Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[CH:22][CH:21]=1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:36]1[CH:40]=[CH:39][N:38]=[C:37]1[CH:41]=[O:42].[Li]N1C(C)(C)CCCC1(C)C>>[Si:1]([O:18][CH2:19][C:20]1[C:25]([N:26]2[CH2:31][C@H:30]([CH3:32])[O:29][C@H:28]([CH3:33])[CH2:27]2)=[C:24]([Cl:34])[C:23]([F:35])=[C:22]([C:40]2[S:36][C:37]([CH2:41][OH:42])=[N:38][CH:39]=2)[CH:21]=1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)ccc(F)c2Cl)C[C@H](C)O1
Reactant: O=Cc1nccs1
Agent: [Li]N1C(C)(C)CCCC1(C)C
Product: C[C@@H]1CN(c2c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc(-c3cnc(CO)s3)c(F)c2Cl)C[C@H](C)O1

Procedure:
Starting material: (2R,6S)-4-[6-({[tert-butyl(diphenyl)silyl]oxy}methyl)-2-chloro-3-fluorophenyl]-2,6-dimethylmorpholine (Intermediate 42), 1,3-thiazole-2-carbaldehyde and lithium 2,2,6,6-tetramethylpiperidide.
Reaction SMILES: [C-:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH2:10][OH:11])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[CH:2]1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19].[Cr](Cl)([O-])(=O)=O.[NH+]1C=CC=CC=1.CCOCC>C(Cl)Cl>[C-:1]1([C:6]2[CH:13]=[CH:12][C:9]([CH:10]=[O:11])=[CH:8][CH:7]=2)[CH:2]=[CH:3][CH:4]=[CH:5]1.[CH-:14]1[CH:18]=[CH:17][CH:16]=[CH:15]1.[Fe+2:19]
Reactant: OCc1ccc(-[c-]2cccc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: [Fe+2]
Agent: c1cc[cH-]c1
Solvent: ClCCl
Solvent: CCOCC
Product: O=Cc1ccc(-[c-]2cccc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A sample of 4-ferrocenylbenzyl alcohol 16 (630 mg, 2.15 mmol) was added to a suspension of pyridinium chlorochromate (1.22 g, 3.23 mmol) in CH2Cl2 (5 mL) and the mixture was stirred under argon at rt for 18 h. Then Et2O (20 mL) was added and the mixture was filtered through a pad of Celite. The filtrate was concentrated and chromatographed (silica, CH2Cl2/hexanes, 4:1) affording 306 mg (47.8%). TLC (silica, CH2Cl2), Rf=0.35; mp 122-125° C. (lit.35a 121-125° C.); 1H NMR δ 4.07 (s, 5H), 4.46 (A2B2, J=1.5 Hz, 2H), 4.47 (A2B2, J=1.5 Hz, 2H), 7.60, 7.78 (AA′BB′, J=8.7 Hz, 4H), 9.97 (s, 1H); 13C NMR δ 67.8, 70.5, 70.6, 70.8, 127.0, 127.7, 130.7, 130.7, 134.7, 192.5; EI-MS obsd 290.0406 (M+), calcd exact mass 290.0394; Anal. Calcd for C17H14FeO: C, 70.37; H, 4.86. Found: C, 70.50; H, 4.81.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]([NH:13][C:14](=[O:30])[CH2:15][NH:16][S:17]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=1)(=[O:19])=[O:18])[C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=[O:6].C(N(CC)CC)C.[N:38]1[CH:43]=[CH:42][C:41]([N:44]2[CH2:49][CH2:48][CH:47]([C:50](Cl)=[O:51])[CH2:46][CH2:45]2)=[CH:40][CH:39]=1>C(Cl)Cl>[CH:21]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH:28]=[CH:29][C:20]=1[S:17]([NH:16][CH2:15][C:14]([NH:13][CH:4]([C:5]([N:7]1[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]1)=[O:6])[CH2:3][NH:2][C:50]([CH:47]1[CH2:46][CH2:45][N:44]([C:41]2[CH:40]=[CH:39][N:38]=[CH:43][CH:42]=2)[CH2:49][CH2:48]1)=[O:51])=[O:30])(=[O:19])=[O:18]
Reactant: NCC(NC(=O)CNS(=O)(=O)c1ccc2ccccc2c1)C(=O)N1CCCCC1
Reactant: O=C(Cl)C1CCN(c2ccncc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCCCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.8 %

Procedure:
N-[2-Amino-1-(piperidinocarbonyl)ethyl]-2-(2-naphthalene-sulphonamido)acetamide hydrochloride salt (2.6 g) and triethylamine (3.18 ml) were added in turn to a stirred solution of 1-(4-pyridyl)piperidine-4-carbonyl chloride (1.54 g) in methylene chloride (20 ml) and the mixture was stirred at ambient temperature for 16 hours. The mixture was partitioned between ethyl acetate and water. The organic phase was washed with water, dried (MgSO4) and evaporated. The residue was purified by column chromatography using a 89:10:1 mixture of ethyl acetate, methanol and ammonia as eluent. The material so obtained was triturated under diethyl ether to give 2-(2-naphthalenesulphonamido)-N-{1-piperidinocarbonyl-2-[1-(4-pyridyl)-piperidin-4-ylcarbonylamino]ethyl}acetamide as a foam (1.9 g, 55%);
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5](Cl)=[C:4]2[CH:9]=[N:10][C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)=[C:12]([CH3:13])[C:3]=12.[CH3:20][CH:21]1[O:26][CH2:25][CH2:24][NH:23][CH2:22]1>>[CH3:13][C:12]1[C:3]2[C:4](=[C:5]([N:23]3[CH2:24][CH2:25][O:26][CH:21]([CH3:20])[CH2:22]3)[N:6]=[N:7][C:2]=2[N:23]2[CH2:24][CH2:25][O:26][CH:21]([CH3:20])[CH2:22]2)[CH:9]=[N:10][C:11]=1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: Cc1c(-c2ccccc2)ncc2c(Cl)nnc(Cl)c12
Reactant: CC1CNCCO1
Product: Cc1c(-c2ccccc2)ncc2c(N3CCOC(C)C3)nnc(N3CCOC(C)C3)c12

Procedure:
8.00 mg. of 1,4-dichloro-8-methyl-7-phenylpyrido[3,4-d]pyridazine was heated together with 2 g. of 2-methyl-morpholine at 120° C for 1.5 hours, after which time the excess 2-methylmorpholine was distilled off. To the residue was added 30 ml. of water and the resultant crystals were recovered by filtration and purified by column chromatography (silica gel; acetone: benzene=1:8) in the same manner described in Example 3. After removal of the solvent, the residue was dissolved in 20 ml. of ethanol. Following the addition of 2 ml. of water, the solution was concentrated to dryness. To the residue was added 20 ml. of water, followed by stirring. The resultant crystals were dried in a vacuum dryer at 50°-60° C for 12 hours, whereupon 600 mg. of 8-methyl-1,4-bis(2-methylmorpholino)-7-phenylpyrido-[3,4-d]pyridazine was obtained. Melting point: 96°-99° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.C([O-])(=O)C.[Na+].[I:14]Cl>C(O)(=O)C>[Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([I:14])=[CH:4][N:3]=1
Reactant: ClI
Reactant: Nc1ccnc(Cl)c1
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: Nc1cc(Cl)ncc1I
Temperature: 60 °C
Reaction time: 2 h

Procedure:
A 100 mL round bottom flask was charged with 2-chloro-4-amino pyridine (3.0 g, 23.34 mmol), sodium acetate (11.49 g, 140 mmol) and acetic acid (60 mL). To this iodine monochloride (3.98 g, 24.50 mmol) was added and the reaction mixture stirred at 60° C. for 2 h. The reaction was cooled to room temperature and quenched with 1N saturated sodium bis-sulfite solution and extracted with DCM. The organic layer was dried over sodium sulfate and concentrated in vacuo. The crude was purified by silica gel flash chromatography using DCM-MeOH:95-5. 2-Chloro-5-iodo-pyridin-4-ylamine was obtained as a white color solid. ESI-MS: m/z 255.0 (M+H)+
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][CH:7]=1.O.NN.CCCCCC>C(O)C.[Pt]>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(-c2cccs2)cc1
Agent: [Pt]
Agent: NN
Solvent: CCO
Solvent: CCCCCC
Solvent: O
Product: Nc1ccc(-c2cccs2)cc1
Yield: 98 %

Procedure:
A solution of 1-(2-thienyl)-4-nitrobenzene (1.65 g, 8.05 mmol) in 95% ethanol (210 mL) containing platinum on sulfide carbon (50 mg) was added hydrazine hydrate (0.5 mL). The mixture was refluxed for 2 hours. After cooling, the mixture was filtered and the solvent was evaporated to give a solid. Addition of hexane followed by filtration gave pure 1-(2-thienyl)-4-aminobenzene, yield=98%, 70-72° C. IR (KBr, in cm-1) 3440, 3344, 3098, 1620, 1500, 1281, 1183 and 813. 1H NMR (CDCl3 ; δ in ppm): 3.978 (brs, 2H), 6.670 (d, J=9.6 Hz, 2H), 7.011 (dd, J=5.6 and 4.4 Hz, 1H), 7.139 (m, 2H) and 7.382 (d, J=9.6 Hz, 2H). 13C NMR (CDCl3 ; δ in ppm): 115.07, 120.95, 122.82, 124.40, 126.91, 127.77, 144.77 and 146.46. MS(EI) m/z (rel int): 175 [(M)+, 100%], 143 [(M+ --S), 10%] and 130 [(M+ --HCS), 57%]. Anal. Calcd for C10H9NS: C, 68.53%; H 5.18; N 7.99. Found: C, 68.50; H, 5.21; N, 7.74.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:4]1=[O:32].C(N(CC)CC)C.[CH3:40][C:41]([CH3:46])=[CH:42][C:43](Cl)=[O:44]>C(Cl)Cl>[CH3:40][C:41]([CH3:46])=[CH:42][C:43]([NH:2][C@@H:3]1[CH2:9][CH2:8][C:7]2[CH:10]=[CH:11][CH:12]=[CH:13][C:6]=2[N:5]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:27]3[NH:31][N:30]=[N:29][N:28]=3)=[CH:17][CH:16]=2)[C:4]1=[O:32])=[O:44]
Reactant: N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Reactant: CC(C)=CC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3nnn[nH]3)cc2)C1=O
Temperature: -15 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
To a suspension of 1.18 g (2.64 mmol) of 3(R)-amino-1,3,4,5-tetrahydro-1-[[2'-(1H-tetrazol-5-yl)[1,1'-biphenyl]-4-yl]methyl]-2H-1-benzazepin-2-one, hydrochloride (Example 4, Step C) in 30 mL of methylene chloride under nitrogen at -15° C. was added 0.923 mL (2.64 mmol) of triethylamine followed by 0.294 mL (2.64 mmol) of 3,3-dimethylacryloyl chloride. The reaction mixture was stirred at -15° C. for 2 hours then quenched by the addition of 1N hydrochloric acid. The mixture was diluted with 50 mL of methylene chloride and washed with 50 mL of 1N hydrochloric acid and brine. The organic layer was removed and concentrated to dryness under vacuum. The residue was redissolved in 30 mL of methanol and treated with 1.5 mL of 9N hydrochloric acid. After stirring for 30 minutes, the mixture was concentrated to dryness under vacuum to give 1.3 g (2.63 mmol, 99%) of the product as a white solid.
Reaction SMILES: [OH:1][N:2]=[C:3](Cl)[C:4]1[CH:9]=[N:8][CH:7]=[CH:6][N:5]=1.[C:11]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=1)#[CH:12].N>>[F:20][C:15]1[CH:14]=[C:13]([C:11]2[O:1][N:2]=[C:3]([C:4]3[CH:9]=[N:8][CH:7]=[CH:6][N:5]=3)[CH:12]=2)[CH:18]=[CH:17][C:16]=1[F:19]
Reactant: ON=C(Cl)c1cnccn1
Reactant: C#Cc1ccc(F)c(F)c1
Agent: N
Product: Fc1ccc(-c2cc(-c3cnccn3)no2)cc1F

Procedure:
The titled compound was prepared according to Method CB using the product of Example 83D (79 mg, 0.5 mmol) and 4-ethynyl-1,2-difluorobenzene (Apollo, 69 mg, 0.5 mmol). 1H NMR (300 MHz, MeOH-d4) δ 7.38-7.54 (m, 2H), 7.74-7.84 (m, 1H), 7.90 (ddd, J=11.1, 7.5, 2.0 Hz, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.76 (dd, J=2.4, 1.6 Hz, 1H), 9.29 (d, J=1.6 Hz, 1H) ppm; MS (DCI/NH3) m/z 260 (M+H)+.
Reaction SMILES: CS(O[CH2:6][CH2:7][N:8]1[CH2:12][CH:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:10]([C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]3[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=3)=[CH:25][CH:24]=2)[C:9]1=[O:37])(=O)=O.[NH2:38][CH2:39][CH2:40][OH:41]>C1COCC1>[Cl:36][C:33]1[CH:32]=[CH:31][C:30]([O:29][C:26]2[CH:25]=[CH:24][C:23]([N:10]3[CH:11]([C:13]4[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:20])([F:22])[F:21])[CH:14]=4)[CH2:12][N:8]([CH2:7][CH2:6][NH:38][CH2:39][CH2:40][OH:41])[C:9]3=[O:37])=[CH:28][CH:27]=2)=[CH:35][CH:34]=1
Reactant: CS(=O)(=O)OCCN1CC(c2cccc(C(F)(F)F)c2)N(c2ccc(Oc3ccc(Cl)cc3)cc2)C1=O
Reactant: NCCO
Solvent: C1CCOC1
Product: O=C1N(CCNCCO)CC(c2cccc(C(F)(F)F)c2)N1c1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 80 °C

Procedure:
To a solution of 2-(3-(4-(4-chlorophenoxy)phenyl)-2-oxo-4-(3-(trifluoromethyl)phenyl)imidazolidin-1-yl)ethyl methanesulfonate (12.0 mg, 0.0216 mmol) in THF (0.3 mL) is added 2-aminoethanol (6.53 μL, 0.108 mmol). The reaction mixture is heated at 80° C. for 2 h before removal of the solvent. The residue is purified by preparatory LC/MS to provide the title compound; HPLC-MS calculated for C26H25ClF3N3O3 (M+H+) 520.2, found 520.2.
Reaction SMILES: [F:1][C:2]1([F:26])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:24][CH2:23][C:13]4([CH2:22][CH2:21][C:16]5(OCC[O:17]5)[CH2:15][CH2:14]4)[C:12]3=[O:25])=[CH:10][C:4]=2[O:3]1.Cl>>[F:26][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:24][CH2:23][C:13]4([CH2:14][CH2:15][C:16](=[O:17])[CH2:21][CH2:22]4)[C:12]3=[O:25])=[CH:10][C:4]=2[O:3]1
Reactant: O=C1N(c2ccc3c(c2)OC(F)(F)O3)CCC12CCC1(CC2)OCCO1
Agent: Cl
Product: O=C1CCC2(CC1)CCN(c1ccc3c(c1)OC(F)(F)O3)C2=O

Procedure:
The title compound was prepared in analogy to example 133 step 5 from 10-(2,2-difluoro-benzo[1,3]dioxol-5-yl)-1,4-dioxa-10-aza-dispiro[4.2.4.2]tetradecan-9-one (described in example 336, step 1) by treatment with 2M HCl. White solid. MS (m/e): 324.2 [MH+].
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=1)=O.[N:16]1([C:22]2[CH:23]=[CH:24][C:25]3[N:26]([C:28]([C:31]([F:34])([F:33])[F:32])=[N:29][N:30]=3)[N:27]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>>[F:34][C:31]([F:32])([F:33])[C:28]1[N:26]2[N:27]=[C:22]([N:16]3[CH2:21][CH2:20][N:19]([CH2:1][C:3]4[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][CH:4]=4)[CH2:18][CH2:17]3)[CH:23]=[CH:24][C:25]2=[N:30][N:29]=1
Reactant: CCOC(=O)/C=C/c1ccc(C=O)cc1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Product: CCOC(=O)/C=C/c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1
Yield: 59 %

Procedure:
A mixture of ethyl (E)-3-(4-formylphenyl)prop-2-enoate and 6-(piperazin-1-yl)-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 7 to give ethyl (2E)-3-[4-([4-[3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl)phenyl]prop-2-enoate in 59% yield.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[CH:6]3[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1.IC.[CH3:24]C([O-])(C)C.[Na+]>CS(C)=O>[Cl:1][C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH2:12][C:13]([F:16])([F:15])[CH3:14])[C:7](=[O:17])[C:6]3([CH3:24])[CH2:18][O:19][CH2:20][CH2:21][N:5]3[C:4]=2[N:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(F)(F)CN1C(=O)C2COCCN2c2nc(Cl)ncc21
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CI
Product: CC(F)(F)CN1C(=O)C2(C)COCCN2c2nc(Cl)ncc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.3 %

Procedure:
To a mixture of 2-chloro-5-(2,2-difluoropropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (466 mg, 1.46 mmol) and iodomethane (0.365 ml, 5.84 mmol) in DMSO (8 ml) at 0° C. was added sodium 2-methylpropan-2-olate (211 mg, 2.19 mmol). The ice-bath was removed and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was poured into water and extracted with EtOAc. The organic layers were washed with water (containing Na2S2O3), dried and concentrated in vacuo to give a crude solid. The solid was purified by silica gel chromatography (hexane/ethyl acetate, 19:1 to 2:1) to afford 2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (264 mg, 0.793 mmol, 54% yield) as a white solid. MS [M+H] found 333.
Reaction SMILES: [CH3:1][C:2]1([CH3:25])[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([OH:24])=[CH:7][CH:8]=2)[O:3]1.[H-].[Na+].[CH3:28][N:29]([CH3:33])[CH2:30][CH2:31]Cl.O>C1(C)C=CC=CC=1.CCOCC>[CH3:1][C:2]1([CH3:25])[CH:11]=[C:10]([C:12]2[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([O:22][CH3:23])[CH:18]=3)[CH:13]=2)[C:9]2[C:4](=[CH:5][C:6]([O:24][CH2:31][CH2:30][N:29]([CH3:33])[CH3:28])=[CH:7][CH:8]=2)[O:3]1
Reactant: CN(C)CCCl
Reactant: COc1ccc2cc(C3=CC(C)(C)Oc4cc(O)ccc43)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: COc1ccc2cc(C3=CC(C)(C)Oc4cc(OCCN(C)C)ccc43)ccc2c1

Procedure:
To a refluxing solution of 2,2-dimethyl-7-hydroxy-4(6-methoxy-2-naphthyl)-2H-chromene (6.4 g, 0.019 mole) and sodium hydride (1.4 g, 80% depression in oil) in toluene (150 ml) was added dropwise 2-dimethylaminoethyl chloride (2.7 g, 0.025 mole). After refluxing for 3 hours the solution was cooled and water added. The organic layer was separated and removal of the solvent gave a residue which dissolved in ether and extracted with dilute hydrochloric acid (3×). The combined acid extracts were basified with 40% sodium hydroxide solution and extracted with ether (3×). The combined ether extracts were dried and removal of the solvent gave a quantitative yield of 2,2-dimethyl-7-(2-dimethylaminoethoxy)-4(6-methoxy-2-naphthyl)-2H-chromene which was converted to the hydrochloride salt m.p. 96°-98° C.
Reaction SMILES: [H-].[Na+].[CH3:3][N:4]1[CH2:8][CH2:7][CH2:6][C@H:5]1[CH2:9][OH:10].[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23](OCC(Cl)(Cl)Cl)=[O:24])([CH3:13])[CH3:12]>C1COCC1>[CH:11]([CH:14]1[C:19]2[N:20]=[CH:21][NH:22][C:18]=2[CH2:17][CH2:16][N:15]1[C:23]([O:10][CH2:9][C@@H:5]1[CH2:6][CH2:7][CH2:8][N:4]1[CH3:3])=[O:24])([CH3:13])[CH3:12]
Reactant: CC(C)C1c2nc[nH]c2CCN1C(=O)OCC(Cl)(Cl)Cl
Reactant: CN1CCC[C@H]1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1c2nc[nH]c2CCN1C(=O)OC[C@@H]1CCCN1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 4.3 %

Procedure:
NaH (0.19 g, 5.00 mmol, 60% dispersion in mineral oil) was suspended in THF (10 mL) at 0° C. and (S)—N-methylpyrrolidine-2-methanol (0.47 mL, 4.80 mmol) was added. The suspension was stirred at 0° C. for 30 min and added to a solution of Intermediate 2 (1.33 g, 4.00 mmol) in THF (10 mL) and the reaction mixture was stirred at room temperature. An additional such portion of NaH and N-methylpyrrolidine methanol in THF was added after 8 h. After 18 h the reaction mixture was quenched with water (10 mL) and the solvents were removed in vacuo. The residue was dissolved in EtOAc (100 mL), washed with 1 M aq Na2CO3 solution (4×100 mL), dried (MgSO4) and the solvents were removed in vacuo. The residue was purified by column chromatography (normal phase, 20 g, Strata SI-1, silica gigatube, DCM (200 mL) followed by 2%, 4%, 5%, 10%, and 20% MeOH in DCM (200 mL)) and reverse phase HPLC (Phenomenex Synergi, RP-Hydro 150×10 mm, 10 μm, 15 mL per min, gradient 0% to 60% (over 12 min) to 100% (over 3 min) MeOH in water [1% formic acid]). The residue was de-salted using K2CO3 in DCM to give [(2S)-1-methylpyrrolidin-2-yl]methyl 4-isopropyl-1,4,6,7-tetrahydro-5H-imidazo[4,5-c]pyridine-5-carboxylate (52.1 mg, 4.2%) as a colourless gum.
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([OH:12])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1.[H-].[Na+].[CH2:15]([N:21]=[C:22]=[O:23])[CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>O1CCCC1>[CH3:1][N:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][C:22](=[O:23])[NH:21][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:9][CH:10]=2)[CH2:5][CH2:4][CH2:3]1
Reactant: CN1CCCc2cc(O)ccc21
Reactant: CCCCCCN=C=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCCCCCNC(=O)Oc1ccc2c(c1)CCCN2C
Reaction time: 0.33 h

Procedure:
A solution of 1-methyl-1, 2, 3, 4-tetrahydro-quinolin-6-ol (0.244 g., 1 mmol) in dry tetrahydrofuran (5 ml) was added to a stirred suspension of sodium hydride (0.024 g., 1 mmol) in dry tetrahydrofuran (5 ml) at −10° C. during 5 min. The reaction mixture was stirred for 20 min. Then hexyl isocyanate (0.26 g., 1 mmol) was added to the stirring reaction mixture. Stirring was continued for additional 2.5 hours during which the temperature was allowed to rise to room temperature (34° C.). The reaction mixture was quenched with water (0.2 ml), concentrated under vaccum, diluted with water (5 ml), extracted with chloroform (2×5 ml) and dried over sodium sulphate. The combined fractions of chloroform were concentrated under vaccum. The residue was chromatographed on silica gel using chloroform: hexane (20.80) as eluant to give 2m; yield: 0.25 g. (57.9%), m.p. 50° C., C17H26N2O2; 1H NMR δ ppm (CDCl3): 0.88 (bs, 3H), 1.26-1.54 (m, 8H), 1.96-1.99 (m, 2H), 2.71 (t, 2H), 2.85 (s, 3H), 3.14-3.25 (m, 4H), 4.90 (bs, 1H), 6.54 (d, 1H), 6.71-6.87 (m, 2H); IR vmax (KBr) (cm−1): 656, 757, 895, 1160, 1226, 1319, 1387, 1502, 1721, 2932, 1914, 2370, 2863, 3339, 3773; MS: m/z: 391 (M+).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([OH:9])=[O:8])([O-])=O.S(=O)(=O)(O)O.[CH3:21]O>[Pd]>[NH2:1][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[CH2:13][CH2:14][CH3:15])[C:7]([O:9][CH3:21])=[O:8]
Reactant: CCCc1ccc(C(=O)O)cc1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Agent: O=S(=O)(O)O
Product: CCCc1ccc(C(=O)OC)cc1N
Reaction time: 6 h

Procedure:
To 3-nitro-4-propylbenzoic acid (31.0 g) were added sulfuric acid (1.0 g) and methanol (300 ml) and the mixture was heated under reflux for 24 hr. After cooling, 5% Pd-C (0.60 g) was added to the reaction mixture and the mixture was stirred under a hydrogen atmosphere (normal pressure) for 6 hr. The reaction mixture was filtered through Celite and concentrated. To the residue was added a saturated aqueous sodium hydrogencarbonate solution, and the mixture was extracted with toluene. The toluene layer was dried over sodium sulfate and concentrated to give the object compound (28.7 g) as an brown oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:35]=[CH:34][C:6]([CH2:7][N:8]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[C:17]([F:24])=[N:18][CH:19]=[C:20]([CH:23]=3)[CH:21]=[O:22])[N:10]=2)=[CH:5][CH:4]=1.C[Si](C)(C)[C:38]([F:41])([F:40])[F:39].[F-].[Cs+]>C1COCC1>[CH3:33][O:32][C:29]1[CH:28]=[CH:27][C:26]([CH2:25][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:35][CH:34]=2)[C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]3[CH:23]=[C:20]([CH:21]([OH:22])[C:38]([F:41])([F:40])[F:39])[CH:19]=[N:18][C:17]=3[F:24])[N:10]=2)=[CH:31][CH:30]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C=O)cnc3F)n2)cc1
Reactant: C[Si](C)(C)C(F)(F)F
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(O)C(F)(F)F)cnc3F)n2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 108 %

Procedure:
To a stirred solution of 5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoronicotinaldehyde (3.7810 g, 7.99 mmol; Example 143, Step 1-2) in THF (50.00 mL) was added trimethyl(trifluoromethyl)silane (TCI America, Inc.; 1.703 g, 11.98 mmol) followed by CsF (0.243 g, 1.597 mmol) at 0° C. and the mixture was stirred at the same temperature for 10 min before warming to room temperature and stirring for 3.5 h. The reaction was quenched with 1 N HCl and stirred for another 30 min, and then EtOAc (10 mL) was added. The separated aqueous layer was extracted with ethyl acetate (2×20 mL) and the combined organic layers were washed with brine, dried over Na2SO4, and concentrated to give a brown foam residue as the desired product 1-(5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)-2,2,2-trifluoroethanol (4.69 g, 8.63 mmol, 108% yield) which was used directly for the next step.
Reaction SMILES: [CH3:1][CH:2]([C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=1[CH3:26].[CH2:27]=[O:28].S(=O)(=O)(O)O>C(O)(=O)C>[CH3:1][CH:2]([C:9]1[CH:17]=[C:13]([C:14]([OH:16])=[O:15])[C:12]([OH:18])=[CH:11][CH:10]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1.[C:20]1([CH3:19])[CH:21]=[CH:22][CH:23]=[C:24]([CH:27]=[O:28])[C:25]=1[CH3:26]
Reactant: C=O
Reactant: Cc1ccccc1C
Agent: CC(c1ccccc1)c1ccc(O)c(C(=O)O)c1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: Cc1cccc(C=O)c1C

Procedure:
To a mixture of 24.2 parts of 5-α-methylbenzylsalicylic acid, 21.2 parts of o-xylene, 8.9 parts of 37% formalin and 25 parts of acetic acid was added 4.0 parts of 95% sulfuric acid (catalyst). After being heated under reflux for 5 hours, the reaction mixture was washed with water, and unreacted o-xylene and water were removed by vacuum distillation to give 35 parts of 5-α-methylbenzylsalicylic acid-o-xylene-formaldehyde co-condensation product. 10 parts of the co-condensation product was converted into its tin salt in a similar manner as in Synthesis Example 3. There was obtained 13 parts of tin salt of 5-α-methylbenzylsalicylic acid-o-xylene-formaldehyde co-condensation product.