Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=1)([CH3:4])([CH3:3])[CH3:2].[C:19]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:24]=[CH:23][CH:22]=[C:21]([C:25](Cl)=[O:26])[CH:20]=1.C(N(CC)CC)C.O>C(#N)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:18])[NH:7][C@@H:8]1[CH2:10][C@H:9]1[C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:25]([C:21]2[CH:20]=[C:19]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH:24]=[CH:23][CH:22]=2)=[O:26])=[CH:13][CH:12]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1cccc(-c2ccccc2)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(N)cc1
Solvent: O
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N[C@@H]1C[C@H]1c1ccc(NC(=O)c2cccc(-c3ccccc3)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.2 %

Procedure:
To a solution of tert-butyl[trans-2-(4-aminophenyl)cyclopropyl]carbamate (100 mg) described in a document (J. Am. Chem. Soc., 2010, 132, 6827.) in acetonitrile (4 mL) were added biphenyl-3-carbonyl chloride (131 mg) and triethylamine (61.1 mg). The mixture was stirred at room temperature overnight and water was added. To the reaction mixture was added ethyl acetate, and the resulting solid was collected by filtration to give the title compound (154 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:50]=[CH:49][C:6]([CH2:7][N:8]([C:44]2[S:45][CH:46]=[CH:47][N:48]=2)[S:9]([C:12]2[CH:13]=[CH:14][C:15]3[N:20]([C:21]4[CH:26]=[CH:25][C:24]([N+:27]([O-])=O)=[CH:23][C:22]=4[C:30]4[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH:31]=4)[CH2:19][CH2:18][O:17][C:16]=3[CH:43]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.[Sn](Cl)Cl>CO>[NH2:27][C:24]1[CH:25]=[CH:26][C:21]([N:20]2[CH2:19][CH2:18][O:17][C:16]3[CH:43]=[C:12]([S:9](=[O:10])(=[O:11])[N:8]([CH2:7][C:6]4[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:50][CH:49]=4)[C:44]4[S:45][CH:46]=[CH:47][N:48]=4)[CH:13]=[CH:14][C:15]2=3)=[C:22]([C:30]2[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:41])([CH3:42])[CH3:40])=[O:37])[CH2:32][CH:31]=2)[CH:23]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc([N+](=O)[O-])cc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Agent: Cl[Sn]Cl
Solvent: CO
Product: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(c2)OCCN3c2ccc(N)cc2C2=CCN(C(=O)OC(C)(C)C)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-(2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)-5-nitrophenyl)-5,6-dihydropyridine-1(2H)-carboxylate (0.159 g, 0.221 mmol) in methanol (1.104 mL) was added tin(II) chloride (0.168 g, 0.884 mmol) and the reaction was stirred at RT for 1 h. The reaction was then heated to 60° C. for 1.5 h. The reaction mixture was concentrated under a vacuum. The residue was taken up in EtOAc, and washed with 1N NaOH (to a pH that is basic) and the layers were separated. The organic layer was washed with brine and dried over magnesium sulfate, filtered, and concentrated under a vacuum. The material was dissolved in methanol and purified via 2 g SCX column to provide tert-butyl 4-(5-amino-2-(7-(N-(4-methoxybenzyl)-N-(thiazol-2-yl)sulfamoyl)-2H-benzo[b][1,4]oxazin-4(3H)-yl)phenyl)-5,6-dihydropyridine-1(2H)-carboxylate, which was taken forward without further purification. m/z (ESI) 690.2 (M+H)+.
Reaction SMILES: C(OC([N:8]1[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]([C:18]([C:20]3[C:25]([N:26]([S:30]([C:33]4[CH:38]=[CH:37][C:36]([Cl:39])=[C:35]([C:40]([F:43])([F:42])[F:41])[CH:34]=4)(=[O:32])=[O:31])COC)=[CH:24][C:23]([Cl:44])=[CH:22][N:21]=3)=[O:19])[C:12]=2[O:11][CH2:10][CH2:9]1)=O)(C)(C)C>Cl.O>[Cl:39][C:36]1[CH:37]=[CH:38][C:33]([S:30]([NH:26][C:25]2[C:20]([C:18]([C:17]3[C:12]4[O:11][CH2:10][CH2:9][NH:8][C:13]=4[CH:14]=[CH:15][CH:16]=3)=[O:19])=[N:21][CH:22]=[C:23]([Cl:44])[CH:24]=2)(=[O:31])=[O:32])=[CH:34][C:35]=1[C:40]([F:42])([F:43])[F:41]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1cccc2c1OCCN2C(=O)OC(C)(C)C)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Product: O=C(c1cccc2c1OCCN2)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 52.4 %

Procedure:
A solution of 8-{5-chloro-3-[(4-chloro-3-trifluoromethyl-benzenesulfonyl)-methoxymethyl-amino]-pyridine-2-carbonyl}-2,3-dihydro-benzo[1,4]oxazine-4-carboxylic acid tert-butyl ester (510.2 mg) in 3 mL HCl (4 M in dioxane) and water (1 mL) was heated at 80° C. for overnight. Upon cooling to room temperature, the mixture was concentrated and the residue was purified by flash column chromatography on silica gel to afford 4-chloro-N-[5-chloro-2-(3,4-dihydro-2H-benzo[1,4]oxazine-8-carbonyl)-pyridin-3-yl]-3-trifluoromethyl-benzenesulfonamide (210.2 mg) as white solid. MS m/z: 531.9 (M+H)+.
Reaction SMILES: C([O:3][C:4](=[O:48])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:39]=[CH:38][C:37]([F:40])=[CH:36][CH:35]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:30])=[O:29])[CH:27]=2)[C:10]=1[CH2:41][CH2:42][C:43]([O:45]CC)=[O:44])C.[OH-].[Na+]>>[C:43]([CH2:42][CH2:41][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:34]3[CH:35]=[CH:36][C:37]([F:40])=[CH:38][CH:39]=3)[CH:25]=[C:26]([S:28]([CH2:31][CH2:32][CH3:33])(=[O:29])=[O:30])[CH:27]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:48])=[O:3])([OH:45])=[O:44]
Reactant: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)OCC)c2CCC(=O)OCC)cc(-c2ccc(F)cc2)c1
Agent: [Na+]
Agent: [OH-]
Product: CCCS(=O)(=O)c1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2ccc(F)cc2)c1
Yield: 85.6 %

Procedure:
A similar procedure as described in Example 40, step 8 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(5-(propane-1-sulfonyl)-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid ethyl ester (195 mg, 0.29 mmol) and 1.0 N aqueous sodium hydroxide (2.9 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(5-(propane-1-sulfonyl)-4′-fluoro-biphenyl-3-yloxy)-hexyl]-phenoxy]-butyric acid (156 mg, 87%) as an amorphous white solid: ES(+)-HRMS m/e calcd for C34H41FO8S (M+Na)+ 651.2398, found 651.2398.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([C:17](O)=[O:18])[CH:15]=3)[N:10]([C:20]([C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:39][N:40]1[CH2:45][CH2:44][CH2:43][C:42]([CH2:55][OH:56])([O:46][C:47]2[CH:52]=[C:51]([F:53])[CH:50]=[CH:49][C:48]=2[F:54])[CH2:41]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[F:54][C:48]1[CH:49]=[CH:50][C:51]([F:53])=[CH:52][C:47]=1[O:46][C:42]1([CH2:55][OH:56])[CH2:43][CH2:44][CH2:45][N:40]([NH:39][C:17]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[N:10]([C:20]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[N:9]=[C:8]3[C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:1])[CH:7]=2)=[O:18])[CH2:41]1
Reactant: NN1CCCC(CO)(Oc2cc(F)ccc2F)C1
Reactant: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)O)cc23)ccn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(-c2nn(C(c3ccccc3)(c3ccccc3)c3ccccc3)c3ccc(C(=O)NN4CCCC(CO)(Oc5cc(F)ccc5F)C4)cc23)ccn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A reaction mixture of 3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxylic acid (0.3 mmol, 150 mg), (1-amino-3-(2,5-difluorophenoxy)piperidin-3-yl)methanol (0.28 mmol, 81 mg), HATU (0.3 mmol, 115 mg) and DIEA in DMA was stirred at room temperature for overnight. The product, N-(3-(2,5-difluorophenoxy)-3-(hydroxymethyl)piperidin-1-yl)-3-(2-methylpyridin-4-yl)-1-trityl-1H-indazole-5-carboxamide, was obtained after rotary evaporation of solvent.
Reaction SMILES: [CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([O:14]C)=[O:13])=[CH:10][C:9]=1[C:18]([F:21])([F:20])[F:19].[OH-].[Li+]>C1COCC1.O>[CH3:1][CH:2]1[CH2:7][CH2:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:17]=[CH:16][C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]=1[C:18]([F:20])([F:19])[F:21]
Reactant: COC(=O)c1ccc(N2CCCCC2C)c(C(F)(F)F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC1CCCCN1c1ccc(C(=O)O)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a stirred solution of methyl 4-(2-methylpiperidin-1-yl)-3-(trifluoromethyl)benzoate (6.6 g, 21.9 mmol) in THF (50 mL) and water (5 mL) was added lithium hydroxide (1.84 g, 43.8 mmol). The resulting mixture was stirred at RT for 12 hours. Solvents were removed under vacuum and the resulting mass was diluted with water. The aqueous layer was washed with DCM (2×50 mL), and then acidified with a concentrated aqueous solution of HCl (pH=4). It was extracted with EtOAc (2×100 mL). The EtOAc layer was washed with brine and dried over sodium sulfate, affording the title compound as a white solid. 1H NMR (DMSO-d6, 400 MHz) δ 13.30 (bs, 1H), 8.17 (m, 2H), 7.69 (d, 1H), 3.08 (m, 1H), 2.88 (m, 1H), 2.50 (m, 1H), 1.90 (m, 2H), 1.75 (m, 2H), 1.45 (m, 1H), 1.41 (m, 1H), 0.77 (d, 3H). LC/MS (Method A): 288.1 (M+H)+. HPLC (Method B) Rt 3.71 min (Purity: 98.3%).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2Br)[CH:5]=[CH:4]1)[CH3:2].[Li]C(C)(C)C.CCCCC.C(=O)=O.[C:26](OC)(=[O:31])[C:27]([O:29][CH3:30])=[O:28]>C1COCC1.CCOC(C)=O>[CH3:30][O:29][C:27](=[O:28])[C:26]([C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[N:3]([CH2:1][CH3:2])[CH:4]=[CH:5]2)=[O:31]
Reactant: COC(=O)C(=O)OC
Reactant: CCn1ccc2cccc(Br)c21
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCn1ccc2cccc(C(=O)C(=O)OC)c21
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 82.8 %

Procedure:
A solution of 1-ethyl-7-bromoindole (2.1 g, 9.4 mmol) in THF (50 mL) was cooled to −78° C. and a 1.7 M solution of tBuLi in pentane (13.8 mL, 23.5 mmol) was added dropwise over 10 min. After 15 min, the resultant brown solution was transferred over 30 min via a cannula cooled with dry ice to a solution of dimethyl oxalate (3.88 g, 32.9 mmol) in THF (40 mL) maintained at −78° C. After 15 min, the mixture was allowed to warm to room temperature and stirred 4 h. The brown solution was treated with pH 7.0 buffer, poured into EtOAc and the EtOAc washed with pH 7.0 buffer, saturated aq NaHCO3, brine, dried (MgSO4) and concentrated to a brown oil. Flash chromatography (20% EtOAc/hexanes) afforded the title compound (1.8 g, 83%) as a yellow oil, which was used without further purification. 1H NMR (400 MHz, DMSO-d6) 7.9 (d, J=8, 1H), 7.55 (m, 2H), 7.2 (dd, J=8, 8 Hz, 1H), 6.66 (d, J=3 Hz, 1H), 4.25 (q, J=7 Hz, 2H), 3.94 (t, J=7 Hz, 3H). MS (electrospray, m/z) 232 (M++1).
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-])=O)=[CH:9][CH:8]=1>C(O)C.O.[Fe]>[OH:2][CH2:3][CH2:4][CH2:5][S:6][C:7]1[CH:12]=[CH:11][C:10]([NH2:13])=[CH:9][CH:8]=1
Reactant: O=[N+]([O-])c1ccc(SCCCO)cc1
Agent: [Fe]
Agent: Cl
Solvent: CCO
Solvent: O
Product: Nc1ccc(SCCCO)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 104.7 %

Procedure:
Iron powder (330 mg) and conc. hydrochloric acid (0.3 ml) were added to a solution of 1-(3-hydroxypropylthio)-4-nitrobenzene (Method 82; 1 g, 4.69 mmol) in ethanol (6 ml) and water (3 ml). The mixture was stirred and heated at 90° C. for 3 hours, further iron powder (300 mg) and conc. HCl (0.2 ml) were added and heating continued for a further 2 hours. The volatiles were removed by evaporation and water (20 ml) added to the residue. The mixture was acidified to pH 1 with 2M hydrochloric acid, filtered through diatomaceous earth, and the filtrate washed with EtOAc (2×25 ml). The aqueous layer was basified to pH11 with conc. aqueous sodium hydroxide solution and extracted with EtOAc (2×25 ml). The extracts were combined, washed with brine (15 ml), dried and evaporated under reduced pressure to give the title compound (900 mg, 100%). m/z 184.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:12])[F:11])[C@H:3]1[C:14]([OH:16])=[O:15].[C:18]([C@@H:20](O)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:22]=1)#[N:19]>>[CH3:1][C:2]1([CH3:17])[C@@H:4]([C:5]#[C:6][C:7](=[O:13])[O:8][CH2:9][CH:10]([F:11])[F:12])[C@H:3]1[C:14]([O:16][C@H:20]([C:18]#[N:19])[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([O:27][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1)=[O:15]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1C#CC(=O)OCC(F)F
Product: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1C#CC(=O)OCC(F)F
Yield: 62.2 %

Procedure:
Using the procedure of Step F of Example 9, 4.1 g of the acid of Step C and 4.5 g of (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain 4.7 g of (S)α-cyano-3-phenoxy-benzyl (1R,cis) 2,2-dimethyl-3-[3-oxo-3-(2,2-difluoroethoxy)-1-propynyl]-cyclopropane-carboxylate after elution with a 6-4 mixture of petroleum ether (B. Pt. 40°-70° C.)-isopropyl ether.
Reaction SMILES: NC1N=CN=C2N(C3CN(C(OC(C)(C)C)=O)C3)N=C(I)C=12.[NH2:23][C:24]1[N:29]=[CH:28][N:27]=[C:26]2[N:30]([CH:45]3[CH2:49]C[N:47](C(OC(C)(C)C)=O)[CH2:46]3)[N:31]=[C:32]([C:33]#[C:34][C:35]3[CH:40]=[C:39]([O:41][CH3:42])[CH:38]=[C:37]([O:43][CH3:44])[CH:36]=3)[C:25]=12>>[NH:47]1[CH2:46][CH:45]([N:30]2[C:26]3=[N:27][CH:28]=[N:29][C:24]([NH2:23])=[C:25]3[C:32]([C:33]#[C:34][C:35]3[CH:36]=[C:37]([O:43][CH3:44])[CH:38]=[C:39]([O:41][CH3:42])[CH:40]=3)=[N:31]2)[CH2:49]1
Reactant: COc1cc(C#Cc2nn(C3CCN(C(=O)OC(C)(C)C)C3)c3ncnc(N)c23)cc(OC)c1
Agent: CC(C)(C)OC(=O)N1CC(n2nc(I)c3c(N)ncnc32)C1
Product: COc1cc(C#Cc2nn(C3CNC3)c3ncnc(N)c23)cc(OC)c1

Procedure:
In accordance with Example 1 (Step 4), except that tert-butyl 3-(4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)azetidine-1-carboxylate obtained in Step 3 above was used in place of tert-butyl 3-(4-amino-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)pyrrolidine-1-carboxylate, a crude product of 1-(azetidin-3-yl)-3-((3,5-dimethoxyphenyl)ethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine was obtained by removing a Boc group under acidic conditions. Thereafter, amidation was conducted to obtain the title compound as a white solid. Table 1 shows the physical properties thereof.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[OH:14].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:46][N:47]([CH3:51])[CH2:48][CH2:49]O.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[CH:6]=[N:5][N:4]([CH3:7])[C:3]=1[C:8]1[CH:9]=[C:10]([NH:15][C:16]([NH:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])=[O:17])[CH:11]=[CH:12][C:13]=1[O:14][CH2:49][CH2:48][N:47]([CH3:51])[CH3:46]
Reactant: Cn1ncc(Br)c1-c1cc(NC(=O)Nc2ccc(F)cc2F)ccc1O
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(C)CCOc1ccc(NC(=O)Nc2ccc(F)cc2F)cc1-c1c(Br)cnn1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.4 %

Procedure:
Compound 103 (73.7 mg, 0.17 mmol) was dissolved in anhydrous THF (5 mL). PPh3 (173 mg, 0.64 mmol) and 2-Dimethylamino ethanol (65.5 μL, 0.63 mmol) were then added to the solution, and the reaction was stirred at room temperature. After stirring for five minutes, DIAD (127 μL, 0.64 mmol) was added to the reaction dropwise. The reaction was found to be complete by TLC and LC/MS after 30 minutes. The solvent was then removed under reduced pressure. The residue was purified twice by flash chromatography (Biotage, SiO2, Dichloromethane/Methanol gradient elution) and twice by HPLC to afford 26.4 mg (31%) of Compound 123 as a light brown oil: LCMS m/z (%)=496 (M+H81Br, 100), 494 (M+H79Br, 94). 1H NMR (400 MHz, DMSO-d6) δ 8.99 (s, 1H), 8.44 (s, 1H), 8.07-8.01 (m, 1H), 7.59 (s, 1H), 7.52 (dd, J1=8 Hz, J2=4 Hz, 1H), 7.35 (d, J=4, 1H), 7.32-7.26 (m, 1H), 7.17 (d, J=12 Hz, 1H), 7.05-7.00 (m, 1H), 4.11 (dm, 2H), 3.65 (s, 3H), 2.58 (dm, 2H), 2.11 (s, 6H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:23])[N:14]3[CH:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[C:10]([C:24]([O:26]C)=O)[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[Si](OC1C=C(C2N=C3C(NC(=O)N3C3CCOCC3)=C(C(OC)=O)[N:53]=2)C=CC=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1>[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:1][C:2]1[CH:3]=[C:4]([C:8]2[N:16]=[C:15]3[C:11]([NH:12][C:13](=[O:23])[N:14]3[CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)=[C:10]([C:24]([NH2:53])=[O:26])[N:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1nc(-c2cccc(O[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Reactant: COC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: NC(=O)c1nc(-c2cccc(O)c2)nc2c1[nH]c(=O)n2C1CCOCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 58 %

Procedure:
Methyl 2-(3-hydroxyphenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylate. Methyl 2-(3-(tert-butyldiphenylsilyloxy)phenyl)-8-oxo-9-(tetrahydro-2H-pyran-4-yl)-8,9-dihydro-7H-purine-6-carboxylate (0.270 g, 0.513 mmol) was dissolved in tetrahyrdrofuran (10 mL) and tetrabutylammonium fluoride on silica gel (0.410 g, 0.615 mmol) was added to the solution. The solution stirred at ambient temperature for two hours. LCMS confirms product and no starting materials. The solution was filtered and condensed to give the crude title compound (0.110 g, 58%) which is used in the next step without further purification or characterization.
Reaction SMILES: [CH3:1][CH:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12]([N+:16]([O-])=O)=[CH:11][CH:10]=3)=[N:5][NH:4][C:3]1=[O:19].[Cl-].[NH4+]>CO.[Zn]>[NH2:16][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][C:6]1[N:15]2[CH:2]([CH3:1])[C:3](=[O:19])[NH:4][N:5]=1
Reactant: CC1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Product: CC1C(=O)NN=C2COc3ccc(N)cc3N21
Temperature: 25 °C
Reaction time: 24 h
Yield: 76.6 %

Procedure:
To a solution of 4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (10 g, 38.2 mmol) and ammonium chloride (20.5 g, 382.0 mmol) in MeOH (200 mL) was added zinc powder (24.8 g, 382.0 mol) and the resulting mixture was stirred for 24 h at 25° C. The reaction mixture was filtered and the filtrate was washed with methanol (5×30 mL). The filtrate was combined and concentrated in vacuo and the residue was purified by chromatography on silica gel (eluting with 10% MeOH in DCM) to give 6-amino-4-methyl-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (6.8 g, 77%) as a yellow solid. 1H NMR (DMSO-d6, 400 MHz): δ 10.72 (s, 1H), 6.67 (d, J=8.4 Hz, 1H), 6.42 (d, J=2.4 Hz, 1H), 6.15 (q, J=8.4 Hz, J=2.4 Hz, 1H), 4.82 (brs, 2H), 4.52 (q, J=6.4 Hz, 1H), 4.43 (d, J=12.8 Hz, 2H), 1.30 (d, =6.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:16][CH:15]3[N:17](C(OCC(Cl)(Cl)Cl)=O)[CH:12]([CH2:13][CH2:14]3)[CH2:11]2)=[CH:5][CH:4]=1.P([O-])([O-])(O)=O.[K+].[K+].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.[Zn]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9][CH:10]2[CH2:11][CH:12]3[NH:17][CH:15]([CH2:14][CH2:13]3)[CH2:16]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(SC2CC3CCC(C2)N3C(=O)OCC(Cl)(Cl)Cl)cc1
Agent: O=C([O-])[O-]
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(SC2CC3CCC(C2)N3)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.9 %

Procedure:
To a stirred solution of 2,2,2-trichloroethyl 3-[(4-methoxyphenyl)sulfanyl]-8-azabicyclo[3.2.1]octane-8-carboxylate (Preparation 11, 52.7 g, 0.12 moles) in tetrahydrofuran under nitrogen was added zinc dust (20 g,) and potassium hydrogenphosphate (1 M, 125 ml). The reaction mixture was stirred for 2 h at room temperature before adding more zinc dust (30 g) followed by heating on a steam bath for 30 min. The reaction mixture was cooled to room temperature and diluted with water (1 l). Sodium carbonate was added to adjust the pH to 10. The reaction mixture was filtered and the filtrate was separated and then extracted with dichloromethane. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give the title compound as a yellow oil (26.0 g, 84%). The oil was purified by column chromatography on silica gel (350 g) eluting with methanol:dichloromethane:0.88 ammonia solution (10:90:1) to give the product as an oil which crystallised on standing (13 g, 42%). The solid was further purified by stirring in ether and filtering to give a light yellow solid (9 g, 29%).
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([OH:24])=O)[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([C:22]([NH:33][CH2:32][CH2:31][N:28]3[CH2:29][CH2:30][O:25][CH2:26][CH2:27]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CC(C)(C)n1ncc(-c2nc(C(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: NCCN1CCOCC1
Product: CC(C)(C)n1ncc(-c2nc(C(=O)NCCN3CCOCC3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazole-4-carboxylic acid and 2-morpholinoethanamine and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: [CH2:1]([NH:4][CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)CC.O=[CH:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]>>[CH3:1][N:4]([CH:5]1[CH2:13][CH2:12][C:8]2[N:9]=[CH:10][S:11][C:7]=2[CH2:6]1)[CH2:15][CH2:16][CH2:17][CH2:18][NH:19][C:20]([C:22]1[S:26][C:25]2[CH:27]=[CH:28][CH:29]=[CH:30][C:24]=2[CH:23]=1)=[O:21]
Reactant: CCCNC1CCc2ncsc2C1
Reactant: O=CCCCNC(=O)c1cc2ccccc2s1
Product: CN(CCCCNC(=O)c1cc2ccccc2s1)C1CCc2ncsc2C1
Yield: 58 %

Procedure:
Compound 11 is prepared as described for 1 from 1C and 11A. The salt of oxalic acid is crystallized from ethanol/diethylether.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13](O)[CH3:14].[C:16]1(=[O:26])[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][CH:25]=[C:17]12.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]2[CH:9]=[CH:10][CH:11]=[CH:12][C:5]2=[N:4][C:3]=1[CH:13]([N:20]1[C:16](=[O:26])[C:17]2[C:18](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:19]1=[O:21])[CH3:14]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: CC(O)c1nc2ccccn2c(=O)c1Br
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(c1nc2ccccn2c(=O)c1Br)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 500 mL of round-bottom flask was charged with 3-bromo-2-(1-hydroxyethyl)-4H-pyrido[1,2-a]pyrimidin-4-one (0.76 g, 2.86 mmol), phthalimide (0.504 g, 3.43 mmol) and PPh3 (0.899 g, 3.43 mmol) in THF (20 mL) followed by the dropwise addition of diisopropylazodicarboxylate (0.675 g, 3.43 mmol) in THF (3 mL). The reaction mixture was stirred overnight at rt. After the completion of the reaction, monitored by TLC, the reaction mass was cond under vacuum and purified by silica gel column chromatography using 5 to 35% EtOAc in hexane to provide 2-(1-(3-bromo-4-oxo-4H-pyrido[1,2-a]pyrimidin-2-yl)ethyl)isoindoline-1,3-dione as light yellow solid: 1HNMR (400 MHz, DMSO-d6): δ8.95-8.96 (dd,1H), 8.00-8.06 (m,1H), 7.8 (s,4H), 7.5-7.6 (m,2H), 7.4 (d,1H), 5.6 (q,1H), 1.84 (d,3H).