Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:24][CH2:25][CH2:26][CH3:27])=[C:6]([C:8]2[NH:13][C:12](=[O:14])[C:11]3=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]4[CH2:22][CH2:21][CH2:20][CH2:19]4)[N:10]3[N:9]=2)[CH:7]=1.[CH2:28]([S:31](Cl)(=[O:33])=[O:32])[CH2:29][CH3:30].C(N(CC)CC)C>O1CCCC1>[CH2:25]([O:24][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:31]([CH2:28][CH2:29][CH3:30])(=[O:33])=[O:32])=[CH:7][C:6]=1[C:8]1[NH:13][C:12](=[O:14])[C:11]2=[C:15]([CH3:23])[N:16]=[C:17]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:10]2[N:9]=1)[CH2:26][CH3:27]
Reactant: CCCS(=O)(=O)Cl
Reactant: CCCOc1ccc(N)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCOc1ccc(NS(=O)(=O)CCC)cc1-c1nn2c(C3CCCC3)nc(C)c2c(=O)[nH]1

Procedure:
150 mg (0.408 mmol) of the compound from example 44A are treated with 116 mg (0.816 mmol) of 1-propanesulfonyl chloride and 87 mg (0.816 mmol) of triethylamine in 15 ml of tetrahydrofuran for 1 hour.
Reaction SMILES: CI.FC(F)(F)C(O)=O.C(O[C:15](=O)[NH:16][C:17]1[C:18]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=2[CH3:36])=[N:19][C:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[N:21][CH:22]=1)(C)(C)C.C(O)(C)(C)C.[F:43][C:44]([F:62])([F:61])[C:45]1[CH:46]=[C:47]([C:55]([CH3:60])([CH3:59])[C:56](Cl)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1>>[F:43][C:44]([F:62])([F:61])[C:45]1[CH:46]=[C:47]([C:55]([CH3:60])([CH3:59])[C:56]([N:16]([CH3:15])[C:17]2[C:18]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[CH3:36])=[N:19][C:20]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[N:21][CH:22]=2)=[O:57])[CH:48]=[C:49]([C:51]([F:54])([F:53])[F:52])[CH:50]=1
Reactant: CC(C)(C(=O)Cl)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: Cc1ccccc1Oc1nc(-c2ccccc2)ncc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CI
Solvent: CC(C)(C)O
Product: Cc1ccccc1Oc1nc(-c2ccccc2)ncc1N(C)C(=O)C(C)(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1

Procedure:
In an analougous manner to that described in Examle 72 a) there was obtained from 2-phenyl-4-o-tolyloxy-pyrimidine-5-carboxylic acid, diphenylphosphorylazide and t-butanol (2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-carbamic acid tert.-butyl ester, which was methylated with methyliodide and than deprotected with trifluoracetic acid according to Example 72 b) c). The resulting methyl-(2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-amine was treated with 2-(3,5-bis-trifluormethyl-phenyl)-2-methyl-propionyl chloride as described in Example 72 e) to give 2-(3,5-bis-trifluoromethyl-phenyl)-N-methyl-N-(2-phenyl-4-o-tolyloxy-pyrimidin-5-yl)-isobutyramide as a white foam, MS (ISP): 574.1 (M+H)+.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[NH2:4].[C:11]([O-:14])(=O)[CH3:12].[Na+].[C:16]([OH:19])(=O)[CH3:17]>CC(C)=O>[CH2:3]([O:14][C:11]1[CH:12]=[CH:8][CH:2]=[CH:1][C:17]=1[C:16]([NH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[C:1]([NH2:10])=[O:9])=[O:19])[CH2:5][CH3:6]
Reactant: CC(=O)[O-]
Reactant: CC(=O)O
Reactant: NC(=O)c1ccccc1N
Agent: [Na+]
Solvent: CC(C)=O
Product: CCCOc1ccccc1C(=O)Nc1ccccc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-propoxybenzoic acid (5 g) in thionyl chloride (20 ml) was heated under reflux for three hours. Thionyl chloride was removed under reduced pressure and the residue was azeotroped with toluene to yield the acid chloride as a yellow oil (5.5 g). A solution of anthranilamide (3.77 g) in a mixture of saturated aqueous sodium acetate (20 ml) and acetic acid (20 ml) was added to the yellow oil in acetone (4 ml). The resulting solution was stirred at ambient temperature for one hour to yield as a light brown precipitate 2-(2-propoxybenzamido)benzamide, 3.78 g. A sample recrystallized from ether had m.p. 149-150° C.
Reaction SMILES: C1(C)C=CC(S([Cl:10])(=O)=O)=CC=1.[CH3:12][C:13]1(C)[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=2)[NH+:14]1[O-]>ClC(Cl)C>[Cl:10][CH2:12][C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([CH3:23])[CH:19]=2)[N:14]=1
Reactant: Cc1ccc2c(c1)C=CC(C)(C)[NH+]2[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CC(Cl)Cl
Product: Cc1ccc2nc(CCl)ccc2c1
Temperature: 100 °C
Yield: 59.8 %

Procedure:
To a stirring solution of p-toluenesulfonyl chloride (6.19 g, 0.0325 mol) in dichloroethane (75 mL) was added 2,6 dimethylquinaldine N-oxide (2) (5 g, 0.0289 mol) under N2. The reaction mixture was then heated to 100° C. for 24 hours, cooled, concentrated and extracted with 10% K2CO3 and ethyl acetate. The organic layer was dried with MgSO4, concentrated and purified on a small silica flash column (2:1 dichloromethane:hexanes). The resulting yellow solid was then recrystallized in hexanes to afford 3.31 g (60%) of a white solid. H1 NMR (CDCl3): δ 2.50 (s, 3H) 4.80 (s, 2H), 7.40-7.50 (m, 2H), 7.58-7.61 (d, 1H), 8.02-8.99 (m, 1H), 8.11-8.14 (d, 1H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1)#[N:2].[ClH:12].[CH3:13][OH:14]>>[ClH:12].[CH3:13][O:14][N:2]=[CH:1][C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[C:5]([O:10][CH3:11])[CH:4]=1
Reactant: COc1cc(C#N)ccc1O
Reactant: CO
Agent: Cl
Product: CON=Cc1ccc(O)c(OC)c1

Procedure:
In 50 ml of anhydrous methanol, was dissolved 7.5 g of 4-cyano-2-methoxyphenol. The solution was saturated with dried gaseous hydrogen chloride, while being cooled in ice and stirred, and then stirred overnight at room temperature to precipitate yellow crystals. After addition of ethyl ether, the crystals were collected by filtration, washed with ethyl ether and dried to obtain 9.4 g of 4-methoxyiminomethyl-2-methoxyphenol hydrochloride.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8]3=[C:9]([CH2:11][CH2:12][N:7]3[C@H:6]3[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]23)[CH:10]=1.[Cl:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[C:27]([F:34])[CH:26]=1>>[Cl:24][C:25]1[CH:30]=[CH:29][C:28]([C:2]2[CH:3]=[C:4]3[C:8]4=[C:9]([CH2:11][CH2:12][N:7]4[C@H:6]4[CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16][C@@H:5]34)[CH:10]=2)=[C:27]([F:34])[CH:26]=1
Reactant: OB(O)c1ccc(Cl)cc1F
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CC3
Product: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(-c3ccc(Cl)cc3F)cc3c1N2CC3

Procedure:
The title compound was prepared by the method of Example 89 step C from tert-butyl(6aS,10aR)-2-bromo-4,5,7,8,10,10a-hexahydropyrido[4,3-b]pyrrolo[3,2,1-hi]indole-9(6aH)carboxylate (189 mg, 0.5 mmol) and corresponding 4-chloro-2-fluorophenyl boronic acid (175 mg, 1.0 mmol) to afford after chromatographic purification the title compound (128 mg, 60%). 1H NMR (CDCl3, 300 MHz) δ 7.28–7.29 (m,1H), 7.05–7.15 (m, 4H), 3.6–4.2 (m, 3H), 2.80–3.50 (m, 7H), 1.80–1.90 (m, 2H), 1.48 (s, 9H) ppm. MS-ApCI: 429 [M+H+].
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9](O)=O)=[CH:5][NH:4][C:3]1=[O:12].[ClH:13]>>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([CH2:9][Cl:13])=[CH:5][NH:4][C:3]1=[O:12]
Reactant: Cn1c(=O)[nH]cc(C(=O)O)c1=O
Reactant: Cl
Product: Cn1c(=O)[nH]cc(CCl)c1=O
Yield: 52 %

Procedure:
3-methyluracil-5-carboxylic acid was treated with HCl and CH2 using standard chloromethylation conditions to give 3-methyl-5-chloromethyl uracil in 52% yield (following standard work-up and recrystallization from ethyl acetate). NMR (DMSO-d6): chemical shifts, peak integrations & D2O exchange experiments diagnostic for structure.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2(C3C=CC(O)=CC=3)[CH:14]=[CH:13][CH:12]=[CH:11][CH2:10]2)=[CH:4][C:3]=1[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26].[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:49]=[CH:48][C:42]([O:43][CH2:44][C:45]([OH:47])=O)=[CH:41][CH:40]=2)[S:33]1.C(N([CH2:55][CH3:56])CC)C>O1CCCC1>[O:31]=[C:32]1[NH:36][C:35](=[O:37])[CH:34]([CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:43][CH2:44][C:45]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][C:9]4[CH:14]=[CH:13][C:12]([C:56]5[CH:55]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=5)=[CH:11][CH:10]=4)=[CH:4][C:3]=3[N:22]([CH3:30])[C:23](=[O:29])[O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:47])=[CH:48][CH:49]=2)[S:33]1
Reactant: CCN(CC)CC
Reactant: CN(C(=O)OC(C)(C)C)c1cc(OC2(c3ccc(O)cc3)C=CC=CC2)ccc1N
Reactant: O=C(O)COc1ccc(CC2SC(=O)NC2=O)cc1
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1cc(Oc2ccc(-c3ccc(O)cc3)cc2)ccc1NC(=O)COc1ccc(CC2SC(=O)NC2=O)cc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A mixture of t-butyl N-[2-amino-5-(4′-hydroxybiphenyl-1-yloxy)phenyl]-N-methylcarbamate (0.61 g), 4-(2,4-dioxothiazolidin-5-ylmethyl)phenoxyacetic acid (0.51 g), diethyl cyanophsphonate (0.29 g), triethylamine (0.18 g) and anhydrous tetrahydrofuran (10 ml) was stirred at ambient temperature for 2 days. The reaction mixture was concentrated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was dried over anhydrous sodium sulfate. The ethyl acetate was distilled off under reduced pressure and the residue was purified by chromatography on a silica gel column using n-hexane/ethyl acetate=1/1 as the eluant to give the desired product.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[C:20]([O:32][CH3:33])[CH:19]=3)[CH:9]=[C:10]([CH2:11][N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)[N:6]2[N:5]=[CH:4][N:3]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:8]2[CH:9]=[C:10]([CH2:11][N:12]3[CH2:13][CH2:14][O:15][CH2:16][CH2:17]3)[N:6]3[C:7]=2[C:2]([NH2:1])=[N:3][CH:4]=[N:5]3)=[CH:19][C:20]=1[O:32][CH3:33]
Reactant: COc1cc(-c2cc(CN3CCOCC3)n3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(-c2cc(CN3CCOCC3)n3ncnc(N)c23)ccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 102.6 %

Procedure:
To a solution of t-butyl {4-[4-amino-7-(morpholin-4-ylmethyl)pyrrolo[2,1-f][1,2,4]triazin-5-yl]-2-methoxyphenyl}carbamate (100 mg, 0.22 mmol) in CH2Cl2 (4 ml) was added trifluoroacetic acid (1.5 ml) and was stirred at rt for 3 h. The reaction mixture was partially evaporated and was added 10 ml ethyl acetate and washed with saturated aq. NaHCO3. The organic was dried over Na2SO4 and concentrated to afford 80 mg of the title compound. 1H-NMR (DMSO-d6) δ 7.84 (s, 1H), 6.84 (d, J=2 Hz, 1H), 6.84 to 6.68 (m, 2H), 6.55 (s, 1H), 4.87 (s, 2H), 4.01 to 3.99 (m, 5H), 3.53 (t, J=4 Hz, 4H), 2.42 (t, J=4 Hz, 4H).
Reaction SMILES: [C:1]1(=[O:8])[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[CH:9]1[CH2:13][CH:12]=[CH:11][CH:10]=1.[OH-].[Na+].S(OC)(O[CH3:20])(=O)=O.C1C=CC2C(=CC=CC=2O)C=1>O>[CH3:20][O:7][C:4]1[C:5]2[CH:13]3[CH2:9][CH:10]([CH:11]=[CH:12]3)[C:6]=2[C:1]([OH:8])=[CH:2][CH:3]=1
Reactant: O=C1C=CC(=O)C=C1
Reactant: COS(=O)(=O)OC
Reactant: C1=CCC=C1
Agent: Oc1cccc2ccccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COc1ccc(O)c2c1C1C=CC2C1
Reaction time: 3 h

Procedure:
Adduct (VII) (34.8 g.) was added to a solution of 32 g. NaOH in 200 ml. water. The solution was stirred and 30.8 g. dimethyl sulfate added dropwise, giving a mild exotherm. Stirring was continued at room temperature for 3 hours. Then, the mixture was filtered, acidified with concentrated HCl, and extracted with chloroform. The organic layer was dried and evaporated to give a viscous brown oil. Distillation gave 6.1 g. of naphthol (VIII) as a thick yellow, viscous liquid, b. 178° C./0.1 mm.
Reaction SMILES: I.[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH2:14].Cl.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1.C(N(C(C)C)CC)(C)C>ClC(Cl)C>[S:2]1[C:6]2[CH2:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[N:4]=[C:3]1[NH:14][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[N:19][CH:18]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: Nc1nc2c(s1)Cc1ccccc1-2
Agent: Cl
Agent: I
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(Cl)Cl
Product: O=C(Nc1nc2c(s1)Cc1ccccc1-2)c1cccnc1
Temperature: 120 °C

Procedure:
A suspension of 8H-Indeno[1,2-d]thiazol-2-ylamine hydroiodide 1a (Prepared in Example 1, Step 1, mg; mmol), nicotinoyl chloride hydrochloride (92 mg; 0.50 mmol) and diisopropylethylamine (0.50 mL; 2.77 mmol) in dichloroethane was heated in a sealed tube to 120° C. in a microwave oven for 10 minutes. The mixture was allowed to cool to room temperature and the solvent removed in vacuo. The residue was taken up into 2 M sodium carbonate solution and extracted with ethyl acetate. The extracts were dried (sodium sulfate), filtered and concentrated in vacuo. The crude product was chromatographed on silica gel (eluent=50% ethyl acetate/hexanes to 100% ethyl acetate/hexanes gradient) to provide 43 mg of N-(8H-Indeno[1,2-d]thiazol-2-yl)-nicotinamide 7. EI-HRMS m/e calcd for C16H11N4OS (M+) 293.0623, found 293.0620.
Reaction SMILES: Br[C:2]1[N:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:12])[NH:7]2.[CH3:13][C:14]1[CH:18]=[CH:17][NH:16][N:15]=1.CN1CCCC1=O>O>[CH3:13][C:14]1[CH:18]=[CH:17][N:16]([C:2]2[N:11]=[CH:10][CH:9]=[C:8]3[C:3]=2[CH:4]=[CH:5][C:6](=[O:12])[NH:7]3)[N:15]=1
Reactant: Cc1cc[nH]n1
Reactant: O=c1ccc2c(Br)nccc2[nH]1
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccn(-c2nccc3[nH]c(=O)ccc23)n1
Temperature: 200 °C

Procedure:
A stirred mixture containing 13.5 g of 5-bromo-1,6-naphthyridin-2(1H)-one, 18 ml of 3-methyl-1H-pyrazole and 75 ml of N-methylpyrrolidinone was heated in an oil bath at 170°-180° C. for 18 hours, after which a tlc analysis indicated some remaining starting material. The temperature of the oil bath was raised to 200° C.; and, the reaction mixture was heated for an additional 5 hours and then poured into water. The solid that separated was collected, dried and combined with 1.7 g of corresponding material obtained in another run starting with 2.25 g of 5-bromo-1,6-naphthyridin-2(1H)-one. The combined solids were recrystallized from dimethylformamide and dried in an oven for three days at 100° C. to yield 6.6 g of 5-(3-methyl-1H-pyrazol-1-yl)-1,6-naphthyridin-2(1H)-one, m.p. >300° C.
Reaction SMILES: COC([NH:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:27])=O.[OH-].[K+]>CO>[NH2:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]=1[C:16]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:19]=[CH:18][C:17]=1[P:26]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)([C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)=[O:27]
Reactant: COC(=O)Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: Nc1ccc2ccccc2c1-c1c(P(=O)(c2ccccc2)c2ccccc2)ccc2ccccc12
Temperature: 95 °C
Reaction time: 2 h
Yield: 100.3 %

Procedure:
8.01 gram (15.2 mmol) of (−)-2-methoxycarbonylamino-2′-diphenylphosphinyl-1,1′-binaphthyl (the formula (1-2b-1)) was dissolved in 304 ml of methanol. To the solution, 152 ml of 40 percent aqueous solution of potassium hydroxide was added dropwise over 30 minutes and then stirred at 95° C. for 2 hours. The resultant mixture was extracted with 300 ml of ethyl acetate, and the extract was washed with brine, and then dried over anhydrous sodium sulfate. The solvent was evaporated under a reduced pressure and the residue was purified using a silica gel column chromatography (eluent:ethyl acetate) to obtain 7.16 gram of the titled compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9](=O)[NH:10][N:11]=[CH:12][C:13]=2[C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.O=P(Cl)(Cl)[Cl:30]>C1(C)C=CC=CC=1>[Cl:30][C:9]1[N:10]=[N:11][CH:12]=[C:13]([C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: O=c1[nH]ncc(-c2ccc(Cl)cc2)c1-c1ccc(Cl)cc1
Reactant: O=P(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: Clc1ccc(-c2cnnc(Cl)c2-c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.3 %

Procedure:
4,5-Bis(4-chlorophenyl)pyridazin-3(2H)-one (16.5 g, 52.2 mmol) was suspended in toluene (50 mL). To the resultant solution was added pyridine (8.3 mL, 104.4 mmol), followed by the addition of POCl3 (14.3 mL, 156.6 mmol). The reaction mixture was placed in an oil bath preheated at 110° C. After 4 h, the reaction mixture was cooled to RT, then poured over 500 g ice to quench the excess POCl3. The dark mixture was extracted with EtOAc (2×300 mL). The combined organic layers were washed with water (500 mL), and filtered through a silica gel pad (˜50 g). The filtrate was concentrated under reduced pressure to give the title compound, 3-chloro-4,5-bis(4-chlorophenyl)pyridazine as a pale colored solid (16.0 g, 92%). MS: M+H=335. 1H NMR (CDCl3, 500 MHz): δ 9.24 (1H, s), 7.35 (2H, d, J=10 Hz), 7.26 (2H, d, J=10.0 Hz), 7.08-7.16 (4H, m).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.CCN=C=NCCCN(C)C.[CH2:24]([C:26]1[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[N:30][CH:31]=1)[CH3:25].C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[CH2:24]([C:26]1[C:27]([C:32]([NH:1][C:2]2[C:3]([OH:12])=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:9])[F:10])[CH:7]=2)=[O:33])=[N:28][CH:29]=[N:30][CH:31]=1)[CH3:25]
Reactant: Nc1cc(C(F)(F)F)cnc1O
Reactant: CCc1cncnc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: CCc1cncnc1C(=O)Nc1cc(C(F)(F)F)cnc1O
Temperature: 80 °C
Reaction time: 10 h

Procedure:
To a mixture of 3-amino-5-trifluoromethylpyridin-2-ol (0.27 g), WSC (0.58 g), and pyridine (10 ml), 5-ethyl-pyrimidine-4-carboxylic acid was added under ice-cooling, and the reaction mixture was stirred at 80° C. for 10 hours. After standing to cool the reaction mixture to room temperature, to the reaction mixture, saturated aqueous sodium hydrogen carbonate solution was added, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to give 0.26 g of 5-ethyl-N-(2-hydroxy-5-trifluoromethyl-pyridin-3-yl)-pyrimidine-4-carboxamide.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].[C:8]1([CH3:14])[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:11]1[CH:12]=[CH:13][C:8]([CH3:14])=[CH:9][CH:10]=1)=[O:6]
Reactant: O=C(Cl)CCCCl
Reactant: Cc1ccccc1
Product: Cc1ccc(C(=O)CCCCl)cc1
Temperature: 3 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
Suspend anhydrous AlC13 (156 g, 1.15 mol) in toluene (1500 mL) and cool to 2-4° C. Add, by slow addition, a solution of 4-chlorobutyryl chloride (165.5 g, 1.15 mol) in toluene (300 mL). Stir for 15 minutes and pour into stirring ice-water (2.5L). Stir for 30 hours, decant the toluene and extract the aqueous phase with toluene (700 mL). Combine the organic layers and wash three times with water (1L, 1L, 500 mL). Evaporate the solvent in vacuo to give the title compound as a pale yellow oil (292.3 g, 95%).
Reaction SMILES: CC[CH:3]([NH:6][C:7]1[CH:12]=[N:11][CH:10]=[C:9](Cl)[N:8]=1)[CH2:4]C.[CH3:14][O-:15].[Na+].CN1[CH2:22][CH2:21][CH2:20]C1=O>CO>[CH2:3]([NH:6][C:7]1[C:12]([CH2:20][CH2:21][CH3:22])=[N:11][CH:10]=[C:9]([O:15][CH3:14])[N:8]=1)[CH3:4]
Reactant: CCC(CC)Nc1cncc(Cl)n1
Reactant: CN1CCCC1=O
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCc1ncc(OC)nc1NCC
Temperature: 50 °C
Yield: 98 %

Procedure:
To a solution of 2-(3-pentylamino)-6-chloropyrazine (3.3 g, 16.5 mmol) (obtained in example 75) in 1-methyl-2-pyrrolidinone (15 mL) at room temperature is added a solution of sodium methoxide in methanol (5.0M, 10 ml). The resulting solution was heated to 50° C. for 20 h then evaporated and poured into water and extracted twice with ethyl acetate/hexane (1:1). Combined extracts were dried (sodium sulfate), filtered, concentrated, and chromatographed to give N-(1-ethyl)propyl-6-methoxypyrazine-2-amine as a light yellow solid(98%).
Reaction SMILES: [CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[H-].[Na+].I[CH3:33]>CN(C)C=O>[CH:1]1([C:7]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[N:11]([CH3:33])[C:10](=[O:18])[CH:9]([NH:19][C:20]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[O:21])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(NC1N=C(C2CCCCC2)c2ccccc2NC1=O)OCc1ccccc1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)C(NC(=O)OCc2ccccc2)N=C(C2CCCCC2)c2ccccc21
Reaction time: 0.5 h
Yield: 66.1 %

Procedure:
A solution of 5-cyclohexyl-1,3-dihydro-3(R,S)-[(benzyloxycarbonyl)amino]-2H- 1,4-benzodiazepin-2-one (1.1 g, 2.8 mmol) in dimethyl formamide (13 ml), under an atmosphere of nitrogen, was treated with sodium hydride (117 mg of a 55-60% dispersion in mineral oil, 2.8 mmol) in one portion, at -10° C. After 30 min at -10° C., iodomethane (174 μl, 2.8 mmol) was added in one portion and the solution allowed to reach 0° C. over 1 h. The solvent was then removed in vacuo and the crude residue partitioned between water (100 ml) and dichloromethane (100 ml). The organic phase was separated and the aqueous phase extracted with dichloromethane (2×100 ml). The combined organic layers were washed with brine, dried (MgSO4) and evaporated. The residue was chromatographed on silica, using 1:1 petrol:ethyl acetate as the eluant, to afford the title compound (0.75 g, 66%) as a white solid. mp 205°-207° C. 1H NMR (360MHz, CDCl3) δ1.03-2.04 (10H, m), 2.76 (1H, m), 3.36 (3H, s), 5.10 (3H, m), 6.52 (1H, d, J=8Hz), 7.25-7.55 (9H, m).
Reaction SMILES: [NH2:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3].[NH:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[C@H:8]([C:10](ON1C(=O)CCC1=O)=[O:11])[CH3:9].CN1CCOCC1>CN(C=O)C>[NH:7]([C:20]([O:22][C:23]([CH3:24])([CH3:26])[CH3:25])=[O:21])[C@H:8]([C:10]([NH:1][C@H:2]([C:4]([OH:6])=[O:5])[CH3:3])=[O:11])[CH3:9]
Reactant: C[C@H](N)C(=O)O
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)ON1C(=O)CCC1=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: C[C@H](NC(=O)[C@H](C)NC(=O)OC(C)(C)C)C(=O)O

Procedure:
L-Alanine (3.57 g, 40 mmol) was dissolved in 18.8 ml of Triton B (40 mmol), evaporated to dryness, and the oily residue re-evaporated twice with DMF (30 ml each). The salt obtained was stirred with 11.45 g of Boc-Ala-OSu (40 mmol) in 40 ml DMF, with 4 ml of NMM added, for 20 hours. The solvent was removed and the residue taken up in 10% HOAc (100 ml). The product was extracted into EtOAc (4 times 100 ml), washed twice with a small volume of H2O, dried over Na2SO4, evaporated to a small volume, and treated with petroleum ether until cloudiness developed. A crystalline product formed on storage in the refrigerator overnight: Yield, 8.2 g (76.3%); mp 115°-118°.
Reaction SMILES: [CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=1)[C:14]([OH:16])=[O:15])=[O:11].C(N(CC)CC)C.[CH2:32](Br)[CH2:33][CH3:34].O>CN(C)C=O>[CH2:1]1[C@@H:9]2[C@@H:4]([CH2:5][CH2:6][CH2:7][CH2:8]2)[CH2:3][N:2]1[C:10]([CH2:12][CH:13]([CH2:17][C:18]1[CH:19]=[CH:20][C:21]([CH3:24])=[CH:22][CH:23]=1)[C:14]([O:16][CH2:32][CH2:33][CH3:34])=[O:15])=[O:11]
Reactant: CCCBr
Reactant: Cc1ccc(CC(CC(=O)N2C[C@H]3CCCC[C@H]3C2)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCCOC(=O)C(CC(=O)N1C[C@H]2CCCC[C@H]2C1)Cc1ccc(C)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 26.6 %

Procedure:
To a solution of 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionic acid (100 mg) in N,N-dimethylformamide (2 ml) were added triethylamine (50 mg) and propyl bromide (100 mg) and the mixture was stirred at room temperature for 15 hours. To the reaction mixture was added water (10 ml) and the mixture was extracted with ethyl acetate. The organic layer was washed succesively with 1N hydrochloric acid, saturated sodium bicarbonate solution, and brine and dried over MgSO4. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (4/1) to give 30 mg of propyl 3-(cis-hexahydro-2-isoindolinylcarbonyl)-2-(4-methylbenzyl)propionate as a colorless viscous oil.