Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:10])[O:9][C:6]([CH3:8])([CH3:7])[O:5][C:3](=[O:4])[CH2:2]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:20]=[C:21]([N:26]=[C:27]=[O:28])[CH:22]=[CH:23][C:24]=1[Cl:25].Cl>CS(C)=O.O>[CH3:7][C:6]1([CH3:8])[O:9][C:1](=[O:10])[C:2]([C:27](=[O:28])[NH:26][C:21]2[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=2)=[C:3]([OH:4])[O:5]1
Reactant: CC1(C)OC(=O)CC(=O)O1
Reactant: O=C=Nc1ccc(Cl)c(Cl)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: CS(C)=O
Product: CC1(C)OC(=O)C(C(=O)Nc2ccc(Cl)c(Cl)c2)=C(O)O1

Procedure:
To a solution of 14.4 g of isopropylidene malonate in 150 ml of dimethyl sulphoxide were added dropwise, at room temperature, 10.1 g of triethylamine and thereafter, at 20° to 30° C, 18.8 g of 3,4-dichlorophenylisocyanate in 30 ml of dimethyl sulphoxide. The mixture was reacted for 12 to 15 hours at room temperature and the resultant solution was poured into a solution of 20 ml of concentrated hydrochloric acid in 200 ml of water. The precipitate which formed was collected with suction. Recrystallisation from 130 ml of acetone yielded the product of the formula ##STR5## with a melting point of 132°-134° C.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]23[O:16][CH2:15][CH2:14][C@H:13]2[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[N:9]3)[CH:7]=1.[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33](O)=[O:34])=[N:31][CH:32]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[Br:26][C:27]1[CH:28]=[CH:29][C:30]([C:33]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([F:25])=[C:6]([C@:8]34[O:16][CH2:15][CH2:14][C@H:13]3[CH2:12][S:11][C:10]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])=[N:9]4)[CH:7]=2)=[O:34])=[N:31][CH:32]=1
Reactant: O=C(O)c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(N)ccc3F)OCC[C@H]2CS1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)NC1=N[C@@]2(c3cc(NC(=O)c4ccc(Br)cn4)ccc3F)OCC[C@H]2CS1
Yield: 68.8 %

Procedure:
A solution of (±)-tert-butyl (4aR,7aR)-7a-(5-amino-2-fluorophenyl)-4a,5,6,7a-tetrahydro-4H-furo[2,3-d][1,3]thiazin-2-ylcarbamate (31 mg), 5-bromopicolinic acid (26 mg), HATU (48 mg), and DIEA (44 μL) in DMF (0.41 mL) was stirred at rt for 2 h, and the crude reaction mixture was subjected to preparative HPLC eluting with 0-100% A/B (A: 95% H2O/5% MeCN, 10 mM NH4OAc; B: 5% H2O/95% MeCN, 10 mM NH4OAC over 12 min period to give the title compound as a yellow foam (32 mg, 68%). 1H NMR (500 MHz, CDCl3) δ 9.89 (1H, s), 8.71 (1H, s),8.21 (1H, dd, J=0.4, 8.0 Hz), 8.07 (1H, dd, J=2.0, 8.0 Hz), 8.03 (1H, m), 7.72 (1H, m), 7.14 (1H, t, J=10.5 Hz), 4.15 (2H, m), 3.32 (1H, m), 3.03 (1H, m), 2.90 (1H, m), 2.40 (1H, m), 2.22 (1H, m), and 1.51 (9H, s). MS (M+H)+: 553.3.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([NH:16][C@H:17]([C:21]([O:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.FC(C(O)=O)(F)F.[NH:38](C(OC(C)(C)C)=O)[CH2:39][C:40](ON1C(=O)CCC1=O)=[O:41].CN1CCOCC1>C(OCC)(=O)C>[NH2:38][CH2:39][C:40]([NH:1][C@H:2]([C:14]([NH:16][C@H:17]([C:21]([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:3][C:4](=[O:13])[O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:41]
Reactant: CC(C)(C)OC(=O)NCC(=O)ON1C(=O)CCC1=O
Reactant: CC(C)[C@H](NC(=O)[C@@H](N)CC(=O)OCc1ccccc1)C(=O)OCc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: CN1CCOCC1
Solvent: CCOC(C)=O
Product: CC(C)[C@H](NC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)CN)C(=O)OCc1ccccc1
Temperature: 20 °C
Reaction time: 72 h

Procedure:
A solution of 4.2 g. of H-Asp(OBzl)-Val-OBzl.TFA in 50 ml of ethyl acetate is treated in succession with 2.72 g of Boc-Gly-OSu and 0.88 ml of N-methylmorpholine and then stirred at 20° C. for 72 hours. The reaction mixture is partitioned between ethyl acetate and water and the organic phase is washed with 5% KHSO4 /10% K2SO4 solution, water, saturated NaHCO3 solution, water and saturated NaCl solution. After drying the solution is concentrated. The residue is dissolved in 30 ml of trifluoroacetic acid held at 20° C. for 20 minutes and then concentrated. After crystallization from ethyl acetate/hexane there are obtained 3.5 g of H-Gly-Asp(OBzl)-Val-OBzl, TFA (1:1), m.p. 150°-151° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][C:16]2[C:17](=[O:41])[N:18]([C@H:28]3[CH2:33][CH2:32][C@H:31]([O:34][CH2:35][C:36](OCC)=[O:37])[CH2:30][CH2:29]3)[C:19]3[N:20]([N:25]=[CH:26][CH:27]=3)[C:21]=2[CH2:22][CH2:23][CH3:24])=[CH:11][CH:10]=1)#[N:2].C(O)C.[BH4-].[Li+].[Cl-].[NH4+]>O1CCCC1.C(OCC)(=O)C>[OH:37][CH2:36][CH2:35][O:34][C@H:31]1[CH2:32][CH2:33][C@H:28]([N:18]2[C:17](=[O:41])[C:16]([CH2:15][C:12]3[CH:13]=[CH:14][C:9]([C:4]4[C:3]([C:1]#[N:2])=[CH:8][CH:7]=[CH:6][CH:5]=4)=[CH:10][CH:11]=3)=[C:21]([CH2:22][CH2:23][CH3:24])[N:20]3[N:25]=[CH:26][CH:27]=[C:19]23)[CH2:29][CH2:30]1
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCC(=O)OCC)CC2)c2ccnn12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n([C@H]2CC[C@H](OCCO)CC2)c2ccnn12
Reaction time: 18 h

Procedure:
To a solution of ethyl [(trans-4-{6-[(2′-cyanobiphenyl-4-yl)methyl]-5-oxo-7-propylpyrazolo[1,5-a]pyrimidin-4(5H)-yl}cyclohexyl)oxy]acetate (1.16 g) in tetrahydrofuran (8 mL)-ethanol (2 mL) was added lithium borohydride (0.46 g), and the mixture was stirred for 18 hr. To the reaction mixture were added ethyl acetate and saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and then with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.64 g, 60%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH:10]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][C:28]([C:32]4[CH:37]=[C:36]([F:38])[C:35]([O:39]COCC[Si](C)(C)C)=[CH:34][C:33]=4[CH2:48][CH3:49])=[CH:29][CH:30]=3)[N:25]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)[N:24]=2)=[NH:22])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C(=O)([O-])O.[Na+]>C(O)C>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11]([O:17][CH2:18][CH3:19])([O:14][CH2:15][CH3:16])[CH:10]([NH:20][C:21]([C:23]2[C:31]3[C:26](=[CH:27][C:28]([C:32]4[CH:37]=[C:36]([F:38])[C:35]([OH:39])=[CH:34][C:33]=4[CH2:48][CH3:49])=[CH:29][CH:30]=3)[N:25]([CH:50]3[CH2:55][CH2:54][CH2:53][CH2:52][O:51]3)[N:24]=2)=[NH:22])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC1(OCC)CCN(Cc2ccccc2)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(OCOCC[Si](C)(C)C)cc3CC)ccc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC1(OCC)CCN(Cc2ccccc2)CC1NC(=N)c1nn(C2CCCCO2)c2cc(-c3cc(F)c(O)cc3CC)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.1 %

Procedure:
To a solution of N-(1-benzyl-4,4-diethoxy-piperidin-3-yl)-6-[2-ethyl-5-fluoro-4-(2-trimethylsilanyl-ethoxymethoxy)-phenyl]-1-(tetrahydro-pyran-2-yl)-1H-indazole-3-carboxamidine (Preparation 8, 7.28 g, 9.4 mmol) in ethanol (32 mL) was added concentrated hydrochloric acid (12M, 3.92 mL, 47 mmol) and the resulting solution was allowed to stir at room temperature for 18 hours. The reaction mixture was cooled to 0° C. and neutralised by dropwise addition of a saturated aqueous solution of sodium hydrogen carbonate (150 mL). The mixture was extracted with EtOAc (2×200 mL). The combined organic layers were washed with further saturated aqueous sodium hydrogen carbonate solution (100 mL), dried over MgSO4 and concentrated in vacuo to give the title compound as a foam (6.06 g).
Reaction SMILES: O=[C:2]1[CH2:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[S:5][C:4]2[CH:13]=[CH:14][C:15]([CH2:17][C:18]([OH:20])=[O:19])=[CH:16][C:3]1=2.O.NN>C(O)C>[CH:16]1[C:3]2[CH2:2][CH2:8][C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[S:5][C:4]=2[CH:13]=[CH:14][C:15]=1[CH2:17][C:18]([OH:20])=[O:19]
Reactant: O=C(O)Cc1ccc2c(c1)C(=O)Cc1ccccc1S2
Agent: NN
Solvent: O
Solvent: CCO
Product: O=C(O)Cc1ccc2c(c1)CCc1ccccc1S2
Reaction time: 5 h
Yield: 84.4 %

Procedure:
To 400 mg of (10,11-dihydro-11-oxo dibenzo[b,f]thiepin-2-yl)-acetic acid were added 20 ml of ethanol and 1 ml of hydrazine hydrate, and the mixture was refluxed with stirring under a dry atmosphere for 5 hours. After cooling, the solvent was removed by distillation under reduced pressure, and to the resulting mixture were added 20 ml of diethylene glycol and 4.0 g of sodium hydroxide. Thereafter, the resulting mixture was stirred under a dry atmosphere at 130° C. for 2 hours. After subsequent cooling, water was added to the mixture which was then washed with ethyl acetate. The aqueous layer was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with a saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain a residue, which was chromatographed over 18 g of silica gel and eluted with n-hexane/acetone (5/1) to obtain pale yellow crystals. These crystals were recrystallized from acetone/n-hexane to give 321 mg (yield: 84%) of (10,11-dihydro dibenzo[b,f]-thiepin-2-yl)-acetic acid as colorless crystals having a melting point of 111°-112° C.
Reaction SMILES: [C:1]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:2][C:3]([CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])([C:5]([O:7][CH2:8][CH3:9])=[O:6])O.O1CCCC1.[H][H]>C(O)C>[CH2:2]([C:1]([O:17][CH2:18][CH3:19])=[O:16])[CH:3]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: [H][H]
Reactant: CCOC(=O)CC(O)(CC(=O)OCC)C(=O)OCC
Solvent: C1CCOC1
Solvent: CCO
Product: CCOC(=O)CC(CC(=O)OCC)C(=O)OCC
Yield: 45 %

Procedure:
400 ml of triethyl citrate were hydrogenated at 175° C. and 10 bar together with 1100 ml of tetrahydrofuran and 60 g of catalyst G (4-mm tablets) until the take-up of hydrogen had ceased. The reaction product was freed from ethanol and distilled under reduced pressure, giving 193 g (45%) of triethyl propane-1,2,3-tricarboxylate.
Reaction SMILES: CO[C:3](=[O:25])[CH2:4][CH2:5][C:6](=[O:24])[C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=2)=[CH:9][CH:8]=1.[CH2:26]([NH2:29])[CH:27]=[CH2:28].[Cl-].[NH4+]>>[CH2:26]([NH:29][C:3](=[O:25])[CH2:4][CH2:5][C:6](=[O:24])[C:7]1[CH:8]=[CH:9][C:10]([C:13]2[CH:14]=[CH:15][C:16]([O:19][C:20]([F:22])([F:23])[F:21])=[CH:17][CH:18]=2)=[CH:11][CH:12]=1)[CH:27]=[CH2:28]
Reactant: COC(=O)CCC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Reactant: C=CCN
Agent: [Cl-]
Agent: [NH4+]
Product: C=CCNC(=O)CCC(=O)c1ccc(-c2ccc(OC(F)(F)F)cc2)cc1
Temperature: 0 °C

Procedure:
Methyl-4-oxo-4-[4′-(trifluoromethoxy)-1,1′-biphenyl-4-yl]butanoate (VIII-a-1) (18.2 g, 52 mmol) is treated with allylamine (41.6 g, 730 mmol) and ammonium chloride (1.8 g, 33 mmol) and heated under reflux for 6 h. For work-up, the mixture is poured into ice-cold aqueous HCl (2 M) and extracted with ethyl acetate. The combined organic phases are dried (Na2SO4) and concentrated. The crude product (17.7 g, content: 84.5%, HPLC, 100% method) is recrystallized from toluene.
Reaction SMILES: ClC1C=CC=CC=1.CO[CH:10](OC)[CH2:11][S:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].[CH3:22][O:23]C(Cl)Cl.C([O-])(O)=O.[Na+]>O.C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:19][C:14]1[C:13]2[S:12][CH:11]=[C:10]([CH:22]=[O:23])[C:18]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(Cl)Cl
Reactant: COC(CSc1ccccc1F)OC
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: Clc1ccccc1
Solvent: ClCCl
Product: O=Cc1csc2c(F)cccc12
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
2-Fluorothiophenol (4.14 g, 32.6 mmol) was dissolved in anhydrous THF (100 mL). Potassium tert-butoxide (1.0 M in THF, 35.8 mL) was added and the suspension was stirred at room temperature for 15 minutes. 2-Chloroacetaldehyde dimethyl acetal was added and the mixture was stirred for 3 days. Water (100 mL) was added and the solution was extracted with diethyl ether (3×100 mL). The extracts were concentrated to a yellow oil and chromatographed (5 to 20% ethyl acetate in hexane) to yield 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene (6.42 g) as a colorless oil. Chlorobenzene (25 mL) was heated to reflux and polyphosphoric acid (1 mL) was added. The 1-(2,2-dimethoxy-ethylsulfanyl)-2-fluoro-benzene was then added slowly turning the solution dark. After 3 hours of heating, the reaction was cooled to room temperature and diluted with water (50 mL). The solution was extracted with benzene (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophenyl (0.77 g). The 7-fluorobenzothiophenyl (0.77 g, 5.1 mmol) and dichloromethyl methyl ether (0.872 g, 7.6 mmol) were dissolved in anhydrous DCM (25 mL). Titanium tetrachloride (1.0 M in DCM, 7.6 mL, 7.6 mmol) was added, turning the solution dark. After 30 minutes at room temperature, the reaction was poured into a mixture of saturated aqueous NaHCO3 and ice. The mixture was stirred for about 30 minutes and then was extracted with DCM (2×50 mL). The extracts were concentrated and chromatographed (0 to 15% ethyl acetate in hexane) to yield 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g). The 7-fluorobenzothiophene-3-carboxaldehyde (0.642 g, 3.77 mmol) and sulfamide (1.7 g, 18 mmol) were combined in anhydrous ethanol (20 mL) and heated to reflux for three days. The reaction was cooled to room temperature and sodium borohydride (0.148 g, 3.92 mmol) was added. After two hours, water (25 ml) was added and the solution was extracted with chloroform (3×25 mL). The extracts were concentrated, suspended in a minimal amount of DCM, and filtered to yield the title compound as a yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:13])([F:12])[F:11])[CH:9]=1)([O-])=O>[OH-].[OH-].[Pd+2].CCOC(C)=O>[NH2:1][C:4]1[CH:5]=[C:6]([OH:14])[CH:7]=[C:8]([C:10]([F:11])([F:12])[F:13])[CH:9]=1
Reactant: O=[N+]([O-])c1cc(O)cc(C(F)(F)F)c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Nc1cc(O)cc(C(F)(F)F)c1
Yield: 87.5 %

Procedure:
To a solution of 3-Nitro-5-trifluoromethyl-phenol 44 (1.6 g, 7.73 mmol) was added a catalytic amount of 20% palladium hydroxide on carbon and the reaction was stirred under a hydrogen atmosphere (balloon) over the weekend resulting in complete conversion to product by TLC (40% EtOAc:Hexanes). The reaction was filtered to give 3-Amino-5-trifluoromethyl-phenol (1.2 g, 6.76 mmol) as a brown/red oil.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br)([O-:10])=[O:9].C(N(CC)CC)C>CN(C)C=O>[N+:8]([C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)([O-:10])=[O:9]
Reactant: O=[N+]([O-])c1ccccc1CBr
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccccc1CN1CCC(O)CC1
Reaction time: 16 h
Yield: 69.7 %

Procedure:
0.75 g (0.00741 mol) of 4-hydroxy-piperidine were dissolved in 40 ml of dimethylformamide and cooled to 0°. 3.0 g (0.00926 mol) of 2-nitro-benzyl bromide and 2.87 ml (0.0204 mol) of triethylamine were added under argon and the mixture was left to come to room temperature. It was stirred for 16 hrs., the solvent was distilled off and the residue was taken up in dichloromethane. The organic phase was washed with water and saturated sodium chloride solution, dried over magnesium sulfate and concentrated and the residue was chromatographed on silica gel with dichloromethane/methanol (9:1) as the eluent. 1.22 g (56%) of 1-(2-nitro-benzyl)-piperidin-4-ol were obtained as a yellow oil. MS: me/e=237 (C12H17N2O3+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:34][CH2:35][CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1>CN1C(=O)CCC1>[CH3:24][O:23][C:13]1[C:11]2[N:12]=[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:25]=[CH:26][N:27]=[C:2]([NH:34][CH2:35][CH2:36][C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=4)[CH:3]=3)[S:9][C:10]=2[C:16]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)=[CH:15][CH:14]=1
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Br)c3)nc12
Reactant: NCCc1ccccn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN1CCCC1=O
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(NCCc4ccccn4)c3)nc12

Procedure:
From 2-bromo-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with cesium carbonate and 2-(2-aminoethyl)-pyridine in NMP. ES-MS m/e (%): 491 (M+H+, 100).
Reaction SMILES: ClC1C=C(N[C:16]2[C:25]3[C:20](=[CH:21][C:22](F)=[C:23](OCCOC)[CH:24]=3)[N:19]=[CH:18][C:17]=2[C:32]#[N:33])C=CC=1SC1N(C)C=CN=1.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][C:36]1=O>>[N:35]1([CH:34]2[CH2:21][CH2:20][N:19]([C:18]3[C:17]([C:32]#[N:33])=[CH:16][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[N:19]=3)[CH2:18][CH2:17]2)[CH2:39][CH2:38][CH2:37][CH2:36]1
Reactant: CN1CCCC1=O
Reactant: COCCOc1cc2c(Nc3ccc(Sc4nccn4C)c(Cl)c3)c(C#N)cnc2cc1F
Product: N#Cc1cc2ccccc2nc1N1CCC(N2CCCC2)CC1
Temperature: 105 °C

Procedure:
Following the procedure of Example 11, a mixture of 150 mg (0.31 mmol) of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)sulfanyl]phenyl}amino)-7-fluoro-6-(2-methoxyethoxy)-3-quinolinecarbonitrile and 287 mg (1.86 mmol) of 4-(1-pyrrolidinylpiperidine) in 1 mL of 1-methyl 2-pyrrolidinone is heated at 105° C. for 17 hours to yield the crude product. Purification by silica gel chromatography (gradient 98:2 methylene chloride/methanol to 4:1 methylene chloride/methanol) gives 120 mg of 4-({3-chloro-4-[(1-methyl-1H-imidazole-2-yl)thio]phenyl}amino)-6-(2-methoxyethoxy)-7-(4-pyrrolidin-1-ylpiperidin-1-yl quinoline-3-carbonitrile as a yellow solid, mp 238-241° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[C:21](N1CCOCC1)(=[O:23])[CH3:22].[Cl-].[NH4+]>C1COCC1.C(OCC)(=O)C>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:5]([C:21](=[O:23])[CH3:22])=[CH:4][CH:3]=1
Reactant: CC(=O)N1CCOCC1
Reactant: CC(C)(C)OC(=O)Nc1cccc(Cl)n1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(Cl)nc1NC(=O)OC(C)(C)C
Temperature: -50 °C
Reaction time: 2 h

Procedure:
0.65 g (2.9 mmol) of tert-butyl (6-chloropyridin-2-yl)carbamate (Example 105A) is introduced into 10 ml of THF and cooled to −50° C. 4.5 ml (7.2 mmol) of butyllithium (1.6 M) are added dropwise. After the dropwise addition is complete, the reaction is slowly warmed to −10° C. and kept at 0° C. for 2 h. It is then cooled to −40° C. again, and 740 mg (5.7 mmol) of N-acetylmorpholine dissolved in 4 ml of THF are added. The reaction solution is stirred at −40° C. for 1 h and then, at −40° C., poured into 1 l of ethyl acetate and 350 ml of ammonium chloride solution and extracted. The organic phase is separated off, dried over magnesium sulphate and concentrated in a rotary evaporator. The reaction mixture is chromatographed on silica gel (mobile phase cyclohexane/ethyl acetate 2:1). 218 mg (28% of theory) of the product are obtained as an oil.
Reaction SMILES: [CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([OH:7])=[O:6].N12CCCN=C1CCCCC2.Cl[CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[N:34][C:35]([Cl:41])=[CH:36][CH:37]=2)[N:32]=1.O>CN(C)C=O.ClCCl>[CH3:1][CH:2]([CH3:8])[CH2:3][CH2:4][C:5]([O:7][CH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23](=[O:30])[N:22]1[C:31]1[CH:40]=[CH:39][C:38]2[C:33](=[N:34][C:35]([Cl:41])=[CH:36][CH:37]=2)[N:32]=1)=[O:6]
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC(C)CCC(=O)O
Solvent: CN(C)C=O
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCC(=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Temperature: 20 °C
Reaction time: 24 h
Yield: 48.8 %

Procedure:
4-Methylpentanoic acid (2.4 g) and 1,8-diazabicyclo[5.4.0]undec-7-ene (3.05 g) are added at a temperature in the region of 20° C. to a solution, maintained under an argon atmosphere, of 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (6.6 g) in anhydrous dimethylformamide (60 cc), and the suspension obtained is stirred for 24 hours at a temperature in the region of 20° C. Distilled water (500 cc) and dichloromethane (150 cc) are then added. The aqueous phase is separated after settling has occurred and then re-extracted with dichloromethane (2×150 cc). The organic phases are combined, washed with distilled water (3×50 cc), dried over magnesium sulphate, filtered and then concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. The oily residue is purified by chromatography on silica gel (150 g) contained in a column 3.5 cm in diameter [eluant: dichloromethane/methanol (98.2 by volume)]. Elution is first performed with 200 cc of solvent: the corresponding eluate is discarded; elution is then performed with 900 cc of solvent: the corresponding eluate is concentrated to dryness under reduced pressure (2.7 kPa) at 40° C. After recrystallization in ethanol, 2-(7-chloro-1,8-naphthyridin-2-yl)-3-oxo-1-isoindolinyl 4-methylpentanoate (4 g), m.p. 147° C., is obtained.
Reaction SMILES: [N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]([C:12](=[S:15])[NH:13][NH2:14])[N:10]=[C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:8]1)=[N+:2]=[N-:3].[CH3:30]OC(OC)OC.CC1C=CC(S(O)(=O)=O)=CC=1>>[N:1]([CH2:4][CH2:5][CH2:6][C:7]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:11]([C:12]2[S:15][CH:30]=[N:14][N:13]=2)[N:10]=[C:9]([C:16]2[CH:21]=[C:20]([F:22])[CH:19]=[CH:18][C:17]=2[F:23])[S:8]1)=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1C(=S)NN
Reactant: COC(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Product: [N-]=[N+]=NCCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nncs1
Temperature: 80 °C
Yield: 89.3 %

Procedure:
2-(3-azidopropyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazole-3(2H)-carbothiohydrazide (220 mg, 0.51 mmol) was dissolved in trimethyl-orthoformate (1.62 g, 15.2 mmol) with a few crystals of pTsOH (10 mg, 0.05 mmol), and heated to 80° C. for 20 minutes. The reaction mixture was then concentrated and purified by flash column chromatography, eluting with 4:1 (hexanes/ethyl acetate), to afford the desired product as a light yellow oil (202 mg, 90%).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:14])([F:13])[F:12])=[C:8]([OH:10])[CH:9]=1)([O-:3])=[O:2].Cl.[CH3:16][N:17]([CH3:21])[CH2:18][CH2:19]Cl.C([O-])([O-])=O.[K+].[K+].CC(C)=O>O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:11]([F:12])([F:13])[F:14])=[C:8]([O:10][CH2:19][CH2:18][N:17]([CH3:21])[CH3:16])[CH:9]=1)([O-:3])=[O:2]
Reactant: CN(C)CCCl
Reactant: O=[N+]([O-])c1ccc(C(F)(F)F)c(O)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Product: CN(C)CCOc1cc([N+](=O)[O-])ccc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h

Procedure:
5-Nitro-2-trifluoromethylphenol (3.48 g, 16.8 mmol) was heated in a sealed tube at 105° C. along with 2-(dimethylamino)ethylchloride hydrochloride (5.32 g, 37.0 mmol), K2CO3 (9.76 g, 70.7 mmol), 114 mL acetone, 33 mL H2O, and Bu4N+I− (0.5 g, 1.34 mmol) for 24 h, then at 120° C. for 24 h. The reaction was cooled to RT and concentrated to aqueous layer, which was diluted with brine and 6 N NaOH and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel column chromatography yielded the title compound as a light brown oil.