Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]([CH2:13]N)=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12].[Cl-].[NH4+].[NH:21]1[C:25]2=[N:26][CH:27]=[CH:28][CH:29]=[C:24]2[C:23]([CH2:30][C:31]([OH:33])=O)=[N:22]1.C1C=[N:38]C2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:15]=[C:16]([Cl:18])[CH:17]=1)[O:5][C:6]1[C:7]([CH2:13][CH:30]([C:23]2[C:24]3[C:25](=[N:26][CH:27]=[CH:28][CH:29]=3)[NH:21][N:22]=2)[C:31]([NH2:38])=[O:33])=[N:8][CH:9]=[CH:10][C:11]=1[CH3:12]
Reactant: Cc1ccnc(CN)c1Oc1cc(Cl)cc(Br)c1
Reactant: On1nnc2cccnc21
Reactant: O=C(O)Cc1n[nH]c2ncccc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccnc(CC(C(N)=O)c2n[nH]c3ncccc23)c1Oc1cc(Cl)cc(Br)c1
Reaction time: 2.2 h

Procedure:
To a solution of 1-[3-(3-bromo-5-chlorophenoxy)-4-methylpyridin-2-yl]methanamine (125 mg, 0.382 mmol), 1H-pyrazolo[3,4-b]pyridin-3-ylacetic acid compound with ammonium chloride (1:1), (102 mg, 0.443 mmol), HOAT (5.2 mg, 0.038 mmol) and TEA (53 μL, 0.382 mmol) in DMF (2 mL) was added EDC (80 mg, 0.42 mmol), and the mixture was stirred for 2.2 hours. The mixture was then filtered and purified using Waters PrepPak column and eluting with a gradient of 5-95% ACN/H2O with 0.1% TFA. The desired fractions were lyophilized to give title compound.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Cl)=[CH:16][CH:15]=1.[C:22](=[O:25])([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][O:1][C:2]2[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=2[O:11][CH2:5][C:4]2[CH:8]=[CH:9][C:10]([O:25][CH3:22])=[CH:2][CH:3]=2)[C:5]([O:7][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([O:13][CH3:12])=[CH:15][CH:16]=2)=[O:6])=[CH:16][CH:15]=1
Reactant: O=C([O-])[O-]
Reactant: COc1ccc(CCl)cc1
Reactant: O=C(O)c1ccc(O)c(O)c1
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(COC(=O)c2ccc(OCc3ccc(OC)cc3)c(OCc3ccc(OC)cc3)c2)cc1
Temperature: 60 °C
Reaction time: 8 h
Yield: 125.9 %

Procedure:
3,4-Dihydroxybenzoic acid (3.08 g, 0.02 mol) was dissolved in N,N-dimethylformamide (50 ml) and treated with 4-methoxybenzyl chloride (10 ml, 0.07 mol) and potassium carbonate (10 g, 0.07 mol). The mixture was warmed to 60° C. for 6 h and then stirred overnight. The mixture was partitioned between water and ethyl acetate. The organic phase was washed exhaustively with water and then the product was purified on silica gel 60 eluting with mixtures of ethyl acetate and hexane to give the title compound (6.48 g, 63%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH:23]2[C:32]3[C:27](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=3)[CH2:26][N:25]([CH2:35][CH3:36])[CH2:24]2)[CH:18]=1)(=[O:16])=[O:15].[OH:37][CH:38]([CH:49]([OH:60])[C:50]([O:52]N1C(=O)CCC1=O)=O)[C:39]([O:41]N1C(=O)CCC1=O)=O.[CH2:61]([N:63]([CH2:66][CH3:67])[CH2:64][CH3:65])[CH3:62]>CN(C=O)C>[Cl:33][C:30]1[CH:31]=[C:32]2[C:27](=[C:28]([Cl:34])[CH:29]=1)[CH2:26][N:25]([CH2:35][CH3:36])[CH2:24][CH:23]2[C:19]1[CH:18]=[C:17]([S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][O:7][CH2:6][CH2:5][O:4][CH2:3][CH2:2][NH:1][C:39](=[O:41])[CH:38]([OH:37])[CH:49]([OH:60])[C:50]([NH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH:62]3[C:32]4[C:65](=[C:28]([Cl:34])[CH:29]=[C:30]([Cl:33])[CH:31]=4)[CH2:64][N:63]([CH2:66][CH3:67])[CH2:61]3)[CH:18]=2)(=[O:16])=[O:15])=[O:52])(=[O:16])=[O:15])[CH:22]=[CH:21][CH:20]=1
Reactant: CCN(CC)CC
Reactant: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN)c2)C1
Reactant: O=C(ON1C(=O)CCC1=O)C(O)C(O)C(=O)ON1C(=O)CCC1=O
Solvent: CN(C)C=O
Product: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCNC(=O)C(O)C(O)C(=O)NCCOCCOCCOCCNS(=O)(=O)c3cccc(C4CN(CC)Cc5c(Cl)cc(Cl)cc54)c3)c2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of N-(2-(2-(2-(2-aminoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide (100 mg, 0.18 mmol, 1.00 equiv) in DMF (3 mL), bis(2,5-dioxopyrrolidin-1-yl) 2,3-dihydroxysuccinate (Intermediate 168.1) (25 mg, 0.07 mmol, 0.45 equiv) and triethylamine (75 mg, 4.50 equiv). The resulting solution was stirred overnight at room temperature. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The crude product was purified by Flash-Prep-HPLC with water:methanol (1:10-1:100). This resulted in 12.1 mg (5%) of N1,N4-bis(2-(2-(2-(2-(3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenylsulfonamido)ethoxy)ethoxy)ethoxy)ethyl)-2,3-dihydroxysuccinamide as yellow oil. 1H-NMR (300 MHz, DMSO, ppm): δ 7.70-7.60 (m, 8H), 7.53-7.49 (m, 6H), 6.88 (s, 2H), 5.61-5.59 (m, 2H), 4.38 (m, 2H), 4.24-4.22 (m, 2H), 3.78-3.72 (m, 2H), 3.58-3.48 (m, 2H), 3.43 (m, 7H), 3.43-3.40 (m, 11H), 3.27-3.20 (m, 5H), 2.91-2.87 (m, 6H), 2.76-2.70 (m, 2H), 2.61-2.55 (m, 3H), 1.04-0.99 (m, 6H). MS (m/z): 1235 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH2:7][C:6]([CH3:9])([CH3:8])[NH:5][C:4]([CH3:11])([CH3:10])N=1.O.C1(C)C=CC(S(O)(=O)=[O:20])=CC=1.[OH-].[Na+]>CN(C)C=O>[CH3:10][C:4]1([CH3:11])[NH:5][C:6]([CH3:9])([CH3:8])[CH2:7][C:2](=[O:20])[CH2:1]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC1=NC(C)(C)NC(C)(C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)CC(=O)CC(C)(C)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 88.8 %

Procedure:
A solution of 15.4 g. of acetonine in 100 ml. of dimethylformamide was added with 19.0 g. of p-toluenesulfonic acid monohydrate. The mixture was stirred at room temperature for 8 hours, then allowed to stand overnight to complete the reaction. After completion of the reaction, the reaction mixture was added with 30% aqueous sodium hydroxide solution and extracted with ether. The extract was dried over anhydrous potassium carbonate and ether was distilled off. The resulting residue was purified by distillation under reduced pressure to obtain triacetonamine in a yield of 88.8%.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2]1.[C:30]1(S(CC2C(C(OCC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=C[CH:31]=1.C1(B(O)O)C=CC=CC=1>>[C:21]1([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[CH:2]=[CH:31][CH:30]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Agent: OB(O)c1ccccc1
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccccc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 28, starting from ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61) and phenylboronic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:23])=[N:14][C:15]4[C:20]([N:21]=3)=[CH:19][C:18]([F:22])=[CH:17][CH:16]=4)[CH:11]=[C:4]2[N:3]=1.[NH2:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([NH:24][CH2:25][C:26]([CH3:29])([OH:28])[CH3:27])[N:5]2[N:9]=[C:10]([C:12]3[C:13]([CH3:23])=[N:14][C:15]4[C:20](=[CH:19][C:18]([F:22])=[CH:17][CH:16]=4)[N:21]=3)[CH:11]=[C:4]2[N:3]=1
Reactant: CC(C)(O)CN
Reactant: Cc1nc2ccc(F)cc2nc1-c1cc2nc(Cl)cc(Cl)n2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc2ccc(F)cc2nc1-c1cc2nc(Cl)cc(NCC(C)(C)O)n2n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A suspension of 3-(5,7-dichloropyrazolo[1,5-a]pyrimidin-2-yl)-6-fluoro-2-methylquinoxaline (157 mg, 0.451 mmol) in N,N-dimethylformamide (4.0 mL), 1-amino-2-methyl-propan-2-ol (48 mg, 0.541 mmol), and potassium carbonate (187 mg, 1.35 mmol) was stirred at room temperature for 2 h. The reaction mixture was poured into ice-cooled water, and the resulting precipitate was collected and washed with water to give 1-{[5-chloro-2-(7-fluoro-3-methylquinoxalin-2-yl)pyrazolo[1,5-a]pyrimidin-7-yl]amino}-2-methylpropan-2-ol. MS (APCI): m/z 401/403 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[C:11]([C:13]([O:15]CC)=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:4][CH:3]=1.[Li+].[OH-].O.Cl>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[C:11]([C:13]([OH:15])=[O:14])[N:10]=[C:9]2[C:18]2[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][C:19]=2[Cl:25])=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cn(-c2ccc(Br)cc2)c(-c2ccc(Cl)cc2Cl)n1
Temperature: 50 °C
Reaction time: 16 h
Yield: 85.9 %

Procedure:
Part A: To a stirred solution of ethyl 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylate (6.10 gram, 0.0139 mol) in THF (70 mL) is added LiOH (0.67 gram, 0.0278 mol) and water (70 mL). The resulting mixture is stirred for 16 hours at 50° C. to give a clear solution. After cooling to room temperature, HCl (1N solution, 28 mL) is added to give an oily precipitate which completely solidifies on continued stirring and addition of water (70 mL). The precipitate is collected by filtration, washed with water and dried in vacuo to give 1-(4-bromophenyl)-2-(2,4-dichlorophenyl)-1H-imidazole-4-carboxylic acid (4.92 gram, 86% yield). Melting point: 138-142° C.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[C:5]([F:18])=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:26][O:27][C:28]1[CH:49]=[CH:48][C:31]([C:32](Cl)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)=[CH:30][CH:29]=1>C(Cl)Cl>[CH3:40][O:39][C:36]1[CH:35]=[CH:34][C:33]([C:32]([NH:16][C:10]2[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]3[C:5]([F:18])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:17])[N:9]=2)([C:31]2[CH:30]=[CH:29][C:28]([O:27][CH3:26])=[CH:49][CH:48]=2)[C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[CH:38][CH:37]=1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: C[C@]1(c2nc(Br)ccc2F)N=C(N)OCC1(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)C(F)(F)CO2)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 69.2 %

Procedure:
(R)-4-(6-bromo-3-fluoro-pyridin-2-yl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazine-2-ylamine (5 g, 15.43 mmol, Example 1 intermediate h) was dissolved in DCM (154 ml) under argon, triethylamine (4.30 mL, 30.9 mmol) and 4,4′-dimethoxytrityl chloride (5.75 g, 16.97 mmol) were added and the reaction mixture was stirred at rt for 18 hours. The solvent was removed in vacuo and the residue was taken up in ethyl acetate. The organic layer was washed with aq 10% citric acid, water, aqueous saturated sodium bicarbonate solution and brine, dried over sodium sulfate, filtered and concentrated. The crude product was chromatographed over silica gel (Redisep column 120 g, cyclohexane/ethyl) to give the title compound: 8.16 g (69.2% yield).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([N:14]2[CH:18]=[C:17]([C:19]3[CH:20]=[N:21][C:22]([NH2:37])=[C:23]([O:25][C@@H:26]([C:28]4[C:33]([Cl:34])=[CH:32][CH:31]=[C:30]([F:35])[C:29]=4[Cl:36])[CH3:27])[CH:24]=3)[CH:16]=[N:15]2)[CH2:10][CH2:9]1)=O)(C)(C)C.Cl.[O:39]1CCOCC1>CO>[C:26]([OH:39])(=[O:25])[CH3:28].[Cl:36][C:29]1[C:30]([F:35])=[CH:31][CH:32]=[C:33]([Cl:34])[C:28]=1[C@H:26]([O:25][C:23]1[C:22]([NH2:37])=[N:21][CH:20]=[C:19]([C:17]2[CH:16]=[N:15][N:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)[CH:18]=2)[CH:24]=1)[CH3:27]
Reactant: C1COCCO1
Reactant: C[C@@H](Oc1cc(-c2cnn(C3CCN(C(=O)OC(C)(C)C)CC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Agent: Cl
Solvent: CO
Product: CC(=O)O
Product: C[C@@H](Oc1cc(-c2cnn(C3CCNCC3)c2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 1 h
Yield: 78 %

Procedure:
To a solution of 4-(4-{6-amino-5-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-pyridin-3-yl}-pyrazol-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (566.7 mg, 1.03 mmol) in methanol (5 mL) or dichlorometha[pi]e (30 mL) was added 4N HCl/dioxane (15 mL). The solution was stirred for about 1 hour or until the de-protection was complete. The solvents were evaporated and the residue was dissolved in methanol and purified on a reversed phase C-18 preparative HPLC eluting with acetonitrile/water with 0.1% acetic acid from 5% to 30% with a linear gradient. After lyophilization, 3-[(R)-1-(2,6-dichloro-3-fluoro-phenyl)-ethoxy]-5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-pyridin-2-ylamine acetate was obtained as a white solid (410 mg, 78% yield, 100% HPLC purity, 96.4% ee). 1H NMR (DMSO-d6, 400 MHz) δ 7.84 (s, 1H), 7.68 (d, 1H), 7.50 (dd, 1H), 7.46 (s, 1H), 7.37 (t, 1H), 6.83 (d, 1H), 6.02 (q, 1H), 5.57 (bs, 2H), 4.09 (m, 1H), 2.98 (m, 2H), 2.53 (m, 2H), 1.88 (m, 2H), 1.82 (s, 3H), 1.73 (d, 3H), 1.70 (m, 2H). MS m/e 450 (M+1)+.
Reaction SMILES: Br[C:2]([CH3:13])([CH3:12])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)=[O:4].FC1C=CC([C:21](=[O:25])C(C)C)=CC=1.CC(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)(C1C=CC(OCC(O)COC(C=C)=O)=CC=1)C.C[O-].[Na+]>CO.ClC1C=CC=CC=1>[F:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]2([O:25][CH3:21])[C:2]([CH3:13])([CH3:12])[O:4]2)=[CH:6][CH:7]=1
Reactant: CC(C)(Br)C(=O)c1ccc(F)cc1
Reactant: CC(C)C(=O)c1ccc(F)cc1
Agent: C=CC(=O)OCC(O)COc1ccc(C(C)(C)c2ccc(OCC(O)COC(=O)C=C)cc2)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: Clc1ccccc1
Product: COC1(c2ccc(F)cc2)OC1(C)C

Procedure:
100.32 g (0.41 mol) of 2-bromo-1-(4-fluorophenyl)-2-methylpropan-1-one, prepared by brominating 1-(4-fluorophenyl)-2-methylpropan-1-one (as is described in EP-A-3002), are dissolved in 80 ml of dry methanol and 24.3 g (0.45 mol) of sodium methoxide in a solvent mixture of 60 ml dry methanol and 120 ml of chlorobenzene are added dropwise at 20° C. The methanol is then distilled off and the chlorobenzene solution is concentrated. The liquid crude product (90.8 g) is further purified by distillation at 60° C. and 0.2 mm Hg.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][N:4]([CH2:7][CH2:8][CH2:9][OH:10])[CH2:3][CH2:2]1.[CH:11]([NH:14][C:15]([C@H:17]1[CH2:22][CH2:21][C@@H:20]([NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26](OCCOC)[CH:25]=2)[CH2:19][CH2:18]1)=[O:16])([CH3:13])[CH3:12]>>[CH:11]([NH:14][C:15]([C@H:17]1[CH2:18][CH2:19][C@@H:20]([NH:23][C:24]2[C:29]([N+:30]([O-:32])=[O:31])=[CH:28][N:27]=[C:26]([O:10][CH2:9][CH2:8][CH2:7][N:4]3[CH2:5][CH2:6][O:1][CH2:2][CH2:3]3)[CH:25]=2)[CH2:21][CH2:22]1)=[O:16])([CH3:13])[CH3:12]
Reactant: COCCOc1cc(N[C@H]2CC[C@@H](C(=O)NC(C)C)CC2)c([N+](=O)[O-])cn1
Reactant: OCCCN1CCOCC1
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(OCCCN3CCOCC3)ncc2[N+](=O)[O-])CC1

Procedure:
Intermediate cis-N-isopropyl-4-(2-(3-morpholinopropoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide was prepared with 3-morpholinopropan-1-ol using a 2 step procedure analogous to that used to prepare cis-N-isopropyl-4-(2-(2-methoxyethoxy)-5-nitropyridin-4-ylamino)cyclohexanecarboxamide (200 mg).
Reaction SMILES: [OH:1][N:2]=[C:3]([NH2:16])[CH2:4][C:5]1[C:14]2[C:9](=[C:10](Cl)[CH:11]=[CH:12]C=2)[CH:8]=[CH:7][CH:6]=1.N1C=CC=CC=1.[S:23](Cl)(Cl)=[O:24].O.[CH2:28]([Cl:30])Cl>>[Cl:30][C:28]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:8]=1[CH:7]=[CH:6][C:5]([CH2:4][C:3]1[NH:16][S:23](=[O:24])[O:1][N:2]=1)=[CH:14]2
Reactant: O=S(Cl)Cl
Reactant: NC(Cc1cccc2c(Cl)cccc12)=NO
Reactant: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: O=S1NC(Cc2ccc3c(Cl)cccc3c2)=NO1
Temperature: 0 °C
Yield: 16 %

Procedure:
To a cooled (0° C.), stirred suspension of N'-hydroxy-2-(5-chloronaphthalenyl)ethanimidamide (470 mg, 2.00 mmol) in CH2Cl2 (3 mL) and pyridine (325 μL, 4.00 mmol) was added thionyl chloride (160 μL, 2.20 mmol) over 2 minutes. The resulting solution was stirred for 25 minutes. H2O (10 mL) was added and the mixture was extracted with CH2Cl2 (2×25 mL). The combined extracts were dried (MgSO4) and concentrated. Purification by flash chromatography (eluant EtOAc/hexane (20:80)) and recrystallization from ethanol/ether gave off-white needles (88 mg, 16%), m.p. 164°-165° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:34])[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Cl.Cl[CH2:40][CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:35])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([O:32][CH2:40][CH2:41][N:42]5[CH2:47][CH2:46][O:45][CH2:44][CH2:43]5)=[CH:31][C:18]3=4)[CH2:10][C:9]2([CH3:33])[CH3:34])=[CH:4][CH:3]=1
Reactant: CC1(C)CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)CN(CCC=C2c3cc(OCCN4CCOCC4)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 29.6 %

Procedure:
To a solution of 5-{3-[4-(4-chloro-phenyl)-4-hydroxy-3,3-dimethyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.15 g, 0.28 mmol) in DMF (1.5 mL) was added NaH (0.034 g, 0.84 mmol) and stirred for 20 min. at room temperature. 4-(2-Chloro-ethyl)-morpholine HCl (0.063 g, 0.34 mmol) was added and the solution was heated to 50° C. for 16 h. The reaction was quenched with water and extracted with ethyl acetate (3×). The organics were combined, dried over Mg2SO4, filtered and concentrated, then purified by Biotage flash chromatography (5-10% methanol/dichloromethane) to yield the title compound (0.050 g). 1H-NMR (MeOD) δ: 0.73 (3H, s), 0.85 (3H, s), 2.39-2.90 (1H, m), 3.29-3.31 (3H, m), 3.69-3.72 (4H, m), 4.1 (2H, t), 5.20 (2H, br s), 6.18 (1H, t), 6.74-6.79 (2H, m), 6.89 (1H, d), 7.27-7.30 (2H, m), 7.43-7.47 (3H, m), 7.79 (1H, dd), 8.46 (1H, dd). ESI-MS m/z: 604 (M), UV retention time: 1.20 min.
Reaction SMILES: C([O:9][C:10]1[C:19](=[O:20])[C:18]2[C:13](=[CH:14][C:15]([Cl:21])=[CH:16][CH:17]=2)[N:12]([CH3:22])[CH:11]=1)(=O)C1C=CC=CC=1.N1CCCCC1>ClCCl>[Cl:21][C:15]1[CH:14]=[C:13]2[C:18]([C:19](=[O:20])[C:10]([OH:9])=[CH:11][N:12]2[CH3:22])=[CH:17][CH:16]=1
Reactant: Cn1cc(OC(=O)c2ccccc2)c(=O)c2ccc(Cl)cc21
Solvent: ClCCl
Solvent: C1CCNCC1
Product: Cn1cc(O)c(=O)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A mixture of 7-chloro-1-methyl-4-oxo-1,4-dihydro-quinol-3-yl benzoate (3.45 g), piperidine (1.2 ml) and dichloromethane (100 ml) was stirred at ambient temperature for 2.5 days. The solvent was removed by distillation and the residue triturated with diethyl ether (100 ml) to give the novel compound 7-chloro-3-hydroxy-1-methyl-4-quinolone, m.p. 225°-228°.
Reaction SMILES: [CH2:1]([Mg]Br)[CH2:2][CH:3]=[CH2:4].C[O:8][C:9]1[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=[CH:11][CH:10]=1.Cl[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21]>O1CCCC1>[CH2:1]([CH:11]1[CH2:10][C:9](=[O:8])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]1[C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCC[Mg]Br
Reactant: COc1ccnc2ccccc12
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Product: C=CCCC1CC(=O)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Butenylmagnesium bromide (0.5 M in THF, 100 mL, 50.0 mmol, 1.7 equiv) was added was added to a solution of 4-methoxyquinoline (4.65 g, 29.2 mmol, 1 equiv) in tetrahydrofuran (195 mL) at −78° C. The reaction mixture was stirred at −78° C. for 1 h, then benzyl chloroformate (8.34 mL, 58.4 mmol, 2.00 equiv) was added via syringe over 5 min. Stirred for an additional 15 minutes at −78° C., then the cooling bath was removed and the reaction mixture was allowed to warm to 23° C. After 1 h, methanol was added (20 mL). After stirring for 5 min, aqueous hydrochloric acid solution (2 N, 20 mL) was added and the mixture was stirred for 10 min. The mixture was then concentrated by rotary evaporation to remove most of the tetrahydrofuran and methanol, and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, and the washed solution was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (5% ethyl acetate-hexanes, grading to 20% ethyl acetate-hexanes) to afford 28A as a colorless oil. [M+H]+: 336.2.
Reaction SMILES: [CH2:1]([S:4]([C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[C:8]([NH2:13])[CH:7]=1)=[O:5])[CH2:2][CH3:3].C(O)(=O)C.[CH3:18][O:19][C:20]([NH:22][C:23](=NC(OC)=O)SC)=[O:21].O>CO>[CH2:1]([S:4]([C:6]1[CH:11]=[CH:10][C:9]2[NH:12][C:23]([NH:22][C:20](=[O:21])[O:19][CH3:18])=[N:13][C:8]=2[CH:7]=1)=[O:5])[CH2:2][CH3:3]
Reactant: COC(=O)N=C(NC(=O)OC)SC
Reactant: CCCS(=O)c1ccc(N)c(N)c1
Solvent: CO
Solvent: O
Solvent: CC(=O)O
Product: CCCS(=O)c1ccc2[nH]c(NC(=O)OC)nc2c1
Yield: 81 %

Procedure:
To 3.56 g (18 mMol) 4-(1-propylsulfinyl)-1,2-diaminobenzene in 45 ml methanol is added 1.03 ml acetic acid and 3.84 g (19.8 mMol) 1,3-bis(methoxycarbonyl)-S-methyl isothiourea. The resulting solution is heated to reflux for 21/2 hours, cooled and the solvent stripped. The white solid is digested with water, filtered, washed with ether and dried to yield 4.1 g of the title compound in the form of a white solid, m.p. 215°-216°, yield 81%.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:14][N:15]3[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)=[CH:7][C:5]=2[N:6]=1.C(N(CC)CC)C.[CH:32]1[C:44]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][C:33]=1[N:45]=[C:46]=[O:47]>O1CCCC1>[CH:32]1[C:44]2[CH2:43][C:42]3[C:37](=[CH:38][CH:39]=[CH:40][CH:41]=3)[C:36]=2[CH:35]=[CH:34][C:33]=1[NH:45][C:46]([N:18]1[CH2:17][CH2:16][N:15]([CH2:14][CH:13]([NH:21][C:22](=[O:24])[CH3:23])[CH2:12][O:11][C:8]2[CH:9]=[CH:10][C:4]3[S:3][C:2]([CH3:1])=[N:6][C:5]=3[CH:7]=2)[CH2:20][CH2:19]1)=[O:47]
Reactant: O=C=Nc1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NC(COc1ccc2sc(C)nc2c1)CN1CCN(C(=O)Nc2ccc3c(c2)Cc2ccccc2-3)CC1
Temperature: 55 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
To a solution of N-[2-(2-methylbenzothiazol-5-yloxy)-1-(piperazinylmethyl)ethyl]-acetamide (18.4 mg) in tetrahydrofuran (1 ml) was added triethylamine (25.6 μl) and 2-fluorenyl isocyanate (9.5 mg). The reaction mixture was stirred at 55° C. for 4 hours, producing a white precipitate. The precipitate was filtered off, and solvent removed from the filtrate under reduced pressure. The residue was purified by thin layer chromatography, developing with 4% methanol/methylene chloride, to provide N-{2-[4-(N-fluoren-2-ylcarbamoyl)piperazinyl]-1-[(2-methylbenzothiazol-5-yloxy)methyl]ethyl}acetamide (11.2 mg), a compound of Formula I.
Reaction SMILES: C[N:2]([CH:4]=[C:5]([N:11]1[CH:15]=[C:14]([C:16]#[N:17])[N:13]=[CH:12]1)[C:6]([O:8]CC)=O)C.[NH:18]([C:20]1[N:25]=[CH:24][N:23]=[C:22]([N:26]2[CH2:32][CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[CH:21]=1)N.FC(F)(F)C(O)=O>O>[O:29]1[CH2:30][CH2:31][CH2:32][N:26]([C:22]2[N:23]=[CH:24][N:25]=[C:20]([N:18]3[C:6](=[O:8])[C:5]([N:11]4[CH:15]=[C:14]([C:16]#[N:17])[N:13]=[CH:12]4)=[CH:4][NH:2]3)[CH:21]=2)[CH2:27][CH2:28]1
Reactant: NNc1cc(N2CCCOCC2)ncn1
Reactant: CCOC(=O)C(=CN(C)C)n1cnc(C#N)c1
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: N#Cc1cn(-c2c[nH]n(-c3cc(N4CCCOCC4)ncn3)c2=O)cn1
Temperature: 100 °C
Reaction time: 16 h

Procedure:
A mixture of 200 mg (0.9 mmol) of the compound from Example 6A, 178 mg (0.9 mmol) of the compound from Example 14A and 33 μl (49 mg, 0.4 mmol) of trifluoroacetic acid in 3 ml of water is stirred at 100° C. for 16 h. The precipitated solid is filtered off and washed first with water and then with diethyl ether. The product is dried under reduced pressure. Yield: 120 mg (40% of theory)