Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5].[BrH:20].OO>>[NH2:1][C:2]1[C:18]([CH3:19])=[CH:17][C:16]([Br:20])=[CH:15][C:3]=1[C:4]([O:6][CH2:7][CH:8]([CH2:13][CH3:14])[CH2:9][CH2:10][CH2:11][CH3:12])=[O:5]
Reactant: CCCCC(CC)COC(=O)c1cccc(C)c1N
Reactant: Br
Agent: OO
Product: CCCCC(CC)COC(=O)c1cc(Br)cc(C)c1N
Yield: 98.6 %

Procedure:
The above-described method (Example 1) was repeated to react 2-ethylhexyl 2-amino-3-methylbenzoate (3.00 g, 10.6 mmol) with hydrogen bromide (2.33 g, 13 8 mmol, 48% in water) and hydrogen peroxide (1.81 g, 15.9 mmol, 30% in water). Following working up similar to Example 1 and additional column chromatography, 2-ethylhexyl 2-amino-5-bromo-3-methylbenzoate (2.7 g, 74.0% of theory, >99 area % LC) was obtained as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[CH:12]N(C)C)[CH:10]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:17][C:18]([NH2:20])=[NH:19].[H-].[Na+].O>CN1CCCC1=O>[CH2:1]([O:8][C:9]1[CH:10]=[N:19][C:18]([NH2:20])=[N:17][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N=C(N)N
Reactant: CN(C)C=C(C=O)OCc1ccccc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Nc1ncc(OCc2ccccc2)cn1
Yield: 65.5 %

Procedure:
2-(Benzyloxy)-3-(dimethylamino)acrylaldehyde (10.9 g, 53 mmol) was dissolved in N-methylpyrrolidone (85 mL), the solution was added with guanidine hydrochloride (15.3 g, 160 mmol), and then the mixture was added with sodium hydride (50% in oil, 15.3 g, 320 mmol) with stirring on an ice bath, and stirred on an oil bath at 80° C. for 1 hour. The reaction mixture was added with water on an ice bath to decompose excessive sodium hydride, and then extracted with ether and water, and the organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:acetone=10:1→4:1→2:1→1:1), and the eluate was concentrated under reduced pressure. Then, the resulting residue was washed with ether-hexane, and taken by filtration to obtain 5-(benzyloxy)pyrimidin-2-amine (6.99 g, 65%) as a pale yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.CO[CH:11](OC)[N:12]([CH3:14])[CH3:13]>C1(C)C=CC=CC=1>[CH3:11][N:12]([CH:14]=[C:4]1[C:5](=[O:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]1)[CH3:13]
Reactant: CN1CCC(=O)CC1
Reactant: COC(OC)N(C)C
Solvent: Cc1ccccc1
Product: CN(C)C=C1CN(C)CCC1=O

Procedure:
To a solution of 1-methylpiperidin-4-one (10 g, 88 mmol) in toluene (100 mL) was added 1,1-dimethoxy-N,N-dimethylmethanamine (52.7 g, 0.442 mol). The solution was heated to reflux overnight. The solvents were evaporated in vacuo, heptane (100 ml) was added and the solvents evaporated again to give the desired product. NMR indicated that the product was 70-80% pure and it was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:22][C:23]#[N:24])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1.Cl.[NH2:26][OH:27].C(=O)([O-])[O-].[Na+].[Na+]>O.CN(C=O)C>[Cl:1][C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]=[C:13]([CH2:22][C:23]([NH:26][OH:27])=[NH:24])[N:14]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[Cl:21])[C:5]=3[C:4]=2[CH:3]=1
Reactant: N#CCc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(Cc1nc2cnc3ccc(Cl)cc3c2n1-c1ccccc1Cl)NO

Procedure:
The title compound is prepared in analogy to Example 86, starting from 500 mg (1.415 mmol) of [8-chloro-1-(2-chloro-phenyl)-1H-imidazo[4,5-]quinolin-2-yl]-acetonitrile (Example 85), 590 mg (8.5 mmol) hydroxylamin hydrochloride, 495 mg (4.67 mmol) sodium carbonate in 2.8 ml water and 11.5 ml DMF. mp: 114° C.; MS: 386 (M++1); HPLC: tret=70.40 min (Grad 1).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26](Br)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1.[CH3:31][O:32][C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.C(OCC)(=O)C.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>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9](=[O:30])[CH2:10][C:11]1([C:24]2[S:25][C:26]([C:36]3[CH:37]=[CH:38][C:33]([O:32][CH3:31])=[CH:34][CH:35]=3)=[CH:27][CH:28]=2)[S:17](=[O:19])(=[O:18])[CH2:16][CH2:15][N:14]([S:20]([CH3:23])(=[O:22])=[O:21])[CH2:13][CH2:12]1
Reactant: COc1ccc(B(O)O)cc1
Reactant: CS(=O)(=O)N1CCC(CC(=O)NOC2CCCCO2)(c2ccc(Br)s2)S(=O)(=O)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: CCOC(C)=O
Solvent: COCCOC
Product: COc1ccc(-c2ccc(C3(CC(=O)NOC4CCCCO4)CCN(S(C)(=O)=O)CCS3(=O)=O)s2)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 61.9 %

Procedure:
A mixture of N-(2-tetrahydropyranyloxy)-2-[7-(5-bromo-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (200 mg), 4-methoxyphenylboronic acid (83.6 mg) and tetrakis(triphenylphosphine)palladium(0) (21.2 mg) in a mixture of 1,2-dimethoxyethane (2 ml) and aqueous 2M sodium carbonate (0.75 ml) was stirred for 2 hours at 80° C. After cooling to room temperature, the mixture was diluted with ethyl acetate, washed with aqueous saturated sodium bicarbonate and brine, dried over sodium sulfate and concentrated in vacuo. The obtained residue was purified with silica gel column chromatography (eluent; 0.5-3% methanol in chloroform) to give N-(2-tetrahydropyranyloxy)-2-[7-(5-(4-methoxyphenyl)-2-thienyl)-4-methanesulfonyl-1,1-dioxoperhydro-1,4-thiazepin-7-yl]acetamide (130 mg) as an amorphous powder.
Reaction SMILES: [CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH:18]=[C:17]([C:24]4[CH:29]=[CH:28][C:27](N5CCOCC5)=[CH:26][CH:25]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:36](O)[CH3:37]>>[CH:1]1([CH:6]([N:10]2[CH:14]=[C:13]([C:15]3[N:20]4[CH:21]=[CH:22][N:23]=[C:19]4[CH:18]=[C:17]([C:24]4[CH:25]=[CH:26][C:27]([CH:37]5[CH2:36][CH2:15][N:20]([CH3:21])[CH2:19][CH2:18]5)=[CH:28][CH:29]=4)[N:16]=3)[CH:12]=[N:11]2)[CH2:7][C:8]#[N:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: N#CCC(C1CCCC1)n1cc(-c2nc(-c3ccc(N4CCOCC4)cc3)cc3nccn23)cn1
Reactant: CCO
Product: CN1CCC(c2ccc(-c3cc4nccn4c(-c4cnn(C(CC#N)C5CCCC5)c4)n3)cc2)CC1
Yield: 33 %

Procedure:
3-Cyclopentyl-3-(4-(7-(4-morpholinophenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (Example 113; 0.015 g, 0.032 mmol) was separated by chiral HPLC (Chiral Tech. OD-H, 2.2 cm×250 mm; 220 nm, 21 mL/min; 50% Ethanol: 50% Hexanes). Peak 2 was isolated to afford the single Enantiomer 2 of 3-cyclopentyl-3-(4-(7-(4-(1-methylpiperidin-4-yl)phenyl)imidazo[1,2-c]pyrimidin-5-yl)-1H-pyrazol-1-yl)propanenitrile (5.0 mg, 33% yield). MS (apci) m/z=468.2 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:10])=[C:6]([CH:9]=1)[CH:7]=[O:8].C([O-])([O-])=O.[K+].[K+].Br[CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22].O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH2:18][CH2:19][O:20][Si:21]([C:24]([CH3:27])([CH3:26])[CH3:25])([CH3:23])[CH3:22])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: O=Cc1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCOc1ccc(Br)cc1C=O
Temperature: 60 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a solution of 5-bromo-2-hydroxy-benzaldehyde (14 g, 69.6 mmol) (Aldrich) in N,N-dimethylformamide (300 mL) was added K2CO3 (29 g, 208.9 mmol) and (2-bromo-ethoxy)-tert-butyl-dimethyl-silane (20 g, 83.5 mmol) (Aldrich). The reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water, extracted with ethyl acetate. The organic layers were combined, washed with water, brine, dried over MgSO4, filtered and concentrated to give 5-bromo-2-[2-(tert-butyl-dimethyl-silanyloxy)-ethoxy]-benzaldehyde as brown oil (Yield: 25 g, 100%).
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.Cl.[C:12]([NH:16][NH2:17])([CH3:15])([CH3:14])[CH3:13].[CH2:18](N(CC)CC)C>C(O)C>[C:12]([N:16]1[C:9]([NH2:10])=[C:6]([C:7]#[N:8])[C:4]([CH2:5][CH3:18])=[N:17]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CCN(CC)CC
Reactant: CC(C)(C)NN
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Solvent: CCO
Product: CCc1nn(C(C)(C)C)c(N)c1C#N
Temperature: 25 °C
Yield: 98.3 %

Procedure:
A mixture of 1-ethoxyethylidene malononitrile (60.0 g, 0.4 mol), tert-butylhydrazine hydrochloride (50.0 g, 0.4 mol) and ethanol (500 ml) was heated to reflux. The heat was removed and triethylamine (55.8 ml, 0.4 mol) was added dropwise at such a rate as to maintain a gentle reflux. The reaction mixture was refluxed for an additional 1 hour, cooled to room temperature and the solvent was removed in vacuo. The residue was taken up in ethyl acetate (300 ml) and washed with water (200 ml). The organic layer was separated, washed with brine and dried over sodium sulfate. The solvent was removed in vacuo to afford 75.6 g (67%) of 1-tert-butyl-3-ethyl-5-amino-1H-pyrazole-4-carbonitrile.
Reaction SMILES: [CH3:1][N:2]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=S)[NH2:26])=[CH:21][CH:20]=1)[NH:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5].[I:29]C.C([O-])(=O)C.[NH4+:35].CO>CC(C)=O.ClCCl>[IH:29].[CH3:1][N:2]([C:18](=[O:28])[C:19]1[CH:24]=[CH:23][C:22]([C:25](=[NH:35])[NH2:26])=[CH:21][CH:20]=1)[NH:3][C:4]([C:6]1[CH:17]=[CH:16][C:9]([O:10][CH2:11][C:12]([O:14][CH3:15])=[O:13])=[CH:8][CH:7]=1)=[O:5]
Reactant: [NH4+]
Reactant: COC(=O)COc1ccc(C(=O)NN(C)C(=O)c2ccc(C(N)=S)cc2)cc1
Reactant: CI
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CO
Solvent: CC(C)=O
Product: COC(=O)COc1ccc(C(=O)NN(C)C(=O)c2ccc(C(=N)N)cc2)cc1
Product: I

Procedure:
In a similar manner to Example 12, methyl 4-[3-methyl-3-(4-thio-carbamoylbenzoyl) carbazoyl]phenoxyacetate (2 g) was reacted with iodomethane (15 ml) in acetone (200 ml) and the resultant product was treated with ammonium acetate (5 g), methanol (150 ml) and dichloromethane (150 ml). This yielded a crude yellow solid, which was triturated with methanol/dichloromethane, rather than crystallised, to give the title compound (800 mg) as a pale yellow hydroiodide salt; m.p. 208° C. (decomposes); NMR Spectrum (DMSO--d6) 3.15-3.30 (3H, br), 3.70 (3H, s), 4.86 (2H, s), 6.97 (2H, d), 7.63 (2H, d), 7.67-7.80 (4H, m), 8.70-9.20 (4H, br s); Mass Spectrum m/Z 385 (M+H)+ ; Elemental Analysis: calculated for C19H20N4O5. 1.0 HI. 1.0 H2O: C, 43.0%; H, 4.4%; N, 10.6%; found: C, 43.4%; H, 4.5%; N, 10.1%.
Reaction SMILES: [Cl:1][C:2]1[CH:44]=[C:43]([CH3:45])[CH:42]=[C:41]([Cl:46])[C:3]=1[O:4][CH2:5][CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH:15]([C:25]2[CH:30]=[CH:29][C:28](B3OC(C)(C)C(C)(C)O3)=[CH:27][C:26]=2[CH3:40])[CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:10][CH:9]=1.[C:47](#[N:50])[CH2:48][CH3:49]>>[C:20]([O:19][C:18](=[O:24])[NH:17][CH2:16][CH:15]([C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:44]=[CH:43][CH:42]=[CH:41][C:3]=2[CH2:49][CH2:48][C:47]#[N:50])=[CH:27][C:26]=1[CH3:40])[CH2:14][C:11]1[CH:10]=[CH:9][C:8]([O:7][CH2:6][CH2:5][O:4][C:3]2[C:41]([Cl:46])=[CH:42][C:43]([CH3:45])=[CH:44][C:2]=2[Cl:1])=[CH:13][CH:12]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CCC#N
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(B4OC(C)(C)C(C)(C)O4)cc3C)cc2)c(Cl)c1
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)c3ccc(-c4ccccc4CCC#N)cc3C)cc2)c(Cl)c1

Procedure:
Prepared according to the procedure described in EXAMPLE 7, step 2 using tert-butyl {3-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]phenyl}-2-[2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propyl}carbamate from EXAMPLE 9, step 1 and 342-bromophenyl)propanenitrile (V.6) as starting materials. Purification by column chromatography on silica gel (Combi-Flash by ISCO), eluting with Hex/EtOAc (0 to 75% in 30 min) afforded the desired compound as a colorless oil.
Reaction SMILES: [H-].[Na+].[CH3:3][S:4][CH2:5][CH2:6][CH2:7][OH:8].C(S[C:13]1[N:14]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:27][CH:26]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:17]=2[N:18]=1)CC.O>O1CCCC1>[CH3:3][S:4][CH2:5][CH2:6][CH2:7][O:8][C:13]1[N:14]([C:25]2[CH:26]=[CH:27][C:28]([O:31][CH2:32][C:33]([F:36])([F:35])[F:34])=[CH:29][CH:30]=2)[C:15](=[O:24])[C:16]2[CH:22]=[CH:21][C:20](=[O:23])[NH:19][C:17]=2[N:18]=1
Reactant: CSCCCO
Reactant: CCCSc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CSCCCOc1nc2[nH]c(=O)ccc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a suspension of sodium hydride (60% in oil, 48 mg) in tetrahydrofuran (5 ml) was added 3-(methylsulfanyl)propan-1-ol (0.206 ml) at room temperature, and the mixture was stirred at room temperature for 10 min. To the reaction mixture was added 2-(propylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrido[2,3-d]pyrimidine-4,7(3H,8H)-dione (165 mg), and the mixture was stirred at room temperature for 5 hr. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (acetic acid ethyl/hexane) to give the title compound (96 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([OH:6])=[O:5].[C:12]([O-])([O-])=O.[K+].[K+].CI>CC(C)=O>[OH:1][CH2:2][C:3]([CH2:10][OH:11])([CH2:7][CH:8]=[CH2:9])[C:4]([O:6][CH3:12])=[O:5]
Reactant: O=C([O-])[O-]
Reactant: C=CCC(CO)(CO)C(=O)O
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: C=CCC(CO)(CO)C(=O)OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 23.2 %

Procedure:
A mixture of crude 2,2-bis(hydroxymethyl)pent-4-enoic acid (1 eq., 8.72 g), K2CO3 (3 eq., 22.9 g) and acetone (109 ml) was stirred at room temperature for 30 min. MeI (6 eq., 46.4 g) was added at 0° C. The mixture was stirred at room temperature for 2 days and concentrated. Water and EtOAc were added. The aqueous layer was extracted with 3×EtOAc. The organic layers were dried over MgSO4. Silica gel chromatography using 4-40% ACN (containing 5% MeOH)-DCM yields the title compound as colorless oil (2.2 g, 23% for two steps).
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]1.CN1CCOCC1.F[C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1.O>CN(C)C=O>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([N:2]2[CH2:5][CH:4]([C:6]([O:8][CH3:9])=[O:7])[CH2:3]2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: COC(=O)C1CNC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)C1CN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of methyl azetidine-3-carboxylate hydrochloride (1.236 g, 8.15 mmol) and N-methylmorpholine (2.338 ml, 21.26 mmol) in dimethylformamide (10 mL) was treated with a solution of 1-fluoro-4-nitrobenzene (1 g, 7.09 mmol) in dimethylformamide (7 mL) and the reaction was allowed to stir at room temperature for 60 hours. Water (50 mL) was added and the resulting suspension was stirred 10 minutes and filtered. The collected solid was washed with water and dried under vacuum. Flash chromatography of the collected solid provided the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:14]([O-])=O)=[C:6]([CH:13]=1)/[CH:7]=[CH:8]/[C:9]([O:11]C)=[O:10].[Cl-].[NH4+:18].[CH2:19]([OH:21])[CH3:20]>[Fe].O>[Cl:1][C:2]1[CH:13]=[C:6]2[C:5](=[CH:4][CH:3]=1)[NH:14][C:20]([C:19]([C:8]1[CH:7]=[C:6]([CH3:13])[CH:5]=[CH:4][N:18]=1)=[O:21])=[C:7]2[CH2:8][C:9]([OH:11])=[O:10]
Reactant: CCO
Reactant: [NH4+]
Reactant: COC(=O)/C=C/c1cc(Cl)ccc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Solvent: O
Product: Cc1ccnc(C(=O)c2[nH]c3ccc(Cl)cc3c2CC(=O)O)c1
Yield: 98 %

Procedure:
A mixture of methyl trans-5-chloro-2-nitrocinnamate (step 1, 3.00 g, 12.42 mmol), iron powder (3.65 g, 62.08 mmol), ammonium chloride (332 mg, 6.21 mmol), ethanol (60 ml) and water (10 ml) was heated at reflux temperature for 2 h. The mixture was cooled and filtered through a pad of Celite. The filtrate was concentrated. The residue was diluted with ethyl acetate (200 ml) and washed with water (100 ml×2). After drying (MgSO4), removal of solvent gave 2.57 g (98%) of the title compound as crystals.
Reaction SMILES: [CH:1]1([CH2:5][OH:6])[CH2:4][CH2:3][CH2:2]1.[CH3:7][S:8](Cl)(=[O:10])=[O:9].C(N(CC)CC)C>CCOCC>[CH3:7][S:8]([O:6][CH2:5][CH:1]1[CH2:4][CH2:3][CH2:2]1)(=[O:10])=[O:9]
Reactant: OCC1CCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: CS(=O)(=O)OCC1CCC1
Temperature: 25 °C
Yield: 103.4 %

Procedure:
Cyclobutanemethanol (24.9 g; 0.287 mol) and methanesulfonyl chloride (35.3 g; 0.302 mol) in dry ether (250 ml) was cooled to -20° C. under dry nitrogen. Triethylamine (44 ml; 0.32 mol) was added dropwise over 15 min with external cooling so that the reaction temperature remained below -5° C. The reaction mixture was allowed to warm to room temperature over 1 h and then filtered. The remaining solid was washed with ether. The ether solutions were combined and the ether evaporated, to afford crude cyclobutylmethyl methanesulfonate (48.75 g) as a pale yellow liquid, which was used in the next step without further purification. NMR - d(CDCl3 ; 60 MHz) 1.6-2.9 (7H, m), 3.0 (3H, s) and 4.1 (2H, d, J=7 Hz).
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([SH:7])=[CH:3][CH:2]=1.[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[OH:21])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[C:14]2Cl)(=[O:10])[CH3:9]>CO>[C:8]([C:11]1[CH:12]=[C:13]2[C:18](=[C:19]([CH2:22][CH2:23][CH3:24])[C:20]=1[OH:21])[N:17]=[C:16]([C:25]([O:27][CH3:28])=[O:26])[CH:15]=[C:14]2[S:7][C:4]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:10])[CH3:9]
Reactant: CCCc1c(O)c(C(C)=O)cc2c(Cl)cc(C(=O)OC)nc12
Reactant: Sc1ccccc1
Solvent: CO
Product: CCCc1c(O)c(C(C)=O)cc2c(Sc3ccccc3)cc(C(=O)OC)nc12
Reaction time: 6 h

Procedure:
Phenylthiol (1.87 g) was added to a stirred boiling solution of methyl 6-acetyl-4-chloro-7-hydroxy-8-propyl-quinoline-2-carboxylate (4.97 g) in dry methanol (600 ml) and the solution was boiled for 6 hours. The resulting suspension was cooled and the sub-title compound (2.2 g) filtered off and recrystallised from methanol as yellow needles m.p. 171°-2° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](N(OC)C)=[O:12])=[CH:5]2.[CH2:17]([Li])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].Cl>O1CCCC1.CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11](=[O:12])[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])=[CH:5]2
Reactant: CON(C)C(=O)c1cc2cc(Cl)ccc2[nH]1
Reactant: [Li]CCCCCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCCCC(=O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 1.5 h
Yield: 68 %

Procedure:
To a solution (100 mL) of 5-chloro-N-methoxy-N-methyl-1H-indole-2-carboxamide (9.14 g) synthesized above in tetrahydrofuran was added a 2.3M solution (50.0 mL) of hexyllithium in hexane at −78° C., and the mixture was stirred under nitrogen atmosphere for 1.5 hr. A 2.3M solution (38.3 mL) of hexyllithium in hexane was additionally added, and the mixture was stirred at −78° C. for 2 hr. 1N Hydrochloric acid was added to quench the reaction, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with hexane to give the title object compound (6.90 g, 68%) as a pale-yellow solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1>CCOC(C)=O.CCOCC.Cl.CCOCC>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:32]=[CH:33][CH:34]=1)[O:9][CH2:10][CH2:11][O:12][C:13]1[C:14]([N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:15][CH:16]=[CH:17][N:18]=1
Reactant: COCCOc1cccc(OCCOc2nccnc2N2CCN(C(=O)OC(C)(C)C)CC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COCCOc1cccc(OCCOc2nccnc2N2CCNCC2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
The product obtained in Step 1 above was dissolved in a mixture of EtOAc (18 mL) and ether (9 mL) and 5 M HCl/ether (9 mL) was added. The mixture was stirred at room temperature for 3 h. The precipitated hydrochloride salt was filtered off and washed thoroughly with ether. The hydrochloride was dissolved in EtOAc/MeOH/Et3N (100:40:5) and purified by column chromatography) on silica using NH3-satd. EtOAc/CH3OH (100:15) as eluent. The combined pure fractions were concentrated in vacuo and the resulting oil was dried (˜0.8 torr, room temperature) to give 0.36 g (69%) of the title product. HRMS m/z calcd for C19H26N4O4 (M)+374.1954, found 374.1947.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[N:11]1[C:14](=[O:15])[C:13]([CH3:17])([CH3:16])[NH:12]1)[CH2:8]2.[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21]Br>>[Cl:18][C:19]1[CH:26]=[CH:25][C:24]([Cl:27])=[CH:23][C:20]=1[CH2:21][N:12]1[C:13]([CH3:17])([CH3:16])[C:14](=[O:15])[N:11]1[CH:2]1[CH:3]2[CH2:4][CH:5]3[CH2:6][CH:7]([CH2:8][CH:1]1[CH2:10]3)[CH2:9]2
Reactant: Clc1ccc(Cl)c(CBr)c1
Reactant: CC1(C)NN(C2C3CC4CC(C3)CC2C4)C1=O
Product: CC1(C)C(=O)N(C2C3CC4CC(C3)CC2C4)N1Cc1cc(Cl)ccc1Cl

Procedure:
2-(Adamantan-2-yl)-4,4-dimethyl-1,2-diazetidin-3-one and 2,5-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a white crystalline powder.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1.O.[F:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1B(O)O>COCCOC.C(O)C.C(=O)([O-])[O-].[Na+].[Na+].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>[F:28][C:29]1[CH:30]=[N:31][CH:32]=[CH:33][C:34]=1[C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([C:23]([F:26])([F:25])[F:24])[CH:3]=1
Reactant: OB(O)c1ccncc1F
Reactant: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2C(F)(F)F)sc2ccc(F)cc12
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: O
Solvent: COCCOC
Solvent: CCO
Product: Cc1c(S(=O)(=O)Nc2ccc(-c3ccncc3F)cc2C(F)(F)F)sc2ccc(F)cc12
Yield: 20.1 %

Procedure:
This compound was prepared in analogy to Example 2 starting from 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-trifluoromethyl-phenyl)-amide (0.12 g) and 3-fluoropyridine-4-boronic acid hydrate (0.061 g) in 1,2-dimethoxyethane (1.5 ml), ethanol (0.32 ml) and 2 M aqueous sodium carbonate solution (1.0 ml) with tetrakis(triphenylphosphine)palladium (0.050 g) to obtain the title compound (0.025 g) as a yellowish foam. MS (ISP): 485.3 (M+H)+