Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Br[C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][N:15]=2)=[N:12][CH:13]=1>C1COCC1.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.[Cu]I>[CH3:1][Si:2]([C:5]#[C:6][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:6]#[C:5][Si:2]([CH3:4])([CH3:3])[CH3:1])=[CH:16][N:15]=2)=[N:12][CH:13]=1)([CH3:4])[CH3:3]
Reactant: C#C[Si](C)(C)C
Reactant: Brc1ccc(-c2ccc(Br)cn2)nc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C[Si](C)(C)C#Cc1ccc(-c2ccc(C#C[Si](C)(C)C)cn2)nc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Under dry nitrogen atmosphere, successively trimethylsilyl-acetylene (619 mg, 6.30 mmol), [Pd(PPh3)2Cl2] (112 mg, 159 μmol), CuI (54.5 mg, 286 μmol) and DIPA (4 ml) were added to a stirred suspension of 3 (500 mg, 1.59 mmol) in 30 ml THF. While the mixture was stirred for 24 hours at room temperature, its color turned black. It was stirred together with activated carbon for 20 minutes and filtered over celite. Then the solvent was removed under reduced pressure, the residue was resuspended in hexane, sonicated for 15 minutes and filtered over celite again yielding an orange solution. The solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica (eluent: CH2Cl2) to yield 430 mg (1.23 mmol, 78%) of pure 4 as an off-white solid. 1H NMR (CDCl3, 250 MHz): δ=8.71 (s, 2H, bpy-H), 8.33 (d, 2H, JHH=8.3 Hz, bpy-H), 7.85 (d, 2H, JHH=7.8 Hz, bpy-H), 0.27 (s, 18H, Si(CH3)3).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[C:4]([C:13]([OH:15])=O)[CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.C(N(CC)C(C)C)(C)C.Cl.[CH3:48][O:49][C:50](=[O:55])[C:51]([NH2:54])([CH3:53])[CH3:52]>CN(C=O)C>[CH3:48][O:49][C:50](=[O:55])[C:51]([NH:54][C:13]([C:4]1[CH:3]=[C:2]([Br:1])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]=1[OH:12])=[O:15])([CH3:53])[CH3:52]
Reactant: O=C(O)c1cc(Br)c2ccccc2c1O
Reactant: COC(=O)C(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)C(C)(C)NC(=O)c1cc(Br)c2ccccc2c1O
Reaction time: 24 h
Yield: 70.2 %

Procedure:
To a solution of 1.5 g 4-bromo-1-hydroxy-2-naphthoic acid in 20 ml abs. DMF under inert atmosphere 0.84 g 1-hydroxybenzotriazole, 1.18 g 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 1.1 ml of N,N-diisopropylethylamine were added. After 15 minutes 0.86 g of 2-amino-2-methyl-propionic acid methyl ester hydrochloride, followed by 1.1 ml of N,N-diisopropylethylamine were added. After 24 h at room temperature and 2 h at 50° C. the reaction mixture was concentrated, the residue was taken up in ethyl acetate and washed with 2 M HCl, aqueous sodium carbonate solution (10%) and brine. The organic layer was dried over magnesium sulphate, and concentrated to yield 1.44 g of 2-[(4-bromo-1-hydroxy-naphthalene-2-carbonyl)-amino]-2-methyl-propionic acid methyl ester.
Reaction SMILES: [N+:1]([C:4]1[C:13]2[N:14]=[CH:15][CH:16]=[CH:17][C:12]=2[C:11]2[C:6](=[N:7][C:8](=[O:19])[C:9](=[O:18])[N:10]=2)[CH:5]=1)([O-:3])=[O:2].Cl[S:21]([C:24]1[S:25][CH:26]=[CH:27][CH:28]=1)(=[O:23])=[O:22].C(N(CC)CC)C.C(OCC)C>C1COCC1.CN(C=O)C>[N+:1]([C:4]1[C:17]2[CH2:16][CH2:15][N:14]([S:21]([C:24]3[S:25][CH:26]=[CH:27][CH:28]=3)(=[O:23])=[O:22])[CH2:13][C:12]=2[C:11]2[NH:10][C:9](=[O:18])[C:8](=[O:19])[NH:7][C:6]=2[CH:5]=1)([O-:3])=[O:2]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: O=C1N=c2cc([N+](=O)[O-])c3ncccc3c2=NC1=O
Solvent: CCN(CC)CC
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CN(S(=O)(=O)c1cccs1)CC3
Temperature: 60 °C
Reaction time: 24 h
Yield: 51.5 %

Procedure:
A mixture of the 6-nitropyridoquinoxalinedione (0.1 g, 0.38 mmol), 2-chlorosulfonyl thiophene (104 mg, 0.57 mmol), triethylamine (70 μl) in THF (5 mL) and DMF (5 mL) was stirred at 60° C. for 24 hours. The mixture was poured onto water and diethyl ether. The precipitate was collected by filtration, washed with water and ether, and dried in vacuo to give product as a yellow solid (80 mg) in 52% yield; mp >300° C. m/e, M+1 409 nmR, IR, CHN.
Reaction SMILES: ClC1C=CC2C3N=C(NC4C=CC=C(I)C=4)N=CC=3CC(=O)NC=2C=1.C(NC(=O)OC(C)(C)C)C#C.C(OC(=O)[NH:43][CH2:44][C:45]#[C:46][C:47]1[CH:52]=[CH:51][CH:50]=[C:49]([NH:53][C:54]2[N:55]=[CH:56][C:57]3[CH2:63][C:62](=[O:64])[NH:61][C:60]4[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:59]=4[C:58]=3[N:70]=2)[CH:48]=1)(C)(C)C>>[NH2:43][CH2:44][C:45]#[C:46][C:47]1[CH:48]=[C:49]([NH:53][C:54]2[N:55]=[CH:56][C:57]3[CH2:63][C:62](=[O:64])[NH:61][C:60]4[CH:65]=[C:66]([Cl:69])[CH:67]=[CH:68][C:59]=4[C:58]=3[N:70]=2)[CH:50]=[CH:51][CH:52]=1
Reactant: CC(C)(C)OC(=O)NCC#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1
Agent: C#CCNC(=O)OC(C)(C)C
Agent: O=C1Cc2cnc(Nc3cccc(I)c3)nc2-c2ccc(Cl)cc2N1
Product: NCC#Cc1cccc(Nc2ncc3c(n2)-c2ccc(Cl)cc2NC(=O)C3)c1

Procedure:
In a manner similar to that described for Method O, 9-chloro-2-(3-iodo-phenylamino)-5H,7H-benzo[b]pyrimido[4,5-d]azepin-6-one (I-58) and tert-butyl prop-2-ynylcarbamate was converted to {3-[3-(9-chloro-6-oxo-6,7-dihydro-5H-benzo[b]pyrimido[4,5-d]azepin-2-ylamino)-phenyl]-prop-2-ynyl}-carbamic acid tert-butyl ester, which was subsequently deprotected according to Method K to give I-67 (62%): HRMS Calcd. for C21H16ClN5O: 390.1121, Found 390.1117.
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12](O)=O)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C)C=O.[NH2:22][C:23]1[CH:24]=[C:25]([CH:31]=[CH:32][C:33]=1[OH:34])[C:26]([O:28][CH2:29][CH3:30])=[O:27].C(OC1C=CC(C(Cl)=O)=CC=1)CCCCC>C(Cl)(=O)C(Cl)=O.ClCCl.CN(C)C1C=CN=CC=1.C(N(CC)CC)C>[CH2:1]([O:7][C:8]1[CH:16]=[CH:15][C:11]([C:12]2[O:34][C:33]3[CH:32]=[CH:31][C:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])=[CH:24][C:23]=3[N:22]=2)=[CH:10][CH:9]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCOc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)c1ccc(O)c(N)c1
Agent: CCCCCCOc1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCOc1ccc(-c2nc3cc(C(=O)OCC)ccc3o2)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 4-hexyloxybenzoic acid in oxalyl chloride (10 ml) and dichloromethane (10 ml) was added N,N-dimethylformamide (0.1 ml). The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure to give crude 4-hexyloxybenzoyl chloride. To a suspension of Ethyl 3-amino-4-hydroxybenzoate (733 mg) and triethylamine (1.38 ml) and 4-dimethylaminopyridine (DMAP, 10 mg) in methylene chloride (10 ml) was added the solution of 4-hexyloxybenzoyl chloride obtained above in dichloromethane (5 ml) dropwise at 10° C. The reaction mixture was stirred at 10° C. for 1.5 hours and diluted with dichloromethane (20 ml). The solution was washed with H2O (20 ml), 1 N HCl aq. (20 ml×2), H2O (20 ml) and brine (20 ml) successively. The organic layer was dried over MgSO4 and the solvent was removed under reduced pressure. To the residue was added toluene (15 ml) and p-toluenesulfonic acid (10 mg). The mixture was refluxed for 6 hours and the solvent was removed under reduced pressure. The residue was triturated with acetonitrile, and precipitate was collected with filtration and dried over PO5 to give 2-(4-Hexyloxyphenyl)-5-ethoxycarbonylbenzoxazole (0.60 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:12][CH2:11]2)[NH2:9])=[CH:4][CH:3]=1.Cl[C:27]1[N:32]=[CH:31][CH:30]=[CH:29][N:28]=1>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([CH:10]2[CH2:11][CH2:12][N:13]([CH2:16][CH2:17][CH2:18][O:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:14][CH2:15]2)[NH:9][C:27]2[N:32]=[CH:31][CH:30]=[CH:29][N:28]=2)=[CH:6][CH:7]=1
Reactant: Clc1ncccn1
Reactant: NC(c1ccc(F)cc1)C1CCN(CCCOc2ccccc2)CC1
Solvent: C1CCOC1
Product: Fc1ccc(C(Nc2ncccn2)C2CCN(CCCOc3ccccc3)CC2)cc1

Procedure:
α-(4-Fluorophenyl)-1-(3-phenoxypropyl)-4-piperidinemethanamine and 2-chloropyrimidine (equimolar quantities) are heated together in tetrahydrofuran at reflux temperature until the reaction is judged complete. The reaction mixture is concentrated and the residual material is partitioned between 1N NaOH solution and methylene chloride. The methylene chloride layer is dried and concentrated to obtain the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=1.[OH:19][C@@H:20]1[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1.[H-].[Na+]>C1COCC1>[Cl:8][C:6]1[N:5]=[C:4]([S:9][CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=2[F:18])[N:3]=[C:2]([O:19][C@@H:20]2[CH2:24][O:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]2)[CH:7]=1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)CO1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](Oc2cc(Cl)nc(SCc3cccc(F)c3F)n2)CO1
Temperature: 60 °C

Procedure:
To a stirred solution of 4,6-Dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of Example 1, step ii) (0.25 g) and 1,1-dimethylethyl (S)-4-hydroxyisoxazolidine-2-carboxylate (0.16 g) in dry THF (5 mL) was added 60% Sodium hydride (0.034 g) over 5 min. The reaction mixture was stirred and heated at 60° C. for 7 days, 1120 was added and the solvents were partially evaporated. The residue was extracted with EtOAc which was washed with H2O, dried (MgSO4) and the solvent evaporated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with Et2O/iso-hexane (1:9) to give the subtitle compound as a gum. Yield: 0.15 g.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[N:12]2[C:13]3[C:18]([CH:19]=[CH:20][C:11]2=[C:10]([C:21]([O:23]C)=[O:22])[CH:9]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7].Cl>CO.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:25]=[CH:26][CH:27]=1)[C:6]([C:8]1[N:12]2[C:13]3[C:18]([CH:19]=[CH:20][C:11]2=[C:10]([C:21]([OH:23])=[O:22])[CH:9]=1)=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:7]
Reactant: COC(=O)c1cc(C(=O)c2cccc(OC)c2)n2c1ccc1ccccc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1cccc(C(=O)c2cc(C(=O)O)c3ccc4ccccc4n23)c1

Procedure:
A solution of 1-(3-methoxy-benzoyl)-pyrrolo[1,2-a]quinoline-3-carboxylic acid, methyl ester (130 mg, 0.348 mmol) in MeOH (5 mL) and NaOH (2N, 5 mL) was stirred at 50° C. for 24 h. The reaction mixture was acidified to pH=3 with 10% HCl to produce a light yellow precipitate. The mixture was filtered and the solid was washed with water, and dried in vacuo (114 mg, 95%): 1H NMR (DMSO-D6): 8.28 (d, J=9.3 Hz, 1H), 8.04 (dd, J=1.2, 8.7 Hz, 1H), 7.97 (d, J=9.3 Hz, 2H), 7.70–7.52 (m, 5H), 7.46 (s, 1H), 7.33 (m, 1H), 3.86 (s, 3H), 3.35 (s, 1H).
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@@H:16]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30](Br)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:41][C:42]([F:51])([F:50])[C:43]1[CH:48]=[CH:47][C:46]([OH:49])=[CH:45][CH:44]=1>CN(C=O)C.O>[CH2:1]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14](=[O:34])[CH2:15][C@H:16]([C:17]1[CH:21]=[CH:20][O:19][N:18]=1)[C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][CH:30]([O:49][C:46]2[CH:47]=[CH:48][C:43]([C:42]([F:41])([F:50])[F:51])=[CH:44][CH:45]=2)[CH2:31][CH3:32])=[CH:24][CH:23]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Oc1ccc(C(F)(F)F)cc1
Reactant: CCC(Br)COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCC(COc1ccc([C@H](CC(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)c2ccon2)cc1)Oc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 22.2 %

Procedure:
The bromide 49.1 (90 mg, 0.17 mmol) was dissolved in DMF (2.0 mL). Cesium carbonate (220 mg, 0.68 mmol) and 4-trifluoromethylphenol (110 mg, 0.68 mmol) were added to the solution and the mixture was then heated with stirring for three hours. The reaction mixture was then cooled to room temperature and diluted with water. The mixture was extracted with EtOAc (2×50 mL). The combined organic layers were washed with 1M lithium chloride solution (1×25 mL), water (1×25 mL) and brine (1×25 mL), and dried over magnesium sulfate. The filtrate was concentrated under reduced pressure and the residue purified by medium pressure chromatography (silica, 0 to 60% EtOAc:hexanes) to obtain 49.2 (23 mg). MS ESI (pos.): m/e 609.1 (M+H).
Reaction SMILES: COC[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[C:15]=2[O:24]COC)[CH2:13][CH2:12]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[OH:24][C:15]1[C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=[CH:19][C:14]=1[C:11]1([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[OH:4])[CH2:12][CH2:13]1
Reactant: COCOc1ccccc1C1(c2ccc(OC)c(OC)c2OCOC)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Product: COc1ccc(C2(c3ccccc3O)CC2)c(O)c1OC
Reaction time: 2 h
Yield: 99.1 %

Procedure:
A solution of 1.16 g (3.1 mmol) of 1-(2-methoxymethoxyphenyl)-1-(3,4-dimethoxy-2-methoxymethoxyphenyl)cyclopropane and 80 mg (0.47 mmol) of p-toluenesulfonic acid in 26 ml of methanol was heated at reflux with stirring for 2 hours under an argon atmosphere. The mixture was concentrated to half by evaporation under reduced pressure and 40 ml of ether was added. The resulting solution was extracted with 30 ml of 5 percent aqueous sodium bicarbonate then 30 ml of water, dried over magnesium sulfate, and concentrated by evaporation under reduced pressure to obtain 880 mg of the title compound as a foamy oil. The proton NMR spectrum was consistent with the assigned structure.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[NH:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1)=[O:4].[C:15]1([O:21][C:22]#[N:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[C:15]1([O:21][C:22]([N:10]2[C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]=[C:6]2[NH:5][C:3]([O:2][CH3:1])=[O:4])=[NH:23])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)Nc1nc2ccccc2[nH]1
Reactant: N#COc1ccccc1
Solvent: ClC(Cl)Cl
Product: COC(=O)Nc1nc2ccccc2n1C(=N)Oc1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
To a suspension of 420.6 g (2.2 mole) 2-(methoxycarbonylamino)-benzimidazole in 10 ltr chloroform a solution of 274 g (2.3 moles) phenyl cyanate in 2 ltr chloroform is added in drops while stirring at 20°C. The reaction mixture is stirred for 6 hours at room temperature and then left standing overnight. The product is then filtered and the solvent removed under vacuum. The colorless, crystalline residue is treated with ether.
Reaction SMILES: [OH:1][CH2:2][C:3]1[NH:11][C:10]2[C:9](=[O:12])[N:8]([CH3:13])[C:7](=[O:14])[N:6]([CH3:15])[C:5]=2[N:4]=1.[OH-].[Na+].[O-:18][Mn](=O)(=O)=O.[K+]>O>[CH3:13][N:8]1[C:9](=[O:12])[C:10]2[NH:11][C:3]([C:2]([OH:18])=[O:1])=[N:4][C:5]=2[N:6]([CH3:15])[C:7]1=[O:14]
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: Cn1c(=O)c2[nH]c(CO)nc2n(C)c1=O
Agent: [K+]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1c(=O)c2[nH]c(C(=O)O)nc2n(C)c1=O
Temperature: 5 °C
Reaction time: 4 h

Procedure:
5.00 g (24.0 mmol) 8-Hydroxymethyl-1,3-dimethyl-3,7-dihydro-purine-2,6-dione were suspended in 15 mL water. 16.8 mL (33.6 mmol) of a 2 N NaOH-solution were added. The resulting mixture was cooled to 5° C. At that temperature a solution of 5.05 g (32.2 mmol) KMnO4 in 86 mL water was added. After stirring at room temperature for 4 h the reaction mixture was filtered over Celite. After addition of activated carbon the filtrate was again filtered over Celite. The filtrate was concentrated to a volume of 200 mL and 5 mL of conc. HCl-solution were added. After standing at 4° C. for 16 h the crystaline product was filtered off, washed twice with cold water and acetone and dried under reduced pressure at 40° C.
Reaction SMILES: [C:1]1(C)[CH:6]=[CH:5][C:4](S(O)(=O)=O)=[CH:3][CH:2]=1.C1(=O)CCCCC1.[NH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1>C1C=CC=CC=1>[C:1]1([N:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]=1
Reactant: C1CCNC1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: O=C1CCCCC1
Product: C1=C(N2CCCC2)CCCC1

Procedure:
1 g of para-toluenesulphonic acid is added to a mixture of 20 mmol of cyclohexanone and 22 mmol of pyrrolidine in 200 ml of dry benzene. The reaction mixture is stirred at reflux until, in the infra-red, the ketone has disappeared, with the enamine concomitantly appearing. The solvent is then evaporated off and the crude residue is purified by distillation in vacuo.
Reaction SMILES: [C:1]([C:4]1[CH:8]=[C:7]([C:9]([NH:11][C@@H:12]([CH3:29])[CH2:13][N:14]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[C:23]([Cl:25])[C:22]([C:26]#[N:27])=[C:21]([Cl:28])[CH:20]=3)=[N:15]2)=[O:10])[NH:6][N:5]=1)(=[O:3])[CH3:2].[BH4-].[Na+]>>[Cl:25][C:23]1[CH:24]=[C:19]([C:16]2[CH:17]=[CH:18][N:14]([CH2:13][C@@H:12]([NH:11][C:9]([C:7]3[NH:6][N:5]=[C:4]([CH:1]([OH:3])[CH3:2])[CH:8]=3)=[O:10])[CH3:29])[N:15]=2)[CH:20]=[C:21]([Cl:28])[C:22]=1[C:26]#[N:27]
Reactant: CC(=O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(Cl)c(C#N)c(Cl)c3)n2)[nH]n1
Agent: [BH4-]
Agent: [Na+]
Product: CC(O)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3cc(Cl)c(C#N)c(Cl)c3)n2)[nH]n1

Procedure:
The title compound was prepared from (S)-3-acetyl-N-(1-(3-(3,5-dichloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-1H-pyrazole-5-carboxamide (63 mg, 0.15 mmol) and sodium borohydride (11 mg, 0.29 mmol) using the method of Example 84. Yield 15 mg. 1H NMR (400 MHz; CDCl3): δ 1.23 (d, 3H), 1.54 (d, 3H), 4.34 (m, 2H), 4.54 (m, 1H), 4.96 (q, 1H), 6.61 (m, 2H), 7.52 (d, 1H), 7.90 (m, 2H).
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:13][C:14]1[N:23]([CH2:24][CH3:25])[C:22]2[N:21]=[C:20]([C:26]3[CH:31]=[CH:30][C:29]([CH2:32][C:33](O)=[O:34])=[CH:28][CH:27]=3)[CH:19]=[CH:18][C:17]=2[C:16](=[O:36])[C:15]=1[C:37](=[O:40])[NH:38][CH3:39].[ClH:41].[CH3:42][CH:43]([N:45]1[CH2:50][CH2:49][O:48][CH2:47][CH:46]1[CH2:51][NH2:52])[CH3:44].C(=O)([O-])[O-].[Na+].[Na+]>CN(C=O)C>[ClH:41].[NH2:13][C:14]1[N:23]([CH2:24][CH3:25])[C:22]2[C:17]([C:16](=[O:36])[C:15]=1[C:37]([NH:38][CH3:39])=[O:40])=[CH:18][CH:19]=[C:20]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][C:33]([NH:52][CH2:51][CH:46]3[CH2:47][O:48][CH2:49][CH2:50][N:45]3[CH:43]([CH3:44])[CH3:42])=[O:34])=[CH:28][CH:27]=1)[N:21]=2
Reactant: CC(C)N1CCOCC1CN
Reactant: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(-c3ccc(CC(=O)O)cc3)nc21
Agent: Cl
Agent: O=C([O-])[O-]
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CCn1c(N)c(C(=O)NC)c(=O)c2ccc(-c3ccc(CC(=O)NCC4COCCN4C(C)C)cc3)nc21
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
Under an inert atmosphere, 0.18 g of N,N-carbonyldiimidazole is added to a suspension of 0.4 g (1.1 mmol) of the compound obtained from step 2.5 in DMF (5 ml). The reaction mixture is stirred at room temperature for 1 hour 30 minutes, 0.225 g (1.2 mmol) of the compound obtained from step 2.2 dissolved in DMF (1 ml), and stirred beforehand in the presence of 0.13 g (1.3 mmol) of sodium carbonate, is then added and the mixture is heated at 80° C. for 2 hours. The DMF is removed by evaporation under reduced pressure, and the residue is then purified by flash chromatography on silica gel (eluent: dichloromethane/methanol/1% NH4OH), with a gradient of 0% to 5% methanol. 0.3 g of product is obtained, in the form of a white powder. Yield: 57%. MH+: 521.3
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([OH:7])=O.[CH:12]1([NH2:15])[CH2:14][CH2:13]1.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O>[OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[F:11])[C:5]([NH:15][CH:12]1[CH2:14][CH2:13]1)=[O:7]
Reactant: O=C(O)c1ccc(F)c(O)c1
Reactant: NC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NC1CC1)c1ccc(F)c(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.5 %

Procedure:
To a mixture of 3-hydroxy-4-fluorobenzoic acid (1.56 g, 10 mmol), cyclopropylamine (0.6 g, 10.5 mmol), triethylamine (1.02 g, 10 mmol) and HOBt (0.3 g, 2 mol) in DMF (10 mL) was added EDCI (2.0 g, 10.5 mmol) at RT. The mixture was stirred at RT overnight. The mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The extract was washed with water and concentrated to afford 3-hydroxy-4-fluoro-N-cyclopropylbenzamide as a solid (1.2 g, 61.5%).
Reaction SMILES: Cl[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].Cl.Cl.[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][NH:22]2.N12CCCN=C1CCCCC2>C(#N)C>[CH:21]12[CH2:28][CH2:27][CH:24]([NH:25][CH2:26]1)[CH2:23][N:22]2[C:2]1[N:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)nc21
Reactant: C1CC2CNC1CN2
Agent: Cl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CC4CCC3CN4)nc21
Yield: 90.9 %

Procedure:
A solution of 0.54 g (2.0 mmole) of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 0.46 g (2.5 mmole) of 2,5-diazabicyclo[2.2.2]octane dihydrochloride [P. A. Sturm et al., J. Med. Chem., 17, 481 (1974)], 1.05 ml (7.0 mmole) of 1,8-diazabicyclo (5.4.0) undec-7-ene, and 30 ml of acetonitrile was stirred at room temperature for 23 hours. The reaction mixture was filtered and the solid was washed with acetonitrile to give 0.63 g of the title compound, mp 250°-253°.
Reaction SMILES: [Cl:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[CH2:6][CH:7]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[Cl:19])[CH2:8][C:9](=O)[C:10]=2[C:11]=1[CH3:12].[C:22]([NH:25][NH2:26])([NH2:24])=[NH:23].Cl.C(OCCO)C.Cl>>[ClH:1].[Cl:1][C:2]1[C:3](=[O:21])[N:4]([CH3:20])[C:5]2[CH2:6][CH:7]([C:14]3[CH:18]=[CH:17][S:16][C:15]=3[Cl:19])[CH2:8][C:9](=[N:26][NH:25][C:22]([NH2:24])=[NH:23])[C:10]=2[C:11]=1[CH3:12]
Reactant: N=C(N)NN
Reactant: Cc1c2c(n(C)c(=O)c1Cl)CC(c1ccsc1Cl)CC2=O
Agent: Cl
Solvent: CCOCCO
Product: Cc1c2c(n(C)c(=O)c1Cl)CC(c1ccsc1Cl)CC2=NNC(=N)N
Temperature: 135 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a mixture of 3-chloro-7-(2-chlorothiophen-3-yl)-1,4-dimethyl-1,2,5,6,7,8-hexahydroquinoline-2,5-dione (0.098 g) and aminoguanidine hydrochloride (32 mg) were added 2-ethoxyethanol (1.5 ml) and concentrated hydrochloric acid (0.05 ml), and the mixture was stirred at 135° C. for 1 hour and cooled. Precipitated crystals were filtered, washed with methanol and dried to give 3-chloro-7-(2-chlorothiophen-3-yl)-5-guanidinoimino-1,4-dimethyl-1,2,5,6,7,8-hexahydroquinolin-2-one hydrochloride (Compound 140) (0.04 g) as crystals.