Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:15]([N:16]2[C:20](=[O:21])[C:19](=[C:22]([CH3:24])[CH3:23])[NH:18][C:17]2=[O:25])=[CH:14][C:5]2[N:6]([CH2:11][C:12]#[CH:13])[C:7](=[O:10])[CH2:8][O:9][C:4]=2[CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].IC.O>CN(C)C=O>[CH3:26][N:18]1[C:19](=[C:22]([CH3:23])[CH3:24])[C:20](=[O:21])[N:16]([C:15]2[C:2]([F:1])=[CH:3][C:4]3[O:9][CH2:8][C:7](=[O:10])[N:6]([CH2:11][C:12]#[CH:13])[C:5]=3[CH:14]=2)[C:17]1=[O:25]
Reactant: C#CCN1C(=O)COc2cc(F)c(N3C(=O)NC(=C(C)C)C3=O)cc21
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CI
Product: C#CCN1C(=O)COc2cc(F)c(N3C(=O)C(=C(C)C)N(C)C3=O)cc21
Temperature: 70 °C

Procedure:
3-[7-fluoro-4-propargyl-2H-1,4-bezoxazin-3(4H)-on-6-yl]-5-isopropylidenehydantoin (1.2 g), potassium carbonate (3.0 g) and iodomethane (3.0 g) were dissolved in N,N-dimethylformamide (30 ml), followed by heating at 70° C. for 6 hours. The reaction mixture was allowed to cool, combined with water and extracted with ethyl acetate. The organic layer was purified by silica gel column chromatography using a mixture of toluene and ethyl acetate as the eluent to give Compound No. 32 (1.1 g).
Reaction SMILES: [N:1]1([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:6][CH2:5][CH2:4][C@H:3]([C:7](OCC)=[O:8])[CH2:2]1.O.[NH2:20][NH2:21]>CO.CCOC(C)=O>[NH:20]([C:7]([C@H:3]1[CH2:4][CH2:5][CH2:6][N:1]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:2]1)=[O:8])[NH2:21]
Reactant: NN
Reactant: CCOC(=O)[C@H]1CCCN(C(=O)OC(C)(C)C)C1
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@H](C(=O)NN)C1
Yield: 54.1 %

Procedure:
To a solution of 6.28 g (24.4 mmol) of 1-(1,1-dimethylethyl) 3-ethyl (3S)-piperidine-1,3-dicarboxylate in 25 mL of MeOH was added 7.11 mL of hydrazine monohydrate (146 mmol, 5.98 eq.). The mixture was refluxed for 2 h and concentrated. The reaction could be monitored by LC/MS on a reversed-phase column at 220 nm wavelength. The crude material was taken up in EtOAc, and washed with 2×H2O, 1× sat. aqueous NaCl, and dried over Na2SO4. Filtration and concentration afforded 3.21 g of product (54.0% yield) as a viscous oil. The product was ca. 80% pure by hplc analysis and was used as such without further purification.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4]/[N:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][CH2:13][C@:12]2([OH:29])[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@@H:18]([CH2:19][C@@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3.[N+]([O-])(O)=O.[C:34](N1C(C)=CC(C)=N1)(=[NH:36])[NH2:35]>C(O)C>[NH:1]([CH2:2][CH2:3][O:4][N:5]=[CH:6]/[CH:7]=[CH:8]/[C@H:9]1[CH2:14][CH2:13][C@:12]2([OH:29])[C@H:15]3[C@H:25]([CH2:26][CH2:27][C@:10]12[CH3:11])[C@:23]1([CH3:24])[C@@H:18]([CH2:19][C@@H:20]([OH:28])[CH2:21][CH2:22]1)[CH2:17][CH2:16]3)[C:34]([NH2:36])=[NH:35]
Reactant: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=N/OCCN)CC[C@]12O
Reactant: Cc1cc(C)n(C(=N)N)n1
Solvent: O=[N+]([O-])O
Solvent: CCO
Product: C[C@]12CC[C@H](O)C[C@H]1CC[C@@H]1[C@@H]2CC[C@]2(C)[C@@H](/C=C/C=NOCCNC(=N)N)CC[C@]12O
Yield: 58.9 %

Procedure:
A solution of 1.00 g of (E,E)-17β-[3-(2-aminoethoxyimino)-1-propenyl]-5β-androstane-3β,14β-diol (I-ao) and 1.05 g of 1-amidino-3,5-dimethylpyrazole nitrate in 20 ml of ethanol was heated at reflux for 10 hrs. The solution was evaporated to dryness under reduced pressure and the crude product was ground with water and then with diethyl ether/ethanol to give 0.65 g of the title compound (I-as), as a nitrate, white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[N:12]=[CH:13][O:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:48])[C@H:20]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[NH:21][C@H:22]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:51](=O)([O-])[O-].[K+].[K+].CN(C)P(=O)(N(C)C)N(C)C>C(OCC)(=O)C>[CH2:1]([O:8][C:9]([C:11]1[N:12]=[CH:13][O:14][C:15]=1[CH2:16][CH2:17][NH:18][C:19](=[O:48])[C@H:20]([CH2:41][C:42]1[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=1)[N:21]([C@H:22]([C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32])[CH2:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)[CH3:51])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(OCc1ccccc1)c1ncoc1CCNC(=O)[C@H](Cc1ccccc1)N[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CN([C@@H](Cc1ccccc1)C(=O)NCCc1ocnc1C(=O)OCc1ccccc1)[C@@H](CCc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.1 %

Procedure:
A mixture of 2.6 g of the compound obtained in Example 1, 0.4 ml of methyl iodide, 0.83 g of potassium carbonate and 3 ml of hexamethylphosphoric triamide was stirred at room temperature overnight. Then, ethyl acetate was added to the mixture, and the insolubles were removed by filtration. The filtrate was washed and dried, and then the solvent was removed. The residue was purified by silica gel column chromatography (solvent: chloroform:ethyl acetate=95:5) to obtain 1.81 g (Yield: 68%) of 4-benzyloxycarbonyl-5-(2-[N-((1S)-1-benzyloxycarbonyl-3-phenylpropyl)-N-methyl-(L)-phenylalanyl]aminoethyl}oxazole as an oily product.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)[CH2:8]1.[O:19]1[CH2:24][CH2:23][CH:22]([C:25](Cl)=[O:26])[CH2:21][CH2:20]1.N1C=CC=CC=1.N.CO>C(Cl)Cl>[CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH:7]1[CH2:11][CH2:10][C@H:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:25]([CH:22]3[CH2:23][CH2:24][O:19][CH2:20][CH2:21]3)=[O:26])=[CH:14][CH:13]=2)[CH2:8]1
Reactant: O=C(Cl)C1CCOCC1
Reactant: C[C@H]1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Agent: N
Solvent: CO
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H]1CCCN1C1CC[C@H](c2ccc(NC(=O)C3CCOCC3)cc2)C1
Reaction time: 0.5 h
Yield: 87.7 %

Procedure:
4-[(S)-3-((S)-2-Methyl-pyrrolidin-1-yl)-cyclopentyl]-phenylamine (Intermediate 14) (40 mg, 0.16 mmol) was dissolved in DCM (2 mL). To this solution was transferred a solution of tetrahydro-pyran-4-carboxylic acid chloride (71.3 mg, 0.5 mmol, 3.0 equiv.) in DCM (1 mL), followed by pyridine (0.5 mL). The solution was stirred at r.t. for 2 h when TLC (5% of 7N NH3 MeOH in DCM) and LC/MS showed that the reaction was complete. The reaction was quenched by addition of polymer bound diethylenetriamine (4 mmol/g) (0.1 g) and the suspension was stirred for 30 min. Then, 10 mL of DCM was added to the suspension and the suspension was filtered through a celite pad, rinsed with DCM and 10% MeOH in DCM. The crude product was purified on a silica gel column eluted with 5% of 7N NH3 MeOH in DCM to obtain 50 mg (87% yield) of the title compound.
Reaction SMILES: [CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)=[CH:18][CH:17]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33](=O)([O-])[O-].[K+].[K+].IC.C(Cl)(Cl)Cl>CN(C)C=O>[CH2:1]([NH:8][C:9]1[CH:14]=[C:13]([NH:15][C:16]2[CH:17]=[CH:18][C:19]([N:22]3[CH2:28][CH2:27][CH2:26][N:25]([CH3:33])[CH2:24][CH2:23]3)=[CH:20][CH:21]=2)[N:12]=[CH:11][C:10]=1[CH2:29][C:30]([NH2:32])=[O:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCCNCC3)cc2)cc1NCc1ccccc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Solvent: CI
Product: CN1CCCN(c2ccc(Nc3cc(NCc4ccccc4)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.9 %

Procedure:
25 mg of 4-(benzylamino)-6-{[4-(1,4-diazepan-1-yl)phenyl]amino}pyridine-3-carboxyamide (the compound of Example 226) was dissolved in 0.3 mL of N,N-dimethylformamide, to which, under ice cooling, 10 mg of potassium carbonate and 4.3 mg of iodomethane were added, and stirred at the same temperature for 30 minutes and at room temperature for further 30 minutes. To the reaction mixture, chloroform was added, and the insoluble substances were filtered off. The solvent was evaporated and the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 9 mg (35%) of the title compound as a light brown solid.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N+:9]([O-])=O)[C:5]([OH:8])=[N:6][CH:7]=1>O1CCCC1.CO.[C].[Pd]>[NH2:9][C:4]1[C:5]([OH:8])=[N:6][CH:7]=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cnc(O)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1cnc(O)c(N)c1
Reaction time: 24 h
Yield: 100.1 %

Procedure:
At room temperature, to a mixed solvent solution of 5-methyl-3-nitropyridin-2-ol (5.0 g) in tetrahydrofuran (200 ml) and methanol (200 ml) was added 10% palladium carbon (0.5 g), followed by stirring for 24 hours under a hydrogen atmosphere. The reaction solution was filtered through Celite, and then the filtrate was concentrated under reduced pressure to afford 3-amino-5-methylpyridin-2-ol (4.03 g).
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:22])[CH2:18]S(C)=O.[Al]>O.O1CCCC1>[Cl:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17](=[O:22])[CH3:18]
Reactant: Cc1ccc(Cl)c(Nc2ccccc2C(=O)CS(C)=O)c1Cl
Agent: [Al]
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)c1ccccc1Nc1c(Cl)ccc(C)c1Cl
Temperature: 0 °C
Reaction time: 0 h
Yield: 60.6 %

Procedure:
1-[2-[(2,6-Dichloro-3-methylphenyl)amino]phenyl]-2-(methylsulfinyl)ethanone (2.0 g, 5.61 mmol) is dissolved in 100 ml of 10% water/tetrahydrofuran and cooled to 0° C. in an ice bath. Aluminum amalgam is prepared by addition of aluminum foil (1.5 g, 56.1 mmol) to 350 ml of 2% aqueous mercuric chloride. After 15 seconds, the liquid is decanted, and the foil is washed twice with absolute ethanol followed by tetrahydrofuran. The freshly prepared aluminum amalgam is added to the reaction mixture which is then stirred for 30 minutes at 0° C. The reaction mixture is filtered through celite, and the solids are washed with tetrahydrofuran. The filtrate is evaporated, and the residue is taken up in ether. The ether solution is washed with 100 ml of water and dried over magnesium sulfate. Evaporation of the solvent gives a yellow solid which is recrystallized from diethyl ether/hexane. Yield (1.0 g, 60%) of 1-[2-[(2,6-dichloro-3 -methylphenyl)amino]phenyl]ethanone; mp 122°-125° C.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]([C:16]#[N:17])[C:7](=[O:15])[NH:8][C:9]=1[CH:10]=[CH:11][N:12](C)C)(=O)[CH3:2].C(O)(=O)C.C(N)=N>CN(C)C=O>[CH3:2][C:1]1[N:12]=[CH:11][CH:10]=[C:9]2[C:4]=1[CH:5]=[C:6]([C:16]#[N:17])[C:7](=[O:15])[NH:8]2
Reactant: CC(=O)c1cc(C#N)c(=O)[nH]c1C=CN(C)C
Agent: N=CN
Solvent: CC(=O)O
Solvent: CN(C)C=O
Product: Cc1nccc2[nH]c(=O)c(C#N)cc12
Yield: 103.1 %

Procedure:
E-1. 1,2-Dihydro-5-methvl-2-oxo-1,6-naphthyridine-3-carbonitrile--A mixture containing 33.2 g of 5-acetyl-1,2-dihydro-6-(2-dimethylaminoethenyl)-2-oxo-3-pyridincarbonitrile, 32.1 g of formamidine acetate and 300 ml of dimethylformamide was heated in a oil bath at 120°-130° C. for 3 hours, the original yellow solid dissolving and dark solution resulting. The reaction mixture was evaporated to dryness and then treated with 400 ml of water followed by 30 ml of acetic acid. The resulting insoluble solid was collected, washed with water, air-dried, recrystallized from dimethylformamide and dried at 90° C. to yield 27.4 g of 1,2-dihydro-5-methyl-2-oxo-1,6-naphthyridine-3-carbonitrile as a compound containing 1/2 mole of dimethylformamide, m.p. 278°-280° C. with decomposition.
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][C:4]([CH2:7][S:8]([NH:11]CC2C=CC(OC)=CC=2OC)(=[O:10])=[O:9])=[CH:3][CH:2]=1.C([Li])CCC.[CH3:34][C:35]([CH3:37])=[O:36].FC(F)(F)C(O)=O>C1COCC1.CCCCCC.ClCCl>[C:1]1([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:2]=[CH:3][C:4]([CH:7]([S:8]([NH2:11])(=[O:9])=[O:10])[C:35]([OH:36])([CH3:37])[CH3:34])=[CH:5][CH:6]=1
Reactant: COc1ccc(CNS(=O)(=O)Cc2ccc(-c3ccccc3)cc2)c(OC)c1
Reactant: CC(C)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(O)C(c1ccc(-c2ccccc2)cc1)S(N)(=O)=O
Reaction time: 0.17 h

Procedure:
Under inert gas, 4.01 g of C-biphenyl-4-yl-N-(2,4-dimethoxybenzyl)methanesulfonamide were initially charged in 100 ml of THF and then, at a temperature of −71° C., 12.60 ml of a 1.6 N butyllithium solution in hexane were added dropwise. The reaction mixture was stirred for a further 10 minutes and then admixed dropwise with 4.53 ml of acetone. The mixture was stirred at constant temperature for 10 minutes, 2 ml of trifluoroacetic acid were added and the mixture was allowed to come to room temperature. The residue was dissolved in 100 ml of dichloromethane, and 20 ml of trifluoroacetic acid were added. After stirring at room temperature for 20 minutes, the reaction solution was washed with saturated aqueous sodium hydrogencarbonate solution, and the organic phase together with the precipitate was concentrated by rotary evaporation and then coevaporated with toluene. The crude product was purified by means of normal phase chromatography using a Flashmaster with a dichloromethane/methanol gradient. The product-containing fractions were combined and concentrated by rotary evaporation. This gave the product (3.15 g) with a molecular weight of 305.4 g/mol (C16H19NO3S).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19]C#N)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].SC[C@@H]([C@@H](CS)O)O.[N:37](=[CH:45][CH2:46]Cl)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]Cl>>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([N:10]([C@H:22]2[CH2:27][CH2:26][C@H:25]([CH3:28])[CH2:24][CH2:23]2)[C:11]([NH:13][C:14]2[S:15][C:16]([S:19][CH2:46][CH2:45][N:37]3[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38]3)=[CH:17][N:18]=2)=[O:12])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: ClCC=NCCCCCCCl
Reactant: CC(=O)N1CCC(N(C(=O)Nc2ncc(SC#N)s2)[C@H]2CC[C@H](C)CC2)CC1
Agent: O[C@H](CS)[C@@H](O)CS
Product: CC(=O)N1CCC(N(C(=O)Nc2ncc(SCCN3CCCCCC3)s2)[C@H]2CC[C@H](C)CC2)CC1

Procedure:
Prepared as described in general procedures (H) and (I) using 1-(1-acetyl-piperidin-4-yl)-1-(trans-4-methyl-cyclohexyl)-3-(5-thiocyanato-thiazol-2-yl)-urea, dithioerythritol and 2-(hexamethyleneimino) ethylchloride
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([P:9]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[C:10]2[N:15]=[C:14]([NH2:16])[CH:13]=[CH:12][CH:11]=2)[CH:5]=[C:6]([CH3:8])[CH:7]=1.C(N(CC)CC)C.[C:32](Cl)(=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34]>ClCCl>[CH3:8][C:6]1[CH:5]=[C:4]([P:9]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[C:19]([CH3:24])[CH:18]=2)[C:10]2[N:15]([C:32](=[O:37])[C:33]([CH3:36])([CH3:35])[CH3:34])[CH:14]([NH2:16])[CH:13]=[CH:12][CH:11]=2)[CH:3]=[C:2]([CH3:1])[CH:7]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cc1cc(C)cc(P(c2cc(C)cc(C)c2)c2cccc(N)n2)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)cc(P(C2=CC=CC(N)N2C(=O)C(C)(C)C)c2cc(C)cc(C)c2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 65.6 %

Procedure:
To a solution of 6-bis(3,5-dimethylphenyl)phosphino-2-aminopyridine (0.19 g, 0.58 mmol) in dichloromethane (45 mL) at 0° C., triethylamine (152 μL, 1.1 mmol) and pivaloyl chloride (107 μL, 0.87 mmol) are added consecutively. The solution is slowly warmed to ambient temperature, stirred for 40 hours, and concentrated under reduced pressure. The remaining suspension is stirred with activated charcoal (0.25 g) and filtered through a Celite pad. The filtrate is concentrated under reduced pressure and the white residue is purified by column chromatography to yield 6-bis(3,5-dimethylphenyl)phosphino-N-pivaloyl-2-aminopyridine (0.16 g, 65%).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][O:5][C:6]1[C:7]([O:20][CH3:21])=[CH:8][C:9]2[O:14][C:13](=[O:15])[C:12]3[CH2:16][CH2:17][CH2:18][C:11]=3[C:10]=2[CH:19]=1.Cl.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(Cl)(Cl)Cl.C([O-])(=O)/C=C/C([O-])=O>CC(C)=O.C(O)C>[CH3:21][O:20][C:7]1[C:6]([O:5][CH2:4][CH2:3][CH2:2][N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[CH:19][C:10]2[C:11]3[CH2:18][CH2:17][CH2:16][C:12]=3[C:13](=[O:15])[O:14][C:9]=2[CH:8]=1
Reactant: COc1ccccc1N1CCNCC1
Reactant: COc1cc2oc(=O)c3c(c2cc1OCCCCl)CCC3
Agent: Cl
Agent: O=C([O-])/C=C/C(=O)[O-]
Solvent: CCO
Solvent: ClC(Cl)Cl
Solvent: CC(C)=O
Product: COc1cc2oc(=O)c3c(c2cc1OCCCN1CCN(c2ccccc2OC)CC1)CCC3
Yield: 56 %

Procedure:
Method A (40 h at 50° C.); starting materials: 8-(3-chloropropoxy)-2,3-dihydro-7-methoxy-cyclopenta[c][1]benzopyran-4(1H)-one (example 83) and 1-(2-methoxyphenyl)piperazine hydrochloride; yield 56%; fusion point 177°-178° C. (from chloroform and ethanol). Fumarate: method E; yield 87%; fusion point 173°-174° C. (from acetone).
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C@@H:4]1[NH:8][C:9](=[O:22])[C:10]1[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=1[N:17]1[N:21]=[CH:20][CH:19]=[N:18]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:76]1[CH:81]=[CH:80][C:79]([Cl:82])=[CH:78][N:77]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O>[Cl:82][C:79]1[CH:80]=[CH:81][C:76]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C@@H:4]2[NH:8][C:9](=[O:22])[C:10]2[CH:15]=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=2[N:17]2[N:18]=[CH:19][CH:20]=[N:21]2)=[N:77][CH:78]=1
Reactant: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2N)c1
Reactant: Clc1ccc(Br)nc1
Agent: [Pd]
Agent: Cl
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc(-n2nccn2)c(C(=O)N[C@H]2CCC[C@@H]2Nc2ccc(Cl)cn2)c1
Temperature: 100 °C
Reaction time: 15 h

Procedure:
To a solution of N-[(1S,2S)-2-aminocyclopentyl]-5-methyl-2-(2H-1,2,3-triazol-2-yl)benzamide hydrochloride (Intermediate 7; 100 mg, 0.31 mmol) in toluene (1.0 ml) was added BINAP (19 mg, 0.03 mmol), cesium carbonate (405 mg, 1.25 mmol) and 2-bromo-5-chloropyridine (CAS number 40473-01-6; 72 mg, 0.38 mmol). The mixture was purged with nitrogen for 5 minutes and then tris(dibenzylideneacetone)dipalladium(0) (14 mg, 0.02 mmol) was added and the resulting mixture was stirred at 100° C. for 15 hours. The resulting mass was poured into water (3 ml) and extracted into ethyl acetate (3×10 ml). The combined organics were dried over sodium sulfate and concentrated in vacuo. The crude product was purified by reverse phase preparative HPLC (eluted with acetonitrile/water containing 0.1% ammonia) to afford the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:13]([NH:14][C:15]4[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]5[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=5)=[C:17]([Cl:29])[CH:16]=4)=[N:12][CH:11]=[N:10][C:9]=3[S:30][C:4]=2[CH:3]=1.[K].C(=O)([O-])[O-].[Na+].[Na+].[CH3:38][CH2:39]OC(C)=O>COCCOC.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:17]1[CH:16]=[C:15]([NH:14][C:13]2[C:8]3[C:5]4[CH:6]=[CH:7][C:2]([CH:38]=[CH2:39])=[CH:3][C:4]=4[S:30][C:9]=3[N:10]=[CH:11][N:12]=2)[CH:20]=[CH:19][C:18]=1[O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][N:24]=1
Reactant: CCOC(C)=O
Reactant: Clc1cc(Nc2ncnc3sc4cc(Br)ccc4c23)ccc1OCc1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K]
Solvent: O
Solvent: COCCOC
Product: C=Cc1ccc2c(c1)sc1ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 7-bromo-N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl][1]benzothieno[2,3-d]pyrimidin-4-amine (5.0 g, 10.0 mmol) in 1,2-dimethoxyethane (50 mL) and water (5.0 mL) were added Pd(PPh3)4 (580 mg, 0.50 mmol, 0.05 equiv), Potassium vinyltrifluoroorate (1.48 g, 11.1 mmol, 1.1 equiv), and sodium carbonate (2.66 g, 25.1 mmol, 2.5 equiv) under nitrogen. The reaction mixture was heated to reflux for 15 hours. The reaction mixture was cooled to rt then poured into a flask contains a mixture of water (100 mL) and EtOAc (100 mL). The resulting mixture was extracted with EtOAc (3×50 mL), dried over sodium sulfate then concentrated in vacuo. The crude material was purified by chromatography (5% EtOAc/hexane) to give an off-white solid (4.84 g, 97%). 1H-NMR (CD3OD) δ 8.72 (d, J=5.4 Hz, 1H), 8.47 (s, 1H), 8.37 (d, J=8.4 Hz, 1H), 8.28 (t, 1H), 8.06 (s, 1H), 7.98 (d, J=7.4 Hz, 1H), 7.81 (d, J=2.7 Hz, 1H), 7.72 (m, 2H), 7.55 (dd, J=2.1, 8.9 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 6.89 (m, 1H), 5.97 (d, J=17.6 Hz, 1H), 5.43 (s, 2H), 5.39 (d, J=10.9 Hz, 1H); LCMS RT=3.30 min, [M+H]+=445.10.
Reaction SMILES: [I-:1].[Na+].Cl[CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1.C(N)(=S)C1C=CC=CC=1.ClCC(CCl)=O>CC(C)=O.O.COC(C)(C)C>[I:1][CH2:4][C:5]1[N:6]=[C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:8][CH:9]=1
Reactant: [I-]
Reactant: ClCc1csc(-c2ccccc2)n1
Agent: NC(=S)c1ccccc1
Agent: O=C(CCl)CCl
Agent: [Na+]
Solvent: O
Solvent: COC(C)(C)C
Solvent: CC(C)=O
Product: ICc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 99.5 %

Procedure:
2 g (13.35 mmol) of sodium iodide were added to a solution of 0.56 g (2.67 mmol) of 4-chloromethyl-2-phenyl-thiazole (prepared from thiobenzamide and 1,3-dichloroacetone in analogy to the procedure described in example 4 a]) in 10 ml of acetone and the suspension was stirred at reflux for 2 hours. After cooling to ambient temperature, 30 ml of tert-butyl methyl ether and 10 ml of water were added and the mixture was transferred to a separatory funnel. The organic phase was washed with water and brine, dried with anhydrous sodium sulfate and finally evaporated, leaving 0.8 g of 4-iodomethyl-2-phenyl-thiazole as light yellow solid (99% of theory).