Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[CH2:27][CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:41][O:42][C:43]1[CH:50]=[CH:49][C:46]([CH2:47]I)=[CH:45][CH:44]=1.C(O)(=O)CC>C1COCC1.CN1C(=O)N(C)CCC1.O.CCCCCC.C(OCC)(=O)C>[C:1]([NH:8][C@H:9]([C@H:25]1[O:29][C:28](=[O:30])[C@H:27]([CH2:47][C:46]2[CH:49]=[CH:50][C:43]([O:42][CH3:41])=[CH:44][CH:45]=2)[CH2:26]1)[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: COc1ccc(CI)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(OCc2ccccc2)cc1)[C@@H]1CCC(=O)O1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCC(=O)O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(C[C@@H]2C[C@@H]([C@H](Cc3ccc(OCc4ccccc4)cc3)NC(=O)OC(C)(C)C)OC2=O)cc1

Procedure:
In analogy with Example 5d), 2.9 g (7.04 mmol) of 5(S)-[1(S)-(Boc-amino)-2-(p-benzyloxy-phenyl)ethyl]dihydrofuran-2-(3H)-one (preparation, see Example 1g)], dissolved in 10.3 ml of THF and 1.2 ml of DMPU, are deprotonated, at -70° C., with 14.1 ml of a 1 M solution of lithium bis(trimethylsilyl)amide in THF, and alkylated (at from -75° C. to -50° C.), with 2.6 g (10.57 mmol) of p-methoxybenzyl iodide [preparation, see Example 7e)] in 10 ml of THF. Protonation, at -75° C., with 2.6 ml (35.2 mmol) of propionic acid and 2.6 ml of water, extraction and column chromatography (SiO2, hexane/ethyl acetate, 2:1) affords the title compound: TLC Rf (D)=0.48; tRet (II)=18.8 min.
Reaction SMILES: COC1C=C(C=CC=1OC)[CH2:6][N:7]=[CH:8][C:9]1[S:17][C:12]2[N:13]=[CH:14][N:15]=[CH:16][C:11]=2[CH:10]=1.[CH3:23][S:24]C1C2C=C(C=O)SC=2N=CN=1.N1C2SC(C=O)=CC=2C=NC=1.CN>>[CH3:23][S:24][C:16]1[C:11]2[CH:10]=[C:9]([CH:8]=[N:7][CH3:6])[S:17][C:12]=2[N:13]=[CH:14][N:15]=1
Reactant: COc1ccc(CN=Cc2cc3cncnc3s2)cc1OC
Reactant: CSc1ncnc2sc(C=O)cc12
Agent: CN
Agent: O=Cc1cc2cncnc2s1
Product: CN=Cc1cc2c(SC)ncnc2s1

Procedure:
The title compound was prepared by a similar process to that described for Intermediate 14 but using 4-(methylthio)thieno[2,3-d]pyrimidine-6-carbaldehyde (Intermediate 15) in place of thieno[2,3-d]pyrimidine-6-carbaldehyde (intermediate 13) and methylamine (33% in methylated spirits) in place of 3,4-dimethoxybenzylamine. Colourless solid (73 mg, 98%);
Reaction SMILES: [C:1]1([C:7]2[CH:16]=[N:15][C:10]3[O:11][CH2:12][CH2:13][NH:14][C:9]=3[CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28])[C:21](Cl)=[O:22].C(N(CC)CC)C.Cl>ClCCl>[Br:17][C:18]1[CH:19]=[C:20]([C:21]([N:14]2[CH2:13][CH2:12][O:11][C:10]3[N:15]=[CH:16][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[CH:8][C:9]2=3)=[O:22])[CH:24]=[C:25]([Br:29])[C:26]=1[O:27][CH3:28]
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Reactant: c1ccc(-c2cnc3c(c2)NCCO3)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4ccccc4)cc32)cc1Br
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.5 %

Procedure:
To a 5 ml flask, 7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (10 mg, 0.05 mmol) and 3,5-dibromo-4-methoxy-benzoyl chloride (17 mg, 0.05 mmol) were dissolved in dichloromethane. Triethylamine (0.02 ml, 0.14 mmol) was added thereto and then stirred at room temperature for 1 hour. After neutralizing with 1N hydrochloric acid solution, the mixture was extracted with dichloromethane and the combined organic layer was dried over anhydrous sodium sulfate (Na2SO4), filtered and evaporated under reduced pressure. The residue was purified by column chromatography on silica eluting with a solvent of dichloromethane:methanol=40:1. The fractions containing the product were collected and evaporated to obtain white solid (14 mg, 59%).
Reaction SMILES: CC(C)([O-])C.[K+].C1COCC1.[CH3:12][C:13]1([CH3:25])[C:17]([CH3:19])([CH3:18])[O:16][B:15]([C:20]2[CH:21]=[N:22][NH:23][CH:24]=2)[O:14]1.Br[CH2:27][CH2:28][O:29][Si:30]([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]>CN(C)C=O.C(OCC)(=O)C>[Si:30]([O:29][CH2:28][CH2:27][N:23]1[CH:24]=[C:20]([B:15]2[O:16][C:17]([CH3:18])([CH3:19])[C:13]([CH3:25])([CH3:12])[O:14]2)[CH:21]=[N:22]1)([C:33]([CH3:36])([CH3:35])[CH3:34])([CH3:32])[CH3:31]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC1(C)OB(c2cn[nH]c2)OC1(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: CC1(C)OB(c2cnn(CCO[Si](C)(C)C(C)(C)C)c2)OC1(C)C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Potassium tert-butoxide (1.0 M) in THF (0.60 mL, 0.60 mmol) was added to a solution of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.1 g, 0.5 mmol) in N,N-dimethylformamide (1.5 mL) at 0° C. The reaction mixture was stirred at room temperature for 5 minutes, then cooled to 0° C. and treated with (2-bromoethoxy)(tert-butyl)dimethylsilane (0.2 mL, 0.8 mmol). The reaction was stirred at room temperature overnight, then diluted with ethyl acetate, washed with sat. NaHCO3, water, brine, dried over Na2SO4, filtered and concentrated to provide the crude product which was purified by silica gel chromatography eluting with 0 to 30% EtOAc in hexanes. Calculated for C17H34BN2O3Si (M+H)+: m/z=353.2; Found: 353.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[C@@H:11]1([NH2:21])[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6][NH:21][C@@H:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:14][CH2:13][CH2:12]1
Reactant: N[C@H]1CCCc2ccccc21
Reactant: COc1cccc(C=O)c1
Product: COc1cccc(CN[C@H]2CCCc3ccccc32)c1

Procedure:
3-Methoxybenzaldehyde and (1S)-1,2,3,4-tetrahydro-1-naphthalenylamine were processed as described in Example 1A to provide the title compound.
Reaction SMILES: F[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2.[Na].[CH2:22]([SH:24])[CH3:23].CN(C=O)C>O>[CH2:22]([S:24][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([F:20])([F:19])[F:18])=[CH:12][N:11]=2)[CH3:23]
Reactant: Fc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reactant: CCS
Agent: [Na]
Solvent: CN(C)C=O
Solvent: O
Product: CCSc1cnccc1-c1nc2cc(C(F)(F)F)cnc2s1
Reaction time: 1 h
Yield: 86.7 %

Procedure:
A mixture of 0.90 g of 2-(3-fluoropyridin-4-yl)-6-(trifluoromethyl)thiazolo[5,4-b]pyridine, 0.32 g of ethylmercaptan sodium salt and 12 ml of DMF was stirred for 1 hour under ice cool. To the reaction mixture was added water, and the deposited solid was collected by filtration. This solid was washed with water, then, dissolved in ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, then, concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, to obtain 0.89 g of 2-[3-(ethylthio)pyridin-4-yl]-6-(trifluoromethyl)thiazolo[5,4-b]pyridine (hereinafter, referred to as the present compound 15).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1)[CH3:2].[Br:13][C:14]1[CH:15]=[C:16]([CH:19]=[C:20]([O:22][CH3:23])[CH:21]=1)[CH:17]=O>C(O)C>[CH2:1]([O:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:11]=[CH:17][C:16]2[CH:19]=[C:20]([O:22][CH3:23])[CH:21]=[C:14]([Br:13])[CH:15]=2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1ccc(N)cc1
Reactant: COc1cc(Br)cc(C=O)c1
Solvent: CCO
Product: CCOC(=O)c1ccc(N=Cc2cc(Br)cc(OC)c2)cc1
Temperature: 25 °C
Yield: 33.7 %

Procedure:
A mixture of 4-amino-benzoic acid ethyl ester (6.1 g, 36.9 mmol) and 3-bromo-5-methoxy-benzaldehyde (8.0 g, 36.9 mmol) in ethanol (100 mL) was prepared. The reaction mixture was heated to reflux for 2 hours. Then the reaction mixture cooled to room temperature. The solvent was removed in vacuo and the residue was washed with ether to afford 4-{[1-(3-bromo-5-methoxy-phenyl)-methylidene]-amino}-benzoic acid ethyl ester (4.5 g, 34%) as a white solid: LC/MS m/e calcd for C17H16BrNO3 M+: 362.2, observed: 362.1.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][CH2:7][CH2:8][N:9]1[N:13]=[N:12][C:11]([C@@H:14]2[CH2:20][C@:19]3([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:21]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[C@H:15]2[CH2:16][CH2:17][C@H:18]3[O:35][CH2:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([C:47]([F:50])([F:49])[F:48])[CH:38]=2)=[N:10]1.C(N(CC)CC)C>ClCCl>[CH2:22]([N:21]1[C@@H:15]2[C@H:14]([C:11]3[N:12]=[N:13][N:9]([CH2:8][CH2:7][NH:6][S:2]([CH3:1])(=[O:4])=[O:3])[N:10]=3)[CH2:20][C@@:19]1([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C@H:18]([O:35][CH2:36][C:37]1[CH:42]=[C:41]([C:43]([F:44])([F:45])[F:46])[CH:40]=[C:39]([C:47]([F:49])([F:50])[F:48])[CH:38]=1)[CH2:17][CH2:16]2)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)NCCn1nnc([C@@H]2C[C@@]3(c4ccccc4)[C@H](OCc4cc(C(F)(F)F)cc(C(F)(F)F)c4)CC[C@@H]2N3Cc2ccccc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 93.4 %

Procedure:
Methanesulphonyl chloride (90 mg, 0.78 mmol) was added to a solution of (1R*,2R*,5S*6R*)-6-[2-(2-aminoethyl)-2H-tetrazol-5-yl]-8-benzyl-2-{[3,5-bis(trifluoromethyl)phenyl]methoxy}-1-phenyl-8-azabicyclo[3.2.1]octane (Example 141; 0.45 g, 0.71 mmol) and triethylamine (101 mg, 1 mmol) in dichloromethane (10 ml). The reaction mixture was stirred at room temperature for 3 hours then washed with water (×2). The organic layer was separated, dried (MgSO4), filtered and concentrated to yield the title compound (0.47 g, 94%).
Reaction SMILES: Br[C:2]1[C:3]([OH:16])=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12](=[O:14])[CH3:13])[C@@H:7]([CH3:15])[CH2:6][CH2:5]2.CC1(C)C(C)(C)OB([C:25]2[CH:26]=[N:27][N:28]([CH:30]3[CH2:35][CH2:34][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:32][CH2:31]3)[CH:29]=2)O1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:12]([N:8]1[C:9]2[C:4](=[C:3]([OH:16])[C:2]([C:25]3[CH:26]=[N:27][N:28]([CH:30]4[CH2:31][CH2:32][N:33]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:35]4)[CH:29]=3)=[CH:11][CH:10]=2)[CH2:5][CH2:6][C@@H:7]1[CH3:15])(=[O:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: CC(=O)N1c2ccc(Br)c(O)c2CC[C@@H]1C
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N1c2ccc(-c3cnn(C4CCN(C(=O)OC(C)(C)C)CC4)c3)c(O)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 21 %

Procedure:
XPhos Precatalyst 2nd Generation (0.186 g, 0.24 mmol) was added to a nitrogen purged solution of (S)-1-(6-bromo-5-hydroxy-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (0.672 g, 2.36 mmol), tert-butyl 4-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (0.892 g, 2.36 mmol), and potassium phosphate (2.51 g, 11.8 mmol) in 1,4-dioxane (4.0 mL) and water (0.8 mL), and the reaction mixture was heated at 100° C. overnight. The crude reaction mixture was purified directly via column chromatography on silica gel (Biotage 25 g column, gradient elution with 30-10% hexanes in ethyl acetate) to afford tert-butyl (S)-4-(4-(1-acetyl-5-hydroxy-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)-1H-pyrazol-1-yl)piperidine-1-carboxylate (225 mg, 21%) as a white fluffy powder. MS (ESI, pos. ion) m/z 455 [M+H]+.
Reaction SMILES: [C:1]([O:5][P:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23]C)=[O:22])=[CH:16][CH:15]=1)([O:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Li+]>C1COCC1.O>[C:9]([O:8][P:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([OH:23])=[O:22])=[CH:16][CH:15]=1)([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])([CH3:10])([CH3:11])[CH3:12]
Reactant: COC(=O)Cc1ccc(OP(=O)(OC(C)(C)C)OC(C)(C)C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OP(=O)(Oc1ccc(CC(=O)O)cc1)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.7 %

Procedure:
To a stirred solution of Intermediate 43B (0.635 g, 1.772 mmol) in THF (12.0 mL) and water (3.00 mL) was added lithium hydroxide (0.122 g, 2.14 mmol). The reaction mixture was stirred at room temperature for 2 hr and then the organics were removed under reduced pressure. The resulting mixture was diluted with 10 mL of pH 4 phosphate solution. The resulting mixture was extracted with EtOAc. The combined EtOAc extracts were washed with brine, dried with anhydrous magnesium sulfate, filtered and concentrated to afford Intermediate 43C (0.462 g, 76%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.30 (br. s., 1H), 7.25 (d, J=8.4 Hz, 2H), 7.13-7.03 (m, 2H), 3.55 (s, 2H), 1.44 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:4][C:3]=1[N:16]1[N+:20]([O-])=[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=[N:17]1.C1(C)C=CC=CC=1.CNC.[H][H]>[C].[Pd].O>[OH:1][C:2]1[C:7]([C:8]([CH3:11])([CH3:10])[CH3:9])=[CH:6][C:5]([C:12]([CH3:13])([CH3:14])[CH3:15])=[CH:4][C:3]=1[N:16]1[N:20]=[C:19]2[CH:22]=[CH:23][CH:24]=[CH:25][C:18]2=[N:17]1
Reactant: CC(C)(C)c1cc(-n2nc3ccccc3[n+]2[O-])c(O)c(C(C)(C)C)c1
Reactant: [H][H]
Agent: [Pd]
Agent: CNC
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)(C)c1cc(-n2nc3ccccc3n2)c(O)c(C(C)(C)C)c1
Temperature: 50 °C
Yield: 73.2 %

Procedure:
10 g (0.03 mol) of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole-N-oxide, 100 mg of palladium carbon, 100 ml of a solvent mixture comprising toluene and water (ratio by volume, 4:1) and 3 g of 50% dimethylamine were charged into a 500-ml autoclave equipped with an agitator. After the air in the autoclave had been replaced by hydrogen, the pressure of hydrogen was set to 10 kg/cm2. The temperature was increased to 50° C. under agitation, and reaction was effected at the same temperature while agitation being continued until no more hydrogen was absorbed by the mixture. After the reaction had been completed, the autoclave was cooled, and the catalyst was filtered off. When part of the filtrate was subjected to quantitative analysis using GC, it was found that the yield of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole is 85.6%. After the solvent had been distilled off from the filtrate, the residual solid was crystallized by ethanol and then washed with ethanol to obtain 7.1 g of 2-(2'-hydroxy-3',5'-di-t-butylphenyl)benzotriazole (yield, 71%; melting point, 152° to 155° C.).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH2:36][OH:37])[CH3:35])=[O:29])([CH3:26])([CH3:25])[CH3:24]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[CH2:34][CH2:33][CH2:32][C:31]1([CH:36]=[O:37])[CH3:35])=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCCC1(C)CO
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCCC1(C)C=O
Reaction time: 2 h
Yield: 80.7 %

Procedure:
Dess Martin Periodinane (7.8 g, 0.0186 mol) was added in one portion to the solution of (rac)-2-hydroxymethyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester (2 g, 0.0093 mol) in DCM (50 mL) under an inert atmosphere. The reaction was stirred until completion (about 2 h) then quenched with saturated solution of sodium thiosulphate, extracted with DCM (3×100 mL) washed with brine (50 mL), dried over anhydrous sodium sulphate, and concentrated using a rotary evaporator to afford 1.6 g (84%) of (rac)-2-formyl-2-methyl-pyrrolidine-1-carboxylic acid tert-butyl ester as a light brown colored oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1)=[O:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[K+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C@H:10]([CH2:35][CH:34]=[CH2:33])[C:11]([O:13][CH3:14])=[O:12])[C:15]([N:17]1[CH2:21][CH2:20][C@H:19]([F:22])[CH2:18]1)=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CCBr
Reactant: COC(=O)C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: C=CC[C@H](C(=O)OC)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of the product from Step A (4.51 g, 14.2 mmol) in THF (150 mL) was added potassium hexamethyldisilazide (65.0 mL, 0.5M in toluene, 32.5.0 mmol) at −78° C. The resulting mixture was stirred at −78° C. for 30 min. Allyl bromide (6.2 mL, 71.7 mmol) was then added. After stirring at −78° C. for 2 h, the reaction was quenched with saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (30:70 hexanes/ethyl acetate) afforded the desired product (major diastereoisomer from the reaction).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[CH:16][C:15]=1[Cl:26].C(N(CC)CC)C>O>[Cl:26][C:15]1[CH:16]=[C:17]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:18]=[CH:19][C:14]=1[NH:13][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1)=[O:12]
Reactant: O=C(O)c1c[nH]c2ccccc12
Reactant: CCOC(=O)Cc1ccc(N)c(Cl)c1
Solvent: O
Solvent: CCN(CC)CC
Product: CCOC(=O)Cc1ccc(NC(=O)c2c[nH]c3ccccc23)c(Cl)c1
Temperature: 70 °C
Reaction time: 24 h
Yield: 56.4 %

Procedure:
EDC•HCL (1.78 g, 9.28 mmol) was added to a solution of indole-3-carboxylic acid (1.00 g, 6.21 mmol), ethyl 4-amino-3-chlorophenylacetate (1.33 g, 6.22 mmol) and triethylamine (1.80 mL, 12.9 mmol). The mixture was stirred at 70° C. for 24 hours. After cooling to room temperature, the reaction mixture was added with water (30 ml), followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from hexane-ethyl acetate (1:1, v/v) eluate fractions, ethyl 3-chloro-4-(3-indolylcarbonylamino)phenylacetate (1.25 g, 56%) was obtained as a pale yellow solid.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]2[NH:10][CH:11]=[CH:12][C:5]=12)([O-:3])=[O:2].C1C(=O)N([I:20])C(=O)C1>C(Cl)Cl>[I:20][C:12]1[C:5]2[C:6](=[N:7][CH:8]=[CH:9][C:4]=2[N+:1]([O-:3])=[O:2])[NH:10][CH:11]=1
Reactant: O=C1CCC(=O)N1I
Reactant: O=[N+]([O-])c1ccnc2[nH]ccc12
Solvent: ClCCl
Product: O=[N+]([O-])c1ccnc2[nH]cc(I)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 106.7 %

Procedure:
To a stirred solution of 4-nitro-1H-pyrrolo[2,3-b]pyridine (4.5 g, 27.6 mmol) in DCM (180 mL) was added NIS (6.83 g, 30.3 mmol) over 30 mins at 0° C. The resulting mixture was stirred at 0° C. for another 1 hour. The reaction mixture was concentrated. The residue was suspended in DCM (ca. 25 mL), the solid was filtered and dried in a vacuum oven to give the title compound (8.51 g). LCMS (A): m/z (M+H)+ 290, C7H4IN3O2 requires 289 (acidic).
Reaction SMILES: [CH:1]1([C:4]#[CH:5])[CH2:3][CH2:2]1.[Li]CCCC.[Si:11](Cl)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]>C1(C)C=CC=CC=1.C1COCC1>[Si:11]([C:5]#[C:4][CH:1]1[CH2:3][CH2:2]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([CH3:13])[CH3:12]
Reactant: C#CC1CC1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)C#CC1CC1
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 42 %

Procedure:
To a stirred, cooled (0° C.) solution of 188 mL (658 mmol) of a 3.5M solution of cyclopropylacetylene in toluene was added 200 mL of THF. The solution was re-cooled to 0° C. and treated with 264 mL (660 mmol) of a 2.5M solution of n-BuLi in hexanes over 15 min. The solution was stirred an additional 40 min. at 0° C. and treated with 100 g(663 mmol) of t-butyldimethylsilyl chloride in 60 mL of THF over 10 min. After stirring 90 min. at 0° C. the reaction was quenched with saturated aq. NH4Cl and poured into 500 mL of water. The mixture was extracted with 500 mL of ether, and the organic extract was washed three times with water and once with brine. Concentration under reduced pressure followed by distillation afforded 49 g(42%) of 1-(t-butyldimethylsilyl)-2-cyclopropylacetylene as a colorless oil (b.p. 39°-42° C. at 0.5 torr). 1H NMR(CDCl3, 300 MHz ) δ1.17-1.24(m, 1H); 0.95(s, 9H); 0.61-0.75(m, 4H); 0.00(s, 6H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH:18]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][CH2:19]4)[C:12](=[O:31])[N:11]([CH2:32][C:33]4[O:37][N:36]=[C:35]([CH2:38][O:39][CH3:40])[N:34]=4)[C:10]=3[CH:9]=2)=[C:4]([O:41][CH3:42])[CH:3]=1.[ClH:43]>O1CCOCC1>[ClH:43].[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:16][C:15]3[C:14](=[O:17])[N:13]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:12](=[O:31])[N:11]([CH2:32][C:33]4[O:37][N:36]=[C:35]([CH2:38][O:39][CH3:40])[N:34]=4)[C:10]=3[CH:9]=2)=[C:4]([O:41][CH3:42])[CH:3]=1
Reactant: COCc1noc(Cn2c(=O)n(C3CCN(C(=O)OC(C)(C)C)CC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Agent: Cl
Solvent: C1COCCO1
Product: COCc1noc(Cn2c(=O)n(C3CCNCC3)c(=O)c3sc(-c4ccc(F)cc4OC)cc32)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To a solution of tert-butyl 4-[6-(4-fluoro-2-methoxyphenyl)-1-{[3-(methoxymethyl)-1,2,4-oxadiazol-5-yl]methyl}-2,4-dioxo-1,4-dihydrothieno[3,2-d]pyrimidin-3(2H)-yl]piperidine-1-carboxylate (890 mg, compound B62) in 1,4 dioxane (13 ml) is added a solution of hydrogen chloride in 1,4-dioxane (7.4 ml, 4.0 M). The reaction mixture is stirred for 2.5 h at RT. All volatiles are evaporated and the residue is treated with DCM and after removal of the solvent under reduced pressure the title compound is obtained as a solid.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:26]=[C:14]3[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].C([O-])(=O)C.[Na+].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:59][CH2:58][N:50]3[C:51]4[CH2:52][CH2:53][CH2:54][CH2:55][C:56]=4[CH:57]=[C:49]3[C:48]2=[O:60])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:26]=[C:14]3[CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18][N:13]3[N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(C(=O)OC(C)(C)C)C3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3cc4n(n3)CCN(C(=O)OC(C)(C)C)C4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Temperature: 100 °C
Yield: 82 %

Procedure:
A sealed tube equipped with a magnetic stirrer was charged with 205d (213 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(1-oxo-3,4,6,7,8,9-hexahydropyrazino[1,2-a]indol-2(1H)-yl)pyridin-4-ylboronic acid 113i (192 mg, 0.50 mmol), Pd(dppf)Cl2 (41 mg, 0.050 mmol), sodium acetate (82 mg, 1.0 mmol), K3PO4 (212 mg, 1.0 mmol), acetonitrile (10 mL), and water (0.5 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then filtered and the filtrate was evaporated in vacuo. The residue was purified by silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 205e (280 mg, 82%) as a yellow solid. MS-ESI: [M+H]+ 683.3