Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][CH:3]=1.[OH:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20].O>CN(C)C1C=CN=CC=1.ClC1C=CC=CC=1>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH3:15])[N:5]=[CH:4][CH:3]=[C:2]2[O:16][C:17]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:18]=1[CH:19]=[O:20]
Reactant: COc1ccc(O)c(C=O)c1
Reactant: COc1cc2nccc(Cl)c2cc1OC
Agent: CN(C)c1ccncc1
Solvent: O
Solvent: Clc1ccccc1
Product: COc1ccc(Oc2ccnc3cc(OC)c(OC)cc23)c(C=O)c1
Temperature: 130 °C
Reaction time: 8 h
Yield: 80.4 %

Procedure:
4-Chloro-6,7-dimethoxyquinoline (2.23 g), 2-hydroxy-5-methoxybenzaldehyde (6.08 g), and 4-dimethylaminopyridine (4.88 g) were suspended in monochlorobenzene (40 ml), and the suspension was stirred at 130° C. overnight. The reaction solution was cooled to room temperature, and water was then added to the reaction solution. The mixture was extracted with ethyl acetate. The ethyl acetate layer was then washed with water and saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed therefrom by distillation under the reduced pressure, and the residue was purified by chromatography on silica gel using ethyl acetate-hexane for development to give 2-[(6,7-dimethoxy-4-quinolyl)oxy]-5-methoxybenzaldehyde (2.72 g).
Reaction SMILES: [CH3:1][N:2]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1>C1COCC1.C(O)(C)C.[Pd]>[CH3:1][N:2]([C:11](=[O:16])[C:12]([CH3:14])([CH3:13])[CH3:15])[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH2:8])=[CH:9][CH:10]=1
Reactant: CN(C(=O)C(C)(C)C)c1ccc(C#N)cc1
Agent: [Pd]
Solvent: CC(C)O
Solvent: C1CCOC1
Product: CN(C(=O)C(C)(C)C)c1ccc(CN)cc1
Reaction time: 1 h
Yield: 74.4 %

Procedure:
Add a solution of 4-(N-methyl-2,2-dimethyl-propionylamino)-benzonitrile (55 mg, 0.25 mmol) in THF/iso-propanol (1:1, 8 mL) to 10% Pd/C (Degussa type E101, 31 mg, 0.15 mmol) under nitrogen. Purge the reaction mixture with nitrogen and then submit to hydrogenation at 50 psi for 1 h. Filter the catalyst through Celite® and wash thoroughly with THF (100 mL) and iso-propanol (100 mL). Concentrate in vacuo and purify the crude mixture by chromatography on silica gel eluting with DCM/2M ammonia in methanol (1:0 to 9:1 gradient over 30 min and 9:1 over 3 min; 35 mL/min) to obtain the title compound as a colorless oil (41 mg, 73%). MS (ES+) m/z: 221.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:40][CH2:39][CH:38]([CH3:41])[CH2:37][CH2:36]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([OH:24])=O)[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42].[CH3:43][N:44](C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.CN>CN(C=O)C.C1COCC1>[F:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16]([N:29]3[CH2:34][CH2:33][CH:32]([N:35]4[CH2:36][CH2:37][CH:38]([CH3:41])[CH2:39][CH2:40]4)[CH2:31][CH2:30]3)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=3[CH3:28])[C:22]([NH:44][CH3:43])=[O:24])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:42]
Reactant: Cc1ccc(C(=O)O)cc1-c1nc(N2CCC(N3CCC(C)CC3)CC2)nc2c1ccc(=O)n2-c1c(F)cccc1F
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: CN
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CNC(=O)c1ccc(C)c(-c2nc(N3CCC(N4CCC(C)CC4)CC3)nc3c2ccc(=O)n3-c2c(F)cccc2F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.3 %

Procedure:
To the compound 3-[8-(2,6-difluorophenyl)-2-(4-methyl-1,4′-bipiperidin-1′-yl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylbenzoic acid (31.6 mg, 0.055 mmol) in DMF (0.5 mL) were added HBTU (25 mg, 0.066 mmol), triethylamine (15.5 uL, 0.11 mmol) and methylamine (41.3 uL, 0.0825 mmol, 2M soln in THF). The mixture was stirred at rt overnight. Separation by HPLC with TFA, followed by neutralization with SPE amine cartridge afforded the title compound (7.2 mg, 22%). LC-MS m/z 587 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[CH:5]2.N1C=CC=CC=1.ClC(Cl)(Cl)[C:20](Cl)=[O:21].[C:25](=O)([O-])[O-:26].[K+].[K+]>CN(C1C=CN=CC=1)C.CO.O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[Cl:11])[NH:7][CH:6]=[C:5]2[C:25]([O:21][CH3:20])=[O:26]
Reactant: Clc1cc2[nH]ccc2cc1Br
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: O=C([O-])[O-]
Agent: CN(C)c1ccncc1
Agent: [K+]
Solvent: CO
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: COC(=O)c1c[nH]c2cc(Cl)c(Br)cc12
Temperature: 0 °C
Reaction time: 64 h
Yield: 99 %

Procedure:
A mixture of 5-bromo-6-chloro-1H-indole (15.1 g, 65.5 mmol), tetrahydrofuran (100 mL), pyridine (18.4 mL, 229 mmol) and DMAP (808 mg, 6.55 mmol) was cooled to 0° C. and treated with trichloroacetyl chloride (22.1 mL, 197 mmol) dropwise over 30 minutes. The reaction mixture was stirred at room temperature for 64 hours then cooled to 10° C. Methanol (100 mL) was added dropwise to the reaction mixture over 10 minutes, producing a dark homogenous solution. Potassium carbonate (54.9 g, 393 mmol) was then added portion-wise and the ice bath was removed. Stirring was kept at a vigorous pace and allowed to continue for 2 hours, during which time the reaction turned dark green and produced an exotherm. The reaction was quenched slowly with 1M HCl (until acidic pH was maintained) and diluted with ethyl acetate. The organic layer was washed with 1M HCl. The aqueous layer was back-extracted twice with ethyl acetate. The combined organic layers were then washed carefully with saturated sodium bicarbonate solution followed by brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to provide the title compound as a brown solid (18.7 g, 99%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]([O:18]CC)=[O:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2].[OH-].[Na+].Cl.CCOCC>C(O)C>[CH:1]([C:3]1[CH:4]=[C:5]([O:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:6]=[CH:7][C:8]=1[N+:9]([O-:11])=[O:10])=[O:2]
Reactant: CCOC(=O)CCCOc1ccc([N+](=O)[O-])c(C=O)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOCC
Product: O=Cc1cc(OCCCC(=O)O)ccc1[N+](=O)[O-]
Reaction time: 0.5 h
Yield: 94 %

Procedure:
To a solution of ethyl 4-(3-formyl-4-nitrophenyl)oxybutanoate (65 g) in ethanol (400 ml) was added 3N NaOH (100 ml) in small portions. After 30 minutes at room temperature, the reaction mixture was acidified with concentrated HCl and the ethanol evaporated. The aqueous residue was extracted with ethyl acetate (4×200 ml). The combined organic layers were washed with brine (2×200 ml), dried over Na2SO4, filtered and evaporated to give a light yellow solid. Trituration with ether afforded 4-(3-formyl-4-nitrophenyl)oxybutanoic acid (55 g), m.p. 109°-110° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:9]=[N:10][CH:11]=1.[CH3:16][NH2:17]>CO>[CH3:16][NH:17][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[N:10][CH:9]=[C:8]([O:12][CH:13]([CH3:15])[CH3:14])[CH:7]=1
Reactant: CN
Reactant: CC(C)Oc1cncc(OCCCCl)c1
Solvent: CO
Product: CNCCCOc1cncc(OC(C)C)c1
Temperature: 100 °C

Procedure:
Crude 5-(3-chloropropoxy)-3-isopropoxypyridine (0.92 g, 4.01 mmol) was dissolved in methanol (10 mL) and added to a 40 wt % aqueous solution of methylamine (10 mL) in a heavy-walled glass pressure-tube apparatus. The tube was sealed and the mixture was stirred and heated at 100° C. (oil bath temperature) for 4 h. After cooling, the solution was concentrated by rotary evaporation. Saturated NaCl solution (50 mL) was added, and the mixture was basified with 10% NaOH solution to pH 11. The mixture was extracted with ether (4×50 mL). The combined ether extracts were dried (MgSO4), filtered and concentrated by rotary evaporation to give 1.98 g of a brown oil. The product was purified by column chromatography on silica gel (60 g) eluting with hexane to remove impurities, followed by CHCl3—CH3OH-Et3N (50:50:2, v/v/v) to collect the product. Selected fractions containing the product were combined and concentrated by rotary evaporation. The resulting brown oil was dissolved in CHCl3 (25 mL), dried (MgSO4), filtered, and concentrated by rotary evaporation to give 0.64 g (71.6%) of a brown oil.
Reaction SMILES: Cl[C:2]1[C:3](=[O:21])[O:4][C:5]([CH:16]2[CH2:20][CH2:19][CH2:18][CH2:17]2)(CCC2CCCC2)[CH2:6][C:7]=1[OH:8].ClC1C(=O)O[C:26]([CH2:35]CC2CCCCC=2)([CH:30]2[CH2:34][CH2:33][CH2:32][CH2:31]2)CC=1O.[Cl:44][C:45]1[CH:57]=[CH:56][C:48]2[N:49]([CH:53]([CH3:55])[CH3:54])[C:50]([SH:52])=[N:51][C:47]=2[CH:46]=1.N1C=CC(C2NC(S)=NN=2)=CC=1>>[Cl:44][C:45]1[CH:57]=[CH:56][C:48]2[N:49]([CH:53]([CH3:55])[CH3:54])[C:50]([S:52][CH:2]3[C:7]([CH2:35][CH2:26][CH:30]4[CH2:31][CH2:32][CH2:33][CH2:34]4)([OH:8])[CH2:6][CH:5]([CH:16]4[CH2:17][CH2:18][CH2:19][CH2:20]4)[O:4][C:3]3=[O:21])=[N:51][C:47]=2[CH:46]=1
Reactant: CC(C)n1c(S)nc2cc(Cl)ccc21
Reactant: O=C1OC(CCC2=CCCCC2)(C2CCCC2)CC(O)=C1Cl
Reactant: O=C1OC(CCC2CCCC2)(C2CCCC2)CC(O)=C1Cl
Agent: Sc1nnc(-c2ccncc2)[nH]1
Product: CC(C)n1c(SC2C(=O)OC(C3CCCC3)CC2(O)CCC2CCCC2)nc2cc(Cl)ccc21

Procedure:
The title compound was prepared analogously to Example C(4), where 3-Chloro-6-cyclopentyl-6-(2-cyclopentyl-ethyl)-4-hydroxy-5,6-dihydro-pyran-2-one from Step 2 of example C(28) was substituted in place of 3-Chloro-6-(2-cyclohex-1-enyl-ethyl)-6-cyclopentyl-4-hydroxy-5,6-dihydro-pyran-2-one and 5-Chloro-1-isopropyl-2-mercapto benzimidazole was substituted in place of 5-Pyridin-4-yl-4H-[1,2,4]triazole-3-thiol of that example.
Reaction SMILES: [OH:1][CH:2]([C@@H:4]1[C@@H:7]([S:8][CH3:9])[N:6]([C:10](=[C:15]([CH3:17])[CH3:16])[C:11]([O:13][CH3:14])=[O:12])[C:5]1=[O:18])[CH3:3].Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:21]>CN(C)C1C=CN=CC=1.ClCCl.C(OCC)(=O)C>[CH3:16][C:15]([CH3:17])=[C:10]([N:6]1[C@H:7]([S:8][CH3:9])[C@@H:4]([CH:2]([O:1][C:20]([O:22][CH2:23][C:24]2[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=2)=[O:21])[CH3:3])[C:5]1=[O:18])[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)O)[C@H]1SC
Reactant: O=C(Cl)OCc1ccc([N+](=O)[O-])cc1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COC(=O)C(=C(C)C)N1C(=O)[C@H](C(C)OC(=O)OCc2ccc([N+](=O)[O-])cc2)[C@H]1SC
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 95.2 %

Procedure:
To a solution of a mixture (1:3) of methyl 2-[(3S,4R)-3-{(1RS)-1-hydroxyethyl}-4-methylthio-2-oxoazetidin-1-yl]-3-methylbut-2-enoate (1.84 g) and 4-dimethylaminopyridine (1.23 g) in dichloromethane (20 ml) was added a solution of p-nitrobenzyl chloroformate (1.60 g) in dichloromethane (3 ml) at 0° C. After stirring at 0° C. for 1.5 hours, the mixture was diluted with ethyl acetate (150 ml) and washed with dilute hydrochloric acid, water, a dilute aqueous sodium bicarbonate, and brine. Drying over magnesium sulfate and removal of the solvent left an oil (3.1 g), which was chromatographed on silica gel (90 g) eluting with 10-25% ethyl acetate in hexane to give a mixture (1:3) of methyl 3-methyl-2-[(3S,4R)-4-methylthio-3-{(1RS)-1-(p-nitrobenzyloxycarbonyloxy)ethyl}-2-oxoazetidin-1-yl]-but-2-enoate (2.90 g) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH2:4][C:5]1[C:6]([Cl:20])=[N:7][C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=2)=[N:9][C:10]=1[Cl:11].[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[C:32](O)=[O:33].CCOC(C)=O>C1COCC1>[Cl:20][C:6]1[C:5]([CH2:4][C:3]([O:2][CH3:1])=[O:21])=[C:10]([Cl:11])[N:9]=[C:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:32]([C:23]3[CH:24]=[CH:25][C:26]4[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:22]=3)=[O:33])=[CH:15][CH:14]=2)[N:7]=1
Reactant: O=C(O)c1ccc2ccccc2c1
Reactant: COC(=O)Cc1c(Cl)nc(Cc2ccc(N)cc2)nc1Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)Cc1c(Cl)nc(Cc2ccc(NC(=O)c3ccc4ccccc4c3)cc2)nc1Cl
Temperature: 25 °C
Reaction time: 10 h
Yield: 669.2 %

Procedure:
A mixture of methyl[2-(4-aminobenzyl)-4,6-dichloropyrimidin-5-yl]acetate (0.073 g, 0.23 mmol), 2-naphthoic acid (0.048 g, 0.028 mmol), and WSCI (0.049 g, 0.026 mmol) in anhydrous THF (3 mL) was stirred at room temperature under Ar atmosphere for 10 hours. EtOAc (80 mL) was then introduced and the organic phase was washed sequentially with saturated NaHCO3, water, and brine, dried over anhydrous MgSO4, filtered, and concentrated in vacuo. The crude product thus obtained as a light orange oil was triturated with diisopropyl ether and the separated solids was collected by suction to give methyl {4,6-dichloro-2-[4-(2-naphthoylamino)benzyl]pyrimidin-5-yl}acetate (0.090 g, 78% yield) as a white powder.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1.BrC[C:33]1[N:34]([CH3:41])[CH:35]=[C:36]([N+:38]([O-:40])=[O:39])[N:37]=1.[CH3:42]COC(C)=O>CN1C(=O)CCC1>[Br-:1].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][N+:26]([CH3:42])([CH2:29][C:35]5[N:34]([CH3:41])[CH:33]=[N:37][C:36]=5[N+:38]([O-:40])=[O:39])[CH2:25][CH2:24]4)=[C:16]([O:19][CH3:20])[CH:17]=3)[N:12]=[CH:11][N:10]=2)=[C:4]([F:30])[CH:3]=1
Reactant: CCOC(C)=O
Reactant: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cn1cc([N+](=O)[O-])nc1CBr
Solvent: CN1CCCC1=O
Product: COc1cc2c(Nc3ccc(Br)cc3F)ncnc2cc1OCC1CC[N+](C)(Cc2c([N+](=O)[O-])ncn2C)CC1
Product: [Br-]
Reaction time: 48 h

Procedure:
To a solution of N-(4-bromo-2-fluorophenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl)methoxy]-4-quinazolinamine (ZD6474; Hennequin et al, J Med Chem, 2002, 45, 1300-1312) (250 mg, 0.53 mmol) in NMP (1 mL) was added 5-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (105) (139 mg, 0.63 mmol) according to general procedure C, except the reaction was stirred for 48 hours and EtOAc was used instead of MeCN in the work-up to give 4-({[4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinyl]oxy}methyl)-1-methyl-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium bromide (392 mg), which was further purified by preparative HPLC eluting with CH3CN/H2O/TFA to give 4-({[4-(4-bromo-2-fluoroanilino)-6-methoxy-7-quinazolinyl]oxy}methyl)-1-methyl-1-[(1-methyl-4-nitro-1H-imidazol-5-yl)methyl]piperidinium trifluoroacetate (146) (246 mg, 64%) as a mixture of trans/cis isomers in a ratio of ˜2:5 by 1H NMR, hereafter named as A for the minor isomer and B for the major isomer, m.p. 185-188° C. (dec.). 1H NMR [(CD3)2SO] δ 10.42 (br, 1H), 8.60 (s, 1H), 8.114 & 8.110 (s×2, A & B isomers, 1H), 7.74-7.71 (m, 1H), 7.56-7.53 (m, 1H), 7.34 & 7.27 (s×2, A & B isomers, 1H), 5.07 (br, 2H), 4.29 & 4.14 (d×2, A & B isomers, J=6.6 Hz, 2H), 3.99 & 3.97 (s×2, A & B isomers, 3H), 3.88 (s, 3H), 3.75-3.60 (m, 4H), 3.15 & 3.01 (s×2, A & B isomers, 3H), 2.33-1.82 (m, 5H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[CH:11]=[CH:10][NH:9][C:5]=2[N:6]=[CH:7][N:8]=1.[I:12]N1C(=O)CCC1=O.O>ClCCl>[I:12][C:11]1[C:4]2[C:3]([O:2][CH3:1])=[N:8][CH:7]=[N:6][C:5]=2[NH:9][CH:10]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1ncnc2[nH]ccc12
Solvent: O
Solvent: ClCCl
Product: COc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
To 4-methoxy-7H-pyrrolo[2,3-d]pyrimidine (3, 3.20 g, 21.4 mmol) in 280 mL of dichloromethane, N-iodosuccinimide (5.3 g, 24.0 mmol) suspended in dichloromethane was added. The reaction was stirred at room temperature for 2 hours, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and the filtrate concentrated under vacuum. The resulting material was washed with ethyl acetate and hexane to provide the desired compound (35, 4.80 g).
Reaction SMILES: Cl.[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[C:11]([OH:13])=[O:12].S(Cl)([Cl:16])=O.[CH3:18]O>>[ClH:16].[NH:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[CH:4]=[C:3]1[C:11]([O:13][CH3:18])=[O:12]
Reactant: O=C(O)c1cc2cccnc2[nH]1
Reactant: O=S(Cl)Cl
Reactant: CO
Agent: Cl
Product: COC(=O)c1cc2cccnc2[nH]1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 4 g of 1H-pyrrolo[2,3-b]pyridine-2-carboxylic acid hydrochloride in 100 mL of methanol are added dropwise 6 mL of thionyl chloride at room temperature. The reaction mixture is then stirred for 5 hours at room temperature, and then concentrated under reduced pressure. The residue obtained is triturated in 50 mL of ethyl ether and then dried under vacuum at 40° C. 3.22 g of methyl 1H-pyrrolo[2,3-b]pyridine-2-carboxylate hydrochloride are obtained in the form of a pale yellow solid, which is used in unmodified form in the following step.
Reaction SMILES: C1(OC)C=CC=CC=1.[CH3:9][N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[NH:23][C:22](=O)[C:21]=2[CH:31]=1.[OH-].[NH4+]>[Ti](Cl)(Cl)(Cl)Cl.C(O)(C)C.C1(C)C=CC=CC=1>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]2[NH:26][C:25]3=[CH:27][S:28][CH:29]=[C:24]3[N:23]=[C:22]([N:13]3[CH2:14][CH2:15][N:10]([CH3:9])[CH2:11][CH2:12]3)[C:21]=2[CH:31]=1
Reactant: O=C1Nc2cscc2Nc2ccc(Cl)cc21
Reactant: CN1CCNCC1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: COc1ccccc1
Solvent: CC(C)O
Product: CN1CCN(C2=Nc3cscc3Nc3ccc(Cl)cc32)CC1
Reaction time: 8 h

Procedure:
To a solution of 7 ml. of anisole, 3.8 ml. of titanium tetrachloride and 1.5 g. of methylpiperazine in 67 ml. of toluene is added a mixture of 6.7 g. of 7-chloro-4H-thieno-[3,4-b][1,4]benzodiazepin-9(10H)-one and 7.6 g. of methylpiperazine in 7 ml. of toluene. The mixture is refluxed with stirring overnight, cooled and 10 ml. of isopropyl alcohol, 5 g. of diatomaceous earth and 10 ml. of ammonium hydroxide are added. The mixture is filtered and washed with toluene. The toluene is washed with water and then extracted with three 150 ml. portions of 3 N hydrochloric acid. The acid extracts are made alkaline with ammonium hydroxide and extracted with dichloromethane. This extract is dried over magnesium sulfate, filtered and the solvent is evaporated. The residue is crystallized from dichloromethane-hexane giving the desired product, m.p. 191°-194° C.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:15]=[C:14]([O:16][C:17]2[C:18]([F:39])=[C:19]3[C:23](=[CH:24][CH:25]=2)[N:22]([C:26](=[O:37])[NH:27][C:28]2[CH:32]=[C:31]([C:33]([CH3:36])([CH3:35])[CH3:34])[O:30][N:29]=2)[C:21]([CH3:38])=[CH:20]3)[N:13]=[CH:12][N:11]=1)C)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:33]([C:31]1[O:30][N:29]=[C:28]([NH:27][C:26]([N:22]2[C:23]3[C:19](=[C:18]([F:39])[C:17]([O:16][C:14]4[CH:15]=[C:10]([CH2:9][NH:7][CH3:6])[N:11]=[CH:12][N:13]=4)=[CH:25][CH:24]=3)[CH:20]=[C:21]2[CH3:38])=[O:37])[CH:32]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: Cc1cc2c(F)c(Oc3cc(CN(C)C(=O)OC(C)(C)C)ncn3)ccc2n1C(=O)Nc1cc(C(C)(C)C)on1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNCc1cc(Oc2ccc3c(cc(C)n3C(=O)Nc3cc(C(C)(C)C)on3)c2F)ncn1

Procedure:
To a solution of {6-[1-(5-tert-Butyl-isoxazol-3-ylcarbamoyl)-4-fluoro-2-methyl-1H-indol-5-yloxy]-pyrimidin-4-ylmethyl}-methyl-carbamic acid tert-butyl ester (0.25 g, 0.452 mmol) in DCM (10 mL) is added TFA (1.5 mL). After 3 h the solvent is removed by rotary evaporation and the residue is diluted with DCM and water. Concentrated NH4OH is added to neutralize and the aqueous phase is extracted twice with DCM. The organic layers are washed with brine, dried over Na2SO4, and concentrated to give the title compound. MS (ESI) m/z 453.1 (M+1); 1H NMR (400 MHz, DMSO-d6) δ ppm 8.64 (d, J=1.01 Hz, 1 H) 7.52 (d, J=8.59 Hz, 1 H) 7.19 (s, 1 H) 7.15 (dd, J=8.72, 7.71 Hz, 1H) 6.65 (s, 1 H) 6.58 (s, 1 H) 3.76 (s, 2 H) 2.56 (s, 3 H) 2.33 (s, 3 H) 1.34 (s, 9 H).
Reaction SMILES: [OH:1][C:2]1[C:7]2[S:8][CH:9]=[CH:10][C:6]=2[CH:5]=[CH:4][C:3]=1[C:11]([OH:13])=O.Cl.[CH3:15][O:16][C:17](=[O:22])[C:18]([NH2:21])([CH3:20])[CH3:19].C(N(C(C)C)C(C)C)C.Cl.CN(C)CCCN=C=NCC>CN(C)C=O>[CH3:15][O:16][C:17](=[O:22])[C:18]([NH:21][C:11]([C:3]1[CH:4]=[CH:5][C:6]2[CH:10]=[CH:9][S:8][C:7]=2[C:2]=1[OH:1])=[O:13])([CH3:20])[CH3:19]
Reactant: COC(=O)C(C)(C)N
Reactant: O=C(O)c1ccc2ccsc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1ccc2ccsc2c1O
Yield: 39.7 %

Procedure:
To a solution of 1.40 g 7-hydroxy-benzo[b]thiophene-6-carboxylic acid in 20 ml N,N-dimethylformamide were added 0.21 g 1-hydroxy-benzotriaziole and 1.42 g 2-amino-2-methyl-propionic acid methyl ester hydrochloride. At 0° C. 6.4 ml (4.99 g) ethyl-diiso-propyl-amine and 2.22 g (3-dimethylamino-propyl)-ethyl-carbodiimide hydrochloride were added. After 2 days at room temperature the reaction mixture was concentrated in vacuo, and the resulting residue was diluted with ethyl acetate and washed with brine. The organic layer was dried over magnesium sulphate and concentrated. The resulting residue was purified by flash chromatography (silica, heptane/ethyl acetate) to afford 0.84 g 2-[(7-hydroxy-benzo[b]thiophene-6-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1.[CH2:24](Cl)[CH2:25][CH2:26][CH3:27]>CN(C)C=O>[CH2:24]([O:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=2)[CH2:3]1)[CH2:25][CH2:26][CH3:27]
Reactant: CCCCCl
Reactant: OC1CCCN(c2nc(-c3ccccc3)nc3ccccc23)C1
Solvent: CN(C)C=O
Product: CCCCOC1CCCN(c2nc(-c3ccccc3)nc3ccccc23)C1

Procedure:
Equimolar amounts of 4-(3-hydroxypiperidinyl-2-phenylquinazoline and soda amide are mixed in dimethylformamide and reacted with butyl chloride to prepare the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH:19]C(OCC2C=CC=CC=2)=O)[CH2:8][C@@H:7]1[CH3:30])=[O:5])[CH3:2]>[Pd].C(O)C.C1CCCCC=1>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[CH:11][C:12]3[CH2:18][CH2:17][CH2:16][C:13]=3[CH:14]=2)[C@H:9]([NH2:19])[CH2:8][C@@H:7]1[CH3:30])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2cc3c(cc2[C@H](NC(=O)OCc2ccccc2)C[C@@H]1C)CCC3
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CCO
Product: CCOC(=O)N1c2cc3c(cc2[C@H](N)C[C@@H]1C)CCC3
Temperature: 25 °C
Yield: 104.2 %

Procedure:
cis-4-Benzyloxycarbonylamino-2-methyl-2,3,4,6,7,8-hexahydro-cyclopenta[g]quinoline-1-carboxylic acid ethyl ester (Example 1C) (500 mg), 10% palladium on carbon (150 mg), and a mixture of ethanol-cyclohexene (1:1, 50 mL) was heated at reflux for 2 h. The reaction mixture was cooled to room temperature, filtered through Celite®, and concentrated in vacuo. Purification by silica gel chromatography using 5% methanol/ethyl acetate afforded the title product (350 mg). MS m/z 258 (M+−16); 1H NMR (CDCl3) δ 1.1 (d, 3H), 1.3 (t, 3H), 2.1 (m, 2H), 2.4 (m, 1H), 4.2 (m, 2H), 4.5 (m, 1H), 3.8 (dd, 1H), 7.2 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:2].[OH:11]N1C(=O)C2=CC=CC=C2C1=O>C(#N)C>[CH:4](=[O:3])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[C:4]([O:3][CH2:1][CH3:2])(=[O:11])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CCOCc1ccccc1
Solvent: CC#N
Product: CCOC(=O)c1ccccc1
Product: O=Cc1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 18 %
Yield: 57 %

Procedure:
A mixture of 1 mmol of benzyl ethyl ether, 0.1 mmol of N-hydroxyphthalimide, and 5 ml of acetonitrile was stirred at 60° C. under a nitrogen monoxide atmosphere (1 atm) for 5 hours. Gas chromatographic analysis of products in the reaction mixture revealed that benzyl ethyl ether was converted, at a rate of 82%, into benzaldehyde (yield: 57%), and ethyl benzoate (yield: 18%).