Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:7](C(O)=O)=[C:6]([CH3:11])[N:5]=[C:4]2[S:12][C:13]([Br:23])=[C:14]([C:15]3[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=3)[C:3]=12.C1(OC2C=CC=CC=2)C=CC=CC=1>>[Br:23][C:13]1[S:12][C:4]2[N:5]=[C:6]([CH3:11])[CH:7]=[C:2]([NH2:1])[C:3]=2[C:14]=1[C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH3:22])[CH:16]=1
Reactant: COc1cccc(-c2c(Br)sc3nc(C)c(C(=O)O)c(N)c23)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1cccc(-c2c(Br)sc3nc(C)cc(N)c23)c1
Reaction time: 16 h
Yield: 61.9 %

Procedure:
Alternatively, 4-amino-2-bromo-6-methyl-3-[3-(methyloxy)-phenyl]thieno-[2,3-b]pyridine-5-carboxylic acid (856 mg, 2.177 mmol) (Description 16) in diphenyl ether (8 mL, 50.3 mmol) was heated at 200° C. for 4.5 h and stand at RT overnight for 16 h. The mixture was purified by chromatography on silica gel, eluting with a gradient of 0-100% ethyl acetate in cyclohexane, to give the title compound (471 mg).
Reaction SMILES: Br[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1.[CH3:11][O-:12].[Na+]>CN(C=O)C>[CH3:11][O:12][C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[C:4]([I:10])[N:3]=1
Reactant: C[O-]
Reactant: COc1ccc(I)nc1Br
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(I)nc1OC
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of 2-bromo-3-methoxy-6-iodopyridine (5-3, 34 g, 108 mmol) in DMF (65 mL) was added sodium methoxide (37 mL, 162 mmol, 4.37 M in methanol) and heated to 100° C. The mixture was stirred for 10 minutes and partitioned between saturated NaHCO3 and DCM. The organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude material was purified by gradient elution on silica (0 to 20% EtOAc in hexanes) to afford the title compound (5-4) as a white powder. ESI+MS [M+H]+ C7H8INO2: 265.8 found, 266.0 required.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[S:4][CH:5]=[C:6]([C:8](OCC)=[O:9])[N:7]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:14][C:2]([F:1])([F:13])[C:3]1[S:4][CH:5]=[C:6]([CH2:8][OH:9])[N:7]=1
Reactant: CCOC(=O)c1csc(C(F)(F)F)n1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCc1csc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 56 %

Procedure:
To a stirring solution of ethyl 2-(trifluoromethyl)thiazole-4-carboxylate (1.0 g, 4.44 mmol) in THF (10 ml) was added LiAlH4 (0.169 g, 4.44 mmol) at 0-10° C. and stirred for 1 h at RT. Reaction mixture was cooled and quenched with saturated sodium sulfate solution till precipitates observed. Precipitates obtained were filtered and filtrate was evaporated to get desired product in 56% yield.
Reaction SMILES: [CH:1]([C:4]1[C:12](C(=O)C(C)C)=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].S(=O)(=O)(O)O.[OH-].[Na+]>O>[CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)C(=O)c1c(C(C)C)nn2ccccc12
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)c1cc2ccccn2n1
Temperature: 130 °C
Reaction time: 18 h
Yield: 80.9 %

Procedure:
1-(2-Isopropyl-pyrazolo[1,5-a]pyridin-3-yl)-2-methyl-propan-1-one (30.0 g, 115 mmole), water (100 ml), and concentrated sulfuric acid (100 ml) were combined and stirred at 130° C. for 18 hours. The mixture was cooled to room temperature and poured into a solution of ice (400 g) and water (200 ml). The solution was neutralized with sodium hydroxide solution and extracted with chloroform. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The oil was purified by vacuum distillation to give 14.9 g (81%) of 2-isopropyl-pyrazolo[1,5-a]pyridine. 1H-NMR (250 MHz, DMSO-d6) δ 8.37 (d, J=7.3 Hz, 1H), 7.41 (d, J=9.0 Hz, 1H), 7.00 (t, J=7.3 Hz, 1H), 6.66 (t, J=7.5 Hz, 1H), 6.28 (s, 1H), 3.16 (sept, J=7.0 Hz, 1H), 1.35 (d, J=6.8 Hz, 6H).
Reaction SMILES: [CH3:1][C@:2]([OH:17])([CH2:15][CH3:16])[C@@H:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].O([Sn](CCCC)(CCCC)CCCC)[Sn](CCCC)(CCCC)CCCC.BrBr>C(Cl)Cl.[F-].[K+].CCOCC>[OH:17][C@@:2]([CH3:1])([CH2:15][CH3:16])[C:3]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:9][CH:10]=1)=[O:4]
Reactant: CC[C@](C)(O)[C@H](O)c1ccc(S(C)(=O)=O)cc1
Agent: BrBr
Agent: CCCC[Sn](CCCC)(CCCC)O[Sn](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOCC
Solvent: ClCCl
Product: CC[C@](C)(O)C(=O)c1ccc(S(C)(=O)=O)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a solution of the crude product from Step 7 (7 g) and (Bu3Sn)2O (30 mL) in 150 mL of CH2Cl2 cooled at 10° C. was added a solution of Br2 (9.3 g in 30 mL of CH2Cl2). After stirring at r.t. for 30 min. the mixture was diluted with a solution of KF (500 mL, 3N) and 500 mL of Et2O. The solid generated was removed by filtration and the filtrate was separated. The organic layer was dried over MgSO4 and concentrated. The residue was purified by silica gel chromatography eluted with 1:1 hexane/EtOAc to give 5 g of the title compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:16]2[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=2)(O)[CH:9]2[S:14][CH2:13][S:12][CH2:11][S:10]2)=[CH:4][CH:3]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1C=CC=CC=1>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:8](=[C:9]2[S:10][CH2:11][S:12][CH2:13][S:14]2)[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=2)=[CH:17][CH:18]=1
Reactant: OC(c1ccc(F)cc1)(c1ccc(F)cc1)C1SCSCS1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Fc1ccc(C(=C2SCSCS2)c2ccc(F)cc2)cc1
Yield: 89.5 %

Procedure:
A mixture of 2.0 g of 2-{bis(4-fluorophenyl)hydroxymethyl}-1,3,5-trithiane, 0.2 g of p-toluenesulfonic acid and 50 ml of benzene was refluxed with heating for 15 minutes by means of a Dean-Stark reflux condenser. After being cooled, the mixture was extracted with ethyl acetate and the extract was washed with a saturated aqueous sodium hydrogencarbonate solution. The washed extract was dried over anhydrous magnesium sulfate and the solvent was removed by distillation under reduced pressure to obtain a material, which was recrystalized from cyclohexane to give 1.7 g of the desired compound.
Reaction SMILES: C(OC[N:10]1[CH:14]=[C:13]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([C:32]5[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:33]=5)[N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[C:21]=34)[CH:19]=2)[CH:12]=[N:11]1)C1C=CC=CC=1.C(OCN1C=C(C2N=CN(C3C=CN=C4N(C5C=CC(C#N)=C(Br)C=5)N=C(C(C)C)C=34)C=2)C=N1)C1C=CC=CC=1.C(N)(C)C.O[C@H]1CC[C@H](N)CC1.[OH-].[Na+]>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(Cl)(Cl)Cl>[NH:10]1[CH:14]=[C:13]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[CH:25]=[CH:24][N:23]=[C:22]4[N:26]([C:32]5[CH:39]=[CH:38][C:35]([C:36]#[N:37])=[C:34]([NH:40][CH:41]([CH3:43])[CH3:42])[CH:33]=5)[N:27]=[C:28]([CH:29]([CH3:31])[CH3:30])[C:21]=34)[CH:19]=2)[CH:12]=[N:11]1
Reactant: CC(C)Nc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cnn(COCc6ccccc6)c5)c4)ccnc32)ccc1C#N
Agent: CC(C)c1nn(-c2ccc(C#N)c(Br)c2)c2nccc(-n3cnc(-c4cnn(COCc5ccccc5)c4)c3)c12
Agent: N[C@H]1CC[C@H](O)CC1
Agent: [Na+]
Solvent: CC(C)N
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)Nc1cc(-n2nc(C(C)C)c3c(-n4cnc(-c5cn[nH]c5)c4)ccnc32)ccc1C#N
Temperature: 70 °C
Reaction time: 3 h
Yield: 43 %

Procedure:
According to Example 1(6), 4-{4-(4-(1-(benzyloxymethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile (65%) was prepared using compound (143a) and isopropylamine instead of compound (1e) and trans-4-hydroxycyclohexylamine, respectively, and this 4-{4-(4-(1-(benzyloxymethyl)-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile was dissolved in anisole and trifluoroacetic acid, followed by stirring at 70° C. for 3 hr. The reaction solution was distributed between chloroform and a 2 M aqueous sodium hydroxide solution. The organic layer was dried over anhydrous sodium sulfate, and the solvent was distilled away to obtain 4-{4-(4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile, which was used in the subsequent reaction without being purified. Lastly, according to Example 1(7), compound (143) (the second stage yield: 43%) was prepared as a white solid using 4-{4-(4-(1H-pyrazol-4-yl)-1H-imidazol-1-yl)-3-isopropyl-1H-pyrazolo[3,4-b]pyridin-1-yl}-2-(isopropylamino)benzonitrile instead of compound (1f).
Reaction SMILES: [F:1][C:2]1([F:30])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:11][CH2:10][N:9]2C(OCC2C=CC=CC=2)=O)[CH2:3]1.[H-].[Na+].N1C=CN=C1.C(=S)=S.IC.CC(N=NC(C#N)(C)C)(C#N)C.CCCC[SnH](CCCC)CCCC>C1COCC1.C1(C)C=CC=CC=1.O>[F:30][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][CH:4]([C@@H:8]2[CH2:13][C@H:12]([C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)[CH2:11][CH2:10][NH:9]2)[CH2:3]1
Reactant: O=C(OCc1ccccc1)N1CC[C@@H](c2ccccc2)C[C@H]1C1CCCC(F)(F)C1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Agent: [H-]
Solvent: CI
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: FC1(F)CCCC([C@@H]2C[C@H](c3ccccc3)CCN2)C1
Reaction time: 1 h
Yield: 39.5 %

Procedure:
A mixture of 6 (647 mg, 2.9 mmol), NaH (232 mg, 5.8 mmol, 60% in mineral oil), imidazole (26 mg, 0.3 mmol) in THF (30 mL) was stirred for a half an hour at room temperature before CS2 (2 mL, 33.3 mmol) was introduced. After stirring for 1 h, iodomethane (0.3 mL, 4.8 mmol) was added. The resultant reaction mixture was stirred for another hour, poured into water (30 mL), extracted with EtOAc two times. The combined organic layers were washed with water and brine, dried over Na2SO4, filtered, and concentrated in vacuo to give a yellow oil. The residue was dissolved in toluene (30 mL), to which catalytic AIBN (100 mg) was added. The reaction mixture was refluxed under N2 while a solution of Bu3SnH (3 mL, 11 mmol) in toluene (3 mL) was added slowly over 30 minutes. After refluxing overnight, the reaction mixture was cooled, partitioned between saturated NaHCO3 aqueous solution and EtOAc. The combined organic layers were washed with water and brine, dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by silica gel column (PE:EA=20:1) to afford 0.32 g of 7 (yield 53%).
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:18]4[C:13](=[CH:14][CH:15]=[CH:16][N:17]=4)[NH:12][CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1.[C:19]1([S:29](Cl)(=[O:31])=[O:30])[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH:22]=[CH:21][CH:20]=1>C1COCC1>[CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][CH:7]([C:10]3[C:14]4[C:13](=[CH:18][N:17]=[CH:16][CH:15]=4)[N:12]([S:29]([C:19]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH:22]=[CH:21][CH:20]=4)(=[O:31])=[O:30])[CH:11]=3)[CH2:8]2)[CH2:3][CH2:2]1
Reactant: O=S(=O)(Cl)c1cccc2ccccc12
Reactant: c1cnc2c(C3CCN4CCCC4C3)c[nH]c2c1
Solvent: C1CCOC1
Product: O=S(=O)(c1cccc2ccccc12)n1cc(C2CCN3CCCC3C2)c2ccncc21

Procedure:
from 3-(octahydro-7-indolizinyl)-1-H-4-azaindole (more polar isomer) (12 mg, 0.05 mmol), 1-naphthalenesulfonyl chloride (20.9 mg, 0.1 mmol) and 1M NaN((TMS)2 (100 μL, 0.10 mmol) in THF (1 mL) at RT.
Reaction SMILES: [CH2:1]1[CH2:11][C:9](=O)[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2]1.Cl.[NH2:13][OH:14].C(N(CC)CC)C>CO>[C:9]1(=[N:13][OH:14])[C:8]2[C:3](=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH2:2][CH2:1][CH2:11]1
Reactant: O=C1CCCc2ccccc21
Reactant: NO
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: ON=C1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 108.7 %

Procedure:
To a solution of α-tetralone (10 g, 68.5 mmol) in anhydrous MeOH (175 mL), hydroxylamine hydrochloride (7.6 g, 109.6 mmol) and triethylamine (15.3 mL, 109.6 mmol) were added. The mixture was stirred at room temperature for 16 hrs, followed by removal of the solvent in vacuo. The residue was dissolved in DCM, washed with water and brine, dried (Na2SO4), filtered and concentrated in vacuo to yield crude 3,4-dihydro-2H-naphthalen-1-one oxime (12 g). MS [M+H]+: 162.1; tR=2.03 min. (method 1)
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 100 %

Procedure:
To a stirring solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl bromide (9.9 g, 57.8 mmol) in acetone (150 mL) was added K2CO3 (12.0 g, 86.7 mmol). After stirring at reflux for 4h, the mixture was partitioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol), 1HNMR (400 MHz, CDCl3) δ 7.62 (m, 1H), 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 7.28 (m, 1H), 6.98 (m, 1H), 6.91 (m, 1H), 5.17 (s, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CC(C)=O.O>[CH2:9]([O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[Br:1])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Oc1ccccc1Br
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: Brc1ccccc1OCc1ccccc1
Yield: 100 %

Procedure:
To a stirring solution of 2-bromophenol (10.0 g, 57.8 mmol), and benzyl bromide (9.9 g, 57.8 mmol) in acetone (150 mL) was added K2CO3 (12.0 g, 86.7 mmol). After stirring at reflux for 4 h, the mixture was portioned between ethyl acetate and water. The organic layer was washed with brine, dried (MgSO4), filtered and concentrated. The residue was purified by column chromatography (silica gel, ethyl acetate/hexane) to yield the title compound as a colorless oil (15.2 g, 57.8 mmol). 1HNMR (400 MHz, CDCl3) δ7.62 (m, 1H), 7.54 (m, 2H), 7.45 (m, 2H), 7.37 (m, 1H), 7.28 (m, 1H), 6.98 (m, 1H), 6.91 (m, 1H), 5.17 (s, 2H).
Reaction SMILES: O1CCCC1.[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[NH:10]1)([CH3:8])[CH3:7].[C:15](Cl)(=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19]>O>[CH:6]([C@H:9]1[CH2:13][O:12][C:11](=[O:14])[N:10]1[C:15](=[O:20])[CH2:16][CH2:17][CH:18]=[CH2:19])([CH3:8])[CH3:7]
Reactant: C=CCCC(=O)Cl
Reactant: CC(C)[C@H]1COC(=O)N1
Solvent: O
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@@H]1C(C)C
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
Tetrahydrofuran (2 L) solution of 108 g of (S)-4-isopropyl-oxazolidin-2-one was cooled in a dry ice bath at −70° C., 345 mL of 2.66 M n-butyllithium-hexane solution was added thereto, and the reaction liquid was stirred at −70° C. for 30 minutes. Next, 102 mL of 4-pentenoyl chloride was added thereto at −70° C., the reaction liquid was stirred for 30 minutes, and water was added thereto to stop the reaction. This was extracted with ethyl acetate, the organic layer was washed with aqueous saturated sodium deuteride solution, and dried with anhydrous sodium sulfate. The solvent was evaporated off under reduced pressure to obtain a crude product of the entitled compound.
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8]Cl)=[CH:4][CH:3]=1.[CH3:10][NH2:11]>O>[CH3:10][NH:11][CH2:8][C:5]1[CH:6]=[CH:7][N:2]=[CH:3][CH:4]=1
Reactant: ClCc1ccncc1
Reactant: CN
Agent: Cl
Solvent: O
Product: CNCc1ccncc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 65.5 %

Procedure:
To 4-picolyl chloride, hydrochloride (10 g, 0.06 mol) was added methylamine (50 mL of 40% aqueous solution, 0.58 mol), and the resulting purple solution was stirred at rt for 30 min, then poured into H2O. The mixture was extracted with CH2Cl2 (6×), and the combined organic extracts were evaporated. The residue was filtered under reduced pressure through a silica gel column, eluting with a solvent gradient of 0-10% MeOH/CHCl3 to provide the title compound as a light yellow oil (4.8 g, 66%): 1H NMR (CDCl3): d 8.50 (dd, 2H); 7.20 (dd, 2H); 3.70 (s, 2H); 2.40 (s, 3H); 1.70 (br, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[CH:8][CH:7]=1.CC(O)(CC)C.[NH:20]1[CH:24]=[CH:23][N:22]=[N:21]1.[I-].[K+].[OH-].[Na+].[CH3:29][S:30]([OH:33])(=[O:32])=[O:31]>O.C1(C)C=CC=CC=1>[CH3:29][S:30]([OH:33])(=[O:32])=[O:31].[CH3:13][O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][CH2:3][CH2:2][N:20]2[CH:24]=[CH:23][N:22]=[N:21]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(CCCCCl)cc1
Reactant: c1c[nH]nn1
Agent: CS(=O)(=O)O
Agent: [I-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCC(C)(C)O
Solvent: O
Product: COc1ccc(CCCCn2ccnn2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.4 %

Procedure:
To 1-(4-Chlorobutyl)-4-methoxybenzene (2468 mg, 12.42 mmol) was added 2-methyl-2-butanol (5 ml), and then 1H-1,2,3-triazole (1286 mg, 18.62 mmol) and potassium iodide (2062 mg, 14.24 mmol) were added. Sodium hydroxide (745 mg, 18.62 mmol) was added and the mixture was refluxed under heating for 4 hours. After cooling to room temperature, toluene and water were added and the mixture was partitioned. The organic layer was washed with water, 20%citric acid (twice), saturated aqueous sodium hydrogen carbonate and water (twice). The organic layer was concentrated under reduced pressure. To the residue was added ethyl acetate and the mixture was concentrated under reduced pressure. Ethyl acetate (20 ml) and isopropyl ether (10 ml) were added and then seed crystal was added. Methanesulfonic acid (1021 mg, 10.62 mmol) was added dropwise while keeping the mixture at 20-30° C. The mixture was stirred at 20-30° C. for 1 hour. The precipitated crystals were collected by filtration and washed with ethyl acetate/isopropyl ether=1/1. The crystals were dried under reduced pressure to give 1-[4-(4-methoxyphenyl)butan-1-yl]-1H-1,2,3-triazole methanesulfonate (3.04 g) as white crystals (yield 75%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10](Cl)(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH3:14].Cl>C1COCC1.O>[C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:14])(=[O:12])=[O:11])=[CH:6][CH:5]=1)(=[O:3])[CH3:2]
Reactant: N
Reactant: CC(=O)c1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc(S(N)(=O)=O)cc1
Reaction time: 1 h

Procedure:
Commercially available 4-acetyl-benzenesulfonyl chloride (1.25 g, 5.7 mmol) was dissolved in THF (20 mL) and slowly added to a stirred solution of 25% NH3 in H2O (50 mL). The reaction mixture was stirred at it for 1 h. The reaction mixture was acidified using conc. HCl to pH=2. The white precipitation was collected by filtration, washed with H2O and dried in vacuo affording 975 mg of the title compound as off-white crystals.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([Cl:20])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[F:23][C:24]1[CH:30]=[C:29]([CH3:31])[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])=[CH:27][C:25]=1[NH2:26]>C(O)(C)C>[ClH:20].[CH2:2]([O:9][C:10]1[CH:19]=[C:18]2[C:13]([C:14]([NH:26][C:25]3[CH:27]=[C:28]([O:32][C:33]([O:35][CH3:36])=[O:34])[C:29]([CH3:31])=[CH:30][C:24]=3[F:23])=[N:15][CH:16]=[N:17]2)=[CH:12][C:11]=1[O:21][CH3:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCc1ccccc1
Reactant: COC(=O)Oc1cc(N)c(F)cc1C
Agent: Cl
Solvent: CC(C)O
Product: COC(=O)Oc1cc(Nc2ncnc3cc(OCc4ccccc4)c(OC)cc23)c(F)cc1C
Temperature: 25 °C
Yield: 83.3 %

Procedure:
A solution of 7-benzyloxy-4-chloro-6-methoxyquinazoline hydrochloride (800 mg, 2.4 mmol), (prepared as described for the starting material in Example 1), and 2-fluoro-5-methoxycarbonyloxy-4-methylaniline (570 mg, 2.89mmol) in isopropanol (20 ml) was refluxed for 2 hours. After cooling to ambient temperature, the solid was filtered, washed with isopropanol and dried under vacuum to give 7-benzyloxy-4-(2-fluoro-5-methoxycarbonyloxy-4-methylanilino)-6-methoxyquinazoline hydrochloride (1.0 g, 87%)
Reaction SMILES: Br[CH2:2]Br.[CH3:4][C:5]1[CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[C:6]=1[OH:12]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].O>[CH3:4][C:5]1[C:6]2[O:12][CH2:2][O:8][C:7]=2[CH:9]=[CH:10][CH:11]=1
Reactant: BrCBr
Reactant: Cc1cccc(O)c1O
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: O
Product: Cc1cccc2c1OCO2

Procedure:
11.6 g Adogen 464 and 7 mL of dibromomethane were refluxed in 50 mL of H2O for 0.5 hours under argon. 3-Methylcatechol (8.89 g, 71.6 mmol) was added over 2 hours and the mixture refluxed for an additional 1 hour. Distillation of the product from the reaction mixture afforded the title compound as a yellow oil: HRMS m/e 136.0524 (calc'd for C8H8O2, 136.0524).
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.[F:12][C:13]([F:23])([O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1)[CH3:14]>>[Br:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([NH:20][C:19]1[CH:21]=[CH:22][C:16]([O:15][C:13]([F:12])([F:23])[CH3:14])=[CH:17][CH:18]=1)=[O:9]
Reactant: O=C(O)c1cnc(Cl)c(Br)c1
Reactant: CC(F)(F)Oc1ccc(N)cc1
Product: CC(F)(F)Oc1ccc(NC(=O)c2cnc(Cl)c(Br)c2)cc1

Procedure:
The title compound was prepared in an analogous fashion to that described in Stage 185.2 using 5-bromo-6-chloro-nicotinic acid and 4-(1,1-difluoroethoxy)aniline (Stage 215.3) to afford an off-white crystalline solid. HPLC (Condition 5) tR=7.3 min, UPLC-MS (Condition 3) tR=1.16 min, m/z=391/393 [M+H]+.
Reaction SMILES: [CH:1]1(B(O)O)[CH2:3][CH2:2]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].Br[C:16]1[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][CH:19]=[CH:18][N:17]=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:1]1([C:16]2[C:21]([O:22][CH:23]([F:25])[F:24])=[CH:20][CH:19]=[CH:18][N:17]=2)[CH2:3][CH2:2]1
Reactant: OB(O)C1CC1
Reactant: FC(F)Oc1cccnc1Br
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: CC(=O)[O-]
Product: FC(F)Oc1cccnc1C1CC1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 59 %

Procedure:
Cyclopropylboronic acid (383 mg, 4.5 mmol) and potassium phosphate tribasic (1.89 g, 8.9 mmol) were added to a solution of 2-bromo-3-difluoromethoxypyridine (Preparation 102, 570 mg, 2.5 mmol). The mixture was heated to 80° C. and degassed thoroughly by bubbling nitrogen through the mixture. After 30 minutes, the reaction was heated to 95° C. and tricyclohexylphosphine (84 mg, 0.30 mmol) was added followed by palladium acetate (32 mg, 0.14 mmol). The reaction was stirred at 95° C. for 18 hours then cooled to room temperature. The mixture was filtered through arbocel, washing with EtOAc and the filtrate concentrated in vacuo. The residue was then purified by flash column chromatography eluting with EtOAc:heptane 1:5 to afford the title compound as a colourless oil (273 mg, 58%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]23[CH2:17][CH2:16][CH2:15][C:14]2=[CH:13][N:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1.COC1C=C([C@@]23CCC[C@H]2CN(C)CC3)C=CC=1>[Pt]=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@@:9]23[CH2:17][CH2:16][CH2:15][C@@H:14]2[CH2:13][N:12]([CH3:18])[CH2:11][CH2:10]3)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(C23CCCC2=CN(C)CC3)c1
Agent: O=[Pt]
Agent: COc1cccc([C@@]23CCC[C@H]2CN(C)CC3)c1
Product: COc1cccc([C@@]23CCC[C@@H]2CN(C)CC3)c1

Procedure:
Following the procedure set forth in Example 5, 4a-(3-methoxyphenyl)-2-methyl-3,4,4a,5,6,7-hexahydro-2-pyrindine was hydrogenated over platinum oxide to provide a 60:40 mixture of trans-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine and the corresponding cis-isomer. The trans isomer was crystallized asthe picrate salt. The cis isomer was isolated as the free base, namely cis-4a-(3-methoxyphenyl)-2-methyl-2,3,4,4a,5,6,7,7a-octahydro-1H-2-pyrindine; M.P.=40°-43° C.