Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([SH:20])=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.CS(O[CH2:33][C:34]1[CH:39]=[CH:38][C:37]([C:40]([C:42]2[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=2)=[O:41])=[CH:36][CH:35]=1)(=O)=O>CS(C)=O.CCCCCC.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20][CH2:33][C:34]3[CH:35]=[CH:36][C:37]([C:40]([C:42]4[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=4)=[O:41])=[CH:38][CH:39]=3)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(S)c2CC1
Reactant: CS(=O)(=O)OCc1ccc(C(=O)c2cccnc2)cc1
Solvent: CCCCCC
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCc2ccc(Cl)c(SCc3ccc(C(=O)c4cccnc4)cc3)c2CC1
Temperature: 40 °C
Yield: 62 %

Procedure:
Dissolve 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine (150 mg, 0.39 mmol) in methanol (10 mL) and add potassium hydroxide (0.7 g, 12.47 mmol). Heat at 60° C. for 4 h. Cool the reaction mixture to ambient temperature, add aqueous saturated ammonium chloride and concentrate in vacuo. Partition the residue between EtOAc and water. Dry the organic phase over anhydrous Na2SO4 and concentrate in vacuo to give 3-tert-butoxycarbonyl-7-chloro-6-mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.12 g). Dissolve the crude 3-tert-butoxycarbonyl-7-chloro-6mercapto-2,3,4,5-tetrahydro-1H-benzo[d]azepine (0.12 g, 5.2 mmol) in anhydrous DMSO (6 mL) and add triethylamine (0.325 mL, 2.34 mmol) and 4-(pyridine-3-carbonyl)-benzyl methanesulfonate (114 mg, 0.39 mmol). Heat the solution at 40° C. overnight. Cool to ambient temperature, dilute the mixture with hexane/EtOAc (1:1, 100 mL), and wash the organic solution sequentially with brine and ice-cold water. Dry the organic layer over anhydrous Na2SO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane and hexane/EtOAc (1:1) to give 3-tert-butoxycarbonyl-7-chloro-6-[4-(pyridine-3-carbonyl)-benzylthio]-2,3,4,5-tetrahydro-1H-benzo[d]azepine as oil (123 mg, 64%).
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:14][CH:13]=[CH:12][C:11]2=[O:15])=[CH:6][CH:5]=1.[O:16]=[C:17]([NH:32][C@@H:33]1[CH2:37][CH2:36][NH:35][CH2:34]1)[CH2:18][NH:19][C:20](=[O:31])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=1.[NH4+].[OH-]>CCOC(C)=O.CO>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[C:11](=[O:15])[CH2:12][CH:13]([N:35]3[CH2:36][CH2:37][C@@H:33]([NH:32][C:17](=[O:16])[CH2:18][NH:19][C:20](=[O:31])[C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:30])[F:29])[CH:22]=4)[CH2:34]3)[CH2:14]2)=[CH:8][CH:9]=1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Reactant: COc1ccc(N2CC=CC2=O)cc1
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc(N2CC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2=O)cc1
Yield: 21.5 %

Procedure:
A slurry of water (20 μL, 0.10 mmol), 1-(4-methoxyphenyl)-1,5-dihydro-2H-pyrrol-2-one (200 mg, 1.06 mmol) and N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (666 mg, 2.12 mmol) was heated to 90° C. overnight. The crude mixture was subjected to flash chromatography (1% NH4OH, 15% MeOH, EtOAc) to afford, as a mixture of diastereomers, N-(2-{[(3R)-1′-(4-methoxyphenyl)-5′-oxo-1,3′-bipyrrolidin-3-yl]amino}-2-oxoethyl)-3-(trifluoromethyl)benzamide as a white solid (115 mg, 21%). 1H-NMR (CDCl3) δ: 1.50-1.82 (m, 1H), 1.83-2.00 (m, 1H), 2.18-2.40 (m, 1H), 2.40-2.58 (m, 1H), 2.56-2.81 (m, 3H), 2.83-3.00 (m, 2H), 3.29-3.33 (m, 2H), 3.60-3.71 (m, 2H), 3.79 (s, 3H), 4.04-4.20 (m, 2H), 4.38-4.47 (m, 1H), 6.94 (m, 2H), 7.19-7.30 (m, 2H), 7.69-7.80 (m, 2H), 7.99 (d, J=7.8 Hz, 1H), 8.18 (s, 1H). MS m/z: 505 (M+1).
Reaction SMILES: [CH:1]([NH:4][CH:5]([CH3:7])[CH3:6])([CH3:3])[CH3:2].CN(C)CCN.[C:14]([C:16]1[CH:39]=[CH:38][C:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:18][CH:17]=1)#[N:15].O>ClCCl>[C:14]([C:16]1[CH:17]=[CH:18][C:19]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][O:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([N:4]([CH:5]([CH3:7])[CH3:6])[CH:1]([CH3:3])[CH3:2])=[O:32])=[CH:29][C:28]=2[O:36][CH3:37])=[CH:38][CH:39]=1)#[N:15]
Reactant: CC(C)NC(C)C
Reactant: COc1cc(C(=O)O)ccc1OCCCCCOc1ccc(C#N)cc1
Agent: CN(C)CCN
Solvent: ClCCl
Solvent: O
Product: COc1cc(C(=O)N(C(C)C)C(C)C)ccc1OCCCCCOc1ccc(C#N)cc1
Temperature: 5 °C
Reaction time: 3 h

Procedure:
4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoic acid (3600 g, 10.13 mol) is suspended in dichloromethane (36 L) and to this is added thionyl chloride (1345 g, 11.30 mol) dropwise over 20 minutes followed by dimethylformamide (74.4 g, 10.0 mmol). The reaction mixture is stirred at room temperature for 21 hours; after 6 hours a complete solution is obtained. The solution is concentrated in vacuo (50° C, 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxybenzoyl chloride as a solid, which is then redissolved in dichloromethane (36 L) without further purification and cooled to 5° C. with an ice bath. Diisopropylamine (3077 g, 30.40 mmol) is added dropwise over a period of 1 hour. The reaction mixture is stirred at 20° C. for 3 hours and then, N,N-dimethylethylenediamine (80.3 g, 0.91 mmol) is added. The reaction is followed by TLC (2:1 ethyl acetate/hexanes, silica plates) until no more byproduct (bis-anhydride of 4-[5-(4-cyanophenoxy)pentoxy]3-methoxybenzoic acid) is detected. The reaction mixture is then stirred overnight at room temperature. Water (18 L) is added,stirred and the layers separated. The organic layer is washed with hydrochloric acid (1.0 N, 23 L), water (18 L), ammonium hydroxide (0.5 N, 2×23 L), water (18 L) and brine solution (18 L). The separated dichloromethane solution is dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo (50° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide as a solid. The solid is dissolved in 2 B ethanol (21.5 L) by warming and to the solution is added water (8.6 L). The product is allowed to crystallize overnight in an ice bath. The product is filtered, washed with EtOH/H2O (5:2, 2×2 L) and dried in vacuo (54° C., 3 mm Hg) to give 4-[5-(4-cyanophenoxy)pentoxy]-3-methoxy-N,N-bis(1-methylethyl)- benzamide, mp 90°-92° C. HPLC indicates a purity of >99.7%.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[N:10]=[C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([S:18]([CH3:21])(=[O:20])=[O:19])[CH2:14][CH2:13]3)[S:8][C:6]=2[N:7]=1.CC1(C)C(C)(C)OB([C:36]2[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=2)O1>>[CH3:21][S:18]([N:15]1[CH2:16][CH2:17][N:12]([CH2:11][C:9]2[S:8][C:6]3[N:7]=[C:2]([C:36]4[CH:37]=[CH:38][C:39]([NH2:42])=[N:40][CH:41]=4)[N:3]=[C:4]([N:22]4[CH2:27][CH2:26][O:25][CH2:24][CH2:23]4)[C:5]=3[N:10]=2)[CH2:13][CH2:14]1)(=[O:20])=[O:19]
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Reactant: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(Cl)nc3s2)CC1
Product: CS(=O)(=O)N1CCN(Cc2nc3c(N4CCOCC4)nc(-c4ccc(N)nc4)nc3s2)CC1
Yield: 26.8 %

Procedure:
5-Chloro-2-(4-methanesulfonyl-piperazin-1-ylmethyl)-7-morpholin-4-yl-thiazolo[5,4-d]pyrimidine (80 mg) was reacted with 49 mg of 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-2-ylamine via General Procedure A. The product was purified by reverse phase HPLC to yield 24.3 mg of 111. MS (Q1) 491.0 (M)+.
Reaction SMILES: [C:1](Cl)(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[NH2:8][C:9]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]([Br:19])=[CH:11][N:10]=1.C(N(CC)CC)C.O>ClCCl>[Br:19][C:12]1[C:13]([C:15]([F:18])([F:16])[F:17])=[CH:14][C:9]([NH:8][C:1](=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3])=[N:10][CH:11]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(C(F)(F)F)c(Br)cn1
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)Nc1cc(C(F)(F)F)c(Br)cn1
Reaction time: 2 h
Yield: 85.7 %

Procedure:
In an ice bath, 29.8 g of pivaloyl chloride (226 mmol) was added dropwise to a solution of compound 5 (50.0 g, 207 mmol) and triethylamine (37.9 mL) in dichloromethane (300.0 mL) within one hour and then stirred for 2 hours until the starting materials disappeared. 150 mL of water was added into the reaction solution and stirred at room temperature for 10 minutes. The organic layer was separated, dried over anhydrous sodium sulfate, concentrated, and separated through a short column with ethyl acetate to give white solid (57.7 g, 85.6%).
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:20]=3)[S:18][C:14]=2[C:13]=1OS(C(F)(F)F)(=O)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:3])[CH3:2].[Cl:46][C:47]1[CH:52]=[CH:51][C:50](B(O)O)=[CH:49][CH:48]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]4[CH:26]=[C:27]5[C:31](=[CH:32][CH:33]=4)[N:30]([CH3:34])[N:29]=[CH:28]5)[N:20]=3)[S:18][C:14]=2[C:13]=1[C:50]1[CH:51]=[CH:52][C:47]([Cl:46])=[CH:48][CH:49]=1)[C:7]([O:9][CH2:10][CH3:11])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: OB(O)c1ccc(Cl)cc1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1OS(=O)(=O)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3cccc(-c4ccc5c(cnn5C)c4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 120 °C

Procedure:
In a 10 mL reaction vial, (S)-ethyl 2-tert-butoxy-2-(5-methyl-2-(6-(1-methyl-1H-indazol-5-yl)pyridin-2-yl)-7-(trifluoromethylsulfonyloxy)benzo[d]thiazol-6-yl)acetate (33 mg, 0.050 mmol) and p-chlorophenyl boronic acid (48 mg, 0.20 mmol) were dissolved in dioxane (2.5 mL) under argon atmosphere. The solution was bubbled with argon for 5 min. Then potassium carbonate (45 mg, 0.32 mmol) and Pd(PPh3)4 (10 mg, 0.0075 mmol) were added sequentially. The reaction mixture was sealed and heated in oil bath at 120° C. for 4.5 h. Reaction was then diluted with EtOAc (10 mL) and filtered to remove solid. The filtrate was concentrated and purified on silica gel column with 0-40% EtOAc/Hex to afford product. LCMS-ESI+: calc'd for: C35H33ClN4O3S: 625.2, 626.2, 627.2 (M+H+); found: 625.1, 626.2, 627.1 (M+H+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][C:17]=2F)=O)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:27]([O:31][CH3:32])(=[O:30])[CH2:28][SH:29].CN(C=O)C.C([O-])([O-])=O.[K+].[K+]>C(OCC)(=O)C>[CH3:32][O:31][C:27]([C:28]1[S:29][C:17]2[CH:18]=[C:19]([C:22]([F:25])([F:24])[F:23])[CH:20]=[CH:21][C:16]=2[C:14]=1[CH:11]1[CH2:12][CH2:13][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9][CH2:10]1)=[O:30]
Reactant: O=C(c1ccc(C(F)(F)F)cc1F)C1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)CS
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1sc2cc(C(F)(F)F)ccc2c1C1CCN(Cc2ccccc2)CC1
Temperature: 60 °C
Reaction time: 24 h

Procedure:
To a room temperature solution of (1-benzyl-piperidin-4-yl)-(2-fluoro-4-trifluoromethyl-phenyl)-methanone (7.5 g, 20.5 mmol), methyl thioglycolate (2.0 mL, 22.5 mmol), and DMF (100 mL) was added K2CO3 (5.65 g, 41.0 mmol). The reaction was stirred at 60° C. for 24 hours, cooled to room temperature and diluted with ethyl acetate (500 mL). The mixture was washed with water (2×300 mL) and brine (300 mL) successively, dried over magnesium sulfate, filtered, and the solvent removed to afford an oil. The oil was purified via chromatography (30% EtOAc in heptane) yielding 5.91 g (67%) as a solid.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:17][CH:16]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[NH:20][CH:19]=3)[CH2:14][CH2:13]2)=[CH:2]1.[CH3:27]CCCCC.CI>C1COCC1>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([CH2:10][CH2:11][N:12]2[CH2:13][CH:14]=[C:15]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH2:16][CH2:17]2)=[CH:2]1
Reactant: C1=C(c2c[nH]c3ccccc23)CCN(CCc2csc3ccccc23)C1
Reactant: CCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: Cn1cc(C2=CCN(CCc3csc4ccccc34)CC2)c2ccccc21
Reaction time: 0.5 h

Procedure:
3-{1-[2-(1-benzothiophene-3-yl)ethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole (358 mg, 1 mmol) (obtained from example 29, step 2) in dry THF (50 ml) was slowly added to a stirred suspension of hexane and washed with 60% sodium hydride (44 mg) at 0° C. After the addition, the reaction mixture was stirred for 30 min and methyl iodide (213 mg, 1.5 mmol) was added. The reaction mixture was stirred for 4 hrs and quenched carefully with ice cold water. The reaction mixture was extracted with chloroform; washed well with water; dried over anhydrous MgSO4; filtered and concentrated. The residue obtained was purified by silica-gel column chromatography by eluting it with 50% ethyl acetate:hexane. Light green semi-solid. Yield: 98 mg (26%); 373 (M+H); 1HNMR (400 MHz, CDCl3): 8.08˜7.82 (m, 3H); 7.40˜6.90 (m, 7H); 6.21˜6.19 (s, 1H); 3.80 (s, 3H); 3.48˜2.60 (m, 10H).
Reaction SMILES: I.CS[C:4](=[N:18][CH3:19])[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.[CH3:20][NH2:21]>C(O)C>[CH3:19][NH:18][C:4]([NH:21][CH3:20])=[N:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: CN=C(Nc1ccccc1N1CCOCC1)SC
Reactant: CN
Agent: I
Solvent: CCO
Product: CNC(=Nc1ccccc1N1CCOCC1)NC

Procedure:
A mixture of 2-methyl-1-(2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (3.9 g) and 33% methylamine in solution in absolute ethanol (40 ml) was heated for 28 hours at 50°-55° C. to yield 1,3-dimethyl-2-(2-morpholinophenyl)guanidine which was recrystallised from hexane (m.p. 137°-138° C.).
Reaction SMILES: Br[C:2]([CH3:7])([CH3:6])[C:3]([NH2:5])=[O:4].[CH3:8][N:9]1[C:17]([CH2:18][CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[N:16][C:15]2[C:10]1=[N:11][C:12]([N:31]1[C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=3[N:33]=[C:32]1[CH3:40])=[N:13][C:14]=2[N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1>>[CH3:6][C:2]([N:22]1[CH2:21][CH2:20][CH:19]([CH2:18][C:17]2[N:9]([CH3:8])[C:10]3[C:15]([N:16]=2)=[C:14]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[N:13]=[C:12]([N:31]2[C:35]4[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=4[N:33]=[C:32]2[CH3:40])[N:11]=3)[CH2:24][CH2:23]1)([CH3:7])[C:3]([NH2:5])=[O:4]
Reactant: CC(C)(Br)C(N)=O
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCNCC3)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CC3CCN(C(C)(C)C(N)=O)CC3)n(C)c2n1

Procedure:
Following General Procedure C, 2-bromo-2-methyl-propionamide and 4-(9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-8-(piperidin-4-ylmethyl)-9H-purin-6-yl)morpholine were reacted to give 508. LCMS m/z: 532.2 (MH+)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@H:8]1[CH2:17][CH2:16][CH2:15][C@@H:14]2[N:9]1[C:10](=[O:19])[CH:11](I)[CH2:12][CH2:13]2.[P:20]([O:27]CC)([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23]>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C@@H:8]1[CH2:17][CH2:16][CH2:15][C@H:14]2[N:9]1[C:10](=[O:19])[CH:11]([P:20](=[O:27])([O:24][CH2:25][CH3:26])[O:21][CH2:22][CH3:23])[CH2:12][CH2:13]2
Reactant: O=C1C(I)CC[C@@H]2CCC[C@H](c3ccccc3F)N12
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(OCC)C1CC[C@H]2CCC[C@@H](c3ccccc3F)N2C1=O
Temperature: 120 °C
Reaction time: 5 h

Procedure:
A mixture of (6R*,9aS*)-6-(2-fluorophenyl)-3-iodooctahydroquinolizin-4-one (500 mg) with triethyl phosphite (6 mL) was stirred at 120° C. for five hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure to obtain 501 mg of the title compound. The property value of the compound is as follows.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:16]=[CH:15][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=3[O:31]C)=[O:19])=[CH:13][CH:12]=2)[NH:4][N:3]=1.B(Br)(Br)Br.O>ClCCl>[NH2:1][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][C:9]=2[C:11]2[CH:12]=[CH:13][C:14]([NH:17][C:18]([NH:20][C:21]3[CH:26]=[C:25]([C:27]([F:30])([F:28])[F:29])[CH:24]=[CH:23][C:22]=3[OH:31])=[O:19])=[CH:15][CH:16]=2)[NH:4][N:3]=1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(-c2ccnc3[nH]nc(N)c23)cc1
Agent: BrB(Br)Br
Solvent: O
Solvent: ClCCl
Product: Nc1n[nH]c2nccc(-c3ccc(NC(=O)Nc4cc(C(F)(F)F)ccc4O)cc3)c12
Reaction time: 0.5 h

Procedure:
To a solution of 1-[4-(3-amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-methoxy-5-trifluoromethylphenyl)urea, described in Example 5, in 6 mL of dichloromethane at −40° C. are added dropwise 1.6 mL of 1M boron tribromide solution, and the temperature is allowed to return to 20° C. After 30 minutes, the reaction is cooled on an ice bath and water is then added. After stirring for 15 minutes, the mixture is filtered off and the insoluble orange material is washed with water and with dichloromethane. The solid is purified on a prepacked Biotage KP-Sil column of 60 Å SiO2 32-63 μm (eluent: 95/5 then 90/10 then 80/20 then 70/30 dichloromethane/solution A; solution A=38/17/2 dichloromethane/methanol/aqueous ammonia). 29 mg of a yellow powder of 1-[4-(3-Amino-1H-pyrazolo[3,4-b]pyrid-4-yl)phenyl]-3-(2-hydroxy-5-trifluoromethylphenyl)urea are obtained, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][N:6]=[CH:5]2.[CH2:11](Br)[CH:12]=[CH2:13].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:13]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([Br:1])=[CH:10][CH:9]=2)[CH:5]=[N:6]1)[CH:12]=[CH2:11]
Reactant: C=CCBr
Reactant: Brc1ccc2[nH]ncc2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCn1ncc2cc(Br)ccc21
Yield: 35.9 %

Procedure:
5-Bromoindazole (Bioorg. Med. Chem. Lett., 11:1153-1156 (2001)) (3.94 g, 20.0 mmol), allyl bromide (2.6 mL, 30 mmol) and potassium carbonate (4.15 g, 30.0 mmol) were heated in DMF (25 mL) at 100° C. for 18 hours. The reaction was cooled, filtered through celite, and the solids were washed with EtOAc. The solution was concentrated to near dryness and then partitioned between EtOAc and water. The organic phase was washed with NaHCO3, dried (MgSO4), concentrated, and purified by column chromatography (silica gel, 7% EtOAc/hexanes) to provide the N1 isomer (faster eluting) 1-allyl-5-bromo-1H-indazole (is) (1.7 g, 36% yield). 1H NMR (400 MHz, CDCl3) δ 7.95 (s, 1H), 7.88 (d, J=2.3 Hz, 1H), 7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.29 (d, J=8.6 Hz, 1H), 6.06-5.97 (m, 1H), 5.24 (dd, J=10.2, 1.6 Hz, 1H), 5.12 (d, J=16.4 Hz, 1H), 5.01-5.00 (m, 2H); MS (ESI+) m/z 237, 239 (M+H, Br pattern) detected; HPLC (5 to 95%) 2.98 min.
Reaction SMILES: [CH3:1][C:2]1[C:38]([CH3:39])=[CH:37][CH:36]=[CH:35][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([N:10]1[C:19]2[C:14](=[C:15]([C:20]3[CH:21]=[C:22]([CH:32]=[CH:33][CH:34]=3)[CH2:23][NH:24]C(=O)OC(C)(C)C)[CH:16]=[CH:17][CH:18]=2)[CH2:13][CH2:12][CH2:11]1)=[O:9].C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][CH2:23][C:22]1[CH:21]=[C:20]([C:15]2[CH:16]=[CH:17][CH:18]=[C:19]3[C:14]=2[CH2:13][CH2:12][CH2:11][N:10]3[C:8](=[O:9])[CH2:7][CH2:6][CH2:5][O:4][C:3]2[CH:35]=[CH:36][CH:37]=[C:38]([CH3:39])[C:2]=2[CH3:1])[CH:34]=[CH:33][CH:32]=1
Reactant: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CNC(=O)OC(C)(C)C)c4)cccc32)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cccc(OCCCC(=O)N2CCCc3c(-c4cccc(CN)c4)cccc32)c1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.1 %

Procedure:
To a solution of tert-butyl 3-(1-(4-(2,3-dimethylphenoxy)butanoyl)-1,2,3,4-tetrahydroquinolin-5-yl)benzylcarbamate (0.12 g, 0.227 mmol) in DCM (2.5 mL) at 0° C. was added TFA (0.35 mL, 4.54 mmol) dropwise. The reaction mixture was slowly warmed to room temperature and stirred for 16 h. After this time, the reaction mixture was quenched with 50% saturated NaHCO3, and the aqueous phase was extracted with DCM. The combined organic layer was dried over anhydrous MgSO4, filtered, and concentrated in vacuo to afford the title compound (0.075 g, 77% yield). LCMS, [M+H]+=429.2.
Reaction SMILES: [OH:1][C@@H:2]([CH2:11][CH3:12])[C@@H:3]([CH3:10])[C:4]([N:6]([O:8][CH3:9])[CH3:7])=[O:5].N1C(C)=CC=CC=1C.[CH2:21]([Si:23](OS(C(F)(F)F)(=O)=O)([CH2:26][CH3:27])[CH2:24][CH3:25])[CH3:22]>ClCCl>[CH3:9][O:8][N:6]([CH3:7])[C:4](=[O:5])[C@H:3]([CH3:10])[C@@H:2]([O:1][Si:23]([CH2:26][CH3:27])([CH2:24][CH3:25])[CH2:21][CH3:22])[CH2:11][CH3:12]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: CC[C@H](O)[C@@H](C)C(=O)N(C)OC
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Product: CC[C@H](O[Si](CC)(CC)CC)[C@@H](C)C(=O)N(C)OC
Reaction time: 5 h
Yield: 99 %

Procedure:
The above (2R,3S)-3-hydroxy-N-methoxy-N,2-dimethylpentanamide (7.3 g, 41.7 mmol) was dissolved in dichloromethane (150 ml), followed by addition of 2,6-lutidine (10.2 ml, 87 mmol) and trifluoromethanesulfonic acid triethylsilyl ester (14.1 ml, 62 mmol) while ice cooling, and the reaction solution was stirred for five hours. The reaction solution was diluted with dichloromethane and washed with a saturated ammonium chloride aqueous solution and brine. After the organic layer was dried over anhydrous sodium sulfate and the drying agent was filtered off, the organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Merck, commercial name Silica Gel 60, 230-400 mesh; hexane:ethyl acetate=10:1) to obtain the title compound (11.95 g) as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH3:11])[C:5]=2[S:4][CH:3]=1.C1C(=O)N([Br:20])C(=O)C1.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[C:6]2[C:7]([Cl:12])=[N:8][CH:9]=[C:10]([CH2:11][Br:20])[C:5]=2[S:4][CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cnc(Cl)c2c(Br)csc12
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1ncc(CBr)c2scc(Br)c12
Temperature: 25 °C

Procedure:
A solution of Example 277C (1 g, 3.81 mmol) in CCl4 (30 mL) was treated with NBS (0.755 g, 4.24 mmol) and benzoyl peroxide (0.093 g, 0.38 mmol), heated to reflux for 24 hours, cooled to room temperature, and filtered. The filtrate was concentrated to provide 3-bromo-7-(bromomethyl)-4-chlorothieno[3,2-c]pyridine, which was used directly. MS (ESI(+)) m/e 339.5, 341.6, 343.4 (M+H)+. The crude product was dissolved in DMF (7.5 mL), treated with sodium acetate (1.6 g, 19.5 mmol), heated to 100° C. overnight, and partitioned between water and ethyl acetate. The organic extract was washed with brine, dried (NaSO4), filtered, and concentrated. The residue was purified by silica gel chromatography with 10% ethyl acetate/hexanes to provide 0.65 g (53% yield) of the desired product. MS (ESI(+)) m/e 319.7, 321.7, 323.7 (M+H)+.