Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].CCN(CC)CC.[NH2:22][C:23]1[CH:24]=[N:25][C:26]2[C:31]([CH:32]=1)=[CH:30][CH:29]=[CH:28][CH:27]=2>C(#N)C>[CH2:1]([O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:22][C:23]2[CH:24]=[N:25][C:26]3[C:31]([CH:32]=2)=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:11])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: Nc1cnc2ccccc2c1
Reactant: CCCCOc1ccc(C(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCCCOc1ccc(C(=O)Nc2cnc3ccccc3c2)cc1
Yield: 84 %

Procedure:
4-Butoxy-benzoyl chloride (0.21 mL, 1.11 mmol), Et3N (0.16 mL, 1.15 mL) and 3-aminoquinoline (0.153 g, 1.06 mmol) were stirred together in 10 mL acetonitrile in a round bottom flask for 4 hours. The reaction mixture was then evaporated in vacuo and the residue was triturated with 5 mL acetonitrile. The resulting solid was collected by filtration, rinsed with acetonitrile and dried to yield the title product as a cream-colored powder (0.284 g, 0.89 mmol). 1H NMR (CDCl3): δ 8.91 (s, 2H), 8.20 (s, 1H), 8.08 (d, 1H), 7.94 (d, 2H), 7.84 (d, 1H), 7.67 (t, 1H), 7.57 (t, 1H), 7.01 (d, 2H), 4.05 (t, 2H), 1.83 (p, 2H), 1.52 (h, 2H), 1.01 (t, 3H); MS: m/z 321.0 (MH+).
Reaction SMILES: [NH:1]1[C:10]2[CH2:9][CH2:8][CH2:7][C:6](=[O:11])[C:5]=2[CH2:4][CH2:3][CH2:2]1.[H][H]>C(O)(=O)C.O=[Pt]=O>[NH:1]1[CH:10]2[CH:5]([CH:6]([OH:11])[CH2:7][CH2:8][CH2:9]2)[CH2:4][CH2:3][CH2:2]1
Reactant: [H][H]
Reactant: O=C1CCCC2=C1CCCN2
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: OC1CCCC2NCCCC12
Temperature: 0 °C
Yield: 36.2 %

Procedure:
The procedure of Grob et al. (Helv. Chim. Acta 1965, 48, 799-808) was followed. A solution of 66.70 g (0.441 mol) of 2,3,4,6,7,8-hexahydro-5(1H)-quinolinone in 250 ml of glacial acetic acid containing 2 g of PtO2 was hydrogenated at 450 psi and 50° C. for 75 hours. Hydrogen uptake was only 57.2% of the theoretical. The sample was filtered, concentrated (to remove most of the acetic acid), cooled to 0° C., basified with 6N sodium hydroxide to a pH of 12 and extracted three times with 500 ml of methylene chloride. The combined methylene chloride extract was dried over magnesium sulfate, filtered and concentrated to give 24.80 g (36.2%) of decahydro-5-quinolinol, which was a three component isomeric mixture by gas chromatography (GC) analysis, as a light brown oily-solid. This mixture was carried on to the next step without further purification.
Reaction SMILES: C(O)C.[N:4]1[S:8][N:7]=[C:6]2[CH:9]=[C:10]([C:13]([O:15]C)=[O:14])[CH:11]=[CH:12][C:5]=12.[OH-].[Na+].Cl>O>[N:4]1[S:8][N:7]=[C:6]2[CH:9]=[C:10]([C:13]([OH:15])=[O:14])[CH:11]=[CH:12][C:5]=12
Reactant: COC(=O)c1ccc2nsnc2c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1ccc2nsnc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.3 %

Procedure:
To 30 ml of ethanol was dissolved 2.0 g (10 mmol) of methyl benzo[1,2,5]thiadiazole-5-carboxylate, followed by the addition of 3.3 g of a 25% aqueous solution of sodium hydroxide and stirring at room temperature for 3 hours. To the reaction liquid was added 50 ml of water and a dilute hydrochloric acid to make pH of 2. Crystal precipitated was filtered off and dried under reduced pressure to obtain 1.7 g (yield: 92%) of benzo[1,2, 5]thiadiazole-5-carboxylic acid. In a separate reactor, 0.50 g (2.2 mmol) of 6,6-difluoro-5-methyl-5-hexenyl methanesulfonate and 0.43 g (2.4 mmol) of benzo[1,2,5]thiadiazole-5-carboxylic acid were dissolved in 7 ml of N,N-dimethylformamide, followed by the addition of 0.37 g (4.4 mmol) of sodium hydrogencarbonate and stirring at 100° C. for 3 hours. The reaction liquid was then poured in water and extracted with ethyl acetate. The organic layer was washed with water and a saturated saline solution in this order, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure. The residue was purified with silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 0.44 g (yield: 64%) of 6,6-difluoro-5-methyl-5-hexenyl benzo[1,2,5]thiadiazole-5-carboxylate.
Reaction SMILES: [F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]([NH:5][C:6]1[C:14]([C:15](=[O:17])[NH2:16])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9])=O.Cl.[CH3:27]COCC>CO>[F:1][C:2]([F:25])([C:18]1[CH:23]=[CH:22][C:21]([F:24])=[CH:20][N:19]=1)[C:3]1[NH:16][C:15](=[O:17])[C:14]2[C:6](=[C:7]([C:8]([O:10][CH3:27])=[O:9])[CH:11]=[CH:12][CH:13]=2)[N:5]=1
Reactant: CCOCC
Reactant: NC(=O)c1cccc(C(=O)O)c1NC(=O)C(F)(F)c1ccc(F)cn1
Agent: Cl
Solvent: CO
Product: COC(=O)c1cccc2c(=O)[nH]c(C(F)(F)c3ccc(F)cn3)nc12
Yield: 62 %

Procedure:
2-(2,2-difluoro-2-(5-fluoropyridin-2-yl)acetamido)-3-carbamoylbenzoic acid (28.5 g, 81 mmol) in MeOH (1000 mL) was treated with 2M HCl/ether (4 mL) and then heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (17.5 g, 62%). Separately, 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-hydroxyquinazoline-8-carboxylic acid (10.5 g, 31 mmol) in MeOH (200 mL) was treated with 2M HCl/ether (1 mL) and was heated at reflux overnight. The mixture was concentrated to 10% of the original volume and the resulting precipitate was collected by filtration and washed with a small amount of MeOH to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (5.5 g, 51%). The filtrates from the two procedures above were concentrated at 65° C. and allowed to cool. The solid was collected by filtration to afford additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (3 g). Purification of the filtrate by silica gel chromatography eluting with EtOAc/hexanes afforded additional methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate (4 g). The isolated solids were combined to afford methyl 2-(difluoro(5-fluoropyridin-2-yl)methyl)-4-oxo-3,4-dihydroquinazoline-8-carboxylate as a solid (30 g). LC-MS (ESI) m/z 350 (M+H+).
Reaction SMILES: [CH2:1]([C:4]#[N:5])[C:2]#[N:3].C(O)C.Cl.N[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[SH:17]>C(Cl)(Cl)Cl>[S:17]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[N:3]=[C:2]1[CH2:1][C:4]#[N:5]
Reactant: N#CCC#N
Reactant: Nc1ccccc1S
Agent: Cl
Solvent: CCO
Solvent: ClC(Cl)Cl
Product: N#CCc1nc2ccccc2s1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of malonodinitrile (13.22 g, 0.200 mole) in dry chloroform (100 mL) was added ethanol (9.2 g, 0.200 mole). Hydrogen chloride (8.0 g, 0.220 mole) was passed into the solution at room temperature and the resulting suspension was stirred for an additional 16 hours at room temperature. The excess of hydrogen chloride was removed by passing dry nitrogen into the reaction mixture. A solution of o-aminothiophenol (25 g, 0.200 mole) in chloroform was added to the reaction mixture dropwise during 30 min and the reaction mixture was stirred for 1 hour at 60° C. After that the reaction mixture was cooled to room temperature, washed with water (2×100 mL) and dried with magnesium sulfate. Chloroform was removed using a rotary evaporator. The solid residue was recrystallized from ethyl alcohol. White crystals. The yield was 26.1 g (75% of theory). Mp=101-103° C.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:18]=[CH:17][CH:16]=[C:15]2[C:10]=1[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]1[S:27][N:26]=[CH:25][N:24]=1)(=[O:21])=[O:20])=[CH:14]2.C(=O)([O-])[O-].[K+].[K+].[CH3:34][N:35]1[C:39](B(O)O)=[CH:38][CH:37]=[N:36]1.O1CCOCC1>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>[Cl:8][C:6]1[CH:5]=[CH:4][C:3]([C:9]2[CH:18]=[CH:17][CH:16]=[C:15]3[C:10]=2[CH:11]=[CH:12][C:13]([S:19]([NH:22][C:23]2[S:27][N:26]=[CH:25][N:24]=2)(=[O:21])=[O:20])=[CH:14]3)=[C:2]([C:39]2[N:35]([CH3:34])[N:36]=[CH:37][CH:38]=2)[CH:7]=1
Reactant: Cn1nccc1B(O)O
Reactant: O=S(=O)(Nc1ncns1)c1ccc2c(-c3ccc(Cl)cc3Br)cccc2c1
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: C1COCCO1
Solvent: O
Product: Cn1nccc1-c1cc(Cl)ccc1-c1cccc2cc(S(=O)(=O)Nc3ncns3)ccc12
Temperature: 100 °C
Yield: 6 %

Procedure:
A pressure vessel was charged with 5-(2-bromo-4-chlorophenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (80 mg, 0.166 mmol), potassium carbonate (115 mg, 0.832 mmol), (1-methyl-1H-pyrazol-5-yl)boronic acid (84 mg, 0.666 mmol), tetrakis(triphenylphosphine)palladium(0) (19.23 mg, 0.017 mmol), dioxane (1109 μl) and water (555 μl). The reaction was heated in a microwave at 100° C. for 30 min. The resulting mixture was concentrated and purified by reverse phase HPLC (Column: Xbridge 19×100 mm, 5 μm, Waters, Milford, Mass., Flow rate: 40 mL/min, Mobile phase: 0.1% TFA in ACN and water). The fractions containing product were dried under a vacuum to provide a white solid 5-(4-chloro-2-(1-methyl-1H-pyrazol-5-yl)phenyl)-N-(1,2,4-thiadiazol-5-yl)naphthalene-2-sulfonamide (5 mg, 0.01 mmol). 1H NMR (500 MHz, DMSO-d6) δ ppm 3.48 (s, 3H) 7.01 (s, 1H) 7.05 (d, J=1.82 Hz, 1H) 7.11 (s, 1H) 7.21 (s, 1H) 7.43 (d, J=6.41 Hz, 1H) 7.49 (d, J=8.55 Hz, 1H) 7.53-7.64 (m, 3H) 7.64-7.75 (m, 3H) 8.11 (d, J=8.23 Hz, 1H) 8.34 (s, 1H) 8.43 (d, J=1.60 Hz, 1H); m/z (ESI) 482.0 (M+H)+.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[CH:17][CH:16]=2)[CH:3]=1.[OH:25][CH:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)CCC>[CH3:24][S:21]([C:18]1[CH:19]=[CH:20][C:15]([NH:14][C:4]2[N:5]=[C:6]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:7]=[C:2]([N:29]3[CH2:30][CH2:31][CH:26]([OH:25])[CH2:27][CH2:28]3)[CH:3]=2)=[CH:16][CH:17]=1)(=[O:23])=[O:22]
Reactant: OC1CCNCC1
Reactant: CS(=O)(=O)c1ccc(Nc2cc(Cl)nc(-c3ccccc3)n2)cc1
Solvent: CCCCO
Product: CS(=O)(=O)c1ccc(Nc2cc(N3CCC(O)CC3)nc(-c3ccccc3)n2)cc1

Procedure:
The (6-chloro-2-phenyl-pyrimidin-4-yl)-(4-methanesulfonyl-phenyl)-amine (0.18 g, 0.48 mmol) was treated with 4-hydroxy piperidine (0.097 g, 0.97 mmol) in n-butanol at refluxing temperature for 12 hour to give the desired product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[C:12]2[C:4]=1[C@@:5]1([CH3:26])[C@H:10]([CH2:11]2)[C@@:9]2([CH3:25])[CH2:18][CH2:19][C@H:20]([OH:24])[C:21]([CH3:23])([CH3:22])[C@@H:8]2[CH2:7][CH2:6]1.N1C=CC=CC=1.CN(C1C=CC=CN=1)C.[CH3:42][O:43][C@:44]([C:54]([F:57])([F:56])[F:55])([C:51](Cl)=[O:52])[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1>C(Cl)Cl>[F:55][C:54]([F:56])([F:57])[C@:44]([O:43][CH3:42])([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:51]([O:24][C@H:20]1[CH2:19][CH2:18][C@:9]2([CH3:25])[C@@H:10]3[C@@:5]([CH3:26])([CH2:6][CH2:7][C@H:8]2[C:21]1([CH3:22])[CH3:23])[C:4]1[C:12](=[CH:13][C:14]([O:16][CH3:17])=[CH:15][C:3]=1[O:2][CH3:1])[CH2:11]3)=[O:52]
Reactant: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](O)CC[C@]3(C)[C@H]1C2
Reactant: CO[C@](C(=O)Cl)(c1ccccc1)C(F)(F)F
Agent: CN(C)c1ccccn1
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1cc2c(c(OC)c1)[C@]1(C)CC[C@H]3C(C)(C)[C@@H](OC(=O)[C@@](OC)(c4ccccc4)C(F)(F)F)CC[C@]3(C)[C@H]1C2
Temperature: 25 °C

Procedure:
Alcohol 5b (219 mg, 0.610 mmol) was dissolved in 4 mL of methylene chloride (DCM). To this mixture was added pyridine (0.074 mL, 0.92 mmol) and dimethylaminopyridine (DMAP) (7.4 mg, 0.061 mmol), and the mixture was taken to 0° C. To this mixture was added (R)-(−)-MTPA-Cl (170 mg, 0.671 mmol), and the mixture was allowed to warm to room temperature overnight. The reaction was quenched with saturated aqueous NH4Cl (50 mL), and the aqueous layer was extracted 3 times with methylene chloride (3×50 mL). The organic extracts were combined and dried with MgSO4 and concentrated. A 1H NMR (400 MHz) spectrum of the crude mixture showed the absence of diastereomers, meaning that alcohol 5b was enantiomerically pure after crystallization. The product mixture was then purified using flash chromatography (hexanes:ethyl acetate 12:1) to give 10b quantitatively. 1H NMR (400 MHz, CDCl3) δ 7.54 (m, 2H), 7.41 (m, 3H), 6.40 (d, J=1.8 Hz, 1H), 6.26 (d, J=1.9 Hz, 1H), 4.72 (dd, J=12, 4.9 Hz, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.54 (s, 3H), 2.62 (m, 1H), 2.51 (dd, J=14, 6.2 Hz, 1H), 2.46 (dd, J=8.4, 2.9 Hz, 1H), 1.85-1.76 (m, 1H), 1.74-1.67 (m, 3H), 1.65-1.57 (m, 3H), 1.23 (td, J=13, 4.2 Hz, 1H), 1.07 (s, 3H), 1.04 (s, 3H), 1.04 (m, 1H), 0.92 (s, 3H), 0.87 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 166.3, 159.5, 155.8, 144.7, 133.2, 132.3, 129.5, 128.3 (2C), 127.6 (2C), 124.9, 122.0, 101.9, 96.9, 84.5, 64.2, 56.2, 55.4, 55.3, 55.1, 46.1, 38.1, 38.0, 37.9, 36.5, 29.5, 28.1, 23.0, 20.3, 19.0, 16.2, 16.1. ESIMS [M+Na]+ calcd for C33H41O5F3Na 597.2804, found 597.2814. [α]24D=−31.76°.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][NH:11][C:10](=[O:14])[N:9]=2)[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:18][CH2:19][CH2:20][CH2:21][Cl:22].O>CN(C=O)C>[Cl:22][CH2:21][CH2:20][CH2:19][CH2:18][N:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[N:7]=2)=[N:9][C:10]1=[O:14]
Reactant: Cc1cccc(-c2cc[nH]c(=O)n2)n1
Reactant: ClCCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cccc(-c2ccn(CCCCCl)c(=O)n2)n1
Temperature: 100 °C
Reaction time: 8 h
Yield: 58.8 %

Procedure:
To a solution of 4-(6-methyl-pyridin-2-yl)-1H-pyrimidin-2-one (200 mg, 1.06 mmol) in dry DMF (20 ml), 60% NaH (55 mg, 1.39 mmol) was added portionwise. After heating the mixture at 100° C. for 1 hour, 1-bromo-4-chloro-butane (187 μl 1.39 mmol) was added and the mixture was stirred overnight at room temperature. Water was added and the mixture extracted with diethyl ether to remove the dialkylated product and finally with ethyl acetate. Ethyl acetate was washed with brine, dried (Na2SO4) and evaporated. The residue was triturated with petroleum ether to give 173 mg of the title compound as a solid (58% yield).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Br:11])[C:9]=1[Cl:10])[C:5]#[N:6].[O:12](C(OC(C)(C)C)=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Br:11][C:8]1[C:9]([Cl:10])=[C:2]([NH:1][C:13](=[O:12])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:3]=[C:4]([C:5]#[N:6])[CH:7]=1
Reactant: N#Cc1cc(N)c(Cl)c(Br)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Nc1cc(C#N)cc(Br)c1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.9 %

Procedure:
To a solution of 3-amino-5-bromo-4-chlorobenzonitrile (0.88 g, 3.80 mmol) in DCM (25 mL) was added TEA (1.590 mL, 11.41 mmol), BOC2O (1.059 mL, 4.56 mmol) and DMAP (0.464 g, 3.80 mmol). The mixture was stirred at RT for 16 h. The reaction mixture was concentrated, the crude product was purified using ISCO silica gel column (24 g, EtOAc/hexane=0-30%) to give 0.667 g of tert-butyl 3-bromo-2-chloro-5-cyanophenylcarbamate as white solid
Reaction SMILES: [CH2:1]([PH:5](=[O:7])[OH:6])[CH2:2][CH2:3][CH3:4].C(N(CC)CC)C.[CH2:15]([O:17]C(Cl)=O)[CH3:16]>ClCCl>[CH2:15]([O:17][P:5]([CH2:1][CH2:2][CH2:3][CH3:4])(=[O:6])[OH:7])[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: CCCC[PH](=O)O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCP(=O)(O)OCC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
51 g of n-butylphosphinic acid are dissolved in 200 ml of dichloromethane, the solution is cooled to 10°, and 42.3 g of triethylamine are added dropwise. An exothermic reaction takes place. The mixture is cooled to 10° again and 45.3 g of chloroformic acid ethyl ester are added dropwise within a period of 75 minutes. A precipitate forms in an exothermic reaction with the evolution of gas. A further 200 ml of dichloromethane are then added and the mixture is allowed to warm to room temperature and is then stirred for 2 hours at room temperature, washed with water and dried over sodium sulfate, and the organic solvent is removed. The crude product is distilled under a high vacuum, yielding n-butyl-phosphonic acid ethyl ester having a boiling point of 95° (5×10-5 bar).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:9]Br>C(Cl)Cl>[Br:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2](=[O:1])[NH:3][CH:4]=1
Reactant: BrBr
Reactant: Cc1cccnc1O
Solvent: ClCCl
Product: Cc1cc(Br)c[nH]c1=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 2-hydroxy-3-methylpyridine (0.500 g, 4.58 mmol, Acros Organics) in DCM (15 mL) was slowly added bromine (0.282 mL, 5.50 mmol). After addition, the mixture was stirred at rt for 18 h. The mixture was cooled to 0° C. and was quenched with saturated aqueous NaHCO3 (5 mL). The mixture was then extracted with EtOAc (3×20 mL). The combined organic layer were dried over MgSO4 and concentrated. The residue was then dissolved in MeOH (20 mL) and silica gel was added. The mixture was concentrated and dried in vacuo. The resulting mixture was then purified by silica gel flash column chromatography (solid loading, 0%-100% EtOAc/hexane) to afford the title compound as a light pink solid. MS (ESI, positive ion) m/z: 188,190 (M+H).
Reaction SMILES: [C:1]([C@H:3]1[C@H:7](O[Si](C)(C)C)[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)#[N:2].CCN(S(F)(F)[F:26])CC.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[C:1]([C@H:3]1[C@@H:7]([F:26])[CH2:6][N:5]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:4]1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1C[C@@H](C#N)[C@H](O[Si](C)(C)C)C1
Reactant: CCN(CC)S(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](C#N)[C@@H](F)C1
Reaction time: 3 h
Yield: 67 %

Procedure:
To a stirred solution of (±)-1,1-dimethylethyl trans-3-cyano-4-[(trimethylsilyl)oxy]-1-pyrrolidinecarboxylate (1.0 g, 3.52 mmole), in DCM (50 mL) at −78° C. was added DAST dropwise (0.90 mL, 7.40 mmole). After 3 h, Aqueous Na2CO3 was added to the reaction solution and the layers separated. The organic layer was dried over Na2SO4 and concentrated under vacuum. Purification on silica (hexanes/EtOAc, 1:1) provided the title compound (0.51 g, 67%) as a colorless oil: LC-MS (ES) m/e 215 (M+H)+.
Reaction SMILES: O[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[N:3]=1.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]([C@H:13]2[CH2:18][CH2:17][C@H:16]([CH2:19][CH2:20][CH3:21])[CH2:15][CH2:14]2)[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(O)n2)CC1
Product: CCC[C@H]1CC[C@H](c2ncc(C(=O)OCC)c(Cl)n2)CC1

Procedure:
32.85 g of ethyl trans-4-hydroxy-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate are boiled under reflux for 3.5 hours with 210 ml of phosphorus oxychloride. After cooling, the mixture is concentrated in vacuo and evaporated twice further with 100 ml of toluene each time. The residue is chromatographed with methylene chloride on a column of 300 g of silica gel. There are obtained 31.3 g of crude ethyl trans-4-chloro-2-(4-propylcyclohexyl)-5-pyrimidinecarboxylate as a yellow oil.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9].[ClH:11].[CH3:12]O>>[ClH:11].[CH3:12][O:9][C:8](=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][NH2:1]
Reactant: CO
Reactant: NCCCCCCC(=O)O
Agent: Cl
Product: COC(=O)CCCCCCN
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 7-amino-heptanoic acid (3.0 g, 21.0 mmol), in 25 mL MeOH and 2.4 mL concentrated HCl was heated at reflux for 4 hours and was stirred at room temperature for 60 h. The mixture was concentrated in vacuo to afford the title compound (3.3 g). 1H NMR (400 MHz, CD3OD) δ 3.62 (s, 3H), 2.89 (m, 2H), 2.31 (t, 2H), 1.62 (m, 4H), 1.37 (m, 4H).
Reaction SMILES: [N:1]([CH:4]1[CH2:10][CH2:9][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:7][CH2:6][CH:5]1[OH:20])=[N+:2]=[N-:3].[H-].[Na+].I[CH3:24].O>CN(C=O)C>[N:1]([CH:4]1[CH:5]([O:20][CH3:24])[CH2:6][CH2:7][N:8]([C:11]2[N:15]([CH3:16])[N:14]=[CH:13][C:12]=2[N+:17]([O-:19])=[O:18])[CH2:9][CH2:10]1)=[N+:2]=[N-:3]
Reactant: Cn1ncc([N+](=O)[O-])c1N1CCC(O)C(N=[N+]=[N-])CC1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COC1CCN(c2c([N+](=O)[O-])cnn2C)CCC1N=[N+]=[N-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 79.5 %

Procedure:
To a solution of 5-azido-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ol (420 mg, 1.49 mmol) in dry DMF (15 mL) cooled to 0° C. was added sodium hydride (60% in mineral oil, 90 mg, 2.24 mmol). After stirring for 15 min, iodomethane (0.14 mL, 2.24 mmol) was added and the reaction mixture was allowed to warm to room temperature and stirred for 1 hr. Water (20 mL) was added and the mixture was extracted with EtOAc (150 mL). The organic layer was washed with water (6×30 mL) and brine (20 mL), separated, dried over MgSO4, and concentrated under reduced pressure. Purification via silica gel column chromatography gave 4-azido-5-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepane as a yellow oil (350 mg). A solution of this oil (350 mg, 1.19 mmol) in THF/water (15 mL/3 mL) was treated with triphenylphosphine (311 mg, 1.19 mmol) and the reaction mixture was heated at 60° C. behind a blast screen for 18 hr. Water (2 mL) was added and the mixture was extracted with EtOAc (2×50 mL) The combined organic layers were dried over MgSO4 and concentrated under reduced pressure. The resulting oil was triturated in Et2O, the resulting solid was filtered off and the filtrate concentrated under reduced pressure to give a yellow oil. To a solution of this oil (319 mg, 1.19 mmol) in dry DCM (10 mL) at 0° C. was added a solution of di-tert-butyl-dicarbonate (310 mg, 1.42 mmol) in DCM (10 mL) and DIPEA (1.0 mL, 5.93 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 72 hr. Water (20 mL) was added and the mixture extracted with DCM (100 mL). The organic layer was separated, dried over MgSO4 and concentrated under reduced pressure. Purification via silica gel column chromatography (40-50% EtOAc/isohexane) gave tert-butyl 5-methoxy-1-(1-methyl-4-nitro-1H-pyrazol-5-yl)azepan-4-ylcarbamate as a yellow oil (355 mg, 64% over three steps). 1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 5.14 (d, J=8.9 Hz, 1H), 4.00-3.90 (m, 1H), 3.78 (s, 3H), 3.68-3.60 (m, 1H), 3.48 (t, J=12.6 Hz, 1H), 3.39 (s, 3H), 3.33-3.23 (m, 1H), 3.19-3.11 (m, 1H), 3.04-2.95 (m, 1H), 2.25-2.06 (m, 2H), 1.88-1.76 (m, 2H), 1.45 (s, 9H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[F:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([C:21]3[CH:30]=[CH:29][C:28]4[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:22]=3)[N:19]=[C:18]([CH:31]([CH3:33])[CH3:32])[CH:17]=2)=[CH:12][CH:11]=1.O>CN(C=O)C>[Br:1][C:17]1[C:18]([CH:31]([CH3:33])[CH3:32])=[N:19][N:20]([C:21]2[CH:30]=[CH:29][C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[N:22]=2)[C:16]=1[C:13]1[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=1
Reactant: CC(C)c1cc(-c2ccc(F)cc2)n(-c2ccc3ccccc3n2)n1
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)c1nn(-c2ccc3ccccc3n2)c(-c2ccc(F)cc2)c1Br
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.5 %

Procedure:
N-bromosuccinimide (21.03 g, 118 mmoles) was added in one portion to a solution of 2-[5-(4-fluorophenyl)-3-(1-methylethyl)-1H-pyrazol-1-yl]quinoline (39.16 g, 118 mmoles) in 400 mL DMF at 0° C. under an inert atmosphere. The mixture was warmed to room temperature and stirred for 16 hours, then poured into 500 mL H2O and the resulting precipitate was collected. The precipitate was air dried on a vacuum filter for 16 hours to give 47.20 g (97%) of the title compound as a white solid, mp 110°-114° C.