Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:17][CH2:16][C@H:15]([C:18]([O:20]C)=[O:19])[CH2:14][CH2:13]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][CH2:23][CH3:24].Cl>C1COCC1.CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:13][CH2:14][C@H:15]([C:18]([OH:20])=[O:19])[CH2:16][CH2:17]2)(=[O:10])=[O:9])=[CH:4][C:3]=1[NH:22][CH2:23][CH3:24]
Reactant: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)OC)CC2)ccc1Cl
Agent: Cl
Solvent: CO
Solvent: C1CCOC1
Product: CCNc1cc(S(=O)(=O)N[C@H]2CC[C@H](C(=O)O)CC2)ccc1Cl
Temperature: 25 °C

Procedure:
Methyl trans-4-(4-chloro-3-(ethylamino)phenylsulfonamido)cyclohexane-carboxylate (Intermediate 12, 220 mg, 0.552 mmol) in 1/1/1 THF/MeOH/1N LiOH was warmed to 45° C. overnight. The reaction was cooled to room temperature, then acidified to pH 3 with 1N HCl and extracted with multiple volumes EtOAc. The combined organic layers were dried over sodium sulfate, filtered and concentrated to give the title compound as colorless solid (169 mg, 0.468 mmol, 85% yield). MS MH+ 361.2
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([CH3:11])[C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].Br[CH2:15][CH2:16][O:17][CH3:18]>CN(C=O)C>[CH3:18][O:17][CH2:16][CH2:15][O:10][C:9]1[C:8]([CH3:11])=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cc(C=O)cc(C)c1O
Reactant: COCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1c(C)cc(C=O)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 75.6 %

Procedure:
To a solution of 3,5-dimethyl-4-hydroxy benzaldehyde (2.0 g, 13.33 mmol) in DMF was added NaH (640 mg, 16.0 mmol, 60% in oil) and the mixture was stirred for 1 h at room temperature. A solution of 1-bromo-2-methoxy ethane (1.85 g, 13.33 mmol) was added and the mixture was stirred for 72 h at room temperature. The reaction mixture was quenched by addition of saturated NH4Cl solution and diluted with water. The product was extracted with ethyl acetate. The combined organic layers were washed with water, brine and dried over Na2SO4. Upon removal of solvent, it gave 2.1 g of 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (76 yield). To a solution of 2-amino-4,6-dimethoxy-benzamide (200 mg, 1.02 mmol) and 4-(2-methoxy ethoxy)-3,5-dimethyl benzaldehyde (212 mg, 1.02 mmol) in N,N-dimethyl acetamide (10 mL), NaHSO3 (199 mg, 1.12 mmol) and p-TSA (22 mg, 0.102 mmol) were added and the reaction mixture was heated at 150° C. for 3 h. Cooled to room temperature and the solvent was evaporated under reduced pressure. The residue was diluted with water and the solid was collected to give the crude product. The crude product was purified by chromatography using 2% MeOH in CH2Cl2 to give 5,7-dimethoxy-2-(4-(2-methoxyethoxy)-3,5-dimethylphenyl)quinazolin-4(3H)-one (170 mg, 43%). Selected data: MS (ES) m/z: 385.10; MP 201-202° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8].[CH3:13][N:14](C=O)C>C(OCC)(=O)C.O>[C:13]([C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=[O:11])[CH:5]=[CH:6][C:7]=1[F:8])#[N:14]
Reactant: CN(C)C=O
Reactant: O=C(O)Cc1ccc(F)c(Br)c1
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1cc(CC(=O)O)ccc1F
Temperature: 130 °C
Reaction time: 12 h
Yield: 73 %

Procedure:
2-(3-Bromo-4-fluorophenyl)acetic acid (64 g, 275 mmol) was diluted with DMF (400 mL) followed by the addition of Cu(I)CN (49 g, 549 mmol). The reaction was heated to 130° C. and stirred for 12 hours. The reaction was allowed to cool and diluted with ethyl acetate and water, and the mixture was filtered. The organic layer was washed with water, 1N HCl, water and the brine. The organic layer was dried over MgSO4, filtered and concentrated to yield 2-(3-cyano-4-fluorophenyl)acetic acid (36 g, 73% yield) as light yellow oil that solidified to a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1.C([O-])(=O)C.[K+].[Br:26]Br>C(O)(=O)C.O>[Cl:1][C:2]1[C:7]([NH:8][C:9]([C:11]2[C:12]([NH:17][CH2:18][CH3:19])=[N:13][CH:14]=[C:15]([Br:26])[CH:16]=2)=[O:10])=[CH:6][CH:5]=[C:4]([Cl:20])[N:3]=1
Reactant: BrBr
Reactant: CCNc1ncccc1C(=O)Nc1ccc(Cl)nc1Cl
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CCNc1ncc(Br)cc1C(=O)Nc1ccc(Cl)nc1Cl
Reaction time: 0.25 h
Yield: 91.4 %

Procedure:
To a solution of N-(2,6-dichloro-3-pyridinyl)-2-ethylamino-3-pyridinecarboxamide (7.4 g, 24 mmol) and potassium acetate (2.8 g, 28 mmol) in 90 mL of acetic acid was added bromine (1.2 mL, 23 mmol). After 15 min, the reaction mixture was diluted with water and the precipitate was collected by suction filtration to give 8.2 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[NH2:7].[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([CH3:23])[C:19](=O)[CH2:20]Br)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1>CCO>[CH2:8]([O:15][C:16](=[O:24])[NH:17][CH:18]([C:19]1[N:7]=[C:2]2[N:3]=[CH:4][CH:5]=[CH:6][N:1]2[CH:20]=1)[CH3:23])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CC(NC(=O)OCc1ccccc1)C(=O)CBr
Reactant: Nc1ncccn1
Solvent: CCO
Product: CC(NC(=O)OCc1ccccc1)c1cn2cccnc2n1
Temperature: 25 °C

Procedure:
A mixture of pyrimidin-2-ylamine (3 gm, 31.5 mmol) and (3-bromo-1-methyl-2-oxopropyl)-carbamic acid benzyl ester (9.4 gm, 31.54 mmol) in EtOH (20 mL) was heated to reflux overnight. After completion, the reaction mixture was cooled to rt and EtOH was removed in vacuo. The residue was dissolved in EtOAc and washed with satd. sodium bicarbonate solution. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purified by column chromatography using silica gel (100-200 mesh) and 0-5% MeOH in DCM to provide (1-imidazo[1,2-a]pyrimidin-2-yl-ethyl)-carbamic acid benzyl ester: LC-MS (ESI) m/z 297.1 [M+H]+.
Reaction SMILES: [CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[NH:11][C:10](/[CH:15]=[CH:16]/[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3].[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[CH2:1]([N:4]1[C:13](=[O:14])[C:12]2[N:11]([CH3:26])[C:10](/[CH:15]=[CH:16]/[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)=[N:9][C:8]=2[N:7]([CH2:23][CH2:24][CH3:25])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(=O)c2[nH]c(/C=C/c3ccccc3)nc2n(CCC)c1=O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CCCn1c(=O)c2c(nc(/C=C/c3ccccc3)n2C)n(CCC)c1=O
Yield: 84.2 %

Procedure:
Compound 1 obtained in Example 1 (2.00 g, 5.90 mmol) was dissolved in 65 ml of N,N-dimethylformamide. To the solution were added 2.04 g (14.8 mmol) of potassium carbonate and then 0.74 ml (11.8 mmol) of methyl iodide, and the mixture was stirred at 50° C. for 30 minutes. After cooling, insoluble substances were removed by filtration, and 500 ml of water was added to the filtrate. The mixture was extracted three times with chloroform, and the combined organic layers were washed twice with water and twice with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: 20% ethyl acetate/hexane), followed by recrystallization from ethanol/water to give 1.75 g (yield: 84%) of Compound 2 as white needles.
Reaction SMILES: [CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[NH:5][C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2].Br[CH2:15][C:16]#[CH:17]>>[CH:1]([C:3]1[C:7]([CH3:8])=[C:6]([CH3:9])[N:5]([CH2:17][C:16]#[CH:15])[C:4]=1[C:10]([O:12][CH3:13])=[O:11])=[O:2]
Reactant: COC(=O)c1[nH]c(C)c(C)c1C=O
Reactant: C#CCBr
Product: C#CCn1c(C)c(C)c(C=O)c1C(=O)OC

Procedure:
The title compound was prepared as white crystals in 89.3% yeild in a similar procedure to that described in Referential Example 9 by using methyl 3-formyl-4,5-dimethylpyrrole-2-carboxylate and 3-bromo-1-propyne.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[N:13]1[NH:14][N:15]=[C:16]([CH2:18][C:19]([NH2:21])=[O:20])[CH:17]=1.N[CH2:23][CH2:24][C:25]([N:27]1[CH2:46][CH2:45][C:30]2[N:31]=[C:32]([NH:35][CH:36]3[CH2:44][C:43]4[C:38](=[CH:39][CH:40]=[CH:41][CH:42]=4)[CH2:37]3)[N:33]=[CH:34][C:29]=2[CH2:28]1)=[O:26]>CN(C)C1C=CN=CC=1.ClCCl>[CH2:37]1[C:38]2[C:43](=[CH:42][CH:41]=[CH:40][CH:39]=2)[CH2:44][CH:36]1[NH:35][C:32]1[N:33]=[CH:34][C:29]2[CH2:28][N:27]([C:25](=[O:26])[CH2:24][CH2:23][NH:21][C:19](=[O:20])[CH2:18][C:16]3[NH:15][N:14]=[N:13][CH:17]=3)[CH2:46][CH2:45][C:30]=2[N:31]=1
Reactant: NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Reactant: NC(=O)Cc1cn[nH]n1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: O=C(Cc1cnn[nH]1)NCCC(=O)N1CCc2nc(NC3Cc4ccccc4C3)ncc2C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56.3 %

Procedure:
Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.111 g; 1.5 equiv; 0.58 mmoles) to a solution of 2-(2H-triazol-4-yl)acetamide (0.056 g; 1.1 equiv; 0.42 mmoles), 3-amino-1-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]propan-1-one (0.13 g; 1.0 equiv; 0.39 mmoles), and N,N-dimethyl-4-pyridinamine, (0.0094 g; 0.2 equiv; 0.077 mmoles) in dichloromethane (1.28 mL). Stir the reaction mixture for 16 hours at ambient temperature. Load the solution directly onto a silica gel column and purify by column chromatography (0 to 10% methanol in dichloromethane) to give N-{3-[2-(2,3-dihydro-1H-inden-2-ylamino)-7,8-dihydropyrido[4,3-d]pyrimidin-6(5H)-yl]-3-oxopropyl}-2-(1H-1,2,3-triazol-5-yl)acetamide (0.098 g; 57%) as a white solid: MS (m/z): 447(M+1).
Reaction SMILES: [C:1]1([C@H:7]([NH:9][C@@H:10]2[CH2:14][S:13][CH2:12][C@H:11]2[C:15]([OH:17])=O)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N2CCCC2)(N2CCCC2)N2CCCC2)C2C=CC=CC=2N=N1.C(N(CC)CC)C.[F:58][C:59]1[CH:71]=[CH:70][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][NH:66][CH2:65]2)=[CH:61][CH:60]=1>ClCCl>[F:58][C:59]1[CH:60]=[CH:61][C:62]([CH2:63][C@@H:64]2[CH2:69][CH2:68][CH2:67][N:66]([C:15]([C@H:11]3[C@H:10]([NH:9][C@@H:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)[CH3:8])[CH2:14][S:13][CH2:12]3)=[O:17])[CH2:65]2)=[CH:70][CH:71]=1
Reactant: Fc1ccc(C[C@@H]2CCCNC2)cc1
Reactant: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)O)c1ccccc1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H](N[C@@H]1CSC[C@H]1C(=O)N1CCC[C@@H](Cc2ccc(F)cc2)C1)c1ccccc1
Reaction time: 0.08 h
Yield: 94 %

Procedure:
A cloudy solution of (3R,4S)-4-[(R)-1-phenyl-ethylamino]-tetrahydrothiophene-3-carboxylic acid (containing sodium chloride; 928 mg, 2.54 mmol) in dichloromethane (20 mL) was treated with benzotriazol-1-yloxy-tripyrrolidinophosphonium hexafluorophosphate (1.59 g, 3.05 mmol) and triethylamine (814 μL, 5.84 mmol) and stirred for 5 minutes. A solution of the (S)-3-(4-fluorobenzyl)-piperidine prepared above in dichloromethane (5 mL) was added and the mixture was stirred at room temperature. After 21.5 h, the mixture was diluted with dichloromethane, washed with water and saturated NaHCO3, dried (Na2SO4) and concentrated. The residue was purified by flash column chromatography (55% ethyl acetate/hexanes) to provide the product as a gum (1.05 g, 94%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1.[CH3:24][S:25](Cl)(=[O:27])=[O:26].C(N(CC)C(C)C)(C)C>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3](=[O:23])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([CH:16]2[CH2:17][CH2:18][N:19]([S:25]([CH3:24])(=[O:27])=[O:26])[CH2:20][CH2:21]2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:22])[CH:11]=2)[CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(S(C)(=O)=O)CC2)c1C
Temperature: 25 °C
Reaction time: 15 h
Yield: 54.7 %

Procedure:
To a solution of (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester (which may be prepared as described above; 82 mg, 0.26 mmol) and methanesulfonyl chloride (59.6 mg, 0.52 mmol) in THF (6.0 mL) was added N,N-diisopropylethylamine (227 μL, 1.3 mmol) at 0° C. under a nitrogen atmosphere. The resulting suspension was allowed to warm to room temperature during a period of 2 hours and then stirred for 15 hours under a nitrogen atmosphere. The reaction mixture was diluted with water and brine solution, and the organic compound was extracted with ethyl acetate (2×75 mL). The combined organic extracts were washed with brine solution and dried over anhydrous MgSO4, filtered, and concentrated to give a crude brown oil which was purified by flash chromatography (40 g ISCO column, eluting with 0-100% ethyl acetate/hexanes) to give [6-fluoro-4-(1-methanesulfonyl-piperidin-4-yl)-3-methyl-naphthalen-2-yl]-acetic acid methyl ester (56 mg, 55%) as an off-white solid. MS cald. for C20H25FNO4S [(M+H)+] 394, obsd. 393.9.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:15][CH2:14][CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[F:16][C:17]([F:28])([F:27])[C:18]1[C:26]2[CH2:25][CH2:24][CH2:23][CH2:22][C:21]=2[NH:20][N:19]=1>>[N:11]1([S:8]([C:5]2[CH:6]=[CH:7][C:2]([N:20]3[C:21]4[CH2:22][CH2:23][CH2:24][CH2:25][C:26]=4[C:18]([C:17]([F:16])([F:28])[F:27])=[N:19]3)=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:15][CH2:14][CH2:13][CH2:12]1
Reactant: O=S(=O)(c1ccc(I)cc1)N1CCCC1
Reactant: FC(F)(F)c1n[nH]c2c1CCCC2
Product: O=S(=O)(c1ccc(-n2nc(C(F)(F)F)c3c2CCCC3)cc1)N1CCCC1

Procedure:
The title compound was prepared from 1-[(4-iodophenyl)sulfonyl]pyrrolidine and 3-(trifluoromethyl)-4,5,6,7-tetrahydro-1H-indazole using a similar procedure to that described for Example 87.
Reaction SMILES: BrCCCCCCCCCCCCCCCC[C:18]1[C:35]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[CH:34][C:33]2[C:32]3[C:27](=[CH:28][C:29]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[C:30]([O:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])[CH:31]=3)[C:26]3[C:21](=[CH:22][C:23]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[C:24]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:25]=3)[C:20]=2[CH:19]=1.[P:71]([O:78][CH2:79][CH3:80])([O:75][CH2:76][CH3:77])[O:72]CC>>[CH2:79]([O:78][P:71]([CH2:23][CH2:22][CH2:21][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:49][CH2:48][CH2:47][CH2:46][CH2:45][CH2:44][O:43][C:30]1[C:29]([O:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH3:56])=[CH:28][C:27]2[C:26]3[C:21](=[CH:22][C:23]([O:64][CH2:65][CH2:66][CH2:67][CH2:68][CH2:69][CH3:70])=[C:24]([O:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH3:63])[CH:25]=3)[C:20]3[C:33](=[CH:34][C:35]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH3:42])=[C:18]([O:36][CH2:35][CH2:34][CH2:33][CH2:20][CH2:19][CH3:18])[CH:19]=3)[C:32]=2[CH:31]=1)(=[O:72])[O:75][CH2:76][CH3:77])[CH3:80]
Reactant: CCCCCCOc1cc2c(cc1CCCCCCCCCCCCCCCCBr)c1cc(OCCCCCC)c(OCCCCCC)cc1c1cc(OCCCCCC)c(OCCCCCC)cc21
Reactant: CCOP(OCC)OCC
Product: CCCCCCOc1cc2c3cc(OCCCCCC)c(OCCCCCC)cc3c3cc(OCCCCCCCCCCCCCCCCP(=O)(OCC)OCC)c(OCCCCCC)cc3c2cc1OCCCCCC
Temperature: 150 °C
Reaction time: 27 h

Procedure:
Under argon, 20 mL of triethyl phosphite was added to 6.1 g (5.8 mmol) of 2-(16-bromohexadecyl)-3,6,7,10,11-pentakishexyloxytriphenylene, and the mixture was stirred at 150° C. for 27 hours. Excess triethyl phosphite was evaporated from the mixture and the residue was purified by silica-gel column chromatography. As a result, 5.4 g of a white solid was obtained.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2[CH:11]=[C:10](Br)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27][N:26]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C(Cl)Cl>O.C(COC)OC>[NH2:1][C:2]1[N:3]=[C:4]([CH3:22])[C:5]2[CH:11]=[C:10]([C:28]3[CH:27]=[N:26][C:25]([O:24][CH3:23])=[CH:30][CH:29]=3)[C:9](=[O:13])[N:8]([C@H:14]3[CH2:19][CH2:18][C@H:17]([O:20][CH3:21])[CH2:16][CH2:15]3)[C:6]=2[N:7]=1
Reactant: CO[C@H]1CC[C@H](n2c(=O)c(Br)cc3c(C)nc(N)nc32)CC1
Reactant: COc1ccc(B(O)O)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Solvent: ClCCl
Product: COc1ccc(-c2cc3c(C)nc(N)nc3n([C@H]3CC[C@H](OC)CC3)c2=O)cn1
Temperature: 100 °C

Procedure:
To a vial containing 2-amino-6-bromo-8-(trans-4-methoxycyclohexyl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (75 mg, 0.20 mmol), 2-methoxy-5-pyridineboronic acid (37.5 mg, 0.245 mmol) and cesium carbonate was added PdCl2(dppf)1:1 w/CH2Cl2 followed by 5:1 dimethoxyethane:water (3 mL, degassed by bubbling with argon). The vial was capped and heated in the microwave for 30 minutes at 100° C. The reaction mixture was concentrated and the crude product was purified by flash chromatography eluting with chloroform/methanol (0-5%). The fractions containing the desired product were concentrated and the solids were triturated with methyltertbutyl ether to afford 2-amino-8-(trans-4-methoxycyclohexyl)-6-(6-methoxypyridin-3-yl)-4-methylpyrido[2,3-d]pyrimidin-7(8H)-one (33 mg, 40%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.C[Mg]Br.[O:13]1[CH:20]([CH3:21])[CH:14]1[C:15]([O:17]CC)=[O:16].Cl>ClCCl.C(OCC)C>[OH:13][CH:14]([CH:20]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)[CH3:21])[C:15]([OH:17])=[O:16]
Reactant: CCOC(=O)C1OC1C
Reactant: c1ccc2[nH]ccc2c1
Agent: C[Mg]Br
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: CC(c1c[nH]c2ccccc12)C(O)C(=O)O
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 66.3 %

Procedure:
Indole (5.86 g) was dissolved in dichloromethane (50 ml) and to the solution was added dropwise 2.89 M solution of methyl magnesium bromide in diethyl ether (40 ml) over a period of 45 minutes at room temperature. After the dropwise addition was completed, the mixture was stirred for 45 minutes at room temperature. Under cooling at −10° C., a solution of ethyl (2RS,3SR)-2,3-epoxybutanoate (6.51 g) in dichloromethane (50 ml) was added dropwise over a period of 20 minutes. The mixture was stirred for 1 hour at −10 ° C. To the mixture was added 1 N aqueous solution of hydrochloric acid (150 ml). The organic layer was removed, and the aqueous layer was extracted with dichloromethane (50 ml). The organic layers were combined, and concentrated under reduced pressure. The residue was dissolved by adding ethanol (56 ml) and water (24 ml). To the solution was added 1 N aqueous solution of sodium hydroxide (50 ml) under ice cooling. The mixture was stirred for 3.5 hours under ice cooling and 12 hours at room temperature. To the mixture was added 1 N aqueous solution of sodium hydroxide (25 ml), and the mixture was stirred for 1 hour at room temperature. The ethanol was distilled off under reduced pressure, and aqueous layer was washed twice with ethyl acetate (70 ml). The aqueous layer was acidified by adding conc. hydrochloric acid (10 ml). The mixture was extracted twice with ethyl acetate (100 ml). The ethyl acetate layers were combined and dried over anhydrous magnesium sulfate. To the ethyl acetate layer was added activated carbon (1 g) and mixture was stirred. After filtration, the filtrate was concentrated under reduced pressure. The residue was recrystallized from water to give (2RS,3SR)-2-hydroxy-3-(indol-3-yl)butyric acid (7.27 g) as pale brown solid.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:7]([O:9][C:10](=[O:29])[C:11]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:20])[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=1)[CH3:8].[CH3:30][O:31][C:32]1[CH:58]=[CH:57][C:35]([CH2:36][N:37]2[CH2:41][CH:40]([CH2:42][CH2:43]OS(C3C=CC(C)=CC=3)(=O)=O)[N:39]([CH3:55])[C:38]2=[O:56])=[CH:34][CH:33]=1>CN(C=O)C.C(OCC)(=O)C>[CH2:7]([O:9][C:10](=[O:29])[C:11]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:20])[CH2:12][C:13]1[CH:14]=[CH:15][C:16]([O:19][CH2:43][CH2:42][CH:40]2[CH2:41][N:37]([CH2:36][C:35]3[CH:57]=[CH:58][C:32]([O:31][CH3:30])=[CH:33][CH:34]=3)[C:38](=[O:56])[N:39]2[CH3:55])=[CH:17][CH:18]=1)[CH3:8]
Reactant: COc1ccc(CN2CC(CCOS(=O)(=O)c3ccc(C)cc3)N(C)C2=O)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(OCCC2CN(Cc3ccc(OC)cc3)C(=O)N2C)cc1)Oc1ccccc1F
Yield: 92.4 %

Procedure:
Cesium carbonate (8.23 g, 25.3 nmol) is added to a solution of 2-(2-Fluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester (2.68 g, 8.43 mmol) and toluene-4-sulfonic acid 2-[1-(4-methoxy-benzyl)-3-methyl-2-oxo-imidazolidin-4-yl]-ethyl ester (3.88 g, 9.27 mmol) in DMF (30 mL). The resultant mixture is stirred at 65° C. under an atmosphere of nitrogen for 18 h, then diluted with ethyl acetate. The organic layer is washed with 1N HCl, water, and brine. The organic layer is dried, concentrated in vacuo, and purified by flash chromatography (17% acetone in hexanes) to provide the title compound (4.4 g, 93%). 1H NMR 400 MHz, CDCl3): δ 7.19-7.15 (m, 4H), 7.06-7.01 (m, 1H), 6.97-6.87 (m, 3H), 6.83 (d, 2H, J=8.6 Hz), 6.74 (d, 2H, J=8.6 Hz), 4.31, 4.27 (ABq 2H, J=14.8 Hz), 4.21, 4.17 (ABq, 2H, J=7.2 Hz), 3.96-3.92 (m, 2H), 3.76 (s, 3H), 3.60-3.53 (m, 1H), 3.33 (t, 1H, J=8.6 Hz), 3.25, 3.13 (ABq 2H, J=13.8 Hz), 2.994-2.83 (m, 2H), 2.82 (s, 3H), 2.24-2.16 (m, 1H), 1.89-1.80 (m, 1H), 1.37 (s, 3H), 1.22 (t, 3H, J=7.2 Hz). MS [EI+] 565 (M+H)+. Rf=0.56 in 50% acetone in hexanes.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][NH:16][C:17]2[C:26]([NH:27][C:28]([O:30]C)=O)=[CH:25][CH:24]=[CH:23][C:18]=2[C:19]([O:21][CH3:22])=[O:20])=[CH:11][CH:10]=1)#[N:2].C[O-].[Na+].Cl>CO>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][N:16]2[C:17]3[C:18]([C:19]([O:21][CH3:22])=[O:20])=[CH:23][CH:24]=[CH:25][C:26]=3[NH:27][C:28]2=[O:30])=[CH:11][CH:10]=1)#[N:2]
Reactant: COC(=O)Nc1cccc(C(=O)OC)c1NCc1ccc(-c2ccccc2C#N)cc1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1cccc2[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c12
Yield: 89.5 %

Procedure:
To a solution of methyl 2-[(2'-cyanobiphenyl-4-yl)methylamino]-3-methoxycarbonylaminobenzoate (10.5 g) in methanol (100 ml) was added NaOMe (10 g), and the mixture was heated under reflux for 20 hours. The reaction mixture was neutralized with 1N-HCl and concentrated to dryness. The residue was extracted with chloroform-water. The organic layer was washed with water, dried and evaporated to dryness. The resulting crystals were recrystallized from chloroform-methanol to afford colorless needles (8.67 g, 89%), m.p. 250°-253° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:9]([C:16]2[CH:28]=[CH:27][C:19]([C:20]([N:22]([CH2:25][CH3:26])[CH2:23][CH3:24])=[O:21])=[CH:18][CH:17]=2)[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH:29](=O)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.ClCCl>[CH2:25]([N:22]([CH2:23][CH3:24])[C:20]([C:19]1[CH:27]=[CH:28][C:16]([CH:9]([N:10]2[CH2:11][CH2:12][N:13]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:14][CH2:15]2)[C:5]2[CH:4]=[C:3]([CH:8]=[CH:7][CH:6]=2)[C:1]#[N:2])=[CH:17][CH:18]=1)=[O:21])[CH3:26]
Reactant: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCNCC2)cc1
Reactant: O=Cc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(C(c2cccc(C#N)c2)N2CCN(Cc3ccccc3)CC2)cc1
Yield: 57 %

Procedure:
To a solution of INTERMEDIATE 3 (606 mg) in 1,2-dichloroethane (15 mL) was added benzaldehyde (220 μL, 1.3 eq) and sodium triacetoxyborohydride (480 mg, 1.4 eq). After 3 days the reaction was diluted with dichloromethane (50 mL) and washed with saturated aqueous sodium bicarbonate. The aqueous layer was washed with dichloromethane (2×25 mL) and the combined organic extracts were dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography, eluting 5% methanol in dichloromethane to yield INTERMEDIATE 4a as a colorless foam (428mg, 57%).