Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C@H:2]([CH2:15][CH2:16][C:17]1[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=1)[C@H:3]([CH3:14])[O:4][C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1.Br[C:24]1[CH:25]=[N:26][CH:27]=[N:28][CH:29]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(O)C>[N:19]1[CH:20]=[CH:21][CH:22]=[C:17]([CH2:16][CH2:15][C@@H:2]([OH:1])[C@@H:3]([O:4][C:5]2[CH:10]=[CH:9][C:8]([C:24]3[CH:25]=[N:26][CH:27]=[N:28][CH:29]=3)=[CH:7][CH:6]=2)[CH3:14])[CH:18]=1
Reactant: Brc1cncnc1
Reactant: C[C@H](Oc1ccc(B(O)O)cc1)[C@H](O)CCc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: C[C@H](Oc1ccc(-c2cncnc2)cc1)[C@H](O)CCc1cccnc1
Temperature: 90 °C
Yield: 31.4 %

Procedure:
Prepared according to the method described in Example 21b) from (1S,2R)-4-(2-hydroxy-1-methyl-4-pyridin-3-ylbutoxy)benzeneboronic acid (0.200 g, Example 21a)), 5-bromopyrimidine (0.159 g), ethanol (3 ml), 2M aqueous sodium carbonate (0.67 ml) and tetrakistriphenylphosphine palladium(0) (0.030 g) with heating at 90° C. for 4 hours. After work up, the residue was purified by reverse phase HPLC, eluting with a gradient of 15:85 to 95:5 acetonitrile in 0.1M ammonium acetate. The compound was subsequently purified by flash chromatography on silica gel, eluting with 1:1 isohexane/acetone to give the title compound as an oil (0.070 g).
Reaction SMILES: CI.[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH2:20]N(C)C)=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:25]1>CC(C)=O>[Cl:3][C:4]1[CH:41]=[CH:40][CH:39]=[CH:38][C:5]=1[CH2:6][N:7]1[C:15]2[C:14](=[O:16])[N:13]([CH3:17])[C:12](=[O:18])[N:11]([CH3:19])[C:10]=2[C:9]([CH3:20])=[C:8]1[N:24]1[CH2:29][CH2:28][CH2:27][C@@H:26]([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:34])([CH3:35])[CH3:36])[CH2:25]1
Reactant: CN(C)Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Solvent: CC(C)=O
Solvent: CI
Product: Cc1c(N2CCC[C@@H](NC(=O)OC(C)(C)C)C2)n(Cc2ccccc2Cl)c2c(=O)n(C)c(=O)n(C)c12
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
Methyl iodide (38 μl) was added to a solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-7-[(dimethylamino)methyl]-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (168 mg) in acetone (4 ml), and the resulting mixture was stirred overnight in a sealed tube at room temperature. The reaction solution was concentrated under reduced pressure, and to a solution of the resulting residue in tetrahydrofuran (5 ml) was added a 1N aqueous sodium hydroxide solution (3 ml), followed by stirring with heating at 60° C. for 3 hours. The tetrahydrofuran was distilled off under reduced pressure and water was added to the residue, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. Then, a solution of the resulting residue in dichloromethane (6 ml) was added dropwise to an ice-cooled solution of triethylsilane (144 μl) and methanesulfonic acid (60 μl) in dichloromethane (10 ml), and the resulting mixture was stirred at 0° C. for 1 hour. A 10% aqueous potassium carbonate solution was added thereto, followed by two runs of extraction with chloroform (50 ml). The organic layer was dried over sodium sulfate and filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (101 mg).
Reaction SMILES: CN(C)C=O.Cl[C:7]1[CH:12]=[C:11]([O:13][CH2:14][C:15]#[C:16][CH3:17])[N:10]=[CH:9][N:8]=1.C(=O)([O-])[O-].[K+].[K+].[NH:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>C(OCC)(=O)C>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)[N:8]=[CH:9][N:10]=1)[C:15]#[C:16][CH3:17]
Reactant: C1CCNC1
Reactant: CC#CCOc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC#CCOc1cc(N2CCCC2)ncn1
Temperature: 57.5 °C
Reaction time: 4 h
Yield: 78.4 %

Procedure:
Into 2 ml of N,N-dimethylformamide was resolved 183 mg of 4-chloro-6-(2-butynyloxy)pyrimidine, 166 mg of potassium carbonate and 71 mg of pyrrolidine was added therein, and the mixture was stirred for 4 hours at 55-60° C. The reaction mixture was cooled to near room temperature, ethyl acetate was added therein, and the mixture was washed with a saturated sodium chloride aqueous solution three times. The organic layers were dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to obtain 170 mg of 4-(2-butynyloxy)-6-(1-pyrrolidinyl)pyrimidine (hereinafter, referred to as Compound (17)).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][NH:20][CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1>>[Br:14][C:15]1[C:23]2[CH2:22][CH2:21][N:20]([C:11]([C:9]3[CH:10]=[C:5]4[N:4]=[CH:3][C:2]([Br:1])=[CH:7][N:6]4[N:8]=3)=[O:13])[CH:19]([CH3:24])[C:18]=2[O:17][CH:16]=1
Reactant: CC1NCCc2c(Br)coc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2occ(Br)c2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 3-bromo-7-methyl-4,5,6,7-tetrahydrofuro[2,3-c]pyridine to provide the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=1)=[O:5])[CH3:2].Cl.C(=O)([O-])[O-].[NH4+:46].[NH4+]>C(O)C>[CH2:1]([O:3][C:4]([CH2:6][N:7]1[C:11]2[CH:12]=[C:13]([N:16]([S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)(=[O:24])=[O:23])[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([C:39](=[NH:46])[NH2:40])=[CH:37][CH:38]=1)=[O:5])[CH3:2]
Reactant: [NH4+]
Reactant: CCOC(=O)Cn1c(COc2ccc(C#N)cc2)nc2ccc(N(CCN(C)C)S(=O)(=O)c3ccccc3)cc21
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: CCO
Product: CCOC(=O)Cn1c(COc2ccc(C(=N)N)cc2)nc2ccc(N(CCN(C)C)S(=O)(=O)c3ccccc3)cc21

Procedure:
Prepared analogously to Example 1e from 1-ethoxycarbonylmethyl-2-[(4-cyanophenyl)-oxymethyl]-6-[N-(2-dimethylaminoethyl)-benzenesulphonylamino]-benzimidazole and hydrochloric acid/ammonium carbonate in ethanol.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:10]1[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=1[CH3:17].C1C(=O)N([Br:31])C(=O)C1>ClCCl.[Cl-].[Na+].O>[Br:31][C:21]1[CH:22]=[CH:23][C:18]([N:9]([C:3]2[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[C:10]2[CH:15]=[CH:14][C:13]([CH3:16])=[CH:12][C:11]=2[CH3:17])=[CH:19][CH:20]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(N(c2ccccc2)c2ccc(C)cc2C)c(C)c1
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: Cc1ccc(N(c2ccc(Br)cc2)c2ccc(C)cc2C)c(C)c1
Reaction time: 3 h
Yield: 96 %

Procedure:
To a solution of N-(2,4-dimethylphenyl)-2,4-dimethyl-N-phenylaniline (Compound 15) (12.4 g, 41 mmol) in dichloromethane (200 mL), was added NBS (8.01 g, 45 mmol) at 0° C. The whole was stirred for about 3 hours and worked up with brine. The organic phase was dried over Na2SO4, loaded on silica gel and purified by flash column using eluents of hexanes. After removal of solvents, a colorless oil (Compound 16) was obtained (15 g, in 96% yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17][OH:18])[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[N:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1B(O)O>>[F:25][C:22]1[CH:23]=[CH:24][C:19]([C@:13]2([CH2:16][CH2:17][OH:18])[O:12][C:11](=[O:26])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][N:27]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:20][CH:21]=1
Reactant: OB(O)c1ccccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(-c2ccccn2)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and pyridine-2-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=1.462 min, m/z=420.18; 1H NMR (CDCl3) 1.48 (d, 3H), 2.03-2.30 (m, 5H), 2.85 (m, 1H), 3.50 (m, 1H), 3.72 (m, 1H), 5.65 (m, 1H), 6.98 (m, 4H), 7.24 (m, 2H), 7.60 (m, 1H), 7.74 (m, 3H), 8.62 (m, 1H).
Reaction SMILES: [OH-].[K+].C([O:5][C:6]([C:8]1[CH:9]=[N:10][N:11]([C:13]2[NH:22][C:21](=[O:23])[C:20]3[C:15](=[CH:16][C:17]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)=[CH:18][CH:19]=3)[N:14]=2)[CH:12]=1)=[O:7])C.O>C1COCC1>[O:23]=[C:21]1[C:20]2[C:15](=[CH:16][C:17]([C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=3)=[CH:18][CH:19]=2)[N:14]=[C:13]([N:11]2[CH:12]=[C:8]([C:6]([OH:7])=[O:5])[CH:9]=[N:10]2)[NH:22]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1cnn(-c2nc3cc(-c4ccccc4)ccc3c(=O)[nH]2)c1
Temperature: 23 °C
Reaction time: 16 h
Yield: 95 %

Procedure:
Potassium hydroxide (37.4 mg, 0.666 mmol) was added to a mixture of 1-(4-oxo-7-phenyl-3,4-dihydro-quinazolin-2-yl)-1H-pyrazole-4-carboxylic acid ethyl ester (48.0 mg, 0.133 mmol), water (0.8 mL) and THF (0.8 mL). The mixture was stirred for 16 h at 23° C. The reaction mixture was concentrated under reduced pressure to remove the THF and the aqueous residue was acidified to pH 2 with 1M aq. HCl. The resulting precipitate was collected by filtration to provide the titled compound (42.0 mg, 85%). MS (ESI): mass calcd. for C18H12N4O3, 332.1; m/z found, 333.1 [M+H]+. 1H NMR (400 MHz, DMSO-d6): 8.45 (d, J=0.8 Hz, 1H), 7.99 (d, J=8.2 Hz, 1H), 7.78-7.72 (m, 2H), 7.62 (d, J=1.5 Hz, 1H), 7.55 (d, J=0.8 Hz, 1H), 7.49 (t, J=7.6 Hz, 2H), 7.41-7.36 (m, 2H).
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:15](=[O:32])[NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@H:50]([C:52]([F:55])([F:54])[F:53])[CH2:51][N:43]2[C:42]1=[O:56]>>[CH2:33]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:40][C@H:41]1[CH2:47][CH2:46][S:45][C@H:44]2[CH2:48][CH2:49][C@H:50]([C:52]([F:53])([F:55])[F:54])[CH2:51][N:43]2[C:42]1=[O:56])=[O:10])[C:15]([NH:16][C@H:17]1[CH2:23][CH2:22][CH2:21][CH2:20][N:19]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=2[CH3:30])[C:18]1=[O:31])=[O:32])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: N[C@H]1CCS[C@H]2CC[C@H](C(F)(F)F)CN2C1=O
Reactant: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: Cc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CC[C@H](C(F)(F)F)CN3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-2-oxo-1-o-tolylazepan-3-yl)-N6-((4S,8S,10aS)-5-oxo-8-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 71 (8.2 mg, 0.016 mmol) and Intermediate 60 (3.5 mg, 0.013 mmol) to give a white solid (5.9 mg, 58% yield). Anal. Calcd. for C43H51F3N4O4S m/z 776.7. found: 777.6 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.42-6.89 (m, 14H), 5.86 (s, 2H), 5.11 (dd, J=14.2, 7.0 Hz, 1H), 4.81 (dd, J=10.6, 6.6 Hz, 2H), 4.38-4.26 (m, 1H), 4.09-3.86 (m, 2H), 3.54 (d, J=16.2 Hz, 1H), 3.40-3.09 (m, 3H), 2.91-2.38 (m, 7H), 2.21 and 2.14 (s, 3H), 2.28-2.07 (m, 1H), 2.07-1.77 (m, 5H), 1.75-1.22 (m, 9H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([N+:10]([O-])=O)=[CH:5][C:4]=1[C:13]1[NH:14][C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([CH3:18])[N:17]=1.Cl.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([Cl:9])[C:6]([NH2:10])=[CH:5][C:4]=1[C:13]1[NH:14][C:15]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)=[C:16]([CH3:18])[N:17]=1
Reactant: COc1cc(Cl)c([N+](=O)[O-])cc1-c1nc(C)c(-c2cccnc2)[nH]1
Reactant: [H][H]
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COc1cc(Cl)c(N)cc1-c1nc(C)c(-c2cccnc2)[nH]1
Yield: 35.9 %

Procedure:
A mixture of 2-(2-methoxy-4-chloro-5-nitrophenyl)-4-methyl-5-(3-pyridyl)imidazole (6.4 g), 1N-hydrochloric acid (37 ml) and 10% palladium on carbon (3 g) in methanol (100 ml) was subjected to catalytic reduction at ambient temperature under atmospheric pressure of hydrogen gas for 3 hours. The reaction mixture was filtered and the filtrate was evaporated in vacuo. The residue was dissolved in water and the solution was adjusted to pH 8.0 with 20% aqueous potassium carbonate. The resultant mixture was extracted with ethyl acetate and extract was dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was subjected to column chromatography on silica gel and eluted with a mixture of chloroform and methanol (96:4 V/V). The fractions containing object compound were evaporated in vacuo and the residue was recrystallized from a mixture of ethyl acetate and diisopropyl ether to give 2-(2-methoxy-4-chloro-5-aminophenyl)-4-methyl-5-(3-pyridyl)imidazole (2.1 g).
Reaction SMILES: C1(C)C=CC(S([N:10]2[CH2:26][CH2:25][CH2:24][N:23](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:22][CH2:21][CH2:20][N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:18][CH2:17][N:16](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:15][CH2:14][N:13](S(C3C=CC(C)=CC=3)(=O)=O)[CH2:12][CH2:11]2)(=O)=O)=CC=1.OS(O)(=O)=O.C(O)C>C(OCC)C>[NH:10]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21][CH2:20][NH:19][CH2:18][CH2:17][NH:16][CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1
Reactant: Cc1ccc(S(=O)(=O)N2CCCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCN(S(=O)(=O)c3ccc(C)cc3)CCC2)cc1
Agent: O=S(=O)(O)O
Solvent: CCO
Solvent: CCOCC
Product: C1CNCCCNCCNCCNCCNC1
Temperature: 100 °C
Yield: 39 %

Procedure:
A mixture of 1,4,7,10,14-penta(p-toluenesulfonyl)-1,4,7,10,14-pentaazacycloheptadecane prepared as in Example 12 A (28.5 g, 0.0279 mole) and concentrated H2SO4 (100 ml) was heated at 100° C. with stirring under a dry argon atmosphere for 72 H. To the resulting brown solution, ethanol (100 ml) was added dropwise with stirring at 0° C. followed by ethyl ether (1 l). The tan solid was filtered and washed thoroughly with ethyl ether. The solid was then dissolved in H2O (100 ml) and the resulting solution filtered and washed with ethyl ether. The pH of the solution was adjusted to 11 with 10N NaOH and the solvent was removed in vacuo. The resulting brown oily solid was extracted with hot THF (2×500 ml) and the THF extracts were filtered. The filtrates were combined and the solvent was removed in vacuo. The oily residue was dissolved in hot hexane and the insoluble impurities were removed by filtration. The solvent was removed in vacuo and the residual oil was purified by vacuum distillation to give 2.68 g (39% yield) of the product as a light yellow oil: bp 140°-5° C. (0.10 mm Hg); 1H NMR (CDCl3) δ1.51 (br s, 5 H), 1.68 (quint, J=6.1 Hz, 4 H), 2.73 (m, 20 H); Exact mass (M+H)+: calcd., 244.2501; Found: 244.2555 (C12H30N5).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[CH:4][C:3]=1[S:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([O:15]C)=[O:14].[OH-].[Na+]>C1COCC1.CO>[NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][Cl:9])[CH:5]=[CH:4][C:3]=1[S:10][C:11]1[C:12](=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:13]([OH:15])=[O:14]
Reactant: COC(=O)c1ccccc1Sc1ccc(CCl)cc1N
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Nc1cc(CCl)ccc1Sc1ccccc1C(=O)O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
8.16 g Methyl S-(2-amino-4-chloromethylphenyl)thiosalicylate was dissolved in THF (50 mL) and methanol (50 mL), and treated with 5N sodium hydroxide solution (20 mL) with stirring at room temperature for 17 h. The reaction mixture was concentrated in vacuo, diluted with water, and acidified to pH 1-2 with 6N hydrochloric acid. The resulting suspension was filtered, and recrystallized from n-heptane to provide S-(2-amino-4-chloromethylphenyl)thiosalicylic acid as a light gray solid, 1H NMR (300 MHz, CDCl3), δ 6.77 (dd, 1H, J=2.7 Hz, J=2.1 Hz), 6.83 (d, 1H, J=2.1 Hz), 7.18 (t, 1H), 7.367 (s, 1H), 7.32 (t, 1H), 7.38 (d, 1H, J=8.4 Hz), 8.13 (d, 1H, J=1.8 Hz).
Reaction SMILES: ClN1C(=O)CCC1=O.[N:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=[N:16][OH:17])[CH:10]=1.[Cl:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:35][O:36][CH2:37][CH3:38])[N:31]([CH2:32][C:33]#[CH:34])[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1.C(N(CC)CC)C>O1CCCC1>[Cl:18][C:19]1[C:28]2[N:29]=[C:30]([CH2:35][O:36][CH2:37][CH3:38])[N:31]([CH2:32][C:33]3[O:17][N:16]=[C:15]([C:11]4[CH:10]=[N:9][CH:14]=[CH:13][CH:12]=4)[CH:34]=3)[C:27]=2[C:26]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[N:20]=1
Reactant: ON=Cc1cccnc1
Reactant: C#CCn1c(COCC)nc2c(Cl)nc3ccccc3c21
Agent: O=C1CCC(=O)N1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOCc1nc2c(Cl)nc3ccccc3c2n1Cc1cc(-c2cccnc2)no1
Temperature: 50 °C
Yield: 55.3 %

Procedure:
N-Chlorosuccinimide (1.09 g, 8.19 mmol) was added to a 6° C. solution of 3-pyridinecarboxaldehyde oxime (1.00 g, 8.19 mmol) in tetrahydrofuran (THF) (25 mL). The solution was heated at 50° C. for 2 h. 4-Chloro-2-(ethoxymethyl)-1-prop-2-ynyl-1H-imidazo[4,5-c]quinoline (prepared as described in Part D of Example 3, 1.96 g, 6.55 mmol) and triethylamine (1.70 mL, 12.3 mmol) were added to the reaction, which was heated at 50° C. for 17 hours. The volatiles were removed under reduced pressure and the residue was partitioned between dichloromethane and saturated aqueous potassium carbonate. The aqueous layer was extracted multiple times with dichloromethane and chloroform. The organic layers were combined, dried over sodium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography (silica gel, gradient elution with 1:1 to 1:4 hexanes/ethyl acetate) to yield 4-chloro-2-(ethoxymethyl)-1-[(3-pyridin-3-ylisoxazol-5-yl)methyl]-1H-imidazo[4,5-c]quinoline (1.52 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[C:10]([OH:11])=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2].Cl.[NH2:13][C:14]1[O:15][C:16]2[CH:22]=[C:21]([CH2:23]Cl)[CH:20]=[CH:19][C:17]=2[N:18]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:1]([NH:4][C:5]1[C:10]([O:11][CH2:23][C:21]2[CH:20]=[CH:19][C:17]3[N:18]=[C:14]([NH2:13])[O:15][C:16]=3[CH:22]=2)=[CH:9][CH:8]=[CH:7][N:6]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Nc1ncccc1O
Reactant: Nc1nc2ccc(CCl)cc2o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)Nc1ncccc1OCc1ccc2nc(N)oc2c1
Temperature: 40 °C
Reaction time: 4.3 h
Yield: 40.6 %

Procedure:
A mixture of 2-acetamido-3-hydroxypyridine (1.3 g), 2-amino-6-chloromethylbenzoxazolehydrochloride (1.5 g) and potassium carbonate (2.8 g) in N,N-dimethylformamide (20 ml) was stirred for 4.3 hours at 40° C. The reaction mixture was added to water and the mixture was extracted with a mixture of ethyl acetate and tetrahydrofuran. The extract was washed with brine and dried over magnesium sulfate. The solvent was evaporated and the residue was crystallized from ethyl acetate to give 6-(2-acetamido-pyridin-3-yloxymethyl}-2-aminobenzoxazole (0.83 g).
Reaction SMILES: C(=O)([O-])O.[K+].[C:6]1([S:12]([NH:15][C:16]2[CH:17]=[C:18]([C@@H:22]([OH:42])[CH2:23][NH:24][C:25]([CH3:41])([CH3:40])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([OH:39])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl[CH2:44][C:45]([N:47]([CH3:49])[CH3:48])=[O:46]>CN(C=O)C.O>[C:6]1([S:12]([NH:15][C:16]2[CH:17]=[C:18]([C@@H:22]([OH:42])[CH2:23][NH:24][C:25]([CH3:40])([CH3:41])[CH2:26][CH2:27][N:28]3[C:36]4[C:31](=[CH:32][C:33]([C:37]([O:39][CH2:44][C:45](=[O:46])[N:47]([CH3:49])[CH3:48])=[O:38])=[CH:34][CH:35]=4)[CH:30]=[CH:29]3)[CH:19]=[CH:20][CH:21]=2)(=[O:14])=[O:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: CC(C)(CCn1ccc2cc(C(=O)O)ccc21)NC[C@H](O)c1cccc(NS(=O)(=O)c2ccccc2)c1
Reactant: CN(C)C(=O)CCl
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C(=O)COC(=O)c1ccc2c(ccn2CCC(C)(C)NC[C@H](O)c2cccc(NS(=O)(=O)c3ccccc3)c2)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Potassium hydrogen carbonate (141 mg, 1.4 mmol) is added to a solution of 1-{3-[(R)-2-[3-(phenylsulphonylamino)-phenyl]-2-hydroxy-ethylamino]-3-methyl-butyl}-1H-indole-5-carboxylic acid-hydrotrifluoroacetate (Example 6; 300 mg, 0.47 mmol) in 2 ml DMF. Then the reaction mixture is stirred for 20 minutes at RT and 2-chloro-N,N-dimethylacetamide (143 mg, 1.18 mmol) is added. After 90 hours stirring at RT the reaction mixture is diluted with 50 ml of water and extracted with ethyl acetate. The organic phase is dried on magnesium sulphate and the solvent is eliminated in vacuo. The residue is chromatographed on silica gel (DCM/methanol=100:0→95:5).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)[N:3]=1.[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH2:20]>>[Cl:17][C:18]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:19]=1[NH:20][C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)[N:3]=1
Reactant: COCc1cc(Cl)nc(-c2csc(C)n2)n1
Reactant: COc1ccc(Cl)c(N)c1
Product: COCc1cc(Nc2cc(OC)ccc2Cl)nc(-c2csc(C)n2)n1

Procedure:
The title compound was prepared from a mixture of 4-chloro-6-(methoxymethyl)-2-(2-methyl-1,3-thiazol-4-yl)pyrimidine (50 mg, 0.196 mmol) and 2-chloro-5-methoxyaniline (38 mg, 0.196 mmol) similar to Example 13 and isolated as a white solid (33 mg, 45%). 1H NMR (CDCl3): 8.14 (s, 1H), 7.93 (d, J=3.0 Hz, 1H), 7.32 (d, J=8.7 Hz, 1H), 7.22 (s, 1H), 6.86 (s, 1H), 6.64 (dd, J=3.0, 9.3 Hz, 1H), 4.60 (s, 2H), 3.88 (s, 3H), 3.52 (s, 3H), 2.84 (s, 3H).
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([OH:21])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].C(S(C1C=C(C2C=[CH:45][C:44]([O:47][C@H](C)CO)=[C:43]3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[CH:19][C:18]([O:21][CH2:43][CH:44]([OH:47])[CH3:45])=[C:17]3[C:13]=2[C:14]2[CH:25]=[C:24]([CH3:26])[CH:23]=[N:22][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O[C@H](C)CO)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCC(C)O)c3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was synthesized from Compound 157 using an analogous procedure to that outlined in the preparation of Compound 211. 1H NMR (400 MHz, Methanol-d4) δ 8.28 (s, 1 H) 8.19 (m, 1 H) 8.06 (m, 1 H) 8.00 (m, 1 H) 7.92 (s, 1 H) 7.87 (t, J=8.0 Hz, 1 H) 7.26 (m, 2 H) 4.31 (m, 2 H) 4.10 (m, 1 H) 3.30 (q, J=7.5 Hz, 2 H) 2.40 (s, 3 H) 1.40 (d, J=8 Hz, 3 H) 1.31 (t, J=7.5 Hz, 3 H). [M+H] calc'd for C23H25N2O4S, 425; found, 425.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH2:14]1[O:24][C:23]2[C:16](=[C:17]([CH:20]=[CH:21][CH:22]=2)[CH:18]=O)[O:15]1>>[O:24]1[C:23]2[CH:22]=[CH:21][CH:20]=[C:17]([CH2:18][N:4]3[CH2:5][CH2:6][N:1]([C:7]4[N:12]=[CH:11][NH:10][C:9](=[O:13])[CH:8]=4)[CH2:2][CH2:3]3)[C:16]=2[O:15][CH2:14]1
Reactant: O=c1cc(N2CCNCC2)nc[nH]1
Reactant: O=Cc1cccc2c1OCO2
Product: O=c1cc(N2CCN(Cc3cccc4c3OCO4)CC2)nc[nH]1

Procedure:
6-(4-Benzo[1,3]dioxol-4-ylmethyl-piperazin-1-yl)-3H -pyrimidin-4-one was prepared using Procedure B from 6-piperazin-1-yl-3H-pyrimidin-4-one (Intermediate 4) and 2,3-(methylenedioxy)benzaldehyde (available from Aldrich). 1H NMR (400 MHz, CDCl3) δ 2.51-2.54 (m, 4H), 3.48-3.58 (m, 6H), 5.35 (s, 1H), 5.95 (s, 2H), 6.74-6.82 (m, 2H), 7.81 (s, 1H). Mass spectrum (ES) MH+=315.