Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:12]=[N+:13]=[N-:14].[Na+]>CC(C)=O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:12]=[N+:13]=[N-:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(F)cc1

Procedure:
Suspend 4-fluorobenzenesulfonyl chloride (0.500 g, 2.57 mmol) and sodium azide (0.200 g, 3.08 mmol) in acetone. Heat at reflux overnight before concentrating the reaction mixture. Purify by flash 40 chromatography, eluting with 10% ethyl acetate in hexanes to give the title compound: 1H NMR (DMSO-d6) δ 7.58 (tt, J=8.04, 2.02 Hz, 2H), 8.12 (td, 4.89, 1.96 Hz, 2H); HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), acetonitrile in water containing 0.01% concentrated HCl at 1.0 mL/min, 50-99% over 19 min], tR=16.5 min, 92.4% purity.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[Cl:24][C:25]([O:27][CH2:28][CH:29]([CH3:31])[CH3:30])=[O:26]>O.O1CCCC1>[ClH:24].[CH3:30][CH:29]([CH3:31])[CH2:28][O:27][C:25]([NH:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]([N:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[NH:12])[CH:7]=[CH:8][CH:9]=1)=[O:26]
Reactant: CC(C)COC(=O)Cl
Reactant: N=C(Nc1cccc(N)c1)N1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COC(=O)Nc1cccc(NC(=N)N2CCCC2)c1
Temperature: 0 °C

Procedure:
A solution of the product of Example 1, step (b), 1.38 g, 0.0050 moles, was dissolved in 20 ml of water. The solution was gradually treated with sodium carbonate, 0.84 g, 0.0100 moles, and cooled to 0° C. A solution of 0.71 ml of isobutyl chloroformate in 10 ml of tetrahydrofuran was added. After 16 hours the mixture was diluted with water to 100 ml and washed with 20 ml of chloroform. This solution was then made basic with 50% aqueous sodium hydroxide and extracted with 20 ml chloroform (twice). The chloroform layer was dried over potassium carbonate, filtered and the solvent was driven off by vacuum evaporation. The remaining oil was dissolved in 20 ml of isopropanol and 1 ml of concentrated aqueous hydrochloric acid was added. The solution was then made up to 250 ml with ether. Crystals developed and were washed with 10 ml of ether (twice) and dried in a vacuum oven overnight to yield N-(3-(((2-methylpropyloxy)carbonyl)amino)phenyl)-1-pyrrolidinecarboximidamide monohydrochloride. Yield: 1.1 g, m.p. 233°-235 ° C.
Reaction SMILES: [OH-:1].[K+].[C:3]1([CH:9]([OH:18])[CH:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[OH:11])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[S:19](Cl)([C:22]1[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=1)(=[O:21])=[O:20]>CCOCC>[C:25]1([CH3:26])[CH:27]=[CH:28][C:22]([S:19]([O:18][CH:9]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:10]([O:11][S:19]([C:22]2[CH:28]=[CH:27][C:25]([CH3:26])=[CH:24][CH:23]=2)(=[O:20])=[O:1])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)(=[O:21])=[O:20])=[CH:23][CH:24]=1
Reactant: [OH-]
Reactant: OC(c1ccccc1)C(O)c1ccccc1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [K+]
Solvent: CCOCC
Product: Cc1ccc(S(=O)(=O)OC(c2ccccc2)C(OS(=O)(=O)c2ccc(C)cc2)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 412.1 %

Procedure:
Potassium hydroxide (400 mg, 7.0 mmole) was added to a solution of 1,2-diphenylethane-l,2-diol (I40 mg, 0.65 mmole) in dry ether (30 mL). TsCl (286 mg, 1.5 mmole) was added. The reaction was completed after 1 hour with stirring under N2 atmosphere at RT. A white solid was obtained. The white solid was filtered and washed with dichloromethane. The combined filtrate was concentrated, Recrystallization with methylene chloride and hexane gave the crystalline solid (1.4 g, 44.6%), mp, 110-112 (decomposed), 'H-NMR(CDCl3) δ, 2.39(s, 6H CH3), 5.61(s, 2H, CH), 6.89-7.55(m, 18H, ArH).
Reaction SMILES: C([O:3][C:4](=[O:39])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][C:18]2[N:19]=[C:20]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)=[CH:26][CH:25]=3)[O:21][C:22]=2[CH3:23])=[C:11]([CH2:36][CH2:37][CH3:38])[CH:10]=1)([CH3:7])[CH3:6])C.[OH-].[Na+]>C(O)C>[C:27]1([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:26]=[CH:25][C:24]([C:20]2[O:21][C:22]([CH3:23])=[C:18]([CH2:17][CH2:16][O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]([CH3:6])([CH3:7])[C:4]([OH:39])=[O:3])=[CH:10][C:11]=3[CH2:36][CH2:37][CH3:38])[N:19]=2)=[CH:29][CH:28]=1
Reactant: CCCc1cc(OC(C)(C)C(=O)OCC)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCc1cc(OC(C)(C)C(=O)O)ccc1OCCc1nc(-c2ccc(-c3ccccc3)cc2)oc1C
Temperature: 55 °C

Procedure:
A solution of 2-{4-[2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid ethyl ester, (0.57 mmol) in ethanol (10 mL) was treated with 2.5 N aqueous NaOH (1.1 mL), and heated at 55° C. for 2 h. The reaction was cooled to ambient temperature and concentrated down to near dryness. The residue was then diluted with ethyl acetate (40 mL) and water (20 mL) and acidified to pH=1 with 1N aqueous HCl. The organic layer was washed with brine (20 mL), dried (Na2SO4) and concentrated in vacuo to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyloxazol-4-yl)ethoxy]-3-propylphenoxy}-2-methylpropionic acid 1H NMR (400 MHz, CDCl3), δ8.04 (dd, J=6.6, 1.7 Hz, 2H), 7.68-7.62 (m, 4H), 7.47-7.44 (m, 2H), 7.39-7.35 (m, 1H), 6.78 (d, J=8.8 Hz, 1H), 6.72 (d, J=2.9 Hz, 1H), 6.61 (dd, J=8.8, 2.9 Hz, 1H), 4.18 (t, J=6.6 Hz, 2H), 2.99 (t, J=6.6 Hz, 2H), 2.53 (t, J=7.8 Hz, 2H), 2.39 (s, 3H), 1.59 (quintet, J=7.5 Hz, 2H), 1.55 (s, 6H), 0.94 (t, J=7.3 Hz, 3H), MS (ES) m/e 500 M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[S:11][C:12]3[CH:18]=[C:17]([C:19]#[N:20])[CH:16]=[CH:15][C:13]=3[N:14]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2].Cl.[NH2:22][OH:23].O.C(=O)([O-])[O-].[K+].[K+]>C(O)C>[OH:23][NH:22][C:19]([C:17]1[CH:16]=[CH:15][C:13]2[N:14]=[C:10]([N:7]3[CH2:6][CH2:5][N:4]([CH:1]([CH3:2])[CH3:3])[CH2:9][CH2:8]3)[S:11][C:12]=2[CH:18]=1)=[NH:20]
Reactant: CC(C)N1CCN(c2nc3ccc(C#N)cc3s2)CC1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CC(C)N1CCN(c2nc3ccc(C(=N)NO)cc3s2)CC1
Yield: 71.6 %

Procedure:
To a solution of 2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carbonitrile (5.0 g, 17.5 mmol) in ethanol (50 mL) was added hydroxylamine hydrochloride (3.6 g, 52.4 mmol), water (8 mL) and potassium carbonate (7.2 g, 52.4 mmol). The reaction mixture was heated overnight at reflux. The mixture was allowed to cool and then concentrated in vacuo. The residue was dissolved into THF (30 mL) and then filtered. The filtrate was concentrated in vacuo to give 4 g of crude N-hydroxy-2-(4-isopropylpiperazin-1-yl)benzothiazole-6-carboxamidine.
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8].[CH:20](=[O:28])[C:21]1[C:22](=[CH:24][CH:25]=[CH:26][CH:27]=1)O.Cl>C(Cl)(=O)C(Cl)=O.C1C=CC=CC=1.N1C=CC=CC=1.O>[CH3:1][C:2]1[C:3](=[O:19])[C:4]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([O:18][C:27]2[CH:26]=[CH:25][CH:24]=[CH:22][C:21]=2[CH:20]=[O:28])=[O:17])=[C:5]([CH3:10])[C:6](=[O:9])[C:7]=1[CH3:8]
Reactant: O=Cc1ccccc1O
Reactant: CC1=C(C)C(=O)C(CCCCCC(=O)O)=C(C)C1=O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Solvent: O
Solvent: c1ccncc1
Product: CC1=C(C)C(=O)C(CCCCCC(=O)Oc2ccccc2C=O)=C(C)C1=O
Reaction time: 2.5 h

Procedure:
The acid chloride (1.01 part) synthesized from 2,3,5-trimethyl-6-(5'-carboxypentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the free form) (1 part) and oxalyl chloride (5 volume parts) was dissolved in anhydrous benzene (10 volume parts) and the solution was added dropwise to a solution of salicylaldehyde (0.6 part) in pyridine (10 volume parts) at 25° C. After stirring for 2.5 hours, the reaction mixture was diluted with cold water (300 volume parts) and rendered acidic with dilute hydrochloric acid. It was then extracted twice with diethyl ether (300 volume parts). The extracts were pooled, washed with water and dried. The solvent was then distilled off under reduced pressure and the residue was subjected to column chromatography on silica gel. Elution with chloroform provided a yellow oil of 2,3,5-trimethyl-6-(5'-(o-formylphenyloxycarbonyl) pentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of o-formylphenolate) (1.3 part). To a cooled, stirred solution of this product (1.1 part) in acetone (25 volume parts) was added standard Jones reagent (2 volume parts). The solution was stirred for 100 minutes, after which it was diluted with cold water (500 volume parts), followed by extraction with ethyl acetate (500 volume parts). The extract was washed with water and dried. The solvent was then distilled off under reduced pressure and the residue was purified by column chromatography on silica gel (50 parts). The procedure provided a yellow oil of 2,3,5-trimethyl-6-(5'-(o-carboxyphenyloxycarbonyl)-pentyl)-1,4-benzoquinone (formula I-2 wherein R=H3C, n=4, in the form of o-carboxyphenalate (1.1 part).
Reaction SMILES: Cl.[N:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]([OH:15])=O)[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:18]=[C:19]([C:23]([C:25]2[C:33]3[CH:32]=[N:31][CH:30]=[N:29][C:28]=3[N:27]([CH:34]([CH3:36])[CH3:35])[CH:26]=2)=[O:24])[CH:20]=[N:21][CH:22]=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>C(OCC)(=O)C.CN(C=O)C>[N:2]1[C:11]2[CH2:10][N:9]([CH2:12][C:13]([NH:16][C:17]3[CH:22]=[N:21][CH:20]=[C:19]([C:23]([C:25]4[C:33]5[CH:32]=[N:31][CH:30]=[N:29][C:28]=5[N:27]([CH:34]([CH3:36])[CH3:35])[CH:26]=4)=[O:24])[CH:18]=3)=[O:15])[CH2:8][CH2:7][C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)CN1CCc2cccnc2C1
Reactant: CC(C)n1cc(C(=O)c2cncc(N)c2)c2cncnc21
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)n1cc(C(=O)c2cncc(NC(=O)CN3CCc4cccnc4C3)c2)c2cncnc21
Temperature: 50 °C
Yield: 26 %

Procedure:
To a DMF solution of (5,8-Dihydro-6H-[1,7]naphthyridin-7-yl)-acetic acid hydrochloride (Preparation 235) (34.2 mg, 0.18 mmol) were added (5-Amino-pyridin-3-yl)-(7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-methanone (Preparation 95) (50 mg, 0.18 mmol), HATU (136.4 mg, 0.36 mmol) and Hunig's base (0.092 ml, 0.54 mmol). The mixture was heated at 50° C. for 20 hours and then diluted with ethyl acetate, washed with water, brine, dried over sodium sulphate and evaporated to dryness in vacuo. The crude solid was purified over preparative TLC eluting with 5% MeOH/EtOAc to afford the title compound as off white solid in 26% yield, 21 mg. 1H NMR (400 MHz, DMSO-D6) δ: 1.55 (d, 6H), 2.85-2.92 (m, 4H), 3.45 (s, 2H), 3.80 (s, 2H), 5.10 (m, 1H), 7.19 (dd, 1H), 7.56 (d, 1H), 8.32 (d, 1H), 8.53 (s, 1H), 8.56 (t, 1H), 8.73 (d, 1H), 8.99 (s, 1H), 9.07 (d, 1H), 9.45 (s, 1H), 10.31 (s, 1H); LCMS (system 9): Rt=1.77 min; m/z 456 [M+H]+.
Reaction SMILES: CO[C:3](=[O:17])[C:4]1[C:9]([C:10]([F:13])([F:12])[F:11])=[CH:8][C:7]([Cl:14])=[CH:6][C:5]=1[CH2:15]Br.[F:18][C:19]([F:30])([F:29])[O:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1.CCCCCC>[Cl:14][C:7]1[CH:6]=[C:5]2[C:4](=[C:9]([C:10]([F:11])([F:12])[F:13])[CH:8]=1)[C:3](=[O:17])[N:26]([CH2:25][C:24]1[CH:27]=[CH:28][C:21]([O:20][C:19]([F:18])([F:29])[F:30])=[CH:22][CH:23]=1)[CH2:15]2
Reactant: COC(=O)c1c(CBr)cc(Cl)cc1C(F)(F)F
Reactant: NCc1ccc(OC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: O=C1c2c(cc(Cl)cc2C(F)(F)F)CN1Cc1ccc(OC(F)(F)F)cc1
Temperature: 100 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A mixture of 4-chloro-2-bromomethyl-6-trifluoromethyl-benzoic acid methyl ester (1.33 g, 4.0 mmol), 4-trifluoromethoxy-benzylamine (0.610 mL, 4.1 mmol), and K2CO3 (0.691 g, 5.0 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 2 h. Workup and silica gel column chromatography of the product using 30% ethyl acetate in hexane afforded 5-chloro-2-(4-trifluoromethoxy-benzyl)-7-trifluoromethyl-2,3-dihydro-isoindol-1-one (0.770 g, 47%). 1H NMR (300 MHz, CDCl3): δ (ppm) 4.34 (s, 2H), 4.80 (s, 2H) 7.20 (d, 2H), 7.36 (d, 2H), 7.59 (s, 1H), 7.78 (s, 1H). GC-MS: m/z 409 (M)+, 388 (M−21)+.
Reaction SMILES: [CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH2:15])[CH2:5][CH2:4]1)[CH3:2].C([C@@H]1N[C@@H](C2C=CC=CC=2)[C@@H](N)CC1)C.C([C@H]1N[C@H](C2C=CC=CC=2)[C@H](N)CC1)C.[CH3:46][O:47][C:48]1[CH:49]=[C:50]2[C:55](=[CH:56][C:57]=1[CH:58]=O)[N:54]([CH3:60])[C:53](=[O:61])[CH2:52][CH2:51]2>>[CH2:1]([CH:3]1[NH:8][CH:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:6]([NH:15][CH2:58][C:57]2[CH:56]=[C:55]3[C:50]([CH2:51][CH2:52][C:53](=[O:61])[N:54]3[CH3:60])=[CH:49][C:48]=2[O:47][CH3:46])[CH2:5][CH2:4]1)[CH3:2]
Reactant: CCC1CCC(N)C(c2ccccc2)N1
Reactant: COc1cc2c(cc1C=O)N(C)C(=O)CC2
Agent: CC[C@@H]1CC[C@@H](N)[C@@H](c2ccccc2)N1
Agent: CC[C@H]1CC[C@H](N)[C@H](c2ccccc2)N1
Product: CCC1CCC(NCc2cc3c(cc2OC)CCC(=O)N3C)C(c2ccccc2)N1

Procedure:
By a procedure similar to the previous examples 9 and 9A: prepared through the reaction of 6-ethyl-2-phenyl-piperidin-3-ylamine [or (2S,3S,6S)-6-ethyl-2-phenyl-piperidin-3-ylamine or (2R,3R,6R)-6-ethyl-2-phenyl-piperidin-3-ylamine] with 6-Methoxy-1-methyl-2-oxo-1,2,3,4-tetrahydro-quinoline-7-carbaldehyde.
Reaction SMILES: C(OC(=O)N[CH2:8][C:9]([C:12]1[NH:13][C:14]([C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([O:24]C)[CH:18]=2)[N:16]=1)(C)[CH3:10])(C)(C)C.C(OC([NH:40]C(C)(C)C=O)=O)(C)(C)C>>[NH2:40][C:9]([C:12]1[NH:13][C:14]([C:26]2[CH:27]=[CH:28][N:29]=[CH:30][CH:31]=2)=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[C:19]([OH:24])[CH:18]=2)[N:16]=1)([CH3:10])[CH3:8]
Reactant: COc1cc(-c2nc(C(C)(C)CNC(=O)OC(C)(C)C)[nH]c2-c2ccncc2)ccc1Cl
Reactant: CC(C)(C=O)NC(=O)OC(C)(C)C
Product: CC(C)(N)c1nc(-c2ccc(Cl)c(O)c2)c(-c2ccncc2)[nH]1

Procedure:
The title compound was prepared from the product of Example 1, Step 3 and 2-tert-butoxycarbonylamino-2-methylpropanal (T. Seki et al., Chem. Pharm. Bull.; 1996, 44, 2061) using the methods described in Example 1 Step 4, followed by those of Example 2 and Example 3; MS(ES+) m/e 329/331 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2.[C:42](Cl)(=[O:51])[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.C(N(C(C)C)CC)(C)C>ClCCl>[O:51]=[C:42]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:11]1[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([NH:27][C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=1[N:13]=[CH:14][N:15]3[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:6][CH2:5]2)[CH2:43][CH2:44][C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(N)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](Nc2nc(N3CCc4cc(NC(=O)CCc5ccccc5)ccc43)c3ncn(C(=O)OC(C)(C)C)c3n2)CC1
Reaction time: 1 h

Procedure:
40 mg of product obtained in stage 4 of example 41 are mixed with 11.97 mg of hydrocinnamoyl chloride, 25 μl of diisopropylethylamine and 2 ml of dichloromethane. Stirring is carried out for 1 hour at ambient temperature, followed by washing with brine, drying over magnesium sulfate and evaporation to dryness.
Reaction SMILES: Cl[NH:2][C:3]1[N:8]=[C:7]([NH:9]Cl)[N:6]=[C:5]([NH:11]Cl)[N:4]=1.[Cl:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>C(Cl)(Cl)(Cl)Cl.CCCCCC>[Cl:13][CH2:14][CH2:15][C:16]([NH:2][C:3]1[N:8]=[C:7]([NH:9][C:16](=[O:17])[CH2:15][CH2:14][Cl:13])[N:6]=[C:5]([NH:11][C:16](=[O:17])[CH2:15][CH2:14][Cl:13])[N:4]=1)=[O:17]
Reactant: ClNc1nc(NCl)nc(NCl)n1
Reactant: O=C(Cl)CCCl
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCCCCC
Product: O=C(CCCl)Nc1nc(NC(=O)CCCl)nc(NC(=O)CCCl)n1
Yield: 98 %

Procedure:
To a stirring suspension of 2.3 g trichloromelamine in 40 ml CCl4 was added 7.62 g 3-chloropropionyl chloride under Argon. The reaction mixture was heated in an oil bath at 65°-70° C. for 6 hours. The reaction mixture was cooled and then diluted with 50 ml hexane. The precipitates were filtered, washed with hexane and dried under reduced pressure (3.9 g; 98% yield). The product thus obtained was characterized to be N'N',N"-tris (3-chloropropionyl) melamine by 1H NMR, 13C NMR, IR, and mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33](=O)[O:34]C2C=CC=CC=2)[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]>C1COCC1.CN(C1C=CN=CC=1)C>[F:23][C:24]([C:27]1[CH:31]=[C:30]([NH:32][C:33]([NH:19][C:18]2[CH:20]=[CH:21][CH:22]=[C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH:17]=2)=[O:34])[N:29]([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[N:28]=1)([F:26])[CH3:25]
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(F)(F)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(F)F)nn4-c4ccccc4)c3)c2cc1OC
Yield: 62.2 %

Procedure:
Using the procedure described in Example 306B, to a solution of 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline (89 mg, 0.3 mmol), prepared as described in Example 113A, in THF (3.3 ml) was added DMAP (20 mg, 0.16 mmol) and phenyl 3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-ylcarbamate (103 mg, 0.3 mmol), described in in the previous step. The crude was purified by silica gel chromatography (DCM/MeOH 0-15%) and triturated in diethyl ether to afford 1-(3-(1,1-difluoroethyl)-1-phenyl-1H-pyrazol-5-yl)-3-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)urea (102 mg, 62%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 1.99 (t, J=18 Hz, 3H), 3.99 (s, 6H), 6.66 (s, 1H), 6.94 (d, J=9.6 Hz, 1H), 7.18 (d, J=9.6 Hz, 1H), 7.35-7.40 (m, 2H), 7.51-7.60 (m, 7H), 8.55 (s, 1H), 8.66 (s, 1H), 9.26 (s, 1H); LC-MS (ESI) m/z 547 (M+H)+.
Reaction SMILES: Cl.[CH:2]1([NH2:8])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[CH3:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[NH:16][C:17]#[N:18]>ClC1C=CC=CC=1>[CH:2]1([NH:8][C:17]([NH:16][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=2[CH3:9])=[NH:18])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: Cc1ccccc1NC#N
Reactant: NC1CCCCC1
Agent: Cl
Solvent: Clc1ccccc1
Product: Cc1ccccc1NC(=N)NC1CCCCC1
Reaction time: 8 h
Yield: 26.5 %

Procedure:
A suspension of cyclohexylamine hydrochloride (310 mg, 2.28 mmol) and (2-methylphenyl)cyanamide (365 mg, 2.76 mmol) in dry chlorobenzene was heated at 125°-135° for 4 hrs. The solvent was evaporated in vacuo with heating, and the residue partitioned between CH2Cl2 and 20×8 ml 10% HCl. The aqueous extracts were made alkaline to pH 9-9.5, and the white precipitate collected after standing at 4° C. overnight. Two recrystallizations from EtOH/H2O gave 140 mg (22%) of white needles, mp 145°-146°, 1H (CD3OD) 1.149-2.054 (m, 10H), 2.164 (s, 3H), 3.50 (m, 1H), 6.875 (d, 1H, J=7.5 Hz), 6.968 (t, 1H, J=7.5 Hz), 7.118 (t, 1H, J=7.5 Hz), 7.177 (d, 1H, J=7.5 Hz). Anal. Calcd for C14H21N3 : C, 72.69; H, 9.15; N, 18.16. Found: C, 72.72; H, 9.24; N, 18.18.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=2)[C:5]([C:19]#[N:20])=[C:4](S)[N:3]=1.Br[CH2:23][C:24]([NH2:26])=[O:25].C([O-])(O)=O.[Na+]>CN(C=O)C.O>[C:19]([C:5]1[C:4]([CH2:23][C:24](=[O:25])[NH2:26])=[N:3][C:2]([NH2:1])=[C:7]([C:8]#[N:9])[C:6]=1[C:10]1[CH:15]=[C:14]([Cl:16])[C:13]([OH:17])=[C:12]([Cl:18])[CH:11]=1)#[N:20]
Reactant: NC(=O)CBr
Reactant: N#Cc1c(N)nc(S)c(C#N)c1-c1cc(Cl)c(O)c(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1c(N)nc(CC(N)=O)c(C#N)c1-c1cc(Cl)c(O)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
337.2 mg (1 mmol) of 2-amino-4-(3,5-dichloro-4-hydroxyphenyl)-6-sulfanyl-3,5-pyridinedicarbonitrile and 207 mg (1.5 mmol) of bromoacetamide are dissolved in 4 ml of DMF, 336 mg (4 mmol) of NaHCO3 are added and the mixture is stirred at RT for 8 hours. The mixture is diluted with water and washed with ethyl acetate. The aqueous phase is acidified with 1N HCl and the resulting crystals are filtered off with suction and dried.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25]CC)=[O:24])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:4]=2[N:3]=1.[OH-].[Na+]>C(O)C.C(OCC)(=O)C.O>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:29]=[CH:28][C:17]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[CH:16][CH:15]=3)=[CH:7][C:6]=2[C:5]2[CH:30]=[CH:31][C:32]([CH3:34])=[CH:33][C:4]=2[N:3]=1
Reactant: CCOC(=O)CCCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCCC(=O)O)cc3)cc12
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of ethyl 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)pentanoate (1.0 equiv.) (from Example 139) in ethanol (0.10 M) was added anhydrous sodium hydroxide (2.0 equiv.) and the resulting mixture was allowed to stir at 80° C. for 2 hours. After cooling to ambient temperature, the mixture was diluted with ethyl acetate and water. The biphasic layers were separated and the aqueous layer was washed twice with ethyl acetate. The combined organic layers were dried over anhydrous Na2SO4 and the volatiles were removed in vacuo. The resulting residue was purified by a COMBIFLASH® system (ISCO) using 0-10% methanol in dichloromethane to furnish 5-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)phenoxy)pentanoic acid as a solid. 1H NMR (Methanol-d4): δ 8.61 (s, 1H), 8.57 (s, 1H), 8.20 (d, 1H), 7.40 (s, 1H), 7.20 (d, 1H), 7.07 (d, 2H), 6.81 (d, 2H), 3.93 (t, 2H), 3.18 (t, 2H), 3.00 (t, 2H), 2.48 (s, 3H), 2.25 (t, 2H), 1.74-1.81 (m, 2H), 0.86-0.96 (m, 2H). LRMS [M+H]=430.2
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:10][CH2:11][C:12]([CH2:24][O:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([CH3:23])[C:13]([O:15]CC1C=CC=CC=1)=[O:14])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.O.C(OCC)(=O)C>C1COCC1>[CH2:3]([O:10][CH2:11][C:12]([CH2:24][O:25][CH2:26][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)([CH3:23])[C:13]([OH:15])=[O:14])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(COCc1ccccc1)(COCc1ccccc1)C(=O)OCc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CC(COCc1ccccc1)(COCc1ccccc1)C(=O)O
Yield: 34.7 %

Procedure:
1 N Aqueous sodium hydroxide (2.6 mL) was added to a solution of benzyl 3-benzyloxy-2-benzyloxymethyl-2-methylpropionate obtained in Step A (350 mg, 0.87 mmol) in THF (2.6 mL), and the mixture was stirred under reflux for three hours. Water and ethyl acetate were added to the mixture to separate the aqueous layer. 1 N hydrochloric acid was added to the aqueous layer to make the aqueous layer acidic, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. From the resulting residue, crude 3-benzyloxy-2-benzyloxymethyl-2-methylpropionic acid (95 mg) was obtained as a colorless oil without purification. Condensation was carried out by a method similar to that of Example 3-1 using 3-benzyloxy-2-benzyloxymethyl-2-methylpropionic acid obtained above instead of Boc-Sar-OH and 7-((S)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-13 instead of 7-((R)-5-hydroxymethyl-2-oxooxazolidin-3-yl)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Step B of Example 1-14, and deprotection was carried out by a method similar to that of Example 1-36 using a 10% Pd—C catalyst in a hydrogen atmosphere to synthesize the title compound.