Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][N:25](C(OC(C)(C)C)=O)[CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1.Cl>C(Cl)Cl.O1CCOCC1>[ClH:1].[Cl:1][C:2]1[C:7]2[N:8]=[C:9]([C:11]3[C:20](=[O:21])[O:19][C:18]4[CH:17]=[C:16]([N:22]5[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]5)[N:15]=[CH:14][C:13]=4[CH:12]=3)[S:10][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc3oc(=O)c(-c4nc5c(Cl)cccc5s4)cc3cn2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=c1oc2cc(N3CCNCC3)ncc2cc1-c1nc2c(Cl)cccc2s1
Reaction time: 6 h
Yield: 147.5 %

Procedure:
To a suspension of t-butyl 4-(3-(4-chlorobenzo[d]thiazol-2-yl)-2-oxo-2H-pyrano[3,2-c]pyridin-7-yl)piperazine-1-carboxylate (96 mg, 0.19 mmol) in CH2Cl2 (2 mL) was added 4N HCl in dioxane (1 mL). The mixture was stirred for 6 hours, and filtered. The solid was washed with ether and dried under nitrogen to give 61 mg (82%) of 3-(4-chlorobenzo[d]thiazol-2-yl)-7-(piperazin-1-yl)-2H-pyrano[3,2-c]pyridin-2-one hydrochloride used in the next step without further purification. MS m/z 399.1 [M+H]+; 1H NMR (500 MHz, DMSO-d6) δ (ppm) 9.34 (2H, br), 9.13 (1H, s), 8.96 (1H, s), 8.16 (1H, d, J=6.94 Hz), 7.66 (1H, d, J=6.62 Hz), 7.46 (1H, t, J=7.88 Hz), 7.00 (1H, s), 4.01 (4H, m), 3.22 (4H, m).
Reaction SMILES: [CH3:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:28]=[CH:27][C:24]([CH2:25]Br)=[CH:23][CH:22]=1)=[O:20].O>CN(C=O)C>[Cl:16][C:17]1[CH:32]=[C:31]([Cl:33])[CH:30]=[CH:29][C:18]=1[C:19]([C:21]1[CH:22]=[CH:23][C:24]([CH2:25][N:12]2[C:5]3[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[C:3]([CH3:13])=[C:2]2[CH3:1])=[CH:27][CH:28]=1)=[O:20]
Reactant: O=C(c1ccc(CBr)cc1)c1ccc(Cl)cc1Cl
Reactant: Cc1[nH]c2cnn(C)c(=O)c2c1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1c(C)n(Cc2ccc(C(=O)c3ccc(Cl)cc3Cl)cc2)c2cnn(C)c(=O)c12
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.6 %

Procedure:
A solution of 2,3,5-trimethyl-1H-pyrrolo[2,3-d]-pyridazin-4(5H)-one (354 mg) in DMF (30 ml) was dripped into a suspension of 60% sodium hydride-oil (96 mg) in DMF (8 ml) on an ice-water bath. The mixture was stirred at room temperature for 1 hour, after which a solution of 4-(2,4-dichlorobenzoyl)benzyl bromide (757 mg) in DMF (15 ml) was added and the mixture was further stirred at room temperature for 1.5 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer: n-hexane-ethyl acetate 1:1) to provide the title compound as light-yellow powder (612 mg, yield 70%).
Reaction SMILES: O[C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1.P(Cl)(Cl)([Cl:13])=O>>[Cl:13][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[CH:4][N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: Cc1ccnc(O)c1C#N
Product: Cc1ccnc(Cl)c1C#N
Yield: 89.2 %

Procedure:
To a 250 mL flask equipped with a magnetic stirrer was added 10 g of 2-hydroxy-4-methyl-3-pyridinylcarbonitrile (8) and 60 mL of phosphorous oxychloride. The mixture was refluxed for one hour. The excess POCl3 was distilled under reduced pressure. The residue was poured into water. The crystalline material was filtered and dried at to give 10.2 g (89.2%) of (9). m.p.: 109-110° C., NMR (DMSO); ppm: 2.56 (s,3H); 7.6 (bs,1H); 8.56 (m,1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][N:20]4C3CCCCO3)=[CH:14][C:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1.[ClH:43]>O>[ClH:43].[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]2[C:15]([C:16]3[N:24]=[C:23]([CH3:25])[N:22]=[C:21]4[C:17]=3[N:18]=[CH:19][NH:20]4)=[CH:14][C:13]([CH2:32][C:33]3[CH:38]=[CH:37][C:36]([S:39]([CH3:42])(=[O:41])=[O:40])=[CH:35][CH:34]=3)=[CH:12][N:11]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3c2ncn3C2CCCCO2)cn1
Agent: Cl
Solvent: O
Product: COc1ccc(Nc2ncc(Cc3ccc(S(C)(=O)=O)cc3)cc2-c2nc(C)nc3[nH]cnc23)cn1
Yield: 87 %

Procedure:
N-(6-methoxypyridin-3-yl)-3-(2-methyl-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine (94.5 mg, 0.161 mmol) was suspended in a mixture of 2 M aqueous HCl (2.0 mL) and water (6 mL). The mixture was heated at reflux for 1 h and then allowed to cool and stand at room temperature over the weekend. The resulting solid was collected by filtration, washed with water, and dried to give N-(6-methoxypyridin-3-yl)-3-(2-methyl-9H-purin-6-yl)-5-(4-(methylsulfonyl)benzyl)pyridin-2-amine hydrochloride (75.7 mg, 0.141 mmol, 87% yield) as a yellow solid. 1H NMR (400 MHz, d6-DMSO) δ 12.50 (br. s., 1H); 9.66 (br. s., 1H); 8.60 (s, 1H); 8.52 (d, J=2.54 Hz, 1H); 8.26 (d, J=1.96 Hz, 1H); 8.16 (dd, J=8.80, 2.74 Hz, 1H); 7.87 (d, J=8.22 Hz, 2H); 7.57 (d, J=8.22 Hz, 2H); 6.85 (d, J=8.80 Hz, 1H); 4.13 (s, 2H); 3.85 (s, 3H); 3.17 (s, 3H); 2.84 (s, 3H). m/z (ESI, +ve ion) 502.0 (M+H)+.
Reaction SMILES: [C:1]([O:9][CH2:10][CH:11]1[CH:18]2[CH:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH:13](SC2C=CC=CC=2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Ni].C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@H:18]2[C@@H:14]([O:15][C:16](=[O:19])[CH2:17]2)[CH2:13][O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C1CC2C(COC(=O)c3ccccc3)OC(Sc3ccccc3)C2O1
Agent: [Ni]
Solvent: CCO
Product: O=C1C[C@H]2[C@H](CO[C@@H]2COC(=O)c2ccccc2)O1
Temperature: 25 °C
Yield: 36.4 %

Procedure:
A 3-neck, 1000 mL round-bottom flask, equipped for overhead mechanical stirring, was charged with 29.6 g of 8 (80 mmol), 500 mL of ethanol and approximately 30 g of Raney-Ni (Aldrich, which had been washed to neutrality with distilled water). The resulting slurry was heated at reflux for 5 h while stirring vigorously. The reaction mixture was then cooled to room temperature, and the solids were carefully filtered off through a pad of celite. The residue was washed thoroughly with ethanol, and the combined filtrates were concentrated to afford a yellow solid which was purified by chromatography on silica gel to afford 7.63 g (36% yield) of 9 as a white solid. A small sample was recrystallized from acetone/hexane to afford colorless needles: mp 89.5-90.0° C.; [α]D22 +3.18 (c=0.8 in CHCl3); Rf 0.36 (60% EtOAc/hexane); 1H-NMR (CDCl3) δ8.01 (m, 2H), 7.40-7.65 (m, 3H), 5.15 (m, 1H), 4.41 (m, 2H), 4.05-4.32 (m, 3H), 2.80-3.05 (m, 2H), 2.56 (d, 1H, J=15.7 Hz); MS m/z at 263 for (M+H)+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([C:16]#[N:17])[S:14][CH:15]=2)[N:9]=[C:8]([C:18]([F:21])([F:20])[F:19])[CH:7]=1.[NH:22]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C@H:23]([C:25](ON1C(=O)CCC1=O)=[O:26])[CH3:24].C(N(CC)CC)C>C1COCC1>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[N:10]([C:11]2[CH:12]=[C:13]([CH2:16][NH:17][C:25](=[O:26])[C@@H:23]([NH:22][C:35](=[O:36])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])[CH3:24])[S:14][CH:15]=2)[N:9]=[C:8]([C:18]([F:20])([F:21])[F:19])[CH:7]=1
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Reactant: N#Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)NCc1cc(-n2nc(C(F)(F)F)cc2-c2ccco2)cs1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 50.6 %

Procedure:
To a solution of compound 14 (0.907 g, 2.93 mmol) at 0 degrees in THF (3 mL) and under nitrogen was slowly added 1M borane tetrahydrofuran complex (11.73 mL, 11.73 mmol). The yellow solution was then stirred for 50 minutes at room temperature. It was cooled to 0 degrees and then slowly quenched with methanol (approx. 4 mL). After 10 minutes of stirring at room temperature the reaction solution was concentrated under reduced pressure to a yellow, gummy solid and dried under a high vacuum pump. The crude amine 5 was then dissolved in DCM (15 mL) at zero degrees and to this was added BOC-Ala-OSu (0.839 g, 2.93 mmol) followed by triethylamine (0.898 mL, 6.45 mmol). The reaction was stirred at zero degrees for 1 hour and at room temperature for 16 hours. The solvent was then removed under reduced pressure and the residue partitioned between ethyl acetate and saturated NH4Cl. The layers were separated and the ethyl acetate phase washed further with saturated NH4Cl and then brine, dried over Na2SO4, filtered and concentrated. The residue was absorbed onto silica gel and then purified by silica gel chromatography using a 40M Biotage column with a gradient of 20 to 60% ethyl acetate and hexanes to give compound 6 (0.718 g, 51%) as a white crusty solid. LRMS (ESI): calc. 484.1; found 385.1 (MH-Boc)+, 507.2 (MNa)+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH2:15])[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19].[O:21]([CH2:28][C:29](Cl)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.C(Cl)Cl>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]3[N:12]=[C:13]([NH:15][C:29](=[O:30])[CH2:28][O:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)[S:14][C:10]=3[CH:9]=2)=[CH:4][C:3]=1[N:18]([CH3:20])[CH3:19]
Reactant: CN(C)c1cc(-c2ccc3nc(N)sc3c2)cnc1Cl
Reactant: O=C(Cl)COc1ccccc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CN(C)c1cc(-c2ccc3nc(NC(=O)COc4ccccc4)sc3c2)cnc1Cl

Procedure:
To a mixture of 6-(6-chloro-5-(dimethylamino)pyridin-3-yl)benzo[d]thiazol-2-amine (100 mg, 328 μmol) in pyridine (0.3 mL) and DCM (2 mL) was added 2-phenoxyacetyl chloride (150 μl, 1086 μmol). A clear solution formed. More 2-phenoxyacetyl chloride (150 μl, 1086 μmol) was added until the reaction was complete. The DCM was evaporated and the mixture was diluted with EtOAc (10 mL). The mixture was filtered, washed with EtOAc, H2O (3×5 mL) and dried in air to give a gray powder. MS (ESI, POS. ION) M/Z: calc'd for C22H19ClN4O2S: 438.1. found: 439.1. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.85 (s, 6H) 4.95 (s, 2H) 6.90-7.08 (m, 3H) 7.33 (t, J=7.78 Hz, 2H) 7.75-7.92 (m, 3H) 8.36 (s, 1H) 8.44 (s, 1H) 12.70 (s, 1H).
Reaction SMILES: Cl[C:2]1([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9][C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.[C@@H:22]1([N:30]2[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]2=[O:32])[O:29][C@H:26]([CH2:27][OH:28])[C@@H:24]([OH:25])[CH2:23]1>N1C=CC=CC=1.C(Cl)Cl>[C:16]1([C:2]2([O:28][CH2:27][C@H:26]3[O:29][C@@H:22]([N:30]4[CH:38]=[C:36]([CH3:37])[C:34](=[O:35])[NH:33][C:31]4=[O:32])[CH2:23][C@@H:24]3[OH:25])[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:8]=3[O:9][C:10]3[C:15]2=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: ClC1(c2ccccc2)c2ccccc2Oc2ccccc21
Reactant: Cc1cn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]c1=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cc1cn([C@H]2C[C@H](O)[C@@H](COC3(c4ccccc4)c4ccccc4Oc4ccccc43)O2)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
585 mg (2 mmol) of 9-chloro-9-phenylxanthene were added to a solution of 484 mg (2 mmol) of thymidine in 20 ml of pyridine, and the resulting mixture was stirred at room temperature for 1 hour whilst shading it from light. The reaction mixture was then diluted with 200 ml of methylene chloride, and the diluted mixture was washed twice, each time with 200 ml of a 5% w/v aqueous solution of sodium hydrogencarbonate. The organic layer was dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through 35 g of silica gel (70-230 mesh), using methylene chloride containing from 0 to 2.5% by volume of methanol as the eluent, to give 647.8 mg (yield 65%) of the title compound.
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@@H:6]([CH2:8][CH2:9][CH3:10])[CH2:5][N:4]([C:11]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][C:12]=2[CH:13]=O)[CH2:3]1.[NH:22]1[C:29](=[O:30])[CH2:28][C:26](=[O:27])[NH:25][C:23]1=[O:24]>CO>[CH3:1][C@H:2]1[C@@H:3]2[C:28]3([CH2:13][C:12]4[C:11]([N:4]2[CH2:5][C@@H:6]([CH2:8][CH2:9][CH3:10])[O:7]1)=[CH:18][CH:17]=[C:16]([N+:19]([O-:21])=[O:20])[CH:15]=4)[C:26](=[O:27])[NH:25][C:23](=[O:24])[NH:22][C:29]3=[O:30]
Reactant: CCC[C@H]1CN(c2ccc([N+](=O)[O-])cc2C=O)C[C@@H](C)O1
Reactant: O=C1CC(=O)NC(=O)N1
Solvent: CO
Product: CCC[C@@H]1CN2c3ccc([N+](=O)[O-])cc3CC3(C(=O)NC(=O)NC3=O)[C@H]2[C@H](C)O1
Temperature: 80 °C

Procedure:
2-(cis-2-methyl-6-propylmorpholin-4-yl)-5-nitrobenzaldehyde (446 mg, 1.53 mol) is combined with barbituric acid (217 mg, 1.53 mmol, Aldrich) in a vial with MeOH (6 mL). The sealed reaction is heated to 80° C. on a shaker block for 19 hours and then the solvent is removed by rotary evaporation. The product is purified 2× on a Biotage Flash 75M using 10% MTBE in CH2Cl2 eluent. The product is dried under vacuum at 100° C. yielding a yellow-orange solid. 1H NMR (400 MHz, ACETONITRILE-D3) δ ppm 0.95, 1.00, 1.47, 3.04, 3.34, 3.56, 3.95, 4.14, 6.85, 7.77, 8.02, 9.19.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].[NH2:8][CH2:9][CH2:10][O:11][CH2:12][CH2:13][N:14]1[C:22]2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=[C:18]([NH2:25])[C:17]=2[N:16]=[C:15]1[CH3:26]>>[NH2:25][C:18]1[C:17]2[N:16]=[C:15]([CH3:26])[N:14]([CH2:13][CH2:12][O:11][CH2:10][CH2:9][NH:8][S:3]([N:2]([CH3:7])[CH3:1])(=[O:5])=[O:4])[C:22]=2[C:21]([CH3:23])=[C:20]([CH3:24])[N:19]=1
Reactant: Cc1nc(N)c2nc(C)n(CCOCCN)c2c1C
Reactant: CN(C)S(=O)(=O)Cl
Product: Cc1nc(N)c2nc(C)n(CCOCCNS(=O)(=O)N(C)C)c2c1C

Procedure:
Using the method of Examples 34-50, dimethylsulfamoyl chloride was reacted with 1-[2-(2-aminoethoxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine to provide the desired compound. The product was purified using Method A. The observed accurate mass was 371.1861.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=1)#[N:2].[F:18][C:19]([F:29])([F:28])[CH2:20][N:21]1[CH2:26][CH2:25][CH:24]([NH2:27])[CH2:23][CH2:22]1>CN(C)C=O>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH:24]2[CH2:25][CH2:26][N:21]([CH2:20][C:19]([F:29])([F:18])[F:28])[CH2:22][CH2:23]2)=[O:15])=[CH:11][N:10]=1)#[N:2]
Reactant: NC1CCN(CC(F)(F)F)CC1
Reactant: N#Cc1ccccc1-c1ccc(C(=O)O)cn1
Solvent: CN(C)C=O
Product: N#Cc1ccccc1-c1ccc(C(=O)NC2CCN(CC(F)(F)F)CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a solution of 6-(2-cyanophenyl)nicotinic acid (50.2 mg, 0.224 mmol) in dimethylformamide (1 mL) was added 1,11-carbonylbis(1H-imidazole) (36.3 mg, 0.224 mmol) and the reaction mixture stirred at room temperature for 1 hour. A solution of 1-(2,2,2-trifluoroethyl)piperidin-4-amine (49 mg, 0.269 mmol) in dimethylformamide (0.5 mL) was then added and the reaction stirred overnight at room temperature. Further 1-(2,2,2-trifluoroethyl)piperidin-4-amine (25 mg, 0.134 mmol) in dimethylformamide (0.5 mL) was added and stirred for a further 48 hours. The dimethylformamide was evaporated off and the residue partitioned between ethyl acetate (10 mL) and water (3 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and evaporated to a buff coloured solid. This was triturated with a mixture of heptane and t-butyl methyl ether and the white solid was filtered off and dried to give 6-(2-cyanophenyl)-N-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]nicotinamide (44 mg) 1H NMR (400 MHz, DMSO-d6) ppm 1.58-1.68 (m, 2H) 1.82-1.86 (m, 2H) 2.47-2.54 (m, 2H) 2.97 (m, 2H) 3.20 (q, J=10.25 Hz, 2H) 3.84 (m, 1H) 7.71 (td, J=6.2, 1.6 Hz, 1H) 7.87 (td, J=6.2, 1.6 Hz, 1H) 7.99 (m, 3H) 8.37 (dd, J=13.0, 2.4 Hz, 1H) 8.59 (d, J=7.4 Hz, 1H) 9.15 (dd, J=1.3, 0.8 Hz, 1H) LCMS 389 (M+1) ELSD 1.19 minutes.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([C:17]3[C:18]([Cl:23])=[N:19][CH:20]=[CH:21][CH:22]=3)[CH:12]=2)[CH:10]=1)=[O:5].Br[C:26]1[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=1>>[Cl:23][C:18]1[C:17]([C:13]2[CH:12]=[C:11]([N:9]3[CH:10]=[C:6]([C:4]([C:26]4[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=4)=[O:5])[N:7]=[CH:8]3)[CH:16]=[CH:15][CH:14]=2)=[CH:22][CH:21]=[CH:20][N:19]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3cccnc3Cl)c2)cn1
Reactant: COc1ccc(Br)cc1
Product: COc1ccc(C(=O)c2cn(-c3cccc(-c4cccnc4Cl)c3)cn2)cc1

Procedure:
This compound is prepared by method C using compound 12l and 4-bromoanisole
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.[CH3:27][C:28]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[C:29](O)=[O:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O.C1(C)C=CC=CC=1>O1CCCC1>[CH3:27][C:28]([S:33]([CH3:36])(=[O:35])=[O:34])([CH3:32])[C:29]([O:26][CH:23]([C:5]1[C:6]2[N:7]3[CH2:14][CH2:13][CH2:12][N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[C:8]3=[N:9][C:10]=2[C:2]([Cl:1])=[CH:3][CH:4]=1)[CH2:24][CH3:25])=[O:30]
Reactant: CC(C)(C(=O)O)S(C)(=O)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CCC(OC(=O)C(C)(C)S(C)(=O)=O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 61.3 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol), 2-methyl-2-(methylsulfonyl)propanoic acid (65.6 mg, 0.395 mmol) and triphenylphosphine (104 mg, 0.397 mmol) in tetrahydrofuran (5.0 mL) was added a solution of diethylazodicarboxylate in toluene (2.2 M, 0.18 mL, 0.396 mmol) at 0° C. After stirring at room temperature for 20 hr, the mixture was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 25-60% ethyl acetate/n-hexane gradient mixture to give the title compound (83.0 mg, 0.149 mmol, 61%) as a colorless amorphous.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]([CH3:30])[CH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[C:18]3[C:19]4[CH2:20][NH:21][CH2:22][CH2:23][C:24]=4[S:25][C:26]=3[N:27]=[CH:28][N:29]=2)[CH2:12][CH2:11]1.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:31][S:32]([N:21]1[CH2:20][C:19]2[C:18]3[C:17]([O:16][CH:13]4[CH2:12][CH2:11][CH:10]([N:9]([CH3:30])[CH3:8])[CH2:15][CH2:14]4)=[N:29][CH:28]=[N:27][C:26]=3[S:25][C:24]=2[CH2:23][CH2:22]1)(=[O:34])=[O:33]
Reactant: CS(=O)(=O)Cl
Reactant: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CNCC4)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C1CCC(Oc2ncnc3sc4c(c23)CN(S(C)(=O)=O)CC4)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of N,N-dimethyl-4-[8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yloxy]cyclohexan-1-amine trifluoroacetate (30 mg, 0.09 mmol, 1.00 equiv) in 5 mL of anhydrous dichloromethane was added TEA (40 mg, 0.40 mmol, 4.38 equiv) and MsCl (14 mg, 0.12 mmol, 1.36 equiv) at 0° C. under nitrogen. The resulting solution was stirred for 2 h at room temperature. The reaction mixture was concentrated under vacuum and the residue was purified by preparative HPLC under the following conditions (Waters): Column: XBridge Prep C18 OBD Column, 5 μm, 19*150 mm; mobile phase: water with 0.05% NH4HCO3 and CH3CN (16% CH3CN increasing to 23% in 10 min, up to 100% in 2 min, down to 16% in 2 min); flow rate: 20 mL/min; UV Detection at 254/220 nm. This resulted in 8.0 mg (22%) of 4-([12-methanesulfonyl-8-thia-4,6,12-triazatricyclo[7.4.0.0-[2,7]]trideca-1(9),2(7),3,5-tetraen-3-yl]oxy)-N,N-dimethylcyclohexan-1-amine as a white solid. MS (ES): m/z 411 (M+H)+; 1H NMR (300 MHz, CD3OD): δ 1.59-1.71 (m, 4H), 2.05-2.10 (d, 2H, J=15 Hz), 2.34-2.50 (m, 9H), 2.98 (s, 3H), 3.08 (t, 2H, J=5.7 Hz), 3.06 (t, 2H, J=5.7 Hz), 4.67 (t, 2H, J=1.8 Hz), 5.26 (m, 1H), 8.53 (s, 1H).
Reaction SMILES: [C:1]([O:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([O:12]C(=O)C)[C:6]=1[Cl:16])(=[O:3])[CH3:2].[OH-].[Li+].Cl>O.O1CCOCC1>[C:1]([O:4][C:5]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([OH:12])[C:6]=1[Cl:16])(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cc(I)cc(OC(C)=O)c1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1cc(I)cc(O)c1Cl
Temperature: 60 °C
Reaction time: 4 h
Yield: 107.7 %

Procedure:
A mixture of 2-chloro-5-iodo-1,3-phenylene diacetate (5) (5.16 g, 14.5 mmol) and 1M lithium hydroxide (29.1 mL, 29.1 mmol) in H2O (5 mL) and dioxane (20 mL) was stirred at 60° C. for 4 h then at RT for 20 h. The reaction mixture was acidified by the addition of 1M HCl and the product was extracted with EtOAc (150 mL). The organic solution was dried over MgSO4 and the solvent was removed in vacuo. The resulting oil was slurried with 1:1 DCM: isohexanes and the solvents were removed in vacuo to yield 2-chloro-3-hydroxy-5-iodophenyl acetate (6) (4.88 g, 86%) as a brown solid: m/z 311 [M−H]− (ES−).
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([OH:14])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2].CO.[CH3:17]CN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([O:14][CH3:17])=[O:13])=[CH:9][CH:10]=2)[NH:5][N:4]=1)[CH3:2]
Reactant: CCN=C=NCCCN(C)C
Reactant: CCc1n[nH]c2cc(C(=O)O)ccc12
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CO
Solvent: ClCCl
Product: CCc1n[nH]c2cc(C(=O)OC)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 59.2 %

Procedure:
To a solution of 1.35 g (7.1 mmol) of 3-ethyl-1H-indazol-6-yl-carboxylic acid, [Marfat, A., et al., U.S. Pat. No. 6,262,040], 2.9 mL (71 mmol) of methanol, and 0.95 g (7.8 mmol) of DMAP in 60 mL of CH2Cl2 was added 1.5 g (7.8 mmol) of EDCI-HCl. This mixture was stirred at room temperature overnight, concentrated and the residue dissolved in 50 mL of ethyl acetate. The organic layer was successively washed with 40 mL of 1N HCl, 40 mL of water and 40 mL of brine, dried (Na2SO4), and concentrated. The residue was purified by chromatography over silica gel using a gradient of 35% to 50% ethyl acetate in hexanes over 20 minutes as eluant to yield 860 mg (4.2 mmol) of methyl 3-ethyl-1H-indazol-6-yl-carboxylate. 1H NMR (CDCl3) δ 11.7 (s, 1H), 8.18 (s, 1H), 7.73 (apparent q, 9.0 Hz, 2H), 3.94 (s. 3H), 3.03 (q, 7.5 Hz, 2H), 1.42 (t, 7.5 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11](Cl)(=[O:13])=[O:12])[C:4]=2[O:3]1.[OH-].[NH4+:17]>O1CCCC1>[CH3:1][C:2]1([CH3:15])[CH2:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([S:11]([NH2:17])(=[O:13])=[O:12])[C:4]=2[O:3]1
Reactant: [NH4+]
Reactant: CC1(C)Cc2cccc(S(=O)(=O)Cl)c2O1
Agent: [OH-]
Solvent: C1CCOC1
Product: CC1(C)Cc2cccc(S(N)(=O)=O)c2O1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 26 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonyl chloride prepared in Example 1, in 130 ml of tetrahydrofuran, was cooled in an ice-water bath while about 30 ml of concentrated aqueous ammonium hydroxide was added portionwise at 10° to 30° C. The resulting suspension was stirred at room temperature for 3 hours, then the solvent was evaporated under reduced pressure. The residue was stirred in 150 ml of water for 0.5 hour, then filtered. The crude, wet solid was dissolved in chloroform and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give a dry solid. The solid was washed once with about 100 ml of hot toluene to give 20 g of 2,3-dihydro-2,2-dimethyl-7-benzofuransulfonamide, m.p. 163°-165° C.