Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH:11]([CH3:13])[CH3:12])=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.CCN(C(C)C)C(C)C.[NH2:31][CH2:32][C@H:33]([OH:35])[CH3:34]>CCCCO.CS(C)=O>[CH:11]([N:8]1[CH:7]=[N:6][C:5]2[C:9]1=[N:10][C:2]([NH:31][CH2:32][C@H:33]([OH:35])[CH3:34])=[N:3][C:4]=2[NH:14][CH2:15][C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1)([CH3:13])[CH3:12]
Reactant: CC(C)n1cnc2c(NCc3cccnc3)nc(F)nc21
Reactant: C[C@@H](O)CN
Solvent: CCCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(C)n1cnc2c(NCc3cccnc3)nc(NC[C@@H](C)O)nc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 10.6 %

Procedure:
To a stirred solution of 2-fluoro-9-isopropyl-6-[(pyridin-3-ylmethyl)-amino]purine (300 mg, 1.05 mmol) in n-BuOH/DMSO (5 ml, 4:1) at room temperature under an argon atmosphere was added DIEA (2 ml, 10 eq, 10.5 mmol) followed by (R)-1-aminopropan-2-ol (395 mg, 5.25 mmol). The flask was fitted with a condenser and the reaction mixture was placed in a preheated oil bath at 140° C. and stirred at this temperature for 72 h. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated in vacuo. The residue was partitioned between ethyl acetate (50 mL) and water (50 mL), the aqueous phase was extracted with more ethyl acetate (2×25 mL), and the combined organic phase was washed with brine (50 mL), dried (MgSO4) and evaporated in vacuo. The residue was purified by gradient flash column chromatography on silica gel eluted with CHCl3:MeOH (100:0→95:5), to afford the pure product as a colorless oil (38 mg, 10.6%). δH (250 MHz, CDCl3) 1.15 (3 H, d, J 7.5, CHCH3OH), 1.45 (6 H, d, J 7.5, CH[CH3]2), 3.3-3.2 (1 H, m, NHCHHCHMeOH)), 3.45-3.36 (1 H, m, NHCHHCHMeOH), 3.96-3.9 (1 H, m, CHMe2), 4.58-4.47 (1 H, m, CHMeOH), 4.69 (2 H, d, J 5, NHCH2Ar), 5.23 (1 H, t, J 5, NHCH2CHMeOH), 6.32 (1 H, s, br, NHCH2Ar), 7.16-7.11 (1 H, m, ArH), 7.4 (1 H, s, ArH), 7.6 (1 H, d, J 7.5, ArH), 8.4 (1 H.d, J 2.5, ArH), 8.55 (1 H, s, ArH); δC (250 MHz, CDCl3) 160.07 (C), 154.95 (C), 154.7 (C), 151.1 (C), 149.27 (CH), 148.54 (CH), 135.3 (CH), 134.73 (CH), 123.39 (CH), 114.61 (C), 68.83 (CH), 50.09 (CH2), 46.49 (CH), 41.95 (CH2), 22.49 (2×CH3), 20.85 (CH3); m/z 342.2 (M+H)
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38][CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[N:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:57])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:44]([CH2:45][CH2:46][CH3:47])[CH:43]=[N:42][N:41]=5)=[O:57])=[N:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:48]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nncn4CCC)nc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nncn4CCC)nc2)CCN3CC(C)C)cc1
Temperature: -78 °C
Reaction time: 2 h
Yield: 97.7 %

Procedure:
7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylthiopyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (0.70 g) was dissolved in dichloromethane (50 ml), and the mixture was cooled to −78° C. To the solution, a solution of 3-chloroperbenzoic acid (0.31 g) in dichloromethane (5 ml) was added dropwise. The mixture was stirred for 2 hours at −78° C. and sodium thiosulfate solution was added to the mixture. The mixture was concentrated, and extracted with ethyl acetate. The organic layer was washed with sodium bicarbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off. The residue was purified by silica gel column chromatography (elution solvent: triethylamine/methanol/ethyl acetate), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[2-(4-propyl-4H-1,2,4-triazol-3-yl)methylsulfinylpyridin-5-yl]-2,3-dihydro-1H-1-benzazepine-4-carboxamide (Compound 54) (0.70 g) as yellow crystals.
Reaction SMILES: Cl.[CH:2]1([C:5]2[C:13]3[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=3)[NH:7][N:6]=2)[CH2:4][CH2:3]1.N1C=CN=C1.[CH3:20][C:21]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])[CH3:22].O>CN(C=O)C>[Si:24]([O:14][C:10]1[CH:9]=[C:8]2[C:13]([C:5]([CH:2]3[CH2:4][CH2:3]3)=[N:6][NH:7]2)=[CH:12][CH:11]=1)([C:21]([CH3:23])([CH3:22])[CH3:20])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Oc1ccc2c(C3CC3)n[nH]c2c1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: Cl
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](Oc1ccc2c(C3CC3)n[nH]c2c1)(c1ccccc1)c1ccccc1
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3-Cyclopropylindazol-6-ol hydrochloride (5.18 g) which can be prepared according to the method described in Reference example 4, etc. and imidazole (4.21 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) were dissolved in dehydrated DMF (122 mL; manufactured by Kanto Chemical Co., Inc.). Then, TBDPSCl (15.67 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) was added and the mixture was stirred overnight at 20° C. To the reaction solution, imidazole (1.8 g; manufactured by Tokyo Chemical Industry, Co., Ltd.) and TBDPSCl (6.27 mL; manufactured by Tokyo Chemical Industry, Co., Ltd.) were added and the mixture was stirred for 2 hours at 20° C. To the reaction solution, water was added and extraction was carried out twice with ethyl acetate. The organic layer was washed twice with water and once with brine and dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography (“COLUMN-A”; n-hexane:ethyl acetate=95:5→74:26) to obtain the title compound (4.71 g).
Reaction SMILES: [C:1]([O:4][CH2:5][CH2:6]Br)(=[O:3])[CH3:2].[CH3:8][N:9]([CH3:17])[C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[C:1]([O:4][CH2:5][CH2:6][O:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([N:9]([CH3:17])[CH3:8])[CH:11]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OCCBr
Reactant: CN(C)c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCCOc1cccc(N(C)C)c1
Temperature: 80 °C

Procedure:
2-Bromoethyl acetate (1.34 g, 4.01 mmol) was added to a suspension of 3-(dimethylamino)phenol (0.50 g, 3.64 mmol) and K2CO3 (1.5 g, 10.8 mmol) in anhydrous DMF (3 mL). The reaction mixture was heated to 80° C. for 18 hours, cooled to rt, diluted with water, extracted with DCM. The organic phases were washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The crude material was purified by column chromatography on silica gel eluting with a gradient of PE:EtOAc 90:10-80:20, to provide the desired compound 2-(3-(dimethylamino)phenoxy)ethyl acetate (39A).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][OH:18])=[CH:13][C:12]=2[F:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[H-].[Na+].Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[CH2:31][CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>C1COCC1>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([CH2:17][O:18][C:23]3[CH:24]=[C:25]4[N:32]([CH3:33])[CH2:31][CH2:30][N:26]4[C:27](=[O:29])[N:28]=3)=[CH:13][C:12]=2[F:19])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1Cl
Reactant: CN1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(Cl)c3)c(F)c1)nc2=O

Procedure:
Prepared in a manner similar to that described for E1 using 2-chloro-4-(2-fluoro-4-(hydroxymethyl)phenoxy)benzonitrile (100 mg, 0.360 mmol) in THF (8 mL), sodium hydride (21.6 mg, 0.540 mmol) and 7-chloro-1-methyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one (66.8 mg, 0.360 mmol).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:11]2[S:10](=[O:13])(=[O:12])[N:9]=[C:8]([C:14]3[C:15](=[O:30])[N:16]([NH:25][CH2:26][CH:27]4[CH2:29][CH2:28]4)[C:17]4[C:22]([C:23]=3[OH:24])=[CH:21][CH:20]=[CH:19][CH:18]=4)[NH:7][C:6]=2[S:5][CH:4]=1.C(N(CC)CC)C.[CH:38]([S:41](Cl)(=[O:43])=[O:42])([CH3:40])[CH3:39]>CN(C)C=O>[CH:27]1([CH2:26][NH:25][N:16]2[C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:23]([OH:24])=[C:14]([C:8]3[NH:7][C:6]4[S:5][CH:4]=[C:3]([CH2:2][NH:1][S:41]([CH:38]([CH3:40])[CH3:39])(=[O:43])=[O:42])[C:11]=4[S:10](=[O:12])(=[O:13])[N:9]=3)[C:15]2=[O:30])[CH2:28][CH2:29]1
Reactant: CC(C)S(=O)(=O)Cl
Reactant: NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)S(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(c1c(O)c3ccccc3n(NCC3CC3)c1=O)N2
Temperature: 0 °C
Reaction time: 3 h
Yield: 33 %

Procedure:
To a solution of the product of Example 353E (16.2 mg, 0.036 mmol) in N,N-dimethylformamide (0.4 mL) was added triethylamine (0.011 mL, 0.079 mmol). The mixture was cooled to 0° C. and isopropyl sulfonyl chloride was added (0.0043 mL, 0.038 mmol). The mixture was warmed to 23° C. and stirred for 3 hours. Additional isopropyl sulfonyl chloride (0.006 mL, 0.055 mmol) was added and the reaction mixture was stirred at 23° C. for 15 hours. The reaction mixture was stirred at 50° C. for 2 hours. Additional triethylamine (0.040 mL, 0.287 mmol) and isopropyl sulfonyl chloride (0.010 mL, 0.091 mmol) were added and the reaction mixture was stirred at 50° C. for 2 hours. The reaction mixture was cooled to 25° C. and concentrated under reduced pressure. The residue was purified by reverse phase chromatography, eluting with a gradient of 10% acetonitrile/0.1% trifluoroacetic acid in water to 95% acetonitrile/0.1% trifluoracetic acid in water to give the title compound (6.7 mg, 33%). The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ 0.21 (bs, 2 H) 0.48 (d, 2 H) 0.98 (m, 1 H) 1.24 (d, J=6.99 Hz, 6 H) 3.19 (m, 1 H) 4.25 (s, 2 H) 5.85 (t, 1 H) 6.76 (s, 1 H) 6.92 (t, 1 H) 7.34 (m, 2 H) 7.57 (d, 1 H) 7.96 (d, 1 H).
Reaction SMILES: [C:1]([C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[C:4]([OH:6])=[O:5])#[N:2].C(Cl)(=O)C(Cl)=O.N1C=CC=CC=1.[C:29](O)([CH3:32])([CH3:31])[CH3:30]>C1C=CC=CC=1.CN(C=O)C.C(Cl)Cl>[C:1]([C:3]([C:9]1[CH:14]=[CH:13][C:12]([CH:15]=[CH2:16])=[CH:11][CH:10]=1)([CH2:7][CH3:8])[C:4]([O:6][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:5])#[N:2]
Reactant: CC(C)(C)O
Reactant: C=Cc1ccc(C(C#N)(CC)C(=O)O)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: C=Cc1ccc(C(C#N)(CC)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 4 h
Yield: 68.4 %

Procedure:
To an ice-cooled solution of 2-cyano-2(p-vinylphenyl)-butanoic acid (3 g, 0.014 mol) in benzene (100 mL) was added oxalyl chloride (5.3 g, 0.042 mol). The solution was cooled in an ice-bath and five drops of DMF was added to catalyze the acyl chloride formation. After being stirred at room-temperature for 4 h, all the solvent and excess oxalyl chloride was removed under reduced pressure. The crude acyl chloride was then taken up with small amount of benzene, filtered, concentrated, re-dissolved in CH2Cl2 (10 mL) and cooled in an ice-bath. To the solution, solutions of pyridine (3.2 g 0.042 mol) in CH2Cl2 and tert-butanol (5.2 g, 0.07 mol) in CH2Cl2 (5 mL) were added. After addition, the solution mixture was stirred at room-temperature for 6 h and quenched with diluted HCl (1%, 500-600 mL). The organic layer was separated, washed and saturated K2CO3 and NaCl solutions, dried over anhydrous Na2SO4, concentrated under reduced pressure and purified by liquid chromatography on silica gel with EtOAc-hexanes (1:9) as an eluent to provide an essentially pure product (2.6 g, 70%).
Reaction SMILES: Br[C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:5]([CH2:24][CH2:25][CH2:26][CH3:27])=[N:4][C:3]=1[CH3:28].[F:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:24]([C:5]1[N:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]#[N:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7](=[O:8])[C:2]([C:33]2[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=2)=[C:3]([CH3:28])[N:4]=1)[CH2:25][CH2:26][CH3:27]
Reactant: OB(O)c1ccc(F)cc1
Reactant: CCCCc1nc(C)c(Br)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCCCc1nc(C)c(-c2ccc(F)cc2)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 90 °C
Reaction time: 12 h
Yield: 96.6 %

Procedure:
To a solution of 4′-[(5-bromo-2-butyl-4-methyl-6-oxopyrimidin-1(6H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g) and 4-fluorophenylboronic acid (0.48 g) in 1,4-dioxane (20 mL) were added 2 M aqueous cesium carbonate solution (4 mL) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium (0.1 g), and the mixture was stirred at 90° C. for 12 hr under an argon atmosphere. The reaction mixture was diluted with ethyl acetate, and the insoluble material was filtered off through celite. The filtrate was washed successively with 1 M hydrochloric acid, saturated aqueous sodium hydrogen carbonate and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound (1.0 g, 97%) as a colorless solid.
Reaction SMILES: [CH:1](NC(C)C)(C)C.[Li]CCCC.[CH3:13][O:14][C:15](=[O:38])[CH2:16][C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)(=[O:28])=[O:27])[C:18]=1[CH3:37]>C1COCC1>[CH3:13][O:14][C:15](=[O:38])[CH:16]([C:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][CH:24]=2)[N:19]([S:26]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([Cl:36])[CH:30]=2)(=[O:27])=[O:28])[C:18]=1[CH3:37])[CH3:1]
Reactant: COC(=O)Cc1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)C(C)c1c(C)n(S(=O)(=O)c2ccc(Cl)c(Cl)c2)c2ncccc12
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a stirring solution of diisopropylamine (34 μL, 0.24 mmol) in THF (1 mL), at −78° C., is added a 2.5M solution of n-BuLi in hexanes (105 μL, 0.26 mmol). After 20 minutes, a solution of [1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (Method B; 100 mg, 0.24 mmol) and Mel (15.2 μL, 0.24 mmol) in THF (1 mL) is added. The reaction is continued for 30 minutes, then allowed to warm to room temperature. The reaction mixture is evaporated to dryness and purified by flash chromatography (4:1 iso-hexane/EtOAc elution), to afford 2-[1-(3,4-dichloro-benzenesulfonyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-propionic acid methyl ester; MH+=427.
Reaction SMILES: Br[C:2]1[C:15]2[C@:14]3([CH2:19][O:18][C:17]([NH2:20])=[N:16]3)[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([C:21]4[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=4)[CH:12]=3)[O:7][C:6]=2[CH:5]=[CH:4][C:3]=1[O:27][CH2:28][C:29]([CH3:32])([CH3:31])[CH3:30].[C:33]([Zn]C#N)#[N:34].CN(C=O)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>[NH2:20][C:17]1[O:18][CH2:19][C@@:14]2([N:16]=1)[C:15]1[C:2]([C:33]#[N:34])=[C:3]([O:27][CH2:28][C:29]([CH3:31])([CH3:30])[CH3:32])[CH:4]=[CH:5][C:6]=1[O:7][C:8]1[C:13]2=[CH:12][C:11]([C:21]2[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=2)=[CH:10][CH:9]=1
Reactant: N#C[Zn]C#N
Reactant: CC(C)(C)COc1ccc2c(c1Br)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)COc1ccc2c(c1C#N)[C@]1(COC(N)=N1)c1cc(-c3cccnc3)ccc1O2

Procedure:
A vial was charged with (S)—1′-bromo-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthen]-2-amine (68.1 mg, 0.138 mmol), dicyanozinc (81 mg, 0.689 mmol), tetrakis(triphenylphosphine)palladium(0) (31.8 mg, 0.028 mmol), and DMF (689 μL). The vial was sealed and placed in a 120° C. oil bath for 12 hours. The mixture was diluted with water and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated. The residue was chromatographed on a 25-g SNAP column, eluting with a 90:10:1 mix of DCM/MeOH/NH4OH in DCM. This gave ca. 40 mg of a white powder that was impure by HPLC. The solid was combined with 104487-6-2 in DMSO/MeOH and purified by reverse-phase HPLC (10-90% CH3CN/H2O with 0.1% TFA). The fractions containing product were combined in saturated aq. sodium bicarbonate solution with the aid of methanol and extracted with DCM (3×). The combined organic extracts were dried over sodium sulfate, filtered, and evaporated to give (S)-2-amino-2′-(neopentyloxy)-7′-(pyridin-3-yl)-5H-spiro[oxazole-4,9′-xanthene]-1′-carbonitrile as an off-white powder after evaporation from DCM/hexane.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=[O:8])=[C:4]([CH3:10])[CH:3]=1.[CH2:11](O)[CH3:12]>S(Cl)(Cl)=O>[CH2:11]([O:8][C:7]([C:5]1[S:6][C:2]([Br:1])=[CH:3][C:4]=1[CH3:10])=[O:9])[CH3:12]
Reactant: Cc1cc(Br)sc1C(=O)O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1sc(Br)cc1C
Temperature: 0 °C

Procedure:
5-Bromo-3-methyl-thiophene-2-carboxylic acid (example 1.b, 10.0 g, 45.2 mmol) was suspended in 40 mL of thionyl chloride. The mixture was heated at reflux temperature for 1 hour and then cooled to 0° C. with an external ice bath. Cold ethyl alcohol (150 mL) was carefully added, and the solution was heated at reflux temperature for 16 hours. Under reduced pressure, the solution was concentrated to ca. one third of the original volume and then diluted with ethyl acetate and washed successively twice with saturated sodium bicarbonate solution, and once with brine. The organic fractions were dried over anhydrous sodium sulfate and concentrated to 7.9 g of a yellow oil: 1H NMR (CDCl3, 200 MHz): δ=6.87 (s, 1H), 4.34-4.23 (q, 1H, J=7.0 Hz), 2.50 (s, 3H), 1.39-1.32 (t, 3H, J=7.0 Hz).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1.[CH3:19][C:20]([CH3:24])([C:22]#[CH:23])[OH:21]>>[OH:21][C:20]([CH3:24])([CH3:19])[C:22]#[C:23][C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[CH:12]=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:18]=1
Reactant: C#CC(C)(C)O
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)ccc1OCC2
Product: CC(C)(O)C#Cc1ccc2c(c1)-c1nc(C(N)=O)cn1CCO2

Procedure:
10-Bromo-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide (0.1 g) was reacted with dimethyl ethynyl carbinol similar to as described in Procedure E to afford 52.2 mg of 10-(3-hydroxy-3-methyl-but-1-ynyl)-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide following reverse phase hplc purification. MS (Q1) 338 (M)+. 1H NMR (400 MHz, DMSO) δ 8.50 (d, J=2.1 Hz, 1H), 7.79 (s, 1H), 7.51 (s, 1H), 7.29 (dd, J=8.5, 2.2 Hz, 1H), 7.11 (s, 1H), 7.01 (d, J=8.5 Hz, 1H), 5.42 (s, 1H), 4.48 (s, 4H), 1.48 (s, 7H).
Reaction SMILES: [CH:1]1([CH2:4][C:5]2([C:11]([O:13][CH2:14][CH3:15])=[O:12])SCCCS2)[CH2:3][CH2:2]1.BrN1C(=[O:22])CCC1=O.C(Cl)Cl.CCCCCC.S([O-])([O-])=O.[Na+].[Na+]>CC(C)=O.O>[CH:1]1([CH2:4][C:5](=[O:22])[C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:3][CH2:2]1
Reactant: CCOC(=O)C1(CC2CC2)SCCCS1
Reactant: O=C1CCC(=O)N1Br
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CC(C)=O
Product: CCOC(=O)C(=O)CC1CC1
Reaction time: 1 h
Yield: 93.4 %

Procedure:
A solution of ethyl 2-(cyclopropylmethyl)-1,3-dithiane-2-carboxylate (20.8 g, 0.084 mol) in acetone/water (97/3, v/v; 80 mL) was added drop wise over 30 minutes to a stirred suspension of N-bromosuccinimide in acetone/water (97/3, v/v, 1220 mL) at −5° C. The reaction mixture was stirred at the same temperature for 1 hour, while the progress of the reaction was monitored by thin layer chromatography, and then a mixture of methylene chloride/hexane (1/1, v/v, 500 mL) and aqueous sodium sulphite was added. The mixture was stirred until the colour faded from the organic layer. The phases were separated and the aqueous phase was extracted with methylene chloride/hexane (3×300 mL). The combined extracts were washed with aqueous sodium sulfite, water, aqueous sodium bicarbonate, brine and dried over magnesium sulfate. The solvent was removed under reduced pressure to afford ethyl 3-cyclopropyl-2-oxopropanoate (12.3 g, 93.4%), as a light yellow oil. 1H-NMR (400 MHz, CDCl3): δ=0.13-0.21 (m, 2H), 0.54-0.65 (m, 2H), 0.97-1.10 (m, 1H), 1.38 (t, J=8 Hz, 3H), 2.72 (d, J=8 Hz, 2H), 4.33 (q, J=8 Hz, 2H).
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([NH:16][C:17]3[CH:22]=[C:21]([O:23][C:24]4[CH:29]=[CH:28][C:27]([N+:30]([O-])=O)=[CH:26][CH:25]=4)[CH:20]=[CH:19][N:18]=3)=[O:15])[CH2:10][CH2:9]2)[CH2:4][CH2:3]1>O1CCCC1.[OH-].[Pd+2].[OH-].[C]>[NH2:30][C:27]1[CH:26]=[CH:25][C:24]([O:23][C:21]2[CH:20]=[CH:19][N:18]=[C:17]([NH:16][C:14]([N:11]3[CH2:12][CH2:13][CH:8]([N:5]4[CH2:4][CH2:3][CH:2]([OH:1])[CH2:7][CH2:6]4)[CH2:9][CH2:10]3)=[O:15])[CH:22]=2)=[CH:29][CH:28]=1
Reactant: O=C(Nc1cc(Oc2ccc([N+](=O)[O-])cc2)ccn1)N1CCC(N2CCC(O)CC2)CC1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ccnc(NC(=O)N3CCC(N4CCC(O)CC4)CC3)c2)cc1
Reaction time: 8 h
Yield: 94.5 %

Procedure:
2-{[4-(4-Hydroxypiperidin-1-yl)piperidin-1-yl]carbonylamino}-4-(4-nitrophenoxy)pyridine (243 mg) was dissolved in tetrahydrofuran (25 ml). After then adding 20% palladium hydroxide-carbon (140 mg), the mixture was stirred overnight under a hydrogen atmosphere. The catalyst was filtered and washed with tetrahydrofuran. The filtrate and the washings were then combined and concentrated under reduced pressure, and the resultant residue was dried under reduced pressure to provide the title compound (214 mg) as pale yellow powder.