Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[NH:12]C(=O)[O:10][C:8](=O)[C:7]=12.[NH:14]([CH2:16][C:17]([OH:19])=[O:18])[CH3:15].C(=O)([O-])[O-].[K+].[K+].Cl>CN(C)C=O.O>[I:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]([NH2:12])[C:7]=1[C:8]([N:14]([CH3:15])[CH2:16][C:17]([OH:19])=[O:18])=[O:10]
Reactant: CNCC(=O)O
Reactant: O=c1[nH]c2cccc(I)c2c(=O)o1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)O)C(=O)c1c(N)cccc1I

Procedure:
A suspension of 8.7 g (0.03 mol) of 6-iodoisatoic acid anhydride, 2.95 g (0.033 mol) of sarcosine and 4.2 g of potassium carbonate in 50 ml of dimethylformamide is heated to 50° for 30 minutes. After cooling, the mixture is diluted with 400 ml of water, adjusted to pH 1-2 with 2 N hydrochloric acid and extracted several times with chloroform/isopropanol (4:1). After evaporation of the solvent and recrystallization of the residue from methylene chloride/hexane, there is obtained N-(6-iodoanthraniloyl)-N-methylglycine of melting point 147°-149°.
Reaction SMILES: [CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:34]=[CH:33][C:27]([C:28]([O:30]CC)=[O:29])=[CH:26][CH:25]=3)[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+].Cl>CCO.C1COCC1>[CH3:1][C:2]1([CH3:35])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:20])([F:21])[F:19])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:22]#[C:23][C:24]3[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:33][CH:34]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(c2ccc(C(F)(F)F)cc2)=CCC3(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC1(C)CC=C(c2ccc(C(F)(F)F)cc2)c2cc(C#Cc3ccc(C(=O)O)cc3)ccc21
Temperature: 50 °C

Procedure:
To a solution of ethyl 4-[(5,6-dihydro-5,5-dimethyl-8-(4-trifluoromethylphenyl)-2-naphthalenyl)ethynyl]benzoate (Compound 9) 70.0 mg (0.148 mmol) in 3 ml of EtOH and 2 ml of THF was added 60.0 mg (1.50 mmol, 1.50 ml) of NaOH (1.0M aqueous solution). The solution was heated to 50° C. for 2 hours, cooled to room temperature, and acidified with 10% HCl. Extraction with EtOAc, followed by drying over Na2SO4, and removal of the solvents under reduced pressure afforded the title compound as a colorless solid. 1H NMR (DMSO): δ7.90 (2H, d, J=8.3 Hz), 7.80 (2H, d, J=8.1 Hz), 7.61-7.47 (6H, m), 6.97 (2H, s), 6.16 (1H, t, J=4.5 Hz), 2.37 (2H, d, J=4.6 Hz), 1.30 (6H, s).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([O:11]C)[C:6]=12.[Br-].[Br-].[Br-].B>ClCCl>[Cl:1][C:2]1[C:3]([CH2:13][CH3:14])=[N:4][N:5]2[CH:10]=[CH:9][CH:8]=[C:7]([OH:11])[C:6]=12
Reactant: CCc1nn2cccc(OC)c2c1Cl
Agent: B
Agent: [Br-]
Solvent: ClCCl
Product: CCc1nn2cccc(O)c2c1Cl
Temperature: 0 °C
Reaction time: 26 h
Yield: 101.5 %

Procedure:
The compound of Example 65 (3.07 g) was dissolved in dichloromethane (40 mL) in an argon atmosphere. While this solution was kept at 0° C., borane tribromide (17.6 mL, 1.0 mol/mL dichloromethane solution) was added and the mixture was stirred for 26 hours at 0° C. to reflux temperature. Subsequently, the reaction was terminated by adding water and the mixture was extracted three times with ethylacetate. The organic layer was washed with saturated brine and dried over sodium sulfate. The solvent was evaporated under reduced pressure to afford the title compound as a yellow powder (2.91 g).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[NH:8][C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2].Br[CH2:32][C:33]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:34]>>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:30])[N:8]([CH2:32][C:33](=[O:34])[C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:9]2[C:14]([C:15]=1[N:16]1[CH2:21][CH2:20][N:19]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:18][CH2:17]1)=[CH:13][C:12]([F:29])=[CH:11][N:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2[nH]c1=O
Reactant: O=C(CBr)c1ccccc1
Product: CCOC(=O)c1c(N2CCN(C(=O)c3ccco3)CC2)c2cc(F)cnc2n(CC(=O)c2ccccc2)c1=O

Procedure:
This compound was prepared from 6-fluoro-4-[4-(furan-2-carbonyl)-piperazin-1-yl]-2-oxo-1,2-dihydro-[1,8]-naphthyridine-3-carboxylic acid ethyl ester (81) and 2-bromoacetophenone according to General Procedure B. Yield 298 mg (34%), MP 134° C.; 1H-NMR (DMSO-d6): δ 1.27 (t, J=7.2 Hz, 3H), 3.19 (m, 4H), 3.94 (m, 4H), 4.31 (q, J=7.2 Hz, 2H), 5.88 (s, 2H), 6.66 (dd, J=1.6, 3.2, Hz, 1H), 7.07 (d, J=3.6 Hz, 1H), 7.61 (m, 2H), 7.74 (m, 1H), 7.88 (d, J=1.2 Hz, 1H), 8.11 m, 2H), 8.20 (dd, J=2.8, 8.8 Hz, 1H), 8.64 (d, J=2.8 Hz, 1H); EIMS: 533 (M+1). Anal. (C28H25FN4O6) C, H, N.
Reaction SMILES: [CH2:1]([C:4]1([S:7]([NH:10][C:11]2[CH:16]=[CH:15][C:14](=[O:17])[N:13]([CH3:18])[C:12]=2[N:19]([C:27]2[CH:32]=[CH:31][C:30]([I:33])=[CH:29][C:28]=2[F:34])[C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])(=[O:9])=[O:8])[CH2:6][CH2:5]1)[CH:2]=C.CC1C=CC=C(C)N=1.[O:43]1CCOCC1>O.O=[Os](=O)(=O)=O>[F:34][C:28]1[CH:29]=[C:30]([I:33])[CH:31]=[CH:32][C:27]=1[N:19]([C:12]1[N:13]([CH3:18])[C:14](=[O:17])[CH:15]=[CH:16][C:11]=1[NH:10][S:7]([C:4]1([CH2:1][CH:2]=[O:43])[CH2:5][CH2:6]1)(=[O:9])=[O:8])[C:20](=[O:26])[O:21][C:22]([CH3:24])([CH3:23])[CH3:25]
Reactant: C=CCC1(S(=O)(=O)Nc2ccc(=O)n(C)c2N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)CC1
Reactant: C1COCCO1
Agent: O=[Os](=O)(=O)=O
Solvent: Cc1cccc(C)n1
Solvent: O
Product: Cn1c(N(C(=O)OC(C)(C)C)c2ccc(I)cc2F)c(NS(=O)(=O)C2(CC=O)CC2)ccc1=O
Temperature: 0 °C
Reaction time: 18 h
Yield: 88 %

Procedure:
To a solution of tert-butyl (3-{[(1-allylcyclopropyl)sulfonyl]amino}-1-methyl-6-oxo-1,6-dihydropyridin-2-yl)(2-fluoro-4-iodophenyl)carbamate (140 mg, 0.232 mmol) in dioxane (2.30 ml) under a nitrogen atmosphere was added H2O (0.51 ml). Then NaIO4 (4 eq, 198 mg, 0.928 mmol) and 2,6-dimethyl pyridin (2 eq, 0.054 ml, 0.464 mmol) were added and the mixture was cooled to 0° C. At this temperature OsO4 (4% in H2O, 0.05 eq, 71 μl, 0.012 mmol) was added. The mixture was allowed to come to room temperature and then stirred for 18 hours. The mixture was diluted with H2O (4 ml) to form a fine suspension. After stirring for 30 min the precipitate was filtered off to afford the title compound (140 mg, 88%) in sufficient purity for the next transformation (88% UV) as a mixture of the aldehyde and a cyclised 1,2-thiazolidin-3-ol 1,1-dioxide form.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]([C:10]2[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=1.[OH-].[NH4+:22]>>[NH2:22][C:11]1[C:10]([C:8]([C:6]2[C:5]([C:17]([F:20])([F:19])[F:18])=[CH:4][CH:3]=[C:2]([Cl:1])[N:7]=2)=[O:9])=[CH:15][CH:14]=[CH:13][N:12]=1
Reactant: O=C(c1cccnc1F)c1nc(Cl)ccc1C(F)(F)F
Reactant: [NH4+]
Agent: [OH-]
Product: Nc1ncccc1C(=O)c1nc(Cl)ccc1C(F)(F)F
Temperature: 25 °C
Yield: 94.3 %

Procedure:
A mixture of (6-chloro-3-(trifluoromethyl)pyridin-2-yl)(2-fluoropyridin-3-yl)methanone (2.27 g, 7.452 mmol) and a saturated aqueous solution of ammonium hydroxide (20 mL, 513.6 mmol) was heated to 70° C. for 18 hours. The mixture was cooled down to room temperature and the resulting solid was filtered, washed with water and dried under vacuum to give the title compound as a pale yellow solid (2.12 g, 94% yield).
Reaction SMILES: [CH2:1]([C:3]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[CH2:19][CH2:18]2)=[O:16])=[CH:8][C:4]=1[C:5]([OH:7])=O)[CH3:2].[CH:30]1[C:43]2[C:34](=[N:35][C:36]3[C:41]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54](=[O:58])[CH:55]([NH2:57])[CH3:56])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:40][CH:39]=[CH:38][CH:37]=3)[CH:33]=[CH:32][CH:31]=1>>[CH:40]1[C:41]2[C:36](=[N:35][C:34]3[C:43]([C:42]=2[NH:44][C:45]2[CH:46]=[C:47]([NH:53][C:54]([CH:55]([NH:57][C:5]([C:4]4[CH:8]=[C:9]([NH:14][C:15]([N:17]5[CH2:22][CH2:21][N:20]([C:23]6[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=6)[CH2:19][CH2:18]5)=[O:16])[C:10]([O:12][CH3:13])=[N:11][C:3]=4[CH2:1][CH3:2])=[O:7])[CH3:56])=[O:58])[CH:48]=[C:49]([CH2:51][OH:52])[CH:50]=2)=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:37]=[CH:38][CH:39]=1
Reactant: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C(=O)O
Reactant: CC(N)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Product: CCc1nc(OC)c(NC(=O)N2CCN(c3cccc(O)c3)CC2)cc1C(=O)NC(C)C(=O)Nc1cc(CO)cc(Nc2c3ccccc3nc3ccccc23)c1
Yield: 41.9 %

Procedure:
The same reaction procedure to the example 1 were carried out using 2-ethyl-5-{[4-(3-hydroxyphenyl)-piperazine-1-carbonyl]-amino}-6-methoxy-nicotinic acid and N-[3-(acridine-9-yl-amino)-5-hydroxymethyl-phenyl]-2-aminopropaneamide to give the titled compound.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][N:6]2[CH:11]=1.[N:12]1([C:18]2[CH:26]=[CH:25][C:21]([C:22]([NH2:24])=[O:23])=[CH:20][CH:19]=2)[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.C(N(C(C)C)CC)(C)C>C(O)CO>[N:4]1[C:3]([CH2:2][N:15]2[CH2:14][CH2:13][N:12]([C:18]3[CH:19]=[CH:20][C:21]([C:22]([NH2:24])=[O:23])=[CH:25][CH:26]=3)[CH2:17][CH2:16]2)=[CH:11][N:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=12
Reactant: NC(=O)c1ccc(N2CCNCC2)cc1
Reactant: ClCc1cn2ccccc2n1
Solvent: OCCO
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)c1ccc(N2CCN(Cc3cn4ccccc4n3)CC2)cc1
Yield: 63.5 %

Procedure:
Following the general procedure of Example 2, Step 3, and making noncritical variations, 2-(chloromethyl)imidazo[1,2-a]pyridine (Example 2, Step 1; 0.245 g), 4-(piperazin-1-yl)benzamide (0.302 g), diisopropylethylamine (Aldrich; 0.256 mL), and ethylene glycol (2 mL) gives 0.313 g of the title compound after chromatography (silica gel, methanol/dichloromethane, 8/92, as eluent) and crystallization from methanol/dichloromethane; mp 249-250° C.; IR (mineral oil) 1608, 1398, 1253, 1739, 3133, 756 cm-1. 1H NMR (CDCl3) δ2.74, 3.36, 3.78, 5.7, 6.78, 6.88, 7.16, 7.55, 7.58, 7.71, 8.09.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5](Cl)=[CH:4][C:3]=1[Cl:12].[NH2:13][CH2:14][CH2:15][CH2:16][OH:17].[I-].[K+]>C(O)CCC>[Cl:1][C:2]1[C:3]([Cl:12])=[CH:4][C:5]([NH:13][CH2:14][CH2:15][CH2:16][OH:17])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)cc1Cl
Reactant: NCCCO
Agent: [I-]
Agent: [K+]
Solvent: CCCCO
Product: O=[N+]([O-])c1cc(Cl)c(Cl)cc1NCCCO

Procedure:
A mixture of 113.2 parts of 1,2,4-trichloro-5-nitrobenzene, 75 parts of 3-amino-1-propanol, 0.2 parts of potassium iodide and 200 parts of butanol is stirred and refluxed overnight. The butanol is removed by evaporation in vacuo and water is added to the residue. The product is extracted with 4-methyl-2-pentanone. The extract is washed a few times with water, dried, filtered and evaporated. The oily residue is purified by column-chromatography over silica gel using a mixture of trichloromethane and 5% of methanol as eluent. The pure fractions are collected and the eluent is evaporated. The residue is triturated in 2,2'-oxybispropane. The product is filtered off and crystallized from a mixture of 2,2'-oxybispropane and 2-propanol, yielding 31.7 parts of 3-[(4,5-dichloro2-nitrophenyl)amino]-1-propanol; mp. 97° C.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23](Cl)=[N:24][C:17]=2[N:16]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[CH:29][CH:28]=2)[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(#N)C>[CH2:6]([O:13][N:14]1[C:19](=[O:20])[C:18]2[CH:21]=[C:22]([F:26])[C:23]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[N:24][C:17]=2[N:16]([C:27]2[CH:28]=[CH:29][C:30]([O:33][CH3:34])=[CH:31][CH:32]=2)[C:15]1=[O:35])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(Cl)nc32)cc1
Reactant: C1CCNC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1ccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCCC4)nc32)cc1
Yield: 87.5 %

Procedure:
Using the method of Example N-4, pyrrolidine (0.04 mL, 0.52 mmol), 3-benzyloxy-7-chloro-6-fluoro-1-(4-methoxyphenyl)-1H-pyrido[2,3-d]pyrimidine-2,4-dione (Example W-2, 0.17 g, 0.42 mmol) and triethylamine (0.36 mL, 2.6 mmol) were combined in 20 mL of acetonitrile to give 0.17 g of the title compound as a solid, mp 186-188° C.
Reaction SMILES: ClC1N=C2C(C=[CH:7][C:8]([N:12]3[CH:20](OC(OC4C=CC=CC=4)=O)[C:19]4[C:14](=CC=[CH:17][CH:18]=4)[C:13]3=O)=N2)=CC=1.C(#[N:34])C>>[CH2:20]([N:12]1[CH2:8][CH2:7][NH:34][CH2:14][CH2:13]1)[CH:19]=[CH:18][CH3:17]
Reactant: O=C(Oc1ccccc1)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Reactant: CC#N
Product: CC=CCN1CCNCC1

Procedure:
Following the procedure of Example 36 but starting from 2-(7-chloro-1,8-naphthyridin-2-yl)-3-phenoxycarbonyloxy-1-isoindolinone (4.32 g.) and 1-(but-2-en-1-yl)-piperazine (7 g.) in acetonitrile (25 cc.), 3-[4-(but-2-en-1-yl)-1-piperazinyl]-carbonyloxy-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (1.95 g.) melting at 190° C is obtained.
Reaction SMILES: C([NH:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[Cl:14])(=O)C.Cl[C:16]([O:18][CH2:19][CH2:20][CH3:21])=[O:17]>>[NH2:10][CH2:9][C:8]1[CH:11]=[C:12]([CH3:13])[C:5]([NH:4][C:16](=[O:17])[O:18][CH2:19][CH2:20][CH3:21])=[C:6]([Cl:14])[CH:7]=1
Reactant: CCCOC(=O)Cl
Reactant: CC(=O)Nc1c(C)cc(CN)cc1Cl
Product: CCCOC(=O)Nc1c(C)cc(CN)cc1Cl

Procedure:
The procedure is exactly the same as preparing 4-acetamido-3-chloro-5-methylbenzylamine (Preparation D), except that propyl chloroformate was used instead of acetyl chloride.
Reaction SMILES: [CH3:1][C:2]1[N:6]([C@H:7]2[CH2:13][C@H:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:32][CH2:31][C:30]([F:34])([F:33])[CH2:29][CH2:28]4)=[O:26])[C:18]4[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=4)[C@H:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:5]([CH:35]([CH3:37])[CH3:36])=[N:4][N:3]=1.P([O-])([O-])([O-])=O.N.C1CCCCC1>O>[CH:35]([C:5]1[N:6]([CH:7]2[CH2:13][CH:12]3[N:14]([CH2:15][CH2:16][C@H:17]([NH:24][C:25]([CH:27]4[CH2:28][CH2:29][C:30]([F:34])([F:33])[CH2:31][CH2:32]4)=[O:26])[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:9]([CH2:10][CH2:11]3)[CH2:8]2)[C:2]([CH3:1])=[N:3][N:4]=1)([CH3:36])[CH3:37]
Reactant: Cc1nnc(C(C)C)n1[C@@H]1C[C@H]2CC[C@@H](C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Agent: N
Agent: O=P([O-])([O-])[O-]
Solvent: C1CCCCC1
Solvent: O
Product: Cc1nnc(C(C)C)n1C1CC2CCC(C1)N2CC[C@H](NC(=O)C1CCC(F)(F)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 92.8 %

Procedure:
Maraviroc phosphate (60 gm) was dissolved in water (400 ml) and pH of the reaction mass was adjusted to 8.0 to 8.5 with ammonia solution (30 ml). The layers were separated and the aqueous layer was extracted with methylene chloride. The organic layer was dried with sodium sulfate and treated with carbon. The methylene chloride was distilled off under vacuum at below 45° C. to obtain residual mass. To the residual mass was added cyclohexane (400 ml) and stirred for 15 minutes at room temperature, filtered. The solid obtained was dried under vacuum at 85° C. for 12 hours to obtain 47 gm of maraviroc amorphous form (HPLC Purity: 99.95%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)[CH:5]=[N:6][C:7]=1[CH3:8].C1COCC1.[C:27]1([S:33](Cl)(=[O:35])=[O:34])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:8][C:7]1[N:6]=[CH:5][C:4]([C:9]2[CH:21]=[CH:20][C:12]3[N:13]=[C:14]([NH:16][C:17](=[O:19])[CH3:18])[S:15][C:11]=3[CH:10]=2)=[CH:3][C:2]=1[NH:1][S:33]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:35])=[O:34]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(=O)Nc1nc2ccc(-c3cnc(C)c(N)c3)cc2s1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: CC(=O)Nc1nc2ccc(-c3cnc(C)c(NS(=O)(=O)c4ccccc4)c3)cc2s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 25.3 %

Procedure:
N-(6-(5-amino-6-methylpyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (101.9 mg, 0.342 mmol) and 4-dimethylaminopyridine (4.2 mg, 0.034 mmol) were suspended in pyridine (2.0 ml) and THF (2.0 ml) and benzenesulfonyl chloride (0.21 ml, 1.637 mmol) was added. The reaction was stirred under nitrogen at room temperature. After 1 day, more DMAP (21.3 mg) was added and stirring was continued. After about 2 hours, more benzenesulfonyl chloride (0.18 ml) was added, and stirring was continued. After 3.5 hours, flask put in preheated oil bath (65° C.) and stirring continued. After 45 minutes, LCMS shows mostly product, so reaction cooled to room temperature, concentrated and purified on a silica gel column (20:1 to 10:1 DCM/MeOH to 10:1 DCM/2 N ammonia in MeOH). Fractions with product collected, concentrated, treated with DCM, and filtered. Solid washed with DCM and Et2O, collected, and dried under high vacuum to afford N-(6-(6-methyl-5-(phenylsulfonamido)pyridin-3-yl)benzo[d]thiazol-2-yl)acetamide (38.0 mg, 25% yield). MS (ESI pos. ion) m/z: 439. Calculated exact mass for C21H18N4O3S2: 438.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:7][C:8]([CH3:12])=[C:9]([Cl:11])[CH:10]=1)=[O:5])C>C(O)C.O1CCCC1.[OH-].[Na+]>[Cl:11][C:9]1[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[S:7][C:8]=1[CH3:12]
Reactant: CCOC(=O)c1cc(Cl)c(C)s1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1sc(C(=O)O)cc1Cl
Temperature: 60 °C
Reaction time: 2 h
Yield: 68 %

Procedure:
5-Methyl-2-thiophenecarboxylic acid (2.84 g) was dissolved in N,N-dimethylformamide (30 ml), and iodoethane (1.68 ml) and potassium carbonate (2.76 g) were added. The mixture was stirred at room temperature for 15 hours, poured into water and extracted with diethyl ether. The extract was washed with 5% aqueous potassium hydrogen sulfate, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 2-methyl-3-thiophenecarboxylic acid ethyl ester (1.84 g). 5-Methyl-2-thiophenecarboxylic acid ethyl ester (1.84 g) was dissolved in acetonitrile (30 ml), and sulfuryl chloride (1.31 ml) in acetonitrile (20 ml) was added dropwise. The mixture was stirred for 1.5 hour over a water bath, and 10% aqueous sodium thiosulfate (100 ml) was added. The mixture was stirred at room temperature for 2 hours and extracted with diethyl ether. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, and the desired fractions were concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g). 4-Chloro-5-methyl-2-thiophenecarboxylic acid ethyl ester (1.67 g) was dissolved in a mixture of ethanol (10 ml) and tetrahydrofuran (10 ml), and 1N aqueous sodium hydroxide (16 ml) was added. The mixture was stirred at 60° C. for 2 hours and washed with diethyl ether. The aqueous layer was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 4-chloro-5-methyl-2-thiophenecarboxylic acid (0.98 g) as crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH2:20])=[CH:16][CH:15]=3)=[CH:8][CH:9]=[N:10]2)=[N:5][CH:4]=1.[N:21]1([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31](Cl)=[N:30][N:29]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.C(O)(C(F)(F)F)=O>CCOC(C)=O>[N:21]1([C:28]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:31]([NH:20][C:17]3[CH:18]=[CH:19][C:14]([O:13][C:7]4[C:6]5[C:11](=[CH:12][C:3]([O:2][CH3:1])=[CH:4][N:5]=5)[N:10]=[CH:9][CH:8]=4)=[CH:15][CH:16]=3)=[N:30][N:29]=2)[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]1
Reactant: COc1cnc2c(Oc3ccc(N)cc3)ccnc2c1
Reactant: Clc1nnc(N2CCCCCC2)c2ccccc12
Solvent: CCOC(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cnc2c(Oc3ccc(Nc4nnc(N5CCCCCC5)c5ccccc45)cc3)ccnc2c1
Temperature: 100 °C

Procedure:
A pyrex reaction tube was charged with 4-(7-methoxy-1,5-naphthyridin-4-yloxy)benzenamine (128 mg, 0.478 mmol), 1-(azepan-1-yl)-4-chlorophthalazine (125 mg, 0.478 mmol), TFA (0.029 ml, 0.382 mmol) and 2.4 mL of 2-BuOH. The tube was sealed and the reaction mixture was heated at 100° C. for 1.5 h. Upon cooling, EtOAc was added, and the resulting precipitate was filtered and washed with EtOAc. The solid was dissolved in 90/10/1 CH2Cl2/MeOH/NH4OH and purified by silica gel chromatography with 90/10/1 CH2Cl2/MeOH/NH4OH. The material was further purified by reverse phase chromatography (Gilson, 5-95% ACN over 15 min) to provide 4-(azepan-1-yl)-N-(4-(7-methoxy-1,5-naphthyridin-4-yloxy)phenyl)phthalazin-1-amine as a tan solid. MS m/z=493 [M+H]+. Calc'd for C29H28N6O2: 492.57.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[K+].[CH2:11]([O:13][C:14]([N:16]1[CH2:22][C:21](=O)[C:20]2[CH:24]=[CH:25][S:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])[CH3:12]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[CH2:11]([O:13][C:14]([N:16]1[CH2:22][C:21](=[CH2:1])[C:20]2[CH:24]=[CH:25][S:26][C:19]=2[CH2:18][CH2:17]1)=[O:15])[CH3:12]
Reactant: CCOC(=O)N1CCc2sccc2C(=O)C1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CN(C(=O)OCC)CCc2sccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 87.6 %

Procedure:
Methyl triphenylphosphonium bromide (6.3 g, 17.6 mmol) was dissolved in 150 mL THF and cooled to 0° C. KHMDS (3.2 g, 16.2 mmol) was added portionwise and the reaction was stirred for ½ hour. The product of Example 1, step (c) (3.0 g, 12.5 mmol) was added as a solution in 25 mL THF. The reaction was warmed to room temperature and stirred for 1 hour. The mixture was concentrated and the title product was purified by silica gel chromatography (0% to 40% EtOAc in hexanes) to give 2.6 g of the sub-title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=2)[CH:9]=1)=[O:4].Br[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[O:35][CH3:36].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>O1CCOCC1>[CH3:1][O:2][C:3]([C:5]1[O:6][C:7]([CH3:27])=[C:8]([CH2:10][O:11][C:12]2[CH:13]=[CH:14][C:15]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[O:35][CH3:36])=[CH:16][CH:17]=2)[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc(COc2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c(C)o1
Reactant: COc1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClCCl
Product: COC(=O)c1cc(COc2ccc(-c3ccccc3OC)cc2)c(C)o1
Yield: 21 %

Procedure:
A degassed mixture of 5-methyl-4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxymethyl]-furan-2-carboxylic acid methyl ester (119) (200 mg, 0.54 mmoles), 1-bromo-2-methoxy-benzene (80 μl, 0.65 mmoles), 2M aqueous cesium carbonate (11.0 ml) and), [1,1′-bis(diphenylphosphino) ferrocene]dichloropalladium(II) complex with dichloromethane (1:1) (44 mg) in 1,4-dioxan (30 ml), under an argon atmosphere was heated at 95° C. for 18 hours. After cooling, the mixture was concentrated, the residue dissolved in ethyl acetate and washed with brine and dried. After evaporation of the solvent, the residue was purified by flash chromatography using cyclohexane/ethyl acetate 9:1 v/v as eluent to afford compound 125 (40 mg) as an oil. LC/MS System A; Rt=4.14 mins, m/z (ES+)=353 weak (M+H for C21H20O5).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5].Br[CH2:13][CH2:14][OH:15].CN(C)C=O>>[Cl:1][C:2]1[CH:9]=[C:8]([O:10][CH2:13][CH2:14][OH:15])[CH:7]=[C:6]([Cl:11])[C:3]=1[CH:4]=[O:5]
Reactant: O=Cc1c(Cl)cc(O)cc1Cl
Reactant: OCCBr
Solvent: CN(C)C=O
Product: O=Cc1c(Cl)cc(OCCO)cc1Cl
Temperature: 80 °C

Procedure:
To a solution of 3.00 g (15.7 mmol) A1 and 1.4 ml (19.7 mmol) 2-bromoethanol in 50 ml dry dimethyl formamide 3.06 g (22.1 mmol) potassium carbonate were added the mixture was heated to 80° C. for 2 hours. Every 30 minutes, 0.2 ml 2-bromoethanol were added until no A1 was longer observed by TLC (hexanes/ethyl acetate 1:1). The solvent was removed in vacuo and the residue was partitionated between ethyl acetate and water. The organic layer was dried over sodium sulfate and evaporated to dryness. The residue was treated with ether and filtered off to yield 3.03 g (82%) A12, m.p. 83-85° C.