Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=3)[N:17]=2)=[CH:14][C:5]([CH2:6][NH:7]C(=O)C(F)(F)F)=[C:4]([F:32])[CH:3]=1.[OH-].[K+].O>C1COCC1>[NH2:7][CH2:6][C:5]1[C:4]([F:32])=[CH:3][C:2]([Cl:1])=[C:15]([C:16]2[NH:20][C:19](=[O:21])[N:18]([C:22]3[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:31])[F:29])=[CH:26][CH:27]=3)[N:17]=2)[CH:14]=1
Reactant: O=C(NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F)C(F)(F)F
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NCc1cc(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c(Cl)cc1F
Yield: 99.9 %

Procedure:
The title compound was prepared according to the procedure described in Intermediate-66 by using N-(4-chloro-2-fluoro-5-(1-(4-(trifluoromethyl)phenyl)-4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl)benzyl)-2,2,2-trifluoroacetamide (Example-113, 0.100 g, 0.207 mmol), KOH (0.034 g, 0.622 mol), water (5 mL) and THF (5.0 mL) to afford 0.080 g of the desired product.
Reaction SMILES: [ClH:1].[C:2]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][CH:13]([CH2:18][NH2:19])[CH2:14]2)(=[O:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]=O.[O:22]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[C:25](=[O:32])[CH2:24][CH2:23]1>Cl.CC(O)C>[ClH:1].[C:2]([N:10]1[CH:15]2[CH2:16][CH2:17][CH:11]1[CH2:12][CH:13]([CH2:18][NH:19][CH2:20][CH:24]1[C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:22][CH2:23]1)[CH2:14]2)(=[O:9])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C1CCOc2ccccc21
Reactant: NCC1CC2CCC(C1)N2C(=O)c1ccccc1
Reactant: C=O
Agent: Cl
Solvent: CC(C)O
Product: O=C1c2ccccc2OCC1CNCC1CC2CCC(C1)N2C(=O)c1ccccc1
Reaction time: 18 h

Procedure:
1.71 g (6.1 mmol) of 8-benzoyl-8-azabicyclo[3.2.1]octane-3-methanamine hydrochloride, 0.2 g (6.3 mmol) of paraformaldehyde and a few drops of concentrated hydrochloric acid in 10 ml of 2-propanol are introduced into a three-necked round-bottomed flask, the mixture is refluxed for 5 min, 0.78 g (5.3 mmol) of 2,3-dihydro-4H-1-benzopyran-4-one dissolved in 10 ml of 2-propanol is added and refluxing is continued for 18 h.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][CH2:8][N:7]([C:11]3[S:12][C:13]4[C:14](=[O:22])[NH:15][C:16]([CH3:21])([CH3:20])[CH2:17][C:18]=4[N:19]=3)[C:6]=2[CH:23]=1.[CH3:24][N:25]1[C:29]([C:30](O)=[O:31])=[CH:28][N:27]=[CH:26]1.CCN(C(C)C)C(C)C.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>C(Cl)Cl>[CH3:20][C:16]1([CH3:21])[NH:15][C:14](=[O:22])[C:13]2[S:12][C:11]([N:7]3[C:6]4[CH:23]=[C:2]([NH:1][C:30]([C:29]5[N:25]([CH3:24])[CH:26]=[N:27][CH:28]=5)=[O:31])[CH:3]=[CH:4][C:5]=4[O:10][CH2:9][CH2:8]3)=[N:19][C:18]=2[CH2:17]1
Reactant: CC1(C)Cc2nc(N3CCOc4ccc(N)cc43)sc2C(=O)N1
Reactant: Cn1cncc1C(=O)O
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: Cn1cncc1C(=O)Nc1ccc2c(c1)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 18 h
Yield: 28.5 %

Procedure:
To a stirred solution of Example 42 (0.025 g, 0.08 mmol) in DCM (1 mL) were added 1-methylimidazol-5-ylcarboxylic acid (0.013 g, 0.10 mmol), DIPEA (0.02 mL, 0.10 mmol), EDC (0.030 g, 0.16 mmol) and HOBT (0.05 g, 0.04 mmol). The reaction mixture was stirred at r.t. for 18 h, then concentrated in vacuo. Purification by preparative HPLC (Method 6) gave the title compound (0.01 g, 29%) as a yellow oil. δH (CDCl3) 9.25 (1H, s), 8.46-8.43 (1H, m), 7.33 (1H, dd, J 8.9 and 2.4 Hz), 7.07 (1H, d, J 0.9 Hz), 7.02 (1H, d, J 0.8 Hz), 6.94 (1H, d, J 8.9 Hz), 5.56 (1H, br. s), 4.36-4.29 (2H, m), 4.16-4.09 (2H, m), 4.11 (3H, s), 2.90 (2H, s), 1.40 (6H, s). LCMS (ES+) 439.4 (M+H)+, RT 2.69 minutes (Method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([OH:18])=[O:17])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1.[N+](=[CH2:21])=[N-]>C(Cl)Cl>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[C:4](=[C:5]([C:16]([O:18][CH3:21])=[O:17])[C:6]3[C:11]([N:12]=2)=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH:3]=1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1c2ccccc2nc2ccc(Cl)cc12
Solvent: ClCCl
Product: COC(=O)c1c2ccccc2nc2ccc(Cl)cc12
Reaction time: 1.5 h

Procedure:
4.9 gm of 2-chloro-9-carboxy-acridine were suspended in 5 cc of methylene chloride at room temperature and then 60 cc of a methylene chloride solution of diazomethane titrating 17.9 gm per liter was added thereto. The reaction mixture was then stirred for 90 minutes while bubbling nitrogen therethrough to eliminate excess diazomethane. The methylene chloride solution was washed with an aqueous solution of 10% sodium carbonate, then with water, dried over magnesium sulfate, treated with charcoal, filtered and then evaporated to dryness. The residue was recrystallized from boiling methanol to obtain 3.2 gm of 2-chloro-9-methoxycarbonyl-acridine melting at 130°C. The product occurred as a pale yellow solid soluble in chloroform, slightly soluble in ether and alcohol and insoluble in water.
Reaction SMILES: O.[NH2:2][NH2:3].Cl[C:5]1[C:10]([C:11]#[N:12])=[CH:9][C:8]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[N:7][CH:6]=1>N1C=CC=CC=1>[C:13]1([C:8]2[CH:9]=[C:10]3[C:11]([NH2:12])=[N:3][NH:2][C:5]3=[CH:6][N:7]=2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: N#Cc1cc(-c2ccccc2)ncc1Cl
Reactant: NN
Solvent: O
Solvent: c1ccncc1
Product: Nc1n[nH]c2cnc(-c3ccccc3)cc12

Procedure:
Hydrazine hydrate (0.3 mL, 5.9 mmol) was added to a stirred solution of 5-chloro-2-phenyl-isonicotinonitrile (420 mg, 1.9 mmol) in pyridine (5 mL). The reaction mixture was stirred at reflux for 3 hours, cooled and the resulting solid was filtered and dried in vacuo, affording a crude residue. Purification by column chromatography using a gradient elution of 0–5% methanol in dichloromethane as eluent afforded the title compound as a solid.
Reaction SMILES: S(Cl)(Cl)=O.C1(C2C=CC(C(O)=O)=CC=2)CCCCC1.C1(C2C=CC(C(Cl)=O)=CC=2)CCCCC1.[CH3:35][O:36][C:37]1[CH:38]=[C:39]2[C:44](=[CH:45][C:46]=1[O:47][CH3:48])[N:43]=[CH:42][CH:41]=[C:40]2[O:49][C:50]1[CH:56]=[CH:55][C:53]([NH2:54])=[CH:52][CH:51]=1.[CH:57]1([C:63]2[CH:68]=[CH:67][C:66]([C:69]([N:71]=[C:72]=[S:73])=[O:70])=[CH:65][CH:64]=2)[CH2:62][CH2:61][CH2:60][CH2:59][CH2:58]1>C1(C)C=CC=CC=1.C(O)C>[CH:57]1([C:63]2[CH:64]=[CH:65][C:66]([C:69]([NH:71][C:72]([NH:54][C:53]3[CH:55]=[CH:56][C:50]([O:49][C:40]4[C:39]5[C:44](=[CH:45][C:46]([O:47][CH3:48])=[C:37]([O:36][CH3:35])[CH:38]=5)[N:43]=[CH:42][CH:41]=4)=[CH:51][CH:52]=3)=[S:73])=[O:70])=[CH:67][CH:68]=2)[CH2:58][CH2:59][CH2:60][CH2:61][CH2:62]1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=C(N=C=S)c1ccc(C2CCCCC2)cc1
Agent: O=C(Cl)c1ccc(C2CCCCC2)cc1
Agent: O=C(O)c1ccc(C2CCCCC2)cc1
Solvent: CCO
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C5CCCCC5)cc4)cc3)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-cyclohexylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-cyclohexyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-cyclohexyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-cyclohexyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (44 mg, yield 48%).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]5)=[CH:18][CH:17]=4)[CH:14]=3)[N:9](S(C3C=CC(C)=CC=3)(=O)=O)[CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:57])([F:56])[F:55])[CH:48]=2)[N:3]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH3:1][C:2]1[C:6]([C:7]2[C:15]3[C:10](=[N:11][CH:12]=[C:13]([C:16]4[CH:21]=[CH:20][C:19]([N:22]5[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:32])[CH3:33])=[O:29])[CH2:26][CH2:27]5)=[CH:18][CH:17]=4)[CH:14]=3)[NH:9][CH:8]=2)=[C:5]([CH3:45])[N:4]([CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[C:49]([O:53][C:54]([F:55])([F:56])[F:57])[CH:48]=2)[N:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3c(C)nn(Cc4cccc(OC(F)(F)F)c4)c3C)c3cc(-c4ccc(N5CCN(C(=O)OC(C)(C)C)CC5)cc4)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1nn(Cc2cccc(OC(F)(F)F)c2)c(C)c1-c1c[nH]c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Yield: 80 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, tert-butyl 4-(4-(3-(3,5-dimethyl-1-(3-(trifluoromethoxy)benzyl)-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazine-1-carboxylate (140 mg, 0.174 mmol) was hydrolyzed by lithium hydroxide (36.7 mg, 0.27 mmol), THF/Methanol/water (2/3/1 ml) to afford 90 mg (80.3% yield) of the titled compound. LCMS: m/z=647.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](=[O:17])[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([OH:16])[CH:10]=[CH:9][CH:8]=3.[H-].[Na+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([O:16][C:11]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:12]=1[O:13][C:14]1[CH:15]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=1[C:6]2=[O:17])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: O=c1c2ccc(Cl)cc2oc2c(O)cccc12
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=c1c2ccc(Cl)cc2oc2c(OCc3ccccc3)cccc12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The 3-chloro-5-hydroxyxanthone (11 g.) in dimethylformamide (50 ml.) is added to a suspension of sodium hydride (1.5 g.) in dimethylformamide (100 ml.). The mixture is stirred at room temperature for 15 minutes and benzyl bromide (6 ml.) is added dropwise. The mixture is poured into water/ice (600 ml.), extracted with chloroform and the chloroform extract dried with MgSO4. Evaporation of the solvent gives a lightbrown solid which is recrystallised from ethanol to give 5-benzyloxy-3-chloroxanthone, m.p. 154° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[C:14]4[C@:19]([C:21](Cl)=[O:22])([CH2:20][C:11]=3[CH:10]=[N:9]2)[CH2:18][N:17]([S:24]([C:27]2[CH:28]=[N:29][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[CH:31][CH:32]=2)(=[O:26])=[O:25])[CH2:16][CH2:15]4)=[CH:4][CH:3]=1.[CH3:39][CH:40]([OH:42])[CH3:41]>>[CH:40]([O:42][C:21]([C@@:19]12[CH2:18][N:17]([S:24]([C:27]3[CH:28]=[N:29][C:30]([N:33]4[CH2:38][CH2:37][O:36][CH2:35][CH2:34]4)=[CH:31][CH:32]=3)(=[O:26])=[O:25])[CH2:16][CH2:15][C:14]1=[CH:13][C:12]1[N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[N:9]=[CH:10][C:11]=1[CH2:20]2)=[O:22])([CH3:41])[CH3:39]
Reactant: O=C(Cl)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2
Reactant: CC(C)O
Product: CC(C)OC(=O)[C@]12Cc3cnn(-c4ccc(F)cc4)c3C=C1CCN(S(=O)(=O)c1ccc(N3CCOCC3)nc1)C2

Procedure:
The title compound was prepared by the method of Preparation 48c using (R)-1-(4-fluorophenyl)-6-(6-morpholin-4-yl-pyridine-3-sulfonyl]-1,4,5,6,7,8-hexahydro-1,2,6-triaza-cyclopenta[b]naphthalene-4a-carbonyl chloride and propan-2-ol. LCMS (Method F): 582 (M+H)+, Retention time 5.1 minutes.
Reaction SMILES: [Cl:1][C:2]1[NH:7][C:6](=[O:8])[NH:5][C:4](=[O:9])[CH:3]=1.[Br:10]Br>O>[Br:10][C:3]1[C:4](=[O:9])[NH:5][C:6](=[O:8])[NH:7][C:2]=1[Cl:1]
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Reactant: BrBr
Solvent: O
Product: O=c1[nH]c(Cl)c(Br)c(=O)[nH]1
Yield: 61.1 %

Procedure:
To a stirring and refluxing solution of 6-chloropyrimidine-2,4(1H,3H)-dione (10.0 g, 68.25 mmol) in water (100 mL) was added bromine (4 mL, 79.84 mmol)) over 10 min. The colorless precipitate that formed was collected by filtration, washed with water (50 mL×2), and dried in a vacuum oven at 50° C. overnight, to obtain 9.4 g of the title compound as a white solid. HPLC/MS: retention time=1.05 min, [M+H]30 =225.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:12]([CH2:13]OS(C)(=O)=O)=[CH:11][C:10]([Br:19])=[CH:9][N:8]=1)(=O)=O.[CH3:20][Si:21]([CH3:37])([CH3:36])[CH2:22][CH2:23][O:24][CH2:25][N:26]1[C:30]2=[N:31][CH:32]=[CH:33][CH:34]=[C:29]2[CH2:28][C:27]1=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+]>C(O)C>[Br:19][C:10]1[CH:11]=[C:12]2[CH2:13][C:28]3([C:29]4[C:30](=[N:31][CH:32]=[CH:33][CH:34]=4)[N:26]([CH2:25][O:24][CH2:23][CH2:22][Si:21]([CH3:36])([CH3:20])[CH3:37])[C:27]3=[O:35])[CH2:6][C:7]2=[N:8][CH:9]=1
Reactant: CS(=O)(=O)OCc1cc(Br)cnc1COS(C)(=O)=O
Reactant: C[Si](C)(C)CCOCN1C(=O)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCO
Product: C[Si](C)(C)CCOCN1C(=O)C2(Cc3cc(Br)cnc3C2)c2cccnc21
Reaction time: 20 h

Procedure:
(5-Bromopyridine-2,3-diyl)dimethanediyl dimethanesulfonate (17.0 g, 45.4 mmol) was added to a mixture of 1-{[2-(trimethylsilyl)ethoxy]methyl}-1,3-dihydro-2H-pyrrolo[2,3-b]pyridin-2-one (prepared according to the procedures described in WO2008/020902, 14.0 g, 53.0 mmol) and cesium carbonate (49.0 g, 150 mmol) in ethanol (500 mL) 23° C., and the resulting mixture was stirred for 20 h. The reaction mixture was concentrated then partitioned between ethyl acetate (500 mL) and water (500 mL). The organic layer was dried over magnesium sulfate and concentrated. The residue was purified via silica gel chromatography (heptane initially, grading to 100% EtOAc) to give the title compound. MS: m/z=448.1 (M+1).
Reaction SMILES: [Cl:1][C:2](=[CH:10][C:11]1[CH:16]=[C:15]([C:17]2[C:21]([Cl:22])=[C:20]([O:23][CH:24]([F:26])[F:25])[N:19]([CH3:27])[N:18]=2)[C:14]([F:28])=[CH:13][C:12]=1[Cl:29])[C:3]([O:5]C(C)(C)C)=[O:4].FC(F)(F)C(O)=O>ClCCl>[Cl:1][C:2](=[CH:10][C:11]1[CH:16]=[C:15]([C:17]2[C:21]([Cl:22])=[C:20]([O:23][CH:24]([F:25])[F:26])[N:19]([CH3:27])[N:18]=2)[C:14]([F:28])=[CH:13][C:12]=1[Cl:29])[C:3]([OH:5])=[O:4]
Reactant: Cn1nc(-c2cc(C=C(Cl)C(=O)OC(C)(C)C)c(Cl)cc2F)c(Cl)c1OC(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cn1nc(-c2cc(C=C(Cl)C(=O)O)c(Cl)cc2F)c(Cl)c1OC(F)F
Reaction time: 16 h

Procedure:
A solution of 44 g of tert-butyl 2-chloro-3-(2-chloro-5-(4-chloro-5-difluoromethoxy-1-methyl-1H-pyrazol-3-yl)-4-fluorophenyl)acrylate (93 mmol) in 200 ml of dichloromethane was treated with 200 ml of trifluoroacetic acid. After the mixture had been stirred for 16 hours, it was concentrated. The residue was recrystallized from hexane/ethyl acetate (2:1). Yield: 23 g; a further 4 g by concentrating the mother liquor.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([N:15](C)[CH:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19]C)=[O:18])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[CH:2]=[C:3]=[CH2:4].[OH-].[Li+].O>O1CCCC1.CO>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([S:12]([NH:15][C@H:16]([C:17]([OH:19])=[O:18])[CH:21]([CH3:23])[CH3:22])(=[O:13])=[O:14])=[CH:10][CH:11]=1)[CH:2]=[C:3]=[CH2:4]
Reactant: C=C=CCOc1ccc(S(=O)(=O)N(C)C(C(=O)OC)C(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: C=C=CCOc1ccc(S(=O)(=O)N[C@H](C(=O)O)C(C)C)cc1
Yield: 89.3 %

Procedure:
The procedure of Example 12 was followed using the product from Example 14 (300 mg, 0.85 mmol) and lithium hydroxide (41 mg, 1.7 mmol) in tetrahydrofuran (3 ml), methanol (3 ml), and water (1.5 ml) to give 247 mg (86%) of the product.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH3:21][I:22].O>CS(C)=O>[I-:22].[NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([C:11]3[S:12][C:13]4[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][C:14]=4[N:15]=3)[CH:8]=[CH:7][C:5]=2[N+:6]=1[CH3:21]
Reactant: Cc1ccc2nc(-c3ccc4nc(N)sc4c3)sc2c1
Reactant: CI
Solvent: O
Solvent: CS(C)=O
Product: Cc1ccc2nc(-c3ccc4c(c3)sc(N)[n+]4C)sc2c1
Product: [I-]
Temperature: 110 °C
Reaction time: 17 h
Yield: 86.5 %

Procedure:
The 2-aminobenzothiazole 2 (0.3 g, 1.0 mmol) was dissolved in DMSO (2 ml). Methyl iodide (0.25 ml, 2.0 mmol) was added and the mixture was stirred at 110° C. for 17 hours. The mixture was cooled and poured into water. The precipitate formed was collected by filtration and washed with water to give the product as a yellow solid (0.38 g, 86%). Mp 267-269° C.; 1H NMR (DMSO): δ 2.47 (3H, s, Ar—CH3), 3.74 (3H, s, N—CH3), 7.38 (1H, d, J=8.4, ArH), 7.79 (1H, d, J=8.4, ArH), 7.93 (1H, d, J=8.4, ArH), 7.95 (1H, s, ArH), 8.22 (1H, d, J=8.4, ArH), 8.75 (1H, s, ArH), 10.19 (2H, s, NH2); 13C NMR (DMSO): δ 21.14, 32.39, 113.9, 122.0, 122.2, 122.4, 122.7, 126.6, 128.3, 129.8, 134.7, 135.6, 140.9, 151.6, 164.7, 168.9; HR-FAB-MS m/z Found: 312.0638 C16H14N3S2 (M+): requires M, 312.0629.
Reaction SMILES: N[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:3]1.C=O.[C:33]([BH3-])#[N:34].[Na+].[C:37](=O)([O-])[O-].[K+].[K+]>O.C(O)(=O)C.CO>[CH3:37][N:34]([CH3:33])[CH:2]1[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]([C:12](=[O:30])[C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:29])[C:21]3[CH:26]=[C:25]([Cl:27])[CH:24]=[C:23]([Cl:28])[CH:22]=3)=[CH:15][CH:14]=2)[CH2:3]1
Reactant: [BH3-]C#N
Reactant: NC1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Reactant: O=C([O-])[O-]
Agent: C=O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: CO
Product: CN(C)C1Cc2ccccc2N(C(=O)c2ccc(NC(=O)c3cc(Cl)cc(Cl)c3)cc2)C1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 3-amino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.5 g) are added methanol (10 ml), 37% formaline (0.8 ml) and sodium cyanoborohydride (0.16 g). To the mixture is added acetic acid (0.5 ml) under ice-cooling and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and the mixture is basified with potassium carbonate and extracted with dichloromethane. The solvent is concentrated and the resulting residue is purified by silica gel column chromatography (eluent; dichloromethane→dichloromethane:methanol=20:1) to give 3-dimethylamino-1-[4-(3,5-dichlorobenzoylamino)benzoyl]-1,2,3,4-tetrahydroquinoline (0.3 g) as colorless amorphous.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:11])([O-])=O.C(O)C.O.O.S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10]([NH:13][CH:14]1[CH2:15][CH2:16][N:17]([CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:18][CH2:19]1)(=[O:12])=[O:11]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NC1CCN(Cc2ccccc2)CC1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)NC1CCN(Cc2ccccc2)CC1

Procedure:
To a solution of 75.0 g (0.2 mol) of 2-nitro-N-[1-(phenylmethyl)-4-piperidinyl]-benzenesulphonic acid amide in 2.0 1 ethanol was added dropwise, at room temperature, a solution of 174.0 g (0.828 mol) of sodium dithionite-dihydrate in 700 ml of water. After the heat of the exothermic reaction had died away the mixture was refluxed for 4.5 hours, then the ethanol was distilled off and the aqueous phase remaining was extracted thoroughly with dichloromethane. The combined dichloromethane extracts were dried over sodium sulphate and evaporated down, the residue remaining was purified by column chromatography over silica gel using dichloromethane/methanol/conc. ammonia 80/20/0.25 (v/v/v) as eluant. 6.5 g (8.6% of theory) of a highly viscous oil were obtained.
Reaction SMILES: CS(O[CH2:6][C:7]1[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])=[N:9][C:10]2[N:11]([C:17](=[O:32])[NH:18][C:19]3[CH:24]=[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])[C:22]([C:30]#[N:31])=[CH:21][N:20]=3)[CH2:12][CH2:13][CH2:14][C:15]=2[CH:16]=1)(=O)=O.CCN(CC)CC.[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][C:47]1=[O:52]>C(Cl)Cl>[C:30]([C:22]1[C:23]([NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:24][C:19]([NH:18][C:17]([N:11]2[C:10]3[C:15](=[CH:16][C:7]([CH2:6][N:49]4[CH2:50][CH2:51][N:46]([CH3:45])[C:47](=[O:52])[CH2:48]4)=[C:8]([CH:33]([O:36][CH3:37])[O:34][CH3:35])[N:9]=3)[CH2:14][CH2:13][CH2:12]2)=[O:32])=[N:20][CH:21]=1)#[N:31]
Reactant: COCCNc1cc(NC(=O)N2CCCc3cc(COS(C)(=O)=O)c(C(OC)OC)nc32)ncc1C#N
Reactant: CN1CCNCC1=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COCCNc1cc(NC(=O)N2CCCc3cc(CN4CCN(C)C(=O)C4)c(C(OC)OC)nc32)ncc1C#N
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (8-((5-cyano-4-((2-methoxyethyl)amino)pyridin-2-yl)carbamoyl)-2-(dimethoxymethyl)-5,6,7,8-tetrahydro-1,8-naphthyridin-3-yl)methyl methanesulfonate (intermediate 170, 368 mg, 0.657 mmol) in DCM (2.7 ml) at room temperature was added NEt3 (0.319 ml, 2.301 mmol) followed by 1-methylpiperazin-2-one (120 mg, 1.052 mmol). The reaction mixture was stirred at room temperature for 2 h and partitioned between DCM and water. The water layer was extracted multiple times with DCM, the combined organic layers were dried using Na2SO4, filtered and evaporated. The crude product was purified by silica gel column chromatography using a gradient of MeOH (0-3%) in DCM to yield the title compound as a white solid. (UPLC-MS 3) tR 0.87 min; ESI-MS 553.3 [M+H]+. 1H NMR (600 MHz, CDCl3) δ 13.75 (s, 1H), 8.20 (s, 1H), 7.64 (br s, 1H), 7.58 (s, 1H), 5.56 (s, 1H), 5.23 (d, 1H), 4.06-4.01 (m, 2H), 3.70 (br s, 2H), 3.63 (t, 2H), 3.50-3.42 (m, 8H), 3.40 (s, 3H), 3.31 (br s, 2H), 3.14 (br s, 2H), 2.96 (br s, 3H), 2.87-2.80 (m, 2H), 2.71 (br s, 2H), 2.03-1.96 (m, 2H).
Reaction SMILES: I[CH2:2][CH2:3][N:4]1[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1.[C:16]([OH:19])(=[O:18])[CH3:17].C1CCN2C(=NCCC2)CC1.CCOC(C)=O>C1(C)C=CC=CC=1>[N:4]1([CH2:3][CH2:2][O:19][C:16](=[O:18])[CH3:17])[C:8]2=[N:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:7]2[CH2:6][CH2:5]1
Reactant: ICCN1CCn2c1nc1ccccc12
Reactant: CC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CC(=O)OCCN1CCn2c1nc1ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.4 %

Procedure:
According to the procedure of N. Ono, et al., Bull. Chem. Soc. Jpn., 51 (8), 2401 (1978), a solution of 1-N-(2-iodoethyl)-2,3-dihydro-1H-imidazo[1,2-a]benzimidazole (2.20 g, 7.03 mmol), acetic acid (0.060 mL, 10.54 mmol) and DBU (1.57 mL, 10.54 mmol) in toluene (70 mL) was heated under reflux for 4 hours, cooled, and stirred at room temperature overnight. EtOAc (30 mL) was added and the mixture was washed with brine, dried (MgSO4), and concentrated to give 1.68 g (98%) of a brown solid. This material was used without further purification in the next step (hydrolysis).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:16](=[CH:17][CH:18]=1)[O:15][C:7]1([CH2:12][O:11][C:10]([CH3:14])([CH3:13])[O:9][CH2:8]1)[CH2:6][C:5]2=[O:19].[C:20]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)#[N:21].C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.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>[CH3:13][C:10]1([CH3:14])[O:11][CH2:12][C:7]2([CH2:6][C:5](=[O:19])[C:4]3[C:16](=[CH:17][CH:18]=[C:2]([C:26]4[CH:27]=[C:22]([CH:23]=[CH:24][CH:25]=4)[C:20]#[N:21])[CH:3]=3)[O:15]2)[CH2:8][O:9]1
Reactant: N#Cc1cccc(B(O)O)c1
Reactant: CC1(C)OCC2(CO1)CC(=O)c1cc(Br)ccc1O2
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OCC2(CO1)CC(=O)c1cc(-c3cccc(C#N)c3)ccc1O2
Temperature: 100 °C
Yield: 56.9 %

Procedure:
To a solution of 6-bromo-2′,2′-dimethylspiro[chroman-2,5′-[1,3]dioxan]-4-one (498 mg, 1.5 mmol), 3-cyanophenylboronic acid (440 mg, 3.0 mmol) and Cs2CO3 (1.460 mg, 4.5 mmol) in 1,4-dioxane (4 mL) and H2O (0.5 mL) in a 10 mL CEM microwave test tube was added PdCl2(PPh3)2 (75 mg). After degassed by purging with N2, the mixture was heated to 100° C. for 5 min in a CEM microwave reactor. The solvent was removed under reduced pressure and the residue was purified by flash chromatography on silica gel (12 g, eluted with ethyl acetate in hexane 0-30%) give 3-(2′,2′-dimethyl-4-oxospiro[chroman-2,5′-[1,3]dioxane]-6-yl)benzonitrile as a yellowish solid (298 mg). MS ESI+ve m/z 350 (M+H)+.