Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=3[N:9]=2)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=1.[B-](F)(F)(F)[CH2:26][N:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.[K+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.C(=O)([O-])[O-].[Cs+].[Cs+]>>[N:27]1([CH2:26][C:2]2[CH:7]=[CH:6][C:5]([C:8]3[NH:12][C:11]4[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([O:19][CH3:20])=[O:18])[C:10]=4[N:9]=3)=[C:4]([C:21]([F:24])([F:23])[F:22])[CH:3]=2)[CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: COC(=O)c1cccc2[nH]c(-c3ccc(Cl)cc3C(F)(F)F)nc12
Reactant: F[B-](F)(F)CN1CCCC1
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)c1cccc2[nH]c(-c3ccc(CN4CCCC4)cc3C(F)(F)F)nc12
Temperature: 80 °C

Procedure:
A sealed tube containing the mixture of methyl 2-(4-chloro-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate (390 mg, 1.10 mmol), potassium 1-trifluoroboratom-ethylpyrrolidine (158; 212 mg, 1.11 mmol), Pd (OAc)2 (22 mg, 0.03 mmol), XPhos (31 mg, 0.06 mmol), and cesium carbonate (1.0 g, 3.3 mmol) was evacuated and filled with nitrogen twice. To the mixture was added THF/H2O (10:1, 4.4 mL). The suspension was heated at 80° C. overnight and cooled to room temperature. Water (2 mL) was added and the reaction was extracted with CH2Cl2 twice. The combined organic layers were washed with brine, dried over MgSO4, filtered, and concentrated. Purification by silica gel chromatography (MeOH/CH2Cl2+1% Et3N) afforded methyl 2-(4-(pyrrolidin-1-ylmethyl)-2-(trifluoromethyl)phenyl)-1H-benzo[d]imidazole-4-carboxylate (structure not shown) as a yellow solid (544 mg).
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O.[C:34]([NH:41][C@H:42]([C:45]([OH:47])=[O:46])[CH2:43]O)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].CCOCC>CC#N>[C:37]([O:36][C:34](=[O:35])[NH:41][C@H:42]1[CH2:43][O:47][C:45]1=[O:46])([CH3:38])([CH3:39])[CH3:40]
Reactant: CC(C)(C)OC(=O)N[C@@H](CO)C(=O)O
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@H]1COC1=O
Temperature: -35 °C
Reaction time: 1.5 h

Procedure:
To a stirred solution of dry PPh3 (72 h under vacuum in the presence of P2O5) (5 mmol) in dry CH3CN (31 mL), kept at −50° C. under N2, dimethylazodicarboxylate (5 mmol) and, after 20 min, a solution of 1 (4.47 mmol) in CH3CN (10.4 mL), were added dropwise. The mixture was stirred for 1.5 h at −50/−35° C. and concentrated. Purification of the residue by flash-chromatography (cyclohexane/EtOAc 8:2 to 6:4) gave crude 2, which was finally washed and triturated to afford a white solid. Mp 120-122° C. (Et2O). [α]D20=−27° (c 0.1, CH3CN). 1H NMR is in accordance with literature (Arnold, et al., 1985).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[NH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1>>[CH3:8][O:7][C:5](=[O:6])[C:4]1[CH:9]=[CH:10][CH:11]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:20])([F:21])[F:22])=[CH:15][CH:14]=2)[CH:3]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COC(=O)c1cccc(Br)c1
Product: COC(=O)c1cccc(Nc2ccc(C(F)(F)F)cc2)c1

Procedure:
Reaction of methyl 3-bromobenzoate with 4-aminobenzotrifluoride according to general procedure A provided methyl ester of Compound 7 as a white solid (86% yield). 1H NMR (CDCl3, 500 MHz): δ=7.82 (s, 1H), 7.71 (d, J=7.6 Hz, 1H), 7.50 (d, J=8.4 Hz, 2H), 7.40 (t, J=7.8 Hz, 1H), 7.33 (m, 1H), 7.08 (d, J=8.5 Hz, 2H), 6.11 (bs, 1H), 3.93 (s, 3H). 13C NMR (CDCl3, 125 MHz): δ=167.0, 146.3, 141.9, 131.8, 129.8, 127.0, 123.9, 120.5, 116.1, 52.5.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][NH:4][C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6].[N+:23]([O-])([N+]([O-])=O)=[O:24]>>[Cl:1][CH2:2][CH2:3][N:4]([N:23]=[O:24])[C:5]([N:7]([CH2:19][CH:20]1[CH2:22][CH2:21]1)[CH:8]1[O:16][C@H:15]([CH2:17][OH:18])[C@H:13]([OH:14])[C@H:11]([OH:12])[C@H:9]1[OH:10])=[O:6]
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: O=C(NCCCl)N(CC1CC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Product: O=NN(CCCl)C(=O)N(CC1CC1)C1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O
Yield: 70.4 %

Procedure:
3.4 g of 1-(2-chloroethyl)-3-cyclopropylmethyl-3-(D-galactopyranosyl)urea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 23-(2). 2.6 g of 1-(2-chloroethyl)-1-nitroso-3-cyclopropylmethyl-3-(D-galactopyranosyl)urea are obtained as yellow caramel.
Reaction SMILES: Cl[C:2](OC(Cl)(Cl)Cl)=[O:3].[C:9]1([CH2:15][S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([NH:21][NH2:22])=[O:20])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>O1CCOCC1>[C:9]1([CH2:15][S:16][C:17]2[CH:26]=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]2[O:20][C:2](=[O:3])[NH:22][N:21]=2)[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: NNC(=O)c1ccccc1SCc1ccccc1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Solvent: C1COCCO1
Product: O=c1[nH]nc(-c2ccccc2SCc2ccccc2)o1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
To a solution containing 12.2 g of trichloromethyl chloroformate in 130 ml of p-dioxane was added portionwise 16 g of 2-[(phenylmethyl)thio]benzoic acid, hydrazide [prepared by the procedure of South African Patent Application 838,416 (1983)] to cause a slight exotherm to 37° C. After stirring at ambient temperature for 0.5 hr., the suspension was refluxed for 6 hours, then cooled to 25° C. and poured onto excess ice/water to yield a precipitate. The mixture was filtered, washed with water and the isolated solid was recrystallized from acetonitrile to yield 14 g of the subject compound; m.p. 169°-172° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][C:5]([N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)=[C:6]([CH:20]=1)[C:7]([N:9]1[CH2:14][CH2:13][CH2:12][O:11][CH:10]1[C:15](OCC)=[O:16])=[O:8].[Li+].[BH4-].O>C1COCC1>[OH:16][CH2:15][CH:10]1[N:9]([C:7]([C:6]2[CH:20]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=2[N:21]2[N:25]=[CH:24][CH:23]=[N:22]2)=[O:8])[CH2:14][CH2:13][CH2:12][O:11]1
Reactant: CCOC(=O)C1OCCCN1C(=O)c1cc(C)ccc1-n1nccn1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)N2CCCOC2CO)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (±)-ethyl 3-[5-methyl-2-(2H-1,2,3-triazol-2-yl)benzoyl]-1,3-oxazinane-2-carboxylate obtained in Reference Example 3 (0.50 g, 1.5 mmol) in THF (5 mL), a solution of LiBH4 in THF (0.97 mL, 2.9 mmol) was added and stirred for 2 hours at room temperature. Water was added to the reaction mixture, followed by extraction with CHCl3. The organic layer was washed with a saturated aqueous solution of sodium chloride, dried over Na2SO4, then the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane/EtOAc=88/12 to 0/100) to obtain the title compound (0.34 g) (colorless oil).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[NH:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1.CC(C)([O-])C.[K+]>C1(C)C(C)=CC=CC=1.CCOC(C)=O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: C1CNCCN1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1C
Solvent: CCOC(C)=O
Product: c1cncc(N2CCNCC2)c1
Temperature: 120 °C
Yield: 33.9 %

Procedure:
3-Bromopyridine (1.0 g, 6.32 mmol) and piperazine (3.2 g, 37.9 mmol) were dissolved in xylene (10 mL) and the solution was purged with argon for 10 min. Potassium tert-butoxide (0.99 g, 8.86 mmol) and catalytic Pd(PtBu3)2 (320 mg, 0.63 mmol) were added and the reaction mixture was heated to 120° C. for 10 h, cooled to room temperature, diluted with EtOAc and filtered through Celite. The filtrate was washed with water and brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The crude product was purified by column chromatography (silica 60-120 mesh, eluent 10% MeOH in CH2Cl2) to get 1-(pyridin-3-yl)piperazine (350 mg, yield 35%). 1H NMR (400 MHz, DMSO-d6) δ 8.26 (d, J=3.0 Hz, 1H), 7.97-7.95 (dd, J=4.6 Hz, 1.1 Hz, 1H), 7.29-7.26 (m, 1H), 7.20-7.16 (m, 1H), 3.08-3.06 (m, 4H), 2.83-2.81 (m, 4H). MS (ESI) m/z: Calculated for C9H13N3: 163.11. found: 164.0 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:10][NH:9]2)[CH:5]=[CH:6][CH:7]=1.CCN(C(C)C)C(C)C.[N:38]1([C:44]2[N:49]=[CH:48][C:47]([S:50](Cl)(=[O:52])=[O:51])=[CH:46][CH:45]=2)[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1>C(Cl)Cl>[Cl:1][C:2]1[C:3]([F:28])=[C:4]([CH:8]2[C:12]([C:15]3[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=3[F:22])([C:13]#[N:14])[CH:11]([CH2:23][C:24]([CH3:25])([CH3:27])[CH3:26])[CH2:10][N:9]2[S:50]([C:47]2[CH:48]=[N:49][C:44]([N:38]3[CH2:39][CH2:40][O:41][CH2:42][CH2:43]3)=[CH:45][CH:46]=2)(=[O:52])=[O:51])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(=O)(Cl)c1ccc(N2CCOCC2)nc1
Reactant: CC(C)(C)CC1CNC(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)CC1CN(S(=O)(=O)c2ccc(N3CCOCC3)nc2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 35.6 %

Procedure:
To a mixture of rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-pyrrolidine-3-carbonitrile (35.4 mg, 0.084 mmol) in CH2Cl2 (3 mL) was added DIPEA (44.5 mg, 0.344 mmol) and 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (45.0 mg, 0.171 mmol, Maybridge). It was stirred at rt for 3.5 hrs under argon. More DIPEA (29.7 mg, 0.230 mmol) and 6-morpholin-4-yl-pyridine-3-sulfonyl chloride (18.7 mg, 0.071 mmol, Maybridge) were added. After 1.75 hrs the reaction mixture was extracted with EtOAc, washed with water, saturated sodium bicarbonate, water, and saturated NaCl. The organic phase was separated, and dried over Na2SO4. The reaction mixture was then purified by flash column to give rac-(2S,3S,4S)-2-(3-chloro-2-fluoro-phenyl)-3-(4-chloro-2-fluoro-phenyl)-4-(2,2-dimethyl-propyl)-1-(6-morpholin-4-yl-pyridine-3-sulfonyl)-pyrrolidine-3-carbonitrile (19.4 mg, 35.7%). HRMS (ES+) m/z Calcd for C31H32Cl2F2N4O3S H [(M+H)+]: 649.1613; Found: 649.1615.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:21])(=[O:20])[CH2:18][CH2:17][C:16]([C:22]([O:24]C)=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3].Cl>COCCOC>[CH2:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[S:19](=[O:20])(=[O:21])[CH2:18][CH2:17][C:16]([C:22]([OH:24])=[O:23])=[CH:15][C:14]=3[CH:26]=2)=[CH:6][CH:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCS3(=O)=O)cc1
Agent: Cl
Solvent: COCCOC
Product: CCCc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCS3(=O)=O)cc1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of methyl 7-(4-propylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylate (450 mg) in 1, 2-dimethoxyethane (15 ml) was added 6N hydrochloric acid (7.5 ml), and the mixture was refluxed for 40 hours, cooled to room temperature and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried with magnesium sulfate and concentrated under reduced pressure to give crystals, which were collected by filtration and recrystallized from THF/diisopropylether to give colorless crystals of 7-(4-propylphenyl)-1,1-dioxo-2,3-dihydro-1-benzothiepine-4-carboxylic acid (433.6 mg).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][C:6]2=[O:11].Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15]>[Li+].C[Si]([N-][Si](C)(C)C)(C)C>[CH2:17]([O:16][C:14](=[O:15])[CH2:13][CH:5]1[CH2:4][C:3]2[C:7](=[CH:8][CH:9]=[CH:10][C:2]=2[Br:1])[C:6]1=[O:11])[CH3:18]
Reactant: O=C1CCc2c(Br)cccc21
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Product: CCOC(=O)CC1Cc2c(Br)cccc2C1=O
Temperature: 0 °C
Yield: 87.5 %

Procedure:
To a solution of 4-bromoindanone (15.8 g, 75 mmol) at −78° C. was added LiHMDS (1 M in THF, 90 mL). The slight brown solution was allowed to warm up to 0° C., and was cooled again to −75° C. and ethyl 2-bromoacetate (9.1 mL, 82 mmol) was added dropwise. The mixture was allowed to warm up over night (−75° C. to −20° C. over 12 h). The mixture was quenched with sat. ammonium chloride and was extracted with ethyl acetate. Flash chromatography give 19.5 g of the title compound in a mixture with the starting indanone ethyl 2-[4-bromo-2-(2-ethoxy-2-oxo-ethyl)-1-oxo-indan-2-yl]acetate and which was used without further purification for the next step (purity, 60% of the desired product). LC-MS (Method A) RT 1.11 min., 297/299 (M+H+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:42])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37]Br)[C:24]=1[CH2:39][CH2:40][CH3:41])[CH3:16].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:42])[CH2:19][CH2:20][CH2:21][O:22][C:23]1[CH:28]=[CH:27][C:26]([C:29](=[O:31])[CH3:30])=[C:25]([O:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:24]=1[CH2:39][CH2:40][CH3:41])[CH3:16]
Reactant: CCCc1c(OCCCC(=O)OCC)ccc(C(C)=O)c1OCCCCCBr
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCCCOc2c(C(C)=O)ccc(OCCCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 82.7 %

Procedure:
A mixture of 0.96 g (0.005 mole) of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 2.26 g (0.005 mole) of 4-[4-acetyl-3-[(5-bromopentyl)oxy]-2-propylphenoxy]butanoic acid ethyl ester and 1.36 g (0.010 mole) of anhydrous potassium carbonate in 40 ml of anhydrous acetone and 20 ml of anhydrous dimethylformamide was stirred at reflux for 17 hours. The solvents were removed in vacuo and the residue was purified by HPLC using 25% ethyl acetate-hexane to yield 2.36 g (84% yield) of 4-[4-acetyl-3-[[5-(4-acetyl-3-hydroxy-2-propylphenoxy)pentyl]oxy]-2-propylphenoxy]butanoic acid ethyl ester as an oil.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]([OH:12])[CH:9]=[CH:10][CH:11]=1)([O-:5])=[O:4].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Cl)=[CH:17][CH:16]=1>CN(C)C=O>[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][O:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=2)=[CH:17][CH:16]=1
Reactant: COc1ccc(CCl)cc1
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(COc2cccc([N+](=O)[O-])c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.6 %

Procedure:
NaOH (0.54 g, 13.36 mmol) was added into 10 ml of degassed dimethylformamide at 0° C., then 3-nitrophenol (1.69 g, 12.14 mmol) dissolved in 7 ml of dimethylformamide was dropped slowly, and then para-methoxybenzylchloride (1.81 ml, 13.36 mmol) was added slowly. After stirred for 2 hours at the increased reaction temperature to room temperature, the reaction mixture was extracted using saturated ammonium chloride (100 ml) and ethylacetate (100 ml). The organic layer was washed twice using 100 ml of water, and dried using anhydrous sodium sulfate, then concentrated under vacuum. The resultant solid was solidified using n-hexane to obtain pale yellowish solid of 1-(4-methoxybenzyloxy)-3-nitrobenzene (2.85 g, 90%) finally.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[N+:22]([O-])=O)=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]>[Pd].CO>[NH2:22][C:13]1[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=1[C:10](=[O:11])[CH2:9][C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1
Reactant: COc1cc(C(=O)Cc2ccc(Cl)c(Cl)c2)c([N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: CO
Product: COc1cc(N)c(C(=O)Cc2ccc(Cl)c(Cl)c2)cc1OC
Yield: 57 %

Procedure:
To a mixture of 2-(3,4-dichloro-phenyl)-1-(4,5-dimethoxy-2-nitro-phenyl)-ethanone (9.62 g, 25.98 mmol) and palladium on charcoal (2.88 g, 30% in mass) was added dropwise methanol (500 ml) and the resulting heterogeneous mixture was hydrogenated (1 atm) at RT for 4 days. The reaction mixture was filtered over celite, and the celite cake was washed several times with anhydrous methanol. The filtrate was then evaporated to dryness and the crude brown oil was purified by flash chromatography (dichloromethane/methanol, 360/1) to give the expected aniline derivative as a brown oil (5.04 g, 57%).
Reaction SMILES: [N:1]([C:4]1[S:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[C:7]([CH3:9])[N:8]=1)=[N+:2]=[N-:3].C(N(CC)C(C)C)(C)C.[C:24]1([CH2:30][CH2:31][CH2:32][C:33]#[CH:34])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>O1CCCC1.[Cu]I>[CH3:9][C:7]1[N:8]=[C:4]([N:1]2[CH:34]=[C:33]([CH2:32][CH2:31][CH2:30][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[N:3]=[N:2]2)[S:5][C:6]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)c1sc(N=[N+]=[N-])nc1C
Reactant: C#CCCCc1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1sc(-n2cc(CCCc3ccccc3)nn2)nc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 79 %

Procedure:
To a solution of ethyl 2-azido-4-methylthiazole-5-carboxylate (5.31 g, 25.02 mmol) in tetrahydrofuran (50 mL) was added copper(I) iodide (4.76 g, 25.02 mmol), N,N-diisopropylethylamine (13.07 mL, 75.06 mmol) and 5-phenyl-1-pentyne (3.97 g, 27.52 mmol). The reaction mixture was stirred at ambient temperature for 18 hours and concentrated in vacuo. The residue was purified by column chromatography (ethyl acetate:petroleum ether, 1:4 ratio) to afford the title compound in 79% yield (7.04 g): 1H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.31-7.16 (m, 5H), 4.33 (q, J=6.0 Hz, 2H), 2.82 (t, J=9.0 Hz, 2H), 2.77-2.69 (m, 5H), 2.10-2.04 (m, 2H), 1.38 (t, J=6.0 Hz, 3H); MS (ES+) m/z 357.3 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:12]=[CH:11]N=C[CH:8]=2)[S:5][CH:6]=1.BrC1SC=C(Br)C=1.[N:20]1C=CC=C(B(O)O)[CH:21]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:7]2[CH:8]=[N:20][CH:21]=[CH:11][CH:12]=2)[S:5][CH:6]=1
Reactant: OB(O)c1cccnc1
Reactant: Brc1csc(-c2ccncc2)c1
Agent: Brc1csc(Br)c1
Product: Brc1csc(-c2cccnc2)c1

Procedure:
The title compound was prepared by a method analogous to that described in Example 15 for the preparation of 4-bromo-2-(4-pyridyl)thiophene from 2,4-dibromothiophene and pyridine-3-boronic acid. The sub-title compound (2.30 g) was obtained as a pale solid, m/z 240, 242 (MH+).
Reaction SMILES: O[C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:38]>C1(C)C=CC=CC=1>[Cl:38][C:2](=[C:21]1[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-:32])=[O:31])[CH:28]=2)[N:23]([C:33](=[O:35])[CH3:34])[C:22]1=[O:36])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][N:10]2[C:14](=[O:15])[C:13]3=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]3[C:11]2=[O:20])=[CH:5][CH:4]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: CC(=O)N1C(=O)C(=C(O)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21
Solvent: Cc1ccccc1
Product: CC(=O)N1C(=O)C(=C(Cl)c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)c2cc([N+](=O)[O-])ccc21

Procedure:
Prepared analogously to Example 2b from 3-[1-hydroxy-1-(4-phthalimidomethyl-phenyl)-methylidene]-1-acetyl-5-nitro-2-indolinone and phosphorus pentachloride in toluene.
Reaction SMILES: CO[C:3]([C:5]1[S:6][C:7]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[CH:8][C:9]=1[N:10]=[CH:11][N:12]([CH3:14])C)=[O:4].[CH3:22][N:23]1[CH2:28][CH2:27][N:26]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)CN)[CH2:25][CH2:24]1.C1(O)C=CC=CC=1>CO>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([C:7]2[S:6][C:5]3[C:3](=[O:4])[N:12]([CH2:14][C:35]4[CH:34]=[CH:31][CH:30]=[C:29]([N:26]5[CH2:27][CH2:28][N:23]([CH3:22])[CH2:24][CH2:25]5)[CH:36]=4)[CH:11]=[N:10][C:9]=3[CH:8]=2)=[CH:20][CH:19]=1
Reactant: CN1CCN(c2cccc(CN)c2)CC1
Reactant: COC(=O)c1sc(-c2ccc(Cl)cc2)cc1N=CN(C)C
Solvent: Oc1ccccc1
Solvent: CO
Product: CN1CCN(c2cccc(Cn3cnc4cc(-c5ccc(Cl)cc5)sc4c3=O)c2)CC1
Temperature: 130 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5-(4-chloro-phenyl)-3-(dimethylamino-methyleneamino)-thiophene-2-carboxylic acid methyl ester (0.189 g, 0.585 mmol), 3-(4-methyl-piperazin-1-yl)-benzylamine (0.100 g, 0.487 mmol) and phenol (1.0 g) was stirred at 130° C. for 1.5 hours. The reaction mixture was allowed to cool to r.t. and MeOH (10 mL) was added. After 30 minutes the precipitate was filtered off and washed with MeOH (50 mL). The crude product was purified by flash chromathography using a mixture of EtOAc, MeOH and TEA as eluent to give the product as an off white solid. Yield: 0.079 g (30%). 1H NMR (400 MHz, CDCl3) δ 8.08 (s, 1H), 7.60 (d, 2H, J=7.92 Hz), 7.44 (s, 1H), 7.40 (d, 2H, J=7.92 Hz), 7.22 (m, 1H), 6.92 (bs, 1H), 6.85 (d, 1H, J=7.92 Hz), 6.79 (d, 1H, J=7.46 Hz), 5.15 (s, 2H), 3.19 (m, 4H), 2.53 (m, 4H), 2.32 (s, 3H). MS (ESI+) 450.95 (M+1H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:13]2[CH2:14][CH:9]1[CH2:10][NH:11][CH2:12]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:23]([O:25][CH2:26][CH2:27][O:28][CH3:29])=[O:24]>C(Cl)Cl>[CH3:29][O:28][CH2:27][CH2:26][O:25][C:23]([N:11]1[CH2:10][CH:9]2[CH2:14][CH:13]([N:8]2[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:12]1)=[O:24]
Reactant: COCCOC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1C2CNCC1C2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCOC(=O)N1CC2CC(C1)N2C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane (2) (50 mg, 0.25 mmol) in 5 mL of methylene chloride was added triethylamine (67 μL, 0.5 mmol) and the solution was cooled to 0° C. Methoxyethyl chloroformate (32 μL, 27.5 mmol) was added and the solution was stirred for 1 h. The solvent was removed in vacuo and the residue was washed with 50 mM sodium acetate in methylene chloride solution. The solution was stirred 10 min and passed through a phase separator. The solvent was removed in vacuo to give crude 3-(methoxyethoxycarbonyl)-6-(tert-butoxycarbonyl)-3,6-diazabicyclo[3.1.1]heptane.
Reaction SMILES: [C:1]([C:4]1[C:16](=[O:17])[N:12]2[CH2:13][CH2:14][O:15][C:10]3[C:11]2=[C:6]([CH:7]=[C:8]([O:18][CH3:19])[CH:9]=3)[C:5]=1[OH:20])([OH:3])=O.[CH2:21]([O:23][C:24]([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[NH:27]1)=[O:25])[CH3:22].C1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH2:21]([O:23][C:24]([CH:26]1[CH2:34][C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:27]1[C:1]([C:4]1[C:16](=[O:17])[N:12]2[CH2:13][CH2:14][O:15][C:10]3[C:11]2=[C:6]([CH:7]=[C:8]([O:18][CH3:19])[CH:9]=3)[C:5]=1[OH:20])=[O:3])=[O:25])[CH3:22]
Reactant: CCOC(=O)C1Cc2ccccc2N1
Reactant: COc1cc2c3c(c1)c(O)c(C(=O)O)c(=O)n3CCO2
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Cc2ccccc2N1C(=O)c1c(O)c2cc(OC)cc3c2n(c1=O)CCO3
Temperature: 90 °C
Reaction time: 3 h
Yield: 114.9 %

Procedure:
A mixture of 6-carboxy-2,3-dihydro-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (1.5 g), 2-ethoxycarbonylindoline (2.3 g) and 1,3-dicyclohexylcarbodiimide (3 g) in toluene (20 ml) was stirred at 90° C. for 3 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with chloroform-methanol (30:1) to give 2,3-dihydro-6-(2-ethoxycarbonyl-1-indolinylcarbonyl)-7-hydroxy-9-methoxy-5-oxo-5H-pyrido[1,2,3-de]-1,4-benzoxazine (2.8 g).