Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14]S(C)(=O)=O)[CH2:5]1)(=[O:3])[CH3:2].[Cl:19][C:20]1[CH:28]=[C:27]2[C:23]([C:24]([CH:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:25][NH:26]2)=[CH:22][CH:21]=1>>[C:1]([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]([CH2:13][CH2:14][N:32]2[CH2:33][CH2:34][CH:29]([C:24]3[C:23]4[C:27](=[CH:28][C:20]([Cl:19])=[CH:21][CH:22]=4)[NH:26][CH:25]=3)[CH2:30][CH2:31]2)[CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CC(CCS(C)(=O)=O)c2ccccc21
Reactant: Clc1ccc2c(C3CCNCC3)c[nH]c2c1
Product: CC(=O)N1CC(CCN2CCC(c3c[nH]c4cc(Cl)ccc34)CC2)c2ccccc21

Procedure:
From 19a and 6-chloro-3-(piperidin-4-yl)-1H-indole (EP Patent publication No 465398-A1). Mp 188-90° C. 1H NMR (DMSO-d6) d 1.70-1.90 (m, 3H), 1.95-2.20 (m, 5H), 2.25 (s, 3H), 2.40-2.55 (m, 2H), 2.80 (tt, 1H), 3.00-3.10 (m, 2H), 3.40-3.55 (m, 1H), 3.75 (dd, 1H), 4.20 (t, 1H), 6.95 (d, 1H), 7.05 (ddd, 1H), 7.25 (dt, 1H), 7.35 (d, 1H), 7.55 (d, 1H), 8.00 (s, 1H), 8.25 (d, 1H). MS m/z (%): 422 (MH+, 100%), 249 (15%), 146 (19%).
Reaction SMILES: C([O:8][N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[S:14]1)[CH:10]=[O:11])C1C=CC=CC=1.C1CC=CCC=1>CCO.[Pd]>[CH:10]([N:9]([CH2:12][CH:13]1[C:18](=[O:19])[N:17]([CH2:20][C:21]([NH:23][CH2:24][CH2:25][CH3:26])=[O:22])[C:16]2[CH:27]=[CH:28][CH:29]=[CH:30][C:15]=2[S:14]1)[OH:8])=[O:11]
Reactant: CCCNC(=O)CN1C(=O)C(CN(C=O)OCc2ccccc2)Sc2ccccc21
Agent: [Pd]
Solvent: CCO
Solvent: C1=CCC=CC1
Product: CCCNC(=O)CN1C(=O)C(CN(O)C=O)Sc2ccccc21
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 2-{2-[(benzyloxy-formyl-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide (0.13 mmol) in 9 ml of EtOH is added Pd/C (10%) (65.6 mg) followed by 1,4-cyclohexadiene (1.29 mL). The reaction mixture is stirred at room temperature for 12 hours and the final product 2-{2-[(formyl-hydroxy-amino)-methyl]-3-oxo-2,3-dihydro-benzo[1,4]thiazin-4-yl}-N-propyl-acetamide is obtained by preparative LC/MS using 1 to 99% ACN (in the absence of TFA) as gradient. MS: (ES+): 338.2 [M+1].
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:13]=[CH:14][N:15]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=2.[CH:16]1([NH2:22])[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1>>[CH:16]1([NH:22][C:13]2[N:4]3[C:5]4[C:10]([N:11]=[CH:2][C:3]3=[N:15][CH:14]=2)=[CH:9][CH:8]=[C:7]([Cl:12])[CH:6]=4)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: NC1CCCCC1
Reactant: Clc1ccc2nc(Cl)c3nccn3c2c1
Product: Clc1ccc2ncc3ncc(NC4CCCCC4)n3c2c1

Procedure:
By reaction of 4,8-dichloroimidazo[1,2-a]quinoxaline (example 18) with cyclohexylamine, following a procedure that is similar to that described in example 3, there is obtained 4-(1-cyclohexylamino-8-chloroimidazo[1,2-a]quinoxaline. m.p. (DSC)=126.7° C.(onset); IR (KBr): 3413, 2926, 1555 cm-1 ; 1H-NMR (CDCl3): δ7.85 (1H,s), 7.7÷7.2 (4H,m), 6.1 (1H,d), 4.2 (1H,m), 2.3÷2.0 (4H,m), 2.0÷1.2 (6H,m); UV (EtOH): λmax =229, 245, 289, 301, 326, 340 nm. Elementary analysis for C16H17ClN4 (m.w. 300.79): calcd. C 63.89, H 5.70, N 18.63%; found C 64.07, H 5.79, N 18.80%.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.[Cl:10]N1C(=O)CCC1=O>C(OCC)(=O)C>[NH2:9][C:4]1[C:3]([O:2][CH3:1])=[CH:8][C:7]([Cl:10])=[CH:6][N:5]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: COc1cccnc1N
Solvent: CCOC(C)=O
Product: COc1cc(Cl)cnc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-Methoxy-2-aminopyridine (Wonda Science, cat #01683; 12.4 g, 0.01 mol) is dissolved by stirring in 500 ml of ethyl acetate. A thermometer is placed in the solution to monitor temperature. N-Chlorosuccinimide (13.3 g, 0.01 mol) is added in several portions to keep the solution at room temperature. The solution becomes dark in color and is stirred at room temperature overnight. The supernatant is decanted from the dark solids that formed and transferred to a separatory funnel. The organic solution is washed with 500 ml saturated aqueous sodium bisulfite and then 500 ml brine. The organic layer is dried with MgSO4 and concentrated on a rotovap. The dark brown crude product is chromatographed on 500 g of flash silica-gel eluting with 30% EtOAc/Hexanes. Concentration of the appropriate fractions on a rotovap gives a yellow solid. The solid is suspended in hexanes, stirred and filtered to give the product as a bright yellow solid. (MP 93-94° C.).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.C(=O)(O)[O-].[Na+].[Br:17][C@@H:18]1[C:27]([CH3:29])([CH3:28])[O:26][C:25]2[CH:24]=[CH:23][N:22]=[CH:21][C:20]=2[C@H:19]1[OH:30]>C(Cl)(Cl)Cl>[Br:17][C@@H:18]1[C:27]([CH3:28])([CH3:29])[O:26][C:25]2[CH:24]=[CH:23][N+:22]([O-:9])=[CH:21][C:20]=2[C@H:19]1[OH:30]
Reactant: CC1(C)Oc2ccncc2[C@@H](O)[C@@H]1Br
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC1(C)Oc2cc[n+]([O-])cc2[C@@H](O)[C@@H]1Br

Procedure:
To a white suspension of 7,9 mg of m-chloroperbenzoic acid and 4,4 g of dry sodiumbicarbonate in 90 ml of abs. chloroform a solution of 6,7 g of trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-2H-pyrano[3,2-c]pyridin in 70 ml of chloroform is dropwise added under argon. After 2 hours the suspension is concentrated to dryness, the residue taken up in dichloromethane/methanol and filtrated to a clean filtrate. Concentration of the filtrate and purification by chromatography (silica gel, dichloromethan/methanol) of the residue yields solid trans-3-bromo-3,4-dihydro-4-hydroxy-2,2-dimethyl-6-oxido-2H-pyrano-[3,2-c]pyridine.
Reaction SMILES: [C:1](O)(=O)/C=C/C(O)=O.[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C@H:19]1[CH2:23][CH2:22][C@@H:21]([NH:24][CH2:25][C@@H:26]2[O:40][C:30]3=[C:31]4[C:36](=[CH:37][CH:38]=[C:29]3[O:28][CH2:27]2)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]4)[CH2:20]1.C=O.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>O1CCCC1.CO>[F:9][C:10]1[CH:11]=[C:12]2[C:16](=[CH:17][CH:18]=1)[NH:15][CH:14]=[C:13]2[C@H:19]1[CH2:23][CH2:22][C@@H:21]([N:24]([CH3:1])[CH2:25][C@@H:26]2[O:40][C:30]3=[C:31]4[C:36](=[CH:37][CH:38]=[C:29]3[O:28][CH2:27]2)[N:35]=[C:34]([CH3:39])[CH:33]=[CH:32]4)[CH2:20]1
Reactant: Cc1ccc2c3c(ccc2n1)OC[C@H](CN[C@@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)O3
Reactant: O=C(O)/C=C/C(=O)O
Agent: C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2c3c(ccc2n1)OC[C@H](CN(C)[C@@H]1CC[C@H](c2c[nH]c4ccc(F)cc24)C1)O3
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.7 %

Procedure:
To a mixture of N-[(1R*,3S*)-3-(5-fluoro-1H-indol-3-yl)cyclopentyl]-N-{[(2S)-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinolin-2-yl]methyl}amine fumarate (200 mg, 0.365 mmol) and formaldehyde (37%, 50 μL, 0.67 mmol) in 2:1 tetrahydrofuran/methanol (3 mL) was added sodium triacetoxyborohydride (155 mg, 0.73 mmol). The reaction was allowed to stir at ambient temperature overnight, then was quenched with saturated aqueous sodium bicarbonate (20 mL) and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. Flash chromatography (2×20 cm silica gel, 3% methanol/methylene chloride) afforded 115 mg (70%) of the title compound as a semi-solid, which was converted to its fumarate salt as a white powder: mp 198-199° C. (dec); MS (ES) m/z 446 [M+H]+.[α]D5.3°(c 1.0, DMSO)
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:12]=[C:11]([CH:13]=[O:14])[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[N+:21]([CH:24]([CH3:26])[CH3:25])([O-:23])=[O:22]>C(Cl)Cl>[N+:21]([C:24]([CH:13]([C:11]1[C:10]2[C:5](=[C:6]([C:15]([F:18])([F:16])[F:17])[CH:7]=[CH:8][CH:9]=2)[N:4]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:12]=1)[OH:14])([CH3:26])[CH3:25])([O-:23])=[O:22]
Reactant: O=Cc1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12
Reactant: CC(C)[N+](=O)[O-]
Solvent: ClCCl
Product: CC(C)(C(O)c1cc(C(F)(F)F)nc2c(C(F)(F)F)cccc12)[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 17 h
Yield: 43.1 %

Procedure:
A mixture of 2,8-bis(trifluoromethyl)-4-quinolinecarboxaldehyde (200 mg, 0.85 mmol), 2-nitropropane (0.1 mL, 1.1 mmol) and Amberlyst 21 resin (200 mg) was stirred at room temperature for 17 h, treated with CH2Cl2 (3 mL), filtered to remove the resin, the filtrate concentrated in vacuo to give a viscous oil which was crystallised from heptane to give a white solid which was recrystallised (ether/heptane) to give the product (140 mg, 51%) as a white crystalline solid: IR νmax (Nujol)/cm−1 3484, 2923, 1544, 1311, 1134 and 780; NMR δH (400 MHz, CDCl3) 1.37 (3H, s), 1.54 (3H, s), 3.03 (1H, d, J 4.5 Hz),6.36 (1H, d, J 4.4 Hz), 7.80 (1H, t, J 8.1 Hz), 8.07 (1H, s), 8.21 (1H, d, J 7.1 Hz) and 8.44 (1H, d, J 8.5 Hz).
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:9][C@H:10]([NH2:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:1]([NH:17][C@@H:10]([CH3:9])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](NCc1ccccc1)c1ccccc1
Yield: 96.1 %

Procedure:
Benzaldehyde (3.94 mL, 38.8 mmol) and (S)-α-methylbenzylamine (5.0 mL, 38.8 mmol, 96% ee.) were allowed to react according to the procedure of Example 86 to yield 7.88 g (96%) of N-benzyl-(S)-α-methylbenzylamine as an oil contaminated with ~5% of benzyl alcohol and (S)-α-methylbenzylamine: 1H NMR (DMSO-d6, 250 MHz) δ 7.15-7.45 (m, 10 H, Ar), 3.69 (q, 1 H, J=6.5 Hz), 3.48 (dd, 2 H, j1 =13.6 Hz, J2 =20.9 Hz), 2.45 (br s, 1 H, NH), 1.26 (d, 3 H, J=6.5 Hz, CH3); 13C NMR (DMSO-d6) δ 146.0, 141.0, 128.1, 128.0, 127.8, 126.4, 126.3, 56.7, 50.6, 24.5. This mixture was directly used in the next reaction.
Reaction SMILES: C(S[CH:5]([CH2:16][C:17](=[O:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=O)C.C(Cl)(Cl)(Cl)Cl.[SH:30][CH2:31][C:32]([OH:34])=[O:33]>C(O)C>[C:17]([CH2:16][CH:5]([S:30][CH2:31][C:32]([OH:34])=[O:33])[C:6]([N:8]1[CH2:15][CH2:14][CH2:13][C@H:9]1[C:10]([OH:12])=[O:11])=[O:7])(=[O:24])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C(O)CS
Reactant: CC(=O)SC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCO
Product: O=C(O)CSC(CC(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 72 h

Procedure:
To a suspension of 0.90 g. of 1-(3-benzoylacryloyl)-L-proline (prepared as described in Example 8) in 30 ml. of carbontetrachloride is added 0.28 ml. of mercaptoacetic acid. An additional 30 ml. of carbontetrachloride is added and the mixture stirred 3 days. The solvent is removed under vacuum. Carbontetrachloride (30 ml.) and 0.78 ml. of mercaptoacetic acid is added and the mixture stirred for 3 days. The solvent is removed and the residue chromatographed on a silica gel column with dichloromethane-methanol-acetic acid (90:10:2) as solvent. Fractions showing one spot by thin layer chromatography are combined to give 1.3 g. of clear gum. Placing the gum under high vacuum over night gives the product of the example as a glass, [α]D23° -31°±2(c, 0.534 ethanol).
Reaction SMILES: [CH3:1][Si](C=[N+]=[N-])(C)C.[Br:8][C:9]1[CH:14]=[CH:13][C:12]([NH:15][C:16]2[C:21]([C:22]([OH:24])=[O:23])=[CH:20][N:19]=[C:18]([Cl:25])[C:17]=2[F:26])=[C:11]([F:27])[CH:10]=1.C1COCC1>CO>[CH3:1][O:23][C:22](=[O:24])[C:21]1[C:16]([NH:15][C:12]2[CH:13]=[CH:14][C:9]([Br:8])=[CH:10][C:11]=2[F:27])=[C:17]([F:26])[C:18]([Cl:25])=[N:19][CH:20]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cnc(Cl)c(F)c1Nc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.3 %

Procedure:
A hexanes solution of TMSCH2N2 (9.46 mL, 18,9 mmol) was added to 4-(4-bromo-2-fluorophenylamino)-6-chloro-5-fluoro-nicotinic acid (4.59 g, 12.62 mmol) in a solution of 3:1 THF:MeOH (48 mL) at 0° C. The reaction mixture was warmed to room temperature and stirred for 1 hour. After quenching with AcOH, the reaction mixture was diluted with ethyl acetate and water. The layers were separated and the organic layer was washed with water, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to give 4.40 g (92%) clean desired product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:15])[CH2:7][NH:8][CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[N:23]#[N:24].Cl.[CH3:26][O:27][C:28]1[CH:37]=[C:36]2[C:31]([CH:32]=[CH:33][C:34]([S:38]([NH:41][C@H:42]([C:50](Cl)=[O:51])[CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:49])[NH2:48])(=[O:40])=[O:39])=[CH:35]2)=[CH:30][CH:29]=1>C(Cl)(Cl)Cl>[N:23]#[N:24].[C:1]([O:5][C:6](=[O:15])[CH2:7][N:8]([C:50](=[O:51])[C@H:42]([CH2:43][CH2:44][CH2:45][NH:46][C:47](=[NH:48])[NH2:49])[NH:41][S:38]([C:34]1[CH:33]=[CH:32][C:31]2[C:36](=[CH:37][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)[CH:35]=1)(=[O:39])=[O:40])[CH2:9][CH:10]1[O:14][CH2:13][CH2:12][CH2:11]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CNCC1CCCO1
Reactant: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)Cl)cc2c1
Agent: Cl
Agent: N#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1ccc2ccc(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)N(CC(=O)OC(C)(C)C)CC3CCCO3)cc2c1
Reaction time: 8 h

Procedure:
To a stirred solution of 3.0 g of N-tetrahydrofurfurylglycine tert-butyl ester and 5.6 ml of triethylamine in 80 ml of chloroform which was cooled in an ice bath, there was carefully added N2 -(7-methoxy-2-naphthalene-sulfonyl)-L-arginyl chloride hydrochloride obtained above. The reaction mixture was allowed to stand overnight at room temperature. The reaction mixture was washed twice with 20 ml of saturated sodium chloride solution and evaporated to dryness. The residue was dissolved in water-ethanol and adjusted to pH 12 with 5N NaOH to precipitate a solid. This was collected by filtration to give 4.8 g of N2 -(7-methoxy-2-naphthalenesulfonyl)-L-arginyl-N-tetrahydrofurfurylglycine tert-butyl ester.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[F:19][C:20]1[CH:25]=[C:24]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:54])[C:37]([O:46][Si](C(C)(C)C)(C)C)([C:42]([F:45])([F:44])[F:43])[C:38]([F:41])([F:40])[F:39].C(OCC)(=O)C>C1COCC1>[F:19][C:20]1[CH:25]=[C:24]([S:26][C:27]2[CH:32]=[CH:31][C:30]([S:33][CH3:34])=[CH:29][CH:28]=2)[CH:23]=[CH:22][C:21]=1[NH:35][C:36](=[O:54])[C:37]([OH:46])([C:38]([F:39])([F:40])[F:41])[C:42]([F:44])([F:45])[F:43]
Reactant: CSc1ccc(Sc2ccc(NC(=O)C(O[Si](C)(C)C(C)(C)C)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CSc1ccc(Sc2ccc(NC(=O)C(O)(C(F)(F)F)C(F)(F)F)c(F)c2)cc1
Yield: 89.4 %

Procedure:
Tetra-n-butylammonium fluoride (0.48 ml of a 1M solution in THF) was added to a stirred solution of N-[2-fluoro-4-(4-methylsulphanylphenylsulphanyl)phenyl]-2-(t-butyldimethylsilyloxy)-2-trifluoromethyl-3,3,3-trifluoropropanamide (0.278 g) (Method 55) in anhydrous THF (5 ml) at −78° C. under argon. After 30 minutes ethyl acetate (50 ml) was added and the mixture was washed with aqueous hydrochloric acid (2M, 30 ml) and brine (30 ml) then dried. Volatile material was removed by evaporation and the residue was purified on a silica gel Mega Bond Elut column eluting with 10-30% ethyl acetate/iso-hexane to give the title compound (0.199 g) as a pale yellow solid. NMR (CDCl3): 2.50 (s, 3H), 5.12 (s, 1H), 6.98 (d, 1H), 7.05 (d, 1H), 7.23 (d, 2H), 7.35 (d, 2H), 8.05-8.08 (m, 1H); MS (ESP−): 458,
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([OH:15])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Mg]Cl)(C)C.[C:21]1([CH:27]([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[N:28]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30](=[O:37])[C:29]2=[O:38])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.ClCCl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:30]2([OH:37])[C:31]3[C:36](=[CH:35][CH:34]=[CH:33][CH:32]=3)[N:28]([CH:27]([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[C:29]2=[O:38])=[C:11]([OH:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccccc21
Reactant: Oc1cccc(OCc2ccccc2)c1
Agent: CC(C)[Mg]Cl
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=C1N(C(c2ccccc2)c2ccccc2)c2ccccc2C1(O)c1ccc(OCc2ccccc2)cc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
To a stirred solution of 3-(benzyloxy)phenol (8.7 g, 43.5 mmol) in tetrahydrofuran (100 mL) was added iso-propylmagnesium chloride (22.7 mL, 2 M tetrahydrofuran solution, 45.4 mmol) slowly at 0° C. The mixture was allowed to stir at 0° C. for 30 min, and concentrated in vacuo to dryness. Dichloromethane (100 mL) was added, followed by the addition of a solution of 1-(diphenylmethyl)-1H-indole-2,3-dione (12.4 g, 39.5 mmol) in dichloromethane (50 mL) at 0° C. The mixture was stirred at ambient temperature for 16 h, and quenched with saturated ammonium chloride solution. The organic layer was washed with water, dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to dryness. The obtained solid was recrystallized from ethyl acetate/hexanes to afford 3-[4-(benzyloxy)-2-hydroxyphenyl]-1-(diphenylmethyl)-3-hydroxy-1,3-dihydro-2H-indol-2-one (19.60 g, 97%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.49-7.43 (m, 1H), 7.42-7.25 (m, 13H), 7.23-7.17 (m, 2H), 7.12-7.04 (m, 2H), 6.91 (s, 1H), 6.72-6.62 (m, 2H), 6.51-6.44 (m, 1H), 6.39 (dd, J=8.6, 2.4 Hz, 1H), 4.99 (s, 2H); MS (ES+) m/z 536.3 (M+23).
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11].C(N(CC)CC)C.[CH3:38][S:39](Cl)(=[O:41])=[O:40]>CN(C)C=O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([O:12][C:13]1[C:14]([NH2:30])=[N:15][CH:16]=[C:17]([C:19]2[N:20]=[N:21][N:22]([CH:24]3[CH2:29][CH2:28][N:27]([S:39]([CH3:38])(=[O:41])=[O:40])[CH2:26][CH2:25]3)[CH:23]=2)[CH:18]=1)[CH3:11]
Reactant: CC(Oc1cc(-c2cn(C3CCNCC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(Oc1cc(-c2cn(C3CCN(S(C)(=O)=O)CC3)nn2)cnc1N)c1c(Cl)ccc(F)c1Cl
Reaction time: 8 h

Procedure:
The product of the above mentioned Example 2 3-(1-(2,6-dichloro-3-fluorophenyl)ethoxy)-5-(1-(piperidin-4-yl)-1H-1,2,3-triazol-4-yl)-2-aminopyridine (451 mg, 1 mmol) was added to N,N-dimethyl formamide (10 mL), triethylamine (404 mg, 4 mmol) and methylsulfonyl chloride (343.6 mg, 3 mmol) were added, and the reaction was performed overnight at room temperature. The resultant mixture was washed with water for several times, dried over anhydrous sodium sulfate, filtered, the filtrate was rotatedly concentrated to dryness to yield a solid, which was purified via silica gel column chromatography (dichloromethane/methanol=20:1) to yield the target product as white solid powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([N:13]=[C:14](SC)SC)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1.Cl.Cl.[NH2:21][CH2:22][C@@:23]1([OH:31])[CH:28]2[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]2)[CH2:24]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[CH3:1][O:2][C:3]1[C:4]2[N:12]=[C:11]([NH:13][C:14]3[O:31][C@:23]4([CH2:22][N:21]=3)[CH:28]3[CH2:29][CH2:30][N:25]([CH2:26][CH2:27]3)[CH2:24]4)[S:10][C:5]=2[N:6]=[C:7]([CH3:9])[N:8]=1
Reactant: NC[C@]1(O)CN2CCC1CC2
Reactant: COc1nc(C)nc2sc(N=C(SC)SC)nc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1nc(C)nc2sc(NC3=NC[C@@]4(CN5CCC4CC5)O3)nc12
Temperature: 100 °C
Yield: 49.6 %

Procedure:
A mixture of dimethyl 7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-ylcarbonimidodithioate (56 mg, 0.19 mmol), (S)-3-(aminomethyl)quinuclidin-3-ol dihydrochloride (51 mg, 0.22 mmol) and cesium carbonate (175 mg, 0.54 mmol) in DMF (0.5 mL) was heated to 100° C. for 2 hours. The reaction mixture was cooled to ambient temperature, poured into water and extracted with chloroform (4×). The combined organics were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The mixture was purified by silica gel chromatography (2-40% [9:1 methanol:ammonium hydroxide]-chloroform). The product fractions were combined and concentrated in vacuo to afford (R)—N-(7-methoxy-5-methylthiazolo[5,4-d]pyrimidin-2-yl)-4H-1′-azaspiro[oxazole-5,3′-bicyclo[2.2.2]octan]-2-amine (34 mg, 50% yield). 1H NMR (400 MHz, CDCl3) δ ppm 9.10 (br. s., 1H) 4.14 (s, 3H) 4.03 (d, J=9.54 Hz, 1H) 3.68 (d, J=9.54 Hz, 1H) 3.39 (dd, J=14.93, 1.63 Hz, 1H) 2.74-3.07 (m, 5H) 2.68 (s, 3H) 2.04-2.28 (m, 2H) 1.70-1.86 (m, 1H) 1.44-1.67 (m, 2H). MS (LC/MS) R.T.=1.10; [M+H]+=361.32.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:24](O)=[O:25])[CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.Cl.[CH3:29][O:30][C:31](=[O:40])[CH:32]([CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)[NH2:33].P(C#N)(=O)(OCC)OCC.C(N(CC)CC)C>O1CCCC1>[CH3:29][O:30][C:31](=[O:40])[CH:32]([CH2:34][C:35]1[N:36]=[CH:37][S:38][CH:39]=1)[NH:33][C:24](=[O:25])[C@H:12]([CH2:13][C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=[CH:16][CH:15]=1)[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: O=C(N[C@@H](Cc1cccc2ccccc12)C(=O)O)OCc1ccccc1
Reactant: COC(=O)C(N)Cc1cscn1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)C(Cc1cscn1)NC(=O)[C@H](Cc1cccc2ccccc12)NC(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
2.90 g (8.30 mmole) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanine and 2.15 g (8.30 mmole) of 3-(4-thiazolyl)-DL-alanine methyl ester dihydrochloride were suspended in 30 ml of anhydrous tetrahydrofuran. Whilst ice cooling, 1.51 ml (9.95 mmole) of diethyl phosphorocyanidate and 3.82 ml (27.4 mmole) of triethylamine were added dropwise under a nitrogen gas stream, and the mixture was stirred overnight at room temperature. The reaction product was condensed by evaporation under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with water and then dried over anhydrous magnesium sulfate. The dried product was condensed by evaporation under reduced pressure, and the residue was purified by silica gel column chromatography eluted with a 10:1 by volume mixture of chloroform and methanol, to yield 2.62 g (61%) of N-benzyloxycarbonyl-3-(1-naphthyl)-L-alanyl-3-(4-thiazolyl)-DL-alanine methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][NH:9][CH3:10])[CH:5]=[CH:6][CH:7]=1.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:20]=[CH:21][C:22](=[O:29])[N:23]([CH2:25][C:26]([OH:28])=O)[CH:24]=2)=[CH:15][CH:14]=1.OC1C2N=NNC=2C=CC=1.CCN=C=NCCCN(C)C.Cl>C(Cl)Cl.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][N:9]([CH3:10])[C:26](=[O:28])[CH2:25][N:23]1[CH:24]=[C:19]([C:16]2[CH:15]=[CH:14][C:13]([O:12][CH3:11])=[CH:18][CH:17]=2)[CH:20]=[CH:21][C:22]1=[O:29]
Reactant: COc1ccc(-c2ccc(=O)n(CC(=O)O)c2)cc1
Reactant: CNCc1cccc(Cl)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: COc1ccc(-c2ccc(=O)n(CC(=O)N(C)Cc3cccc(Cl)c3)c2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
According to Scheme 9 Step 3: To a solution of (3-chlorophenyl)-N-methylmethanamine (1 eq, 0.19 mmol, 0.03 g), 2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)acetic acid (1 eq, 0.19 mmol, 0.05 g) and hydroxybenzotriazole (1.1 eq, 0.21 mmol, 0.03 g) in CH2Cl2 (2 mL) at room temperature was added EDCI.HCl (1.5 eq, 0.29 mmol, 55 mg). The reaction was stirred at room temperature for 12 hours then diluted with AcOEt. The reaction washed with brine and the organic phase extracted (×3). The combined organic fractions were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude product was purified by flash chromatography over silica gel (AIT Flashsmart prepacked column 10 g SiO2) using CH2Cl2/AcOEt (50/50) as eluent to afford the N-(3-chlorobenzyl)-2-(5-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-N-methylacetamide (0.11 mmol, 44 mg, 57%) as a yellow oil.