Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([C:12](O)=[O:13])[C:6]=2[O:5][C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:3]1.ON1C2C=CC=CC=2N=N1.[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH2:55])=[CH:51][CH:50]=1)[CH2:37][CH2:36]2.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:31][O:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][C:42]=1[O:43][CH3:44])[CH2:39][N:38]([CH2:45][CH2:46][CH2:47][CH2:48][C:49]1[CH:54]=[CH:53][C:52]([NH:55][C:12]([C:11]3[C:6]4[O:5][C:4]([C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=5)=[CH:3][C:2](=[O:1])[C:7]=4[CH:8]=[CH:9][CH:10]=3)=[O:13])=[CH:51][CH:50]=1)[CH2:37][CH2:36]2
Reactant: COc1cc2c(cc1OC)CN(CCCCc1ccc(N)cc1)CC2
Reactant: O=C(O)c1cccc2c(=O)cc(-c3ccccc3)oc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: COc1cc2c(cc1OC)CN(CCCCc1ccc(NC(=O)c3cccc4c(=O)cc(-c5ccccc5)oc34)cc1)CC2
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
A mixture of 4-oxo-2-phenyl-4H-1-benzopyran-8-carboxylic acid* (1 g) and 1-hydroxybenzotriazole (0.58 g) in DMF (50 ml) was stirred at room temperature for 10 min. 4-[4-(1,2,3,4-Tetrahydro-6,7-dimethoxy-2-isoquinolinyl)butyl]benzenamine (intermediate 2(d) in EP-A-494623) (1.1 g) was then added, followed by dicyclohexylcarbodiimide (0.67 g) and the mixture was stirred at room temperature for 16 h and then filtered. The filtrate was concentrated in vacuo, treated with dilute sodium hydroxide solution and extracted with methylene chloride. The combined, dried, organic extracts were evaporated and the residue was purified by column chromatography on silica gel eluting with methylene chloride/methanol (99:1) to give the title compound (0.6 g) as a white solid, after crystallisation from ethyl acetate, mp=117°-120°.
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH2:21])([CH3:4])([CH3:3])[CH3:2].C([O:27][C:28](=O)[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])(C)(C)C>>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH3:16])[CH3:15])[C:11]([C:17]([F:20])([F:19])[F:18])=[CH:10][C:9]=1[NH:21][C:28](=[O:27])[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][N:35]=[C:34]([C:38]#[N:39])[CH:33]=1)=[O:31])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnc(C#N)c1
Product: CN(C)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2ccnc(C#N)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-dimethylamino-4-trifluoromethyl-phenyl)-carbamic acid tert.-butyl ester (Example J6) (319 mg, 1.0 mmol) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (Example K3) (246 mg, 1.0 mmol) according to the general procedure M. Obtained as an amorphous yellow substance (297 mg).
Reaction SMILES: [C:1]([O:10][CH2:11][Cl:12])(=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].C1(CC(O)=O)C=CC=CC=1.C(=O)([O-])O.[Na+].ClCOS(Cl)(=O)=O>S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC.O.ClCCl.ClCCl>[C:3]1([CH2:2][C:1]([O:10][CH2:11][Cl:12])=[O:9])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCCCCCCC(=O)OCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)Cc1ccccc1
Agent: O=C([O-])O
Solvent: O
Solvent: ClCCl
Product: O=C(Cc1ccccc1)OCCl
Reaction time: 18 h
Yield: 31 %

Procedure:
A similar procedure (Harada, N. et al. Synth. Commun. 1995, 25, 767-772) to that described for the preparation of 43 was followed using phenylacetic acid (4.50 g, 31.2 mmol), sodium hydrogen carbonate (10.48 g, 124.8 mmol) and tetra-n-butylammonium hydrogen sulfate (1.06 g, 3.12 mmol) in water-dichloromethane (125 mL, 1:1 v/v) and chloromethylchlorosulfate (5.15 g, 31.2 mmol) in dichloromethane (15 mL), at room temperature for 18 h. Purification by flash chromatography (hexane/ethyl acetate 9:1) afforded 49 as a yellow oil (1.81 g, 9.82 mmol, 31%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:13]2=[N:14][C:15](S(C)=O)=[N:16][CH:17]=[C:12]2[CH2:11][NH:10][C:9]1=[O:21].[NH2:22][C:23]1[CH:28]=[CH:27][C:26]([N:29]2[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]2)=[CH:25][CH:24]=1.FC(F)(F)C(O)=O>C(#N)C.C(OCC)(=O)C>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[N:8]1[C:13]2=[N:14][C:15]([NH:22][C:23]3[CH:24]=[CH:25][C:26]([N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[CH:27][CH:28]=3)=[N:16][CH:17]=[C:12]2[CH2:11][NH:10][C:9]1=[O:21]
Reactant: CS(=O)c1ncc2c(n1)N(C1CC3CCC1C3)C(=O)NC2
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CN1CCN(c2ccc(Nc3ncc4c(n3)N(C3CC5CCC3C5)C(=O)NC4)cc2)CC1
Temperature: 85 °C
Yield: 62.6 %

Procedure:
To a suspension of 300 mg (0.98 mmol) of 1-bicyclo[2.2.1]hept-2-yl-7-methanesulfinyl-3,4-dihydro-pyrimido[4,5-d]pyrimidin-2(1H)-one and 374 mg (1.96 mmol) of 1-(4-aminophenyl)-4-methylpiperazine in 4.0 mL of acetonitrile is added 377 μL (4.90 mmol) of trifluoroacetic acid. The mixture is heated at 85° C. overnight. The cooled reaction mixture is diluted with ethyl acetate and washed two times with saturated aqueous sodium bicarbonate solution and once with brine. The organic phase is dried over magnesium sulfate and concentrated. The dark solid residue is triturated in 4 mL of 1:1 dichloromethane/ethyl acetate, filtered, washed with ethyl acetate, and dried to give 266 mg (63%) of the title compound: mp 251-254° C. (dec).
Reaction SMILES: [CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15](Br)[CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[CH:23][C:24]=1[F:25]>>[CH:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[C:14](=[C:15]([C:21]4[CH:22]=[CH:23][C:24]([F:25])=[C:19]([Cl:18])[CH:20]=4)[CH:16]=2)[N:13]=[CH:12][CH:11]=[CH:10]3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: Brc1cc(CC2CCCC2)cc2cccnc12
Product: Fc1ccc(-c2cc(CC3CCCC3)cc3cccnc23)cc1Cl

Procedure:
6-(cyclopentylmethyl)-8-bromoquinoline and 3-chloro-4-fluorobenzene boronic acid can be combined to form 6-(cyclopentylmethyl)-8-(3-chloro-4-fluorophenyl)quinoline,
Reaction SMILES: [C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[C:21]3[S:25][C:24](=[S:26])[N:23]([CH2:27][C:28]([OH:30])=[O:29])[C:22]3=[O:31])[N:19]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:32](O)[CH3:33].Cl>O1CCOCC1>[C:1]1([CH:7]([NH:14][C:15]2[S:16][CH:17]=[C:18]([CH:20]=[C:21]3[S:25][C:24](=[S:26])[N:23]([CH2:27][C:28]([O:30][CH2:32][CH3:33])=[O:29])[C:22]3=[O:31])[N:19]=2)[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=C(O)CN1C(=O)C(=Cc2csc(NC(c3ccccc3)c3ccccc3)n2)SC1=S
Reactant: CCO
Agent: Cl
Solvent: C1COCCO1
Product: CCOC(=O)CN1C(=O)C(=Cc2csc(NC(c3ccccc3)c3ccccc3)n2)SC1=S

Procedure:
Following a procedure similar to that described in Example 30, the desired compound was prepared from 0.6 g of 5-(2-diphenylmethylaminothiazol-4-ylmethylene)rhodanine--acetic acid, 7.7 g of ethanol and 15 ml of a 4N dioxane solution of hydrogen chloride. The resulting product was a greenish-yellow powder having the following physical properties.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:18][CH2:19][C:20](Cl)=[O:21]>C(#N)C>[Cl:18][CH2:19][C:20]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:4]=[CH:3][C:2]([CH3:1])=[CH:11][CH:10]=1)=[O:21]
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: Cc1ccc(C(=O)NNC(=O)CCl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 86.1 %

Procedure:
To a mixture of 4-methylbenzohydrazide 14 (10 g, 66.59 mmol) and K2CO3 (16.57 g, 119.86 mmol) in acetonitrile (100 mL) was added 2-chloroacetyl chloride (9.02 g, 79.9 mmol) dropwise at ambient temperature. The resulting mixture was stirred at ambient temperature for 16 hours. The solid was collected, washed with H2O and ether, and dried to afford N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (13 g, 82%) which was used for the next step without further purification. A mixture of N′-(2-chloroacetyl)-4-methylbenzohydrazide 15 (6.0 g, 26.47 mmol) and phosphorous oxychloride (5.0 g, 32.84 mmol) in acetonitrile (20 mL) was stirred under reflux for 16 hours and concentrated. The residue was subjected to flush column chromatography eluting with 10-25% acetone/hexanes to give compound 16 (4 g). Yield: 72%.
Reaction SMILES: [CH:1]([Si:4]([CH:35]([CH3:37])[CH3:36])([CH:32]([CH3:34])[CH3:33])[O:5][C@@H:6]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]3[CH:16]=[C:17]([O:20][C@H:21]4[C:30]5[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=5)[C@@H:24]([NH2:31])[CH2:23][CH2:22]4)[CH:18]=[CH:19][C:14]3=[N:13][N:12]=2)[CH2:7]1)([CH3:3])[CH3:2].ClC(Cl)(Cl)C[O:41][C:42](=O)[NH:43][C:44]1[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=[C:47]([C:49]([CH3:52])([CH3:51])[CH3:50])[CH:48]=1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO.C(Cl)Cl>[C:49]([C:47]1[CH:48]=[C:44]([NH:43][C:42]([NH:31][C@@H:24]2[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C@H:21]([O:20][C:17]3[CH:18]=[CH:19][C:14]4[N:15]([C:11]([N:8]5[CH2:9][CH2:10][C@@H:6]([O:5][Si:4]([CH:1]([CH3:3])[CH3:2])([CH:32]([CH3:34])[CH3:33])[CH:35]([CH3:37])[CH3:36])[CH2:7]5)=[N:12][N:13]=4)[CH:16]=3)[CH2:22][CH2:23]2)=[O:41])[N:45]([C:53]2[CH:58]=[CH:57][C:56]([CH3:59])=[CH:55][CH:54]=2)[N:46]=1)([CH3:52])([CH3:50])[CH3:51]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)[Si](O[C@@H]1CCN(c2nnc3ccc(O[C@@H]4CC[C@H](N)c5ccccc54)cn23)C1)(C(C)C)C(C)C
Agent: N
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)N[C@H]2CC[C@@H](Oc3ccc4nnc(N5CC[C@@H](O[Si](C(C)C)(C(C)C)C(C)C)C5)n4c3)c3ccccc32)cc1
Yield: 53 %

Procedure:
A solution of Intermediate 38c (100 mg, 0.191 mmol), (5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-carbamic acid 2,2,2-trichloro-ethyl ester (Synthetic Communications, 2009, 39, 3999-4009, which is incorporated herein by reference in its entirety; 115 mg, 0.286 mmol) and DIPEA (100 mg, 0.764 mmol) in DMF (2 mL) was stirred at 60° C. for 1 h. The reaction mixture was applied to an SCX-2 cartridge (10 g) and washed with MeOH. The product was eluted with 2M NH3 in MeOH; concentration in vacuo gave a residue. FCC, using 0-10% [2M NH3 in MeOH] in DCM, gave the title compound as a viscous yellow oil (80 mg, 53%). LCMS (Method 4): Rt 4.55 min, m/z 777 [MH+].
Reaction SMILES: C([O:8][C:9]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:16](=[O:40])/[C:17](/[CH3:39])=[CH:18]/[CH:19]=[C:20](\[CH3:38])/[C:21]([N:23]1[CH2:27][CH2:26][CH2:25][C@@H:24]1[C:28]([O:30]CC1C=CC=CC=1)=[O:29])=[O:22])=[O:10])C1C=CC=CC=1>O1CCOCC1>[C:28]([C@H:24]1[CH2:25][CH2:26][CH2:27][N:23]1[C:21](=[O:22])/[C:20](/[CH3:38])=[CH:19]/[CH:18]=[C:17](\[CH3:39])/[C:16]([N:12]1[CH2:13][CH2:14][CH2:15][C@@H:11]1[C:9]([OH:10])=[O:8])=[O:40])([OH:30])=[O:29]
Reactant: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)OCc1ccccc1
Solvent: C1COCCO1
Product: C/C(=C\C=C(/C)C(=O)N1CCC[C@@H]1C(=O)O)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 16.7 %

Procedure:
Using General Procedure B with 1.14 g (2.09 mmol) (2E,4E)-(R)-1-[6-[(R)-2-Benzyloxycarbonyl-pyrrolidin-1-yl]-2,5-dimethyl-6-oxo-hexa-2,4-dienoyl]-pyrrolidine-2-carboxylic acid benzyl ester and with dioxane as solvent afforded 127 mg (16%) of the title compound as a white solid. MS m/e (%): 365 (M+H+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:37]=[CH:38][CH:39]=1)[CH2:5][N:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([C:18]#[N:19])=[CH:14][CH:13]=2)[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:35])([F:34])[F:33])[CH:27]=2)[C:7]1=[O:36].[C:40]([O:44][CH2:45][CH3:46])(=[O:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:18]([C:15]1[CH:16]=[CH:17][C:12]([CH:11]2[C:10]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[C:9]([CH3:25])[N:8]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([C:32]([F:33])([F:34])[F:35])[CH:27]=3)[C:7](=[O:36])[N:6]2[CH2:5][C:4]2[CH:37]=[CH:38][CH:39]=[C:2](/[CH:42]=[CH:41]/[C:40]([O:44][CH2:45][CH3:46])=[O:43])[CH:3]=2)=[CH:13][CH:14]=1)#[N:19]
Reactant: CCOC(=O)C1=C(C)N(c2cccc(C(F)(F)F)c2)C(=O)N(Cc2cccc(Br)c2)C1c1ccc(C#N)cc1
Reactant: C=CC(=O)OCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cccc(CN2C(=O)N(c3cccc(C(F)(F)F)c3)C(C)=C(C(=O)OCC)C2c2ccc(C#N)cc2)c1
Temperature: 120 °C
Reaction time: 16 h

Procedure:
To a stirred solution of ethyl 3-(3-bromobenzyl)-4-(4-cyanophenyl)-6-methyl-2-oxo-1-[3-(trifluoro-methyl-)phenyl]-1,2,3,4-tetrahydropyrimidine-5-carboxylate (Example 35) (500 mg, 0.84 mmol) in dimethylformamide (7.0 ml) is added bis(triphenylphosphine)palladium(II) chloride (117.3 mg, 0.17 mmol), ethyl acrylate (457.2 μl, 4.18 mmol) and triethylamine (232.9 μl, 1.67 mmol). The reaction is stirred overnight (16 h) at 120° C., then cooled to room temperature, diluted with dimethylformamide (8 ml) and purified directly by preparative HPLC(RP18 column; eluent: acetonitrile/0.1% aq. formic acid 10:90→10:10). The title compound, which is still slightly impure, is isolated (356 mg) and then chromatographed again over silica gel 60 with cyclo-hexane/ethyl acetate (5:1) as eluent.
Reaction SMILES: [O:1]([CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])=[N:14][CH:15]=1)[Si](C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-].O>C1COCC1.CCOC(C)=O>[OH:1][CH2:9][C:10]1[CH:11]=[CH:12][C:13]([C:16]2[CH:23]=[CH:22][CH:21]=[CH:20][C:17]=2[C:18]#[N:19])=[N:14][CH:15]=1
Reactant: CC(C)(C)[Si](C)(C)OCc1ccc(-c2ccccc2C#N)nc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: N#Cc1ccccc1-c1ccc(CO)cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
A mixture of 2-[5-(tert-butyldimethylsiloxymethyl)pyridin-2-yl]benzonitrile (4.9 g, 0.021 mol) and nBu4NF hydrate (8.1 g, 0.031 mol) in THF (60 mL) was stirred at room temperature for 18 h. The mixture was diluted with EtOAc, washed with water and brine, dried (MgSO4), and concentrated to give 3.5 g (80%) of product as a brown solid, mp 152°-153° C.
Reaction SMILES: [CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH2:22])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2].[CH2:23]([S:25](Cl)(=[O:27])=[O:26])[CH3:24]>>[CH2:1]([C:3]1([C:13]2[C:21]3[C:16](=[C:17]([NH:22][S:25]([CH2:23][CH3:24])(=[O:27])=[O:26])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCS(=O)(=O)Cl
Reactant: CCC1(c2c[nH]c3c(N)cccc23)CCc2cc(F)ccc21
Product: CCC1(c2c[nH]c3c(NS(=O)(=O)CC)cccc23)CCc2cc(F)ccc21

Procedure:
Utilizing 3-(1-ethyl-5-fluoro-indan-1-yl)-1H-indol-7-ylamine and ethanesulfonyl chloride, the title compound is prepared as in example 15. 0.18 g (35%). LC-MS m/z 387.1 (M++1).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[NH:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1.ClCCl>CN(C=O)C.O>[Cl:8][C:6]1[N:5]=[C:4]([N:9]([CH3:11])[CH3:10])[N:3]=[C:2]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[N:7]=1
Reactant: CN(C)c1nc(Cl)nc(Cl)n1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)c1nc(Cl)nc(N2CCOCC2)n1
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
The obtained 2,4-dichloro-6-dimethylamino-1,3,5-triazine (1.96 g, 10.2 mmol) was dissolved in DMF (20 ml), added with anhydrous potassium carbonate (1.45 g, 10.5 mmol) and cooled to -5° C.-0° C. This mixture was gradually added dropwise with morpholine (0.96 g, 11.0 mmol) dissolved in DMF (5 ml). The reaction mixture was stirred at room temperature for 17 hours and was evaporated under reduced pressure. The residue obtained was added with dichloromethane and water, and then shaken for mixing. The organic layer was separated from the mixture, sufficiently washed with water, dried over anhydrous magnesium sulfate and evaporated. The residue obtained was purified by silica gel column chromatography, using n-hexane and ethyl acetate (8: 2) as eluant, to obtain 1.37 g (yield: 55.4%) of 2-chloro-4-dimethylamino-6-morpholino-1,3,5-triazine as colorless crystals having melting point of 96° C. -97° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([CH:7]([N:10]2C(=O)C3C(=CC=CC=3)C2=O)[CH2:8][CH3:9])=[CH:3][N:2]=1.O.NN>CO>[N:1]1[CH:6]=[CH:5][C:4]([CH:7]([NH2:10])[CH2:8][CH3:9])=[CH:3][N:2]=1
Reactant: CCC(c1ccnnc1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CO
Solvent: O
Product: CCC(N)c1ccnnc1
Temperature: 60 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2-[1-(Pyridazin-4-yl)propyl]isoindoline-1,3-dione (91.8 mg, 0.34 mmol) in methanol (1 mL) was mixed with hydrazine monohydrate (83 μL, 1.7 mmol) at room temperature and stirred at 60° C. for 3 hours. After completion of the reaction, the solid was filtered off with chloroform, and the filtrate was evaporated under reduced pressure repeatedly to give the desired product (100% yield).
Reaction SMILES: [NH:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Na+].[Na+].Cl[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1>CC(CC(C)C)=O>[O:27]1[CH2:28][CH2:29][CH2:30][CH2:31][CH:26]1[O:25][CH2:24][CH2:23][N:1]1[CH2:2][CH:3]=[C:4]([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[NH:9][CH:8]=2)[CH2:5][CH2:6]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCNC1
Reactant: ClCCOC1CCCCO1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC(=O)CC(C)C
Product: C1=C(c2c[nH]c3ccccc23)CCN(CCOC2CCCCO2)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 6.93 g of 3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole [described in French Pat. No. 2,362,628] dissolved at 100° C. in 70 ml of isobutyl methyl ketone admixed with 11.13 g of sodium carbonate and 14 ml of 2-(2-chloroethoxy)-tetrahydro-2H-pyran was refluxed with stirring under an inert atmosphere for 51/2 hours and was then cooled and poured into ice water. The mixture was extracted with ethyl acetate and the organic phase was washed with water, with aqueous sodium chloride solution, dried and evaporated to dryness. The 9.9 g of crystalline residue was chromatographed over silica gel and eluted with an 85-10-5 chloroform-acetonetriethylamine mixture to obtain 7.85 g of 3-[1-(2-{2-tetrahydropyranyloxy}-ethyl)-1,2,3,6-tetrahydro-4-pyridinyl]-1H-indole in the form of crystals melting at 135° C.
Reaction SMILES: [CH2:1]([C:4]1[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)=[N:6][C:7]([Cl:11])=[N:8][C:9]=1[Cl:10])[CH:2]=C.C[N+]1([O-])CC[O:24]CC1>ClCCl.[Os](=O)(=O)(=O)=O>[Cl:11][C:7]1[N:8]=[C:9]([Cl:10])[C:4]([CH2:1][CH:2]=[O:24])=[C:5]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][CH:14]=2)[N:6]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C=CCc1c(Cl)nc(Cl)nc1Nc1ccc(Cl)cc1
Agent: O=[Os](=O)(=O)=O
Solvent: ClCCl
Product: O=CCc1c(Cl)nc(Cl)nc1Nc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of the product from step (i) (2 g) in dichloromethane (40 ml) was added to a solution of osmium tetroxide (1 ml, 2.5% wt in isopropylalcohol) and 4-methylmorpholine N-oxide (1.12 g) in dichloromethane (1 ml). After stirring at room temperature for 24 h the mixture was washed with water, aqueous sodium sulphite solution, dried (MgSO4) and evaporated under reduced pressure. The residue was dissolved in methanol (40 ml), cooled to 0° C. and lead tetraacetate (3.85 g) added. After 1 h the mixture was diluted with water, extracted with ethyl acetate, the organics dried (MgSO4) and evaporated under reduced pressure. Yield 2 g
Reaction SMILES: [CH:1]([C:3]1[C:4]2([CH3:14])[C:9]([CH2:10][CH2:11][CH:12]=1)=[CH:8][C:7](=[O:13])[CH2:6][CH2:5]2)=[CH2:2].C[O-].[Na+].[CH:18](OC)=[O:19].Cl>O1CCCC1>[CH:1]([C:3]1[C:4]2([CH3:14])[C:9]([CH2:10][CH2:11][CH:12]=1)=[CH:8][C:7](=[O:13])[C:6](=[CH:18][OH:19])[CH2:5]2)=[CH2:2]
Reactant: COC=O
Reactant: C=CC1=CCCC2=CC(=O)CCC12C
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CC1=CCCC2=CC(=O)C(=CO)CC12C
Temperature: -5 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
A solution of 50.0 g (0.265 mol) of 5-ethenyl-4,4a,7,8-tetrahydro-4a-methyl-2(3H)-naphthalenone in 350 mL of tetrahydrofuran was cooled to -5° C. in an ice-methanol bath and stirred under nitrogen while 57.2 g (1.06 mol) of sodium methoxide was added. The resulting mixture was stirred for 30 min at -5° C. and then a solution of 114 mL (1.85 mol) of methyl formate in 100 mL of tetrahydrofuran was added slowly. The mixture was stirred overnight at room temperature and then poured onto a mixture of ice-water (1500 mL) and 6N hydrochloric acid (265 mL). The product was extracted with ether and the combined extracts were washed with water. The dried extract was dried over anhydrous magnesium sulfate and concentrated in vacuo to afford an oil. This oil was triturated with hexane (4×250 mL) and the combined triturates were dried over magnesium sulfate and concentrated in vacuo to afford 55.37 g of a red oil, consisting essentially of the above-entitled compound as established by proton NMR (PMR) spectral data.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11].[CH3:12][Mg+].[Br-].[NH4+].[Cl-].O>CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([CH:8]([OH:9])[CH3:12])[CH:5]=[C:4]([Cl:10])[C:3]=1[OH:11]
Reactant: C[Mg+]
Reactant: OCc1cc(Cl)c(O)c(Cl)c1
Agent: [Br-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: O
Product: CC(O)c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 95 %

Procedure:
A sol. of 2,6-dichloro-4-hydroxymethylphenol (1.635 g, 8.56 mmol) in Et2O (30 mL) was cooled to −78° C. MeMgBr (3M in Et2O, 7.15 mL, 21.5 mmol) was added dropwise to the cooled reaction mixture over 18 min. Et2O (20 mL) was added again during the addition of MeMgBr. Stirring was continued at −78° C. for 1 h, and then the reaction mixture was allowed to warm up to rt over 1 h. The mixture was cooled to 0° C., and aq. sat. NH4Cl (10 mL) was added dropwise. The mixture was allowed to warm up to rt, and additional aq. sat. NH4Cl (35 mL) and water (35 mL) were added. The phases were then separated and the aq. phase was extracted with Et2O. The combined org. extracts were then washed with brine (50 mL), dried over MgSO4, filtered, and concentrated under reduced pressure. Purification by FC (EtOAc/heptane, 1:1) yielded the title compound (1.683 g, 95%). LC-MS: tR=0.74 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH2:12])=[N:6][CH:7]=1.[N+](N[C:18]1[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]2[CH:31]=[CH:30][N:29]([CH2:32][C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[C:28](=[O:39])[CH:27]=2)=[CH:20][N:19]=1)([O-])=O>N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:13])[C:5]([CH2:8][CH2:9][CH2:10][CH2:11][NH:12][C:18]2[NH:23][C:22](=[O:24])[C:21]([CH2:25][C:26]3[CH:31]=[CH:30][N:29]([CH2:32][C:33]4[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=4)[C:28](=[O:39])[CH:27]=3)=[CH:20][N:19]=2)=[N:6][CH:7]=1
Reactant: O=c1[nH]c(N[N+](=O)[O-])ncc1Cc1ccn(Cc2ccccc2)c(=O)c1
Reactant: Cc1cc(Br)cnc1CCCCN
Solvent: c1ccncc1
Product: Cc1cc(Br)cnc1CCCCNc1ncc(Cc2ccn(Cc3ccccc3)c(=O)c2)c(=O)[nH]1
Yield: 78 %

Procedure:
4-(5-Bromo-3-methylpyrid-2-yl)butylamine (0.71 gm) and 2-nitroamino-5-(1-benzyl-2-oxo-pyrid-4-ylmethyl)-4-pyrimidone (1.0 gm) were refluxed in pyridine (3 ml) for 8 hrs., an extra 0.13 gm of the amine was added and reaction was refluxed for a further 5.5 hrs. The pyridine was removed in vacuo, the residue was re-evaporated with n-propanol (2×40 ml). The residue was dissolved in warm ethanol (10 ml) ether added and on cooling a white solid was obtained which was recrystallised from acetonitrile-water (9:1) to give 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-(1-benzyl-2-oxo-pyrid-4-ylmethyl)4-pyrimidone (1.18 gm) m.p. 140°-144° C.