Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@@H:1]1(O)[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1.C1(P([N:28]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.N12CCCN=C1CCCCC2>C1(C)C=CC=CC=1>[C@H:1]1([NH2:28])[C:11]2=[C:12]3[C:7](=[CH:8][CH:9]=[CH:10]2)[CH:6]=[CH:5][CH:4]=[C:3]3[CH2:2]1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Reactant: O[C@H]1Cc2cccc3cccc1c23
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: N[C@@H]1Cc2cccc3cccc1c23
Temperature: 0 °C
Reaction time: 20 h

Procedure:
To a cooled (0° C.) and stirred solution of (S)-acenaphthenol (1.74 g, 10.2 mmol) and diphenyl-phosphorylazide in toluene (17.5 ml) was added DBU (1,8-diazabicyclo[5.4.0]undec-7-ene) (1.86 ml, 12.3 mmol) and stirring was continued at RT over a period of 20 h. The reaction mixture was extracted with toluene (2×50 ml), the combined organic phases washed with water, dried (MgSO4) and evaporated in vacuo. The crude product was dissolved in EtOH (120 ml) and hydrogenated at RT over PtO2 (0.24 g). The catalyst was filtered off, the solution evaporated in vacuo and the residue purified by column chromatography on silica gel (dichloromethane/MeOH 9:1) to yield (R)-acenaphthen-1-yl-amine (1.56 g) as a pink oil. MS: m/e=169 (M+).
Reaction SMILES: [O:1]=[S:2]1(=[O:35])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([O:18]CC)=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1.[OH-].[Na+].CC(O)=O>C(O)C>[O:35]=[S:2]1(=[O:1])[C:8]2[CH:9]=[C:10]([O:14][CH2:15][C:16]([OH:18])=[O:17])[C:11]([Br:13])=[CH:12][C:7]=2[N:6]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:5][C:4]([CH2:31][CH2:32][CH2:33][CH3:34])([CH2:27][CH2:28][CH2:29][CH3:30])[CH2:3]1
Reactant: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)OCC)cc2S(=O)(=O)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCO
Product: CCCCC1(CCCC)CN(c2ccccc2)c2cc(Br)c(OCC(=O)O)cc2S(=O)(=O)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
1,1-Dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4,5-tetrahydro-1,5-benzothiazepine (Method 41; 2.2 g, 3.88 mmol) was dissolved in ethanol (15 ml). NaOH (0.8 g in 1.5 ml water) was added to the solution and the mixture was stirred for 30 min at room temperature. AcOH (2 ml) was added. The solvent was evaporated under reduced pressure and the residue was extracted with EtOAc/water. The EtOAc layer was separated, dried and evaporated under reduced pressure to give the title compound 2.0 g (95%). NMR (500 MHz) 0.7-0.8 (m, 6H), 1.0-1.5 (m, 12H), 3.2 (brs, 2H), 3.7 (brs, 2H), 4.7 (s, 2H), 7.0-7.3 (m, 6H), 7.4 (s, 1H).
Reaction SMILES: C([O:4][C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:18]=[CH:17]C(C(N)=O)=[CH:12][CH:11]=1)#[N:9].N([N+]([O-])=O)=O>C(O)(=O)C>[C:8]([C:10]1[CH:18]=[CH:17][C:6]([C:5]([OH:4])=[O:7])=[CH:12][CH:11]=1)#[N:9]
Reactant: N#Cc1ccc(C(N)=O)cc1
Reactant: CC(=O)OC(C)=O
Agent: O=N[N+](=O)[O-]
Solvent: CC(=O)O
Product: N#Cc1ccc(C(=O)O)cc1
Reaction time: 6 h
Yield: 94 %

Procedure:
Acetic acid (30 ml), acetic anhydride (70 ml), and p-cyanobenzamide (5 g) were mixed with stirring under cooling with ice, to thereby obtain a mixture. The mixture was allowed to react while dinitrogen trioxide gas was introduced thereto at 190 N ml/hour for six hours. The residual solvent was removed through distillation in vacuum, and water was added to the residue, to thereby form crystals. The precipitated crystals were collected through filtration, washed with water, and dried, to thereby obtain 4.73 g of p-cyanobenzoic acid (yield 94%, based on p-cyanobenzamide). High performance liquid chromatographic analysis revealed that the p-cyanobenzoic acid obtained had a purity of 99% or more.
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])C)[C:3]=1[O:20][CH2:21][CH3:22].C([N-][CH:27]([CH3:29])[CH3:28])(C)C.[Li+].CI>C1COCC1>[Br:1][C:2]1[C:11]2[C:10]([CH3:13])([CH3:12])[CH2:9][CH:8]=[C:7]([CH:14]([CH3:16])[CH3:15])[C:6]=2[CH:5]=[C:4]([C:17](=[O:19])[CH:27]([CH3:28])[CH3:29])[C:3]=1[O:20][CH2:21][CH3:22]
Reactant: CC(C)[N-]C(C)C
Reactant: CCOc1c(C(C)=O)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CI
Product: CCOc1c(C(=O)C(C)C)cc2c(c1Br)C(C)(C)CC=C2C(C)C
Temperature: -78 °C
Reaction time: 3 h

Procedure:
To a solution of 1-(4-bromo-3-ethoxy-8-isopropyl-5,5-dimethyl-5,6-dihydro-naphthalen-2-yl)-ethanone (Compound A-109, 512 mg, 1.4 mmol) in THF (10 mL) at −78° C. was added lithium diisopropylamide (1.5 M in cyclohexane, 2.0 mL, 3.0 mmol). The cold bath was removed and the mixture was stirred for 3 h. The mixture was cooled to −78° C. again and methyl iodide (0.52 mL, 8.34 mmol) was added. The mixture was stirred at room temperature for 16 h then quenched with ammonium chloride (sat), extracted with diethyl ether. The combined ethereal layers were washed with water, brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude residue was purified by flash chromatography (silica gel, 2% ethyl acetate in hexanes) followed by HPLC (Waters-Nova Pak column, 2% ethyl acetate in hexanes) to give the title compound.
Reaction SMILES: [CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH2:24])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:27])[F:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:29][C:30]1[CH:31]=[CH:32][C:33]([O:38][CH3:39])=[C:34]([CH:37]=1)[CH:35]=O>>[CH2:1]([C:8]1[CH:9]=[N:10][C:11]2[C:16]([C:17]=1[C:18]1[CH:19]=[C:20]([NH:24][CH2:35][C:34]3[CH:37]=[C:30]([F:29])[CH:31]=[CH:32][C:33]=3[O:38][CH3:39])[CH:21]=[CH:22][CH:23]=1)=[CH:15][CH:14]=[CH:13][C:12]=2[C:25]([F:28])([F:26])[F:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(F)cc1C=O
Reactant: Nc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: COc1ccc(F)cc1CNc1cccc(-c2c(Cc3ccccc3)cnc3c(C(F)(F)F)cccc23)c1

Procedure:
The title compound was prepared from {3-[3-benzyl-8-(trifluoromethyl)quinolin-4-yl]phenyl}amine and 5-fluoro-2-methoxy-benzaldehyde according to the procedure of Example 66. MS (ESI) m/z 517.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=1>>[Cl:21][C:22]1[CH:28]=[CH:27][C:25]([NH:26][C:2]2[CH:11]=[CH:10][N:9]=[C:8]3[C:3]=2[C:4]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=2[C:6](=[O:12])[NH:7]3)=[CH:24][CH:23]=1
Reactant: Nc1ccc(Cl)cc1
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Product: COc1cc2c(=O)[nH]c3nccc(Nc4ccc(Cl)cc4)c3c2cc1OC
Yield: 30.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 4-chloroaniline (29 mg, 0.22 mmol) to provide 213 (20 mg, 30% yield) as a white solid. LC-MS (M+H=382, obsd.=382).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([Cl:12])[CH:9]=[C:8]2[C:3]=1[C:4](O)=[CH:5][CH:6]=[N:7]2.S(Cl)([Cl:16])=O.C(N(CC)C=O)C>CN(C)C=O>[Cl:16][C:4]1[C:3]2[C:8](=[CH:9][C:10]([Cl:12])=[CH:11][C:2]=2[Cl:1])[N:7]=[CH:6][CH:5]=1
Reactant: Oc1ccnc2cc(Cl)cc(Cl)c12
Reactant: O=S(Cl)Cl
Agent: CCN(C=O)CC
Solvent: CN(C)C=O
Product: Clc1cc(Cl)c2c(Cl)ccnc2c1

Procedure:
reacting 5,7-dichloro-4-hydoxyquinoline with thionyl chloride in the presence of N,N-dimethylformamide or N,N-diethylformamide to obtain 4,5,7-trichloroquinoline,
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[C:6]3[CH2:18][CH2:19][N:20](C(OCC4C=CC=CC=4)=O)[CH2:21][C:5]=3[C:4]=2[CH:3]=1>C(OCC)(=O)C.CO.[Pd]>[F:1][C:2]1[CH:10]=[CH:9][C:8]2[N:7]([C:11]3[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=3)[C:6]3[CH2:18][CH2:19][NH:20][CH2:21][C:5]=3[C:4]=2[CH:3]=1
Reactant: O=C(OCc1ccccc1)N1CCc2c(c3cc(F)ccc3n2-c2ccc(F)cc2)C1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: Fc1ccc(-n2c3c(c4cc(F)ccc42)CNCC3)cc1
Reaction time: 4 h

Procedure:
In a Parr bottle were combined 5% Pd/C (10 g of 50% water-wet) and 60 g of 8-fluoro-5- (p-fluorophenyl)-2-carbobenzoxy-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]-indole (60 g, 0.143 mole) in 400 ml ethyl acetate and 100 ml methanol and the mixture hydrogenated at 44-80 psig for 4 hours. Catalyst was recovered by filtration and the filtrate evaporated to solids in vacuo. The residue taken into CH2Cl2, carbon treated, dried (Na2SO4) and CH2Cl2 displaced with hexane by distillation to a final pot temperature of 70° C. The white, crystalline product was recovered by filtration, 35.6 g, m.p. 126°-129° C.
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]1([C:26]3[CH:27]=[C:28]([F:32])[C:29]([F:31])=[CH:30][C:25]=3[O:24][CH2:23]1)[C:5](=[O:22])[N:6]2[CH2:11][C:12]([NH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[F:21])=[O:13].[N:33]1[CH:38]=[C:37](B(O)O)[CH:36]=[N:35][CH:34]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.C(OCC)(=O)C.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>[F:32][C:28]1[C:29]([F:31])=[CH:30][C:25]2[O:24][CH2:23][C:4]3([C:3]4[C:7](=[CH:8][CH:9]=[CH:10][C:2]=4[C:37]4[CH:38]=[N:33][CH:34]=[N:35][CH:36]=4)[N:6]([CH2:11][C:12]([NH:14][C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=4[F:21])=[O:13])[C:5]3=[O:22])[C:26]=2[CH:27]=1
Reactant: OB(O)c1cncnc1
Reactant: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(Br)cccc21)Nc1ccccc1F
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: [Na+]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=C(CN1C(=O)C2(COc3cc(F)c(F)cc32)c2c(-c3cncnc3)cccc21)Nc1ccccc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 86.2 %

Procedure:
To a solution of 2-(4′-bromo-5,6-difluoro-2′-oxospiro[1-benzofuran-3,3′-indol]-1′(2′H)-yl)-N-(2-fluorophenyl)acetamide (0.15 g, 0.30 mmol) in anhydrous 1,4-dioxane (5.00 mL) was added Pd(PPh3)4 (0.03 g, 0.03 mmol) and stirred at ambient temperature for 10 min. Pyrimidine-5-boronic acid (0.06 g, 0.45 mmol) and sodium carbonate (0.90 mL of 2 M solution, 1.80 mmol) were added. The reaction mixture was reluxed at 120° C. for 16 h, diluted with ethyl acetate (50.0 mL). The organic layer was washed with water, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo. The residue was subjected to column chromatography (ethyl acetate/hexane, 1/1) to give the title compound (0.13 g, 84%): 1H NMR (300 MHz, CDCl3) δ 9.13 (s, 1H), 8.29-8.10 (m, 3H), 7.62 (s, 1H), 7.44 (t, 1H), 7.16-7.03 (m, 4H), 6.91 (d, 1H), 6.85-6.76 (m, 1H), 6.46-6.37 (m, 1H), 4.85-4.73 (m, 2H), 4.61-4.47 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 177.1, 163.9, 157.7, 156.4, 155.7, 141.9, 132.9, 130.0, 126.0, 124.7, 121.9, 115.0, 111.6, 109.8, 100.2, 79.4, 57.9, 44.7; MS (ES+) m/z 503.5 (M+1).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:21])([F:20])[S:9]([O:12]S(C(F)(F)F)(=O)=O)(=[O:11])=[O:10].O[C:23]1[CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1.[Cl-].[NH4+]>C(Cl)(Cl)Cl>[F:7][C:8]([F:21])([F:20])[S:9]([O:12][C:23]1[CH:24]=[C:25]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=[C:27]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:28]=1)(=[O:11])=[O:10]
Reactant: COC(=O)c1cc(O)cc(-c2ccccc2)c1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COC(=O)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccccc2)c1
Reaction time: 0.5 h

Procedure:
With cooling with ice, pyridine (1.2 mL) and trifluoromethanesulfonic acid anhydride (1.2 mL) were added to a CHCl3 (40 mL) solution of methyl 5-hydroxybiphenyl-3-carboxylate, and stirred for 30 minutes with cooling with ice. Aqueous ammonium chloride was added to the reaction liquid, extracted with ethyl acetate, and the organic layer was washed with water, aqueous saturated sodium bicarbonate solution and saturated saline water. This was dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to obtain the title compound as a yellow oil. Not purified, this was used in the next step.
Reaction SMILES: [Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5](Br)=[N:4][CH:3]=1.[CH:12]([N:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][N:18]2[C:22]1[CH:27]=[CH:26][C:25]([NH2:28])=[CH:24][CH:23]=1)([CH3:14])[CH3:13].CCN(C(C)C)C(C)C>C(O)(C)C>[Br:1][C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([NH:28][C:25]2[CH:24]=[CH:23][C:22]([N:18]3[CH2:17][C@@H:16]4[CH2:21][C@H:19]3[CH2:20][N:15]4[CH:12]([CH3:14])[CH3:13])=[CH:27][CH:26]=2)=[N:4][CH:3]=1
Reactant: Brc1ncc(Br)n2ncnc12
Reactant: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(N)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CC(C)O
Product: CC(C)N1C[C@@H]2C[C@H]1CN2c1ccc(Nc2ncc(Br)n3ncnc23)cc1
Temperature: 85 °C
Yield: 105.3 %

Procedure:
5,8-Dibromo-[1,2,4]triazolo[1,5-a]pyrazine (2.26 g, 8.14 mmol), 4-((1S,4S)-5-Isopropyl-2,5-diaza-bicyclo[2.2.1]hept-2-yl)-phenylamine (2.07 g, 8.95 mmol, 1.10 equiv.) and DiPEA (4.3 mL, 24.42 mmol, 3.00 equiv.) are mixed in isopropanol (28 mL) under nitrogen. The reaction is heated to 85° C. until completion of the reaction (typically 5 h). The solvent is removed under vacuum and the residue is partitioned between 60 mL aqueous sodium phosphates buffer (pH 7) and 200 mL DCM, the organic layer is washed with 60 mL satd. NaCl, dried on anhydrous Na2SO4, filtered and evaporated in vacuo to yield the title compound (3.67 g) as a green-black foamy solid.
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[C@H:11]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[C:14]([Cl:19])[CH:13]=2)[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6]1)=[N+:2]=[N-:3].C(=O)([O-])[O-].[K+].[K+].[C:33]([O:39][CH3:40])(=[O:38])[CH2:34][C:35]([CH3:37])=O>CS(C)=O.C(OCC)(=O)C>[Cl:19][C:14]1[CH:13]=[C:12]([C@@H:11]2[O:10][CH2:9][CH2:8][N:7]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C@H:5]2[CH2:4][N:1]2[C:35]([CH3:37])=[C:34]([C:33]([O:39][CH3:40])=[O:38])[N:3]=[N:2]2)[CH:17]=[CH:16][C:15]=1[Cl:18]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](CN=[N+]=[N-])C1
Reactant: COC(=O)CC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1nnn(C[C@@H]2CN(C(=O)OC(C)(C)C)CCO[C@H]2c2ccc(Cl)c(Cl)c2)c1C
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl (6S,7R)-6-(azidomethyl)-7-(3,4-dichlorophenyl)-1,4-oxazepane-4-carboxylate (200 mg) in DMSO (2 mL) were added potassium carbonate (276 mg) and methyl acetoacetate (0.08 mL) at room temperature, and the mixture was stirred at 80° C. overnight. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (149 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH2:9])=[O:8])[C:5]([OH:11])=[CH:4][CH:3]=1.C(C1C=CC(C)=NC=1)C.Cl[C:22](OCC)=[O:23].Cl>C(OCCCC)(=O)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[O:11][C:22](=[O:23])[NH:9][C:7](=[O:8])[C:6]=2[CH:10]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1cc(Cl)ccc1O
Agent: CCc1ccc(C)nc1
Agent: Cl
Solvent: CCCCOC(C)=O
Solvent: O
Product: O=c1[nH]c(=O)c2cc(Cl)ccc2o1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 92.8 %

Procedure:
5-chlorosalicylamide (300 g, 1.75 mol) and water (900 ml) were placed in a 3 liter, 4-neck round-bottomed flask under a nitrogen atmosphere and stirred. 5-ethyl-2-methyl-pyridine (284 g, 2.27 mol) and n-butyl acetate (900 ml) were added to the mixture. The mixture was cooled to 0-5° C. (jacket-10° C.) and dropwise addition of ethyl chloroformate (233 g, 2.10 mol) was started. This addition continued over a period of approximately one hour. When the addition was completed, the reaction mixture was slowly heated (in about two hours) to reflux and kept under reflux for an additional period of about 5 hours (jacket 110° C., internal temperature (IT) 90° C.). The resulting slurry was allowed to cool to room temperature, and hydrochloric acid (28 ml, 37% m/m, 0.34 mol) was added and the mixture stirred for about 30 minutes. The resulting slurry was vacuum filtered, the filter cake was washed with n-butyl acetate followed by water (600 ml) and was allowed to dry overnight in vacuo at 60° C. 321 g (93%) of 6-chloro-2H-1,3-benzoxazine-2,4(3H)-dione (6-chloro carsalam) was isolated after drying.
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:16][CH2:15][C@H:14]([OH:17])[CH2:13][CH2:12]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:18]1OCCOCCOCCOCCOC1.IC>C1COCC1>[C:3]([O:7][C:8]([NH:10][C@H:11]1[CH2:12][CH2:13][C@H:14]([O:17][CH3:18])[CH2:15][CH2:16]1)=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](O)CC1
Reactant: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60% in mineral oil, 278 mg, 6.96 mmol) was suspended in THF (5 mL) and cooled to 0° C. trans-tert-Butoxy-N-(4-hydroxycyclohexyl)carboxamide (1 g, 4.64 mmol) and 15-crown-5 (0.965 mL, 4.88 mmol) were added and the reaction mixture was stirred at 0° C. for about 30 minutes. Iodomethane (0.289 mL, 4.64 mmol) was added and the reaction stirred at 0° C. for about 1 hour after which the LCMS showed it was complete. The reaction was quenched with methanol, the solvents removed in vacuo and the crude purified by column chromatography (SiO2, 8:2 n-hexanes/ethyl acetate) to afford 642 mg of the methyl ether. ES-MS: 230 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][OH:16])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.O[C:18]1[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=1.CCOC(/N=N/C(OCC)=O)=O>O1CCCC1>[CH3:1][O:2][C:3]1[N:8]=[N:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([CH2:15][O:16][C:18]3[CH:28]=[CH:27][C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:20][CH:19]=3)[CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: COc1ccc(N2CCC(CO)CC2)nn1
Agent: CCOC(=O)/N=N/C(=O)OCC
Solvent: C1CCOC1
Product: CCOC(=O)c1ccc(OCC2CCN(c3ccc(OC)nn3)CC2)cc1
Reaction time: 8 h
Yield: 60.1 %

Procedure:
To a stirred and cooled solution of 6.7 parts of 1-(6-methoxy-3-pyridazinyl)-4-piperidinemethanol, 5 parts of ethyl 4-hydroxybenzoate and 7.8 parts of triphenylposphine in 135 of tetrahydrofuran was added a solution of 5.6 parts of diethyl diazenedicarboxylate in 45 parts of tetrahydrofuran. Upon complete addition, stirring was continued overnight at room temperature. After evaporation, the residue was taken up in water and the product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and ethanol (99.5:0.5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from 2-propanol. The product was filtered off and dried, yielding 6.7 parts (60.1%) of ethyl 4-[[1-(6-methoxy-3-pyridazinyl)-4-piperidinyl]methoxy]benzoate; mp. 147.2° C. (comp. 142).
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:10][CH2:11][CH:12]1[CH2:14][CH2:13]1>>[CH:12]1([CH2:11][NH:10][C:2]2[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][N:3]=2)[CH2:14][CH2:13]1
Reactant: NCC1CC1
Reactant: COc1cccnc1Cl
Product: COc1cccnc1NCC1CC1
Temperature: 125 °C
Yield: 50 %

Procedure:
A mixture of 2.00 g (13.9 mmol) of 2-chloro-3-methoxypyridine (Lancaster) in 13.3 mL of aminomethylcyclopropane was heated at 125° C. in a sealed tube for 4 days. The mixture was then cooled to room temperature and partitioned between Et2O and water. The aqueous layer was washed with Et2O, and the combined extracts were washed with brine, dried with MgSO4, filtered, and concentrated. The residue was passed through a plug of silica gel with CH2Cl2 to provide 1.25 g (7.01 mmol; 50%) of 2-cyclopropylmethylamino-3-methoxypyridine. To a mixture of 2-cyclopropyl-methylamino-3-methoxypyridine (430 mg; 2.41 mmol) in 7.5 mL of 2:1 HOAc and water was added 612 mg (2.41 mmol) of I2. The mixture was heated to 100° C. for 4 h, and an additional 320 mg of I2 was added. The mixture was heated for 2 h, then cooled to room temperature and stirred for 12 h. Saturated NaHCO3 (20 mL) and water (20 mL) were added and the suspension was extracted with EtOAc. The extract was then washed with 10% Na2S2O3, water, and brine, dried with MgSO4, filtered, and concentrated. The pure fractions from chromatography (1–4% MeOH in CH2Cl2) were concentrated to provide 145 mg of 2-cyclopropylmethylamino-3-methoxy-5-iodopyridine.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:10]([NH2:11])=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=2)[N:8]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])[N:7]=1)=O)C.C(O)(=O)C.[CH:30](N)=[NH:31]>C(OCCO)C>[Cl:18][C:15]1[CH:14]=[CH:13][C:12]([C:9]2[N:8]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])[N:7]=[C:6]3[C:4]([OH:3])=[N:31][CH:30]=[N:11][C:10]=23)=[CH:17][CH:16]=1
Reactant: N=CN
Reactant: CCOC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1N
Solvent: CCOCCO
Solvent: CC(=O)O
Product: Oc1ncnc2c(-c3ccc(Cl)cc3)n(-c3ccccc3Cl)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 87 %

Procedure:
A mixture of 4-amino-1-(2-chlorophenyl)-5-(4-chlorophenyl)-1H-pyrazole-3-carboxylic acid ethyl ester I-2A-1a (19.27 g, 51.2 mmol) and formamidine acetate (15.99 g, 153.6 mmol) in 100 ml of 2-ethoxyethanol was refluxed for 3.5 hours under nitrogen. The reaction mixture was then cooled to room temperature and poured into ice-cold water. The yellow precipitate that formed was collected by filtration and washed with water. The solid was stirred in 45 ml methyl tert-butyl ether for 30 minutes. Cyclohexane (90 ml) was added, and the stirring was continued for another 45 minutes. The pale yellow solid was collected by filtration and dried to give 3-(4-chlorophenyl)-2-(2-chlorophenyl)-2H-pyrazolo[4,3-d]pyrimidin-7-ol I-2A-1b (17.55 g, 87%): MS 357.1 (M+1)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][N:12](CC3C=CC=CC=3)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[H][H]>[Pd].CC(O)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH:10]2[CH:14]([CH2:13][NH:12][CH2:11]2)[CH2:15]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: [H][H]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3ccccc3)CC2C1
Agent: [Pd]
Solvent: CO
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CC2CNCC2C1

Procedure:
5-Benzyl-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (19.85 g, 65.6 mmol), MeOH (200 mL), HOAc (3 mL) and 10% Pd/C Degussa type (400 mg) were charged to a Parr shaker vial and shaken for 3 days at 70 psi hydrogen gas. The resulting material was filtered through Celite® and concentrated. The crude mixture was purified by flash column chromatography (FCC), DCM to 10% MeOH/DCM containing 1% NH4OH, to afford the product. MS (ESI) mass calcd. for C11H20N2O2, 212.29; m/z found, 213.2 [M+H]+. 1H NMR (400 MHz, CDCl3): 3.60-3.55 (m, 2H), 3.38-3.25 (m, 4H), 2.95-2.86 (m, 4H), 1.47 (s, 9H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[OH:9])=[CH:4][CH:3]=1>C(Cl)Cl.C(OCC)(=O)C.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([CH:10]2[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]2)=[O:9])=[CH:6][CH:7]=1
Reactant: OC(c1ccc(Br)cc1)C1CCCCC1
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: O=C(c1ccc(Br)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (4-bromophenyl)(cyclohexyl)methanol (3.45 g, 12.82 mmol) in DCM (100 ml) was added manganese dioxide (11.14 g, 128 mmol) at room temperature. The reaction mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate and the organic phase was washed with aqueous NaHCO3 solution and brine. The organic phase was dried over Na2SO4, filtered and concentrated in vacuo to obtain the title compound as slightly orange solid.