Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)[CH:14]=[CH:15][CH:16]=3)[C:11]([NH:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=3)=[N:10][N:9]=2)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.[C:38](Cl)(=[O:43])[O:39][CH:40]([CH3:42])[CH3:41]>ClCCl>[C:18]1([C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:12]=2[C:11]([NH:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][N:27]=2)=[N:10][N:9]=[C:8]3[C:4]2[CH:3]=[C:2]([NH:1][C:38](=[O:43])[O:39][CH:40]([CH3:42])[CH3:41])[CH:7]=[N:6][CH:5]=2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)OC(=O)Cl
Reactant: Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(C)OC(=O)Nc1cncc(-c2nnc(NCc3ccccn3)c3c(-c4ccccc4)cccc23)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.5 %

Procedure:
To a solution of 4-(5-aminopyridin-3-yl)-8-phenyl-N-(pyridin-2-ylmethyl) phthalazin-1-amine (50.0 mg, 0.124 mmol) in dichloromethane (5 mL) at room temperature was added pyridine (0.0200 mL, 0.247 mmol) followed by isopropyl carbonochloridate (18.2 mg, 0.148 mmol). The reaction mixture was stirred at ambient temperature for 12 h then diluted with dichloromethane (50 mL) and the organic portion washed with water (10 mL) followed by brine (10 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was purified by preparative HPLC (Condition 32 as described in general methods) to afford isopropyl (5-(5-phenyl-4-((pyridin-2-ylmethyl)amino)phthalazin-1-yl)pyridin-3-yl)carbamate (35.0 mg, 57.7%). LCMS (Condition 4): retention time 2.16 min, [M+1]=491.0. HPLC (Condition 28): retention time=6.66 min, purity 95.13%. 1H NMR (400 MHz, DMSO-d6) δ 1.29 (d, J=6.0 Hz, 6 H), 4.65 (d, J=4.0 Hz, 2 H), 4.93 (sept, J=6.0 Hz, 1 H), 6.28 (t, J=4.0 Hz, 1 H), 7.22 (dd, J=6.0 Hz, J=7.6 Hz, 1 H), 7.28 (d, J=8.0 Hz, 1 H), 7.45-7.60 (m, 5 H), 7.68-7.73 (m, 2 H), 7.84-7.93 (m, 2 H), 8.17 (t, J=2.0 Hz, 1 H), 8.22-8.24 (m, 1 H), 8.48 (d, J=2.0 Hz, 1 H), 8.81 (d, J=2.0 Hz, 1 H), 10.00 (s, 1 H).
Reaction SMILES: O[CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].CN(C)C=O.S(Cl)([Cl:31])=O>C1C=CC=CC=1>[Cl:31][CH2:2][CH2:3][N:4]([CH2:21][CH:22]=[CH2:23])[C:5]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:8]([C:14]([F:17])([F:16])[F:15])=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19]
Reactant: C=CCN(CCO)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: C=CCN(CCCl)c1c([N+](=O)[O-])cc(C(F)(F)F)cc1[N+](=O)[O-]
Reaction time: 2 h

Procedure:
16.7 parts by weight of N-hydroxyethyl-N-allyl-2,6-dinitro-4-trifluoromethylaniline is dissolved in 50 parts by weight of benzene. After adding 1 part by weight of dimethylformamide and dripping in 30 parts by weight of thionyl chloride at room temperature the whole is boiled for two hours under reflux. The volatile constituents are distilled off from the reaction mixture at 20 mm Hg, the residue is taken up in ethyl acetate, the solution is washed with ice-water, then with 10% sodium bicarbonate solution and finally again with water and the organic phase is dried over sodium sulfate.
Reaction SMILES: Br[CH:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][C:6]([C:12]#[N:13])=[CH:7][CH:8]=2)[C:3]1=O.Cl.[NH:16]1[CH:20]=[C:19]([CH2:21][C:22]([NH2:24])=[S:23])[N:18]=[CH:17]1>>[C:12]([C:6]1[CH:5]=[C:4]2[C:9]([CH2:10][CH2:11][C:2]3[S:23][C:22]([CH2:21][C:19]4[N:18]=[CH:17][NH:16][CH:20]=4)=[N:24][C:3]=32)=[CH:8][CH:7]=1)#[N:13]
Reactant: N#Cc1ccc2c(c1)C(=O)C(Br)CC2
Reactant: NC(=S)Cc1c[nH]cn1
Agent: Cl
Product: N#Cc1ccc2c(c1)-c1nc(Cc3c[nH]cn3)sc1CC2

Procedure:
Starting compounds: 2-bromo-7-cyano-1-tetralone, 4-imidazolylthioacetamide hydrochloride
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2[N:7]=[C:8]([Cl:19])[N:9]=[C:10]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[C:11]=2[N:12]=1.[NH:20]1[CH2:23][CH:22]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH2:21]1>>[Cl:19][C:8]1[N:9]=[C:10]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:11]2[N:12]=[C:3]([CH2:2][N:20]3[CH2:23][CH:22]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)[CH2:21]3)[CH:4]=[CH:5][C:6]=2[N:7]=1
Reactant: C1CN(C2CNC2)CCO1
Reactant: Clc1nc(N2CCOCC2)c2nc(CBr)ccc2n1
Product: Clc1nc(N2CCOCC2)c2nc(CN3CC(N4CCOCC4)C3)ccc2n1

Procedure:
tert-butyl 3-morpholinoazetidine-1-carboxylate (31 mg) was treated with 4N HCl in dioxane (5 eq) in 1 mL of DCM. The reaction mixture was stirred for 3 hours at room temperature and then concentrated to dryness to yield 4-(azetidin-3-yl)morpholine in quantitative yield. 4-(6-(Bromomethyl)-2-chloropyrido[3,2-d]pyrimidin-4-yl)morpholine 7 (0.413 g) was reacted with 4-(azetidin-3-yl)morpholine via General Procedure B to afford 0.4 g 4-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)azetidin-3-yl)morpholine
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[C:9]([C:17]3[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][CH2:27]4)=[CH:19][CH:18]=3)[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][NH2:41])[CH2:35][CH2:34]1)[CH3:32].CCN(C(C)C)C(C)C>C(Cl)Cl.CC#N>[CH2:31]([N:33]1[CH2:38][CH2:37][N:36]([CH2:39][CH2:40][NH:41][C:2]2[C:3]3[C:10]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=4)=[C:9]([C:17]4[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][N:26]5[CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:19][CH:18]=4)[O:8][C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:35][CH2:34]1)[CH3:32]
Reactant: CCN1CCN(CCN)CC1
Reactant: Clc1ncnc2oc(-c3ccc(OCCN4CCCC4)cc3)c(-c3ccccc3)c12
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: CCN1CCN(CCNc2ncnc3oc(-c4ccc(OCCN5CCCC5)cc4)c(-c4ccccc4)c23)CC1

Procedure:
A solution of 27 (60 mg, 0.143 mmol), 2-(4-ethylpiperazin-1-yl)ethanamine (57 mg, 0.362 mmol), and DIEA (0.062 mL, 0.357 mmol) in CH2Cl2 (1 mL) and CH3CN (1 mL) was heated at 70° C. over night, then concentrated. Preparative TLC (SiO2, 20% MeOH in CH2Cl2) afforded the title compound 28. MS for C32H40N6O2: found 541 (M+H+), 539 (M−H+).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([CH:10]([O:12][CH3:13])[CH3:11])[C:3]=1[O:14][CH3:15].[C:16]1([C:22]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[N:23]2[CH:27]=[C:26]([CH:28]=[O:29])[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>>[CH3:15][O:14][C:3]1[C:4]([CH:10]([O:12][CH3:13])[CH3:11])=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:28]([C:26]1[N:25]=[CH:24][N:23]([C:22]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:27]=1)[OH:29]
Reactant: COc1ccc(C(C)OC)c(OC)c1Br
Reactant: O=Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Product: COc1ccc(C(C)OC)c(OC)c1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Yield: 49.7 %

Procedure:
Starting from 1-bromo-2,6-dimethoxy-3-(1-methoxyethyl)benzene and 1-triphenylmethyl-1H-imidazole-4-carboxaldehyde. The reaction product is purified by chromatography on silica (eluent: 98:2 v/v dichloromethanemethanol). Yield: 49.7% of theory; M.P.: 96°-99° C. (recrystallized from acetonitrile).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:23])[C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[CH:16]=2)=[C:12]([CH2:24][CH3:25])[C:11](=[O:26])[NH:10][C:9]1=[O:27])=[O:4].O.[C:29]1(C)C=CC(S(O)(=O)=O)=CC=1.C(=O)(O)[O-].[Na+]>C(O)C>[CH2:1]([O:2][C:3]([CH:5]=[CH:6][CH2:7][N:8]1[C:13]([C:14](=[O:23])[C:15]2[CH:16]=[C:17]([CH3:22])[CH:18]=[C:19]([CH3:21])[CH:20]=2)=[C:12]([CH2:24][CH3:25])[C:11](=[O:26])[NH:10][C:9]1=[O:27])=[O:4])[CH3:29]
Reactant: CCc1c(C(=O)c2cc(C)cc(C)c2)n(CC=CC(=O)OC)c(=O)[nH]c1=O
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C=CCn1c(C(=O)c2cc(C)cc(C)c2)c(CC)c(=O)[nH]c1=O
Reaction time: 48 h
Yield: 148.4 %

Procedure:
To a solution of 100 mg (0.27 mmol) of the compound obtained from Example 8 in 10 ml of anhydrous ethanol was added 20 mg of p-toluenesulfonic acid monohydrate. The reaction mixture was refluxed with stirring for about 48 hours, neutralized with sodium bicarbonate, and evaporated under reduced pressure to give a light brown residue, which was purified by flash chromatography using a mixture of ethyl acetate and hexane (1:2) as an eluent to afford 60 mg (yield 58%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13](=O)[CH:14]=[CH:15][NH:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:24])=O>CN(C=O)C>[ClH:24].[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([Cl:24])=[CH:14][CH:15]=[N:16]2)=[CH:11][C:10]=1[O:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ccnc2cc1OCc1ccccc1
Product: Cl
Yield: 89 %

Procedure:
A suspension of 7-benzyloxy-6-methoxy-1,4-dihydroquinolin-4-one (3.37 g, 13 mmol) in thionyl chloride (50 ml) and DMF (0.25 ml) was heated at reflux for 1 hour. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene and triturated with ether, the product collected by filtration and dried under vacuum to give 7-benzyloxy-4-chloro-6-methoxyquinoline hydrochloride (3.9 g, 89%).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[N:6][C:7]([CH3:11])=[CH:8][CH:9]=2)[S:4][C:3]=1[C:12]#[N:13].[ClH:14].[N:15]([O-])=O.[Na+]>O>[Cl:14][C:12]1[C:3]2[S:4][C:5]3[N:6]=[C:7]([CH3:11])[CH:8]=[CH:9][C:10]=3[C:2]=2[N:1]=[N:15][N:13]=1
Reactant: Cc1ccc2c(N)c(C#N)sc2n1
Reactant: O=N[O-]
Reactant: Cl
Agent: [Na+]
Solvent: O
Product: Cc1ccc2c(n1)sc1c(Cl)nnnc12

Procedure:
To a cold solution of 4.2 g. (0.022 M) of 3-amino-2-cyano-6-methylthieno[2,3-b]pyridine in 30 ml. conc. HCl and 30 ml. HOAC was added a solution of 1.9 g. (0.028 M) of NaNO2 in 20 ml. of H2O. After completion of addition, the ice bath was removed and stirring continued for 2 more hours. The mixture was then poured on ice water and filtered. The crude product was recrystallized from methanol, m.p. 188°-189° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1.NC1N=C(N)C(C2C=CC([N+:32]([O-:34])=[O:33])=C(Cl)C=2Cl)=CN=1.NC1N=C(N)C(C2C=C([N+]([O-])=O)C=C(Cl)C=2Cl)=C(C)N=1>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[CH:13][C:12]([N+:32]([O-:34])=[O:33])=[C:11]([Cl:15])[C:10]=2[Cl:16])=[C:4]([CH3:17])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cccc(Cl)c1Cl
Reactant: Nc1ncc(-c2ccc([N+](=O)[O-])c(Cl)c2Cl)c(N)n1
Agent: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])cc(Cl)c1Cl
Product: Cc1nc(N)nc(N)c1-c1ccc([N+](=O)[O-])c(Cl)c1Cl

Procedure:
This compound was made from the compound of Example 15 in an analogous manner to the compound of Example 39, mp. 265° C. Also obtained from this reaction was 2,4-diamino-5(2,3-dichloro-5-nitrophenyl)-6-methyl pyrimidine.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.[C:12](O)([CH3:15])([CH3:14])[CH3:13].C1(N=C=NC2CCCCC2)CCCCC1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[CH:6][CH:7]=1
Reactant: CC(C)(C)O
Reactant: Cc1ccc(CC(=O)O)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: Cc1ccc(CC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
450 g (3 mol) of 4-methylphenyl-acetic acid (Aldrich), 1.13 l (12 mol) of tert-butanol and 90 g (0.74 mol) of 4-(N,N-dimethylamino)pyridine are dissolved in 2 l of methylene chloride. After addition of 680 g (3.3 mol) of dicyclohexylcarbodiimide, dissolved in 400 ml of methylene chloride, the mixture is stirred at 25° C. for 20 hours, the urea which has precipitated out is filtered off with suction and washed with 200 ml of methylene chloride and the organic phase is washed in each case twice with 500 ml of 2M hydrochloric acid and water. The organic phase is concentrated and distilled. Yield: 408 g (66% of theory) Boiling point: 73°-78° C./0.2 mm
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:16])[C:11]=1[NH:12][C:13](=[O:15])[NH2:14])[CH:5]([OH:8])[CH2:6]Br.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].C(=O)([O-])[O-].[Na+].[Na+].[Cl-].[Na+]>O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([Cl:16])[C:11]=1[NH:12][C:13](=[O:15])[NH:14][C:4]([CH3:9])([CH3:5])[CH3:3])[CH:5]([OH:8])[CH2:6][NH:21][C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: NC(=O)Nc1c(Cl)cc(C(O)CBr)cc1Cl
Reactant: CC(C)(C)N
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)NCC(O)c1cc(Cl)c(NC(=O)NC(C)(C)C)c(Cl)c1
Reaction time: 0.5 h

Procedure:
A mixture of 0.86 g. of 3,5-dichloro-4-carbamoylamino-α-bromomethylbenzyl alcohol and 10 ml. of tert-butylamine was heated to 90°-100° C. for 2 days in a sealed tube. After cooling the reaction mixture, the solvent was distilled off under reduced pressure and after adding to the residue formed 50 ml. of ethyl acetate, 50 ml. of water, and an excessive amount of sodium carbonate followed by stirring for 30 minutes, sodium chloride was added to the mixture until the mixture was saturated. Then, the mixture was separated into an ethyl acetate layer and an aqueous layer. The ethyl acetate layer formed was washed with a saturated aqueous sodium chloride solution, and then dried over anhydrous magnesium sulfate. Then, after filtering, the solvent was distilled off from the filtrate under reduced pressure. By recrystallizing the residue from ethyl acetate, 0.24 g. of 3,5-dichloro-4-tert-butylcarbamoylamino-α-(tert-butylaminomethyl)benzyl alcohol having a melting point of 167°-169° C. was obtained.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH3:12].[Br:14]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[CH:6][C:5]=1[CH2:12][Br:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(OC)cc1C
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1ccc(OC)cc1CBr
Temperature: 5 °C
Yield: 57.7 %

Procedure:
A mixture of 4-methoxy-2-methyl-benzoic acid methyl ester (20 g, 111 mmol), N-bromosuccinimide (20.7 g, 117 mmol) and dibenzoylperoxide (0.54 g, 2 mmol) in CCl4 (150 mL) was irradiated with a 300 W lamp. The reaction maintains a steady reflux and after 4.5 h, the lamp was removed and the mixture cooled to 5° C. The mixture was then filtered, the filtrate evaporated and the residue purified twice by chromatography (SiO2, Heptane:Diethyl ether: 95:5 to 85:15) to afford the title product (16.6 g, 58%) as a white solid. MS m/e=258.1 (M−H+).
Reaction SMILES: [CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([O:29]CC)=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[OH-].[Li+]>O1CCOCC1.O>[CH2:1]([O:8][NH:9][C:10](=[O:32])[CH2:11][C@H:12]([C:22]1[O:23][CH:24]=[C:25]([C:27]([OH:29])=[O:28])[N:26]=1)[CH2:13][CH2:14][CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1coc([C@H](CCCC2CCCCC2)CC(=O)NOCc2ccccc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(C[C@@H](CCCC1CCCCC1)c1nc(C(=O)O)co1)NOCc1ccccc1
Reaction time: 3.5 h
Yield: 61.1 %

Procedure:
A solution of ethyl 2-((1R)-1-{2-[(benzyloxy)amino]-2-oxoethyl}-4-cyclohexylbutyl)-1,3-oxazole-4-carboxylate (Preparation 64) (1.31 g, 2.96 mmol) in 1,4-dioxane:water (10 ml:5 ml) was treated with lithium hydroxide monohydrate (0.19 g, 4.44 mmol) and stirred in a cold water bath for 3.5 hours. The mixture was diluted with water (100 ml) and washed with ethyl acetate. The layers were separated and the aqueous layer was acidified with solid citric acid then extracted with ethyl acetate. The layers were separated and the organic layer was dried over anhydrous sodium sulphate, filtered and the solvent removed under reduced pressure to afford the title compound as a white solid (0.75 g).
Reaction SMILES: C([NH:9][C:10]1[O:11][C@H:12]([C:36]([F:39])([F:38])[F:37])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])([CH2:16][F:17])[N:15]=1)(=O)C1C=CC=CC=1.N12CCCN=C1CCCCC2>CO>[NH2:9][C:10]1[O:11][C@H:12]([C:36]([F:37])([F:39])[F:38])[CH2:13][C@:14]([C:18]2[CH:19]=[C:20]([NH:25][C:26]([C:28]3[CH:33]=[N:32][C:31]([O:34][CH3:35])=[CH:30][N:29]=3)=[O:27])[CH:21]=[CH:22][C:23]=2[F:24])([CH2:16][F:17])[N:15]=1
Reactant: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(NC(=O)c4ccccc4)=N3)c2)cn1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CO
Product: COc1cnc(C(=O)Nc2ccc(F)c([C@]3(CF)C[C@@H](C(F)(F)F)OC(N)=N3)c2)cn1
Temperature: 75 °C
Yield: 83 %

Procedure:
A microwave vial was charged with N-(3-((4S,6S)-2-benzamido-4-(fluoromethyl)-6-(trifluoromethyl)-5,6-dihydro-4H-1,3-oxazin-4-yl)-4-fluorophenyl)-5-methoxypyrazine-2-carboxamide (0.11 g, 0.200 mmol, step 1). MeOH (2 ml) was added followed by 1,8-diazabicyclo[5.4.0]undec-7-ene (0.122 g, 0.801 mmol, Aldrich). The vial was sealed and heated to 75° C. in a microwave (Biotage Initiator) for 1.5 hours. The reaction was cooled to RT and concentrated under reduced pressure. The crude material was purified via silica gel flash chromatography using a gradient of 5-70% EtOAc in hexanes to afford the title compound as a white solid (0.0741 g, 0.166 mmol, 83% yield). MS m/z=446.0 [M+H]+. Calculated for C18H16F5N5O3: 445.343
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH2:16][S:17][C:18]([CH3:21])([CH3:20])[CH3:19].[C-:22]#[N:23].[K+]>CS(C)=O>[C:18]([S:17][CH2:16][C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:8][C:3]=1[CH2:2][C:22]#[N:23])([CH3:21])([CH3:20])[CH3:19]
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CBr
Reactant: [C-]#N
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide (1.8 g, 4.8 mmol) in DMSO (40 mL) was treated with potassium cyanide (0.325 g, 5.0 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH2:11][CH2:12][C:13](O)=O)=[CH:2]1.O.ON1C2C=CC=CC=2N=N1.C(N=C=NC(C)C)(C)C.Cl.[O:37]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[O:40][CH2:39][CH:38]1[CH2:47][NH2:48]>CN(C=O)C>[O:37]1[C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][C:41]=2[O:40][CH2:39][CH:38]1[CH2:47][NH:48][CH2:13][CH2:12][CH2:11][CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: NCC1COc2ccccc2O1
Reactant: O=C(O)CCCc1c[nH]c2ccccc12
Agent: CC(C)N=C=NC(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Product: c1ccc2c(c1)OCC(CNCCCCc1c[nH]c3ccccc13)O2
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.4 %

Procedure:
3-Indolebutyric acid (1.2 g, 6.0 mmole), 1-hydroxybenzotriazole hydrate (0.97 g, 7.2 mmole) and 1,3-diisopropylcarbodiimide (2.3 ml, 14.4 mmole) were combined in 100 ml of DMF and stirred at room temperature for 2 hours under a nitrogen atmosphere. To this was added dropwise 2,3-dihydro-1,4-benzodioxin-2methanamine hydrochloride (1.2 g, 6.0 mmole) in 50 ml of DMF and the mixture was further stirred for 24 hours. The solvent was removed and the residue partitioned between dichloromethane and water. The separated dichloromethane layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuum. The residue was chromatographed on a silica gel column using ethyl acetate as the eluant. Fractions were concentrated and washed with a minimum amount of THF to remove a by-product and to give 1.2 g (57%) of the desired product, (2,3-dihydro-benzo [1,4]dioxin-2-ylmethyl)-4-(1H-indol-3-yl)-butanamide, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.N1CCOCC1.[CH3:16][C:17]1([CH3:27])[O:21][C:20](=[CH:22][C:23](Cl)=[O:24])[C:19](=[O:26])[O:18]1>C(Cl)Cl>[CH3:16][C:17]1([CH3:27])[O:21][C:20](=[CH:22][C:23]([NH:7][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[O:24])[C:19](=[O:26])[O:18]1
Reactant: CC1(C)OC(=O)C(=CC(=O)Cl)O1
Reactant: NCc1ccc(F)cc1
Solvent: C1COCCN1
Solvent: ClCCl
Product: CC1(C)OC(=O)C(=CC(=O)NCc2ccc(F)cc2)O1
Reaction time: 1 h
Yield: 100.7 %

Procedure:
To a stirred suspension of 4-fluorobenzylamine (37.5 mg, 0.3 mmol) and resin bound morpholine (200 mg, 2.5–4.0 mmol/1 g) was added a solution of (2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-acetyl chloride (60 mg, 0.31 mmol) in CH2Cl2 (3 mL) and the mixture shaken for 1 h. The mixture was filtered and the filtrate concentrated to give the title product as a white solid (84.4 mg, 100% yield). MS calc for C14H14FNO4 (M+Na): 302.29; found: 302.29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]([OH:14])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8].C(O)(C)C.Cl[C:20]([O:22][CH2:23][CH3:24])=[O:21]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]([O:14][C:20]([O:22][CH2:23][CH3:24])=[O:21])[C:10]([NH:12][CH3:13])=[O:11])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC(=O)N(O)c1ccc(Cl)c(Cl)c1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)O
Product: CCOC(=O)ON(C(=O)NC)c1ccc(Cl)c(Cl)c1

Procedure:
A solution of 1-(3,4-dichlorophenyl)-1-hydroxy-3-methylurea (15 grams; 0.06 mol) is isopropyl alcohol (50 ml), and pyridine (7 ml) were charged into a glass reaction vessel equipped with a mechanical stirrer. Ethyl chloroformate (7 ml; 0.09 mol) was then slowly added, with stirring, at a temperature of 10° to 15°C. After the addition was completed stirring was continued for an additional period of about one-half hour resulting in the formation of a precipitate. After this time, the reaction mixture was poured onto ice and the precipitate recovered by filtration. The precipitate was recrystallized from a benzene-hexane mixture to yield 1-(3,4-dichlorophenyl)-1-ethoxycarbonyloxy-3-methylurea having a melting point of 97°-98°C and having the following elemental analysis as calculated for C11H12Cl2N2O4 :
Reaction SMILES: [Na+:1].[NH:2]1[CH:6]=[CH:5][C:4]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([O-:11])=[O:10])=[N:3]1.[F:16][C:17]1[CH:18]=[C:19]([N:24]=[C:25]=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1.[N-]=C=O.O>CN(C=O)C>[Na+:1].[F:16][C:17]1[CH:18]=[C:19]([NH:24][C:25]([N:2]2[CH:6]=[CH:5][C:4]([C:7]3[N:15]=[CH:14][CH:13]=[CH:12][C:8]=3[C:9]([O-:11])=[O:10])=[N:3]2)=[O:26])[CH:20]=[C:21]([F:23])[CH:22]=1
Reactant: O=C([O-])c1cccnc1-c1cc[nH]n1
Reactant: O=C=Nc1cc(F)cc(F)c1
Agent: [N-]=C=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C([O-])c1cccnc1-c1ccn(C(=O)Nc2cc(F)cc(F)c2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
0.95 g (4.5 mM) of 2-(pyrazol-3-yl)-nicotinic acid sodium salt are stirred in 20 ml of DMF and 0.7 g (4.5 mM) of 3,5-difluorophenyl isocyanate added. After stirring for 1 hr at RT, a further 0.21 g of isocyanate in DMF are added. The DMF is stripped-off on a Kugelrohr and the resulting solid stirred with 4 ml water and filtered. The filtrate is chromatographed on a reverse phase column with 100 ml of water followed by 100 ml water-methanol. The product containing fraction was lypholized to yield the title product m.p. 165°-170° C.