Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]([C@@H:5]([NH:38][CH3:39])[CH2:6][S:7][CH2:8][C:9]1[C:27]([O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30])=[CH:26][C:25]([O:36][CH3:37])=[CH:24][C:10]=1[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])=[O:4].[C:40]([O:59][CH2:60][CH2:61][C:62](Cl)=[O:63])([C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)([C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1)[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(CC)CC)C>C(Cl)Cl>[Si:29]([O:28][C:27]1[C:9]([CH2:8][S:7][CH2:6][C@H:5]([N:38]([C:62](=[O:63])[CH2:61][CH2:60][O:59][C:40]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)[CH3:39])[C:3]([O:2][CH3:1])=[O:4])=[C:10]([CH:24]=[C:25]([O:36][CH3:37])[CH:26]=1)[C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][CH:16]=1)=[O:12])([C:32]([CH3:34])([CH3:35])[CH3:33])([CH3:31])[CH3:30]
Reactant: CN[C@@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Reactant: O=C(Cl)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)N(C)C(=O)CCOC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 65.8 %

Procedure:
A solution of 0.64 g of p-nitrobenzyl (R)-2-[[[2-(methoxycarbonyl)-2-(methylamino)-ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate and 0.58 g of 3-trityloxypropionyl chloride in 6 ml of methylene chloride was treated at 0° C. with 0.17 g of triethylamine. The mixture was stirred at 0° C. for 30 minutes, then diluted with methylene chloride, and washed successively with 5% sodium bicarbonate solution and brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:2, v/v) as eluent to yield 0.65 g of p-nitrobenzyl (R)-3-(tert-butyldimethylsilyloxy)-5-methoxy-2-[[[2-(3-trityloxypropionyl-methylamino)-2-methoxycarbonyl-ethyl]thio]methyl]-benzoate as an oil.
Reaction SMILES: [F:1][C:2]1[C:9]([CH3:10])=[CH:8][C:5](C=O)=[CH:4][C:3]=1[CH3:11].C1C=C(Cl)C=C([C:19]([O:21]O)=[O:20])C=1>C(Cl)Cl>[F:1][C:2]1[C:3]([CH3:11])=[CH:4][C:5]([O:21][CH:19]=[O:20])=[CH:8][C:9]=1[CH3:10]
Reactant: Cc1cc(C=O)cc(C)c1F
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1cc(OC=O)cc(C)c1F
Temperature: 25 °C
Reaction time: 20 h

Procedure:
To a solution of 4-fluoro-3,5-dimethyl-benzaldehyde (1.0 g, 6.4 mmol) in 20 mL DCM was added mCPBA (1.2 g, 7.6 mmol) at 25° C. After being stirred for 20 h at 25° C., the reaction was quenched by the addition of 40 mL of 5% aqueous potassium carbonate. The mixture was extracted DCM (3×30 mL) and the combined DCM layer was washed with brine (2×30 mL). The solution was dried over Na2SO4 before being concentrated under reduced pressure. The crude product was used directly in the next reaction without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]([C:8]1[CH:9]=[CH:10][C:11]([N:14]([CH3:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:12][CH:13]=1)=O.C(OP([CH2:35][C:36]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)=[O:37])(OCC)=O)C.[H-].[Na+]>>[CH3:21][N:14]([C:11]1[CH:10]=[CH:9][C:8]([C:6]([C:5]2[CH:22]=[CH:23][C:24]([O:25][CH3:26])=[C:3]([O:2][CH3:1])[CH:4]=2)=[CH:35][C:36]([N:38]2[CH2:43][CH2:42][O:41][CH2:40][CH2:39]2)=[O:37])=[CH:13][N:12]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COc1ccc(C(=O)c2ccc(N(C)c3ccccc3)nc2)cc1OC
Reactant: CCOP(=O)(CC(=O)N1CCOCC1)OCC
Agent: [H-]
Agent: [Na+]
Product: COc1ccc(C(=CC(=O)N2CCOCC2)c2ccc(N(C)c3ccccc3)nc2)cc1OC
Yield: 32.1 %

Procedure:
In the same manner as in Example 1, using 5-(3,4-dimethoxybenzoyl)-2-(N-methylanilino)pyridine (500 mg), diethylphosphonoacetic acid morpholide (800 mg) and 60% sodium hydride (150 mg), E-isomer (250 mg) and Z-isomer (212 mg) of 4-[3-(2-(N-methylanilino)-5-pyridyl)-3-(3,4-dimethoxyphenyl)acryloyl]morpholine (Compound No.62) were obtained.
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[CH2:12]([C:14]1[CH:26]=[CH:25][C:24]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][C:16]=2[CH:15]=1)[CH3:13].Cl>ClC(Cl)C>[C:1]([C:20]1[CH:21]=[CH:22][C:23]2[C:24]3[C:16](=[CH:15][C:14]([CH2:12][CH3:13])=[CH:26][CH:25]=3)[CH2:17][C:18]=2[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCc1ccc2c(c1)Cc1ccccc1-2
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Product: CCc1ccc2c(c1)Cc1cc(C(C)=O)ccc1-2

Procedure:
Acetic anhydride (2.67 g.) in dichloroethane (10 ml.) was added dropwise to a stirred, cooled (0°) suspension of aluminum chloride (6.95 g.) in dichloroethane (20 ml.). Cooling and stirring were continued during the dropwise addition of a solution of 2-ethylfluorene (4.61 g.) in dichloroethane (50 ml.). The mixture was stirred for one hour at room temperature and then decomposed by the dropwise addition of 2N-hydrochloric acid (40 ml.) to the cooled solution. The organic layer was separated, washed with water and with aqueous sodium bicarbonate, dried over anhydrous sodium sulphate, filtered, and evaporated under reduced pressure. The residue was recrystallised from light petroleum (ca 250 ml., b.p. 60°-80°) to give 2-acetyl-7-ethylfluorene m.p. 120°-122°.
Reaction SMILES: [Na+].[C:2]([O:5][CH2:6][C:7]1[CH2:14][S:13][CH:12]2[N:9]([C:10](=[O:26])[CH:11]2[NH:15][C:16](=[O:25])[CH2:17][N:18]2[CH:22]=[CH:21][CH:20]=[C:19]2[CH:23]=[O:24])[C:8]=1[C:27]([O-:29])=[O:28])(=[O:4])[CH3:3].Cl[CH2:31][O:32][C:33](=[O:46])[C@H:34]([CH:43]([CH3:45])[CH3:44])[NH:35][C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37]>CN(C)C=O.C(OCC)(=O)C>[C:39]([O:38][C:36]([NH:35][CH:34]([CH:43]([CH3:45])[CH3:44])[C:33]([O:32][CH2:31][O:28][C:27]([C:8]1[N:9]2[CH:12]([S:13][CH2:14][C:7]=1[CH2:6][O:5][C:2](=[O:4])[CH3:3])[CH:11]([NH:15][C:16](=[O:25])[CH2:17][N:18]1[CH:22]=[CH:21][CH:20]=[C:19]1[CH:23]=[O:24])[C:10]2=[O:26])=[O:29])=[O:46])=[O:37])([CH3:42])([CH3:41])[CH3:40]
Reactant: CC(=O)OCC1=C(C(=O)[O-])N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCCl
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)OCC1=C(C(=O)OCOC(=O)C(NC(=O)OC(C)(C)C)C(C)C)N2C(=O)C(NC(=O)Cn3cccc3C=O)C2SC1
Reaction time: 72 h

Procedure:
A suspension of 5 grams of 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt and 8.5 grams of N-tert-butoxycarbonyl-L-valine chloromethyl ester, prepared according to the general procedure described in W. German Offen. No. 2,236,620, are mixed in 100 ml of dimethylformamide (DMF) and stirred for 72 hours. The mixture is diluted with ethyl acetate, washed with water and aqueous sodium bicarbonate and again with water. The ethyl acetate portion is dried over magnesium sulfate, filtered and evaporated to dryness to give 3-[(acetyloxy)methyl]-7-[[(2-formyl-1-pyrryl)acetyl]amino]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid N-tert-butoxycarbonyl-2-amino-3-methylbutyryloxymethyl ester from which the protecting group can be removed by standard procedures to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)[C:5]([CH2:19][C:20]([O:22][CH2:23]C)=[O:21])=[CH:4][N:3]=1.[H-].[Na+].CI.[CH:29]([O:31][CH3:32])=O>CCOCC>[CH3:1][C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:16])([F:17])[F:18])[CH:10]=2)[C:5]([C:19](=[CH:29][O:31][CH3:32])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1cnc(C)nc1Oc1cccc(C(F)(F)F)c1
Reactant: COC=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CCOCC
Product: COC=C(C(=O)OC)c1cnc(C)nc1Oc1cccc(C(F)(F)F)c1

Procedure:
Ethyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-acetate (3 g, 8 mmol) are dissolved in methyl formate (10 ml) and added to a suspension of NaH (0.6 g, 80% in oil, 20 mmol) in 1,2-dimethoxyaethane at room temperature. After 16 hours methyl iodide (2.5 ml, 40 mmol) is added with cooling. After further 2 hours the reaction mixture is diluted with ether and washed with brine. Drying and chromatography on silicagel (eluant:hexane/ethyl acetate 1:1) gives the methyl α-[2-methyl-4-(3-trifluoromethylphenoxy)-5-pyrimidinyl]-β-methoxyacrylate compound as a crystalline solid, m.p. 100°-102° C.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=O.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:19]>N1C=CC=CC=1>[CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:5]2[C:10]=1[CH:9]=[N:8][NH:7][C:6]2=[S:19]
Reactant: Cc1nc(-c2ccccc2)n2c(=O)[nH]ncc12
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1nc(-c2ccccc2)n2c(=S)[nH]ncc12
Temperature: 100 °C

Procedure:
To a solution of 4.5 gm. of 8-methyl-6-phenyl-imidazo-[1,5-d]-as-triazin-4(3H)-one in 100 ml. of pyridine is added 5 gm. of phosphorus pentasulfide. The reaction mixture is heated at 100° C. for 8 hours, filtered, and poured into dilute hydrochloric acid. The precipitated product is isolated by filtration, washed with water, and dried.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][C:2]=1[C:10]([OH:12])=O.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)=[CH:29][C:28]=1[NH2:39]>>[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]2[CH2:34][CH2:35][O:36][CH2:37][CH2:38]2)=[CH:29][C:28]=1[NH:39][C:10]([C:2]1[NH:1][C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=1)=[O:12]
Reactant: COc1ccc(N2CCOCC2)cc1N
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(N2CCOCC2)cc1NC(=O)c1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In accordance with scheme 3, to a suspension of a corresponding benzoimidazole-2-carboxylic acid (XIII) was added CDI and stirred at ambient temperature for about 1 h. Then the mixture is refluxed for about 30 min. After cooling to ambient temperature, 2-methoxy-5-morpholin-4-yl-phenylamine (for R1=morpholinyl, IX) was added and the reaction mixture was heated to reflux for about 16 h. After workup, the corresponding 1H-benzoimidazole-2-carboxylic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (XIV) was obtained, which was then taken up in toluene and treated with Lawesson reagent. The reaction mixture was heated to reflux for about 2 h and after workup, the corresponding 1H-benzoimidazole-2-carbothioic acid (2-methoxy-5-morpholin-4-yl-phenyl)-amide (IV) was obtained, which was then taken up in water and treated with KOH and potassium hexacyano ferrate at reflux for about 24 h to obtain the corresponding 2-(1H-benzoimidazol-2-yl)-4-methoxy-7-morpholin-4-yl-benzothiazole (Ib).
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:30])([OH:29])[OH:28])(=[O:25])=[O:24])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+:40]>C(O)C.O>[C:1]1([C:7]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:8]=2[C:9]([NH:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][N:34]=2)=[N:10][C:11]([C:17]2[CH:18]=[C:19]([S:23]([NH:26][P:27](=[O:28])([O-:29])[O-:30])(=[O:24])=[O:25])[CH:20]=[N:21][CH:22]=2)=[N:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1.[Na+:40].[Na+:40]
Reactant: O=P(O)(O)NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=P([O-])([O-])NS(=O)(=O)c1cncc(-c2nc(NCc3ccccn3)c3c(-c4ccccc4)cccc3n2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.6 %

Procedure:
To a suspension of ((5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonyl)phosphoramidic acid (2) (0.070 g, 0.13 mmol) in ethanol (5 mL) was added NaOH (9.95 mg, 0.249 mmol) in 1 mL of water. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 2 h. The reaction mixture was concentrated to dryness and the residue washed with ethyl acetate (2×10 mL), acetone (2×10 mL) and acetonitrile (2×15 mL) to afford disodium (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)quinazolin-2-yl)pyridin-3-yl)sulfonylphosphoramidate (4) (0.040 g, 0.068 mmol, 52% yield) as a yellow solid. 1H NMR (400 MHz, deuterium oxide) δ (ppm) 4.46 (s, 2H), 7.04 (d, J=7.78 Hz, 1H), 7.16 (d, J=6.27 Hz, 1H), 7.18-7.23 (m, 1H), 7.26 (d, J=6.27 Hz, 2H), 7.33 (d, J=6.78 Hz, 3H), 7.57-7.72 (m, 3H), 8.27 (d, J=4.27 Hz, 1H), 8.88 (br. s., 1H), 9.03 (s, 1H), 9.19 (s, 1H); 31P (162.0 MHz, DMSO-d6) δ (ppm) −5.19; LCMS Method I: retention time 1.61 min, [M+1]=549. HPLC Method K: Purity 94%, retention time 8.59 min. Elemental analysis: MF C25H19N6SPO5.2.3 Na.3.8 H2O, Calculated C, 45.03; H, 4.02; N, 12.60; Na, 7.79; H2O, 10.27; Found C, 44.90; H, 3.58; N, 12.40; Na, 7.79; H2O, 10.61.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[C:9]([CH2:16][O:17]COC)=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.[OH-].[Na+]>O1CCOCC1.O>[CH:1]1([CH2:6][N:7]([CH2:21][CH3:22])[C:8]2[C:9]([CH2:16][OH:17])=[N:10][C:11]([O:14][CH3:15])=[CH:12][CH:13]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CCN(CC1CCCC1)c1ccc(OC)nc1COCOC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCN(CC1CCCC1)c1ccc(OC)nc1CO
Temperature: 50 °C
Reaction time: 19 h
Yield: 93.5 %

Procedure:
A solution of N-(cyclopentylmethyl)-N-ethyl-6-methoxy-2-[(methoxymethoxy)methyl]pyridin-3-amine (8.39 g, 27.2 mmol) in a mixture of dioxane (400 mL) and water (100 mL) was added dropwise with concentrated hydrochloric acid (20 mL), and the mixture was stirred at 50° C. for 19 hours. The reaction mixture was made basic by adding aqueous sodium hydroxide, and extracted with ethyl acetate. The organic layers were combined, washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=15:1) to obtain {3-[(cyclopentylmethyl)(ethyl)amino]-6-methoxypyridin-2-yl}methanol (6.72 g, 94%) as pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([OH:32])=O)[C:25]=1[CH3:33])(=[O:12])=[O:11].[N:34]1([CH2:39][C@@H:40]2[CH2:44][CH2:43][CH2:42][NH:41]2)[CH2:38][CH2:37][CH2:36][CH2:35]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl>>[Cl:1][C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10]([C:13]1[CH:14]=[C:15]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17](=[O:22])/[C:16]/2=[CH:23]\[C:24]1[NH:28][C:27]([CH3:29])=[C:26]([C:30]([N:41]2[CH2:42][CH2:43][CH2:44][C@H:40]2[CH2:39][N:34]2[CH2:38][CH2:37][CH2:36][CH2:35]2)=[O:32])[C:25]=1[CH3:33])(=[O:12])=[O:11]
Reactant: C1CN[C@H](CN2CCCC2)C1
Reactant: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: Cc1[nH]c(/C=C2\C(=O)Nc3ccc(S(=O)(=O)Cc4cccc(Cl)c4Cl)cc32)c(C)c1C(=O)N1CCC[C@H]1CN1CCCC1

Procedure:
5-[5-(2,3-Dichloro-phenylmethanesulfonyl)-2-oxo-1,2-dihydro-indol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (110 mg, 0.22 mmol) was coupled with (S)-2-pyrrolidin-1-ylmethyl-pyrrolidine (41 mg, 1.2 eq.) using HOBt (1.2 eq.), EDAC.HCl (1.2 eq.) and TEA (3 eq.) to give the titled compound. MS m/z 639 [M−1].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[CH2:14][C:13]2[C:12]([F:15])=[C:11]([NH:16][C@@H:17]3[CH2:22][CH2:21][CH2:20][CH2:19][C@@H:18]3[NH:23]C(=O)OC(C)(C)C)[N:10]=[C:9]([C:31]3[CH:32]=[N:33][N:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=34)[C:8]=2[C:7]1=[O:40].C(O)(C(F)(F)F)=O>>[NH2:23][C@H:18]1[CH2:19][CH2:20][CH2:21][CH2:22][C@H:17]1[NH:16][C:11]1[N:10]=[C:9]([C:31]2[CH:32]=[N:33][N:34]3[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=23)[C:8]2[C:7](=[O:40])[NH:6][CH2:14][C:13]=2[C:12]=1[F:15]
Reactant: COc1ccc(CN2Cc3c(F)c(N[C@@H]4CCCC[C@@H]4NC(=O)OC(C)(C)C)nc(-c4cnn5ccccc45)c3C2=O)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Product: N[C@H]1CCCC[C@H]1Nc1nc(-c2cnn3ccccc23)c2c(c1F)CNC2=O
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 48.1 %

Procedure:
A mixture of tert-butyl (1S,2R)-2-(2-(2,4-dimethoxybenzyl)-7-fluoro-3-oxo-4-(pyrazolo[1,5-a]pyridin-3-yl)-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-6-ylamino)cyclohexylcarbamate (52 mg, 0.082 mmol) and TFA (1 mL, 12.98 mmol) was stirred at 65° C. for 30 min. The mixture was concentrated and the residue was purified by preparative HPLC to give the title compound as a white solid (15 mg, 47.8%). 1H NMR (500 MHz, DMSO-d6) δ ppm 1.21-2.07 (m, 8H), 3.31 (br s, 1H), 4.18-4.26 (m, 1H), 4.46 (br s, 2H), 6.61 (br s, 1H), 7.09 (d, J=6.35 Hz, 1H), 7.49 (d, J=7.32, 1H), 8.36 (br s, 1H), 8.59 (d, J=7.81 Hz, 1H), 8.83 (d, J=6.83 Hz, 1H), 9.56 (br s, 1H). [M+H] calc'd for C20H21FN6O, 381. found, 381.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:12][C:13]([O:15][CH3:16])=[O:14])[C:9]([OH:11])=[O:10].N[CH:18](C1C=C(C)C=CC=1)C(O)=O>>[CH3:16][O:15][C:13]([NH:12][CH:8]([C:3]1[CH:4]=[C:5]([CH3:18])[CH:6]=[CH:7][CH:2]=1)[C:9]([OH:11])=[O:10])=[O:14]
Reactant: Cc1cccc(C(N)C(=O)O)c1
Reactant: COC(=O)NC(C(=O)O)c1ccccc1F
Product: COC(=O)NC(C(=O)O)c1cccc(C)c1

Procedure:
Methoxycarbonylamino-m-tolyl-acetic acid was prepared using the procedure used to prepare (2-Fluoro-phenyl)-methoxycarbonylamino-acetic acid using Amino-m-tolyl-acetic acid. LCMS-ESI+: calc'd for C11H13NO4: 223.08 (M+); Found: 223.90 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[O:21]C)[C:8]=2[Cl:13])[N:3]=1.B(Br)(Br)Br.[OH-].[NH4+]>C(Cl)Cl>[NH2:1][C:2]1[N:11]=[C:10]([NH2:12])[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:14]3[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=3[OH:21])[C:8]=2[Cl:13])[N:3]=1
Reactant: COc1ccc(Cl)cc1-c1ccc2nc(N)nc(N)c2c1Cl
Agent: BrB(Br)Br
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Product: Nc1nc(N)c2c(Cl)c(-c3cc(Cl)ccc3O)ccc2n1
Temperature: 25 °C
Yield: 8.9 %

Procedure:
A solution of 2.8 grams (0.084 mole) of 2,4-diamino-5-chloro-6-(5-chloro-2-methoxyphenyl)quinazoline (prepared in Example 2)in 300 mL of methylene chloride was stirred, and 35 mL of 1.0M boron tribromide in methylene chloride was added. Upon completion of addition, the reaction mixture was stirred at ambient temperature for about 21 hours. Thin layer chromatographic analysis of the reaction mixture indicated that the reaction was not complete. The reaction mixture was heated at reflux for about 6 hours, then it was allowed to cool to ambient temperature where it was stirred for about 60 hours. After this time, the reaction mixture was poured into 500 mL of ice containing 100 mL of concentrated ammonium hydroxide. The mixture was filtered to collect a solid. The solid was washed with water and dried at 70° C. under reduced pressure, yielding 2.4 grams of 2,4-diamino-5-chloro-6-(5-chloro-2-hydroxyphenyl)quinazoline. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH2:7][CH2:8][CH2:9][CH:10]2[C:13]([OH:15])=O)=[CH:5][CH:4]=1.[CH3:16][N:17]([CH3:35])[C:18]1[CH:23]=[CH:22][C:21]([CH2:24][NH:25][C:26]2[CH:27]=[N:28][C:29]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:31]=2)=[CH:20][CH:19]=1>>[CH3:16][N:17]([CH3:35])[C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]([C:26]2[CH:27]=[N:28][C:29]([CH:32]([CH3:33])[CH3:34])=[CH:30][CH:31]=2)[C:13]([CH:10]2[C:11]3[C:6](=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[CH:12]=3)[CH2:7][CH2:8][CH2:9]2)=[O:15])=[CH:22][CH:23]=1
Reactant: COc1ccc2c(c1)C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cn1
Product: COc1ccc2c(c1)C(C(=O)N(Cc1ccc(N(C)C)cc1)c1ccc(C(C)C)nc1)CCC2
Yield: 14.3 %

Procedure:
By the reaction and treatment in the same manner as in Example 12 using 7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (0.41 g) and [(4-dimethylaminophenyl)methyl](6-isopropylpyridin-3-yl)amine (0.54 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(6-isopropylpyridin-3-yl)-7-methoxy-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.13 g) was obtained.
Reaction SMILES: [N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([OH:23])=O)=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1.C(Cl)(C([Cl:28])=O)=O>C(Cl)Cl.CN(C=O)C>[N:1]1[C:6]2[NH:7][CH:8]=[CH:9][C:5]=2[C:4]([O:10][C:11]2[CH:12]=[C:13]3[C:18](=[CH:19][CH:20]=2)[C:17]([C:21]([Cl:28])=[O:23])=[CH:16][CH:15]=[CH:14]3)=[N:3][CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cccc2cc(Oc3ncnc4[nH]ccc34)ccc12
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 6-(7H-pyrrolo[2,3-d]pyrimidin-4-yloxy)-1-naphthoic acid (357 mg, 1.17 mmol) in DCM (11.7 mL) under an N2 atmosphere, was added DMF (2 drops) followed by (COCl)2 (143 μL, 1.64 mmol) dropwise. After stirring at RT for 4 hours, the reaction mixture became a yellow slurry. An aliquot was removed and placed in a vial containing 500 μl of 1M MeNH2. After 5 min, the resulting solution was analyzed by LCMS to indicate complete conversion to the methylamine and that no acid was present in the reaction mixture. The slurry was concentrated to a yellow stable solid, which was taken directly to the next step of the reaction sequence.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9](/[C:12](/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[C:13](\[CH:16]2[CH2:25][CH2:24][C:19]3(OCC[O:20]3)[CH2:18][CH2:17]2)/[CH2:14][CH3:15])=[CH:8][CH:7]=1.Cl.O.C([O-])(O)=O.[Na+]>CO>[OH:32][C:29]1[CH:28]=[CH:27][C:26](/[C:12](/[C:9]2[CH:10]=[CH:11][C:6]([O:5][CH2:4][CH2:3][NH:2][CH3:1])=[CH:7][CH:8]=2)=[C:13](/[CH:16]2[CH2:25][CH2:24][C:19](=[O:20])[CH2:18][CH2:17]2)\[CH2:14][CH3:15])=[CH:31][CH:30]=1
Reactant: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC2(CC1)OCCO2
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC/C(=C(\c1ccc(O)cc1)c1ccc(OCCNC)cc1)C1CCC(=O)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 27.2 %

Procedure:
To a solution of (Z)-4-(1-(4-(2-(methylamino)ethoxy)phenyl)-2-(1,4-dioxaspiro[4.5]decan-8-yl)but-1-enyl)phenol (90 mg) in MeOH (10 mL) was added aqueous of HCl (3 M, 1.5 mL), the mixture was stirred at room temperature for 2 hours, 20 mL water was added, pH was adjusted to 7-8 by addition of aqueous NaHCO3, and the mixture was extracted with ethyl acetate. The extract was dried, concentrated, and purified by column chromatography (CH2Cl2:MeOH=150:1) to give the desired product (22 mg, 27.5% yield). m/z=394[M+1]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[NH2:22])[O:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1.C1N=CN([C:28](N2C=NC=C2)=[O:29])C=1>C1(C)C=CC=CC=1>[O:29]=[C:28]1[N:22]=[C:21]2[CH:20]=[CH:19][C:4]([O:5][CH2:6][CH2:7][CH2:8][N:9]3[CH2:18][CH2:17][C:16]4[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=4)[CH2:10]3)=[CH:3][C:2]2=[N:1]1
Reactant: Nc1ccc(OCCCN2CCc3ccccc3C2)cc1N
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: Cc1ccccc1
Product: O=C1N=c2ccc(OCCCN3CCc4ccccc4C3)cc2=N1
Yield: 49.7 %

Procedure:
A mixture of N-[(3,4-diaminophenoxy)propyl]-1,2,3,4-tetrahydroisoquinoline (200 mg, 0.67 mmol) and CDI (162 mg, 1.0 mmol) in toluene (15 mL) was refluxed for 16 h, then evaporated. The residual solid was washed with EtOAc (2×5 mL) and CHCl3 (5 mL), then dried to give 107 mg (48%) of the title compound as a yellow powder. 1H NMR (DMSO-d6): 1.90-1.96 (m, 2H), 2.591 (d, 2H, J=7), 2.662 (t, 2H, J=5), 2.803 (t, 2H, J=5), 3.560 (s, 2H), 3.967 (t, 2H, J=6), 6.50-6.52 (m, 2H), 6.76-6.80 (m, 1H), 7.05-7.10 (m, 4H), 10.359 (s, 1H), 10.483 (s, 1H). The hydrochloride, mp. 210-5° C. (dec). Analysis, Calcd. for (C19H22ClN3O2+0.3 HCl): C 61.55, H 6.06, N 11.33; Found: C 61.57, H 6.14, N 11.05.