Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15]NS(C2C=NC=CC=2)(=O)=O)[N:10]=1)([CH3:4])([CH3:3])[CH3:2].S1C=CN=C1C1C=CC(CNS(C2C=NC=CC=2)(=O)=[O:46])=CC=1.N1C=CC(C2C=CC(CO)=CC=2)=CN=1>>[C:1]([O:5][C:6](=[O:33])[CH2:7][N:8]([C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][OH:46])[N:10]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=S(=O)(NCc1ccc(-c2nccs2)cc1)c1cccnc1
Reactant: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CNS(=O)(=O)c2cccnc2)n1
Agent: OCc1ccc(-c2ccnnc2)cc1
Product: CC(C)(C)OC(=O)CN(C(=O)OC(C)(C)C)c1cccc(CO)n1

Procedure:
Reaction and post-treatment were carried out in the same manner as in Example 2-(a) except for using tert-butyl(tert-butoxycarbonyl{6-[(pyridin-3-ylsulfonyl)aminomethyl]pyridin-2-yl}amino)acetate (158 mg, 0.330 mmol) obtained in Reference Example 12-(d) in place of N-[4-(thiazol-2-yl)benzyl]pyridin-3-ylsulfonamide, and using 4-(pyridazin-4-yl)benzyl alcohol (60.2 mg, 0.323 mmol) obtained in Reference Example 13 in place of tert-butyl[tert-butoxycarbonyl(6-hydroxymethylpyridin-2-yl)amino]acetate to afford the title compound (152 mg) as a white foam. (Yield: 73%)
Reaction SMILES: [CH:1]1[C:14]2[C:5](=[N:6][CH:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)[CH:4]=[CH:3][CH:2]=1.II.C(N(CC)CC)C.[F:24]F>S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>[F:24][C:7]1[N:6]=[C:5]2[C:14](=[C:13]3[C:8]=1[CH:9]=[CH:10][CH:11]=[CH:12]3)[CH:1]=[CH:2][CH:3]=[CH:4]2
Reactant: c1ccc2c(c1)cnc1ccccc12
Reactant: FF
Agent: II
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Fc1nc2ccccc2c2ccccc12
Yield: 35.3 %

Procedure:
A solution containing phenanthridine (1.0 g, 5.6 mmol), iodine (1.4 g, 5.6 mmol) and triethylamine (0.56 g, 5.6 mmol) in CF2ClCFCl2 (30 ml) was placed in a fluorination apparatus fitted with a drying tube filled with soda lime. Elemental fluorine (7 mmol) as a 10% mixture in dry nitrogen was then passed through the stirred solution using narrow bore PTFE tubing at ca. 15 ml/min. After the fluorine had been added the solution was poured into 10% aqueous sodium metabisulfite solution (30 ml) and extracted with dichloromethane. The organic extracts were dried and evaporated to a brown oil (0.92 g). GC/MS analysis showed a 53% conversion of starting material. Column chromatography on silica gel with dichloromethane as eluant gave 6-fluoro-phenanthridine (0.39 g, 67%), RF 0.78 (CH2Cl2); δH (400 MHz, CDCl3, Me4Si) 7.61 ppm (1H, d d d, JH1,H2 =JH2,H3 =7.8, JH2,H4 1.2, H-2), 7.69 (2H, m, H-3 and H-9), 7.88 (1H, d d d, JH7,H8 8.4, JH8,H9 7.2, JH8,H10 1.4, H-8), 7.97 (1H, d d, JH3,H4 8.0, JH2,H4 1.2, H-4), 8.21 (1H, d d, JH9,H10 8.0, JH8,H10 1.4, H-10) 8.45 (1H, d d, JH1,H2 8.0, JH1,H3 0.8, H-1), 8.52 (1H, d d, JH7,H8 8.4 JH7,H9 1.2, H-7); δF (376 MHz, CDCl3, CFCl3), 68.2 ppm (s); δC (100 MHz, CDCl3, Me4Si) 117.3 ppm (d, 2J 35.1, C-6a), 122.2 (d, 3J 3.8, C-7), 122.2 (s, C-1), 123.9 (d, 4J 1.9, C-10b), 124.2 (s, C-10), 126.5, (d, 6J 2.3, C-2), 127.9 (s, C-9), 128.7 (d, 4J 1.6, C-4), 129.4 (s, C-3), 132.1 (s, C8), 136.5 (d, 3J 7.2, C-10a), 141.5 (d, 3J 17.9, C-4a), 158.1 (d, 1J 248.7, C-6); m/z (E1+) 197 (M+, 100%).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[O:3][C:4]1[CH:5]=[C:6]([C:10]#[C:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[F:1][C:2]([F:14])([F:15])[O:3][C:4]1[CH:5]=[C:6]([CH2:10][CH2:11][CH2:12][OH:13])[CH:7]=[CH:8][CH:9]=1
Reactant: OCC#Cc1cccc(OC(F)(F)F)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: OCCCc1cccc(OC(F)(F)F)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 85 %

Procedure:
To a solution of 3-(3-(trifluoromethoxy)phenyl)prop-2-yn-1-ol (0.3 g, 1.39 mmol) in THF (10 mL) was added LAH (63 mg, 1.68 mmol) portionwise at 0° C. The reaction was stirred at 0° C. for 3 h. The reaction was carefully quenched by dropwise addition of ethyl acetate at 0° C. and the mixture was partitioned between ethyl acetate and water. The combined organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with ethyl acetate/petroleum ether (1:4 to 1:1) to give 3-(3-(trifluoromethoxy)phenyl)propan-1-ol (0.26 g, 85.2%) as a yellow oil which was used without purification. 1H-NMR (CD3OD) δ 7.37-7.39(d, 1H), 7.31-7.35(m, 1H), 7.15-7.17 (d, 1H), 4.07-4.11(t, 2H), 2.72-2.76(t, 2H), 1.83-1.90(m, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([OH:19])=O)[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4].FC1C(O)=C(F)C(F)=C(F)C=1F.Cl.[F:34][C:35]1([F:40])[CH2:39][CH2:38][NH:37][CH2:36]1.C(N1CCOCC1)C>CN(C=O)C.C(Cl)Cl.C(Cl)CCl>[CH3:1][O:2][C:3]([C:5]1[CH:14]=[C:13]([O:15][CH2:16][C:17]([N:37]2[CH2:38][CH2:39][C:35]([F:40])([F:34])[CH2:36]2)=[O:19])[C:12]2[C:7](=[CH:8][C:9]([CH3:20])=[CH:10][CH:11]=2)[N:6]=1)=[O:4]
Reactant: COC(=O)c1cc(OCC(=O)O)c2ccc(C)cc2n1
Reactant: FC1(F)CCNC1
Agent: CCN1CCOCC1
Agent: Cl
Agent: Oc1c(F)c(F)c(F)c(F)c1F
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)c1cc(OCC(=O)N2CCC(F)(F)C2)c2ccc(C)cc2n1

Procedure:
To a solution of 900 mg 4-Carboxymethoxy-7-methyl-quinoline-2-carboxylic acid methyl ester in 5 ml DMF were added 902 mg pentafluorophenol and 940 mg EDC. The mixture was stirred under exclusion of moisture until LCMS indicated complete conversion to the corresponding pentafluorophenolester. 3,3-Difluoropyrrolidine hydrochloride (455 mg) was mixed with 1.2 ml N-ethylmorpholine and 5 ml DMF and this mixture added dropwise to the solution of the pentafluorophenolester. After 12 h the reaction mixture was diluted with DCM and washed with aqueous LiCl (4%), saturated aqueous NaHCO3 and brine. The crude product obtained after evaporation of the solvent was purified by flash chromatography on silica eluting with ethyl acetate/heptane gradient. Yield: 815 mg.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[OH:20][C:21]1[CH:30]=[C:29]2[C:24]([C:25](=[O:39])[N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])[CH:27]=[N:28]2)=[CH:23][C:22]=1[O:40][CH3:41].[CH3:42][S:43]([CH2:46][CH2:47][CH2:48]O)(=[O:45])=[O:44].N(C(OCC)=O)=NC(OCC)=O>C(Cl)Cl>[CH3:41][O:40][C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][C:21]=1[O:20][CH2:48][CH2:47][CH2:46][S:43]([CH3:42])(=[O:45])=[O:44])[N:28]=[CH:27][N:26]([CH2:31][O:32][C:33](=[O:38])[C:34]([CH3:35])([CH3:36])[CH3:37])[C:25]2=[O:39]
Reactant: CS(=O)(=O)CCCO
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCS(C)(=O)=O
Yield: 90.7 %

Procedure:
Triphenylphosphine (8.9 g, 35.2 mmol) was added to a suspension of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (6 g, 19.6 mmol), (prepared as described for the starting material in Example 12), in methylene chloride (150 ml). This was followed by the addition of 3-(methylsulphonyl)-1-propanol (3.5 g, 25.4 mmol) and diethyl azodicarboxylate (5.55 ml, 35.2 mmol) in portions. The reaction was complete once the reaction became homogeneous. Silica was added and the volatiles were removed by evaporation. The free flowing powder was placed on the top of a flash chromatography column pre-equilibrated with ethyl acetate (100%). Elution was done using ethyl acetate (100%) followed by methylene chloride/ethyl acetate/methanol (60/35/5). The volatiles were removed by evaporation to give 6-methoxy-7-(3-methylsulphonylpropoxy)-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (7.58 g, 91%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([Cl:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]([N:31](C)[C:32]1[N:37]=[CH:36][C:35](B2OC(C)(C)C(C)(C)O2)=[CH:34][C:33]=1[CH3:47])(OC(C)(C)C)=O>>[Cl:21][C:16]1[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:35]5[CH:36]=[N:37][C:32]([NH:31][CH3:24])=[C:33]([CH3:47])[CH:34]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])=[CH:19][N:18]([CH3:20])[N:17]=1
Reactant: Cc1cc(B2OC(C)(C)C(C)(C)O2)cnc1N(C)C(=O)OC(C)(C)C
Reactant: Cn1cc(-n2c(=O)n(C)c3cnc4ccc(Br)cc4c32)c(Cl)n1
Product: CNc1ncc(-c2ccc3ncc4c(c3c2)n(-c2cn(C)nc2Cl)c(=O)n4C)cc1C

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(3-chloro-1-methyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate K) and 6-(N-boc-methylamino)-5-methylpyridine-3-boronic acid pinacol ester (Combi-Blocks, San Diego, USA, 58.8 mg, 0.176 mmol) to give crude boc-protected title compound that was treated for 30 min at rt with trifluoroacetic acid (0.5 ml) and then purified by prep. HPLC to give the title compound as an off-white foam. (HPLC: tR 2.24 min (Method A); M+H=434 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.92 (s, 1H), 8.40 (s, 1H), 8.14-8.12 (m, 1H), 8.05-8.03 (m, 1H), 7.90-7.85 (m, 1H), 7.38-7.37 (m, 2H), 6.28-6.20 (br, 1H), 4.01 (s, 3H), 3.58 (s, 3H), 2.88 (m, 3H), 2.11 (s, 3H))
Reaction SMILES: [CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:26][C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:28])[C:5](=[O:25])[NH:6][C@H:7]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[N:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:17])=[O:16])[CH2:9][CH:8]1[OH:24].C(N(CC)CC)C>CS(C)=O.O>[CH3:1][CH:2]([CH3:39])[CH2:3][C@H:4]([NH:26][C:27]([C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2)=[O:28])[C:5](=[O:25])[NH:6][C@H:7]1[CH2:13][CH2:12][C@@H:11]([CH3:14])[N:10]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=2)(=[O:17])=[O:16])[CH2:9][C:8]1=[O:24]
Reactant: CC(C)C[C@H](NC(=O)c1ccc2ncccc2c1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1O
Solvent: CS(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)C[C@H](NC(=O)c1ccc2ncccc2c1)C(=O)N[C@H]1CC[C@@H](C)N(S(=O)(=O)c2ccccn2)CC1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 77.1 %

Procedure:
Sulfur trioxide-pyridine complex (11 mg, 0.7 mmol) was added to a solution of quinoline-6-carboxylic acid {(S)-3-methyl-1-[(4S,7R)-7-methyl-3-hydroxy-1-(pyridine-2-sulfonyl)-azepan-4-ylcarbamoyl]-butyl}-amide (130 mg, 0.235 mmol) in DMSO (2.0 ml) and triethylamine (0.2 ml, 1.4 mmol) was stirred at RT for 1 h. The reaction was incomplete; therefore, additional triethyl amine (0.2 ml, 1.4 mmol) and sulfur trioxide-pyridine complex (11 mg, 0.7 mmol) was added and the reaction was stirred an additional hour. The reaction mixture was diluted with water, then was extracted with EtOAc. Then, the organic layer was was extracted with brine. The combined organics were dried with magnesium sulfate, filtered, concentrated in vacuo, and purified by column chromatography (3% MeOH/CH2Cl2) gave the title compound (100 mg, 77%): 1H NMR:9.0 (sm 1H), 8.70 (s, 1H), 7.90–8.30 (m, 6H), 7.50–7.55 (m, 2H), 7.10 (d, 1H), 7.0 (d, 1H), 5.10–5.15 (m, 1H), 4.70–4.80 (m,2H), 4.35–4.40 (m, 1H), 3.85 (d, 1H), 2.0–2.25 (m, 3H), 1.70–1.80 (m, 2H), 1.60–1.70 (m, 2H), 0.90–1.10 (m, 9H); Electrospray mass spec: M+H+=552.4.
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH2:13][C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1)=[N+]=[N-].[H][H]>C(O)C.[C].[Pd]>[NH2:1][CH2:4][C:5]1[N:6]([CH3:22])[C:7]([CH:13]([C:14]2[CH:19]=[C:18]([Cl:20])[CH:17]=[C:16]([Cl:21])[CH:15]=2)[C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:8]([CH:10]([CH3:12])[CH3:11])[N:9]=1
Reactant: [H][H]
Reactant: CC(C)c1nc(CN=[N+]=[N-])n(C)c1Cc1cc(Cl)cc(Cl)c1
Agent: [Pd]
Solvent: CCO
Product: CC(C)c1nc(CN)n(C)c1C(c1ccccc1)c1cc(Cl)cc(Cl)c1
Reaction time: 4 h
Yield: 110 %

Procedure:
In 8 ml of ethanol was dissolved 150 mg (0.44 mmol)of 2-azidomethyl-5-(3,5-dichlorobenzyl)-4-isopropyl-1-methyl-1H-imidazole (60), and 50 mg of 10% palladium carbon was added at -20° C. The mixture was stirred at room temperature under a stream of hydrogen. After 4 hours, the reaction mixture was filtered through Celite, and the filtrate was concentrated to give 94 mg of Compound I-101 (yield 68%).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].C[CH2:26][O:27][C:28]([CH2:30]Br)=[O:29]>CC(C)=O>[CH3:26][O:27][C:28](=[O:29])[CH2:30][O:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:18])[C:7]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:8][O:9]2)=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=c1c(-c2ccccc2)coc2cc(O)ccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)COc1ccc2c(=O)c(-c3ccccc3)coc2c1
Yield: 72.3 %

Procedure:
To a mixture of 7-Hydroxy isoflavone (35 grams, 147 mmol), anhydrous K2CO3 (84 grams, 608 mmol) in anhydrous acetone (500 mL) was added ethyl bromo acetate (29 grams, 174 mmol) and refluxed for 8 hours. Acetone was distilled and water (500 mL) was added. Crude 49 was filtered, dried, and recrystallized from toluene to give pure 49 (33 grams, 72.4%) as a white shining powder. The melting point was found to be 105-106.5° C. The structure was confirmed with IR and NMR. IHNMR (CDCl3) δ 1.31 (t, 3H,OCH2,CH3), 4.30(q, 2H, OCH2, CH3), 4.70(s, 2H,OCH2), 6.84 (d, 1H,Ar), 7.05 (dd,1H,Ar), 7.41 (m, 3H,Ar), 7.57 (m, 2H,Ar), 7.97(s, 1H, Pyran), 8.24(d,1H,Ar).
Reaction SMILES: CC(C)[C@H](N1CC2C(=CC(C3C=CC(NS(C4C=CC=CC=4)(=O)=O)=CC=3)=CC=2)C1=O)C(O)=O.[Cl:34][C:35]1[CH:36]=[C:37]([S:41]([NH:44][C:45]2[CH:50]=[CH:49][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([O:64]C)=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:47][CH:46]=2)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1>>[Cl:34][C:35]1[CH:36]=[C:37]([S:41]([NH:44][C:45]2[CH:46]=[CH:47][C:48]([C:51]3[CH:59]=[C:58]4[C:54]([CH2:55][N:56]([C@@H:61]([CH:66]([CH3:68])[CH3:67])[C:62]([OH:64])=[O:63])[C:57]4=[O:60])=[CH:53][CH:52]=3)=[CH:49][CH:50]=2)(=[O:43])=[O:42])[CH:38]=[CH:39][CH:40]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4)cc3)cc2C1=O
Agent: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4ccccc4)cc3)cc2C1=O
Product: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NS(=O)(=O)c4cccc(Cl)c4)cc3)cc2C1=O
Yield: 89 %

Procedure:
The compound of example 88 was prepared analogous to compound of example 78 by hydrolysis of compound of example 87.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1)=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2]>O1CCCC1.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[CH:18][CH:19]=1)[CH2:6][N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][NH2:16])[CH2:10][CH2:9]1
Reactant: COc1cccc(C(=O)N2CCC(CCN)CC2)c1
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: COc1cccc(CN2CCC(CCN)CC2)c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
A solution of 2-[1-(3-methoxybenzoyl)piperidin-4-yl]ethylamine (4.5 g) in tetrahydrofuran (40 ml) was added dropwise to a suspension of lithium aluminum hydride (1.63 g) in tetrahydrofuran (50 ml) under refluxing. After 30 minutes, the mixture was cooled to 0° C., and ethyl acetate (5 ml), water (2 ml), 4N sodium hydroxide (4 ml), water (2 ml) and magnesium sulfate were added thereto successively. The resulting precipitates were removed out by filtration and the filtrate was evaporated in vacuo. The residue was chromagographed on alumina eluting with 2% methanol in chloroform to give 2-[1-(3-methoxybenzyl)piperidin-4-yl]ethylamine (1.8 g) as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:21](O)=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)=[O:8].CN.O.O[N:30]1[C:34]2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.Cl>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([OH:25])=[C:6]([CH:24]=1)[C:7]([NH:9][C:10]1[S:11][C:12]([C:21]([NH:30][CH3:34])=[O:22])=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[N:14]=1)=[O:8]
Reactant: On1nnc2ccccc21
Reactant: O=C(Nc1nc(-c2ccccc2)c(C(=O)O)s1)c1cc(Br)ccc1O
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)c1sc(NC(=O)c2cc(Br)ccc2O)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 42.4 %

Procedure:
A mixture of 2-(5-bromo-2-hydroxybenzoyl)amino-4-phenylthiazole-5-carboxylic acid (0.20 g, 0.48 mmol), methylamine 40% methanol solution (0.2 ml), 1-hydroxybenzotriazole hydrate (96.7 mg, 0.72 mmol), WSC.HCl (137.2 mg, 0.72 mmol) and tetrahydrofuran (15 mL) was stirred at room temperature for 18 hours. The reaction mixture was poured into 2N hydrochloric acid and extracted with ethyl acetate. After the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, the residue obtained by evaporation under reduced pressure was purified by chromatography on silica gel (n-hexane:ethyl acetate=1:2), and crystallized (dichloromethane/n-hexane) to give the title compound (87.9 mg, 42.6%) as a white powder.
Reaction SMILES: Cl[C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3.[OH:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH2:22]>>[OH:19][C:20]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[C:21]=1[NH:22][C:2]1[CH:17]=[C:6]2[C:7]3[C:12]([CH2:13][CH2:14][N:5]2[C:4](=[O:18])[N:3]=1)=[CH:11][C:10]([O:15][CH3:16])=[CH:9][CH:8]=3
Reactant: Cc1cccc(O)c1N
Reactant: COc1ccc2c(c1)CCn1c-2cc(Cl)nc1=O
Product: COc1ccc2c(c1)CCn1c-2cc(Nc2c(C)cccc2O)nc1=O

Procedure:
The title compound was prepared from 2-chloro-9-methoxy-6,7-dihydro-pyrimido[6,1-a]isoquinolin-4-one (4) and 2-hydroxy-6-methyl-aniline as in Example 1 d. 1H-NMR (400 MHz, d6-DMSO, at 60° C.) δ 9.39 (br, 1H), 8.60 (br, 1H), 7.61 (br, 1H), 7.05-6.95 (3H), 6.75 (d, 1H), 6.73 (d, 1H), 6.34 (br, 1H), 3.95 (t, 2H), 3.83 (s, 3H), 2.95 (t, 2H), and 2.19 (s, 3H); MS (ESI) (M+H)+ 350.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[CH3:9][N:10]([CH3:20])[C:11]1[N:16]=[CH:15][C:14](B(O)O)=[CH:13][CH:12]=1.C(N(CC)CC)C>ClC1C=C[C-](P(C2C=CC=CC=2)C2C=CC=CC=2)C=1Cl.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd].C(Cl)Cl.COCCOC>[Cl:1][C:2]1[N:7]=[C:6]([C:14]2[CH:15]=[N:16][C:11]([N:10]([CH3:20])[CH3:9])=[CH:12][CH:13]=2)[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: CN(C)c1ccc(B(O)O)cn1
Agent: [Fe+2]
Agent: [Pd]
Agent: Clc1cc[c-](P(c2ccccc2)c2ccccc2)c1Cl
Solvent: COCCOC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1ccc(-c2ccnc(Cl)n2)cn1
Temperature: 90 °C
Yield: 71.2 %

Procedure:
A flask containing 2,4-dichloropyrimidine (0.5 g, 3.35 mmol), [6-(dimethylamino)pyridin-3-yl]boronic acid (0.61 g, 3.67 mmol) and DME (10 mL) was purged with N2 for 10 min. Dichloro[1,1′-bis(diphenylphosphino)]ferrocene-palladium CH2Cl2 adduct (0.37 g, 0.50 mmol) and triethylamine (0.85 g, 1.17 mL, 8.33 mmol) were added successively to the flask with continuous bubbling of N2 including 5 min. post addition of the reagents. The reaction mixture was stirred and heated at 90° C. for 5 h. Reaction progress was monitored by TLC (silica gel). The reaction mixture was concentrated and diluted with water, wherein a tan solid formed. The solid was filtered, dried and purified by silica gel column chromatography using 50% EtOAc/hexanes as eluent to provide 2-chloro-4-(6-dimethylaminopyridin-3-yl)pyrimidine as a white solid (0.56 g, 71%); 1H NMR (DMSO-d6): δ 8.91 (s, 1H), 8.60 (d, 1H, J=5.3 Hz), 8.20 (dd, 1H, J=2.3 and 9.1 Hz), 7.95 (d, 1H, J=5.3 Hz), 6.74 (d, 1H, J=9.1 Hz), 3.11 (s, 3H). LCMS: purity: 98%; MS (m/e): 235 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[C:4]([F:11])[C:3]=1[N:12]1[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]#[N:21])[C:13]1=[O:22].[Cl-].[NH4+].C(O)C.C(=O)([O-])O.[Na+]>[Fe].O>[NH2:8][C:6]1[CH:5]=[C:4]([F:11])[C:3]([N:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[C:14]([C:20]#[N:21])[C:13]2=[O:22])=[C:2]([F:1])[CH:7]=1
Reactant: COc1ccn(-c2c(F)cc([N+](=O)[O-])cc2F)c(=O)c1C#N
Agent: [Fe]
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: O
Solvent: CCO
Product: COc1ccn(-c2c(F)cc(N)cc2F)c(=O)c1C#N
Temperature: 90 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
To a mixture of 1-(2,6-difluoro-4-nitrophenyl)-4-methoxy-2-oxo-1,2-dihydropyridine-3-carbonitrile obtained in Step A (3.00 g), ammonium chloride (5.22 g), ethanol (48 mL) and water (12 mL) was added iron powder (2.18 g) at room temperature, and the reaction mixture was heated at 90° C. for 1 hr. The reaction mixture was cooled to room temperature, and slowly poured into saturated sodium hydrogen carbonate solution, and the mixture was extracted with a mixed solvent of tetrahydrofuran/ethyl acetate=3/1. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. To the residue was added isopropyl ether (10 mL), and the mixture was stirred for 15 min. The precipitate was collected by filtration to give the title compound (1.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].Cl[CH2:13][CH2:14][OH:15].[OH-].[Na+]>CS(C)=O>[OH:15][CH2:14][CH2:13][O:11][C:3]1[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Nc1ccc([N+](=O)[O-])cc1OCCO
Temperature: 110 °C
Reaction time: 2.5 h
Yield: 58.1 %

Procedure:
A mixture of 2-amino-5-nitrophenol (1, 30 g), 2-chloroethanol (24.2 g) and sodium hydroxide (powdered, 12 g) in DMSO (100 ml) was stirred for 2.5 h at 110° C. The mixture was poured onto crushed ice (200 g) and the dark yellow precipitate was filtered, washed with H2O three times. Recrystallization from ethanol gave 22.4 g (58%) of 2: mp 140°-142° C.; MS m/e 198 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C@@H:27]3[CH2:31][CH2:30][N:29]([N:32]4[CH2:37][CH2:36][CH:35]([O:38][Si](C(C)C)(C(C)C)C(C)C)[CH2:34][CH2:33]4)[C:28]3=[O:49])=[CH:22][CH:21]=2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]([F:19])([F:18])[F:17])[CH2:12][CH2:11]1)=[O:9].C1COCC1.O.C(O)(C(F)(F)F)=O>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:20]2[CH:21]=[CH:22][C:23]([CH2:26][C@@H:27]3[CH2:31][CH2:30][N:29]([N:32]4[CH2:33][CH2:34][CH:35]([OH:38])[CH2:36][CH2:37]4)[C:28]3=[O:49])=[CH:24][CH:25]=2)[CH:5]=[CH:6][C:7]=1[C:8]([N:10]1[CH2:11][CH2:12][CH:13]([C:16]([F:18])([F:19])[F:17])[CH2:14][CH2:15]1)=[O:9]
Reactant: CC(C)[Si](OC1CCN(N2CC[C@@H](Cc3ccc(-c4ccc(C(=O)N5CCC(C(F)(F)F)CC5)c(Cl)c4)cc3)C2=O)CC1)(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: O=C(c1ccc(-c2ccc(C[C@@H]3CCN(N4CCC(O)CC4)C3=O)cc2)cc1Cl)N1CCC(C(F)(F)F)CC1
Yield: 53.2 %

Procedure:
Treat a mixture of (R)-3-[3′-chloro-4′-(4-trifluoromethyl-piperidine-1-carbonyl)-biphenyl-4-ylmethyl]-1-(4-triisopropylsilanyloxy-piperidin-1-yl)-pyrrolidin-2-one (0.12 g), THF (3 mL) and water (3 mL) with TFA (1 mL) at room temperature for 5 hours. Dilute the reaction with ethyl acetate and wash with sodium bicarbonate (sat.). Dry the organic layer (Na2SO4), remove the solvent in vacuo to afford crude product, and purify on silica gel column with 100% ethyl acetate and 10% methanol in methylene chloride to afford 0.05 g (53%) of the titled product. MS (m/z): 564 (M+).