Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8].[Cl-].[Al+3].[Cl-].[Cl-]>C(=S)=S>[CH3:5][O:6][C:7]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([C:1](=[O:3])[CH3:2])=[CH:15][CH:16]=2)[CH2:11][CH2:10]1)=[O:8]
Reactant: COC(=O)N1CCc2ccccc21
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: S=C=S
Product: COC(=O)N1CCc2cc(C(C)=O)ccc21
Temperature: 25 °C
Yield: 40 %

Procedure:
Acetyl chloride (10.66 mL, 0.15 mol) was added slowly to a mixture of 2,3-dihydro-indole-1-carboxylic acid methyl ester, Preparation 17 (17 g, 0.1 mol), and aluminum chloride (40 g, 0.3 mol) in carbon disulfide (150 mL) at 0° C. The reaction mixture was warmed to room temperature and heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature and poured into ice water. The resulting mixture was extracted with CH2Cl2 (3×40 mL). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and the resultant filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica using ethyl acetate/hexane (30%) to provide the title product (8.8 g, 40%) as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:15][C:16]2[N:21]=[C:20]([CH2:22][C:23]([NH2:25])=O)[CH:19]=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=2)[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[C:12]([CH3:14])[N:11]=[CH:10]1)[NH:15][C:16]1[N:21]=[C:20]([CH2:22][C:23]#[N:25])[CH:19]=[C:18]([CH2:26][O:27][CH2:28][C:29]([F:32])([F:31])[F:30])[N:17]=1
Reactant: COc1cc(Nc2nc(COCC(F)(F)F)cc(CC(N)=O)n2)ccc1-n1cnc(C)c1
Solvent: CN(C)c1ccccc1
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(Nc2nc(CC#N)cc(COCC(F)(F)F)n2)ccc1-n1cnc(C)c1
Reaction time: 0.17 h

Procedure:
2-(2-{[3-Methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]amino}-6-[(2,2,2-trifluoroethoxy)-methyl]pyrimidin-4-yl)acetamide (68 mg, 0.15 mmol, 1.0 eq) was added to a solution of Phosphorus oxychloride (4 mL) and dimethylaniline (0.033 mL, 0.26 mmol, 1.75 eq). The reaction mixture was immersed in a pre-heated oil bath at 120° C. for 10 min. The reaction mixture, still hot, was rapidly poured into ice/DCM slurry and stirred for 16 h. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated. The residue was purified on a silica gel cartridge eluting with a gradient of methanol, DCM and EtOAc. The residue was further purified on a C18 reverse phase cartridge eluting with 30% to 70% MeOH/H2O containing 0.05% TFA to give the title compound, 8 mg (12%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[CH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][C:13]=2[N+:21]([O-])=O)=[N:2]1.[Sn].Cl>C(O)C>[NH2:21][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][C:12]=1[CH:11]=[CH:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][N:2]=1)[C:16]([OH:18])=[O:17]
Reactant: O=C(O)c1ccc(C=Cc2n[nH]c3ccccc23)c([N+](=O)[O-])c1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: Nc1cc(C(=O)O)ccc1C=Cc1n[nH]c2ccccc12

Procedure:
Crude 4-[2-(1H-indazol-3-yl)vinyl]-3-nitrobenzoic acid (1.0 g, 3.2 mmol) obtained in Step 1 was dissolved in ethanol (30 mL) and the solution was added with tin (1.2 g, 9.7 mmol) and concentrated hydrochloric acid (7.0 mL), followed by reacting at 40° C. to obtain 3-amino-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid. The crude product (0.65 g, 2.3 mmol) was added with xylene (20 mL), triethylamine (0.16 mL, 1.2 mmol), phthalic anhydride (0.41 g, 2.8 mmol) and molecular sieves 3A (0.65 mg), followed by heating at 140° C. for 4 hours. The reaction mixture was filtered and the filtrate was acidified by hydrochloric acid (2 mol/L). The precipitated crystal was collected by filtration to obtain 3-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid.
Reaction SMILES: [Na].[CH:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([OH:11])[CH:3]=1.[Br:12][CH:13](Br)[CH3:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:12][CH2:13][CH2:14][O:11][C:4]1[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[CH:2][CH:3]=1
Reactant: CC(Br)Br
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na]
Solvent: CC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)cc1

Procedure:
1.97 g of the sodium salt of p-nitrophenol(0.01 mol), 2.16 ml of dibromoethane (0.025 mol) and 0.5g of potassium carbonate were taken in 50 ml of dry acetone (4A activated molecular sieves) and refluxed overnight. Potassium carbonate was filtered and the solvent was removed by rotary evaporation to yield 4-(2-bromoethoxy)nitrobenzene (L) in almost quantitative yield. 1H-NMR: CDCl w: 365 (t,2H), 44 (t,2H), 70-83 (ABq,4H)/
Reaction SMILES: CC1N(CCC2CCNCC2)C=CN=1.[C:15]([Cl:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]CC>>[C:15]([Cl:34])(=[O:33])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Agent: Cc1nccn1CCC1CCNCC1
Product: CCCCCCCCCCCCCCCC(=O)Cl

Procedure:
Following essentially the last step of the procedure for preparing the compound of Example 1, and using in place of stearoyl chloride, an approximately equivalent amount of hexadecanoyl chloride, the title compound was obtained, m.p. 112° to 115° C.
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC(=O)[NH:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:33][CH2:32][C:31]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=4[NH:29][C:28]3=[O:40])[CH2:23][CH2:22]2)[CH:18]=[C:17]([C:41]([C:43]2[CH:53]=[C:52]([CH3:54])[C:46]3[N:47]([CH3:51])[C:48](=[O:50])[O:49][C:45]=3[CH:44]=2)=[O:42])[CH:16]=1)(C)(C)C>C(Cl)Cl>[NH2:14][C:15]1[N:20]=[C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[CH2:33][CH2:32][C:31]4[CH:34]=[C:35]([O:38][CH3:39])[CH:36]=[CH:37][C:30]=4[NH:29][C:28]3=[O:40])[CH2:23][CH2:22]2)[CH:18]=[C:17]([C:41]([C:43]2[CH:53]=[C:52]([CH3:54])[C:46]3[N:47]([CH3:51])[C:48](=[O:50])[O:49][C:45]=3[CH:44]=2)=[O:42])[CH:16]=1
Reactant: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(NC(=O)OC(C)(C)C)n3)CC1)C(=O)N2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)oc(=O)n5C)cc(N)n3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
0.50 mL TFA were added to 57 mg (0.10 mmol) tert-butyl[4′-(3,4-dimethyl-2-oxo-2,3-dihydro-benzoxazole-6-carbonyl)-4-(7-methoxy-2-oxo-1,2,4,5-tetrahydro-benzo[d][1,3]diazepin-3-yl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-6′-yl]-carbamate in 5.00 mL DCM and stirred for 3 h at RT. Then another 0.50 mL TFA were added and the mixture was stirred overnight at RT. Then the reaction mixture was evaporated down, the residue was dissolved in DMF and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6](O)=[O:7])=[C:4]([F:12])[CH:3]=1.CSC>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([CH2:6][OH:7])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Solvent: C1CCOC1
Solvent: CSC
Product: OCc1c(F)cc(Br)cc1F
Temperature: 60 °C
Reaction time: 16 h
Yield: 94.9 %

Procedure:
To a solution of 4-bromo-2,6-difluorobenzoic acid (5 g, 21.10 mmol) in THF (100 mL) was added BH3. DMS (20.03 mL, 211 mmol) dropwise at rt. The resulting mixture was stirred at 60° C. for 16 h. After LCMS analysis showed the starting material had disappeared, the mixture was quenched by MeOH. The solvent was removed in vacuo to yield a white solid of (4-bromo-2,6-difluorophenyl)methanol (4.5 g, 20.02 mmol, 95.2% yield), which was used in the next step without further purification: ES-LCMS m/z 222.1 (M+1).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7](O)=[O:8])(O)=[O:2].[NH2:15]C(N)=O>>[F:14][C:12]1[CH:13]=[C:5]2[C:6](=[CH:10][CH:11]=1)[C:7](=[O:8])[NH:15][C:1](=[O:2])[CH2:4]2
Reactant: NC(N)=O
Reactant: O=C(O)Cc1cc(F)ccc1C(=O)O
Product: O=C1Cc2cc(F)ccc2C(=O)N1
Temperature: 25 °C
Yield: 96.7 %

Procedure:
An amount of 200 mg (1.01 mmol) of 2-carboxymethyl-4-fluoro-benzoic acid and urea (72.47 mg, 1.22 mmol) were heated neat at 180-190° C. for 45 min. The mixture is cooled to room temperature followed by recrystallization from water and anhydrous ether to give 175 mg (80% yield) of brown solid. MS (ESI) m/z 179.15 (M+1).
Reaction SMILES: [Cl:1][C:2]([Cl:33])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH2:30])=[CH:9][CH:8]=1.C([C:36]1[C:37]([N:45]=[CH:46][N:47]([CH3:49])C)=[N:38][C:39]([CH:42]([CH3:44])[CH3:43])=[CH:40][CH:41]=1)#N>C(O)(=O)C>[Cl:33][C:2]([Cl:1])([Cl:32])[CH2:3][O:4][C:5](=[O:31])[NH:6][C:7]1[CH:12]=[CH:11][C:10]([S:13][C:14]2[CH:19]=[CH:18][C:17]([C:20](=[O:29])[NH:21][C:22]3[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][N:23]=3)=[CH:16][C:15]=2[NH:30][C:49]2[C:36]3[CH:41]=[CH:40][C:39]([CH:42]([CH3:43])[CH3:44])=[N:38][C:37]=3[N:45]=[CH:46][N:47]=2)=[CH:9][CH:8]=1
Reactant: Nc1cc(C(=O)Nc2ccc(Br)cn2)ccc1Sc1ccc(NC(=O)OCC(Cl)(Cl)Cl)cc1
Reactant: CC(C)c1ccc(C#N)c(N=CN(C)C)n1
Solvent: CC(=O)O
Product: CC(C)c1ccc2c(Nc3cc(C(=O)Nc4ccc(Br)cn4)ccc3Sc3ccc(NC(=O)OCC(Cl)(Cl)Cl)cc3)ncnc2n1
Temperature: 140 °C
Yield: 79 %

Procedure:
A mixture of the products of Example 364D (3.05 g, 5.16 mmol) and Example 8E (N′-(3-cyano-6-isopropyl-pyridin-2-yl)-N,N-dimethyl-formamidine) (1.34 g, 6.20 mmol, 1.2 equiv.) in 25 mL of glacial acetic acid was heated in a 140° C. preheated oil bath for 45 minutes. The reaction mixture was cooled, evaporated in vacuo and the residue partitioned between ethyl acetate (250 mL) and water (100 mL). The organic phase was then washed with saturated aqueous sodium bicarbonate and then brine, dried over anhydrous magnesium sulfate, filtered, and evaporated under reduced pressure. The resulting residue was triturated with methanol, filtered, and dried in vacuo to provide the title compound (3.10 g, 79%) as a beige solid. MS (ESI+) m/z 762/764 (M+H)+; 1H NMR (300 MHz, DMSO-d6) δ ppm: 1.33 (d, J=6.99 Hz, 6 H), 3.16-3.26 (m, 1 H), 4.97 (s, 2 H), 6.96 (s, 1 H), 7.43 (d, J=8.82 Hz, 2 H), 7.59 (s, 2 H), 7.86 (s, 1 H), 8.01-8.10 (m, 3 H), 8.15-8.20 (m, 1 H), 8.50 (d, J=2.57 Hz, 1 H), 8.57 (s, 1 H), 8.84 (s, 1 H), 10.23 (s, 1 H), 10.40 (s, 1 H), 10.94 (s, 1 H).
Reaction SMILES: [Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[NH:5][CH2:4]1.Br[C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[Cl:1][CH2:2][CH:3]1[O:7][C:6](=[O:8])[N:5]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][N:11]=2)[CH2:4]1
Reactant: O=C1NCC(CCl)O1
Reactant: Clc1ccc(Br)nc1
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=C1OC(CCl)CN1c1ccc(Cl)cn1
Temperature: 85 °C
Reaction time: 12 h
Yield: 82.8 %

Procedure:
A mixture of 5-(chloromethyl)-1,3-oxazolidin-2-one (136 mg), 2-bromo-5-chloropyridine (192 mg), cesium carbonate (489 mg), bispalladium tribenzylideneacetone (137 mg) and (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (260 mg) in 1 ml of dioxane was stirred at 85° C. for 12 h. The sample was then cooled to room temperature, and filtered through a plug of silica gel (5×10 ml) eluting with ethyl acetate (50 ml). The eluent was concentrated in vacuo to provide a clear reddish-brown liquid, which was purified via column chromatography on a Biotage Horizon 40M column eluting with 0% ethyl acetate in hexanes (1 column volume), followed by a gradient to 100% ethyl acetate in hexanes (over 10 column volumes), and held at 100% ethyl acetate for 4 column volumes to provide the title compound (204 mg, 83%). Mass spectrum (ESI) 249.0 (M+2). 1H NMR (500 MHz, CDCl3): δ 8.28 (d, J=2.5 Hz, 1H), 8.20 (d, J=8.9 Hz, 1H), 7.68 (dd, J=9.0, 2.6 Hz, 1H), 4.90 (m, 1H), 4.35 (dd, J=8.9, 11.0 Hz, 1H), 4.17 (dd, J=5.7, 10.8 Hz, 1H), 3.78 (m, 2H).
Reaction SMILES: C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[Br:20][C:21]1[CH:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23]([OH:25])=O.CCN=C=NCCCN(C)C.Cl.Cl.[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:48]=[CH:47][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52](=[O:59])[N:53]2[CH2:58][CH2:57][NH:56][CH2:55][CH2:54]2)=[CH:45][CH:44]=1>CN(C=O)C.O>[C:43]1([C:61]2[CH:66]=[CH:65][CH:64]=[CH:63][CH:62]=2)[CH:44]=[CH:45][C:46]([NH:49][C:50](=[O:60])[CH2:51][C:52]([N:53]2[CH2:54][CH2:55][N:56]([C:23](=[O:25])[C:22]3[CH:26]=[CH:27][CH:28]=[CH:29][C:21]=3[Br:20])[CH2:57][CH2:58]2)=[O:59])=[CH:47][CH:48]=1
Reactant: O=C(CC(=O)N1CCNCC1)Nc1ccc(-c2ccccc2)cc1
Reactant: O=C(O)c1ccccc1Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CC(=O)N1CCN(C(=O)c2ccccc2Br)CC1)Nc1ccc(-c2ccccc2)cc1
Temperature: 10 °C
Reaction time: 8 h
Yield: 34.6 %

Procedure:
HOBt (34 mg, 0.25 mmol) and DIPEA (67.9 mg, 0.51 mmol) were added to a stirred solution of 2-bromobenzoic acid (42 mg, 0.21 mmol) in DMF (2 mL). The reaction mixture was cooled to 10° C. and EDCI.HCl (48 mg, 0.25 mmol) followed by N-biphenyl-4-yl-3-oxo-3-piperazin-1-yl-propionamide hydrochloride (75 mg, 0.2 mmol) were added. The reaction mixture was stirred at room temperature overnight, then diluted with water and the product extracted with ethyl acetate. The ethyl acetate was washed with brine solution, dried over Na2SO4 and evaporated. The residue was purified by column chromatography using silica gel 60-120 mesh (80% ethyl acetate in hexane) to afford 35 mg (33%) of N-biphenyl-4-yl-3-[4-(2-bromo-benzoyl)-piperazin-1-yl]-3-oxo-propionamide. LCMS: 506.10 (M+1)+ 96.5%, 1H NMR: (CDCl3): δ 9.6 (d, 1H), 7.6 (m, 6H), 7.35 (m, 5H), 4.0 (m, 1H), 3.74 (m, 4H), 3.54 (d, 2H), 3.3 (m, 2H).
Reaction SMILES: [CH:1](=O)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].[CH2:10]([NH2:14])[CH:11]([NH2:13])[CH3:12]>C(O)(C)C.[Pt]>[OH:4][C:3]1[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=1[CH2:1][NH:14][CH2:10][CH:11]([NH:13][CH2:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[OH:4])[CH3:12]
Reactant: O=Cc1ccccc1O
Reactant: CC(N)CN
Agent: [Pt]
Solvent: CC(C)O
Product: CC(CNCc1ccccc1O)NCc1ccccc1O
Yield: 26.2 %

Procedure:
84.6 g of a bisazomethine prepared from 2 moles of salicylaldehyde and 1 mol of propylenediamine and having a melting point of 57°-58° C. are hydrogenated for 3 hours in 340 ml of isopropanol in an autoclave in the presence of 1.20 g of 5% platinum/charcoal at 45° C. and under a pressure of 50-60 atmospheres. The product crystallises out at room temperature and is dissolved by boiling, with the addition of a further 660 ml of isopropanol. The catalyst is filtered off and the diamine crystallises out on cooling. The crystals are collected by filtration, washed and dried, yielding 75.1 g of N,N'-bis-(2-hydroxybenzyl)-propylenediamine (87.5% of theory); melting point 109°-110° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[CH:4][CH:3]=1.Cl[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=1.[OH-].[K+]>C1(C)C=CC=CC=1.C1OCCOCCOCCOCCOCCOC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([O:10][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: CC(O)c1ccc(Br)cc1
Reactant: Clc1ccccn1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: CC(Oc1ccccn1)c1ccc(Br)cc1
Yield: 93.5 %

Procedure:
A solution of 1-(4-bromophenyl)ethanol (2.0 g, 10.0 mmol), 2-chloropyridine (1237 mg, 11.0 mmol), potassium hydroxide (1839 mg, 32.8 mmol) and 18-crown-6 (132 mg, 0.5 mmol) in toluene (40 mL) was stirred at reflux for 3 hrs. The mixture was concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ethe/ethyl acetate=20:1) to give 2-(1-(4-bromophenyl)ethoxy)pyridine as a white solid (2.6 g, 94%). LRMS (M+H+) m/z: calcd 277.01. found 277.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][C:3]=1[CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:12])[CH3:11])[CH2:6]1.Cl[Sn]Cl>CCO>[NH2:17][C:14]1[CH:15]=[CH:16][C:2]([Cl:1])=[C:3]([CH:13]=1)[CH2:4][N:5]1[CH2:9][CH2:8][CH:7]([N:10]([CH3:11])[CH3:12])[CH2:6]1
Reactant: CN(C)C1CCN(Cc2cc([N+](=O)[O-])ccc2Cl)C1
Agent: Cl[Sn]Cl
Solvent: CCO
Product: CN(C)C1CCN(Cc2cc(N)ccc2Cl)C1
Temperature: 80 °C

Procedure:
[1-(2-Chloro-5-nitro-benzyl)-pyrrolidin-3-yl]-dimethyl-amine (Step e, 7 g, 24.7 mmol, 1.0 eq.) was dissolved into EtOH (400 ml). SnCl2 (14 g, 74.1 mmol, 3.0 eq.) was added and the reaction was heated to 80° C. for 18 h. The mixture was cooled down to RT and quenched with 1N K2CO3 (aq.) until bubbling had ceased. The white solids that had formed were filtered over Celite® and washed with EtOH. The filtrate was concentrated and redissolved in EtOAc (100 mL). Washed with 2 N NaOH (50 ml) and 2N NaOH/brine (50 mL). The organic layer was dried (MgSO4), filtered and concentrated to yield [1-(5-amino-2-chloro-benzyl)-pyrrolidin-3-yl]-dimethyl-amine.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[N:5]=[C:4](Cl)[N:3]=1.[O:10]1[C:14]2([CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1.[OH-].[K+]>O1CCOCC1.C(O)C.O>[O:10]1[C:14]2([CH2:19][CH2:18][N:17]([C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([NH2:8])[N:5]=3)[CH2:16][CH2:15]2)[O:13][CH2:12][CH2:11]1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Nc1nc(N)nc(Cl)n1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1COCCO1
Product: Nc1nc(N)nc(N2CCC3(CC2)OCCO3)n1

Procedure:
A mixture of 2,4-diamino-6-chloro-1,3,5-triazine (2 g, 14 mmol), 1,4-dioxa-8-azaspiro[4.5]decane (3 g, 21 mmol), and KOH (100 mg, 1.8 mmol) in dioxane (10 mL) and ethanol (40 mL) was heated at reflux overnight, diluted with water, and filtered. The precipitate was rinsed with water and dried under vacuum to provide the title compound.
Reaction SMILES: [CH3:1][OH:2].[O:3]1[CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[CH2:4]1>>[CH3:1][O:2][CH2:4][CH:5]([OH:3])[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CO
Reactant: CCCCCCCCCCCCC1CO1
Product: CCCCCCCCCCCCC(O)COC
Temperature: 60 °C
Reaction time: 3 h

Procedure:
The same reactor that was used in Production Example 5 was charged with 64 g (2 mol) of methanol and 2 g of boron trifluoride diethyl ether complex and then the mixture was raised to 60° C. Then, 212.3 g (1 mol) of 1,2-epoxytetradecane was added dropwise to the mixture over one hour and the resulting mixture was kept as it was for 3 hours. The reaction was terminated just after confirming that 1,2-epoxytetradecane left unreacted was less than 1% by gas chromatography and then the reaction mixture was cooled. Thereafter, methanol was removed in the same manner as in Production Example 5 to obtain 2-hydroxytetradecyl methyl ether.
Reaction SMILES: Cl.[NH2:2][C:3]1[N:32]=[C:6]2[N:7]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=3)[C:8]([CH3:21])=[C:9]([C:19]#[N:20])[C@@H:10]([C:11]3[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=3)[N:5]2[N:4]=1.[CH:33]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34]1>N1C=CC=CC=1>[C:19]([C:9]1[C@@H:10]([C:11]2[CH:16]=[CH:15][C:14]([C:17]#[N:18])=[CH:13][CH:12]=2)[N:5]2[N:4]=[C:3]([NH:2][C:38]([CH:33]3[CH2:37][CH2:36][CH2:35][CH2:34]3)=[O:39])[N:32]=[C:6]2[N:7]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=2)[C:8]=1[CH3:21])#[N:20]
Reactant: O=C(Cl)C1CCCC1
Reactant: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(N)nc2N1c1cccc(C(F)(F)F)c1
Agent: Cl
Solvent: c1ccncc1
Product: CC1=C(C#N)[C@@H](c2ccc(C#N)cc2)n2nc(NC(=O)C3CCCC3)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (7R)-2-amino-7-(4-cyanophenyl)-5-methyl-4-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile hydrochloride (30 mg, 66 μmol) was dissolved in abs. pyridine (1.5 ml). At room temperature, cyclopentanecarbonyl chloride (26 mg, 197 μmol, 3 eq.) was added. After 12 h, analysis of the reaction by HPLC showed substantial conversion. The reaction mixture was concentrated under reduced pressure and purified by preparative HPLC (Reprosil C18 column, 30×250 mm; mobile phase: acetonitrile-water-0.1% TFA). After lyophilization, the product was obtained as a solid (14.6 mg, 41% of theory).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:4]=1[NH:10][NH2:11].C(O[CH:17]=[C:18]([C:24]#[N:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20])C.O>C(O)(=O)C>[NH2:25][C:24]1[N:10]([C:4]2[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:3]=2[C:2]([F:1])([F:12])[F:13])[N:11]=[CH:17][C:18]=1[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: NNc1ccc(Cl)cc1C(F)(F)F
Reactant: CCOC=C(C#N)C(=O)OCC
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cnn(-c2ccc(Cl)cc2C(F)(F)F)c1N
Temperature: 25 °C
Yield: 85.9 %

Procedure:
A solution of 31.58 g of 2-(trifluoromethyl)-4-chlorophenylhydrazine and 27.92 g of ethyl (ethoxymethylene)cyanoacetate dissolved in 225 ml of acetic acid and 75 ml of water was heated on a steam bath for approximately 16 hours. The reaction mixture was cooled to room temperature and placed in the refrigerator. The precipitated solid was collected by filtrate to provide 43 g of 5-amino-1-[2-(trifluoromethyl)-4-chlorophenyl]-1H-pyrazole-4-carboxylic acid, ethyl ester. mp=114°-116° C.
Reaction SMILES: P(Br)(Br)[Br:2].[Br:5][C:6]1[C:7]([CH2:16]O)=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>C(OCC)C>[Br:5][C:6]1[C:7]([CH2:16][Br:2])=[CH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: OCc1cc2ccccc2cc1Br
Reactant: BrP(Br)Br
Solvent: CCOCC
Product: BrCc1cc2ccccc2cc1Br
Reaction time: 1 h

Procedure:
PBr3 (3.7 mL, 0.039 mol) was added dropwise to a suspension of 3-bromo-2-naphthalenyl methanol (8.55 g, 0.036 mol) and diethyl ether (80 mL) at 0° C. After 1 hour, the reaction was concentrated and partitioned between CH2Cl2 and H2O. The organic layer was separated and dried over MgSO4. Concentration in vacuo afforded 3-bromo-2-bromomethylnaphthalene as a crude product (10.6 g). The crude product was flash chromatographed on silica gel to afford the pure product as an off-white powder (6.0 g, m.p. 110°-111° C., yield 56%).
Reaction SMILES: C([O:3][C:4](=[O:17])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([C:11]2[CH2:15][CH2:14][CH2:13][C:12]=2Br)[CH:6]=1)C.C(=O)([O-])[O-].[K+].[K+].[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1B(O)O)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(COC)OC>[CH2:24]([O:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:12]1[CH2:13][CH2:14][CH2:15][C:11]=1[C:7]1[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=1)[C:4]([OH:3])=[O:17])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CCOC(=O)c1cccc(C2=C(Br)CCC2)c1
Reactant: OB(O)c1ccccc1OCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Product: O=C(O)c1cccc(C2=C(c3ccccc3OCc3ccccc3)CCC2)c1

Procedure:
3-(2-Bromo-cyclopent-1-enyl] benzoic acid ethyl ester (0.148 g, 0.0005 mol), tetrakis-triphenylphosphine palladium (o) (30 mg), potassium carbonate (0.200 g) and (2-benzyloxyphenyl) boronic acid (0.110 g, 0.5 mmol) in dimethoxyethane (5 mL) were refluxed for 17 h under nitrogen. The reaction mixture was then filtered through Keiselghur and evaporated down to an oil. Purification was carried out on a Waters separation pack (10 g) cartridge with dichloromethane/iso hexane giving the product (120 mg).