Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N:4]1[C:17]2[CH:16]=[CH:15][C:14]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])=[CH:13][C:12]=2[O:11][C:10]2[C:5]1=[CH:6][CH:7]=[C:8]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])[CH:9]=2)(=O)C.[OH-].[Na+].Cl>O>[CH3:22][S:19]([NH:18][C:14]1[CH:15]=[CH:16][C:17]2[NH:4][C:5]3[C:10]([O:11][C:12]=2[CH:13]=1)=[CH:9][C:8]([NH:23][S:24]([CH3:27])(=[O:26])=[O:25])=[CH:7][CH:6]=3)(=[O:20])=[O:21]
Reactant: CC(=O)N1c2ccc(NS(C)(=O)=O)cc2Oc2cc(NS(C)(=O)=O)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CS(=O)(=O)Nc1ccc2c(c1)Oc1cc(NS(C)(=O)=O)ccc1N2
Temperature: 60 °C
Yield: 27.8 %

Procedure:
To a suspension of 0.2 g of the product of Example 3 in 17 ml of water was added 0.3 g of sodium hydroxide. The blue solution was heated to 60° C. for 30 minutes. After cooling to room temperature hydrochloric acid was added until the mixture was acidic. The product was extracted into ethyl acetate then chromatographed on silica gel to give 0.05 g of 3,7-di(methysulfonamido)(10H)phenoxazine, which was identified by spectroscopic analysis.
Reaction SMILES: [CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[N:14]=[CH:13][CH:12]=[CH:11]N=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2].Br[C:36]1C=CC=CN=1>>[CH2:1]([O:3][C@H:4]1[CH2:8][N:7]([C:9]2[CH:36]=[CH:11][CH:12]=[CH:13][N:14]=2)[CH2:6][C@H:5]1[NH:15][C:16]1[C:21]([CH2:22][CH3:23])=[N:20][C:19]([C:24]2[C:25]([CH3:32])=[N:26][C:27]([O:30][CH3:31])=[CH:28][CH:29]=2)=[C:18]([CH2:33][CH3:34])[N:17]=1)[CH3:2]
Reactant: Brc1ccccn1
Reactant: CCO[C@H]1CN(c2ncccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC
Product: CCO[C@H]1CN(c2ccccn2)C[C@H]1Nc1nc(CC)c(-c2ccc(OC)nc2C)nc1CC

Procedure:
Following the procedure for the preparation of N-[(3R,4S)-4-ethoxy-1-pyrimidin-2-ylpyrrolidin-3-yl]-3,6-diethyl-5-(6-methoxy-2-methylpyridin-3-yl)pyrazin-2-amine but substituting 2-bromo pyridine provided the title compound as an amporphous solid:
Reaction SMILES: CO[C:3](=[O:13])[C:4]1[C:9]([I:10])=[CH:8][CH:7]=[CH:6][C:5]=1[CH2:11]Br.[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][NH2:20])=[CH:17][CH:16]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[F:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:20]2[CH2:11][C:5]3[C:4](=[C:9]([I:10])[CH:8]=[CH:7][CH:6]=3)[C:3]2=[O:13])=[CH:17][CH:16]=1
Reactant: COC(=O)c1c(I)cccc1CBr
Reactant: NCc1ccc(F)cc1
Solvent: Cc1ccccc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: O=C1c2c(I)cccc2CN1Cc1ccc(F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 2-bromomethyl-6-iodo-benzoic acid methyl ester (0.200 g, 0.56 mmol), 4-fluoro-benzylamine (0.7 mmol), and IC2CO3 (0.166 g, 1.2 mmol) in toluene (5 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography using 30% ethyl acetate in hexane afforded 2-(4-fluoro-benzyl)-7-iodo-2,3-dihydro-isoindol-1-one (0.082 g, 40%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.16 (s, 2H), 4.75 (s, 2H), 7.01 (t, 2H), 7.28-7.40 (m, 4H), 7.89 (d, 1H). GC-MS: m/z 367 (M)+.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CN(C)C=O.N1C=CC=CC=1.[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[S:27]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]([NH2:38])=O)(=[O:29])=[O:28]>C(#N)C>[NH:18]1[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=2[N:20]=[C:19]1[S:27]([N:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[C:36]#[N:38])(=[O:28])=[O:29]
Reactant: NC(=O)C1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: CC#N
Product: N#CC1CCCCN1S(=O)(=O)c1nc2ccccc2[nH]1
Reaction time: 0.33 h
Yield: 35.3 %

Procedure:
Oxalyl chloride (5.00 ml) was added dropwise to a solution of dimethylformamide (4.43 ml) in acetonitrile (200 ml) at 0° C. The mixture was stirred for 20 mins. and a suspension of pyridine (9.66 ml) and 1-(1H-benzo[d]imidazol-2-ylsulfonyl-2-piperidinecarboxamide (14.73 g) [see Preparation 17] in acetonitrile (100 ml) was added over a period of 10 mins. The reaction mixture was stirred for a further 20 mins. after which time the solvent was removed under reduced pressure. The residue was diluted with diethyl ether and washed with water, brine, dried over magnesium sulphate and the solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel eluting with 70:30, by volume, hexane:ethyl acetate to afford 1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidinecarbonitrile (4.9 g).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([OH:11])=[CH:6][N:5]=1.[CH3:12]I.O>CN(C=O)C>[Cl:3][C:4]1[C:9]([CH3:10])=[CH:8][C:7]([O:11][CH3:12])=[CH:6][N:5]=1
Reactant: Cc1cc(O)cnc1Cl
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cnc(Cl)c(C)c1
Yield: 101.5 %

Procedure:
Into a flame dried flask under N2 was placed DMF (150 mL), NaH (50% oil dispersion, 4.0 g, 0.08 mol) and 2-chloro-5-hydroxy-3-methylpyridine (11.7 g, 0.08 mol). The solution was stirred at 0°-5° C. until the evolution of H2 ceased and then a solution of CH3I (5.6 mL, 0.09 mol) in DMF (50 mL) was added dropwise. After the addition, the solution was allowed to stir at room temperature overnight. The resulting slurry was added to H2O and extracted with Et2O (3X). The organic layer was concentrated and the residue distilled at 85° C. (0.6 mm) to yield 12.8 g of 2-chloro-5-methoxy-3-methylpyridine (95%) as an oil; 1H NMR (CDCl3) δ 2.35 (3H, s), 3.8 (3H, s), 7.1 (1H, d, J=3) and 7.9 (1H, d, J=3 ); MS m/e (M+) 157.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]=1[C:23]([O:25]CC)=[O:24].[OH-].[Na+]>C(O)C.O>[CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=2)[C:3]=1[C:23]([OH:25])=[O:24]
Reactant: CCOC(=O)c1c(C)nc(-c2ccccc2)nc1-c1ccc([N+](=O)[O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(-c2ccccc2)nc(-c2ccc([N+](=O)[O-])cc2)c1C(=O)O
Yield: 39.7 %

Procedure:
A suspension of ethyl 6-methyl-2-phenyl-4-(4-nitrophenyl)-5-pyrimidinecarboxylate (39 g) and aqueous sodium hydroxide (5.19 g in 10 ml H2O) in ethanol (390 ml) and water (195 ml) was refluxed for 10 hours. After evaporating the solvent, the residue was dissolved in a suspension of water (200 ml) and chloroform (200 ml) under stirring. The separated aqueous layer was adjusted to pH 3.0 with 10% aqueous HCl. The resulting precipitate was collected by filtration, washed with water and dried in vacuo to give 6-methyl-2-phenyl-4-(4-nitrophenyl)-5-pyrimidinecarboxylic acid (14.3 g).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([O:53][CH3:54])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:12]=[CH:11][C:9]([CH3:10])=[CH:8][CH:7]=1.C1(SC)C=CC=CC=1.[F:70][C:71]([F:76])([F:75])[C:72]([OH:74])=[O:73]>C(Cl)Cl>[NH2:1][C@H:2]([C:13]([NH:15][C@H:16]([C:21]([NH:23][C@H:24]([C:29]([NH:31][C@H:32]([C:40]([NH:42][C@H:43]([C:51]([O:53][CH3:54])=[O:52])[CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)=[O:41])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:30])[CH2:25][C:26](=[O:28])[NH2:27])=[O:22])[CH2:17][CH2:18][CH2:19][CH3:20])=[O:14])[CH2:3][S:4][CH2:5][C:6]1[CH:7]=[CH:8][C:9]([CH3:10])=[CH:11][CH:12]=1.[F:70][C:71]([C:72]([OH:74])=[O:73])([F:76])[F:75]
Reactant: CCCC[C@H](NC(=O)[C@H](CSCc1ccc(C)cc1)NC(=O)OC(C)(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Solvent: CSc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC[C@H](NC(=O)[C@@H](N)CSCc1ccc(C)cc1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC
Reaction time: 0.83 h

Procedure:
10 g of BOC-Cys(MBzl)-Nle-Asn-Phe-Phe-OMe and 13.5 ml of thioanisole in 10 ml of CH2Cl2 are dissolved in 180 ml of trifluoroacetic acid and allowed to stand for 50 minutes at room temperature. Precipitation is effected by the addition of ether. After filtration, washing with ether and drying there is obtained H-Cys(MBzl)-Nle-Asn-Phe-Phe-OMe.trifluoroacetate.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=1.C([Li])CCC.[C:27](=[O:29])=[O:28]>C(OCC)C>[CH3:9][N:8]([CH3:10])[C:6]1[CH:5]=[C:4]([O:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])[CH:13]=2)[N:3]=[C:2]([C:27]([OH:29])=[O:28])[CH:7]=1
Reactant: CN(C)c1cc(Br)nc(Oc2cccc(C(F)(F)F)c2)c1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCOCC
Product: CN(C)c1cc(Oc2cccc(C(F)(F)F)c2)nc(C(=O)O)c1
Reaction time: 0.17 h

Procedure:
2-bromo-4-dimethylamino-6-[3-(trifluoromethyl)phenoxy] pyridine (5.00 g, 0.0138 mol) was dissolved in about 200 ml of diethyl ether. While cooling in a dry ice-acetone bath in an argon atmosphere, the obtained solution was mixed with n-butyl lithium [9.2 ml (ca. 1.66 M in hexane solution), 0.0138×1.1 mol], and then stirred for about 10 minutes. After the interior of the reactor was replaced with a carbon dioxide gas, the solution was removed from the bath and stirred at room temperature for about one hour. The reaction solution was mixed with about 15 ml of a 4 N aqueous hydrochloric acid solution, distributed in ethyl acetate-water, and then washed with saturated brine. The organic phase separated from the solution was dried with anhydrous sodium sulfate, concentrated and then purified by silica gel column chromatography (eluting solution: ethyl acetate/hexane), thereby obtaining an aimed product.
Reaction SMILES: [N+:1]([C:4]1[C:12]2[S:11][C:10]([NH2:13])=[N:9][C:8]=2[CH:7]=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH3:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:16]=1[C:17](Cl)=[O:18]>N1C=CC=CC=1>[CH3:14][C:15]1[CH:23]=[C:22]([CH3:24])[CH:21]=[C:20]([CH3:25])[C:16]=1[C:17]([NH:13][C:10]1[S:11][C:12]2[C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=[CH:7][C:8]=2[N:9]=1)=[O:18]
Reactant: Cc1cc(C)c(C(=O)Cl)c(C)c1
Reactant: Nc1nc2cccc([N+](=O)[O-])c2s1
Solvent: c1ccncc1
Product: Cc1cc(C)c(C(=O)Nc2nc3cccc([N+](=O)[O-])c3s2)c(C)c1
Temperature: 75 °C
Yield: 65.6 %

Procedure:
To 0.089 g (0.46 mmol) of 7-nitro-1,3-benzothiazol-2-amine in 1 mL of pyridine was added 0.17 g (0.91 mmol) of 2,4,6-trimethylbenzoyl chloride. The mixture was heated to 75° C. for 18 h and the volatiles were removed in vacuo. The residue was washed with water and 1 N hydrochloric acid, dissolved in ethyl acetate, dried over sodium sulfate, filtered, concentrated in vacuo and the resulting crude solid was purified by flash chromatography eluting with 25% ethyl acetate/hexanes mixture to give 0.103 g (66%) of the title compound as a tan solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:10])[CH3:9])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([CH:21]2[CH2:23][CH2:22]2)[CH3:20])[C:13]=1[N+:24]([O-])=O.Cl[Sn]Cl.O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH3:9])[CH3:10])[C:5]([F:11])=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][N:15]=[C:14]([NH:18][C@@H:19]([CH:21]2[CH2:22][CH2:23]2)[CH3:20])[C:13]=1[NH2:24]
Reactant: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1[N+](=O)[O-])C1CC1
Agent: Cl[Sn]Cl
Solvent: O
Product: C[C@@H](Nc1nccc(-c2cc(F)c(N(C)C)cc2Cl)c1N)C1CC1
Yield: 95.3 %

Procedure:
(R)-[4-(2-Chloro-4-dimethylamino-5-fluoro-phenyl)-3-nitro-pyridin-2-yl]-(1-cyclopropyl-ethyl)-amine (314 mg, 0.83 mmol) and SnCl2.H2O (472 mg, 2.5 mmol) were treated substantially as described in Part D of Example 74a to yield 276 mg of crude (R)-4-(2-chloro-4-dimethylamino-5-fluoro-phenyl)-N2-(1-cyclopropyl-ethyl)-pyridine-2,3-diamine: MS (EI) m/z 349.24 [(M+H)+, 100].
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]([C:5]1[S:6][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:8][CH:9]=1)=[O:4].[Li+].[OH-]>C1COCC1.O>[C:10]([C:7]1[S:6][C:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:16])=[CH:9][CH:8]=1)#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc(C(=O)C(F)(F)F)s1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: C#Cc1ccc(C(=O)C(F)(F)F)s1
Reaction time: 1 h

Procedure:
To a stirred solution of D1 (1.0 eq) in THF (0.1 M) at RT was added a solution of LiOH (2.0 eq) in H2O (0.1 M) and the reaction mixture was stirred for 1 hr, then quenched by adding 6M HCl solution until pH=2. The organic solvent was evaporated and the product was extracted by DCM. Organic layers were washed with brine and dried (Na2SO4). Evaporation of the solvent under reduced pressure gave the crude product which was purified by flash column chromatography using Pentane to yield the desired compound as a brown oil. 1H NMR (300 MHz, CDCl3, 300K) δ 7.85-7.80 (1H, m), 7.32 (1H, d, J=4.2 Hz), 3.66 (1H, s).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-])=O)=[CH:6][C:5]=1[C:13]([F:16])([F:15])[F:14]>C(OCC)(=O)C.[Pd]>[CH3:1][O:2][C:3](=[O:17])[C:4]1[CH:9]=[CH:8][C:7]([NH2:10])=[CH:6][C:5]=1[C:13]([F:14])([F:16])[F:15]
Reactant: COC(=O)c1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(N)cc1C(F)(F)F

Procedure:
A solution of 4-nitro-2-trifluoromethyl benzoic acid methyl ester (Aldrich, 700 mg, 3.24 mmol) in ethyl acetate (50 mL) was treated with 10% Pd/C (50 mg) and hydrogenated at 1 atmosphere for 3 hrs. The mixture was filtered and concentrated to give a light yellow solid which was directly used for the next step.
Reaction SMILES: [C:1]1([C:7]2[CH:11]=[CH:10][O:9][C:8]=2[C:12]([O:14][CH3:15])=[O:13])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C=O.Cl.[CH:19](Cl)(Cl)[Cl:20]>[Cl-].[Na+].O.[Cl-].[Zn+2].[Cl-]>[Cl:20][CH2:19][C:10]1[O:9][C:8]([C:12]([O:14][CH3:15])=[O:13])=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[CH:11]=1
Reactant: COC(=O)c1occc1-c1ccccc1
Reactant: ClC(Cl)Cl
Agent: C=O
Agent: Cl
Agent: [Cl-]
Solvent: O
Product: COC(=O)c1oc(CCl)cc1-c1ccccc1

Procedure:
A mixture of 3-phenyl-2-furancarboxylic acid, methyl ester (4 g), paraformaldehyde (0.87 g) and zinc chloride (0.74 g) in chloroform (5 ml) was treated with hydrogen chloride gas for 21/2 hours. The mixture was poured onto saturated brine (100 ml) and extracted with chloroform (100 ml). The chloroform extracts were dried over sodium sulphate and the solvent evaporated in vacuo. The residue was distilled (Kugelrohr) affording the title compound (3.1 g) as an oil, b.p. 130°-140° C./10-1 mmHg.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[C:14]1([C:20]2[S:21][CH:22]=[C:23]([C:25](O)=[O:26])[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[C:14]1([C:20]2[S:21][CH:22]=[C:23]([C:25]([N:4]3[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]3)=[O:26])[N:24]=2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)c1csc(-c2ccccc2)n1
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2csc(-c3ccccc3)n2)CC1
Yield: 90 %

Procedure:
This compound was synthesized from tert-butyl piperazine-1-carboxylate and 2-phenylthiazole-4-carboxylic acid as described for example 37 step 3 (500 mg, yield 90%). 1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 8.00-7.96 (m, 2H), 7.56-7.53 (m, 3H), 3.76-3.64 (m, 4H), 3.43 (m, 4H), 1.42 (s, 9H). MS (ESI) m/z: Calculated for C19H23N3O3S: 373.15. found: 374.2 (M+H)+
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]2[CH:11]=[CH:12][C:13]3[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=3[CH:20]=2)=[O:9])[CH2:3][CH2:2]1.Br[CH2:22][CH:23]1[CH2:36][C:35]2[C:34]3[C:29](=[CH:30][CH:31]=[C:32]([O:37][CH3:38])[N:33]=3)[N:28]=[CH:27][C:26]=2[O:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:38][O:37][C:32]1[N:33]=[C:34]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][C:26]1[O:25][CH2:24][CH:23]([CH2:22][N:1]3[CH2:6][CH2:5][CH:4]([NH:7][C:8]([C:10]4[CH:11]=[CH:12][C:13]5[S:18][CH2:17][C:16](=[O:19])[NH:15][C:14]=5[CH:20]=4)=[O:9])[CH2:3][CH2:2]3)[CH2:36][C:35]2=1
Reactant: COc1ccc2ncc3c(c2n1)CC(CBr)CO3
Reactant: O=C1CSc2ccc(C(=O)NC3CCNCC3)cc2N1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2ncc3c(c2n1)CC(CN1CCC(NC(=O)c2ccc4c(c2)NC(=O)CS4)CC1)CO3
Temperature: 80 °C
Reaction time: 24 h

Procedure:
3-Oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid piperidin-4-ylamide (56 mg, 0.16 mmol, 1.0 eq) is added at room temperature to a stirred solution of 3-bromomethyl-6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthrene (50 mg, 0.16 mmol, 1.0 eq) in N,N-dimethylformamide (2 mL), followed by N,N-diisopropylethylamine (30 μL, 0.17 mmol, 1.1 eq). After 24 hours stirring at 80° C., solvent is removed and the residue is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by preparative HPLC to afford 3-oxo-3,4-dihydro-2H-benzo[1,4]thiazine-6-carboxylic acid [1-(6-methoxy-3,4-dihydro-2H-1-oxa-5,9-diaza-phenanthren-3-ylmethyl)-piperidin-4-yl]-amide as an off-white lyophilized powder (39 mg, 47% yield).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[C:34]([N:41]1[CH2:46][CH2:45][CH:44](O)[CH2:43][CH2:42]1)([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35].[Cl:48][C:49]1[N:54]=[CH:53][N:52]=[C:51]2[NH:55][N:56]=[CH:57][C:50]=12>O1CCCC1.C1(C)C=CC=CC=1>[C:37]([O:36][C:34]([N:41]1[CH2:46][CH2:45][CH:44]([N:55]2[C:51]3=[N:52][CH:53]=[N:54][C:49]([Cl:48])=[C:50]3[CH:57]=[N:56]2)[CH2:43][CH2:42]1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: Clc1ncnc2[nH]ncc12
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(n2ncc3c(Cl)ncnc32)CC1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 38.8 %

Procedure:
A solution of triphenylphosphine (30.5 g, 116.3 mmol) in anhydrous tetrahydrofuran (450 mL) was cooled to 0° C. under nitrogen. Diisopropylazodicarboxylate (22.9 mL, 116.3 mmol) was added dropwise over 10 min. The mixture was stirred at 0° C. for 15 min and then 1-Boc-4-hydroxy-piperidine (Aldrich, 20.3 g, 100 mmol) was added. The mixture was stirred at 0° C. for 10 min and then solid 4-chloro-1H-pyrazolo[3,4-d]pyrimidine (Intermediate 30; 13.0 g, 84 mmol) was added in portions. The flask containing Intermediate 30 was rinsed with THF and the washings were added to the reaction mixture. The reaction mixture was stirred in the ice-bath for 3 h, and then stored in the refrigerator overnight. The reaction mixture was evaporated to dryness and the residue was taken up in a mixture of ether and hexanes (2:1; 1 L). The mixture was stirred at room temperature for 20 min, and then the white solid was filtered off and washed with a mixture of ether and hexanes (2:1). The filtrate was evaporated to dryness to give a yellow solid. This was taken up in toluene with warming, applied to a column of flash silica gel (90 mm×6″) and eluted with 20-25% ethyl acetate/hexanes to give 4-(4-chloro-pyrazolo[3,4-d]pyrimidin-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (11.0 g, 39%) along with mixed fractions which were repurified by flash chromatography.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([CH:8]=[CH:9][N:10]=2)[N:7]=1.[Br:11]N1C(=O)CCC1=O.FC(F)(F)C(O)=O>C(#N)C>[Br:11][C:8]1[N:6]2[N:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]2=[N:10][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc2nccn2n1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Clc1ccc2ncc(Br)n2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
To a solution of 6-chloroimidazo[1,2-b]pyridazine (5 g, 32.6 mmol) in acetonitrile (300 ml) was added 1-bromopyrrolidine-2,5-dione (6.37 g, 35.8 mmol) and trifluoroacetic acid (0.75 mL). The resulting solution was allowed to stir at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc, washed with NaHCO3 solution, water and brine, dried over Na2SO4 and concentrated in vacuo to afford 7.2 g title compound in 92% yield as a light yellow solid. 1H-NMR (400 MHz, CDCl3) δ ppm 7.91 (d, 1H), 7.79 (s, 1H), 7.12 (d, 1H). LCMS (method A): [MH]+=232/234, tR=4.48 min.
Reaction SMILES: [F:1][C:2]([F:29])([O:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:28]=[CH:27][C:22]([C:23]([O:25]C)=[O:24])=[CH:21][CH:20]=3)=[N:15]2)=[CH:10][CH:9]=1)[C:3]([F:6])([F:5])[F:4].C1COCC1.O.[OH-].[Li+].Cl>O>[F:29][C:2]([F:1])([O:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH:18]=[N:17][C:16]([C:19]3[CH:20]=[CH:21][C:22]([C:23]([OH:25])=[O:24])=[CH:27][CH:28]=3)=[N:15]2)=[CH:12][CH:13]=1)[C:3]([F:6])([F:5])[F:4]
Reactant: COC(=O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-c2ncn(-c3ccc(OC(F)(F)C(F)(F)F)cc3)n2)cc1
Temperature: 23 °C
Reaction time: 39 h
Yield: 95.9 %

Procedure:
In a 250 mL round bottom flask equipped with an overhead stirrer, thermocouple, and nitrogen inlet was added methyl 4-(1-(4-(perfluoroethoxy)phenyl)-1H-1,2,4-triazol-3-yl)benzoate (11.1 g, 26.9 mmol) and THF (100 mL). To this yellow suspension was added water (10 mL) and lithium hydroxide monohydrate (3.4 g, 81 mmol). There was no change in reaction appearance and temperature (20.5° C.). The reaction was stirred at 23° C. for 39 h during which it became a yellow solution. A heating mantle was attached to the reaction flask and the flask was heated to an internal temperature of 60° C. for 2.5 hrs. The reaction was then cooled to 4° C. in an ice bath and water (100 mL) was added, providing a light yellow solution. Concentrated HCl (8.0 g) was added (note: exothermic) which gave a thick white precipitate. The white suspension was stirred at 5° C. for 30 min and then the solid was collected by vacuum filtration and washed with water (2×25 mL). The white wet cake was allowed to dry in air for 3 h, and was then placed into a vacuum oven (50° C., 700 mm Hg vacuum, 16 h). This gave the title compound as a white solid (10.3 g, 96%): mp 227-229° C.; 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 8.32 (d, J=8.4 Hz, 2H), 8.23 (d, J=8.4 Hz, 2H), 7.84 (d, J=8.9 Hz, 1H), 7.42 (d, J=8.9 Hz, 2H).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][N:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:22]=[C:21]([CH3:23])[N:20]([CH3:24])[C:19]=3[CH:25]=2)[C:11](=[O:26])[CH:10]=1)C1C=CC=CC=1>[Pd].CO>[CH3:24][N:20]1[C:19]2[CH:25]=[C:15]([N:12]3[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][C:11]3=[O:26])[CH:16]=[CH:17][C:18]=2[N:22]=[C:21]1[CH3:23]
Reactant: Cc1nc2ccc(-n3ccc(OCc4ccccc4)cc3=O)cc2n1C
Agent: [Pd]
Solvent: CO
Product: Cc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 90.9 %

Procedure:
A mixture of 4-(benzyloxy)-1-(1,2-dimethyl-1H-benzimidazol-6-yl)pyridin-2(1H)-one (627 mg), 10% Pd/C (193 mg) and MeOH (10 ml) was stirred under H2 atmosphere at room temperature for 1 h. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo to give the title compound (421 mg) as white crystals.