Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[NH2:2][C:3]([NH2:5])=[NH:4].[O-]CC.[Na+].[C:10]([CH:12]([C:28](OCC)=[O:29])[CH2:13][CH2:14][CH2:15][S:16][C:17]1[CH:27]=[CH:26][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:19][CH:18]=1)#[N:11].C(O)(=O)C>C(O)C>[NH2:4][C:3]1[NH:5][C:28](=[O:29])[C:12]([CH2:13][CH2:14][CH2:15][S:16][C:17]2[CH:18]=[CH:19][C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:26][CH:27]=2)=[C:10]([NH2:11])[N:2]=1
Reactant: N=C(N)N
Reactant: CCOC(=O)c1ccc(SCCCC(C#N)C(=O)OCC)cc1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(SCCCc2c(N)nc(N)[nH]c2=O)cc1
Yield: 95.6 %

Procedure:
Dry guanidine hydrochloride (3.43 g, 35.9 mmoles) was added to a solution of sodium ethoxide 53.5 mmoles) in ethanol (25 mL), and the mixture was treated with 1B (6.00 g, 17.9 mmoles) as a solution in ethanol (25 mL) and refluxed for 5 hours. After cooling, the pH was adjusted to 7.0 with acetic acid, and the mixture was evaporated to a viscous residue in vacuo. The residue was treated with water (70 mL) and was filtered to give an off white solid, which was washed with 3 volumes (30 mL) of water and 3 volumes (30 mL) of ether and was dried in vacuo to give crude product title compound, 1C, (5.96 g, 95%) as a white solid. NMR (DMSO-d6) δ1.3 (t, 3H, CH3 of ester), 1.65 (m, 2H, CH2 --CH2 --CH2), 2.3 (t, 2H, CH2 --CH2 --CH2 --S), 2.95 (m, 2H, CH2 --S), 4.3 (q, 2H, CH2 of ester), 5.7 (br s, 2H, NH2), 5.95 (br s, 2H, NH2), 7.3 (d, 2H) (benzoate H's ortho to sulfur), 7.85 (d, 1H, 7.95 (d, 1H), 9.8 (br s, 1H, ring NH). The aromatic region of the NMR spectrum indicated slight impurities; compound 1C was used in the next reaction without further purification.
Reaction SMILES: [F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C@H:7]([C:9]([OH:11])=[O:10])[CH3:8])=[O:5].[OH-].[Na+].[F:19][C:20](=[C:24]([F:26])[F:25])[CH2:21][CH2:22]Br>CS(C)=O.O>[F:1][C:2]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:3]=1[C:4]([NH:6][C@H:7]([C:9]([O:11][CH2:22][CH2:21][C:20]([F:19])=[C:24]([F:26])[F:25])=[O:10])[CH3:8])=[O:5]
Reactant: C[C@H](NC(=O)c1c(F)cccc1F)C(=O)O
Reactant: FC(F)=C(F)CCBr
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: C[C@H](NC(=O)c1c(F)cccc1F)C(=O)OCCC(F)=C(F)F
Temperature: 20 °C
Reaction time: 8 h
Yield: 26.5 %

Procedure:
6.4 g (28 mmol) of N-(2,6-difluorobenzoyl)alanine are dissolved in 50 ml of dimethyl sulphoxide (DMSO) and admixed with 1.2 g (31 mmol) of sodium hydroxide dissolved in a little water. 5.7 g (30 mmol) of 3,4,4-trifluorobut-3-enyl bromide are subsequently added, and the mixture is stirred at 20° C. overnight. The mixture is then poured into water and the product is extracted with ethyl acetate and subsequently purified by column chromatography over silica gel using the system ethyl acetate. In this manner, 2.5 g (26.5% of theory) of 3,4,4-trifluorobut-3-enyl N-(2,6-difluorobenzoyl)-alaninate are obtained as an oil. log p (pH 2)=2.42.
Reaction SMILES: C([CH:5]([OH:35])[C@H:6]1[O:10][C@@H:9]([N:11]2[C:26]3[C:14]([C:15]([N:17]=[C:18]([N:25]=3)[NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])=[O:16])=[N:13][C:12]2=[SiH2])[C@H:8]([O:28][CH3:29])[C@@H:7]1[O:30]C(C)(C)C)(C)(C)C.N1C=CC=CC=1.N1C=CC=CC=1.F>ClCCl>[CH3:29][O:28][C@@H:8]1[C@H:7]([OH:30])[C@@H:6]([CH2:5][OH:35])[O:10][C@H:9]1[N:11]1[C:26]2[N:25]=[C:18]([NH:19][C:20](=[O:24])[CH:21]([CH3:23])[CH3:22])[NH:17][C:15](=[O:16])[C:14]=2[N:13]=[CH:12]1
Reactant: CO[C@@H]1[C@H](OC(C)(C)C)[C@@H](C(O)C(C)(C)C)O[C@H]1n1c(=[SiH2])nc2c1=NC(NC(=O)C(C)C)=NC2=O
Agent: F
Solvent: ClCCl
Solvent: c1ccncc1
Product: CO[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1cnc2c(=O)[nH]c(NC(=O)C(C)C)nc21
Yield: 93 %

Procedure:
To a stirred solution of (66) (0.51 g, 1 mmol) in anhydrous dichloromethane (5 ml) was added pyridine (0.5 ml) followed by hydrogen fluoride—pyridine (38.5 M, 0.1 ml). After 15 min the solvent was removed in vacuo. Flash chromatography using a gradient of 5-10% methanol in dichloromethane afforded (67) as white foam, 0.34 g, 93% yield.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6](Cl)[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1.[O:14]1[C:22]2[C:17](=[CH:18][C:19]([CH2:23][NH2:24])=[CH:20][CH:21]=2)[O:16][CH2:15]1>C(Cl)Cl>[CH3:1][C:2]1[N:7]=[C:6]([NH:24][CH2:23][C:19]2[CH:18]=[C:17]3[C:22](=[CH:21][CH:20]=2)[O:14][CH2:15][O:16]3)[C:5]([C:9]2[S:10][CH:11]=[CH:12][CH:13]=2)=[CH:4][N:3]=1
Reactant: Cc1ncc(-c2cccs2)c(Cl)n1
Reactant: NCc1ccc2c(c1)OCO2
Solvent: ClCCl
Product: Cc1ncc(-c2cccs2)c(NCc2ccc3c(c2)OCO3)n1
Temperature: 50 °C

Procedure:
2-Methyl-5-(2-thienyl)-4-chloropyrimidine (590 mg; prepared by the same procedure as described in reference example 1) was dissolved into methylene chloride (6 ml). To the solution, (1,3-dioxaindan-5-yl)methylamine (2 ml) was added. The mixture was refluxed at 50° C. for 2 days. After reaction, the mixture was extracted with methylene chloride. The organic layer was washed with water and an aqueous saturated solution of ammonium chloride, respectively. The solution was dried over anhydrous sodium sulfate and evaporated. The residue was washed with ether to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:24])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])=[CH:4][CH:3]=1.[H-].[Na+].Cl.O>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([OH:24])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(OC)cc1)C(O)c1ccc(F)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(C(=O)O)C(O)c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 70.9 %

Procedure:
To a solution of ethyl (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionate (22.8 g, 68.6 mmol) in methanol (100 ml) was added 2N aqueous sodium hydride solution (69 ml, 0.137 mol) and the mixture was stirred at room temperature for 4 hrs. The reaction solution was acidified with 6N hydrochloric acid, water (300 ml) was added, and the mixture was extracted with ethyl acetate (200 ml×2). The extract was washed with water, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was crystallized from a mixture of hexane and diethyl ether to give (2RS,3RS)-3-(4-fluorophenyl)-3-hydroxy-2-(4-methoxybenzyl)propionic acid (14.8 g, 71%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([OH:10])=O)[S:5][C:6]=1[Br:7].S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:3]=[C:4]([C:8]([Cl:13])=[O:10])[S:5][C:6]=1[Br:7]
Reactant: O=C(O)c1cc(Br)c(Br)s1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(Br)c(Br)s1

Procedure:
Using the procedure of Preparation A, 2.86 g (10.0 mmoles) of commercially available 4,5-dibromo-2-thiophenecarboxylic acid was added to 10 ml of thionyl chloride to give a heterogeneous mixture. Heating the reaction mixture helped the solution become homogenous. Concentration of the reaction solution gave 3.15 g of crude 4,5-dibromo-2-thiophenecarbonyl chloride as a brown oil. The crude acid chloride, dissolved in 10 ml of N,N-dimethylformamide was slowly added to 1.76 g (8.33 mmoles) of 5-chloro-2,3-dihydro-2-oxo-1H-indole-1-carboxamide and 3.05 g (25.0 mmoles) of 4-(N,N-diemthylamino)pyridine in 40 ml of N,N-dimethylformamide. Workup gave 2.82 g of orange solid which was recrystallized from 2-butanone to give 1.61 g (3.37 mmoles, 40% yield) of pure title compound as a yellow solid, m.p. 229°-231° C.
Reaction SMILES: OC1C=C[C:5]([N:8]2[C:16]3C(=CC(OC)=C[CH:15]=3)[CH:10]=[C:9]2C2C=CC=CC=2)=[CH:4]C=1.[OH:25][C:26]1[CH:31]=[CH:30][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37]([O:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:38][CH:39]=3)[CH:34]=[C:33]2[C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)=[CH:28][CH:27]=1>>[CH2:5]([N:8]([CH2:16][CH3:15])[CH2:9][CH2:10][O:25][C:26]1[CH:27]=[CH:28][C:29]([N:32]2[C:40]3[C:35](=[CH:36][C:37]([O:41][C:42](=[O:49])[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[CH:38][CH:39]=3)[CH:34]=[C:33]2[C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)=[CH:30][CH:31]=1)[CH3:4]
Reactant: COc1ccc2c(c1)cc(-c1ccccc1)n2-c1ccc(O)cc1
Reactant: O=C(Oc1ccc2c(c1)cc(-c1ccccc1)n2-c1ccc(O)cc1)c1ccccc1
Product: CCN(CC)CCOc1ccc(-n2c(-c3ccccc3)cc3cc(OC(=O)c4ccccc4)ccc32)cc1

Procedure:
Following a procedure similar to that described in Example 1E but substituting for 1-(4-hydroxyphenyl)-5-methoxy-2-phenylindole an equivalent amount of 1-(4-hydroxyphenyl)-5-benzoyloxy-2-phenylindole there can be obtained 1-{4-[2-(diethylamino)ethoxy]phenyl}-5-benzoyloxy-2-phenylindole.
Reaction SMILES: [O:1]=[S:2]1(=[O:30])[CH2:7][CH2:6][N:5]([C:8]([C:10]2[NH:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH:27]([CH3:29])[CH3:28])[CH2:23][CH2:22]2)=[O:20])=[CH:14][CH:13]=3)=[O:9])[CH2:4][CH2:3]1.[Cl:31][C:32]1[CH:37]=[C:36](B(O)O)[CH:35]=[CH:34][N:33]=1.N1C=CC=CC=1>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(Cl)(Cl)Cl>[Cl:31][C:32]1[CH:37]=[C:36]([N:11]2[C:12]3[C:17](=[CH:16][C:15]([C:19]([N:21]4[CH2:22][CH2:23][N:24]([CH:27]([CH3:28])[CH3:29])[CH2:25][CH2:26]4)=[O:20])=[CH:14][CH:13]=3)[CH:18]=[C:10]2[C:8]([N:5]2[CH2:6][CH2:7][S:2](=[O:1])(=[O:30])[CH2:3][CH2:4]2)=[O:9])[CH:35]=[CH:34][N:33]=1
Reactant: OB(O)c1ccnc(Cl)c1
Reactant: CC(C)N1CCN(C(=O)c2ccc3[nH]c(C(=O)N4CCS(=O)(=O)CC4)cc3c2)CC1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: CC(C)N1CCN(C(=O)c2ccc3c(c2)cc(C(=O)N2CCS(=O)(=O)CC2)n3-c2ccnc(Cl)c2)CC1
Yield: 10 %

Procedure:
The title compound was synthesized in analogy to example 66, from [2-(1,1-dioxo-thiomorpholine-4-carbonyl)-1H-indol-5-yl]-(4-isopropyl-piperazin-1-yl)-methanone (example 1), 2-chloropyridine-4-boronic acid, copper(II) acetate, pyridine and using chloroforme instead of dichloromethane as solvent, to give the desired product as a light brown solid (10%).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][OH:14])[CH2:4][CH2:5][CH2:6][CH3:7].Br[CH2:16][CH2:17][CH2:18][CH2:19][C:20]#[N:21].Cl>>[C:20](#[N:21])[CH2:19][CH2:18][CH2:17][CH2:16][O:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][O:8][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCOCCCCCO
Reactant: N#CCCCCBr
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: CCCCCOCCCCCOCCCCC#N
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Sodium hydride (60%, 0.75 g) was added to a solution of 3 g of 5-pentyloxy-1-pentanol prepared in the above-described step (1) in 50 ml of N,N-dimetnylformamide. Then 2 ml of 5-bromopentanenitrile was added thereto and the mixture was stirred at 60° C. for 2 h. 3% hydrochloric acid was added to the reaction solution. After extraction with ether, the organic layer was dried and concentrated and the residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=9/1) to obtain 1 g of the intended product.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Cl[C:14]1[CH:19]=[C:18]([CH3:20])[N:17]=[C:16]([NH:21][C:22]2[CH:27]=[CH:26][C:25]([N:28]3[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]3)=[C:24]([O:34][CH3:35])[CH:23]=2)[N:15]=1>>[CH3:35][O:34][C:24]1[CH:23]=[C:22]([NH:21][C:16]2[N:17]=[C:18]([CH3:20])[CH:19]=[C:14]([O:10][C:6]3[CH:7]=[CH:8][CH:9]=[C:4]([O:3][C:2]([F:11])([F:12])[F:1])[CH:5]=3)[N:15]=2)[CH:27]=[CH:26][C:25]=1[N:28]1[CH:32]=[C:31]([CH3:33])[N:30]=[CH:29]1
Reactant: Oc1cccc(OC(F)(F)F)c1
Reactant: COc1cc(Nc2nc(C)cc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2nc(C)cc(Oc3cccc(OC(F)(F)F)c3)n2)ccc1-n1cnc(C)c1
Yield: 95 %

Procedure:
The title compound was prepared in analogous manners as described in example 9 from 3-trifluoromethoxy-phenol and (4-chloro-6-methyl-pyrimidin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. It was obtained in 95% yield as a pale-brown solid. MS ISP (m/e): 472.0 (100) [(M+H)+].
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:24])OC2C=CC=CC=2)=[CH:11][N:10]=1.[F:25][C:26]([F:37])([F:36])[C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH2:31][CH2:30]2>CN(C)C=O>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([C:26]([F:25])([F:36])[F:37])=[CH:35][CH:34]=3)[CH2:30][CH2:31]2)=[O:24])=[CH:11][N:10]=1
Reactant: FC(F)(F)c1ccc2c(c1)CCN2
Reactant: O=C(Nc1ccc(OCc2ccccn2)nc1)Oc1ccccc1
Solvent: CN(C)C=O
Product: O=C(Nc1ccc(OCc2ccccn2)nc1)N1CCc2cc(C(F)(F)F)ccc21
Temperature: 100 °C
Yield: 31.1 %

Procedure:
Phenyl N-[2-(pyridin-2-ylmethyloxy)pyridin-5-yl] carbamate (D3, 0.20 g, 0.62 mmol) in dry dimethylformamide (10 ml) was treated with 5-trifluoromethylindoline (D6, 0.12 g, 0.62 mmol) and heated at 100° C. for 1 hour. After cooling to ambient temperature, the solvent was removed in vacuo. The residue was dissolved in dichloromethane, washed with 10% aqueous sodium hydroxide solution, dried (Na2SO4) and evaporated in vacuo. The resulting oil was chromatographed on silica gel eluting with 2% methanol/dichloromethane and triturated with diethyl ether to afford the title compound (0.08 g, 31%) as an off-white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=C(C2C=CC=CC=2)C(C2C=CC=CC=2)=[N:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:41][C:42]1[CH:47]=[CH:46][C:45]([C:48]([C:50]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)=O)=O)=[CH:44][CH:43]=1>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:48]([C:45]2[CH:46]=[CH:47][C:42]([CH3:41])=[CH:43][CH:44]=2)[C:50]([C:52]2[CH:57]=[CH:56][C:55]([CH3:58])=[CH:54][CH:53]=2)=[N:22]3)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4ccccc4)c(-c4ccccc4)nc3c1)n2C1CCCCC1
Reactant: Cc1ccc(C(=O)C(=O)c2ccc(C)cc2)cc1
Product: Cc1ccc(-c2nc3ccc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)cc3nc2-c2ccc(C)cc2)cc1

Procedure:
Prepared as described for Compound 406 using 4,4′-dimethylbenzil in place of benzil.
Reaction SMILES: [C:1](Cl)(=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8][S:9][C:10]1[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=1[C:12](Cl)=[O:13].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[Cl:29])[NH2:25]>ClCCl.N1C=CC=CC=1>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:1](=[O:19])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[S:8][S:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([NH:25][C:24]2[CH:26]=[CH:27][C:28]([Cl:29])=[C:22]([Cl:21])[CH:23]=2)=[O:13])[CH:26]=[CH:27][C:28]=1[Cl:29]
Reactant: Nc1ccc(Cl)c(Cl)c1
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(Nc1ccc(Cl)c(Cl)c1)c1ccccc1SSc1ccccc1C(=O)Nc1ccc(Cl)c(Cl)c1
Yield: 10.2 %

Procedure:
This compound was prepared according to the general method of Example 77 using 2,2'-dithiobisbenzoyl chloride (1.04 g, 3.03 mmol) in 25 mL of dichloromethane and 3,4-dichloroaniline (0.982 g, 6.06 mmol) in 8 mL of pyridine. The crude product was recrystallized from ethyl acetate-hexanes to yield 0.184 g of the title compound, mp 230-233° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([CH2:6][NH:7][NH2:8])=[CH:4][C:3]=1[Cl:11].C([O:14][C:15](=O)[CH:16]=[C:17]([NH2:21])OCC)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[NH2:21][C:17]1[NH:8][N:7]([CH2:6][C:5]2[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([Cl:11])[CH:4]=2)[C:15](=[O:14])[CH:16]=1
Reactant: CCOC(=O)C=C(N)OCC
Reactant: Cc1ccc(CNN)cc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: Cc1ccc(Cn2[nH]c(N)cc2=O)cc1Cl
Reaction time: 2 h

Procedure:
50 g of 4-methyl-3-chlorobenzylhydrazine were added dropwise, under nitrogen, to a solution of 46.7 g of β-amino-β-ethoxyacrylic acid ethyl ester and 1.5 g of p-toluenesulphonic acid in 200 ml of ethanol. After stirring for a further two hours, the compound identified above precipitated. It was filtered off and recrystallised from ethanol. Melting point: 130°-131°, 35 g (50%).
Reaction SMILES: CN(C=O)C.[C:6]([C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1)([CH3:9])([CH3:8])[CH3:7].Cl[C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([C:10]1[CH:11]=[C:12]([CH:13]=[CH:14][CH:15]=1)[O:16][C:18]1[C:23]([CH3:24])=[CH:22][C:21]([N+:25]([O-:27])=[O:26])=[CH:20][N:19]=1)([CH3:9])([CH3:7])[CH3:8]
Reactant: Cc1cc([N+](=O)[O-])cnc1Cl
Reactant: CC(C)(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc([N+](=O)[O-])cnc1Oc1cccc(C(C)(C)C)c1
Temperature: 60 °C
Yield: 89.2 %

Procedure:
A 50 ml two-necked round-bottomed flask equipped with a magnetic bar, a thermometer and a reflux condenser is charged with DMF (50 ml), 3-tert-butyl-phenol (1.5 g), 2-chloro-3-methyl-5-nitro-pyridine (1.73 g) and potassium carbonate (2.76 g). The reaction mixture is heated at 60° C. for 2 hours. After cooling the mixture to room temperature it is then poured into water (200 ml). The mixture is then extracted with ethylacetate (2×40 ml). The combined organic layers are dried over sodium sulfate, filtered and the solvent is removed in vacuo. Purification of this crude material by flash chromatography over silica gel with hexane/ethyl acetate 4:1 (v:v) gives 2.55 g of the compound as a yellow oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:17][CH:16]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:35][C:36]1[S:40][C:39]2[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:38]=2[CH:37]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])([CH2:35][C:36]2[S:40][C:39]3[CH:41]=[CH:42][C:43]([C:45]#[N:46])=[CH:44][C:38]=3[CH:37]=2)[C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:19][CH:20]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc2sc(CBr)cc2c1
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1cc2cc(C#N)ccc2s1)(C(=O)OCC)c1ccc(OC[C@H]2CCCN2C(=O)OC(C)(C)C)cc1
Reaction time: 0.5 h
Yield: 85.9 %

Procedure:
4.1 g of ethyl 2-[4-[((2R)-1-tert-butoxycarbonyl-2-pyrrolidinyl)methoxy]phenyl]-2-ethoxycarbonylacetate was dissolved in 100 ml of tetrahydrofuran. At room temperature, the thus prepared solution was mixed with 0.38 g of 60% sodium hydride and stirred for 30 minutes. With stirring at room temperature, to the resulting reaction solution was added dropwise 10 ml of a tetrahydrofuran solution containing 2.1 g of 2-bromomethylbenzo[b]-thiophene-5-carbonitrile. After concentrating the reaction solution to dryness, the resulting residue was purified by subjecting it to silica gel column chromatography using a toluene/chloroform mixture as an elution solvent, thereby obtaining 4.34 g of the title compound in an oily form.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14].[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH3:25])=[CH:19][C:17]=1[NH2:18].Cl.N1C=CC=CC=1>>[Cl:15][C:16]1[CH:22]=[C:21]([Cl:23])[C:20]([O:24][CH3:25])=[CH:19][C:17]=1[NH:18][C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:12])=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[C:13]#[N:14]
Reactant: N#Cc1cnc2cc(F)ccc2c1Cl
Reactant: COc1cc(N)c(Cl)cc1Cl
Agent: Cl
Solvent: c1ccncc1
Product: COc1cc(Nc2c(C#N)cnc3cc(F)ccc23)c(Cl)cc1Cl
Yield: 48.2 %

Procedure:
Following the procedure of Reference Example 8, a mixture of 4-chloro-7-fluoro-3-quinolinecarbonitrile (2.10 g, 10.2 mmol), 2,4-dichloro-5-methoxyaniline (2.15 g, 11.2 mmol) and pyridine hydrochloride (1.18 g, 10.2 mmol) provides 1.78 g of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-fluoro-3-quinolinecarbonitrile, mp 199-201° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](SCC)=[CH:6][C:5]2=[O:15].[NH:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7]([N:16]1[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)=[CH:6][C:5]2=[O:15]
Reactant: CCSc1cc(=O)c2cc(Br)ccc2o1
Reactant: C1COCCN1
Product: O=c1cc(N2CCOCC2)oc2ccc(Br)cc12

Procedure:
Prepared from 6-Bromo-2-ethylsulfanyl-chromen-4-one (0.375 g, 1.35 mmol) and morpholine (0.54 ml, 6.25 mmol), affording a pale yellow solid. (0354 g, 1.14 mmol, 84%); m.p. 147-149° C.; ES+(m/e)=310.24 (M++1); (200 MHz, CDCl3) δ 3.44 (4H, m); 3.77 (4H, m); 5.42 (1H, s); 7.11 (1H, d); 7.57 (1H, dd); 8.20 (1H, d)
Reaction SMILES: CN(C)C=O.[O:6]=[C:7]1[NH:12][CH:11]=[N:10][C:9]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[N:8]1.C(=O)([O-])[O-].[K+].[K+].[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37]Br)=[CH:35][CH:34]=1>O>[Cl:32][C:33]1[CH:40]=[CH:39][C:36]([CH2:37][N:12]2[CH:11]=[N:10][C:9]([N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[N:8][C:7]2=[O:6])=[CH:35][CH:34]=1
Reactant: Clc1ccc(CBr)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc[nH]c(=O)n2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCN(c2ncn(Cc3ccc(Cl)cc3)c(=O)n2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 68 %

Procedure:
To an N,N-dimethylformamide solution (200 mL) of the crude product of tert-butyl 4-(4-oxo-4,5-dihydro-1,3,5-triazin-2-yl)piperazine-1-carboxylate synthesized in Reference Synthesis Example 7 and potassium carbonate (7.46 g, 54.0 mmol), 4-chlorobenzyl bromide (10.2 g, 49.5 mmol) was added at room temperature and the resultant reaction solution was stirred at room temperature for 1 day. After completion of the reaction, water was added to the reaction solution and a deposited solid was collected by filtration. The filtered residue was suspended in ethyl acetate and the suspended solid was collected by filtration and dried under reduced pressure to obtain the title compound (12.4 g, two step yield 68%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([N+:21]([O-])=O)[CH:18]=[N:17]1)[CH2:7][CH2:6]2>CO.CCO.O=[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[N:8]([CH2:14][CH2:15][N:16]1[CH:20]=[C:19]([NH2:21])[CH:18]=[N:17]1)[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)N(CCn1cc([N+](=O)[O-])cn1)CC2
Agent: O=[Pt]=O
Solvent: CO
Solvent: CCO
Product: COc1cc2c(cc1OC)N(CCn1cc(N)cn1)CC2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5,6-dimethoxy-1-(2-(4-nitro-1H-pyrazol-1-yl)ethyl)indoline (1.53 g, 4.81 mmol) in MeOH (50 mL), PtO2 (200 mg, 0.88 mmol) was added and the reaction mixture was stirred at rt under a H2-atmosphere for 1 h. The mixture was diluted with EtOH, filtered over celite and the filter cake was rinsed with MeOH. The filtrate was concentrated under reduced pressure to obtain 1-(2-(5,6-dimethoxyindolin-1-yl)ethyl)-1H-pyrazol-4-amine as a brown oil, which was used in the next step without further purification. LC-MS conditions B: tR=0.38 min, [M+H]+=289.18.