:9]=1)[C:5]#[N:6])=[CH2:13]
Reactant: Cc1c(Br)ccc(F)c1C#N
Reactant: CCO
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Product: C=Cc1ccc(F)c(C#N)c1C

Procedure:
3-Bromo-6-fluoro-2-methylbenzonitrile (23.6 g, 110 mmol), potassium vinyl trifluoroborate (29.5 g, 221 mmol), PdCl2(dppf)-CH2Cl2 Adduct (4.03 g, 5.51 mmol), and TEA (30.7 mL, 221 mmol) were added to 250 mL of ethanol. The reaction mixture was degassed then stirred at reflux for 4 h. LC-MS confirmed the presence of product. The reaction mixture was diluted with ethyl acetate, washed twice with brine, dried, and evaporated to dryness. The crude material was then purified by MPLC chromatography using a 330 g Redi-sep column and eluting with a 10% EtOAc/Hexane solvent system to yield 3-ethenyl-6-fluoro-2-methylbenzonitrile.