Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]([F:35])([F:34])[F:33])[CH:20]=[C:21]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=4[O:30][CH3:31])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:36][NH2:37]>>[CH3:36][NH:37][CH2:12][CH:13]1[CH2:17][C:16]2[CH:18]=[C:19]([C:32]([F:35])([F:34])[F:33])[CH:20]=[C:21]([C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][C:23]=3[O:30][CH3:31])[C:15]=2[O:14]1
Reactant: CN
Reactant: COc1ccc(-c2cc(C(F)(F)F)cc3c2OC(COS(=O)(=O)c2ccc(C)cc2)C3)c(OC)c1
Product: CNCC1Cc2cc(C(F)(F)F)cc(-c3ccc(OC)cc3OC)c2O1

Procedure:
The title compound was prepared (0.048 g, 76%) following the general procedure of Example 390 as a white solid, hydrochloride salt from [7-(2,4-dimethoxyphenyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.080 g, 0.16 mmol) and methylamine (0.12 g, 3.9 mmol). mp 234-236° C.
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]2=[N:4][C:3]=1[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12].[F:17][C:18]1[CH:19]=[C:20](B(O)O)[CH:21]=[CH:22][CH:23]=1>>[F:17][C:18]1[CH:23]=[C:22]([C:2]2[N:6]3[CH:7]=[CH:8][CH:9]=[CH:10][C:5]3=[N:4][C:3]=2[C:11]([N:13]([O:15][CH3:16])[CH3:14])=[O:12])[CH:21]=[CH:20][CH:19]=1
Reactant: CON(C)C(=O)c1nc2ccccn2c1Br
Reactant: OB(O)c1cccc(F)c1
Product: CON(C)C(=O)c1nc2ccccn2c1-c1cccc(F)c1
Yield: 80 %

Procedure:
The desired compound was prepared according to the procedure of Example 1, step E, using 3-bromo-N-methoxy-N-methylimidazo[1,2-a]pyridine-2-carboxamide and (3-fluorophenyl)boronic acid as the starting materials in 80% yield. LCMS for C16H15FN3O2 (M+H)+: m/z=300.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:8]2[CH2:16][CH:15]3[CH2:17][N:11]4[CH2:12][CH:13]([CH2:18][CH:9]2[CH2:10]4)[CH2:14]3)[CH:5]=[N:6][CH:7]=1.[C:19]1(B(O)O)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:19]1([C:2]2[CH:3]=[C:4]([N:8]3[CH2:16][CH:15]4[CH2:17][N:11]5[CH2:12][CH:13]([CH2:18][CH:9]3[CH2:10]5)[CH2:14]4)[CH:5]=[N:6][CH:7]=2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Brc1cncc(N2CC3CC4CC2CN(C4)C3)c1
Reactant: OB(O)c1ccccc1
Product: c1ccc(-c2cncc(N3CC4CC5CC3CN(C5)C4)c2)cc1

Procedure:
The title compound was prepared from the product of Example 65A and phenylboronic acid according to General Method B: 1H NMR (500 MHz, CDCl3) δ ppm 6 ppm 8.14 (d, 2 H), 7.56 (d, 2 H), 7.46 (t, 2 H), 7.39 (t, 1 H), 7.10 (s, 1 H), 3.73-3.37 (m, 5 H), 3.05-2.97 (m, 3 H), 2.27-2.17 (m, 4 H), 1.88-1.77 (m, 3 H); LC-MS Method D (ESI+) m/z 306.0 (M+H)+, retention time 1.28 minutes.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[CH:18]=[N:19][C:20](C)=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:3])[CH3:2].Br[C:45]1C=C(C2C=C3C(=CC=2)N(C)N=C3)C=NC=1C>>[C:1]([O:5][C@@H:6]([C:10]1[C:35]([CH3:36])=[CH:34][C:13]2[N:14]=[C:15]([C:17]3[C:18]([CH3:45])=[N:19][CH:20]=[C:21]([C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[N:28]([CH3:32])[N:27]=[CH:26]5)[CH:22]=3)[S:16][C:12]=2[C:11]=1[C:37]1[CH:42]=[CH:41][C:40]([Cl:43])=[CH:39][CH:38]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc2nc(-c3cnc(C)c(-c4ccc5c(cnn5C)c4)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Reactant: Cc1ncc(-c2ccc3c(cnn3C)c2)cc1Br
Product: Cc1cc2nc(-c3cc(-c4ccc5c(cnn5C)c4)cnc3C)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O

Procedure:
(S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-methyl-5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)acetic acid was prepared in a similar manner as (S)-2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(6-methyl-5-(1-methyl-1H-indazol-5-yl)pyridin-3-yl)benzo[d]thiazol-6-yl)acetic acid except using 5-(5-bromo-6-methylpyridin-3-yl)-1-methyl-1H-indazole instead of 5-(5-bromo-2-methylpyridin-3-yl)-1-methyl-1H-indazole. LCMS-ESI+: calc'd for C34H32ClN4O3S: 611.2 (M+H+); Found: 611.2 (M+H+). 1H NMR (400 MHz, CD3OD): δ 9.00 (s, 1H), 8.77 (s, 1H), 8.20 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.84 (m, 1H), 7.72 (m, 2H), 7.60 (m, 3H), 5.28 (s, 1H), 4.11 (s, 3H), 3.00 (s, 3H), 2.64 (s, 3H), 0.98 (s, 9H).
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1.[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[C:25]([N:27]2[CH2:40][CH2:39][C:30]3[NH:31][C:32]4[C:33]([OH:38])=[CH:34][CH:35]=[CH:36][C:37]=4[C:29]=3[CH2:28]2)=[O:26])=[O:18])[CH2:15][CH2:14]1)#[N:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:11]([C:13]1([NH:16][C:17]([C@@H:19]2[CH2:24][CH2:23][CH2:22][CH2:21][C@H:20]2[C:25]([N:27]2[CH2:40][CH2:39][C:30]3[NH:31][C:32]4[C:33]([O:38][CH2:3][CH2:4][N:5]5[CH2:10][CH2:9][O:8][CH2:7][CH2:6]5)=[CH:34][CH:35]=[CH:36][C:37]=4[C:29]=3[CH2:28]2)=[O:26])=[O:18])[CH2:15][CH2:14]1)#[N:12]
Reactant: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(O)cccc4c3C2)CC1
Reactant: ClCCN1CCOCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#CC1(NC(=O)[C@@H]2CCCC[C@H]2C(=O)N2CCc3[nH]c4c(OCCN5CCOCC5)cccc4c3C2)CC1
Temperature: 25 °C
Reaction time: 45 h

Procedure:
Following on from Example 34, 4-(2-Chloroethyl)morpholine hydrochloride (90 mg, 0.48 mmol) was added to (1R,2R)-N-(1-cyanocyclopropyl)-2-(6-hydroxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole-2-carbonyl)cyclohexanecarboxamide (131 mg, 0.32 mmol) and potassium carbonate (134 mg, 0.97 mmol) in DMF (5 ml) at 25° C. under air. The resulting solution was stirred at room temperature for 45 hours, to yield after purification a cream solid. (4.00 mg, 2.4%).
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][C:21](=O)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1.[CH3:25][C@H:26]1[O:31][C@H:30]([CH3:32])[CH2:29][NH:28][CH2:27]1>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]3[CH2:16][C:5]([CH2:17][N:18]4[CH2:23][CH2:22][CH:21]([N:28]5[CH2:27][C@@H:26]([CH3:25])[O:31][C@H:30]([CH3:32])[CH2:29]5)[CH2:20][CH2:19]4)([C:6]4[C:11]3=[CH:10][CH:9]=[CH:8][CH:7]=4)[C:4]=2[CH:3]=1
Reactant: C[C@@H]1CNC[C@@H](C)O1
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccc(Cl)cc23)CC1
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(C2CCN(CC34CC(c5ccccc53)c3ccc(Cl)cc34)CC2)C[C@@H](C)O1

Procedure:
To a solution of 1-(2-chloro-9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (380 mg, 1.12 mmol) in toluene (10 mL) under nitrogen was added trans 2,6-dimethylmorpholine (155 mg, 1.34 mmol, 1.23 eq). The trans 2,6-dimethylmorpholine isomer was obtained by spinning band distillation of the commercially available mixture of 2,6-dimethylmorpholines. The solution was heated to reflux passing the solvent through 3 A molecular sieves in a modified Dean Stark arrangement. After 2 h, the solvent was removed, replaced with tetrahydrofuran (1.0 mL), and cooled to 0° C. Excess hydrogen chloride gas was bubbled into the solution and then purged with nitrogen. The reaction was warmed to room temperature and a solution of sodium cyanoborohydride (210 mg, 3.35 mmol, 9 eq) in methanol (0.50 mL) was added. A significant amount of gas was evolved. The reaction was stirred for 18 h and quenched with 2.5 N NaOH (10 mL). The aqueous phase was extracted with ethyl acetate (3×10 mL). Combined organic extracts were dried over anhydrous magnesium sulfate, filtered and concentrated to an oil. The reaction product was purified by flash chromatography over silica gel (40 mL, eluent: 30% ethyl acetate in hexane) to yield the title compound as a white solid (371 mg, 76%), mp 237° C. (dec); NMR (CDCl3, 300 MHz) 7.23 (dd, J=5.9, 1.6 Hz, 1H), 7.12 (m, 4H), 6.92 (m, 3H), 4.22 (s, 1H), 3.97 (m, 2H), 3.67 (t, J=6.3 Hz, 1H), 3.58 (t, J=6.2 Hz, 1H), 3.32 (s, 2H), 2.52 (dd, J=11.0, 3.1 Hz, 2H), 2.19 (m, 4H), 1.71 (m, 3H), 1.20 (d, J=6.4 Hz, 6H) MS (CI, CH4) m/z 437 (M+1,100), 439 (34), 465 (M+29,15) The free base was dissolved in diethyl ether and acidified with ethereal HCl. The hydrochloride salt was filtered, rinsed with fresh ether and dried in vacuo (50° C., 13 pascal, 18 h) to yield a white solid, mp 237°-240° C. (dec).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][O:11][Si:12]([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:4][CH:3]=1.Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[Si:12]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([O:1][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[CH:7][CH:6]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)[Si](OCCCc1ccc(O)cc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Yield: 94.2 %

Procedure:
A solution of 3(4-hydroxyphenyl)-1-(tert-butyldiphenylsilyloxy)propane (3.91 g, 10.0 mmol) and methyl bromoacetate (3.0 g, 19.7 mmol) in acetonitrile (100 ml) was treated with powdered anhydrous potassium carbonate (10 g) and the resulting mixture was heated under reflux for 1 hour. The cooled mixture was filtered and the filtrate was concentrated in vacuo. Chromatography of the residue on silica gel (elution toluene-ethyl acetate, 98:2) gave 4.36 g (94%) of the title material as clear oil.
Reaction SMILES: O[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][C:13]([CH3:15])=[O:14].N1CCCC1>C1(C)C=CC=CC=1>[CH3:12][C:13]1([CH3:15])[CH:2]([CH3:11])[C:3](=[O:4])[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:10]=2[O:14]1
Reactant: CC(C)=O
Reactant: CC(O)C(=O)c1ccccc1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CC1C(=O)c2ccccc2OC1(C)C

Procedure:
A solution of 2-hydroxypropiophenone (500 ml, 3.64 mol), acetone (400 ml), and pyrrolidine (150 ml, 1.8 mol) in toluene (1000 ml) was heated at 85° C. for 66 hours. The cooled solution was then washed successively with water, aqueous hydrochloric acid and aqueous sodium hydroxide solution. The toluene layer was separated and the solvent removed under reduced pressure. The residue was chromatographed on silica gel, eluting with dichloromethane/heptane (50/50), to give 81 g of 2,2,3-trimethyl-3,4-dihydro-2H-1-benzopyran-4-one as an oil, a compound of formula (3 a) ; 1H NMR (CDCl3): δ 1.3 (d, 3H) , 1.4 (s,3H), 1.6 (s,3H), 2.5-3.0 (q,1H), 6.8-8.1 (m,4H).
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[CH3:6][O:7][C:8]1[N:13]=[CH:12][C:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=O)[NH:16][N:15]=2)=[CH:10][CH:9]=1>N1C=CC=CC=1>[Cl:3][C:17]1[C:18]2[C:23](=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:14]([C:11]2[CH:12]=[N:13][C:8]([O:7][CH3:6])=[CH:9][CH:10]=2)=[N:15][N:16]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(-c2n[nH]c(=O)c3ccccc23)cn1
Solvent: c1ccncc1
Product: COc1ccc(-c2nnc(Cl)c3ccccc23)cn1
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 55.2 %

Procedure:
932 μl (10 mmol) of phosphorus oxychloride was added to a pyridine solution (5 ml) of 507 mg (2 mmol) of 4-(6-methoxypyridin-3-yl)-2H-phthalazin-1-on, and the reaction liquid was stirred at 120° C. for 30 minutes. This was concentrated under reduced pressure, aqueous saturated sodium hydrogencarbonate solution was added to the reaction liquid, extracted with chloroform, and the organic layer was washed with saturated saline water. This was dried with anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 300 mg (yield: 55%) of 1-chloro-4-(6-methoxypyridin-3-yl)-phthalazine as a brown solid.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[C:16]([CH3:18])[NH:15][N:14]=2)[N:3]=1.[C:19]([NH:22][C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][CH:24]=1)(=[O:21])[CH3:20]>>[CH3:18][C:16]1[NH:15][N:14]=[C:13]([NH:12][C:4]2[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([NH:22][C:19](=[O:21])[CH3:20])=[CH:24][CH:25]=3)[C:11]3[C:6]([CH:5]=2)=[CH:7][CH:8]=[CH:9][CH:10]=3)[CH:17]=1
Reactant: CC(=O)Nc1ccc(B(O)O)cc1
Reactant: Cc1cc(Nc2cc3ccccc3c(Cl)n2)n[nH]1
Product: CC(=O)Nc1ccc(-c2nc(Nc3cc(C)[nH]n3)cc3ccccc23)cc1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-isoquinolin-3-yl)-(5-methyl-1H-pyrazol-3-yl)-amine and 4-acetylamino-phenylboronic acid to give N-{4-[3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-1-yl]-phenyl}-acetamide. LC-MS m/e 358(MH+).
Reaction SMILES: [C:1]([NH:5][C:6]1[C:7]([NH2:20])=[CH:8][C:9]([C:12]2[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=2)=[CH:10][CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[CH:21]([C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])=O.OOS([O-])=O.[K+]>CN(C=O)C.O>[C:1]([N:5]1[C:6]2[CH:11]=[CH:10][C:9]([C:12]3[CH:13]=[N:14][CH:15]=[C:16]([O:18][CH3:19])[CH:17]=3)=[CH:8][C:7]=2[N:20]=[C:21]1[C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=1)[C:26]#[N:27])([CH3:4])([CH3:3])[CH3:2]
Reactant: N#Cc1cccc(C=O)c1
Reactant: COc1cncc(-c2ccc(NC(C)(C)C)c(N)c2)c1
Agent: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cncc(-c2ccc3c(c2)nc(-c2cccc(C#N)c2)n3C(C)(C)C)c1
Yield: 64.8 %

Procedure:
N1-tert-Butyl-4-(5-methoxy-pyridin-3-yl)-benzene-1,2-diamine (0.630 g, 2.32 mmol) is dissolved in DMF (5 mL) and water (1 mL). To this solution is added 3-formyl-benzonitrile (0.315 g, 2.40 mmol), followed by Oxone (1.54 g, 2.50 mmol). This reaction mixture is sonicated at room temperature for 1 hour. The solvent is removed in vacuum. The residue is partitioned between EtOAc (3×10 mL) and saturated sodium bicarbonate solution (10 mL). The organic layer is washed with brine, dried over sodium sulfate and is filtered. The filtrate is concentrated and the residue is purified by flash chromatography (40 g silica gel, eluted with 0-100% EtOAc in hexane) to give 3-[1-tert-butyl-5-(5-methoxy-pyridin-3-yl)-1H-benzimidazol-2-yl]-benzonitrile (0.575 g, 65%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@H:10]([OH:12])[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[Br:15][C:16]1[C:17](Cl)=[N:18][CH:19]=[CH:20][CH:21]=1>CN(C=O)C>[CH2:1]([O:8][CH2:9][C@H:10]([O:12][C:17]1[C:16]([Br:15])=[CH:21][CH:20]=[CH:19][N:18]=1)[CH3:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[C@@H](O)COCc1ccccc1
Reactant: Clc1ncccc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[C@H](COCc1ccccc1)Oc1ncccc1Br
Reaction time: 0.5 h

Procedure:
To a stirred solution of (R)-1-(benzyloxy)propan-2-ol (2.0 g, 12 mmol) in dry DMF (5 mL) was added NaH (1.5 g, 36 mmol) at 0 Celsius. The reaction mixture was then stirred for 30 min before adding 3-bromo-2-chloropyridine (2.3 g, 12 mmol) and stirring continued for another 4 h. The reaction was quenched by slow addition of water (10 mL) and the resultant mixture extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over Na2SO4, filtered, concentrated to dryness, and the crude product purified by FCC to provide the title compound.
Reaction SMILES: [CH3:1][CH:2]([CH3:27])[C:3]([NH:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[N:14]([S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]2)=O.P(Cl)(Cl)(Cl)=O>C(#N)C>[CH:2]([C:3]1[C:10]2=[C:11]3[C:15](=[CH:16][CH:17]=[C:9]2[O:8][CH2:7][CH2:6][N:5]=1)[N:14]([S:18]([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)(=[O:20])=[O:19])[CH:13]=[CH:12]3)([CH3:1])[CH3:27]
Reactant: CC(C)C(=O)NCCOc1ccc2c(ccn2S(=O)(=O)c2ccccc2)c1
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: CC(C)C1=NCCOc2ccc3c(ccn3S(=O)(=O)c3ccccc3)c21
Yield: 98.7 %

Procedure:
To 2-methyl-N-(2-{[1-(phenylsulfonyl)-1H-indol-5-yl]oxy}ethyl)propanamide (Intermediate 37, 0.13 g, 0.33 mmol) in acetonitrile (200 mL) was phosphoryl chloride (2.5 mL) added and the reaction mixture was heated at reflux for 20 hours. The reaction mixture was evaporated to give the title compound (120 mg). MS m/z 369 [M+H]+.
Reaction SMILES: [C:1](=O)([O-])[O-].[K+].[K+].[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([OH:30])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:9])[CH3:8].IC>CN(C=O)C>[C:7]([O:11][C:12]([NH:14][C@H:15]([C:28]([O:30][CH3:1])=[O:29])[CH2:16][C:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[N:19]([CH:26]=[O:27])[CH:18]=1)=[O:13])([CH3:10])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cn(C=O)c2ccccc12)C(=O)O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)[C@H](Cc1cn(C=O)c2ccccc12)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To DMF (50 mL) suspension of potassium carbonate (6.2 g) was added dropwise DMF (70 mL) solution of Nα-tert-butoxycarbonyl-1-formyl-L-tryptophan (10.0 g) at 0° C., and the mixture was stirred for 1 hour at room temperature. Next, DMF (25 mL) solution of iodomethane (2.8 mL) was added dropwise at 0° C., and the mixture was stirred for 20 hours at room temperature. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and thereafter the residue obtained by distilling off the solvent under a reduced pressure was purified with silica gel column chromatography (BZ-127ZH, n-hexane:ethyl acetate=7:3), to give the captioned compound (9.0 g, 86%) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1.[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1I>>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[S:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=1
Reactant: COc1ccc(S)cc1
Reactant: Brc1ccccc1I
Product: COc1ccc(Sc2ccccc2Br)cc1

Procedure:
Prepared from 4-methoxy-benzenethiol and 1-bromo-2-iodo-benzene.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[CH:15]=[C:14]([N:16](C)[C:17](=O)C)[CH:13]=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].[ClH:21]>O.O1CCOCC1>[ClH:21].[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[CH:15]=[C:14]([NH:16][CH3:17])[CH:13]=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(=O)N(C)c1ccnc(N2CCN(C(C)C)CC2)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: CNc1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 25 °C
Yield: 76 %

Procedure:
A mixture of 2.5 g (9 mmol) N-[2-(4-isopropyl-piperazin-1-yl)-pyridin-4-yl]-N-methyl-acetamide and 10 ml 4N HCl in 5 ml water and 25 ml dioxane was stirred at room temperature. After evaporation of the volatiles the residue was triturated with a mixture formed from acetone and dioxane and dried under vacuum to yield 1.8 g (76%) of the title compound (intermediate 11) as light red solid. MS: (m/e): 235.2 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[NH:11][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)=[O:5])[CH3:2].[O:20]=[S:21]1(=[O:35])[C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=2[NH:24][C:23]([CH2:31][C:32](O)=[O:33])=[N:22]1.CN1CCOCC1.Cl.CN(C)CCCN=C=NCC.Cl>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1[N:11]([C:32](=[O:33])[CH2:31][C:23]1[NH:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[S:21](=[O:20])(=[O:35])[N:22]=1)[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CCCC1NCc1ccc(F)cc1
Reactant: O=C(O)CC1=NS(=O)(=O)c2ccccc2N1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)C1CCCC1N(Cc1ccc(F)cc1)C(=O)CC1=NS(=O)(=O)c2ccccc2N1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-(4-Fluoro-benzylamino)-cyclopentanecarboxylic acid ethyl ester (prepared as described in Example 11, 133.5 mg, 0.503 mmol) was mixed with (1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetic acid (132.9 mg, 0.554 mmol) in N,N-dimethylformamide (4.6 mL). N-methylmorpholine (122 μL, 1.11 mmol) was added followed by 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (106.2 mg, 0.554 mmol). The reaction mixture was shaken at 25° C. for 16 h. A 1.0 M aqueous hydrochloric acid solution (4.6 mL) was added at 25° C., and the aqueous layer was extracted with ethyl acetate (3×15 mL). The combined organic layers were washed with saturated aqueous brine solution (10 mL). The organic layer was dried over sodium sulfate, filtered, concentrated and dried in vacuo to afford the crude product, 2-[[2-(1,1-dioxo-1,4-dihydro-1λ6-benzo[1,2,4]thiadiazin-3-yl)-acetyl]-(4-fluoro-benzyl)-amino]-cyclopentanecarboxylic acid ethyl ester, as a pale yellow oil, which was directly used in the next step without further purification. LC-MS (ESI) calcd for C24H26FN3O5S 487.16, found 488.3 [M+H+].
Reaction SMILES: F[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:5]2=[CH:4][CH:3]=1.[CH3:13][N:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.O>CN1CCCC1=O>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([C:2]2[N:7]=[C:6]3[NH:8][N:9]=[C:10]([C:11]#[N:12])[C:5]3=[CH:4][CH:3]=2)[CH2:16][CH2:15]1
Reactant: N#Cc1n[nH]c2nc(F)ccc12
Reactant: CN1CCNCC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CN1CCN(c2ccc3c(C#N)n[nH]c3n2)CC1

Procedure:
6-Fluoro-1H-pyrazolo[3,4-b]pyridine-3-carbonitrile (1.62 g, 10.0 mmole) was dissolved in 20 mL of N-methylpyrrolidone. N-methylpiperazine (3.0 g, 30.0 mmole) was added and the reaction mixture was warmed for 2 hours at 80°. It was poured into H2O and then the product was filtered off and recrystallized from MeOH-H2H2O to give 1.41 g (58%) of analytically pure product, mp 255°(dec).
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:27]=[CH:26][C:8]3[C:9]4[N:10]=[C:11]([C:17]5[N:18]([CH:23]([CH3:25])[CH3:24])[N:19]=[C:20]([CH3:22])[N:21]=5)[S:12][C:13]=4[CH2:14][CH2:15][O:16][C:7]=3[CH:6]=2)[CH2:2]1.[Si]([O:35][CH2:36][CH2:37][CH:38]=O)(C(C)(C)C)(C)C>>[CH:23]([N:18]1[C:17]([C:11]2[S:12][C:13]3[CH2:14][CH2:15][O:16][C:7]4[CH:6]=[C:5]([CH:3]5[CH2:4][N:1]([CH2:38][CH2:37][CH2:36][OH:35])[CH2:2]5)[CH:27]=[CH:26][C:8]=4[C:9]=3[N:10]=2)=[N:21][C:20]([CH3:22])=[N:19]1)([CH3:25])[CH3:24]
Reactant: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CNC4)ccc2-3)n(C(C)C)n1
Reactant: CC(C)(C)[Si](C)(C)OCCC=O
Product: Cc1nc(-c2nc3c(s2)CCOc2cc(C4CN(CCCO)C4)ccc2-3)n(C(C)C)n1

Procedure:
Following the procedures for 519, 8-azetidin-3-yl-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene was reacted with 3-(tert-butyldimethylsilyloxy)propanal to give 526. MS (ESI+) 440.2
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[CH:18]=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=[O:13])=[CH:5][CH:4]=1.Cl[C:20](OCC)=[O:21]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:20](=[O:21])[O:14][C:12](=[O:13])[C:11]3=[CH:15][CH:16]=[CH:17][CH:18]=[C:10]23)=[CH:7][CH:8]=1
Reactant: COc1ccc(Nc2ccccc2C(=O)O)cc1
Reactant: CCOC(=O)Cl
Product: COc1ccc(-n2c(=O)oc(=O)c3ccccc32)cc1

Procedure:
A suspension of 40 g of 2-(4-methoxyphenylamino)benzoic acid in 200 ml of ethyl chloroformate was heated at reflux for 24 hours. The reaction mixture was cooled in an ice-bath and the solid which separated was collected by filtration to give 31 g of N-(4-methoxyphenyl)isatoic anhydride after 6 hours of drying in a vacuum oven. An additional 9 g of product was obtained by concentration of the filtrate in vacuo.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH2:9])=[CH:4][CH:3]=1.[C:10](#[N:13])[CH:11]=[CH2:12].[O-]CC.[Na+].BrN1C(=O)CCC1=O>C(O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[CH:11][C:10]([NH2:13])=[N:9]2)=[CH:4][CH:3]=1
Reactant: C=CC#N
Reactant: NNc1ccc(Br)cc1
Agent: CC[O-]
Agent: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: CCO
Product: Nc1ccn(-c2ccc(Br)cc2)n1

Procedure:
The title compound was prepared by the reaction of 4-bromophenylhydrazine with acrylonitrile in the presence of a suitable base such as sodium ethoxide in refluxing ethanol followed by oxidation with N-bromosuccinimide; 1H NMR (300 MHz, DMSO-d6) δ 3.81 (br s, 2H), 5.84 (s, 1H), 7.41 (d, J=8.7 Hz, 2H), 7.47 (d, J=8.7 Hz, 2H), 7.63 (s, 1H).