Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.FC(F)(F)C(O)=O.[NH2:39][C@H:40]([CH3:45])[CH2:41][CH2:42][C:43]#[N:44].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CCOC(C)=O.CN(C=O)C>[C:43]([CH2:42][CH2:41][C@H:40]([NH:39][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:30])([CH3:29])[CH3:31])[CH:19]=1)=[O:23])[CH3:45])#[N:44]
Reactant: C[C@@H](N)CCC#N
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: C[C@H](CCC#N)NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3nn(C)c4cc(Cl)ccc34)nc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.8 %

Procedure:
In a 20 mL scintillation vial, 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (120 mg, 0.26 mmol), (R)-4-aminopentanenitrile trifluoroacetate (51 mg, 0.524 mmol), HBTU (129 mg, 0.341 mmol), HOBt (46 mg, 0.341 mmol) and DIPEA (169 mg, 1.31 mmol) were combined with DMF (1.8 ml) to give a light yellow solution. After stirring at room temperature overnight the reaction mixture was diluted with EtOAc (50 mL) and washed with sat NaHCO3 (3×25 mL) and H2O (3×25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 4 g, 0% to 10% MeOH in DCM with 0.1% NH4OH) to provide 99 mg (70%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid ((R)-3-cyano-1-methyl-propyl)-amide as an off-white solid. MS: (M+H)+=539.
Reaction SMILES: [N:1]1C=CC=CC=1N1CCNCC1.[CH3:13][CH:14]([NH:28][C:29]([C:31]1[O:35][C:34]([C:36]2[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=2)=[N:33][C:32]=1[CH2:43][CH2:44][CH3:45])=[O:30])[CH2:15][N:16]1[CH2:21][CH2:20][N:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:18][CH2:17]1>>[NH2:1][C:24]1[N:23]=[C:22]([N:19]2[CH2:18][CH2:17][N:16]([CH2:15][CH:14]([NH:28][C:29]([C:31]3[O:35][C:34]([C:36]4[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=4)=[N:33][C:32]=3[CH2:43][CH2:44][CH3:45])=[O:30])[CH3:13])[CH2:21][CH2:20]2)[CH:27]=[CH:26][CH:25]=1
Reactant: CCCc1nc(-c2ccc(F)cc2)oc1C(=O)NC(C)CN1CCN(c2ccccn2)CC1
Reactant: c1ccc(N2CCNCC2)nc1
Product: CCCc1nc(-c2ccc(F)cc2)oc1C(=O)NC(C)CN1CCN(c2cccc(N)n2)CC1

Procedure:
Similarly, following the procedure set forth in Example 1(B-G) substituting 1-pyridin-2-yl-piperazine for (intermediate “Ia”), 2-(4-fluorophenyl)-4-propyl-oxazole-5-carboxylic acid [1-methyl-2-(4-pyridin-2-yl-piperazin-1-yl)-ethyl]-amide (compound 24) was prepared.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1>>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH:16]1[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]1)[N:5]=[CH:4][N:3]=[C:2]2[O:23][C:24]1[CH:33]=[C:32]2[C:27]([CH:28]=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCC1CCN(C)CC1
Reactant: Cc1ccc2ccc(O)cc2n1
Product: COc1cc2c(Oc3ccc4ccc(C)nc4c3)ncnc2cc1OCC1CCN(C)CC1
Yield: 62.4 %

Procedure:
Using an analogous procedure to that described in Example 42, 4-chloro-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 10), was reacted with 7-hydroxy-2-methylquinoline (54 mg, 0.34 mmol), (J. Med. Chem. 1998, 41, 4062), to give 6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)-4-(2-methylquinolin-7-yloxy)quinazoline (86 mg, 63%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6].C(N(C(C)C)C(C)C)C.[CH3:19][O:20][CH2:21]Cl>ClCCl>[CH3:19][O:20][CH2:21][O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH:5]=[O:6]
Reactant: O=Cc1cccc(O)c1
Reactant: COCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COCOc1cccc(C=O)c1
Reaction time: 1 h

Procedure:
A solution of 100 g of 3-hydroxybenzaldehyde and 214 ml of N-ethyldiisopropylamine in 800 ml of dichloromethane was ice-cooled and a solution of 68.4 ml of chloromethyl methyl ether in 200 ml of dichloromethane was added dropwise. After stirring for one hour, an ice bath was removed and the mixture was continuously stirred at room temperature overnight. The reaction solution was washed in turn with an aqueous 10% sodium hydroxide solution and 10% citric acid and dried over magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was distilled off under reduced pressure to obtain 81.3 g of the desired compound as a colorless oily substance. Boiling point: 125 to 127° C./10 mmHg
Reaction SMILES: [NH2:1][C:2]1[C:11]([SH:12])=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[F:20])[C:3]=1[F:21].[CH3:22]C1C=CC(S(O)(=O)=O)=CC=1.O>C(OC)(OC)OC>[F:21][C:3]1[C:2]2[N:1]=[CH:22][S:12][C:11]=2[CH:10]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[C:4]=1[NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[F:20]
Reactant: COC(=O)c1cc(S)c(N)c(F)c1Nc1ccccc1F
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(OC)OC
Solvent: O
Product: COC(=O)c1cc2scnc2c(F)c1Nc1ccccc1F
Reaction time: 1 h
Yield: 85.1 %

Procedure:
To a solution of methyl 4-amino-3-fluoro-2-((2-fluorophenyl)amino)-5-mercaptobenzoate in trimethyl orthoformate (50 mL) was added p-TsOH (0.61 g, 3.17 mmol). The reaction mixture was stirred for 1 h and treated with water (100 mL). The precipitate was filtered off and the filter cake was washed with water to afford the desired product (pale yellow solid, 8.64 g, 85.1% yield for two steps). 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H), 8.68 (s, 1H), 8.46 (s, 1H), 7.10 (m, 1H), 7.01 (m, 1H), 6.92 (s, 2H), 3.97 (s, 3H).
Reaction SMILES: C(Cl)(=O)C(C)(C)C.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH:20]=[CH:21][CH:22]=1)[O:15][CH2:16][C:17]([OH:19])=O)=[O:11].C(N(CC)CC)C.[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][C:39]2[CH:40]=[C:41]([NH:46][CH3:47])[C:42]([NH2:45])=[CH:43][CH:44]=2)[CH:35]=[CH:34][N:33]=1>ClCCl>[CH3:30][O:31][C:32]1[CH:37]=[C:36]([O:38][C:39]2[CH:44]=[CH:43][C:42]([NH:45][C:17](=[O:19])[CH2:16][O:15][C:14]3[CH:13]=[C:12]([CH:22]=[CH:21][CH:20]=3)[C:10]([O:9][CH3:8])=[O:11])=[C:41]([NH:46][CH3:47])[CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: CNc1cc(Oc2ccnc(OC)c2)ccc1N
Reactant: COC(=O)c1cccc(OCC(=O)O)c1
Agent: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CNc1cc(Oc2ccnc(OC)c2)ccc1NC(=O)COc1cccc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.4 %

Procedure:
Pivaloyl chloride (1.74 mL, 14.2 mmol) was added dropwise to a solution of [3-(methoxycarbonyl)phenoxy]acetic acid produced in Example (1c) (3.27 g, 15.6 mmol) and triethylamine (1.97 mL, 14.2 mmol) in dichloromethane (40 mL) in a nitrogen atmosphere at 0° C. After one hour, a solution of 4-[(2-methoxypyridin-4-yl)oxy]-N2-methylbenzene-1,2-diamine produced in Example (16d) (3.46 g, 14.2 mmol) and triethylamine (1.97 mL, 14.2 mmol) in dichloromethane (40 mL) was added dropwise at 0° C., and the mixture was stirred at room temperature for two hours. The reaction mixture was concentrated under reduced pressure. Then, the residue was purified by silica gel chromatography (ethyl acetate) to obtain the title compound (4.81 g, 78%) as a pale brown oil.
Reaction SMILES: [OH:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([NH:9][C:10]([NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[O:11])=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33](Cl)(=[O:35])=[O:34]>>[F:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:27]=1[S:33]([O:1][C:2]1[CH:22]=[CH:21][C:5]2[NH:6][C:7]([NH:9][C:10](=[O:11])[NH:12][CH2:13][CH2:14][N:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[N:8][C:4]=2[CH:3]=1)(=[O:35])=[O:34]
Reactant: O=C(NCCN1CCOCC1)Nc1nc2cc(O)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1c(F)cccc1F
Agent: [Na+]
Agent: [OH-]
Product: O=C(NCCN1CCOCC1)Nc1nc2cc(OS(=O)(=O)c3c(F)cccc3F)ccc2[nH]1
Temperature: 20 °C
Reaction time: 24 h
Yield: 42.4 %

Procedure:
To a solution of 250 mg of 1-(5-hydroxy-1H-benzimidazol-2-yl)-3-(2-morpholin-4-ylethyl)urea in 16.4 cm3 of aqueous 0.1N sodium hydroxide solution are added 191 mg of 2,6-difluorobenzenesulfonyl chloride. The solution is stirred for 24 hours at a temperature in the region of 20° C. After addition of 40 mg of 2,6-difluorobenzenesulfonyl chloride, the mixture is stirred for 5 hours at a temperature in the region of 20° C. The reaction medium is placed in an ice bath and the precipitate is then filtered off by suction, washed with three times 5 cm3 of ice-cold water and dried under reduced pressure over phosphorus pentoxide. After flash chromatography on a column of silica [eluent: dichloromethane/methanol (93/7 by volume)], 167 mg of 2-{[(2-morpholin-4-ylethyl)carbamoyl]amino}-1H-benzimidazol-5-yl 2,6-difluorobenzenesulfonate are obtained in the form of a pale yellow powder, the characteristics of which are as follows:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][CH:43]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([OH:33])=[O:32])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[OH:49][CH2:50][CH:51]([CH2:53]O)[OH:52].C(Cl)CCl>CN(C=O)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([C:23]([NH:25][CH2:26][CH2:27][CH2:28][CH2:29][C@H:30]([N:34]([S:39]([C:42]2[CH:43]=[CH:44][C:45]([CH3:48])=[CH:46][CH:47]=2)(=[O:41])=[O:40])[CH2:35][CH:36]([CH3:38])[CH3:37])[C:31]([O:33][CH2:53][CH:51]([OH:52])[CH2:50][OH:49])=[O:32])=[O:24])[CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[NH:16][CH:15]=2)(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)O)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Reactant: OCC(O)CO
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)N[C@@H](Cc2c[nH]c3ccccc23)C(=O)NCCCC[C@@H](C(=O)OCC(O)CO)N(CC(C)C)S(=O)(=O)c2ccc(C)cc2)cc1
Reaction time: 8 h
Yield: 38.9 %

Procedure:
A solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(4-methylbenzenesulfonyl)-L-tryptophanyl]-L-lysine (product of example 2, 70 mg, 0.1 mmol) in DMF (1 mL) was treated with glycerol (100 mg) and EDC (100 mg, 0.5 mmol) and stirred overnight. The solution is then poured in 5% citric acid and extracted with EtOAc (5 mL). The solvent was evaporated and the residue was purified by preparative HPLC to yield 30 mg (40%) of the desired ester.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([NH:24][S:25]([CH3:28])(=[O:27])=[O:26])[CH3:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].CI.[C:33](OCC)(=O)C>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[O:20][CH2:21][CH:22]([N:24]([S:25]([CH3:28])(=[O:27])=[O:26])[CH3:33])[CH3:23])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)NS(C)(=O)=O
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(COc1ccccc1N1CCN(C(=O)OC(C)(C)C)CC1)N(C)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 36 h
Yield: 100 %

Procedure:
4-[2-(2-Methanesulfonylamino-propoxy)-phenyl]-piperazine-1-carboxylic acid tert-butyl ester (470 mg, 1.14 mmol) was dissolved in THF (20 mL) and cooled to 0° C. Sodium hydride (29 mg of 60% dispersion in oil, 1.2 mmol) was added followed by dropwise addition of methyl iodide (78 μL, 1.25 mmol). The mixture was warmed to r.t. and stirred for about 36 hours. Ethyl acetate (20 mL) was added, and the solution was washed with saturated NaHCO3 (5 mL), H2O (5 mL) and brine (5 mL) and then dried over magnesium sulfate. The solvents were removed under reduced pressure to afford the final compound as a clear oil (486 mg, 100%).
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]1[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=1[N:19]1[N:23]=[CH:22][CH:21]=[N:20]1)=[O:11].Cl[C:25]1[N:30]=[CH:29][C:28]([Cl:31])=[CH:27][N:26]=1>>[Cl:31][C:28]1[CH:27]=[N:26][C:25]([NH:1][CH2:2][C@@H:3]2[C@H:8]([CH3:9])[CH2:7][CH2:6][CH2:5][N:4]2[C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([F:18])[C:13]=2[N:19]2[N:23]=[CH:22][CH:21]=[N:20]2)=[O:11])=[N:30][CH:29]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CN
Reactant: Clc1cnc(Cl)nc1
Product: C[C@@H]1CCCN(C(=O)c2cccc(F)c2-n2nccn2)[C@@H]1CNc1ncc(Cl)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A1 using ((2S,3R)-2-(aminomethyl)-3-methylpiperidin-1-yl)(3-fluoro-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone and 2,5-dichloropyrimidine. ESI-MS (m/z): 430 [M+1]+.
Reaction SMILES: [CH2:1](O)[CH:2]([OH:5])[CH:3]=[O:4].[CH2:7]([NH2:14])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>CO.[Pd]>[CH2:7]([NH:14][CH2:1][CH:2]([OH:5])[CH2:3][OH:4])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=CC(O)CO
Reactant: NCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: OCC(O)CNCc1ccccc1
Yield: 53.7 %

Procedure:
In yet a further method, N-benzyl-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2-hydroxypropylamine was formed in the following manner. D,L-Glyceraldehyde (5.0 g) was added to benzylamine (18.19 g) in methanol (90 ml) and the mixture was hydrogenated at 344 kPa (50 p.s.i.) over 5% palladium on carbon (1.0 g) for 31/2 hours. The mixture was filtered, evaporated under reduced pressure and subjected to column chromatography on silica (eluant dichloromethane:methanol saturated with ammonia 9:1) to give as an oil 3-benzylamino-1,2-propanediol (5.4 g). Part of this (4.9 g) and benzaldehyde (10 ml) were heated to 150° C. for 30 minutes. Volatiles including water were collected by distillation. The mixture was then cooled, benzaldehyde distilled off at low pressure, and the desired product 2-phenyl-3-benzyl-5-hydroxymethyloxazolidine (2.7 g) distilled at 190° C. (0.2 mm Hg). To this oil (2.69 g) in pyridine (4 ml) was added in portions toluene-p-sulphonyl chloride (1.90 g) at 5° C. The mixture was stirred at room temperature for 2 hours, treated with potassium carbonate (1.65 g) in water (7.5 ml), extracted into dichloromethane (3×10 ml) and evaporated under reduced pressure to give an oil. This oil dissolved in dimethylformamide (5 ml) was added in portions, to a solution of the anion of 4-[2-(cyclopropylmethoxy)ethyl]phenol (1.9 g) (prepared in situ using sodium hydride (0.5 g)) in dimethylformamide (5 ml) at 5° C. The mixture was heated for 6 hours to 60°-70° C., cooled, poured on to ice (30 g), extracted into diethyl ether (3×30 ml) and evaporated under reduced pressure to give an oil. This was slurried under water (30 ml), concentrated hydrochloric acid (6 ml) was added, stirred for 30 minutes and ether (30 ml) added. The resultant solid (1.1 g) was filtered off, slurried with ether, filtered and separated between dichloromethane and dilute sodium hydroxide. The dichloromethane layer was dried, filtered and evaporated to give an oil which crystallised on standing to afford N-benzyl-3-[4-[2-(cyclopropylmethoxy)ethyl]phenoxy]-2-hydroxypropylamine (0.8 g), identical with an authentic sample by chromatography and a nuclear magnetic resonance spectrum.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[CH3:10][CH:11]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH2:12][OH:13].[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([O:13][CH2:12][CH:11]([CH3:10])[CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[N+:3]=1[O-:9]
Reactant: CC(CO)CC(C)(C)C
Reactant: [O-][n+]1c(Cl)cccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(COc1cccc(Cl)[n+]1[O-])CC(C)(C)C

Procedure:
The 0.82 g (0.0050 moles) of 2,6-dichloropyridine N-oxide and 0.664 g (98%) (0.0050 moles) of 2,4,4-trimethyl-1-pentanol was reacted with 0.211 g (0.0050 moles) of ground sodium hydroxide in 8.2 ml of DMSO at 100° C. overnight to give 2-chloro-6-(2,4,4-trimethypentyloxy) pyridine N-oxide. It was reacted with 0.600 g (0.015 moles) of ground sodium hydroxide at 100° C. for 4.5 hours to give 1-hydroxy-6-(2,4,4-trimethylpentyloxy)pyridine-2(1H)-one. After cooling, it was added 74 ml of water and was adjusted with 6N HCl to pH 3. It was extracted with ethyl acetate (3×25 ml). The combined ethyl acetate extract was washed with a saturated sodium chloride solution (2×10 ml) and dried over sodium sulfate. The ethyl acetate extract was filtered and stripped in vacuo to give 1.08 g (90%). It was recrystallized from ethyl acetate and hexanes: mp 133.5°-134° C.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([C:34]4[CH:39]=[CH:38][C:37]([C:40]([F:43])([F:42])[F:41])=[CH:36][CH:35]=4)[C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.[OH-].[Na+].Cl>C(O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:20]=[C:21]([C:34]4[CH:35]=[CH:36][C:37]([C:40]([F:43])([F:41])[F:42])=[CH:38][CH:39]=4)[C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[CH:23][CH:24]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(-c3ccc(C(F)(F)F)cc3)c2)c1)C1CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2-c2ccc(C(F)(F)F)cc2)c1
Temperature: 50 °C
Reaction time: 15 h
Yield: 97 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2-fluoro-5-methoxy-4″-(trifluoromethyl)-1,1′:2′,1″-terphenyl-4′-yl)oxy)methyl)phenyl)propanoate (92 mg) in ethanol (3.0 mL) was added 2N aqueous sodium hydroxide solution (0.16 mL), and the mixture was stirred at 50° C. for 15 hr. To the reaction mixture was added 1N hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (85 mg) as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH2:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[CH3:21][N:22](C=O)C>[C-]#N.[Zn+2].[C-]#N.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2]>[NH2:20][CH2:19][C:13]1([C:10]2[S:11][CH:12]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([C:21]#[N:22])=[CH:3][CH:4]=3)[N:9]=2)[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CN(C)C=O
Reactant: NCC1(c2nc(-c3ccc(Br)cc3)cs2)CCOCC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: [C-]#N
Product: N#Cc1ccc(-c2csc(C3(CN)CCOCC3)n2)cc1
Yield: 10 %

Procedure:
(4-(4-(4-Bromophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine (200 mg, 0.56 mmol), zinc cyanide (53 mg, 0.45 mmol), and DMF (2 mL) were placed in microwave tube and degassed. 1,1′-Bis(diphenylphosphino)ferrocene-palladium(II)dichloride (41 mg, 0.05 mmol) was added. Reaction was microwaved at 200° C. for 10 min intervals until complete. The reaction was quenched with ammonium hydroxide/water (1:4) and washed with ethyl acetate. Organic layer was dried over sodium sulfate. Crude was purified using silica chromatography with an ethyl acetate wash followed by 10% Methanol in dichloromethane with 1% triethylamine to yield 4-(2-(4-(aminomethyl)tetrahydro-2H-pyran-4-yl)thiazol-4-yl)benzonitrile (20 mg, 10% yield). MS (ESI) m/z: Calculated for C16H17N3OS: 299.11. found: 300.1 (M+H)+.
Reaction SMILES: [CH:1]([CH:3]1[CH2:8][CH:7]2[CH2:9][CH:4]1[CH:5]=[CH:6]2)=[CH2:2].C1C2C3C=CC(C2C=C1)C3>>[CH2:8]1[C:3]2[CH:4]([CH2:5][CH:6]=[CH:2][CH:1]=2)[CH2:9][CH2:7]1
Reactant: C=CC1CC2C=CC1C2
Solvent: C1=CC2C3C=CC(C3)C2C1
Product: C1=CCC2CCCC2=C1

Procedure:
The fraction (C-1) is fed to the fourth distillation column, and rectified at a column top pressure of 0.08 atmosphere, a column bottom pressure of 0.09 atmosphere, and a reflux ratio of 30. A fraction containing components having a boiling point lower than that of 5-vinyl-2-norbornene is obtained from the column top, and a fraction containing 5-vinyl-2-norbornene, dicyclopentadiene and tetrahydroindene is obtained from the column bottom. Further, the fraction from the column bottom is fed to the fifth distillation column (distillation "d1 "), and rectified at a column top pressure of 0.03 atmosphere, a column bottom pressure of 0.06 atmosphere, and a reflux ratio of 4.6. Component (D-1) composed mainly of 5-vinyl-2-norbornene is obtained from the column top, and component (D-2) composed mainly of dicyclopentadiene is obtained from the column bottom. The fraction (D-2) is recycled to the decomposition reactor.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=2[F:12])[N:5]=[C:4]([C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=2)[C:3]=1[CH3:21].[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[NH:25][CH2:24]1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[CH3:22][C:23]1([CH3:38])[C:27]2=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=[C:26]2[N:25]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([F:13])=[CH:9][C:10]=3[F:12])[N:5]=[C:4]([C:14]3[CH:19]=[C:18]([CH3:20])[CH:17]=[CH:16][N:15]=3)[C:3]=2[CH3:21])[CH2:24]1
Reactant: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(Cl)c2C)c1
Reactant: CC1(C)CNc2cc(N3CCOCC3)cnc21
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: Cc1ccccc1
Product: Cc1ccnc(-c2nc3cc(F)cc(F)c3c(N3CC(C)(C)c4ncc(N5CCOCC5)cc43)c2C)c1

Procedure:
Prepared according to procedure Y by stirring 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (65 mg, 0.213 mmol), 4-(3,3-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-6-yl)morpholine (54.7 mg, 0.235 mmol), Pd2dba3 (29.3 mg, 0.032 mmol), XPhos (30.5 mg, 0.064 mmol), sodium tert-butoxide (51 mg, 0.533 mmol), and toluene (2.1 mL) at 100° C. for 2 h. Purification by reverse-phase HPLC (0-90% acetonitrile in water) gave 4-(3,3-dimethyl-6-(4-morpholinyl)-2,3-dihydro-1H-pyrrolo[3,2-b]pyridin-1-yl)-5,7-difluoro-3-methyl-2-(4-methyl-2-pyridinyl)quinoline. 1H NMR (400 MHz, chloroform-d) δ ppm 8.59 (1H, s), 7.75 (1H, d), 7.71 (2H, m), 7.55 (1H, br. s.), 7.00 (1H, m), 5.76 (1H, s), 3.67-3.92 (6H, m), 3.00 (4H, br. s.), 2.46 (3H, s), 2.41 (3H, s), 1.57 (3H, br. s.), 1.51 (3H, br. s.). Mass Spectrum (ESI) m/e=502.2 (M+1).