Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])[C:5]([Cl:23])=[CH:4][N:3]=1.[NH2:24][C:25]1[CH:38]=[CH:37][C:28]2[NH:29][C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:35])([CH3:34])[C:27]=2[CH:26]=1.Cl.O1CCO[CH2:42][CH2:41]1>COCCO>[Cl:23][C:5]1[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:11][C:10]=2[O:21][CH3:22])=[N:7][C:2]([NH:24][C:25]2[CH:38]=[CH:37][C:28]3[N:29]([CH2:41][CH3:42])[C:30](=[O:36])[CH2:31][CH2:32][C:33]([CH3:35])([CH3:34])[C:27]=3[CH:26]=2)=[N:3][CH:4]=1
Reactant: C1COCCO1
Reactant: CC1(C)CCC(=O)Nc2ccc(N)cc21
Reactant: COc1cc(N2CCOCC2)ccc1Nc1nc(Cl)ncc1Cl
Agent: Cl
Solvent: COCCO
Product: CCN1C(=O)CCC(C)(C)c2cc(Nc3ncc(Cl)c(Nc4ccc(N5CCOCC5)cc4OC)n3)ccc21
Yield: 51 %

Procedure:
Combined (2,5-Dichloro-pyrimidin-4-yl)-(2-methoxy-4-morpholin-4-yl-phenyl)-amine (108 mg, 0.304 mmol), 7-Amino-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (79 mg, 0.387 mmol), 4 N HCl in dioxane (100 ul) and 2-methoxyethanol (4 mL). Heated reaction to 120° C. for 2 hours. Evaporated off solvent and purified with normal phase chromatography to yield an off-white solid, 7-[5-Chloro-4-(2-methoxy-4-morpholin-4-yl-phenylamino)-pyrimidin-2-ylamino]-1-ethyl-5,5-dimethyl-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (81 mg, 51%). mp 255° C.; LCMS: m/z=523.06 (M+H+), 1H NMR (400 MHz, CDCl3) δ 8.21 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=1.5 Hz), 7.65 (d, 1H, J=8.3 Hz), 7.61 (s, 1H), 7.37 (s, 1H), 7.15 (s, 1H), 6.96 (s, 1H), 6.87 (d, 1H, J=8.6 Hz), 6.56 (s, 1H), 6.49 (d, 1H, J=8.8 Hz), 3.94 (s, 3H), 3.91 (m, 4H), 3.17 (m, 4H), 2.41 (m, 2H), 2.12 (m, 2H), 1.40 (s, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]([CH3:11])([CH3:10])[CH3:9])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:3]=1[OH:16].C(N(C(C)C)CC)(C)C.[CH3:26][O:27][CH2:28]Cl>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C(Cl)Cl>[CH3:26][O:27][CH2:28][C:2]1([Br:1])[CH:7]=[C:6]([C:8]([CH3:9])([CH3:10])[CH3:11])[CH:5]=[C:4]([C:12]([CH3:15])([CH3:14])[CH3:13])[CH:3]1[OH:16]
Reactant: CC(C)(C)c1cc(Br)c(O)c(C(C)(C)C)c1
Reactant: COCCl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC1(Br)C=C(C(C)(C)C)C=C(C(C)(C)C)C1O
Temperature: 45 °C
Yield: 94.8 %

Procedure:
To a solution of 2-bromo-4,6-di-t-butylphenol (Compound D 2.54 g, 8.88 mmol) and catalytic amount of Bu4NI in 20 ml of dry CH2Cl2 at 0° C. was added diisopropylethylamine (9.51 ml, 53 mmol), followed by methoxymethyl chloride (2.02 ml, 26.6 mmol). The reaction mixture was heated to 45° C. for 12 hours. The reaction mixture was then washed with 10% citric acid, then NaHCO3 (sat.), brine, and dried over MgSO4. After filtration and removal of the solvent under reduced pressure, the residue was purified by column chromatography (pure hexane) to yield the title compound (2.79 g) as a colorless oil. 1H NMR δ 7.40 (d, J=2.44 Hz, 1H), 7.30 (d, J=2.4 Hz, 1H), 5.22 (s, 2H), 3.70 (s, 3H), 1.43 (s, 9H), 1.29 (s, 9H).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11](O)=O.C(Cl)(=O)C(Cl)=O.S(N)([NH2:23])(=O)=O.[OH-].[Na+]>ClCCl.CN(C=O)C>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][CH2:10][C:11]#[N:23]
Reactant: O=C(O)CCc1cccc(F)c1F
Reactant: NS(N)(=O)=O
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: N#CCCc1cccc(F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.4 %

Procedure:
To a solution of 3-(2,3-difluorophenyl)-propionic acid (A1) (6.83 g, 36 mmol) in anhydrous dichloromethane (50 ml) containing a few drops of DMF was added oxalyl chloride (6.4 ml, 73 mmol) at 0° C. under argon. The solution was stirred at ambient temperature for 2 h and the solvent removed in vacuo. The residue was dissolved in sulfolane (30 ml) and added to sulfamide (4.23 g, 44 mmol) and the mixture heated at 120° C. for 3 h. The brown solution was cooled, poured into 2M sodium hydroxide solution (300 ml) and extracted with ether. The combined extracts were washed with water, dried (MgSO4) and evaporated to give the title compound as a brown oil (6.04 g, 98%). 1H-NMR (CDCl3) δ 2.68 (2H, t), 3.04 (2H, t), 7.01-7.15 (3H, m).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@@H:27]2[CH2:31][O:30]C(C)(C)[O:28]2)[N:12]=1.O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:9][S:10][C:11]1[N:16]=[C:15]([NH:17][S:18]([N:21]2[CH2:24][CH2:23][CH2:22]2)(=[O:20])=[O:19])[CH:14]=[C:13]([O:25][CH2:26][C@@H:27]([OH:28])[CH2:31][OH:30])[N:12]=1
Reactant: CC1(C)OC[C@@H](COc2cc(NS(=O)(=O)N3CCC3)nc(SCc3cccc(F)c3F)n2)O1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: O=S(=O)(Nc1cc(OC[C@@H](O)CO)nc(SCc2cccc(F)c2F)n1)N1CCC1

Procedure:
To a solution of N-[2-[[(2,3-difluorophenyl)methyl]thio]-6-[[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy]-4-pyrimidinyl]-1-azetidinesulfonamide (the product of step ii) (0.48 g) in methanol (5 mL)/H2O (0.1 mL) was added pyridinium p-toluenesulfonate (0.12 g) and the mixture was stirred at reflux for 2 h. The reaction mixture was evaporated, suspended in H2O and extracted with EtOAc (×2). The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was triturated with DCM to give the title compound as a white solid, Yield: 0.30 g
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:12]=[CH:11][S:10][C:9]=1[C:13]1[CH:18]=[CH:17][C:16]([Br:19])=[CH:15][CH:14]=1)(C)(C)C.Cl.CC(O)C.[OH-].[Na+]>CCOC(C)=O>[Br:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[S:10][CH:11]=[CH:12][C:8]=2[NH2:7])=[CH:14][CH:15]=1
Reactant: CC(C)(C)OC(=O)Nc1ccsc1-c1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: Nc1ccsc1-c1ccc(Br)cc1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 98.2 %

Procedure:
Charge a 10 L double jacketed reactor equipped with mechanical stirring, set under inert atmosphere of argon with [2-(4-bromo-phenyl)-thiophen-3-yl]-carbamic acid tert-butyl ester (800 g, 2.25 mol) and EtOAc (3.2 L). Cool the yellow solution is down to 16.9° C. and add a solution of 5-6N HCl/IPA (1600 mL) in 10 minutes via a dropping funnel between 10° C. and 25° C. Heat the reaction mixture to 50° C. Stir the resulting suspension for 90 minutes at 50° C. Cool the suspension below 10° C. and add 2N NaOH solution (2773 mL) over 25 minutes, maintaining the temperature below 20° C. Add 2N NaOH (450 mL) to reach a pH of 12-13. Separate the two layers by decantation. Re-extract the aqueous phase with EtOAc (500 mL). Dry the combined organic layers over MgSO4 (200 g) and evaporate to dryness to yield 2-(4-Bromo-phenyl)-thiophen-3-ylamine (562.3 g, 2.21 mol) as a beige solid. 1H NMR (250 MHz, CDCl3): 3.70(s (broad), 2 H) 6.65(d,1 H, J=5.4 Hz), 7.06(d, 1 H, J=5.2 Hz), 7.32(d, 2 H, J=8.9 Hz), 7.45 (d, 2H, J=8.8 Hz).
Reaction SMILES: [CH3:1][CH:2]([CH3:22])[C:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[CH:11][C:8]=2[C:9]=1[CH3:10])=[O:4].[BH4-].[Na+].O>CO.O1CCCC1>[CH3:1][CH:2]([CH3:22])[CH:3]([C:5]1[O:6][C:7]2[CH:14]=[CH:13][C:12]([O:15][CH:16]3[CH2:17][CH2:18][S:19][CH2:20][CH2:21]3)=[CH:11][C:8]=2[C:9]=1[CH3:10])[OH:4]
Reactant: Cc1c(C(=O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: Cc1c(C(O)C(C)C)oc2ccc(OC3CCSCC3)cc12
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72.7 %

Procedure:
2-Methyl-1-[3-methyl-5-(tetrahydro-2H-thiopyran-4-yloxy)-1-benzofuran-2-yl]propan-1-one (849 mg) synthesized above was dissolved in methanol (3 mL)-tetrahydrofuran (15 mL), and sodium tetrahydroborate (90%) (202 mg) was added to the solution at 0° C. The reaction mixture was stirred at 0° C. for 30 min. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. After filtration, the filtrate was concentrated. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate 100:0-85:15, v/v) to give the title compound (621 mg, 73%) as a colorless oil.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[F:38][C:39]1[CH:44]=[CH:43][C:42]([S:45](Cl)(=[O:47])=[O:46])=[CH:41][CH:40]=1.C(=O)([O-])O.[Na+]>ClCCl.C1COCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([NH:30][S:45]([C:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][CH:41]=3)(=[O:47])=[O:46])[CH2:28][CH2:29]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(N)CC2)c2ccc(Cl)c(Cl)c2)CC1
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(NS(=O)(=O)c3ccc(F)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To the mixture of the compound obtained in Example 194 (528 mg, 1.00 mmol), triethylamine (0.502 mL, 3.60 mmol), THF (10 mL) and dichloromethane (10 mL) was added 4-fluorobenzenesulfonyl chloride (234 mg, 1.20 mmol), and the mixture was stirred at room temperature for 16 hours. To the mixture was added a saturated aqueous solution of sodium hydrogen carbonate (15 ml), and the organic solvent was distilled off under reduced pressure. The aqueous layer was extracted with ethyl acetate (15 mL×3). The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate (5 mL×3), saturated sodium chloride solution (5 mL), successively, dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to column chromatography (silica gel log, ethyl acetate/methanol=1/0 to 9/1), and the desired fraction was concentrated under reduced pressure. To the concentrate was added ethyl acetate and resulting precipitates were filtered off. The filtrate was concentrated under reduced pressure to give the titled compound (516 mg, 0.84 mmol, Yield 84%) as colorless foam like substance.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.[OH-:19].[K+].Cl.[NH2:22]O.Cl>O.C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:22][OH:19])[C:9]2[CH:14]=[C:13]([CH2:15][CH3:16])[CH:12]=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: [OH-]
Reactant: CCc1ccc(O)c(C(=O)c2ccc(Cl)cc2)c1
Reactant: NO
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: O
Product: CCc1ccc(O)c(C(=NO)c2ccc(Cl)cc2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.4 %

Procedure:
4'-Chloro-5-ethyl-2-hydroxybenzophenone (65.2 g) and potassium hydroxide (170 g) in water (700 ml) and ethanol (150 ml.) were treated with hydroxylamine hydrochloride (70.0 g), with cooling, and the resulting mixture was stirred for 18 hours at ambient temperature. Dissolution occurred during this time. The solution was acidified with 5N-hydrochloric acid and then extracted with ether (3 × 200 ml.). The combined ether solutions were washed with 10% aqueous sodium carbonate solution (2 × 200 ml.) and evaporated to dryness to give an off-white solid. This solid was recrystallised from 40% benzene/60°-80° C. petrol ether to give a white crystalline solid (29.9 g), second crop (14.5 g) m.p. 117° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:7]1[CH:11]=[C:10]([NH:12][C:13](=[O:21])OC2C=CC=CC=2)[N:9]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:8]=1)([CH3:6])[CH3:5])[CH3:2].[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([CH:47]=[CH:48][CH:49]=1)[NH2:46].C(N(CC)C(C)C)(C)C>C1COCC1>[CH3:28][O:29][C:30]1[CH:31]=[C:32]2[C:37](=[CH:38][C:39]=1[O:40][CH3:41])[N:36]=[CH:35][N:34]=[C:33]2[S:42][C:43]1[CH:44]=[C:45]([NH:46][C:13]([NH:12][C:10]2[N:9]([C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:8]=[C:7]([C:4]([O:3][CH2:1][CH3:2])([CH3:5])[CH3:6])[CH:11]=2)=[O:21])[CH:47]=[CH:48][CH:49]=1
Reactant: CCOC(C)(C)c1cc(NC(=O)Oc2ccccc2)n(-c2ccccc2)n1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(C)(C)c1cc(NC(=O)Nc2cccc(Sc3ncnc4cc(OC)c(OC)cc34)c2)n(-c2ccccc2)n1
Yield: 64 %

Procedure:
Using the procedure described in Example 159B, using phenyl 3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-ylcarbamate described in Example 168B (0.115 g, 0.33 mmol), 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline from Example 115B (0.103 g, 0.33 mmol), and N,N-diisopropylethylamine (0.8 mL) in THF (6 mL) at 50° C. for 5 hours, to afford 1-[3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl]-3-[3-(2-ethoxypropan-2-yl)-1-phenyl-1H-pyrazol-5-yl]urea as solid (123 mg, 64%). 1H NMR (300 MHz, DMSO-d6) δ 9.26 (br, 1H), 8.69 (s, 1H), 8.54 (s, 1H), 7.80 (s, 1H), 7.54 (m, 4H), 7.23-7.45 (m, 5H), 7.24 (d, 1H), 6.42 (s, 1H), 3.99 (s, 6H), 3.25 (q, 2H), 1.46 (s, 6H), 1.04 (t, 3H); LC-MS (ESI) m/z 539 (M-OEt)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]([NH2:17])[C:14]([NH2:18])=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:5]2=[N:6][CH:7]=1.C1N=CN([C:32](N2C=NC=C2)=[O:33])C=1.C(N(CC)CC)C>CN(C)C=O.O.C(=O)([O-])O.[Na+]>[F:1][C:2]1[CH:3]=[C:4]2[N:10]([C:11]3[N:16]=[C:15]4[NH:17][C:32](=[O:33])[NH:18][C:14]4=[CH:13][CH:12]=3)[N:9]=[C:8]([CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[F:26])[C:5]2=[N:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1ccc(-n2nc(Cc3ccccc3F)c3ncc(F)cc32)nc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1[nH]c2ccc(-n3nc(Cc4ccccc4F)c4ncc(F)cc43)nc2[nH]1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
70 mg (0.20 mmol) of the compound from example 40A were initially charged in dimethylformamide (5 ml), then 161 mg (0.993 mmol) of N,N-carbonyldiimidazole and 0.33 ml (2.38 mmol) of triethylamine were added and the mixture was stirred at 100° C. overnight. The reaction mixture was subsequently diluted with water and saturated aqueous sodium hydrogencarbonate solution and extracted twice with ethyl acetate. The collected organic phases were dried over sodium sulfate, filtered and concentrated by rotary evaporation. Preparative HPLC (eluent: acetonitrile-water with 0.1% formic acid gradient) of the residue gave 38 mg (48% of theory) of the desired title compound in solid form.
Reaction SMILES: [C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][NH:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:25]1([CH2:31][C:32]([NH:34][C@@H:35]([C:39]([CH3:42])([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[C:1]([O:5][C:6]([C@@H:8]1[CH2:24][C@@:11]2([O:15][C:14](=[O:16])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[CH:18]=3)[CH2:12]2)[CH2:10][N:9]1[C:36](=[O:37])[C@@H:35]([NH:34][C:32](=[O:33])[CH2:31][CH:25]1[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1)[C:39]([CH3:41])([CH3:42])[CH3:40])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)[C@H](NC(=O)CC1CCCCC1)C(=O)O
Reactant: CC(C)(C)OC(=O)[C@@H]1C[C@@]2(CN1)CN(c1cccc(Cl)c1)C(=O)O2
Product: CC(C)(C)OC(=O)[C@@H]1C[C@]2(CN(c3cccc(Cl)c3)C(=O)O2)CN1C(=O)[C@@H](NC(=O)CC1CCCCC1)C(C)(C)C
Yield: 50 %

Procedure:
Following the procedure from Example 1 step G using (5R,8S)-tert-butyl-3-(3-chlorophenyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (B4) (20 mg, 54 μmol, 1 eq.) and (S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoic acid (16 mg, 63 μmol, 1.2 eq.) gave 16 mg (27 μmol) of (5R,8S)-tert-butyl-3-(3-chlorophenyl)-7-((S)-2-(2-cyclohexylacetamido)-3,3-dimethylbutanoyl)-2-oxo-1-oxa-3,7-diazaspiro[4.4]nonane-8-carboxylate (C4). LC MS+/−: 590.31/589.47 at 3.95 min (10-90%, 3-5 min, Formic Acid).
Reaction SMILES: [N:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O)=[N+:2]=[N-:3].S(Cl)(Cl)=O.[Cl:18][C:19]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:20]=1[NH2:21]>C1(C)C=CC=CC=1.N1C=CC=CC=1>[N:1]([C:4]1[CH:12]=[C:11]([Cl:13])[CH:10]=[CH:9][C:5]=1[C:6]([NH:21][C:20]1[CH:22]=[CH:23][C:24]([Cl:26])=[CH:25][C:19]=1[Cl:18])=[O:8])=[N+:2]=[N-:3]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: [N-]=[N+]=Nc1cc(Cl)ccc1C(=O)O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: [N-]=[N+]=Nc1cc(Cl)ccc1C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 0 °C
Reaction time: 0.42 h

Procedure:
2-Azido-4-chlorobenzoic acid (130 g) was stirred with thionyl chloride (52 ml) in dry toluene at room temperature for 24 hours. The solution was evaporated to give crude 2-azido-4-chlorobenzoyl chloride. This product (14.2 g) was added to a solution of 2,4-dichloroaniline (10.65 g) in dry pyridine (70 ml) and the mixture stirred for 25 mins. It was then poured into ice-water and the precipitate filtered off, washed with water, sucked dry, heated in boiling ethanol and the residue filtered off, washed with ethanol and air-dried to give 2-azido-4-chloro-N-(2,4-dichlorophenyl)benzamide, m.p. 169.5° C. (dec.)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][N:4]1[N:13]=[CH:12][C:11]2[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:18].[C:19]1([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(N(CC)CC)C.[I-].[K+]>C(#N)C>[ClH:1].[ClH:1].[C:19]1([N:25]2[CH2:30][CH2:29][N:28]([CH2:2][CH2:3][N:4]3[N:13]=[CH:12][C:11]4[C:6](=[CH:7][C:8]([O:16][CH3:17])=[C:9]([O:14][CH3:15])[CH:10]=4)[C:5]3=[O:18])[CH2:27][CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: COc1cc2cnn(CCCl)c(=O)c2cc1OC
Reactant: c1ccc(N2CCNCC2)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: CCN(CC)CC
Product: COc1cc2cnn(CCN3CCN(c4ccccc4)CC3)c(=O)c2cc1OC
Product: Cl

Procedure:
A mixture of 2-(2-chloroethyl)-6,7-dimethoxy-1(2H)-phthalazinone (2.68 g; 0.01 mole) obtained as described in Example 2, N-phenyl piperazin (1.5 ml), triethyl amine (2.78 ml) and potassium iodide (0.16 g; 0,001 mole) in acetonitrile (50 ml), is refluxed for 12 hours. The solvent is evaporated under reduced pressure and the residue is dissolved in dilute HCl, washed with methylene chloride and after alkalinization with NaHCO3, the mixture is extracted with methylene chloride, dried on sodium sulphate, filtered and evaporated. The residue is dissolved in acetone, made acid with HCl in ethyl ether and the product which separates is filtered and recrystallized from 95% ethanol to give 2-[2-(4-phenylpiperazin-1-yl)-ethyl]-6,7-dimethoxy-1(2H)-phthalazinone dihydrochloride (m.p. 222°-226° C.).
Reaction SMILES: FC1C=C(NC(C2(C(NC3C=CC(F)=CC=3)=O)CC2)=O)C=CC=1OC1C2C(=CC(OC)=C(OC)C=2)[N:12]=[C:11](NC)C=1.[CH3:41][O:42][C:43]1[CH:44]=[C:45]([NH:51][C:52](SC)=[C:53]2[C:58](=[O:59])[O:57][C:56]([CH3:61])([CH3:60])[O:55][C:54]2=[O:62])[CH:46]=[CH:47][C:48]=1[O:49][CH3:50].CN>C1COCC1.Cl[Hg]Cl>[CH3:41][O:42][C:43]1[CH:44]=[C:45]([NH:51][C:52]([NH:12][CH3:11])=[C:53]2[C:58](=[O:59])[O:57][C:56]([CH3:61])([CH3:60])[O:55][C:54]2=[O:62])[CH:46]=[CH:47][C:48]=1[O:49][CH3:50]
Reactant: CNc1cc(Oc2ccc(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)c2cc(OC)c(OC)cc2n1
Reactant: COc1ccc(NC(SC)=C2C(=O)OC(C)(C)OC2=O)cc1OC
Agent: CN
Agent: Cl[Hg]Cl
Solvent: C1CCOC1
Product: CNC(Nc1ccc(OC)c(OC)c1)=C1C(=O)OC(C)(C)OC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 99 %

Procedure:
Synthesis of ′N-(3-fluoro-4-{[2-(methylamino)-6,7-bis(methyloxy)quinolin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide. A mixture of 5-[(3,4-dimethoxy-phenylamino)-methylsulfanyl-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione (0.50 g, 1.4 mmol), methylamine (2 M in THF, 0.75 mL. 1.5 mmol), HgCl2 (0.38 g, 1.4 mmol) in THF (5 mL) was stirred at room temperature for 30 minutes. The mixture was extracted with DCM and water (3×) and dried with Na2SO4. Concentration in vacuo afforded 5-[(3,4-dimethoxy-phenylamino)-methylamino-methylene]-2,2-dimethyl-[1,3]dioxane-4,6-dione as a yellow solid (0.48 g, 99% yield) and this compound was used without further purification. LCMS: m/z 335 (M−H)−.
Reaction SMILES: Cl[C:2](Cl)(Cl)/[C:3](=N\[H])/[O:4][CH:5]1[O:10][CH:9]([CH3:11])[CH:8]2[O:12][CH2:13][C:14](=C)[CH:7]2[CH2:6]1.[Cl:20][CH:21]1[CH:32]([CH3:33])[CH:31]2[CH:23]([C@@:24]3([CH:51]=[O:52])[CH2:36][C@H:28]4[C@@](CO)([CH2:30]2)[C@:25]3([C:40]([O:42]COC(=O)C(C)(C)C)=[O:41])[C:26]([CH:37]([CH3:39])[CH3:38])=[CH:27]4)[CH2:22]1>C(Cl)Cl.CCOCC.CO.[Cl-].[Cl-].[Zn+2]>[Cl:20][CH:21]1[CH:32]([CH3:33])[CH:31]2[CH:23]([C@@:24]3([CH:51]=[O:52])[CH2:36][C@H:28]4[C@@:2]([CH2:3][O:4][CH:5]5[O:10][C:9](=[CH2:11])[CH:8]6[O:12][CH2:13][CH2:14][CH:7]6[CH2:6]5)([CH2:30]2)[C@:25]3([C:40]([OH:42])=[O:41])[C:26]([CH:37]([CH3:38])[CH3:39])=[CH:27]4)[CH2:22]1
Reactant: [H]/N=C(/OC1CC2C(=C)COC2C(C)O1)C(Cl)(Cl)Cl
Reactant: CC(C)C1=C[C@H]2C[C@]3(C=O)C4CC(Cl)C(C)C4C[C@@]2(CO)[C@]13C(=O)OCOC(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Zn+2]
Solvent: ClCCl
Solvent: CCOCC
Solvent: CO
Product: C=C1OC(OC[C@@]23CC4C(C)C(Cl)CC4[C@@]4(C=O)C[C@@H]2C=C(C(C)C)[C@@]34C(=O)O)CC2CCOC12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of imidate 37 prepared above in CH2Cl2 (5 mL) was added 42 (16 mg, 0.033 mmol) in CH2Cl2 (1 mL), followed by ZnCl2 (0.6 mL of a 1M solution in ether, 0.6 mmol). The mixture was stirred at room temperature for 2 hours. After aqueous work-up (CH2Cl2) and purification by PTLC, about 12.6 mg of crude product 43 (•- and •-isomers) was obtained. To a solution of this crude product 43 (4 mg) in CH3OH (2 mL) was added K2CO2 (20 mg). The mixture was stirred at room temperature for about two hours. After aqueous work-up (CH2Cl2) and purification by HPLC, about 1 mg of 44 was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=1.[Br:11][C:12]1[CH:13]=[C:14]([CH:16]=[C:17]([CH3:19])[CH:18]=1)[NH2:15].C(O)(=O)C>O1CCOCC1.ClCCl>[Br:11][C:12]1[CH:13]=[C:14]([NH:15][C:2]2[N:7]=[C:6]([CH:8]([OH:10])[CH3:9])[CH:5]=[CH:4][N:3]=2)[CH:16]=[C:17]([CH3:19])[CH:18]=1
Reactant: CC(O)c1ccnc(Cl)n1
Reactant: Cc1cc(N)cc(Br)c1
Solvent: ClCCl
Solvent: C1COCCO1
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(Nc2nccc(C(C)O)n2)c1
Temperature: 25 °C

Procedure:
1-(2-Chloropyrimidin-4-yl)ethanol (5.25 g, 33.1 mmol) and 3-bromo-5-methylaniline (9.24 g, 49.7 mmol) were suspended in 1,4-dioxane (30 mL). Acetic acid (1.90 ml, 33.1 mmol) was added, and the resultant mixture was heated to 100° C. for 14 h. The reaction mixture was allowed to cool to room temperature and then was diluted with dichloromethane. The resultant solution was adsorbed on silica gel and purified by column chromatography on silica (10-100% ethyl acetate/hexanes) to afford 1-(2-((3-bromo-5-methylphenyl)amino)pyrimidin-4-yl)ethanol as a black semi-solid. MS ESI calc'd. for C13H15BrN3O [M+H]+ 308, 310. found 308, 310.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][C:9]([F:12])([F:11])[F:10])=[CH:6][C:5]([NH2:13])=[C:4]([F:14])[CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22](Cl)=[O:23])=[CH:18][N:17]=1>C(Cl)Cl.CC(N(C)C)=O>[Br:1][C:2]1[C:7]([O:8][C:9]([F:11])([F:12])[F:10])=[CH:6][C:5]([NH:13][C:22](=[O:23])[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[N:17][CH:18]=2)=[C:4]([F:14])[CH:3]=1
Reactant: Nc1cc(OC(F)(F)F)c(Br)cc1F
Reactant: O=C(Cl)c1ccc(F)nc1
Solvent: ClCCl
Solvent: CC(=O)N(C)C
Product: O=C(Nc1cc(OC(F)(F)F)c(Br)cc1F)c1ccc(F)nc1

Procedure:
To a solution of 4-bromo-2-fluoro-5-trifluoromethoxy-phenylamine (500 mg, 2 mmol) dissolved in DCM (1 mL) was slowly added a solution of 2-fluoropyridine-5-carbonyl chloride (290 mg, 1.8 mmol) in DCM (1 mL). A few drops of DMA were added and the reaction mixture was concentrated to form N-(4-bromo-2-fluoro-5-trifluoromethoxy-phenyl)-6-fluoro-nicotinamide as a purple solid.