Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C@@H:14]([OH:20])[CH:15]=[CH:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1.C(C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Pd].C1CCCCC1>[CH3:1][N:2]1[C@@H:18]2[CH2:19][C:7]3[CH:8]=[CH:9][C:10]([O:21][CH3:22])=[C:11]4[O:12][C@H:13]5[C:14]([CH2:15][CH2:16][C@@H:17]2[C@:5]5([C:6]=34)[CH2:4][CH2:3]1)=[O:20]
Reactant: COc1ccc2c3c1O[C@H]1[C@@H](O)C=C[C@H]4[C@@H](C2)N(C)CC[C@@]341
Agent: [Pd]
Agent: O=C(c1ccccc1)c1ccccc1
Solvent: C1CCCCC1
Product: COc1ccc2c3c1O[C@H]1C(=O)CC[C@H]4[C@@H](C2)N(C)CC[C@]314
Temperature: 25 °C
Yield: 90 %

Procedure:
Codeine (11.71 g), benzophenone (48.32 g), 5% palladium on carbon wet (67% water) catalyst (0.37 g), and cyclohexane (57 mL) were charged into a stainless steel autoclave. The autoclave was evacuated and filled with hydrogen. The mixture was mechanically agitated at ambient temperature (25–29° C.) while the hydrogen pressure was maintained at 19–38 psi until the pressure drop caused by the hydrogen consumption stopped. Cyclohexane (120 mL) was charged into the autoclave followed by solid potassium tert-butylate (16.22 g), the mixture was mechanically agitated under nitrogen at ambient temperature for overnight, and then quenched with 1.5N acetic acid (150 mL) with mixing and cooling in the ice bath. The mixture was filtered, aqueous layer was separated and the organic layer was extracted with 1.5N acetic acid (5 mL). Combined aqueous layer was washed with isopropyl acetate (12 mL) and assayed by HPLC. Aqueous solution (176 mL) contains 58.4 mg/mL hydrocodone (90% yield), purity 96 area %.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][C:8]2[C:17]3[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[CH2:3][CH2:2]1.CS(O[CH2:24][CH2:25][O:26][C:27]1[CH:36]=[CH:35][CH:34]=[C:33]2[C:28]=1[CH:29]=[N:30][C:31]([CH3:37])=[N:32]2)(=O)=O>>[CH3:37][C:31]1[N:30]=[CH:29][C:28]2[C:33](=[CH:34][CH:35]=[CH:36][C:27]=2[O:26][CH2:25][CH2:24][N:1]2[CH2:6][CH2:5][CH:4]([CH2:7][C:8]3[C:17]4[O:16][CH2:15][C:14](=[O:18])[NH:13][C:12]=4[CH:11]=[CH:10][CH:9]=3)[CH2:3][CH2:2]2)[N:32]=1
Reactant: O=C1COc2c(CC3CCNCC3)cccc2N1
Reactant: Cc1ncc2c(OCCOS(C)(=O)=O)cccc2n1
Product: Cc1ncc2c(OCCN3CCC(Cc4cccc5c4OCC(=O)N5)CC3)cccc2n1

Procedure:
The title compound was prepared from 8-(piperidin-4-ylmethyl)-4H-benzo[1,4]oxazin-3-one and 5-(2-(methanesulphonyloxy)ethoxy)-2-methylquinazoline in a similar manner to Example 1.
Reaction SMILES: ClC1C=CC(C(F)(F)F)=CC=1[NH2:4].C(O[CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19])C>C1(OC2C=CC=CC=2)C=CC=CC=1>[NH2:4][CH:16]=[C:17]([C:23]([O:25][CH2:26][CH3:27])=[O:24])[C:18]([O:20][CH2:21][CH3:22])=[O:19]
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Reactant: Nc1cc(C(F)(F)F)ccc1Cl
Solvent: c1ccc(Oc2ccccc2)cc1
Product: CCOC(=O)C(=CN)C(=O)OCC
Temperature: 190 °C

Procedure:
A mixture of 2-chloro-5-trifluoromethylaniline (3.91 g) and diethyl ethoxymethylenemalonate (4.0 mL) is heated at 190° C. for 2 h and is then diluted with diphenyl ether (30 mL). The mixture is allowed to cool to rt, filtered, and the white solid is washed with hexane (2×10 mL) to afford 1.632 g of the diethyl amino-methylenemalonate. The resulting intermediate (2.63 g) is suspended in diphenyl ether (30 mL) and heated to reflux with a Dean-Stark trap for 3 h. The mixture is allowed to cool to rft and is then poured into hexane (50 mL). The solid is filtered and then washed with hexane (20 mL) and hexane/diethyl ether (1/1, 20 mL) to afford 1.273 g of the quinolinecarboxylate ethyl ester. Te he ester (4 00 mg) and 4-chlorobenzylamine (1.52 mL) are heated at 190° C. for 1 h. The resulting mixture is diluted with toluene (4 mL), allowed to cool to rt, and then poured into hexane (50 mL). The solvent is decanted and the remaining oil is crystallized (acetic acid, water) to afford 285 mg of the title compound as a brown solid.
Reaction SMILES: [C:1]1([NH:7][C:8](=[O:12])[CH2:9][C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:13][C:14]1[CH:15]=[C:16]([CH:19]=[CH:20][C:21]=1[OH:22])[CH:17]=O>>[C:1]1([NH:7][C:8](=[O:12])[C:9]([C:10]#[N:11])=[CH:17][C:16]2[CH:19]=[CH:20][C:21]([OH:22])=[C:14]([OH:13])[CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: O=Cc1ccc(O)c(O)c1
Reactant: N#CCC(=O)Nc1ccccc1
Product: N#CC(=Cc1ccc(O)c(O)c1)C(=O)Nc1ccccc1

Procedure:
Following the procedure as set forth in Example 6 above, N-phenylcyanoacetamide was condensed with 3,4-dihydroxybenzaldehyde to yield the title compound, m.p. 258° C.
Reaction SMILES: [NH2:1][CH2:2][C@H:3]1[C@@H:8]([CH2:9]/[CH:10]=[CH:11]\[CH2:12][CH2:13][CH2:14][C:15]([OH:17])=[O:16])[CH2:7][O:6][C@@H:5]([CH3:18])[O:4]1.[C:19]1([N:25]=[C:26]=[O:27])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.O>N1C=CC=CC=1.C(OCC)(=O)C>[C:15]([CH2:14][CH2:13][CH2:12]/[CH:11]=[CH:10]\[CH2:9][C@H:8]1[CH2:7][O:6][C@@H:5]([CH3:18])[O:4][C@H:3]1[CH2:2][NH:1][C:26]([NH:25][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:27])([OH:17])=[O:16]
Reactant: O=C=Nc1ccccc1
Reactant: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CN)O1
Solvent: O
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: C[C@@H]1OC[C@H](C/C=C\CCCC(=O)O)[C@H](CNC(=O)Nc2ccccc2)O1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2R,4R,5S)-4-aminomethyl-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-1,3-dioxane (50 mg) in pyridine (0.5 ml) was added phenylisocyanate (0.1 ml) and stirred at room temperature for 1 hour. To this mixture water (1 ml) was added and stirred for 2 hours. The reaction mixture was diluted with ethyl acetate and the organic layer was washed with 1N hydrochloric acid. The organic layer was evaporated in vacuo and the crude residue was purified with preparative TLC to give (2R,4R,5S)-5-[(Z)-6-carboxy-2-hexenyl]-2-methyl-4-(3-phenylureidomethyl)-1,3-dioxane (27 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[OH:24].C(S(C1C=C(C2C=CC(O[CH2:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52])=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[Cl:1][C:2]1[CH:26]=[N:25][C:5]2[NH:6][C:7]3[C:12]([C:4]=2[CH:3]=1)=[C:11]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([S:19]([CH2:22][CH3:23])(=[O:21])=[O:20])[CH:14]=1)[CH:10]=[CH:9][C:8]=3[O:24][CH2:48][CH2:49][CH2:50][N:51]([CH3:53])[CH3:52]
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(C)cc4c23)c1
Reactant: CCS(=O)(=O)c1cccc(-c2ccc(O)c3[nH]c4ncc(Cl)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2ccc(OCCCN(C)C)c3[nH]c4ncc(Cl)cc4c23)c1

Procedure:
The title compound was prepared from Compound 218 by using an analogous procedure to that outlined in the preparation of Compound 205. 1H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1 H) 8.15(m, 1 H) 8.07 (m, 1 H) 7.97 (m, 1 H) 7.88 (t, J=8.0 Hz, 1 H) 7.66 (s, 1 H) 7.23 (d, J=8.36 Hz, 1 H) 7.16 (d, J=8.36 Hz, 1 H) 4.44 (t, J=5.8 Hz, 2 H) 3.72 (t, J=8.0 Hz, 2 H) 3.43 (q, J=7.32 Hz, 2 H) 3.03 (s, 6 H) 2.41 (m, 2 H) 1.34 (t, J=7.32 Hz, 3 H). [M+H] calc'd for C24H27ClN3O3S, 472; found, 472.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[C:7](Br)[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][CH3:27])[C:21]=1B(O)O>>[NH2:1][C:2]1[C:11]2[C:6](=[C:7]([C:21]3[C:22]([O:26][CH3:27])=[CH:23][CH:24]=[CH:25][C:20]=3[Cl:19])[CH:8]=[CH:9][CH:10]=2)[N:5]=[N:4][C:3]=1[C:13]([NH:15][CH2:16][CH2:17][CH3:18])=[O:14]
Reactant: COc1cccc(Cl)c1B(O)O
Reactant: CCCNC(=O)c1nnc2c(Br)cccc2c1N
Product: CCCNC(=O)c1nnc2c(-c3c(Cl)cccc3OC)cccc2c1N
Yield: 36.5 %

Procedure:
Using Method G, 4-amino-8-bromo-N-propyl-cinnoline-3-carboxamide (600 mg) and 2-chloro-6-methoxy-phenylboronic acid (1051 mg) were reacted to afford the title compound (263 mg) as a off-white solid. 1H NMR (300 MHz, CDCl3) δ 8.55(br, 1H), 7.94-7.88 (m, 1H), 7.79-7.65 (m, 2H), 7.37-7.29 (m, 1H), 7.15 (m, 1H), 6.94 (m, 1H), 3.65 (s, 3H), 3.44 (apparent quartet, J=7.0 Hz, 2H), 1.64 (apparent sextet, J=7.0 Hz, 2H), 0.99 (t, J=7.0 Hz, 3H). MS APCI, m/z=371 (M+H) HPLC 1.86 min.
Reaction SMILES: [NH2:1][CH2:2][C@@H:3]1[CH2:8][C@H:7]2[C@H:5]([CH2:6]2)[N:4]1[C:9]([C:11]1[N:12]=[C:13]([CH3:23])[S:14][C:15]=1[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[CH:17]=1)=[O:10].[CH3:24][N:25]1[C:33]2[C:28](=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:27]([C:34](O)=[O:35])=[C:26]1[CH3:37]>>[F:22][C:18]1[CH:17]=[C:16]([C:15]2[S:14][C:13]([CH3:23])=[N:12][C:11]=2[C:9]([N:4]2[C@H:3]([CH2:2][NH:1][C:34]([C:27]3[C:28]4[C:33](=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:25]([CH3:24])[C:26]=3[CH3:37])=[O:35])[CH2:8][C@H:7]3[C@@H:5]2[CH2:6]3)=[O:10])[CH:21]=[CH:20][CH:19]=1
Reactant: Cc1nc(C(=O)N2[C@H](CN)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1
Reactant: Cc1c(C(=O)O)c2ccccc2n1C
Product: Cc1nc(C(=O)N2[C@H](CNC(=O)c3c(C)n(C)c4ccccc34)C[C@@H]3C[C@@H]32)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [(1S,3S,5S)-3-aminomethyl-2-aza-bicyclo[3.1.0]hex-2-yl]-[5-(3-fluoro-phenyl)-2-methyl-thiazol-4-yl]-methanone with 1,2-dimethyl-1H-indole-3-carboxylic acid. LC-MS (basic): tR=0.90 min; [M+H]+=503.2.
Reaction SMILES: CS[C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1.[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][OH:29]>>[Cl:24][C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:28][O:29][C:3]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)[C:6]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[Cl:23])=[CH:5][N:4]=1
Reactant: CSc1ncc(-c2ccc(Cl)cc2Cl)c(-c2ccc(Cl)cc2)n1
Reactant: OCc1ccc(Cl)c(Cl)c1
Product: Clc1ccc(-c2nc(OCc3ccc(Cl)c(Cl)c3)ncc2-c2ccc(Cl)cc2Cl)cc1

Procedure:
2-Methylthio-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine from Reference Example 3 was reacted with 3,4-dichlorobenzyl alcohol according to the procedure described in Example 59 to afford 2-(3,4-dichlorobenzyloxy)-4-(4-chlorophenyl)-5-(2,4-dichlorophenyl)pyrimidine (HRf): HPLC/MS: m/e=509 (M++1); Rt=5.14 min; 1H-NMR 400 MHz (CDCl3): δ 5.56 (s, 2H), 7.12 (d, J=9 Hz, 1H), 7.22-7.25 (m, 4H), 7.27-7.40 (m, 3H), 7.28 (m, 1H), 7.68 (d, J=2 Hz, 1H), 8.45 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[N:19](S(C3C=CC(C)=CC=3)(=O)=O)[CH:18]=2)[N:11]=1.[Li+].[OH-]>C1COCC1.CCOC(C)=O>[NH2:1][C@@H:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C@H:3]1[CH2:8][NH:9][C:10]1[C:15]([F:16])=[CH:14][N:13]=[C:12]([C:17]2[C:25]3[C:20](=[N:21][CH:22]=[C:23]([Cl:26])[CH:24]=3)[NH:19][CH:18]=2)[N:11]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NC[C@@H]4CCCC[C@H]4N)n3)c3cc(Cl)cnc32)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N[C@@H]1CCCC[C@H]1CNc1nc(-c2c[nH]c3ncc(Cl)cc23)ncc1F
Reaction time: 0.08 h
Yield: 33 %

Procedure:
A solution of N-((trans-2-aminocyclohexyl)methyl)-2-(5-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-5-fluoropyrimidin-4-amine, 14f, (0.050 g, 0.077 mmol) in THF was treated with LiOH (0.5 mL, 1.0M) at 60° C. After 5 min, at 120° C., the solution was diluted with EtOAc, and washed with brine, filtered and concentrated in vacuo. Preparative HPLC provided the desired compound, 555, as a racemic mixture of trans isomers (12 mg, 33% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:13])[NH:7][C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15]
Reactant: O=c1[nH]c(=O)c2ccc(Cl)cc2[nH]1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=c1[nH]c(=O)c2cc([N+](=O)[O-])c(Cl)cc2[nH]1
Temperature: 100 °C
Yield: 54 %

Procedure:
20 g (101.7 mmol) 7-chloro-1,2,3,4-tetrahydroquinazoline-2,4-dione were dissolved in 100 ml of conc. sulphuric acid and treated with 7 ml of conc. nitric acid. The mixture was heated to 100° C. for 10 min. After cooling the reaction mixture was poured on to ice-water. The precipitate was filtered off, dried in a high vacuum and recrystallized from acetic acid. 13.3 g (54%) of 7-chloro-6-nitro-1,2,3,4-tetrahydroquinazoline-2,4-dione were obtained as beige crystals;
Reaction SMILES: C([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[CH:6]=1)C.C([O-])([O-])=O.[K+].[K+].C(I)CCCCCCC>CC(C)=O.C1OCCOCCOCCOCCOCCOC1>[OH:11][C:9]1[CH:10]=[C:5]([CH:6]=[C:7]([OH:12])[CH:8]=1)[C:4]([OH:13])=[O:3]
Reactant: CCOC(=O)c1cc(O)cc(O)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CCCCCCCCI
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Product: O=C(O)c1cc(O)cc(O)c1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 62.7 %

Procedure:
Ethyl-3,5-dihydroxybenzoate 1a (27.3 g, 150 mmol) was dissolved in acetone (750 mL). To this solution were added K2CO3 (20.7 g, 150 mmol) and 18-Crown-6 (1.9 g, 7.5 mmol) and stirred for 5 min. To this mixture, C8H17I (21.7 mL, 120 mmol) was added and stirred to reflux for 7 h. The reaction mixture was then cooled to room temperature and the solvent was evaporated to dryness. To this residue, water and ethyl acetate were added and stirred for 30 min. The organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water and brine solution. The organic layer was evaporated to dry ness and purified by silica gel column chromatography (3-4% ethyl acetate in dichloromethane) to afford 14.5 g (33% yield) of 4. The major by-product of this reaction is the compound, where two octyl groups are added to the two phenolic groups of compound 1a. 1H NMR (400 MHz, CDCl3) δ 7.14 (s, 2H), 6.6 (t, J=2.2 Hz, 1H), 5.32 (s, 1H), 4.35 (q, J=7.2 Hz, 2H), 3.95 (t, J=6.6 Hz, 2H), 1.80-1.73 (quintet, 2H), 1.46-1.28 (m, 13H), 0.88 (t, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 160.3, 156.8, 132.0, 109.0, 107.8, 106.9, 68.3, 61.3, 31.7, 29.3, 29.2, 29.1, 25.9, 22.6, 14.2, 14.0; GC/MS (m/z, r.i): 294 (M+, 68), 249 (12), 182 (100), 167 (8), 137 (25), 110 (12), 69 (12), 57 (8).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].C[O:8][C:9](=O)[C:10]1[C:15]([O:16][CH3:17])=[CH:14][C:13]([C:18]2[C:23]([CH2:24][CH3:25])=[CH:22][CH:21]=[CH:20][C:19]=2[CH2:26][CH3:27])=[N:12][CH:11]=1>C1COCC1.CCOCC>[CH2:26]([C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:24][CH3:25])[C:18]=1[C:13]1[N:12]=[CH:11][C:10]([CH2:9][OH:8])=[C:15]([O:16][CH3:17])[CH:14]=1)[CH3:27]
Reactant: CCc1cccc(CC)c1-c1cc(OC)c(C(=O)OC)cn1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cccc(CC)c1-c1cc(OC)c(CO)cn1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A solution of LiAlH4 (1 M in THF, 15 mL) is added dropwise to a solution of 6-(2,6-diethyl-phenyl)-4-methoxy-nicotinic acid methyl ester (1.5 g, 5 mmol) in THF (10 mL). The reaction mixture is stirred at room temperature for 6 hours, then diluted with ether (10 mL) and quenched with Na2SO4.10H2O (10 g). The resulting mixture is stirred for one hour, filtered through celite and concentrated to give [6-(2,6-diethyl-phenyl)-4-methoxy-pyridin-3-yl]-methanol. 1H NMR (CDCl3) 8.47 (s, 1H), 7.28 (t, 1H), 7.13 (d, 2H), 6.79 (s, 1H), 4.72 (s, 2H), 3.89 (s, 3H), 2.55 (br, 1H), 2.34 (m, 4H), 1.06 (t, 6H).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[N:11][CH2:12][CH:13](OC)OC)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[OH-].[Na+]>S(=O)(=O)(O)O>[CH:1]([C:4]1[CH:9]=[C:8]2[C:7](=[CH:6][CH:5]=1)[CH:10]=[N:11][CH:12]=[CH:13]2)([CH3:3])[CH3:2]
Reactant: COC(CN=Cc1ccc(C(C)C)cc1)OC
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: CC(C)c1ccc2cnccc2c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 5.5 %

Procedure:
N-[(4-isopropylphenyl)methylene]-2,2-dimethoxyethanamine (5.0 g) was added to hot concentrated sulfuric acid (50 ml) at 140° C. dropwise over a period of 10 min. The mixture was stirred at this temperature for additional 10 min and cooled to RT. The mixture was basified with an aqueous solution of NaOH and the product was extracted with MTBE (6×75 ml). The combined organic layers were dried (MgSO4) and evaporated under reduced pressure. The residue was purified by flash chromatography on silica (pet. ether/EtOAc 9/1) to afford the titled compound as a solid (200 mg, 15%). TLC—Chloroform/methanol: (9.5/0.5): Rf=0.55. 1H NMR (CDCl3, 400 MHz) δ 1.28 (6H, d), 3.10 (1H, m), 7.49 (1H, d), 7.53 (2H, m), 7.89 (1H, d), 8.49 (1H, d), 9.19 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7]O.S(Cl)([Cl:13])=O>C1(C)C=CC=CC=1.N1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:10])=[C:6]([CH:9]=1)[CH2:7][Cl:13]
Reactant: O=S(Cl)Cl
Reactant: OCc1cc(Br)ccc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: ClCc1cc(Br)ccc1Cl
Temperature: 100 °C

Procedure:
To a solution of 5-bromo-2-chlorobenzyl alcohol (10.66 g) in toluene (100 ml) solution were added thionyl chloride (10 ml), and pyridine (2 drops), and the mixture was stirred under heating at 100° C. overnight. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, a 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorobenzyl chloride as pale yellow crystals, which was used in the subsequent step without further purification. (2) The above 5-bromo-2-chlorobenzyl chloride was dissolved in acetonitrile (100 ml), and the mixture was cooled to 0° C. Added thereto was tetraethylammonium cyanide (8.8 g), and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure, and the residue was dissolved in ethyl acetate. The solution was washed successively with water, 10% aqueous hydrochloric acid solution, a saturated aqueous sodium hydrogen carbonate solution and brine, and dried over sodium sulfate. The solvent was evaporated under reduced pressure to give 5-bromo-2-chlorophenylacetonitrile as a pale yellow solid, which was used in the subsequent step without further purification. (3) The above 5-bromo-2-chlorophenylacetonitrile was added to water (90 ml)-sulfuric acid (75 ml), and the mixture was stirred under heating at 160° C. overnight. The mixture was further diluted with water, and cooled to 0° C. The solvent was removed by decant, and the residue was dissolved in diethyl ether. The solution was washed with water and brine, and extracted with 10% sodium hydroxide. To the extract was added concentrated hydrochloric acid to make the solution acidic. The precipitates were collected by filtration, and purified by silica gel column chromatography (chloroform) to give 5-bromo-2-chlorophenylacetic acid (6.67 g) as colorless crystals. ESI-Mass m/Z 247/249 (M−H). (4) The above 5-bromo-2-chlorophenylacetic acid was treated in a manner similar to Reference Example 118-(4) and (5) to give the desired 5-bromo-2-chloro-1-(2-(5-phenyl-2-thienyl)ethyl)benzene as a pale yellow solid. APCI-Mass m/Z 377/379 (M+H).
Reaction SMILES: [CH3:1][Li].[C:3]([C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)(=[O:5])[CH3:4]>C(OCC)C.C1COCC1>[N:9]1[CH:10]=[CH:11][C:6]([C:3]([OH:5])([CH3:1])[CH3:4])=[CH:7][CH:8]=1
Reactant: CC(=O)c1ccncc1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(O)c1ccncc1
Yield: 45 %

Procedure:
A solution of methyllithium (1.4 M; 30 ml, 42 mmol) in diethyl ether was added dropwise to a stirred solution of 4-acetylpyridine (4.65 ml, 42 mmol) in dry THF (100 ml) at -76° C., and the deep blue solution allowed to reach ambient temperature. After 24 hours the mixture was partitioned between ether and saturated aqueous sodium bicarbonate, and the ether phase was concentrated. Chromatography, on elution with ethyl acetate-dichloromethane-triethylamine 60:40:1, gave the title compound (2.59 g, 45%) as an oil. 1H-NMR (CDCl3) δ1.58 (6H, s, CMe2), 7.40 (2H, d, J 6.2 Hz, Py 3 and 5-H), 8.55 (2H, d, J 6.2 Hz, Py 2 and 6-H); MS m/z 137 (M+).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][C:16]=2[CH2:25][NH:26][CH2:27][CH3:28])[CH:7]=1)[CH3:2].Cl[C:31]([O:33][CH3:34])=[O:32]>>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][C:16]=2[CH2:25][N:26]([CH2:27][CH3:28])[C:31]([O:33][CH3:34])=[O:32])[CH:7]=1)[CH3:2]
Reactant: COC(=O)Cl
Reactant: CCNCc1cc(C(F)(F)F)ccc1Oc1cc(CC(=O)OCC)ccc1OC
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc(C(F)(F)F)cc2CN(CC)C(=O)OC)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 3, using the following starting materials: [3-(2-ethylaminomethyl-4-trifluoromethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and methyl chloroformate.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[C:15]2[C:10]([C:11]([NH:19][C:20]3[CH:25]=[C:24]([O:26][CH3:27])[C:23]([Cl:28])=[CH:22][C:21]=3[Cl:29])=[C:12]([C:17]#[N:18])[CH:13]=[N:14]2)=[CH:9][C:8]=1[O:30][CH3:31])(=O)=O.[CH:34]([C:36]1[O:37][CH:38]=[C:39](B(O)O)[CH:40]=1)=[O:35]>COCCOC.C(=O)(O)[O-].[Na+]>[Cl:29][C:21]1[CH:22]=[C:23]([Cl:28])[C:24]([O:26][CH3:27])=[CH:25][C:20]=1[NH:19][C:11]1[C:10]2[C:15](=[CH:16][C:7]([C:39]3[CH:40]=[C:36]([CH:34]=[O:35])[O:37][CH:38]=3)=[C:8]([O:30][CH3:31])[CH:9]=2)[N:14]=[CH:13][C:12]=1[C:17]#[N:18]
Reactant: O=Cc1cc(B(O)O)co1
Reactant: COc1cc(Nc2c(C#N)cnc3cc(OS(=O)(=O)C(F)(F)F)c(OC)cc23)c(Cl)cc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: COCCOC
Product: COc1cc(Nc2c(C#N)cnc3cc(-c4coc(C=O)c4)c(OC)cc23)c(Cl)cc1Cl
Temperature: 25 °C
Yield: 96.5 %

Procedure:
A mixture of 3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl trifluoromethanesulfonate (835 mg, 1.60 mmol), 2-formyl-4-furan boronic acid (446 mg, 3.21 mmol), and tetrakis(triphenylphosphine)pallidium (0) (20 mg) in 40 mL of ethylene glycol dimethyl ether and 25 mL of saturated aqueous sodium bicarbonate is heated at reflux for 3 hours and then cooled to room temperature. The reaction mixture is partitioned between dichloromethane and water. The aqueous layer is extracted with 10% methanol in ethyl acetate. The organic layers are combined, dried over magnesium sulfate, filtered and concentrated in vacuo. Diethyl ether is added to the residue and the solid is collected by filtration to provide 723 mg of 4-[(2,4-dichloro-5-methoxyphenyl)amino]-7-(5-formyl-3-furyl)-6-methoxy-3-quinolinecarbonitrile as a light yellow solid, mp 238-241° C.; 1H NMR (DMSO-d6) δ 3.88 (s, 3H), 4.09 (s, 3H), 7.38 (s, 1H), 7.76 (s, 1H), 8.01 (s, 1H), 8.29 (broad s, 2H), 8.48 (s, 1H), 8.77 (s, 1H), 9.71 (s, 1H), 9.87 (s, 1H); MS 468.0, 470.0 (M+H)+; HRMS calcd: 468.05124, found: 468.0511 (M+H)+.
Reaction SMILES: C(OC(N1CC2C(C[N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:31][CH2:30][O:29][CH2:28][CH2:27]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13]2)C1)=O)(C)(C)C.Cl.[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][C:43]2([CH2:50]CN[CH2:47][CH2:46]2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]>>[C:34]([O:38][C:39]([N:41]1[CH2:45][CH2:44][C:43]2([CH2:46][CH2:47][N:12]([CH2:16][C:17]3[S:25][C:24]4[C:23]([N:26]5[CH2:27][CH2:28][O:29][CH2:30][CH2:31]5)=[N:22][C:21]([Cl:32])=[N:20][C:19]=4[CH:18]=3)[CH2:13][CH2:50]2)[CH2:42]1)=[O:40])([CH3:37])([CH3:36])[CH3:35]
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Reactant: CC(C)(C)OC(=O)N1CCC2(CCNCC2)C1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC2(CCN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2)C1

Procedure:
Prepared according to the method used in the preparation of 5-(2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-6-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 2,8-diaza-spiro[4.5]decane-2-carboxylic acid tert-butyl ester hydrochloride in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a tan solid (104 mg, 71%).