Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:5]=[C:4]([O:17][C:18]2[C:25]([CH3:26])=[CH:24][C:21]([C:22]#[N:23])=[CH:20][C:19]=2[CH3:27])[CH:3]=1.[Br:28]Br.[OH-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>ClCCl.O>[CH3:27][C:19]1[CH:20]=[C:21]([C:22]#[N:23])[CH:24]=[C:25]([CH3:26])[C:18]=1[O:17][C:4]1[N:5]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][CH:10]=2)[N:7]=[C:2]([NH2:1])[C:3]=1[Br:28]
Reactant: Cc1cc(C#N)cc(C)c1Oc1cc(N)nc(Nc2ccc(C#N)cc2)n1
Reactant: BrBr
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: Cc1cc(C#N)cc(C)c1Oc1nc(Nc2ccc(C#N)cc2)nc(N)c1Br
Temperature: 2.5 °C
Reaction time: 4 h

Procedure:
4-[[6-amino-2-[(4-cyanophenyl)amino]-4-pyrimidinyl]oxy]-3,5-dimethyl-benzonitrile (10 gm) was dissolved in dichloromethane (100 ml) at 0 to 5° C. and then added bromine solution (4.7 gm in 50 ml of dichloromethane). The reaction mass was stirred for 4 hours at 0 to 5° C. and then added water (100 ml). The pH of the reaction mass was adjusted to 9 to 10 with sodium hydroxide solution (4N, 10 ml). Sodium metabisulphite solution (0.5 gm in 2 ml of water) was added to the reaction mass and pH of the reaction mass was maintained between 7.5 to 8.5 with sodium hydroxide solution (4N, 10 ml). The separated solid was filtered and dried at 50 to 55° C. to obtain crude etravirine.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:17][CH:18]=[C:19]([C:21]3[CH:26]=[CH:25][C:24](Br)=[CH:23][CH:22]=3)[N:20]=2)[CH2:14][N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7].[CH3:37][O:38][C:39](=[O:72])[NH:40][CH:41]([C:45]([N:47]1[CH2:51][CH2:50][CH2:49][CH:48]1[C:52]1[NH:53][CH:54]=[C:55]([C:57]2[CH:62]=[CH:61][C:60](B3OC(C)(C)C(C)(C)O3)=[CH:59][CH:58]=2)[N:56]=1)=[O:46])[CH:42]([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+].COCCOC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O>[CH3:1][O:2][C:3](=[O:36])[NH:4][CH:5]([C:9]([N:11]1[CH:15]([C:16]2[NH:20][C:19]([C:21]3[CH:26]=[CH:25][C:24]([C:60]4[CH:61]=[CH:62][C:57]([C:55]5[NH:56][C:52]([CH:48]6[CH2:49][CH2:50][CH2:51][N:47]6[C:45](=[O:46])[CH:41]([NH:40][C:39]([O:38][CH3:37])=[O:72])[CH:42]([CH3:44])[CH3:43])=[N:53][CH:54]=5)=[CH:58][CH:59]=4)=[CH:23][CH:22]=3)=[CH:18][N:17]=2)[CH2:14][N:13]([C:28](=[O:35])[C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:12]1)=[O:10])[CH:6]([CH3:8])[CH3:7]
Reactant: COC(=O)NC(C(=O)N1CN(C(=O)c2ccccc2)CC1c1nc(-c2ccc(Br)cc2)c[nH]1)C(C)C
Reactant: COC(=O)NC(C(=O)N1CCCC1c1nc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)c[nH]1)C(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: COC(=O)NC(C(=O)N1CCCC1c1ncc(-c2ccc(-c3ccc(-c4cnc(C5CN(C(=O)c6ccccc6)CN5C(=O)C(NC(=O)OC)C(C)C)[nH]4)cc3)cc2)[nH]1)C(C)C
Temperature: 120 °C

Procedure:
{1-[1′-Benzoyl-4-(4-bromo-phenyl)-1′,2′,4′,5′-tetrahydro-1H-[2,4′]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (crude, <0.101 mmol) was combined with [2-Methyl-1-(2-{4-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-1H-imidazol-2-yl}-pyrrolidine-1-carbonyl)-propyl]-carbamic acid methyl ester (45.1 mg, 0.091 mmol) under an argon atmosphere. Potassium carbonate (27.8 mg, 0.202 mmol) and Pd(PPh3)4 (10 mg, 0.009 mmol) were added, followed by DME (2.0 mL) and water (0.4 mL). The mixture was heated under microwave conditions for 20 minutes at 120° C. All volatiles were removed in vacuo and the crude material was dissolved in DMF and purified via RP-HPLC (eluent: water/MeCN w 0.1% TFA) to yield the product {1-[1′-Benzoyl-5-(4′-{2-[1-(2-methoxycarbonylamino-3-methyl-butyryl)-pyrrolidin-2-yl]-3H-imidazol-4-yl}-biphenyl-4-yl)-1′,2′,4′,5′-tetrahydro-1H-[2,4]biimidazolyl-3′-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (20.7 mg): LCMS-ESI+: calc'd for C46H53N9O7: 843.9 (M+). Found: 844.3 (M+H+); 1H-NMR: 300 MHz, (MeOH-d4) δ: 7.90-7.84 (m, 10H), 7.66-7.52 (m, 5H), 5.68 (m, 1H), 5.59 (m, 1H), 5.49 (m, 1H), 5.26 (m, 1H), 4.24 (d, J=7.5 Hz, 1H), 4.11 (m, 2H), 3.86 (m, 2H), 3.66 (s, 3H), 3.65 (s, 3H), 3.46 (d, J=5.7 Hz, 1H), 2.57 (m, 1H), 2.29-2.09 (m, 5H), 1.01-0.85 (m, 12H).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([OH:43])=O.C(N(C(C)C)CC)(C)C.[NH2:53][C:54]1[CH:55]=[CH:56][C:57]([C:60]([F:63])([F:62])[F:61])=[N:58][CH:59]=1>CN(C=O)C>[Br:25][C:26]1[CH:27]=[C:28]2[C:32](=[CH:33][CH:34]=1)[N:31]([CH:35]1[CH2:40][CH2:39][CH2:38][CH2:37][O:36]1)[N:30]=[C:29]2[C:41]([NH:53][C:54]1[CH:59]=[N:58][C:57]([C:60]([F:63])([F:61])[F:62])=[CH:56][CH:55]=1)=[O:43]
Reactant: Nc1ccc(C(F)(F)F)nc1
Reactant: O=C(O)c1nn(C2CCCCO2)c2ccc(Br)cc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(C(F)(F)F)nc1)c1nn(C2CCCCO2)c2ccc(Br)cc12
Temperature: 25 °C
Yield: 92.9 %

Procedure:
HATU (1.125 g, 2.96 mmol) was added to a solution of 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole-3-carboxylic acid (CXVIII) (0.876 g, 2.69 mmol) and diisopropylethylamine (1.03 mL, 5.92 mmol) in DMF stirred at room temperature under argon. After stirring 5 min, the solution was added with 5-amino-2-trifluoromethylpyridine (CXXVII) (0.479 g, 2.96 mmol). The solution was stirred 24 h at room temperature under argon. The DMF was removed under reduced pressure, and the residue was treated with water, sonicated briefly and filtered. The solids were washed with cold water and dried at room temperature. The product was purified by silica gel column chromatography (100% hexanes→7:93 EtOAc:hexanes) to afford 5-bromo-1-(tetrahydro-2H-pyran-2-yl)-N-(6-(trifluoromethyl)pyridin-3-yl)-1H-indazole-3-carboxamide (CXXVIII) as a white solid (1.17 g, 2.50 mmol, 93% yield). 1H NMR (DMSO-d6) δ ppm 10.93 (s, 1H), 9.23 (d, J=1.9 Hz, 1H), 8.60 (dd, J=6.8, 1.4 Hz, 1H), 8.38 (d, J=4.4 Hz, 1H), 7.95 (m, 2H), 7.70 (dd, J=7.1, 1.5 Hz, 1H),), 6.04 (dd, J=8.1, 1.9 Hz, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.59-2.54 (m, 1H), 2.08-2.03 (m, 2H), 1.81-1.77 (m, 1H). 1.66-1.61 (m, 2H); ESIMS found for C19H16BrF3N4O2 m/z 470.0 (M+H).
Reaction SMILES: CCO[C:4]([CH:6]1[CH2:12][CH2:11][C:9](=[O:10])[CH2:8][CH2:7]1)=[O:5].[CH2:13](O)[CH2:14][OH:15].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[CH2:13]1[O:10][C:9]2([CH2:8][CH2:7][CH:6]([CH2:4][OH:5])[CH2:12][CH2:11]2)[O:15][CH2:14]1
Reactant: CCOC(=O)C1CCC(=O)CC1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: OCC1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl cyclohexanone-4-carboxylate (335 g.), 550 ml. ethylene glycol and 21 g. of p-toluenesulfonic acid in 5.5 liters of benzene were heated at reflux with stirring for 24 hours while water was separated by means of a water trap. The mixture was cooled and poured into 4 liters of ice water. The benzene layer was separated, washed with 1 liter of 5% sodium bicarbonate, 1 liter of water and 1 liter of saturated sodium chloride solution, dried and evaporated to dryness to give, after distillation, 245.6 g. of ethyl cyclohexanone-4-carboxylate ethylene ketal; b.p. 95-99.5°C. (0.07 mm.); N25D 1.4620. A solution of 35 g. of the ketal-ester in 50 ml. of dry tetrahydrofuran was added dropwise to 5.7 g. of lithium aluminum hydride in 250 ml. of dry tetrahydrofuran, and the mixture was heated at reflux for 5 hours and cooled to room temperature. A saturated sodium chloride solution (11.4 ml.) was added dropwise and heating at reflux was continued for one hour. The mixture was cooled and filtered, and the filtrate was dried and evaporated to dryness to give 26.9 g. of 4-hydroxymethylcyclohexanone ethylene ketal as a clear, colorless oil which was used without further purification.
Reaction SMILES: [ClH:1].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:19])/[CH2:17]O)=[CH:11][CH:10]=2)[CH:3]=1.S(Cl)([Cl:22])=O>C(Cl)Cl>[ClH:22].[N:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12](/[CH:15]=[C:16](\[CH3:19])/[CH2:17][Cl:1])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: C/C(=C\c1ccc(Oc2cccnc2)cc1)CO
Agent: Cl
Solvent: ClCCl
Product: C/C(=C\c1ccc(Oc2cccnc2)cc1)CCl

Procedure:
In 5 ml of methylene chloride was suspended 350 mg of (E)-3-[4-(pyridin-3-yloxy)phenyl]-2-methylallyl alcohol hydrochloride and to the suspension was added 0.18 ml of thionyl chloride with ice-cooling, after which the resulting mixture was subjected to reaction under reflux for 30 minutes. The solvent and the excessive thionyl chloride were removed by distillation under reduced pressure to obtain oily (E)-3-[4-(pyridin-3-yloxy)phenyl]-2-methylallyl chloride hydrochloride. This was dissolved in 2 ml of methylene chloride.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:8]([Cl:12])=[N:9]2)=[CH:4][C:3]=1[F:19].[N:20]1[CH:25]=[CH:24][CH:23]=[C:22](B(O)O)[CH:21]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C=O)C>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O>[Cl:12][C:8]1[N:7]=[C:6]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[C:10](=[CH:11][C:2]([C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)=[C:3]([F:19])[CH:4]=2)[N:9]=1
Reactant: OB(O)c1cccnc1
Reactant: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1cc2c(N3CCOCC3)nc(Cl)nc2cc1-c1cccnc1
Temperature: 95 °C
Reaction time: 2 h
Yield: 100.6 %

Procedure:
To a 50 mL round bottom flask, 7-bromo-2-chloro-6-fluoro-4-morpholin-4-yl-quinazoline (200 mg, 0.0005764 mol), pyridine-3-boronic acid (63.3 mg, 0.0005188 mol), sodium carbonate (152.6 mg, 0.001441 mol), DMF (10 mL) and water (5 mL) were added and degassed the reaction vessel with nitrogen for 5-10 min. To the same reaction mixture, Pd(PPh3)2Cl2 (20.1 mg, 0.0000288 mol) was added and again degassed with N2 for 5-10 min. The reaction mixture was stirred at 95° C. for 2 h. The reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water, brine and dried over sodium sulfate. The solvent was removed under reduced pressure to afford the crude product. The crude product was purified using column chromatography (60-120 silica gel, 2% MeOH in chloroform) to yield the desired product (180 mg, 91%). 1H NMR (300 MHz, CD3OD): δ 8.27-8.30 (m, 1H), 8.21-8.25 (m, 1H), 8.15-8.18 (m, 1H), 7.91-7.92 (m, 1H), 7.74-7.78 (m, 1H), 7.47-7.51 (m, 1H), 3.99-4.01 (m, 4H), 3.85-3.88 (m, 4H); LC-MS (ESI): Calculated mass: 344.1; Observed mass: 344.9 [M+H]+ (RT: 1.3 min).
Reaction SMILES: CO[C:3]([C:5]1([CH2:10][CH2:11][CH:12]=O)[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:4].[CH3:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][C@H:22]([C:25]2[CH:30]=[CH:29][C:28]([NH2:31])=[CH:27][CH:26]=2)[CH2:21]1>>[CH3:14][CH:15]1[CH2:19][CH2:18][CH2:17][N:16]1[CH:20]1[CH2:24][CH2:23][CH:22]([C:25]2[CH:30]=[CH:29][C:28]([N:31]3[CH2:12][CH2:11][CH2:10][C:5]4([CH2:9][CH2:8][CH2:7][CH2:6]4)[C:3]3=[O:4])=[CH:27][CH:26]=2)[CH2:21]1
Reactant: COC(=O)C1(CCC=O)CCCC1
Reactant: CC1CCCN1C1CC[C@H](c2ccc(N)cc2)C1
Product: CC1CCCN1C1CCC(c2ccc(N3CCCC4(CCCC4)C3=O)cc2)C1

Procedure:
The title compound was synthesized in the manner essentially the same as the Example 1 by condensing 1-(3-oxo-propyl)-cyclopentanecarboxylic acid methyl ester (Intermediate 7) with 4-[(S)-3-(2-methyl-pyrrolidin-1-yl)cyclopentyl]-phenylamine (Intermediate 15), and subsequently cyclization.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10](=[O:12])[CH3:11])=[N:2]1.C(N(CC)CC)C.[C:20](Cl)(=[O:23])[O:21][CH3:22]>C(Cl)(Cl)Cl>[C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([C:20]([O:21][CH3:22])=[O:23])[N:2]=1)(=[O:12])[CH3:11]
Reactant: CC(=O)c1n[nH]c2ccccc12
Reactant: COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)n1nc(C(C)=O)c2ccccc21
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of 1-(1H-indazol-3-yl)ethanone (5.0 g) and triethylamine (6.53 mL) in chloroform (80 mL) was added dropwise a solution of methyl chlorocarbonate (3.24 g) in chloroform (20 mL) under ice-cooling over 1 hour, and the mixture was stirred at room temperature for 14 hours. The reaction solution was washed with aqueous saturated sodium chloride solution, dried over magnesium sulfate, and then concentrated tinder reduced pressure. The resulting residue was triturated with n-hexane to give methyl 3-acetyl-1H-indazole-1-carboxylate) [REx(101-1)] (6.67 g) as a colorless powder.
Reaction SMILES: C(N(CC)CC)C.[C:8]([O:11][C:12](=[O:14])[CH3:13])(=O)[CH3:9].OCC[CH2:18][CH2:19][NH:20][C:21](=[O:56])[C@H:22]([CH3:55])[CH2:23][C@H:24]([OH:54])[C@@H:25]([NH:46][C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[CH2:26][C@@H:27]([CH:43]([CH3:45])[CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1>CN(C1C=CN=CC=1)C.O1CCCC1>[C:12]([O:11][CH2:8][CH2:9][CH2:18][CH2:19][NH:20][C:21](=[O:56])[C@H:22]([CH3:55])[CH2:23][C@H:24]([OH:54])[C@@H:25]([NH:46][C:47]([O:49][C:50]([CH3:51])([CH3:53])[CH3:52])=[O:48])[CH2:26][C@@H:27]([CH:43]([CH3:45])[CH3:44])[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[C:31]([O:37][CH2:38][CH2:39][CH2:40][O:41][CH3:42])[CH:30]=1)(=[O:14])[CH3:13]
Reactant: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCCO)C(C)C)ccc1OC
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCCCOc1cc(C[C@@H](C[C@H](NC(=O)OC(C)(C)C)[C@@H](O)C[C@@H](C)C(=O)NCCCCOC(C)=O)C(C)C)ccc1OC
Temperature: 25 °C
Reaction time: 18 h

Procedure:
30 ml of triethylamine, 2 mg of 4-(N,N'-dimethylamino)pyridine (DMAP) and 20 ml of acetic anhydride are added at 0° C. to 116 mg of 5(S)-tert-butoxycarbonylamino-4(S)-hydroxy-7(S)-isopropyl-2(R)-methyl-8-[4-methoxy-3-(3-methoxypropyloxy)-phenyl]-octanoic acid [N-(4-hydroxybutyl)]amide (Example 93) in 5 ml of tetrahydrofuran. The reaction solution is stirred for 18 hours at room temperature. The reaction mixture is partitioned between diethyl ether and water/saturated sodium chloride solution. The organic phases are concentrated by evaporation and the residue is purified by FC (40 g of silica gel, eluant: dichloromethane/methanol=95:5). The title compound is obtained: Rf (dichloromethane/methanol=9:1)=0.60.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][CH:9]=1)[NH2:6].C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45](O)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]>C(Cl)Cl>[CH3:28][O:29][C:30]1[C:31](=[O:54])[C:32]([CH3:53])=[C:33]([CH2:39][C:40]2[CH:41]=[CH:42][C:43]([O:49][C:50](=[O:52])[CH3:51])=[C:44]([CH:48]=2)[C:45]([NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=2)=[O:46])[C:34](=[O:38])[C:35]=1[O:36][CH3:37]
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cccc(C(F)(F)F)c3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 12 h
Yield: 45.4 %

Procedure:
3-Trifluoromethylaniline (0.483 g, 3.000 mmol), triethylamine (0.304 g, 3.000 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.507 g, 3.000 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.374 g, 1.000 mmol) and the resulting solution was stirred at room temperature for 12 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) and then recrystallized from ether to obtain the titled compound (0.235 g, 0.454 mmol, 45%).
Reaction SMILES: [CH:1]1([N:7]2[CH2:13][C@@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28](O)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)C[CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:59][CH:60]1[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]1>>[CH:1]1([N:7]2[CH2:13][C@@:12]([F:16])([CH:14]=[CH2:15])[C:11](=[O:17])[N:10]([CH3:18])[C:9]3[CH:19]=[N:20][C:21]([NH:23][C:24]4[CH:32]=[CH:31][C:27]([C:28]([NH:59][CH:60]5[CH2:65][CH2:64][N:63]([CH3:66])[CH2:62][CH2:61]5)=[O:29])=[CH:26][C:25]=4[O:33][CH3:34])=[N:22][C:8]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=C[C@]1(F)CN(C2CCCCC2)c2nc(Nc3ccc(C(=O)O)cc3OC)ncc2N(C)C1=O
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: C=C[C@]1(F)CN(C2CCCC2)c2nc(Nc3ccc(C(=O)NC4CCN(C)CC4)cc3OC)ncc2N(C)C1=O

Procedure:
The title compound was synthesized from (S)-4-(9-cyclohexyl-7-fluoro-7-vinyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[5,4-b][1,4]diazepin-2-ylamino)-3-methoxybenzoic acid as described in the General procedure for amide bond synthesis using HATU and 4-amino 1-N-methyl piperidine. 1H NMR (400 MHz, DMSO-d6) δ ppm 0.79-0.93 (m, 2H) 1.18-1.31 (m, 2H) 1.50-1.80 (m, 6H) 1.83-2.00 (m, 4H) 2.17 (s, 3H) 2.71-2.95 (m, 2H) 3.29 (s, 3H) 3.67-3.87 (m, 3H) 3.94 (s, 3H) 4.89 (d, J=8.59 Hz, 1H) 5.30-5.47 (m, 2H) 6.01 (ddd, J=17.49, 12.69, 10.74 Hz, 1H) 7.41-7.54 (m, 2H) 7.82 (s, 1H) 8.12 (s, 2H) 8.30 (d, J=8.34 Hz, 1H) [M+H] calc'd for C29H38FN7O3, 552. found 552.
Reaction SMILES: CN(C)C(N1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[CH:24]=[C:23]([F:25])[CH:22]=[C:21]([NH2:26])[C:20]=4[CH3:27])[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1)=O.ClC1C2C=C(C3CC[S:43]CC=3)NC=2N=CN=1>>[S:43]1[CH2:10][CH:9]=[C:8]([C:11]2[NH:28][C:14]3[N:15]=[CH:16][N:17]=[C:18]([C:19]4[C:20]([CH3:27])=[C:21]([NH2:26])[CH:22]=[C:23]([F:25])[CH:24]=4)[C:13]=3[CH:12]=2)[CH2:7][CH2:6]1
Reactant: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCN(C(=O)N(C)C)CC3)cc12
Reactant: Clc1ncnc2[nH]c(C3=CCSCC3)cc12
Product: Cc1c(N)cc(F)cc1-c1ncnc2[nH]c(C3=CCSCC3)cc12

Procedure:
Intermediate 16 was prepared analogue to Intermediate 6 by replacing Intermediate 3 with Intermediate 15.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10](C(S)C(OCC)=O)=[S:11])=[CH:5][CH:4]=1.[NH:19]([C:21]([O:23][CH3:24])=[O:22])[NH2:20]>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:20][NH:19][C:21]([O:23][CH3:24])=[O:22])=[S:11])=[CH:7][CH:8]=1
Reactant: CCOC(=O)C(S)C(=S)Cc1ccc(OC)cc1
Reactant: COC(=O)NN
Solvent: ClCCl
Product: COC(=O)NNC(=S)Cc1ccc(OC)cc1

Procedure:
A mixture of 50 g of the above ester, 18.g. of methyl hydrazinocarboxylate and 300 ml of dichloromethane was refluxed for 2 hours, then washed twice with water, once with saturated sodium chloride and dried. The resulting oily residue was concentrated under high vacuum at 50° C. for 2 hours and the semi-solid crystallized from toluene-hexane, giving 36 g of the desired compound as ivory colored crystals, mp 94.5-95° C. Proton nuclear magnetic resonance (δ[ppm], CDCl3) 90MHz: 3.78 (s, 3H, OCH3); 3.80 (s, 3H, OCH3); 4.03 (s, 2H, CH2CS); [6.89 (d, 2H, J=8.2Hz) and 7.21 (d, 2H)(C6H4)]8.60 (bs, 1H, NH); 9.40 (bs, 1H, NH).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=1.[N:11]1([CH2:17][CH2:18][NH2:19])[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1>>[N:11]1([CH2:17][CH2:18][NH:19][C:2]2[CH:7]=[CH:6][CH:5]=[C:4]([N+:8]([O-:10])=[O:9])[CH:3]=2)[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: O=[N+]([O-])c1cccc(Br)c1
Reactant: NCCN1CCOCC1
Product: O=[N+]([O-])c1cccc(NCCN2CCOCC2)c1

Procedure:
Using 1-bromo-3-nitro-benzene (303 mg) and 2-morpholin-4-yl-ethylamine (315 μl) instead of morpholine, in the same manner as Step A in Example 1-D-105, the desired compound was obtained (374.6 mg, 74%).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]2=[CH:12][S:13][C:14]([NH2:15])=[C:10]2[C:9](=[O:16])[N:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:7]=1)=O)C.O.[NH2:24][NH2:25]>C(O)C>[NH2:15][C:14]1[S:13][CH:12]=[C:11]2[C:10]=1[C:9](=[O:16])[N:8]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[N:7]=[C:6]2[C:4]([NH:24][NH2:25])=[O:3]
Reactant: CCOC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Reactant: NN
Solvent: O
Solvent: CCO
Product: NNC(=O)c1nn(-c2ccccc2)c(=O)c2c(N)scc12
Yield: 94.3 %

Procedure:
To a solution of 5-Amino-4-oxo-3-phenyl-3,4-dihydro-thieno[3,4-d]pyridazine-1-carboxylic acid ethyl ester (20 g, 0.063 mol, prepared as described in example 25) in ethanol (400 ml) was added hydrazine hydrate (3.3 g, 0.066 mol). The reaction mixture was stirred at reflux temperature for 6 h at which time an additional portion of hydrazine hydrate (3.3 g, 0.066 mol) was added and the resulting mixture was stirred for an additional 66 h at reflux temperature. An additional portion of hydrazine hydrate (1.5 g, 0.03 mol) was added and the reaction mixture was stirred for an additional 16 h at reflux temperature. The reaction mixture was cooled and the precipitated was filtered off, washed with small portions of ethanol and dried in vacuo at 50° C. for 18 h which afforded 17.9 g (94%) of the title compound as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1([C:24]([NH:26][CH2:27][CH:28]=[CH2:29])=[O:25])C=CN=C1.C(N(CC)C(C)C)(C)C>C(#N)C>[C:1]([O:5][C:6]([C:8]1[S:9][C:10]([CH2:13][N:14]([C:24](=[O:25])[NH:26][CH2:27][CH:28]=[CH2:29])[CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:11][CH:12]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CCNC(=O)n1ccnc1
Reactant: CC(C)CNCc1ccc(C(=O)OC(C)(C)C)s1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCNC(=O)N(Cc1ccc(C(=O)OC(C)(C)C)s1)CC(C)C
Temperature: 60 °C
Reaction time: 8 h
Yield: 100 %

Procedure:
5-{[(2-Methylpropyl)amino]methyl}thiophene-2-carboxylic acid tert-butyl ester (0.55 g, 2.0 mmol) obtained in Example 24, step 1 and N-(1H-imidazol-1-ylcarbonyl)-allylamine (0.49 g, 3.2 mmol) obtained in step 1 were dissolved in acetonitrile (20 ml), N,N-diisopropylethylamine (0.56 mL, 3.2 mmol) was added, and the mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under reduced pressure and the obtained residue was purified by column chromatography (hexane/ethyl acetate) to give the title compound (0.72 g, 2.0 mmol).
Reaction SMILES: [N:1]([C:4]1[CH:5]=[CH:6][C:7]([CH3:10])=[N:8][CH:9]=1)=[C:2]=[O:3].C([O-])(O)=O.[Na+].[NH2:16][C:17]1[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=1)[CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>CCOC(C)=O>[CH3:10][C:7]1[N:8]=[CH:9][C:4]([NH:1][C:2](=[O:3])[NH:16][C:17]2[CH:18]=[C:19]([CH:35]=[CH:36][CH:37]=2)[CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([C:28]([O:30][C:31]([CH3:33])([CH3:34])[CH3:32])=[O:29])[CH2:26][CH2:27]2)=[CH:5][CH:6]=1
Reactant: Cc1ccc(N=C=O)cn1
Reactant: CC(C)(C)OC(=O)N1CCN(CCc2cccc(N)c2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(=O)Nc2cccc(CCN3CCN(C(=O)OC(C)(C)C)CC3)c2)cn1
Reaction time: 2 h
Yield: 63 %

Procedure:
To a solution of tert-butyl 4-(3-aminophenethyl)piperazine-1-carboxylate (7D, 1.0 eq) in THF (about 0.3 M 7D in THF) was added 5-isocyanato-2-methylpyridine (1.0 eq) dropwise. The resulting reaction mixture was stirred for 2 h. To the reaction mixture was added saturated aq. NaHCO3. The mixture was diluted with EtOAc, and the layers were separated. The organic layer was washed twice with saturated aq. NaHCO3 and once with brine. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. Purification over silica gel using 5-12% MeOH/CH2Cl2 as the gradient eluant provided tert-butyl 4-(3-(3-(6-methylpyridin-3-yl)ureido)phenethyl)piperazine-1-carboxylate (7E, 63%).