Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1](O)([C:3](F)(F)F)=[O:2].OC(C(F)(F)F)=O.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[C:23]1[N:24]=[C:25]([N:43]2[CH2:48][C@@H:47]([CH3:49])[NH:46][CH2:45][C@@H:44]2[CH3:50])[C:26]2[CH2:32][N:31]([C:33]3[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=3[CH3:42])[CH2:30][CH2:29][C:27]=2[N:28]=1.CCN(C(C)C)C(C)C.CC(OC(C)=O)=O>CCOC(C)=O.C(Cl)Cl>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]=1[C:23]1[N:24]=[C:25]([N:43]2[C@H:44]([CH3:50])[CH2:45][N:46]([C:1](=[O:2])[CH3:3])[C@@H:47]([CH3:49])[CH2:48]2)[C:26]2[CH2:32][N:31]([C:33]3[CH:38]=[C:37]([CH:39]([CH3:41])[CH3:40])[CH:36]=[CH:35][C:34]=3[CH3:42])[CH2:30][CH2:29][C:27]=2[N:28]=1
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccc(C(C)C)cc1N1CCc2nc(-c3c(C)cccc3C)nc(N3C[C@@H](C)NC[C@@H]3C)c2C1
Solvent: CCOC(C)=O
Solvent: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N1C[C@@H](C)N(c2nc(-c3c(C)cccc3C)nc3c2CN(c2cc(C(C)C)ccc2C)CC3)C[C@@H]1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of the TFA salt of 2-(2,6-dimethylphenyl)-4-((trans)-2,5-dimethylpiperazin-1-yl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine TFA salt (0.113 g, 0.233 mmol), DIEA (0.33 mL, 1.87 mmol) and DCM (5 mL) was added Ac2O (0.044 mL, 0.467 mmol). The reaction was stirred at rt for 1 h before being diluted with EtOAc. The solution was washed with sat aq NaHCO3 and then brine before the organic layers were separated and then dried (Na2SO4), filtered and concentrated. The residue was then purified by FCC (35-45% EtOAc/heptane) to give racemic-1-(4-(2-(2,6-dimethylphenyl)-6-(5-isopropyl-2-methylphenyl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidin-4-yl)-(trans)-2,5-dimethylpiperazin-1-yl)ethanone. 1H NMR (400 MHz, DMSO-d6, at 100° C.) δ ppm 7.14-7.19 (m, 1 H) 7.05-7.12 (m, 3 H) 6.91 (d, J=1.39 Hz, 1 H) 6.86 (dd, J=7.71, 1.52 Hz, 1 H) 4.29 (dt, J=6.22, 3.27 Hz, 1 H) 4.12-4.18 (m, 1 H) 4.00-4.07 (m, 1 H) 3.50-3.58 (m, 1 H) 3.41-3.47 (m, 1 H) 3.39 (t, J=6.19 Hz, 2 H) 2.93 (br. s., 4 H) 2.84 (dt, J=13.80, 6.93 Hz, 1 H) 2.52 (br. s., 1 H) 2.25 (s, 3 H) 2.08 (s, 6 H) 2.01 (s, 3 H) 1.19 (dd, J=6.95, 2.40 Hz, 6 H) 1.10-1.17 (m, 6 H); MS (ESI+) m/z 526.4 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([CH2:13][C:14](OCC)=O)[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].C1C[O:28]CC1>>[CH2:1]([N:8]1[CH:12]=[C:11]([CH:13]([OH:28])[CH3:14])[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)Cc1cn(Cc2ccccc2)cn1
Reactant: C1CCOC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CC(O)c1cn(Cc2ccccc2)cn1
Reaction time: 1 h

Procedure:
A solution of 25-2 (4.6 g, 18.8 mmol) in THF (50 mL) at ambient temperature was treated dropwise with LiAlH4 (9.4 mL, 9.4 mmol, 1M in THF). After stirring for 1 hour the reaction was quenched with a saturated sodium potassium tartrate solution. The mixture was then poured into EtOAc and washed with H2O and brine, dried (MgSO4) and concentrated to yield 25-3 as a yellow oil.
Reaction SMILES: [OH-].[K+].[Cl:3][C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=2)[C:5]=1[CH2:16][CH2:17][CH:18](O)[CH2:19][CH:20]([OH:26])[CH2:21][C:22]([O:24]C)=[O:23]>O.CO.C1(C)C=CC=CC=1>[Cl:3][C:4]1[CH:13]=[C:12]([Cl:14])[C:11]2[C:6](=[CH:7][C:8]([Cl:15])=[CH:9][CH:10]=2)[C:5]=1[CH2:16][CH2:17][C@@H:18]1[O:24][C:22](=[O:23])[CH2:21][C@@H:20]([OH:26])[CH2:19]1
Reactant: COC(=O)CC(O)CC(O)CCc1c(Cl)cc(Cl)c2ccc(Cl)cc12
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Solvent: O
Product: O=C1C[C@@H](O)C[C@H](CCc2c(Cl)cc(Cl)c3ccc(Cl)cc23)O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.5 %

Procedure:
A solution of potassium hydroxide (0.1 g, 1.5 mmole) in water (2 ml) was added dropwise to a solution of methyl 7-(2,4,7-trichloronaphthalene-1-yl)-3,5-dihydroxyheptanoate (0.22 g, 0.7 mmole) in methanol (10 ml) with cooling (ice bath). The bath was removed and the reaction mixture stirred at room temperature for one hour and then concentrated in vacuo. The residue was diluted with ice and water, acidified with dilute aqueous HCl and extracted with ether. The ether extracts were combined, washed with water and brine and dried over MgSO4. The ether solution was filtered and concentrated in vacuo to give a yellow oil, which was taken up in toluene (75 ml). After heating at reflux for 4 hours, using a Soxhlet Apparatus containing molecular sieves, the toluene solution was concentrated in vacuo to give a viscous yellow oil (0.2 g). This material was chromatographed using a 30 mm flash column containing 50 g of silica gel (230-400 mesh) eluting with 5% acetone in methylene chloride (v/v) to give 0.035 g of the title compound as a white crystalline solid, mp 111°-115° C.
Reaction SMILES: [F:1][CH:2](F)[C:3](C(OCC)=O)([CH3:11])[C:4]([O:6][C:7](C)(C)[CH3:8])=[O:5]>FC(F)(F)C(O)=O>[CH3:11]/[C:3](=[CH:2]\[F:1])/[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)(C(=O)OC(C)(C)C)C(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)/C(C)=C/F

Procedure:
A solution of tert-butyl 2-difluoromethyl-2-carbethoxypropionate (392 g) (prepared in Step B) in trifluoroacetic acid (TFA) (400 ml) is stirred at room temperature for several hours, then the excess TFA is removed by evaporation at reduced pressure. The residue is treated with carbon tetrachloride and re-evaporated.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:10].CN1CCOCC1.Cl[C:33]([O:35][CH3:36])=[O:34].O>CC1CCCO1>[CH3:36][O:35][C:33]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([NH:11][CH:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][CH2:13]1)=[O:10])=[O:34]
Reactant: Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1
Reactant: COC(=O)Cl
Solvent: CC1CCCO1
Solvent: O
Solvent: CN1CCOCC1
Product: COC(=O)Nc1ccccc1CC(=O)NC1CCN(Cc2ccccc2)CC1
Temperature: -12 °C
Reaction time: 1 h

Procedure:
50 ml of 2-methyltetrahydrofuran are distilled off from the solution consisting of 9.15 g (28.29 mmol, 1.0 eq) 2-amino-N-[1-(phenylmethyl)-4-piperidinyl]-phenylacetamide in 162 ml of 2-methyltetrahydrofuran. The solution is cooled to −12° C. and 4.56 g (45.10 mmol, 1.6 eq) 4-methylmorpholine are added, followed by 4.26 g (45.10 mmol, 1.6 eq) methyl chloroformate. The reaction mixture is stirred for another 1 hour at 20° C. and then combined with 100 ml of water. After phase separation the aqueous phase is washed with 20 ml 2-methyltetrahydrofuran and the combined organic phases are washed with 50 ml of water. The organic solvent is distilled off in vacuo. The residue is combined with 50 ml of acetone and refluxed. Then 100 ml of water are added and the suspension obtained is cooled to 20° C. To complete the crystallisation the mixture is stirred for 30 minutes at 20° C. Then the product is suction filtered, washed with 30 ml acetone-water mixture (1:2) and dried in the dryer at 45° C. while being rendered inert.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[C:14]([O:20][CH2:21]Cl)(=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[N:9][N:8]([CH2:21][O:20][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)(C)C(=O)OCCl
Reactant: Brc1cnc2[nH]nc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)C(=O)OCn1nc(I)c2cc(Br)cnc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 69 %

Procedure:
5-Bromo-3-iodo-1H-pyrazolo[3,4-b]pyridine (3.00 g, 9.26 mmol) was dissolved in N,N-dimethylformamide (150 ml) at 4° C. To the solution was added sodium hydride (60%, 519 mg, 12.98 mmol) in small portions. The flask was warmed to room temperature and stirred for 1 hour. To the mixture was added chloromethyl pivalate (2.29 ml, 15.78 mmol). The reaction mixture was stirred for 2 hours at room temperature, and quenched with methanol. Saturated ammonium chloride solution was added, and the mixture was concentrated in vacuo. The residue was dissolved in dichloromethane, and the organic layer was washed four times with. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was dissolved in acetone. The solution was filtered and the solid material collected was discarded. The filtrate was concentrated in vacuo. The crude material was re-crystallized in ether to give 2.80 g (69%) of 2,2-dimethyl-propionic acid 5-bromo-3-iodo-pyrazolo[3,4-b]pyridin-1-ylmethyl ester. 1H-NMR (250 MHz, DMSO-d6) δ 8.63 (s, 1H), 8.20 (s, 1H), 6.43 (s, 2H), 1.14 (s, 9H); MS m/z 437.8, 439.8 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]1([C:34]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42]O)[N:37]=[CH:36]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:50]1([C:34]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:35]2[CH:39]=[C:38]([CH2:40][CH2:41][CH2:42][O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)[N:37]=[CH:36]2)[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1
Reactant: Oc1ccc(F)cc1
Reactant: OCCCc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Fc1ccc(OCCCc2cn(C(c3ccccc3)(c3ccccc3)c3ccccc3)cn2)cc1
Reaction time: 0.08 h

Procedure:
5 ml of freshly distilled tetrahydrofuran, 120 mg (1 mmol) of 4-fluorophenol and 270 mg (1 mmol) of triphenylphosphine are added, under nitrogen, to 368 mg (1 mmol) of 1-triphenylmethyl-4-(3-hydroxypropyl)-1H-imidazole. The resulting mixture is cooled and stirred for 5 min. 180 mg (1 mmol) of diethyl azodicarboxylate in 5 ml of tetrahydrofuran are then slowly added. Stirring is continued at room temperature for 3 days under nitrogen. The solvent is then evaporated under reduced pressure and the residue is subjected to chromatography on a column of silica gel, using diethyl ether as eluent, to give 1-triphenylmethyl-4-[3-(4-fluorophenoxy)propyl]-1H-imidazole.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=2)=[CH:5][CH:4]=1.[F:29][C:30]1[CH:37]=[CH:36][C:33]([NH:34][CH3:35])=[CH:32][CH:31]=1>>[F:29][C:30]1[CH:37]=[CH:36][C:33]([N:34]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([C:9]3[C:10]([NH:15][S:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[C:25]([F:28])([F:27])[F:26])(=[O:18])=[O:17])=[N:11][CH:12]=[CH:13][N:14]=3)=[CH:5][CH:4]=2)[CH3:35])=[CH:32][CH:31]=1
Reactant: CNc1ccc(F)cc1
Reactant: O=S(=O)(Nc1nccnc1-c1ccc(CCl)cc1)c1ccccc1C(F)(F)F
Product: CN(Cc1ccc(-c2nccnc2NS(=O)(=O)c2ccccc2C(F)(F)F)cc1)c1ccc(F)cc1
Yield: 78 %

Procedure:
Following the general method as outlined in Example 1 (Method B), starting from N-{3-[4-(chloromethyl)phenyl]pyrazin-2-yl}-2-(trifluoromethyl)benzenesulfonamide (Intermediate 9), and 4-Fluoro-N-methylaniline, the title compound was isolated as a yellow solid in 78% yield (98% purity by HPLC).
Reaction SMILES: [CH:1]([C:4]1[C:13]([OH:14])=[C:12]([CH:15]([CH3:17])[CH3:16])[CH:11]=[C:10]2[C:5]=1[CH2:6][CH2:7][C:8]([CH3:21])([C:18]([OH:20])=[O:19])[O:9]2)([CH3:3])[CH3:2].C(N1C=CN=C1)(N1C=CN=C1)=O.O[C@@H:35]1[C@H:41]([C:42]2[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=2)[S:40][C:39]2[C:50]3[C:55]([CH:56]=[CH:57][C:38]=2[N:37]([CH2:58][CH2:59][N:60]([CH3:62])[CH3:61])[C:36]1=[O:63])=[CH:54][CH:53]=[CH:52][CH:51]=3>O1CCCC1.CN(C)C1C=CN=CC=1>[OH:14][C:13]1[C:12]([CH:15]([CH3:16])[CH3:17])=[CH:11][C:10]2[O:9][C:8]([C:18]([O:20][CH:35]3[CH:41]([C:42]4[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=4)[S:40][C:39]4[C:50]5[C:55]([CH:56]=[CH:57][C:38]=4[N:37]([CH2:58][CH2:59][N:60]([CH3:62])[CH3:61])[C:36]3=[O:63])=[CH:54][CH:53]=[CH:52][CH:51]=5)=[O:19])([CH3:21])[CH2:7][CH2:6][C:5]=2[C:4]=1[CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)c1cc2c(c(C(C)C)c1O)CCC(C)(C(=O)O)O2
Reactant: COc1ccc([C@@H]2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)[C@@H]2O)cc1
Agent: CN(C)c1ccncc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: COc1ccc(C2Sc3c(ccc4ccccc34)N(CCN(C)C)C(=O)C2OC(=O)C2(C)CCc3c(cc(C(C)C)c(O)c3C(C)C)O2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 1.4 g (0.0048 mol) of (±)-5,7-diisopropyl-6-hydroxy-2-methylchroman-2-carboxylic acid in 25 ml dry tetrahydrofuran was added 0.09 g (0.0055 mol) of 1,1'-carbonyldiimidazol. After stirring at room temperature for 30 minutes, 2.0 g (0.0047 mol) (±)-cis-2,3-dihydro-3-hydroxy-2-(4-methoxyphenyl)-5-[2-(dimethylamino)ethyl]naphtho[1,2-b][1,4]thiazepin-4(5H)-one and 20 mg of 4-dimethylaminopyridine were added. The reaction mixture was stirred at room temperature for 17 hours, concentrated to dryness and the residue was partitioned between ethyl acetate and dilute ammonium hydroxide. The combined ethyl acetate solutions were washed with brine, dried (MgSO4) and the solvent was removed under reduced pressure. The residue was dissolved in acetonitrile and chromatographed on 70 g silica gel. The column was eluted with 75 ml portions of acetonitrile. Fractions 5-8 were combined and the solvent removed to give 1.3 g (40%) of isomer "A" as an amorphous solid, [α]D25 -74.31° (C 1.03, MeOH).
Reaction SMILES: [C:1]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([O:31]C)=[O:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[OH-].[Na+].O>CO>[C:1]([C:20]1[C:28]2[C:23](=[CH:24][C:25]([C:29]([OH:31])=[O:30])=[CH:26][CH:27]=2)[NH:22][CH:21]=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)OC)ccc12
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCCCCCCCCCC(=O)c1c[nH]c2cc(C(=O)O)ccc12
Temperature: 25 °C
Yield: 82.2 %

Procedure:
Methyl 3-(n-octadecanoyl)indole-6-carboxylate (35.2 g) in methanol (1620 ml), containing sodium hydroxide (32 g) and water (49 ml), was stirred and refluxed for 2 hours. The solution was cooled to room temperature and the solid was collected. The solid was suspended in water (500 ml) and aqueous hydrochloric acid (20 ml, of strength 36% w/v) was added to the suspension with rapid stirring. The solid was collected and was recrystallised from glacial acetic acid to give 3-(n-octadecanoyl)indole-6-carboxylic acid (28 g), in the form of a white solid, m.p. 268°-270° C.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=2)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])O1.Br[C:26]1[C:34]2[C:29](=[N:30][CH:31]=[CH:32][C:33]=2[Cl:35])[N:28]([S:36]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)(=[O:38])=[O:37])[CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>>[Cl:35][C:33]1[CH:32]=[CH:31][N:30]=[C:29]2[N:28]([S:36]([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)(=[O:38])=[O:37])[CH:27]=[C:26]([C:9]3[CH:10]=[C:11]([CH:21]=[CH:22][CH:23]=3)[CH2:12][NH:13][C:14](=[O:20])[O:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:34]=12
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ccnc21
Reactant: CC(C)(C)OC(=O)NCc1cccc(B2OC(C)(C)C(C)(C)O2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)(C)OC(=O)NCc1cccc(-c2cn(S(=O)(=O)c3ccccc3)c3nccc(Cl)c23)c1
Temperature: 90 °C
Yield: 40.4 %

Procedure:
tert-butyl 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzylcarbamate (333 mg, 1.0 mmol), 3-bromo-4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine (372 mg, 1.0 mmol), potassium carbonate (270 mg, 2 mmol) and PdCl2(dppf)CH2Cl2 (41 mg, 0.05 mmol) were added to a reaction flask which was purged thoroughly with N2. 10 ml of dried dioxane was added via syringe and the reaction was heated to 90° C. for overnight. After LC-MS showed the reaction was complete, the solution was then cooled to room temperature and filtered and concentrated. The residue was purified by chromatography (0-50% EtOAc:hexane), giving 201 mg of tert-butyl 3-(4-chloro-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)benzylcarbamate as a white solid, yield: 40.4%.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:14]2OCC[O:15]2)[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.O>C1(C)C(C)=CC=CC=1>[O:1]([C:8]1[CH:9]=[C:10]([CH:11]=[CH:12][CH:13]=1)[CH:14]=[O:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(Oc2cccc(C3OCCO3)c2)cc1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: Cc1ccccc1C
Product: O=Cc1cccc(Oc2ccccc2)c1
Yield: 71 %

Procedure:
As a starting material a solution of crude 2-(3-phenoxyphenyl)-1,3-dioxolane obtained in Example 7 after neutralization is used. The solution in xylene is boiled with a mixture of 48 ml. of concentrated sulfuric acid and 530 ml. of water with stirring for 3 hours. Upon cooling the phases are separated. 211 g. (71%) of 3-phenoxybenzaldehyde are obtained, boiling at 128° to 130° C./0.4 mmHg. The yield is calculated for the starting material of Example 7. The purity of the obtained product is better than 95% (determined by gas chromatography);
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[C:8]([O:20][CH3:21])=[CH:9][C:10]([C:18]#[N:19])=[C:11]([N:13]=[CH:14][N:15](C)C)[CH:12]=1.C(O)(=O)C.N[C:27]1[CH:31]=[C:30]([CH2:32][C:33]([OH:35])=[O:34])[NH:29][N:28]=1>C(O)C>[Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[C:11]2[C:10]([C:18]([NH:19][C:27]3[CH:31]=[C:30]([CH2:32][C:33]([OH:35])=[O:34])[NH:29][N:28]=3)=[N:15][CH:14]=[N:13]2)=[CH:9][C:8]=1[O:20][CH3:21]
Reactant: Nc1cc(CC(=O)O)[nH]n1
Reactant: COc1cc(C#N)c(N=CN(C)C)cc1OCCCCCl
Solvent: CCO
Solvent: CC(=O)O
Product: COc1cc2c(Nc3cc(CC(=O)O)[nH]n3)ncnc2cc1OCCCCCl
Reaction time: 1 h
Yield: 73.9 %

Procedure:
N′-[5-(4-chlorobutoxy)-2-cyano-4-methoxyphenyl]-N,N-dimethylimidoformamide (464 g, 15 mmol) in acetic acid (13.5 ml, 225 mmol) was reacted with (3-amino-1H-pyrazol-5-yl)acetic acid (2.22 g, 15.8 mmol) at reflux for 1 hour. The mixture was cooled, diluted with ethanol (25 ml) and the resultant precipitate recovered by suction filtration. The solid was stirred in water for 1 hour, collected by suction filtration and dried to yield (3-([7-(4-chlorobutoxy)-6-methoxyquinazolin-4-yl]amino)-1H-pyrazol-5-yl)acetic acid (4.5 g, 74% yield):
Reaction SMILES: CO[C:3](=[C:10]1[C:18]2[C:13](=[CH:14][C:15]3[O:21][CH2:20][O:19][C:16]=3[CH:17]=2)[NH:12][C:11]1=[O:22])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:23][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1)[CH3:25]>>[CH3:25][N:24]([CH2:26][C:27]1[CH:33]=[CH:32][C:30]([NH:31]/[C:3](=[C:10]2\[C:11](=[O:22])[NH:12][C:13]3[C:18]\2=[CH:17][C:16]2[O:19][CH2:20][O:21][C:15]=2[CH:14]=3)/[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH:29][CH:28]=1)[CH3:23]
Reactant: CN(C)Cc1ccc(N)cc1
Reactant: COC(=C1C(=O)Nc2cc3c(cc21)OCO3)c1ccccc1
Product: CN(C)Cc1ccc(N/C(=C2\C(=O)Nc3cc4c(cc32)OCO4)c2ccccc2)cc1

Procedure:
Prepared from 3-(1-methoxy-1-phenyl-methylidene)-5,6-methylenedioxy-2-indolinone and 4-(dimethylaminomethyl)-aniline
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:17]=1.Cl[C:19]1[N:24]=[CH:23][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:21][N:20]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:11]3[CH2:16][CH2:15][N:14]([C:19]4[N:24]=[CH:23][C:22]([CH:25]5[CH2:27][CH2:26]5)=[CH:21][N:20]=4)[CH2:13][CH2:12]3)([CH3:10])[CH2:7][C:6]=2[CH:17]=1
Reactant: Clc1ncc(C2CC2)cn1
Reactant: CC1(C2CCNCC2)Cc2cc(Br)ccc2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC1(C2CCN(c3ncc(C4CC4)cn3)CC2)Cc2cc(Br)ccc2O1
Temperature: 90 °C
Yield: 75 %

Procedure:
A mixture of 4-(5-bromo-2-methyl-2,3-dihydrobenzofuran-2-yl)piperidine (0.3 g, 1.013 mmol), 2-chloro-5-cyclopropylpyrimidine (0.204 g, 1.317 mmol) and K2CO3 (0.42 g, 3.04 mmol) in DMF (5 mL) was heated in 90° C. oil bath overnight. At the conclusion of this period, the reaction mixture was cooled to room temperature, quenched with H2O (5 mL), and then extracted with EtOAc (3×5 mL). The combined organic layers were washed with H2O (3×5 mL) and brine (5 mL). The organic layer was separated, dried (Na2SO4), filtered, and concentrated to yield a residue. The residue was purified by column chromatography (silica gel, hexanes/EtOAc gradient 0 to 35% EtOAc) to afford Compound 11E as white solid (0.315 g, 31% yield). LC/MS (m/z)=414 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[NH:33]1[CH2:40][CH2:39][CH2:38][C@@H:34]1[C:35]([OH:37])=[O:36]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:33]3[CH2:40][CH2:39][CH2:38][CH:34]3[C:35]([OH:37])=[O:36])[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: O=C(O)[C@H]1CCCN1
Agent: OC1CCNC1
Product: COc1ccccc1Sc1ccc(-c2ccnc(N3CCCC3C(=O)O)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with (D)-proline. A yellow solid 100 was obtained (0.0366 g, 78%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:13][CH2:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.[Mg].[F:15][C:16]([F:24])([F:23])[C:17](=[O:22])[CH:18]=[C:19]([CH3:21])[CH3:20]>C1COCC1.[Cu]I>[O:9]1[CH2:10][CH2:11][CH2:12][O:13][CH:8]1[C:4]1[CH:3]=[C:2]([C:19]([CH3:21])([CH3:20])[CH2:18][C:17](=[O:22])[C:16]([F:24])([F:23])[F:15])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCCO2)c1
Reactant: CC(C)=CC(=O)C(F)(F)F
Agent: [Cu]I
Agent: [Mg]
Solvent: C1CCOC1
Product: CC(C)(CC(=O)C(F)(F)F)c1cccc(C2OCCCO2)c1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A solution of the Grignard reagent (generated from the reaction of 2-(3-bromophenyl)-[1,3]dioxane with magnesium turnings in THF, 0.25 M, 52.6 mL, 13.1 mmol) was treated with copper (I) iodide (2.5 g, 13.1 mmol) at 0° C. After 45 minutes, 1,1,1-trifluoro-4-methylpent-3-en-2-one (2 g, 13.1 mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred overnight. The mixture was quenched with aqueous saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with aqueous saturated sodium chloride solution, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was triturated with hexanes and filtered. The filtrate was concentrated in vacuo to give 1.78 g of the crude product, which was used without purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])[C:5]([Cl:20])=[CH:4][N:3]=1.[CH3:21][O:22][C:23]1[N:28]=[C:27]([CH:29]=O)[CH:26]=[CH:25][CH:24]=1.C([O-])(=O)C.[NH4+]>>[Cl:20][C:5]1[C:6]([NH:9][C@@H:10]2[C@@H:15]3[CH2:16][C@@H:12]([CH:13]=[CH:14]3)[C@@H:11]2[C:17]([NH2:19])=[O:18])=[C:7]2[N:8]=[C:29]([C:27]3[CH:26]=[CH:25][CH:24]=[C:23]([O:22][CH3:21])[N:28]=3)[NH:1][C:2]2=[N:3][CH:4]=1
Reactant: NC(=O)[C@@H]1[C@H](Nc2c(Cl)cnc(N)c2N)[C@H]2C=C[C@@H]1C2
Reactant: COc1cccc(C=O)n1
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1cccc(-c2nc3c(N[C@H]4[C@@H](C(N)=O)[C@@H]5C=C[C@H]4C5)c(Cl)cnc3[nH]2)n1
Yield: 15.8 %

Procedure:
In a similar fashion to Compound LXXXVII, (1S,2S,3R,4R)-3-(2,3-Diamino-5-chloro-pyridin-4-ylamino)-bicyclo[2.2.1]hept-5-ene-2-carboxylic acid amide (50.00 mg, 0.1702 mmol), 6-Methoxy-pyridine-2-carbaldehyde (25.7 mg, 0.187 mmol), and Ammonium acetate (26.2 mg, 0.340 mmol) were reacted to produce 11.03 mg (19%) of the title compound. (300 MHz, DMSO-d6) 13.30 (s, 1H), 8.01 (s, 1H), 7.89 (t, J=15 Hz, 7.5 Hz, 1H), 7.79 (m, 2H), 7.30 (d, J=9 Hz, 1H), 7.25 (s, 1H), 6.90 (d, J=8 Hz, 1H), 6.44 (s, 1H), 6.37 (s, 1H), 5.17 (t, J=17 Hz, J=9 Hz, 1H), 4.06 (s, 3H), 2.90 (s, 1H), 2.82 (s, 1H), 2.63 (d, J=8 Hz, 1H), 2.24 (d, J=8 Hz, 1H), 1.39 (d, J=8 Hz, 1H). MS=411 (M+H), HPLC: 2.53 min. (G Method)