Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[N:8]=1.[C:14]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C1COCC1>[Br:13][C:9]1[N:8]=[C:7]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[OH:21])[CH:12]=[CH:11][CH:10]=1
Reactant: Brc1cccc(Br)n1
Reactant: O=C(c1ccccc1)c1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1ccccc1)(c1ccccc1)c1cccc(Br)n1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 35 %

Procedure:
At −78° C. a 2.5 M solution of n-butyl lithium in hexanes (18.6 mL, 46.4 mmol, 1.1 equiv) was added dropwise to 2,6-dibromopyridine (1) (10.0 g, 42.2 mmol, 1.0 equiv) in THF (780 mL). The solution was then stirred for 20 min at which point benzophenone (8.07 g, 44.3 mmol, 1.05 equiv) was added. The reaction was allowed to stir an additional 0.5 hr at −78° C., at this time the cooling bath was removed and the reaction allowed to warm room temperature. The reaction was stirred at room temperature for 1 hr and quenched with saturated sodium bicarbonate (250 mL). The layers were separated and the aqueous layer extracted with dichloromethane (250 mL). The combined organic layers were dried over sodium sulfate and absorbed onto silica gel (30 g) by concentration under reduced pressure. This material was then purified on a silica gel column (300 g) by eluting with heptanes (2 L), ethyl acetate (2%) in heptanes (2 L) and finally ethyl acetate (5%) in heptanes (2 L). The desired product was isolated pure in 35% yield (5.0 g). A second fraction (5.4 g) of product and benzophenone was also isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[CH:4][C:3]=1[OH:12].P(=O)(O)(O)O.[N+:18]([O-])([OH:20])=[O:19]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[C:4]([N+:18]([O-:20])=[O:19])[C:3]=1[OH:12]
Reactant: O=[N+]([O-])O
Reactant: CC(=O)Nc1ccc(Cl)c(O)c1
Agent: O=P(O)(O)O
Agent: O=S(=O)(O)O
Product: CC(=O)Nc1ccc(Cl)c(O)c1[N+](=O)[O-]
Temperature: -30 °C

Procedure:
0.23 mole (43 g) of 2-chloro-5-acetylamino phenol is dissolved, with agitation, in 500 cc of sulfuric acid (d=1.83) at a temperature of about +5° C. There are then added 15 cc of phosphoric acid and the resulting reaction medium is cooled to -30° C. There are then slowly added, over a 35 minute period, while vigorously agitating, 9.7 cc of nitric acid (d=1.52) in 1.5 cc of sulfuric acid (d=1.83). The reaction mixture is then poured over 3 kgs of shaved ice to precipitate the desired product which is separated by filtration, washed with water and dried, yielding 47 g of product.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:16])[CH2:15][CH2:14][CH2:13]1.CCN(C(C)C)C(C)C>CC#N>[CH:12]1([NH:16][C:2]2[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=2[N+:9]([O-:11])=[O:10])[CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCC1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(F)cc1NC1CCC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2,4-difluoro-1-nitrobenzene (0.7 mL, 6.3 mmol) in CH3CN (10 mL) were added cyclobutylamine (0.54 mL, 6.3 mmol) and DIPEA (1.1 mL, 6.3 mmol). The reaction mixture was stirred at RT for 18 h then concentrated in vacuo. The resulting residue was purified by column chromatography (Si—PCC, gradient 0-10% EtOAc in cyclohexane) to afford cyclobutyl-(5-fluoro-2-nitrophenyl)amine as a yellow oil (1.38 g, quantitative). To a solution of the product thus obtained (6.3 mmol) in EtOAc (60 mL) was added 10% Pd/C (150 mg) and the reaction mixture stirred at RT for 18 h under a hydrogen atmosphere. The suspension was filtered through a pad of Celite® and the filtrate concentrated in vacuo to afford the title compound as an orange oil (1.1 g, quantitative). 1H NMR (CDCl3, 300 MHz): δ 6.63-6.56 (1H, m), 6.35-6.19 (2H, m), 3.92-3.78 (1H, m), 3.66-2.91 (2H, m), 2.53-2.36 (2H, m), 1.94-1.73 (4H, m).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([OH:23])=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[CH2:24]([O:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([C:35]#[C:36][CH:37]2[CH2:41][CH2:40][CH2:39][NH:38]2)=[CH:31][CH:30]=1)=[O:28])[CH3:25].C(Cl)CCl.Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([N:38]2[CH2:39][CH2:40][CH2:41][CH:37]2[C:36]#[C:35][C:32]2[CH:33]=[CH:34][C:29]([C:27]([O:26][CH2:24][CH3:25])=[O:28])=[CH:30][CH:31]=2)=[O:23])[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11]
Reactant: CCOC(=O)c1ccc(C#CC2CCCN2)cc1
Reactant: COc1cc(CC(=O)O)ccc1NC(=O)Nc1ccccc1C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(C#CC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)cc1
Reaction time: 8 h
Yield: 88.6 %

Procedure:
A mixture of 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetic acid (1.45 g, 4.6 mmol), 2-(2-(4-ethoxycarbonylphenyl)ethynyl)pyrrolidine (1.12 g, 4.6 mmol), EDC 1.32 g (6.9 mmol), DMAP (562 mg, 4.6 mmol) in DMF (20 ml-) was stirred overnight. The mixture was poured into 1 N HCl and the solid was collected with suction. The solid was dissolved in CHCl3 and dried over MgSO4. After removal of the solvent, the residue was chromatographed on silica-gel with CHCl3-MeOH (100:1, v/v) as eluent to give 2.20 g (89%) ethyl 4-[2-[1-[3-methoxy-4-(N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]ethynyl]benzoate as a white amorphous solid.
Reaction SMILES: [Br:1][C:2]1[C:17]([CH2:18][N:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[CH:16][C:5]([C:6]([O:8]CC2C=CC=CC=2)=[O:7])=[C:4]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1.[OH-].[Li+].O.Cl>O1CCCC1>[Br:1][C:2]1[C:17]([CH2:18][N:19]2[CH2:20][CH2:21][O:22][CH2:23][CH2:24]2)=[CH:16][C:5]([C:6]([OH:8])=[O:7])=[C:4]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:3]=1
Reactant: O=C(OCc1ccccc1)c1cc(CN2CCOCC2)c(Br)cc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(CN2CCOCC2)c(Br)cc1OCc1ccccc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
To a solution of phenylmethyl 4-bromo-5-(4-morpholinylmethyl)-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 34; 305 mg, 0.61 mmol) in tetrahydrofuran (6 ml) was added lithium hydroxide (44.1 mg, 1.84 mmol) and water (1.5 ml). The mixture was stirred at 40° C. overnight, cooled and 2N HCl added. The solvent was removed, water (3 ml) was added and the product filtered to yield the title compound as a white solid which was used directly in the next step without further purification. 170 mg.
Reaction SMILES: [CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH2:15][CH2:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1.ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>O1CCOCC1>[CH2:1]=[C:2]1[C:19]2[C@:14]([CH3:21])([CH:15]=[CH:16][C:17](=[O:20])[CH:18]=2)[C@@H:13]2[C@H:4]([C@H:5]3[C@@:9]([CH2:11][CH2:12]2)([CH3:10])[C:8](=[O:22])[CH2:7][CH2:6]3)[CH2:3]1
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)C=C12
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: C1COCCO1
Product: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)C=CC(=O)C=C12
Yield: 50.3 %

Procedure:
0.50 g of 6-methylenandrost-4-ene-3,17-dione and 0.57 g of dichlorodicyanobenzoquinone were refluxed in 20 ml of anhydrous dioxane for about 15 hours. To remove the DDQ the suspension was filtered through alumina. After evaporation of the solvent the residue was dissolved in ethyl acetate, the organic layer washed with water, dried over sodium sulfate and the solent removed under vacuum. The crude product was chromatographed on silica gel using hexane/ethyl acetate 40% to yield 0.25 g of pure 6-methylenandrosta-1,4-diene-3,17-dione, m.p. 188°-191° C., λmax 247 mμ (ε13.750). Found: C 81.01, H 8.05. C20H24O2 requires: C 81.04, H 8.16.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=[N:3]1.C(Cl)(=O)C([Cl:13])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:7]([Cl:13])=[O:9])=[CH:5][CH:4]=[N:3]1
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1nccc1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cn1nccc1C(=O)Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 97.5 %

Procedure:
A suspension of 800 mg (6.03 mmol) of 2-methyl-2H-pyrazole-3-carboxylic acid in 30 mL of DCM is placed under argon and cooled to 0° C. When the temperature is reached, 1.32 mL (15.07 mmol) of oxalyl chloride and a catalytic amount of DMF are added. The reaction mixture is stirred at room temperature for 2 hours and then evaporated to dryness and the residue is taken up in DCM and evaporated again to give 850 mg of 2-methyl-2H-pyrazole-3-carbonyl chloride, the characteristics of which are as follows:
Reaction SMILES: FC(F)(C(F)(F)F)COC1N=C(C(O)=O)C=CC=1.[CH:19]1([C:22]2[CH:23]=[CH:24][C:25]([C:37](O)=[O:38])=[N:26][C:27]=2[O:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[CH2:21][CH2:20]1.[NH2:40][C@@H:41]([CH2:46][C:47]([CH3:50])([CH3:49])[CH3:48])[C:42]([NH:44][CH3:45])=[O:43]>>[CH3:48][C:47]([CH3:50])([CH3:49])[CH2:46][C@H:41]([NH:40][C:37]([C:25]1[CH:24]=[CH:23][C:22]([CH:19]2[CH2:20][CH2:21]2)=[C:27]([O:28][CH2:29][C:30]([F:35])([F:36])[C:31]([F:32])([F:33])[F:34])[N:26]=1)=[O:38])[C:42](=[O:43])[NH:44][CH3:45]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1
Reactant: CNC(=O)[C@@H](N)CC(C)(C)C
Agent: O=C(O)c1cccc(OCC(F)(F)C(F)(F)F)n1
Product: CNC(=O)[C@H](CC(C)(C)C)NC(=O)c1ccc(C2CC2)c(OCC(F)(F)C(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 1, using the mixture of 6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid and 5-cyclopropyl-6-(2,2,3,3,3-pentafluoro-propoxy)-pyridine-2-carboxylic acid (Example 297b) and (2S)-2-amino-N,4,4-trimethyl-pentanamide (CAN 1160161-70-5) as starting materials, the product was isolated by preparative HPLC; LC-MS (UV peak area/ESI) 100%, 452.1962 (M+H)+.
Reaction SMILES: [S:1]1([C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[C:5](=[O:6])[NH:4]1)(=[O:3])=[O:2].[Na].[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18]Cl>CN(C)C=O>[Cl:14][CH2:15][CH2:16][CH2:17][CH2:18][N:4]1[C:5](=[O:6])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=2[S:1]1(=[O:2])=[O:3]
Reactant: O=C1NS(=O)(=O)c2ccccc21
Reactant: ClCCCCCl
Agent: [Na]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2S(=O)(=O)N1CCCCCl
Yield: 12.9 %

Procedure:
Sodium saccharin (5.6 g, 0.027 mole) and 1,4-dichlorobutane (14.9 ml, 0.135 mole) were taken into 100 ml of dimethylformamide and heated on a steam bath for 4 hours. The reaction mixture was evaporated in vacuo to an oil and the oil extracted with 100 ml of hexane. Residual hexane was removed from the remaining oil by vacuum evaporation to yield the title product (956 mg).
Reaction SMILES: NC1N=[C:6](N2CCC3(CN[C@H](C(OC(C)C)=O)C3)CC2)[CH:5]=[C:4](O[C@H](C2C=CC(C3C=CC(C)=C(C)C=3)=CC=2N2C=CC(C)=N2)C(F)(F)F)N=1.[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([OH:67])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([C:82]3[CH:87]=[CH:86][C:85]([O:88][CH:89]([CH3:91])[CH3:90])=[CH:84][CH:83]=3)=[CH:78][C:77]=2[N:92]2[CH:96]=[CH:95][C:94]([CH3:97])=[N:93]2)[C:72]([F:75])([F:74])[F:73])[N:52]=1>>[NH2:50][C:51]1[N:56]=[C:55]([N:57]2[CH2:69][CH2:68][C:60]3([CH2:64][NH:63][C@H:62]([C:65]([O:67][CH:5]([CH3:6])[CH3:4])=[O:66])[CH2:61]3)[CH2:59][CH2:58]2)[CH:54]=[C:53]([O:70][C@H:71]([C:76]2[CH:81]=[CH:80][C:79]([C:82]3[CH:87]=[CH:86][C:85]([O:88][CH:89]([CH3:91])[CH3:90])=[CH:84][CH:83]=3)=[CH:78][C:77]=2[N:92]2[CH:96]=[CH:95][C:94]([CH3:97])=[N:93]2)[C:72]([F:73])([F:74])[F:75])[N:52]=1
Reactant: Cc1ccn(-c2cc(-c3ccc(OC(C)C)cc3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1
Reactant: Cc1ccn(-c2cc(-c3ccc(C)c(C)c3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1
Product: Cc1ccn(-c2cc(-c3ccc(OC(C)C)cc3)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)OC(C)C)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
The title compound was prepared as described for (S)-isopropyl 8-(2-amino-6-((R)-1-(3′,4′-dimethyl-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate (Example 67a) starting with (S)-8-(2-amino-6-((R)-2,2,2-trifluoro-1-(4′-isopropoxy-3-(3-methyl-1H-pyrazol-1-yl)-[1,1′-biphenyl]-4-yl)ethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylic acid (Example 11).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][C@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]>>[C:32]([O:36][C:37]([N:39]1[CH2:44][CH2:43][N:42]([C:20]2[S:21][C:17](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:26]=[CH:27][C:2]([Cl:1])=[CH:3][C:4]=3[C:28]([F:31])([F:29])[F:30])[N:8]=[CH:9]4)[C:18](=[O:25])[N:19]=2)[CH2:41][C@H:40]1[CH2:45][O:46][CH3:47])=[O:38])([CH3:35])([CH3:34])[CH3:33]
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: COC[C@@H]1CNCCN1C(=O)OC(C)(C)C
Product: COC[C@@H]1CN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CCN1C(=O)OC(C)(C)C

Procedure:
4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(S)-methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-(S)-Methoxymethyl-piperazine-1-carboxylic acid tert-butyl ester following General Procedure C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([NH:22][CH2:23][CH2:24][N:25]([C:31](=[O:53])[CH2:32][C:33]2[C:41]3[C:36](=[N:37][CH:38]=[N:39][C:40]=3[NH:42][C:43]([C:45]3[CH:50]=[CH:49][C:48]([O:51][CH3:52])=[CH:47][CH:46]=3)=[O:44])[NH:35][N:34]=2)[CH2:26][C:27]([O:29]C)=[O:28])([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:5][CH:4]=1.[OH-].[Na+]>O1CCOCC1>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]([NH:22][CH2:23][CH2:24][N:25]([C:31](=[O:53])[CH2:32][C:33]2[C:41]3[C:36](=[N:37][CH:38]=[N:39][C:40]=3[NH:42][C:43]([C:45]3[CH:46]=[CH:47][C:48]([O:51][CH3:52])=[CH:49][CH:50]=3)=[O:44])[NH:35][N:34]=2)[CH2:26][C:27]([OH:29])=[O:28])([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:7][CH:8]=1
Reactant: COC(=O)CN(CCNC(c1ccccc1)(c1ccccc1)c1ccc(OC)cc1)C(=O)Cc1n[nH]c2ncnc(NC(=O)c3ccc(OC)cc3)c12
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(C(=O)Nc2ncnc3[nH]nc(CC(=O)N(CCNC(c4ccccc4)(c4ccccc4)c4ccc(OC)cc4)CC(=O)O)c23)cc1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Compound (12) (1.43 g; 2 mmole) is dissolved in dioxane (10 ml). The solution is cooled to 0° C., and 1 M aqueous NaOH (8.66 ml) is added drop-wise in 5 aliquots over 2.5 hours. After an additional 2 hours at room temperature, the pH is adjusted to 5 by drop-wise addition of 2M HKSO4. Precipitated salts are filtered off, washed with dioxane, then the combined filtrates are dried in vacuo. The residue (13) is co-evaporated with ethanol and methanol/CH2Cl2, then purified by silica gel chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][NH:6]2.Cl.CN(C)CCCN=C=NCC.[CH3:25][N:26]1[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=[C:27]1[CH2:39][C:40]([O-])=[O:41].[Na+].O>CN(C)C=O.N1C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH3:12])([CH3:11])[CH2:5][N:6]2[C:40](=[O:41])[CH2:39][C:27]1[N:26]([CH3:25])[C:31](=[O:32])[CH:30]=[C:29]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[N:28]=1
Reactant: CC1(C)CNc2cccc(Cl)c21
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: O
Solvent: CN(C)C=O
Product: Cn1c(CC(=O)N2CC(C)(C)c3c(Cl)cccc32)nc(N2CCOCC2)cc1=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 26.4 %

Procedure:
20 mg of 4-chloro-3,3-dimethyl-2,3-dihydro-1H-indole [which can be prepared according to Tet. Let. (1987) (28), 5291-5294] and 34 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride are added to a solution of 30 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate in 0.5 ml of N,N-dimethylformamide and 0.5 ml of pyridine. The reaction mixture is stirred at ambient temperature for 16 hours, and then 10 ml of water are added and the mixture is extracted with ethyl acetate. The organic phase is washed successively with water and a saturated sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica column chromatography, elution being carried out with ethyl acetate, so as to give 12 mg of 2-[2-(4-chloro-3,3-dimethyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-3-methyl-6-(morpholin-4-yl)pyrimidin-4(3H)-one, the characteristics of which are the following:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:12])[CH3:11])[CH:6]=[CH:7][CH:8]=1)#[CH:2].Br[C:14]1[CH:15]=[N:16][CH:17]=[C:18]([CH:31]=1)[C:19]([N:21]=[S@@:22]([CH3:30])(=[O:29])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>>[C:10]([NH:9][C:5]1[CH:4]=[C:3]([C:1]#[C:2][C:14]2[CH:15]=[N:16][CH:17]=[C:18]([CH:31]=2)[C:19]([N:21]=[S@@:22]([CH3:30])(=[O:29])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:8]=[CH:7][CH:6]=1)(=[O:12])[CH3:11]
Reactant: C[S@@](=O)(=NC(=O)c1cncc(Br)c1)c1ccccc1
Reactant: C#Cc1cccc(NC(C)=O)c1
Product: CC(=O)Nc1cccc(C#Cc2cncc(C(=O)N=[S@@](C)(=O)c3ccccc3)c2)c1
Yield: 67.8 %

Procedure:
In a manner similar to that described in Example 449, N-(3-ethynyl-phenyl)-acetamide (0.0469 g, 0.443 mmol) and (S)-5-bromo-N-[methyl(oxo)phenyl-λ6-sulfanylidene]nicotinamide (100 mg, 0.295 mmol) were reacted to give the title compound as a solid (83 mg, 0.20 mmol, 67%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]([F:48])([F:47])[C:10]1[N:14]2[N:15]=[C:16]([N:19]3[CH2:24][CH2:23][CH:22]([C:25]4[CH:46]=[CH:45][C:28]([O:29][CH2:30][CH2:31][N:32]5[CH2:37][CH2:36][N:35](C(OC(C)(C)C)=O)[CH2:34][CH2:33]5)=[CH:27][CH:26]=4)[CH2:21][CH2:20]3)[CH2:17][CH2:18][C:13]2=[N:12][N:11]=1>C(Cl)Cl>[N:32]1([CH2:31][CH2:30][O:29][C:28]2[CH:45]=[CH:46][C:25]([CH:22]3[CH2:23][CH2:24][N:19]([C:16]4[CH2:17][CH2:18][C:13]5[N:14]([C:10]([C:9]([F:47])([F:48])[F:8])=[N:11][N:12]=5)[N:15]=4)[CH2:20][CH2:21]3)=[CH:26][CH:27]=2)[CH2:33][CH2:34][NH:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: FC(F)(F)c1nnc2n1N=C(N1CCC(c3ccc(OCCN4CCNCC4)cc3)CC1)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
TFA (10 mL) was added to tert-butyl 4-[2-[4-[1-[3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazin-6-yl)piperidin-4-yl]phenoxy]ethyl]piperazine-1-carboxylate (2.02 g, 3.50 mmol) in DCM (10 mL). The resulting solution was stirred at ambient temperature for 1 hour then added to an SCX column. The desired product was eluted from the column using 2M ammonia/MeOH and the solvents were evaporated to afford 6-[4-[4-[2-(piperazin-1-yl)ethoxy]phenyl]piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro-[1,2,4]triazolo[4,3-b]pyridazine (1.660 g, 99%) as a solid.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:30])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>O.C(O)C>[NH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:21]([CH:18]2[CH2:19][CH2:20][N:15]([CH2:14][CH2:13][O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[C:5]([OH:30])=[O:4])[CH2:16][CH2:17]2)=[CH:22]1
Reactant: COC(=O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccccc1OCCN1CCC(c2c[nH]c3ccccc23)CC1
Temperature: 60 °C

Procedure:
A solution of 1.33 g (33 mmol) of sodium hydroxide in 120 mL of water was added to a suspension of 6.31 g (16.6 mmol) of 2-{2-[4-(1H-indol-3-yl)-piperidin-1-yl]-ethoxy}-benzoic acid methyl ester (prepared in Example 1, part D) in 120 mL of ethanol. This mixture was heated at 60° C. for 3 hours and the solvent was removed under reduced pressure. After addition of 50 mL of water, the crude mixture was neutralised with HCl 2N and the solid formed was isolated. After recrystallisation from acetonitrile, 2.6 g (43% of yield) of a white solid corresponding to the desired product were obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:19])[C:8](=[O:18])[N:9]2[CH2:12][CH:13]([CH2:16][CH3:17])[CH2:14][CH3:15])=[CH:4][C:3]=1[N+:20]([O-:22])=[O:21].[CH3:23][O:24][C:25]([C:27]1(OC)[CH2:31][CH2:30][CH:29](OC)O1)=[O:26]>C(O)(=O)C>[CH2:14]([CH:13]([CH2:16][CH3:17])[CH2:12][N:9]1[C:10]2[C:5](=[CH:4][C:3]([N+:20]([O-:22])=[O:21])=[C:2]([N:1]3[CH:29]=[CH:30][CH:31]=[C:27]3[C:25]([O:24][CH3:23])=[O:26])[CH:11]=2)[NH:6][C:7](=[O:19])[C:8]1=[O:18])[CH3:15]
Reactant: COC(=O)C1(OC)CCC(OC)O1
Reactant: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(N)cc21
Solvent: CC(=O)O
Product: CCC(CC)Cn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3cccc3C(=O)OC)cc21
Temperature: 0 °C
Yield: 27.1 %

Procedure:
3.0 g (9.8 mmol) of 7-amino-1-(2-ethylbutyl)-6-nitro-2,3(1H,4H)-quinoxalinedione (Example 40h) and 1.8 g (9.8 mmol) of 2-methoxycarbonyl-2,5-dimethoxytetrahydrofuran were refluxed in 150 ml of concentrated acetic acid for 1 h. The mixture was then poured into ice-water, and the precipitate was filtered off with suction to yield 1.1 g (28%) of the product. Melting point 240°-241° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:17]2[CH:16]=[C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:14]3[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=3[C:12]=2[C:11]2[CH:10]=[C:9]([OH:29])[CH:8]=[CH:7][C:6]1=2.[NH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[OH:29][C:9]1[CH:8]=[CH:7][C:6]2[N:5]([CH2:4][CH2:3][CH2:2][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:17]3[CH:16]=[C:15]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[C:14]4[C:24](=[O:28])[NH:25][C:26](=[O:27])[C:13]=4[C:12]=3[C:11]=2[CH:10]=1
Reactant: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCBr
Reactant: C1COCCN1
Product: O=C1NC(=O)c2c1c(-c1ccccc1)cc1c2c2cc(O)ccc2n1CCCN1CCOCC1
Yield: 72 %

Procedure:
Bromide (204) (0.01 g, 0.22 mmol) prepared as described in example 173 was reacted with morpholine according to the procedure described in example 179 to give amine (210) (73 mg, 72%) as a yellow powder, mp 252–255° C. 1H NMR δ [(CD3)2SO] 11.04 (br s, 1H), 9.33 (s, 1H), 8.41 (d, J=2.5 Hz, 1H), 7.81 (s, 1H), 7.62 (m, 2H), 7.57 (d, J=8.9 Hz, 1H), 7.47 (m, 3H), 7.12 (dd, J=8.9, 2.5 Hz, 1H), 4.51 (t, J=6.3 Hz, 2H), 3.38 (t, J=4.0 Hz, 4H), 2.18 (br s, 4H), 2.14 (t, J=6.3 Hz, 2H), 1.93 (m, 2H). Found: C, 71.11; H, 5.46; N, 9.29. C27H25N3O4 requires: C, 71.19; H, 5.53; N, 9.22.
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[C:6]([O:14]C(=O)C)=[CH:5]1)(=[O:3])[CH3:2].S([O-])([O-])=O.[Na+].[Na+]>O>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][C:9]([Cl:13])=[CH:10][CH:11]=2)[C:6]([OH:14])=[CH:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cn(C(C)=O)c2ccc(Cl)cc12
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)n1cc(O)c2cc(Cl)ccc21
Temperature: 80 °C
Yield: 66.1 %

Procedure:
1-acetyl-5-chloro-3-acetoxyindole (1.0 g, 3.97 mmol) and sodium sulfite (1.0 g, 7.94 mmol) were mixed in 20 ml water. After heated for 3 hours at 80° C., the reaction mixture was cooled down to room temperature, and then extracted with ethyl acetate (50 ml×2). The combined organic phases were dried and evaporated to obtain a solid as white needles (1-acetyl-5-chloro-3-hydroxyindole) (0.55 g, yield: 66%; mp: 186-188° C.).